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["Retinoids and liver/metabolic",null,null,null,null,null,"(retinoid OR retinoic OR Vitamin A) AND (Liver[mh] OR liver OR metabolic disease OR diabetes OR Liver Diseases[mh] OR Metabolic Diseases[mh]) AND (review[pt] OR review[tiab])"]
[null,"Your search terms"]
["PMID","retin","ppar","diabetes","Total","Pub Yr","Title","Fauthor","LinkPMID","tiab"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I4,I4)","v":8801182},{"$f":"(LEN($J4) - LEN(SUBSTITUTE(LOWER($J4),LOWER(B$3),\"\")))/LEN(B$3)","v":31},{"$f":"(LEN($J4) - LEN(SUBSTITUTE(LOWER($J4),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J4) - LEN(SUBSTITUTE(LOWER($J4),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B4:D4)","v":31},1996,"Retinoic acid biosynthesis and metabolism.","Napoli",8801182,"Retinoic acid biosynthesis and metabolism.    Abstract:   Metabolic activation of retinol into the hormone retinoic acid and metabolism of retinoic acid entail essential aspects of retinoid biology that seem interdependent with functions of retinoid binding-proteins. Cellular retinol binding protein and cellular retinoic acid binding protein enjoy widespread expression and, where expressed, their liganded forms represent the major physiological forms of retinol and retinoic acid, respectively. These retinoid binding proteins may protect cells from the amphipathic properties of retinoids and protect the structurally sensitive retinoids from the cellular milieu. Starting from the perspective that the enzymes most likely to metabolize retinoids in vivo might recognize the major forms of retinoids that occur in vivo, several laboratories have produced results that support a model of retinoid metabolism with prominent roles for the cellular retinoid binding proteins. In this model, liganded cellular retinoid binding proteins serve as substrates for the metabolism of some retinoids (retinol, retinoic acid), restricting access to those enzymes that recognize both the binding protein and the retinoid. Other retinoids (3,4-didehydroretinol, 4-oxo-retinoic acid) liganded to binding-proteins have their metabolism arrested. In its unliganded form, at least one retinoid binding protein (cellular retinol binding protein) serves as a retinoid concentration-sensitive modulator of enzymes that catalyze retinol metabolism. This review will describe the model and the intrinsic relationships among retinoid-specific enzymes and retinoid binding proteins."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I5,I5)","v":12440979},{"$f":"(LEN($J5) - LEN(SUBSTITUTE(LOWER($J5),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J5) - LEN(SUBSTITUTE(LOWER($J5),LOWER(C$3),\"\")))/LEN(C$3)","v":21},{"$f":"(LEN($J5) - LEN(SUBSTITUTE(LOWER($J5),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B5:D5)","v":23},2002,"Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism.","Smith",12440979,"Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of ligand-activated nuclear transcription factors. Three PPAR subtypes, PPARalpha, PPARdelta (PPARbeta) and PPARgamma, have been described in mammals. The tissue distribution of PPARs is heterogeneous: PPARalpha is highly expressed in liver and skeletal muscle, PPARgamma is preferentially expressed in adipose tissues, and PPARdelta is expressed in most cell types with relative abundance. Unlike most receptors, PPARs show low ligand specificity, being activated by many long-chain saturated and unsaturated fatty acids, or by eicosanoids. PPARs are transcriptionally active as heterodimeric complexes with the retinoid X receptor and bind to specific recognition sequences in the regulatory region of target genes. Many PPAR-regulated genes encode proteins that regulate fatty acid oxidation and storage. Elucidation of the biological functions of PPARs has been aided by the development of PPAR-null mice and the identification of humans bearing PPAR mutations, together with the discovery of synthetic small-molecule ligands that selectively activate individual PPAR subtypes. Using these genetic and pharmacological approaches, it has been shown that PPARalpha predominantly regulates pathways of fatty acid oxidation, whereas PPARgamma modifies fatty acid synthesis and storage in adipose tissues. By reducing systemic fatty acid availability, thiazolidinedione PPARgamma activators regulate glucose metabolism and are now used clinically in the treatment of Type II diabetes. In summary, PPARs play a central role in the mechanisms that balance fatty acid oxidation and storage in the face of fluctuations of dietary fat intake and energy expenditure."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I6,I6)","v":10874003},{"$f":"(LEN($J6) - LEN(SUBSTITUTE(LOWER($J6),LOWER(B$3),\"\")))/LEN(B$3)","v":23},{"$f":"(LEN($J6) - LEN(SUBSTITUTE(LOWER($J6),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J6) - LEN(SUBSTITUTE(LOWER($J6),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B6:D6)","v":23},2000,"Retinoids in chemoprevention and differentiation therapy.","Hansen",10874003,"Retinoids in chemoprevention and differentiation therapy.    Abstract:   Retinoids are essential for the maintenance of epithelial differentiation. As such, they play a fundamental role in chemoprevention of epithelial carcinogenesis and in differentiation therapy. Physiological retinoic acid is obtained through two oxidation steps from dietary retinol, i.e. retinol--gt;retinal--gt;retinoic acid. The latter retinal--gt;retinoic acid step is irreversible and eventually marks disposal of this essential nutrient, through cytochrome P450-dependent oxidative steps. Mutant mice deficient in aryl hydrocarbon receptor (AHR) accumulate retinyl palmitate, retinol and retinoic acid. This suggests a direct connection between the AHR and retinoid homeostasis. Retinoids control gene expression through the nuclear retinoic acid receptors (RARs) alpha, beta and gamma and 9-cis-retinoic acid receptors alpha, beta and gamma, which bind with high affinity the natural ligands all-trans-retinoic acid and 9-cis-retinoic acid, respectively. Retinoids are effective chemopreventive agents against skin, head and neck, breast, liver and other forms of cancer. Differentiation therapy of acute promyelocytic leukemia (APL) is based on the ability of retinoic acid to induce differentiation of leukemic promyelocytes. Patients with relapsed, retinoid-resistant APL are now being treated with arsenic oxide, which results in apoptosis of the leukemic cells. Interestingly, induction of differentiation in promyelocytes and consequent remission of APL following retinoid therapy depends on expression of a chimeric PML-RAR alpha fusion protein resulting from a t(15;17) chromosomal translocation. This protein functions as a dominant negative against the function of both PML and RARs and its overexpression is able to recreate the phenotypes of the disease in transgenic mice. The development of new, more effective and less toxic retinoids, alone or in combination with other drugs, may provide additional avenues for cancer chemoprevention and differentiation therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I7,I7)","v":17148746},{"$f":"(LEN($J7) - LEN(SUBSTITUTE(LOWER($J7),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J7) - LEN(SUBSTITUTE(LOWER($J7),LOWER(C$3),\"\")))/LEN(C$3)","v":20},{"$f":"(LEN($J7) - LEN(SUBSTITUTE(LOWER($J7),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B7:D7)","v":22},2006,"Targeting components of the stress system as potential therapies for the metabolic syndrome: the peroxisome-proliferator-activated receptors.","Yumuk",17148746,"Targeting components of the stress system as potential therapies for the metabolic syndrome: the peroxisome-proliferator-activated receptors.    Abstract:   The three peroxisome-proliferator-activated receptor (PPAR) subtypes PPAR-alpha, PPAR-gamma, and PPAR-delta are ligand-activated transcription factors of the nuclear receptor family. PPARs form obligate heterodimers with the retinoid X receptor, which bind to peroxisome-proliferator-response elements (PPREs). PPAR-alpha is expressed mainly in liver, brown fat, kidney, heart, and skeletal muscle; PPAR-gamma in intestine and adipose tissue; PPAR-alpha and PPAR-gamma are both expressed in vascular endothelium, smooth muscle cells, macrophages, and foam cells; PPAR-delta in skeletal muscle, human embryonic kidney, intestine, heart, adipose tissue, developing brain, and keratinocytes. Intense interest in the development of drugs with new mechanisms of action for the metabolic syndrome has focused attention on nuclear receptors, such as PPARs that function as regulators of energy homeostasis. Agonists of PPAR-alpha and PPAR-gamma are currently used to treat diabetic dyslipidemia and type 2 diabetes. Dual PPAR-alpha/gamma agonists and PPAR-alpha/gamma/delta pan-agonists are under investigation for treatment of cardiovascular disease and the metabolic syndrome. Selective PPAR modulators (SPPARMs) are PPAR ligands that possess desirable efficacy and improved tolerance. Efforts are being made to identify novel partial agonists or antagonists for PPAR-gamma in order to combine their antidiabetic and antiobesity effects. Glucocorticoids are major mediators of the stress response and could be the link between stress and PPAR activator signaling and thus may affect the downstream metabolic pathways involved in fuel homeostasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I8,I8)","v":16433796},{"$f":"(LEN($J8) - LEN(SUBSTITUTE(LOWER($J8),LOWER(B$3),\"\")))/LEN(B$3)","v":22},{"$f":"(LEN($J8) - LEN(SUBSTITUTE(LOWER($J8),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J8) - LEN(SUBSTITUTE(LOWER($J8),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B8:D8)","v":22},2006,"Oral retinoid therapy for disorders of keratinization: single-centre retrospective 25 years experience on 23 patients.","Katugampola",16433796,"Oral retinoid therapy for disorders of keratinization: single-centre retrospective 25 years experience on 23 patients.    Abstract:    BACKGROUND : Over the last three decades, the oral retinoids etretinate and acitretin have revolutionized the treatment of disorders of keratinization (DOK). Many patients with DOK require life-long treatment with oral retinoids. However, the longest follow-up data of patients with DOK on oral retinoid therapy is 10 years for adults and up to 11 years for children.  OBJECTIVES : The aim of our study was to collect long-term retrospective data including disease response, side-effects and pregnancy outcome in a cohort of patients with DOK who were among the first in the world to commence oral retinoids 25 years ago.  METHODS : Between 1979 and 1981, 30 patients with DOK were commenced on oral etretinate in our department. Case notes of these patients were reviewed retrospectively, and patients interviewed where possible to obtain the following information: diagnosis, age when treatment commenced, duration of treatment, reason for discontinuation of therapy, side-effects, abnormal investigation results and pregnancy outcomes.  RESULTS : Case notes of 23 of the 30 patients were available for review; of these, two patients were deceased and 14 were interviewed. In the 23 patients, the mean age of commencing treatment was 33.5 years (range 4.2-61) and the mean duration of etretinate therapy was 5.2 years (range 1 month to 14 years). Reasons for discontinuing treatment were an overall improvement in the skin disease (six of 23), no benefit +/- side-effects (11 of 23) and noncompliance (one of 23). Two patients died of causes unrelated to their skin disease or treatment, 12 and 4 years after stopping etretinate. Five patients (one female, four males) subsequently changed to acitretin and are currently continuing therapy. The mean total duration of retinoid therapy (etretinate and acitretin) for the four males was 23.7 years (range 20.6-25.1). The female patient continued intermittent courses (due to planned pregnancies) of oral retinoids for a total of 10.1 years over the last 25 years. Abnormal investigation results included elevated serum triglycerides and cholesterol (two of 23), isolated high triglycerides (three of 23), isolated high cholesterol (three of 23), worsening of liver enzymes in a patient with alcohol dependence, and elevated serum alkaline phosphatase (ALP) in healthy adults (three of 23). In two children, the elevated pretreatment ALP levels increased further after commencing etretinate but returned to normal in adulthood while treatment continued. One patient developed diffuse idiopathic skeletal hyperostosis after 21 years of retinoid therapy. One female patient had two early spontaneous abortions 2.75 and 3.2 years after discontinuing etretinate; she subsequently had two normal children. Two other females had normal children 1, 3 and 5 years after stopping etretinate. Two male patients fathered a total of three healthy children while on etretinate.  CONCLUSIONS : This study provides the longest available follow-up data of children and adults with DOK on oral retinoid therapy. Such information is essential for clinicians and their patients with DOK embarking on life-long treatment with retinoids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I9,I9)","v":10521699},{"$f":"(LEN($J9) - LEN(SUBSTITUTE(LOWER($J9),LOWER(B$3),\"\")))/LEN(B$3)","v":21},{"$f":"(LEN($J9) - LEN(SUBSTITUTE(LOWER($J9),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J9) - LEN(SUBSTITUTE(LOWER($J9),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B9:D9)","v":22},1999,"Interactions of retinoid binding proteins and enzymes in retinoid metabolism.","Napoli",10521699,"Interactions of retinoid binding proteins and enzymes in retinoid metabolism.    Abstract:   Naturally occurring retinoids (vitamin A or retinol and its active metabolites) are vital for vision, controlling the differentiation program of epithelial cells in the digestive tract and respiratory system, skin, bone, the nervous system, the immune system, and for hematopoiesis. Retinoids are essential for growth, reproduction (conception and embryonic development), and resistance to and recovery from infection. The functions of retinoids in the embryo begin soon after conception and continue throughout the lifespan of all vertebrates. Both naturally occurring and synthetic retinoids are used in the therapy of various skin diseases, especially acne, for augmenting the treatment of diabetes, and as cancer chemopreventive agents. Retinol metabolites serve as ligands that activate specific transcription factors in the superfamily of steroid/retinoid/thyroid/vitamin D/orphan receptors and thereby control gene expression. Additionally, retinoids may also function through non-genomic actions. Various retinoid binding proteins serve as partners in retinoid function. These binding proteins show high specificity and affinity for specific retinoids and seem to control retinoid metabolism in vivo qualitatively and quantitatively by reducing free retinoid concentrations, protecting retinoids from non-specific interactions, and chaperoning access of metabolic enzymes to retinoids. Implementation of the physiological effects of retinoids depends on the spatial-temporal expressions of binding proteins, receptors and metabolic enzymes. This review will discuss current understanding of the enzymes that catalyze retinol and retinoic acid metabolism and their unique and integral relationship to retinoid binding proteins."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I10,I10)","v":15959399},{"$f":"(LEN($J10) - LEN(SUBSTITUTE(LOWER($J10),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J10) - LEN(SUBSTITUTE(LOWER($J10),LOWER(C$3),\"\")))/LEN(C$3)","v":19},{"$f":"(LEN($J10) - LEN(SUBSTITUTE(LOWER($J10),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B10:D10)","v":20},2005,"[PPAR receptors: recent data].","Vidal",15959399,"[PPAR receptors: recent data].    Abstract:   The nuclear receptors PPAR (Peroxisome Proliferator-Activated Receptors) are transcription factors which form with the retinoid receptor RXR, a PPAR/RXR heterodimer, the functional transcription factor within cells. PPAR receptors are activated by their ligands, either naturals or synthetics, and modulate target gene transcription. There are three PPAR subtypes (PPARalpha, PPARbeta/delta et PPARgamma) coded by different genes, and two isoforms of PPARgamma proteins have been detected in humans (PPARgamma1 and PPARgamma2). PPAR are mainly modulators of lipid metabolism, but each receptor subtype is pharmacologically distinct, and development of synthetic PPAR agonists has shown their role in cellular (mainly adipocyte) differentiation and in glucose homeostasis. This review summarise the main data, currently available, on expression, biological functions, natural and synthetic (activators) ligands for the PPAR receptor subtypes. PPAR receptors key-role in lipid and glucose métabolisms, has lead to a large clinical use of pharmacological agents acting as PPAR ligands: fibrates, PPARalpha agonists as hypolipidaemic treatment, thiazolidinediones (glitazones), PPARalpha agonists as antidiabetics. Lipid metabolism is impaired in insulin resistant skeletal muscles, fatty acids role in the pathophysiology of insulin resistance generates several hypothesis we briefly describe. Finally, we present and discuss experimental data, suggesting the activation of PPARbeta/delta in skeletal muscle to be a potential new approach in the treatment of insulin resistance and metabolic syndrome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I11,I11)","v":8144697},{"$f":"(LEN($J11) - LEN(SUBSTITUTE(LOWER($J11),LOWER(B$3),\"\")))/LEN(B$3)","v":20},{"$f":"(LEN($J11) - LEN(SUBSTITUTE(LOWER($J11),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J11) - LEN(SUBSTITUTE(LOWER($J11),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B11:D11)","v":20},1993,"The retinal pigment epithelium: a versatile partner in vision.","Bok",8144697,"The retinal pigment epithelium: a versatile partner in vision.    Abstract:   The retinal pigment epithelium (RPE) is a monolayer of cuboidal cells that lies in close association with the rod and cone photoreceptors. This epithelium has diverse features, three of which are discussed in some detail in this review, namely the daily phagocytosis of rod and cone outer segment fragments that are shed from their distal ends; the uptake, processing, transport and release of vitamin A (retinol) and some of its visual cycle intermediates (retinoids); and some of the aspects of its apical and basolateral membrane polarity that are the reverse of most other epithelia. Phagocytosis takes place at the apical surface via membrane receptor-mediated processes that are not yet well defined. Retinol uptake occurs at both the basolateral and apical surfaces by what appear to be separate receptor-mediated processes. The release of a crucial retinoid, 11-cis retinaldehyde (11-cis retinal), occurs solely across the apical membrane. Delivery of retinol across the basolateral membrane is mediated by a retinol binding protein (RBP) that is secreted by the liver as a complex with retinol (vitamin A). Within the cell, retinol and its derivatives are solubilized by intracellular retinoid binding proteins that are selective for retinol (cellular retinol binding protein, CRBP) and 11-cis retinoids (cellular retinal binding protein, CRALBP). Release of 11-cis retinal across the apical membrane and re-uptake of retinol from the photoreceptors during the visual cycle is promoted by an intercellular retinoid binding protein (IRBP). Na,K-ATPase, the membrane-integrated enzyme required to set up the ion gradients that drive other ion transporters, is largely localized to the apical membrane.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I12,I12)","v":21763780},{"$f":"(LEN($J12) - LEN(SUBSTITUTE(LOWER($J12),LOWER(B$3),\"\")))/LEN(B$3)","v":19},{"$f":"(LEN($J12) - LEN(SUBSTITUTE(LOWER($J12),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J12) - LEN(SUBSTITUTE(LOWER($J12),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B12:D12)","v":19},2012,"Hepatic metabolism of retinoids and disease associations.","Shirakami",21763780,"Hepatic metabolism of retinoids and disease associations.    Abstract:   The liver is the most important tissue site in the body for uptake of postprandial retinoid, as well as for retinoid storage. Within the liver, both hepatocytes and hepatic stellate cells (HSCs) are importantly involved in retinoid metabolism. Hepatocytes play an indispensable role in uptake and processing of dietary retinoid into the liver, and in synthesis and secretion of retinol-binding protein (RBP), which is required for mobilizing hepatic retinoid stores. HSCs are the central cellular site for retinoid storage in the healthy animal, accounting for as much as 50-60% of the total retinoid present in the entire body. The liver is also an important target organ for retinoid actions. Retinoic acid is synthesized in the liver and can interact with retinoid receptors which control expression of a large number of genes involved in hepatic processes. Altered retinoid metabolism and the accompanying dysregulation of retinoid signaling in the liver contribute to hepatic disease. This is related to HSCs, which contribute significantly to the development of hepatic disease when they undergo a process of cellular activation. HSC activation results in the loss of HSC retinoid stores and changes in extracellular matrix deposition leading to the onset of liver fibrosis. An association between hepatic disease progression and decreased hepatic retinoid storage has been demonstrated. In this review article, we summarize the essential role of the liver in retinoid metabolism and consider briefly associations between hepatic retinoid metabolism and disease. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I13,I13)","v":20026355},{"$f":"(LEN($J13) - LEN(SUBSTITUTE(LOWER($J13),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J13) - LEN(SUBSTITUTE(LOWER($J13),LOWER(C$3),\"\")))/LEN(C$3)","v":17},{"$f":"(LEN($J13) - LEN(SUBSTITUTE(LOWER($J13),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B13:D13)","v":19},2010,"Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) acts as regulator of metabolism linked to multiple cellular functions.","Wagner",20026355,"Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) acts as regulator of metabolism linked to multiple cellular functions.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors. They function as ligand activated transcription factors. They exist in three isoforms, PPARalpha, PPARbeta (formerly PPARdelta), and PPARgamma. For all PPARs lipids are endogenous ligands, linking them directly to metabolism. PPARs form heterodimers with retinoic X receptors, and, upon ligand binding, modulate gene expression of downstream target genes dependent on the presence of co-repressors or co-activators. This results in cell-type specific complex regulations of proliferation, differentiation and cell survival. Specific synthetic agonists for all PPARs are available. PPARalpha and PPARgamma agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPARbeta activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases. Although the initial notion was that PPARbeta is expressed ubiquitously, more recently extensive investigations have been performed demonstrating high PPARbeta expression in a variety of tissues, e.g. skin, skeletal muscle, adipose tissue, inflammatory cells, heart, and various types of cancer. In addition, in vitro and in vivo studies using specific PPARbeta agonists, tissue-specific over-expression or knockout mouse models have demonstrated a variety of functions of PPARbeta in adipose tissue, muscle, skin, inflammation, and cancer. We will focus here on functions of PPARbeta in adipose tissue, skeletal muscle, heart, angiogenesis and cancer related to modifications in metabolism and the identified underlying molecular mechanisms."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I14,I14)","v":15612519},{"$f":"(LEN($J14) - LEN(SUBSTITUTE(LOWER($J14),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J14) - LEN(SUBSTITUTE(LOWER($J14),LOWER(C$3),\"\")))/LEN(C$3)","v":18},{"$f":"(LEN($J14) - LEN(SUBSTITUTE(LOWER($J14),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B14:D14)","v":19},2004,"[Peroxisome proliferator-activated receptors (PPARs) in obesity and insulin resistance development].","Alemán",15612519,"[Peroxisome proliferator-activated receptors (PPARs) in obesity and insulin resistance development].    Abstract:   The peroxisome proliferator-activated receptors (PPARs) are a family of nuclear transcription factors that belong to the steroid receptor superfamily. PPARs family includes PPARalpha, PPARbeta/delta, PPARgamma1 and PPARgamma2. PPARs form an heterodimer with the 9-cis retinoic acid receptor (RXR) and bind to response elements present in target genes activated by these transcription factors. PPARs control the expression of genes involved in fatty acid synthesis, oxidation and storage. PPARs are present in most tissues, where PPARalpha is most abundant in liver and skeletal muscle, whereas PPARgamma is found mainly in adipose tissue. Natural ligands for PPARs are polyunsaturated fatty acids (PUFAs) and some eicosanoids, however they are also activated by compounds such as fibrates and thiazolidinediones (TZDs). In this review is shown the different PPARs isoforms, identification, and regulation of their expression and activity. Also shows which are the natural ligands, and the chemical compounds that activate PPARs. Finally, it shows the target genes activated by the different isoforms of PPARs, the metabolic integration between the different PPAR isoforms to maintain a balance between fatty acid synthesis and oxidation and the association with the development of obesity and insulin resistance. Also shows information about the nutritional requirements of PUFAs that are the main natural ligands of PPARs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I15,I15)","v":14561188},{"$f":"(LEN($J15) - LEN(SUBSTITUTE(LOWER($J15),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J15) - LEN(SUBSTITUTE(LOWER($J15),LOWER(C$3),\"\")))/LEN(C$3)","v":18},{"$f":"(LEN($J15) - LEN(SUBSTITUTE(LOWER($J15),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B15:D15)","v":19},2002,"Peroxisome proliferator-activated receptors and the control of inflammation.","Cabrero",14561188,"Peroxisome proliferator-activated receptors and the control of inflammation.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which form a subfamily of the nuclear receptor gene family. This subfamily consists of three isotypes, alpha (NR1C1), gamma (NR1C3), and beta/delta (NRC1C2) with a differential tissue distribution. PPARalpha is expressed primarily in tissues with a high level of fatty acid catabolism such as liver, brown fat, kidney, heart and skeletal muscle. PPARbeta is ubiquitously expressed, and PPARgamma has a restricted pattern of expression, mainly in white and brown adipose tissues, whereas other tissues such as skeletal muscle and heart contain limited amounts. Furthermore, PPARalpha and gamma isotypes are expressed in vascular cells including endothelial and smooth muscle cells and macrophages/foam cells. PPARs are activated by ligands, such as naturally occurring fatty acids, which are activators of all three PPAR isotypes. In addition to fatty acids, several synthetic compounds, such as fibrates and thiazolidinediones, bind and activate PPARalpha and PPARgamma, respectively. In order to be transcriptionally active, PPARs need to heterodimerize with the retinoid-X-receptor (RXR). Upon activation, PPAR-RXR heterodimers bind to DNA specific sequences called peroxisome proliferator-response elements (PPRE) and stimulate transcription of target genes. PPARs play a critical role in lipid and glucose homeostasis, but lately they have been implicated as regulators of inflammatory responses. The first evidence of the involvement of PPARs in the control of inflammation came from the PPARalpha null mice, which showed a prolonged inflammatory response. PPARalpha activation results in the repression of NF-kappaB signaling and inflammatory cytokine production in different cell-types. A role for PPARgamma in inflammation has also been reported in monocyte/macrophages, where ligands of this receptor inhibited the activation of macrophages and the production of inflammatory cytokines (TNFalpha, interleukin 6 and 1beta), although part of the anti-inflammatory effects of these ligands seems to be mediated by a mechanism not involving PPARgamma. All these findings suggest a role of PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I16,I16)","v":11306068},{"$f":"(LEN($J16) - LEN(SUBSTITUTE(LOWER($J16),LOWER(B$3),\"\")))/LEN(B$3)","v":19},{"$f":"(LEN($J16) - LEN(SUBSTITUTE(LOWER($J16),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J16) - LEN(SUBSTITUTE(LOWER($J16),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B16:D16)","v":19},2001,"Genetic dissection of retinoid dehydrogenases.","Duester",11306068,"Genetic dissection of retinoid dehydrogenases.    Abstract:   Biochemical studies indicate that alcohol dehydrogenase (ADH) metabolizes retinol to retinal, and that aldehyde dehydrogenase (ALDH) metabolizes retinal to retinoic acid, a molecule essential for growth and development. Summarized herein are several genetic studies supporting in vivo functions for ADH and ALDH in retinoic acid synthesis. Gene targeting was used to create knockout mice for either Adh1 or Adh4. Both knockout mice were viable and fertile without obvious defects. However, when wild-type and Adh4 knockout mice were subjected to vitamin A deficiency during gestation, the survival rate at birth was 3.3-fold lower for Adh4 knockout mice. When adult mice were examined for production of retinoic acid following retinol administration, Adh1 knockout mice exhibited 10-fold lower retinoic acid levels in liver compared with wild-type, whereas Adh4 knockout mice differed from wild-type by less than 2-fold. Thus, Adh1 plays a major role in the metabolism of a large dose of retinol to retinoic acid in adults, whereas Adh4 plays a role in maintaining sufficient retinol metabolism for development during retinol deficiency. ALDHs were examined by overexpression studies in frog embryos. Injection of mRNAs for either mouse Raldh1 or Raldh2 stimulated retinoic acid synthesis in frog embryos at the blastula stage when retinoic acid is normally undetectable. Overexpression of human ALDH2, human ALDH3, and mouse Aldh-pb did not stimulate retinoic acid production. In addition, Raldh2 knockout mice exhibit embryonic lethality with defects in retinoid-dependent tissues. Overall, these studies provide genetic evidence that Adh1, Adh4, Raldh1, and Raldh2 encode retinoid dehydrogenases involved in retinoic acid synthesis in vivo."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I17,I17)","v":21447403},{"$f":"(LEN($J17) - LEN(SUBSTITUTE(LOWER($J17),LOWER(B$3),\"\")))/LEN(B$3)","v":18},{"$f":"(LEN($J17) - LEN(SUBSTITUTE(LOWER($J17),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J17) - LEN(SUBSTITUTE(LOWER($J17),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B17:D17)","v":18},2012,"Key enzymes of the retinoid (visual) cycle in vertebrate retina.","Kiser",21447403,"Key enzymes of the retinoid (visual) cycle in vertebrate retina.    Abstract:   A major goal in vision research over the past few decades has been to understand the molecular details of retinoid processing within the retinoid (visual) cycle. This includes the consequences of side reactions that result from delayed all-trans-retinal clearance and condensation with phospholipids that characterize a variety of serious retinal diseases. Knowledge of the basic retinoid biochemistry involved in these diseases is essential for development of effective therapeutics. Photoisomerization of the 11-cis-retinal chromophore of rhodopsin triggers a complex set of metabolic transformations collectively termed phototransduction that ultimately lead to light perception. Continuity of vision depends on continuous conversion of all-trans-retinal back to the 11-cis-retinal isomer. This process takes place in a series of reactions known as the retinoid cycle, which occur in photoreceptor and RPE cells. All-trans-retinal, the initial substrate of this cycle, is a chemically reactive aldehyde that can form toxic conjugates with proteins and lipids. Therefore, much experimental effort has been devoted to elucidate molecular mechanisms of the retinoid cycle and all-trans-retinal-mediated retinal degeneration, resulting in delineation of many key steps involved in regenerating 11-cis-retinal. Three particularly important reactions are catalyzed by enzymes broadly classified as acyltransferases, short-chain dehydrogenases/reductases and carotenoid/retinoid isomerases/oxygenases. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I18,I18)","v":19011747},{"$f":"(LEN($J18) - LEN(SUBSTITUTE(LOWER($J18),LOWER(B$3),\"\")))/LEN(B$3)","v":18},{"$f":"(LEN($J18) - LEN(SUBSTITUTE(LOWER($J18),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J18) - LEN(SUBSTITUTE(LOWER($J18),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B18:D18)","v":18},2008,"Medium- and short-chain dehydrogenase/reductase gene and protein families : Medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism.","Parés",19011747,"Medium- and short-chain dehydrogenase/reductase gene and protein families : Medium-chain and short-chain dehydrogenases/reductases in retinoid metabolism.    Abstract:   Retinoic acid (RA), the most active retinoid, is synthesized in two steps from retinol. The first step, oxidation of retinol to retinaldehyde, is catalyzed by cytosolic alcohol dehydrogenases (ADHs) of the medium-chain dehydrogenase/reductase (MDR) superfamily and microsomal retinol dehydrogenases (RDHs) of the short-chain dehydrogenase/reductase (SDR) superfamily. The second step, oxidation of retinaldehyde to RA, is catalyzed by several aldehyde dehydrogenases. ADH1 and ADH2 are the major MDR enzymes in liver retinol detoxification, while ADH3 (less active) and ADH4 (most active) participate in RA generation in tissues. Several NAD(+)- and NADP(+)-dependent SDRs are retinoid active. Their in vivo contribution has been demonstrated in the visual cycle (RDH5, RDH12), adult retinoid homeostasis (RDH1) and embryogenesis (RDH10). K(m) values for most retinoid-active ADHs and RDHs are close to 1 microM or lower, suggesting that they participate physiologically in retinol/retinaldehyde interconversion. Probably none of these enzymes uses retinoids bound to cellular retinol-binding protein, but only free retinoids. The large number of enzymes involved in the two directions of this step, also including aldo-keto reductases, suggests that retinaldehyde levels are strictly regulated."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I19,I19)","v":15555528},{"$f":"(LEN($J19) - LEN(SUBSTITUTE(LOWER($J19),LOWER(B$3),\"\")))/LEN(B$3)","v":16},{"$f":"(LEN($J19) - LEN(SUBSTITUTE(LOWER($J19),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J19) - LEN(SUBSTITUTE(LOWER($J19),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B19:D19)","v":18},2005,"The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina.","SanGiovanni",15555528,"The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina.    Abstract:   In this work we advance the hypothesis that omega-3 (omega-3) long-chain polyunsaturated fatty acids (LCPUFAs) exhibit cytoprotective and cytotherapeutic actions contributing to a number of anti-angiogenic and neuroprotective mechanisms within the retina. omega-3 LCPUFAs may modulate metabolic processes and attenuate effects of environmental exposures that activate molecules implicated in pathogenesis of vasoproliferative and neurodegenerative retinal diseases. These processes and exposures include ischemia, chronic light exposure, oxidative stress, inflammation, cellular signaling mechanisms, and aging. A number of bioactive molecules within the retina affect, and are effected by such conditions. These molecules operate within complex systems and include compounds classified as eicosanoids, angiogenic factors, matrix metalloproteinases, reactive oxygen species, cyclic nucleotides, neurotransmitters and neuromodulators, pro-inflammatory and immunoregulatory cytokines, and inflammatory phospholipids. We discuss the relationship of LCPUFAs with these bioactivators and bioactive compounds in the context of three blinding retinal diseases of public health significance that exhibit both vascular and neural pathology. How is omega-3 LCPUFA status related to retinal structure and function? Docosahexaenoic acid (DHA), a major dietary omega-3 LCPUFA, is also a major structural lipid of retinal photoreceptor outer segment membranes. Biophysical and biochemical properties of DHA may affect photoreceptor membrane function by altering permeability, fluidity, thickness, and lipid phase properties. Tissue DHA status affects retinal cell signaling mechanisms involved in phototransduction. DHA may operate in signaling cascades to enhance activation of membrane-bound retinal proteins and may also be involved in rhodopsin regeneration. Tissue DHA insufficiency is associated with alterations in retinal function. Visual processing deficits have been ameliorated with DHA supplementation in some cases. What evidence exists to suggest that LCPUFAs modulate factors and processes implicated in diseases of the vascular and neural retina? Tissue status of LCPUFAs is modifiable by and dependent upon dietary intake. Certain LCPUFAs are selectively accreted and efficiently conserved within the neural retina. On the most basic level, omega-3 LCPUFAs influence retinal cell gene expression, cellular differentiation, and cellular survival. DHA activates a number of nuclear hormone receptors that operate as transcription factors for molecules that modulate reduction-oxidation-sensitive and proinflammatory genes; these include the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and the retinoid X receptor. In the case of PPAR-alpha, this action is thought to prevent endothelial cell dysfunction and vascular remodeling through inhibition of: vascular smooth muscle cell proliferation, inducible nitric oxide synthase production, interleukin-1 induced cyclooxygenase (COX)-2 production, and thrombin-induced endothelin 1 production. Research on model systems demonstrates that omega-3 LCPUFAs also have the capacity to affect production and activation of angiogenic growth factors, arachidonic acid (AA)-based vasoregulatory eicosanoids, and MMPs. Eicosapentaenoic acid (EPA), a substrate for DHA, is the parent fatty acid for a family of eicosanoids that have the potential to affect AA-derived eicosanoids implicated in abnormal retinal neovascularization, vascular permeability, and inflammation. EPA depresses vascular endothelial growth factor (VEGF)-specific tyrosine kinase receptor activation and expression. VEGF plays an essential role in induction of: endothelial cell migration and proliferation, microvascular permeability, endothelial cell release of metalloproteinases and interstitial collagenases, and endothelial cell tube formation. The mechanism of VEGF receptor down-regulation is believed to occur at the tyrosine kinase nuclear factor-kappa B (NFkappaB). NFkappaB is a nuclear transcription factor that up-regulates COX-2 expression, intracellular adhesion molecule, thrombin, and nitric oxide synthase. All four factors are associated with vascular instability. COX-2 drives conversion of AA to a number angiogenic and proinflammatory eicosanoids. Our general conclusion is that there is consistent evidence to suggest that omega-3 LCPUFAs may act in a protective role against ischemia-, light-, oxygen-, inflammatory-, and age-associated pathology of the vascular and neural retina."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I20,I20)","v":14585315},{"$f":"(LEN($J20) - LEN(SUBSTITUTE(LOWER($J20),LOWER(B$3),\"\")))/LEN(B$3)","v":18},{"$f":"(LEN($J20) - LEN(SUBSTITUTE(LOWER($J20),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J20) - LEN(SUBSTITUTE(LOWER($J20),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B20:D20)","v":18},2003,"Carotenoid and retinoid transport to fish oocytes and eggs: what is the role of retinol binding protein?","Lubzens",14585315,"Carotenoid and retinoid transport to fish oocytes and eggs: what is the role of retinol binding protein?    Abstract:   Fish eggs contain carotenoids, retinals (retinal and dehydroretinal) and retinols (retinol, dehydroretinol and retinyl-esters) that are utilized during embryonic development, after fertilization. The carotenoids (mainly astaxanthins) are transported in the plasma by the low density lipoproteins, high density lipoproteins, and very high density lipoproteins (VHDL) and were found to be associated also with serum albumin. Retinals were found to be associated vitellogenin (VTG), a component of the plasma VHDL fraction that is internalized by oocytes during vitellogenesis. However, the transport of retinols and retinyl-esters that were located in the oil droplet fraction of homogenized eggs, has yet to be elucidated. Retinols are more abundant in freshwater fish eggs than in eggs of marine fish species. Since retinol is transported in the plasma of vertebrates in association with retinol binding protein (RBP), recent studies on the molecular characterization and expression sites of RBP, could contribute to determining the involvement of RBP in transporting retinol to developing oocytes in vertebrates.Recently, results from our laboratory show that RBP mRNA levels in the liver and RBP plasma levels did not significantly change with the onset and during vitellogenesis in the Rainbow trout. These results were in contrast with a dramatic elevation in the mRNA levels of VTG in the liver and an increase in VTG plasma levels that was observed in the same females. Moreover, 17beta-estradiol treatment of immature fish, resulted in relatively lower mRNA levels of RBP in the liver, concomitantly with an increase in the level of VTG transcripts and the appearance of VTG in the plasma of treated fish. In addition, RBP was localized in the cytosol of ovulated oocytes. These results for Rainbow trout are similar to those reported for the chicken but differ from those of Xenopus, where an increase in RBP mRNA was reported in the liver and higher levels of retinal and retinol were found in the plasma of 17beta-estradiol treated animals. The results, reported here for the first time in Rainbow trout, showing RBP transcripts in the ovary, oviduct (the ovarian tissue adjacent to the gonopore) and oocytes, suggest a modulating role for RBP in follicular development, as has been suggested for the bovine ovary."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I21,I21)","v":11330046},{"$f":"(LEN($J21) - LEN(SUBSTITUTE(LOWER($J21),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J21) - LEN(SUBSTITUTE(LOWER($J21),LOWER(C$3),\"\")))/LEN(C$3)","v":16},{"$f":"(LEN($J21) - LEN(SUBSTITUTE(LOWER($J21),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B21:D21)","v":18},2000,"Peroxisome proliferator-activated receptors, coactivators, and downstream targets.","Qi",11330046,"Peroxisome proliferator-activated receptors, coactivators, and downstream targets.    Abstract:   Peroxisomes in liver parenchymal cells proliferate in response to structurally diverse nonmutagenic compounds designated as peroxisome proliferators (PP). Sustained induction of peroxisome proliferation and peroxisomal fatty acid beta-oxidation system in rats and mice leads to the development of liver tumors. Two mechanistic issues are important for consideration: elucidation of the upstream events responsible for the tissue and species specific induction of the characteristic pleiotropic responses by PPs; and delineation of the downstream events associated with peroxisome proliferation, and their role in the development of liver tumors in species that are sensitive to the induction of peroxisome proliferation. The induction of peroxisome proliferation is mediated by PP-activated receptor alpha (PPAR alpha), a member of a group of transcription factors that regulate the expression of genes associated with lipid metabolism and adipocyte differentiation. Three isotypes of this family of nuclear receptors, namely PPAR alpha, PPAR gamma, and PPAR delta (also called beta), have been identified as products of separate genes. Although PPAR alpha is responsible for the PP-induced pleiotropic responses, PPAR gamma seems to be involved in adipogenesis and differentiation, but the events associated with PPAR gamma do not directly involve peroxisomes and peroxisome proliferation. PPARs heterodimerize with 9-cis retinoic acid receptor (RXR), and bind to PP response element(s) (PPREs) on the target gene promoter to initiate inducible transcriptional activity. Tissue and species responses to PPs depend on pharmacokinetics, relative abundance of PPAR isotypes, nature of PPRE in the upstream regions of target genes, the extent of competition or cross-talk among nuclear transcription factors for PPAR heterodimerization partner retinoid X receptor and the modulating role of coactivators and corepressors on ligand-dependent transcription of PPARs. Using PPAR as bait in the yeast two-hybrid system, the authors recently cloned mouse steroid receptor coactivator-1 (SRC-1) and PPAR-binding protein (PBP), and identified them as PPAR coactivators. Both SRC-1 and PBP contain LXXLL signature motifs, considered necessary and sufficient for the binding of coactivators to nuclear receptors. A multifaceted approach, which includes the identification of additional coactivators that may be responsible for cell specific transcriptional activation of PPAR-mediated target genes, and generation of genetically modified animals (transgenic and gene disrupted), will be necessary to gain more insight into the upstream and downstream targets responsible for the induction of early and delayed PP-induced pleiotropic responses. In this context, it is important to note that mice deficient in fatty acyl-CoA oxidase, the first and rate-limiting enzyme of the peroxisomal beta-oxidation system, revealed that this enzyme is indispensable for the physiological regulation of PPAR alpha, and the absence of this enzyme leads to sustained transcriptional activation of genes regulated by this receptor."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I22,I22)","v":1503802},{"$f":"(LEN($J22) - LEN(SUBSTITUTE(LOWER($J22),LOWER(B$3),\"\")))/LEN(B$3)","v":18},{"$f":"(LEN($J22) - LEN(SUBSTITUTE(LOWER($J22),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J22) - LEN(SUBSTITUTE(LOWER($J22),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B22:D22)","v":18},1992,"Retinoids and cancer prevention.","Hill",1503802,"Retinoids and cancer prevention.    Abstract:   As indicated above, in some cases the effects of retinoids appear to be species-specific. Although retinyl acetate and 4-HPR are ineffective in preventing mammary cancer induced by DMBA or occurring spontaneously in mice, these retinoids prevent carcinogen-induced mammary cancer in rats. In contrast, retinoids have modest chemopreventive activity for bladder cancer in various strains of both mice and rats and may have some therapeutic and preventive effects in human bladder. Retinyl palmitate is reported to reduce the incidence of esophageal lesions in hamsters; however, retinyl acetate may increase the incidence of esophageal tumors in rats. Although 13-cis-RA reduces the incidence of spontaneous thymic lymphomas in AKR mice and C57Bl/10W mice exposed to X rays and has some therapeutic effect on myelodysplastic syndromes in humans, 4-HPR may enhance leukemic progression in patients with this syndrome. For treatment of this syndrome, selection of the proper retinoid appears to be important. Topically applied retinyl palmitate reduces the incidence of cervical cancer in hamsters, and topically applied RA has a therapeutic effect on cervical dysplasia in humans. Retinamides have a modest chemopreventive effect against pancreatic cancer in rats dosed with azaserine; these compounds are reported both to increase and to decrease the incidence of pancreatic cancer in hamsters. Retinoids may, or may not, be carcinogen-specific in different species. Some are effective in preventing mammary cancer in rats, regardless of which carcinogen is used. Applied to mouse skin, retinoids are active with either DMBA or BP as the carcinogen and 12-tetradecanoyl phorbol-13-acetate (TPA) as the promoter. Nevertheless, retinoids are not effective in preventing skin papillomas and carcinomas caused by UV light. There is no comparable system for humans, although retinoids demonstrate activity against basal cell carcinomas, squamous cell carcinomas, and actinic keratoses on the skin of humans. Fewer bladder tumors develop in rats dosed with HO-BBN when they are put on diets containing certain retinoids, but those dosed with FANFT are not affected. Similarly, retinyl acetate is reported to be active against liver tumors induced by 3-MeDAB but not against those induced by aflatoxin B1. In contrast, forestomach carcinomas induced in hamsters by either DMBA or BP are prevented by retinyl palmitate. The route of administration of retinoids may also be important.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I23,I23)","v":16054987},{"$f":"(LEN($J23) - LEN(SUBSTITUTE(LOWER($J23),LOWER(B$3),\"\")))/LEN(B$3)","v":17},{"$f":"(LEN($J23) - LEN(SUBSTITUTE(LOWER($J23),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J23) - LEN(SUBSTITUTE(LOWER($J23),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B23:D23)","v":17},2005,"Alcohol, vitamin A, and cancer.","Wang",16054987,"Alcohol, vitamin A, and cancer.    Abstract:   Chronic and excessive alcohol intake is associated with an increased risk of a variety of cancers (e.g., oral cavity, larynx, esophagus, liver, lung, colorectal, and breast). Retinoids (vitamin A and its derivatives) are known to exert profound effects on cellular growth, cellular differentiation, and apoptosis, thereby controlling carcinogenesis. Lower hepatic vitamin A levels have been well documented in alcoholics. Substantial research has been done, investigating the mechanisms by which excessive alcohol interferes with retinoid metabolism. More specifically, (1) alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases; (2) alcohol-induced cytochrome P450 enzymes (CYP), particularly CYP2E1, enhance catabolism of vitamin A and retinoic acid; and (3) alcohol alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues. As a consequence, long-term and excessive alcohol intake results in impaired status of retinoic acid, the most active derivative of vitamin A and a ligand for both retinoic acid receptors and retinoid X receptors. Moreover, this alcohol-impaired retinoic acid homeostasis interferes with (1) retinoic acid signaling (e.g., down-regulates retinoid target gene expression) and (2) retinoic acid quot;cross-talkquot; with the mitogen-activated protein kinase [(MAPK), including Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 kinase] signaling pathway. In addition, restoration of retinoic acid homeostasis by retinoic acid supplementation restored the normal status of both retinoid and MAPK signaling, thereby maintaining normal cell proliferation and apoptosis in alcohol-fed animals. These observations would have implications for the prevention of alcohol-promoted liver (and peripheral tissue) carcinogenesis. However, a better understanding of the alcohol-retinoid interaction and the molecular mechanisms involved is needed before retinoids can be pursued in the prevention of alcohol-related carcinogenesis in human beings, particularly regarding the detrimental effects of polar metabolites of vitamin A."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I24,I24)","v":15142970},{"$f":"(LEN($J24) - LEN(SUBSTITUTE(LOWER($J24),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J24) - LEN(SUBSTITUTE(LOWER($J24),LOWER(C$3),\"\")))/LEN(C$3)","v":16},{"$f":"(LEN($J24) - LEN(SUBSTITUTE(LOWER($J24),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B24:D24)","v":17},2004,"Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells.","Marx",15142970,"Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells.    Abstract:   A large body of data gathered over the past couple of years has identified the peroxisome proliferator-activated receptors (PPAR) alpha, gamma, and beta/delta as transcription factors exerting modulatory actions in vascular cells. PPARs, which belong to the nuclear receptor family of ligand-activated transcription factors, were originally described as gene regulators of various metabolic pathways. Although the PPARalpha, gamma, and beta/delta subtypes are approximately 60% to 80% homologous in their ligand- and DNA-binding domains, significant differences in ligand and target gene specificities are observed. PPARalpha is activated by polyunsaturated fatty acids and oxidized derivatives and by lipid-modifying drugs of the fibrate family, including fenofibrate or gemfibrozil. PPARalpha controls expression of genes implicated in lipid metabolism. PPARgamma, in contrast, is a key regulator of glucose homeostasis and adipogenesis. Ligands of PPARgamma include naturally occurring FA derivatives, such as hydroxyoctadecadienoic acids (HODEs), prostaglandin derivatives such as 15-deoxyDelta12,14-prostaglandin J2, and glitazones, insulin-sensitizing drugs presently used to treat patients with type 2 diabetes. Ligands for PPARbeta/delta are polyunsaturated fatty acids, prostaglandins, and synthetic compounds, some of which are presently in clinical development. PPARbeta/delta stimulates fatty acid oxidation predominantly acting in muscle. All PPARs are expressed in vascular cells, where they exhibit antiinflammatory and antiatherogenic properties. In addition, studies in various animal models as well as clinical data suggest that PPARalpha and PPARgamma activators can modulate atherogenesis in vivo. At present, no data are available relating to possible effects of PPARbeta/delta agonists on atherogenesis. Given the widespread use of PPARalpha and PPARgamma agonists in patients at high risk for cardiovascular disease, the understanding of their function in the vasculature is not only of basic interest but also has important clinical implications. This review will focus on the role of PPARs in the vasculature and summarize the present understanding of their effects on atherogenesis and its cardiovascular complications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I25,I25)","v":11729635},{"$f":"(LEN($J25) - LEN(SUBSTITUTE(LOWER($J25),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J25) - LEN(SUBSTITUTE(LOWER($J25),LOWER(C$3),\"\")))/LEN(C$3)","v":13},{"$f":"(LEN($J25) - LEN(SUBSTITUTE(LOWER($J25),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B25:D25)","v":17},2001,"[PPAR gamma agonist and antagonist].","Kadowaki",11729635,"[PPAR gamma agonist and antagonist].    Abstract:   Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPAR gamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPAR gamma activity observed in heterozygous PPAR gamma-deficient mice or the Pro 12 Ala polymorphism in human PPAR gamma has been shown to prevent insulin resistance and obesity induced by a high-fat (HF) diet. We investigated whether functional antagonism toward PPAR gamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that moderate reduction of PPAR gamma with an RXR antagonist or a PPAR gamma antagonist decreases triglyceride (TG) content in white adipose tissue, skeletal muscle and liver. These inhibitors potentiate leptins effects and stimulated adiponectin levels, which increases fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, severe reduction of PPAR gamma by treatment of heterozygous PPAR gamma-deficient mice with an RXR antagonist or a PPAR gamma antagonist depletes white adipose tissue and markedly decreases leptin and adiponectin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggest that appropriate functional antagonism of PPAR gamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I26,I26)","v":17001693},{"$f":"(LEN($J26) - LEN(SUBSTITUTE(LOWER($J26),LOWER(B$3),\"\")))/LEN(B$3)","v":15},{"$f":"(LEN($J26) - LEN(SUBSTITUTE(LOWER($J26),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J26) - LEN(SUBSTITUTE(LOWER($J26),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B26:D26)","v":16},2006,"Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease.","Goodman",17001693,"Retinoid receptors, transporters, and metabolizers as therapeutic targets in late onset Alzheimer disease.    Abstract:   Vitamin A (retinoid) is required in the adult brain to enable cognition, learning, and memory. While brain levels of retinoid diminish over the course of normal ageing, retinoid deficit is greater in late onset Alzheimer disease (LOAD) brains than in normal-aged controls. This paper reviews recent evidence supporting these statements and further suggests that genes necessary for the synthesis, transport and function of retinoid to and within the ageing brain are appropriate targets for treatment of LOAD. These genes tend to be clustered with genes that have been proposed as candidates in LOAD, are found at chromosomal regions linked to LOAD, and suggest the possibility of an overall coordinated regulation. This phenomenon is termed Chromeron and is analogous to the operon mechanism observed in prokaryotes. Suggested treatment targets are the retinoic-acid inactivating enzymes (CYP26)s, the retinol binding and transport proteins, retinol-binding protein (RBP)4 and transthyretin (TTR), and the retinoid receptors. TTR as a LOAD target is the subject of active investigation. The retinoid receptors and the retinoid-inactivating enzymes have previously been proposed as targets. This is the first report to suggest that RBP4 is an amenable treatment target in LOAD. RBP4 is elevated in type-2 diabetes and obesity, conditions associated with increased risk for LOAD. Fenretinide, a novel synthetic retinoic acid (RA) analog lowers RBP4 in glucose intolerant obese mice. The feasibility of using fenretinide either as an adjunct to present LOAD therapies, or on its own as an early prevention strategy should be determined."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I27,I27)","v":15882777},{"$f":"(LEN($J27) - LEN(SUBSTITUTE(LOWER($J27),LOWER(B$3),\"\")))/LEN(B$3)","v":16},{"$f":"(LEN($J27) - LEN(SUBSTITUTE(LOWER($J27),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J27) - LEN(SUBSTITUTE(LOWER($J27),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B27:D27)","v":16},2005,"Role of retinoid signalling in the adult brain.","Lane",15882777,"Role of retinoid signalling in the adult brain.    Abstract:   Vitamin A (all-trans-retinol) is the parent compound of a family of natural and synthetic compounds, the retinoids. Retinoids regulate gene transcription in numerous cells and tissues by binding to nuclear retinoid receptor proteins, which act as transcription factors. Much of the research conducted on retinoid signalling in the nervous system has focussed on developmental effects in the embryonic or early postnatal brain. Here, we review the increasing body of evidence indicating that retinoid signalling plays an important role in the function of the mature brain. Components of the metabolic pathway for retinoids have been identified in adult brain tissues, suggesting that all-trans-retinoic acid (ATRA) can be synthesized in discrete regions of the brain. The distribution of retinoid receptor proteins in the adult nervous system is different from that seen during development; and suggests that retinoid signalling is likely to have a physiological role in adult cortex, amygdala, hypothalamus, hippocampus, striatum and associated brain regions. A number of neuronal specific genes contain recognition sequences for the retinoid receptor proteins and can be directly regulated by retinoids. Disruption of retinoid signalling pathways in rodent models indicates their involvement in regulating synaptic plasticity and associated learning and memory behaviours. Retinoid signalling pathways have also been implicated in the pathophysiology of Alzheimers disease, schizophrenia and depression. Overall, the data underscore the likely importance of adequate nutritional Vitamin A status for adult brain function and highlight retinoid signalling pathways as potential novel therapeutic targets for neurological diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I28,I28)","v":15320743},{"$f":"(LEN($J28) - LEN(SUBSTITUTE(LOWER($J28),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J28) - LEN(SUBSTITUTE(LOWER($J28),LOWER(C$3),\"\")))/LEN(C$3)","v":14},{"$f":"(LEN($J28) - LEN(SUBSTITUTE(LOWER($J28),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B28:D28)","v":16},2004,"Pleiotropic actions of PPAR gamma activators thiazolidinediones in cardiovascular diseases.","Takano",15320743,"Pleiotropic actions of PPAR gamma activators thiazolidinediones in cardiovascular diseases.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily and form heterodimers with retinoid X receptor. To date, three PPARs isoforms have been isolated and termed alpha, beta (or delta), and gamma. Although PPAR gamma is expressed predominantly in adipose tissue and associated with adipocyte differentiation and glucose homeostasis, it has been recently demonstrated that PPAR gamma is present in a variety of cell types. Synthetic antidiabetic thiazolidinediones (TZDs) and natural prostaglandin D(2) (PGD(2)) metabolite, 15-deoxy-Delta(12, 14)-prostaglandin J(2) (15d-PGJ(2)), are well-known as ligands for PPAR gamma. After it has been reported that activation of PPAR gamma suppresses production of proinflammatory cytokines in activated macrophages, medical interest in PPAR gamma have grown and a huge research effort has been concentrated. PPAR gamma, is currently known to be implicated in various human chronic diseases such as diabetes mellitus, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, and Alzheimers disease. Moreover, PPAR gamma ligands have potent tumor modulatory effects against colorectal, prostate, and breast cancers. Recent studies suggest that TZDs not only ameliorate insulin sensitivity but also have pleiotropic effects on many tissues and cell types. Although activation of PPAR gamma seems to have beneficial effects on atherosclerosis and heart failure, the mechanisms by which PPAR gamma ligands prevent the development of cardiovascular diseases are not fully understood. This review will focus on the latest developments in the PPAR gamma field and the roles of PPAR gamma-dependent pathway in cardiovascular diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I29,I29)","v":12553421},{"$f":"(LEN($J29) - LEN(SUBSTITUTE(LOWER($J29),LOWER(B$3),\"\")))/LEN(B$3)","v":16},{"$f":"(LEN($J29) - LEN(SUBSTITUTE(LOWER($J29),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J29) - LEN(SUBSTITUTE(LOWER($J29),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B29:D29)","v":16},2002,"Hepatic synthesis, maturation and complex formation between retinol-binding protein and transthyretin.","Gaetani",12553421,"Hepatic synthesis, maturation and complex formation between retinol-binding protein and transthyretin.    Abstract:   The retinol/retinol-binding protein/transthyretin complex, that carries and delivers hydrophobic retinol molecules to target cells, is assembled in the hepatocyte endoplasmic reticulum. In this paper, we review data related to events that lead to the formation of this complex, including transthyretin oligomerization and retinol-binding protein secretion. Our studies on transthyretin oligomerization have demonstrated that cleavage of signal peptide and the environment of endoplasmic reticulum influence transthyretin oligomerization. In vitro, mutated transthyretin without signal sequence fails to form dimers, while wild-type transthyretin is translocated into the microsomes where it forms dimers and small amounts of tetramers. In vivo, tetramers were detected in HepG2 cells but not in transfected Cos cells, suggesting that tissue-specific factors affect tetramer stability. In vitamin A deficiency, retinol-binding protein secretion is blocked and the protein accumulates in the endoplasmic reticulum, from where it is promptly released after retinol repletion. We use MMH cells to identify factors involved in complex formation, retention and secretion, the crucial steps to understand the molecular mechanisms underlying vitamin A homeostasis. In parallel, studies on vitamin A transport in fish are in progress; retinol-binding protein and transthyretin have already been characterized in different fish species."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I30,I30)","v":11411341},{"$f":"(LEN($J30) - LEN(SUBSTITUTE(LOWER($J30),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J30) - LEN(SUBSTITUTE(LOWER($J30),LOWER(C$3),\"\")))/LEN(C$3)","v":14},{"$f":"(LEN($J30) - LEN(SUBSTITUTE(LOWER($J30),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B30:D30)","v":16},2001,"[Physiological and pharmacological function of PPARs].","Takahashi",11411341,"[Physiological and pharmacological function of PPARs].    Abstract:   The finding of nuclear receptors has greatly enhanced our understanding of gene regulation by lipophilic hormones such as steroids, thyroxine, vitamin D and retinoids. These receptors comprise a superfamily of transcription factors containing highly related DNA-binding domains. In mammals, the peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors consists of three subtypes by separate genes: PPAR alpha, PPAR delta (also referred to as hNUC1 or PPAR beta), and PPAR gamma. PPARs have been associated with several distinct biological programs. PPARs function as a heterodimer with the retinoid X receptor. This complex binds to sequences termed direct repeat-1 response element in enhancer sites of regulated genes and activates transcription upon ligand and coactivator binding. Three different PPAR subtypes have specific roles in different organs. PPAR alpha, mainly expressed in liver, plays an important role in fatty acid metabolism. PPAR gamma predominantly is expressed in adipose cells. PPAR delta displays a high level of expression in lipid-metabolizing organs such as small intestine, heart and adipose tissue. Naturally occurring and synthetic molecules (anti-hyperlipidemia and diabetic drugs) that are ligands for these nuclear receptors control transcriptional activity of PPARs. We believe that the pharmacological and genomic researches on PPAR will develop powerful tools for prevention and medical care against common diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I31,I31)","v":6192964},{"$f":"(LEN($J31) - LEN(SUBSTITUTE(LOWER($J31),LOWER(B$3),\"\")))/LEN(B$3)","v":15},{"$f":"(LEN($J31) - LEN(SUBSTITUTE(LOWER($J31),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J31) - LEN(SUBSTITUTE(LOWER($J31),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B31:D31)","v":16},1983,"Isotretinoin: new therapy for severe acne.","Perry",6192964,"Isotretinoin: new therapy for severe acne.    Abstract:   The chemistry, pharmacology, pharmacokinetics, clinical use, adverse effects, dosage and administration, and FDA-approved indications of isotretinoin, a new agent used for treating acne, are reviewed. Isotretinoin is a synthetic retinoid compound with pharmacologic actions similar to those of other retinoids. Isotretinoins effects on nodulocystic acne lesions apparently result from its reduction of the size of sebaceous glands, inhibition of sebum production, and inhibition of follicular keratinization. Isotretinoin is administered orally; peak serum drug concentrations occur approximately three hours after ingestion. The drug is widely distributed throughout body tissues and metabolized by the liver by oxidation and glucuronidation; both parent drug and metabolites are excreted in the urine and feces. Clinical trials of isotretinoin have shown the drug to be effective in treating cystic or conglobate acne that is unresponsive to therapy with oral or topical antibiotics, topical tretinoin, or topical benzoyl peroxide. Isotretinoin is unique in that acne remission continues after discontinuance of therapy. The most frequent adverse effects involve mucocutaneous tissues and include cheilitis, xerosis, xerostomia, dry nose, epistaxis, and pruritus. Other adverse effects--including some serious ones--have been found rarely in humans or animals receiving isotretinoin. The usual oral dosage of isotretinoin for patients with cystic acne is 1-2 mg/kg/day in two divided doses; administration should continue for 15-20 weeks. Isotretinoin is currently more expensive than other acne treatments. Isotretinoin is an effective agent for treating cystic acne; pending accumulation of further data, its use should be limited to patients with severe conditions that do not respond to older therapies because of isotretinoins cost and sometimes serious adverse effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I32,I32)","v":25069047},{"$f":"(LEN($J32) - LEN(SUBSTITUTE(LOWER($J32),LOWER(B$3),\"\")))/LEN(B$3)","v":14},{"$f":"(LEN($J32) - LEN(SUBSTITUTE(LOWER($J32),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J32) - LEN(SUBSTITUTE(LOWER($J32),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B32:D32)","v":15},2014,"The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes.","Mody",25069047,"The mechanisms of Fenretinide-mediated anti-cancer activity and prevention of obesity and type-2 diabetes.    Abstract:   Fenretinide remains the most investigated retinoid compound for the prevention of cancer. Its clinical use remains a genuine possibility due to a favourable toxicological profile and accumulation in fatty tissues. Like other well-characterised pharmacological therapies, Fenretinide has been shown to affect multiple signalling pathways. Recent findings have discovered additional beneficial properties the synthetic retinoid was not intentionally designed for, including the prevention of high-fat diet-induced obesity and insulin resistance. These preclinical findings in rodents are timely since obesity has reached pandemic proportions and safe effective therapeutics are severely lacking. Recent investigations have proposed various mechanisms of action for the beneficial effects of Fenretinide. This review covers the current knowledge about Fenretinides use as a therapy for cancer and potential to treat obesity, insulin resistance and glucose intolerance. An overview of the signalling pathways manipulated by Fenretinide including retinoid homeostasis, reactive oxygen species generation and inhibition of ceramide synthesis will be presented and insights into apoptosis and/or autophagy induction by Fenretinide will also be discussed. The largely unexplored area of Fenretinide metabolites as alternative therapeutic options and how these may be relevant will also be presented. Fenretinide shows great promise, but unfortunately evidence is lacking from clinical trials on Fenretinides effectiveness in humans. Finally we identify what action can be taken to further progress the investigation of this extremely important retinoid."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I33,I33)","v":21493923},{"$f":"(LEN($J33) - LEN(SUBSTITUTE(LOWER($J33),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J33) - LEN(SUBSTITUTE(LOWER($J33),LOWER(C$3),\"\")))/LEN(C$3)","v":12},{"$f":"(LEN($J33) - LEN(SUBSTITUTE(LOWER($J33),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B33:D33)","v":15},2011,"The PPAR-RXR transcriptional complex in the vasculature: energy in the balance.","Plutzky",21493923,"The PPAR-RXR transcriptional complex in the vasculature: energy in the balance.    Abstract:   The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs) are ligand-activated transcription factors that coordinately regulate gene expression. This PPAR-RXR transcriptional complex plays a critical role in energy balance, including triglyceride metabolism, fatty acid handling and storage, and glucose homeostasis: processes whose dysregulation characterize obesity, diabetes, and atherosclerosis. PPARs and RXRs are also involved directly in inflammatory and vascular responses in endothelial and vascular smooth muscle cells. New insights into fundamental aspects of PPAR and RXR biology, and their actions in the vasculature, continue to appear. Although RXRs are obligate heterodimeric partners for PPAR action, the part that RXRs, and their endogenous retinoid mediators, exert in the vessel wall is less well understood. Biological insights into PPAR-RXRs may help inform interpretation of clinical trials with synthetic PPAR agonists and prospects for future PPAR therapeutics. Importantly, the extensive data establishing a key role for PPARs and RXRs in energy balance, inflammation, and vascular biology stands separately from the clinical experience with any given synthetic PPAR agonist. Both the basic science data and the clinical experience with PPAR agonists identify the need to better understand these important transcriptional regulators."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I34,I34)","v":21350678},{"$f":"(LEN($J34) - LEN(SUBSTITUTE(LOWER($J34),LOWER(B$3),\"\")))/LEN(B$3)","v":15},{"$f":"(LEN($J34) - LEN(SUBSTITUTE(LOWER($J34),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J34) - LEN(SUBSTITUTE(LOWER($J34),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B34:D34)","v":15},2011,"Vitamin A metabolism: an update.","DAmbrosio",21350678,"Vitamin A metabolism: an update.    Abstract:   Retinoids are required for maintaining many essential physiological processes in the body, including normal growth and development, normal vision, a healthy immune system, normal reproduction, and healthy skin and barrier functions. In excess of 500 genes are thought to be regulated by retinoic acid. 11-cis-retinal serves as the visual chromophore in vision. The body must acquire retinoid from the diet in order to maintain these essential physiological processes. Retinoid metabolism is complex and involves many different retinoid forms, including retinyl esters, retinol, retinal, retinoic acid and oxidized and conjugated metabolites of both retinol and retinoic acid. In addition, retinoid metabolism involves many carrier proteins and enzymes that are specific to retinoid metabolism, as well as other proteins which may be involved in mediating also triglyceride and/or cholesterol metabolism. This review will focus on recent advances for understanding retinoid metabolism that have taken place in the last ten to fifteen years."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I35,I35)","v":16782410},{"$f":"(LEN($J35) - LEN(SUBSTITUTE(LOWER($J35),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J35) - LEN(SUBSTITUTE(LOWER($J35),LOWER(C$3),\"\")))/LEN(C$3)","v":14},{"$f":"(LEN($J35) - LEN(SUBSTITUTE(LOWER($J35),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B35:D35)","v":15},2006,"Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications.","Touyz",16782410,"Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications.    Abstract:   Peroxisome proliferator-activated receptors (PPAR)alpha, gamma and beta/delta belong to the nuclear receptor family of ligand-activated transcription factors. PPARs heterodimerize with the retinoid X receptor (RXR) and then act as transcription factors to modulate the function of many target genes. PPARalpha, gamma and beta/delta subtypes have significant differences in their ligand and gene specificities. PPARalpha is activated by polyunsaturated fatty acids and by fibrate drugs (fenofibrate and gemfibrozil) and controls expression of genes involved in lipid metabolism. PPARgamma is activated by fatty acid derivatives, such as hydroxyoctadecadienoic acid (HODEs), prostaglandin derivatives, such as 15-deoxy-Delta12,14-prostaglandin J2, and thiazolidinedione (glitazone) drugs, such as pioglitazone and rosiglitazone. PPARgamma is a key regulator of glucose homeostasis and adipogenesis. PPARbeta/delta ligands include polyunsaturated fatty acids, prostaglandins and synthetic compounds and stimulate fatty acid oxidation. All PPARs are expressed in vascular cells where they exert antiatherogenic, anti-inflammatory and vasculoprotective actions. Activators of PPARalpha (fibrates) and PPARgamma (thiazolidinediones or glitazones) antagonize angiotensin II effects in vivo and in vitro and have cardiovascular antioxidant and anti-inflammatory actions. PPAR agonists slightly reduce blood pressure are cardio-protective and correct vascular structure and endothelial dysfunction in experimental models of hypertension. Because of these beneficial effects, activators of PPARs may have therapeutic potential in the prevention of cardiovascular disease beyond their actions on carbohydrate and lipid metabolism. The present chapter focuses on the role of PPARs in vascular biology and discusses the clinical implications of using PPAR agonists in the management of vascular disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I36,I36)","v":16129372},{"$f":"(LEN($J36) - LEN(SUBSTITUTE(LOWER($J36),LOWER(B$3),\"\")))/LEN(B$3)","v":15},{"$f":"(LEN($J36) - LEN(SUBSTITUTE(LOWER($J36),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J36) - LEN(SUBSTITUTE(LOWER($J36),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B36:D36)","v":15},2005,"Retinoic acid and retinoid receptors: potential chemopreventive and therapeutic role in cervical cancer.","Abu",16129372,"Retinoic acid and retinoid receptors: potential chemopreventive and therapeutic role in cervical cancer.    Abstract:   Retinoids are natural and synthetic derivatives of vitamin A, which can be obtained from animal products (milk, liver, beef, fish oils, and eggs) and vegetables (carrots, mangos, sweet potatoes, and spinach). Retinoids regulate various important cellular functions in the body through specific nuclear retinoic-acid receptors and retinoid-X receptors, which are encoded by separate genes. Retinoic-acid receptors specifically bind tretinoin and alitretinoin, whereas retinoid-X receptors bind only alitretinoin. Retinoids have long been established as crucial for several essential life processes-healthy growth, vision, maintenance of tissues, reproduction, metabolism, tissue differentiation (normal, premalignant cells, and malignant cells), haemopoiesis, bone development, spermatogenesis, embryogenesis, and overall survival. Therefore, deficiency of vitamin A can lead to various unwanted biological effects. Several experimental and epidemiological studies have shown the antiproliferative activity of retinoids and their potential use in cancer treatment and chemoprevention. Emerging clinical trials have shown the chemotherapeutic and chemopreventive potential of retinoids in cancerous and precancerous conditions of the uterine cervix. In this review, we explore the potential chemopreventive and therapeutic roles of retinoids in preinvasive and invasive cervical neoplasia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I37,I37)","v":12185990},{"$f":"(LEN($J37) - LEN(SUBSTITUTE(LOWER($J37),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J37) - LEN(SUBSTITUTE(LOWER($J37),LOWER(C$3),\"\")))/LEN(C$3)","v":15},{"$f":"(LEN($J37) - LEN(SUBSTITUTE(LOWER($J37),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B37:D37)","v":15},2002,"Targeting peroxisome proliferator-activated receptors (PPARs) in kidney and urologic disease.","Guan",12185990,"Targeting peroxisome proliferator-activated receptors (PPARs) in kidney and urologic disease.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Three PPAR isoforms, designated PPAR-alpha, beta/delta and -gamma, have been identified and were initially investigated in the tissues along urinary tract because of their known role in regulating lipid-activated gene transcription, lipid metabolism, inflammation and cell proliferation and differentiation. Gene distribution studies suggested that 3 PPAR isoforms are differentially expressed in the kidney. PPAR-alpha is predominantly expressed in renal proximal tubules and medullary thick ascending limbs. PPAR-gamma is mainly localized in renal medullary collecting duct with lower expression in renal glomeruli and renal microvasculature. Unlike PPAR-alpha and -gamma, PPAR-beta/delta is ubiquitously expressed in every segment along the nephron. In ureter and urinary bladder, all PPAR isoforms are mainly localized in urothelium of ureter and bladder. The emerging data have suggested physiological and pathophysiological roles of PPARs in tissues along urinary tract. PPAR-alpha plays a major role in triggering fatty acid utilization and the adaptive response to dietary lipids in the kidney. PPAR-beta/delta contributes to cell survival of renal interstitial cell in medullary hyperosmality. PPAR-gamma is involved in regulating renal hemodynamic and water and sodium transport. Furthermore, it also participates in the pathogenesis of glomerulopathy, antidiabetic thiazolidinedione-related water and sodium retention and renal, bladder and prostate carcinomas. PPARs may serve as potential therapeutic targets for certain diseases along urinary tract including glomerulosclerosis, diabetic nephropathy and kidney, prostate and bladder tumors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I38,I38)","v":11818483},{"$f":"(LEN($J38) - LEN(SUBSTITUTE(LOWER($J38),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J38) - LEN(SUBSTITUTE(LOWER($J38),LOWER(C$3),\"\")))/LEN(C$3)","v":13},{"$f":"(LEN($J38) - LEN(SUBSTITUTE(LOWER($J38),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B38:D38)","v":15},2002,"The mechanisms of action of PPARs.","Berger",11818483,"The mechanisms of action of PPARs.    Abstract:   The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPAR gamma, PPAR alpha, and PPAR delta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we present the current state of knowledge regarding the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I39,I39)","v":11237216},{"$f":"(LEN($J39) - LEN(SUBSTITUTE(LOWER($J39),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J39) - LEN(SUBSTITUTE(LOWER($J39),LOWER(C$3),\"\")))/LEN(C$3)","v":12},{"$f":"(LEN($J39) - LEN(SUBSTITUTE(LOWER($J39),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B39:D39)","v":15},2001,"Peroxisome proliferator-activated receptors: from genes to physiology.","Kliewer",11237216,"Peroxisome proliferator-activated receptors: from genes to physiology.    Abstract:   The peroxisome proliferator-activated receptors (PPARalpha, gamma, delta) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have central roles in the storage and catabolism of fatty acids. Although the three PPAR subtypes are closely related and bind to similar DNA response elements as heterodimers with the 9-cis retinoic acid receptor RXR, each subserves a distinct physiology. PPARalpha (NR1C1) is the receptor for the fibrate drugs, which are widely used to lower triglycerides and raise high-density lipoprotein cholesterol levels in the treatment and prevention of coronary artery disease. In rodents, PPARalpha agonists induce hepatomegaly and stimulate a dramatic proliferation of peroxisomes as part of a coordinated physiological response to lipid overload. PPARgamma (NR1C3) plays a critical role in adipocyte differentiation and serves as the receptor for the glitazone class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. In contrast to PPARalpha and PPARgamma, relatively little is known about the biology of PPARdelta (NR1C2), although recent findings suggest that this subtype also has a role in lipid homeostasis. All three PPARs are activated by naturally occurring fatty acids and fatty acid metabolites, indicating that they function as the bodys fatty acid sensors. Three-dimensional crystal structures reveal that the ligand-binding pockets of the PPARs are much larger and more accessible than those of other nuclear receptors, providing a molecular basis for the promiscuous ligand-binding properties of these receptors. Given the fundamental roles that the PPARs play in energy balance, drugs that modulate PPAR activity are likely to be useful for treating a wide range of metabolic disorders, including atherosclerosis, dyslipidemia, obesity, and type 2 diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I40,I40)","v":10828316},{"$f":"(LEN($J40) - LEN(SUBSTITUTE(LOWER($J40),LOWER(B$3),\"\")))/LEN(B$3)","v":14},{"$f":"(LEN($J40) - LEN(SUBSTITUTE(LOWER($J40),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J40) - LEN(SUBSTITUTE(LOWER($J40),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B40:D40)","v":15},2000,"Recent developments in receptor-selective retinoids.","Nagpal",10828316,"Recent developments in receptor-selective retinoids.    Abstract:   Natural (all trans-retinoic acid, RA) and synthetic retinoids exhibit potent anti-proliferative, normalization of differentiation and anti-inflammatory activities which appear to account for their therapeutic effects in acne, psoriasis, photoaging, precancerous lesions and established cancers. Although RA has shown considerable promise in dermatologic indications, certain side effects have restricted its use as a choice of agent for chronic administration. Systematic synthesis of receptor-selective retinoids has resulted in two topical drugs, Tazorac/Zorac (tazarotene) and Differin (adapalene). Tazorac is indicated for psoriasis and acne and Differin gel for the treatment of acne. These drugs bind to the retinoic acid receptor (RAR) family members. Various RAR subtype-specific and function-selective retinoids have been synthesized. These retinoids, which are in various stages of pre-clinical development for the treatment of cancers, psoriasis and as an antidote to Accutane-mediated mucocutaneous toxicity, will also be discussed in this review. Discovery of another retinoid receptor, retinoid X receptor (RXR), revealed that RXR-specific retinoids already existed in retinoid chemical libraries. Structure activity relationship studies based upon binding and transactivation assays led to the synthesis of RXR-specific ligands with high affinities for RXR subtypes. These compounds were found to be effective in the treatment of hyperglycemia in animal models of type II diabetes. The discovery of novel retinoids along with an increased understanding of the biological functions and mechanisms of action of retinoid receptors are likely to result in improved treatments for existing responsive indications and identification of new retinoid therapeutic targets."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I41,I41)","v":10637381},{"$f":"(LEN($J41) - LEN(SUBSTITUTE(LOWER($J41),LOWER(B$3),\"\")))/LEN(B$3)","v":14},{"$f":"(LEN($J41) - LEN(SUBSTITUTE(LOWER($J41),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J41) - LEN(SUBSTITUTE(LOWER($J41),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B41:D41)","v":15},2000,"The importance of vitamin A in nutrition.","Dawson",10637381,"The importance of vitamin A in nutrition.    Abstract:   Preformed vitamin A (all-trans-retinol and its esters) and provitamin A (beta-carotene) are essential dietary nutrients that provide a source of retinol. Both retinyl esters and beta-carotene are metabolized to retinol. The retinol-binding proteins on binding retinol provide a means for solubilizing retinol for delivery to target tissues and for regulating retinol plasma concentrations. Oxidation of retinol provides retinal, which is essential for vision, and retinoic acid, a transcription factor ligand that has important roles in regulating genes involved in cell morphogenesis, differentiation, and proliferation. The observations that vitamin A can produce cell and tissue changes similar to those found during neoplastic transformation and that vitamin supplementation can reverse this process indicated a potential role for vitamin A in cancer prevention. Thus far, correlative epidemiological studies on vitamin A use and cancer prevention have produced mixed results, as this review indicates. Apparently, in populations deficient in vitamin A (caused by an inadequate diet or tobacco use), supplementation programs appear to be effective in reducing cancer incidence. In groups already having sufficient dietary or supplemental vitamin A, cancer prevention by added vitamin A may not be particularly effective. The most likely reason for the low efficacy in the latter groups is that feedback mechanisms that increase retinol storage in the liver limit retinol plasma levels; whereas, supplementation at higher doses causes toxicity. In addition to serving as a metabolic source of retinol, beta-carotene, along with other dietary carotenoids, function as antioxidants that can prevent carcinogenesis by decreasing the levels of the free-radicals that cause DNA damage."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I42,I42)","v":25083916},{"$f":"(LEN($J42) - LEN(SUBSTITUTE(LOWER($J42),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J42) - LEN(SUBSTITUTE(LOWER($J42),LOWER(C$3),\"\")))/LEN(C$3)","v":12},{"$f":"(LEN($J42) - LEN(SUBSTITUTE(LOWER($J42),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B42:D42)","v":14},2014,"Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review.","Wang",25083916,"Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a review.    Abstract:   Agonists of the nuclear receptor PPARγ are therapeutically used to combat hyperglycaemia associated with the metabolic syndrome and type 2 diabetes. In spite of being effective in normalization of blood glucose levels, the currently used PPARγ agonists from the thiazolidinedione type have serious side effects, making the discovery of novel ligands highly relevant. Natural products have proven historically to be a promising pool of structures for drug discovery, and a significant research effort has recently been undertaken to explore the PPARγ-activating potential of a wide range of natural products originating from traditionally used medicinal plants or dietary sources. The majority of identified compounds are selective PPARγ modulators (SPPARMs), transactivating the expression of PPARγ-dependent reporter genes as partial agonists. Those natural PPARγ ligands have different binding modes to the receptor in comparison to the full thiazolidinedione agonists, and on some occasions activate in addition PPARα (e.g. genistein, biochanin A, sargaquinoic acid, sargahydroquinoic acid, resveratrol, amorphastilbol) or the PPARγ-dimer partner retinoid X receptor (RXR; e.g. the neolignans magnolol and honokiol). A number of in vivo studies suggest that some of the natural product activators of PPARγ (e.g. honokiol, amorfrutin 1, amorfrutin B, amorphastilbol) improve metabolic parameters in diabetic animal models, partly with reduced side effects in comparison to full thiazolidinedione agonists. The bioactivity pattern as well as the dietary use of several of the identified active compounds and plant extracts warrants future research regarding their therapeutic potential and the possibility to modulate PPARγ activation by dietary interventions or food supplements."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I43,I43)","v":15850670},{"$f":"(LEN($J43) - LEN(SUBSTITUTE(LOWER($J43),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J43) - LEN(SUBSTITUTE(LOWER($J43),LOWER(C$3),\"\")))/LEN(C$3)","v":10},{"$f":"(LEN($J43) - LEN(SUBSTITUTE(LOWER($J43),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B43:D43)","v":14},2005,"Hormone regulation of microglial cell activation: relevance to multiple sclerosis.","Drew",15850670,"Hormone regulation of microglial cell activation: relevance to multiple sclerosis.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses. Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-alpha that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS. Previously, we and others demonstrated that PPAR-gamma agonists including 15d-PGJ(2) are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-gamma modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ(2) is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ(2) acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ(2) and 9-cis RA inhibit cell activation through the formation of PPAR-gamma/RXR heterodimers. Interestingly, PGA(2), which like 15d-PGJ(2) is a cyclopentenone prostaglandin, but which unlike 15d-PGJ(2) does not bind PPAR-gamma, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ(2) inhibits microglial cell activation by PPAR-gamma-dependent as well as PPAR-gamma-independent mechanisms. The studies further suggest that the PPAR-gamma agonist 15d-PGJ(2) in combination with retinoids may be effective in the treatment of MS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I44,I44)","v":15134535},{"$f":"(LEN($J44) - LEN(SUBSTITUTE(LOWER($J44),LOWER(B$3),\"\")))/LEN(B$3)","v":14},{"$f":"(LEN($J44) - LEN(SUBSTITUTE(LOWER($J44),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J44) - LEN(SUBSTITUTE(LOWER($J44),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B44:D44)","v":14},2004,"Retinoids in cancer chemoprevention.","Okuno",15134535,"Retinoids in cancer chemoprevention.    Abstract:   We review the therapeutic and preventive applications of a retinoid analog (vitamin A and its derivatives) for human cancers. Chemoprevention of cancer is an intervention in the carcinogenic process by chemical agents that block or reverse the malignant transformation of cells. Retinoids are prime candidates for cancer chemoprevention since cancer is characterized by abnormal growth with a lack of differentiation, which could be modified by retinoids. Retinoids exert their biological functions through nuclear receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR). A number of experimental and clinical studies have been performed in the past two decades with retinoids showing that they inhibit or reverse the carcinogenic process in some organs, including hematological malignancy as well as premalignant and malignant lesions in the oral cavity, head and neck, breast, skin and liver. We particularly focus upon the therapeutic application of all-trans RA (atRA) to acute promyelocytic leukemia (APL) and on the preventive approach to hepatocellular carcinoma (HCC) by a synthetic retinoid analog, acyclic retinoid. In both malignancies, malfunction of retinoid nuclear receptors is closely related to their carcinogenic process. In APL, a chromosomal translocation produces a chimeric protein between RAR alpha and a protein called promyelocyte leukemia protein (PML). PML-RAR alpha works as a dominant negative receptor in the leukemic cells, interfering with the normal function of RAR alpha and/or PML, which in turn results in the arrest of cell maturation at the stage of promyelocytes. Oral administration of atRA induces differentiation of promyelocytic leukemic cells to mature neutrophils, and leads to a high rates (over 90%) of complete remission. AtRA therapy has become standard in the treatment of APL. In the case of HCC, post-translational modification of RXR by phosphorylation impairs its function, which leads to uncontrolled cell growth. Acyclic retinoid suppresses the phosphorylation of RXR alpha, restores its function in the presence of its endogenous ligand, 9-cis RA, and thereby induces apoptosis of the cancer cells. Acyclic retinoid given orally successfully suppresses the development of second primary tumors in cirrhotic patients who undergo curative removal of preceding HCC. Eradication of (pre)malignant clones (clonal deletion) from the liver is suggested as a mechanism of the chemopreventive effect. Further development of more effective retinoids as well as their use in combination with other classes of anticancer agents including immunopreventive drugs like interferons may provide strategies for cancer prevention."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I45,I45)","v":12500431},{"$f":"(LEN($J45) - LEN(SUBSTITUTE(LOWER($J45),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J45) - LEN(SUBSTITUTE(LOWER($J45),LOWER(C$3),\"\")))/LEN(C$3)","v":10},{"$f":"(LEN($J45) - LEN(SUBSTITUTE(LOWER($J45),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B45:D45)","v":14},2002,"Experimental approaches to study PPAR gamma agonists as antidiabetic drugs.","Vázquez",12500431,"Experimental approaches to study PPAR gamma agonists as antidiabetic drugs.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. Since PPARs appear to be closely involved in the regulation of dietary fat storage and catabolism, they have been established as an important target for the treatment of type 2 diabetes and other disorders associated with the high intake of dietary fat. Thiazolidinediones (TZDs) were the first class of compounds to be identified as PPAR gamma-ligands, constituting a new class of antidiabetic drugs that have recently been introduced as therapeutic agents for the treatment of type 2 diabetes mellitus by acting as insulin sensitizers. These compounds improve insulin resistance by increasing cell sensitivity to insulin. In fact, PPAR gamma agonists increase peripheral insulin sensitivity by increasing the transcription of genes, which, in turn, increase glucose uptake, also improving insulin-stimulated glucose disposal in muscle. PPAR gamma agonists increase insulin signaling, reduce circulating levels of free fatty acids and stimulate adipocyte differentiation, thus favoring the formation of smaller, more insulin-sensitive adipocytes. TZDs have been proven effective in different experimental models to evaluate their effectiveness as an antidiabetic agent, and the involvement of PPAR gamma in the pharmacological effects of these compounds has been supported by studies showing an excellent correlation between the hypoglycemic action of these drugs and their affinity for PPAR gamma. Despite this evidence, the site of action and the molecular mechanism of TZDs remain unclear. The aim of the present article was to review and discuss the most relevant pharmacological studies performed in the search for establishing the mechanism of action of antidiabetic TZDs and related compounds acting as PPAR gamma agonists, as well as to summarize those representative experimental approaches currently used to evaluate PPAR gamma agonists as therapeutic agents for the treatment of insulin-resistant type 2 diabetes mellitus."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I46,I46)","v":12079620},{"$f":"(LEN($J46) - LEN(SUBSTITUTE(LOWER($J46),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J46) - LEN(SUBSTITUTE(LOWER($J46),LOWER(C$3),\"\")))/LEN(C$3)","v":12},{"$f":"(LEN($J46) - LEN(SUBSTITUTE(LOWER($J46),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B46:D46)","v":14},2002,"Physiological and therapeutic roles of peroxisome proliferator-activated receptors.","Berger",12079620,"Physiological and therapeutic roles of peroxisome proliferator-activated receptors.    Abstract:   The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor isoforms, including PPARgamma, PPARalpha, and PPARdelta, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors increasing the rate of transcription initiation. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Natural ligands for the PPARs include fatty acids and eicosanoids. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, are effective in the treatment of dyslipidemia and diabetes. Use of selective ligands led to the discovery of additional potential roles for the PPARs in pathological states, including atherosclerosis, inflammation, and hypertension. This review provides an overview of the molecular mechanisms of PPAR action and the involvement of the PPARs in the etiology and treatment of several chronic diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I47,I47)","v":11007938},{"$f":"(LEN($J47) - LEN(SUBSTITUTE(LOWER($J47),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J47) - LEN(SUBSTITUTE(LOWER($J47),LOWER(C$3),\"\")))/LEN(C$3)","v":13},{"$f":"(LEN($J47) - LEN(SUBSTITUTE(LOWER($J47),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B47:D47)","v":14},2000,"Regulation of the peroxisomal beta-oxidation-dependent pathway by peroxisome proliferator-activated receptor alpha and kinases.","Latruffe",11007938,"Regulation of the peroxisomal beta-oxidation-dependent pathway by peroxisome proliferator-activated receptor alpha and kinases.    Abstract:   The first PPAR (peroxisome proliferator-activated receptor) was cloned in 1990 by Issemann and Green (Nature 347:645-650). This nuclear receptor was so named since it is activated by peroxisome proliferators including several drugs of the fibrate family, plasticizers, and herbicides. This receptor belongs to the steroid receptor superfamily. After activation by a specific ligand, it binds to a DNA response element, PPRE (peroxisome proliferator response element), which is a DR-1 direct repeat of the consensus sequence TGACCT x TGACCT. This mechanism leads to the transcriptional activation of target genes (Motojima et al., J Biol Chem 273:16710-16714, 1998). After the first discovery, several isoforms were characterized in most of the vertebrates investigated. PPAR alpha, activated by hypolipidemic agents of the fibrate family or by leukotrienes; regulates lipid metabolism as well as the detoxifying enzyme-encoding genes. PPAR beta/delta, which is not very well known yet, appears to be more specifically activated by fatty acids. PPAR gamma (subisoforms 1, 2, 3) is activated by the prostaglandin PGJ2 or by antidiabetic thiazolidinediones (Vamecq and Latruffe, Lancet 354:411-418, 1999). This latter isoform is involved in adipogenesis. The level of PPAR expression is largely dependent on the tissue type. PPAR alpha is mainly expressed in liver and kidney, while PPAR beta/delta is almost constitutively expressed. In contrast, PPAR gamma is largely expressed in white adipose tissue. PPAR is a transcriptional factor that requires other nuclear proteins in order to function, i.e. RXRalpha (9-cis-retinoic acid receptor alpha) in all cases in addition to other regulatory proteins. Peroxisomes are specific organelles for very long-chain and polyunsaturated fatty acid catabolism. From our results and those of others, the inventory of the role of PPAR alpha in the regulation of peroxisomal fatty acid beta-oxidation is presented. In relation to this, we showed that PPAR alpha activates peroxisomal beta-oxidation-encoding genes such as acyl-CoA oxidase, multifunctional protein, and thiolase (Bardot et al., FEBS Lett 360:183-186, 1995). Moreover, rat liver PPAR alpha regulatory activity is dependent on its phosphorylated state (Passilly et al., Biochem Pharmacol 58:1001-1008, 1999). On the other hand, some signal transduction pathways such as protein kinase C are modified by peroxisome proliferators that increase the phosphorylation level of some specific proteins (Passilly et al. Eur J Biochem 230:316-321, 1995). From all these findings, PPAR alpha and kinases appear to play an important role in lipid homeostasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I48,I48)","v":10731129},{"$f":"(LEN($J48) - LEN(SUBSTITUTE(LOWER($J48),LOWER(B$3),\"\")))/LEN(B$3)","v":13},{"$f":"(LEN($J48) - LEN(SUBSTITUTE(LOWER($J48),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J48) - LEN(SUBSTITUTE(LOWER($J48),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B48:D48)","v":14},1999,"Novel retinoids with receptor selectivity and functional selectivity.","Johnson",10731129,"Novel retinoids with receptor selectivity and functional selectivity.    Abstract:   Retinoids mediate a number of physiological pathways through their effects on cellular growth and differentiation. Upon binding to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), retinoids regulate cellular processes by directly modulating the expression of responsive genes. The wide-ranging effects of retinoid action are attributable to two main factors-the ubiquitous distribution of several subtypes and isoforms of RARs and RXRs, and the ability of these receptors to regulate numerous genes upon ligand activation. The broad range of effects mediated by retinoids means not only that they have many potential therapeutic applications but also that non-selective retinoids are associated with a high incidence of adverse effects. The design of retinoids that are receptor-selective and function-selective is a strategy that is proving successful in developing novel retinoids that offer not only good efficacy but also good tolerability. Tazarotene, a receptor-selective retinoid indicated for the topical treatment of psoriasis, is at the forefront of this new generation of retinoids. In the near future, other receptor-selective retinoids may prove useful for the treatment of other dermatological diseases, cancer, and diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I49,I49)","v":9787993},{"$f":"(LEN($J49) - LEN(SUBSTITUTE(LOWER($J49),LOWER(B$3),\"\")))/LEN(B$3)","v":14},{"$f":"(LEN($J49) - LEN(SUBSTITUTE(LOWER($J49),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J49) - LEN(SUBSTITUTE(LOWER($J49),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B49:D49)","v":14},1998,"Current research and future developments in retinoids: oral and topical agents.","Chandraratna",9787993,"Current research and future developments in retinoids: oral and topical agents.    Abstract:   The retinoids are a class of small molecules capable of affecting biological systems in a fundamental way by interacting with a variety of nuclear receptors and affecting gene transcription. As such, they have powerful therapeutic potential in the treatment of a variety of diseases. However, non-selective retinoid drugs that indiscriminately activate many or all of the different retinoid receptors and their signaling pathways will invariably produce both undesirable and beneficial effects. Therefore, current and future retinoid research must employ a rational approach to drug discovery, the goal of which is to design retinoid drugs with sufficient receptor or function selectivity that only those biological systems relevant to a specific disease are affected. Tazarotene is a retinoid with properties that are a result of this rational approach to drug discovery. Its molecular structure was engineered in such a way as to make it selective for the retinoic acid receptor (RAR) class of nuclear receptors over retinoid X receptors (RXRs), with preferential activation of RAR beta and RAR gamma over RAR alpha. It was further engineered to possess clinically favorable pharmacokinetic properties. To date, all retinoid drugs available for therapeutic use are retinoid agonists; they bind to retinoid receptors and facilitate gene transcription. However, ongoing research has developed retinoid antagonists (that bind to receptors without activating gene transcription) and inverse agonists (that bind to receptors and inhibit gene transcription). These new drugs and other retinoids currently under development represent new opportunities for the treatment of a variety of disorders in dermatology, oncology, and metabolic disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I50,I50)","v":9035704},{"$f":"(LEN($J50) - LEN(SUBSTITUTE(LOWER($J50),LOWER(B$3),\"\")))/LEN(B$3)","v":14},{"$f":"(LEN($J50) - LEN(SUBSTITUTE(LOWER($J50),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J50) - LEN(SUBSTITUTE(LOWER($J50),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B50:D50)","v":14},1996,"Oral retinoids--efficacy and toxicity in psoriasis.","Gollnick",9035704,"Oral retinoids--efficacy and toxicity in psoriasis.    Abstract:   Psoriasis is a disease of unknown aetiology, affecting approximately 1-3% of the population. In most cases involving relatively localized disease, patients are best managed with either topical therapy alone or topical therapy in combination with UV-phototherapy. However, approximately 35% of patients do not respond well to these conventional treatments or have moderate-to-severe disease requiring more aggressive forms of therapy. The second-generation retinoids, etretinate and its metabolite acitretin, are important additions to the armamentarium of agents used to treat these recalcitrant or severe forms of the disease. Generalized pustular psoriasis generally responds well to high-dose (0.7-1 mg/kg/day) oral retinoid monotherapy. In contrast, increasing small doses of the retinoid are recommended initially in erythrodermic psoriasis in order not to provoke the disease. Long-term clinical experience favours a combination treatment of the retinoid with either topical and/or UV irradiation in chronic plaque-like psoriasis. Both oral retinoids have comparable efficacy and tolerability profiles, and the relapse rates for both drugs are similar. The toxicities associated with both short- and long-term treatment with oral retinoids are significant and include mucocutaneous effects, adverse modulation of serum lipid chemistries, elevation of liver enzymes, and after long-term chronic dosing, skeletal and ligamentous calcification, and hyperostosis. Both etretinate and acitretin, like all retinoids, are known teratogens in animal models, and documented evidence exists for teratogenic activity in humans as well. Consequently, women of childbearing age are strongly advised to avoid pregnancy during treatment and up to 5 years following cessation of therapy with both etretinate and the carboxylic acid metabolite acitretin."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I51,I51)","v":7641581},{"$f":"(LEN($J51) - LEN(SUBSTITUTE(LOWER($J51),LOWER(B$3),\"\")))/LEN(B$3)","v":14},{"$f":"(LEN($J51) - LEN(SUBSTITUTE(LOWER($J51),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J51) - LEN(SUBSTITUTE(LOWER($J51),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B51:D51)","v":14},1995,"Alterations in chemically induced tissue injury related to all-trans-retinol pretreatment in rodents.","Sauer",7641581,"Alterations in chemically induced tissue injury related to all-trans-retinol pretreatment in rodents.    Abstract:   Retinol (vitamin A) is an essential nutrient which has many physiological effects throughout the body. Our studies have demonstrated that retinol modulation of immune response, through alteration of macrophage and neutrophil function, can have dramatic effects on the toxicity of some compounds. Based on these studies, our current hypothesis for retinol potentiation of chemical-induced liver injury is that retinol administered to rats prior to the hepatotoxicant (CCl4 and AA in rats; and AA, APAP, and GalN in mice) primes the Kupffer cells to a more active state. This may occur in part as a result of increases in chemical mediators such as TNF from these Kupffer cells. Following hepatocyte damage by a toxicant, Kupffer cells are activated to release reactive oxygen species, immune mediators, and chemotactic factors which all serve to enhance the inflammatory response. This increased inflammatory response then results in increased injury to the already toxicant-damaged hepatocytes. In addition, retinol modulation of toxicant activation and detoxification may also make important contributions to the potentiation of some toxicants such as AA. Retinol protection of CCl4 hepatotoxicity in mice is more difficult to explain at this time but is possibly related to alterations in CCl4 metabolism in this species. Differences in response between pulmonary and liver macrophages (Kupffer cells) may explain the retinol protection from 1-NN pulmonary toxicity. Retinol may decrease the inflammatory response through downregulation of pulmonary macrophage function, thus resulting in decreased pulmonary injury. Finally, since retinol protection of cadmium toxicity in the liver and testis requires 7 days of retinol pretreatment, we suspect that retinol is inducing protective protein(s) in these organs. Aside from its normal biological role in rhe body, clinical medicine has found new uses for retinol in the treatment and prevention of some cancers, and in the treatment of certain dermatologic conditions. Since these patients are frequently administered or exposed to other potentially toxic compounds, it is obviously prudent and necessary to continue research into the effects of retinol on immune modulation and interaction with other compounds. More importantly, these studies demonstrate the modulation of immune function is one mechanism by which one chemical can influence the toxicity of another."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I52,I52)","v":24393720},{"$f":"(LEN($J52) - LEN(SUBSTITUTE(LOWER($J52),LOWER(B$3),\"\")))/LEN(B$3)","v":13},{"$f":"(LEN($J52) - LEN(SUBSTITUTE(LOWER($J52),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J52) - LEN(SUBSTITUTE(LOWER($J52),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B52:D52)","v":13},2014,"Retinoic acid signaling pathways in development and diseases.","Das",24393720,"Retinoic acid signaling pathways in development and diseases.    Abstract:   Retinoids comprise a group of compounds each composed of three basic parts: a trimethylated cyclohexene ring that is a bulky hydrophobic group, a conjugated tetraene side chain that functions as a linker unit, and a polar carbon-oxygen functional group. Biochemical conversion of carotenoid or other retinoids to retinoic acid (RA) is essential for normal regulation of a wide range of biological processes including development, differentiation, proliferation, and apoptosis. Retinoids regulate various physiological outputs by binding to nuclear receptors called retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which themselves are DNA-binding transcriptional regulators. The functional response of RA and their receptors are modulated by a host of coactivators and corepressors. Retinoids are essential in the development and function of several organ systems; however, deregulated retinoid signaling can contribute to serious diseases. Several natural and synthetic retinoids are in clinical use or undergoing trials for treating specific diseases including cancer. In this review, we provide a broad overview on the importance of retinoids in development and various diseases, highlighting various retinoids in the drug discovery process, ranging all the way from retinoid chemistry to clinical uses and imaging."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I53,I53)","v":22320921},{"$f":"(LEN($J53) - LEN(SUBSTITUTE(LOWER($J53),LOWER(B$3),\"\")))/LEN(B$3)","v":13},{"$f":"(LEN($J53) - LEN(SUBSTITUTE(LOWER($J53),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J53) - LEN(SUBSTITUTE(LOWER($J53),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B53:D53)","v":13},2012,"Retinoic acids and hepatic stellate cells in liver disease.","Lee",22320921,"Retinoic acids and hepatic stellate cells in liver disease.    Abstract:   Quiescent hepatic stellate cells (HSCs) in healthy liver store 80% of total liver retinols and release them depending on the extracellular retinol status. However, HSCs activated by liver injury lose their retinols and produce a considerable amount of extracellular matrix, subsequently leading to liver fibrosis. Emerging evidence suggests that retinols and their metabolites such as retinoic acids (RAs) contribute to liver regeneration, fibrosis and tumor. However, it is not clear yet why HSCs lose retinol, which enzymes are involved in the retinol metabolism of HSCs and what function of retinol metabolites on HSCs upon liver injury. Recently, our group and collaborators have demonstrated that during activation, HSCs not only lose retinols but also metabolize them into RAs by alcohol dehydrogenases and retinaldehyde dehydrogenases. As transcriptional factors, metabolized RAs induce retinoic acid early inducible-1 and suppressor of cytokine signaling 1 in HSCs, which plays an important role in the interaction between HSCs and natural killer cells. In addition, RAs released from HSCs may induce hepatic cannabinoid receptor 1 expression in alcoholic liver steatosis or regulate immune responses upon liver inflammation. The present review summarizes the role of endogenous metabolized RAs on HSCs themselves and on other liver cells including hepatocytes and immune cells. Moreover, the effects of exogenous retinol and RA treatments on HSCs and liver disease are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I54,I54)","v":22166499},{"$f":"(LEN($J54) - LEN(SUBSTITUTE(LOWER($J54),LOWER(B$3),\"\")))/LEN(B$3)","v":13},{"$f":"(LEN($J54) - LEN(SUBSTITUTE(LOWER($J54),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J54) - LEN(SUBSTITUTE(LOWER($J54),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B54:D54)","v":13},2011,"Chemical pathology of homocysteine. V. Thioretinamide, thioretinaco, and cystathionine synthase function in degenerative diseases.","McCully",22166499,"Chemical pathology of homocysteine. V. Thioretinamide, thioretinaco, and cystathionine synthase function in degenerative diseases.    Abstract:   Hyperhomocysteinemia was first associated with degenerative disease by observation of accelerated arteriosclerosis in children with inherited disorders of cystathionine synthase, methionine synthase, and methylene tetrohydrofolate reductase. The metabolic blockade of sulfate synthesis from homocysteine thiolactone in malignant cells is ascribed to a deficiency of a chemopreventive derivative of homocysteine thiolactone that occurs in normal cells. Its chemical structure was elucidated by the organic synthesis of thioretinamide from retinoic acid and homocysteine thiolactone. Oxidation of the sulfur atom of homocysteine is inhibited in scorbutic guinea pigs, demonstrating ascorbate function in sulfate synthesis from homocysteine. Studies of homocysteine metabolism in protein energy malnutrition led to the conclusion that the biosynthesis of thioretinamide from the retinol of transthyretin is catalyzed by dehydroascorbate and superoxide generated from the heme oxygenase group of cystathionine synthase. Newly synthesized thioretinamide is complexed with cobalamin to form thioretinaco, which is activated by ozone and oxygen to function as the active site of oxidative phosphorylation. In accordance with the trophoblastic theory of cancer, pancreatic enzymes are believed to be oncolytic because they hydrolyze the homocysteinylated proteins, nucleic acids and glycosaminoglycans of malignant tissues. The clonal selection of malignant cells that are deficient in the heme oxygenase function of cystathionine synthase produces cells dependent upon glycolysis for ATP synthesis, since they are deficient in synthesis of thioretinamide, thioretinaco and thioretinaco ozonide. The vulnerable plaque of arteriosclerosis originates from complexes of microbes with homocysteinylated lipoproteins, obstructing vasa vasorum narrowed by endothelial dysfunction, causing arterial ischemia, and intimal micro-abscesses. Degenerative diseases may be ameliorated by a proposed therapeutic protocol of thioretinamide with pancreatic enzymes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I55,I55)","v":19906796},{"$f":"(LEN($J55) - LEN(SUBSTITUTE(LOWER($J55),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J55) - LEN(SUBSTITUTE(LOWER($J55),LOWER(C$3),\"\")))/LEN(C$3)","v":12},{"$f":"(LEN($J55) - LEN(SUBSTITUTE(LOWER($J55),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B55:D55)","v":13},2010,"Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation.","Higgins",19906796,"Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation.    Abstract:   Peroxisome proliferator-activated receptor gamma (PPARgamma) is a clinically validated target for treatment of insulin resistance. PPARgamma activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPARgamma provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPARgamma is a nuclear receptor that forms a complex with coreceptor RXR and a cell type- and cell state-specific array of coregulators to control gene transcription. PPARgamma affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPARgamma modulator profile would include high-affinity interaction with the PPARgamma-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPARgamma modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I56,I56)","v":19260526},{"$f":"(LEN($J56) - LEN(SUBSTITUTE(LOWER($J56),LOWER(B$3),\"\")))/LEN(B$3)","v":13},{"$f":"(LEN($J56) - LEN(SUBSTITUTE(LOWER($J56),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J56) - LEN(SUBSTITUTE(LOWER($J56),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B56:D56)","v":13},2009,"[Retinal degeneration diseases and the retinoid cycle].","Maeda",19260526,"[Retinal degeneration diseases and the retinoid cycle].    Abstract:   The retinoid cycle is a vitamin A metabolic circuit which occurs between the photoreceptor outer segment and the retinal pigmented epithelium to maintain visual function. Abnormalities in the retinoid cycle are involved in some hereditary retinal degenerative diseases and age-related retinal degeneration. Here, we summarize the entire process of the retinoid cycle and the pathophysiology of those retinal diseases due to molecular abnormalities of the cycle. Gene transfer and pharmacologic treatment have been developed based on recent studies revealing characteristic clinical features initiated by each aberrant reaction in the retinoid cycle. The molecular mechanisms of retinal degeneration caused by an abnormal retinoid cycle have been investigated intensively, and practical therapies have been introduced for currently incurable retinal diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I57,I57)","v":19129679},{"$f":"(LEN($J57) - LEN(SUBSTITUTE(LOWER($J57),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J57) - LEN(SUBSTITUTE(LOWER($J57),LOWER(C$3),\"\")))/LEN(C$3)","v":11},{"$f":"(LEN($J57) - LEN(SUBSTITUTE(LOWER($J57),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B57:D57)","v":13},2009,"Peroxisome proliferator-activated receptor gamma and cardiovascular diseases.","Takano",19129679,"Peroxisome proliferator-activated receptor gamma and cardiovascular diseases.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and form heterodimers with retinoid X receptor. Three PPAR isoforms have been isolated and termed alpha, beta (or delta) and gamma. Although PPARgamma is expressed predominantly in adipose tissue and associated with adipocyte differentiation and glucose homeostasis, PPARgamma is also present in a variety of cell types. Synthetic antidiabetic thiazolidinediones (TZDs) are well known as ligands and activators for PPARgamma. After it was reported that activation of PPARgamma suppressed production of pro-inflammatory cytokines in activated macrophages, medical interest in PPARgamma has grown and there has been a huge research effort. PPARgamma is currently known to be implicated in various human chronic diseases such as diabetes mellitus, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, and Alzheimers disease. Many studies suggest that TZDs not only ameliorate insulin sensitivity, but also have pleiotropic effects on many tissues and cell types. Although activation of PPARgamma seems to have beneficial effects on cardiovascular diseases, the mechanisms by which PPARgamma ligands prevent their development are not fully understood. Recent data about the actions and its mechanisms of PPARgamma-dependent pathway in cardiovascular diseases are discussed here."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I58,I58)","v":15721857},{"$f":"(LEN($J58) - LEN(SUBSTITUTE(LOWER($J58),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J58) - LEN(SUBSTITUTE(LOWER($J58),LOWER(C$3),\"\")))/LEN(C$3)","v":11},{"$f":"(LEN($J58) - LEN(SUBSTITUTE(LOWER($J58),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B58:D58)","v":13},2005,"Beneficial effects of PPAR-gamma ligands in ischemia-reperfusion injury, inflammation and shock.","Abdelrahman",15721857,"Beneficial effects of PPAR-gamma ligands in ischemia-reperfusion injury, inflammation and shock.    Abstract:   Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPAR-gamma regulates gene expression by forming a heterodimer with the retinoid X receptor (RXR) before binding to sequence-specific PPAR response elements (PPREs) in the promoter region of target genes, thereby regulating several metabolic pathways, including lipid biosynthesis and glucose metabolism. Thiazolidinediones (TZDs, i.e. rosiglitazone, pioglitazone), which are synthetic PPAR-gamma agonists, act as insulin sensitizers and are used in the treatment of type 2 diabetes. In the last few years, it has, however, become evident that the therapeutic effects of PPAR-gamma ligands reach far beyond their use as insulin sensitizers. Recently, PPAR-gamma has been implicated as a regulator of cellular inflammatory and ischemic responses. PPAR-gamma agonists may exert their anti-inflammatory effects by negatively regulating the expression of pro-inflammatory genes induced during macrophage differentiation and activation, by either PPAR-gamma-dependent or -independent mechanisms. Several lines of evidence suggest that TZDs protect the heart and other organs against the tissue injury caused by ischemia/reperfusion (I/R) injury and shock. This review discusses the anti-inflammatory signalling pathways activated by PPAR-gamma, as well as the potential therapeutic effects of PPAR-gamma agonists in animal models of ischemia/reperfusion, inflammation and shock."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I59,I59)","v":15032732},{"$f":"(LEN($J59) - LEN(SUBSTITUTE(LOWER($J59),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J59) - LEN(SUBSTITUTE(LOWER($J59),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J59) - LEN(SUBSTITUTE(LOWER($J59),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B59:D59)","v":13},2004,"Retinoids and retinoid receptors in the control of energy balance: novel pharmacological strategies in obesity and diabetes.","Villarroya",15032732,"Retinoids and retinoid receptors in the control of energy balance: novel pharmacological strategies in obesity and diabetes.    Abstract:   Obesity and type II diabetes are closely related metabolic diseases with an increasing incidence worldwide. No clear-cut pharmacological treatment for these complex metabolic disturbances is available despite current efforts. New directions and perspectives for the pharmacological or nutritional treatment of these diseases should be defined. In recent years, a growing body of evidence shows that retinoids and retinoic acid receptors are involved in the control of biological aspects (e.g. adiposity and energy expenditure mechanisms), which offers great potential for research on the treatment of obesity and type II diabetes. All-trans retinoic acid is known to inhibit adipocyte differentiation, whereas, molecules activating the retinoid X-receptor (rexinoids) promote the differentiation of adipocytes. Treatment with rexinoids ameliorates glycemic control in rodent models of type II diabetes and obesity, although other findings indicate similar positive effects by inhibiting the receptor. Moreover, natural products of dietary origin, such as phytanic acid can activate RXR and thus, trigger adipose cell differentiation. Finally, the activation of retinoic acid receptors or retinoid X receptors has been reported to induce the gene expression of uncoupling proteins, which are mitochondrial proteins involved in the regulation of energy expenditure and fatty acid metabolism. Further research is required to exploit the capacities of the retinoid-dependent pathways of regulation of adiposity, insulin sensitivity and energy expenditure for drug development in metabolic disturbances."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I60,I60)","v":12055342},{"$f":"(LEN($J60) - LEN(SUBSTITUTE(LOWER($J60),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J60) - LEN(SUBSTITUTE(LOWER($J60),LOWER(C$3),\"\")))/LEN(C$3)","v":12},{"$f":"(LEN($J60) - LEN(SUBSTITUTE(LOWER($J60),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B60:D60)","v":13},2002,"PPAR(gamma) and glucose homeostasis.","Picard",12055342,"PPAR(gamma) and glucose homeostasis.    Abstract:   Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor involved in the control of metabolism. Research on PPARgamma is oriented towards understanding its role in insulin sensitization, which was inspired by the discovery that antidiabetic agents, the thiazolidinediones, were agonists for PPARgamma. PPARgamma stimulation improves glucose tolerance and insulin sensitivity in type 2 diabetic patients and in animal models of insulin resistance through mechanisms that are incompletely understood. Upon activation, PPARgamma heterodimerizes with retinoid X receptor, recruits specific cofactors, and binds to responsive DNA elements, thereby stimulating the transcription of target genes. Because PPARgamma is highly enriched in adipose tissue and because of its major role in adipocyte differentiation, it is thought that the effects of PPARgamma in adipose tissue are crucial to explain its role in insulin sensitization, but recent studies have highlighted the contribution of other tissues as well. Although relatively potent for their insulin-sensitizing action, currently marketed PPARgamma activators have some important undesirable side effects. These concerns led to the discovery of new ligands with potent antidiabetic properties but devoid of certain of these side effects. Data from human genetic studies and from PPARgamma heterozygous knockout mice indicate that a reduction in PPARgamma activity could paradoxically improve insulin sensitivity. These findings suggest that modulation of PPARgamma activity by partial agonists or compounds that affect cofactor recruitment might hold promise for the treatment of insulin resistance."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I61,I61)","v":11460037},{"$f":"(LEN($J61) - LEN(SUBSTITUTE(LOWER($J61),LOWER(B$3),\"\")))/LEN(B$3)","v":13},{"$f":"(LEN($J61) - LEN(SUBSTITUTE(LOWER($J61),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J61) - LEN(SUBSTITUTE(LOWER($J61),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B61:D61)","v":13},2001,"[Acitretine].","Berbis",11460037,"[Acitretine].    Abstract:   Acitretin (Soriatane(R)) is an aromatic retinoïd (carboxylic acid metabolite of etretinate). Acitretin has a terminal elimination half-life of about 55 to 60 hours. However, concomitant intake of alcohol induces transformation to etretinate (lipophilic ester) which has a longer terminal elimination half life (84 to 168 days). Due to the teratogenic effect of acitretin, contraception should be used during therapy and 2 years afterwards. Acitretin monotherapy is effective in pustular psoriasis and psoriatic palmo-plantar keratoderma. In the other forms of psoriasis, combination with phototherapy (PUVA, UVB) or topical therapy is necessary (calcipotriol, corticosteroids). Acitretin is effective in cutaneous disorders of keratinization (ichtyosis, palmo-plantar keratoderma, Dariers disease). Severe cutaneous forms of lichen planus were recently recognized as indications of acitretin treatment; 35 to 40 mg daily is the mean effective dosage in adults (0.5 mg/kg/j in children). Acitretin was shown effective in preventing the development of new skin carcinomas in predisposed patients (Xeroderma pigmentosum, immunosupression). Acitretin is a potent teratogen. Mucocutaneous side effects are varied (cheilitis, dry mucosae, xerosis, palmo-plantar peeling, hair loss.), dose-dependent and reversible. Biological side-effects consist principally in elevations of transaminases (5 to 8% of patients). Acute hepatotoxic reactions are rare. Hyperlipidemia is another side-effect commonly observed. Bony changes (ligament calcifications, osteoporosis) have been reported with various incidence. In children, growth and development have to be monitored. Combination of acitretin with potentially hepatotoxic molecules (methotrexate) is contraindicated, as is combination with cyclines (risk of intracranial hypertension)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I62,I62)","v":8538617},{"$f":"(LEN($J62) - LEN(SUBSTITUTE(LOWER($J62),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J62) - LEN(SUBSTITUTE(LOWER($J62),LOWER(C$3),\"\")))/LEN(C$3)","v":12},{"$f":"(LEN($J62) - LEN(SUBSTITUTE(LOWER($J62),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B62:D62)","v":13},1995,"PPAR: a mediator of peroxisome proliferator action.","Green",8538617,"PPAR: a mediator of peroxisome proliferator action.    Abstract:   Peroxisome proliferators are a diverse group of rodent hepatocarcinogens that include hypolipidemic drugs, plasticizers and herbicides. These compounds when administered to rats and mice produce a dramatic increase in the size and number of hepatic peroxisomes and increase the capacity of the hepatocyte to metabolise fatty acids by inducing peroxisomal beta-oxidation enzymes such as acyl CoA oxidase. Members of the steroid hormone receptor superfamily of ligand-activated transcription factors have been identified that can be activated by peroxisome proliferators and are therefore called peroxisome proliferator activated receptors (PPAR). There appear to be four PPAR isoforms within vertebrates termed alpha, beta, gamma and delta and the alpha isoform appears to be the one that is most strongly activated by synthetic peroxisome proliferators such as Wy-14,643. It has been demonstrated that PPAR alpha forms a heterodimer with the retinoid X receptor (RXR) and binds to specific DNA sequences located upstream of peroxisome proliferator responsive genes. It is therefore suggested that PPARs mediate the pleiotropic effects of peroxisome proliferators including the regulation of gene expression and rodent hepatocarcinogenesis. Rodents fed a high-fat diet develop peroxisome proliferation and many of the enzymes induced by peroxisome proliferators are involved in fatty acid metabolism. Furthermore, PPARs are activated by a wide range of fatty acids and hypolipidemic drugs, such as clofibrate, that lower triglyceride levels in man. Although it remains to be determined whether fatty acids and peroxisome proliferators bind directly to any PPAR these data suggest that the natural role of PPARs in man is to regulate lipid homeostasis. Interestingly, hypolipidaemic drugs fail to elicit peroxisome proliferation in human hepatocytes although hypolipidaemic effects are observed in patients. A further understanding of the role of PPAR in man will require: (1) the identification of additional human PPARs combined with functional analyses using these and other nuclear receptors that can antagonise PPAR action; (2) a comparison of the expression of these different receptors in human tissues; (3) a clearer understanding of how peroxisome proliferators and fatty acids activate PPAR; and (4) sequence analysis of the regulatory regions in the human counterparts of rodent peroxisome proliferator responsive genes. Together, these data will provide an important mechanism-based framework to assess the hazard of peroxisome proliferators to humans."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I63,I63)","v":2258296},{"$f":"(LEN($J63) - LEN(SUBSTITUTE(LOWER($J63),LOWER(B$3),\"\")))/LEN(B$3)","v":13},{"$f":"(LEN($J63) - LEN(SUBSTITUTE(LOWER($J63),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J63) - LEN(SUBSTITUTE(LOWER($J63),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B63:D63)","v":13},1990,"[Retinoid-induced changes of the bones and ligaments].","Zelger",2258296,"[Retinoid-induced changes of the bones and ligaments].    Abstract:   Bone and ligament lesions induced by systemic retinoids (premature epiphyseal closure, osteophytes, calcification of ligaments, osteoporosis, etc.) are radiologically nonspecific. We assessed the incidence of quot;possibly retinoid-induced bone and ligament lesionsquot; (MRKBV) in 46 patients (aged 24-82 years) who had been treated with various systemic retinoids for a variety of chronic dermatoses for an average of 4.5 years and compared the data with observations in a similarly structured group of control patients. All types of MRKBV were found more frequently in the retinoid group (41.3% vs 30.2%) and were more severe. Differences were only slight, however, being statistically significant only for moderate and severe MRKBV and for calcification of ligaments. Within the retinoid group, MRKBV were strikingly correlated with age, whereas no correlation was found with duration of treatment, mean daily and cumulative retinoid dose, underlying dermatosis, type of retinoid used or presence of other retinoid side-effects. Within the control group, MRKBV were also correlated with age, although to a lesser degree. We conclude that retinoids amplify and accelerate physiological and pathophysiological remodelling of the bones, thereby producing a varied range of lesions, which are characteristic for the age and the individual constitution of the patient treated. Retinoid-induced bone and ligament lesions, as a rule, do not cause subjective symptoms and are not associated with predictive or accompanying laboratory values. Also, MRKBV are not paralleled by other retinoid-induced side-effects (hyperlipidaemia, elevation of liver transaminases). In 16 cases in which bone X-ray had been performed prior to retinoid treatment, no indication of reversibility of MRKBV was found.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I64,I64)","v":27768859},{"$f":"(LEN($J64) - LEN(SUBSTITUTE(LOWER($J64),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J64) - LEN(SUBSTITUTE(LOWER($J64),LOWER(C$3),\"\")))/LEN(C$3)","v":9},{"$f":"(LEN($J64) - LEN(SUBSTITUTE(LOWER($J64),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B64:D64)","v":12},2016,"4-Hydroxyalkenal-activated PPARδ mediates hormetic interactions in diabetes.","Sasson",27768859,"4-Hydroxyalkenal-activated PPARδ mediates hormetic interactions in diabetes.    Abstract:    NlmCategory=UNASSIGNEDActivated peroxisome proliferator-activated receptor-δ (PPARδ) induces the expression of genes encoding enzymes that metabolize fatty acids and carbohydrate. Attempts to identify cellular activators of PPARδ produced large lists of various fatty acids and their metabolic derivatives; however, there is no consensus on specific and selective binding interactions of natural ligands with PPARδ. Most models on binding interactions within the ligand binding domain (LBD) of PPARδ have been derived from analyses of PPARδ-LBD crystals formed with synthetic low molecular weight ligands. Nonetheless, crystals of the whole receptor with natural ligands or of its heterodimer with its cognate retinoid X receptor (RXR) are not yet available for analysis. We have found that 4-hydroxyalkenals, non-enzymatic peroxidation products of polyunsaturated fatty acids (PUFA), namely, 4-hydroxy-2E,6Z-dodecadienal (4-HDDE) and 4-hydroxy-2E-nonenal (4-HNE), activate PPARδ in vascular endothelial cells and insulin-secreting beta cells, respectively. In both cases activated PPARδ induced adaptive responses that allowed the cells to adjust to ambient stressful metabolic conditions. This review article addresses the interactions of 4-hydroxyalkenals with PPARδ and the resulting hormetic interactions in cells exposed to nutrient overload conditions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I65,I65)","v":27320332},{"$f":"(LEN($J65) - LEN(SUBSTITUTE(LOWER($J65),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J65) - LEN(SUBSTITUTE(LOWER($J65),LOWER(C$3),\"\")))/LEN(C$3)","v":6},{"$f":"(LEN($J65) - LEN(SUBSTITUTE(LOWER($J65),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B65:D65)","v":12},2016,"Retinoid X Receptor Ligands With Anti-type 2 Diabetic Activity.","Morishita",27320332,"Retinoid X Receptor Ligands With Anti-type 2 Diabetic Activity.    Abstract:    NlmCategory=UNASSIGNEDPeroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor that plays an important role in regulating glucose metabolism. Agonists of PPARγ, such as thiazolidinediones, have anti-hyperglycemic activity, and are therefore used to treat type 2 diabetes. However, the functional activity of PPARγ is manifested by heterodimers of PPARγ with retinoid X receptors (RXRs). Since RXR/PPARγ heterodimers can be activated not only by PPARγ agonists, but also by RXR agonists, RXR agonists are also attractive candidates for treatment of type 2 diabetes. However, RXR full agonists have side effects, such as triglyceride elevation and hypothyroidism. Therefore, RXR partial agonists have been developed as new anti-type 2 diabetes agent candidates with reduced side effects. In addition, RXR antagonists also show therapeutic potency in type 2 diabetes patients. Here, we review RXR full agonists, RXR antagonists, and RXR modulators (partial agonists) with reported anti-diabetic effects, and we discuss their potential suitability as anti-diabetic agents."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I66,I66)","v":25430543},{"$f":"(LEN($J66) - LEN(SUBSTITUTE(LOWER($J66),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J66) - LEN(SUBSTITUTE(LOWER($J66),LOWER(C$3),\"\")))/LEN(C$3)","v":10},{"$f":"(LEN($J66) - LEN(SUBSTITUTE(LOWER($J66),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B66:D66)","v":12},2015,"Pleiotropic role of PPARγ in intracerebral hemorrhage: an intricate system involving Nrf2, RXR, and NF-κB.","Zhao",25430543,"Pleiotropic role of PPARγ in intracerebral hemorrhage: an intricate system involving Nrf2, RXR, and NF-κB.    Abstract:   Intracerebral hemorrhage (ICH) is a subtype of stroke involving formation of hematoma within brain parenchyma, which accounts for 8-15% of all strokes in Western societies and 20-30% among Asian populations, and has a 1-year mortality rate gt;50%. The high mortality and severe morbidity make ICH a major public health problem. Only a few evidence-based targeted treatments are used for ICH management, and interventions focus primarily on supportive care and comorbidity prevention. Even in patients who survive the ictus, extravasated blood (including plasma components) and subsequent intrahematoma hemolytic products trigger a series of adverse events within the brain parenchyma, leading to secondary brain injury, edema and severe neurological deficits or death. Although the hematoma in humans gradually resolves within months, full restoration of neurological function can be slow and often incomplete, leaving survivors with devastating neurological deficits. During past years, peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor and its agonists received recognition as important players in regulating not only glucose and lipid metabolism (which underlies its therapeutic effect in type 2 diabetes mellitus), and more recently, as an instrumental pleiotropic regulator of antiinflammation, antioxidative regulation, and phagocyte-mediated cleanup processes. PPARγ agonists have emerged as potential therapeutic target for stroke. The use of PPARγ as a therapeutic target appears to have particularly strong compatibility toward pathogenic components of ICH. In addition to its direct genomic effect, PPARγ may interact with transcription factor, NF-κB, which may underlie many aspects of the antiinflammatory effect of PPARγ. Furthermore, PPARγ appears to regulate expression of Nrf2, another transcription factor and master regulator of detoxification and antioxidative regulation. Finally, the synergistic costimulation of PPARγ and retinoid X receptor, RXR, may play an additional role in the therapeutic modulation of PPARγ function. In this article, we outline the main components of the role of PPARγ in ICH pathogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I67,I67)","v":24524207},{"$f":"(LEN($J67) - LEN(SUBSTITUTE(LOWER($J67),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J67) - LEN(SUBSTITUTE(LOWER($J67),LOWER(C$3),\"\")))/LEN(C$3)","v":11},{"$f":"(LEN($J67) - LEN(SUBSTITUTE(LOWER($J67),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B67:D67)","v":12},2014,"Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review.","Grygiel-Górniak",24524207,"Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review.    Abstract:   Peroxisome proliferator-activated receptors are expressed in many tissues, including adipocytes, hepatocytes, muscles and endothelial cells; however, the affinity depends on the isoform of PPAR, and different distribution and expression profiles, which ultimately lead to different clinical outcomes. Because they play an important role in lipid and glucose homeostasis, they are called lipid and insulin sensors. Their actions are limited to specific tissue types and thus, reveal a characteristic influence on target cells. PPARα mainly influences fatty acid metabolism and its activation lowers lipid levels, while PPARγ is mostly involved in the regulation of the adipogenesis, energy balance, and lipid biosynthesis. PPARβ/δ participates in fatty acid oxidation, mostly in skeletal and cardiac muscles, but it also regulates blood glucose and cholesterol levels. Many natural and synthetic ligands influence the expression of these receptors. Synthetic ligands are widely used in the treatment of dyslipidemia (e.g. fibrates--PPARα activators) or in diabetes mellitus (e.g. thiazolidinediones--PPARγ agonists). New generation drugs--PPARα/γ dual agonists--reveal hypolipemic, hypotensive, antiatherogenic, anti-inflammatory and anticoagulant action while the overexpression of PPARβ/δ prevents the development of obesity and reduces lipid accumulation in cardiac cells, even during a high-fat diet. Precise data on the expression and function of natural PPAR agonists on glucose and lipid metabolism are still missing, mostly because the same ligand influences several receptors and a number of reports have provided conflicting results. To date, we know that PPARs have the capability to accommodate and bind a variety of natural and synthetic lipophilic acids, such as essential fatty acids, eicosanoids, phytanic acid and palmitoylethanolamide. A current understanding of the effects of PPARs, their molecular mechanisms and the role of these receptors in nutrition and therapeutic treatment are delineated in this paper."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I68,I68)","v":23281051},{"$f":"(LEN($J68) - LEN(SUBSTITUTE(LOWER($J68),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J68) - LEN(SUBSTITUTE(LOWER($J68),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J68) - LEN(SUBSTITUTE(LOWER($J68),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B68:D68)","v":12},2013,"Retinoids: Potent regulators of metabolism.","Brun",23281051,"Retinoids: Potent regulators of metabolism.    Abstract:   Retinoids (vitamin A and its analogs) are highly potent regulators of cell differentiation, cell proliferation, and apoptosis. Because of these activities, retinoids have been most extensively studied in the contexts of embryonic development and of proliferative diseases, especially cancer and skin disease. Recently, there has been considerable new research interest focused on gaining understanding of the roles that retinoids and/or retinoid-related proteins may have in the development of metabolic diseases, primarily obesity, diabetes, and dyslipidemia. This review will summarize recent advances that have been made in these areas, focusing on the role of retinoids in modulating adipogenesis, the roles of retinoids and retinoid-related proteins as signaling molecules linking obesity with the development of type II diabetes, the roles of retinoids in pancreatic β-cell biology/insulin secretion, and the actions of retinoids in hepatic steatosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I69,I69)","v":20182540},{"$f":"(LEN($J69) - LEN(SUBSTITUTE(LOWER($J69),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J69) - LEN(SUBSTITUTE(LOWER($J69),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J69) - LEN(SUBSTITUTE(LOWER($J69),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B69:D69)","v":12},2010,"The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier--implications for the pathogenesis of diabetic retinopathy.","Simó",20182540,"The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier--implications for the pathogenesis of diabetic retinopathy.    Abstract:   The retinal pigment epithelium (RPE) is an specialized epithelium lying in the interface between the neural retina and the choriocapillaris where it forms the outer blood-retinal barrier (BRB). The main functions of the RPE are the following: (1) transport of nutrients, ions, and water, (2) absorption of light and protection against photooxidation, (3) reisomerization of all-trans-retinal into 11-cis-retinal, which is crucial for the visual cycle, (4) phagocytosis of shed photoreceptor membranes, and (5) secretion of essential factors for the structural integrity of the retina. An overview of these functions will be given. Most of the research on the physiopathology of diabetic retinopathy has been focused on the impairment of the neuroretina and the breakdown of the inner BRB. By contrast, the effects of diabetes on the RPE and in particular on its secretory activity have received less attention. In this regard, new therapeutic strategies addressed to modulating RPE impairment are warranted."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I70,I70)","v":15670663},{"$f":"(LEN($J70) - LEN(SUBSTITUTE(LOWER($J70),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J70) - LEN(SUBSTITUTE(LOWER($J70),LOWER(C$3),\"\")))/LEN(C$3)","v":11},{"$f":"(LEN($J70) - LEN(SUBSTITUTE(LOWER($J70),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B70:D70)","v":12},2004,"Molecular mechanisms of alcoholic fatty liver: role of peroxisome proliferator-activated receptor alpha.","Crabb",15670663,"Molecular mechanisms of alcoholic fatty liver: role of peroxisome proliferator-activated receptor alpha.    Abstract:   Normal function of the peroxisome proliferator-activated receptor alpha (PPARalpha) is crucial for the regulation of hepatic fatty acid metabolism. Fatty acids serve as ligands for PPARalpha, and when fatty acid levels increase, activation of PPARalpha induces a battery of fatty acid-metabolizing enzymes to restore fatty acid levels to normal. Hepatic fatty acid levels are increased during ethanol consumption. However, results of in vitro work showed that ethanol metabolism inhibited the ability of PPARalpha to bind DNA and activate reporter genes. This observation has been further studied in mice. Four weeks of ethanol feeding of C57BL/6J mice also impairs fatty acid catabolism in liver by blocking PPARalpha-mediated responses. Ethanol feeding decreased the level of retinoid X receptor alpha (RXRalpha) as well as the ability of PPARalpha/RXR in liver nuclear extracts to bind its consensus sequence, and the levels of mRNAs for several PPARalpha-regulated genes were reduced [long-chain acyl coenzyme A (acyl-CoA) dehydrogenase and medium-chain acyl-CoA dehydrogenase] or failed to be induced (acyl-CoA dehydrogenase, liver carnitine palmitoyl-CoA transferase I, very long-chain acyl-CoA synthetase, very long-chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals. Consistent with this finding, ethanol feeding did not induce the rate of fatty acid beta-oxidation, as assayed in liver homogenates. Inclusion of WY14,643, a PPARalpha agonist, in the diet restored the DNA-binding activity of PPARalpha/RXR, induced mRNA levels of several PPARalpha target genes, stimulated the rate of fatty acid beta-oxidation in liver homogenates, and prevented fatty liver in ethanol-fed animals. Blockade of PPARalpha function during ethanol consumption contributes to the development of alcoholic fatty liver, which can be overcome by WY14,643."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I71,I71)","v":14749265},{"$f":"(LEN($J71) - LEN(SUBSTITUTE(LOWER($J71),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J71) - LEN(SUBSTITUTE(LOWER($J71),LOWER(C$3),\"\")))/LEN(C$3)","v":10},{"$f":"(LEN($J71) - LEN(SUBSTITUTE(LOWER($J71),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B71:D71)","v":12},2004,"The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity.","Ferré",14749265,"The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the superfamily of nuclear receptors. Three isoforms (alpha, delta, and gamma) have been described. They act on DNA response elements as heterodimers with the nuclear retinoic acid receptor. Their natural activating ligands are fatty acids and lipid-derived substrates. PPAR-alpha is present in liver, heart, and, to a lesser extent, skeletal muscle. When activated, it promotes fatty acid oxidation, ketone body synthesis, and glucose sparing. Fibrates, which are used as hypolipidemic drugs, are ligands of PPAR-alpha. PPAR-delta is ubiquitous and could also favor fatty acid oxidation in tissues in which PPAR-alpha is absent or less expressed. PPAR-gamma is expressed in adipose tissue, lower intestine, and cells involved in immunity. Activation of PPAR-gamma induces the differentiation of preadipocytes into adipocytes and stimulates triglyceride storage. Thiazolidinediones are compounds used as hypoglycemic, muscle insulin-sensitizing agents in type 2 diabetes. Unexpectedly, they are activators of PPAR-gamma. Their action on muscle insulin sensitivity may be secondary to the lowering of circulating lipids on PPAR-gamma activation and to the secretion by adipocytes of insulin-sensitizing hormones such as adiponectin, all promoting glucose utilization. The PPARs are thus major regulators of lipid and glucose metabolism, allowing adaptation to the prevailing nutritional environment."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I72,I72)","v":14704336},{"$f":"(LEN($J72) - LEN(SUBSTITUTE(LOWER($J72),LOWER(B$3),\"\")))/LEN(B$3)","v":12},{"$f":"(LEN($J72) - LEN(SUBSTITUTE(LOWER($J72),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J72) - LEN(SUBSTITUTE(LOWER($J72),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B72:D72)","v":12},2004,"Assessing vitamin A status: past, present and future.","Tanumihardjo",14704336,"Assessing vitamin A status: past, present and future.    Abstract:   Xerophthalmia classification was traditionally used to identify populations with vitamin A deficiency. Currently, night blindness and dark adaptometry have been proposed as population assessment methods. While eye signs and function tests are still used in areas where vitamin A deficiency is severe, a subclinical vitamin A deficiency is more prevalent. Serum and breast milk retinol concentrations are used to identify vitamin A deficiency risk. However, in healthy individuals, serum retinol concentrations are homeostatically controlled and do not begin to decline until liver reserves of vitamin A are dangerously low. Moreover, serum retinol and retinol binding protein (RBP) concentrations fall during times of infection. The RBP:transthyretin ratio may help to determine if serum retinol concentrations are depressed by infection. Other methods better reflect liver reserves of vitamin A, the quot;goldquot; standard. The relative dose response and modified relative dose response tests involve giving a small dose of retinyl or dehydroretinyl ester, respectively, and determining a response in the serum at about 5 h. A new response test where retinoyl beta-glucuronide is administered and the degree of hydrolysis to retinoic acid is measured has been investigated. Unlike isotope dilution tests, the dose response tests lack utility in defining the total body reserve of vitamin A. The deuterated retinol isotope dilution test has been used in several different groups. Recently, a new isotope assay was developed using 13C-retinyl acetate and gas chromatography-combustion-isotope ratio mass spectrometry for analysis. Thus, having many choices of vitamin A assessment methods, laboratory sophistication and resources available will usually dictate which methods are chosen."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I73,I73)","v":11697231},{"$f":"(LEN($J73) - LEN(SUBSTITUTE(LOWER($J73),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J73) - LEN(SUBSTITUTE(LOWER($J73),LOWER(C$3),\"\")))/LEN(C$3)","v":7},{"$f":"(LEN($J73) - LEN(SUBSTITUTE(LOWER($J73),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B73:D73)","v":12},2001,"PPAR gamma/RXR as a molecular target for diabetes.","Lenhard",11697231,"PPAR gamma/RXR as a molecular target for diabetes.    Abstract:   Type 2 diabetes is associated with insulin resistance in peripheral tissues, such as muscle and fat. Novel therapies that improve insulin action include ligands that bind and activate the nuclear receptors peroxisome proliferator activating receptor gamma (PPAR gamma) and retinoid X receptor (RXR). PPAR gamma/RXR form heterodimers that regulate transcription of genes involved in insulin action, adipocyte differentiation, lipid metabolism and inflammation. PPAR gamma activators include prostanoids, fatty acids, thiazolidinediones and N-(2-benzoylphenyl)tyrosine analogues. RXR ligands include naturally occurring retinoic acid and synthetic rexinoids. Selective ligands for these receptors improve metabolic abnormalities associated with type 2 diabetes, such as hyperglycemia, hyperlipidemia, insulin resistance and other cardiovascular risk factors. Although adipose tissue mediates some of the effects of PPAR gamma/RXR ligands, other tissues also regulate the effects of these receptors. The activity of the PPAR gamma/RXR heterodimer is influenced by posttranslational modifications, receptor turnover, polymorphisms, splice variants, coactivators and corepressors. This article reviews recent developments in research on these receptors, with particular emphasis on metabolic effects, ligand selectivity, structure and regulation of the PPAR gamma/RXR heterodimer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I74,I74)","v":9777794},{"$f":"(LEN($J74) - LEN(SUBSTITUTE(LOWER($J74),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J74) - LEN(SUBSTITUTE(LOWER($J74),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J74) - LEN(SUBSTITUTE(LOWER($J74),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B74:D74)","v":12},1998,"Future trends: a new generation of retinoids.","Chandraratna",9777794,"Future trends: a new generation of retinoids.    Abstract:   The existence of several different types of retinoid receptors, response elements, and cofactors means that retinoid physiology is mediated by multiple discrete pathways and is highly complex. As a result, non-selective retinoids have a multitude of physiologic effects and are usually associated with toxicity problems that limit their therapeutic usefulness. In contrast, because receptor-selective retinoids have a more focused and targeted action, they are likely to have a better therapeutic index. Tazarotene is the first of a new generation of receptor-selective retinoids. Its actions are targeted on 2 retinoic acid receptors (RARs), RAR-beta and RAR-gamma. Current retinoid research is leading to the development not only of many more novel receptor-selective retinoids but also of novel types of function-selective retinoids such as RAR inverse agonists and RAR antagonists. These retinoids are expected to be of clinical benefit not only in dermatology but also in oncology, diabetes, and diseases associated with the human papilloma virus."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I75,I75)","v":9739911},{"$f":"(LEN($J75) - LEN(SUBSTITUTE(LOWER($J75),LOWER(B$3),\"\")))/LEN(B$3)","v":12},{"$f":"(LEN($J75) - LEN(SUBSTITUTE(LOWER($J75),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J75) - LEN(SUBSTITUTE(LOWER($J75),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B75:D75)","v":12},1997,"[Gilbert disease and isotretinoin].","Le Gal",9739911,"[Gilbert disease and isotretinoin].    Abstract:    INTRODUCTION : Because of the potential hepatotoxicity of retinoids, prescription of isotretinoin is always very carefully made in healthy subjects, and prohibited in case of concomitant hepatopathy. Gilberts syndrome consists of chronic, mild, unconjugated hyperbilirubinemia. In this syndrome, isotretinoin has been reported twice to be perfectly tolerated, and once even beneficial. We report here a new case of good tolerance and even improvement of a Gilberts syndrome during isotretinoin therapy.  CASE REPORT : A 17-year-old man with Gilberts syndrome presented with a nodulocystic acne. Topical agents had been inefficient, and cyclines bad tolerated. Thus isotretinoin has been gradually introduced, with a regular monitoring of the liver function. We observed a steady decrease of the bilirubinemia during the course of isotretinoin, and then a reappearance of hyperbilirubinemia as soon as posology was diminished and particularly after completion of isotretinoin therapy.  DISCUSSION : A review of the literature finds only very few cases of hepatic injuries caused by isotretinoin, contrary to etretinate. Safety of isotretinoin in Gilberts syndrome was first observed in 1984, but its beneficial effects have only recently been described by Wang et al., and we report here a similar case. Pharmacological mechanisms remain hypothetic. However, considering the prevalence of Gilberts syndrome and its usual first expression during postpubertal period, it seems to us interesting for therapeutic practice to know that isotretinoin is not less safe in these patients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I76,I76)","v":7610285},{"$f":"(LEN($J76) - LEN(SUBSTITUTE(LOWER($J76),LOWER(B$3),\"\")))/LEN(B$3)","v":12},{"$f":"(LEN($J76) - LEN(SUBSTITUTE(LOWER($J76),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J76) - LEN(SUBSTITUTE(LOWER($J76),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B76:D76)","v":12},1995,"[Advances in vitamin A and retinoid-binding proteins].","Torres y Torres",7610285,"[Advances in vitamin A and retinoid-binding proteins].    Abstract:   The recent interest in the study of vitamin A is due to the discovery of an increasing variety of functions, actions or associations of this vitamin with cellular differentiation of epithelial tissues, growth, reproduction and vision. This review describes the recent advances on the metabolism of vitamin A especially in regard to the retinoid-binding proteins in the transport of hydrophobic retinoids and their participation in the transformation of the different retinoids in the organism as well as in the interior of the cell. Seven binding proteins have been discovered and well characterized: retinol binding protein (RBP); cellular retinol-binding protein (CRBP); cellular retinol-binding protein type two (CRBP-II); cellular retinoic acid binding protein (CRABP); cellular retinoic acid binding protein type two (CRABP-II); cellular retinal-binding protein (CRALBP) and interphotoreceptor retinol-binding protein (IRBP). Their specific roles are presented. Also the function and mechanisms of the regulation of gene expression by retinoic acid is described."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I77,I77)","v":8056148},{"$f":"(LEN($J77) - LEN(SUBSTITUTE(LOWER($J77),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J77) - LEN(SUBSTITUTE(LOWER($J77),LOWER(C$3),\"\")))/LEN(C$3)","v":8},{"$f":"(LEN($J77) - LEN(SUBSTITUTE(LOWER($J77),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B77:D77)","v":12},1994,"Peroxisome proliferator-activated receptors: finding the orphan a home.","Green",8056148,"Peroxisome proliferator-activated receptors: finding the orphan a home.    Abstract:   The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcinogens that are collectively termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl CoA oxidase, which is elevated about ten fold in the livers of treated rodents. Additional peroxisome proliferator responsive genes include other peroxisomal beta-oxidation enzymes and members of the cytochrome P450 IVA family. A peroxisome proliferator response element (PPRE), consisting of an almost perfect direct repeat of the sequence TGACCT spaced by a single base pair, has been identified in the upstream regulatory sequences of each of these genes. The retinoid X receptor (RXR) forms a heterodimer with PPAR and binds to the PPRE. Furthermore, the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retinoids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechanism to explain the toxicity of peroxisome proliferators. Interestingly, a variety of fatty acids can activate PPAR supporting the suggestion that fatty acids, or their acyl CoA derivatives, may be the natural ligands of PPAR and that the physiological role of PPAR is to regulate fatty acid homeostasis. Taken together, the discovery of PPAR has opened up new opportunities in understanding how lipid homeostasis is regulated, how the fibrate hypolipidaemic drugs may act and should lead to improvements in the assessment of human risk from peroxisome proliferators based upon a better understanding of their mechanism of action."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I78,I78)","v":7832047},{"$f":"(LEN($J78) - LEN(SUBSTITUTE(LOWER($J78),LOWER(B$3),\"\")))/LEN(B$3)","v":12},{"$f":"(LEN($J78) - LEN(SUBSTITUTE(LOWER($J78),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J78) - LEN(SUBSTITUTE(LOWER($J78),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B78:D78)","v":12},1994,"The function of vitamin A in cellular growth and differentiation, and its roles during pregnancy and lactation.","Ross",7832047,"The function of vitamin A in cellular growth and differentiation, and its roles during pregnancy and lactation.    Abstract:   Recent advances in the molecular biology of the retinoids have provided a mechanistic explanation for the observations, first made several decades ago, that vitamin A profoundly influences the differentiation of tissues throughout the body. A central concept has recently emerged, namely that retinoids seldom exist quot;freequot; in solution but, rather, are nearly always associated with specific retinoid-binding proteins. In plasma, these include RBP and the chylomicron whereas, in cells two distinct classes of retinoid-binding proteins exist: the cellular (cytoplasmic) proteins (CRBPs and CRABPs) and the nuclear receptors proteins (RARs and RXRs). Whereas the cellular retinoid-binding proteins serve as buffers and as chaperones during metabolism (Ross, 1993b), the nuclear receptors are now recognized to be the direct mediators of retinoid actions on the genome. Both the cytoplasmic and nuclear classes of retinoid-binding proteins are expressed early in development and are proposed to control the concentration of retinoic acid and the transcription of retinoid-responsive genes, respectively. Given the profound effects of retinoic deficiency or excess on the developing fetus, it is not surprising that mechanisms have evolved to control the placental transfer of vitamin A. Transfer is nearly uniform over a rather wide range of maternal dietary vitamin A intake. The importance of RBP in transporting retinol to tissues is suggested by the observations that the visceral yolk sac and the liver of the fetus transcribe and translate RBP. In comparison to pregnancy, vitamin A transport during lactation is much more responsive to variations in maternal vitamin A intake. The young of mothers with good vitamin A nutriture may thus accumulate significant retinol reserves during the suckling period. Conversely, young nursed by mothers with poor vitamin A status and low intake during lactation may fail to develop adequate stores and be vulnerable to vitamin A deficiency if the post-weaning diet is also poor in vitamin A. In populations with low vitamin A status, the lactation period provides an excellent window of opportunity for supplementing mothers and, indirectly, their offspring, with vitamin A to replenish the mothers vitamin A reserves and assure that the infants growth and development are not limited by an inadequate quantity of this essential nutrient."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I79,I79)","v":3054426},{"$f":"(LEN($J79) - LEN(SUBSTITUTE(LOWER($J79),LOWER(B$3),\"\")))/LEN(B$3)","v":12},{"$f":"(LEN($J79) - LEN(SUBSTITUTE(LOWER($J79),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J79) - LEN(SUBSTITUTE(LOWER($J79),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B79:D79)","v":12},1988,"Adverse effects of retinoids.","David",3054426,"Adverse effects of retinoids.    Abstract:   Oral retinoids, synthetic derivatives of vitamin A, have been used in the treatment of various dermatoses over the last decade. The most useful drugs have been isotretinoin (13-cis-retinoic acid) for nodulocystic acne and etretinate for psoriasis vulgaris. Retinoids are also effective in the treatment of papulosquamous dermatoses other than psoriasis (i.e. inherited disorders of keratinisation), cutaneous T-cell lymphoma and in chemotherapy and chemoprevention of cancer. However, systemic administration of these compounds is frequently associated with mucocutaneous side effects, liver toxicity and abnormalities of serum lipid profiles, which might be related to an increased risk of coronary heart disease. Of particular concern is the teratogenic effect of all retinoids, which limits their use in women of child-bearing potential. Chronic toxicities from long term therapy with retinoids may result in skeletal abnormalities, usually mimicking diffuse idiopathic hyperostosis syndrome. Furthermore, the chronic use of retinoids in children may inhibit their growth due to premature epiphyseal closure. In contrast to other side effects of retinoids which are dose dependent and reversible upon withdrawal of the drug, it seems unlikely that bone abnormalities will resolve after discontinuation of the medication. In view of the wide spectrum of toxicities, treatment with retinoids requires appropriate selection of patients, careful consideration of the benefit to risk ratio for each individual, periodic monitoring of clinical response and laboratory tests. Clinicians should use special management techniques in order to prevent or minimize slide effects. Extensive investigations are currently being conducted in an attempt to develop new retinoids which will improve the therapeutic efficacy and reduce unwanted reactions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I80,I80)","v":363444},{"$f":"(LEN($J80) - LEN(SUBSTITUTE(LOWER($J80),LOWER(B$3),\"\")))/LEN(B$3)","v":12},{"$f":"(LEN($J80) - LEN(SUBSTITUTE(LOWER($J80),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J80) - LEN(SUBSTITUTE(LOWER($J80),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B80:D80)","v":12},1978,"Retinoids, a new class of compounds with prophylactic and therapeutic activities in oncology and dermatology.","Mayer",363444,"Retinoids, a new class of compounds with prophylactic and therapeutic activities in oncology and dermatology.    Abstract:   A review of recent investigations in the retinoid field is presented. Retinoic acid exerts a prophylactic and a therapeutic effect on chemically induced benign and malignant epithelial tumors in mice. In clinical studies positive therapeutic results have been obtained in patients with preneoplastic and neoplastic epithelial lesions. However, treatment with retinoic acid is limited by serious side effects (hypervitaminosis A syndrome). Therefore, the synthesis of analogs of retinoic acid (retinoids) possessing a more favorable therapeutic ratio has been initiated. Among a large series of synthesized compounds, certain aromatic analogs proved to have a particularly favorable therapeutic ratio. The structure-activity relationship of the most active retinoids is discussed including some biological data concerning prophylaxis and therapy of epithelial tumors. The total synthesis of retinoids according to various building schemes is discussed in detail. Methods for the synthesis of the cyclic end group, of the polyene chain component, and of the full retinoid skeleton are described. Metabolic studies of retinoic acid and of the most active retinoid, as well as the synthesis of some isolated metabolites are outlined. Suggestions concerning the mechanism of action of retinoids are made. Some clinical results on the treatment of acne, psoriasis and precancerous conditions are reported."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I81,I81)","v":26729422},{"$f":"(LEN($J81) - LEN(SUBSTITUTE(LOWER($J81),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J81) - LEN(SUBSTITUTE(LOWER($J81),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J81) - LEN(SUBSTITUTE(LOWER($J81),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B81:D81)","v":11},2016,"Vitamin A in regulation of insulin responsiveness: mini review.","Noy",26729422,"Vitamin A in regulation of insulin responsiveness: mini review.    Abstract:   Vitamin A, retinol, circulates in blood bound to retinol-binding protein (RBP4) which, in turn, associates with another serum protein, transthyretin (TTR), to form a ternary retinol-RBP4-TTR complex. At some tissues, retinol-bound (holo-) RBP4 is recognised by a receptor termed stimulated by retinoic acid 6 (STRA6) which transports retinol into cells. This mini-review summarises evidence demonstrating that, in addition to functioning as a retinol transporter, STRA6 is also a signalling receptor which is activated by holo-RBP4. The data show that STRA6-mediated retinol transport induces receptor phosphorylation, in turn activating a Janus kinases2/signal transducers and activators of transcription (STAT)3/5 cascade that culminates in induction of STAT target genes. STRA6-mediated retinol transport and cell signalling are inter-dependent, and both functions critically rely on intracellular retinol trafficking and metabolism. Hence, STRA6 couples sensing of vitamin A homeostasis and metabolism to cell signalling, allowing it to control important biological functions. For example, by inducing the expression of the STAT target gene suppressor of cytokine signalling 3, STRA6 potently suppresses insulin responses. These observations provide a rationale for understanding the reports that elevation in serum levels of RBP4, often observed in obese mice and human subjects, causes insulin resistance. The observations indicate that the holo-RBP4 /STRA6 signalling cascade may comprise an important link through which obesity leads to insulin resistance and suggest that the pathway may be a novel target for treatment of metabolic diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I82,I82)","v":26311412},{"$f":"(LEN($J82) - LEN(SUBSTITUTE(LOWER($J82),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J82) - LEN(SUBSTITUTE(LOWER($J82),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J82) - LEN(SUBSTITUTE(LOWER($J82),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B82:D82)","v":11},2015,"Retinoid roles in blocking hepatocellular carcinoma.","Shirakami",26311412,"Retinoid roles in blocking hepatocellular carcinoma.    Abstract:   Hepatocellular carcinoma (HCC) is a major health issue in many countries. The prognosis of HCC is still poor due to its high recurrence rate and its resistance to chemotherapy. Retinoids have long been known to have a connection with liver diseases, including HCC. Many experimental and clinical investigations have demonstrated associations between retinoids and hepatic disease, including the loss of retinoid activity in HCC cell lines and decreased hepatic retinoid stores and altered retinoid signaling in patients with cirrhosis and HCC. Based on these findings, preclinical and clinical investigations of retinoid effects on HCC have been undertaken. Recently, clinical trial results for the use of a synthetic retinoid, acyclic retinoid (ACR), to prevent HCC recurrence were published. In addition, extensive experimental studies on the action of retinoids in liver disease, including chronic viral hepatitis and non-alcoholic fatty liver disease (NAFLD), which lead to HCC have been performed. In the first section of this review, we will summarize the effectiveness and roles of retinoid for treating liver disease and blocking HCC. Subsequently, we will focus on ACR actions in blocking HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I83,I83)","v":25019074},{"$f":"(LEN($J83) - LEN(SUBSTITUTE(LOWER($J83),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J83) - LEN(SUBSTITUTE(LOWER($J83),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J83) - LEN(SUBSTITUTE(LOWER($J83),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B83:D83)","v":11},2014,"The multifaceted nature of retinoid transport and metabolism.","Li",25019074,"The multifaceted nature of retinoid transport and metabolism.    Abstract:   Since their discovery over a century ago, retinoids have been the most studied of the fat-soluble vitamins. Unlike most vitamins, retinoids are stored at relatively high concentrations in the body to buffer against nutritional insufficiency. Until recently, it was thought that the sole important retinoid delivery pathway to tissues involved retinol bound to retinol-binding protein (RBP4). More recent findings, however, indicate that retinoids can be delivered to tissues through multiple overlapping delivery pathways, involving chylomicrons, very low density lipoprotein (VLDL) and low density lipoprotein (LDL), retinoic acid bound to albumin, water soluble β-glucuronides of retinol and retinoic acid, and provitamin A carotenoids. This review will focus on explaining this evolving understanding of retinoid metabolism and transport within the body."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I84,I84)","v":24523914},{"$f":"(LEN($J84) - LEN(SUBSTITUTE(LOWER($J84),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J84) - LEN(SUBSTITUTE(LOWER($J84),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J84) - LEN(SUBSTITUTE(LOWER($J84),LOWER(D$3),\"\")))/LEN(D$3)","v":11},{"$f":"SUM(B84:D84)","v":11},2014,"Taiwanese vegetarians and omnivores: dietary composition, prevalence of diabetes and IFG.","Chiu",24523914,"Taiwanese vegetarians and omnivores: dietary composition, prevalence of diabetes and IFG.    Abstract:    INTRODUCTION : Vegetarian diets have been shown to improve glucose metabolism and reduce risk for diabetes in Westerners but whether Chinese vegetarian diets have the same benefits is unknown.  METHODS : We evaluated the association between diet and diabetes/impaired fasting glucose (IFG) among 4384 Taiwanese Buddhist volunteers and identified diabetes/IFG cases from a comprehensive review of medical history and fasting plasma glucose.  RESULTS : Vegetarians had higher intakes of carbohydrates, fiber, calcium, magnesium, total and non-heme iron, folate, vitamin A, and lower intakes of saturated fat, cholesterol, and vitamin B12. Besides avoiding meat and fish, vegetarians had higher intakes of soy products, vegetables, whole grains, but similar intakes of dairy and fruits, compared with omnivores. The crude prevalence of diabetes in vegetarians versus omnivores is 0.6% versus 2.3% in pre-menopausal women, 2.8% versus 10% in menopausal women, and 4.3% versus 8.1% in men. Polytomous logistic regression adjusting for age, body mass index, family history of diabetes, education, leisure time physical activity, smoking and alcohol, showed that this vegetarian diet was negatively associated with diabetes and IFG in men (OR for diabetes: 0.49, 95% CI: 0.28-0.89; OR for IFG: 0.66, 95% CI: 0.46-0.95); in pre-menopausal women (OR for diabetes: 0.26, 95% CI: 0.06-1.21; OR for IFG: 0.60, 95% CI: 0.35-1.04); and in menopausal women (OR for diabetes: 0.25, 95% CI: 0.15-0.42; OR for IFG: 0.73, 95% CI: 0.56-0.95).  CONCLUSION : We found a strong protective association between Taiwanese vegetarian diet and diabetes/IFG, after controlling for various potential confounders and risk factors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I85,I85)","v":23855293},{"$f":"(LEN($J85) - LEN(SUBSTITUTE(LOWER($J85),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J85) - LEN(SUBSTITUTE(LOWER($J85),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J85) - LEN(SUBSTITUTE(LOWER($J85),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B85:D85)","v":11},2013,"Retinoids and their target genes in liver functions and diseases.","Shiota",23855293,"Retinoids and their target genes in liver functions and diseases.    Abstract:   Retinoids have been reported to prevent several kinds of cancers, including hepatocellular carcinoma (HCC). Retinoic acid (RA) coupled with retinoic acid receptor/retinoid X receptor heterodimer exerts its functions by regulating its target genes. We previously reported that transgenic mice, in which RA signaling is suppressed in a hepatocyte-specific manner, developed liver cancer at a high rate, and that disruption of RA functions led to the increased oxidative stress via aberrant metabolisms of lipid and iron, indicating that retinoids play an important role in liver pathophysiology. These data suggest that exploring the metabolism of retinoids in liver diseases and their target genes provides us with useful information to understand the liver functions and diseases. Consequently, the altered metabolism of retinoids was observed in liver diseases, including non-alcoholic fatty liver disease. In this review, we summarize the metabolism of retinoids in the liver, highlight the functions of retinoids in HCC, non-alcoholic fatty liver disease, and alcoholic liver disease, and discuss the target genes of RA. Investigation of retinoids in the liver will likely help us identify novel therapies and diagnostic modalities for HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I86,I86)","v":23344030},{"$f":"(LEN($J86) - LEN(SUBSTITUTE(LOWER($J86),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J86) - LEN(SUBSTITUTE(LOWER($J86),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J86) - LEN(SUBSTITUTE(LOWER($J86),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B86:D86)","v":11},2012,"The controversial role of retinoic acid in fibrotic diseases: analysis of involved signaling pathways.","Zhou",23344030,"The controversial role of retinoic acid in fibrotic diseases: analysis of involved signaling pathways.    Abstract:   Fibrotic diseases, such as liver, pulmonary and renal fibrosis, are common end-stage conditions and represent a major global health problem. Furthermore, effective therapeutic measures are presently unavailable. Extracellular matrix accumulation is the most prominent characteristic in the pathogenesis of fibrotic disease. Retinoic acid, including all-trans retinoic acid, 9-cis and 13-cis retinoic acid, play important roles in various physiological processes, such as in embryonic development, reproduction, vision, cell growth, differentiation, apoptosis and inflammation. Present studies report that retinoic acid treatment may affect various processes involved in the onset and progression of fibrotic disease. However, the therapeutic effects of retinoic acid in such diseases remain controversial. Several reports indicate that retinoic acid positively affects the progression of fibrosis and alleviates the accumulation of the extracellular matrix, whereas other studies report the opposite; that retinoic acid exacerbates fibrosis and induces extracellular matrix accumulation. Signaling pathways might be an important influencing factor and differences in signaling events might be responsible for the contradictory role of retinoic acid in fibrotic diseases. Since there was no review available that investigated the role of retinoic acid and the signaling pathways involved, we retrospectively studied the literature and provide a comprehensive analysis of retinoic acids role in fibrotic diseases, and provide an overview of the signal transduction pathways involved in its pathogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I87,I87)","v":21057731},{"$f":"(LEN($J87) - LEN(SUBSTITUTE(LOWER($J87),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J87) - LEN(SUBSTITUTE(LOWER($J87),LOWER(C$3),\"\")))/LEN(C$3)","v":9},{"$f":"(LEN($J87) - LEN(SUBSTITUTE(LOWER($J87),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B87:D87)","v":11},2010,"The nuclear hormone receptor PPARγ as a therapeutic target in major diseases.","Schmidt",21057731,"The nuclear hormone receptor PPARγ as a therapeutic target in major diseases.    Abstract:   The peroxisome proliferator-activated receptor γ (PPARγ belongs to the nuclear hormone receptor superfamily and regulates gene expression upon heterodimerization with the retinoid X receptor by ligating to peroxisome proliferator response elements (PPREs) in the promoter region of target genes. Originally, PPARγ was identified as being essential for glucose metabolism. Thus, synthetic PPARγ agonists, the thiazolidinediones (TZDs), are used in type 2 diabetes therapy as insulin sensitizers. More recent evidence implied an important role for the nuclear hormone receptor PPARγ in controlling various diseases based on its anti-inflammatory, cell cycle arresting, and proapoptotic properties. In this regard, expression of PPARγ is not restricted to adipocytes, but is also found in immune cells, such as B and T lymphocytes, monocytes, macrophages, dendritic cells, and granulocytes. The expression of PPARγ in lymphoid organs and its modulation of macrophage inflammatory responses, lymphocyte proliferation, cytokine production, and apoptosis underscore its immune regulating functions. Moreover, PPARγ expression is found in tumor cells, where its activation facilitates antitumorigenic actions. This review provides an overview about the role of PPARγ as a possible therapeutic target approaching major, severe diseases, such as sepsis, cancer, and atherosclerosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I88,I88)","v":15834303},{"$f":"(LEN($J88) - LEN(SUBSTITUTE(LOWER($J88),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J88) - LEN(SUBSTITUTE(LOWER($J88),LOWER(C$3),\"\")))/LEN(C$3)","v":9},{"$f":"(LEN($J88) - LEN(SUBSTITUTE(LOWER($J88),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B88:D88)","v":11},2005,"Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation.","Zingarelli",15834303,"Peroxisome proliferator-activated receptor-gamma is a new therapeutic target in sepsis and inflammation.    Abstract:   Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear receptor superfamily and a ligand-activated transcription factor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. PPARgamma forms a heterodimer with the retinoid X receptor and upon ligand-activation binds to the PPAR response element in the promoter of genes to allow transcription. The class of insulin-sensitizing drugs known as thiazolidinediones have been identified as specific PPARgamma agonists that have allowed the characterization of many genes regulated by PPARgamma. Thiazolidinediones include rosiglitazone, pioglitazone, troglitazone, and ciglitazone. In addition to these synthetic agonists, cyclopentenone prostaglandins of the J2 series have been identified as natural ligands for PPARgamma. Several in vitro and in vivo studies have demonstrated that pharmacological activation of PPARgamma by 15-deoxy-Delta(12,14)-PGJ2 (15d-PGJ2) or thiazolidinediones has anti-inflammatory effects. This article provides an overview of the role of PPARgamma in regulating the inflammatory response and emphasizes the potential efficacy of PPARgamma ligands as novel therapeutic approaches beyond diabetes in sepsis, inflammation, and reperfusion injury."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I89,I89)","v":15374828},{"$f":"(LEN($J89) - LEN(SUBSTITUTE(LOWER($J89),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J89) - LEN(SUBSTITUTE(LOWER($J89),LOWER(C$3),\"\")))/LEN(C$3)","v":10},{"$f":"(LEN($J89) - LEN(SUBSTITUTE(LOWER($J89),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B89:D89)","v":11},2005,"Peroxisome proliferator-activated receptors and cardiovascular remodeling.","Schiffrin",15374828,"Peroxisome proliferator-activated receptors and cardiovascular remodeling.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptor and then modulate the function of many target genes. Three PPARs are known: alpha, beta/delta, and gamma. The better known are PPAR-alpha and PPAR-gamma, which may be activated by different synthetic agonists, although the endogenous ligands are unknown. PPAR-alpha is involved in fatty acid oxidation and expressed in the liver, kidney, and skeletal muscle, whereas PPAR-gamma is involved in fat cell differentiation, lipid storage, and insulin sensitivity. However, both have been shown to be present in variable amounts in cardiovascular tissues, including endothelium, smooth muscle cells, macrophages, and the heart. The activators of PPAR-alpha (fibrates) and PPAR-gamma (thiazolidinediones or glitazones) antagonized the actions of angiotensin II in vivo and in vitro and exerted cardiovascular antioxidant and anti-inflammatory effects. PPAR activators lowered blood pressure, induced favorable effects on the heart, and corrected vascular structure and endothelial dysfunction in several rodent models of hypertension. Activators of PPARs may become therapeutic agents useful in the prevention of cardiovascular disease beyond their effects on carbohydrate and lipid metabolism. Some side effects, such as weight gain, as well as documented aggravation of advanced heart failure through fluid retention by glitazones, may, however, limit their therapeutic application in prevention of cardiovascular disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I90,I90)","v":14704332},{"$f":"(LEN($J90) - LEN(SUBSTITUTE(LOWER($J90),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J90) - LEN(SUBSTITUTE(LOWER($J90),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J90) - LEN(SUBSTITUTE(LOWER($J90),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B90:D90)","v":11},2004,"Regulation of hepatic retinol metabolism: perspectives from studies on vitamin A status.","Ross",14704332,"Regulation of hepatic retinol metabolism: perspectives from studies on vitamin A status.    Abstract:   Liver vitamin A (retinol) is obtained from several sources and is subject to multiple fates. Lecithin:retinol acyltransferase (LRAT), a microsomal enzyme present in liver and several other retinol-metabolizing tissues, esterifies retinol that is associated with a cellular retinol-binding protein, CRBP or CRBP-II. Recent research has shown that LRAT mRNA expression and enzyme activity are regulated in a tissue-specific manner. In vitamin A-deficient liver, both LRAT mRNA and activity are significantly down-regulated as well as rapidly induced after the administration of vitamin A or its principal hormonal metabolite, retinoic acid (RA). In long-term feeding studies and the metabolic steady state, liver LRAT is expressed dose-dependently across a wide range of dietary vitamin A. Additionally, an RA-inducible cytochrome P450, P450RAI or CYP26, is down-regulated in liver during vitamin A deficiency and up-regulated dose-dependently by dietary vitamin A and exogenous RA. Based on these results, we propose that LRAT and CYP26 serve as two molecular mechanisms, coordinately regulated by all-trans-RA, to control the availability of retinol and RA, respectively. The LRAT reaction, besides providing a readily retrievable storage form of vitamin A, may regulate the availability of retinol to other pathways, while the CYP26 reaction may serve to prevent a detrimental quot;overshootquot; of RA concentration. Moreover, retinoid metabolism in the liver is likely to be closely integrated with that in peripheral tissues through the rapid interorgan transfer and recycling of retinoids, affecting the whole-body economy of vitamin A."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I91,I91)","v":10637371},{"$f":"(LEN($J91) - LEN(SUBSTITUTE(LOWER($J91),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J91) - LEN(SUBSTITUTE(LOWER($J91),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J91) - LEN(SUBSTITUTE(LOWER($J91),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B91:D91)","v":11},2000,"Therapeutic applications for ligands of retinoid receptors.","Thacher",10637371,"Therapeutic applications for ligands of retinoid receptors.    Abstract:   Synthetic retinoids, ligands for the RAR and RXR members of the steroid/thyroid superfamily of nuclear hormone receptors, are used for the treatment of psoriasis, acne, photoaging and cancer. Retinoid mechanisms of action for these conditions largely involve effects on epithelial differentiation and modulation of inflammation with some impact on the immune system. Retinoid medicinal chemistry in recent years has identified ligands highly specific for one of the three RAR subtypes (RAR-alpha) and for the RXR family of receptors, as well as antagonists for the RARs, RARalpha and the RXRs. Structure-activity relationships among the novel retinoid classes are reviewed along with potential therapeutic activities and side effects. RAR-alpha specific retinoids inhibit cancer cell growth but lack other retinoid toxicities, including skin irritation now ascribed to RAR-gama. RXR-specific retinoids lower blood glucose in animal models of type 2 diabetes albeit with a potential for mild hypothyroidism. Function-selective retinoids, especially a class of RAR antagonists called inverse agonists, have unexpected gene regulatory activity. Given the diverse properties and tissue distributions of the retinoid receptors, synthesis of additional classes of receptor-specific and function-selective ligands has the potential to produce novel therapeutic applications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I92,I92)","v":9706226},{"$f":"(LEN($J92) - LEN(SUBSTITUTE(LOWER($J92),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J92) - LEN(SUBSTITUTE(LOWER($J92),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J92) - LEN(SUBSTITUTE(LOWER($J92),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B92:D92)","v":11},1998,"Lipases and carboxylesterases: possible roles in the hepatic metabolism of retinol.","Harrison",9706226,"Lipases and carboxylesterases: possible roles in the hepatic metabolism of retinol.    Abstract:   The formation of hydrolysis of retinyl esters are key processes in the metabolism of the fat-soluble micronutrient vitamin A. Long-chain acyl esters of retinol are the major chemical form of vitamin A (retinoid) stored in the body. Retinyl esters are found in a variety of tissues and cell types, but most of the total body retinoid is accounted for by the retinyl esters stored in the liver. Thus, these esters represent the major endogenous source of retinoid that can be delivered to peripheral tissues for conversion to biologically active forms. This review summarizes current knowledge about the identity, function, and regulation of the hepatic enzymes potentially involved in catalyzing the hydrolysis of retinyl esters. These enzymes include several known and characterized lipases and carboxylesterases. Although there is accumulating evidence that these enzymes function as retinyl ester hydrolases in vitro, it is not clear which play important physiological roles in hepatic retinyl ester metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I93,I93)","v":1617858},{"$f":"(LEN($J93) - LEN(SUBSTITUTE(LOWER($J93),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J93) - LEN(SUBSTITUTE(LOWER($J93),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J93) - LEN(SUBSTITUTE(LOWER($J93),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B93:D93)","v":11},1992,"Pharmacokinetics and therapeutic efficacy of retinoids in skin diseases.","Larsen",1617858,"Pharmacokinetics and therapeutic efficacy of retinoids in skin diseases.    Abstract:   The retinoids are a class of compounds that includes the natural forms and synthetic analogues of vitamin A. Isotretinoin, often referred to as a first generation retinoid, may be of considerable benefit to patients with severe, recalcitrant acne. Etretinate and acitretin, 2 aromatic compounds representing the second generation, have found their major success in the treatment of psoriasis, particularly in combination with more traditional therapies. Retinoid therapy is associated with a distinctive adverse effect profile typical of hypervitaminosis A; thus, it is especially important that fertile women undergoing retinoid therapy adhere to a contraceptive regimen. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. The terminal elimination half-lives of isotretinoin, etretinate and acitretin after long term treatment are up to 20h, 120 days and 48h, respectively. Because of lack of definite correlation between plasma concentration and desired pharmacological effects, in conjunction with the very pronounced inter- and intraindividual variation in systemic availability (15 to 90%) after oral administration of these drugs, initial dosages in individual patients can only be roughly judged on the basis of the general pharmacokinetics of the agents. Later dosage adjustments should be made on the basis of monitoring of both plasma drug (and possible metabolite) concentrations, and the efficacy and tolerability of the drugs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I94,I94)","v":3303134},{"$f":"(LEN($J94) - LEN(SUBSTITUTE(LOWER($J94),LOWER(B$3),\"\")))/LEN(B$3)","v":11},{"$f":"(LEN($J94) - LEN(SUBSTITUTE(LOWER($J94),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J94) - LEN(SUBSTITUTE(LOWER($J94),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B94:D94)","v":11},1987,"Vitamin A in human nutrition.","Sklan",3303134,"Vitamin A in human nutrition.    Abstract:   Vitamin A, an unsaturated 20 carbon cyclic alcohol, has a variety of physiological functions including a role in vision, reproduction, growth and maintenance of epithelial and bone structures. The main sources of vitamin A are from preformed vitamin A in animal foods or from -carotene in green plants. Carotene is cleaved in the intestinal mucosa to retinol, which is transported in chylomicrons mainly to the liver which is the major storage site of vitamin A, where stores are mainly of retinyl palmitate. Utilization of vitamin A appears to be a highly regulated process; retinol is transported in the serum bound to a specific binding protein. There also may be some control of the level of retinol in cells possibly through membrane receptors or of excretion from the cell. Intracellular cytosolic retinol binding proteins transport retinol to the nucleus where specific receptors for retinol have been found. Intracellular binding proteins for retinoic acid and retinal, metabolites of retinol have also been found, and an interstitial protein transporting retinol is present in the eye. Vitamin A deficiency causes cessation of growth, night blindness, and renders the organism more susceptible to infection, and vitamin A supplementation has been shown to enhance immune response. Epidemiological studies have shown low vitamin A and carotene to be correlated with incidence of cancer. Excess vitamin A intake results in hypervitaminosis with severe detrimental effects. Vitamin A requirements appear to be met in most developed countries although in the populations at greatest risk, newborns and pregnant and nursing women, cases of deficiency are observed. However, in large areas of the world vitamin A deficiency is endemic, causing widespread blindness and mortality."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I95,I95)","v":27655446},{"$f":"(LEN($J95) - LEN(SUBSTITUTE(LOWER($J95),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J95) - LEN(SUBSTITUTE(LOWER($J95),LOWER(C$3),\"\")))/LEN(C$3)","v":3},{"$f":"(LEN($J95) - LEN(SUBSTITUTE(LOWER($J95),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B95:D95)","v":10},2016,"Senescence in hepatic stellate cells as a mechanism of liver fibrosis reversal: a putative synergy between retinoic acid and PPAR-gamma signalings.","Panebianco",27655446,"Senescence in hepatic stellate cells as a mechanism of liver fibrosis reversal: a putative synergy between retinoic acid and PPAR-gamma signalings.    Abstract:    NlmCategory=UNASSIGNEDHepatic stellate cells (HSCs), also known as perisinusoidal cells, are pericytes found in the perisinusoidal space of the liver. HSCs are the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage. When the liver is damaged, stellate cells can shift into an activated state, characterized by proliferation, contractility and chemotaxis. The activated HSCs secrete collagen scar tissue, which can lead to cirrhosis. Recent studies have shown that in vivo activation of HSCs by fibrogenic agents can eventually lead to senescence of these cells, which would contribute to reversal of fibrosis although it may also favor the insurgence of liver cancer. HSCs in their non-active form store huge amounts of retinoic acid derivatives in lipid droplets, which are progressively depleted upon cell activation in injured liver. Retinoic acid is a metabolite of vitamin A (retinol) that mediates the functions of vitamin A, generally required for growth and development. The precise function of retinoic acid and its alterations in HSCs has yet to be elucidated, and nonetheless in various cell types retinoic acid and its receptors (RAR and RXR) are known to act synergistically with peroxisome proliferator-activated receptor gamma (PPAR-gamma) signaling through the activity of transcriptional heterodimers. Here, we review the recent advancements in the understanding of how retinoic acid signaling modulates the fibrogenic potential of HSCs and proposes a synergistic combined action with PPAR-gamma in the reversal of liver fibrosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I96,I96)","v":26904552},{"$f":"(LEN($J96) - LEN(SUBSTITUTE(LOWER($J96),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J96) - LEN(SUBSTITUTE(LOWER($J96),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J96) - LEN(SUBSTITUTE(LOWER($J96),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B96:D96)","v":10},2016,"Retinoids in the pancreas.","Brun",26904552,"Retinoids in the pancreas.    Abstract:   Retinoids (vitamin A and its natural and synthetic analogs) are required by most tissues for maintaining the normal health of the tissue. This is certainly true for the pancreas. The recent literature is convincing that retinoids are needed by the adult to assure normal pancreatic endocrine functions, especially those of the α- and β-cells. It is also well established that retinoids are required to insure normal pancreas development in utero, including the development of the endocrine pancreas. The actions of retinoids for maintaining normal pancreatic islet functions has drawn considerable research interest from investigators interested in understanding and treating metabolic disease. Pancreatic retinoids are also of interest to investigators studying the origins of pancreatic disease, including the development of pancreatic fibrosis and its sequelae. This research interest is focused on pancreatic stellate cells (PSCs) which store retinoids and possess the metabolic machinery needed to metabolize retinoids. The literature on pancreatic disease and retinoids suggests that there is an association between impairments in pancreatic retinoid storage and metabolism and the development of pancreatic disease. These topics will be considered in this review."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I97,I97)","v":23744414},{"$f":"(LEN($J97) - LEN(SUBSTITUTE(LOWER($J97),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J97) - LEN(SUBSTITUTE(LOWER($J97),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J97) - LEN(SUBSTITUTE(LOWER($J97),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B97:D97)","v":10},2013,"Oxidative stress, polyunsaturated fatty acids-derived oxidation products and bisretinoids as potential inducers of CNS diseases: focus on age-related macular degeneration.","Nowak",23744414,"Oxidative stress, polyunsaturated fatty acids-derived oxidation products and bisretinoids as potential inducers of CNS diseases: focus on age-related macular degeneration.    Abstract:   Many pathologies of the central nervous system (CNS) originate from excess of reactive free radicals, notably reactive oxygen species (ROS), and oxidative stress. A phenomenon which usually runs in parallel with oxidative stress is unsaturated lipid peroxidation, which, via a chain reaction, contributes to the progression of disbalanced redox homeostasis. Among long-chain (LC) polyunsaturated fatty acids (PUFAs) abundantly occurring in the CNS, docosahexaenoic acid (DHA), a member of ω-3 LC-PUFAs, deserves special attention, as it is avidly retained and uniquely concentrated in the nervous system, particularly in retinal photoreceptors and synaptic membranes; owing to the presence of the six double bonds between carbon atoms in its polyene chain (C=C), DHA is exquisitely sensitive to oxidative damage. In addition to oxidative stress and LC-PUFAs peroxidation, other stress-related mechanisms may also contribute to the development of various CNS malfunctions, and a good example of such mechanisms is the process of lipofuscin formation occurring particularly in the retina, an integral part of the CNS. The retinal lipofuscin is formed and accumulated by the retinal pigment epithelial (RPE) cells as a consequence of both visual process taking place in photoreceptor-RPE functional complex and metabolic insufficiency of RPE lysosomal compartment. Among various retinal lipofuscin constituents, bisretinoids, originating from all-trans retinal substrate--a photometabolite of visual pigment cofactor 11-cis-retinal (responsible for photon capturing), are endowed with cytotoxic and complement-activating potential which increases upon illumination and oxidation. This survey deals with oxidative stress, PUFAs (especially DHA) peroxidation products of carboxyalkylpyrrole type and bisretinoids as potential inducers of the CNS pathology. A focus is put on vision-threatening disease, i.e., age-related macular degeneration (AMD), as an example of the CNS disorder whose pathogenesis has strong background in both oxidative stress and lipid peroxidation products."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I98,I98)","v":22292422},{"$f":"(LEN($J98) - LEN(SUBSTITUTE(LOWER($J98),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J98) - LEN(SUBSTITUTE(LOWER($J98),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J98) - LEN(SUBSTITUTE(LOWER($J98),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B98:D98)","v":10},2012,"Roles of vitamin A status and retinoids in glucose and fatty acid metabolism.","Zhao",22292422,"Roles of vitamin A status and retinoids in glucose and fatty acid metabolism.    Abstract:   The rising prevalence of metabolic diseases, such as obesity and diabetes, has become a public health concern. Vitamin A (VA, retinol) is an essential micronutrient for a variety of physiological processes, such as tissue differentiation, immunity, and vision. However, its role in glucose and lipid metabolism has not been clearly defined. VA activities are mediated by the metabolite of retinol catabolism, retinoic acid, which activates the retinoic acid receptor and retinoid X receptor (RXR). Since RXR is an obligate heterodimeric partner for many nuclear receptors involved in metabolism, it is reasonable to assume that VA status and retinoids contribute to glucose and lipid homeostasis. To date, the impacts of VA and retinoids on energy metabolism in animals and humans have been demonstrated in some basic and clinical investigations. This review summarizes the effects of VA status and retinoid treatments on metabolism of the liver, adipocytes, pancreatic β-cells, and skeletal muscle. It proposes a mechanism by which the dietary and hormonal signals converge on the promoter of sterol regulatory element-binding protein 1c gene to induce its expression, and in turn, the expression of lipogenic genes in hepatocytes. Future research projects relevant to the VAs roles in metabolic diseases are also discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I99,I99)","v":21628978},{"$f":"(LEN($J99) - LEN(SUBSTITUTE(LOWER($J99),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J99) - LEN(SUBSTITUTE(LOWER($J99),LOWER(C$3),\"\")))/LEN(C$3)","v":3},{"$f":"(LEN($J99) - LEN(SUBSTITUTE(LOWER($J99),LOWER(D$3),\"\")))/LEN(D$3)","v":5},{"$f":"SUM(B99:D99)","v":10},2011,"[Challenge of creating single-agents for the treatment of type 1 and 2 diabetes by targeting retinoid X receptor].","Kakuta",21628978,"[Challenge of creating single-agents for the treatment of type 1 and 2 diabetes by targeting retinoid X receptor].    Abstract:   It might be seen as reckless to challenge to create single-agents for the treatment of both type 1 diabetes caused by the destruction of the Langerhans β cells in pancreas by excessive autoimmunity, and type 2 diabetes caused by the obesity. However, we hypothesized that retinoid X receptor (RXR) agonists, which are researched for the treatment of type 2 diabetes, will also be useful like metformin, which shows insulin-sparing effect in type 1 diabetes. This is because PPARγ/RXR is known to be a target of thiazolidinediones (TZDs), which are used for the treatment of insulin resistance, LXR/RXR is reported to be involved in glucose/lipid metabolism, and these heterodimers can be activated by RXR agonists alone (permissive mechanism). However, repeated administration of RXR agonists can elevate blood triglyceride and induce hypothyroidism. In this study, we performed systematic conversion of the alkoxy side chain of 5a (6-[ethyl-(3-isopropoxy-4-isopropylphenyl)amino] nicotinic acid: NEt-3IP) and evaluated the RXR-, PPAR/RXR- and LXR/RXR-agonist activities of the products. The cyclopropylmethoxy analog (5c) showed similar RXR- and LXR/RXR-agonistic activities to the benzyloxy analog (5i) and n-propoxy analog (5k), but exhibited more potent PPAR/RXR-agonistic activity than 5i or 5k. Differential modulation of RXR heterodimer-activating ability by conversion of the alkoxy group located in the lipophilic domain of the RXR-agonist common structure is expected to be a useful approach in the design of new RXR agonists for the treatment of hyperlipidemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I100,I100)","v":21091043},{"$f":"(LEN($J100) - LEN(SUBSTITUTE(LOWER($J100),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J100) - LEN(SUBSTITUTE(LOWER($J100),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J100) - LEN(SUBSTITUTE(LOWER($J100),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B100:D100)","v":10},2011,"Retinoic acid receptor modulators: a perspective on recent advances and promises.","Alvarez",21091043,"Retinoic acid receptor modulators: a perspective on recent advances and promises.    Abstract:    IMPORTANCE OF THE FIELD : Retinoids are currently used in the clinic for the treatment of skin diseases and acute promielocytic leukemia and are known to contribute to early development and organogenesis in embryo and throughout life. Most of these activities are primarily due to the binding of the retinoid to the retinoic acid receptors (RARs, subtypes α, β and γ). Ligand modulates, via allosteric conformational changes, the ability of RARs to interact with different sets of co-regulators. Structure-based insights on the ligand-binding domain of the ligand-bound RARs have clearly linked retinoid function to co-activator (CoA) recruitment for agonists, CoA dissociation for antagonists and corepressor stabilization for inverse agonists.  AREAS COVERED IN THIS REVIEW : To help understand ligand-modulated RAR action as a consequence of its interaction with different sets of co-regulators, we present the chemical engineering of subsets of retinoid chemotypes (rexinoids, i.e., the ligands of the retinoid X receptors, α, β and γ, with impact in the treatment of cancer and metabolic diseases, are not covered) that display the whole range of ligand functions, including subtype- and isotype-selectivities.  WHAT THE READER WILL GAIN : An understanding of the correlation of retinoid ligand structure and function. Structural insights into ligand action and retinoid chemotypes. Potential for clinical application of retinoid receptor modulators.  TAKE HOME MESSAGE : Potential pharmacological/therapeutic applications of these chemical tools extend beyond cancer prevention and therapy to the treatment of autoimmune and neurodegenerative diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I101,I101)","v":16503871},{"$f":"(LEN($J101) - LEN(SUBSTITUTE(LOWER($J101),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J101) - LEN(SUBSTITUTE(LOWER($J101),LOWER(C$3),\"\")))/LEN(C$3)","v":9},{"$f":"(LEN($J101) - LEN(SUBSTITUTE(LOWER($J101),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B101:D101)","v":10},2005,"Peroxisome proliferator-activated receptor alpha (PPARalpha) and athero-sclerosis.","Gouni-Berthold",16503871,"Peroxisome proliferator-activated receptor alpha (PPARalpha) and athero-sclerosis.    Abstract:   The peroxisome proliferator-activated receptors (PPARs) alpha, beta/delta and gamma are ligand-activated transcription factors belonging to the nuclear receptor superfamily. PPARs heterodimerize with the retinoid X receptor (RXR) and modulate the function of many target genes. They were originally described as regulators of various metabolic, pathways, but have been recently found to also exert modulating actions in the vascular wall. PPARalpha is activated by endogenous ligands, such as polyunsaturated fatty acids and by synthetic agonists such as the fibrates. PPARalpha is expressed mainly in the liver, kidney and skeletal muscle and is involved in fatty acid oxidation. However, it is also expressed in vascular cells such as the endothelial cells, vascular smooth muscle cells and macrophages, where it exerts anti-inflammatory and antioxidant effects. Since atherosclerosis is both a chronic inflammatory and a lipid disorder and since PPARalpha is expressed in vascular cells and regulates the expression of genes involved in lipid metabolism and inflammation, PPARalpha activators may constitute useful agents for the prevention of atherosclerosis, beyond their effects on lipid metabolism. This review will focus on the functions of PPARalpha on lipid metabolism, on vascular inflammation and its relationship to atherosclerosis. Furthermore, the currently available preclinical and clinical data on PPARalpha activators as well as their future perspectives will be discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I102,I102)","v":15588697},{"$f":"(LEN($J102) - LEN(SUBSTITUTE(LOWER($J102),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J102) - LEN(SUBSTITUTE(LOWER($J102),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J102) - LEN(SUBSTITUTE(LOWER($J102),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B102:D102)","v":10},2004,"Interactions amongst plasma retinol-binding protein, transthyretin and their ligands: implications in vitamin A homeostasis and transthyretin amyloidosis.","Raghu",15588697,"Interactions amongst plasma retinol-binding protein, transthyretin and their ligands: implications in vitamin A homeostasis and transthyretin amyloidosis.    Abstract:   Retinol transport complex consisting of retinol-binding protein (RBP) and transthyretin (TTR) is involved in the transport of retinol (vitamin A) and thyroxine (T(4)) in the human plasma. RBP is a 21-kDa single polypeptide chain protein, synthesized in the liver, which binds and transports retinol to the target organs. The circulating RBP binds to another protein called TTR, a 55-kDa homotetrameric T(4) transport protein. Such protein-protein complex formation is thought to prevent glomerular filtration of low molecular mass RBP. Misfolding and aggregation of TTR is implicated in amyloid disorders such as familial amyloid polyneuropathy (FAP) and senile systemic amyloidosis (SSA). Recent observations suggest that both RBP and T(4), the physiological ligands of TTR, prevent its misfolding and amyloid fibril formation, suggesting yet another structure-function relationship to this protein-protein complex. TTR2, a poorly characterized protein, was also found bound to RBP in human and pig plasma but its significance remains to be understood. Furthermore, knockout models of both RBP and TTR unequivocally demonstrated the importance of this protein-protein complex in retinoid transport. Thus, interactions amongst multiple components of retinol transport play critical roles in vitamin A homeostasis and TTR amyloidosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I103,I103)","v":15570053},{"$f":"(LEN($J103) - LEN(SUBSTITUTE(LOWER($J103),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J103) - LEN(SUBSTITUTE(LOWER($J103),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J103) - LEN(SUBSTITUTE(LOWER($J103),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B103:D103)","v":10},2004,"New aspects in vitamin a metabolism: the role of retinyl esters as systemic and local sources for retinol in mucous epithelia.","Biesalski",15570053,"New aspects in vitamin a metabolism: the role of retinyl esters as systemic and local sources for retinol in mucous epithelia.    Abstract:   Vitamin A and its active metabolites are important for growth and differentiation of a variety of cells, mainly in mucosa-associated epithelia, where they exhibit a wide spectrum of activities. Vitamin A, stored as retinyl esters (REs), is delivered from liver stores into the bloodstream as retinol bound to retinol binding protein. This process is regulated homeostatically, ending up in a more or less constant plasma retinol level. In situations of a high vitamin A demand (e.g., inflammation, diseases, prenatal period), this supply can be insufficient because of delayed production of retinol binding protein, leading to local deficiencies and impairment of structure and function in the respective tissues. This delay may be overcome by cellular RE stores. Several cell types, including buccal mucosa cells, can take up RE. Retinyl palmitate is taken up when it is applied topically to either metaplastically mutated rat vaginal epithelium (as a gel) or to human meta- and dysplastic bronchial epithelia (via inhalation) that have a vitamin A deficiency. In rats and humans, the modified epithelia can be normalized, at least in part. In conclusion, topically applied retinyl esters may be a promising therapy for local retinol deficiencies and may reverse the morphological alterations of the epithelium in tissues that are vitamin A deficient."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I104,I104)","v":12505311},{"$f":"(LEN($J104) - LEN(SUBSTITUTE(LOWER($J104),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J104) - LEN(SUBSTITUTE(LOWER($J104),LOWER(C$3),\"\")))/LEN(C$3)","v":9},{"$f":"(LEN($J104) - LEN(SUBSTITUTE(LOWER($J104),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B104:D104)","v":10},2002,"Regulation of P450 4A expression by peroxisome proliferator activated receptors.","Johnson",12505311,"Regulation of P450 4A expression by peroxisome proliferator activated receptors.    Abstract:   The induction of P450 4A enzymes by peroxisome proliferators (PPs) and fatty acids is mediated by the peroxisome proliferator activated receptor alpha (PPAR alpha) that binds to response elements in target genes as a heterodimer with the retinoid X receptor (RXR). The consensus sequence recognized by PPAR/RXR heterodimers, contains an imperfect direct repeat of two nuclear receptor binding motifs separated by a single nucleotide. This repeat is preceded by a conserved A/T rich sequence that is required for function. In mice, chronic exposure to PPs results in PPAR alpha mediated liver hypertrophy, hyperplasia and carcinogenesis accompanied by a proliferation of peroxisomes. In contrast, humans exhibit a reduced sensitivity to PP pathogenesis. This could reflect gt;10-fold lower PPAR alpha levels relative to mice as well as differences in targeted genes. In order to identify PPAR responsive human genes, the human hepatoma cell line, HepG2, was engineered to express increased levels of PPAR alpha. Several genes encoding rate-limiting enzymes and branch points in ketone body formation are regulated by PPAR alpha in these cells. In contrast, significant induction by PP is not evident for peroxisomal fatty acid oxidation that is associated with peroxisome proliferation in mice. Human P450 4A11 is not expressed in dividing cultures of cells with enhanced PPAR alpha levels, but it is expressed in confluent cultures expressing elevated amounts of PPAR alpha."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I105,I105)","v":12195157},{"$f":"(LEN($J105) - LEN(SUBSTITUTE(LOWER($J105),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J105) - LEN(SUBSTITUTE(LOWER($J105),LOWER(C$3),\"\")))/LEN(C$3)","v":4},{"$f":"(LEN($J105) - LEN(SUBSTITUTE(LOWER($J105),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B105:D105)","v":10},2002,"Linkage between retinoid and fatty acid receptors: implications for breast cancer prevention.","Stoll",12195157,"Linkage between retinoid and fatty acid receptors: implications for breast cancer prevention.    Abstract:   Certain dietary retinoids and polyunsaturated fatty acids (PUFAs) consistently inhibit progression of mammary carcinogenesis both in animal studies and cell culture, but clinically, their effect is inconsistent. New evidence of synergistic interaction between the nuclear receptors for the two groups of nutritional agents suggests that appropriate selective ligands from each group might be combined in breast cancer chemoprevention studies. Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear receptor that is activated by PUFAs, eicosanoids and antidiabetic agents such as troglitazone. Such activation can cause growth inhibition in human mammary cancer cells in culture and the effect is enhanced by ligands of retinoic acid receptor (RAR) and retinoid X receptor (RXR). In mouse mammary tissue in organ culture, an RXR-selective ligand has been shown to enhance the effect of troglitazone in suppressing carcinogen-induced pre-neoplastic changes. A PPAR/RXR heterodimer is involved in tumour growth inhibition and has been shown to bind directly to nuclear oestrogen response elements (ERE) independently of oestrogen receptor (ER) activity. A combination of an RXR-selective retinoid with either troglitazone or else a long-chain n-3 PUFA, is proposed for a short-term study in postmenopausal women after primary surgery for intraductal breast cancer. The resulting activation of PPAR/RXR expression may increase response to retinoid administration, especially in the presence of obesity and insulin resistance, because of the ability of PPAR gamma ligands to reduce insulin-like growth factor I (IGF-I) concentrations. Serial core biopsies of breast tissue over a short term are proposed to identify changes in phenotype, which may influence progression to invasiveness. In addition to cytomorphological criteria, expression of ER alpha and beta, RAR alpha and beta, and IGF-I receptor in the nucleus should be examined."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I106,I106)","v":11327101},{"$f":"(LEN($J106) - LEN(SUBSTITUTE(LOWER($J106),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J106) - LEN(SUBSTITUTE(LOWER($J106),LOWER(C$3),\"\")))/LEN(C$3)","v":8},{"$f":"(LEN($J106) - LEN(SUBSTITUTE(LOWER($J106),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B106:D106)","v":10},2001,"The pleiotropic functions of peroxisome proliferator-activated receptor gamma.","Debril",11327101,"The pleiotropic functions of peroxisome proliferator-activated receptor gamma.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors, initially described as molecular targets for synthetic compounds that induce peroxisome proliferation. PPARgamma is the best characterized of the PPARs. The heterodimer of PPARgamma with the retinoid X receptor (RXR) plays a crucial role in adipogenesis and insulin sensitization. The RXR/PPARgamma heterodimer furthermore has been reported to have important immunomodulatory activities and to affect cell proliferation/differentiation pathways in various malignancies. PPARgamma is activated by a number of naturally occurring fatty acid derivatives and by several synthetic compounds, including the thiazolidinediones and L-tyrosine-based insulin sensitizers. This review gives an overview of the pleiotropic functions of PPARgamma and discusses the wide-ranging medical implications that modulation of PPARgamma activity might have for various diseases, ranging from obesity and type 2 diabetes to cancer and inflammation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I107,I107)","v":10936415},{"$f":"(LEN($J107) - LEN(SUBSTITUTE(LOWER($J107),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J107) - LEN(SUBSTITUTE(LOWER($J107),LOWER(C$3),\"\")))/LEN(C$3)","v":9},{"$f":"(LEN($J107) - LEN(SUBSTITUTE(LOWER($J107),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B107:D107)","v":10},2000,"PPARgamma: observations in the hematopoietic system.","Greene",10936415,"PPARgamma: observations in the hematopoietic system.    Abstract:   Human Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) was originally cloned from a human bone marrow library. What role does this ligand activated transcription factor play in hematopoiesis and the immune system? We note that: a) PPARgamma has potential to interact/interfere or synergize with retinoid biology, b) fatty acids and a prostaglandin have been identified as ligands, and c) lymphocytes, monocytes and neutrophils use fatty acids as a major source of energy production, d) PPARgamma has been shown to oppose TNFalpha and down regulate cytokine production in monocytes. Therefore, we undertook a review of the literature and an expression survey of PPARgamma in a number of major organs and cells involved in the hematopoietic system, for the purpose of building a database towards understanding the role and function of PPARgamma gene regulation in the developing blood and immune systems. PPARgamma is expressed before mesodermal induction in tissue in and around Speymanns organizer in the xenopus blastocyst, in erythroid precursors of blood islands and in the circulation of the day 10.0 murine embryo, in human 19 week fetal liver, in some but not all murine and human bone marrow erythroid, myeloid, and monocytoid progenitors, bone marrow stromal cells and adipocytes, osteoblasts, endothelial cells, some T, and B lymphocytes, monocytes, macrophages, and other monocytic derivatives. It can be found in the cells of Peyers patches, lymphoid follicles, spleen, and thymus. It is not clear if it is ever or transiently expressed in megakaryocytes, mast cells, or neutrophils. Based on the above data and a review of the literature, PPARgamma seems to play a role during the elicitation of immune responses. We propose PPARgamma may be involved in changes in energy states required during activation and development of many cell types involved, and has additional immunologically relevant effects in erythroid, myeloid, monocytic, T and B lymphocytic, stromal, and endothelial cell function."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I108,I108)","v":10696077},{"$f":"(LEN($J108) - LEN(SUBSTITUTE(LOWER($J108),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J108) - LEN(SUBSTITUTE(LOWER($J108),LOWER(C$3),\"\")))/LEN(C$3)","v":10},{"$f":"(LEN($J108) - LEN(SUBSTITUTE(LOWER($J108),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B108:D108)","v":10},2000,"Peroxisome proliferator-activated receptors in the cardiovascular system.","Bishop-Bailey",10696077,"Peroxisome proliferator-activated receptors in the cardiovascular system.    Abstract:   Peroxisome proliferator-activated receptor (PPAR)s are a family of three nuclear hormone receptors, PPARalpha, -delta, and -gamma, which are members of the steriod receptor superfamily. The first member of the family (PPARalpha) was originally discovered as the mediator by which a number of xenobiotic drugs cause peroxisome proliferation in the liver. Defined functions for all these receptors, until recently, mainly concerned their ability to regulate energy balance, with PPARalpha being involved in beta-oxidation pathways, and PPARgamma in the differentiation of adipocytes. Little is known about the functions of PPARdelta, though it is the most ubiquitously expressed. Since their discovery, PPARs have been shown to be expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by a vast number of compounds including synthetic drugs, of the clofibrate, and anti-diabetic thiazoldinedione classes, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low density lipoprotein. This review will aim to introduce the field of PPAR nuclear hormone receptors, and discuss the discovery and actions of PPARs in the cardiovascular system, as well as the source of potential ligands."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I109,I109)","v":10459140},{"$f":"(LEN($J109) - LEN(SUBSTITUTE(LOWER($J109),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J109) - LEN(SUBSTITUTE(LOWER($J109),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J109) - LEN(SUBSTITUTE(LOWER($J109),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B109:D109)","v":10},1999,"Acitretin in psoriasis: an overview of adverse effects.","Katz",10459140,"Acitretin in psoriasis: an overview of adverse effects.    Abstract:   Oral retinoids are among the drugs of choice for pustular and erythrodermic psoriasis. In addition, retinoids are effective in combination with other topical and systemic agents for the treatment of plaque-type psoriasis. Acitretin, the active retinoid metabolite, has replaced etretinate in retinoid therapy of psoriasis because of its more favorable pharmacokinetic profile, including a significantly shorter half-life. Retinoids, including acitretin, are potent teratogens, leading to strict requirements for pregnancy prevention during and after their use. Other retinoid side effects are generally preventable or manageable through proper patient selection, dose adjustments, and routine monitoring. Mucocutaneous side effects such as cheilitis and hair loss are the most common dose-dependent side effects, requiring dose reduction in some patients. Less common effects such as hepatotoxicity, serum lipid alterations, pancreatitis, and possible skeletal effects are also discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I110,I110)","v":10191129},{"$f":"(LEN($J110) - LEN(SUBSTITUTE(LOWER($J110),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J110) - LEN(SUBSTITUTE(LOWER($J110),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J110) - LEN(SUBSTITUTE(LOWER($J110),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B110:D110)","v":10},1999,"Retinal degeneration in retinitis pigmentosa and neuronal ceroid lipofuscinosis: An overview.","Birch",10191129,"Retinal degeneration in retinitis pigmentosa and neuronal ceroid lipofuscinosis: An overview.    Abstract:   Retinal degeneration is an early consequence of the group of lysosomal storage diseases collectively referred to as the neuronal ceroid lipofuscinoses (NCLs). This review details specialized techniques that have evolved for retinal assessment in patients with hereditary retinal degeneration. A standard ERG protocol is described for assessing rod- and cone-mediated function. Standardization will be crucial for planning and implementing multicenter trials as rational therapeutic intervention becomes available. In recent years, there has been a dramatic increase in knowledge of the molecular biological bases of retinitis pigmentosa and allied retinal degenerations. Rather than attempting a comprehensive summary, this review stresses the concepts of genetic, allelic, and clinical heterogeneity, which have obvious parallels in the NCLs. Many of the mutations that cause retinal degeneration are in genes that encode photoreceptor cascade proteins; others are in genes that encode photoreceptor structural proteins. Recent advances in linking the retinal degeneration slow (RDS) and ATP-binding cassette transporter retina (ABCR) genes to a variety of disease phenotypes will be summarized. Clinical heterogeneity even among family members with the same mutation raises the possibility that modifying factors, either genetic or environmental, could influence the severity of the disease. Here, we focus on vitamin A and docosahexaenoic acid, two potential nutritional modifiers that have received considerable attention in recent years."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I111,I111)","v":7561630},{"$f":"(LEN($J111) - LEN(SUBSTITUTE(LOWER($J111),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J111) - LEN(SUBSTITUTE(LOWER($J111),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J111) - LEN(SUBSTITUTE(LOWER($J111),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B111:D111)","v":10},1995,"Retinoids: transport, metabolism, and mechanisms of action.","Vieira",7561630,"Retinoids: transport, metabolism, and mechanisms of action.    Abstract:   The retinoids comprise a family of polyisoprenoid lipids that includes vitamin A (retinol) and structurally related compounds. The biological activity of retinoids can be modified, for example, by changes in the molecules state of oxidation and cis/trans isomerization. Their activity is also dependent on the levels of specific types of retinoid-binding proteins which exist in extracellular, cytosolic and nuclear compartments. The role of retinoids in gene expression represents an important biological function for this family of molecules. Retinoid-dependent modulation of gene expression is critical for normal cell and tissue function in mature as well as developing animals. Despite significant advances in the understanding of retinoid biological activity, important questions remain concerning aspects of retinoid metabolism, cellular uptake, intracellular trafficking and regulation of gene transcription. The purpose of this review is to present these topics as a compendium of retinoid endocrinology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I112,I112)","v":8137334},{"$f":"(LEN($J112) - LEN(SUBSTITUTE(LOWER($J112),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J112) - LEN(SUBSTITUTE(LOWER($J112),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J112) - LEN(SUBSTITUTE(LOWER($J112),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B112:D112)","v":10},1994,"Prospects of chemoprevention of human cancers with the synthetic retinoid fenretinide.","Costa",8137334,"Prospects of chemoprevention of human cancers with the synthetic retinoid fenretinide.    Abstract:   Fenretinide or N-(4-hydroxyphenyl)retinamide is a vitamin A analogue synthesized in the United States in the late 1960s. This retinoid shows a preferential accumulation in breast instead of liver, is effective in the inhibition of chemically induced mammary carcinoma in rats, and has proved to be less toxic than many other vitamin A analogues. The Milan Cancer Institute has put a particular effort in this molecule in both the experimental and clinical fields. We have demonstrated, in animals and humans, that fenretinide induces a rapid reduction of retinol plasma concentration, that its blood levels remain constant during administration for as long as 5 years, and that the drug is able to accumulate in the human breast. To date, 2969 stage I breast cancer patients have been randomized to evaluate the efficacy of this retinoid to prevent contralateral new primaries, 709 subjects have been accrued in a prevention trial of basal cell carcinoma of the head and neck, and 153 patients entered a study the preliminary results of which already show the capability of fenretinide to prevent recurrences and new localizations of oral leukoplakia. Further studies on fenretinide will be aimed at evaluating its preventive efficacy in superficial bladder and prostate cancers and at exploring possible synergism with tamoxifen and interferons in breast cancer and skin cancer, respectively."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I113,I113)","v":8232263},{"$f":"(LEN($J113) - LEN(SUBSTITUTE(LOWER($J113),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J113) - LEN(SUBSTITUTE(LOWER($J113),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J113) - LEN(SUBSTITUTE(LOWER($J113),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B113:D113)","v":10},1993,"Cellular binding proteins for fatty acids and retinoids: similar or specialized functions?","Bass",8232263,"Cellular binding proteins for fatty acids and retinoids: similar or specialized functions?    Abstract:   The cellular fatty acid-binding proteins (FABP) and cellular retinoid (retinol, retinoic acid)-binding proteins (CRtBP) are structurally and functionally-defined groups within an evolutionarily conserved gene family. CRtBP are expressed in both fully differentiated and developing tissues in a manner that supports a relationship to the action of retinoic acid in morphogenesis and cellular differentiation. The FABP are, by contrast, expressed only in fully differentiated tissues in a manner compatible with a major function in the metabolism of long-chain fatty acids (LCFA) for energy production or storage. The precise function(s) of FABP and CRtBP remain imperfectly understood, while subspecialization of function(s) within the two groups is suggested by the complex diversity in both of structurally distinct members that display striking tissue and temporal specificity of expression in addition to ligand specificity. Notwithstanding this considerable apparent functional diversity among the FABP and CRtBP, available evidence supports a dual set of generic functions for both protein groups in a) promoting cellular flux of poorly water-soluble ligands and their subsequent metabolic utilization or transformation, and b) sequestration of ligands in a manner that limits their association with alternative binding sites within the cell, of which members of the steroid hormone nuclear receptor superfamily (HNR) are a potentially important category. Theoretical as well as experimental models probing diffusional fluxes of LCFA in vitro and in living cells have provided support for a function for FABP in intracellular LCFA transport. Protein-bound ligand also appears to provide the substrate for metabolic transformation of retinoids bound to CRtBP, but convincing evidence is lacking for an analogous mechanism in the direct facilitation of fatty acid utilization by FABP. An emerging relationship between FABP and CRtBP function centers on their binding of, and induction by, ligands which activate or transform specific HNR-the retinoic acid receptors and the peroxisome proliferator activated receptor in the case of CRtBP and FABP, respectively. Evidence consistent with both a promotive role (provision of ligands for HNR) and a protective role (limiting availability of free ligand for HNR association) has been advanced for CRtBP. Available data supports a protective function for cellular retinoic acid-binding proteins (CRABP) and liver FABP (L-FABP) and points to the existence of ligand-defined, lipid-binding-protein-HNR relationships in which CRABP serve to attenuate the induction of gene expression by retinoic acid, and in which L-FABP may modulate a cellular adaptive multigene response to increased LCFA flux or compromised LCFA utilization.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I114,I114)","v":2672772},{"$f":"(LEN($J114) - LEN(SUBSTITUTE(LOWER($J114),LOWER(B$3),\"\")))/LEN(B$3)","v":10},{"$f":"(LEN($J114) - LEN(SUBSTITUTE(LOWER($J114),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J114) - LEN(SUBSTITUTE(LOWER($J114),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B114:D114)","v":10},1989,"Retinol (vitamin A) and the neonate: special problems of the human premature infant.","Zachman",2672772,"Retinol (vitamin A) and the neonate: special problems of the human premature infant.    Abstract:   Retinol stores accumulate in fetal tissue during gestation. Hence, the premature infant faces extrauterine adaptation with less total reserves of retinol than does the term infant. Retinol-binding protein in serum is also lower in the premature infant population. The parenteral retinol supplementation frequently required for these infants has only recently become adequate by the finding of methods to avoid large losses of retinol onto intravenous tubing. Retinol is an essential vitamin for epithelial cell function; nearly 40% of lung cells are of epithelial origin. The premature infants lung often is the initial site of difficulties during extrauterine adaptation, and respiratory system epithelial-cell damage and chronic lung disease frequently develop. Because these infants have associated low retinol reserves, retinol supplementation to help repair pulmonary injury is being considered. Some of these relationships are beginning to be clarified by basic research on the metabolism and function of retinol in lung."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I115,I115)","v":25929424},{"$f":"(LEN($J115) - LEN(SUBSTITUTE(LOWER($J115),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J115) - LEN(SUBSTITUTE(LOWER($J115),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J115) - LEN(SUBSTITUTE(LOWER($J115),LOWER(D$3),\"\")))/LEN(D$3)","v":6},{"$f":"SUM(B115:D115)","v":9},2015,"Vitamins and their derivatives in the prevention and treatment of metabolic syndrome diseases (diabetes).","Dakshinamurti",25929424,"Vitamins and their derivatives in the prevention and treatment of metabolic syndrome diseases (diabetes).    Abstract:   A cluster of inter-related conditions such as central obesity, dyslipidemia, impaired glucose metabolism, and hypertension is referred to as Metabolic Syndrome, which is a risk factor for the development of type-2 diabetes. The micro- and macro-vascular complications of diabetes contribute to its morbidity and mortality. In addition to its calcitropic effect, vitamin D is a regulator of gene expression as well as cell proliferation and differentiation. Various cross-sectional and longitudinal cohort studies have indicated a beneficial effect from vitamin D supplementation on the development of type-2 diabetes. Binding of retinol-bound retinol-binding protein to a membrane-binding protein suppresses insulin signaling. All-trans retinoic acid, a derivative of vitamin A, reverses these effects, resulting in increased insulin sensitivity, suppression of the phosphoenolpyruvate carboxy kinase (PEPCK) gene, and the induction of the glucokinase gene. Glucokinase and PEPCK are also regulated in opposite directions by the vitamin biotin, acting at the transcriptional level. Biotin also regulates the synthesis of insulin by the islet of Langerhans cells of the pancreas. The increase in advanced glycation end products (AGEs) is implicated in the initiation and progression of diabetes-associated microvascular diseases. Benfotiamine, a derivative of thiamine, and pyridoxamine, a vitamer of vitamin B6, both have anti-AGE properties, making them valuable therapeutic adjuvants in the treatment of diabetic complications. Thus, various vitamins and their derivatives have profound therapeutic potential in the prevention and treatment of type-2 diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I116,I116)","v":22737656},{"$f":"(LEN($J116) - LEN(SUBSTITUTE(LOWER($J116),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J116) - LEN(SUBSTITUTE(LOWER($J116),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J116) - LEN(SUBSTITUTE(LOWER($J116),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B116:D116)","v":9},2012,"Retinoid metabolism and diabetes mellitus.","Rhee",22737656,"Retinoid metabolism and diabetes mellitus.    Abstract:   Retinoid acid is a metabolite of vitamin A and functions as an important factor in cell survival, differentiation and death. Most previous studies on retinoid metabolism have focused on its association with cancer, hematologic and dermatologic disorders. Given the special concern over the recent increase in the prevalence of diabetes worldwide, the role of retinoid metabolism on glucose metabolism and insulin resistance in the human body is of marked importance. Therefore, in this issue, we review the literature on the association of retinoid metabolism with glucose tolerance, with regard to insulin secretion, pancreatic autoimmunity, insulin sensitivity and lipid metabolism. Further, we tried to assess the possibility of using retinoids as a novel therapeutic strategy for diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I117,I117)","v":22690322},{"$f":"(LEN($J117) - LEN(SUBSTITUTE(LOWER($J117),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J117) - LEN(SUBSTITUTE(LOWER($J117),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J117) - LEN(SUBSTITUTE(LOWER($J117),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B117:D117)","v":9},2012,"The adverse effects of alcohol on vitamin A metabolism.","Clugston",22690322,"The adverse effects of alcohol on vitamin A metabolism.    Abstract:   The objective of this review is to explore the relationship between alcohol and the metabolism of the essential micronutrient, vitamin A; as well as the impact this interaction has on alcohol-induced disease in adults. Depleted hepatic vitamin A content has been reported in human alcoholics, an observation that has been confirmed in animal models of chronic alcohol consumption. Indeed, alcohol consumption has been associated with declines in hepatic levels of retinol (vitamin A), as well as retinyl ester and retinoic acid; collectively referred to as retinoids. Through the use of animal models, the complex interplay between alcohol metabolism and vitamin A homeostasis has been studied; the reviewed research supports the notion that chronic alcohol consumption precipitates a decline in hepatic retinoid levels through increased breakdown, as well as increased export to extra-hepatic tissues. While the precise biochemical mechanisms governing alcohols effect remain to be elucidated, its profound effect on hepatic retinoid status is irrefutable. In addition to a review of the literature related to studies on tissue retinoid levels and the metabolic interactions between alcohol and retinoids, the significance of altered hepatic retinoid metabolism in the context of alcoholic liver disease is also considered."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I118,I118)","v":21983272},{"$f":"(LEN($J118) - LEN(SUBSTITUTE(LOWER($J118),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J118) - LEN(SUBSTITUTE(LOWER($J118),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J118) - LEN(SUBSTITUTE(LOWER($J118),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B118:D118)","v":9},2012,"Analysis, occurrence, and function of 9-cis-retinoic acid.","Kane",21983272,"Analysis, occurrence, and function of 9-cis-retinoic acid.    Abstract:   Metabolic conversion of vitamin A (retinol) into retinoic acid (RA) controls numerous physiological processes. 9-cis-retinoic acid (9cRA), an active metabolite of vitamin A, is a high affinity ligand for retinoid X receptor (RXR) and also activates retinoic acid receptor (RAR). Despite the identification of candidate enzymes that produce 9cRA and the importance of RXRs as established by knockout experiments, in vivo detection of 9cRA in tissue was elusive until recently when 9cRA was identified as an endogenous pancreas retinoid by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology. This review will discuss the current status of the analysis, occurrence, and function of 9cRA. Understanding both the nuclear receptor-mediated and non-genomic mechanisms of 9cRA will aid in the elucidation of disease physiology and possibly lead to the development of new retinoid-based therapeutics. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I119,I119)","v":21669299},{"$f":"(LEN($J119) - LEN(SUBSTITUTE(LOWER($J119),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J119) - LEN(SUBSTITUTE(LOWER($J119),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J119) - LEN(SUBSTITUTE(LOWER($J119),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B119:D119)","v":9},2012,"Lipid metabolism in mammalian tissues and its control by retinoic acid.","Bonet",21669299,"Lipid metabolism in mammalian tissues and its control by retinoic acid.    Abstract:   Evidence has accumulated that specific retinoids impact on developmental and biochemical processes influencing mammalian adiposity including adipogenesis, lipogenesis, adaptive thermogenesis, lipolysis and fatty acid oxidation in tissues. Treatment with retinoic acid, in particular, has been shown to reduce body fat and improve insulin sensitivity in lean and obese rodents by enhancing fat mobilization and energy utilization systemically, in tissues including brown and white adipose tissues, skeletal muscle and the liver. Nevertheless, controversial data have been reported, particularly regarding retinoids effects on hepatic lipid and lipoprotein metabolism and blood lipid profile. Moreover, the molecular mechanisms underlying retinoid effects on lipid metabolism are complex and remain incompletely understood. Here, we present a brief overview of mammalian lipid metabolism and its control, introduce mechanisms through which retinoids can impact on lipid metabolism, and review reported activities of retinoids on different aspects of lipid metabolism in key tissues, focusing on retinoic acid. Possible implications of this knowledge in the context of the management of obesity and the metabolic syndrome are also addressed. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I120,I120)","v":20042001},{"$f":"(LEN($J120) - LEN(SUBSTITUTE(LOWER($J120),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J120) - LEN(SUBSTITUTE(LOWER($J120),LOWER(C$3),\"\")))/LEN(C$3)","v":6},{"$f":"(LEN($J120) - LEN(SUBSTITUTE(LOWER($J120),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B120:D120)","v":9},2010,"Retinoic acid activation of peroxisome proliferation-activated receptor delta represses obesity and insulin resistance.","Wolf",20042001,"Retinoic acid activation of peroxisome proliferation-activated receptor delta represses obesity and insulin resistance.    Abstract:   Retinoic acid (RA) was found to be a ligand for peroxisome proliferation-activated receptor delta (PPARdelta) as well as the classical RA receptor (RAR). Carrier proteins that move the RA from the cytosol into the nucleus are the fatty acid-binding protein 5 (FABP5), activating PPARdelta, and the cellular retinoic acid-binding protein II (CRABPII), activating RAR. The ratio of FABP5/CRABPII concentrations determines which receptor is activated. By activating PPARdelta, RA was found to induce expression of genes affecting lipid and glucose homeostasis, in particular, leading to expression of the insulin-signaling gene PDK1 and improvement of insulin action. Hence, RA stimulates lipolysis and reduces triglyceride content. In vivo, obesity has led to downregulation of adipose PPARdelta expression. RA implantation into obese mice has caused upregulation of levels of PPARdelta and consequent weight loss as well as increased expression of PPARdelta target genes, including the insulin-signaling gene PDK1."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I121,I121)","v":19892132},{"$f":"(LEN($J121) - LEN(SUBSTITUTE(LOWER($J121),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J121) - LEN(SUBSTITUTE(LOWER($J121),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J121) - LEN(SUBSTITUTE(LOWER($J121),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B121:D121)","v":9},2010,"Chapter 29: historical aspects of the major neurological vitamin deficiency disorders: overview and fat-soluble vitamin A.","Lanska",19892132,"Chapter 29: historical aspects of the major neurological vitamin deficiency disorders: overview and fat-soluble vitamin A.    Abstract:   The vitamine doctrine: Although diseases resulting from vitamin deficiencies have been known for millennia, such disorders were generally attributed to toxic or infectious causes until the quot;vitamin doctrinequot; was developed in the early 20th century. In the late-19th century, a physiologically complete diet was believed to require only sufficient proteins, carbohydrates, fats, inorganic salts, and water. From 1880-1912, Lunin, Pekelharing, and Hopkins found that animals fed purified mixtures of known food components failed to grow or even lost weight and died, unless the diet was supplemented with small amounts of milk, suggesting that quot;accessory food factorsquot; are required in trace amounts for normal growth. By this time, Funk suggested that deficiencies of trace dietary factors, which he labeled quot;vitaminesquot; on the mistaken notion that they were quot;vital amines,quot; were responsible for such diseases as beriberi, scurvy, rickets, and pellagra. Vitamin A deficiency eye disease: Night blindness was recognized by the ancient Egyptians and Greeks, and many authorities from Galen onward advocated liver as a curative. Outbreaks of night blindness were linked to nutritional causes in the 18th and 19th centuries by von Bergen, Schwarz, and others. Corneal ulceration was reported in 1817 by Magendie among vitamin A-deficient dogs fed for several weeks on a diet limited to sugar and water, although he erroneously attributed this to a deficiency of dietary nitrogen (i.e. protein). Subsequently, corneal epithelial defects, often in association with night blindness, were recognized in malnourished individuals subsisting on diets now recognizable as deficient in vitamin A by Budd, Livingstone, von Hubbenet, Bitot, Mori, Ishihari, and others. During World War I, Bloch conducted a controlled clinical trial of different diets among malnourished Danish children with night blindness and keratomalacia and concluded that whole milk, butter, and cod-liver oil contain a fat-soluble substance that protects against xerophthalmia. Early retinal photochemistry: In the 1870s, Boll found that light causes bleaching of the retinal pigment, and suggested that the outer segments of the rods contain a substance that conveys an impression of light to the brain by a photochemical process. Shortly thereafter, Kühne demonstrated that the bleaching process depends upon light, and was reversible if the retinal pigment epithelium was intact. Kühne proposed an quot;optochemical hypothesis,quot; a prescient concept of photochemical transduction, attributing vision to a photochemical change in visual purple (rhodopsin) with resulting chemical products stimulating the visual cells and thereby conveying a visual image. Vitamin A: In 1913, Ishihara proposed that a quot;fatty substancequot; in blood is necessary for synthesis of both rhodopsin and the surface layer of the cornea, and that night blindness and keratomalacia develop when this substance is deficient. That year McCollum and Davis (and almost simultaneously Mendel and Osborne) discovered a fat-soluble accessory food factor (later called quot;fat-soluble Aquot;) distinct from the water-soluble anti-beriberi factor (later called quot;fat-soluble Bquot;). By 1922 McCollum and colleagues distinguished two vitamins within the fat-soluble fraction, later named vitamins A and D. In 1925 Fridericia and Holm directly linked vitamin A to night blindness in animal experiments using rats, and in 1929 Holm demonstrated the presence of vitamin A in retinal tissue. In the 1930s, Moore, Karrer, Wald, and others established the provitamin role of beta-carotene. Karrer and colleagues isolated beta-carotene (the main dietary precursor of vitamin A) and retinol (vitamin A), and determined their chemical structures. In 1947, Isler and colleagues completed the full chemical synthesis of vitamin A. Modern retinal photochemistry: Beginning in the 1930s, Wald and colleagues greatly elaborated the photochemistry of vision, with the discovery of the visual cycle of vitamin A, demonstration that rhodopsin is decomposed by light into retinal (the aldehyde form of vitamin A) and a protein (opsin), elaboration of the enzymatic conversions of various elements in the rhodopsin system, and discovery that the rhodopsin system is dependent on a photoisomerization of retinal. In 1942, Hecht and colleagues demonstrated that a single photon could trigger excitation in a rod. In 1965, Wald suggested that a large chemical amplification was necessary for this degree of light sensitivity, likely by a cascade of enzymatic reactions. Later studies elaborated this cascade and found that an intermediary in the photoisomerization of retinal interacts with transducin, a G-protein, to activate phosphodiesterases that control cyclic GMP levels, which in turn modulate the release of neurotransmitter from the rod cell. Public health: Although the availability of vitamin A through food fortification and medicinal supplements virtually eliminated ocular vitamin A deficiency from developed countries by the second half of the 20th century, vitamin A deficiency remains a serious problem in developing countries as indicated by global surveys beginning in the 1960s. Millions of children were shown to be vitamin A deficient, with resultant blindness, increased susceptibility to infection, and increased childhood mortality. Beginning in the 1960s, intervention trials showed that vitamin A deficiency disorders could be prevented in developing countries with periodic vitamin A dosing, and in the 1980s and 1990s, large randomized, double-blind, placebo-controlled clinical trials demonstrated the marked efficacy of vitamin A supplementation in reducing childhood mortality."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I122,I122)","v":19071229},{"$f":"(LEN($J122) - LEN(SUBSTITUTE(LOWER($J122),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J122) - LEN(SUBSTITUTE(LOWER($J122),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J122) - LEN(SUBSTITUTE(LOWER($J122),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B122:D122)","v":9},2009,"Hepatic stellate cell lipid droplets: a specialized lipid droplet for retinoid storage.","Blaner",19071229,"Hepatic stellate cell lipid droplets: a specialized lipid droplet for retinoid storage.    Abstract:   The majority of retinoid (vitamin A and its metabolites) present in the body of a healthy vertebrate is contained within lipid droplets present in the cytoplasm of hepatic stellate cells (HSCs). Two types of lipid droplets have been identified through histological analysis of HSCs within the liver: smaller droplets bounded by a unit membrane and larger membrane-free droplets. Dietary retinoid intake but not triglyceride intake markedly influences the number and size of HSC lipid droplets. The lipids present in rat HSC lipid droplets include retinyl ester, triglyceride, cholesteryl ester, cholesterol, phospholipids and free fatty acids. Retinyl ester and triglyceride are present at similar concentrations, and together these two classes of lipid account for approximately three-quarters of the total lipid in HSC lipid droplets. Both adipocyte-differentiation related protein and TIP47 have been identified by immunohistochemical analysis to be present in HSC lipid droplets. Lecithin:retinol acyltransferase (LRAT), an enzyme responsible for all retinyl ester synthesis within the liver, is required for HSC lipid droplet formation, since Lrat-deficient mice completely lack HSC lipid droplets. When HSCs become activated in response to hepatic injury, the lipid droplets and their retinoid contents are rapidly lost. Although loss of HSC lipid droplets is a hallmark of developing liver disease, it is not known whether this contributes to disease development or occurs simply as a consequence of disease progression. Collectively, the available information suggests that HSC lipid droplets are specialized organelles for hepatic retinoid storage and that loss of HSC lipid droplets may contribute to the development of hepatic disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I123,I123)","v":16484546},{"$f":"(LEN($J123) - LEN(SUBSTITUTE(LOWER($J123),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J123) - LEN(SUBSTITUTE(LOWER($J123),LOWER(C$3),\"\")))/LEN(C$3)","v":8},{"$f":"(LEN($J123) - LEN(SUBSTITUTE(LOWER($J123),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B123:D123)","v":9},2006,"Nuclear receptors and autoimmune disease: the potential of PPAR agonists to treat multiple sclerosis.","Racke",16484546,"Nuclear receptors and autoimmune disease: the potential of PPAR agonists to treat multiple sclerosis.    Abstract:   Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated, autoimmune disorder characterized by central nervous system inflammation and demyelination, features reminiscent of the human disease, multiple sclerosis (MS). Prior work in the EAE model has suggested that encephalitogenic T cells are of the T helper (Th)-1 phenotype. Our group has performed several studies in the EAE model that suggest that a strategy for treating autoimmune disorders is to convert the pathogenic cells from the Th1 to Th2 phenotype. Peroxisome proliferator-activated receptors (PPARs) are members of a nuclear hormone receptor superfamily that include receptors for steroids, retinoids, and thyroid hormone, all of which are known to affect the immune response. Recently, we examined the role of PPARgamma in EAE and observed that administration of the PPARgamma agonist 15-deoxy-Delta(12,14) prostaglandin J2 exerted a significant therapeutic effect predominantly by inhibiting the activation and expansion of encephalitogenic T cells. One potential advantage in studying PPARalpha agonists is that they have been very well tolerated when used in humans to treat conditions such as elevated triglycerides. Building on prior work in immune deviation and with PPAR agonists, we have demonstrated that PPARalpha agonists can alter the cytokine phenotype of myelin-reactive T cells, alter their encephalitogenicity, and be useful in the treatment of EAE. The fact that PPARalpha agonists have been used as therapeutic agents in humans to treat metabolic conditions for over 25 years with little toxicity makes them attractive candidates for use as adjunctive therapies in MS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I124,I124)","v":14585313},{"$f":"(LEN($J124) - LEN(SUBSTITUTE(LOWER($J124),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J124) - LEN(SUBSTITUTE(LOWER($J124),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J124) - LEN(SUBSTITUTE(LOWER($J124),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B124:D124)","v":9},2003,"Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models.","Quadro",14585313,"Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models.    Abstract:   Retinoids (vitamin A and its derivatives) play an essential role in many biological functions. However mammals are incapable of de novo synthesis of vitamin A and must acquire it from the diet. In the intestine, dietary retinoids are incorporated in chylomicrons as retinyl esters, along with other dietary lipids. The majority of dietary retinoid is cleared by and stored within the liver. To meet vitamin A requirements of tissues, the liver secretes retinol (vitamin A alcohol) into the circulation bound to its sole specific carrier protein, retinol-binding protein (RBP). The single known function of this protein is to transport retinol from the hepatic stores to target tissues. Over the last few years, the generation of knockout and transgenic mouse models has significantly contributed to our understanding of RBP function in the metabolism of vitamin A. We discuss below the role of RBP in maintaining normal vision and a steady flux of retinol throughout the body in times of need."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I125,I125)","v":12876835},{"$f":"(LEN($J125) - LEN(SUBSTITUTE(LOWER($J125),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J125) - LEN(SUBSTITUTE(LOWER($J125),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J125) - LEN(SUBSTITUTE(LOWER($J125),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B125:D125)","v":9},2003,"Genetic defects in vitamin A metabolism of the retinal pigment epithelium.","Thompson",12876835,"Genetic defects in vitamin A metabolism of the retinal pigment epithelium.    Abstract:   The metabolism of vitamin A and cycling of retinoids between the retinal pigment epithelium (RPE) and the neural retina is a complex process involving a specialized enzymes and proteins. Mutations in a number of the corresponding genes are responsible for various forms of inherited retinal dystrophy and dysfunction. Research into the causes and treatment of retinal diseases resulting from defects in vitamin A metabolism is currently the subject of intense interest, since disorders affecting RPE function are, in principle, more accessible to therapeutic intervention than those affecting the proteins of the photoreceptor cells. In this chapter we present an overview of the visual cycle, as well as the function of the known RPE genes involved in the conversion of vitamin A (all-trans retinol) to 11-cis retinal, the chromophore of the visual pigments. We describe the identification of disease-associated mutations in this set of genes in patients with diverse forms of retinal dystrophy and dysfunction, as well as the spectrum of mutations and associated phenotypes. We also discuss the results of recent studies using animal models of the disease caused by mutations of RPE65. On the basis of these advances, it is hoped that patients with defects in RPE vitamin A metabolism will be among the first successfully treated by targeted therapies likely to become available in the near future."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I126,I126)","v":12514312},{"$f":"(LEN($J126) - LEN(SUBSTITUTE(LOWER($J126),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J126) - LEN(SUBSTITUTE(LOWER($J126),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J126) - LEN(SUBSTITUTE(LOWER($J126),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B126:D126)","v":9},2003,"Retinoid production and catabolism: role of diet in regulating retinol esterification and retinoic Acid oxidation.","Ross",12514312,"Retinoid production and catabolism: role of diet in regulating retinol esterification and retinoic Acid oxidation.    Abstract:   Retinoic acid (RA), a transcriptionally active metabolite of vitamin A (retinol), activates two families of nuclear retinoid receptors that have the potential to regulate the expression of a large number of genes. Although it may be presumed that the concentration of RA is closely regulated, the mechanisms underlying such regulation are not well understood. Our research has examined the expression and function of two enzymes, lecithin:retinol acyltransferase (LRAT) and a cytochrome P450, CYP26, in the liver and lung of rats and mice, over a wide range of vitamin A status or after treatment of vitamin A-deficient animals with exogenous RA. LRAT expression at both the mRNA and protein activity levels and CYP26 mRNA are regulated by dietary vitamin A in a steady-state model and are acutely regulated by RA in an acute repletion model. In the liver, the level of expression of LRAT and CYP26 is as follows: vitamin A deficient lt; vitamin A marginal lt; vitamin A adequate lt; vitamin A supplemented lt; RA treated. The regulation of LRAT shows strong tissue specificity (highly regulated in liver and lung but not in small intestine), whereas CYP26 is strongly regulated in the liver, lung, testis and intestine. RA may function as a signal of the bodys vitamin A adequacy. The regulated expression of LRAT, CYP26 and other genes by RA may provide a sensitive response mechanism that overall serves to adjust the metabolism of vitamin A to maintain retinoid homeostasis and prevent retinoid excess."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I127,I127)","v":12042703},{"$f":"(LEN($J127) - LEN(SUBSTITUTE(LOWER($J127),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J127) - LEN(SUBSTITUTE(LOWER($J127),LOWER(C$3),\"\")))/LEN(C$3)","v":6},{"$f":"(LEN($J127) - LEN(SUBSTITUTE(LOWER($J127),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B127:D127)","v":9},2002,"Role of peroxisome proliferator-activated receptor-gamma in hematologic malignancies.","Konopleva",12042703,"Role of peroxisome proliferator-activated receptor-gamma in hematologic malignancies.    Abstract:   Members of the nuclear receptor superfamily, including retinoic acid receptors (RARs), retinoid X receptors (RXRs), and vitamin D receptors (VDRs), are transcription factors that control many important cellular functions, and their ligands are widely used in several clinical indications. The latest family member is the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is highly expressed in normal monocytes, different leukemias, and epithelial malignancies. PPARgamma ligands have been developed and signal differentiation, growth arrest, and apoptosis. PPARgamma forms heterodimers with RXR, and ligation of both receptors is required for maximal signaling. PPARgamma signaling, its expression in hematologic malignancies, and role in differentiation are discussed. Interactions of PPARgamma with X-RARalpha, protein kinase R (PKR), PTEN, and mitogen-activated protein kinase (MAPK) have been described. PPARgamma ligands have been developed for the management of diabetes, but new and more potent ligands, including triterpenoids, are being investigated as therapeutic agents for epithelial and hematologic malignancies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I128,I128)","v":11729749},{"$f":"(LEN($J128) - LEN(SUBSTITUTE(LOWER($J128),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J128) - LEN(SUBSTITUTE(LOWER($J128),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J128) - LEN(SUBSTITUTE(LOWER($J128),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B128:D128)","v":9},2001,"Cooperation of liver cells in health and disease.","Kmieć",11729749,"Cooperation of liver cells in health and disease.    Abstract:   The liver lobule is formed by parenchymal cells, i.e., hepatocytes and nonparenchymal cells. In contrast to hepatocytes that occupy almost 80% of the total liver volume and perform the majority of numerous liver functions, nonparenchymal liver cells, which contribute only 6.5% to the liver volume, but 40% to the total number of liver cells, are localized in the sinusoidal compartment of the tissue. The walls of hepatic sinusoid are lined by three different cell types: sinusoidal endothelial cells (SEC), Kupffer cells (KC), and hepatic stellate cells (HSC, formerly known as fat-storing cells, Ito cells, lipocytes, perisinusoidal cells, or vitamin A-rich cells). Additionally, intrahepatic lymphocytes (IHL), including pit cells, i.e., liver-specific natural killer cells, are often present in the sinusoidal lumen. It has been increasingly recognized that both under normal and pathological conditions, many hepatocyte functions are regulated by substances released from neighboring nonparenchymal cells. Liver sinusoidal endothelial cells constitute the lining or wall of the hepatic sinusoid. They perform important filtration function due to the presence of small fenestrations that allow free diffusion of many substances, but not of particles of the size of chylomicrons, between the blood and the hepatocyte surface. SEC show huge endocytic capacity for many ligands including glycoproteins, components of the extracellular matrix (ECM; such as hyaluronate, collagen fragments, fibronectin, or chondroitin sulphate proteoglycan), immune complexes, transferrin and ceruloplasmin. SEC may function as antigen-presenting cells (APC) in the context of both MHC-I and MHC-II restriction with the resulting development of antigen-specific T-cell tolerance. They are also active in the secretion of cytokines, eicosanoids (i.e., prostanoids and leukotrienes), endothelin-1, nitric oxide, and some ECM components. Kupffer cells are intrasinusoidally located tissue macrophages with a pronounced endocytic and phagocytic capacity. They are in constant contact with gut-derived particulate materials and soluble bacterial products so that a subthreshold level of their activation in the normal liver may be anticipated. Hepatic macrophages secrete potent mediators of the inflammatory response (reactive oxygen species, eicosanoids, nitric oxide, carbon monoxide, TNF-alpha, and other cytokines), and thus control the early phase of liver inflammation, playing an important part in innate immune defense. High exposure of Kupffer cells to bacterial products, especially endotoxin (lipopolysaccharide, LPS), can lead to the intensive production of inflammatory mediators, and ultimately to liver injury. Besides typical macrophage activities, Kupffer cells play an important role in the clearance of senescent and damaged erythrocytes. Liver macrophages modulate immune responses via antigen presentation, suppression of T-cell activation by antigen-presenting sinusoidal endothelial cells via paracrine actions of IL-10, prostanoids, and TNF-alpha, and participation in the development of oral tolerance to bacterial superantigens. Moreover, during liver injury and inflammation, Kupffer cells secrete enzymes and cytokines that may damage hepatocytes, and are active in the remodeling of extracellular matrix. Hepatic stellate cells are present in the perisinusoidal space. They are characterized by abundance of intracytoplasmic fat droplets and the presence of well-branched cytoplasmic processes, which embrace endothelial cells and provide focally a double lining for sinusoid. In the normal liver HSC store vitamin A, control turnover of extracellular matrix, and regulate the contractility of sinusoids. Acute damage to hepatocytes activates transformation of quiescent stellate cells into myofibroblast-like cells that play a key role in the development of inflammatory fibrotic response. Pit cells represent a liver-associated population of large granular lymphocytes, i.e., natural killer (NK) cells. They spontaneously kill a variety of tumor cells in an MHC-unrestricted way, and this antitumor activity may be enhanced by the secretion of interferon-gamma. Besides pit cells, the adult liver contains other subpopulations of lymphocytes such as gamma delta T cells, and both quot;conventionalquot; and quot;unconventionalquot; alpha beta T cells, the latter containing liver-specific NK T cells. The development of methods for the isolation and culture of main liver cell types allowed to demonstrate that both nonparenchymal and parenchymal cells secrete tens of mediators that exert multiple paracrine and autocrine actions. Co-culture experiments and analyses of the effects of conditioned media on cultures of another liver cell type have enabled the identification of many substances released from non-parenchymal liver cells that evidently regulate some important functions of neighboring hepatocytes and non-hepatocytes. To the key mediators involved in the intercellular communication in the liver belong prostanoids, nitric oxide, endothelin-1, TNF-alpha, interleukins, and chemokines, many growth factors (TGF-beta, PDGF, IGF-I, HGF), and reactive oxygen species (ROS). Paradoxically, the cooperation of liver cells is better understood under some pathological conditions (i.e., in experimental models of liver injury) than in normal liver due to the possibility of comparing cellular phenotype under in vivo and in vitro conditions with the functions of the injured organ. The regulation of vitamin A metabolism provides an example of the physiological role for cellular cross-talk in the normal liver. The majority (up to 80%) of the total body vitamin A is stored in the liver as long-chain fatty acid esters of retinal, serving as the main source of retinoids that are utilized by all tissues throughout the body. Hepatocytes are directly involved in the uptake from blood of chylomicron remnants, and the synthesis of retinol-binding protein that transfers retinol to other tissues. However, more than 80% of the liver retinoids are stored in lipid droplets of hepatic stellate cells. HSC are capable of both uptake and release of retinol depending on the bodys retinol status. The activity of some major enzymes of vitamin A metabolism have been found to be many times higher per protein basis in stellate cells than in hepatocytes. Despite progress in the understanding of the roles played by these two cell types in hepatic retinoid metabolism, the way in which retinoids move between the parenchymal cells, stellate cells, and blood plasma has not been fully elucidated. Sinusoidal blood flow is, to a great extent, regulated by hepatic stellate cells that can contract due to the presence of smooth muscle alpha-actin. The main vasoactive substances that affect constriction or relaxation of HSC derive both from distant sources and from neighboring hepatocytes (carbon monoxide, leukotrienes), endothelial cells (endothelin, nitric oxide, prostaglandins), Kupffer cells (prostaglandins, NO), and stellate cells themselves (endothelin, NO). The cellular cross-talk reflected by the fine-tuned modulation of sinusoidal contraction becomes disturbed under pathological conditions, such as endotoxemia or liver fibrosis, through the excess synthesis of vasoregulatory compounds and the involvement of additional mediators acting in a paracrine way. The liver is an important source of some growth factors and growth factor-binding proteins. Although hepatocytes synthesize the bulk of insulin-like growth factor I (IGF-I), also other types of nonparenchymal liver cells may produce this peptide. Cell-specific expression of distinct IGF-binding proteins observed in the rat and human liver provides the potential for specific regulation of hepatic IGF-I synthesis not only by growth hormone, insulin, and IGF-I, but also by cytokines released from activated Kupffer (IL-1, TNF-alpha, TGF-beta) or stellate cells (TGF-alpha, TGF-beta). Hepatic stellate cells may affect turnover of hepatocytes through the synthesis of potent positive as well as negative signals such as, respectively, hepatocyte-growth-factor or TGF-beta. Although hepatocytes seem not to produce TGF-beta, a pleiotropic cytokine synthesized and secreted in the latent form by Kupffer and stellate cells, they may contribute to its actions in the liver by the intracellular activation of latent TGF-beta, and secretion of the biologically active isoform. Many mediators that reach the liver during inflammatory processes, such as endotoxins, immune-complexes, anaphylatoxins, and PAF, increase glucose output in the perfused liver, but fail to do so in isolated hepatocytes, acting indirectly via prostaglandins released from Kupffer cells. In the liver, prostaglandins synthesized from arachidonic acid mainly in Kupffer cells in a response to various inflammatory stimuli, modulate hepatic glucose metabolism by increasing glycogenolysis in adjacent hepatocytes. The release of glucose from glycogen supports the increased demand for energetic fuel by the inflammatory cells such as leukocytes, and additionally enables enhanced glucose turnover in sinusoidal endothelial cells and Kupffer cells which is necessary for effective defense of these cells against invading microorganisms and oxidative stress in the liver. Leukotrienes, another oxidation product of arachidonic acid, have vasoconstrictive, cholestatic, and metabolic effects in the liver. A transcellular synthesis of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) functions in the liver: LTA4, an important intermediate, is synthesized in Kupffer cells, taken up by hepatocytes, converted into the potent LTC4, and then released into extracellular space, acting in a paracrine way on Kupffer and sinusoidal endothelial cells. Thus, hepatocytes are target cells for the action of eicosanoids and the site of their transformation and degradation, but can not directly oxidate arachidonic acid to eicosanoids. (ABSTRACT TRUNCATED)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I129,I129)","v":11082709},{"$f":"(LEN($J129) - LEN(SUBSTITUTE(LOWER($J129),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J129) - LEN(SUBSTITUTE(LOWER($J129),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J129) - LEN(SUBSTITUTE(LOWER($J129),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B129:D129)","v":9},2000,"[From cancer prevention to cancer treatment].","Shudo",11082709,"[From cancer prevention to cancer treatment].    Abstract:   Cancer is a common life-threatening disease. Prevention and therapy of the disease are the desire of everybody. This paper summarizes our attempt to the tough challenge. Chronologically we began the study of carcinogenesis, and then turned to the research of anticancer agents. Identification of food mutagens was extensively studied. Once they were identified, the mechanism of nucleic acid modifications by these mutagens had been studied. The modification study gave information on the nucleic acid modification by mitomycin and bleomycin. The structure-activity relationship study of phorbol esters and teleocidines whose tumor promotion is epigenetic, was extensively studied. On the other hand, retinoic acid, a vitamin A metabolite, suppresses the epigenetic tumor promotion. This suggests that an epigenetically active compound rather than a cytotoxic anticancer agent can be used for tumor suppression. In the retinoid research, we found a number of characteristic new active substances which may be of therapeutic use: some of them are in the clinical trial stages in the field of dermatology and cancer. During the chemical study of retinoids, we encountered the retinoic acid receptor, coded by the retinoic acid receptor (RAR) gene which had just reported. Further retinoid research yielded retinoids antagonists, and then RXR(retinoic acid-X-receptor)-agonists and RXR-antagonists. These ligands have a big potential in the therapy of diabetes and obesity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I130,I130)","v":10946560},{"$f":"(LEN($J130) - LEN(SUBSTITUTE(LOWER($J130),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J130) - LEN(SUBSTITUTE(LOWER($J130),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J130) - LEN(SUBSTITUTE(LOWER($J130),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B130:D130)","v":9},2000,"A gene knockout corroborates the integral function of cellular retinol-binding protein in retinoid metabolism.","Napoli",10946560,"A gene knockout corroborates the integral function of cellular retinol-binding protein in retinoid metabolism.    Abstract:   Continually expanding evidence has moved inexorably toward establishing key functions for cellular retinol-binding protein (CRBP) in retinoid metabolism. These experimental data integrate into a model of CRBP as a chaperone that protects retinol from the cellular milieu and interacts with certain retinoid-metabolizing enzymes. Mutant mice with an inactivated CRBP gene show decreased liver retinyl ester storage, a shorter elimination half-life of liver retinoids, and predisposition to vitamin A deficiency. No morphologic phenotype was observed until vitamin A was exhausted. Although the mechanisms underlying diminished vitamin A in the CRBP-null mice have not been elucidated, the observations support the model of CRBP as a chaperone of retinoid metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I131,I131)","v":10357725},{"$f":"(LEN($J131) - LEN(SUBSTITUTE(LOWER($J131),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J131) - LEN(SUBSTITUTE(LOWER($J131),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J131) - LEN(SUBSTITUTE(LOWER($J131),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B131:D131)","v":9},1999,"Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity.","Leo",10357725,"Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity.    Abstract:   Isozymes of alcohol and other dehydrogenases convert ethanol and retinol to their corresponding aldehydes in vitro. In addition, new pathways of retinol metabolism have been described in hepatic microsomes that involve, in part, cytochrome P450s, which can also metabolize various drugs. In view of these overlapping metabolic pathways, it is not surprising that multiple interactions between retinol, ethanol, and other drugs occur. Accordingly, prolonged use of alcohol, drugs, or both, results not only in decreased dietary intake of retinoids and carotenoids, but also accelerates the breakdown of retinol through cross-induction of degradative enzymes. There is also competition between ethanol and retinoic acid precursors. Depletion ensues, with associated hepatic and extrahepatic pathology, including carcinogenesis and contribution to fetal defects. Correction of deficiency through vitamin A supplementation has been advocated. It is, however, complicated by the intrinsic hepatotoxicity of retinol, which is potentiated by concomitant alcohol consumption. By contrast, beta-carotene, a precursor of vitamin A, was considered innocuous until recently, when it was found to also interact with ethanol, which interferes with its conversion to retinol. Furthermore, the combination of beta-carotene with ethanol results in hepatotoxicity. Moreover, in smokers who also consume alcohol, beta-carotene supplementation promotes pulmonary cancer and, possibly, cardiovascular complications. Experimentally, beta-carotene toxicity was exacerbated when administered as part of beadlets. Thus ethanol, while promoting a deficiency of vitamin A also enhances its toxicity as well as that of beta-carotene. This narrowing of the therapeutic window for retinol and beta-carotene must be taken into account when formulating treatments aimed at correcting vitamin A deficiency, especially in drinking populations."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I132,I132)","v":9290094},{"$f":"(LEN($J132) - LEN(SUBSTITUTE(LOWER($J132),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J132) - LEN(SUBSTITUTE(LOWER($J132),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J132) - LEN(SUBSTITUTE(LOWER($J132),LOWER(D$3),\"\")))/LEN(D$3)","v":5},{"$f":"SUM(B132:D132)","v":9},1997,"Vitamin A homeostasis and diabetes mellitus.","Basu",9290094,"Vitamin A homeostasis and diabetes mellitus.    Abstract:   Recent studies have shown that plasma concentrations of vitamin A (retinol) and its carrier proteins, retinol-binding protein (RBP), and transthyretin (TTR), are decreased in human subjects with insulin-dependent (IDDM) but not with noninsulin dependent diabetes mellitus (NIDDM). Rats made diabetic with streptozotocin (STZ) have also been shown to have reduced levels of plasma vitamin A while its hepatic concentrations elevate. The circulatory vitamin A levels remained low while its hepatic concentrations were further elevated following supplementation of the vitamin. The reduced circulatory status of vitamin A in diabetic animals was not caused by its impaired intestinal absorption. Further experimental studies have pointed to the fact that IDDM is associated with a deficiency of vitamin A, which is secondary to an impaired transport mechanism of this vitamin from its hepatic storage to the target site, such as retina of the eyes. The diabetes-associated changes in vitamin A metabolism were reserved to normal by insulin treatment. The underlying cause for decreased metabolic availability in uncontrolled diabetes, is not clearly understood. It appears that the increased hepatic store of vitamin A is attributed to a decreased availability of its carrier proteins. Subnormal vitamin A status in poorly controlled diabetic subjects may not respond to vitamin A supplementation, rather it may increase its load in the liver leading to hepatoxicity. These results clearly suggest that there is need for further research identifying the importance of vitamin A in diabetes mellitus."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I133,I133)","v":8810827},{"$f":"(LEN($J133) - LEN(SUBSTITUTE(LOWER($J133),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J133) - LEN(SUBSTITUTE(LOWER($J133),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J133) - LEN(SUBSTITUTE(LOWER($J133),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B133:D133)","v":9},1996,"The regulation of retinoic acid formation.","Wolf",8810827,"The regulation of retinoic acid formation.    Abstract:   Rat liver microsomal as well as cytosolic retinol dehydrogenases from cellular retinal-binding protein (CRBP)-retinal from CRBP-retinol. A cytosolic dehydrogenase transforms retinal into retinoic acid. Apo-CRBP and ethanol inhibit the cytosolic but not the microsomal retinol dehydrogenase, the latter being the primary enzyme in the rate-limiting step in retinoic acid synthesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I134,I134)","v":7617333},{"$f":"(LEN($J134) - LEN(SUBSTITUTE(LOWER($J134),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J134) - LEN(SUBSTITUTE(LOWER($J134),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J134) - LEN(SUBSTITUTE(LOWER($J134),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B134:D134)","v":9},1995,"Use of acitretin for the skin complications in renal transplant recipients.","Yuan",7617333,"Use of acitretin for the skin complications in renal transplant recipients.    Abstract:    AIM : To review our experience using acitretin for the skin complications in renal transplant recipients.  METHODS : Fifteen longterm caucasian renal transplant recipients suffering skin complications were treated with acitretin (10-50 mg daily), a second generation retinoid. Indications for its use were progressive actinic keratoses, widespread warts or recurrent skin malignancies. The therapeutic benefit was assessed by the general condition of of the skin and the number of skin malignancies excised, and the side effects by regular enquiry, skin examination and laboratory tests.  RESULTS : All 15 patients reported that the skin became softer and smoother. Actinic keratoses and warts improved or disappeared. Six patients had been on acitretin for over 12 months. The number of malignancies decreased in four of these six patients. Nine patients had cutaneous side effects due to acitretin necessitating a reduction in dose in five patients and discontinuation in the remaining four patients. No patient had any disturbance of their liver or renal function tests or lipid profile. No interaction was found between cyclosporin A and acitretin (seven patients).  CONCLUSIONS : Most patients treated with acitretin experienced subjective improvement and actinic keratoses and warts improved or disappeared. Its effect on the skin malignancy rate was variable. Acitretin was reasonably well tolerated. The benefits of this drug remain anecdotal, making a prospective, multicentre, placebo controlled study essential."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I135,I135)","v":8304928},{"$f":"(LEN($J135) - LEN(SUBSTITUTE(LOWER($J135),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J135) - LEN(SUBSTITUTE(LOWER($J135),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J135) - LEN(SUBSTITUTE(LOWER($J135),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B135:D135)","v":9},1993,"Multiple mechanisms: the example of vitamin A.","De Luca",8304928,"Multiple mechanisms: the example of vitamin A.    Abstract:   It has become evident that retinoids control differentiation, embryonal development, and tumorigenesis. In animal models, skin tumorigenesis has been shown to be prevented by retinoids, which in this organ function as antitumor promoters in the two-stage system using 7,12-dimethylbenz(a)anthracene (DMBA) as the initiator, and 12-tetradecanoyl-phorbol-13-acetate (TPA) as tumor promoter. Even though pharmacological doses applied topically appear to inhibit tumor formation, we found that papilloma and keratoacanthoma growth required physiological concentrations of retinoic acid and that vitamin A deficiency was even more effective than excess retinoid in inhibiting SENCAR mouse skin tumorigenesis. In human beings, oral administration of retinoic acid after tumor resection was effective in inhibiting the appearance of new tumors on the skin of four patients with Xeroderma Pigmentosum, and was effective in preventing new primary tumor formations in patients treated for head and neck cancer. The newly-discovered nuclear receptors for retinoic acid function as transcriptional activators for several genes. In patients with acute promyelocytic leukemia presenting with a reciprocal translocation of chromosome 17 to chromosome 15, the breakpoint has been identified in the retinoic acid receptor alpha gene, which forms a fusion gene with a new gene termed myl, on chromosome 15. Treatment of the patients with retinoic acid causes complete remission of the APL. It also appears to generate cells that do not bear the translocation. Therefore, retinoids may well function as modulators of carcinogenesis both at the promotion level as well as by causing differentiation of neoplastically transformed cells."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I136,I136)","v":3721869},{"$f":"(LEN($J136) - LEN(SUBSTITUTE(LOWER($J136),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J136) - LEN(SUBSTITUTE(LOWER($J136),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J136) - LEN(SUBSTITUTE(LOWER($J136),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B136:D136)","v":9},1986,"[Retinoids and lipid metabolism].","Melnik",3721869,"[Retinoids and lipid metabolism].    Abstract:   Since systemic administration of synthetic retinoids was introduced into dermatology and oncology, side-effects of synthetic vitamin-A derivatives on lipid and lipoprotein metabolism have become apparent. Retinoids of the first and second generation, 13-cis-retinoic acid and etretinate, are capable of inducing secondary hyperlipoproteinemias. For further evaluation of the atherogenic risk of retinoid-induced hyperlipoproteinemias, the most relevant effects of natural and synthetic retinoids on lipid metabolism as well as the interactions between lipid and retinoid metabolism are considered in this review."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I137,I137)","v":6279709},{"$f":"(LEN($J137) - LEN(SUBSTITUTE(LOWER($J137),LOWER(B$3),\"\")))/LEN(B$3)","v":9},{"$f":"(LEN($J137) - LEN(SUBSTITUTE(LOWER($J137),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J137) - LEN(SUBSTITUTE(LOWER($J137),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B137:D137)","v":9},1982,"Retinoid-binding proteins.","Goodman",6279709,"Retinoid-binding proteins.    Abstract:   Much has been learned during the past decade about the specific retinoid-binding proteins that exist in plasma and in the intracellular compartment in a number of tissues. Vitamin A is mobilized from liver stores and transported in plasma in the form of the lipid alcohol retinol, bound to a specific transport protein, retinol-binding protein (RBP). A great deal is now known about the chemical structure, metabolism, and biologic roles of RBP. A number of tissues of rats, humans, and other species contain soluble binding proteins with specificity for either retinol (cellular retinol-binding protein, CRBP) or retinoic acid (cellular retinoic acid-binding protein, CRABP). These intracellular proteins have been purified from several tissues and partly characterized. This paper provides a concise review of our current knowledge about the three retinoid-binding proteins, RBP, CRBP, and CRABP."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I138,I138)","v":27336223},{"$f":"(LEN($J138) - LEN(SUBSTITUTE(LOWER($J138),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J138) - LEN(SUBSTITUTE(LOWER($J138),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J138) - LEN(SUBSTITUTE(LOWER($J138),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B138:D138)","v":8},2016,"Therapeutic use of selective synthetic ligands for retinoic acid receptors: a patent review.","Marchwicka",27336223,"Therapeutic use of selective synthetic ligands for retinoic acid receptors: a patent review.    Abstract:    INTRODUCTION : Differentiation therapy using all-trans retinoic acid (ATRA) revolutionised the treatment of acute promyelocytic leukaemia to such an extent that it is now one of the most curable types of leukaemia, with ATRA and anthracycline-based chemotherapy providing cure rates above 80%. Isotretinoin is used to treat chronic acne. Here, we examine the information described in recent patents and the extent to which new findings are influencing extending retinoid-based differentiation therapy to other cancers, as well as the development of new therapies for other disorders.  AREAS COVERED : A search has been performed on the literature and worldwide patents filed during 2014 to the present time, focusing on synthetic agonists and antagonists of retinoic acid receptors and novel compositions for the delivery of these agents.  EXPERT OPINION : New potential therapeutic applications have been described, including lung, breast and head and neck cancers, T cell lymphoma and neurodegenerative, metabolic, ophthalmic, muscle, and inflammatory disorders. Recent patents have described the means to maximise retinoid activity. Two decades of efforts to extend retinoid-based therapies have been disappointing and new synthetic retinoids, target diseases and modes of delivery may well resolve this long standing issue."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I139,I139)","v":26723986},{"$f":"(LEN($J139) - LEN(SUBSTITUTE(LOWER($J139),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J139) - LEN(SUBSTITUTE(LOWER($J139),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J139) - LEN(SUBSTITUTE(LOWER($J139),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B139:D139)","v":8},2016,"Retinoids and motor neuron disease: Potential role in amyotrophic lateral sclerosis.","Riancho",26723986,"Retinoids and motor neuron disease: Potential role in amyotrophic lateral sclerosis.    Abstract:   Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MN). This fatal disease is characterized by progressive muscular atrophy and unfortunately it does not have an effective treatment. Although a small proportion of ALS cases have a familiar origin, the vast majority of them are thought to have a sporadic origin. Although the pathogenesis of ALS has not been fully elucidated, various disorders in different cellular functions such as gene expression, protein metabolism, axonal transport and glial cell disorders have been linked to MN degeneration. Among them, proteostasis is one of the best studied. Retinoids are vitamin A-derived substances that play a crucial role in embryogenesis, development, programmed cell death and other cellular functions. Retinoid agonists behave as transcription factors throughout the activation of the nuclear retinoid receptors. Several reports in the literature suggest that retinoids are involved in proteostasis regulation, by modulating its two major pathways, the ubiquitin-proteasome system and the autophagy-lysosome response. Additionally, there are some evidences for a role of retinoids themselves, in ALS pathogenesis. In this review, we discuss the importance of proteostasis disruption as a trigger for MN degeneration and the capability of retinoids to modulate it, as well as the potential therapeutic role of retinoids as a new therapy in ALS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I140,I140)","v":25775629},{"$f":"(LEN($J140) - LEN(SUBSTITUTE(LOWER($J140),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J140) - LEN(SUBSTITUTE(LOWER($J140),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J140) - LEN(SUBSTITUTE(LOWER($J140),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B140:D140)","v":8},2015,"Acitretin-induced hepatitis: when to monitor cholestatic enzymes.","Sauder",25775629,"Acitretin-induced hepatitis: when to monitor cholestatic enzymes.    Abstract:    IMPORTANCE : Acitretin is a systemic retinoid that is used in dermatology for a variety of conditions. A well-recognized potential adverse event from acitretin is elevated transaminases, indicating acute hepatocyte damage. Less well known is the possible cholestatic injury that can occur, signaled by elevated γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP).  OBSERVATIONS : Our patient presented with an acute acitretin-induced hepatitis with a mixed pattern of elevated transaminases as well as GGT and ALP. A literature review demonstrated that most cases of acitretin-induced hepatitis, outside clinical trials, describe patients with a similar mixed hepatitis pattern.  CONCLUSIONS : This is the first literature review on acitretin-induced hepatitis. Although acitretin-induced hepatoxicity is rare, the seemingly unusual presentation of a mixed pattern of hepatocyte injury and cholestasis may be more common than previously thought. The findings should encourage clinicians not only to monitor transaminases but also to consider measuring cholestatic enzymes (ALP/GGT) in patients with transaminase abnormalities."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I141,I141)","v":25540407},{"$f":"(LEN($J141) - LEN(SUBSTITUTE(LOWER($J141),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J141) - LEN(SUBSTITUTE(LOWER($J141),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J141) - LEN(SUBSTITUTE(LOWER($J141),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B141:D141)","v":8},2015,"Vitamin A kinetics in neonatal rats vs. adult rats: comparisons from model-based compartmental analysis.","Tan",25540407,"Vitamin A kinetics in neonatal rats vs. adult rats: comparisons from model-based compartmental analysis.    Abstract:   A critical role for vitamin A (VA) in development is well established, but still relatively little is known about whole-body VA metabolism in early postnatal life. Recently, methods of mathematical modeling have begun to shed light on retinol kinetics in the postnatal growth period and on the effect of retinoid supplementation on retinol kinetics. Comparison of kinetic parameters from tracer studies in neonatal rats with those previously determined in models of VA metabolism in the adult suggests both similarities and differences in the relative transfer rates of plasma retinol to extrahepatic tissues, resulting in similarities and differences in kinetic parameters and inferences about physiologic processes. Similarities between neonatal and adult models include the capacity for efficient digestion and absorption of VA; characteristics of a high-response system; extensive retinol recycling among liver, plasma, and extrahepatic tissues; and comparable VA disposal rates. Differences between neonatal and adult models include that, in neonates, retinol turnover is faster and retinol recycling is much more extensive; there is a greater role for extrahepatic tissues in the uptake of chylomicron VA; and the intestine plays an important role in chylomicron VA uptake, especially in neonatal rats treated with a supplement containing VA. In summary, retinol kinetic modeling in the neonatal rat has provided a first view of whole-body VA metabolism in this age group and suggests that VA kinetics in neonatal rats differs in many ways from that in adults, perhaps reflecting an adaption to the lower VA concentration found in neonates compared with adults."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I142,I142)","v":24755475},{"$f":"(LEN($J142) - LEN(SUBSTITUTE(LOWER($J142),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J142) - LEN(SUBSTITUTE(LOWER($J142),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J142) - LEN(SUBSTITUTE(LOWER($J142),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B142:D142)","v":8},2014,"Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study.","Kang",24755475,"Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study.    Abstract:    BACKGROUND : Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study.  CASE PRESENTATION : On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patients condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity.  CONCLUSIONS : After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I143,I143)","v":26237391},{"$f":"(LEN($J143) - LEN(SUBSTITUTE(LOWER($J143),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J143) - LEN(SUBSTITUTE(LOWER($J143),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J143) - LEN(SUBSTITUTE(LOWER($J143),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B143:D143)","v":8},2014,"Molecular Mechanisms of Retinoid Receptors in Diabetes-Induced Cardiac Remodeling.","Pan",26237391,"Molecular Mechanisms of Retinoid Receptors in Diabetes-Induced Cardiac Remodeling.    Abstract:   Diabetic cardiomyopathy (DCM), a significant contributor to morbidity and mortality in diabetic patients, is characterized by ventricular dysfunction, in the absence of coronary atherosclerosis and hypertension. There is no specific therapeutic strategy to effectively treat patients with DCM, due to a lack of a mechanistic understanding of the disease process. Retinoic acid, the active metabolite of vitamin A, is involved in a wide range of biological processes, through binding and activation of nuclear receptors: retinoic acid receptors (RAR) and retinoid X receptors (RXR). RAR/RXR-mediated signaling has been implicated in the regulation of glucose and lipid metabolism. Recently, it has been reported that activation of RAR/RXR has an important role in preventing the development of diabetic cardiomyopathy, through improving cardiac insulin resistance, inhibition of intracellular oxidative stress, NF-κB-mediated inflammatory responses and the renin-angiotensin system. Moreover, downregulated RAR/RXR signaling has been demonstrated in diabetic myocardium, suggesting that impaired RAR/RXR signaling may be a trigger to accelerate diabetes-induced development of DCM. Understanding the molecular mechanisms of retinoid receptors in the regulation of cardiac metabolism and remodeling under diabetic conditions is important in providing the impetus for generating novel therapeutic approaches for the prevention and treatment of diabetes-induced cardiac complications and heart failure."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I144,I144)","v":24362249},{"$f":"(LEN($J144) - LEN(SUBSTITUTE(LOWER($J144),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J144) - LEN(SUBSTITUTE(LOWER($J144),LOWER(C$3),\"\")))/LEN(C$3)","v":8},{"$f":"(LEN($J144) - LEN(SUBSTITUTE(LOWER($J144),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B144:D144)","v":8},2014,"Regulation of energy metabolism by long-chain fatty acids.","Nakamura",24362249,"Regulation of energy metabolism by long-chain fatty acids.    Abstract:   In mammals, excess energy is stored primarily as triglycerides, which are mobilized when energy demands arise. This review mainly focuses on the role of long chain fatty acids (LCFAs) in regulating energy metabolism as ligands of peroxisome proliferator-activated receptors (PPARs). PPAR-alpha expressed primarily in liver is essential for metabolic adaptation to starvation by inducing genes for beta-oxidation and ketogenesis and by downregulating energy expenditure through fibroblast growth factor 21. PPAR-delta is highly expressed in skeletal muscle and induces genes for LCFA oxidation during fasting and endurance exercise. PPAR-delta also regulates glucose metabolism and mitochondrial biogenesis by inducing FOXO1 and PGC1-alpha. Genes targeted by PPAR-gamma in adipocytes suggest that PPAR-gamma senses incoming non-esterified LCFAs and induces the pathways to store LCFAs as triglycerides. Adiponectin, another important target of PPAR-gamma may act as a spacer between adipocytes to maintain their metabolic activity and insulin sensitivity. Another topic of this review is effects of skin LCFAs on energy metabolism. Specific LCFAs are required for the synthesis of skin lipids, which are essential for water barrier and thermal insulation functions of the skin. Disturbance of skin lipid metabolism often causes apparent resistance to developing obesity at the expense of normal skin function."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I145,I145)","v":23720297},{"$f":"(LEN($J145) - LEN(SUBSTITUTE(LOWER($J145),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J145) - LEN(SUBSTITUTE(LOWER($J145),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J145) - LEN(SUBSTITUTE(LOWER($J145),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B145:D145)","v":8},2013,"Vitamin a metabolism, action, and role in skeletal homeostasis.","Conaway",23720297,"Vitamin a metabolism, action, and role in skeletal homeostasis.    Abstract:   Vitamin A (retinol) is ingested as either retinyl esters or carotenoids and metabolized to active compounds such as 11-cis-retinal, which is important for vision, and all-trans-retinoic acid, which is the primary mediator of biological actions of vitamin A. All-trans-retinoic acid binds to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors. RAR-retinoid X receptor heterodimers function as transcription factors, binding RAR-responsive elements in promoters of different genes. Numerous cellular functions, including bone cell functions, are mediated by vitamin A; however, it has long been recognized that increased levels of vitamin A can have deleterious effects on bone, resulting in increased skeletal fragility. Bone mass is dependent on the balance between bone resorption and bone formation. A decrease in bone mass may be caused by either an excess of resorption or decreased bone formation. Early studies indicated that the primary skeletal effect of vitamin A was to increase bone resorption, but later studies have shown that vitamin A can not only stimulate the formation of bone-resorbing osteoclasts but also inhibit their formation. Effects of vitamin A on bone formation have not been studied in as great a detail and are not as well characterized as effects on bone resorption. Several epidemiological studies have shown an association between vitamin A, decreased bone mass, and osteoporotic fractures, but the data are not conclusive because other studies have found no associations, and some studies have suggested that vitamin A primarily promotes skeletal health. In this presentation, we have summarized how vitamin A is absorbed and metabolized and how it functions intracellularly. Vitamin A deficiency and excess are introduced, and detailed descriptions of clinical and preclinical studies of the effects of vitamin A on the skeleton are presented."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I146,I146)","v":23676507},{"$f":"(LEN($J146) - LEN(SUBSTITUTE(LOWER($J146),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J146) - LEN(SUBSTITUTE(LOWER($J146),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J146) - LEN(SUBSTITUTE(LOWER($J146),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B146:D146)","v":8},2014,"Isotretinoin maintenance therapy for glioblastoma: a retrospective review.","Chen",23676507,"Isotretinoin maintenance therapy for glioblastoma: a retrospective review.    Abstract:    OBJECTIVES : The current standard treatment of glioblastoma includes maximal safe surgical resection, radiation, and temozolomide. Although isotretinoin has been used for maintenance therapy to delay tumor recurrence, this approach has not been proven to be effective. The objectives of the study are to compare the overall survival, progression-free survival and tolerability of isotretinoin maintenance therapy in patients who received isotretinoin maintenance therapy to patients who did not receive this treatment.  METHODS : This study is a retrospective review of adult patients with glioblastoma treated at MD Anderson Cancer Center from 2004 to 2009. Patients who underwent surgical resection, radiation with concurrent temozolomide, and adjuvant treatment with temozolomide were included in the control group, and compared to similarly treated patients who received isotretinoin maintenance following adjuvant temozolomide.  RESULTS : Eighteen patients who received isotretinoin maintenance therapy and 70 control patients were included in the analysis. Progression-free survival was 25.3 months with maintenance therapy versus 8.3 months for those not receiving maintenance (p = 0.04). There was no difference in the 2-year or 3-year overall survival estimates (p = 0.11). The common toxicities of isotretinoin included dermatologic-, metabolic-, and psychiatric-related adverse effects.  CONCLUSIONS : Isotretinoin maintenance therapy was associated with increased progression-free survival, but did not increase the overall survival in this retrospective review. The potential benefit of maintenance therapy should be weighed against toxicities and negative impact on quality of life in this patient population."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I147,I147)","v":19118026},{"$f":"(LEN($J147) - LEN(SUBSTITUTE(LOWER($J147),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J147) - LEN(SUBSTITUTE(LOWER($J147),LOWER(C$3),\"\")))/LEN(C$3)","v":6},{"$f":"(LEN($J147) - LEN(SUBSTITUTE(LOWER($J147),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B147:D147)","v":8},2009,"Peroxisome proliferator-activated receptor gamma pathway targeting in carcinogenesis: implications for chemoprevention.","Ondrey",19118026,"Peroxisome proliferator-activated receptor gamma pathway targeting in carcinogenesis: implications for chemoprevention.    Abstract:   The peroxisome proliferator-activated receptor (PPAR) gamma is one member of the nuclear receptor superfamily that contains in excess of 80 described receptors. PPARgamma activators are a diverse group of agents that range from endogenous fatty acids or derivatives (linolenic, linoleic, and 15-deoxy-Delta(12,14)-prostaglandin J(2)) to Food and Drug Administration-approved thiazolidinedione drugs [pioglitazone (Actos) and rosiglitazone (Avandia)] for the treatment of diabetes. Once activated, PPARgamma will preferentially bind with retinoid X receptor alpha and signal antiproliferative, antiangiogenic, and prodifferentiation pathways in several tissue types, thus making it a highly useful target for down-regulation of carcinogenesis. Although PPAR-gamma activators show many anticancer effects on cell lines, their advancement into human advanced cancer clinical trials has met with limited success. This article will review translational findings in PPARgamma activation and targeting in carcinogenesis prevention as they relate to the potential use of PPARgamma activators clinically as cancer chemoprevention strategies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I148,I148)","v":17826041},{"$f":"(LEN($J148) - LEN(SUBSTITUTE(LOWER($J148),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J148) - LEN(SUBSTITUTE(LOWER($J148),LOWER(C$3),\"\")))/LEN(C$3)","v":3},{"$f":"(LEN($J148) - LEN(SUBSTITUTE(LOWER($J148),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B148:D148)","v":8},2007,"Diabetes mellitus and macrovascular disease: mechanisms and mediators.","Boyle",17826041,"Diabetes mellitus and macrovascular disease: mechanisms and mediators.    Abstract:   Atherosclerosis is a chronic inflammatory condition initiated in the endothelium in response to injury and maintained through the interactions between modified lipoproteins, macrophages, and arterial wall constituents. Risk for macrovascular disease is substantially increased in patients with type 2 diabetes mellitus. Factors underlying the link between insulin resistance/type 2 diabetes and macrovascular disease include reduced adiponectin concentration, increased expression of vascular cell adhesion molecule-1 and consequent adhesion of T-lymphocytes to the coronary endothelium, procoagulability with increased expression of plasminogen activator inhibitor-1 (PAI)-1, and instability of atherosclerotic plaques resulting from increased expression by macrophages of matrix metalloproteinases (MMPs). Thiazolidinediones (TZDs) are agonists of peroxisome proliferator-activated receptor (PPAR)-gamma and increase adiponectin. TZD therapy is associated with decreases in hepatic fat content and glycosylated hemoglobin and an increase in hepatic glucose disposal. TZDs lower circulating free fatty acid concentration and triglyceride content in the liver, but not in skeletal muscle. Effects of PPAR-gamma agonists in vitro and in animal models provide evidence for additional potential antiatherosclerotic benefits in patients with diabetes beyond the treatment of hyperglycemia and dyslipidemia, including the reduction of expression of macrophage MMPs and scavenger receptor-1, and indirect reduction of PAI-1 and inhibition of vascular smooth muscle cell proliferation, via suppression of type 1 angiotensin-2 receptor expression. Dual PPAR-alpha/gamma agonists, retinoid receptor agonists, and, to a lesser extent, TZDs, also stimulate cholesterol efflux from macrophages in vitro."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I149,I149)","v":17214727},{"$f":"(LEN($J149) - LEN(SUBSTITUTE(LOWER($J149),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J149) - LEN(SUBSTITUTE(LOWER($J149),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J149) - LEN(SUBSTITUTE(LOWER($J149),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B149:D149)","v":8},2007,"Multiple keratoacanthomas in a young woman: report of a case emphasizing medical management and a review of the spectrum of multiple keratoacanthomas.","Feldman",17214727,"Multiple keratoacanthomas in a young woman: report of a case emphasizing medical management and a review of the spectrum of multiple keratoacanthomas.    Abstract:   A 27-year-old white woman was referred for consultation with regard to the presence of extensive multiple keratotic lesions. She began to develop these lesions at the age of 9 years, with healing of the lesions resulting in scar formation. A biopsy was performed at the age of 16 years, but the patient was unsure of the results. Since then, she had not had any treatment or biopsies, and stated that she had not suffered from any health problems during the intervening period. She was most concerned about the tumors on her heels and soles, which caused difficulty with ambulation. The family history was negative for skin diseases, including melanoma, nonmelanoma skin cancer, psoriasis, and eczema, and positive for Type II diabetes mellitus. A relative reported that the patients grandfather had similar lesions, but the patients parents and siblings were healthy. She was married and had one child, a 9-year-old daughter. Her child had no skin lesions. The patients only medication was Ortho-Tricyclene birth control pills. She had no known drug allergies. Physical examination revealed the presence of multiple lesions on her body (Fig. 1). Her left superior helix contained a well-demarcated, dome-shaped nodule with a rolled, mildly erythematous border with a central hyperkeratotic plug. A similar lesion was present in the scaphoid fossa of the left ear and smaller lesions were scattered on her face. Numerous lesions were present on the arms and legs bilaterally, with the majority of lesions being located on the anterior lower legs. There were also lesions present on the palms and soles. The lesions ranged in size from 5 mm to 3 cm, the largest being a verrucous exophytic nodule on the anterior aspect of her left leg. Overall, there appeared to be two distinct types of lesion. One type appeared round, oval, and symmetric with a central keratotic plug, similar to that on the ear. The other type was larger, more exophytic, and verrucous, including the lesions on the volar surfaces. Also present were numerous, irregularly shaped atrophic scars where previous lesions had healed spontaneously. There were no oral lesions or lesions on her fingernails or toenails, and her teeth and hair were normal. A biopsy was obtained from an early lesion on the right dorsal forearm. Histology revealed an exo-/endophytic growth having a central crater containing keratinous material (Fig. 2). The crater was surrounded by markedly hyperplastic squamous epithelium with large squamous epithelial cells having abundant glassy cytoplasm. Some cells were dyskeratotic. Within the dermis was a dense, chiefly mononuclear inflammatory infiltrate. A buttress of epidermis surrounded the crater. The clinical and pathologic data were consistent with keratoacanthomas. Initial laboratory screenings revealed elevated triglycerides and total cholesterol, 537 mg/dL (normal, lt; 150 mg/dL) and 225 mg/dL (normal, lt; 200 mg/dL), respectively, with all other laboratory results within normal limits. In anticipation of starting oral retinoid therapy for her multiple keratoacanthomas, she was referred to her primary care physician for control of hyperlipidemia. After her lipids had been controlled, she was placed on isotretinoin (Accutane) 40 mg/day. There was some interval improvement with regression of some lesions leaving atrophic scars. She was also started on topical application of tazarotene (Tazorac) for all nonresolving lesions. Possible side-effects from the isotretinoin occurred, including dry mouth and eyes. After 8 months of isotretinoin, the patient was switched to acitretin (Soriatane) 25 mg to determine whether it might have a more beneficial effect on the resistant lesions. Many of the larger lesions regressed leaving atrophic scars. The dose of acitretin was subsequently increased to 35 mg because the lesions on her heel and the ball of her foot persisted. Almost all of the lesions resolved, except those on her feet, which are slowly regressing. Currently, the patient is on a regimen of acitretin 25 mg once a day with tazarotene 0.1% gel applied directly to the few residual keratoacanthomas on her feet, which are slowly improving."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I150,I150)","v":16996300},{"$f":"(LEN($J150) - LEN(SUBSTITUTE(LOWER($J150),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J150) - LEN(SUBSTITUTE(LOWER($J150),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J150) - LEN(SUBSTITUTE(LOWER($J150),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B150:D150)","v":8},2006,"The liver as a target organ of retinoids.","Shiota",16996300,"The liver as a target organ of retinoids.    Abstract:   Retinoids have several biological functions including cell growth, differentiation and apoptosis. In liver, retinoids are known to be associated with regeneration, fibrosis and carcinogenesis. The facts that retinoid droplets in stellate cells are lost with progression of liver disease and that effectiveness of an acyclic retinoid on second primary liver cancer suggest the importance of liver as a target organ of retinoids. Our recent work has indicated that retinoids have antioxidant effects in association with regulation of fatty acid metabolism. In this review article, we discussed the important function of retinoids in liver, mainly from molecular aspects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I151,I151)","v":16700009},{"$f":"(LEN($J151) - LEN(SUBSTITUTE(LOWER($J151),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J151) - LEN(SUBSTITUTE(LOWER($J151),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J151) - LEN(SUBSTITUTE(LOWER($J151),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B151:D151)","v":8},2006,"The retinol-binding protein system: a potential paradigm for steroid-binding globulins?","Redondo",16700009,"The retinol-binding protein system: a potential paradigm for steroid-binding globulins?    Abstract:   Retinol (vitamin A) is an example of a small molecule that is essential for higher organisms; its utilisation has been involved in the evolution of a number of proteins. In mammalian species, retinol is obtained from the diet and controls the release of its binding protein from hepatocytes into the blood stream. Subsequent influx into cells under normal situations usually involves a specific membrane-bound receptor for retinol-binding protein, which facilitates the uptake of retinol alone or bound to its carrier. This specific receptor has not yet been identified, but a receptor for a related lipocalin has been cloned. It represents a relatively new family, and there are a number of related genes in various eukaryotic genomes, suggesting that the system is very widespread in multicellular organisms. Its significance has been highlighted recently by the suggestion that retinol-binding protein, through its receptor, may play a major role in type 2 diabetes, perhaps the greatest scourge of modern society. This system may provide a new paradigm in mammalian biology, another example of which may exist in the processes responsible for steroid handling. This review outlines the characteristics of retinol utilisation in mammalian species, focusing primarily on the uptake system."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I152,I152)","v":16611163},{"$f":"(LEN($J152) - LEN(SUBSTITUTE(LOWER($J152),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J152) - LEN(SUBSTITUTE(LOWER($J152),LOWER(C$3),\"\")))/LEN(C$3)","v":7},{"$f":"(LEN($J152) - LEN(SUBSTITUTE(LOWER($J152),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B152:D152)","v":8},2006,"Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases.","Balint",16611163,"Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases.    Abstract:   Peroxisome Proliferator Activated Receptors (PPARs) are regulators of metabolic pathways mainly of lipid metabolism and energy balance. Their medical importance is given by the fact that they have been implicated in development of insulin resistance, obesity and atherosclerosis. In recent years, major progress has been made in understanding the molecular basis of the function of these receptors. As a result of structural studies and identification of putative natural as well as synthetic ligands and activators of PPARs a new concept emerged and new drugs are on their ways to the clinic. The concept of Selective PPAR Modulators (SPPARM) was suggested by analogy to Selective Estrogen Receptor Modulators (SERM). SPPARMs activate the receptors in distinct ways leading to differential gene expression and biological response. The key features in understanding their action is most likely at the molecular details of ligand binding and the subsequently induced conformational changes as well as cofactor binding. A key aspect of this is that unlike classical steroid hormone receptors such as the retinoic acid receptor, the PPAR receptors have a rather large ligand-binding pocket which is not filled with the ligand entirely and the ligand also stabilizes the receptors structure. The liganded receptor can have distinct conformations and this leads to different binding affinities for the various cofactors (coactivators and corepressors). In this review, we will introduce this concept, review the literature that supports it and present an overview of the receptor selective ligands including data about their mechanism of action and biological effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I153,I153)","v":15787821},{"$f":"(LEN($J153) - LEN(SUBSTITUTE(LOWER($J153),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J153) - LEN(SUBSTITUTE(LOWER($J153),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J153) - LEN(SUBSTITUTE(LOWER($J153),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B153:D153)","v":8},2005,"Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials.","Chen",15787821,"Oral retinoids for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomized controlled trials.    Abstract:    BACKGROUND : The increased incidence of skin cancers after solid organ transplantation is well recognized. Skin cancers developing in transplant recipients are more aggressive in behaviour. Therapeutic options to reduce and/or delay the development of cutaneous neoplasms are therefore of interest.  OBJECTIVES : The objective of this review was to summarize the available medical literature from randomized controlled trials on the use of oral retinoids as a preventive agent for skin cancers in the solid organ transplant population.  METHODS : Three electronic databases were searched for relevant trials: MEDLINE (1966-October 2003), EMBASE (1980-week 44, 2003) and the Cochrane Controlled Trials Register (third quarter 2003). Randomized or quasi-randomized controlled clinical trials on subjects of any age or ethnic background who had received a solid organ transplant (cardiac, renal, liver, etc.) were evaluated. All titles and abstracts found by the search strategy were independently reviewed by two researchers for inclusion into the review.  RESULTS : Eighty-one abstracts were identified through the electronic databases for consideration. Review of the abstracts identified three eligible trials. One cross-over trial involving 23 subjects treated with acitretin 25 mg daily for 12 months reported 46 squamous cell carcinomas (SCCs) developing in six subjects during acitretin treatment vs. 65 SCCs developing in 15 subjects during the drug-free period. Another trial involving 44 subjects treated with acitretin 30 mg daily or placebo for 6 months reported two of 19 subjects developing two SCCs in the treatment group vs. nine of 19 subjects developing 18 new skin cancers (15 SCCs, one Bowens disease, two basal cell carcinomas) in the placebo group. One dose comparison trial involving 26 renal transplant recipients treated with acitretin did not find a significant difference in numbers of skin cancers developing at the doses examined. The major limitation to the use of acitretin was poor tolerance due to adverse events. Headaches, rash, musculoskeletal symptoms and hyperlipidaemia were the most common causes of withdrawal from treatment. No alterations in renal or liver function were detected during the periods of treatment or follow-up.  CONCLUSIONS : The available data from a small number of randomized controlled trials suggest that acitretin may have a role in the management of solid organ transplant recipients with skin cancers. Tolerability of the drug is a major factor limiting its use. Appropriate selection of patients may help improve the risk-benefit ratio."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I154,I154)","v":15057600},{"$f":"(LEN($J154) - LEN(SUBSTITUTE(LOWER($J154),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J154) - LEN(SUBSTITUTE(LOWER($J154),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J154) - LEN(SUBSTITUTE(LOWER($J154),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B154:D154)","v":8},2004,"Structure and function of hepatic stellate cells.","Senoo",15057600,"Structure and function of hepatic stellate cells.    Abstract:   Hepatic stellate cells (vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, Ito cells) exist in the space between parenchymal cells and sinusoidal endothelial cells of the hepatic lobule and store 80% of retinoids in the whole body as retinyl palmitate in lipid droplets in the cytoplasm. In physiological conditions, these cells play pivotal roles in the regulation of retinoid homeostasis; they express specific receptors for retinol-binding protein (RBP), a binding protein specific for retinol, on their cell surface, and take up the complex of retinol and RBP by receptor-mediated endocytosis. Hepatic stellate cells in arctic animals such as polar bears and arctic foxes store 20-100 times the levels of retinoids found in humans or rats. In pathological conditions such as liver fibrosis, hepatic stellate cells lose retinoids, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, and adhesive glycoproteins. Morphology of these cells also changes from the star-shaped stellate cells to that of fibroblasts or myofibroblasts. The three-dimensional structure of ECM components was found to regulate reversibly the morphology, proliferation, and functions of the hepatic stellate cells. Molecular mechanisms in the reversible regulation of the stellate cells by ECM imply cell-surface integrin binding to ECM components, followed by signal transduction processes and then cytoskeleton assembly. Stellate cells also exist in extrahepatic organs such as pancreas, lung, kidney, and intestine. Hepatic and extrahepatic stellate cells form the stellate cell system."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I155,I155)","v":14970372},{"$f":"(LEN($J155) - LEN(SUBSTITUTE(LOWER($J155),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J155) - LEN(SUBSTITUTE(LOWER($J155),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J155) - LEN(SUBSTITUTE(LOWER($J155),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B155:D155)","v":8},2004,"Isotretinoin in the treatment of granuloma annulare.","Looney",14970372,"Isotretinoin in the treatment of granuloma annulare.    Abstract:    OBJECTIVE : To assess the utility and safety of isotretinoin in the treatment of granuloma annulare (GA).  DATA SOURCES : Searches of MEDLINE (1966-January 2003), EMBASE (1989-January 2003), International Pharmaceutical Abstracts (1970-2002), and Allied and Complementary Medicine Database (1985-2002) were conducted. Key terms included granuloma annulare, isotretinoin, retinoids, and antioxidants.  DATA SYNTHESIS : Isotretinoin may have proliferative and inhibitory effects on collagen synthesis that improve GA symptoms. Cases reporting use of isotretinoin in the treatment of GA were reviewed. Several reports detail the successful use of isotretinoin 0.5-1 mg/kg/day, primarily in the disseminated form of the disease. However, some patients required dosage decreases in response to drug-related liver function test elevations, and 2 instances of drug failure were identified.  CONCLUSIONS : Isotretinoin should be reserved for patients with disseminated or refractory GA. Potential serious adverse effects associated with its use require careful monitoring."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I156,I156)","v":14738139},{"$f":"(LEN($J156) - LEN(SUBSTITUTE(LOWER($J156),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J156) - LEN(SUBSTITUTE(LOWER($J156),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J156) - LEN(SUBSTITUTE(LOWER($J156),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B156:D156)","v":8},2003,"Hematopoiesis and retinoids: development and disease.","Oren",14738139,"Hematopoiesis and retinoids: development and disease.    Abstract:   Retinoids function as activating ligands for a class of nuclear receptors that control gene expression programs for a wide range of tissues and organs during embryogenesis and throughout life. Over the years, three sets of observations have spurred interest in the function of retinoids with respect to development and disease of hematopoietic cells. Since the 1920s, epidemiological studies indicated altered hematopoiesis in vitamin A-deficient (VAD) human populations. More recently, the ability of retinoids to affect various aspects of hematopoietic development has been demonstrated in vitro. Finally, it was discovered that the gene encoding a retinoid receptor is a key target for chromosomal translocations that cause acute promyelocytic leukemia (APL). More recent investigations using targeted gene disruptions, VAD animal models, and mouse models of leukemia have continued to shed light on the function of the retinoid pathway in blood cells. It is now clear that retinoids are required for normal hematopoiesis during both yolk sac and fetal liver stages of hematopoiesis, while the pathway has at least modulatory functions for bone marrow derived progenitors. Studies of normal development and APL have provided complementary insight into the molecular control of blood cell differentiation. Here we review the evidence for retinoid requirements in hematopoiesis and also summarize current ideas regarding how this pathway is subverted in leukemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I157,I157)","v":14704326},{"$f":"(LEN($J157) - LEN(SUBSTITUTE(LOWER($J157),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J157) - LEN(SUBSTITUTE(LOWER($J157),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J157) - LEN(SUBSTITUTE(LOWER($J157),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B157:D157)","v":8},2004,"Oxidative conversion of carotenoids to retinoids and other products.","Nagao",14704326,"Oxidative conversion of carotenoids to retinoids and other products.    Abstract:   In vertebrates, provitamin A carotenoids are converted to retinal by beta-carotene-15,15-dioxygenase. The enzyme activity is expressed specifically in intestinal epithelium and in liver. The intestinal enzyme not only plays an important role in providing animals with vitamin A, but also determines whether provitamin A carotenoids are converted to vitamin A or circulated in the body as intact carotenoids. We have found that a high fat diet enhanced the beta-carotene dioxygenase activity together with the cellular retinol binding protein type II level in rat intestines. Flavonols with a catechol structure in the B-ring and 2,6-di-tert-butyl-4-methylphenol inhibited the dioxygenase activity of pig intestinal homogenates and the conversion of beta-carotene to retinol in Caco-2 human intestinal cells. Thus, the bioavailability of dietary provitamin A carotenoids might be modulated by the other food components ingested. Regulation of the dioxygenase activity and its relation to the retinoid metabolism as well as to lipid metabolism deserve further study. In contrast to enzymatic cleavage, it is known that both retinal and beta-apocarotenals are formed in vitro from beta-carotene by chemical transformation, which cleaves conjugated double bonds at random positions under various oxidative conditions. Moreover, recent studies have indicated that the oxidation products formed by chemical transformation might have specific actions on the proliferation of certain cancer cells. We have found that lycopene, a typical nonprovitamin A carotenoid, was cleaved in vitro to acycloretinal, acycloretinoic acid and apolycopenals in a nonenzymatic manner, and that the mixture of oxidation products of lycopene induced apoptosis of HL-60 human promyelocytic leukemia cells. Thus, it is worth evaluating the formation of oxidation products and their biological actions, in order to elucidate the underlying mechanisms of the beneficial effects of carotenoids on human health."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I158,I158)","v":12604774},{"$f":"(LEN($J158) - LEN(SUBSTITUTE(LOWER($J158),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J158) - LEN(SUBSTITUTE(LOWER($J158),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J158) - LEN(SUBSTITUTE(LOWER($J158),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B158:D158)","v":8},2003,"Evidence for defective retinoid transport and function in late onset Alzheimers disease.","Goodman",12604774,"Evidence for defective retinoid transport and function in late onset Alzheimers disease.    Abstract:   The hypothesis of this article is that late onset Alzheimers disease (AD) is influenced by the availability in brain of retinoic acid (RA), the final product of the vitamin A (retinoid) metabolic cascade. Genetic, metabolic, and environmental/dietary evidence is cited supporting this hypothesis. Significant genetic linkages to AD are demonstrated for markers close to four of the six RA receptors, RA receptor G at 12q13, retinoid X receptor B at 6p21.3, retinoid X receptor G at 1q21, and RA receptor A at 17q21. Three of the four retinol-binding proteins at 3q23 and 10q23 and the RA-degrading cytochrome P450 enzymes at 10q23 and 2p13 map to AD linkages. Synthesis of the evidence supports retinoid hypofunction and impaired transport as contributing factors. These findings suggest testable experiments to determine whether increasing the availability of retinoid in brain, possibly through pharmacologic targeting of the RA receptors and the cytochrome P450 RA-inactivating enzymes, can prevent or decrease amyloid plaque formation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I159,I159)","v":12572888},{"$f":"(LEN($J159) - LEN(SUBSTITUTE(LOWER($J159),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J159) - LEN(SUBSTITUTE(LOWER($J159),LOWER(C$3),\"\")))/LEN(C$3)","v":6},{"$f":"(LEN($J159) - LEN(SUBSTITUTE(LOWER($J159),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B159:D159)","v":8},2002,"Peroxisome proliferator-activated receptors (PPARs) in health and disease.","Ehrmann",12572888,"Peroxisome proliferator-activated receptors (PPARs) in health and disease.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) belong to the superfamily of steroid-thyroid-retinoid nuclear receptors. PPARs are transcription factors activated by specific ligands and play an important role during cell signalling. Intensive study of PPARs during recent years has revealed their importance in both normal physiology and in the pathology of various tissues. They participate in the regulation of lipid metabolism, inflammation and the development of atherosclerosis or diabetes. They also play a role in the regulation of growth and differentiation of cancer. It has been suggested that PPAR ligands may have potent anticancer effects and therefore may serve as potential anticancer drugs. In this review we focus on a role of PPARs in breast cancer and in glial tumors of the brain."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I160,I160)","v":11766909},{"$f":"(LEN($J160) - LEN(SUBSTITUTE(LOWER($J160),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J160) - LEN(SUBSTITUTE(LOWER($J160),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J160) - LEN(SUBSTITUTE(LOWER($J160),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B160:D160)","v":8},2001,"Retinoic acid homeostasis: retinoic acid regulates liver retinol esterification as well as its own catabolic oxidation in liver.","Wolf",11766909,"Retinoic acid homeostasis: retinoic acid regulates liver retinol esterification as well as its own catabolic oxidation in liver.    Abstract:   Retinol is stored in liver in the form of its esters. The retinol-esterifying enzyme lecithin:retinol acyltransferase (LRAT) catalyzes the conversion of retinol into its storage form. Expression of the LRAT mRNA is induced by retinoic acid (RA), or by dietary vitamin A, and is downregulated upon vitamin A depletion. RA also induces the expression in liver of the mRNA for CYP26, the enzyme that disposes of excess RA by oxidizing RA to 4-oxo-RA. CYP26 is downregulated upon vitamin A depletion."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I161,I161)","v":11606948},{"$f":"(LEN($J161) - LEN(SUBSTITUTE(LOWER($J161),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J161) - LEN(SUBSTITUTE(LOWER($J161),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J161) - LEN(SUBSTITUTE(LOWER($J161),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B161:D161)","v":8},2001,"Regulation of lipid and lipoprotein metabolism by retinoids.","Staels",11606948,"Regulation of lipid and lipoprotein metabolism by retinoids.    Abstract:   Retinoids are small vitamin A-derived lipophilic compounds that influence a wide variety of developmental and metabolic processes. Retinoids exert their action by activating transcription factors belonging to the retinoic acid receptor (RAR) and retinoid X receptor (RXR) subfamilies of nuclear receptors. Therapeutically, retinoids are used for the treatment of dermatological disorders and certain cancers. Dyslipidemia is a common side-effect of therapy with the currently available retinoids. This review summarizes our current understanding of the molecular mechanisms of regulation of lipid and lipoprotein metabolism by retinoids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I162,I162)","v":11391073},{"$f":"(LEN($J162) - LEN(SUBSTITUTE(LOWER($J162),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J162) - LEN(SUBSTITUTE(LOWER($J162),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J162) - LEN(SUBSTITUTE(LOWER($J162),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B162:D162)","v":8},2001,"Alcohol and retinoids.","Crabb",11391073,"Alcohol and retinoids.    Abstract:   This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Hirokazu Yokoyama and David Crabb. The presentations were (1) Roles of vitamin A, retinoic acid, and retinoid receptors in the expression of liver ALDH2, by J. Pinaire, R. Hasanadka, M. Fang, and David W. Crabb; (2) Alcohol, vitamin A, and beta-carotene: Adverse interactions, by M. A. Leo and Charles S. Lieber; (3) Retinoic acid, hepatic stellate cells, and Kupffer cells, by Hidekazu Tsukamoto, K. Motomura, T. Miyahara, and M. Ohata; (4) Retinoid storage and metabolism in liver, by William Bosron, S. Sanghani, and N. Kedishvili; (5) Characterization of oxidation pathway from retinol to retinoic acid in esophageal mucosa, by Haruko Shiraishi, Hirokazu Yokoyama, Michiko Miyagi, and Hiromasa Ishii; and (6) Ethanol in an inhibitor of the cytosolic oxidation of retinol in the liver and the large intestine of rats as well as in the human colon mucosa, by Ina Bergheim, Ina Menzl, Alexandr Parlesak, and Christiane Bode."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I163,I163)","v":10721902},{"$f":"(LEN($J163) - LEN(SUBSTITUTE(LOWER($J163),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J163) - LEN(SUBSTITUTE(LOWER($J163),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J163) - LEN(SUBSTITUTE(LOWER($J163),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B163:D163)","v":8},2000,"Lipases and carboxylesterases: possible roles in the hepatic utilization of vitamin A.","Harrison",10721902,"Lipases and carboxylesterases: possible roles in the hepatic utilization of vitamin A.    Abstract:   The formation and hydrolysis of retinyl esters are key processes in the metabolism of the fat-soluble micronutrient vitamin A. Long-chain acyl esters of retinol are the major chemical form of vitamin A (retinoid) stored in the body. Although retinyl esters are found in a variety of tissues and cell types, most of the total body retinoid is accounted for by the retinyl esters stored in the liver. Thus, these esters represent the major endogenous source of retinoid that can be delivered to peripheral tissues for conversion to biologically active forms. This paper summarizes the current state of our knowledge about the identity, function and regulation of the hepatic enzymes that are potentially involved in catalyzing the hydrolysis of retinyl esters. These enzymes include several known and characterized lipases and carboxylesterases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I164,I164)","v":10643290},{"$f":"(LEN($J164) - LEN(SUBSTITUTE(LOWER($J164),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J164) - LEN(SUBSTITUTE(LOWER($J164),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J164) - LEN(SUBSTITUTE(LOWER($J164),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B164:D164)","v":8},1999,"[The eye and nutrition].","Amemiya",10643290,"[The eye and nutrition].    Abstract:    PURPOSE : To examine the effect of vitamins and trace elements on ocular tissue.  MATERIALS AND METHODS : Rats or mice were fed diets deficient in the trace elements Zn, Cu, Mn, Se, Mg, and Cr or in vitamins A, B12, C, and E. In some rats Al and vitamin A were injected in excessive amounts. We studied the conjunctiva, cornea, retina, and optic nerve with a light microscope, transmission and scanning electron microscopes, an energy dispersive X-ray analyser, and an ion microscope. Histochemical, cytochemical, and immunohistochemical techniques were applied to the pathological specimens.  RESULTS : Deficiencies of Zn, Cu, Mn, and vitamins A, C and E caused a loss of goblet cells in the conjunctiva and a prominent decrease of microvilli and microplicae in the conjunctiva and cornea. The elements in the goblet cells were changed in these conditions. In addition, epithelial cells showed poor fibrous development and abnormal distribution of chromatin in the nucleus. Zn, Cu, Mn, and vitamins A and E deficiencies caused photoreceptor cells to degenerate and disappear. Se deficiency reduced the horizontal and amacrine cells. Vitamin B12 deficiency reduced nerve fibers in the nerve fiber layer of the retina. Mg deficiency induced multifocal necrosis in the retinal pigment epithelium and apoptotic nuclear changes in the photoreceptor cells. Cr deficiency showed abnormal phagocytosis of the photoreceptor outer segment discs in the retinal pigment epithelium. Vitamin B12 was found to be related to the circadian rhythm in the retina. Deficiencies of Zn, Cu, Mn, and vitamins A, B12, and E induced degeneration and disappearance of myelin lamellae in the myelinated optic nerve fibers. In hypervitaminosis A, lipid droplets appeared in the retinal pigment epithelium and alcohol dehydrogenase disappeared in the retinal pigment epithelium and photoreceptor outer segments. Excessive Al was toxic to the retina, which showed disappearance of photoreceptor cells. Al deposits were seen in dendrites and neurons in the outer plexiform layer. Zn seemed to be necessary for corneal epithelial cell wound healing.  DISCUSSION : Trace elements usually are contained in enzymes, which have many metabolic functions. They are related to synthesis and breakdown of many substances. Some trace elements such as Zn, Cu, Mn, and Se and vitamins including vitamins A, C, and E prevent peroxidation of lipids. Some vitamins have an affinity for specific tissues such as epithelial cells, nerve fibers, and neuronal cells and are needed for cell differentiation, development, and maintenance.  CONCLUSION : Cu, Zn, Mn, Se, Mg, and Cr and vitamins A, B12, C, and E are necessary for maintenance of cellular structure and metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I165,I165)","v":10466190},{"$f":"(LEN($J165) - LEN(SUBSTITUTE(LOWER($J165),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J165) - LEN(SUBSTITUTE(LOWER($J165),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J165) - LEN(SUBSTITUTE(LOWER($J165),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B165:D165)","v":8},1999,"Optimal nutrition: vitamin A and the carotenoids.","Thurnham",10466190,"Optimal nutrition: vitamin A and the carotenoids.    Abstract:   There are two major dietary sources of vitamin A: easily absorbed retinyl palmitate in foods of animal origin, and poorly bioavailable carotenoids from plant foods. Plasma retinol is tightly controlled, probably by regulation of retinol-binding protein (RBP) formation in the liver, and only hormonal factors (e.g. oral contraceptives) and infection will alter the homeostasis. Delivery of retinol to the tissues is facilitated by the RBP-retinol complex; however, there is evidence that this mechanism can be bypassed when very high doses of vitamin A are given. Some retinyl ester may be released to tissues from chylomicrons when the latter bind to tissue lipoprotein receptors during their passage from the gut to the liver following a meal. High-dose vitamin A therapy is a means of rapidly improving vitamin A status in persons with sub-optimal vitamin A nutrition but there are dangers of toxic symptoms (e.g. teratogenicity) from excess vitamin A usage. Evidence is presented to suggest that the plasma retinol: RBP may be a guide to optimal vitamin A status, since values less than one frequently occur in less-developed countries and during infection. In contrast to plasma retinol, plasma carotenoids reflect the dietary intake of plant foods. However, absorption is limited by poor bioavailability and a saturable uptake mechanism in competition with other phytochemicals. Recent work on bioavailability suggests that the calculation of plant food vitamin A activity should be re-examined. Illness has little influence on plasma levels except by suppressing appetite. Carotenoids are generally regarded as non-toxic yet intervention studies with beta-carotene in smokers have been associated with increased lung cancer and heart disease. Some carotenoids are important as vitamin A precursors, but the physiological importance of their antioxidant properties is not known and consequently the amount needed for optimal nutrition is uncertain."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I166,I166)","v":10319365},{"$f":"(LEN($J166) - LEN(SUBSTITUTE(LOWER($J166),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J166) - LEN(SUBSTITUTE(LOWER($J166),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J166) - LEN(SUBSTITUTE(LOWER($J166),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B166:D166)","v":8},1999,"The stressful condition as a nutritionally dependent adaptive dichotomy.","Ingenbleek",10319365,"The stressful condition as a nutritionally dependent adaptive dichotomy.    Abstract:   The injured body manifests a cascade of cytokine-induced metabolic events aimed at developing defense mechanisms and tissue repair. Rising concentrations of counterregulatory hormones work in concert with cytokines to generate overall insulin and insulin-like growth factor 1 (IGF-1), postreceptor resistance and energy requirements grounded on lipid dependency. Salient features are self-sustained hypercortisolemia persisting as long as cytokines are oversecreted and down-regulation of the hypothalamo-pituitary-thyroid axis stabilized at low basal levels. Inhibition of thyroxine 5-deiodinating activity (5-DA) accounts for the depressed T3 values associated with the sparing of both N and energy-consuming processes. Both the liver and damaged territories adapt to stressful signals along up-regulated pathways disconnected from the central and peripheral control systems. Cytokines stimulate liver 5-DA and suppress the synthesis of transthyretin (TTR), causing the drop of retinol-binding protein (RBP) and the leakage of increased amounts of T4 and retinol in free form. TTR and RBP thus work as prohormonal reservoirs of precursor molecules which need to be converted into bioactive derivatives (T3 and retinoic acids) to reach transcriptional efficiency. The converting steps (5-DA and cellular retinol-binding protein-I) are activated by T4 and retinol, themselves operating as limiting factors of positive feedback loops. Healthy adults with normal macrophage functioning and liver parenchymal integrity, who submitted to a stress of medium severity, are characterized by TTR-RBP plasma levels reduced by half and an estimated ten-fold increase in free ligand disposal to target cells during the days ensuing injury. This transient hyperthyroid and hyperretinoid climate creates a second defense line strengthening and fine-tuning the effects primarily initiated by cytokines. The suicidal behavior of thyroxine-binding globulin (TBG), corticosteroid-binding globulin (CBG), and IGFBP-3 allows the occurrence of peak endocrine and mitogenic influences at the site of inflammation. The production rate of TTR by the liver is the main determinant of both the hepatic release and blood transport of holoRBP, which explains why poor nutritional status concomitantly impairs thyroid- and retinoid-dependent acute-phase responses, hindering the stressed body to appropriately face the survival crisis. The prognostic significance of low TT4 blood levels may be assigned to the exhaustion of extrathyroidal hormonal pools normally stored in liver and plasma but markedly shrunken in protein-depleted states. These data offer new insights into the mechanisms whereby preexisting malnutrition and stressful complications are interrelated, emphasizing the pivotal role played by TTR in that context."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I167,I167)","v":9153961},{"$f":"(LEN($J167) - LEN(SUBSTITUTE(LOWER($J167),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J167) - LEN(SUBSTITUTE(LOWER($J167),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J167) - LEN(SUBSTITUTE(LOWER($J167),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B167:D167)","v":8},1997,"Hepatic stellate cells--from the viewpoint of retinoid handling and function of the extracellular matrix.","Senoo",9153961,"Hepatic stellate cells--from the viewpoint of retinoid handling and function of the extracellular matrix.    Abstract:   Hepatic stellate cells (vitamin A-storing cells, lipocytes, fat-storing cells, Ito cells) exist in the perisinusoidal space of the hepatic lobule, and store 80% of retinoids in the whole body as retinyl palmitate in lipid droplets in the cytoplasm. In physiological conditions, these cells play pivotal roles in the regulation of retinoid homeostasis; they express specific receptors for retinol-binding protein (RBP), a binding protein specific for retinol, on their cell surface, and take up the complex of retinol and RBP by receptor-mediated endocytosis. By contrast, in pathological conditions such as liver fibrosis, these cells lose retinoids, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan and adhesive glycoproteins. The morphology of these cells also changes from the star-shaped stellate cells to that of fibroblasts or myofibroblasts. It is concluded that three-dimensional structure of the ECM components reversibly regulates the morphology, proliferation, and functions of the hepatic stellate cells."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I168,I168)","v":9361824},{"$f":"(LEN($J168) - LEN(SUBSTITUTE(LOWER($J168),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J168) - LEN(SUBSTITUTE(LOWER($J168),LOWER(C$3),\"\")))/LEN(C$3)","v":7},{"$f":"(LEN($J168) - LEN(SUBSTITUTE(LOWER($J168),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B168:D168)","v":8},1997,"Dietary fat, genes, and human health.","Jump",9361824,"Dietary fat, genes, and human health.    Abstract:   These studies show that a macronutrient like dietary fat plays an important role in gene expression. In the cases presented here, dietary fat regulates gene expression leading to changes in carbohydrate and lipid metabolism. The interesting outcome of these studies is the finding that the molecular targets for dietary fat action did not converge with the principal targets for hormonal regulation of gene transcription, like hormone receptors. Instead, PUFA-RF targets elements that play key ancillary roles in gene transcription. This is important because it shows how PUFA can interfere with hormone regulation of a specific gene without having generalized effect on overall hormonal control, i.e. PUFA effects are promoter-specific. How PUFA-RF interferes with gene transcription will require the isolation and characterization of PUFA-RF along with the tissue-specific factors targeted by PUFA-RF. A different story emerges when fatty acids activate PPAR. Based on the studies presented here and elsewhere, long chain-highly unsaturated fatty acids (like 20:5,n-3 and 22:6, n-3) or high levels of fat activate PPAR. PPAR directly activates genes like AOX, but also inhibits transcription of genes like S14, FAS, apolipoprotein CIII, transferrin. For S14, the mechanism of inhibition involves sequestration of RXR, a critical factor for T3 receptor binding to DNA. Thus, PPAR can have generalized effects on T3 action or on other nuclear receptors, like vit. D (VDR) and retinoic acid (RAR) receptors, that require RXR for action. For apolipoprotein CIII and transferrin, PPAR/RXR heterodimers compete for HNF-4 binding sites (DR + 1). In addition to HNF-4, COUP-TF, ARP-1 and RXR all bind the DR + 1 type motif. These factors are important for tissue-specific regulation of gene transcription. PPAR can potentially interfere with the transcription of multiple genes through disruption of nuclear receptor signaling leading to changes in phenotype. Clearly, more studies are required to assess the role PPAR plays in the fatty acid regulation of gene transcription and its contribution to chronic disease. Finally, it is clear that dietary fat has the potential to affect gene expression through multiple pathways. Depending on the gene examined, PUFA might augment or abrogate gene transcription which leads to specific phenotypic changes altering metabolism, differentiation or cell growth. These effects can be beneficial to the organism, such as the n-3 PUFA-mediated suppression of serum triglycerides or detrimental, like the saturated and n-6 PUFA-mediated promotion of insulin resistance. How such effects contribute to the onset or progression of specific neoplasia is unclear. However, studies in metabolism might provide important clues for this connection."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I169,I169)","v":1460122},{"$f":"(LEN($J169) - LEN(SUBSTITUTE(LOWER($J169),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J169) - LEN(SUBSTITUTE(LOWER($J169),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J169) - LEN(SUBSTITUTE(LOWER($J169),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B169:D169)","v":8},1992,"Long-term safety of retinoid therapy.","Vahlquist",1460122,"Long-term safety of retinoid therapy.    Abstract:   The concern about long-term toxicity of oral synthetic retinoids has developed because many patients, especially those with genodermatoses, require lifelong therapy. Several organ systems are at risk, especially the hepatic, skeletal, and cardiovascular systems. Although acute hepatotoxicity is a rare side effect of etretinate and acitretin therapy, prospective studies have not demonstrated chronic liver toxicity. The frequency of bone changes induced by retinoids is difficult to estimate, because this adverse effect is usually asymptomatic and requires x-ray or scintigraphic examination for detection. Atherosclerosis develops in many patients who receive long-term retinoid therapy, but the extent to which the process is aggravated by drug-induced hyperlipidemia is not known. Many patients have now been treated with either etretinate or isotretinoin continuously for as many as 15 years and have not developed any signs of severe chronic toxicity. However, continued intense surveillance is recommended for patients expected to require lifelong therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I170,I170)","v":2660711},{"$f":"(LEN($J170) - LEN(SUBSTITUTE(LOWER($J170),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J170) - LEN(SUBSTITUTE(LOWER($J170),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J170) - LEN(SUBSTITUTE(LOWER($J170),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B170:D170)","v":8},1989,"[Rheumatologic effects of etretinate].","Cuny",2660711,"[Rheumatologic effects of etretinate].    Abstract:   The effects of chronic hypervitaminosis A and long-term isotretinoin treatment on bone include cortical hyperostosis, ligament calcification and premature epiphyseal closure. Similar effects have now been reported in patients under maintenance treatment with etretinate in high doses. Etretinate, an oral, aromatic, synthetic vitamin A derivative, is widely used in Europe for disorders of keratinization. We report the cases of two patients--one with lamellar ichthyosis, the other with pachyonychia congenita--who developed such bone diseases during treatment with etretinate over 2 and 6 years respectively. The doses ranged from 0.5 to 1 mg/kg/day. Two years after starting treatment (total dose 25 g), the patient with lamellar ichthyosis complained of mechanical pain in the lumbar region and hips. Radiography showed calcification of the extraspinal tendons and ligaments and hyperostosis of the calcaneus bone at the insertion of the plantar ligament. After six years of etretinate treatment (total dose 50 g), the patient with pachyonychia congenita presented with scoliosis and limb length discrepancy. The musculoskeletal abnormalities resembled chronic hypervitaminosis A, with such osseous changes as demineralization, thinning and increased curvature of long bones with osteopenia, and premature closure of the epiphyses. Acroosteolysis was also present. Etretinate has been implicated in the formation of spinal hyperostoses and calcification of extraspinal ligaments in patients who had taken the drug for many years. The occurrence of premature epiphyseal closure in children certainly is a consequence of therapy with relatively high doses of etretinate for six years. But premature epiphyseal closure may also result from trauma to a fragile bone.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I171,I171)","v":2643696},{"$f":"(LEN($J171) - LEN(SUBSTITUTE(LOWER($J171),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J171) - LEN(SUBSTITUTE(LOWER($J171),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J171) - LEN(SUBSTITUTE(LOWER($J171),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B171:D171)","v":8},1989,"Comparative aspects of carotenoids and retinoids as chemopreventive agents for cancer.","Moon",2643696,"Comparative aspects of carotenoids and retinoids as chemopreventive agents for cancer.    Abstract:   Retinoids are well established chemopreventive agents for experimental carcinogenesis of many target organs including mammary gland, urinary bladder, lung, skin, liver, pancreas, colon and esophagus. Modification of the basic retinoid structure has produced analogs with enhanced target organ specificity, increased inhibitory activity and reduced toxicity. N-(4-hydroxyphenyl) retinamide (4-HPR) currently appears to be the most efficaceous retinoid against carcinogen-induced breast, urinary bladder, and lung cancer in rodents. Retinoids are most effective when administered shortly after the carcinogen treatment; however, the treatment can be delayed significantly while maintaining its chemopreventive effect. Under various experimental conditions, combining retinoid treatment with other modifiers of growth enhances its chemopreventive activity; for example, retinoid plus hormonal modulation can provide better protection against mammary cancer than either treatment alone. The role of carotenoids in cancer chemoprevention is less well defined. Studies have been complicated by the poor absorption and low tissue levels of carotenoids in the rodent models used for such studies. Aside from experimental skin carcinogenesis, little information is available relative to the effect of carotenoids on the chemoprevention of cancer at other organ sites."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I172,I172)","v":3158386},{"$f":"(LEN($J172) - LEN(SUBSTITUTE(LOWER($J172),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J172) - LEN(SUBSTITUTE(LOWER($J172),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J172) - LEN(SUBSTITUTE(LOWER($J172),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B172:D172)","v":8},1985,"Synthetic retinoids in dermatology.","Heller",3158386,"Synthetic retinoids in dermatology.    Abstract:   The potential of vitamin A, or retinol, in the treatment of a variety of skin diseases has long been recognized, but because of serious toxic effects this substance generally could not be used. The recent development and marketing of two relatively non-toxic synthetic analogues, which are known as retinoids, has made it possible to treat some of the diseases that are resistant to standard forms of therapy. Isotretinoin is very effective in cystic and conglobate acne, while etretinate is especially useful in the more severe forms of psoriasis. Good results have also been obtained in other disorders of keratinization. Vitamin A and its derivatives apparently have an antineoplastic effect as well and may come to be used in both the prevention and the treatment of epithelial cancer. In many of these diseases the retinoids act by enhancing the normal differentiation and proliferation of epidermal tissues, but the exact mechanisms are not well understood. Their influence on the intracellular polyamines that control the synthesis of nucleic acids and proteins may be an important factor. Although the retinoids have few serious systemic effects, they are teratogenic, and because they persist in the body their use in women of childbearing potential is limited."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I173,I173)","v":6347031},{"$f":"(LEN($J173) - LEN(SUBSTITUTE(LOWER($J173),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J173) - LEN(SUBSTITUTE(LOWER($J173),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J173) - LEN(SUBSTITUTE(LOWER($J173),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B173:D173)","v":8},1983,"Pharmacologic disposition of chemopreventive retinoids (review).","Hill",6347031,"Pharmacologic disposition of chemopreventive retinoids (review).    Abstract:   The disposition of natural and synthetic retinoids, some of which effectively prevent cancer in carcinogen-dosed animals, varies with the structure of the compound. Disappearance of retinoids from serum may be either linear or exponential, and there may be a prolonged terminal elimination phase. Metabolism of these compounds is extensive, with little or no absorbed retinoid being excreted unchanged. Compounds giving rise to retinol can be stored as retinyl esters in the liver. In contrast, retinoids with a terminal carboxyl group are not stored but are metabolized on the ring and/or on the sidechain prior to excretion, which occurs often after conjugation of the metabolites with glucuronic acid. Isomerization of the double bonds in the sidechain may also occur. The metabolites of natural retinoids do not appear to possess more biological activity than the parent compounds, leading to the conclusion that their metabolism is, in general, degradative."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I174,I174)","v":337808},{"$f":"(LEN($J174) - LEN(SUBSTITUTE(LOWER($J174),LOWER(B$3),\"\")))/LEN(B$3)","v":8},{"$f":"(LEN($J174) - LEN(SUBSTITUTE(LOWER($J174),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J174) - LEN(SUBSTITUTE(LOWER($J174),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B174:D174)","v":8},1977,"Diseases of the retina: 1975-76 review.","Cohen",337808,"Diseases of the retina: 1975-76 review.    Abstract:   Articles on the retina which appeared in the American Journal of Ophthalmology, Archives of Ophthalmology, and British Journal of Ophthalmology from July 1975 to June 1976 are summarized. Topics include a specific receptor for retinol-binding protein, retinal pigment epithelium, retinitis pigmentosa, diabetic retinopathy, infections, degenerations, maculopathy, sickle hemoglobinopathy, retinoblastoma and retrolent fibroplasia, and macular hole and retinal detachment."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I175,I175)","v":27589347},{"$f":"(LEN($J175) - LEN(SUBSTITUTE(LOWER($J175),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J175) - LEN(SUBSTITUTE(LOWER($J175),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J175) - LEN(SUBSTITUTE(LOWER($J175),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B175:D175)","v":7},2016,"Accelerated Skeletal Maturation in Disorders of Retinoic Acid Metabolism: A Case Report and Focused Review of the Literature.","Nilsson",27589347,"Accelerated Skeletal Maturation in Disorders of Retinoic Acid Metabolism: A Case Report and Focused Review of the Literature.    Abstract:    NlmCategory=UNASSIGNEDNutritional excess of vitamin A, a precursor for retinoic acid (RA), causes premature epiphyseal fusion, craniosynostosis, and light-dependent retinopathy. Similarly, homozygous loss-of-function mutations in CYP26B1, one of the major RA-metabolizing enzymes, cause advanced bone age, premature epiphyseal fusion, and craniosynostosis. In this paper, a patient with markedly accelerated skeletal and dental development, retinal scarring, and autism-spectrum disease is presented and the role of retinoic acid in longitudinal bone growth and skeletal maturation is reviewed. Genetic studies were carried out using SNP array and exome sequencing. RA isomers were measured in the patient, family members, and in 18 age-matched healthy children using high-performance liquid chromatography coupled to tandem mass spectrometry. A genomic SNP array identified a novel 8.3 megabase microdeletion on chromosome 10q23.2-23.33. The 79 deleted genes included CYP26A1 and C1, both major RA-metabolizing enzymes. Exome sequencing did not detect any variants that were predicted to be deleterious in the remaining alleles of these genes or other known retinoic acid-metabolizing enzymes. The patient exhibited elevated plasma total RA (16.5 vs. 12.6±1.5 nM, mean±SD, subject vs. controls) and 13-cisRA (10.7 nM vs. 6.1±1.1). The findings support the hypothesis that elevated RA concentrations accelerate bone and dental maturation in humans. CYP26A1 and C1 haploinsufficiency may contribute to the elevated retinoic acid concentrations and clinical findings of the patient, although this phenotype has not been reported in other patients with similar deletions, suggesting that other unknown genetic or environmental factors may also contribute."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I176,I176)","v":26433844},{"$f":"(LEN($J176) - LEN(SUBSTITUTE(LOWER($J176),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J176) - LEN(SUBSTITUTE(LOWER($J176),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J176) - LEN(SUBSTITUTE(LOWER($J176),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B176:D176)","v":7},2015,"The Role of Systemic Retinoids in the Treatment of Cutaneous T-Cell Lymphoma.","Huen",26433844,"The Role of Systemic Retinoids in the Treatment of Cutaneous T-Cell Lymphoma.    Abstract:   Retinoids are natural and synthetic vitamin A analogs with effects on cell proliferation, differentiation, and apoptosis. They have significant activity in hematologic malignancies and have been studied extensively in cutaneous T-cell lymphoma. Retinoids bind to nuclear receptors and exert their effects through moderation of gene expression. Retinoic acid receptor and retinoic X receptor exert regulatory activity in vivo, binding to distinct ligands. Studies investigating systemic retinoids as monotherapy and in combination with other agents active against cutaneous lymphoma are reviewed. Side effects associated with retinoids include teratogenicity, dyslipidemias, and hypothyroidism, which should be carefully monitored in patients receiving treatment."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I177,I177)","v":25941915},{"$f":"(LEN($J177) - LEN(SUBSTITUTE(LOWER($J177),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J177) - LEN(SUBSTITUTE(LOWER($J177),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J177) - LEN(SUBSTITUTE(LOWER($J177),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B177:D177)","v":7},2015,"Retinol binding protein 4 and its membrane receptors: a metabolic perspective.","Fedders",25941915,"Retinol binding protein 4 and its membrane receptors: a metabolic perspective.    Abstract:   Nearly a decade of intense research has passed since the first report linking circulating retinol binding protein 4 (RBP4) to the development of insulin resistance. By now, a variety of underlying mechanisms have been identified; some of them are adherent to the canonical role of this circulating protein, which is to transport and deliver retinol to target tissues, and others that seem rather independent of retinol transport. Despite all these efforts, a consensus in the basic principles of RBP4s metabolic effects has not been reached and some controversy remains. Using this as an opportunity, we here review and discuss current data on RBP4s action on insulin sensitivity and its dependency on retinol homeostasis. We pay special attention to the involvement of RBP4 membrane receptors that were identified during these years, such as stimulated by retinoic acid 6 (STRA6), and whose identification added another layer of complexity to RBP4s diverse actions. A better understanding of RBP4s functions might allow its therapeutic exploitations, urgently needed in our period that is defined by an epidemic increase in metabolic diseases such as obesity and type 2 diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I178,I178)","v":25814978},{"$f":"(LEN($J178) - LEN(SUBSTITUTE(LOWER($J178),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J178) - LEN(SUBSTITUTE(LOWER($J178),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J178) - LEN(SUBSTITUTE(LOWER($J178),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B178:D178)","v":7},2015,"Retinoid receptors in bone and their role in bone remodeling.","Henning",25814978,"Retinoid receptors in bone and their role in bone remodeling.    Abstract:   Vitamin A (retinol) is a necessary and important constituent of the body which is provided by food intake of retinyl esters and carotenoids. Vitamin A is known best for being important for vision, but in addition to the eye, vitamin A is necessary in numerous other organs in the body, including the skeleton. Vitamin A is converted to an active compound, all-trans-retinoic acid (ATRA), which is responsible for most of its biological actions. ATRA binds to intracellular nuclear receptors called retinoic acid receptors (RARα, RARβ, RARγ). RARs and closely related retinoid X receptors (RXRα, RXRβ, RXRγ) form heterodimers which bind to DNA and function as ligand-activated transcription factors. It has been known for many years that hypervitaminosis A promotes skeleton fragility by increasing osteoclast formation and decreasing cortical bone mass. Some epidemiological studies have suggested that increased intake of vitamin A and increased serum levels of retinoids may decrease bone mineral density and increase fracture rate, but the literature on this is not conclusive. The current review summarizes how vitamin A is taken up by the intestine, metabolized, stored in the liver, and processed to ATRA. ATRAs effects on formation and activity of osteoclasts and osteoblasts are outlined, and a summary of clinical data pertaining to vitamin A and bone is presented."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I179,I179)","v":24456080},{"$f":"(LEN($J179) - LEN(SUBSTITUTE(LOWER($J179),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J179) - LEN(SUBSTITUTE(LOWER($J179),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J179) - LEN(SUBSTITUTE(LOWER($J179),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B179:D179)","v":7},2014,"Retinoid X receptor ligands: a patent review (2007 - 2013).","Yamada",24456080,"Retinoid X receptor ligands: a patent review (2007 - 2013).    Abstract:    INTRODUCTION : Retinoid X receptors (RXRs) are nuclear receptors that act as ligand-dependent transcription factors. RXRs function as homodimers or as heterodimers with other nuclear receptors, such as retinoic acid receptors, PPARs, liver X receptors, farnesoid X receptor, vitamin D receptor or thyroid hormone receptors. RXR ligands (agonists or antagonists) show various physiological effects, depending on their partner receptors. RXR agonist bexarotene (Targretin®) is used for the treatment of cutaneous T-cell lymphoma in clinical practice. RXR agonists were also reported to be useful for treatment of type 2 diabetes, autoimmune disease and Alzheimers disease. RXR antagonists were also reported to be effective in type 2 diabetes treatment.  AREAS COVERED : Here patent applications (2007 - 2013) concerning RXR ligands are summarized, and the usefulness of RXR ligands as pharmaceutical agents is discussed.  EXPERT OPINION : RXR agonists show a wide variety of biological effects. However, they cause serious side effects, such as blood triglyceride elevation, hypothyroidism and others. Thus, for clinical application of RXR agonists, abrogation of these side effects is required. RXR heterodimer-selective agonists and RXR partial agonists exhibiting desired effects without side effects are expected to find clinical application."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I180,I180)","v":24273224},{"$f":"(LEN($J180) - LEN(SUBSTITUTE(LOWER($J180),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J180) - LEN(SUBSTITUTE(LOWER($J180),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J180) - LEN(SUBSTITUTE(LOWER($J180),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B180:D180)","v":7},2014,"Pharmaceutical and nutraceutical approaches for preventing liver carcinogenesis: chemoprevention of hepatocellular carcinoma using acyclic retinoid and branched-chain amino acids.","Shimizu",24273224,"Pharmaceutical and nutraceutical approaches for preventing liver carcinogenesis: chemoprevention of hepatocellular carcinoma using acyclic retinoid and branched-chain amino acids.    Abstract:   The poor prognosis for patients with hepatocellular carcinoma (HCC) is associated with its high rate of recurrence in the cirrhotic liver. Therefore, more effective strategies need to be urgently developed for the chemoprevention of this malignancy. The malfunction of retinoid X receptor α, a retinoid receptor, due to phosphorylation by Ras/mitogen-activated protein kinase is closely associated with liver carcinogenesis and may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), a synthetic retinoid, can prevent HCC development by inhibiting retinoid X receptor α phosphorylation and improve the prognosis for this malignancy. Supplementation with branched-chain amino acids (BCAA), which are used to improve protein malnutrition in patients with liver cirrhosis, can also reduce the risk of HCC in obese cirrhotic patients. In experimental studies, both ACR and BCAA exert suppressive effects on HCC development and the growth of HCC cells. In particular, combined treatment with ACR and BCAA cooperatively inhibits the growth of HCC cells. Furthermore, ACR and BCAA inhibit liver tumorigenesis associated with obesity and diabetes, both of which are critical risk factors for HCC development. These findings suggest that pharmaceutical and nutraceutical approaches using ACR and BCAA may be promising strategies for preventing HCC and improving the prognosis of this malignancy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I181,I181)","v":23891453},{"$f":"(LEN($J181) - LEN(SUBSTITUTE(LOWER($J181),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J181) - LEN(SUBSTITUTE(LOWER($J181),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J181) - LEN(SUBSTITUTE(LOWER($J181),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B181:D181)","v":7},2013,"Guidelines for the use of acitretin in psoriasis. Psoriasis Group of the Spanish Academy of Dermatology and Venereology.","Carretero",23891453,"Guidelines for the use of acitretin in psoriasis. Psoriasis Group of the Spanish Academy of Dermatology and Venereology.    Abstract:   Phototherapy, classic systemic treatments (methotrexate, acitretin, and ciclosporin), and biologic agents (etanercept, infliximab, adalimumab, and ustekinumab) constitute a broad therapeutic arsenal that increases the likelihood of achieving control of severe and extensive disease in patients with psoriasis. Acitretin continues to be a very valuable tool in both monotherapy, in which it is combined with other systemic treatments (classic or biologic), and in sequential therapy. Thanks to its lack of a direct immunosuppressive effect and its ability to achieve a long-term response, acitretin has an important role in the treatment of psoriasis, although this has not always been acknowledged in relevant treatment guidelines. We present consensus guidelines for the use of acitretin in psoriasis drawn up by the Psoriasis Group of the Spanish Academy of Dermatology and Venereology. These guidelines provide a detailed account of acitretin, including pharmacological properties, indications and contraindications, adverse effects, and factors that should be taken into account to enhance the safe use of this drug. They also propose treatment strategies for use in routine clinical practice. The overall aim of these guidelines is to define the criteria for the use and management of acetretin in psoriasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I182,I182)","v":23774118},{"$f":"(LEN($J182) - LEN(SUBSTITUTE(LOWER($J182),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J182) - LEN(SUBSTITUTE(LOWER($J182),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J182) - LEN(SUBSTITUTE(LOWER($J182),LOWER(D$3),\"\")))/LEN(D$3)","v":6},{"$f":"SUM(B182:D182)","v":7},2013,"Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes.","Tanaka",23774118,"Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes.    Abstract:   Fulminant type 1 diabetes is characterized by a rapid onset of severe hyperglycemia and ketoacidosis, with subsequent poor prognosis of diabetic complications. This review summarizes new findings related to the pathophysiology of accelerated β-cell failure in fulminant type 1 diabetes. Immunohistological examination revealed the presence of enterovirus in pancreatic islet cells and exocrine tissues and hyperexpression of pattern recognition receptors (PRRs) including melanoma differentiation-associated antigen 5 (MDA5), retinoic acid-inducible gene-I (RIG-I), Toll-like receptor (TLR)3 and TLR4, essential sensors of innate immunity, in islet cells and mononuclear cells (MNCs) infiltrating islets. Interferon (IFN)-α and IFN-β, products of PRR cascades, were expressed in both islet cells and infiltrating MNCs. Phenotypes of infiltrating cells around and/or into islets were mainly dendritic cells, macrophages and CD8+ T cells. Islet β-cells simultaneously expressed CXC chemokine ligand 10 (CXCL10), IFN-γ and interleukin-18, indicating that these chemokines/ cytotoxic cytokines mutually amplify their cytoplasmic expression in the islet cells. These positive feedback systems might enhance adaptive immunity, leading to rapid and complete loss of β-cells in fulminant type 1 diabetes. In innate and adaptive/autoimmune immune processes, the mechanisms behind bystander activation/killing might further amplify β-cell destruction. In addition to intrinsic pathway of cell apoptosis, the Fas and Fas ligand pathway are also involved as an extrinsic pathway of cell apoptosis. A high prevalence of anti-amylase autoantibodies was recognized in patients with fulminant type 1 diabetes, which suggests that Th2 T-cell reactive immunity against amylase might contribute to β-cell destruction in fulminant type 1 diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I183,I183)","v":27335827},{"$f":"(LEN($J183) - LEN(SUBSTITUTE(LOWER($J183),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J183) - LEN(SUBSTITUTE(LOWER($J183),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J183) - LEN(SUBSTITUTE(LOWER($J183),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B183:D183)","v":7},2013,"Roles of Vitamin A Metabolism in the Development of Hepatic Insulin Resistance.","Chen",27335827,"Roles of Vitamin A Metabolism in the Development of Hepatic Insulin Resistance.    Abstract:   The increase in the number of people with obesity- and noninsulin-dependent diabetes mellitus has become a major public health concern. Insulin resistance is a common feature closely associated with human obesity and diabetes. Insulin regulates metabolism, at least in part, via the control of the expression of the hepatic genes involved in glucose and fatty acid metabolism. Insulin resistance is always associated with profound changes of the expression of hepatic genes for glucose and lipid metabolism. As an essential micronutrient, vitamin A (VA) is needed in a variety of physiological functions. The active metablite of VA, retinoic acid (RA), regulates the expression of genes through the activation of transcription factors bound to the RA-responsive elements in the promoters of RA-targeted genes. Recently, retinoids have been proposed to play roles in glucose and lipid metabolism and energy homeostasis. This paper summarizes the recent progresses in our understanding of VA metabolism in the liver and of the potential transcription factors mediating RA responses. These transcription factors are the retinoic acid receptor, the retinoid X receptor, the hepatocyte nuclear factor 4α, the chicken ovalbumin upstream promoter-transcription factor II, and the peroxisome proliferator-activated receptor β/δ. This paper also summarizes the effects of VA status and RA treatments on the glucose and lipid metabolism in vivo and the effects of retinoid treatments on the expression of insulin-regulated genes involved in the glucose and fatty acid metabolism in the primary hepatocytes. I discuss the roles of RA production in the development of insulin resistance in hepatocytes and proposes a mechanism by which RA production may contribute to hepatic insulin resistance. Given the large amount of information and progresses regarding the physiological functions of VA, this paper mainly focuses on the findings in the liver and hepatocytes and only mentions the relative findings in other tissues and cells."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I184,I184)","v":23129325},{"$f":"(LEN($J184) - LEN(SUBSTITUTE(LOWER($J184),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J184) - LEN(SUBSTITUTE(LOWER($J184),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J184) - LEN(SUBSTITUTE(LOWER($J184),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B184:D184)","v":7},2012,"Contrasting effects of type 2 and type 1 diabetes on plasma RBP4 levels: the significance of transthyretin.","Pullakhandam",23129325,"Contrasting effects of type 2 and type 1 diabetes on plasma RBP4 levels: the significance of transthyretin.    Abstract:   Retinol-binding protein 4 (RBP4) is the principle carrier of retinol in the human plasma, which circulates as a complex with transthyretin (TTR), a homotetrameric thyroxine transport protein. Although this complex formation is thought to prevent glomerular filtration of RBP4, it also stabilizes the quaternary structure of TTR. Recent studies indicate elevated plasma levels of RBP4 in type 2 diabetes (T2D). In contrast, reduced RBP4 levels were observed in type 1 diabetes (T1D). Herein, we critically examine the probable mechanisms involved in the regulation of RBP4 and TTR levels during T2D and T1D. The available evidences point to the involvement of pancreatic factors in regulating the expression of both RBP4 and TTR. It appears that during T1D, TTR levels are reduced and it exists predominantly as a monomer that may interfere its interaction with RBP4 resulting in its loss through glomerular filtration. However, plasma TTR levels remain high under T2D conditions and thus reducing glomerular filtration of RBP4. Therefore, the plasma TTR levels appear to be an important determinant of plasma RBP4 levels in these two diabetic conditions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I185,I185)","v":23053561},{"$f":"(LEN($J185) - LEN(SUBSTITUTE(LOWER($J185),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J185) - LEN(SUBSTITUTE(LOWER($J185),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J185) - LEN(SUBSTITUTE(LOWER($J185),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B185:D185)","v":7},2012,"The formation, occurrence, and function of β-apocarotenoids: β-carotene metabolites that may modulate nuclear receptor signaling.","Harrison",23053561,"The formation, occurrence, and function of β-apocarotenoids: β-carotene metabolites that may modulate nuclear receptor signaling.    Abstract:   β-Carotene is the major dietary source of provitamin A. Central cleavage of β-carotene yields 2 molecules of retinal followed by further oxidation to retinoic acid. Eccentric cleavage of β-carotene occurs at double bonds other than the central double bond, and the products of these reactions are β-apocarotenals and β-apocarotenones. We reviewed recent developments in 3 areas: 1): the enzymatic production of β-apocarotenoids in higher animals; 2) the occurrence of β-apocarotenoids in foods and animal tissues; and 3) the biological activity of β-apocarotenoids, particularly on retinoid receptors. HPLC-mass spectrometry techniques were developed to quantify these compounds in mouse serum and tissues and in foods. β-Apo-10- and -12-carotenals were detected in mouse serum and liver. β-Apo-8-, β-apo-10-, β-apo-12-, and β-apo-14-carotenals and β-apo-13-carotenone were detected in orange-fleshed melons. Transactivation assays were performed to see whether apocarotenoids activate or antagonize retinoid X receptor (RXR) α. Reporter gene constructs and retinoid receptor (RXRα) were transfected into cells, which were used to perform quantitative assays for the activation of this ligand-dependent transcription factor. None of the β-apocarotenoids significantly activated RXRα. However, β-apo-13-carotenone antagonized the 9-cis-retinoic acid activation of RXRα. Competitive radioligand binding assays showed that this antagonist competes directly with the agonist for binding to purified receptor, a finding confirmed by molecular modeling studies. These findings suggest that a possible biological function of β-apocarotenoids is their ability to interfere with nuclear receptor signaling. Recent work showed that β-apo-13-carotenone is also a high-affinity antagonist of all 3 retinoic acid receptors (RARα, RARβ, and RARγ)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I186,I186)","v":22577845},{"$f":"(LEN($J186) - LEN(SUBSTITUTE(LOWER($J186),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J186) - LEN(SUBSTITUTE(LOWER($J186),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J186) - LEN(SUBSTITUTE(LOWER($J186),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B186:D186)","v":7},2012,"Retinoids: novel immunomodulators and tumour-suppressive agents?","Carratù",22577845,"Retinoids: novel immunomodulators and tumour-suppressive agents?    Abstract:   Retinoids play important roles in the transcriptional activity of normal, degenerative and tumour cells. Retinoid analogues may be promising therapeutic agents for the treatment of immune disorders as different as type I diabetes and systemic lupus erythematosus. In addition, the use of retinoids in cancer treatment has progressed significantly in the last two decades; thus, numerous retinoid compounds have been synthesized and tested. In this paper, the actual or potential use of retinoids as immunomodulators or tumour-suppressive agents is discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I187,I187)","v":21782034},{"$f":"(LEN($J187) - LEN(SUBSTITUTE(LOWER($J187),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J187) - LEN(SUBSTITUTE(LOWER($J187),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J187) - LEN(SUBSTITUTE(LOWER($J187),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B187:D187)","v":7},2012,"Signaling by vitamin A and retinol-binding protein in regulation of insulin responses and lipid homeostasis.","Berry",21782034,"Signaling by vitamin A and retinol-binding protein in regulation of insulin responses and lipid homeostasis.    Abstract:   Vitamin A, retinol, circulates in blood bound to serum retinol binding protein (RBP) and is transported into cells by a membrane protein termed stimulated by retinoic acid 6 (STRA6). It was reported that serum levels of RBP are elevated in obese rodents and humans, and that increased level of RBP in blood causes insulin resistance. A molecular mechanism by which RBP can exert such an effect is suggested by the recent discovery that STRA6 is not only a vitamin A transporter but also functions as a surface signaling receptor. Binding of RBP-ROH to STRA6 induces the phosphorylation of a tyrosine residue in the receptor C-terminus, thereby activating a JAK/STAT signaling cascade. Consequently, in STRA6-expressing cells such as adipocytes, RBP-ROH induces the expression of STAT target genes, including SOCS3, which suppresses insulin signaling, and PPARγ, which enhances lipid accumulation. RBP-retinol thus joins the myriad of cytokines, growth factors and hormones which regulate gene transcription by activating cell surface receptors that signal through activation of Janus kinases and their associated transcription factors STATs. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I188,I188)","v":21515403},{"$f":"(LEN($J188) - LEN(SUBSTITUTE(LOWER($J188),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J188) - LEN(SUBSTITUTE(LOWER($J188),LOWER(C$3),\"\")))/LEN(C$3)","v":4},{"$f":"(LEN($J188) - LEN(SUBSTITUTE(LOWER($J188),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B188:D188)","v":7},2012,"Modulation of RXR function through ligand design.","Pérez",21515403,"Modulation of RXR function through ligand design.    Abstract:   As the promiscuous partner of heterodimeric associations, retinoid X receptors (RXRs) play a key role within the Nuclear Receptor (NR) superfamily. Some of the heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) are quot;permissivequot; as they become transcriptionally active in the sole presence of either an RXR-selective ligand (quot;rexinoidquot;) or a NR partner ligand. In contrast, quot;non-permissivequot; heterodimers (including RAR/RXR, VDR/RXR and TR/RXR) are unresponsive to rexinoids alone but these agonists superactivate transcription by synergizing with partner agonists. Despite their promiscuity in heterodimer formation and activation of multiple pathways, RXR is a target for drug discovery. Indeed, a rexinoid is used in the clinic for the treatment of cutaneous T-cell lymphoma. In addition to cancer RXR modulators hold therapeutical potential for the treatment of metabolic diseases. The modulation potential of the rexinoid (as agonist or antagonist ligand) is dictated by the precise conformation of the ligand-receptor complexes and the nature and extent of their interaction with co-regulators, which determine the specific physiological responses through transcription modulation of cognate gene networks. Notwithstanding the advances in this field, it is not yet possible to predict the correlation between ligand structure and physiological response. We will focus on this review on the modulation of PPARγ/RXR and LXR/RXR heterodimer activities by rexinoids. The genetic and pharmacological data from animal models of insulin resistance, diabetes and obesity demonstrate that RXR agonists and antagonists have promise as anti-obesity agents. However, the treatment with rexinoids raises triglycerides levels, suppresses the thyroid hormone axis, and induces hepatomegaly, which has complicated the development of these compounds as therapeutic agents for the treatment of type 2 diabetes and insulin resistance. The discovery of PPARγ/RXR and LXR/RXR heterodimer-selective rexinoids, which act differently than PPARγ or LXR agonists, might overcome some of these limitations."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I189,I189)","v":20140749},{"$f":"(LEN($J189) - LEN(SUBSTITUTE(LOWER($J189),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J189) - LEN(SUBSTITUTE(LOWER($J189),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J189) - LEN(SUBSTITUTE(LOWER($J189),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B189:D189)","v":7},2010,"From carrot to clinic: an overview of the retinoic acid signaling pathway.","Theodosiou",20140749,"From carrot to clinic: an overview of the retinoic acid signaling pathway.    Abstract:   Vitamin A is essential for the formation and maintenance of many body tissues. It is also important for embryonic growth and development and can act as a teratogen at critical periods of development. Retinoic acid (RA) is the biologically active form of vitamin A and its signaling is mediated by the RA and retinoid X receptors. In addition to its role as an important molecule during development, RA has also been implicated in clinical applications, both as a potential anti-tumor agent as well as for the treatment of skin diseases. This review presents an overview of how dietary retinoids are converted to RA, hence presenting the major players in RA metabolism and signaling, and highlights examples of treatment applications of retinoids. Moreover, we discuss the origin and diversification of the retinoid pathway, which are important factors for understanding the evolution of ligand-specificity among retinoid receptors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I190,I190)","v":17882463},{"$f":"(LEN($J190) - LEN(SUBSTITUTE(LOWER($J190),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J190) - LEN(SUBSTITUTE(LOWER($J190),LOWER(C$3),\"\")))/LEN(C$3)","v":4},{"$f":"(LEN($J190) - LEN(SUBSTITUTE(LOWER($J190),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B190:D190)","v":7},2008,"Role of fatty acid binding proteins and long chain fatty acids in modulating nuclear receptors and gene transcription.","Schroeder",17882463,"Role of fatty acid binding proteins and long chain fatty acids in modulating nuclear receptors and gene transcription.    Abstract:   Abnormal energy regulation may significantly contribute to the pathogenesis of obesity, diabetes mellitus, cardiovascular disease, and cancer. For rapid control of energy homeostasis, allosteric and posttranslational events activate or alter activity of key metabolic enzymes. For longer impact, transcriptional regulation is more effective, especially in response to nutrients such as long chain fatty acids (LCFA). Recent advances provide insights into how poorly water-soluble lipid nutrients [LCFA; retinoic acid (RA)] and their metabolites (long chain fatty acyl Coenzyme A, LCFA-CoA) reach nuclei, bind their cognate ligand-activated receptors, and regulate transcription for signaling lipid and glucose catabolism or storage: (i) while serum and cytoplasmic LCFA levels are in the 200 mircroM-mM range, real-time imaging recently revealed that LCFA and LCFA-CoA are also located within nuclei (nM range); (ii) sensitive fluorescence binding assays show that LCFA-activated nuclear receptors [peroxisome proliferator-activated receptor-alpha (PPARalpha) and hepatocyte nuclear factor 4alpha (HNF4alpha)] exhibit high affinity (low nM KdS) for LCFA (PPARalpha) and/or LCFA-CoA (PPARalpha, HNF4alpha)-in the same range as nuclear levels of these ligands; (iii) live and fixed cell immunolabeling and imaging revealed that some cytoplasmic lipid binding proteins [liver fatty acid binding protein (L-FABP), acyl CoA binding protein (ACBP), cellular retinoic acid binding protein-2 (CRABP-2)] enter nuclei, bind nuclear receptors (PPARalpha, HNF4alpha, CRABP-2), and activate transcription of genes in fatty acid and glucose metabolism; and (iv) studies with gene ablated mice provided physiological relevance of LCFA and LCFA-CoA binding proteins in nuclear signaling. This led to the hypothesis that cytoplasmic lipid binding proteins transfer and channel lipidic ligands into nuclei for initiating nuclear receptor transcriptional activity to provide new lipid nutrient signaling pathways that affect lipid and glucose catabolism and storage."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I191,I191)","v":17867372},{"$f":"(LEN($J191) - LEN(SUBSTITUTE(LOWER($J191),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J191) - LEN(SUBSTITUTE(LOWER($J191),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J191) - LEN(SUBSTITUTE(LOWER($J191),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B191:D191)","v":7},2007,"Identification of a membrane receptor for retinol-binding protein functioning in the cellular uptake of retinol.","Wolf",17867372,"Identification of a membrane receptor for retinol-binding protein functioning in the cellular uptake of retinol.    Abstract:   Retinol-binding protein (RBP) is the transport protein that carries retinol in the circulation from the liver to its target tissues. The existence of a cell-surface receptor on the target cells, which mediates the uptake of retinol from RBP, has been known since 1975. Recently, it was identified as an integral transmembrane protein named STRA6 that is inducible by retinoic acid in certain cancer cells. The receptor was found to be highly specific for RBP, with high affinity, and to be localized in all tissues known to require retinol for their function, particularly the pigment epithelium of the eye."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I192,I192)","v":17368314},{"$f":"(LEN($J192) - LEN(SUBSTITUTE(LOWER($J192),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J192) - LEN(SUBSTITUTE(LOWER($J192),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J192) - LEN(SUBSTITUTE(LOWER($J192),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B192:D192)","v":7},2007,"Conversion of beta-carotene to retinal pigment.","Biesalski",17368314,"Conversion of beta-carotene to retinal pigment.    Abstract:   Vitamin A and its active metabolite retinoic acid (RA)(1) play a major role in development, differentiation, and support of various tissues and organs of numerous species. To assure the supply of target tissues with vitamin A, long-lasting stores are built in the liver from which retinol can be transported by a specific protein to the peripheral tissues to be metabolized to either RA or reesterified to form intracellular stores. Vitamin A cannot be synthesized de novo by animals and thus has to be taken up from animal food sources or as provitamin A carotenoids, the latter being converted by central cleavage of the molecule to retinal in the intestine. The recent demonstration that the responsible beta-carotene cleaving enzyme beta,beta-carotene 15,15-monooxygenase (Bcmo1) is also present in other tissues led to numerous investigations on the molecular structure and function of this enzyme in several species, including the fruit fly, chicken, mouse, and also human. Also a second enzyme, beta,beta-carotene-9,10-monooxygenase (Bcmo2), which cleaves beta-carotene eccentrically to apo-carotenals has been described. Retinal pigment epithelial cells were shown to contain Bcmo1 and to be able to cleave beta-carotene into retinal in vitro, offering a new pathway for vitamin A production in another tissue than the intestine, possibly explaining the more mild vitamin A deficiency symptoms of two human siblings lacking the retinol-binding protein for the transport of hepatic vitamin A to the target tissues. In addition, alternative ways to combat vitamin A deficiency of specific targets by the supplementation with beta-carotene or even molecular therapies seem to be the future."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I193,I193)","v":17306620},{"$f":"(LEN($J193) - LEN(SUBSTITUTE(LOWER($J193),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J193) - LEN(SUBSTITUTE(LOWER($J193),LOWER(C$3),\"\")))/LEN(C$3)","v":6},{"$f":"(LEN($J193) - LEN(SUBSTITUTE(LOWER($J193),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B193:D193)","v":7},2007,"Transcription coactivators for peroxisome proliferator-activated receptors.","Yu",17306620,"Transcription coactivators for peroxisome proliferator-activated receptors.    Abstract:   Peroxisome proliferator-activated receptors (PPARs) regulate diverse biological processes such as development, differentiation, neoplastic conversion, inflammation and wound healing in addition to their critical roles in energy (lipid and carbohydrate) metabolism. Unliganded PPARs heterodimerize with retinoid X receptor alpha and repress transcription when bound to DNA by interacting with corepressor molecules. Upon canonical ligand binding, PPARs manifest conformational changes that facilitate the dissociation of corepressor molecules to enable a spatiotemporally orchestrated recruitment (association) of coactivators and coactivator-associated proteins to the liganded receptor. Functional significance for the existence of over 200 nuclear receptor cofactors is not readily evident, but emerging gene knockout mouse models show that some of the coactivators are essential for embryonic growth and survival and for controlling receptor specific target gene expression in a cell specific need based demands. Coactivators contain one or more highly conserved LXXLL amphiphatic alpha-helix motif, called nuclear receptor box, for direct interaction with the activation function 2 (AF-2) regions in nuclear receptors. PPARs interact with large multisubunit coactivator protein complexes, some exhibiting intrinsic histone acetyltransferase or methyltransferase activity, while others functioning as facilitators of ATP-dependent chromatin remodeling or as linkers to the basal transcription machinery. While the dynamic and coordinated changes in nuclear receptor expression and differences in the nature of their key target genes are important, it is becoming increasingly evident that perturbations in the expression of coactivators may affect the function of many nuclear receptors including PPARs. Tissue specific differences in coactivator expression add another dimension to the complexity of gene- and cell-specific transcriptional regulation. Identification of PPAR specific coactivators should further our understanding of the complexities of metabolic diseases associated with energy metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I194,I194)","v":16105480},{"$f":"(LEN($J194) - LEN(SUBSTITUTE(LOWER($J194),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J194) - LEN(SUBSTITUTE(LOWER($J194),LOWER(C$3),\"\")))/LEN(C$3)","v":4},{"$f":"(LEN($J194) - LEN(SUBSTITUTE(LOWER($J194),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B194:D194)","v":7},2005,"Impact of thiazolidinedione therapy on atherogenesis.","van Wijk",16105480,"Impact of thiazolidinedione therapy on atherogenesis.    Abstract:   Thiazolidinediones (TZDs), which are synthetic ligands for peroxisome proliferator activated receptor g (PPARg) activation, have been introduced in clinical medicine to improve insulin resistance and glycemic control in patients with type 2 diabetes. The metabolic effects of TZDs are mediated by receptor-dependent activation of the PPARg-retinoid X receptor (RXR) complex and subsequent transcriptional activation of target genes. The PPARg1 isoform is also expressed in endothelial cells, vascular smooth muscle cells, and monocytes/macrophages in the vasculature. TZDs have been shown to have anti-atherosclerotic effects on these cells in vitro, which appear to be partially independent of the PPARg-RXR-mediated transcriptional effects. Direct anti-atherosclerotic effects of TZDs include increased nitric oxide bioavailability, decreased leukocyte/endothelial cell interaction, reduced vascular smooth muscle cell migration and proliferation, and cholesterol efflux from macrophages. So far, there are no data on the effects of TZDs on cardiovascular events, but studies using surrogate markers of vascular disease provide preliminary evidence that TZDs delay progression of atherosclerosis in different patient groups. TZDs interfere with key processes in atherogenesis and may, therefore, offer additional opportunities to improve cardiovascular risk beyond treatment of glycemic control in patients with type 2 diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I195,I195)","v":15828222},{"$f":"(LEN($J195) - LEN(SUBSTITUTE(LOWER($J195),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J195) - LEN(SUBSTITUTE(LOWER($J195),LOWER(C$3),\"\")))/LEN(C$3)","v":5},{"$f":"(LEN($J195) - LEN(SUBSTITUTE(LOWER($J195),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B195:D195)","v":7},2005,"[PPARs target genes].","Takada",15828222,"[PPARs target genes].    Abstract:   PPAR(alpha, beta/delta, gamma) are ligand-dependent nuclear receptors and regulate homeostasis, cell proliferation/differentiation and associate with hypolipidemia, atherosclerosis, diabetes, and obesity. Through heterodimerization with retinoid X receptors (RXRs), PPARs bind the same consensus response element, formed by a direct repeat of two AGGTCA hexamers separated by one base. Recently, many PPAR direct and indirect target genes have been reported. Here, we summarize the PPAR direct/indirect target genes, and their functions related to lipid metabolism, adipocyte differentiation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I196,I196)","v":15709903},{"$f":"(LEN($J196) - LEN(SUBSTITUTE(LOWER($J196),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J196) - LEN(SUBSTITUTE(LOWER($J196),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J196) - LEN(SUBSTITUTE(LOWER($J196),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B196:D196)","v":7},2005,"Efficacy and safety of oral retinoids in psoriasis.","Van Zander",15709903,"Efficacy and safety of oral retinoids in psoriasis.    Abstract:   With the advent of new biological agents, interest in the treatment of psoriasis has been renewed. Vitamin A and its derivatives (retinoids) have been used successfully in the treatment of psoriasis for over 30 years. In this paper, data on the efficacy and safety of oral retinoids for the treatment of various forms of psoriasis is reviewed. Studies have shown that retinoids are particularly effective in the treatment of pustular and palmoplantar psoriasis. When used in conjunction with ultraviolet therapy, retinoids appear to have a synergistic effect and can be used safely as long-term maintenance therapy. The most common side effects of oral retinoids are usually modest, treatable or reversible, and predominantly affect the liver, musculoskeletal and neurological systems. Potential teratogenicity remains the primary concern with use in women. Oral retinoids appear to be well tolerated in paediatric and HIV-infected patients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I197,I197)","v":15639998},{"$f":"(LEN($J197) - LEN(SUBSTITUTE(LOWER($J197),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J197) - LEN(SUBSTITUTE(LOWER($J197),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J197) - LEN(SUBSTITUTE(LOWER($J197),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B197:D197)","v":7},2004,"[Molecular biology of the retinol-binding proteins and their genes].","Guo",15639998,"[Molecular biology of the retinol-binding proteins and their genes].    Abstract:   Retinol-binding proteins (RBPs) are a kind of circulating carrier proteins for serum and cellular retinol and retinol acid, which are lipid-soluble vitamins, and are members of hydrophobic binding protein family. Serum RBPs were synthesized primarily in liver, then was released into blood streams, and then to various tissues. Under the interaction with substances such as retinol, pre-albumin and the receptors of cellular surface, they play important roles in storage, metabolism of VitA and transport of VitA to the target cells. Cellular RBPs play the similar function as serum RBPs in intracell. This review introduces action mechanism, tissue localization and developmental expression of retinol-binding proteins. This review also introduces the structure, chromosome mapping and their relationships with reproductive performance of retinol-binding protein genes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I198,I198)","v":14754643},{"$f":"(LEN($J198) - LEN(SUBSTITUTE(LOWER($J198),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J198) - LEN(SUBSTITUTE(LOWER($J198),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J198) - LEN(SUBSTITUTE(LOWER($J198),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B198:D198)","v":7},2004,"Single-center retrospective study of long-term use of low-dose acitretin (Soriatane) for psoriasis.","Lee",14754643,"Single-center retrospective study of long-term use of low-dose acitretin (Soriatane) for psoriasis.    Abstract:    BACKGROUND : Indicated as monotherapy for severe psoriasis in adults, acitretin (Soriatane) can be used in combination therapy or as a disease-stabilizing, maintenance agent. While its efficacy for psoriasis and other disorders of keratinization is well established, its safety is often a concern for many dermatologists. The possible side effects associated with short-term treatment of oral retinoids include mucocutaneous effects, elevation in serum lipid chemistries and liver enzymes, and teratogenicity. However, the only possible long-term, cumulative side effect is skeletal and ligamentous calcification such as hyperostosis. There is a specific syndrome of hyperostosis associated with oral retinoids called DISH (diffuse idiopathic skeletal hyperostosis).  OBJECTIVE : To examine the incidence of DISH syndrome in long-term acitretin use for psoriasis and to quantify the incidence of other side effects.  METHODS : All patients seen at the UCSF Psoriasis and Skin Treatment Center who had been on acitretin for more than 1 year were identified.  RESULTS : A chart review of these patients revealed no X-ray-confirmed cases of DISH syndrome, minimal changes in coronary heart disease risk indicators, and extremely rare significant elevation of liver enzymes.  CONCLUSION : Acitretin does not appear to cause significant long-term side effects at low doses; the implications for thousands of patients are that use of this medication can be continued for long periods of time with routine monitoring."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I199,I199)","v":14704327},{"$f":"(LEN($J199) - LEN(SUBSTITUTE(LOWER($J199),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J199) - LEN(SUBSTITUTE(LOWER($J199),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J199) - LEN(SUBSTITUTE(LOWER($J199),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B199:D199)","v":7},2004,"Alpha and omega of carotenoid cleavage.","Lakshman",14704327,"Alpha and omega of carotenoid cleavage.    Abstract:   In early 1900s, based on indirect evidence, Steenbock and Morton independently predicted that beta-carotene could be the biological precursor of vitamin A, although this notion was contested by others. In the 1930s, Thomas Moore showed the in vivo formation of vitamin A from beta-carotene. But it was not until Jim Olson and DeWitt Goodman independently showed in 1965 the formation of retinal, the aldehyde form of vitamin A from beta-carotene in cell-free extracts of liver and intestine, that this vital pathway of beta-carotene was recognized. Despite compelling evidence in several experimental systems for the central cleavage of beta-carotene to retinal by many investigators, there were some careful independent studies by Glover et al., Ganguly et al., Hansen and Meret and Krinsky et al. showing the eccentric cleavage of beta-carotene resulting in the formation of apocarotenoids both in vivo and in vitro. In an attempt to resolve this controversial issue, we revisited this problem in 1989 and showed beyond doubt the formation of retinal as the sole enzymatic product of a cytosolic enzyme from rabbit and rat intestinal mucosa by mass spectrometry and tracer analysis of the crystallized product. This was confirmed in 1996 by Nagao using the pig intestinal extract. Yeum et al. confirmed in 2000 that retinal is the sole product of beta-carotene cleavage in the presence of alpha-tocopherol, and that the observed formation of apocarotenoids occurs only in the absence of an antioxidant like alpha-tocopherol. In the same year, Barua and Olson also concluded from their in vivo studies in rats that central cleavage is by far the major pathway for the formation of vitamin A from beta-carotene. Beta, beta-carotene 15,15-dioxygenase (EC 1.13.11.21) is the key enzyme that cleaves beta-carotene into two molecules of retinal. It is a cytosolic enzyme primarily localized in the duodenal mucosa although it has been found in liver. It is a 66 kDa sulfhydryl protein, requires molecular oxygen and is activated by ferrous ions. It is highly specific for 15:15 ethylenic bond of carotenoids although it has fairly broad specificity towards a number of carotenoids with at least one intact beta-ionone ring. The dioxygenase was recently cloned from Drosophila melanogaster and from the chicken intestine. The recombinant protein was found to form retinal as the sole cleavage product of beta-carotene. No apo-carotenoids were formed. Therefore, it is unequivocally proven that the major, if not the sole, pathway of beta-carotene cleavage to vitamin A is by oxidative cleavage of the central ethylenic bond of beta-carotene to yield two molecules of retinal. Most recently, human dioxygenase has also been cloned. Thus, the wisdom, vision and epoch-making mission of Jim Olson in the science of beta-carotene metabolism have been accomplished. I have no doubt that the impact of his original discovery of the dioxygenase and its importance in vitamin A nutriture should be forthcoming in the near future."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I200,I200)","v":12894062},{"$f":"(LEN($J200) - LEN(SUBSTITUTE(LOWER($J200),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J200) - LEN(SUBSTITUTE(LOWER($J200),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J200) - LEN(SUBSTITUTE(LOWER($J200),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B200:D200)","v":7},2003,"Oral retinoid therapy for dermatologic conditions in children and adolescents.","Brecher",12894062,"Oral retinoid therapy for dermatologic conditions in children and adolescents.    Abstract:   The efficacy of systemic retinoid therapy in a number of dermatologic diseases is well established; however, concerns about potential side effects limit their use, especially in children. We review the efficacy and toxicity of oral retinoids in the pediatric population. The acute mucocutaneous toxicities commonly observed are typically well tolerated, readily treatable, and reversible. Systemic toxicities include teratogenicity and effects on the musculoskeletal, neurologic, and gastrointestinal systems. Children, like adults, generally tolerate short-term retinoid therapy without major complications. Concerns regarding serious systemic side effects are greater for those on high doses of oral synthetic retinoids for longer periods of time. Close patient monitoring and patient education can minimize the occurrence of complications. (J Am Acad Dermatol 2003;49:171-82.)Learning objective At the conclusion of this learning activity, participants should be familiar with use of oral retinoids for childhood dermatologic conditions such as psoriasis, acne, and ichthyoses as well as safety and risks associated with oral retinoid use in children and adolescents."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I201,I201)","v":12644382},{"$f":"(LEN($J201) - LEN(SUBSTITUTE(LOWER($J201),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J201) - LEN(SUBSTITUTE(LOWER($J201),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J201) - LEN(SUBSTITUTE(LOWER($J201),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B201:D201)","v":7},2003,"Differentiation of embryonic stem cells for pharmacological studies on adipose cells.","Phillips",12644382,"Differentiation of embryonic stem cells for pharmacological studies on adipose cells.    Abstract:   The ongoing global explosion in the incidence of obesity has focused attention on the development of adipose cells. Severe obesity is the result of an increase in fat cell size in combination with increased fat cell number. New fat cells arise from a pre-existing pool of adipose stem cells that are present irrespective of age. The development of established preadipocyte cell lines has facilitated the study of different steps leading to terminal differentiation. However, these systems are limited for studying early events of differentiation as they represent cells which are already determined for the adipogenic lineage. In vitro differentiation of mouse embryonic stem (ES) cells towards the adipogenic lineage provides an alternative source of adipocytes for study in tissue culture and offers the possibility to investigate regulation of the first steps of adipose cell development. In this review, we describe the sequential requirement of retinoic acid and PPARgamma during adipogenesis in ES cells. Stimulation of ES cells with synthetic retinoids which are selective ligands of the retinoic acid receptor isotypes allowed the investigation of the contribution of the different retinoic receptors on the RA-dependent differentiation. The effects of thiazolidinediones, a new class of pharmacological agents used for the treatment of type 2 diabetes, and of statins, drugs used in therapy for lowering cholesterol, on the differentiation of ES cells into adipocytes or osteoblasts are described. Finally, we propose a model in which PPARgamma plays a key role in the decision of stem cells to undergo differentiation into adipocytes or osteoblasts, two closely related lineages."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I202,I202)","v":12476796},{"$f":"(LEN($J202) - LEN(SUBSTITUTE(LOWER($J202),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J202) - LEN(SUBSTITUTE(LOWER($J202),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J202) - LEN(SUBSTITUTE(LOWER($J202),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B202:D202)","v":7},2001,"Molecular basis for designing selective modulators of retinoic acid receptor transcriptional activities.","Lefebvre",12476796,"Molecular basis for designing selective modulators of retinoic acid receptor transcriptional activities.    Abstract:   Retinoic acid receptors are ligand-regulated transcription factors belonging to the nuclear receptor superfamily, which comprises 49 members in the human genome. all-trans retinoic acid and 9-cis retinoic acid receptors (RARs and RXRs) are each encoded by three distinct genes and several isoforms arise from alternative splicing and the use of different promoters. While RXRs are promiscuous dimerization partners of several other nuclear receptors, RARs are active, in-vivo, when associated to RXRs. Retinoids are therefore regulators of multiple physiological processes, from embryogenesis to metabolism. Different combinations of RXR:RAR heterodimers occur as a function of their tissue-specific expression and their activity is mostly conditioned by the activation status of RAR. These heterodimers are defined as non permissive heterodimers, in opposition to permissive dimers whose transcriptional activity may be modulated through RXR and its dimerization partner. The transcriptional activity of these dimers also relies on their ability to recruit nuclear coactivators and corepressors, which function as multi proteic complexes harboring several enzymatic activities (acetylases, kinases). The structure of the ligand bound to the RAR moiety of the dimer, as well as the nature of the DNA sequence to which dimers are bound, dictate the relative affinity of dimers for coactivators and thus its overall transcriptional activity. RARs are also able to repress the activity of unrelated transcription factors such as AP1 and NF-kappa-B, and therefore have potent anti proliferative and anti inflammatory properties. This review summarizes our current view of molecular mechanisms governing these various activities and emphasizes the need for a detailed understanding of how retinoids may dictate transactivating and transrepressive properties of RARs and RXRs, which may be considered as highly valuable therapeutic targets in many diseases such as cancer, skin hyperproliferation and metabolical disorders (diabetes, atherosclerosis etc)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I203,I203)","v":11796231},{"$f":"(LEN($J203) - LEN(SUBSTITUTE(LOWER($J203),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J203) - LEN(SUBSTITUTE(LOWER($J203),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J203) - LEN(SUBSTITUTE(LOWER($J203),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B203:D203)","v":7},2002,"Retinoids and their receptors in cancer development and chemoprevention.","Sun",11796231,"Retinoids and their receptors in cancer development and chemoprevention.    Abstract:   Retinoids play an important role in regulating the growth and differentiation of normal, premalignant and malignant cell types, especially epithelial cells, mainly through interaction with two types of nuclear receptors: retinoic acid receptors (RARalpha, beta and gamma) and retinoid X receptors (RXRalpha, beta and gamma). Vitamin A deficiency in experimental animals has been associated with a higher incidence of cancer and with increased susceptibility to chemical carcinogens. This is in agreement with the epidemiological studies indicating that individuals with a lower dietary vitamin A intake are at a higher risk to develop cancer. At the molecular level, aberrant expression and function of nuclear retinoid receptors have been found in various types of cancer including premalignant lesions. Thus, aberrations in retinoid signaling are early events in carcinogenesis. Retinoids at pharmacological doses exhibit a variety of effects associated with cancer prevention. They suppress transformation of cells in vitro, inhibit carcinogenesis in various organs in animal models, reduce premalignant human epithelial lesions and prevent second primary tumors following curative therapy for epithelial malignancies such as head and neck, lung, liver, and breast cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I204,I204)","v":11779708},{"$f":"(LEN($J204) - LEN(SUBSTITUTE(LOWER($J204),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J204) - LEN(SUBSTITUTE(LOWER($J204),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J204) - LEN(SUBSTITUTE(LOWER($J204),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B204:D204)","v":7},2002,"Retinoids in liver fibrosis and cancer.","Okuno",11779708,"Retinoids in liver fibrosis and cancer.    Abstract:   Pathobiological functions and metabolism of retinoids (vitamin A and its derivatives) in liver fibrosis and hepatocellular carcinoma (HCC) are discussed in the present review. Retinoic acid (RA, active metabolite) exacerbates liver fibrosis that is not accompanied by hepatic necroinflammation, in which RA acts directly on hepatic stellate cells (HSCs); RA enhances plasminogen activator/plasmin levels and thereby induces proteolytic activation of latent transforming growth factor-beta (TGF-beta), a strong fibrogenic cytokine, resulting in enhanced collagen production. We have developed a protease inhibitor, camostat mesilate, that suppresses TGF-beta activation and thereby inhibits the transformation of HSCs, leading to reduced matrix production by the cells. The compound is effective not only in preventing but also in reducing hepatic fibrosis in rats when administered orally. HCC is refractory to RA due to its local depletion in the tumors and also due to malfunction of its nuclear receptor, retinoid X receptor-alpha (RXRalpha) Oral supplementation of a synthetic retinoid named acyclic retinoid led to the disappearance of serum lectin-reactive alpha-fetoprotein (AFP-L3) and subsequently suppressed posttherapeutic recurrence of HCC in cirrhotic patients. These results suggest eradication of AFP-L3-producing latent malignant clones from the liver by the retinoid. We propose the concept of quot;clonal deletionquot; therapy for cancer chemoprevention, a new category of cancer chemotherapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I205,I205)","v":11712415},{"$f":"(LEN($J205) - LEN(SUBSTITUTE(LOWER($J205),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J205) - LEN(SUBSTITUTE(LOWER($J205),LOWER(C$3),\"\")))/LEN(C$3)","v":7},{"$f":"(LEN($J205) - LEN(SUBSTITUTE(LOWER($J205),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B205:D205)","v":7},2001,"[The molecular mechanisms by which PPAR gamma/RXR inhibitors improve insulin resistance].","Yamauchi",11712415,"[The molecular mechanisms by which PPAR gamma/RXR inhibitors improve insulin resistance].    Abstract:   Potent activation of PPAR gamma by thiazolidinediones(TZD) increases TG content of WAT, thereby decreasing TG content of liver/muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPAR gamma activity by PPAR gamma/RXR inhibitors decreases TG content of WAT/muscle/liver due to increased leptin and increase in fatty-acid combustion and decrease in lipogenesis, thereby ameliorating HF diet-induced obesity and insulin resistance. Moreover, PPAR gamma/RXR inhibitors decrease lipogenesis in WAT, while TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in FFA, and TNF alpha, and upregulation of adiponectin. We conclude that although by different mechanisms, both PPAR gamma/RXR inhibitors and PPAR gamma agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I206,I206)","v":11452221},{"$f":"(LEN($J206) - LEN(SUBSTITUTE(LOWER($J206),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J206) - LEN(SUBSTITUTE(LOWER($J206),LOWER(C$3),\"\")))/LEN(C$3)","v":6},{"$f":"(LEN($J206) - LEN(SUBSTITUTE(LOWER($J206),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B206:D206)","v":7},2001,"[Mechanisms of action of thiazolidinediones].","Girard",11452221,"[Mechanisms of action of thiazolidinediones].    Abstract:   The recent discovery and marketing of a new class of antidiabetic drug improving insulin sensitivity, the thiazolidinediones (TZD), has opened interesting therapeutic perspectives. Those molecules correct hyperglycemia and hyperinsulinemia in several animal models of NIDDM. Clinical studies in human have confirmed that TZD lowered postprandial and postabsorptive glycemia and insulinemia. Glucose clamp studies have clearly shown an improvement of insulin-induced glucose utilization (in skeletal muscle). In contrast, the inhibition of glucose production in response to insulin was much less reproducible. TZD have also been used with success to treat insulin resistance in non-diabetic obeses, in glucose-intolerant prediabetic subjects and in patients with polycystic ovary syndrome (pcos). Nevertheless, TZD appears less efficient in human than in animal models. TZD bind to an isoform of a nuclear receptor, the PPARgamma (Peroxisome Proliferator Activated Receptor). PPAR gamma is a transcription factor which, after heterodimerization with the retinoid receptor (RXR), bind to specific response elements of a number of target genes and control their transcription. There is an excellent correlation between the hypoglycemic effects of TZD in vivo and their affinity for PPARgamma in vitro, but the site of action and the molecular mechanism of TZD still remain poorly known. In human, skeletal muscles are responsible for more than 80% of glucose uptake in response to insulin. Unfortunately, skeletal muscles contain limited amounts of PPAR gamma. How TZD with the principal site of action being adipose tissue, can improve glucose metabolism in skeletal muscle? One possibility is the following Another possibility is that chronic treatment with TZD induces PPAR gamma expression in skeletal muscles. Finally, TZD could have a direct effect on skeletal muscles, independently of PPARgamma."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I207,I207)","v":11220289},{"$f":"(LEN($J207) - LEN(SUBSTITUTE(LOWER($J207),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J207) - LEN(SUBSTITUTE(LOWER($J207),LOWER(C$3),\"\")))/LEN(C$3)","v":3},{"$f":"(LEN($J207) - LEN(SUBSTITUTE(LOWER($J207),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B207:D207)","v":7},1999,"The relation between insulin resistance and cardiovascular complications of the insulin resistance syndrome.","Rett",11220289,"The relation between insulin resistance and cardiovascular complications of the insulin resistance syndrome.    Abstract:   It has been known for years that cardiovascular disease frequently precedes the development of type 2 diabetes, and that atherosclerosis might not be a complication of type 2 diabetes, but rather the consequence of common genetic and environmental factors (the common soil hypothesis). The insulin resistance syndrome (IRS) is a cluster of closely associated and interdependent abnormalities, including insulin resistance, hyperinsulinaemia, android fat distribution, progressive glucose intolerance, dyslipidaemia (increased triglycerides, decreased HDL, increased small dense LDL), increased prothrombotic and antifibrinolytic factors, and hypertension. Many of these abnormalities are risk factors for type 2 diabetes, and most of them explain the predilection for atherosclerosis to occur in conjunction with IRS. Insulin resistance is a key feature of IRS, and has been suggested to be the common pathophysiological basis of atherosclerosis and type 2 diabetes. The term insulin resistance denotes resistance to insulin-mediated glucose uptake into skeletal muscle, which can be measured by the glucose clamp technique. There are, however, other less understood sites of abnormal insulin action that may also be relevant in IRS. These include liver, adipose, and kidney tissue, and systems such as muscle perfusion, antilipolysis, lipoprotein lipase activity, and cation transport. The development of clinical cardiovascular end-points in a patient with insulin resistance is complex, as it includes the degree of the defect, its associated abnormalities, its consequences, and the ability to compensate for the underlying defect. It is therefore more appropriate to consider the different facets and risk factors of IRS in aggregate, rather than seeking independent effects. Accordingly, treatment of insulin resistance per se has not yet been shown to reduce the incidence of cardiovascular complications. At the cellular level, excess insulin is involved in various elements of atherogenesis. It interacts with cytokines and growth factors in a cross talk among vascular wall cells and a variety of mediators that play a role in the establishment of atheroma. Excess insulin also plays an important role in concert with lipoproteins when they exhibit an abnormal pattern and become modified by oxidation and glycation. It is therefore currently hoped that the introduction of a new class of insulin-sensitizing agents, the thiazolidinediones, may attenuate these processes. The thiazolidinediones act through ligand activation of a nuclear transcription factor, the peroxisomal proliferator-activated receptor-gamma (PPARgamma). Although this receptor was initially linked to lipid and glucose metabolism, recent data suggest that PPARgamma is also involved in the differentiation of mononuclear phagocytes, their inflammatory reactions, and macrophage conversion to foam cells. Thus, PPARgamma ligands may also be important regulators of monocyte/ macrophage gene expression during atherogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I208,I208)","v":9792031},{"$f":"(LEN($J208) - LEN(SUBSTITUTE(LOWER($J208),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J208) - LEN(SUBSTITUTE(LOWER($J208),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J208) - LEN(SUBSTITUTE(LOWER($J208),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B208:D208)","v":7},1998,"Molecular mechanisms in the reversible regulation of morphology, proliferation and collagen metabolism in hepatic stellate cells by the three-dimensional structure of the extracellular matrix.","Senoo",9792031,"Molecular mechanisms in the reversible regulation of morphology, proliferation and collagen metabolism in hepatic stellate cells by the three-dimensional structure of the extracellular matrix.    Abstract:   Hepatic stellate cells (vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, Ito cells) exist in the perisinusoidal space of the hepatic lobule and store 80% of the bodys retinoids as retinyl palmitate in lipid droplets in the cytoplasm. Under physiological conditions, these cells play pivotal roles in the regulation of retinoid homeostasis; they express specific receptors for retinol-binding protein (RBP), a binding protein specific for retinol, on their cell surface, and take up the complex of retinol and RBP by receptor-mediated endocytosis. However, in pathological conditions such as liver fibrosis, these cells lose retinoids and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan and adhesive glycoproteins. The morphology of these cells also changes from star-shaped stellate cells to that of fibroblasts or myofibroblasts. The three-dimensional structure of ECM components was found to regulate reversibly the morphology, proliferation and functions of hepatic stellate cells. Molecular mechanisms in the reversible regulation of stellate cells by ECM imply cell surface integrin binding to ECM components followed by signal transduction processes and then cytoskeleton assembly."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I209,I209)","v":7952338},{"$f":"(LEN($J209) - LEN(SUBSTITUTE(LOWER($J209),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J209) - LEN(SUBSTITUTE(LOWER($J209),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J209) - LEN(SUBSTITUTE(LOWER($J209),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B209:D209)","v":7},1993,"Flecked retina disorders.","De Laey",7952338,"Flecked retina disorders.    Abstract:   This survey describes a number of fundus conditions characterized by flecks in the retina. The term quot;flecked retinaquot; was introduced by Krill and Klien to describe fundus conditions characterized by multiple yellowish-white lesions of various size and configuration, without vascular or optic nerve abnormalities. Originally this group consisted of four diseases: fundus albipunctatus, fundus flavimaculatus, familial drusen and fleck retina of Kandori. However, far more diseases correspond to the rather vague definition, including primary hereditary ocular diseases such as retinitis punctata albescens or Biettis crystalline dystrophy, neuro-ophthalmologic syndromes such as Kjellins syndrome, secundary retinal flecks due to metabolic disorders such as Alports syndrome, cystinosis, oxalosis or membrano-proliferative glomerulonephritis, iatrogenic retinopathy due to Tamoxifen or Canthaxanthin and carential diseases such as vitamin A deficiency. The precise diagnosis is not only based on the close observation of the fundus, but demands often extensive psychophysical examination of the patient and sometimes of his family."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I210,I210)","v":1514108},{"$f":"(LEN($J210) - LEN(SUBSTITUTE(LOWER($J210),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J210) - LEN(SUBSTITUTE(LOWER($J210),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J210) - LEN(SUBSTITUTE(LOWER($J210),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B210:D210)","v":7},1992,"Retinol (vitamin A) and riboflavin (vitamin B2) administration and metabolism in very low birth weight infants.","Porcelli",1514108,"Retinol (vitamin A) and riboflavin (vitamin B2) administration and metabolism in very low birth weight infants.    Abstract:   The combination of marginal hepatic retinol stores at delivery and the reduction of daily retinol dose due to complications with the delivery system places the VLBW infant receiving parenteral nutrition at high risk for retinol deficiency during the first month of life. This has serious health implications because retinol is essential during this period for normal growth and repair of the pulmonary tissue in VLBW infants. Enterally fed VLBW infants, on the other hand, receive relatively higher doses of retinol from vitamin-supplemented premature infant formula and fortified breast milk. Equally serious is the problem of monitoring vitamin A status in infants receiving supplemental doses of vitamin A. It seems clear that while plasma vitamin A levels are the most easily available method of monitoring vitamin A status, further studies are necessary to determine if these levels correlate with hepatic content. This is of particular concern since liver disease is common in VLBW infants and vitamin A hepatotoxicity has been described in a cohort of 41 patients receiving therapeutic doses of the vitamin. While further research of daily enteral and parenteral retinol requirements of VLBW infants should continue, formulation of a specific VLBW parenteral vitamin supplement should also be developed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I211,I211)","v":1336957},{"$f":"(LEN($J211) - LEN(SUBSTITUTE(LOWER($J211),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J211) - LEN(SUBSTITUTE(LOWER($J211),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J211) - LEN(SUBSTITUTE(LOWER($J211),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B211:D211)","v":7},1992,"Physiological and clinical aspects of vitamin A and its metabolites.","Goss",1336957,"Physiological and clinical aspects of vitamin A and its metabolites.    Abstract:   Retinoids, including retinol and retinoic acid (RA), are a group of naturally occurring and synthetic compounds that exhibit vitamin A-like biological activity. They achieve their effects by binding to intracellular proteins. Important sites of action are the nuclear retinoic acid receptors (RAR). These receptors, namely, RAR alpha, RAR beta, and RAR gamma, function as transcription factors by binding to RA-responsive elements (RARE) of multiple genes. Retinoids play a role in vision, embryogenesis, immune modulation, growth and differentiation of normal, premalignant and malignant tissues, the suppression of carcinogenesis, and the inhibition of tumor growth in experimental systems and humans. Reports of the significant antitumor effect of all-trans-RA in acute promyelocytic leukemia and the synthesis of new, less toxic, and more potent retinoids has generated renewed interest in these compounds. Retinoids may have an important role to play in the chemoprevention and therapy of cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I212,I212)","v":2001786},{"$f":"(LEN($J212) - LEN(SUBSTITUTE(LOWER($J212),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J212) - LEN(SUBSTITUTE(LOWER($J212),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J212) - LEN(SUBSTITUTE(LOWER($J212),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B212:D212)","v":7},1991,"Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis.","Blomhoff",2001786,"Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis.    Abstract:   In mammals, liver perisinusoidal stellate cells play an important role as a main store of body retinol (vitamin A). This fat-soluble vitamin is essential for vision, and regulates differentiation and growth of many cell types during embryonal development as well as in adult tissues. Thus, many cell types require a continuous supply of retinol. The storage of retinol (as retinyl esters) in stellate cells ascertains ample access of retinol to such cells also during periods with a low dietary intake. In lower vertebrates such as fish, vitamin A-storing stellate cells are found not only in the hepatic lobule, but also in the connective tissues of organs like intestine, kidney, ovaries, testes, and gills. Extrahepatic vitamin A-storing stellate cells are found in higher vertebrates when excessive doses of vitamin A are administered. It is not clear at present whether these cells also play a role in retinol metabolism under normal conditions. Stellate cells proliferate in a fibrotic liver, and they have been found to synthesize connective tissue compounds such as collagen. It was recently demonstrated that stellate cells are the principal cellular source of collagen and other extracellular substances in normal as well as fibrotic livers. Therefore, stellate cells, which seem to be a specialized type of pericyte, have a central role in the pathological changes observed during the development of liver fibrosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I213,I213)","v":2694156},{"$f":"(LEN($J213) - LEN(SUBSTITUTE(LOWER($J213),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J213) - LEN(SUBSTITUTE(LOWER($J213),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J213) - LEN(SUBSTITUTE(LOWER($J213),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B213:D213)","v":7},1989,"Chemoprevention of experimental carcinogenesis in animals.","Moon",2694156,"Chemoprevention of experimental carcinogenesis in animals.    Abstract:   Retinoids are well-established chemopreventive agents for experimental carcinogenesis of many target organs including mammary glands, urinary bladder, lung, skin, liver, pancreas, colon, and esophagus. Modification of the basic retinoid structure has produced analogs with enhanced target organ specificity, increased inhibitory activity, and reduced toxicity. N-(4-hydroxyphenyl)retinamide (4-HPR) currently appears to be the most efficacious retinoid against carcinogen-induced breast, urinary bladder, and lung cancer in rodents. Retinoids are most effective when administered shortly after the carcinogen treatment; however, the treatment can be delayed significantly while maintaining its chemopreventive effect. Under various experimental conditions combining retinoid treatment with other modifiers of growth enhances its chemopreventive activity; for example retinoid plus hormonal modulation can provide better protection against mammary cancer than either treatment alone. More recently chemopreventive activity of various other classes of agents, such as thiols, phenols, antioxidants, inhibitors of prostaglandin synthesis, etc., have been investigated in experimental mammary, urinary bladder, and lung cancer models."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I214,I214)","v":3310911},{"$f":"(LEN($J214) - LEN(SUBSTITUTE(LOWER($J214),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J214) - LEN(SUBSTITUTE(LOWER($J214),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J214) - LEN(SUBSTITUTE(LOWER($J214),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B214:D214)","v":7},1987,"Side effects and long-term toxicity of synthetic retinoids.","Yob",3310911,"Side effects and long-term toxicity of synthetic retinoids.    Abstract:   The observation that vitamin A (retinol) has antikeratinizing properties has led to the development of synthetic retinol derivatives (retinoids) for the treatment of a variety of skin disorders characterized by abnormal keratinization. The goal of research in this area is the synthesis of retinoids that would have a more favorable therapeutic: toxic ratio than retinol itself. A limiting factor in the use of any vitamin A analogue is that, even with a more favorable therapeutic: toxic ratio, large pharmacologic doses are required that produce side effects related to the drugs action in most individuals. With few exceptions, all of the side effects are those seen from mega-vitamin A ingestion, primarily affecting the mucocutaneous, skeletal, and central nervous systems. Most of the side effects from excess vitamin A are reversible, with notable exceptions being those involving hepatic and osseous tissues. In terms of reversibility from synthetic retinoids, the experience to date has been incomplete, so there remains imprecise information as to the incidence and the persistence of toxic effects after drug withdrawal."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I215,I215)","v":3015289},{"$f":"(LEN($J215) - LEN(SUBSTITUTE(LOWER($J215),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J215) - LEN(SUBSTITUTE(LOWER($J215),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J215) - LEN(SUBSTITUTE(LOWER($J215),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B215:D215)","v":7},1986,"[Metabolism of vitamin A and retinoids].","Jardillier",3015289,"[Metabolism of vitamin A and retinoids].    Abstract:   Dietary vitamin A is stored in the liver as ester derivatives; after hydrolysis it is transported through the organism bound to a Retinol Binding Protein-Prealbumin complex. Intracellular metabolism is complex and involves the binding to specific receptors for retinol (CRBP) and retinoic acid (CRABP) followed by a nuclear translocation. In addition, retinol can be phosphorylated and implicated in glycosylation processes. Retinoids are characterized by their action on cellular growth and differentiation. Such properties result in anticancer activities which have been clearly put in evidence in vitro and begin to be applied in human oncology. Nevertheless there is always a need for a better comprehension on fundamental mechanisms of natural or synthetic retinoids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I216,I216)","v":6224672},{"$f":"(LEN($J216) - LEN(SUBSTITUTE(LOWER($J216),LOWER(B$3),\"\")))/LEN(B$3)","v":7},{"$f":"(LEN($J216) - LEN(SUBSTITUTE(LOWER($J216),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J216) - LEN(SUBSTITUTE(LOWER($J216),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B216:D216)","v":7},1983,"Etretinate. A review of its pharmacological properties and therapeutic efficacy in psoriasis and other skin disorders.","Ward",6224672,"Etretinate. A review of its pharmacological properties and therapeutic efficacy in psoriasis and other skin disorders.    Abstract:   Etretinate (Ro 10-9359) is a new aromatic retinoic acid derivative for the treatment of severe psoriasis and other dyskeratoses. The pharmacological profile of etretinate suggests that it acts by normalizing pathological changes in epidermal and dermal skin, particularly inhibiting hyperkeratinization and cell differentiation, although its specific mode of action in different disorders remains to be elucidated. Etretinate is rapidly and presystemically metabolised to an active metabolite which appears in plasma at about the same time as parent drug. A deep storage compartment with a very extended elimination half-life gives rise to detectable plasma levels of drug for at least 3 to 4 months after discontinuation of long term therapy. Studies suggest that etretinate at an initial dose of 1 mg/kg/day, reducible during maintenance therapy, is an effective alternative to PUVA and other conventional therapy in severe psoriasis. Its greatest immediate value is in the control of eruptive and treatment-resistant psoriasis, and in its potential for use in combination with other therapy to improve the response. In Dariers disease it appears to be the treatment of choice, and preliminary studies also suggest its usefulness in ichthyosis, and most other dyskeratoses and possibly in basal cell carcinoma. Side effects affecting the mucocutaneous system occur in nearly all patients, but rarely lead to drug withdrawal. When withdrawal does become necessary, the primary reason is usually hair loss. A few paradoxical observations of raised and lowered liver enzyme levels have been reported, and also a few cases of suspected liver damage. Etretinate is strictly contraindicated in women of child-bearing potential due to its severe teratogenic properties."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I217,I217)","v":27511929},{"$f":"(LEN($J217) - LEN(SUBSTITUTE(LOWER($J217),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J217) - LEN(SUBSTITUTE(LOWER($J217),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J217) - LEN(SUBSTITUTE(LOWER($J217),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B217:D217)","v":6},2016,"Biomarkers of Nutrition for Development (BOND)-Vitamin A Review.","Tanumihardjo",27511929,"Biomarkers of Nutrition for Development (BOND)-Vitamin A Review.    Abstract:   The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-informed advice to anyone with an interest in the role of nutrition in health. The BOND program provides information with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect, which will be especially useful for readers who want to assess nutrient status. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutritional status at the individual and population levels. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, folate, zinc, iron, vitamin A, and vitamin B-12. This review of vitamin A is the current article in this series. Although the vitamin was discovered gt;100 y ago, vitamin A status assessment is not trivial. Serum retinol concentrations are under homeostatic control due in part to vitamin As use in the body for growth and cellular differentiation and because of its toxic properties at high concentrations. Furthermore, serum retinol concentrations are depressed during infection and inflammation because retinol-binding protein (RBP) is a negative acute-phase reactant, which makes status assessment challenging. Thus, this review describes the clinical and functional indicators related to eye health and biochemical biomarkers of vitamin A status (i.e., serum retinol, RBP, breast-milk retinol, dose-response tests, isotope dilution methodology, and serum retinyl esters). These biomarkers are then related to liver vitamin A concentrations, which are usually considered the gold standard for vitamin A status. With regard to biomarkers, future research questions and gaps in our current understanding as well as limitations of the methods are described."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I218,I218)","v":24315978},{"$f":"(LEN($J218) - LEN(SUBSTITUTE(LOWER($J218),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J218) - LEN(SUBSTITUTE(LOWER($J218),LOWER(C$3),\"\")))/LEN(C$3)","v":5},{"$f":"(LEN($J218) - LEN(SUBSTITUTE(LOWER($J218),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B218:D218)","v":6},2014,"Role of PPAR, LXR, and PXR in epidermal homeostasis and inflammation.","Schmuth",24315978,"Role of PPAR, LXR, and PXR in epidermal homeostasis and inflammation.    Abstract:   Epidermal lipid synthesis and metabolism are regulated by nuclear hormone receptors (NHR) and in turn epidermal lipid metabolites can serve as ligands to NHR. NHR form a large superfamily of receptors modulating gene transcription through DNA binding. A subgroup of these receptors is ligand-activated and heterodimerizes with the retinoid X receptor including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR) and pregnane X receptor (PXR). Several isotypes of these receptors exist, all of which are expressed in skin. In keratinocytes, ligand activation of PPARs and LXRs stimulates differentiation, induces lipid accumulation, and accelerates epidermal barrier regeneration. In the cutaneous immune system, ligand activation of all three receptors, PPAR, LXR, and PXR, has inhibitory properties, partially mediated by downregulation of the NF-kappaB pathway. PXR also has antifibrotic effects in the skin correlating with TGF-beta inhibition. In summary, ligands of PPAR, LXR and PXR exert beneficial therapeutic effects in skin disease and represent promising targets for future therapeutic approaches in dermatology. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I219,I219)","v":24056119},{"$f":"(LEN($J219) - LEN(SUBSTITUTE(LOWER($J219),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J219) - LEN(SUBSTITUTE(LOWER($J219),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J219) - LEN(SUBSTITUTE(LOWER($J219),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B219:D219)","v":6},2014,"Retinoid signaling in pathological remodeling related to cardiovascular disease.","Kotake",24056119,"Retinoid signaling in pathological remodeling related to cardiovascular disease.    Abstract:   Retinoids, the active derivatives of vitamin A, are critical signaling molecules in crucial biological processes such as embryonic development, the maintenance of immune function, and cellular differentiation and proliferation. Preclinical studies have shown that retinoids also regulate morphological changes during the progression of cardiovascular disease (CVD). CVD is complexly formed in a mutual chain reaction of various modern lifestyle-related risk factors such as dyslipidemia, hypertension, diabetes, and obesity. These factors induce the pathological remodeling of adipose tissue, the vasculature, and the ventricles, which are a potential target for retinoid signaling. This perspective highlights emerging topics and future prospectives on the relationship between CVD and retinoid signaling."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I220,I220)","v":25436722},{"$f":"(LEN($J220) - LEN(SUBSTITUTE(LOWER($J220),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J220) - LEN(SUBSTITUTE(LOWER($J220),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J220) - LEN(SUBSTITUTE(LOWER($J220),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B220:D220)","v":6},2013,"Retinoids and nuclear retinoid receptors in white and brown adipose tissues: physiopathologic aspects.","Flajollet",25436722,"Retinoids and nuclear retinoid receptors in white and brown adipose tissues: physiopathologic aspects.    Abstract:   Vitamin A, ingested either as retinol or β-carotene from animal- or plant-derived foods respectively, is a nutrient essential for many biological functions such as embryonic development, vision, immune response, tissue remodeling, and metabolism. Its main active metabolite is all trans-retinoic acid (atRA), which regulates gene expression through the activation of α, β, and γ isotypes of the nuclear atRA receptor (RAR). More recently, retinol derivatives were also shown to control the RAR activity, enlightening the interplay between vitamin A metabolism and RAR-mediated transcriptional control. The white and brown adipose tissues regulate the energy homeostasis by providing dynamic fatty acid storing and oxidizing capacities to the organism, in connection with the other fatty acid-consuming tissues. This concerted interorgan response to fatty acid fluxes is orchestrated, in part, by the endocrine activity of the adipose tissue depots. The adipose tissues are also sites for synthesizing and storing vitamin A derivatives, which will act as hormonal cues or intracellularly to regulate essential aspects of adipocyte biology. As agents that prevent adipocyte differentiation hence, expected to decrease fat mass, and inducers of uncoupling protein expression, thus, favoring energy expenditure, retinoids have prompted many investigations to decipher their roles in adipose tissue pathophysiology, which are summarized in this review."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I221,I221)","v":23252770},{"$f":"(LEN($J221) - LEN(SUBSTITUTE(LOWER($J221),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J221) - LEN(SUBSTITUTE(LOWER($J221),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J221) - LEN(SUBSTITUTE(LOWER($J221),LOWER(D$3),\"\")))/LEN(D$3)","v":6},{"$f":"SUM(B221:D221)","v":6},2013,"The environment and the origins of islet autoimmunity and Type 1 diabetes.","Eringsmark Regnéll",23252770,"The environment and the origins of islet autoimmunity and Type 1 diabetes.    Abstract:   Type 1 diabetes involves the specific destruction of the pancreatic islet β-cells, eventually resulting in a complete dependency of exogenous insulin. The clinical onset of diabetes is preceded by the appearance of autoantibodies against β-cell antigens. The human leukocyte antigen (HLA) region is the single most important genetic determinant of Type 1 diabetes susceptibility, yet variability in the HLA region has been estimated to explain only approximately 60% of the genetic influence of the disease. Over 50 identified non-HLA genetic polymorphisms support the notion that genetics alone cannot explain Type 1 diabetes. Several lines of evidence indicate that environmental triggers may be integral in inducing the onset of islet autoimmunity in genetically susceptible individuals. The association between environmental factors and the clinical onset is complicated by observation that the rate of progression to clinical onset may be affected by environmental determinants. Hence, the environment may be aetiological as well as pathogenic. Putative inductive mechanisms include viral, microbial, diet-related, anthropometric and psychosocial factors. Ongoing observational cohort studies such as The Environmental Determinants of Diabetes in the Young (TEDDY) study aim to ascertain environmental determinants that may trigger islet autoimmunity and either speed up or slow down the progression to clinical onset in subjects with persistent islet autoimmunity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I222,I222)","v":23230390},{"$f":"(LEN($J222) - LEN(SUBSTITUTE(LOWER($J222),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J222) - LEN(SUBSTITUTE(LOWER($J222),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J222) - LEN(SUBSTITUTE(LOWER($J222),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B222:D222)","v":6},2012,"Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis.","Shimizu",23230390,"Acyclic retinoid in chemoprevention of hepatocellular carcinoma: Targeting phosphorylated retinoid X receptor-α for prevention of liver carcinogenesis.    Abstract:   One of the key features of hepatocellular carcinoma (HCC) is the high rate of intrahepatic recurrence that correlates with poor prognosis. Therefore, in order to improve the clinical outcome for patients with HCC, development of a chemopreventive agent that can decrease or delay the incidence of recurrence is a critical issue for urgent investigation. Acyclic retinoid (ACR), a synthetic retinoid, successfully improves HCC patient survival by preventing recurrence and the formation of secondary tumors. A malfunction of the retinoid X receptor-α (RXRα) due to phosphorylation by the Ras-MAPK signaling pathway plays a critical role in liver carcinogenesis, and ACR exerts chemopreventive effects on HCC development by inhibiting RXRα phosphorylation. Here, we review the relationship between retinoid signaling abnormalities and liver disease, the mechanisms of how RXRα phosphorylation contributes to liver carcinogenesis, and the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research. We also outline the concept of quot;clonal deletion and inhibitionquot; therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC, because ACR prevents the development of HCC by implementing this concept. Looking toward the future, we discuss quot;combination chemopreventionquot; using ACR as a key drug since it can generate a synergistic effect, and may thus be an effective new strategy for the prevention of HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I223,I223)","v":22864348},{"$f":"(LEN($J223) - LEN(SUBSTITUTE(LOWER($J223),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J223) - LEN(SUBSTITUTE(LOWER($J223),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J223) - LEN(SUBSTITUTE(LOWER($J223),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B223:D223)","v":6},2012,"[Retinoids as promising treatment for non-alcoholic fatty liver disease].","Tsuchiya",22864348,"[Retinoids as promising treatment for non-alcoholic fatty liver disease].    Abstract:   Non-alcoholic fatty liver disease (NAFLD) is frequently associated with insulin resistance, suggesting its crucial role in the development and progression of NAFLD. We used a mouse model of high-fat, high-fructose (HFHFr) diet-induced NAFLD to examine the effects of retinoids on insulin resistance. Dietary administration of all-trans-retinoic acid (ATRA) significantly improved insulin sensitivity in C57BL/6J mice fed the HFHFr diet, and in KK-Ay mice but not in the leptin-deficient ob/ob mice. ATRA treatment significantly upregulated hepatic leptin receptor (LEPR) expression. In agreement with these observations, in vitro experiments showed ATRA directly induced LEPR gene expression through RARα. In the livers of C57BL/6J mice administered ATRA, insulin receptor substrate-1 (IRS1) was activated concomitantly with the phosphorylation of Janus kinase-2 and signal transducer and activator of transcription-3 (STAT3). STAT3 phosphorylation was also observed in KK-Ay but not in ob/ob mice. In in vitro experiments, ATRA significantly enhanced insulin-induced IRS1 tyrosine phosphorylation solely in the presence of leptin. A selective RARα/β agonist, tamibarotene, also enhanced hepatic LEPR expression, STAT3 phosphorylation, and ameliorated insulin resistance in KK-Ay mice. We discovered an unrecognized mechanism of retinoid action for the activation of hepatic leptin signaling, which resulted in enhancing insulin sensitivity in two mouse models of insulin resistance. Moreover, we also found that retinoids attenuate hepatic iron overload and iron-induced oxidative stress, which have recently emerged as an important factor for the development and progression of insulin resistance. Our data suggest that retinoids might have potential for treating NAFLD associated with insulin resistance."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I224,I224)","v":22535896},{"$f":"(LEN($J224) - LEN(SUBSTITUTE(LOWER($J224),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J224) - LEN(SUBSTITUTE(LOWER($J224),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J224) - LEN(SUBSTITUTE(LOWER($J224),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B224:D224)","v":6},2012,"Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response.","Nagy",22535896,"Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response.    Abstract:   A key issue in the immune system is to generate specific cell types, often with opposing activities. The mechanisms of differentiation and subtype specification of immune cells such as macrophages and dendritic cells are critical to understand the regulatory principles and logic of the immune system. In addition to cytokines and pathogens, it is increasingly appreciated that lipid signaling also has a key role in differentiation and subtype specification. In this review we explore how intracellular lipid signaling via a set of transcription factors regulates cellular differentiation, subtype specification, and immune as well as metabolic homeostasis. We introduce macrophages and dendritic cells and then we focus on a group of transcription factors, nuclear receptors, which regulate gene expression upon receiving lipid signals. The receptors we cover are the ones with a recognized physiological function in these cell types and ones which heterodimerize with the retinoid X receptor. These are as follows: the receptor for a metabolite of vitamin A, retinoic acid: retinoic acid receptor (RAR), the vitamin D receptor (VDR), the fatty acid receptor: peroxisome proliferator-activated receptor γ (PPARγ), the oxysterol receptor liver X receptor (LXR), and their obligate heterodimeric partner, the retinoid X receptor (RXR). We discuss how they can get activated and how ligand is generated and eliminated in these cell types. We also explore how activation of a particular target gene contributes to biological functions and how the regulation of individual target genes adds up to the coordination of gene networks. It appears that RXR heterodimeric nuclear receptors provide these cells with a coordinated and interrelated network of transcriptional regulators for interpreting the lipid milieu and the metabolic changes to bring about gene expression changes leading to subtype and functional specification. We also show that these networks are implicated in various immune diseases and are amenable to therapeutic exploitation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I225,I225)","v":22411366},{"$f":"(LEN($J225) - LEN(SUBSTITUTE(LOWER($J225),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J225) - LEN(SUBSTITUTE(LOWER($J225),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J225) - LEN(SUBSTITUTE(LOWER($J225),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B225:D225)","v":6},2011,"[Meta-analysis on the role of lycopene in type 2 diabetes mellitus].","Valero",22411366,"[Meta-analysis on the role of lycopene in type 2 diabetes mellitus].    Abstract:    INTRODUCTION : lycopene is a carotene with a potent antioxidant effect found in tomato and its derivatives. Given that diabetic patients present an increased oxidative stress, lycopene could be beneficial. The aim of this scientific review has been to analyze the scientific evidence of the role of lycopene as an anti-oxidant agent in diabetes, its prevention and the metabolic control and development of complications.  MATERIALS AND METHODS : We carried out a systematic review and meta-analysis. A literature search was done in Medline and the Cochrane Library, using the MeSH terms quot;carotenoidsquot; OR quot;lycopenequot; AND quot;type 2 diabetes mellitusquot;. The search was manually completed from the references of the papers found. The quality of the studies was assessed by using the JADAD and STROBE scales. We included a total of 10 articles.  RESULTS : After adjusting for other risk factors, the OR for developing DM2 as similar among the different levels of lycopene intake. The plasma levels of lycopene increase in the intervention groups. Lycopene decreases the malonyldialdehyde and lipid peroxidation. The non-provitamin A/provitamin A carotenoids ratio is negatively associated with the risk for suffering from diabetic retinopathy.  CONCLUSION : Tomato or lycopene intake increases the plasma levels of this compound. However, there is no evidence for the association between lycopene intake and the risk for having diabetes. This compound and other tomato derivatives may have a beneficial effect on the oxidative stress in diabetic patients. The non-provitamin A/provitamin A carotenoids ratio is negatively associated with the risk for suffering from diabetic retinopathy, although there are no data available on the relationship between lycopene and other diabetic complications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I226,I226)","v":22254074},{"$f":"(LEN($J226) - LEN(SUBSTITUTE(LOWER($J226),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J226) - LEN(SUBSTITUTE(LOWER($J226),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J226) - LEN(SUBSTITUTE(LOWER($J226),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B226:D226)","v":6},2011,"Vitamin A metabolism and adipose tissue biology.","Frey",22254074,"Vitamin A metabolism and adipose tissue biology.    Abstract:   In recent years, the importance of vitamin A in adipose tissue biology, obesity and type II diabetes has become apparent. This review focuses on recent developments within the area of vitamin A and adipose tissue biology. Adipose tissue has an active vitamin A metabolism as it not only stores vitamin A but retinol is also converted to its active metabolite retinoic acid. Several mouse models point to a relationship between vitamin A metabolism and the development of adiposity. Similarly, in vitro studies provide new molecular mechanisms for the function of different forms of vitamin A and retinol- or retinoic acid-binding proteins in adipose tissue."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I227,I227)","v":21586336},{"$f":"(LEN($J227) - LEN(SUBSTITUTE(LOWER($J227),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J227) - LEN(SUBSTITUTE(LOWER($J227),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J227) - LEN(SUBSTITUTE(LOWER($J227),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B227:D227)","v":6},2012,"Retinyl ester hydrolases and their roles in vitamin A homeostasis.","Schreiber",21586336,"Retinyl ester hydrolases and their roles in vitamin A homeostasis.    Abstract:   In mammals, dietary vitamin A intake is essential for the maintenance of adequate retinoid (vitamin A and metabolites) supply of tissues and organs. Retinoids are taken up from animal or plant sources and subsequently stored in form of hydrophobic, biologically inactive retinyl esters (REs). Accessibility of these REs in the intestine, the circulation, and their mobilization from intracellular lipid droplets depends on the hydrolytic action of RE hydrolases (REHs). In particular, the mobilization of hepatic RE stores requires REHs to maintain steady plasma retinol levels thereby assuring constant vitamin A supply in times of food deprivation or inadequate vitamin A intake. In this review, we focus on the roles of extracellular and intracellular REHs in vitamin A metabolism. Furthermore, we will discuss the tissue-specific function of REHs and highlight major gaps in the understanding of RE catabolism. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I228,I228)","v":21554983},{"$f":"(LEN($J228) - LEN(SUBSTITUTE(LOWER($J228),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J228) - LEN(SUBSTITUTE(LOWER($J228),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J228) - LEN(SUBSTITUTE(LOWER($J228),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B228:D228)","v":6},2012,"Retinoid chemistry: synthesis and application for metabolic disease.","Curley",21554983,"Retinoid chemistry: synthesis and application for metabolic disease.    Abstract:   In this review a discussion of the usual procedures used to synthesize retinoids is followed by an overview of the structure-activity relationships of these molecules. The discussion is then focused on the role and impact of retinoids on metabolic disorders with a particular emphasis on obesity, diabetes, and the metabolic syndrome. In these areas, both natural and synthetic retinoids that are being studied are reviewed and areas where likely future research will occur are suggested. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I229,I229)","v":20676546},{"$f":"(LEN($J229) - LEN(SUBSTITUTE(LOWER($J229),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J229) - LEN(SUBSTITUTE(LOWER($J229),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J229) - LEN(SUBSTITUTE(LOWER($J229),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B229:D229)","v":6},2010,"[Vitamin A and gestational diabetes].","Lira",20676546,"[Vitamin A and gestational diabetes].    Abstract:   Diabetes mellitus (DM) a pathology with chronic evolution, has now acquired a connotation of global epidemic. Gestational diabetes, a condition associated with insulin resistance and decreased beta-cells function is also characterized by a high incidence in different populations and ethnic groups. Recently strong evidence has been found for involvement of retinol levels of pregnant women with DM due to the pathologys evolution. This condition makes these diabetics prone to have a marginal biochemical profile or a vitamin A deficiency when compared to those of healthy pregnant women. Therefore, with an awareness of the physiological role of vitamin A and consequences of diabetes during pregnancy, this review intends to clarify the impact of DM on retinol levels of these pregnant women and the consequences that vitamin A deficiency may cause to these women and their infants."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I230,I230)","v":19068086},{"$f":"(LEN($J230) - LEN(SUBSTITUTE(LOWER($J230),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J230) - LEN(SUBSTITUTE(LOWER($J230),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J230) - LEN(SUBSTITUTE(LOWER($J230),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B230:D230)","v":6},2009,"Strategy and mechanism for the prevention of hepatocellular carcinoma: phosphorylated retinoid X receptor alpha is a critical target for hepatocellular carcinoma chemoprevention.","Shimizu",19068086,"Strategy and mechanism for the prevention of hepatocellular carcinoma: phosphorylated retinoid X receptor alpha is a critical target for hepatocellular carcinoma chemoprevention.    Abstract:   Hepatocellular carcinoma (HCC) is a major health care problem worldwide. The prognosis of patients with HCC is poor because even in the early stages when surgical treatment might be expected to be curative, the incidence of recurrence in patients with underlying cirrhosis is very high due to multicentric carcinogenesis. Therefore, strategies to prevent recurrence and second primary HCC are required to improve the prognosis. One of the most practical approaches to prevent the multicentric development of HCC is clonal deletion therapy, which is defined as the removal of latent (i.e. invisible) (pre)malignant clones from the liver in a hypercarcinogenic state. Retinoids, a group of structural and functional analogs of vitamin A, exert their biological function primarily through two distinct nuclear receptors, retinoic acid receptors and retinoid X receptors (RXR), and abnormalities in the expression and function of these receptors are highly associated with the development of various cancers, including HCC. In particular, a malfunction of RXRalpha due to phosphorylation by the Ras-mitogen-activated protein kinase signaling pathway is profoundly associated with the development of HCC and thus may be a critical target for HCC chemoprevention. Acyclic retinoid, which has been clinically shown to reduce the incidence of a post-therapeutic recurrence of HCC, can inhibit Ras activity and phosphorylation of the extracellular signal-regulated kinase and RXRalpha proteins. In conclusion, the inhibition of RXRalpha phosphorylation and the restoration of its physiological function as a master regulator for nuclear receptors may be a potentially effective strategy for HCC chemoprevention and clonal deletion. Acyclic retinoid, which targets phosphorylated RXRalpha, may thus play a critical role in preventing the development of multicentric HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I231,I231)","v":16454184},{"$f":"(LEN($J231) - LEN(SUBSTITUTE(LOWER($J231),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J231) - LEN(SUBSTITUTE(LOWER($J231),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J231) - LEN(SUBSTITUTE(LOWER($J231),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B231:D231)","v":6},2006,"[Nanotechnology for therapy of type 2 diabetes].","Yamaguchi",16454184,"[Nanotechnology for therapy of type 2 diabetes].    Abstract:   All-trans Retinoic Acid (atRA), is known as a member of retinoid, and the atRA nano-particle with coated by CaCO3 (nanoegg -atRA), was recently developed as a new drug delivery system (DDS). This nanoparticles stimulated insulin secretion from islets in a glucose-dependent manner at streptozotocin (STZ)-induced diabetes. The stains on pancreas of Wistar rat at STZ induced diabetes, which was subcutaneous administered nanoegg -atRA 6 mg/head/week for 141 days, showed not only the expression of PDX-1 but also the presence of beta cell in islet of Langerhans. Furthermore, the increase of insulin concentration in plasma was also observed. Our data indicate that nanoegg -atRA might contribute to the regeneration of beta cells in vivo, and provide useful information for future therapy of diabetes mellitus."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I232,I232)","v":16325258},{"$f":"(LEN($J232) - LEN(SUBSTITUTE(LOWER($J232),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J232) - LEN(SUBSTITUTE(LOWER($J232),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J232) - LEN(SUBSTITUTE(LOWER($J232),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B232:D232)","v":6},2006,"Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia.","Palha",16325258,"Thyroid hormones and retinoids: a possible link between genes and environment in schizophrenia.    Abstract:   Phenotypic discordance for schizophrenia in monozygotic twins clearly indicates involvement of environmental factors as key determinants in disease development. Positive findings from genome scans, linkage and association studies apply in only a minority of those affected, while post-mortem brain investigations reveal altered expression of genes and proteins involved in numerous neurodevelopmental, metabolic and neurotransmitter pathways. Such altered expressions could result, on the one hand, from mutations in coding regions or polymorphisms in the promoter and regulatory regions in genes within those areas identified by gene searches or, on the other hand, from inadequate amounts of modulators, transporters and synthesizers of transcription factors necessary for regulation of the putative genes. Hormones and vitamins are such modulators. They could serve as bridges between genes and environment in schizophrenia. Multiple evidence supports the suggestion of retinoids and thyroid hormones as plausible actors in these roles. Both are not only essential for normal development of the central nervous system but also regulate the expression of many neurotransmitters, their synthesizing enzymes and receptors, and other genes in broader signaling transduction cascades affecting pathways that are altered in response to treatment. Functional and positional candidate genes include retinoic acid and thyroid hormone receptors, retinaldehyde dehydrogenases and deiodinases, which synthesize the powerful morphogens, retinoic acid and triiodothyronine, and the enzymes involved in their inactivation. This review highlights selective evidence supporting the retinoid and thyroid hormone hypotheses of schizophrenia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I233,I233)","v":16251601},{"$f":"(LEN($J233) - LEN(SUBSTITUTE(LOWER($J233),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J233) - LEN(SUBSTITUTE(LOWER($J233),LOWER(C$3),\"\")))/LEN(C$3)","v":5},{"$f":"(LEN($J233) - LEN(SUBSTITUTE(LOWER($J233),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B233:D233)","v":6},2005,"Fatty acid regulation of hepatic gene transcription.","Jump",16251601,"Fatty acid regulation of hepatic gene transcription.    Abstract:   Dietary fat regulates gene expression by controlling the activity or abundance of key transcription factors. In vitro binding and cell culture studies have identified many transcription factors as prospective targets for fatty acid regulation, including peroxisome proliferator-activated receptors (PPARalpha, beta, gamma1, and gamma2), sterol regulatory element binding protein-1c (SREBP-1c), hepatic nuclear factors (HNF-4alpha and gamma), retinoid X receptor (RXRalpha), liver X receptor (LXRalpha), and others. In vivo studies established that PPARalpha- and SREBP-1c-regulated genes are key targets for PUFA control of hepatic gene expression. PUFA activate PPARalpha by direct binding, leading to the induction of hepatic fatty acid oxidation. PUFA inhibit hepatic fatty acid synthesis by suppressing SREBP-1c nuclear abundance through several mechanisms, including suppression of SREBP-1c gene transcription and enhancement of proteasomal degradation and mRNA(SREBP1c) decay. Changes in intracellular nonesterified fatty acids (NEFA) correlate well with changes in PPARalpha activity and mRNA(SREBP-1c) abundance. Several mechanisms regulate intracellular NEFA composition, including fatty acid transport, acyl CoA synthetases and thioesterases, fatty acid elongases and desaturases, neutral and polar lipid lipases, and fatty acid oxidation. Many of these mechanisms are regulated by PPARalpha or SREBP-1c. Together, these mechanisms control hepatic lipid composition and affect whole-body lipid composition."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I234,I234)","v":15981190},{"$f":"(LEN($J234) - LEN(SUBSTITUTE(LOWER($J234),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J234) - LEN(SUBSTITUTE(LOWER($J234),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J234) - LEN(SUBSTITUTE(LOWER($J234),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B234:D234)","v":6},2005,"Congenital diaphragmatic hernia: a retinoid-signaling pathway disruption during lung development?","Gallot",15981190,"Congenital diaphragmatic hernia: a retinoid-signaling pathway disruption during lung development?    Abstract:   Congenital diaphragmatic hernia (CDH) usually occurs sporadically. The prognosis remains poor, with a 50% perinatal mortality rate. Most deaths result from hypoxemia due to lung hypoplasia and abnormal development of pulmonary vasculature that results in persistent pulmonary hypertension. Our current understanding of the pathogenesis of CDH is based on an assumption linking herniation of abdominal viscera into the thorax with compression of the developing lung. Pulmonary hypoplasia, however, can also result from reduced distension of the developing lung secondary to impaired fetal breathing movements. Moreover, a nitrofen-induced CDH model shows that lung hypoplasia precedes the diaphragmatic defect, leading to a quot;dual-hit hypothesis.quot; Recent data reveal the role of a retinoid-signaling pathway disruption in the pathogenesis of CDH. We describe the clinical and epidemiological aspects of human CDH, the metabolic and molecular aspects of the retinoid-signaling pathway, and the implications of retinoids in the development of the diaphragm and the lung. Finally, we highlight the existing links between CDH and disruption of the retinoid-signaling pathway, which may suggest an eventual use of retinoids in the treatment of CDH."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I235,I235)","v":15647709},{"$f":"(LEN($J235) - LEN(SUBSTITUTE(LOWER($J235),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J235) - LEN(SUBSTITUTE(LOWER($J235),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J235) - LEN(SUBSTITUTE(LOWER($J235),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B235:D235)","v":6},2004,"Advances in diabetes for the millennium: vitamins and oxidant stress in diabetes and its complications.","Chertow",15647709,"Advances in diabetes for the millennium: vitamins and oxidant stress in diabetes and its complications.    Abstract:   Hyperinduced oxidant stress may have a role in the pathogenesis of diabetes and its micro- and macrovascular complications. Attaining euglycemia and the use of antioxidant vitamins could reduce oxidant stress and complications. In general, evidence does not support the use of supplements, and supplements are not recommended unless patients are deficient. Use of vitamins in excess may have adverse effects. Vitamin supplements are indicated in patients deficient in vitamins due to inadequate dietary intake or intestinal disease. Treatment with proper amounts of vitamins and antioxidants is best accomplished with a balanced diet including 3 servings of vegetables and 2 servings of fruits. Regarding supplementation of specific vitamins: carotene cannot be recommended in view of the possible harm and lack of benefit in clinical studies. Vitamin A (retinol) and Vitamin D should be repleted if deficient by laboratory assay. Excesses should be avoided. Vitamin A supplements, particularly in pregnancy, should not exceed 10,000 IU daily or a supplement should not exceed 25,000 units weekly. Vitamin E (alpha-tocopherol) alone in doses of 400 units is of questionable value, and larger doses may cause intracranial hemorrhage or interact negatively with lipid-lowering drugs. Vitamin E should not be used in patients who have bleeding disorders or patients on anticoagulants or acetylsalicylic acid (ASA). Vitamin C (ascorbic acid) losses in urine may be excessive in diabetic patients and may require repletion to 200 mg in nonsmokers and 250 mg in smokers. Further studies are needed testing: (1) vitamin supplementation in subgroups of patients at high risk for specific complications using tissue-specific indicators of oxidative stress; (2) the role of oxidative stress in nephropathy, diabetic myocardiopathy, dermopathy, joint limitation syndromes, peripheral edema, metabolic bone disease, and pregnancy; (3) the impact of renal failure on oxidative stress; and (4) the effects of diabetes and dietary vitamins on the relative amounts of retinoids, carotenoids, and vitamin E in the chylomicron and lipoproteins, and how this affects assimilation, oxidation of lipids, and atherosclerotic plaque formation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I236,I236)","v":15010815},{"$f":"(LEN($J236) - LEN(SUBSTITUTE(LOWER($J236),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J236) - LEN(SUBSTITUTE(LOWER($J236),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J236) - LEN(SUBSTITUTE(LOWER($J236),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B236:D236)","v":6},2004,"Acyclic retinoid in the chemoprevention of hepatocellular carcinoma (review).","Kojima",15010815,"Acyclic retinoid in the chemoprevention of hepatocellular carcinoma (review).    Abstract:   We here review therapeutic application of a synthetic analog of retinoids (vitamin A and its derivatives), named acyclic retinoid (AR), towards chemoprevention of hepatocellular carcinoma (HCC), and its underlying molecular mechanisms. A high incidence of post-therapeutic recurrence has become a major determinant of the prognosis of HCC, especially in the patients of hepatitis virus-infected cirrhosis. Oral supplementation of AR successfully prevented the recurrence of HCC, associated with a disappearance in serum levels of lectin-reactive alpha-fetoprotein (AFP-L3), a marker of occult cancer clones in the liver, suggesting eradication of latent malignant clones from patients liver. This led us a novel concept of clonal deletion with AR as an agent that is conceptually similar to cancer chemotherapy. HCC in cirrhotic patients contains lower levels of endogenous retinoids and simultaneously is insensitive to retinoic acid (RA) because of malfunction of its nuclear receptor, retinoid X receptor alpha (RXRalpha). In HCC tissues, RXRalpha is constitutively phosphorylated by the action of extracellular signal-regulated kinase (Erk), thereby losing its transactivation activity and becoming resistant to degradation via ubiquitin/proteasome pathway. This leads to accumulation of phospho-inactivated RXRalpha, that functions as a dominant negative receptor and interferes with transactivation by remaining normal RXRalpha. AR but not natural RA prevents phosphorylation of RXRalpha and restores the function of RXRalpha via down-regulating Ras/Erk system, making HCC cells sensitive to the endogenous ligand, 9-cis-RA. This may link to both caspase-dependent and -independent apoptosis of the cancer cells via induction of growth suppressor(s) such as p21CIP1 and/or apoptosis inducer(s) including tissue transglutaminase. AR also enhances the sensitivity of HCC cells to interferons-alpha and -beta, and thereby indirectly promotes apoptosis induced by these interferons. In summary, our clinical experience and basic research together provide a strong rationale to use AR in the chemoprevention of HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I237,I237)","v":12424006},{"$f":"(LEN($J237) - LEN(SUBSTITUTE(LOWER($J237),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J237) - LEN(SUBSTITUTE(LOWER($J237),LOWER(C$3),\"\")))/LEN(C$3)","v":4},{"$f":"(LEN($J237) - LEN(SUBSTITUTE(LOWER($J237),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B237:D237)","v":6},2002,"Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases.","Dubuquoy",12424006,"Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases.    Abstract:   The peroxisome proliferator-activated receptor gamma (PPARgamma) and its partner the retinoid X receptor (RXR) are two nuclear receptors that are expressed mainly in adipose tissue and which have a role in lipid metabolism and insulin sensitisation. New sites of PPARgamma/RXR expression have been described, especially in the intestinal tract, pancreas, and liver. Concomitantly, new functions have been attributed to this heterodimer in regulation of inflammation, by its inhibition of nuclear factor (NF)-kappaB and via stress-kinase pathways. These new sites and functions of PPARgamma/RXR have led to novel ideas about pathophysiology of different inflammatory digestive diseases and to development of innovative treatment strategies with PPARgamma activators."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I238,I238)","v":12381213},{"$f":"(LEN($J238) - LEN(SUBSTITUTE(LOWER($J238),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J238) - LEN(SUBSTITUTE(LOWER($J238),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J238) - LEN(SUBSTITUTE(LOWER($J238),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B238:D238)","v":6},2002,"Comparative tolerability of systemic treatments for plaque-type psoriasis.","McClure",12381213,"Comparative tolerability of systemic treatments for plaque-type psoriasis.    Abstract:   Psoriasis is a chronic, debilitating skin condition that affects millions of people and is attributed to both genetic and environmental factors. Topical therapy is generally considered to be the first-line treatment of psoriasis. However, many patients do not respond to topical therapy or have disease so extensive that topical therapy is not practical. For these patients, systemic therapy is indicated. Presently, there are four available systemic treatments, psoralen with ultraviolet A (PUVA), methotrexate, oral retinoids (acitretin), and cyclosporin. Unfortunately, all of these treatments have significant potential adverse effects. PUVA may acutely cause nausea, pruritus and sunburn. More chronic and concerning is the development of PUVA lentigines, ocular complications and skin cancer. Non-melanoma skin cancer has been directly linked to PUVA; however, the association with melonoma is more elusive. Methotrexate use most notably carries the risk of hepatic fibrosis and cirrhosis, which is not always evident on liver function tests. Other more rare, but potentially life-threatening adverse effects include pancytopenia, lymphoproliferative disorders and acute pneumonitis. The addition of folic acid may help to reduce the risk of increasing liver enzymes and haematological toxicity seen in those taking methotrexate. Both methotrexate and oral retinoids are teratogenic and should never be used in pregnancy. Oral retinoids are probably the least effective available systemic medication for the treatment of plaque psoriasis. The effects are improved with the addition of other systemic therapies. Acitretin has replaced the formerly used etretinate primarily because of the significantly shorter half-life. The adverse effects are generally mild and reversible, making the drug fairly safe for long-term use. The most commonly seen adverse effects include elevated serum lipids, generalised xerosis and alopecia. Bony abnormalities, while somewhat controversial, have also been described and include diffuse idiopathic skeletal hyperostosis, skeletal calcifications and osteoporosis. Cyclosporin is the most recently approved systemic medication for plaque psoriasis. The nephrotoxicity associated with the use of cyclosporin can be minimised when used in lower doses and for a limited duration. Hypertension is usually mild and can be seen in up to about one-third of patients receiving long-term therapy. Cutaneous and internal malignancies have also been reported with cyclosporin and tend to be correlated with duration of treatment. In this review, we will examine the potential adverse effects with these US Food and Drug Administration-approved treatments in adults, with specific emphasis on the controversies that surround long-term therapy with these agents and their cumulative adverse effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I239,I239)","v":11905660},{"$f":"(LEN($J239) - LEN(SUBSTITUTE(LOWER($J239),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J239) - LEN(SUBSTITUTE(LOWER($J239),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J239) - LEN(SUBSTITUTE(LOWER($J239),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B239:D239)","v":6},2000,"Differentiation and apoptosis induction therapy in acute promyelocytic leukaemia.","Wang",11905660,"Differentiation and apoptosis induction therapy in acute promyelocytic leukaemia.    Abstract:   Induction of differentiation and/or apoptosis is a new and promising approach to cancer therapy, well illustrated by the treatment of acute promyelocytic leukaemia with all-trans-retinoic acid and arsenic compounds. Treatment with all-transretinoic acid results in complete remission in 92 - 95% of patients with this disease. Using the recently advocated combination of all-transretinoic acid and chemotherapy, adverse effects such as retinoic acid syndrome have decreased, and long-term survival has improved. Chemotherapy in combination with all-trans-retinoic acid seems to be the best postremission treatment protocol, with a 5-year relapse-free survival rate of 50 - 60%. Arsenic compounds have recently proved effective in newly diagnosed and relapsed acute promyelocytic leukaemia, with complete remission rates of 80 - 90% according to most reports. As2O3, the most studied arsenic compound, can be given by intravenous infusion at a dose of 0.08 - 0.16 mg/kg daily. A course of 28 - 44 days is required to induce remission. Although the drug is safe in patients who have relapsed, severe liver damage has been observed in some newly diagnosed patients. Combined use of chemotherapy and arsenic as postremission treatment results in longer survival than arsenic alone. Although their mechanisms of action are distinct, both all-trans-retinoic acid and arsenic can modulate PML-RARalpha, an oncoprotein that has a central role in leukaemogenesis, and both can relieve ranscriptional repression by modifying chromatin structure."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I240,I240)","v":11220263},{"$f":"(LEN($J240) - LEN(SUBSTITUTE(LOWER($J240),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J240) - LEN(SUBSTITUTE(LOWER($J240),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J240) - LEN(SUBSTITUTE(LOWER($J240),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B240:D240)","v":6},2001,"[Autofluorescence imaging of the macula].","Holz",11220263,"[Autofluorescence imaging of the macula].    Abstract:   Visualization of the retinal pigment epithelium (RPE) in vivo has proven difficult for various reasons, including the optical properties of the eye and the small size of the cellular elements, forming a single layer between the neurosensory retina and Bruchs membrane. With the advent of scanning laser ophthalmoscopy it is now possible to image topographic distribution and intensity fundus autofluorescence derived from accumulations of lipofuscin granules in RPE cells. Excessive lipofuscin storage in the RPE cytoplasm occurs not only in association with age but also with many hereditary and degenerative retinal diseases including age-related macular degeneration, Stargardt disease, Best disease, and pattern dystrophies. Lipofuscin in the RPE derives mainly from incomplete degradation of phagocytosed distal segments of photoreceptor outer segments, and is composed of various biomolecules including lipids, protein, and retinoids. Some of its constituents have recently been shown to possess toxic properties in vitro and may play a pathophysiological role in diseases such as age-related macular degeneration.Visualizing lipofuscin in vivo may help to better understand the significance of these metabolic alterations in the pathogenesis of retinal disorders. In addition,fundus autofluorescence imaging can be useful in the preclinical diagnosis of hereditary retinal disease. Dynamic alterations of intrinsic RPE fluorescence change may be applicable for monitoring effects at the level of the RPE of novel therapeutic modalities. Furthermore, identification of high-risk characteristics in patients with age-related macular degeneration with this technique may be helpful for indicating and adjusting future therapies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I241,I241)","v":11140907},{"$f":"(LEN($J241) - LEN(SUBSTITUTE(LOWER($J241),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J241) - LEN(SUBSTITUTE(LOWER($J241),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J241) - LEN(SUBSTITUTE(LOWER($J241),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B241:D241)","v":6},2000,"The oxidation of 9-cis-retinol: a possible synthesis pathway for 9-cis-retinoic acid.","Wolf",11140907,"The oxidation of 9-cis-retinol: a possible synthesis pathway for 9-cis-retinoic acid.    Abstract:   A short-chain alcohol dehydrogenase has been discovered that oxidizes 9-cis- and 11-cis-retinol to their corresponding aldehydes. The gene for this enzyme was sequenced and appears to be expressed with highest efficiency in the retinal pigment epithelium of the eye, as well as in human liver and mammary gland and in mouse liver and kidney. Because 9-cis-retinol occurs in liver, it may be a precursor of 9-cis-retinoic acid."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I242,I242)","v":11123853},{"$f":"(LEN($J242) - LEN(SUBSTITUTE(LOWER($J242),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J242) - LEN(SUBSTITUTE(LOWER($J242),LOWER(C$3),\"\")))/LEN(C$3)","v":4},{"$f":"(LEN($J242) - LEN(SUBSTITUTE(LOWER($J242),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B242:D242)","v":6},2001,"The role of fibric acids in atherosclerosis.","Fruchart",11123853,"The role of fibric acids in atherosclerosis.    Abstract:   The hypolipidemic fibric acid drugs are peroxisome proliferator-activated receptor a (PPAR alpha) ligands. PPAR alpha activated by fibric acids form heterodimers with the 9-cis retinoic acid receptor (RXR). The PPAR/RXR heterodimers bind to peroxisome proliferator response elements (PPRE), which are located in numerous gene promoters and increase the level of the expression of mRNAs encoded by PPAR alpha target genes. Fibric acids decrease triglyceride plasma levels through increases in the expression of genes involved in fatty acid-beta oxidation. Furthermore, they decrease triglycerides by increasing lipoprotein lipase gene expression and by decreasing apolipoprotein C-III gene expression. Fibric acids increase high-density lipoprotein (HDL) cholesterol partly by increasing apolipoprotein A-I and apolipoprotein A-II gene expression. Fibric acids also reduce vascular wall inflammation and the expression of genes involved in different vascular functions (ie, vasomotricity, thrombosis). Fibric acids are used to treat primary hypertriglyceridemia and mixed hyperlipidemia. Some fibric acid molecules are active in essential hypercholesterolemia. Clinical evidence shows that fibric acids reduce coronary atherosclerosis progression in dyslipidemic patients (eg, bezafibrate, gemfibrozil) and in type 2 diabetic patients (fenofibrate). Gemfibrozil decreases coronary morbidity and mortality in patients with low HDL cholesterol, normal triglycerides,and normal low-density lipoprotein (LDL) cholesterol plasma levels. Further clinical studies are necessary to investigate if fibric acids decrease cardiovascular mortality in type 2 diabetes and in primary prevention of hypertriglyceridemia and hypolipidemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I243,I243)","v":10340977},{"$f":"(LEN($J243) - LEN(SUBSTITUTE(LOWER($J243),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J243) - LEN(SUBSTITUTE(LOWER($J243),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J243) - LEN(SUBSTITUTE(LOWER($J243),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B243:D243)","v":6},1999,"Ocular signs and symptoms and vitamin A status in patients with cystic fibrosis treated with daily vitamin A supplements.","Ansari",10340977,"Ocular signs and symptoms and vitamin A status in patients with cystic fibrosis treated with daily vitamin A supplements.    Abstract:    BACKGROUND/AIMS : Patients with cystic fibrosis (CF) may have low plasma vitamin A levels from malabsorption, zinc deficiency, liver disease, or poor compliance with prescribed supplements. In view of the increasing number of adults with CF, many of whom drive cars, it is important to assess vitamin A status. In our centre an attempt has been made to achieve normal levels of fat soluble vitamins by annual estimation of plasma levels and appropriate oral supplementation. This study aimed to determine if this approach prevents vitamin A deficiency and the consequent problems with dark adaptation.  METHODS : The study was conducted at the regional adult and paediatric cystic fibrosis unit and the patients were recruited from there. Dark adaptation studies were conducted at the department of ophthalmology, St Jamess University Hospital. All patients are regularly seen in the outpatient department by a CF specialist dietitian and have a comprehensive annual dietary assessment. 28 patients had the following investigations: serum retinol, plasma zinc, serum retinol binding protein, liver function tests, dark adaptation, contrast sensitivity, and anterior ocular surface status. 25 age and sex matched controls without CF or ocular pathology were also recruited for the dark adaptation study.  RESULTS : None of the patients had vitamin A deficiency, the median value of serum retinol being 48 microg/dl, range 31-80 microg/dl (normal range 30-80 microg/dl). Dark adaptation was normal in all cases compared with the control group where the mean value was 3.4 log units of threshold luminance (95% confidence interval 2.4-4.0). None of the test group had a value of threshold luminance 2 SD above the mean value for the control group. Eight patients had reduced contrast sensitivity. The median value for serum zinc was 14.2 micromol/ l, range 13-81 micromol/l (normal range 8-23 micromol/l) and the median value for retinol binding protein was 36 mg/l, range 13-81 mg/l (normal range 35-58 mg/l). There was no correlation between dark adaptation and serum retinol, zinc, or retinol binding protein. Two patients had clinical evidence of dry eye.  CONCLUSION : Regular estimates of plasma vitamin A together with appropriate supplementation and expert dietetic review can maintain normal dark adaptation in patients with cystic fibrosis. The occurrence of reduced contrast sensitivity function is well documented but remains an unexplained phenomenon and deserves further study."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I244,I244)","v":9924174},{"$f":"(LEN($J244) - LEN(SUBSTITUTE(LOWER($J244),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J244) - LEN(SUBSTITUTE(LOWER($J244),LOWER(C$3),\"\")))/LEN(C$3)","v":6},{"$f":"(LEN($J244) - LEN(SUBSTITUTE(LOWER($J244),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B244:D244)","v":6},1999,"Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences.","Holden",9924174,"Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences.    Abstract:   Peroxisome proliferators (PPs) are chemicals of industrial and pharmaceutical importance that elicit liver carcinogenesis by a non-genotoxic mechanism. One of the intriguing properties of PPs is that the pleiotropic effects of these compounds (including increased DNA synthesis and peroxisome proliferation) are seen in rats and mice only, but not humans. It is important to determine the risks to humans of environmental and therapeutic exposure to these compounds by understanding the mechanisms of non-genotoxic hepatocarcinogenesis in rodents. To understand this apparent lack of human susceptibility, attention has focused on the peroxisome proliferator-activated receptor alpha (PPARalpha), which appears to mediate the effects of PPs in rodents. It is also known to mediate the hypolipidaemic effects that fibrate drugs exert on humans with elevated plasma cholesterol and triglyceride levels. Human PPARalphas share many functional characteristics with the rodent receptors, in that they can be transcriptionally activated by PPs and regulate specific gene expression. However, one key difference is that PPARalpha is less abundant in human than in rodent liver, which has led to the suggestion that species differences result from quantitative differences in gene expression. In this review we describe the effects of PPs and what is known of the molecular mechanisms of action and species differences with respect to rodents and man. Attention will be given to differences in the amounts of PPARalpha between species as well as the qualitative aspects of PPARalpha-mediated gene regulation which might also explain the activation of some genes and not of others in human liver by PPs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I245,I245)","v":8841765},{"$f":"(LEN($J245) - LEN(SUBSTITUTE(LOWER($J245),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J245) - LEN(SUBSTITUTE(LOWER($J245),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J245) - LEN(SUBSTITUTE(LOWER($J245),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B245:D245)","v":6},1996,"Retinoid (vitamin A) metabolism.","Hendriks",8841765,"Retinoid (vitamin A) metabolism.    Abstract:    OBJECTIVE AND CONCLUSION : An overview is given of our understanding of the uptake and metabolism of retinoids. The mechanisms underlying retinol uptake by organs and tissues are still unsettled. The retinol-binding proteins CRBP I and CRBP II appear to play an essential role in retinyl ester hydrolysis and formation and in retinoic acid formation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I246,I246)","v":7816354},{"$f":"(LEN($J246) - LEN(SUBSTITUTE(LOWER($J246),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J246) - LEN(SUBSTITUTE(LOWER($J246),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J246) - LEN(SUBSTITUTE(LOWER($J246),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B246:D246)","v":6},1994,"Uptake of retinoids by adipose tissue.","Wolf",7816354,"Uptake of retinoids by adipose tissue.    Abstract:   Adipose tissue was found to contain considerable amounts of retinoids and retinol-binding protein mRNA, particularly in epididymal and perinephric depots. Delivery of retinoids appears to be through the hydrolysis of retinyl esters in postprandial chylomicrons by lipoprotein lipase, with subsequent uptake of retinol by adipocytes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I247,I247)","v":2142437},{"$f":"(LEN($J247) - LEN(SUBSTITUTE(LOWER($J247),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J247) - LEN(SUBSTITUTE(LOWER($J247),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J247) - LEN(SUBSTITUTE(LOWER($J247),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B247:D247)","v":6},1990,"Risk: benefit ratio in the treatment of psoriasis with systemic retinoids.","Halioua",2142437,"Risk: benefit ratio in the treatment of psoriasis with systemic retinoids.    Abstract:   This is a review of the efficacy of etretinate/acitretin in the treatment of psoriasis and of the currently reported side-effects. The data indicate that retinoids bring significant improvement (if not total clearing) with frequent low-morbidity but rarely serious side-effects. The most serious side-effect of etretinate/acitretin is teratogenicity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I248,I248)","v":2680704},{"$f":"(LEN($J248) - LEN(SUBSTITUTE(LOWER($J248),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J248) - LEN(SUBSTITUTE(LOWER($J248),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J248) - LEN(SUBSTITUTE(LOWER($J248),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B248:D248)","v":6},1989,"Cellular lipid binding proteins: expression, function, and nutritional regulation.","Clarke",2680704,"Cellular lipid binding proteins: expression, function, and nutritional regulation.    Abstract:   The membrane transport and cytosolic solubilization of hydrophobic ligands, including sterols, fatty acids, retinoids, and certain hydrophobic carcinogens, are facilitated by a group of similar low molecular weight proteins: plasma membrane transport protein, fatty acid binding proteins, sterol carrier protein, and retinoid binding proteins. The cellular content of these proteins, which establishes the capacity of a cell to utilize the various ligands, is determined by events regulating transcription and translation, e.g., the mRNA abundance of liver- and gut-type FABPs is increased by dietary fat, and translation of hepatic FABP appears to be stimulated by insulin. Functions attributable to these lipid binding proteins remain unclear, but data are presented that indicate physiological roles in 1) fatty acid transport, esterification, and oxidation, 2) steroidogenesis, and 3) retinoid uptake, retinaldehyde reduction, and retinol esterification. An exciting and novel prospect for cellular trafficking proteins is the role they may play in regulating gene expression. In this respect, cellular lipid binding proteins, e.g., retinoid binding proteins, may deliver their ligands to nuclear trans-acting proteins, and thereby modulate genes coding for key proteins involved in lipid metabolism or differentiation. Even though the functions of these proteins still need to be unequivocally established, it is clear that they are important in the overall homeostasis of lipid metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I249,I249)","v":3045876},{"$f":"(LEN($J249) - LEN(SUBSTITUTE(LOWER($J249),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J249) - LEN(SUBSTITUTE(LOWER($J249),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J249) - LEN(SUBSTITUTE(LOWER($J249),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B249:D249)","v":6},1988,"[Skeletal changes following long-term treatment with retinoids].","Montag",3045876,"[Skeletal changes following long-term treatment with retinoids].    Abstract:   The synthetic retinoids, the vitamin-D-derivatives etretinate and isotretinoin, have substantially enlarged the therapeutic arsenal in dermatology. They are primarily used in severe cases of acne and cornification disorders. In the majority of cases, long-term treatment is necessary. Certain side effects in the skeletal system can occur, e.g., osteoporosis, premature epiphyseal closure, and changes similar to DISH (diffuse idiopathic skeletal hyperostosis). We discuss the reports in the literature and our own observations in 31 patients treated at the Westphalian Wilhelms University in Muenster, as well as at the Technical University in Munich. In 3 out of 31 patients treated by retinoids on a long-term basis, skeletal changes were found radiologically as a result of the retinoid medication."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I250,I250)","v":6349358},{"$f":"(LEN($J250) - LEN(SUBSTITUTE(LOWER($J250),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J250) - LEN(SUBSTITUTE(LOWER($J250),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J250) - LEN(SUBSTITUTE(LOWER($J250),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B250:D250)","v":6},1983,"Vitamin A.","Schoeff",6349358,"Vitamin A.    Abstract:   Vitamin A refers collectively to a number of compounds, the most biologically active of which is retinol. Named after its earliest discovered function, visual excitation, retinol is also needed for growth and reproduction, and differentiation of epithelial tissue. A closely related form, retinoic acid, has selective biologic activity for normal growth and epithelial differentiation. The term retinoids has been used in recent years to include both natural and synthetic analogs of vitamin A. Carotene and carotenoids refer to vitamin A precursors (pro-vitamins) of vegetable origin. Following a brief historical account of vitamin A and description of dietary information this article focuses on the chemistry and physiology of retinoids. The biological roles of vitamin A compounds are elaborated, as well as the clinical significance of vitamin A deficiency and excess. Discussion of retinoids in therapy includes their use as anti-cancer agents and as therapeutics for dermatological disorders. Finally, a review of analytical techniques for laboratory assessment of vitamin A is presented."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I251,I251)","v":6994566},{"$f":"(LEN($J251) - LEN(SUBSTITUTE(LOWER($J251),LOWER(B$3),\"\")))/LEN(B$3)","v":6},{"$f":"(LEN($J251) - LEN(SUBSTITUTE(LOWER($J251),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J251) - LEN(SUBSTITUTE(LOWER($J251),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B251:D251)","v":6},1980,"Plasma retinol-binding protein.","Goodman",6994566,"Plasma retinol-binding protein.    Abstract:   Vitamin A is mobilized from liver stores and transported in plasma in the form of the lipid alcohol retinol, bound to a specific transport protein, retinol-binding protein (RBP). A great deal is known about the chemical structure, metabolism, and biological roles of RBP. RBP is a single polypeptide chain with molecular weight close to 20,000. RBP interacts strongly with plasma prealbumin, and normally circulates in plasma as a 1:1 molar RBP-prealbumin complex. Both the primary and the tertiary structure of prealbumin are known, and the primary structure of RBP has recently been reported. Much information is available about the protein-protein and protein-ligand interactions that are involved in this transport system. Many clinical studies have examined the effects of a variety of diseases on the plasma levels of RBP and prealbumin in humans. Plasma RBP levels are low in patients with liver disease and are high in patients with chronic renal disease. These findings reflect the facts that RBP is produced in the liver and mainly catabolized in the kidneys. Delivery of retinol to extra-hepatic tissues appears to involve specific cell surface receptors for RBP. Vitamin A mobilization from the liver, and delivery to peripheral tissues, is highly regulated by factors that control the rates of RBP production and secretion. Retinol deficiency specifically blocks the secretion of RBP, so that plasma RBP levels fall and liver RBP levels rise. Injection of retinol into vitamin A-deficient rats stimulates the rapid secretion of RBP from the liver into the plasma. The cellular and molecular mechanisms that mediate these phenomena are under investigation. Elucidation of these mechanisms should help define the basic mechanisms that control the mobilization, transport, and delivery of vitamin A."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I252,I252)","v":27320333},{"$f":"(LEN($J252) - LEN(SUBSTITUTE(LOWER($J252),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J252) - LEN(SUBSTITUTE(LOWER($J252),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J252) - LEN(SUBSTITUTE(LOWER($J252),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B252:D252)","v":5},2016,"Retinoid X Receptor Selective Agonists and their Synthetic Methods.","Wagner",27320333,"Retinoid X Receptor Selective Agonists and their Synthetic Methods.    Abstract:    NlmCategory=UNASSIGNEDSince the isolation and identification of the retinoid X receptor (RXR) as a member of the nuclear receptor (NR) superfamily in 1990, its analysis has ushered in a new understanding of physiological regulation by nuclear receptors, and novel methods to identify other unknown and orphan receptors. Expression of one or more of the three isoforms of RXR-α, β, and ϒ- can be found in every human cell type. Biologically, RXR plays a critical role through its ability to partner with other nuclear receptors. RXR is able to regulate nutrient metabolism by forming quot;permissivequot; heterodimers with peroxisome proliferator-activated receptor (PPAR), liver-X-receptor (LXR), farnesoid X receptor (FXR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR), which function when ligands are bound to one or both of the heterodimer partners. Conversely, RXR is able to form quot;nonpermissivequot; heterodimers with vitamin D receptor (VDR), thyroid receptor (TR) and retinoic acid receptor (RAR), which function only in the presence of vitamin D, T3 and retinoic acid, respectively. Furthermore, RXR can form homodimers in the presence of a selective agonist, rexinoid, to regulate gene expression and to either inhibit proliferation or induce apoptosis in human cancers. Thus, over the last 25 years there have been several reports on the design and synthesis of small molecule RXR selective agonists, rexinoids. This review summarizes the synthetic methods for several of the most potent rexinoids thus far reported."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I253,I253)","v":26312242},{"$f":"(LEN($J253) - LEN(SUBSTITUTE(LOWER($J253),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J253) - LEN(SUBSTITUTE(LOWER($J253),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J253) - LEN(SUBSTITUTE(LOWER($J253),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B253:D253)","v":5},2015,"STRA6: role in cellular retinol uptake and efflux.","Kelly",26312242,"STRA6: role in cellular retinol uptake and efflux.    Abstract:   Distribution of vitamin A throughout the body is important to maintain retinoid function in peripheral tissues and to ensure optimal vision. A critical step of this process is the transport of vitamin A across cell membranes. Increasing evidence indicates that this process is mediated by a multidomian membrane protein that is encoded by the stimulated by retinoic acid 6 (STRA6) gene. Biochemical studies revealed that STRA6 is a transmembrane pore which transports vitamin A bidirectionally between extra- and intracellular retinoid binding proteins. Vitamin A accumulation in cells is driven by coupling of transport with vitamin A esterification. Loss-of-function studies in zebrafish and mouse models have unraveled the critical importance of STRA6 for vitamin A homeostasis of peripheral tissues. Impairment in vitamin A transport and uptake homeostasis are associated with diseases including type 2 diabetes and a microphthalmic syndrome known as Matthew Wood Syndrome. This review will discuss the advanced state of knowledge about STRA6s biochemistry, biology and association with disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I254,I254)","v":26110391},{"$f":"(LEN($J254) - LEN(SUBSTITUTE(LOWER($J254),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J254) - LEN(SUBSTITUTE(LOWER($J254),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J254) - LEN(SUBSTITUTE(LOWER($J254),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B254:D254)","v":5},2015,"Transcriptional Factors Mediating Retinoic Acid Signals in the Control of Energy Metabolism.","Zhang",26110391,"Transcriptional Factors Mediating Retinoic Acid Signals in the Control of Energy Metabolism.    Abstract:   Retinoic acid (RA), an active metabolite of vitamin A (VA), is important for many physiological processes including energy metabolism. This is mainly achieved through RA-regulated gene expression in metabolically active cells. RA regulates gene expression mainly through the activation of two subfamilies in the nuclear receptor superfamily, retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RAR/RXR heterodimers or RXR/RXR homodimers bind to RA response element in the promoters of RA target genes and regulate their expressions upon ligand binding. The development of metabolic diseases such as obesity and type 2 diabetes is often associated with profound changes in the expressions of genes involved in glucose and lipid metabolism in metabolically active cells. RA regulates some of these gene expressions. Recently, in vivo and in vitro studies have demonstrated that status and metabolism of VA regulate macronutrient metabolism. Some studies have shown that, in addition to RARs and RXRs, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter-transcription factor II, and peroxisome proliferator activated receptor β/δ may function as transcriptional factors mediating RA response. Herein, we summarize current progresses regarding the VA metabolism and the role of nuclear receptors in mediating RA signals, with an emphasis on their implication in energy metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I255,I255)","v":25653125},{"$f":"(LEN($J255) - LEN(SUBSTITUTE(LOWER($J255),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J255) - LEN(SUBSTITUTE(LOWER($J255),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J255) - LEN(SUBSTITUTE(LOWER($J255),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B255:D255)","v":5},2015,"Homocysteine and the pathogenesis of atherosclerosis.","McCully",25653125,"Homocysteine and the pathogenesis of atherosclerosis.    Abstract:   The homocysteine theory of arteriosclerosis was discovered by study of arteriosclerotic plaques occurring in homocystinuria, a disease caused by deficiencies of cystathionine synthase, methionine synthase or methylenetetrahydrofolate reductase. According to the homocysteine theory, metabolic and nutritional abnormalities leading to elevation of plasma homocysteine cause atherosclerosis in the general population without these rare enzymatic abnormalities. Through studies of metabolism of homocysteine thiolactone, the anhydride of homocysteine, in cell cultures from homocystinuric children, the pathway for synthesis of sulfate was found to be dependent upon thioretinamide, the amide formed from retinoic acid and homocysteine thiolactone. Two molecules of thioretinamide form the complex thioretinaco with cobalamin, and oxidative phosphorylation is catalyzed by reduction of oxygen, which is bound to thioretinaco ozonide, by electrons from electron transport particles. Atherogenesis is attributed to formation of aggregates of homocysteinylated lipoproteins with microorganisms, which obstruct the vasa vasorum during formation of arterial vulnerable plaques."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I256,I256)","v":24667133},{"$f":"(LEN($J256) - LEN(SUBSTITUTE(LOWER($J256),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J256) - LEN(SUBSTITUTE(LOWER($J256),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J256) - LEN(SUBSTITUTE(LOWER($J256),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B256:D256)","v":5},2014,"Metabolic interactions between vitamin A and conjugated linoleic acid.","Carta",24667133,"Metabolic interactions between vitamin A and conjugated linoleic acid.    Abstract:   Lipid-soluble molecules share several aspects of their physiology due to their common adaptations to a hydrophilic environment, and may interact to regulate their action in a tissue-specific manner. Dietary conjugated linoleic acid (CLA) is a fatty acid with a conjugated diene structure that is found in low concentrations in ruminant products and available as a nutritional supplement. CLA has been shown to increase tissue levels of retinol (vitamin A alcohol) and its sole specific circulating carrier protein retinol-binding protein (RBP or RBP4). However, the precise mechanism of this action has not been elucidated yet. Here, we provide a summary of the current knowledge in this specific area of research and speculate that retinol and CLA may compete for catabolic pathways modulated by the activity of PPAR-α and RXR heterodimer. We also present preliminary data that may position PPAR-α at the crossroads between the metabolism of lipids and vitamin A."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I257,I257)","v":24594504},{"$f":"(LEN($J257) - LEN(SUBSTITUTE(LOWER($J257),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J257) - LEN(SUBSTITUTE(LOWER($J257),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J257) - LEN(SUBSTITUTE(LOWER($J257),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B257:D257)","v":5},2014,"Aldehyde dehydrogenase 1A1: friend or foe to female metabolism?","Petrosino",24594504,"Aldehyde dehydrogenase 1A1: friend or foe to female metabolism?    Abstract:   In this review, we summarize recent advances in understanding vitamin A-dependent regulation of sex-specific differences in metabolic diseases, inflammation, and certain cancers. We focus on the characterization of the aldehyde dehydrogenase-1 family of enzymes (ALDH1A1, ALDH1A2, ALDH1A3) that catalyze conversion of retinaldehyde to retinoic acid. Additionally, we propose a quot;horizontal transfer of signalingquot; from estrogen to retinoids through the action of ALDH1A1. Although estrogen does not directly influence expression of Aldh1a1, it has the ability to suppress Aldh1a2 and Aldh1a3, thereby establishing a female-specific mechanism for retinoic acid generation in target tissues. ALDH1A1 regulates adipogenesis, abdominal fat formation, glucose tolerance, and suppression of thermogenesis in adipocytes; in B cells, ALDH1A1 plays a protective role by inducing oncogene suppressors Rara and Pparg. Considering the conflicting responses of Aldh1a1 in a multitude of physiological processes, only tissue-specific regulation of Aldh1a1 can result in therapeutic effects. We have shown through successful implantation of tissue-specific Aldh1a1-/- preadipocytes that thermogenesis can be induced in wild-type adipose tissues to resolve diet-induced visceral obesity in females. We will briefly discuss the emerging role of ALDH1A1 in multiple myeloma, the regulation of reproduction, and immune responses, and conclude by discussing the role of ALDH1A1 in future therapeutic applications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I258,I258)","v":24485945},{"$f":"(LEN($J258) - LEN(SUBSTITUTE(LOWER($J258),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J258) - LEN(SUBSTITUTE(LOWER($J258),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J258) - LEN(SUBSTITUTE(LOWER($J258),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B258:D258)","v":5},2014,"Cultured primary human fetal retinal pigment epithelium (hfRPE) as a model for evaluating RPE metabolism.","Adijanto",24485945,"Cultured primary human fetal retinal pigment epithelium (hfRPE) as a model for evaluating RPE metabolism.    Abstract:   Mitochondrial dysfunction has been shown to contribute to age-related and proliferative retinal diseases. Over the past decade, the primary human fetal RPE (hfRPE) culture model has emerged as an effective tool for studying RPE function and mechanisms of retinal diseases. This model system has been rigorously characterized and shown to closely resemble native RPE cells at the genomic and protein level, and that they are capable of accomplishing the characteristic functions of a healthy native RPE (e.g., rod phagocytosis, ion and fluid transport, and retinoid cycle). In this review, we demonstrated that the metabolic activity of the RPE is an indicator of its health and state of differentiation, and present the hfRPE culture model as a valuable in vitro system for evaluating RPE metabolism in the context of RPE differentiation and retinal disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I259,I259)","v":24382226},{"$f":"(LEN($J259) - LEN(SUBSTITUTE(LOWER($J259),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J259) - LEN(SUBSTITUTE(LOWER($J259),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J259) - LEN(SUBSTITUTE(LOWER($J259),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B259:D259)","v":5},2013,"Roles of the lipid metabolism in hepatic stellate cells activation △.","Jing",24382226,"Roles of the lipid metabolism in hepatic stellate cells activation △.    Abstract:   The lipids present in hepatic stellate cells (HSCs) lipid droplets include retinyl ester, triglyceride, cholesteryl ester, cholesterol, phospholipids and free fatty acids. Activation of HSCs is crucial to the development of fibrosis in liver disease. During activation, HSCs transform into myofibroblasts with concomitant loss of their lipid droplets and production of excessive extracellular matrix. Release of lipid droplets containing retinyl esters and triglyceride is a defining feature of activated HSCs. Accumulating evidence supports the proposal that recovering the accumulation of lipids would inhibit the activation of HSCs. In healthy liver, quiescent HSCs store 80% of total liver retinols and release them depending on the extracellular retinol status. However, in injured liver activated HSCs lose their retinols and produce a considerable amount of extracellular matrix, subsequently leading to liver fibrosis. Further findings prove that lipid metabolism of HSCs is closely associated with its activation, yet relationship between activated HSCs and the lipid metabolism has remained mysterious."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I260,I260)","v":23511242},{"$f":"(LEN($J260) - LEN(SUBSTITUTE(LOWER($J260),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J260) - LEN(SUBSTITUTE(LOWER($J260),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J260) - LEN(SUBSTITUTE(LOWER($J260),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B260:D260)","v":5},2013,"Retinoic acid regulation of male meiosis.","Hogarth",23511242,"Retinoic acid regulation of male meiosis.    Abstract:    PURPOSE OF REVIEW : Description of new evidence to support the model for how retinoic acid regulates spermatogonial differentiation, male meiosis and the cycle of the seminiferous epithelium.  RECENT FINDINGS : It has been known since the 1920s that vitamin A is essential for spermatogenesis. However, only recently has significant progress been made toward understanding how the active metabolite of vitamin A, retinoic acid, regulates spermatogenesis at multiple different differentiation steps, including the onset of meiosis. Current publications suggest that the initiation and maintenance of the cycle of the seminiferous epithelium is linked to retinoic-acid-driving spermatogonial differentiation and meiotic onset.  SUMMARY : Retinoic acid appears to act in a pulsatile manner, periodically driving spermatogonial differentiation and meiotic onset at discrete points along testis tubules, and as a result, is likely to be responsible for generating and maintaining the cycle of the seminiferous epithelium."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I261,I261)","v":23400919},{"$f":"(LEN($J261) - LEN(SUBSTITUTE(LOWER($J261),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J261) - LEN(SUBSTITUTE(LOWER($J261),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J261) - LEN(SUBSTITUTE(LOWER($J261),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B261:D261)","v":5},2013,"The role of cytochrome P450 2E1 in ethanol-mediated carcinogenesis.","Seitz",23400919,"The role of cytochrome P450 2E1 in ethanol-mediated carcinogenesis.    Abstract:   We and others have shown that chronic alcohol consumption results in the induction of CYP2E1 in the liver. We have also detected for the first time such an induction in the mucosa of the small intestine and the colon. The overall induction of CYP2E1 shows interindividual variations and occurs already following a daily ingestion of 40 g of ethanol after 1 week. CYP2E1 induction is associated with an increased metabolism of ethanol resulting in the generation of reactive oxygen species (ROS) with direct and indirect carcinogenic action. ROS generated by CYP2E1 may lead to lipid peroxidation and lipid peroxidation products such as 4-hydroxynonenal bind to DNA forming highly carcinogenic exocyclic etheno DNA-adducts. The generation of these adducts has been shown in cell cultures in animal experiments as well as in human liver biopsies. CYP2E1 also metabolizes various procarcinogens present in diets and in tobacco smoke to their carcinogenic metabolites. Among these, nitrosamines seem to be the most important carcinogens. CYP2E1 also degrades retinoic acid and retinol to polar metabolites. Metabolism of retinoic acid not only results in the loss of retinoic acid promoting carcinogenesis through an increase in cell proliferation and dedifferentiation but also in generation of polar metabolites with apoptotic properties. We have shown that chlormethiazole is a specific CYP2E1 inhibitor in humans. Chlormethiazole inhibits CYP2E1 activity and thus blocks the formation of DNA adducts in cell cultures, restores retinoic acids in alcohol fed animals and inhibits chemical induced ethanol mediated hepatocarcinogenesis. Thus, there is increasing evidence that CYP2E1 induced by chronic alcohol consumption plays an important role in alcohol mediated carcinogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I262,I262)","v":21626400},{"$f":"(LEN($J262) - LEN(SUBSTITUTE(LOWER($J262),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J262) - LEN(SUBSTITUTE(LOWER($J262),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J262) - LEN(SUBSTITUTE(LOWER($J262),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B262:D262)","v":5},2011,"Vitamin A and lipid metabolism: relationship between hepatic stellate cells (HSCs) and adipocytes.","Sauvant",21626400,"Vitamin A and lipid metabolism: relationship between hepatic stellate cells (HSCs) and adipocytes.    Abstract:   Vitamin A or retinol plays a major role in the regulation of cellular homeostasis. Retinyl palmitate remains the main chemical form of vitamin A storage and is mainly located in hepatic stellate cells (HSCs) in lipid droplets resembling those found in adipose cells. White adipose tissue (WAT), is essentially involved in the regulation of lipid metabolism, through its role in lipid storage, and might also be considered as a vitamin A storage and metabolism site. WAT contains all the intracellular equipment for vitamin A metabolism and signaling pathways which allows retinol to be metabolized into retinoic acid, known to control genomic expression in WAT. The description of molecular mechanisms involved in the activation of HSCs and the differentiation of preadipocytes reveal similar cellular and molecular mechanisms. Indeed HSCs and adipocytes share a common expression of key transcription factors like PPAR-γ and RXR known to influence perilipin expression, which play fundamental roles in lipid droplet metabolism. Both cells are also sources of important endocrine signaling secretions influencing the expression of these transcription factors. The morphological and functional characteristics of HSCs and adipocytes, including the metabolism of vitamin A and other lipids and their related signaling pathways, are summarized and compared in this review. We highlight the complexity of the interrelationship between lipids and vitamin A metabolism and the role of the complex communication existing between HSCs and WAT in diseases such as non-alcoholic fatty liver disease which is the hepatic manifestation of the metabolic syndrome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I263,I263)","v":18793157},{"$f":"(LEN($J263) - LEN(SUBSTITUTE(LOWER($J263),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J263) - LEN(SUBSTITUTE(LOWER($J263),LOWER(C$3),\"\")))/LEN(C$3)","v":4},{"$f":"(LEN($J263) - LEN(SUBSTITUTE(LOWER($J263),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B263:D263)","v":5},2008,"Role of nuclear receptors in the modulation of insulin secretion in lipid-induced insulin resistance.","Sugden",18793157,"Role of nuclear receptors in the modulation of insulin secretion in lipid-induced insulin resistance.    Abstract:   In healthy individuals, a hyperbolic relationship exists between whole-body insulin-sensitivity and insulin secretion. Thus, for any difference in insulin-sensitivity, a reciprocal proportionate change occurs in insulin secretion. Such a feedback loop is evident in healthy individuals ingesting diets high in saturated fat and in late pregnancy where, despite lipid-induced insulin resistance, glucose tolerance is maintained through augmented GSIS (glucose-stimulated insulin secretion). NRs (nuclear receptors) are members of a superfamily of ligand-regulated and orphan transcription factors. On activation by a cognate ligand, many ligand-activated NRs recruit the RXR (retinoid X receptor) for heterodimer formation. Such NRs include the PPARs (peroxisome-proliferator-activated receptors), which are involved in lipid sensing and liporegulation. PPARs exert important lipid-lowering effects in vivo, thereby opposing the development of lipid-induced insulin resistance by relieving the inhibition of insulin-stimulated glucose disposal by muscle and lowering the necessity for augmented GSIS to counter lipid-induced insulin resistance. Long-chain fatty acids are proposed as natural PPAR ligands and some specific endogenous pathways of lipid metabolism are believed to generate PPAR agonists. Other NRs, e.g. the LXR (liver X receptor), which senses expansion of the metabolically active pool of cholesterol, and the FXR (farnesoid X receptor; NR1H4), which, like the LXR, is involved in sterol metabolism, also modulate systemic lipid levels and insulin-sensitivity. In this review, we discuss how these NRs impact insulin secretion via effects on the insulin-sensitivity-insulin secretion feedback loop and, in some cases, via direct effects on the islet itself. In addition, we discuss interactions between these nutrient/metabolite-responsive NRs and NRs that are central to the action of metabolically important hormones, including (i) the glucocorticoid receptor, critical for maintaining glucose homoeostasis in stress, inflammation and during fasting, and (ii) the thyroid hormone receptors, vital for maintenance of oxidative functions. We present data indicating that the RXR occupies a key role in directly modulating islet function and that its heterodimerization with at least two of its partners modulates GSIS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I264,I264)","v":18289178},{"$f":"(LEN($J264) - LEN(SUBSTITUTE(LOWER($J264),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J264) - LEN(SUBSTITUTE(LOWER($J264),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J264) - LEN(SUBSTITUTE(LOWER($J264),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B264:D264)","v":5},2008,"Influence of iron on vitamin A nutritional status.","Oliveira",18289178,"Influence of iron on vitamin A nutritional status.    Abstract:   Iron deficiency seems to deteriorate vitamin A metabolism leading to a reduction in serum retinol and an increase in hepatic retinol and retinyl ester. These alterations probably result from an increase in retinol sequestration to the liver and/or impairment in the activity of hepatic retinyl ester hydrolases decreasing vitamin A mobilization."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I265,I265)","v":17259011},{"$f":"(LEN($J265) - LEN(SUBSTITUTE(LOWER($J265),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J265) - LEN(SUBSTITUTE(LOWER($J265),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J265) - LEN(SUBSTITUTE(LOWER($J265),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B265:D265)","v":5},2007,"A review of the functional role and of the expression profile of retinoid signaling and of nuclear receptors in human spinal cord.","Malaspina",17259011,"A review of the functional role and of the expression profile of retinoid signaling and of nuclear receptors in human spinal cord.    Abstract:   Spinal cord degenerative pathologies in humans cause extensive disability and require a broad range of specialist and palliative medical interventions. In amyotrophic lateral sclerosis (ALS), motor cell loss leads to extensive paralysis and to death from respiratory failure in 3-5 years form disease onset. A wide range of molecular changes forms the basis of spinal cord involvement in ALS, including the reactivation of molecular pathways with potentially neurorestorative properties. Central to this tissue repair mechanism is the differential regulation of components of the retinoid signaling (ReS), a molecular pathway encompassing a variety of proteins functioning as transporters, signaling factors and metabolizing enzymes for retinoic acid. In this paper, we review the strong body of experimental evidence supporting retinoid signalings primary role in spinal cord embryonic differentiation and its likely survival-promoting function in ALS. We discuss the potential involvement in ALS pathogenesis of a subgroup of nuclear receptors (NRs) that act as functional partners of retinoid receptors in human spinal cord. We also provide a review of the expression profile of 25 ReS and NRs genes in human adult spinal cord and in motor neurons of healthy and ALS individuals, using data retrieved from independent datasets obtained through serial analysis of gene expression and array investigations. Based on published expression data, we outline a tentative expression profile of ReS and functionally synergic NR genes in human spinal cord that could guide further experiments to clarify the role of these molecules in mature nervous tissue and suggest potential treatment strategies that could have therapeutic potentials in ALS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I266,I266)","v":15544481},{"$f":"(LEN($J266) - LEN(SUBSTITUTE(LOWER($J266),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J266) - LEN(SUBSTITUTE(LOWER($J266),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J266) - LEN(SUBSTITUTE(LOWER($J266),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B266:D266)","v":5},2004,"Therapeutic potential of natural compounds that regulate the activity of protein kinase C.","Carter",15544481,"Therapeutic potential of natural compounds that regulate the activity of protein kinase C.    Abstract:   Protein kinase C (PKC) is a family of serine/threonine kinases that regulates a variety of cell functions including proliferation, gene expression, cell cycle, differentiation, cytoskeletal organization, cell migration, and apoptosis. The PKC signal transduction cascade coordinates complex physiological events including normal tissue function and repair. Disruption of the cellular environment through genetic mutation, disease, injury, or exposure to pro-oxidants, alcohol, or other insults can induce pathological PKC activation. Aberrant PKC activation can lead to diseases of cellular dysregulation such as cancer and diabetes. Can aberrant activation of PKC be reversed? Even 25 years after the identification of PKC, therapeutic regulation of PKC activity remains an emerging field. Because the function of each isoform remains to be elucidated, isoform specific control of gene expression is a current challenge. Natural compounds are important regulators of PKC activity, with both preventive and therapeutic efficacy. Antioxidants including vitamin A (retinoids), vitamin C (ascorbic acid) and vitamin E (tocopherols) show promise for reversal of PKC activation. beta-carotene and retinoids function as anticarcinogenic agents and antagonize the biological effects of pro-oxidants on PKC. Vitamin E reverses the deleterious effects of hyperglycemia and diabetes by down-regulating PKC activity. Antioxidants in red wine provide cardioprotective effects. However, alcohol consumption also induces oxidative stress and disrupts PKC and retinoid function in the fetus and the adult. This review examines modulation of PKC activity by natural compounds and pharmacologic analogues which can be used effectively to prevent or treat common diseases associated with aberrant activation of PKC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I267,I267)","v":15379720},{"$f":"(LEN($J267) - LEN(SUBSTITUTE(LOWER($J267),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J267) - LEN(SUBSTITUTE(LOWER($J267),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J267) - LEN(SUBSTITUTE(LOWER($J267),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B267:D267)","v":5},2004,"Redifferentiation therapy in advanced thyroid cancer.","Haugen",15379720,"Redifferentiation therapy in advanced thyroid cancer.    Abstract:   Thyroid cancer is a relatively common malignancy with an estimated prevalence of 250,000 in the U.S. A minority of patients have poorly differentiated thyroid carcinoma that is unresponsive to radioiodine therapy. Redifferentiation agents that reprogram these tumors to concentrate radioiodine would be of great value in treating patients with advanced thyroid cancer. The retinoid isotretinoin is the most extensively studied of these agents. It appears that 20-40% of patients respond to isotretinoin treatment by concentration of radioiodine in metastatic tumors, but the clinical utility of this redifferentiation is still unclear. In vitro studies suggest that the retinoid receptors (RARbeta and RXRgamma) are required for this effect. Abnormal DNA methylation may be an early event in thyroid tumorigenesis and methylation of the sodium iodide symporter (NIS) may play a role in the loss of iodine concentration in these tumors. Inhibitors of methylation (5-azacytidine, phenylacetate and sodium butyrate) have been shown to increase NIS expression and iodine uptake in cell culture models, but published trials in humans are not yet available. Histone acetylation is required for efficient transcription of genes necessary for differentiated function. Proteins that cause histone deacetylation inhibit gene transcription and differentiated function. Inhibitors of histone deacetylation (depsipeptide, trichostatin A) have been shown to increase NIS expression and iodine uptake in poorly differentiated and undifferentiated cell lines. Phase II human trials are currently underway for depsipeptide. Finally, commonly used agents such as thiazolidinediones (diabetes) and HMG-CoA reductase inhibitors (hypercholesterolemia) have shown promise in preliminary in vitro studies in advanced thyroid cancer cell lines. Development of these and other novel agents for the treatment of advanced thyroid cancer is critical for us to treat an uncommon progression of a common malignancy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I268,I268)","v":14529153},{"$f":"(LEN($J268) - LEN(SUBSTITUTE(LOWER($J268),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J268) - LEN(SUBSTITUTE(LOWER($J268),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J268) - LEN(SUBSTITUTE(LOWER($J268),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B268:D268)","v":5},2003,"Functional genetic dissection of nuclear receptor signalling in obesity, diabetes and liver regeneration using spatiotemporally controlled somatic mutagenesis in the mouse.","Imai",14529153,"Functional genetic dissection of nuclear receptor signalling in obesity, diabetes and liver regeneration using spatiotemporally controlled somatic mutagenesis in the mouse.    Abstract:   The mouse is an excellent animal model for defining human diseases. The null allele mutations (knockouts, KO) have already provided valuable information about their functions, but have also revealed major complications and difficulties: (1) an early embryonic lethality, (2) temporal effect (developmental stage or adult stage), (3) functional redundancy and (4) spatio-effect (cell-autonomous or non-autonomous). To overcome these limitations, spatio-temporally controlled somatic mutagenesis, Cre-ER(T)/LoxP system, was established. The nuclear receptors (NRs) play central roles in development, organogenesis, metabolism and energy homeostasis through their ability to transduce hormonal signals into modulation of gene activity. Obesity, excess energy storage in adipose tissue, has a strong link to diabetes. Among NRs, retinoid X receptor alpha (RXRalpha)-peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimers can mediate adipocyte differentiation and obesity which has been demonstrated with in vitro cell culture systems and RXR- and PPARgamma-specific ligand studies. Therefore an adipocyte-specific temporally controlled somatic mutagenesis system was established and analysed. Furthermore, the functional roles of NRs to control liver regeneration were also studied with similar system in hepatocytes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I269,I269)","v":12790775},{"$f":"(LEN($J269) - LEN(SUBSTITUTE(LOWER($J269),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J269) - LEN(SUBSTITUTE(LOWER($J269),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J269) - LEN(SUBSTITUTE(LOWER($J269),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B269:D269)","v":5},2003,"The role of vitamin D and retinoids in controlling prostate cancer progression.","Peehl",12790775,"The role of vitamin D and retinoids in controlling prostate cancer progression.    Abstract:   Prostate cancer is a leading cause of cancer-related deaths in many countries. Premalignant lesions and invasive cancer occur more frequently in the prostate than in any organ other than the skin. Yet, the incidence of clinically detected prostate cancer is much lower than the histopathological incidence. The slow growth of prostate cancer and the low incidence of clinically manifest disease in some geographical locations or racial/ethnic groups suggest that prostate cancer can be controlled, perhaps by dietary factors. Vitamin D and retinoids have emerged as leading candidates both to prevent and to treat prostate cancer. Many of the activities of these compounds, established from epidemiological studies, research with cell culture and animal models, and clinical trials, are consistent with tumor suppressor effects. However, retinoids may have additional tumor enhancer properties that balance or negate anti-cancer activity. This perhaps explains the overall lack of protective effects of vitamin A compounds against prostate cancer found in epidemiological studies, and the minimal efficacy of retinoids in clinical trials to treat prostate cancer. While current efforts focus on developing strategies to use vitamin D compounds to control prostate cancer, the possibility exists that prostate cancer cells may become resistant to tumor suppressor effects of vitamin D. Analyses of experimental model systems show that prostate cancer cells become less sensitive to vitamin D through loss of receptors or signaling molecules that mediate vitamin Ds actions, or through changes in metabolic enzymes that synthesize or degrade vitamin D compounds. The potential promise of exploiting vitamin D to control prostate cancer is tempered by the possibility that prostate cancer, perhaps even at early stages, may develop mechanisms to escape tumor suppressor activities of vitamin D and/or retinoids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I270,I270)","v":12665417},{"$f":"(LEN($J270) - LEN(SUBSTITUTE(LOWER($J270),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J270) - LEN(SUBSTITUTE(LOWER($J270),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J270) - LEN(SUBSTITUTE(LOWER($J270),LOWER(D$3),\"\")))/LEN(D$3)","v":5},{"$f":"SUM(B270:D270)","v":5},2003,"Treatment of non-insulin-dependent diabetes mellitus.","Patel",12665417,"Treatment of non-insulin-dependent diabetes mellitus.    Abstract:   Diabetes mellitus has been declared to be at an epidemic level by the World Health Organization. The syndrome is characterised as either Type I (insulin-dependent) or Type II (non-insulin-dependent) diabetes mellitus. Impaired glucose tolerance for extended periods of time results in serious complications such as kidney damage and impaired blood circulation and is the main cause for blindness and amputations in patients with diabetes. A combination of life-style change, dietary change and oral medications can treat Type II diabetes mellitus effectively and prevent long-term complications. Combination therapy appears to be the most effective approach in controlling blood glucose levels. This review updates the progress made in medicinal chemistry towards promising biological targets, with the development of a new generation of small molecules having improved efficacy and safety profiles."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I271,I271)","v":12037503},{"$f":"(LEN($J271) - LEN(SUBSTITUTE(LOWER($J271),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J271) - LEN(SUBSTITUTE(LOWER($J271),LOWER(C$3),\"\")))/LEN(C$3)","v":4},{"$f":"(LEN($J271) - LEN(SUBSTITUTE(LOWER($J271),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B271:D271)","v":5},2002,"[PPARgamma and insulin resistance].","Girard",12037503,"[PPARgamma and insulin resistance].    Abstract:   The thiazolidinediones (TZD), a new class of oral antidiabetic agent, act by improving insulin sensitivity. TZD correct hyperglycemia and hyperinsulinism in several animal models of NIDDM. Clinical studies in human have confirmed that TZD lowered postprandial and postabsorbtive glycemia and insulinemia. Glucose clamp studies have clearly shown a 30% improvement of insulin-induced glucose utilisation in skeletal muscle. TZD bind to an isoform of a nuclear receptor, the PPARgamma (Peroxisome Proliferator-Activated Receptor). PPARgamma is a transcription factor which, after heterodimerisation with the retinoid receptor (RXR), binds to specific response elements of a number of target genes, and control their transcription. How TZD, with their principal site of action being adipose tissue, can improve glucose metabolism in skeletal muscle? In human, skeletal muscles are responsible for more than 80% of glucose uptake in response to insulin and skeletal muscles contain only a limited amount of PPARgamma! This is the paradox to which we attempt to answer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I272,I272)","v":11978137},{"$f":"(LEN($J272) - LEN(SUBSTITUTE(LOWER($J272),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J272) - LEN(SUBSTITUTE(LOWER($J272),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J272) - LEN(SUBSTITUTE(LOWER($J272),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B272:D272)","v":5},2002,"Novel therapies for psoriasis.","Cather",11978137,"Novel therapies for psoriasis.    Abstract:   The T cell-driven immunopathogenesis of psoriasis has been well recognized since cyclosporine first revolutionized the treatment of psoriasis 20 years ago. Almost all investigative and clinical research subsequently, has concentrated on elucidating the specifics of antigen presentation, T cell interaction and the production of specific cytokines. The role of the keratinocyte, previously thought to be the primary target cell in psoriasis pathogenesis, has been relegated to a secondary role and the mechanism of action of systemic methotrexate in psoriasis has been challenged, the primary role of the T lymphocyte is now well known. While psoriasis has traditionally been treated quot;ab initioquot; with topical medications (corticosteroids, vitamin D(3), and retinoid derivatives), either singly, in combination, or with ultraviolet B (UVB) or psoralens and ultraviolet A (PUVA) therapy, the role of systemic medications has assumed greater prominence. Thus, three systemic medications currently are approved worldwide for the treatment of moderate to severe forms of psoriasis, namely cyclosporine, methotrexate and acitretin. The first two are likely to give significant clearing (greater than 75%) in the majority of cases, whereas acitretin is significantly less effective as monotherapy, but may approach methotrexate and cyclosporine in efficacy, if combined with PUVA or UVB phototherapy. The main limitations of these three drugs remain organ toxicity, especially hepatic toxicity with methotrexate, hypertension and nephrotoxicity with cyclosporine, and teratogenicity and mucocutaneous toxicity with acitretin. Thus, the need for more specific systemic therapy, targeting the T lymphocyte. This has become the major area of clinical research interest over the past 5 years, with the promise of longer-term disease control (improved remissions) and less organ toxicities. Currently, there are over 15 of these quot;biologicquot; drugs in various stages of development and clinical trials, either by the subcutaneous, intramuscular or intravenous route. The three main variables are the rapidity of onset, percentages of improvement and remission rates. Without exception, these new systemic agents appear to be remarkably free of systemic organ toxicities (liver, renal, bone-marrow, etc.), with adverse effects being limited to mild flu-like symptoms with the anticipated increase in infections (e.g., herpes simplex) being either equal to placebo or only marginally increased. Not all these agents under evaluation give clinical responses equal to methotrexate or cyclosporine (75% or greater clearing in 75% of cases). In addition, response rates may be slower with some therapies versus others. However, the need for intermittent administration even by the injectable route, longer remissions, lack of systemic organ toxicities and the potential for safer usage in females of child-bearing age, make a compelling argument for widespread acceptance by both patients and the dermatological community. Other modalities under clinical evaluation include vitamin D and retinoid drugs, topically and systemically, with effects on nuclear receptors, as well as more specific wavelengths (308 to 311 nm) of UVB phototherapy with application for more localized forms of psoriasis. For the 2 to 3% of the worldwide population of patients with psoriasis the future has never looked brighter."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I273,I273)","v":11733105},{"$f":"(LEN($J273) - LEN(SUBSTITUTE(LOWER($J273),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J273) - LEN(SUBSTITUTE(LOWER($J273),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J273) - LEN(SUBSTITUTE(LOWER($J273),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B273:D273)","v":5},2001,"Role of vitamin A in mitochondrial gene expression.","Berdanier",11733105,"Role of vitamin A in mitochondrial gene expression.    Abstract:   Diabetes-prone BHE/Cdb and Sprague-Dawley (SD) rats were studied with respect to mitochondrial (mt) function and mt gene expression. The BHE/Cdb rats carry mutations in the mt ATPase 6 gene that phenotype as decreased OXPHOS efficiency with subsequent development of impaired glucose tolerance. The base substitutions result in amino acid substitutions in the proton channel and this, in turn, affects the efficiency of energy capture in the ATP molecule. Feeding studies showed that BHE/Cdb rats required 10 times more vitamin E and three times more vitamin A in their diets than do normal SD rats. Vitamin A supplementation normalized mt OXPHOS as well as increased the amount of ATPase subunit a protein in the mt compartment. Western blot analysis of retinoic acid receptors in the mitochondrial and nuclear compartments showed that these proteins were present in the mt compartment. The effect of the vitamin A supplementation plus the observation of retinoic acid receptors suggest that vitamin A functions to enhance the transcription of the ATPase 6 gene. Work with primary cultures of hepatocytes showed that not only does retinoic acid increase mitochondrial ATPase 6 gene expression but so too does the steroid hormone intermediate, dehydroepiandrosterone (DHEA). Triiodothyronine also plays a role in this process but not as an independent factor. Rather, this hormone potentiates the effects of retinoic acid and DHEA on ATPase gene expression. These results suggest that mt gene expression requires more than just the mt transcription factor A. More than likely the process requires a number of factors in much the same way as does nuclear gene expression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I274,I274)","v":11573138},{"$f":"(LEN($J274) - LEN(SUBSTITUTE(LOWER($J274),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J274) - LEN(SUBSTITUTE(LOWER($J274),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J274) - LEN(SUBSTITUTE(LOWER($J274),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B274:D274)","v":5},2001,"Regulation of the sodium/iodide symporter by retinoids--a review.","Schmutzler",11573138,"Regulation of the sodium/iodide symporter by retinoids--a review.    Abstract:   Decrease or loss of iodide uptake, due to impaired expression and/or function of the sodium/iodide-symporter (NIS), is a major obstacle to the treatment of advanced thyroid carcinomas by radioiodide therapy. Several approaches are being evaluated to optimise or restore sufficient iodide transport in those cases, among them retinoid therapy. Retinoids with their growth-inhibiting and differentiation-inducing properties have been repeatedly used for treatment and chemoprevention of various cancers. In thyroid carcinoma cell lines they trigger changes in gene expression that may be interpreted as partial redifferentiation. Especially, they stimulate NIS mRNA expression and iodide uptake in human follicular thyroid carcinoma cells. Moreover, they also increase NIS expression and function in human mammary tumour cells. In a clinical pilot study to evaluate the feasibility of retinoid redifferentiation in the case of otherwise untreatable thyroid cancers, 21 of 50 patients showed an increase of radioiodide uptake after 5 weeks. This indicates that increasing NIS activity and radioiodide uptake by retinoic acid redifferentiation may be a therapeutic alternative for thyroid cancers refractory to other therapeutic modalities and probably also for mammary cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I275,I275)","v":11450473},{"$f":"(LEN($J275) - LEN(SUBSTITUTE(LOWER($J275),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J275) - LEN(SUBSTITUTE(LOWER($J275),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J275) - LEN(SUBSTITUTE(LOWER($J275),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B275:D275)","v":5},2001,"[Vitamin A metabolism and retinal degeneration].","Seeliger",11450473,"[Vitamin A metabolism and retinal degeneration].    Abstract:   Vitamin A plays an important role in the pathogenesis and during the course of retinal degenerations. Following a brief overview of the metabolic pathway of Vitamin A from the entrance into the body to the arrival in retinal target structures, the most important retinal degenerations that are related to the Vitamin A-metabolism are presented. Ways of prevention or therapy of such diseases are discussed in the light of the still incomplete knowledge about basic mechanisms of retinol transport and metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I276,I276)","v":11198137},{"$f":"(LEN($J276) - LEN(SUBSTITUTE(LOWER($J276),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J276) - LEN(SUBSTITUTE(LOWER($J276),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J276) - LEN(SUBSTITUTE(LOWER($J276),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B276:D276)","v":5},2001,"Treatable forms of retinitis pigmentosa associated with systemic neurological disorders.","Grant",11198137,"Treatable forms of retinitis pigmentosa associated with systemic neurological disorders.    Abstract:   In this chapter; we have described the role of nutritional supplements or selective dietary restriction (or both) on the maintenance and function of the retina and nervous system in some diseases. Oral vitamin A therapy has proven to be effective in the treatment of the common forms of retinitis pigmentosa. Bassen-Kornzweig disease can be treated with vitamin A and vitamin E and, in some cases, with vitamin K. Vitamin E therapy for Friedreich-like ataxia associated with retinitis pigmentosa has been shown to be effective in the short term. Classic Refsums disease responds to a low phytol-low phytanic acid diet. Undoubtedly, future research will bring more insight into the biochemical pathways responsible for other diseases and, it is hoped, aid in developing treatments for additional retinal degenerations associated with systemic neurological disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I277,I277)","v":11040271},{"$f":"(LEN($J277) - LEN(SUBSTITUTE(LOWER($J277),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J277) - LEN(SUBSTITUTE(LOWER($J277),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J277) - LEN(SUBSTITUTE(LOWER($J277),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B277:D277)","v":5},2000,"The retinoids and cancer prevention mechanisms.","Dragnev",11040271,"The retinoids and cancer prevention mechanisms.    Abstract:   Carcinogenesis is a multistep process that converts normal cells into malignant cells. Once transformed, malignant cells acquire the ability to invade and metastasize, leading to clinically evident disease. During this continuum from normal to metastatic cells, carcinogenic steps can be arrested or reversed through pharmacological treatments, known as cancer chemoprevention. Chemoprevention strategies represent therapeutic interventions at early stages of carcinogenesis, before the onset of invasive cancer. Effective chemoprevention should reduce or avoid the clinical consequences of overt malignancies by treating early neoplastic lesions before development of clinically apparent signs or symptoms. Preclinical, clinical, and epidemiological data provide considerable support for cancer chemoprevention as an attractive therapeutic strategy. This clinical approach was validated in the recent tamoxifen randomized trial, demonstrating that a selective estrogen receptor modulator reduces the risk of breast cancer in women at high risk for this malignancy. Derivatives of vitamin A, the retinoids, have reported activity in treating specific premalignant lesions and reducing incidence of second primary tumors in patients with prior head and neck, lung or liver cancers. Whether the retinoids will prevent primary cancers at these sites is not yet known. Notably, a carotenoid (beta-carotene) was shown as inactive in primary prevention of lung cancers in high-risk individuals. This underscores the need for relevant in vitro models to identify pathways signaling chemopreventive effects. These models should assess the activity of candidate chemoprevention agents before the conduct of large and costly prevention trials. An improved understanding of cancer prevention mechanisms should aid in the discovery of new therapeutic targets and chemoprevention agents. Ideally, these agents should have tolerable clinical toxicities suitable for chronic administration to individuals at high risk for developing primary or second cancers. This article reviews what is now known from clinical and preclinical studies about the retinoids as cancer prevention agents."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I278,I278)","v":10893067},{"$f":"(LEN($J278) - LEN(SUBSTITUTE(LOWER($J278),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J278) - LEN(SUBSTITUTE(LOWER($J278),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J278) - LEN(SUBSTITUTE(LOWER($J278),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B278:D278)","v":5},2000,"Tapetoretinal degenerations: experiences, experiments and expectations.","Ehinger",10893067,"Tapetoretinal degenerations: experiences, experiments and expectations.    Abstract:   Tapetoretinal degenerations are a common cause for vision problems, but have until recently not been amenable to rational treatment. With rapidly increasing insights into basic neurobiology and pathobiology this has now begun to change. From having been a relatively small group of largely unknown yet fairly prevalent disorders, they are rapidly forming a large set of well defined diseases, and it is easy to predict that our knowledge about them will continue to increase for many years to come. Vitamin A (15,000 IU daily) is currently the only rational treatment available. However, in experimental animals, therapy strategies are now actively being developed along several different lines. Apoptotic photoreceptor cell death can be delayed with different drugs, and at least one of them, diltiazem, is approved for human use in cardiovascular diseases. It remains to be seen if it has any clinically significant effect in human tapetoretinal degenerations. Other strategies aim at counteracting the production of harmful protein variants, acting either on DNA or mRNA levels. Transgenes can also be used to induce the production of important but missing metabolic components. Finally, cells or retina sheets can be transplanted, either to replace failing cells or as a source for missing trophic factors. Neither of these strategies has yet been transferred to humans, but trials are under way. With the high increase in the flow of new information on tapetoretinal disorders, much more precise diagnoses and much improved treatments are soon to be expected, augmenting considerably the possibilities for ophthalmologists to help patients with such diseases. It is not likely that there will be a single treatment for all the many varieties. Instead, we are most likely going to see pharmacological treatments for some of them, DNA transfers for some, and transplantations for others."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I279,I279)","v":10673856},{"$f":"(LEN($J279) - LEN(SUBSTITUTE(LOWER($J279),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J279) - LEN(SUBSTITUTE(LOWER($J279),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J279) - LEN(SUBSTITUTE(LOWER($J279),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B279:D279)","v":5},2000,"[Refsum disease].","Bernscherer",10673856,"[Refsum disease].    Abstract:   For the first time in literature the authors interpret the pathography of Refsums disease, in the case of their patient, as pseudo-hypervitaminosis A. The biochemical basis of the clinical picture is a defect in the activity of phytanic-acid-alpha-hydrolase belonging to the peroxisomal system. As a consequence, phytanic acid accumulates in the serum and in the parenchymal tissues. Retinol, an alcohol with high molecular weight, is a natural ligand of nuclear RXR (retinoid-X-receptor), which plays an important role in the regulation of peroxisoma synthesis. In Refsums disease the phytanic acid accumulated because of the enzyme defect competes with the biotransformation derivates (all-trans-retinoic acid, 9-cis-retinoic acid) of the all-trans-retinol (vitamin A) for the nuclear RX receptor binding sites, and as a very potent receptoractivator it causes the intestinal symptoms of hypervitaminosis A. The authors review the procedure of fatty-acid chromatography necessary for the establishment of the diagnosis and discuss--in addition to dietary restrictions--recent therapeutic possibilities, like plasmapheresis, cascade filtration, lipapheresis and oral batylalcohol treatment."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I280,I280)","v":10454290},{"$f":"(LEN($J280) - LEN(SUBSTITUTE(LOWER($J280),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J280) - LEN(SUBSTITUTE(LOWER($J280),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J280) - LEN(SUBSTITUTE(LOWER($J280),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B280:D280)","v":5},1999,"Current understanding on the role of retinal pigment epithelium and its pigmentation.","Schraermeyer",10454290,"Current understanding on the role of retinal pigment epithelium and its pigmentation.    Abstract:   Retinal pigment epithelium (RPE) is a monolayer of cuboidal cells that is strategically placed between the rod and cone photoreceptors and the vascular bed of the choriocapillaris. It has many important functions, such as phagocytic uptake and breakdown of the shedded photoreceptor membranes, uptake, processing, transport and release of vitamin A (retinol), setting up the ion gradients within the interphotoreceptor matrix, building up the blood-retina barrier, and providing all transport from blood to the retina and back. This short review focuses on the role of the pigment granules in RPE. Although the biology of the pigment granules has been neglected in the past, they do seem to be involved in many important functions, such as protection from oxidative stress, detoxification of peroxides, and binding of zinc and drugs, and, therefore, serve as a versatile partner of the RPE cell. Melanin plays a role in the development of the fovea and routing of optic nerves. New findings show that the melanin granules are connected to the lysosomal degradation pathway. Most of these functions are not yet understood. Deficit of melanin pigment is associated with age-related macula degeneration, the leading cause of blindness."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I281,I281)","v":10335455},{"$f":"(LEN($J281) - LEN(SUBSTITUTE(LOWER($J281),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J281) - LEN(SUBSTITUTE(LOWER($J281),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J281) - LEN(SUBSTITUTE(LOWER($J281),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B281:D281)","v":5},1999,"Intervention studies on cancer.","Young",10335455,"Intervention studies on cancer.    Abstract:   This paper (and an extensive supplementary report) considers how far cancer/risk factor associations based on epidemiology have been confirmed by evidence from 226 studies involving interventions other than smoking. Many are small, uncontrolled, of unrepresentative populations, concern cancer markers not cancer, and may involve combinations of agents. Many agents suspected of causing cancer are untested by intervention trials. For seven of 16 agents tested (fibre, folic acid, low-fat diet, riboflavin, zinc, vitamin Bs, and vitamin D), the evidence is clearly inadequate to confirm or deny the epidemiology, while the evidence relating to calcium only concerns biomarkers. For other agents, the evidence relating to cancer itself is weak. In studies where cancer is the endpoint, only three effects have been replicated: (a) selenium supplementation and decreased liver cancer incidence, (b) treatment by the retinoid etretinate and reduced bladder tumours in susceptible individuals, and (c) beta-carotene supplementation and increased lung cancer incidence. Studies involving pre-cancerous conditions as the endpoint, which have a number of practical advantages, more frequently report benefits of intervention. Thus, oral pre-cancerous lesions can certainly be reduced by beta-carotene, vitamin A, and other retinoids, and possibly by vitamin E. It also seems that retinoids can reduce pre-cancerous cervix, skin and lung lesions, that vitamin C and the NSAID sulindac can reduce colonic polyps, and that sunscreens can reduce solar keratoses. Our findings clearly show that the great majority of causal relationships suggested by epidemiology have not been validated by intervention trials. This may be partly due to lack of suitable studies of adequate size or duration, or to using single dietary compounds as agents that are by themselves not responsible for the epidemiologically-observed associations between diet and cancer. However, this lack of validation must cause concern in view of the markedly conflicting evidence on beta-carotene and lung cancer between epidemiological and intervention studies. More intervention studies are needed, but in their absence, caution in interpreting epidemiological findings is warranted."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I282,I282)","v":10079703},{"$f":"(LEN($J282) - LEN(SUBSTITUTE(LOWER($J282),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J282) - LEN(SUBSTITUTE(LOWER($J282),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J282) - LEN(SUBSTITUTE(LOWER($J282),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B282:D282)","v":5},1999,"Chronic alcohol intake interferes with retinoid metabolism and signaling.","Wang",10079703,"Chronic alcohol intake interferes with retinoid metabolism and signaling.    Abstract:   Chronic and excessive ethanol consumption is associated with cellular proliferation, fibrosis, cirrhosis, and cancer of the liver. The critical event in early alcohol-induced hepatic injury is an alcohol-induced activation (cell proliferation and increased fibrogenesis) of hepatic stellate cells. However, the mechanisms by which alcohol causes proliferative activation in hepatic stellate cells have not been identified. An important characteristic of alcohol-induced injury is impaired vitamin A nutritional status. The demonstration that retinoic acid is the most physiologically active derivative of vitamin A and the discovery of retinoic acid receptors provide a mechanistic basis for understanding the actions of vitamin A and alcohol on hepatic cell proliferation. Recent studies have demonstrated that chronic alcohol intake can reduce hepatic retinoic acid concentrations, diminish retinoid signaling, and enhance activator protein-1 (AP-1 (c-Jun and c-Fos)) expression in rat liver. These are the possible biochemical and molecular mechanisms whereby ethanol ingestion results in hepatic stellate cell proliferative activation and hepatic fibrogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I283,I283)","v":9922035},{"$f":"(LEN($J283) - LEN(SUBSTITUTE(LOWER($J283),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J283) - LEN(SUBSTITUTE(LOWER($J283),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J283) - LEN(SUBSTITUTE(LOWER($J283),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B283:D283)","v":5},1998,"Relapsed acute promyelocytic leukemia previously treated with all-trans retinoic acid: clinical experience with a new synthetic retinoid, Am-80.","Takeuchi",9922035,"Relapsed acute promyelocytic leukemia previously treated with all-trans retinoic acid: clinical experience with a new synthetic retinoid, Am-80.    Abstract:   All-trans retinoic acid (ATRA), a potent differentiating drug for acute promyelocytic leukemia (APL), induces a high incidence of complete remission (CR) in patients with APL and is now established as a first-line therapy. However, ATRA resistance has become a clinical problem. Patients who relapsed after ATRA-induced CR have had difficulty in obtaining a second CR with ATRA therapy. Although several mechanisms have been postulated, treatment strategies to overcome resistance have not been established. We used a new synthetic retinoid, Am-80, as reinduction therapy for APL relapse after from ATRA-induced CR. Am-80 was several times more potent than ATRA in inducing differentiation in vitro. At a 6 mg/m2 dose, there were 24 evaluable patients; 14 (58%) achieved CR between days 20 and 58 (median, 37 days). Clinical response correlated with the in vitro response to Am-80. Adverse effects included retinoic acid syndrome (n = 1), hyperleukocytosis (n = 1), xerosis (n = 9), cheilitis (n = 8), hypertriglyceridemia (n = 16), and hypercholesterolemia (n = 15). Am-80 is active in APL after relapse from ATRA-induced CR. Further clinical trials are needed to establish strategies to overcome ATRA resistance."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I284,I284)","v":9652687},{"$f":"(LEN($J284) - LEN(SUBSTITUTE(LOWER($J284),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J284) - LEN(SUBSTITUTE(LOWER($J284),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J284) - LEN(SUBSTITUTE(LOWER($J284),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B284:D284)","v":5},1998,"Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.","Carr",9652687,"Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.    Abstract:   HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidaemia, and insulin resistance. The catalytic region of HIV-1 protease, to which protease inhibitors bind, has approximately 60% homology to regions within two proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). We hypothesise that protease inhibitors inhibit CRABP-1-modified, and cytochrome P450 3A-mediated synthesis of cis-9-retinoic acid, a key activator of the retinoid X receptor; and peroxisome proliferator activated receptor type gamma (PPAR-gamma) heterodimer, an adipocyte receptor that regulates peripheral adipocyte differentiation and apoptosis. Protease-inhibitor binding to LRP would impair hepatic chylomicron uptake and triglyceride clearance by the endothelial LRP-lipoprotein lipase complex. The resulting hyperlipidaemia contributes to central fat deposition (and in the breasts in the presence of oestrogen), insulin resistance, and, in susceptible individuals, type 2 diabetes. Understanding the syndromes pathogenesis should lead to treatment strategies and to the design of protease inhibitors that do not cause this syndrome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I285,I285)","v":9481117},{"$f":"(LEN($J285) - LEN(SUBSTITUTE(LOWER($J285),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J285) - LEN(SUBSTITUTE(LOWER($J285),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J285) - LEN(SUBSTITUTE(LOWER($J285),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B285:D285)","v":5},1998,"Release of stored retinol from adipocytes.","Wolf",9481117,"Release of stored retinol from adipocytes.    Abstract:   Adipose tissue is second only to liver as a retinol depot. Retinol is stored there is part as retinyl esters. In cultured mouse adipocytes, a hormone-sensitive lipase hydrolyzes these esters upon cAMP stimulation, with free retinol being released into the medium."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I286,I286)","v":9350473},{"$f":"(LEN($J286) - LEN(SUBSTITUTE(LOWER($J286),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J286) - LEN(SUBSTITUTE(LOWER($J286),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J286) - LEN(SUBSTITUTE(LOWER($J286),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B286:D286)","v":5},1997,"Antioxidative vitamins in prematurely and maturely born infants.","Böhles",9350473,"Antioxidative vitamins in prematurely and maturely born infants.    Abstract:   Postnatally a rapid change occurs from a relatively hypoxic to a relatively hyperoxic environment, especially during artificial ventilation with all risks of ROS-formation. Among the non enzymatic antioxidative strategies the vitamins E, C, A and B2 are of major importance. Vitamin E is considered the most important radical scavenging vitamin of the lipid soluble compartment. Hereby vitamin E itself is converted into a radical which is handed over to vitamin C and glutathione into the water soluble compartment. The vitamin E content of the fetus increases with the fetal fat mass mainly during the last trimester of pregnancy. Placenta is only slightly permeable to lipid soluble vitamins. Vitamin E deficiency may rapidly develop typically at about 6-8 weeks of age. Vitamin E is able to prolong significantly the onset of retinopathic changes during oxygen therapy and may prevent intraventricular hemorrhage. Vitamin C is together with glutathione a major representative of the non enzymatic antioxidative system in the water soluble compartment. The best determinant of the vitamin C status is its concentration in leukocytes. Vitamin C reduces iron to the divalent state which supports the hydroxyl radical formation (Haber-Weiss reaction). This should be considered mainly in cases of intraventricular hemorrhage. Vitamin B2 acts mainly as cofactor of glutathione reductase which keeps glutathione in the reduced state. It can therefore be considered an indirect antioxidative vitamin. Vitamin B2 is destroyed by light. Phototherapy has been recognized as a cause of riboflavin deficiency. Vitamin A comprises all retinols with properties like trans-retinol. Retinol storage in the fetal liver increases during late pregnancy. In both, premature and mature newborns, the serum concentrations amount to only about 50% of those of their mothers. Vitamin A has a paramount importance for fetal lung development, because the individual surfactant proteins are selectively regulated by retinoic acid."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I287,I287)","v":9310742},{"$f":"(LEN($J287) - LEN(SUBSTITUTE(LOWER($J287),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J287) - LEN(SUBSTITUTE(LOWER($J287),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J287) - LEN(SUBSTITUTE(LOWER($J287),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B287:D287)","v":5},1997,"How safe is oral isotretinoin?","Meigel",9310742,"How safe is oral isotretinoin?    Abstract:   Since oral isotretinoin (Roaccutane/Accutane) is the only therapy to address all major acne causes, it remains the most effective antiacne therapy available. Due to this unique efficacy and its potential side effects that are predictable and can be managed easily and effectively, it is widely used also in acne patients suffering from serious systemic diseases. As the primary mechanism of action of oral isotretinoin is suppression of sebaceous gland activity, mucocutaneous side effects such as dry lips, nasal passages and eyes are predictable. Pretreatment counseling and concomitant use of moisturizing agents usually manage these side effects effectively; in unusual cases of particularly poor tolerability, dose adjustments suffice. Severe side effects are rare, the most common being aches and pains requiring no therapy, aspirin or paracetamol. As with other retinoids, reliable contraception is mandatory for women of childbearing potential. Acne patients with serious concomitant systemic disease, such as insulin-dependent diabetes, epilepsy or spina bifida, transplant patients, patients with renal failure, multiple sclerosis motor neuron disease and other can also safe be treated with a standard cumulative dose of 120 mg/kg per treatment course."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I288,I288)","v":8901853},{"$f":"(LEN($J288) - LEN(SUBSTITUTE(LOWER($J288),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J288) - LEN(SUBSTITUTE(LOWER($J288),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J288) - LEN(SUBSTITUTE(LOWER($J288),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B288:D288)","v":5},1996,"Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.","Omenn",8901853,"Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.    Abstract:    BACKGROUND : Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality.  PURPOSE : We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention.  METHODS : CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. OBrien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 alpha value, and all P values were derived from two-sided statistical tests.  RESULTS : According to CARETs pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations.  CONCLUSIONS : CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29133 male smokers in Finland."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I289,I289)","v":8943797},{"$f":"(LEN($J289) - LEN(SUBSTITUTE(LOWER($J289),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J289) - LEN(SUBSTITUTE(LOWER($J289),LOWER(C$3),\"\")))/LEN(C$3)","v":4},{"$f":"(LEN($J289) - LEN(SUBSTITUTE(LOWER($J289),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B289:D289)","v":5},1996,"Role of metabolism in the activation of dehydroepiandrosterone as a peroxisome proliferator.","Waxman",8943797,"Role of metabolism in the activation of dehydroepiandrosterone as a peroxisome proliferator.    Abstract:   The adrenal steroid dehydroepiandrosterone (DHEA) stimulates a dramatic increase in both the size and the number of peroxisomes present in liver when given at pharmacological doses to rodents. Structurally diverse chemicals including many fatty acids, hypolipidemic drugs and other foreign chemicals, can also induce such a peroxisome proliferative response. This response is associated with a dramatic induction of perosisomal fatty acid beta-oxidation enzymes and microsomal cytochrome P450 4A fatty acid hydroxylases and, long-term, can lead to induction of hepatocellular carcinoma. This review examines the underlying mechanisms by which DHEA induces peroxisome proliferation and evaluates the possible role of peroxisome proliferator-activated receptor (PPAR) in this process. Like DHEA, the 17 beta-reduced metabolite 5-androstene-3 beta. 17 beta-diol (ADIOL) is an active peroxisome proliferator when administered in vivo, whereas androgenic and estrogenic metabolites of DHEA are inactive. In primary rat hepatocytes, however, DHEA and ADIOI are inactive as inducers of P450 4A and peroxisomal enzymes unless first metabolized by steroid sulfotransferase to the 3 beta-sulfates, DHEA-S and ADIOL-S. Investigations as to whether DHEA utilizes the same induction mechanism employed by classic, foreign chemical peroxisome proliferators, namely, activation of the intracellular receptor molecule PPAR, have shown that DHEA-S and ADIOL-S are ineffective with respect to PPAR activation in transient transfection/trans-activation assays. This inactivity of DHEA-S in vitro suggests a requirement for specific cellular transport or for further metabolism of the steroid which is only met in liver cells. Alternatively, the action of DHEA-S may require accessory proteins or other nuclear factors that modulate the activity of PPAR, such as retinoid X receptor (RXR), hepatocyte nuclear factor-4 (HNF-4) or chick ovalbumin upstream promoter transcription factor (COUP-TF). Investigations using Ca(2+)-channel blockers such as nicardipine suggest that there are important mechanistic similarities between the foreign chemical- and DHEA-S-stimulated induction responses, and support the hypothesis that these two classes of peroxisome proliferators both activate Ca(2+)-dependent signaling pathways. Further studies are required to ascertain whether this potential of DHEA and its sulfated metabolites to serve as physiological modulators of fatty acid metabolism and peroxisome enzyme expression contributes to the striking anti-carcinogenic and other useful chemoprotective properties that DHEA is known to possess."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I290,I290)","v":7946531},{"$f":"(LEN($J290) - LEN(SUBSTITUTE(LOWER($J290),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J290) - LEN(SUBSTITUTE(LOWER($J290),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J290) - LEN(SUBSTITUTE(LOWER($J290),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B290:D290)","v":5},1994,"Transthyretin (prealbumin) in health and disease: nutritional implications.","Ingenbleek",7946531,"Transthyretin (prealbumin) in health and disease: nutritional implications.    Abstract:   The name quot;transthyretinquot; reflects the dual physiological roles of this tetrameric unglycosylated plasma protein. TTR is one of three specific carrier proteins involved in the transport of both thyroid hormones and of retinol through the mediation of RBP. TTR is a product of the visceral compartment, and its hepatic synthesis is exquisititely sensitive to both the adequacy and levels of protein and energy intakes--hence the proposal of TTR as a nutritional marker. To date, 38 TTR variants have been described, most of which are associated with variable degrees of cardiac and/or neural tissue amyloid deposits. All known variants arise from a single AA substitution due to single point mutation in the coding region of the TTR gene. Under acute stress conditions, the synthesis of TTR, RBP, and CBG is abruptly depressed by a cytokine-directed orchestration of new metabolic priorities, with a redistribution of organ and tissue protein pools. It is proposed that TTR, RBP, and CBG behave as acute-booster reactants (ABRs), actively participating in the cascade of metabolic events characterizing the stress reaction along pathways best explained by the free hormone/vitamin hypothesis. The latter is governed by the law of mass action--the spontaneous dissociation and instant uptake by hepatocytes of the ligands freed from their specific carrier proteins, which creates a transient hyperthyroid, hyperretinoid, and hypercortisolic climate. This response generally does not exceed four or five days because the initial impact of injury normally subsides, but it may last longer if complications occur. The magnitude and adequacy of the stress responses depend on the preceding nutritional status as assessed by TTR plasma levels and are proportionate to the severity of insult. Clinical, animal, and molecular studies concur to demonstrate the dualistic stimulatory or inhibitory effects triggered by the ligands, whose unmetabolized fractions are excreted in the urinary output. Thyroid hormones and retinoids appear to control the early maturation processes and the synthesis of primary transcripts, whereas cortisol preferentially modulates the secondary responses and confers a protective effect on healthy tissues. During acute stress, the evolutionary patterns of visceral proteins and inflammatory markers exhibit compulsory mirror images. However, they change in independent ways under more chronic circumstances. A relatively simple biochemical micromethod based on the simultaneous measurement of plasma TTR, albumin, CRP, and orosomucoid aggregated into a PINI is proposed for the early recognition and follow-up of both nutritional and inflammatory facets of the disease spectrum."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I291,I291)","v":8491880},{"$f":"(LEN($J291) - LEN(SUBSTITUTE(LOWER($J291),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J291) - LEN(SUBSTITUTE(LOWER($J291),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J291) - LEN(SUBSTITUTE(LOWER($J291),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B291:D291)","v":5},1993,"Retinoid hepatitis.","Sanchez",8491880,"Retinoid hepatitis.    Abstract:   A 65-year-old woman treated with etretinate for pityriasis rubra pilaris developed chronic active hepatitis. The elevated transaminases were noted 2 months after initiation of therapy and peaked 2 months after discontinuation of etretinate. The spectrum of liver toxicity induced by etretinate is reviewed. We suggest that reported cases of retinoid-induced liver disease can be divided into four distinct categories: nonspecific reactive hepatitis, acute hepatitis, chronic active hepatitis, and severe fibrosis or cirrhosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I292,I292)","v":8387630},{"$f":"(LEN($J292) - LEN(SUBSTITUTE(LOWER($J292),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J292) - LEN(SUBSTITUTE(LOWER($J292),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J292) - LEN(SUBSTITUTE(LOWER($J292),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B292:D292)","v":5},1993,"Interaction of fatty acids, acyl-CoA derivatives and retinoids with microsomal membranes: effect of cytosolic proteins.","Catalá",8387630,"Interaction of fatty acids, acyl-CoA derivatives and retinoids with microsomal membranes: effect of cytosolic proteins.    Abstract:   This paper reviews characteristics of microsomal membrane structure; long chain fatty acids, acyl CoA derivatives, retinoids and the microsomal formation of acyl CoA derivatives and retinyl esters. It is analyzed how the movement of these molecules at the intracellular level is affected by their respective binding proteins (Fatty acid binding protein, acyl CoA binding protein and cellular retinol binding protein). Studies with model systems using these hydrophobic ligands and the lipid-binding or transfer proteins are also described. This topic is of interest especially because in the esterification of retinol the three substrates and the three binding proteins may interact."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I293,I293)","v":2218545},{"$f":"(LEN($J293) - LEN(SUBSTITUTE(LOWER($J293),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J293) - LEN(SUBSTITUTE(LOWER($J293),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J293) - LEN(SUBSTITUTE(LOWER($J293),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B293:D293)","v":5},1990,"Transport and storage of vitamin A.","Blomhoff",2218545,"Transport and storage of vitamin A.    Abstract:   The requirement of vitamin A (retinoids) for vision has been recognized for decades. In addition, vitamin A is involved in fetal development and in the regulation of proliferation and differentiation of cells throughout life. This fat-soluble organic compound cannot be synthesized endogenously by humans and thus is an essential nutrient; a well-regulated transport and storage system provides tissues with the correct amounts of retinoids in spite of normal fluctuations in daily vitamin A intake. An overview is presented here of current knowledge and hypotheses about the absorption, transport, storage, and metabolism of vitamin A. Some information is also presented about a group of ligand-dependent transcription factors, the retinoic acid receptors, that apparently mediate many of the extravisual effects of retinoids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I294,I294)","v":3045164},{"$f":"(LEN($J294) - LEN(SUBSTITUTE(LOWER($J294),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J294) - LEN(SUBSTITUTE(LOWER($J294),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J294) - LEN(SUBSTITUTE(LOWER($J294),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B294:D294)","v":5},1988,"Liver toxicity of retinoid therapy.","Roenigk",3045164,"Liver toxicity of retinoid therapy.    Abstract:   Vitamin A metabolism involves storage in the liver. Hypervitaminosis A results in liver abnormalities, including fibrosis and cirrhosis. Ito cells are increased and promote fibrogenesis, which results in cirrhosis. Retinoids (Accutane and Tegison) are used clinically for the treatment of a variety of skin diseases. Since retinoids are analogs of vitamin A, their potential to produce liver disease is reviewed. Animal and human studies of liver function tests suggest some abnormalities in the liver in about 25% of patients treated. Liver biopsy studies have included isolated case reports and two retrospective and one prospective liver biopsy study of retinoids in humans. Although some increase in histologic liver changes have been noted, most liver biopsy specimens showed no change or improvement. Retinoids do not appear to produce consistent toxic liver abnormalities."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I295,I295)","v":6306117},{"$f":"(LEN($J295) - LEN(SUBSTITUTE(LOWER($J295),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J295) - LEN(SUBSTITUTE(LOWER($J295),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J295) - LEN(SUBSTITUTE(LOWER($J295),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B295:D295)","v":5},1983,"Structure and tissue distribution of some retinoid-binding proteins.","Sundelin",6306117,"Structure and tissue distribution of some retinoid-binding proteins.    Abstract:   Vitamin A has, apart from its function in the visual pigments, general effects on several organs. Early signs of vitamin A deficiency include keratinization of epithelia and hyperkeratosis of the skin. To elucidate a generalized function for vitamin A, we have taken the approach of tracing the vitamin from its storage site in the liver via its blood transport by the retinol-binding protein (RBP) to its uptake by susceptible cells. We have also examined the intracellular occurrence of vitamin A as regards its binding to specific receptor proteins. Here we summarize data on the amino acid sequences of several vitamin A-binding proteins. The finding that CRBP and CRABP, the two intracellular proteins, are homologous to each other, to a myelin protein, and to a fatty acid-binding protein may shed light on the functions of these proteins. Retinoic acid, which binds to CRABP but not CRBP, induces differentiation of teratocarcinoma cells. This is accompanied by a lowering of the CRABP concentration, an increase of the CRBP level, and an increase in the uptake of retinol from RBP. The epidermis contains both CRBP and CRABP, and their distributions are rather similar. However, in contrast to CRBP, CRABP is most abundant in cells lining the hair follicles. CRBP occurs in greatest relative amounts in the outer layers of the epidermis. Since techniques have been developed to measure CRBP and CRABP, normal and disease-affected skin may now be explored as to quantity and cellular distribution of the retinoid-binding proteins."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I296,I296)","v":6810745},{"$f":"(LEN($J296) - LEN(SUBSTITUTE(LOWER($J296),LOWER(B$3),\"\")))/LEN(B$3)","v":5},{"$f":"(LEN($J296) - LEN(SUBSTITUTE(LOWER($J296),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J296) - LEN(SUBSTITUTE(LOWER($J296),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B296:D296)","v":5},1982,"Retinoids as chemopreventive and anticancer agents intact animals (review).","Hill",6810745,"Retinoids as chemopreventive and anticancer agents intact animals (review).    Abstract:   Certain retinoids have reproducibly prevented carcinogen-induced cancer of the skin, mammary gland, and urinary bladder of experimental animals and, in isolated experiments, have demonstrated positive activity for carcinogen-induced cancer of the esophagus, cervix, and liver. Attempts to establish activity of retinoids in prevention of lung and colon cancer have generally been unsuccessful. In the chemotherapy of established cancers, retinoids have exhibited modest activity against those that are immunogenic. The preventive activity of retinoids appears to be associated with their role in chemotherapy is consistent with general stimulation of the immune response of the host."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I297,I297)","v":6786155},{"$f":"(LEN($J297) - LEN(SUBSTITUTE(LOWER($J297),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J297) - LEN(SUBSTITUTE(LOWER($J297),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J297) - LEN(SUBSTITUTE(LOWER($J297),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B297:D297)","v":5},1980,"The vitamin A-zinc connection: a review.","Smith",6786155,"The vitamin A-zinc connection: a review.    Abstract:   A general summary of typical results involving animal studies is shown in TABLE 7. A consistent and established finding is a reduction of plasma vitamin A concentration in zinc-deficient animals despite diets adequate in vitamin A. However, it appears that the depressed plasma vitamin A is not a result of zinc deficiency per se but rather is nonspecific, resulting from food- and growth-restriction factors associated with zinc deficiency. Food restriction apparently is the critical factor, since both immature and mature nongrowing zinc-deficient animals have exhibited the decreased plasma vitamin A concentration. However, this point needs clarification. Liver vitamin A concentration is usually unaltered by the zinc deficiency, suggesting no defect in absorption or transport to the liver. In regard to retinol-binding protein, it appears from the animal studies that zinc deficiency per se has an effect on both the plasma and liver RBP concentrations. We have hypothesized that zinc deficiency impairs RBP synthesis. It is speculated that only severe zinc deficiency results in a deficit of a sufficient magnitude for impairment of vitamin A metabolism at the cellular level. For example, retinene reductase, an apparent zinc-metallo alcohol dehydrogenase of the retina, appears to be sensitive to a severe zinc deficiency in animal studies. In humans, impaired dark adaptation may be a result of inadequate supplies of the metabolizable zinc necessary to maintain the activity of the enzyme system. Thus, the conversion (dehydrogenation) of vitamin A alcohol to vitamin A aldehyde is impaired, with a resulting abnormality in dark adaptation, i.e., night blindness. Indeed, the limited number of human studies suggest that zinc supplementation may be beneficial to vitamin A metabolism only in conditions where zinc deficiency is prevalent as indicated by low (less than 70 micrograms/100 ml) plasma zinc. Conversely, zinc supplementation is of little benefit in conditions where vitamin A metabolism is altered but zinc status is normal. Therefore, definitive clinical studies involving primary zinc deficiency must be conducted before final conclusions can be made regarding the interrelationships of zinc and vitamin A in health and disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I298,I298)","v":27621572},{"$f":"(LEN($J298) - LEN(SUBSTITUTE(LOWER($J298),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J298) - LEN(SUBSTITUTE(LOWER($J298),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J298) - LEN(SUBSTITUTE(LOWER($J298),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B298:D298)","v":4},2016,"Supportive therapies for prevention of hepatocellular carcinoma recurrence and preservation of liver function.","Takami",27621572,"Supportive therapies for prevention of hepatocellular carcinoma recurrence and preservation of liver function.    Abstract:   Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world and is associated with a high risk of recurrence. The development of a wide range of new therapies is therefore essential. In this study, from the perspective of supportive therapy for the prevention of HCC recurrence and preservation of liver function in HCC patients, we surveyed a variety of different therapeutic agents. We show that branched chain amino acids (BCAA) supplementation and late evening snack with BCAA, strategies that address issues of protein-energy malnutrition, are important for liver cirrhotic patients with HCC. For chemoprevention of HCC recurrence, we show that viral control after radical treatment is important. We also reviewed the therapeutic potential of antiviral drugs, sorafenib, peretinoin, iron chelators. Sorafenib is a kinase inhibitor and a standard therapy in the treatment of advanced HCC. Peretinoin is a vitamin A-like molecule that targets the retinoid nuclear receptor to induce apoptosis and inhibit tumor growth in HCC cells. Iron chelators, such as deferoxamine and deferasirox, act to prevent cancer cell growth. These chelators may have potential as combination therapies in conjunction with peretinoin. Finally, we review the potential inhibitory effect of bone marrow cells on hepatocarcinogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I299,I299)","v":26535059},{"$f":"(LEN($J299) - LEN(SUBSTITUTE(LOWER($J299),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J299) - LEN(SUBSTITUTE(LOWER($J299),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J299) - LEN(SUBSTITUTE(LOWER($J299),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B299:D299)","v":4},2015,"Vitamin A: a missing link in diabetes?","Trasino",26535059,"Vitamin A: a missing link in diabetes?    Abstract:    NlmCategory=UNASSIGNEDVitamin A has a critical role in embryonic development, immunity and the visual cycle. In recent years, evidence has demonstrated that vitamin A can also regulate metabolic pathways implicated in the pathogenesis of obesity and diabetes. This has increased interest in the possible antiobesity and antidiabetic properties of natural and synthetic vitamin A derivatives. However, whether vitamin A deficiency or aberrations in vitamin A metabolism contribute to the pathogenesis of diabetes is not known. This perspective article will review what is currently known and new data regarding the link between vitamin A and the clinical manifestations of common and atypical forms of diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I300,I300)","v":26001806},{"$f":"(LEN($J300) - LEN(SUBSTITUTE(LOWER($J300),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J300) - LEN(SUBSTITUTE(LOWER($J300),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J300) - LEN(SUBSTITUTE(LOWER($J300),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B300:D300)","v":4},2015,"Role of vitamin A in type 2 diabetes mellitus biology: effects of intervention therapy in a deficient state.","Iqbal",26001806,"Role of vitamin A in type 2 diabetes mellitus biology: effects of intervention therapy in a deficient state.    Abstract:   Diabetes has emerged as the biggest pandemic of our times, growing parallel to obesity. Insulin treatment regimens have been unable to completely inhibit protein glycation, which is responsible for the development of increased oxidative stress in diabetic tissues. Coupled with recent evidences that highlight the role of reactive oxygen species in the onset and progression of type 2 diabetes mellitus (T2DM), the antioxidants have taken prime focus as a possible intervention strategy. Studies have established a role of antioxidant vitamins C and E in improving patient condition in the past. Vitamin A, in addition to its role as an antioxidant, boasts a pleiotropic role in cell regulation through its action on gene regulation, maintenance of epithelial cell integrity, and resistance to infection. Studies have also ascribed a role to vitamin A in up-regulating the antioxidant enzyme functions in the body. Additionally, a link has been found between diabetes and deficient vitamin A levels indicating vitamin A supplementation may have a role in T2DM biology. This review therefore focuses on the vitamin A intervention in T2DM patients having deficient in vitamin A."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I301,I301)","v":25809683},{"$f":"(LEN($J301) - LEN(SUBSTITUTE(LOWER($J301),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J301) - LEN(SUBSTITUTE(LOWER($J301),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J301) - LEN(SUBSTITUTE(LOWER($J301),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B301:D301)","v":4},2015,"Comparisons among Equations Used for Retinol Isotope Dilution in the Assessment of Total Body Stores and Total Liver Reserves.","Gannon",25809683,"Comparisons among Equations Used for Retinol Isotope Dilution in the Assessment of Total Body Stores and Total Liver Reserves.    Abstract:   Vitamin A plays an essential role in animal biology and has negative effects associated with both hypo- and hypervitaminosis A. Many notable interventions are being done globally to eliminate vitamin A deficiency, including supplementation, fortification, and biofortification. At the same time, it is important to monitor vitamin A status in nations where preformed vitamin A intake is high because of consumption of animal source foods (e.g., liver, dairy, eggs), fortified foods (e.g., milk, cereals, oil, sugar, margarine), or vitamin supplements (e.g., one-a-day multivitamins) to ensure the population does not reach hypervitaminosis A. To accurately assess population status and evaluate interventions aimed at improving vitamin A status, accurate assessment methods are needed. The primary storage site of vitamin A is the liver; however, routinely obtaining liver samples from humans is impractical and unethical. Isotope dilution using deuterium- or (13)C-labeled retinol is currently the most sensitive indirect biomarker of vitamin A status across a wide range of liver reserves. The major drawback to its application is the increased technicality in sample analysis and data calculations when compared to less sensitive methodology, such as serum retinol concentrations and dose response tests. Two main equations have emerged for calculating vitamin A body pool size or liver concentrations from isotope dilution data: the quot;Olson equationquot; and the quot;mass balance equation.quot; Different applications of these equations can lead to confusion and lack of consistency if the underlying principles and assumptions used are not clarified. The purpose of this focused review is to describe the evolution of the equations used in retinol stable-isotope work and the assumptions appropriate to different applications of the test. Ultimately, the 2 main equations are shown to be fundamentally the same and differ only in assumptions made for each specific research application."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I302,I302)","v":25579087},{"$f":"(LEN($J302) - LEN(SUBSTITUTE(LOWER($J302),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J302) - LEN(SUBSTITUTE(LOWER($J302),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J302) - LEN(SUBSTITUTE(LOWER($J302),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B302:D302)","v":4},2015,"Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN): could retinoids play a causative role?","Mawson",25579087,"Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN): could retinoids play a causative role?    Abstract:   Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are overlapping manifestations on a spectrum of acute drug-induced conditions associated with severe blistering, skin peeling, and multi-organ damage. TEN is an eruption resembling severe scalding, with ≥30% skin detachment. SJS is a mild form of TEN, characterized histologically by epidermal keratinocyte apoptosis with dermo-epidermal separation and extensive small blisters with lt;10% body surface skin detachment. The syndrome can be induced by numerous medications and typically occurs 1-4 weeks after the initiation of therapy. Granulysin is found in the lesions of patients with SJS/TEN and plays a significant pathogenic role in the condition, but the overall mechanisms linking medications, granulysin, and disease manifestations remain obscure. This paper reviews evidence suggesting that the different medications implicated in SJS/TEN have the common property of interacting and synergizing with endogenous retinoids (vitamin A and its congeners), in many instances causing the latter to accumulate in and damage the liver, the main storage organ for vitamin A. It is hypothesized that liver damage leads to the spillage of toxic retinoid compounds into the circulation, resulting in an endogenous form of hypervitaminosis A and cytotoxicity with widespread apoptosis, mediated by granulysin and recognized as SJS/TEN. Subject to testing, the model suggests that symptom worsening could be arrested at onset by lowering the concentration of circulating retinoids and/or granulysin via phlebotomy or plasmapheresis or by pharmacological measures to limit their expression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I303,I303)","v":25380591},{"$f":"(LEN($J303) - LEN(SUBSTITUTE(LOWER($J303),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J303) - LEN(SUBSTITUTE(LOWER($J303),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J303) - LEN(SUBSTITUTE(LOWER($J303),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B303:D303)","v":4},2015,"Downsizing of lean body mass is a key determinant of Alzheimers disease.","Ingenbleek",25380591,"Downsizing of lean body mass is a key determinant of Alzheimers disease.    Abstract:   Lean body mass (LBM) encompasses all metabolically active organs distributed into visceral and structural tissue compartments and collecting the bulk of N and K stores of the human body. Transthyretin (TTR) is a plasma protein mainly secreted by the liver within a trimolecular TTR-RBP-retinol complex revealing from birth to old age strikingly similar evolutionary patterns with LBM in health and disease. TTR is also synthesized by the choroid plexus along distinct regulatory pathways. Chronic dietary methionine (Met) deprivation or cytokine-induced inflammatory disorders generates LBM downsizing following differentiated physiopathological processes. Met-restricted regimens downregulate the transsulfuration cascade causing upstream elevation of homocysteine (Hcy) safeguarding Met homeostasis and downstream drop of hydrogen sulfide (H2S) impairing anti-oxidative capacities. Elderly persons constitute a vulnerable population group exposed to increasing Hcy burden and declining H2S protection, notably in plant-eating communities or in the course of inflammatory illnesses. Appropriate correction of defective protein status and eradication of inflammatory processes may restore an appropriate LBM size allowing the hepatic production of the retinol circulating complex to resume, in contrast with the refractory choroidal TTR secretory process. As a result of improved health status, augmented concentrations of plasma-derived TTR and retinol may reach the cerebrospinal fluid and dismantle senile amyloid plaques, contributing to the prevention or the delay of the onset of neurodegenerative events in elderly subjects at risk of Alzheimers disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I304,I304)","v":24099071},{"$f":"(LEN($J304) - LEN(SUBSTITUTE(LOWER($J304),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J304) - LEN(SUBSTITUTE(LOWER($J304),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J304) - LEN(SUBSTITUTE(LOWER($J304),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B304:D304)","v":4},2013,"Oral retinoids and plasma lipids.","Lilley",24099071,"Oral retinoids and plasma lipids.    Abstract:   Retinoids and rexinoids are prescribed for conditions ranging from acne vulgaris to hyperkeratosis to cutaneous T cell lymphoma. Dyslipidemia is a frequent consequence of the use of these drugs, with more than one-third of patients manifesting aberrations in triglyceride (TG) levels. The efficacy of retinoic acid derivatives is linked to their influence on lipid metabolism in the skin, which can impair systemic lipid trafficking and metabolism in some patients. Thus, baseline screening for preexisting dyslipidemia and regular follow-up lipid panels are mandated, especially when powerful agents such as bexarotene are used. Dietary modification, increased physical activity, and weight management are the cornerstones of initial management for mild hypertriglyceridemia, which is a contributor to cardiovascular risk. More severe impairments (fasting TG gt; 500 mg/dL) warrant pharmacologic interventions early on to reduce the risk of pancreatitis. Retinoic acid derivative action, lipid metabolism, and treatment of incident dyslipidemias are reviewed to empower prescribers in management of adverse lipid effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I305,I305)","v":23932046},{"$f":"(LEN($J305) - LEN(SUBSTITUTE(LOWER($J305),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J305) - LEN(SUBSTITUTE(LOWER($J305),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J305) - LEN(SUBSTITUTE(LOWER($J305),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B305:D305)","v":4},2013,"An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy.","Palomer",23932046,"An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy.    Abstract:   Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus are all linked to cardiovascular diseases such as cardiac hypertrophy and heart failure. Diabetic cardiomyopathy in particular, is characterized by structural and functional alterations in the heart muscle of people with diabetes that finally lead to heart failure, and which is not directly attributable to coronary artery disease or hypertension. Several mechanisms have been involved in the pathogenesis of diabetic cardiomyopathy, such as alterations in myocardial energy metabolism and calcium signaling. Metabolic disturbances during diabetic cardiomyopathy are characterized by increased lipid oxidation, intramyocardial triglyceride accumulation, and reduced glucose utilization. Overall changes result in enhanced oxidative stress, mitochondrial dysfunction and apoptosis of the cardiomyocytes. On the other hand, the progression of heart failure and cardiac hypertrophy usually entails a local rise in cytokines in cardiac cells and the activation of the proinflammatory transcription factor nuclear factor (NF)-κB. Interestingly, increasing evidences are arising in the recent years that point to a potential link between chronic low-grade inflammation in the heart and metabolic dysregulation. Therefore, in this review we summarize recent new insights into the crosstalk between inflammatory processes and metabolic dysregulation in the failing heart during diabetes, paying special attention to the role of NF-κB and peroxisome proliferator activated receptors (PPARs). In addition, we briefly describe the role of the AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and other pathways regulating cardiac energy metabolism, as well as their relationship with diabetic cardiomyopathy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I306,I306)","v":23163336},{"$f":"(LEN($J306) - LEN(SUBSTITUTE(LOWER($J306),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J306) - LEN(SUBSTITUTE(LOWER($J306),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J306) - LEN(SUBSTITUTE(LOWER($J306),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B306:D306)","v":4},2013,"Side effects of common acne treatments.","Tripathi",23163336,"Side effects of common acne treatments.    Abstract:    INTRODUCTION : A variety of acne treatments exist, including topical benzoyl peroxide, topical retinoids, topical antibiotics, oral antibiotics, hormonal therapy, isotretinoin, and procedural therapies, such as light and laser therapies. Although each of these treatment modalities confer various benefits for the management of acne, it is important for healthcare providers to be aware of their potential side effects, including ones that are most common and most serious, so that these medications can be prescribed in a safe manner.  AREAS COVERED : A systematic literature review was performed to identify publications discussing the side effects of the different treatment modalities used for acne vulgaris. Acne treatments reviewed included benzoyl peroxide gel, topical retinoids, topical antibiotics, oral antibiotics, hormonal therapy, isotretinoin, and light/laser treatments.  EXPERT OPINION : A comprehensive overview of acne treatments side effects is imperative for healthcare professionals and scientists working with and prescribing acne treatments. Side effects to be aware of when prescribing range from local irritation with topical treatments to systemic side effects including liver function abnormalities and teratogenic side effects. The best available options are those that address acne severity while minimizing side effects for the patient. Consequently, personalized medicine must be strongly emphasized to healthcare providers developing patients treatment plans."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I307,I307)","v":22703297},{"$f":"(LEN($J307) - LEN(SUBSTITUTE(LOWER($J307),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J307) - LEN(SUBSTITUTE(LOWER($J307),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J307) - LEN(SUBSTITUTE(LOWER($J307),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B307:D307)","v":4},2013,"Transcriptional repression of mitochondrial function in aging: a novel role for the silencing mediator of retinoid and thyroid hormone receptors co-repressor.","Liu",22703297,"Transcriptional repression of mitochondrial function in aging: a novel role for the silencing mediator of retinoid and thyroid hormone receptors co-repressor.    Abstract:    SIGNIFICANCE : Mitochondrial function plays an important role in metabolic homeostasis and has been implicated in aging. Although there is still ongoing debate regarding whether mitochondrion-derived oxidative stress is causative to the aging process, interventions that increase oxidative metabolism and antioxidant pathways in animal models protect against age-related deterioration, such as metabolic diseases and neurodegenerative disorders.  RECENT ADVANCES : One of the well-characterized transcriptional networks known to improve mitochondrial activity is mediated by transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α), which is activated by AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), two of the major energy sensing molecules that are responsible for the longevity effect of caloric restriction in certain model systems. PGC-1α co-activates several nuclear receptors, notably members of the peroxisome proliferator-activated receptor (PPAR) family, which are key regulators of mitochondrial oxidative metabolism.  CRITICAL ISSUES : Although the AMPK/SIRT1-PGC-1α-PPAR axis plays a prominent role in activating mitochondrial functions, their activities are down-regulated in older animals, suggesting the involvement of dominant negative regulatory mechanisms in the process of aging.  FUTURE DIRECTIONS : In this review, we will discuss the role of a transcriptional co-repressor, silencing mediator of retinoid and thyroid hormone receptors (SMRT), whose activity and expression are increased with age, as a negative regulator of mitochondrial function that promotes aging and age-related metabolic diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I308,I308)","v":22361284},{"$f":"(LEN($J308) - LEN(SUBSTITUTE(LOWER($J308),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J308) - LEN(SUBSTITUTE(LOWER($J308),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J308) - LEN(SUBSTITUTE(LOWER($J308),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B308:D308)","v":4},2012,"Vitamin a: history, current uses, and controversies.","Chapman",22361284,"Vitamin a: history, current uses, and controversies.    Abstract:   Vitamin A is required for the proper functioning of many important metabolic and physiologic activities, including vision, gene transcription, the immune system and skin cell differentiation. Both excessive and deficient levels of vitamin A lead to poor functioning of many human systems. The biologically active form, retinoic acid, binds to nuclear receptors that facilitate transcription that ultimately leads to its physiological effects. Retinoids are derivatives of vitamin A that are medications used to treat acne vulgaris, psoriasis, ichthyosis (and other disorders of keratinization), skin cancer prevention as well as several bone marrow derived neoplasias. Systemic retinoids are teratogenic and have to be prescribed with caution and close oversight. Other potential adverse events are controversial. These include the relationship of retinoid derivatives in sunscreens, their effects on bone mineral density, depression and suicidal ideation and inflammatory bowel disease. These controversies will be discussed in detail."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I309,I309)","v":22242853},{"$f":"(LEN($J309) - LEN(SUBSTITUTE(LOWER($J309),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J309) - LEN(SUBSTITUTE(LOWER($J309),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J309) - LEN(SUBSTITUTE(LOWER($J309),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B309:D309)","v":4},2012,"Retinoid receptors and therapeutic applications of RAR/RXR modulators.","le Maire",22242853,"Retinoid receptors and therapeutic applications of RAR/RXR modulators.    Abstract:   Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth, differentiation, survival and death. Due to their regulatory potential, these nuclear receptors (NRs) are major drug targets for a variety of pathologies, including cancer and metabolic diseases. A large amount of RAR- and RXR-selective ligands, ranging from (partial) agonists to antagonists and inverse agonists, have been designed and the corresponding structural and functional analyses have provided deep insight into the molecular basis of ligand action. Ligands regulate, via allosteric conformational changes, the ability of these NRs to interact with different sets of coregulators, which in turn recruit enzymatically active complexes/machineries. Here, we describe strategies in the design of selective RXR and RAR modulators and review the structural mechanisms by which the diverse pharmacological classes of compounds modulate receptor functions. Finally, we discuss the perspectives for retinoid- and rexinoid-based therapies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I310,I310)","v":21388453},{"$f":"(LEN($J310) - LEN(SUBSTITUTE(LOWER($J310),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J310) - LEN(SUBSTITUTE(LOWER($J310),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J310) - LEN(SUBSTITUTE(LOWER($J310),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B310:D310)","v":4},2011,"Evidence-based recommendations on conventional systemic treatments in psoriasis: systematic review and expert opinion of a panel of dermatologists.","Paul",21388453,"Evidence-based recommendations on conventional systemic treatments in psoriasis: systematic review and expert opinion of a panel of dermatologists.    Abstract:    BACKGROUND : There is a high level of heterogeneity regarding the practical use of conventional systemic treatment in psoriasis.  OBJECTIVES : The aim of this study was to develop evidence-based recommendations for the use of traditional systemic treatments in psoriasis in daily clinical practice: methotrexate (MTX), cyclosporin and retinoids.  METHODS : A scientific committee selected clinically relevant questions concerning the use of MTX, cyclosporin and retinoids in psoriasis. This selection was made using the Delphi method. A systematic literature search was performed in Medline, Embase and the Cochrane Library. The articles selected for analysis were reviewed and the level of evidence was appraised according to the Oxford Levels of Evidence. An Expert consensus meeting took place in June 2010, including 66 dermatologists. Recommendations for daily use of psoriasis systemic treatments were made during interactive workshops where the evidence was reviewed. Agreement among participants and the impact of the recommendations on clinical practice were systematically assessed using voting procedure in a plenary session.  RESULTS : A total of 2800 references were identified, among which 122 articles were included in the systematic reviews. Three key recommendations on the use of MTX in psoriasis were formulated, including optimal dosage and route, use of folic acid, risk factors for liver fibrosis and monitoring of hepatotoxicity. The recommendations for cyclosporin in psoriasis focused on the modalities of cyclosporin prescription: dosage, scheme of treatment, optimal duration of treatment, renal toxicity monitoring and evidence for use of cyclosporin in non-plaque psoriasis (erythrodermic, pustular and ungueal). Recommendations were also made concerning the efficacy and safety of retinoids (mainly acitretin) in plaque and non-plaque psoriasis.  CONCLUSIONS : These recommendations for the use of traditional systemic therapies in psoriasis are evidence based and supported by a panel of dermatologists. The next step will be to disseminate these recommendations and assess the agreement of physicians who were not involved in generating the recommendations."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I311,I311)","v":21196201},{"$f":"(LEN($J311) - LEN(SUBSTITUTE(LOWER($J311),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J311) - LEN(SUBSTITUTE(LOWER($J311),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J311) - LEN(SUBSTITUTE(LOWER($J311),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B311:D311)","v":4},2011,"Chemoprevention of hepatocellular carcinoma by acyclic retinoid.","Shimizu",21196201,"Chemoprevention of hepatocellular carcinoma by acyclic retinoid.    Abstract:   The prognosis for patients with hepatocellular carcinoma (HCC) is poor and effective prevention strategies are urgently required. Here, we review abnormalities in the expression and function of retinoids and their receptors, and how they play a critical role in the development of HCC. In particular, a malfunction of RXRalpha due to phosphorylation by Ras-MAPK signaling pathway is profoundly associated with liver carcinogenesis and thus may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), a synthetic retinoid, inhibits Ras-MAPK activation and RXRalpha phosphorylation, thereby suppressing growth in HCC-derived cells. In clinical trials, ACR has been shown to improve patient survival by preventing viral HCC development, a possible manifestation of the concept of quot;clonal deletionquot; therapy. quot;Combination chemopreventionquot; with ACR as the key drug has great potential to become an effective strategy for the prevention of liver carcinogenesis. In summary, both basic and clinical research strongly suggest that ACR plays a critical role in preventing the development of HCC and that quot;clonal deletionquot; therapy is one of the most practical approaches for this purpose."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I312,I312)","v":20238031},{"$f":"(LEN($J312) - LEN(SUBSTITUTE(LOWER($J312),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J312) - LEN(SUBSTITUTE(LOWER($J312),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J312) - LEN(SUBSTITUTE(LOWER($J312),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B312:D312)","v":4},2010,"Pharmacological manipulation of rhodopsin retinitis pigmentosa.","Mendes",20238031,"Pharmacological manipulation of rhodopsin retinitis pigmentosa.    Abstract:   Mutations in rhodopsin cause autosomal dominant retinitis pigmentosa. The majority of these mutations (class II) lead to protein misfolding. The misfolded protein is retained in the ER then retrotranslocated into the cytoplasm for degradation by the proteasome. If degradation fails, the protein can aggregate to form intracellular inclusions. In addition, the mutant rod opsin exerts a dominant negative effect on the wild-type protein. Here, we review these pathways and how different drug treatments can affect mutant rod opsin. Interestingly, drugs targeted at general protein stability (kosmotropes) or improving the cellular folding and degradation machinery (molecular chaperone inducers and autophagy induction) reduced P23H rod opsin aggregation and inclusion formation together with associated caspase activation and cell death, but did not enhance mutant protein processing or reduce the dominant negative effects. In contrast, pharmacological chaperones (retinoids) enhanced P23H folding and reduced the dominant negative effects, as well as reducing the other gains of function. Therefore, targeting the toxic gain of function did not require improved folding, whereas reducing the dominant negative effects required improved folding. These studies suggest that some forms of rhodopsin retinitis pigmentosa could be treated by targeting protein folding and/or reducing protein aggregation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I313,I313)","v":27635169},{"$f":"(LEN($J313) - LEN(SUBSTITUTE(LOWER($J313),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J313) - LEN(SUBSTITUTE(LOWER($J313),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J313) - LEN(SUBSTITUTE(LOWER($J313),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B313:D313)","v":4},2009,"Retinoic Acid-mediated Nuclear Receptor Activation and Hepatocyte Proliferation.","Bushue",27635169,"Retinoic Acid-mediated Nuclear Receptor Activation and Hepatocyte Proliferation.    Abstract:    NlmCategory=UNASSIGNEDDue to their well-known differentiation and apoptosis-inducing abilities, retinoic acid (RA) and its analogs have strong anti-cancer efficacy in human cancers. However, in vivo RA is a liver mitogen. While speculation has persisted that RA-mediated signaling is likely involved in hepatocyte proliferation during liver regeneration, direct evidence is still required. Findings in support of this proposition include observations that a release of retinyl palmitate (the precursor of RA) occurs in liver stellate cells following liver injury. Nevertheless, the biological action of this released vitamin A is virtually unknown. More likely is that the released vitamin A is converted to RA, the biological form, and then bound to a specific receptor (retinoid x receptor; RXRα), which is most abundantly expressed in the liver. Considering the mitogenic effects of RA, the RA-activated RXRα would likely then influence hepatocyte proliferation and liver tissue repair. At present, the mechanism by which RA stimulates hepatocyte proliferation is largely unknown. This review summarizes the activation of nuclear receptors (peroxisome proliferator activated receptor-α, pregnane x receptor, constitutive androstane receptor, and farnesoid x receptor) in an RXRα dependent manner to induce hepatocyte proliferation, providing a link between RA and its proliferative role."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I314,I314)","v":19710551},{"$f":"(LEN($J314) - LEN(SUBSTITUTE(LOWER($J314),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J314) - LEN(SUBSTITUTE(LOWER($J314),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J314) - LEN(SUBSTITUTE(LOWER($J314),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B314:D314)","v":4},2009,"Retinoids, methotrexate and cyclosporine.","Dubertret",19710551,"Retinoids, methotrexate and cyclosporine.    Abstract:   Acitretin alone is efficient (PASI 90: 40%). In responders, it is the best long-term maintenance treatment (up to 29 years of continuous treatment). The main side effect is its teratogenicity in females. It is necessary to begin retinoid treatment at low doses (10 mg/day), increasing the dose step by step, looking for the maximum well-tolerated dose (usually defined as a mild cheilitis). Doses higher than the highest well-tolerated dose are frequently responsible for the Kobner phenomenon. In children, retinoids are very efficient and nearly always well tolerated, but it seems important to never give more than 0.5 mg/kg/day. Methotrexate is the best treatment for severe psoriasis. Given at low doses once a week, it is a safe, cheap, convenient and efficient treatment, if carefully monitored. The main problem is the possible long-term liver toxicity of methotrexate. The risk is very low in patients not at risk (no liver disease). In these cases, liver biopsies are dangerous and useless. In the other cases, the need for liver biopsy is very rare, decided only by the hepatologist, and should be replaced by FibroTest and FibroScan. The old American guidelines should not be followed, and new guidelines are needed. Cyclosporine at low doses is an outstanding emergency treatment. It was first used as the last possible systemic treatment, but long-term continuous treatments are seldom possible due to alterations in kidney functions. A careful follow-up of kidney functions, with measurement of the glomerular filtration rate after each year of cumulative treatment, is necessary. The cyclosporine dose must be calculated according to the theoretical body weight in obese patients to avoid overdosage. Cyclosporine is mainly used now as a short-term treatment that is very efficient for young people, who find this illness particularly difficult. Cyclosporine is not contraindicated during pregnancy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I315,I315)","v":19557453},{"$f":"(LEN($J315) - LEN(SUBSTITUTE(LOWER($J315),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J315) - LEN(SUBSTITUTE(LOWER($J315),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J315) - LEN(SUBSTITUTE(LOWER($J315),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B315:D315)","v":4},2009,"beta-Carotene conversion products and their effects on adipose tissue.","Tourniaire",19557453,"beta-Carotene conversion products and their effects on adipose tissue.    Abstract:   Recent epidemiological data suggest that beta-carotene may be protective against metabolic diseases in which adipose tissue plays a key role. Adipose tissue constitutes the major beta-carotene storage tissue and its functions have been shown to be modulated in response to beta-carotene breakdown products, especially retinal produced after cleavage by beta-carotene 15,15-monooxygenase (BCMO1), and retinoic acid arising from oxidation of retinal. However, the possibility exists that beta-carotene in its intact form can also affect adipocyte function. Development of a knock out model and identification of a loss-of-function mutation have pointed out BCMO1 as being probably the sole enzyme responsible for provitamin A conversion into retinal in mammals. The utilisation of BCMO1(-/-)mice should provide insights on beta-carotene effect on its own in the future. In humans, intervention studies have highlighted the huge interindividual variation of beta-carotene conversion efficiency, possibly due to genetic polymorphisms, which might impact on response to beta-carotene. This brief review discusses the processes involved in beta-carotene conversion and the effect of cleavage products on body fat and adipose tissue function."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I316,I316)","v":18248399},{"$f":"(LEN($J316) - LEN(SUBSTITUTE(LOWER($J316),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J316) - LEN(SUBSTITUTE(LOWER($J316),LOWER(C$3),\"\")))/LEN(C$3)","v":3},{"$f":"(LEN($J316) - LEN(SUBSTITUTE(LOWER($J316),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B316:D316)","v":4},2008,"Developmental effects: oestrogen-induced vaginal changes and organotin-induced adipogenesis.","Iguchi",18248399,"Developmental effects: oestrogen-induced vaginal changes and organotin-induced adipogenesis.    Abstract:   The emerging paradigm, the foetal origin of adult disease, is a new framework for considering the effects of endocrine disrupters on human and animal health. Prenatal diethylstilbestrol (DES) exposure resulted in various reproductive tract abnormalities in women, which is called as DES syndrome. Similar abnormalities have been demonstrated in experimental animals exposed perinatally to oestrogens. Developmental oestrogen exposure induces persistent proliferation of vaginal epithelial cells in mice. The persistent changes in the vagina of mice neonatally exposed to oestrogens results from persistent phosphorylation of erbB2 and oestrogen receptor alpha, sustained expression of EGF-like growth factors and phosphorylation of JNK1, IGF-I receptor and Akt. The ubiquitous environmental contaminant, tributyltin chloride (TBT) is well known to induce the development of male sex characteristics (imposex) in gastropods. We recently found that TBT and its congeners induce the differentiation of adipocytes in vitro and increase adipose mass in vivo in vertebrates. TBT is a nanomolar affinity ligand for retinoid X receptor (RXR) in the rock shell and for both the RXRalpha and the peroxisome proliferator-activated receptor gamma (PPARgamma) in the amphibian (Xenopus laevis), mouse, and human. TBT promotes adipogenesis in the murine 3T3-L1 cell model and perturbs key regulators of adipogenesis and lipogenic pathways in vivo, primarily through activation of RXRalpha and PPARgamma. Moreover, in utero exposure to TBT leads to strikingly elevated lipid accumulation in adipose depots, liver, and testis of neonate mice and results in increased adipose mass in adults. In X. laevis, ectopic adipocytes form in and around gonadal tissues following organotin, RXRalpha or PPARgamma ligand exposure. TBT represents the first example of an environmental endocrine disrupter that promotes adverse effects from gastropods to mammals. Prenatal (TBT) and early postnatal exposures (oestrogens) stand as strong examples of endocrine disrupting compounds that permanently alter developmental programming."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I317,I317)","v":18177744},{"$f":"(LEN($J317) - LEN(SUBSTITUTE(LOWER($J317),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J317) - LEN(SUBSTITUTE(LOWER($J317),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J317) - LEN(SUBSTITUTE(LOWER($J317),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B317:D317)","v":4},2008,"Bioactive lipids in metabolic syndrome.","Nagao",18177744,"Bioactive lipids in metabolic syndrome.    Abstract:   The metabolic syndrome is a cluster of metabolic disorders, such as abdominal obesity, dyslipidemia, hypertension and impaired fasting glucose that contribute to increased cardiovascular morbidity and mortality. Although the pathogenesis of metabolic syndrome is complicated and the precise mechanisms have not been elucidated, dietary lipids have been recognized as contributory factors in the development and the prevention of cardiovascular risk clustering. This review explores the physiological functions and molecular actions of bioactive lipids, such as n-3 polyunsaturated fatty acids, conjugated fatty acids, sterols, medium-chain fatty acids, diacylglycerols and phospholipids, in the development of metabolic syndrome. Dietary bioactive lipids suppress the accumulation of abdominal adipose tissue and lipids in the liver and serum, and alleviate hypertension and type 2 diabetes through the transcriptional regulation of lipid and glucose metabolism. Peroxisome proliferator-activated receptors (PPARs), sterol regulatory element binding proteins, liver X receptor alpha, retinoid X receptor alpha, farnesoid X receptor alpha, hepatic nuclear factor 4alpha and nuclear factor kappaB contribute to these nuclear actions of bioactive lipids with complex interactions. Recent studies have demonstrated the striking ability of bioactive lipids to regulate the production of physiologically active adipocytokines through PPARgamma activation. In particular, the function of bioactive lipids as dietary adiponectin inducers (dietary insulin sensitizers) deserves attention with respect to alleviation of metabolic syndrome by dietary manipulation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I318,I318)","v":17566551},{"$f":"(LEN($J318) - LEN(SUBSTITUTE(LOWER($J318),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J318) - LEN(SUBSTITUTE(LOWER($J318),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J318) - LEN(SUBSTITUTE(LOWER($J318),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B318:D318)","v":4},2007,"Serum retinol-binding protein: a link between obesity, insulin resistance, and type 2 diabetes.","Wolf",17566551,"Serum retinol-binding protein: a link between obesity, insulin resistance, and type 2 diabetes.    Abstract:   Insulin resistance occurs under conditions of obesity, metabolic syndrome, and type 2 diabetes. It was found to be accompanied by down-regulation of the insulin-responsive glucose transporter GLUT4. Decreased adipocyte GLUT4 caused secretion by adipocytes of the serum retinol-binding protein RBP4. Enhanced levels of serum RBP4 appeared to be the signal for the development of systemic insulin resistance both in experimental animals and in humans. In mice, increased levels of serum RBP4 led to impaired glucose uptake into skeletal muscle and increased glucose production by liver, whereas lowered serum RBP4 levels greatly enhanced insulin sensitivity. Thus, a link has been established between obesity and insulin resistance: RBP4, the vitamin A-transport protein secreted into the circulation by adipocytes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I319,I319)","v":17495601},{"$f":"(LEN($J319) - LEN(SUBSTITUTE(LOWER($J319),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J319) - LEN(SUBSTITUTE(LOWER($J319),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J319) - LEN(SUBSTITUTE(LOWER($J319),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B319:D319)","v":4},2007,"Lipids in the heart: a source of fuel and a source of toxins.","Park",17495601,"Lipids in the heart: a source of fuel and a source of toxins.    Abstract:    PURPOSE OF REVIEW : How do lipids arrive in the heart and other tissues? This review focuses on new information on pathways of lipid uptake into the heart.  RECENT FINDINGS : Fatty acids, the major cardiac fuel, are obtained from either lipoproteins or free fatty acids associated with albumin. The heart is the tissue with the most robust expression of lipoprotein lipase, and recent data attest to the importance of this enzyme in supplying optimal amounts of fatty acids for the heart. Genetic deletion of CD36 also shows that this transporter is important for cardiac uptake of lipids. Retinoid acquisition by the heart involves pathways parallel to those used for fatty acid uptake: a pathway for acquisition of core lipoprotein retinyl ester and another for nonlipoprotein retinol. Dilated lipotoxic cardiomyopathy is the consequence of excess lipid uptake.  SUMMARY : Genetic modifications that affect lipid uptake, oxidation, and storage are being exploited to elucidate the pathophysiology of cardiomyopathies and to discover how lipids relate to heart failure in humans with obesity and diabetes mellitus. This information is likely to lead to new diagnostic categories of cardiomyopathy and more pathophysiologically appropriate treatments."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I320,I320)","v":17368315},{"$f":"(LEN($J320) - LEN(SUBSTITUTE(LOWER($J320),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J320) - LEN(SUBSTITUTE(LOWER($J320),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J320) - LEN(SUBSTITUTE(LOWER($J320),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B320:D320)","v":4},2007,"Vitamin A-storing cells (stellate cells).","Senoo",17368315,"Vitamin A-storing cells (stellate cells).    Abstract:   Hepatic stellate cells (HSCs; also called as vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, Ito cells) exist in the space between parenchymal cells and sinusoidal endothelial cells of the hepatic lobule, and store 80% of vitamin A in the whole body as retinyl palmitate in lipid droplets in the cytoplasm. In physiological conditions, these cells play pivotal roles in the regulation of vitamin A homeostasis; they express specific receptors for retinol-binding protein (RBP), a binding protein specific for retinol, on their cell surface, and take up the complex of retinol and RBP by receptor-mediated endocytosis. HSCs in Arctic animals such as polar bears and Arctic foxes store 20-100 times the levels of vitamin A found in human or rat. HSCs play an important role in the liver regeneration. A gradient of vitamin A-storage capacity exists among the SCs in a hepatic lobule. The gradient was expressed as a symmetrical biphasic distribution starting at the periportal zone, peaking at the middle zone, and sloping down toward the central zone in the hepatic lobule. In pathological conditions such as liver fibrosis, HSCs lose vitamin A and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, and adhesive glycoproteins. Morphology of these cells also changes from the star-shaped SCs to that of fibroblasts or myofibroblasts. The three-dimensional structure of ECM components was found to regulate reversibly the morphology, proliferation, and functions of the HSCs. Molecular mechanisms in the reversible regulation of the SCs by ECM imply cell surface integrin-binding to ECM components followed by signal transduction processes and then cytoskeleton assembly. SCs also exist in extrahepatic organs such as pancreas, lung, kidney, and intestine. Hepatic and extrahepatic SCs form the SC system."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I321,I321)","v":16713393},{"$f":"(LEN($J321) - LEN(SUBSTITUTE(LOWER($J321),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J321) - LEN(SUBSTITUTE(LOWER($J321),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J321) - LEN(SUBSTITUTE(LOWER($J321),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B321:D321)","v":4},2006,"Trans fatty acids - effects on systemic inflammation and endothelial function.","Mozaffarian",16713393,"Trans fatty acids - effects on systemic inflammation and endothelial function.    Abstract:   Consumption of trans fatty acids (TFA) predicts higher risk of coronary heart disease, sudden death, and possibly diabetes mellitus. These associations are greater than would be predicted by effects of TFA on serum lipoproteins alone. Systemic inflammation and endothelial dysfunction may be involved in the pathogenesis of atherosclerosis, acute coronary syndromes, sudden death, insulin resistance, dyslipidemia, and heart failure. Evidence from both observational and experimental studies indicates that TFA are pro-inflammatory. Limited evidence suggests that pro-inflammatory effects may be stronger for trans isomers of linoleic acid (trans-C18:2) and oleic acid (trans-C18:1), rather than of palmitoleic acid (trans-C16:1), but further study of potential isomer-specific effects is needed. TFA also appear to induce endothelial dysfunction. The mechanisms underlying these effects are not well-established, but may involve TFA incorporation into endothelial cell, monocyte/macrophage, or adipocyte cell membranes (affecting membrane signaling pathway relating to inflammation) or ligand-dependent effects on peroxisome proliferator-activated receptor (PPAR) or retinoid X receptor (RXR) pathways. Activation of inflammatory responses and endothelial dysfunction may represent important mediating pathways between TFA consumption and risk of coronary heart disease, sudden death, and diabetes. Further study is indicated to define these effects of TFA and the implications of such effects for cardiovascular health."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I322,I322)","v":16285300},{"$f":"(LEN($J322) - LEN(SUBSTITUTE(LOWER($J322),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J322) - LEN(SUBSTITUTE(LOWER($J322),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J322) - LEN(SUBSTITUTE(LOWER($J322),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B322:D322)","v":4},2003,"[Beyond glucocorticoids, retinoids and vitamin D--the evolution of nuclear hormone type transcription factor targeting in the skin].","Schmuth",16285300,"[Beyond glucocorticoids, retinoids and vitamin D--the evolution of nuclear hormone type transcription factor targeting in the skin].    Abstract:   Nuclear hormone receptors are ligand-dependent transcription factors. The class of nuclear hormone receptors that form heterodimers with retinoid X receptor includes members that are well established targets of current dermatological therapeutics such as the retinoic acid receptor (RAR) and the vitamin D receptor (VDR) as well as more recently discovered receptors including the peroxisome proliferator-activated receptors (PPAR) and the liver X receptor (LXR). After ligand activation (often lipid metabolites), these intracellular receptors exert their functions by binding to specific response elements in regulatory sequences of target genes, preferentially those involved in differentiation, energy expenditure and lipid metabolism. A number of selective activators has been developed by combinational chemistry, initially for their anti-diabetic and lipid lowering properties as well as their ability to regulate bile acid and drug metabolism. However, these activators also have marked effects on cutaneous homeostasis. Therefore, these compounds have important implications for dermatological therapy. In this review, the clinical implications of the more recently discovered members of the nuclear hormone receptor family are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I323,I323)","v":16153329},{"$f":"(LEN($J323) - LEN(SUBSTITUTE(LOWER($J323),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J323) - LEN(SUBSTITUTE(LOWER($J323),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J323) - LEN(SUBSTITUTE(LOWER($J323),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B323:D323)","v":4},2005,"The nutrition and health transition in the North West Province of South Africa: a review of the THUSA (Transition and Health during Urbanisation of South Africans) study.","Vorster",16153329,"The nutrition and health transition in the North West Province of South Africa: a review of the THUSA (Transition and Health during Urbanisation of South Africans) study.    Abstract:    OBJECTIVE : To describe how urbanisation influences the nutrition and health transition in South Africa by using data from the THUSA (Transition and Health during Urbanisation of South Africans) study.  DESIGN : The THUSA study was a cross-sectional, comparative, population-based survey.  SETTING : The North West Province of South Africa.  SUBJECTS : In total, 1854 apparently healthy volunteers, men and women aged 15 years and older, from 37 randomly selected sites. Pregnant and lactating women, those with diagnosed chronic diseases and taking medication, with acute infections or inebriated were excluded but screened for hypertension and diabetes mellitus. Subjects were stratified into five groups representing different levels of urbanisation in rural and urban areas: namely, deep rural, farms, squatter camps, townships and towns/cities. OUTCOME MEASURES AND METHODS: Socio-economic and education profiles, dietary patterns, nutrient intakes, anthropometric and biochemical nutrition status, physical and mental health indicators, and risk factors for non-communicable diseases (NCDs) were measured using questionnaires developed or adapted and validated for this population, as well as appropriate, standardised methods for the biochemical analyses of biological samples.  RESULTS : Subjects from the rural groups had lower household incomes, less formal education, were shorter and had lower body mass indices than those in the urban groups. Urban subjects consumed less maize porridge but more fruits, vegetables, animal-derived foods and fats and oils than rural subjects. Comparing women from rural group 1 with the urban group 5, the following shifts in nutrient intakes were observed: % energy from carbohydrates, 67.4 to 57.3; from fats, 23.6 to 31.8; from protein, 11.4 to 13.4 (with an increase in animal protein from 22.2 to 42.6 g day(-1)); dietary fibre, 15.8 to 17.7 g day(-1); calcium, 348 to 512 mg day(-1); iron from 8.4 to 10.4 mg day(-1); vitamin A from 573 to 1246 mug retinol equivalents day(-1); and ascorbic acid from 30 to 83 mg day(-1). Serum total cholesterol, low-density lipoprotein cholesterol and plasma fibrinogen increased significantly across groups; systolic blood pressure gt;140 mmHg was observed in 10.4-34.8% of subjects in different groups and diabetes mellitus in 0.8-6.0% of subjects. Women in groups 1 to 5 had overweight plus obesity rates of 48, 53, 47, 61 and 61%, showing an increase with urbanisation. Subjects from group 2 (farm dwellers) showed the highest scores of psychopathology and the lowest scores of psychological well-being. The same subjects consistently showed the lowest nutrition status.  CONCLUSIONS : Urbanisation of Africans in the North West Province is accompanied by an improvement in micronutrient intakes and status, but also by increases in overweight, obesity and several risk factors for NCDs. It is recommended that intervention programmes to promote nutritional health should aim to improve micronutrient status further without leading to obesity. The role of psychological strengths in preventing the adverse effects of urbanisation on health needs to be examined in more detail."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I324,I324)","v":16101411},{"$f":"(LEN($J324) - LEN(SUBSTITUTE(LOWER($J324),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J324) - LEN(SUBSTITUTE(LOWER($J324),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J324) - LEN(SUBSTITUTE(LOWER($J324),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B324:D324)","v":4},2005,"Retinoids as therapeutic agents: today and tomorrow.","Vivat-Hannah",16101411,"Retinoids as therapeutic agents: today and tomorrow.    Abstract:   Retinoids have shown beneficial therapeutic effects in pre-clinical and animal models for multiple pathologic indications, however severe adverse effects, restricting dosage and efficacy of oral formulations limit their use in patients. The focus of this review includes the actual medicinal use of retinoids and chemical efforts to generate highly selective and less toxic synthetic retinoids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I325,I325)","v":15922656},{"$f":"(LEN($J325) - LEN(SUBSTITUTE(LOWER($J325),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J325) - LEN(SUBSTITUTE(LOWER($J325),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J325) - LEN(SUBSTITUTE(LOWER($J325),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B325:D325)","v":4},2005,"Transcriptional regulatory networks in lipid metabolism control ABCA1 expression.","Schmitz",15922656,"Transcriptional regulatory networks in lipid metabolism control ABCA1 expression.    Abstract:   The ATP-binding cassette transporters, ABCA1 and ABCG1, are major players in mediating cellular efflux of phospholipids and cholesterol to apoA-I containing lipoproteins including prebeta-HDL and alphaHDL and thereby exert important antiatherogenic properties. Although the exact mechanisms how ABC transporters mediate lipid transport are not completely resolved, recent evidence from several laboratories including ours suggests that vesicular transport processes involving different interactive proteins like beta2-syntrophin, alpha1-syntrophin, Lin7, and cdc42 are critically involved in cellular lipid homeostasis controlled by ABCA1 and ABCG1. Besides sterols and fatty acids as known physiological modulators of the LXR/RXR and SREBP pathways, a growing list of natural and synthetic substances and metabolic regulators such as retinoids, PPAR-ligands, hormones, cytokines, and drugs are particularly effective in modulating ABCA1 and ABCG1 gene expression. Although ABCA1 protein amounts are regulated at the level of stability, the majority of potent activating and repressing mechanisms on ABCA1 function directly act on the ABCA1 gene promoter. Among the inducing factors, liver-X-receptors (LXR), retinoic acid receptors (RAR) and peroxisome proliferator-activated receptors (PPARs) along with their coactivators provide an amplification loop for ABCA1 and ABCG1 expression. The ABCA1 promoter is further stimulated by the ubiquitous factor Sp1 and the hypoxia-induced factor 1 (HIF1), which bind to GC-boxes and the E-box, respectively. Shutdown of ABCA1 expression in the absence of sterols or in certain tissues is mediated by corepressor complexes involving unliganded LXR, sterol-regulatory element binding protein 2 (SREBP2), Sp3, and the SCAN-domain protein ZNF202, which also impacts nuclear receptor signaling. Thus, a highly sophisticated transcriptional network controls the balanced expression of ABCA1."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I326,I326)","v":14611947},{"$f":"(LEN($J326) - LEN(SUBSTITUTE(LOWER($J326),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J326) - LEN(SUBSTITUTE(LOWER($J326),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J326) - LEN(SUBSTITUTE(LOWER($J326),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B326:D326)","v":4},2003,"Inherited multifocal RPE-diseases: mechanisms for local dysfunction in global retinoid cycle gene defects.","Besch",14611947,"Inherited multifocal RPE-diseases: mechanisms for local dysfunction in global retinoid cycle gene defects.    Abstract:   Alterations of retinoid cycle genes are known to cause retinal diseases characterized by focal white dot fundus lesions. Fundus appearances reveal circumscribed RPE-changes, although generalized metabolic defects and global functional abnormalities are present. As a possible explanation, topographic inhomogeneities of the human photoreceptor mosaic and the role of a cone specific visual cycle will be discussed. Due to particular characteristics of photoreceptor subtypes as well as different pathways for photopigment regeneration the metabolic demand of individual RPE cells might differ. In quot;flecked retina diseasesquot; heterogeneity of metabolic demand in individual RPE cells could therefore be responsible for their multifocal appearance."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I327,I327)","v":14585312},{"$f":"(LEN($J327) - LEN(SUBSTITUTE(LOWER($J327),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J327) - LEN(SUBSTITUTE(LOWER($J327),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J327) - LEN(SUBSTITUTE(LOWER($J327),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B327:D327)","v":4},2003,"Vitamin A transport: in vitro models for the study of RBP secretion.","Bellovino",14585312,"Vitamin A transport: in vitro models for the study of RBP secretion.    Abstract:   Retinol-binding protein (RBP) is the specific plasma carrier of retinol, encharged of the vitamin transport from the liver to target cells. Ligand binding influences the RBP affinity for transthyretin (TTR), a homotetrameric protein involved in the RBP/TTR circulating complex, and the secretion rate of RBP. In fact, in vitamin A deficiency, the RBP release from the hepatocytes dramatically decreases and the protein accumulates in the cells, until retinol is available again. The mechanism is still not clear and new cellular models are needed to understand in detail how the soluble RBP can be retained inside the cell. In fish, a vitamin A transport system similar to that of higher vertebrates is emerging, although with significant differences."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I328,I328)","v":12412372},{"$f":"(LEN($J328) - LEN(SUBSTITUTE(LOWER($J328),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J328) - LEN(SUBSTITUTE(LOWER($J328),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J328) - LEN(SUBSTITUTE(LOWER($J328),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B328:D328)","v":4},2002,"[Retinoic acid nuclear receptors: a common molecular basis for liver cancer and acute promyelocytic leukemia].","Dejean",12412372,"[Retinoic acid nuclear receptors: a common molecular basis for liver cancer and acute promyelocytic leukemia].    Abstract:   Our team was at the origin of the discovery of the relationship between rearrangements in genes encoding the retinoic acid receptors and tumorigenesis in human. Studying the molecular basis for hepatitis B virus (HBV)-associated liver cancer, we demonstrated that the viral DNA can behave as an insertional mutagen. This work also led to the identification of the first gene (RAR beta) encoding a receptor for the active derivative of vitamin A, retinoid acid. In collaboration with L. Degos, we then demonstrated the existence a systematic alteration of another retinoic acid receptor, RAR alpha, in acute promyelocytic leukemia (APL). Most recent work allowed us to involve a novel subnuclear organelle, the so-called PML Nuclear Bodies, in APL pathogenesis, underlying the major role played by the functional organization of the nucleus both in the normal and the pathological cell."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I329,I329)","v":12324226},{"$f":"(LEN($J329) - LEN(SUBSTITUTE(LOWER($J329),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J329) - LEN(SUBSTITUTE(LOWER($J329),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J329) - LEN(SUBSTITUTE(LOWER($J329),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B329:D329)","v":4},2002,"Intracellular lipid binding proteins and nuclear receptors involved in branched-chain fatty acid signaling.","Adida",12324226,"Intracellular lipid binding proteins and nuclear receptors involved in branched-chain fatty acid signaling.    Abstract:   Branched-chain fatty acids are potent regulators of gene expression. Among them are the vitamin A-derived retinoic acids, which are involved in cell growth and differentiation, and the chlorophyll-derived phytol metabolites such as phytanic and pristanic acids, which affect catabolic lipid metabolism. Gene expression regulated by these signaling molecules is mediated by two protein families. These are, on the one hand, the intracellular lipid binding proteins, i.e. cellular retinoic acid binding protein and liver-type fatty acid binding protein, which are responsible for ligand-transport to the nucleus. On the other hand are the ligand-activated nuclear receptors, i.e. the retinoic acid receptors for retinoic acids and the peroxisome proliferator-activated receptors for the phytol metabolites. In this review, we discuss the cross-talk between the two protein families and how this cross-talk contributes to targeted signaling with branched-chain fatty acids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I330,I330)","v":11851828},{"$f":"(LEN($J330) - LEN(SUBSTITUTE(LOWER($J330),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J330) - LEN(SUBSTITUTE(LOWER($J330),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J330) - LEN(SUBSTITUTE(LOWER($J330),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B330:D330)","v":4},2001,"Chemoprevention of hepatocellular carcinoma: concept, progress and perspectives.","Okuno",11851828,"Chemoprevention of hepatocellular carcinoma: concept, progress and perspectives.    Abstract:   Hepatocellular carcinoma (HCC) often develops in patients with chronic liver diseases associated with hepatitis B (HBV) and hepatitis C (HCV) virus infections with high incidences. Particularly, post-therapeutic recurrence encountered after the curative treatment of the preceding HCC may limit the prognosis. Thus, prevention of HCC is of great significance. In the present review, immunopreventions with alpha-interferon and glycyrrhizin, as well as chemoprevention with acyclic retinoid, are discussed. alpha-Interferon prevents the development of HCC not only in patients with a long-term elimination of HCV (sustained virological responders), but in ones with normalized serum aminotransferases (sustained biochemical responders). Glycyrrhizin also suppresses serum aminotransferases and thereby prevents the tumor development, even though the compound does not have antiviral activity for HBV or HCV by itself. Therefore, suppression of hepatic necroinflammation by these drugs may serve to prevent hepatocarcinogenesis. In contrast, acyclic retinoid suppresses the post-therapeutic recurrence in cirrhotic patients who underwent curative treatment of preceding tumors. The retinoid induces the disappearance of serum lectin-reactive alpha-fetoprotein (AFP-L3), a tumor marker indicating the presence of unrecognizable tumors in the remnant liver, suggesting a deletion of such minute (pre)malignant clones (clonal deletion). As a molecular mechanism of the clonal deletion, a novel mechanism of apoptosis induction by the retinoid via tissue transglutaminase is implicated. In future, a combination of immunopreventive and chemopreventive therapies may give a clue to the further advances of cancer prevention, and thereby to the improvement of the prognosis of cirrhotic patients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I331,I331)","v":11791378},{"$f":"(LEN($J331) - LEN(SUBSTITUTE(LOWER($J331),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J331) - LEN(SUBSTITUTE(LOWER($J331),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J331) - LEN(SUBSTITUTE(LOWER($J331),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B331:D331)","v":4},2001,"[Prevention of recurrent hepatocellular carcinoma with retinoid].","Moriwaki",11791378,"[Prevention of recurrent hepatocellular carcinoma with retinoid].    Abstract:   The annual rate of recurrent hepatocellular carcinoma (HCC) after curative treatment of the initial tumor is reportedly as high as 20-25%. Such a high recurrence rate is responsible for the poor prognosis of patients with HCC. One third of the recurrent HCC arises from intrahepatic metastasis of the initial tumor, one third from multicentric carcinogenesis, and one third from unknown origin. In any type of recurrence, elimination of the transformed cell clone from the remnant liver is essential to prevent the recurrence of HCC. A retinoid analog, acyclic retinoid, induces differentiation and apoptosis of HCC cell lines in vitro. An early clinical trial showed a preventive effect of the compound on recurrent HCC. A further trial of acyclic retinoid is now under way."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I332,I332)","v":11594672},{"$f":"(LEN($J332) - LEN(SUBSTITUTE(LOWER($J332),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J332) - LEN(SUBSTITUTE(LOWER($J332),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J332) - LEN(SUBSTITUTE(LOWER($J332),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B332:D332)","v":4},2001,"Safety issues in isotretinoin therapy.","Hanson",11594672,"Safety issues in isotretinoin therapy.    Abstract:   Isotretinoin (Accutane, Roche Laboratories Inc, Nutley, NJ) is an important drug, not only for the treatment of severe acne, but also for other diagnoses and in chemoprevention settings. Because the use of isotretinoin is increasing, it is important for physicians to be aware of the adverse events, toxicities, and management issues related to its use. The most important issue is that of congenital defects, which has resulted in new pregnancy prevention policies and programs implemented by the manufacturer. A relatively new concern is that of depression associated with isotretinoin use, also resulting in new policies placed by the manufacturer and the FDA. The most common adverse effects observed during treatment are mucocutaneous and ocular in nature, but laboratory abnormalities and effects in the nervous, musculoskeletal, gastrointestinal, pulmonary, hematologic, and other systems are also described. Additionally, potential drug interactions, follow-up, and toxicity prevention measures are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I333,I333)","v":11520938},{"$f":"(LEN($J333) - LEN(SUBSTITUTE(LOWER($J333),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J333) - LEN(SUBSTITUTE(LOWER($J333),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J333) - LEN(SUBSTITUTE(LOWER($J333),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B333:D333)","v":4},2001,"Possible role of retinoids in hepatitis B virus-associated liver damage.","Mawson",11520938,"Possible role of retinoids in hepatitis B virus-associated liver damage.    Abstract:   Liver damage following hepatitis B virus (HBV) infection may be due to the action of retinoids as modulators of viral replication. The reduced rate of survival of liver grafts in patients with HBV infection could also be due to the continued presence of the virus, stimulated by retinoids in the graft tissue. Subject to obtaining empirical support for this hypothesis, the use of retinoid-blocking agents could be explored to reduce the risk of liver damage in HBV infection and to enhance the survival of liver grafts. Continued use of such agents may need to be used in conjunction with anti-viral modalities such as HBV hyperimmune globulin and lamivudine to prevent recurrent liver damage and to increase the long-term viability of the graft."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I334,I334)","v":11340613},{"$f":"(LEN($J334) - LEN(SUBSTITUTE(LOWER($J334),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J334) - LEN(SUBSTITUTE(LOWER($J334),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J334) - LEN(SUBSTITUTE(LOWER($J334),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B334:D334)","v":4},2001,"Retinoid chemoprevention in patients at high risk for skin cancer.","DiGiovanna",11340613,"Retinoid chemoprevention in patients at high risk for skin cancer.    Abstract:   Patients who develop large numbers of skin cancers suffer increased morbidity and mortality. A high skin cancer risk can result from inherited disorders such as xeroderma pigmentosum (abnormal repair of UV-induced DNA damage) or the nevoid basal cell carcinoma syndrome (tumor suppressor gene abnormality). The efficacy of systemic retinoid skin cancer chemoprevention was first demonstrated in these disorders. Since the mechanism of cancer prevention was not thought to involve correction of the underlying defect causing the disorder, individuals at high risk for new skin cancers from other causes may also benefit from this approach. With the success of organ transplantation, there is a growing population of transplant recipients living long, active lives who also have sustained chronic UV damage. This population is at high risk for developing aggressive squamous cell carcinomas. In this population, extensive skin involvement with human papilloma virus induced warts and actinic keratoses results in difficulty with diagnosis and monitoring for these dangerous malignancies. Patients who have received treatment with agents that cause DNA damage, such as X-radiation, may also have a high skin cancer risk. Retinoid chemoprevention may also be of benefit in the management of selected patients with these iatrogenic conditions. This evolving therapeutic role has heightened the need for the development of new retinoids, with more efficacy and less toxicity, for cancer chemoprevention."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I335,I335)","v":11160559},{"$f":"(LEN($J335) - LEN(SUBSTITUTE(LOWER($J335),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J335) - LEN(SUBSTITUTE(LOWER($J335),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J335) - LEN(SUBSTITUTE(LOWER($J335),LOWER(D$3),\"\")))/LEN(D$3)","v":4},{"$f":"SUM(B335:D335)","v":4},2001,"Diabetes and nutrition: the mitochondrial part.","Berdanier",11160559,"Diabetes and nutrition: the mitochondrial part.    Abstract:   Diabetes mellitus is the most common genetic disease in the Western world today. It is the phenotype for gt;150 genotypes. Each of these genotypes is characterized by impaired glucose tolerance and impaired control of intermediary metabolism. There are many strains of mice and rats that can be used to study diabetes in its various forms. One of these is the BHE/Cdb rat, which mimics the human phenotype with a mutation in the mitochondrial (mt) DNA. The result of such mutation is a loss in metabolic control with respect to the role of the mitochondria in this control. This review addresses those aspects of control that are exerted by mt oxidative phosphorylation (OXPHOS). Diet can have both genomic and nongenomic effects on OXPHOS. The type of dietary fat influences the fluidity of the mt membranes and hence, mt function. The dietary fat effect depends on the genetic background of the consumer. Diabetes-prone BHE/Cdb rats with base substitutions in the mt ATPase 6 gene are more likely to be influenced by the diet effect on mt membrane fluidity than are normal rats. Vitamin A also affects mt function through an effect on mt gene expression. BHE/Cdb rats have a greater need for vitamin A than normal rats and supplemental vitamin A appears to influence OXPHOS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I336,I336)","v":11032176},{"$f":"(LEN($J336) - LEN(SUBSTITUTE(LOWER($J336),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J336) - LEN(SUBSTITUTE(LOWER($J336),LOWER(C$3),\"\")))/LEN(C$3)","v":3},{"$f":"(LEN($J336) - LEN(SUBSTITUTE(LOWER($J336),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B336:D336)","v":4},2000,"Implications of peroxisome proliferator-activated receptors (PPARS) in development, cell life status and disease.","Keller",11032176,"Implications of peroxisome proliferator-activated receptors (PPARS) in development, cell life status and disease.    Abstract:   The past several years have seen an increasing interest in the peroxisome proliferator-activated receptors (PPARs). These transcriptional factors belong to the superfamily of the steroid/thyroid/retinoid receptors. They are activated by fatty acids or their metabolites as well as by different xenobiotic peroxisome proliferators. These receptors are expressed in both the embryo and the adult organism. They have been implicated in cell proliferation, differentiation and apoptosis. In this review, we will attempt to point out some of the more salient features of this expression pattern during development and the different steps of cell life. The current understanding of how PPARs are involved in some human diseases will also be described."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I337,I337)","v":10731492},{"$f":"(LEN($J337) - LEN(SUBSTITUTE(LOWER($J337),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J337) - LEN(SUBSTITUTE(LOWER($J337),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J337) - LEN(SUBSTITUTE(LOWER($J337),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B337:D337)","v":4},2000,"The vitamin A spectrum: from deficiency to toxicity.","Russell",10731492,"The vitamin A spectrum: from deficiency to toxicity.    Abstract:   Dark adaptation has been used as a tool for identifying patients with subclinical vitamin A deficiency. With this functional test it was shown that tissue vitamin A deficiency occurs over a wide range of serum vitamin A concentrations. However, serum vitamin A concentrations gt;1.4 micromol/L predict normal dark adaptation 95% of the time. Other causes of abnormal dark adaptation include zinc and protein deficiencies. Stable isotopes of vitamin A and isotope-dilution techniques were used recently to evaluate body stores of vitamin A and the efficacy of vitamin A intervention programs in field settings and are being used to determine the vitamin A equivalences of dietary carotenoids. Vitamin A toxicity was described in patients taking large doses of vitamin A and in patients with type I hyperlipidemias and alcoholic liver disease. Conversely, tissue retinoic acid deficiency was described in alcoholic rats as a result of hepatic vitamin A mobilization, impaired oxidation of retinaldehyde, and increased destruction of retinoic acid by P450 enzymes. Abnormal oxidation products of carotenoids can cause toxicity in animal models and may have caused the increased incidence of lung cancer seen in 2 epidemiologic studies of the effects of high-dose beta-carotene supplementation. Major issues that remain to be studied include the efficiency of conversion of carotenoids in whole foods to vitamin A by using a variety of foods in various field settings and whether intraluminal factors (eg, parasitism) and vitamin A status affect this conversion. In addition, the biological activity of carotenoid metabolites should be better understood, particularly their effects on retinoid signaling."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I338,I338)","v":10462436},{"$f":"(LEN($J338) - LEN(SUBSTITUTE(LOWER($J338),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J338) - LEN(SUBSTITUTE(LOWER($J338),LOWER(C$3),\"\")))/LEN(C$3)","v":3},{"$f":"(LEN($J338) - LEN(SUBSTITUTE(LOWER($J338),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B338:D338)","v":4},1999,"P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR.","Waxman",10462436,"P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR.    Abstract:   The biochemistry of foreign compound metabolism and the roles played by individual cytochrome P450 (CYP) enzymes in drug metabolism and in the toxification and detoxification of xenochemicals prevalent in the environment are important areas of molecular pharmacology and toxicology that have been widely studied over the past decade. Important advances in our understanding of the mechanisms through which foreign chemicals impact on these P450-dependent metabolic processes have been made during the past 2 years with several key discoveries relating to the mechanisms through which xenochemicals induce the expression of hepatic P450 enzymes. Roles for three quot;orphanquot; nuclear receptor superfamily members, designated CAR, PXR, and PPAR, in respectively mediating the induction of hepatic P450s belonging to families CYP2, CYP3, and CYP4 in response to the prototypical inducers phenobarbital (CAR), pregnenolone 16alpha-carbonitrile and rifampicin (PXR), and clofibric acid (PPAR) have now been established. Two other nuclear receptors, designated LXR and FXR, which are respectively activated by oxysterols and bile acids, also play a role in liver P450 expression, in this case regulation of P450 cholesterol 7alpha-hydroxylase, a key enzyme of bile acid biosynthesis. All five P450-regulatory nuclear receptors belong to the same nuclear receptor gene family (family NR1), share a common heterodimerization partner, retinoid X-receptor (RXR), and are subject to cross-talk interactions with other nuclear receptors and with a broad range of other intracellular signaling pathways, including those activated by certain cytokines and growth factors. Endogenous ligands of each of those nuclear receptors have been identified and physiological receptor functions are emerging, leading to the proposal that these receptors may primarily serve to modulate hepatic P450 activity in response to endogenous dietary or hormonal stimuli. Accordingly, P450 induction by xenobiotics may in some cases lead to a perturbation of endogenous regulatory circuits with associated pathophysiological consequences."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I339,I339)","v":10229917},{"$f":"(LEN($J339) - LEN(SUBSTITUTE(LOWER($J339),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J339) - LEN(SUBSTITUTE(LOWER($J339),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J339) - LEN(SUBSTITUTE(LOWER($J339),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B339:D339)","v":4},1999,"Modulation of genotoxic and related effects by carotenoids and vitamin A in experimental models: mechanistic issues.","De Flora",10229917,"Modulation of genotoxic and related effects by carotenoids and vitamin A in experimental models: mechanistic issues.    Abstract:   The mechanisms involved in the modulation of genotoxic and related effects by carotenoids and vitamin A were inferred from a critical review of an ad hoc constructed database. Almost 500 results were generated in experimental models evaluating the activity of 32 structurally, metabolically and functionally related nutrients, including beta-carotene and 26 other carotenoids, retinol, retinal, all-trans-retinoic acid and retinyl esters. As many as 67 experimental test systems, either in vitro or in vivo, used a variety of cellular targets and/or end-points suggestive of distinctive mechanisms of action. The bulk of available data support the view that carotenoids and vitamin A do not induce genotoxic effects per se. Even in the absence of any genotoxic agent, these nutrients appeared, on the contrary, to display some mechanisms which play protective roles in tumor promotion and progression, such as inhibition of N-myc gene expression resulting in antiproliferative effects, up-regulation of cell-to-cell communication, an increase in connexin 43 gene expression, a decrease in the spontaneous cell transformation frequency and induction of differentiation in vitro. A large number of studies investigated the modulation by carotenoids and vitamin A of genotoxic and related effects produced by 69 genotoxicants, including biological agents, physical agents, chemical compounds and complex mixtures. In spite of some discrepant data, the general trend was that both carotenoids and vitamin A are poorly effective in acting as nucleophiles, nor do they appear to substantially interfere with the induction or repair of DNA damage produced by direct-acting agents. In contrast vitamin A and carotenoids, irrespective of their provitamin A role, in most studies inhibited those genotoxicants which require metabolic activation to electrophilic derivatives in either bacterial or mammalian cells. Coupled with biochemical data, the distinctive patterns observed with genotoxic agents belonging to different chemical classes suggest a complex modulation of both phase I and phase II enzymes involved in the metabolism of xenobiotics. Furthermore, carotenoids and vitamin A shared other protective mechanisms, such as scavenging of genotoxic oxygen species, modulation of signal transduction pathways, inhibition of cell transformation induced by physical and chemical agents, and facilitation of intercellular communication inhibited by genotoxic compounds. Therefore, carotenoids and vitamin A appear to work via multiple mechanisms, which would support a potential protective role in cancer initiation and in the pathogenesis of other mutation-related diseases. These conclusions are consistent with the recognized cancer-preventive activity of these nutrients in certain animal models and with the evidence provided by observational epidemiological studies, which suggested cancer-protective effects at many sites as related to their dietary intake or plasma levels. However, all these lines of evidence and mechanistically based premises contrast with the unexpected outcome of recent clinical intervention trials, which raised the concern that supplemental use of beta-carotene and vitamin A may increase the risk of lung cancer amongst high risk individuals such as tobacco smokers and asbestos-exposed workers."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I340,I340)","v":8801177},{"$f":"(LEN($J340) - LEN(SUBSTITUTE(LOWER($J340),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J340) - LEN(SUBSTITUTE(LOWER($J340),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J340) - LEN(SUBSTITUTE(LOWER($J340),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B340:D340)","v":4},1996,"Altered retinoic acid receptors.","de Thé",8801177,"Altered retinoic acid receptors.    Abstract:   Structurally and functionally altered retinoic acid receptors have been associated with rare human neoplasms: acute promyelocytic leukemia and hepatocellular carcinoma. Whereas the retinoic acid receptor beta (RARbeta) rearrangement in hepatocellular carcinoma is unique, in acute promyelocytic leukemia (APL), RARalpha fusion to the promyelocytic leukemia (PML) gene by the t(15;17) translocation is a general feature of the disease. APL is an important model in cancer biology because retinoic acid induces complete remissions in this malignancy, providing the first example of differentiation therapy and of an antineoplastic drug directly targeted at the underlying genetic lesion. The molecular basis of PML/RARalpha fusion leukemogenesis is discussed with respect to dominant negative inhibition of nuclear receptor and PML functions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I341,I341)","v":7735895},{"$f":"(LEN($J341) - LEN(SUBSTITUTE(LOWER($J341),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J341) - LEN(SUBSTITUTE(LOWER($J341),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J341) - LEN(SUBSTITUTE(LOWER($J341),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B341:D341)","v":4},1994,"Properties and biogenesis of peroxisomes.","Chandoga",7735895,"Properties and biogenesis of peroxisomes.    Abstract:   Many species of monocellular eukaryots as well as the majority of animal cell and plant tissues show the presence of peroxisomes or microperoxisomes. Their size, shape and internal organization may differ in various cellular types significantly. Typical components of animal cell peroxisomes are the membrane, matrix, low density compartment enriched in lipids, and the compartment containing D-amino acid oxidase. The group of four enzymes (catalase, D-amino acid oxidase, L-alpha-OH-acid oxidase) the location of which had been originally discovered in peroxisomes of hepatocytes of rodents was later widened by approximately forty further enzymes. It is though probable that evolution brought along a reduction and loss of various metabolic functions of peroxisomes and a decrease in the number of enzymes. Peroxisomes are characterized by high variability of the enzymatic content in dependence on the nutritional conditions and the effect of xenobiotics. Fasting, diabetes mellitus, high-lipid diet, peroxisome proliferators induce several peroxisomal enzymes, especially fatty acids beta-oxidation. The mechanism of the impact of heterogeneous substances on the gene transcription has been clarified recently. Substances as fibrates, retinoic acid, polyunsaturated fatty acids activate specific types of receptors-PPAR (peroxisome proliferators activated receptors) belonging to the superfamily of receptors activated by steroid hormones, thyroid hormones, and D-vitamins. A simultaneous induction of several peroxisomal enzymes can be achieved by the linkage between PPAR and specific areas of promotors of particular genes. Such areas-PPREs (peroxisomal proliferator response elements) with five repeated TGA(A/C/T)CT hexanucleotide sequences separated by one nucleotide were discovered in several peroxisomal genes. It is assumed that the stimulation of transcription can be achieved by the linkage between homodimers, and heterodimers of nuclear receptors on these DNA sections. The majority of peroxisomal proteins is synthesised in the cytoplasm, namely on polysomes being in matured forms. Unimpaired biogenesis of peroxisomes requires membrane transport proteins and presence of signal in polypeptide chain of imported proteins (PTS-peroxisomal targeting signal). The function of PTS in many peroxisomal proteins is fulfilled by the C-terminal tripeptide which is composed of amino acids, namely serine, lysine, and leucine (SKL-tripeptide), respectively by a tripeptide with a very similar composition in amino acids. Aside from this signal, still another signal exists, which is located at the N-end of peroxisomal proteins. The role of membrane proteins 70, 35, 256, 22, 15 kDa, is being discussed in relationship to the functions and diseases caused by impaired biogenesis of peroxisomes. (Fig. 4, Ref. 128.)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I342,I342)","v":1463588},{"$f":"(LEN($J342) - LEN(SUBSTITUTE(LOWER($J342),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J342) - LEN(SUBSTITUTE(LOWER($J342),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J342) - LEN(SUBSTITUTE(LOWER($J342),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B342:D342)","v":4},1992,"Vitamin neurotoxicity.","Snodgrass",1463588,"Vitamin neurotoxicity.    Abstract:   Vitamins contain reactive functional groups necessary to their established roles as coenzymes and reducing agents. Their reactive potential may produce injury if vitamin concentration, distribution, or metabolism is altered. However, identification of vitamin toxicity has been difficult. The only well-established human vitamin neurotoxic effects are those due to hypervitaminosis A (pseudotumor cerebri) and pyridoxine (sensory neuropathy). In each case, the neurological effects of vitamin deficiency and vitamin excess are similar. Closely related to the neurological symptoms of hypervitaminosis A are symptoms including headache, pseudotumor cerebri, and embryotoxic effects reported in patients given vitamin A analogs or retinoids. Most tissues contain retinoic acid (RA) and vitamin D receptors, members of a steroid receptor superfamily known to regulate development and gene expression. Vitamin D3 effects on central nervous system (CNS) gene expression are predictable, in addition to the indirect effects owing to its influence on calcium and phosphorus homeostasis. Folates and thiamine cause seizures and excitation when administered in high dosage directly into the brain or cerebrospinal fluid (CSF) of experimental animals but have rarely been reported to cause human neurotoxicity, although fatal reactions to i.v. thiamine are well known. Ascorbic acid influences CNS function after peripheral administration and influences brain cell differentiation and 2-deoxyglucose accumulation by cultured glial cells. Biotin influences gene expression in animals that are not vitamin-deficient and alters astrocyte glucose utilization. The multiple enzymes and binding proteins involved in regeneration of retinal vitamin A illustrate the complexity of vitamin processing in the body. Vitamin A toxicity is also a good general model of vitamin neurotoxicity, because it shows the importance of the ratio of vitamin and vitamin-binding proteins in producing vitamin toxicity and of CNS permeability barriers. Because vitamin A and analogs enter the CNS better than most vitamins, and because retinoids have many effects on enzyme activity and gene expression, Vitamin A neurotoxicity is more likely than that of most, perhaps all other vitamins. Megadose vitamin therapy may cause injury that is confused with disease symptoms. High vitamin intake is more hazardous to peripheral organs than to the nervous system, because CNS vitamin entry is restricted. Vitamin administration into the brain or CSF, recommended in certain disease states, is hazardous and best avoided. The lack of controlled trials prevents us from defining the lowest human neurotoxic dose of any vitamin. Large differences in individual susceptibility to vitamin neurotoxicity probably exist, and ordinary vitamin doses may harm occasional patients with genetic disorders.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I343,I343)","v":2976328},{"$f":"(LEN($J343) - LEN(SUBSTITUTE(LOWER($J343),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J343) - LEN(SUBSTITUTE(LOWER($J343),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J343) - LEN(SUBSTITUTE(LOWER($J343),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B343:D343)","v":4},1988,"New retinoids for dermatologic diseases. Uses and toxicity.","Lowe",2976328,"New retinoids for dermatologic diseases. Uses and toxicity.    Abstract:   Systemic administration of retinoids is frequently associated with mucocutaneous side effects, liver toxicity, and abnormalities of the serum lipid profile. Currently, the main factors limiting more common use of retinoids are their teratogenicity and chronic bone toxicity. Treatment with retinoids requires appropriate selection of patients, careful periodic monitoring of the clinical response, and appropriate laboratory tests. Careful therapeutic management is necessary in order to prevent or minimize side effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I344,I344)","v":3546414},{"$f":"(LEN($J344) - LEN(SUBSTITUTE(LOWER($J344),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J344) - LEN(SUBSTITUTE(LOWER($J344),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J344) - LEN(SUBSTITUTE(LOWER($J344),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B344:D344)","v":4},1987,"Etretinate therapy.","Ellis",3546414,"Etretinate therapy.    Abstract:   Etretinate is a retinoid given orally for the treatment of psoriasis and many other dermatoses. Side effects are similar to the hypervitaminosis A condition. Etretinate represents a substantial advance in dermatologic therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I345,I345)","v":6385136},{"$f":"(LEN($J345) - LEN(SUBSTITUTE(LOWER($J345),LOWER(B$3),\"\")))/LEN(B$3)","v":4},{"$f":"(LEN($J345) - LEN(SUBSTITUTE(LOWER($J345),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J345) - LEN(SUBSTITUTE(LOWER($J345),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B345:D345)","v":4},1984,"Vitamin A and carotene in animal nutrition.","Bondi",6385136,"Vitamin A and carotene in animal nutrition.    Abstract:   Vitamin A, an unsaturated 20 carbon cyclic alcohol, subserves a number of important physiological functions. However, the biochemical basis of these roles is not well understood. The main sources of retinol are liver, egg yolk and milk fat. Several carotenoids show vitamin A activity. The conversion of beta-carotene to retinol is affected by copper-containing dioxygenase and zinc-containing retinene reductase. The efficiency of conversion varies in different species. The latter is defined in units as the daily dose required to produce a weight gain of 3 g/week in young rats between the 4th and 8th week. Retinol is unstable on exposure to light or heat, particularly in the presence of heavy metal ions and water. Much recent work has focused on the absorption, metabolism and excretion of vitamin A. It is now recognized that plasma vitamin A levels do not reflect the nutritional status except in severe hypo- and hypervitaminosis A. Also, many dietary factors may influence vitamin A metabolism. These basic and applied aspects of vitamin A are reviewed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I346,I346)","v":27787652},{"$f":"(LEN($J346) - LEN(SUBSTITUTE(LOWER($J346),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J346) - LEN(SUBSTITUTE(LOWER($J346),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J346) - LEN(SUBSTITUTE(LOWER($J346),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B346:D346)","v":3},2016,"Transcriptional control of apoptotic cell clearance by macrophage nuclear receptors.","Röszer",27787652,"Transcriptional control of apoptotic cell clearance by macrophage nuclear receptors.    Abstract:    NlmCategory=UNASSIGNEDApoptotic cell clearance by macrophages is key for normal tissue development and homeostasis. Nuclear receptors, such as peroxisome proliferator activated receptors (PPARs), liver X receptor (LXR), retinoic acid receptor (RAR), retinoid X receptor (RXR) and glucocorticoid receptor (GR) orchestrate this vital process. The underlying mechanism involves the transcriptional control of key genes of apoptotic cell recognition and internalization, such as Cd36, Mertk, Axl, C1qa, Tgm2, Abca1. In addition, apoptotic cell uptake leads to M2 activation of macrophages, and this process is also controlled at the gene transcription level by nuclear receptors. Apoptotic cells provide signals for nuclear receptors, which in turn accelerate the safe disposal of apoptotic debris, which eventually allows renewal of the tissues, and impedes the development of inflammation and autoimmunity against dying cells. Nuclear receptor signaling is vulnerable to endocrine disruptors, which may interfere with the ability of macrophages to phagocytose and acquire M2 activation. This review summarizes the mechanisms, which allow nuclear receptors to control apoptotic cell clearance by macrophages."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I347,I347)","v":26894299},{"$f":"(LEN($J347) - LEN(SUBSTITUTE(LOWER($J347),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J347) - LEN(SUBSTITUTE(LOWER($J347),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J347) - LEN(SUBSTITUTE(LOWER($J347),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B347:D347)","v":3},2016,"Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis.","Coelho",26894299,"Mechanism of Action and Clinical Application of Tafamidis in Hereditary Transthyretin Amyloidosis.    Abstract:   Transthyretin (TTR) transports the retinol-binding protein-vitamin A complex and is a minor transporter of thyroxine in blood. Its tetrameric structure undergoes rate-limiting dissociation and monomer misfolding, enabling TTR to aggregate or to become amyloidogenic. Mutations in the TTR gene generally destabilize the tetramer and/or accelerate tetramer dissociation, promoting amyloidogenesis. TTR-related amyloidoses are rare, fatal, protein-misfolding disorders, characterized by formation of soluble aggregates of variable structure and tissue deposition of amyloid. The TTR amyloidoses present with a spectrum of manifestations, encompassing progressive neuropathy and/or cardiomyopathy. Until recently, the only accepted treatment to halt progression of hereditary TTR amyloidosis was liver transplantation, which replaces the hepatic source of mutant TTR with the less amyloidogenic wild-type TTR. Tafamidis meglumine is a rationally designed, non-NSAID benzoxazole derivative that binds with high affinity and selectivity to TTR and kinetically stabilizes the tetramer, slowing monomer formation, misfolding, and amyloidogenesis. Tafamidis is the first pharmacotherapy approved to slow the progression of peripheral neurologic impairment in TTR familial amyloid polyneuropathy. Here we describe the mechanism of action of tafamidis and review the clinical data, demonstrating that tafamidis treatment slows neurologic deterioration and preserves nutritional status, as well as quality of life in patients with early-stage Val30Met amyloidosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I348,I348)","v":26427449},{"$f":"(LEN($J348) - LEN(SUBSTITUTE(LOWER($J348),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J348) - LEN(SUBSTITUTE(LOWER($J348),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J348) - LEN(SUBSTITUTE(LOWER($J348),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B348:D348)","v":3},2016,"Targeting the Proteostasis Network in Rhodopsin Retinitis Pigmentosa.","Parfitt",26427449,"Targeting the Proteostasis Network in Rhodopsin Retinitis Pigmentosa.    Abstract:   Mutations in rhodopsin are one of the most common causes of retinitis pigmentosa (RP). Misfolding of rhodopsin can result in disruptions in cellular protein homeostasis, or proteostasis. There is currently no available treatment for RP. In this review, we discuss the different approaches currently being investigated for treatment of rhodopsin RP, focusing on the potential of manipulation of the proteostasis network as a therapeutic approach to combat retinal degeneration."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I349,I349)","v":26330146},{"$f":"(LEN($J349) - LEN(SUBSTITUTE(LOWER($J349),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J349) - LEN(SUBSTITUTE(LOWER($J349),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J349) - LEN(SUBSTITUTE(LOWER($J349),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B349:D349)","v":3},2015,"Hypercarotenodermia in Zambia: which children turned orange during mango season?","Tanumihardjo",26330146,"Hypercarotenodermia in Zambia: which children turned orange during mango season?    Abstract:   Vitamin A (VA) deficiency is a public health problem in many countries. The World Health Organization recommends high-dose VA supplements to children aged 6-59 months based on unequivocal evidence that supplements decreased mortality risk. VA supplements were meant as a temporary intervention until more sustainable approaches could be implemented. Fortification of processed foods with preformed VA is a means to improve VA status. The most recent addition of retinyl palmitate to cooking oil in countries that may also fortify margarine and milk will undoubtedly have a positive impact on VA status. However, quantitative measures have not been used to assess the underlying VA status of the groups who have adopted widespread fortification. The addition of preformed VA to otherwise adequate diets in VA may cause excessive total body stores. Monitoring population status will require accurate VA assessment to ensure that hypervitaminosis does not prevail. This perspective describes a cohort of rural Zambian children who have adequate diets in VA, mostly as provitamin A carotenoids; who were given high-dose VA supplements till the age of 5 years; who have access to VA-fortified sugar; and whose mothers had access to VA-fortified sugar throughout pregnancy and lactation. Many of these children turned orange during mango season, and this phenomenon occurred at estimated liver reserve concentrations gt;1 μmol retinol equivalents/g liver. It will be necessary to continue to monitor VA status, including all sectors of the population that have access to successful interventions, to optimize health with the intent to lower retinol content of fortified foods or better target VA supplementation to areas of most need."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I350,I350)","v":26136304},{"$f":"(LEN($J350) - LEN(SUBSTITUTE(LOWER($J350),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J350) - LEN(SUBSTITUTE(LOWER($J350),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J350) - LEN(SUBSTITUTE(LOWER($J350),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B350:D350)","v":3},2015,"Is retinol binding protein 4 a link between adiposity and cancer?","Noy",26136304,"Is retinol binding protein 4 a link between adiposity and cancer?    Abstract:   Retinol binding protein 4 (RBP4) is synthesized in the liver where it binds vitamin A, retinol, and transports it to tissues throughout the body. It has been shown in some studies that the level of circulating RBP4 increases with body mass, and the protein has been implicated as a mediator in the development of insulin resistance and the metabolic disease. Adipose tissue serves as another site of RBP4 synthesis, accounting for its designation as an adipokine. In addition to its function as a transport protein, RBP4 serves as a signaling molecule which, by binding to the membrane receptor STRA6, triggers downstream activation of pro-oncogenic pathways including JAK2/STAT3/5. Taken together, available information suggests the possibility that RBP4 may be a link between obesity and cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I351,I351)","v":25963488},{"$f":"(LEN($J351) - LEN(SUBSTITUTE(LOWER($J351),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J351) - LEN(SUBSTITUTE(LOWER($J351),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J351) - LEN(SUBSTITUTE(LOWER($J351),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B351:D351)","v":3},2015,"Vitamin A as a key regulator of obesity amp; its associated disorders: Evidences from an obese rat model.","Jeyakumar",25963488,"Vitamin A as a key regulator of obesity amp; its associated disorders: Evidences from an obese rat model.    Abstract:   During the last century, vitamin A has evolved from its classical role as a fat-soluble vitamin and attained the status of para-/autocrine hormone. Besides its well-established role in embryogenesis, growth and development, reproduction and vision, vitamin A has also been implicated in several other physiological processes. Emerging experimental evidences emphasize adipose tissue as an active endocrine organ with great propensity to continuous growth (throughout life). Due to various genetic and lifestyle factors, excess energy accumulates in adipose tissue as fat, resulting in obesity and other complications such as type 2 diabetes, hypertension, and cardiovascular disease. Recent in vitro and in vivo studies have shed light on vitamin A metabolites; retinaldehyde and retinoic acid and participation of their pathway proteins in the regulation of adipose tissue metabolism and thus, obesity. In this context, we discuss here some of our important findings, which establish the role of vitamin A (supplementation) in obesity and its associated disorders by employing an obese rat model; WNIN/Ob strain."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I352,I352)","v":25721497},{"$f":"(LEN($J352) - LEN(SUBSTITUTE(LOWER($J352),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J352) - LEN(SUBSTITUTE(LOWER($J352),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J352) - LEN(SUBSTITUTE(LOWER($J352),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B352:D352)","v":3},2015,"Carotenoids and their conversion products in the control of adipocyte function, adiposity and obesity.","Bonet",25721497,"Carotenoids and their conversion products in the control of adipocyte function, adiposity and obesity.    Abstract:   A novel perspective of the function of carotenoids and carotenoid-derived products - including, but not restricted to, the retinoids - is emerging in recent years which connects these compounds to the control of adipocyte biology and body fat accumulation, with implications for the management of obesity, diabetes and cardiovascular disease. Cell and animal studies indicate that carotenoids and carotenoids derivatives can reduce adiposity and impact key aspects of adipose tissue biology including adipocyte differentiation, hypertrophy, capacity for fatty acid oxidation and thermogenesis (including browning of white adipose tissue) and secretory function. Epidemiological studies in humans associate higher dietary intakes and serum levels of carotenoids with decreased adiposity. Specifically designed human intervention studies, though still sparse, indicate a beneficial effect of carotenoid supplementation in the accrual of abdominal adiposity. The objective of this review is to summarize recent findings in this area, place them in physiological contexts, and provide likely regulatory schemes whenever possible. The focus will be on the effects of carotenoids as nutritional regulators of adipose tissue biology and both animal and human studies, which support a role of carotenoids and retinoids in the prevention of abdominal adiposity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I353,I353)","v":25434990},{"$f":"(LEN($J353) - LEN(SUBSTITUTE(LOWER($J353),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J353) - LEN(SUBSTITUTE(LOWER($J353),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J353) - LEN(SUBSTITUTE(LOWER($J353),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B353:D353)","v":3},2015,"Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites.","Zhang",25434990,"Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites.    Abstract:   Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRα ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXRα remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXRα can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXRα have been identified, which mediate the regulation of the nongenomic actions of RXRα by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXRα in the RXRα signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXRα regulation by targeting alternate binding sites on its surface."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I354,I354)","v":25372429},{"$f":"(LEN($J354) - LEN(SUBSTITUTE(LOWER($J354),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J354) - LEN(SUBSTITUTE(LOWER($J354),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J354) - LEN(SUBSTITUTE(LOWER($J354),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B354:D354)","v":3},2014,"Vitamin A deficiency and xerophthalmic fundus in autoimmune hepatitis and cirrhosis.","Chow",25372429,"Vitamin A deficiency and xerophthalmic fundus in autoimmune hepatitis and cirrhosis.    Abstract:    PURPOSE : To report a patient with autoimmune hepatitis and cirrhosis who was diagnosed with severe vitamin A deficiency based on the findings of xerophthalmic fundus.  METHODS : Retrospective chart review.  PATIENT : A 36-year-old African American woman who had a history of autoimmune hepatitis and cirrhosis presents with peripheral retinal white spots, which led to the diagnosis of vitamin A deficiency.  RESULTS : The patient presented to the eye clinic for intermittent blurry vision 3 months after the diagnosis of liver cirrhosis secondary to autoimmune hepatitis since age 15. She also underwent partial large and small intestine resection as an infant for Hirschsprung disease. Anterior segment examination was significant for severe punctate epithelial erosions and posterior segment examination was significant for extensive white spots in the peripheral retina in both eyes. Workup showed near nondetectable levels of vitamin A (lt;0.06 mg/L, normal 0.3-1.2 mg/L) and retinyl palmitate (lt;0.02 mg/L, normal gt; 0.2 mg/L). After treatment with 200,000 IU of vitamin A orally, the white spots slowly resolved in ∼6 months. She never developed nyctalopia and her dry eye symptoms completely resolved.  CONCLUSION : Although rare, vitamin A deficiency should be considered in patients with liver cirrhosis especially in those with a history of intestinal surgeries. Early diagnosis and treatment with vitamin A supplementation can reverse the signs and symptoms of xerophthalmia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I355,I355)","v":25050077},{"$f":"(LEN($J355) - LEN(SUBSTITUTE(LOWER($J355),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J355) - LEN(SUBSTITUTE(LOWER($J355),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J355) - LEN(SUBSTITUTE(LOWER($J355),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B355:D355)","v":3},2014,"Intrauterine nutrition: long-term consequences for vascular health.","Szostak-Wegierek",25050077,"Intrauterine nutrition: long-term consequences for vascular health.    Abstract:   There is a growing body of evidence that improper intrauterine nutrition may negatively influence vascular health in later life. Maternal malnutrition may result in intrauterine growth retardation and, in turn, metabolic disorders such as insulin resistance, diabetes, hypertension, and dyslipidemia, and also enhanced risk of atherosclerosis and cardiovascular death in the offspring. Energy and/or protein restriction is the most critical determinant for fetal programming. However, it has also been proposed that intrauterine n-3 fatty acid deficiency may be linked to later higher blood pressure levels and reduced insulin sensitivity. Moreover, it has been shown that inadequate supply of micronutrients such as folate, vitamin B12, vitamin A, iron, magnesium, zinc, and calcium may contribute to impaired vascular health in the progeny. In addition, hypertensive disorders of pregnancy that are linked to impaired placental blood flow and suboptimal fetal nutrition may also contribute to intrauterine growth retardation and aggravated cardiovascular risk in the offspring. On the other hand, maternal overnutrition, which often contributes to obesity and/or diabetes, may result in macrosomia and enhanced cardiometabolic risk in the offspring. Progeny of obese and/or diabetic mothers are relatively more prone to develop obesity, insulin resistance, diabetes, and hypertension. It was demonstrated that they may have permanently enhanced appetites. Their atheromatous lesions are usually more pronounced. It seems that, particularly, a maternal high-fat/junk food diet may be detrimental for vascular health in the offspring. Fetal exposure to excessive levels of saturated fatty and/or n-6 fatty acids, sucrose, fructose and salt, as well as a maternal high glycemic index diet, may also contribute to later enhanced cardiometabolic risk."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I356,I356)","v":24962879},{"$f":"(LEN($J356) - LEN(SUBSTITUTE(LOWER($J356),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J356) - LEN(SUBSTITUTE(LOWER($J356),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J356) - LEN(SUBSTITUTE(LOWER($J356),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B356:D356)","v":3},2014,"Architecture of DNA Bound RAR heterodimers.","Rochel",24962879,"Architecture of DNA Bound RAR heterodimers.    Abstract:   Nuclear Retinoic Acid receptors (RARs) consist of three subtypes, α, β, and γ, encoded by separate genes. They function as ligand-dependent transcriptional regulators, forming heterodimers with Retinoid X receptors (RXRs). RARs mediate the effects of retinoic acid (RA), the active metabolite of Vitamin A, and regulate many biological functions such as embryonic development, organogenesis, homeostasis, vision, immune functions, and reproduction. During the two last decades, a number of in-depth structure-function relationship studies have been performed, in particular with drug design perspectives in the therapeutics for cancer, dermatology, metabolic disease, and other human diseases. Recent structural results concerning integral receptors in diverse functional states, obtained using a combination of different methods, allow a better understanding of the mechanisms involved in molecular regulation. The structural data highlight the importance of DNA sequences for binding selectivity and the role of promoter response elements in the spatial organization of the protein domains into functional complexes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I357,I357)","v":24928143},{"$f":"(LEN($J357) - LEN(SUBSTITUTE(LOWER($J357),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J357) - LEN(SUBSTITUTE(LOWER($J357),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J357) - LEN(SUBSTITUTE(LOWER($J357),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B357:D357)","v":3},2015,"ZebRA: An overview of retinoic acid signaling during zebrafish development.","Samarut",24928143,"ZebRA: An overview of retinoic acid signaling during zebrafish development.    Abstract:   Retinoic acid (RA), the main active vitamin A derivative, is crucial for embryo development, regulating cellular processes, embryo patterning and organogenesis. Many studies performed in mammalian or avian models have successfully undertaken the investigation of the role played by RA during embryogenesis. Since the early 1980s, the zebraﬁsh (Danio rerio) has emerged as a powerful developmental model to study the in vivo role of RA during embryogenesis. Unlike mammalian models, zebraﬁsh embryogenesis is external, not only allowing the observation of the translucent embryo from the earliest steps but also providing an easily accessible system for pharmacological treatment or genetic approaches. Therefore, zebraﬁsh research largely participates in deciphering the role of RA during development. This review aims at illustrating different concepts of RA signaling based on the research performed on zebraﬁsh. Indeed, RA action relies on a multitude of cross-talk with other signaling pathways and requires a coordinated, dynamic and ﬁne-regulation of its level and activity in both temporal and spatial dimensions. This review also highlights major advances that have been discovered using zebraﬁsh such as the observation of the RA gradient in vivo for the ﬁrst time, the effects of RA signaling in brain patterning, its role in establishing left-right asymmetry and its effects on the development of a variety of organs and tissues including the heart, blood, bone and fat. This review demonstrates that the zebraﬁsh is a convenient and powerful model to study retinoic acid signaling during vertebrate embryogenesis. This article is part of a Special Issue entitled: Nuclear receptors in animal development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I358,I358)","v":24695022},{"$f":"(LEN($J358) - LEN(SUBSTITUTE(LOWER($J358),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J358) - LEN(SUBSTITUTE(LOWER($J358),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J358) - LEN(SUBSTITUTE(LOWER($J358),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B358:D358)","v":3},2014,"Liver X receptor: a cardinal target for atherosclerosis and beyond.","Parikh",24695022,"Liver X receptor: a cardinal target for atherosclerosis and beyond.    Abstract:   The nuclear receptor liver X receptor [LXR] is activated by endogenous oxidized derivatives of cholesterol. It constitutes a critical receptor in the regulation of various physiological functions related to the development of metabolic and cardiovascular diseases, such as atherosclerosis and diabetes, as well as various other disorders. Both isoforms of LXR, LXRα [NR1H3] and LXRβ [NR1H2], form heterodimers with the isoforms of the retinoid X receptor [RXR], which then regulate the gene expression by binding to DNA sequences associated with target genes. LXR acts as a cholesterol sensor in response to an increased concentration of cholesterol in cells and induces the transcription of genes that protect cells from cholesterol overload. LXRs play numerous roles in controlling cholesterol homeostasis via their actions on bile acid synthesis and metabolism/excretion, reverse cholesterol transport and cholesterol absorption/excretion in the intestines. Therefore, these receptors show great potential as pharmacological targets for anti-atherosclerotic activities. Recent discoveries have also emphasized the important involvement of LXRs in the pathogenesis of diabetes, Alzheimers disease, inflammation, adrenal steroid synthesis, skin aging and male fertility. However, LXR activation has also been shown to stimulate lipogenesis via sterol regulatory element binding protein-1c, leading to liver steatosis and hypertriglyceridemia. This review summarizes recent scientific discoveries and the biological actions of LXR with a special focus on the involvement of this type of receptor in important diseases and conditions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I359,I359)","v":24169363},{"$f":"(LEN($J359) - LEN(SUBSTITUTE(LOWER($J359),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J359) - LEN(SUBSTITUTE(LOWER($J359),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J359) - LEN(SUBSTITUTE(LOWER($J359),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B359:D359)","v":3},2014,"Interactions between nutrition and immune function: using inflammation biomarkers to interpret micronutrient status.","Thurnham",24169363,"Interactions between nutrition and immune function: using inflammation biomarkers to interpret micronutrient status.    Abstract:   The immune response promotes a complex series of reactions by the host in an effort to prevent ongoing tissue damage, isolate and destroy the infective organism and activate the repair processes that are necessary for restoring normal function. The homoeostatic process is known as inflammation and the early set of reactions that are induced are known as the acute phase response (APR). The APR has marked effects on the circulation, metabolism in the liver and the plasma concentration of many nutrients. The changes in nutrient concentrations follow a cyclic pattern; occurring before any clinical evidence of disease, being at their most pronounced during the disease and remaining in convalescence when all evidence of disease or trauma has disappeared. Therefore, where susceptibility to disease is high as in people who are HIV+ but still apparently healthy, obtaining an accurate measurement of nutritional status may not be possible. Accurate measurements of status are important for national statistics to plan for the proper utilisation of government resources and they are especially important to evaluate the effectiveness of nutritional interventions. Many acute phase proteins (APP) are synthesised during inflammation and they are used to monitor the progress of disease and recovery but, individually, none of their lifecycles compare well with those of the nutritional biomarkers. Nevertheless, recognising the presence of inflammation can help interpret data and, using two APP, this review paper will illustrate the methods we have developed to assist interpretation of plasma retinol, ferritin and zinc concentrations in apparently healthy, HIV+, Kenyan adults."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I360,I360)","v":24120505},{"$f":"(LEN($J360) - LEN(SUBSTITUTE(LOWER($J360),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J360) - LEN(SUBSTITUTE(LOWER($J360),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J360) - LEN(SUBSTITUTE(LOWER($J360),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B360:D360)","v":3},2013,"Sesquiterpene action, and morphogenetic signaling through the ortholog of retinoid X receptor, in higher Diptera.","Jones",24120505,"Sesquiterpene action, and morphogenetic signaling through the ortholog of retinoid X receptor, in higher Diptera.    Abstract:   Morphogenetic signaling by small terpenoid hormones is a common feature of both vertebrate and invertebrate development. Most attention on insect developmental signaling by small terpenoids has focused on signaling by juvenile hormone through bHLH-PAS proteins (e.g., the MET protein), especially as that signaling axis intersects with ecdysteroid action through the receptor EcR. However, a series of endocrine and pharmacological studies on pupariation in cyclorrhaphous Diptera have remained persistently refractory to explanation with the above two-axis model. Recently, the terpenoid compound methyl farnesoate has been physicochemically demonstrated to exist in circulation at physiological concentrations, in several mecopterid orders, including Diptera. In addition, it has also been recently demonstrated that the receptor to which methyl farnesoate binds with nanomolar affinity (ultraspiracle, an ortholog of retinoid X receptor) requires a functioning ligand binding pocket to sustain the morphogenetic transition to puparium formation. This review evaluates endocrine and pharmacological evidence for developmental pathways reached by methyl farnesoate action, and assesses the participation of the retinoid X receptor ligand pocket in signal transduction to those developmental endpoints."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I361,I361)","v":24059308},{"$f":"(LEN($J361) - LEN(SUBSTITUTE(LOWER($J361),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J361) - LEN(SUBSTITUTE(LOWER($J361),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J361) - LEN(SUBSTITUTE(LOWER($J361),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B361:D361)","v":3},2014,"Establishing genomic/transcriptomic links between Alzheimers disease and type 2 diabetes mellitus by meta-analysis approach.","Mirza",24059308,"Establishing genomic/transcriptomic links between Alzheimers disease and type 2 diabetes mellitus by meta-analysis approach.    Abstract:   Meta-analysis methods exist for combining multiple microarray datasets. However, there are a wide range of issues associated with microarray meta-analysis and a limited ability to compare the performance of different metaanalysis methods. Using cDNA microarray technology (Partek Genomics Suite 6.6) and global pathway analysis with Ingenuity Pathway Analysis tool (IPA, Inc), we examined the transcript level in type 2 diabetes mellitus (T2DM) and Alzheimers disease (AD) patients and controls. To understand the molecular link between T2DM and AD, we compared the gene expression pattern and pathway involved. Microarray analysis identified 235 differentially expressed genes between T2DM patients and controls; and 834 between AD and controls at two fold change and a false discovery rate of 0.05. Significantly changed expression of quot;myeloid leukemia cell differentiation protein 1; RAS guanyl releasing protein 1; S100 calcium-binding protein A8; prostaglandin- endoperoxide synthase 2; parvalbumin; endoplasmic reticulum aminopeptidase 1; phosphoglycerate kinase 1; Eukaryotic translation initiation factor 3 subunit F; Interleukin-1 beta; tubulin, beta 2A; glycine receptor alpha 1 and ribosomal protein S24quot; genes were highly associated with T2DM, whereas quot;neuronal differentiation 6; G-protein coupled receptor 83; phosphoserine phosphatase; bobby sox homolog or HMG box -containing protein 2; Glutathione S-transferase theta 1; alpha-2-glycoprotein 1 zinc-binding; Heat shock 70kDa protein 1B; transportin 1, Acidic leucine-rich nuclear phosphoprotein 32 family member B; Nuclear factor of activated T-cells 5; inositol 1,4,5-trisphosphate 3-kinase B; prenylcysteine oxidase 1 likequot; were found to be strongly related with AD. We also found a set of differentially expressed genes; quot;ARP2 actin-related protein 2; Cell division control protein 42; cytoplasmic polyadenylation element binding protein 4; Early growth response protein 1; ectonucleotide pyrophosphatase/phosphodiesterase 5; folate receptor 1; glutamate-ammonia ligase; hydroxy-3-methylglutaryl-Coenzyme A reductase; 3-hydroxy-3- methylglutaryl-CoA synthase; interleukin 1 receptor- like 1; leukemia inhibitory factor receptor; metastasis associated lung adenocarcinoma transcript 1; pyruvate dehydrogenase kinase, isozyme 4; phosphoserine phosphatase, parvalbumin, and tubulin, beta 2Aquot; to be present in both dataset. Altered regulation of intracellular signaling pathways, including Ephrin receptor, liver X receptor/ retinoid X receptor; interleukin 6; insulinlike growth factor 1; interleukin 10 and 14-3-3-mediated signaling pathways were associated with T2DM as well as Alzheimer-type pathology. Our findings implicate diabetic disorders in the pathogenesis of AD, and provide a basis for future candidate studies based on specific pathways."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I362,I362)","v":23845149},{"$f":"(LEN($J362) - LEN(SUBSTITUTE(LOWER($J362),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J362) - LEN(SUBSTITUTE(LOWER($J362),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J362) - LEN(SUBSTITUTE(LOWER($J362),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B362:D362)","v":3},2013,"Cardiovascular morbidity and mortality in psoriasis and psoriatic arthritis: a systematic literature review.","Horreau",23845149,"Cardiovascular morbidity and mortality in psoriasis and psoriatic arthritis: a systematic literature review.    Abstract:    UNLABELLEDPrevious epidemiological studies have demonstrated a high prevalence of cardiovascular (CV) risk factors in psoriasis patients, including metabolic syndrome, cigarette smoking, obesity, hypertension, diabetes mellitus, insulin resistance and dyslipidaemia. An increase in CV morbidity and mortality attributable to psoriasis is still under question.  PRIMARY OBJECTIVE : to assess CV morbidity and mortality in psoriasis and psoriatic arthritis (PsA) including stroke, coronary artery disease, myocardial infarction (MI) and peripheral artery disease.  SECONDARY OBJECTIVES : to assess if psoriasis per se is an independent CV risk factor and if psoriasis severity is a predictor of CV risk. We also evaluated the effect of conventional systemic treatments for psoriasis on CV mortality. A systematic literature search was carried out from 1980 to December 2011, in the Embase, Medline and Cochrane Library databases, in English and French using a combination of keywords including (Psoriasis) OR (Psoriatic arthritis) AND (Myocardial infarction) OR (Coronaropathy) OR (Stroke) OR (Cardiovascular) AND (Methotrexate) AND (Ciclosporin) AND (Retinoids). Of the 929 identified references, 33 observational studies evaluating the rates of cardiovascular events (CVE) in patients with psoriasis and PsA compared with controls were selected. Meta-analysis of both cohort and cross-sectional studies showed an increased risk of MI with Odds Ratio (OR) of 1.25 (95% CI 1.03-1.52) and 1.57 (95% CI 1.08-2.27) in psoriasis and PsA, respectively, compared with the general population. The risk of MI was more pronounced for patients having severe psoriasis and for patients with psoriasis of early onset. It remained significantly elevated after controlling for major CV risk factors. The meta-analysis identified a small, but significant association between psoriasis, PsA and coronary artery disease with an OR between 1.19 (95% CI 1.14-1.24) for cross-sectional studies, 1.20 (95% CI 1.13-1.27) for cohort studies and 1.84 (95% CI 1.09-3.09) for case-control studies. The risk of coronary artery disease seemed to be more pronounced in patients with severe psoriasis and in patients with psoriasis of early onset. The meta-analysis assessing the risk of stroke gave inconclusive results: analysis of cross-sectional studies suggested that psoriasis patients had a slightly higher risk of stroke with an OR of 1.14 (95% CI 1.08-1.99), whereas the meta-analysis of cohort studies failed to show an association. There was also an increased risk of peripheral artery disease in psoriasis. No significant increased risk of CV mortality could be shown for both psoriasis and PsA patients. The use of methotrexate was associated with a reduced incidence of cardiovascular disease in two studies. The use of etretinate was associated with a reduction of CV mortality in one study. Potential selection bias such as the healthy user effect prevents from drawing definite conclusions. There may be a small, but significant increased risk of CVE, but not of CV mortality in psoriasis and PsA patients. The psoriasis attributable risk remains difficult to assess due to confounding factors. The moderate quality of CV risk factors reporting in studies should be acknowledged. In addition, heterogeneity in study design, outcome definition and assessment represent major limitations. Nevertheless, screening and management of CV risk factors are important in psoriasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I363,I363)","v":22963233},{"$f":"(LEN($J363) - LEN(SUBSTITUTE(LOWER($J363),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J363) - LEN(SUBSTITUTE(LOWER($J363),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J363) - LEN(SUBSTITUTE(LOWER($J363),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B363:D363)","v":3},2013,"U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T-cell lymphoma.","Scarisbrick",22963233,"U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T-cell lymphoma.    Abstract:    BACKGROUND : Bexarotene is a synthetic retinoid from the subclass of retinoids called rexinoids which selectively activate retinoid X receptors. It has activity in cutaneous T-cell lymphoma (CTCL) and has been approved by the European Medicines Agency since 1999 for treatment of the skin manifestations of advanced-stage (IIB-IVB) CTCL in adult patients refractory to at least one systemic treatment. In vivo bexarotene produces primary hypothyroidism which may be managed with thyroxine replacement. It also affects lipid metabolism, typically resulting in raised triglycerides, which requires prophylactic lipid-modification therapy. Effects on neutrophils, glucose and liver function may also occur. These side-effects are dose dependent and may be controlled with corrective therapy or dose adjustments.  OBJECTIVES :   To produce a U.K. statement outlining a bexarotene dosing schedule and monitoring protocol to enable bexarotene prescribers to deliver bexarotene safely for optimal effect.  METHODS :  Leaders from U.K. supraregional centres produced this consensus statement after a series of meetings and a review of the literature.  RESULTS :  The statement outlines a bexarotene dosing schedule and monitoring protocol. This gives instructions on monitoring and treating thyroid, lipid, liver, blood count, creatine kinase, glucose and amylase abnormalities. The statement also includes algorithms for a bexarotene protocol and lipid management, which may be used in the clinical setting.  CONCLUSION :  Clinical prescribing of bexarotene for patients with CTCL requires careful monitoring to allow safe administration of bexarotene at the optimal dose."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I364,I364)","v":22954251},{"$f":"(LEN($J364) - LEN(SUBSTITUTE(LOWER($J364),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J364) - LEN(SUBSTITUTE(LOWER($J364),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J364) - LEN(SUBSTITUTE(LOWER($J364),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B364:D364)","v":3},2012,"Advances in drug design with RXR modulators.","Vaz",22954251,"Advances in drug design with RXR modulators.    Abstract:    INTRODUCTION : Retinoid X receptors (subtypes RXRα or NR2B1, RXRβ or NR2B2 and RXRγ or NR2B3, which originate from three distinct genes) are promiscuous partners with heterodimeric associations to other members of the Nuclear Receptor (NR) superfamily. Some of the heterodimers are quot;permissivequot; and transcriptionally active in the presence of either an RXR ligand (quot;rexinoidquot;) or a NR partner ligand, whereas others are quot;non-permissivequot; and unresponsive to rexinoids alone. In rodent models, rexinoids and partner agonists (mainly PPARγ, LXR, FXR) produce beneficial effects on insulin sensitization, diabetes and obesity, but secondary effects have also been noted, such as a raise in tryglyceride levels, supression of the thyroid hormone axis and induction of hepatomegaly.  AREAS COVERED : The authors review recent advances in rexinoid design, including further optimization of known scaffolds, and the discovery of novel RXR modulators by virtual ligand screening or from bioactive natural products. The understanding of rexinoid functions in permissive and non-permissive heterodimers is firmly based on structural knowledge. By strenghtening or disrupting the interaction surface with coregulators rexinoids exert agonist or (partial) antagonist activities. The activity state of the heterodimer can also be fine-tuned by the cellular context and the nature of coregulators.  EXPERT OPINION : The synthetic chemistry toolbox has provided a panel of agonists, partial (ant)agonists and/or heterodimer-selective rexinoids starting from existing, naturally occurring or serendipitously discovered scaffolds. These compounds have an unexplored therapeutic potential that might overcome some of the current limitations of rexinoids in therapy, such as hypertriglyceridemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I365,I365)","v":22873214},{"$f":"(LEN($J365) - LEN(SUBSTITUTE(LOWER($J365),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J365) - LEN(SUBSTITUTE(LOWER($J365),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J365) - LEN(SUBSTITUTE(LOWER($J365),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B365:D365)","v":3},2012,"Role of acyclic retinoid in the chemoprevention of hepatocellular carcinoma: basic aspects, clinical applications, and future prospects.","Shimizu",22873214,"Role of acyclic retinoid in the chemoprevention of hepatocellular carcinoma: basic aspects, clinical applications, and future prospects.    Abstract:   The poor prognosis for hepatocellular carcinoma (HCC) is associated with its high rate of recurrence in the cirrhotic liver. Therefore, development of effective strategies for preventing recurrence and secondary tumors will improve the clinical outcome of HCC patients. A malfunction of the retinoid X receptor-α (RXRα) due to phosphorylation by the Ras-MAPK signaling pathway is profoundly associated with liver carcinogenesis, and thus, may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), which inhibits Ras-MAPK activation and RXRα phosphorylation, successfully prevents HCC recurrence, thus improving patient survival. The fundamental concept of HCC chemoprevention by ACR is quot;clonal deletion,quot; which is defined as the removal of latent malignant clones from the liver before they expand into clinically detectable HCC. quot;Combination chemopreventionquot; using ACR as a key drug holds great promise of a new effective strategy for the prevention of HCC because of its synergism. ACR is also expected to prevent the development of HCC in obese people, who are at an increased risk to HCC, because this agent significantly inhibits obesity-related liver tumorigenesis in the rodent model. Here, we review the detailed effects of ACR on preventing HCC development, especially based on the results of our basic and clinical research."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I366,I366)","v":21715511},{"$f":"(LEN($J366) - LEN(SUBSTITUTE(LOWER($J366),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J366) - LEN(SUBSTITUTE(LOWER($J366),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J366) - LEN(SUBSTITUTE(LOWER($J366),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B366:D366)","v":3},2011,"Vitamin A: biomarkers of nutrition for development.","Tanumihardjo",21715511,"Vitamin A: biomarkers of nutrition for development.    Abstract:   Vitamin A is essential for multiple functions in mammals. Without vitamin A, mammals cannot grow, reproduce, or fight off disease. Because of its numerous functions in humans, biomarkers of vitamin A status are quite diverse. Assessment of liver reserves of vitamin A is considered the gold standard because the liver is the major storage organ. However, this measure is not feasible in human studies. Alternative biomarkers of status can be classified as biological, functional, histologic, and biochemical. Historically, signs of xerophthalmia were used to determine vitamin A deficiency. Before overt clinical damage to the eye, individuals who suffer from vitamin A deficiency are plagued by night blindness and longer vision-restoration times. These types of assessments require large population-based evaluations. Therefore, surrogate biochemical measures of vitamin A status, as defined by liver reserves, have been developed. Serum retinol concentrations are a common method used to evaluate vitamin A deficiency. Serum retinol concentrations are homeostatically controlled until liver reserves are dangerously low. Therefore, other biochemical methods that respond to liver reserves in the marginal category were developed. These included dose-response tests and isotope dilution assays. Dose-response tests work on the principle that apo-retinol-binding protein builds up in the liver as liver reserves become depleted. A challenge dose of vitamin A binds to this protein, and serum concentrations increase within a few hours if liver vitamin A concentrations are low. Isotope dilution assays use stable isotopes as tracers of total body reserves of vitamin A and evaluate a wide range of liver reserves. Resources available and study objectives often dictate the choice of a biomarker."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I367,I367)","v":21419268},{"$f":"(LEN($J367) - LEN(SUBSTITUTE(LOWER($J367),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J367) - LEN(SUBSTITUTE(LOWER($J367),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J367) - LEN(SUBSTITUTE(LOWER($J367),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B367:D367)","v":3},2011,"Retinoic acid, immunity, and inflammation.","Kim",21419268,"Retinoic acid, immunity, and inflammation.    Abstract:   Vitamin A (also called retinol), absorbed in the intestine and stored mainly in the liver and fat, is normally maintained at significant concentrations in the human blood plasma. Vitamin A is constitutively metabolized at high levels in certain tissues such as the small intestine and eyes. Retinoic acid (RA) produced at high levels in the intestine plays important roles in mucosal immunity and immune tolerance. RA at basal levels is required for immune cell survival and activation. During immune responses, enzymes metabolizing vitamin A are induced in certain types of immune cells such as dendritic cells (DCs) and tissue cells for induced production of RA. As a result, induced gradients of RA are formed during immune responses in the body. RA regulates gene expression, differentiation, and function of diverse immune cells. The cells under the influence of RA in terms of differentiation include myeloid cells such as neutrophils, macrophages, and DCs. Also included are lymphoid cells such as effector T cells, regulatory T cells, and B cells. Our current understanding of the function of RA in regulation of these immune cells is reviewed in this chapter."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I368,I368)","v":21111773},{"$f":"(LEN($J368) - LEN(SUBSTITUTE(LOWER($J368),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J368) - LEN(SUBSTITUTE(LOWER($J368),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J368) - LEN(SUBSTITUTE(LOWER($J368),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B368:D368)","v":3},2011,"Inhibition of estrogen actions in human gynecological malignancies: new aspects of endocrine therapy for endometrial cancer and ovarian cancer.","Ito",21111773,"Inhibition of estrogen actions in human gynecological malignancies: new aspects of endocrine therapy for endometrial cancer and ovarian cancer.    Abstract:   Endometrial carcinoma and possibly ovarian carcinoma are considered quot;estrogen-dependent tumorsquot; in human gynecological malignancies. In endometrial carcinoma, the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are different from those in human breast carcinoma, although both of them are considered quot;estrogen-dependent malignanciesquot;. Specific and effective endocrine treatment of endometrial carcinoma should be explored, although progestin agents have been widely used for a long time. Aromatase inhibitors, the most effective endocrine agents of breast carcinoma, retinoids, metabolites of vitamin A, and synthetic peroxisome proliferator-activated receptor (PPAR) gamma ligands, used for the treatment of insulin resistance in type II diabetes mellitus, may be the important candidates for possible endocrine treatment of endometrial carcinoma. In ovarian carcinoma, several clinical studies recently demonstrated that aromatase inhibitors had some therapeutic activity against recurrent ovarian carcinoma. However, at least at this juncture, further studies should be required to establish an aromatase inhibitor treatment as one form of endocrine therapy of ovarian carcinoma in future."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I369,I369)","v":21050917},{"$f":"(LEN($J369) - LEN(SUBSTITUTE(LOWER($J369),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J369) - LEN(SUBSTITUTE(LOWER($J369),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J369) - LEN(SUBSTITUTE(LOWER($J369),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B369:D369)","v":3},2010,"Inverse agonists and antagonists of retinoid receptors.","Bourguet",21050917,"Inverse agonists and antagonists of retinoid receptors.    Abstract:   Nuclear receptors (NRs) are ligand-inducible transcription factors that regulate a plethora of cell biological phenomena, thus orchestrating complex events like development, organ homeostasis, immune function, and reproduction. Due to their regulatory potential, NRs are major drug targets for a variety of diseases, including cancer and metabolic diseases, and had a major societal impact following the development of contraceptives and abortifacients. Not surprisingly in view of this medical and societal importance, a large amount of diverse NR ligands have been generated and the corresponding structural and functional analyses have provided a deep insight into the molecular basis of ligand action. What we have learnt is that ligands regulate, via allosteric conformational changes, the ability of NRs to interact with different sets of coregulators which in turn recruit enzymatically active complexes, the workhorses of the ligand-induced epigenetic and transcription-regulatory events. Thus, ligands essentially direct the communication of a given NR with its intracellular environment at the chromatin and extragenomic level to modulate gene programs directly at the chromatin level or via less well-understood extranuclear actions. Here we will review our current structural and mechanistic insight into the functionalities of subsets of retinoid and rexinoid ligands that act generically as antagonists but follow different mechanistic principles, resulting in quot;classicalquot; or neutral antagonism, or inverse agonism. In addition, we describe the chemical features and guidelines for the synthesis of retinoids/rexinoids that exert specific functions and we provide protocols for a number of experimental approaches that are useful for studies of the agonistic and antagonistic features of NR ligands."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I370,I370)","v":20463469},{"$f":"(LEN($J370) - LEN(SUBSTITUTE(LOWER($J370),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J370) - LEN(SUBSTITUTE(LOWER($J370),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J370) - LEN(SUBSTITUTE(LOWER($J370),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B370:D370)","v":3},2010,"Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics.","Solt",20463469,"Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics.    Abstract:    PURPOSE OF REVIEW : In the late 1980s, the cloning of several nuclear receptors led to the intense search and isolation of new members of this superfamily. Despite their identification, many of these receptors were dubbed orphan receptors, as their physiological ligands remained unknown. Recent reports have presented evidence for one family of orphan receptors, the retinoic acid receptor-related orphan receptors (RORs), in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, diabetes and obesity. The present review summarizes the studies identifying ligands for the RORs and evaluates their role as targets for potential therapeutics.  RECENT FINDINGS : Significant progress was made in the initial identification of ligands for the RORs when X-ray crystallographic studies identified several molecules within the ligand-binding pockets of RORalpha and RORbeta. Recently, we identified endogenous and synthetic ligands for RORalpha and RORgamma, thereby solidifying their function as ligand-dependent transcription factors.  SUMMARY : Recent studies have established roles for the RORs in physiological development and the advent of disease. Identification of ligands for the RORs, both endogenous and synthetic, has established these receptors as attractive new therapeutic targets for the treatment of ROR-related diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I371,I371)","v":19778546},{"$f":"(LEN($J371) - LEN(SUBSTITUTE(LOWER($J371),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J371) - LEN(SUBSTITUTE(LOWER($J371),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J371) - LEN(SUBSTITUTE(LOWER($J371),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B371:D371)","v":3},2010,"The platelet as a model system for the acute actions of nuclear receptors.","Bishop-Bailey",19778546,"The platelet as a model system for the acute actions of nuclear receptors.    Abstract:   Platelets are circulating cell fragments which play a critical role in thrombosis, and whose activity is associated with the progress of cardiovascular diseases, diabetes, inflammation, and cancer cell metastasis. Recently, a number of nuclear receptors have been found present in human platelets, including the receptors for sex steroids, and glucocorticoids, along with peroxisome proliferator-activated receptors (PPAR)s and retinoid X receptors (RXR)s. Although the platelet contains no nucleus, selective ligands for these receptors activate their respective platelet nuclear receptors and regulate platelet aggregation and activation. The human platelet, because of its abundance and accessibility therefore represents an excellent model system to study the rapid non-genomic mechanism of nuclear receptors. Moreover, since targeting platelets is a major clinical therapeutic area, analysis of platelet nuclear receptors may provide clues for new drug targets as well as provide important information regarding the physiological roles of nuclear receptors in the circulation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I372,I372)","v":19594405},{"$f":"(LEN($J372) - LEN(SUBSTITUTE(LOWER($J372),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J372) - LEN(SUBSTITUTE(LOWER($J372),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J372) - LEN(SUBSTITUTE(LOWER($J372),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B372:D372)","v":3},2009,"Oxidation of endobiotics mediated by xenobiotic-metabolizing forms of human cytochrome.","Niwa",19594405,"Oxidation of endobiotics mediated by xenobiotic-metabolizing forms of human cytochrome.    Abstract:   Cytochrome P450s (P450 or CYPs) comprise a superfamily of enzymes that catalyze the oxidation of a wide variety of xenobiotic chemicals including drugs and environmental carcinogens. Recent studies have demonstrated that endogenous chemicals are also oxidized by human P450s which mainly metabolize xenobiotics. In this review, we summarize the expected physiological significance of the biotransfornation as well as Michaelis-Menten constants (Km), maximal velocities (Vmax), Vmax/Km (intrinsic clearance) values, and/or metabolic activities for 33 endogenous substrates, including (1) arachidonic acid and fatty acids, (2) steroid hormones, such as testosterone, progesterone, and allopregnanolone, (3) amines, such as tyramine, and (4) lipid-soluble vitamins, such as retinol and vitamin D3 analogues, mediated human P450 isoforms consisting of so-called drug-metabolizing enzymes for the purpose of predicting the key enzyme(s) in vivo. Arachidonic acid is metabolized via the epoxidation and omega-hydroxylation to many biologically active eicosanoids such as epoxyeicosatrienoic acids and hydroxyeicosatetraenoic acids by multiple P450 isoforms including CYP2C, CYP2E1 and CYP4A11. CYP2D in the brain may be involved in the metabolism of neuronal amines and steroids and in the regulation of the central nervous system. CYP1A2 and CYP3A4 appear to be the major P450 enzymes catalyzing the oxidation of all-trans-retinol to all-trans-retinoic acid in human liver, and CYP3A4 is one of the vitamin D3 25-hydroxylases. Although the significance of the contribution is still unknown in detail, the collective findings provide fundamental and useful information for the biological contribution of the metabolism of endogenous substances by drug-metabolizing enzymes, P450s. In addition, genetic polymorphism of these drug-metabolizing P450s may affect the metabolism of the endobiotics. Forthermore, these findings imply that xenobiotic oxidations by P450 enzymes are affected by endobiotic molecules and that the endobiotic-xenobiotic interactions as well as drug-drug interactions or drug-food/beverage interactions may be of great importance when understanding the basis for pharmacological and toxicological actions of a number of xenobiotic chemicals."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I373,I373)","v":19381306},{"$f":"(LEN($J373) - LEN(SUBSTITUTE(LOWER($J373),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J373) - LEN(SUBSTITUTE(LOWER($J373),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J373) - LEN(SUBSTITUTE(LOWER($J373),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B373:D373)","v":3},2009,"Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism.","Jetten",19381306,"Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism.    Abstract:   The last few years have witnessed a rapid increase in our knowledge of the retinoid-related orphan receptors RORalpha, -beta, and -gamma (NR1F1-3), their mechanism of action, physiological functions, and their potential role in several pathologies. The characterization of ROR-deficient mice and gene expression profiling in particular have provided great insights into the critical functions of RORs in the regulation of a variety of physiological processes. These studies revealed that RORalpha plays a critical role in the development of the cerebellum, that both RORalpha and RORbeta are required for the maturation of photoreceptors in the retina, and that RORgamma is essential for the development of several secondary lymphoid tissues, including lymph nodes. RORs have been further implicated in the regulation of various metabolic pathways, energy homeostasis, and thymopoiesis. Recent studies identified a critical role for RORgamma in lineage specification of uncommitted CD4+ T helper cells into Th17 cells. In addition, RORs regulate the expression of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expression of downstream (metabolic) genes. Study of ROR target genes has provided insights into the mechanisms by which RORs control these processes. Moreover, several reports have presented evidence for a potential role of RORs in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, and obesity, and raised the possibility that RORs may serve as potential targets for chemotherapeutic intervention. This prospect was strengthened by recent evidence showing that RORs can function as ligand-dependent transcription factors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I374,I374)","v":23074532},{"$f":"(LEN($J374) - LEN(SUBSTITUTE(LOWER($J374),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J374) - LEN(SUBSTITUTE(LOWER($J374),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J374) - LEN(SUBSTITUTE(LOWER($J374),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B374:D374)","v":3},2009,"Ultraviolet Phototherapy Management of Moderate-to-Severe Plaque Psoriasis: An Evidence-Based Analysis.","Ondrey",23074532,"Ultraviolet Phototherapy Management of Moderate-to-Severe Plaque Psoriasis: An Evidence-Based Analysis.    Abstract:    OBJECTIVE : The purpose of this evidence based analysis was to determine the effectiveness and safety of ultraviolet phototherapy for moderate-to-severe plaque psoriasis.  RESEARCH QUESTIONS : The specific research questions for the evidence review were as follows: What is the safety of ultraviolet phototherapy for moderate-to-severe plaque psoriasis?What is the effectiveness of ultraviolet phototherapy for moderate-to-severe plaque psoriasis?  CLINICAL NEED : TARGET POPULATION AND CONDITION Psoriasis is a common chronic, systemic inflammatory disease affecting the skin, nails and occasionally the joints and has a lifelong waning and waxing course. It has a worldwide occurrence with a prevalence of at least 2% of the general population, making it one of the most common systemic inflammatory diseases. The immune-mediated disease has several clinical presentations with the most common (85% - 90%) being plaque psoriasis. Characteristic features of psoriasis include scaling, redness, and elevation of the skin. Patients with psoriasis may also present with a range of disabling symptoms such as pruritus (itching), pain, bleeding, or burning associated with plaque lesions and up to 30% are classified as having moderate-to-severe disease. Further, some psoriasis patients can be complex medical cases in which diabetes, inflammatory bowel disease, and hypertension are more likely to be present than in control populations and 10% also suffer from arthritis (psoriatic arthritis). The etiology of psoriasis is unknown but is thought to result from complex interactions between the environment and predisposing genes. Management of psoriasis is related to the extent of the skin involvement, although its presence on the hands, feet, face or genitalia can present challenges. Moderate-to-severe psoriasis is managed by phototherapy and a range of systemic agents including traditional immunosuppressants such as methotrexate and cyclospsorin. Treatment with modern immunosuppressant agents known as biologicals, which more specifically target the immune defects of the disease, is usually reserved for patients with contraindications and those failing or unresponsive to treatments with traditional immunosuppressants or phototherapy. Treatment plans are based on a long-term approach to managing the disease, patients expectations, individual responses and risk of complications. The treatment goals are several fold but primarily to: 1) improve physical signs and secondary psychological effects,2) reduce inflammation and control skin shedding,3) control physical signs as long as possible, and to4) avoid factors that can aggravate the condition.Approaches are generally individualized because of the variable presentation, quality of life implications, co-existent medical conditions, and triggering factors (e.g. stress, infections and medications). Individual responses and commitments to therapy also present possible limitations. PHOTOTHERAPY: Ultraviolet phototherapy units have been licensed since February 1993 as a class 2 device in Canada. Units are available as hand held devices, hand and foot devices, full-body panel, and booth styles for institutional and home use. Units are also available with a range of ultraviolet A, broad and narrow band ultraviolet B (BB-UVB and NB-UVB) lamps. After establishing appropriate ultraviolet doses, three-times weekly treatment schedules for 20 to 25 treatments are generally needed to control symptoms.  EVIDENCE-BASED ANALYSIS METHODS : The literature search strategy employed keywords and subject headings to capture the concepts of 1) phototherapy and 2) psoriasis. The search involved runs in the following databases: Ovid MEDLINE (1996 to March Week 3 2009), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2009 Week 13), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 1999 and March 31, 2009. Search alerts were generated and reviewed for relevant literature up until May 31, 2009. Inclusion CriteriaExclusion CriteriaEnglish language reports and human studiesUltraviolet phototherapy interventions for plaque-type psoriasisReports involving efficacy and/or safety outcome studiesOriginal reports with defined study methodologyStandardized measurements on outcome events such as technical success, safety, effectiveness, durability, quality of life or patient satisfactionNon-systematic reviews, letters, comments and editorialsRandomized trials involving side-to-side or half body comparisonsRandomized trials not involving ultraviolet phototherapy intervention for plaque-type psoriasisTrials involving dosing studies, pilot feasibility studies or lacking control groups  SUMMARY OF FINDINGS : A 2000 health technology evidence report on the overall management of psoriasis by The National Institute Health Research (NIHR) Health Technology Assessment Program of the UK was identified in the MAS evidence-based review. The report included 109 RCT studies published between 1966 and June 1999 involving four major treatment approaches - 51 on phototherapy, 32 on oral retinoids, 18 on cyclosporin and five on fumarates.. The absence of RCTs on methotrexate was noted as original studies with this agent had been performed prior to 1966. Of the 51 RCT studies involving phototherapy, 22 involved UVA, 21 involved UVB, five involved both UVA and UVB and three involved natural light as a source of UV. The RCT studies included comparisons of treatment schedules, ultraviolet source, addition of adjuvant therapies, and comparisons between phototherapy and topical treatment schedules. Because of heterogeneity, no synthesis or meta-analysis could be performed. Overall, the reviewers concluded that the efficacy of only five therapies could be supported from the RCT-based evidence review: photochemotherapy or phototherapy, cyclosporin, systemic retinoids, combination topical vitamin D(3) analogues (calcipotriol) and corticosteroids in combination with phototherapy and fumarates. Although there was no RCT evidence supporting methotrexate, its efficacy for psoriasis is well known and it continues to be a treatment mainstay. The conclusion of the NIHR evidence review was that both photochemotherapy and phototherapy were effective treatments for clearing psoriasis, although their comparative effectiveness was unknown. Despite the conclusions on efficacy, a number of issues were identified in the evidence review and several areas for future research were discussed to address these limitations. Trials focusing on comparative effectiveness, either between ultraviolet sources or between classes of treatment such as methotrexate versus phototherapy, were recommended to refine treatment algorithms. The need for better assessment of cost-effectiveness of therapies to consider systemic drug costs and costs of surveillance, as well as drug efficacy, were also noted. Overall, the authors concluded that phototherapy and photochemotherapy had important roles in psoriasis management and were standard therapeutic options for psoriasis offered in dermatology practices. The MAS evidence-based review focusing on the RCT trial evidence for ultraviolet phototherapy management of moderate-to-severe plaque psoriasis was performed as an update to the NIHR 2000 systemic review on treatments for severe psoriasis. In this review, an additional 26 RCT reports examining phototherapy or photochemotherapy for psoriasis were identified. Among the studies were two RCTs comparing ultraviolet wavelength sources, five RCTs comparing different forms of phototherapy, four RCTs combining phototherapy with prior spa saline bathing, nine RCTs combining phototherapy with topical agents, two RCTs combining phototherapy with the systemic immunosuppressive agents methotrexate or alefacept, one RCT comparing phototherapy with an additional light source (the excimer laser), and one comparing a combination therapy with phototherapy and psychological intervention involving simultaneous audiotape sessions on mindfulness and stress reduction. Two trials also examined the effect of treatment setting on effectiveness of phototherapy, one on inpatient versus outpatient therapy and one on outpatient clinic versus home-based phototherapy.  CONCLUSIONS : The conclusions of the MAS evidence-based review are outlined in Table ES1. In summary, phototherapy provides good control of clinical symptoms in the short term for patients with moderate-to-severe plaque-type psoriasis that have failed or are unresponsive to management with topical agents. However, many of the evidence gaps identified in the NIHR 2000 evidence review on psoriasis management persisted. In particular, the lack of evidence on the comparative effectiveness and/or cost-effectiveness between the major treatment options for moderate-to-severe psoriasis remained. The evidence on effectiveness and safety of longer term strategies for disease management has also not been addressed. Evidence for the safety, effectiveness, or cost-effectiveness of phototherapy delivered in various settings is emerging but is limited. In addition, because all available treatments for psoriasis - a disease with a high prevalence, chronicity, and cost - are palliative rather than curative, strategies for disease control and improvements in self-efficacy employed in other chronic disease management strategies should be investigated. (ABSTRACT TRUNCATED)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I375,I375)","v":18375192},{"$f":"(LEN($J375) - LEN(SUBSTITUTE(LOWER($J375),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J375) - LEN(SUBSTITUTE(LOWER($J375),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J375) - LEN(SUBSTITUTE(LOWER($J375),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B375:D375)","v":3},2008,"Nuclear receptors, mitochondria and lipid metabolism.","Alaynick",18375192,"Nuclear receptors, mitochondria and lipid metabolism.    Abstract:   Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome-proliferator activated receptors (PPARs) and liver X receptors (LXRs), acting in concert with PPARgamma Coactivator 1alpha (PGC-1alpha), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia and obesity). Recently, additional partners of PGC-1alpha have moved to the forefront of metabolic research, the estrogen-related receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I376,I376)","v":17979744},{"$f":"(LEN($J376) - LEN(SUBSTITUTE(LOWER($J376),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J376) - LEN(SUBSTITUTE(LOWER($J376),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J376) - LEN(SUBSTITUTE(LOWER($J376),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B376:D376)","v":3},2007,"Prospective teratology of retinoic acid metabolic blocking agents (RAMBAs) and loss of CYP26 activity.","McCaffery",17979744,"Prospective teratology of retinoic acid metabolic blocking agents (RAMBAs) and loss of CYP26 activity.    Abstract:   All-trans retinoic acid (atRA) is the transcriptionally active product of vitamin A and induces gene expression via specific receptors at nM concentrations. Essential enzymes that regulate the local levels of atRA are the CYP26 members of the cytochrome P450 family, which catabolize atRA. Compounds that have been designed to inhibit these enzymes are known as Retinoic Acid Metabolic Blocking Agents (RAMBAs). Treatment with these compounds will raise endogenous atRA levels and may be therapeutic for the treatment of diseases that respond to high atRA concentrations, including several types of cancer as well as skin conditions such as psoriasis and acne. This review describes the mechanism of action of the RAMBAs and discusses the potential side effects of these compounds. atRA is highly teratogenic and the potential teratogenicity of the RAMBAs is described by comparison with the abnormalities resulting from null mutation of individual CYP26 genes. The possible effects of RAMBAs on the adult brain are also described that have the potential for harm but, in the right circumstances, may also be beneficial."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I377,I377)","v":17906642},{"$f":"(LEN($J377) - LEN(SUBSTITUTE(LOWER($J377),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J377) - LEN(SUBSTITUTE(LOWER($J377),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J377) - LEN(SUBSTITUTE(LOWER($J377),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B377:D377)","v":3},2007,"RAR and RXR modulation in cancer and metabolic disease.","Altucci",17906642,"RAR and RXR modulation in cancer and metabolic disease.    Abstract:   Retinoic acid receptors (RARs) are ligand-controlled transcription factors that function as heterodimers with retinoid X receptors (RXRs) to regulate cell growth and survival. The success of RAR modulation in the treatment of acute promyelocytic leukaemia (APL) has stimulated considerable interest in the development of RAR and RXR modulators. This has been aided by recent advances in the understanding of the biological role of RARs and RXRs and in the design of selective receptor modulators that might overcome the limitations of current drugs. Here, we discuss the challenges and opportunities for therapeutic strategies based on RXR and RAR modulators, with a focus on cancer and metabolic diseases such as diabetes and obesity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I378,I378)","v":17785917},{"$f":"(LEN($J378) - LEN(SUBSTITUTE(LOWER($J378),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J378) - LEN(SUBSTITUTE(LOWER($J378),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J378) - LEN(SUBSTITUTE(LOWER($J378),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B378:D378)","v":3},2007,"Biological roles of estrogen and progesterone in human endometrial carcinoma--new developments in potential endocrine therapy for endometrial cancer.","Ito",17785917,"Biological roles of estrogen and progesterone in human endometrial carcinoma--new developments in potential endocrine therapy for endometrial cancer.    Abstract:   Endometrial carcinoma is one of the most common female pelvic malignancies. It is well known that uterine endometrial cell proliferation is under the control of both estrogen and progesterone. In this review, results of the recent studies on the biosynthesis and action of estrogen and progestin in normal endometrium and its disorders will be summarized and the new aspects of hormonal therapies in the patients with endometrial carcinoma will be discussed including its future prospectives. We reported that the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are markedly different between human breast and endometrial carcinoma, although both of them are considered quot;estrogen-dependent malignanciesquot;. In addition, the biological significance of Progesterone receptor (PR) isoforms is considered to differ between endometrial and breast carcinomas. Clinical data concerning Hormone replacement therapy (HRT) and estrogen-dependent cancer risk also support these findings. These basic and clinical findings help to understand the biology and provide the new knowledge for prevention, diagnosis and treatment of human endomerial carcinoma. Specific endocrine treatment of endometrial carcinoma should be explored in future, although aromatase inhibitors are the most effective endocrine treatments of estrogen-responsive breast carcinoma. Retinoid, metabolities of vitamin A, and synthetic peroxisome proliferator-activated receptor (PPAR) gamma ligands, which have been used for the treatment of insulin resistance in type II diabetes mellitus, may be the important candidates as drugs not only for prevention but also for possible endocrine treatment of endometrial carcinoma."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I379,I379)","v":17550551},{"$f":"(LEN($J379) - LEN(SUBSTITUTE(LOWER($J379),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J379) - LEN(SUBSTITUTE(LOWER($J379),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J379) - LEN(SUBSTITUTE(LOWER($J379),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B379:D379)","v":3},2007,"Thiazolidinediones in dermatology.","Boyd",17550551,"Thiazolidinediones in dermatology.    Abstract:   Thiazolidinediones, also known as glitazones, represent a relatively new class of medication used for glycemic control in patients with type II diabetes mellitus. These drugs interact with the peroxisome proliferator-activated receptor gamma, a member of the nuclear receptor superfamily, which in turn heterodimerizes with retinoid X receptors to stimulate gene transcription. At a physiologic level, glitazones stimulate adipocyte differentiation, enhance insulin-sensitive glucose uptake by muscle and fat cells, suppress angiogenesis, inhibit tumor cell growth, and normalize keratinocyte differentiation. They have also demonstrated the capacity to diminish inflammatory cytokine production, most notably, that of tumor necrosis factor alpha. Patients with such disparate conditions as psoriasis, hirsutism, melanoma, angiosarcoma, lipodystrophy, and necrobiosis lipoidica have benefited from the administration of thiazolidinediones. Clinicians should become familiar with glitazones as they are experiencing a burgeoning use among patients with non-insulin-dependent diabetes mellitus and have demonstrated clinical efficacy in treating certain skin conditions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I380,I380)","v":17497022},{"$f":"(LEN($J380) - LEN(SUBSTITUTE(LOWER($J380),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J380) - LEN(SUBSTITUTE(LOWER($J380),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J380) - LEN(SUBSTITUTE(LOWER($J380),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B380:D380)","v":3},2007,"Therapeutic potential of retinoid x receptor modulators for the treatment of the metabolic syndrome.","Pinaire",17497022,"Therapeutic potential of retinoid x receptor modulators for the treatment of the metabolic syndrome.    Abstract:   The increasing prevalence of obesity is a fundamental contributor to the growing prevalence of the metabolic syndrome. Rexinoids, a class of compounds that selectively bind and activate RXR, are being studied as a potential option for the treatment of metabolic syndrome. These compounds have glucose-lowering, insulin-sensitizing, and antiobesity effects in animal models of insulin resistance and type 2 diabetes. However, undesirable side effects such as hypertriglyceridemia and suppression of the thyroid hormone axis also occur. This review examines and compares the effects of four RXR-selective ligands: LGD1069, LG100268, AGN194204, and LG101506, a selective RXR modulator. Similar to selective modulators of other nuclear receptors such as the estrogen receptor (SERMs), LG101506 binding to RXR selectively maintains the desirable characteristic effects of rexinoids while minimizing the undesirable effects. These recent findings suggest that, with continued research efforts, RXR-specific ligands with improved pharmacological profiles may eventually be available as additional treatment options for the current epidemic of obesity, insulin resistance, type 2 diabetes, and all of the associated metabolic sequelae."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I381,I381)","v":16925464},{"$f":"(LEN($J381) - LEN(SUBSTITUTE(LOWER($J381),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J381) - LEN(SUBSTITUTE(LOWER($J381),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J381) - LEN(SUBSTITUTE(LOWER($J381),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B381:D381)","v":3},2007,"White adipose tissue: storage and effector site for environmental pollutants.","Müllerová",16925464,"White adipose tissue: storage and effector site for environmental pollutants.    Abstract:   White adipose tissue (WAT) represents a reservoir of lipophilic environmental pollutants, especially of those which are resistant to biological and chemical degradation - so-called persistent organic pollutants (POPs). Large amounts of different congeners and isomers of these compounds exhibit a variety of adverse biological effects. Interactions among different classes of compounds, frequently with opposing effects, complicate hazard evaluation and risk assessment. WAT is the key organ for energy homeostasis and it also releases metabolites into the circulation and adipokines with systemic effects on insulin sensitivity and fuel partitioning in muscles and other tissues. Its beneficial role is lost in obesity when excessive accumulation of WAT contributes to severe diseases, such as diabetes. POPs may crossroad or modulate the effect of endogenous ligands of nuclear transcription factors, participating in differentiation, metabolism and the secretory function of adipocytes. These mechanisms include, most importantly: i) endocrine disrupting potency of POPs mixtures on androgen, estrogen or thyroid hormone metabolism/functions in WAT, ii) interference of dioxin-like chemicals with retinoic acid homeostasis, where impact on retinoid receptors is expected, and iii) interaction with transcriptional activity of peroxisome proliferator-activated receptors is likely. Thus, the accumulation and action of POPs in WAT represents a unitary mechanism explaining, at least in part, the effects of POPs in the whole organism. By modulating WAT differentiation, metabolism and function, the POPs could affect not only the physiological role of WAT, but they may also influence the development of obesity-associated diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I382,I382)","v":16797999},{"$f":"(LEN($J382) - LEN(SUBSTITUTE(LOWER($J382),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J382) - LEN(SUBSTITUTE(LOWER($J382),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J382) - LEN(SUBSTITUTE(LOWER($J382),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B382:D382)","v":3},2006,"Role of small bioorganic molecules in stem cell differentiation to insulin-producing cells.","Roche",16797999,"Role of small bioorganic molecules in stem cell differentiation to insulin-producing cells.    Abstract:   The use of small specific molecules has been instrumental in the modulation of stem cell proliferation and differentiation to obtain insulin-containing cells. Examples include nutrients (glucose, nicotinamide and retinoic acid), acids (butyrate), alkaloids (cyclopamine and conophylline) and pharmacological agents (LY294002 and wortmannin). These molecules, alone or in combination with specific growth factors and hormones, will likely provide key information to design specific culture media in order to obtain customized cells for implantation in diabetes. In addition, the study of such molecules will help to understand the mechanisms involved in stem cell biology as well as contribute to the design of specific drugs for islet repair and regeneration in diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I383,I383)","v":15917448},{"$f":"(LEN($J383) - LEN(SUBSTITUTE(LOWER($J383),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J383) - LEN(SUBSTITUTE(LOWER($J383),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J383) - LEN(SUBSTITUTE(LOWER($J383),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B383:D383)","v":3},2005,"Autoantigens act as tissue-specific chemoattractants.","Oppenheim",15917448,"Autoantigens act as tissue-specific chemoattractants.    Abstract:   We have investigated the chemoattractant properties of self-antigens associated with autoimmune diseases and solid tumors. Many autoantigens induced leukocyte migration, especially by immature dendritic cells (iDC) by interacting with various chemoattractant Gi-protein-coupled receptors (GiPCR). Our initial observation that myositis-associated autoantigens, histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, were chemotactic for CC chemokine receptor 5 (CCR5)- and CCR3-expressing leukocytes, while other nonautoantigenic aminoacyl-tRNA synthesases were not, suggested that only self-antigens capable of interacting with receptors on antigen-presenting cells were immunogenic. We next determined that self-antigens associated with autoimmune diseases, e.g., multiple sclerosis or experimental autoimmune encephalomyelitis, type I diabetes, scleroderma, systemic lupus erythematosus, autoimmune uveitis, or experimental autoimmune uveitis (EAU), were chemotactic for GiPCR expressed by iDC. The majority of autoantigens were DC chemoattractants at 10-100 ng/ml, but did not induce DC maturation until they reached 1000-fold higher concentrations. Interphotoreceptor retinoid-binding protein and retinal arrestin (S-antigen) are targets of autoantibodies in human uveitis and are chemotactic for CXC chemokine receptor 5 (CXCR5)- and/or CXCR3-expressing iDC. However, although S-antigen does not induce EAU in wild-type mice, it is nevertheless a chemoattractant for murine iDC. These unexpected observations suggested that the chemotactic activity of these tissue-specific self-antigens could be involved in promotion of tissue repair and restoration. Thus, the primary role of autoantigens may be to alert the immune system to danger signals from invaded and damaged tissues to facilitate repair, and autoimmune responses subsequently develop only in subjects with impaired immunoregulatory function."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I384,I384)","v":15832810},{"$f":"(LEN($J384) - LEN(SUBSTITUTE(LOWER($J384),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J384) - LEN(SUBSTITUTE(LOWER($J384),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J384) - LEN(SUBSTITUTE(LOWER($J384),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B384:D384)","v":3},2005,"Induction of phase I, II and III drug metabolism/transport by xenobiotics.","Xu",15832810,"Induction of phase I, II and III drug metabolism/transport by xenobiotics.    Abstract:   Drug metabolizing enzymes (DMEs) play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Most of the tissues and organs in our body are well equipped with diverse and various DMEs including phase I, phase II metabolizing enzymes and phase III transporters, which are present in abundance either at the basal unstimulated level, and/or are inducible at elevated level after exposure to xenobiotics. Recently, many important advances have been made in the mechanisms that regulate the expression of these drug metabolism genes. Various nuclear receptors including the aryl hydrocarbon receptor (AhR), orphan nuclear receptors, and nuclear factor-erythoroid 2 p45-related factor 2 (Nrf2) have been shown to be the key mediators of drug-induced changes in phase I, phase II metabolizing enzymes as well as phase III transporters involved in efflux mechanisms. For instance, the expression of CYP1 genes can be induced by AhR, which dimerizes with the AhR nuclear translocator (Arnt), in response to many polycyclic aromatic hydrocarbon (PAHs). Similarly, the steroid family of orphan nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both heterodimerize with the retinoid X receptor (RXR), are shown to transcriptionally activate the promoters of CYP2B and CYP3A gene expression by xenobiotics such as phenobarbital-like compounds (CAR) and dexamethasone and rifampin-type of agents (PXR). The peroxisome proliferator activated receptor (PPAR), which is one of the first characterized members of the nuclear hormone receptor, also dimerizes with RXR and has been shown to be activated by lipid lowering agent fibrate-type of compounds leading to transcriptional activation of the promoters on CYP4A gene. CYP7A was recognized as the first target gene of the liver X receptor (LXR), in which the elimination of cholesterol depends on CYP7A. Farnesoid X receptor (FXR) was identified as a bile acid receptor, and its activation results in the inhibition of hepatic acid biosynthesis and increased transport of bile acids from intestinal lumen to the liver, and CYP7A is one of its target genes. The transcriptional activation by these receptors upon binding to the promoters located at the 5-flanking region of these CYP genes generally leads to the induction of their mRNA gene expression. The physiological and the pharmacological implications of common partner of RXR for CAR, PXR, PPAR, LXR and FXR receptors largely remain unknown and are under intense investigations. For the phase II DMEs, phase II gene inducers such as the phenolic compounds butylated hydroxyanisol (BHA), tert-butylhydroquinone (tBHQ), green tea polyphenol (GTP), (-)-epigallocatechin-3-gallate (EGCG) and the isothiocyanates (PEITC, sulforaphane) generally appear to be electrophiles. They generally possess electrophilic-mediated stress response, resulting in the activation of bZIP transcription factors Nrf2 which dimerizes with Mafs and binds to the antioxidant/electrophile response element (ARE/EpRE) promoter, which is located in many phase II DMEs as well as many cellular defensive enzymes such as heme oxygenase-1 (HO-1), with the subsequent induction of the expression of these genes. Phase III transporters, for example, P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptide 2 (OATP2) are expressed in many tissues such as the liver, intestine, kidney, and brain, and play crucial roles in drug absorption, distribution, and excretion. The orphan nuclear receptors PXR and CAR have been shown to be involved in the regulation of these transporters. Along with phase I and phase II enzyme induction, pretreatment with several kinds of inducers has been shown to alter the expression of phase III transporters, and alter the excretion of xenobiotics, which implies that phase III transporters may also be similarly regulated in a coordinated fashion, and provides an important mean to protect the body from xenobiotics insults. It appears that in general, exposure to phase I, phase II and phase III gene inducers may trigger cellular quot;stressquot; response leading to the increase in their gene expression, which ultimately enhance the elimination and clearance of these xenobiotics and/or other quot;cellular stressesquot; including harmful reactive intermediates such as reactive oxygen species (ROS), so that the body will remove the quot;stressquot; expeditiously. Consequently, this homeostatic response of the body plays a central role in the protection of the body against quot;environmentalquot; insults such as those elicited by exposure to xenobiotics."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I385,I385)","v":15608692},{"$f":"(LEN($J385) - LEN(SUBSTITUTE(LOWER($J385),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J385) - LEN(SUBSTITUTE(LOWER($J385),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J385) - LEN(SUBSTITUTE(LOWER($J385),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B385:D385)","v":3},2004,"Retinoid X receptors: X-ploring their (patho)physiological functions.","Szanto",15608692,"Retinoid X receptors: X-ploring their (patho)physiological functions.    Abstract:   Retinoid X receptor (RXR) belongs to a family of ligand-activated transcription factors that regulate many aspects of metazoan life. A class of nuclear receptors requires RXR as heterodimerization partner for their function. This places RXR in the crossroad of multiple distinct biological pathways. This and the fact that the debate on the endogenous ligand requirement for RXR is not yet settled make RXR still an enigmatic transcription factor. Here, we review some of the biology of RXR. We place RXR into the evolution of nuclear receptors, review structural details and ligands of the receptor. Then processes regulated by RXR are discussed focusing on the developmental roles deduced from studies on knockout animals and metabolic roles in diseases such as diabetes and atherosclerosis deduced from pharmacological studies. Finally, aspects of RXRs involvement in myeloid differentiation and apoptosis are summarized along with issues on RXRs suitability as a therapeutic target."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I386,I386)","v":15563242},{"$f":"(LEN($J386) - LEN(SUBSTITUTE(LOWER($J386),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J386) - LEN(SUBSTITUTE(LOWER($J386),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J386) - LEN(SUBSTITUTE(LOWER($J386),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B386:D386)","v":3},2004,"Tamibarotene: AM 80, retinobenzoic acid, Tamibaro.","Biesalski",15563242,"Tamibarotene: AM 80, retinobenzoic acid, Tamibaro.    Abstract:   Tamibarotene [AM 80, retinobenzoic acid, Amnoid, Tamibaro] is a novel synthetic retinoid that is in development with Nippon Shinyaku as a potential treatment for acute promyelocytic leukaemia (APL) and is pending approval in Japan. Tamibarotene was being developed by Shionogi in Japan but the company subsequently discontinued its involvement. Various nonindustrial sources, such as the University of Tokyo, Japan, have also played a role in the development of tamibarotene. Nippon Shinyaku has licensed the rights to tamibarotene from Toko Pharmaceutical Industries for the treatment of acute promyelocytic leukaemia, according to Nippon Shinyakus June 2004 pipeline update. However it is unclear when Toko Pharmaceutical Industries acquired rights to the compound."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I387,I387)","v":15559237},{"$f":"(LEN($J387) - LEN(SUBSTITUTE(LOWER($J387),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J387) - LEN(SUBSTITUTE(LOWER($J387),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J387) - LEN(SUBSTITUTE(LOWER($J387),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B387:D387)","v":3},2004,"[All-trans retinoic acid syndrome. Case report and a review of the literature].","Carrillo-Esper",15559237,"[All-trans retinoic acid syndrome. Case report and a review of the literature].    Abstract:   We described a patient with acute promyelocytic leukemia (APL) who developed all-trans retinoic acid syndrome (ATRAS) and reviewed the literature. ATRAS presents in patients with APL treated with all-trans retinoic acid (ATRA). It has an incidence from 5%-27% with mortality of 29%. It is secondary to ATRA effect on promyelocyte differentiation, which causes systemic inflammatory response syndrome, endothelium damage with increase in capillary permeability, microcirculation obstruction, and tissue infiltration. ATRAS clinical manifestations are fever, hypotension, respiratory, renal and hepatic insufficiency, lung infiltrates, pleural and pericardic effusion, and generalized edema. Treatment is based on ATRA suspension, support measures, and steroids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I388,I388)","v":15359008},{"$f":"(LEN($J388) - LEN(SUBSTITUTE(LOWER($J388),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J388) - LEN(SUBSTITUTE(LOWER($J388),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J388) - LEN(SUBSTITUTE(LOWER($J388),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B388:D388)","v":3},2004,"Retinoic acid signaling in the nervous system of adult vertebrates.","Mey",15359008,"Retinoic acid signaling in the nervous system of adult vertebrates.    Abstract:   The majority of the functions of vitamin A are carried out by its metabolite, retinoic acid (RA), a potent transcriptional activator acting through members of the nuclear receptor family of transcription factors. In the CNS, RA was first recognized to be essential for the control of patterning and differentiation in the developing embryo. It has recently come to light, however, that many of the same functions that RA directs in the embryo are involved in the regulation of plasticity and regeneration in the adult brain. The same intricate metabolic control system of synthetic and catabolic enzymes, combined with cytoplasmic binding proteins, is used in both embryo and adult to create regions of high and low RA to modulate gene transcription. This review summarizes some of the discoveries in the new field of retinoid neurobiology including its functions in neural plasticity and LTP in the hippocampus; its possible role in motor disorders such as Parkinsons disease, motoneuron disease, and Huntingtons disease; its role in regeneration after sciatic nerve and spinal cord injury; and its possible involvement in psychiatric diseases such as depression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I389,I389)","v":15106616},{"$f":"(LEN($J389) - LEN(SUBSTITUTE(LOWER($J389),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J389) - LEN(SUBSTITUTE(LOWER($J389),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J389) - LEN(SUBSTITUTE(LOWER($J389),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B389:D389)","v":3},2004,"Recent advances in early-onset severe retinal degeneration: more than just basic research.","Preising",15106616,"Recent advances in early-onset severe retinal degeneration: more than just basic research.    Abstract:   Successful treatment of early-onset sever retinal degeneration (EOSRD) in an animal model of the disease has provided the first proof-o-principle for retinal gene therapy of higher mammals. Currently, large sets of DNA samples are screened to identify patients with Lebers congenital amaurosis (LCA) carrying mutations in RPE65 as possible candidates for gene therapy trials. Research into EOSRD and LCA aims to identify the function of proteins involved or phenotypic changes upon mutation. These data will be used to describe the disease phenotype and identify parameters that can predict the outcome of gene therapy trials."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I390,I390)","v":14739073},{"$f":"(LEN($J390) - LEN(SUBSTITUTE(LOWER($J390),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J390) - LEN(SUBSTITUTE(LOWER($J390),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J390) - LEN(SUBSTITUTE(LOWER($J390),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B390:D390)","v":3},2003,"Regulation of glyceroneogenesis and phosphoenolpyruvate carboxykinase by fatty acids, retinoic acids and thiazolidinediones: potential relevance to type 2 diabetes.","Tordjman",14739073,"Regulation of glyceroneogenesis and phosphoenolpyruvate carboxykinase by fatty acids, retinoic acids and thiazolidinediones: potential relevance to type 2 diabetes.    Abstract:   Recent studies brought adipocyte glyceroneogenesis back to the fore as an important pathway in fatty acid homeostasis and underlined the key role played by cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) in this pathway. The present review analyses the mechanisms by which a series of hormones and nutrients affect PEPCK-C gene transcription and glyceroneogenesis and describes evidence for disregulation of this pathway in type 2 diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I391,I391)","v":14704328},{"$f":"(LEN($J391) - LEN(SUBSTITUTE(LOWER($J391),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J391) - LEN(SUBSTITUTE(LOWER($J391),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J391) - LEN(SUBSTITUTE(LOWER($J391),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B391:D391)","v":3},2004,"Carotene oxygenases: a new family of double bond cleavage enzymes.","Wyss",14704328,"Carotene oxygenases: a new family of double bond cleavage enzymes.    Abstract:   Beta,beta-carotene 15,15-monooxygensae (betaCMOOX) is the key enzyme involved in the metabolism of provitamin A carotenoids to retinal. Although the enzyme has been known for gt;40 y, it has been only within the last 2 y that the cloning and the molecular characterization of the betaCMOOX from several species was reported in literature. New clones of the carotene metabolizing enzyme have emerged, all belonging to the family of double bond cleavage enzymes, suggesting common ancestry. BetaCMOOX cleaves beta,beta-carotene to retinal in an in vitro activity assay; no apo-carotenals were identified. The second enzyme involved in carotenoid metabolism, beta,beta-carotene 9,10-dioxygenase, is responsible for the excentric cleavage pathway of carotenoids, cleaving beta,beta-carotene to 10-apo-carotenal and beta-ionone. In an expression overview, the betaCMOOX was detected in duodenum, liver, kidney and in the lungs of chickens. In mice, the mRNA for the central cleavage enzyme was highly expressed in liver, testes, small intestine, and kidney. betaCMOOX expression was highest in epithelial and endothelial structures in both species. These results suggest that the source of vitamin A originates from carotenoids in the corresponding tissues, in addition to retinol supplied from liver stores."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I392,I392)","v":14527633},{"$f":"(LEN($J392) - LEN(SUBSTITUTE(LOWER($J392),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J392) - LEN(SUBSTITUTE(LOWER($J392),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J392) - LEN(SUBSTITUTE(LOWER($J392),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B392:D392)","v":3},2003,"Hyperinsulinemic diseases of civilization: more than just Syndrome X.","Cordain",14527633,"Hyperinsulinemic diseases of civilization: more than just Syndrome X.    Abstract:   Compensatory hyperinsulinemia stemming from peripheral insulin resistance is a well-recognized metabolic disturbance that is at the root cause of diseases and maladies of Syndrome X (hypertension, type 2 diabetes, dyslipidemia, coronary artery disease, obesity, abnormal glucose tolerance). Abnormalities of fibrinolysis and hyperuricemia also appear to be members of the cluster of illnesses comprising Syndrome X. Insulin is a well-established growth-promoting hormone, and recent evidence indicates that hyperinsulinemia causes a shift in a number of endocrine pathways that may favor unregulated tissue growth leading to additional illnesses. Specifically, hyperinsulinemia elevates serum concentrations of free insulin-like growth factor-1 (IGF-1) and androgens, while simultaneously reducing insulin-like growth factor-binding protein 3 (IGFBP-3) and sex hormone-binding globulin (SHBG). Since IGFBP-3 is a ligand for the nuclear retinoid X receptor alpha, insulin-mediated reductions in IGFBP-3 may also influence transcription of anti-proliferative genes normally activated by the bodys endogenous retinoids. These endocrine shifts alter cellular proliferation and growth in a variety of tissues, the clinical course of which may promote acne, early menarche, certain epithelial cell carcinomas, increased stature, myopia, cutaneous papillomas (skin tags), acanthosis nigricans, polycystic ovary syndrome (PCOS) and male vertex balding. Consequently, these illnesses and conditions may, in part, have hyperinsulinemia at their root cause and therefore should be classified among the diseases of Syndrome X."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I393,I393)","v":12864868},{"$f":"(LEN($J393) - LEN(SUBSTITUTE(LOWER($J393),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J393) - LEN(SUBSTITUTE(LOWER($J393),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J393) - LEN(SUBSTITUTE(LOWER($J393),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B393:D393)","v":3},2003,"Intrauterine determinants of diabetic kidney disease in disadvantaged populations.","Nelson",12864868,"Intrauterine determinants of diabetic kidney disease in disadvantaged populations.    Abstract:   Disadvantaged populations worldwide are experiencing an increasing incidence of kidney disease, much of which is attributable to diabetes. This report reviews the evidence that intrauterine exposure to growth retardation, diabetes, and vitamin A deficiency contribute disproportionately to the rising incidence of kidney disease in disadvantaged people, because they encounter these exposures more frequently than people from developed countries. These abnormal intrauterine exposures reduce nephron mass by impairing nephrogenesis, thereby increasing the susceptibility to kidney damage from diseases such as hypertension and diabetes that commonly affect disadvantaged people."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I394,I394)","v":12757020},{"$f":"(LEN($J394) - LEN(SUBSTITUTE(LOWER($J394),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J394) - LEN(SUBSTITUTE(LOWER($J394),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J394) - LEN(SUBSTITUTE(LOWER($J394),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B394:D394)","v":3},2003,"The retinoid X receptor and its ligands: versatile regulators of metabolic function, cell differentiation and cell death.","Ahuja",12757020,"The retinoid X receptor and its ligands: versatile regulators of metabolic function, cell differentiation and cell death.    Abstract:   Retinoid X Receptors (RXRs) consist of a family of nuclear receptors that target and regulate multiple signalling pathways. The early evolutionary emergence of RXRs in comparison to other nuclear receptors may have allowed for the development of unique properties as transcriptional regulators. Indeed, the complexity of these receptors is derived from their ability to activate transcription as homodimers or as obligate heterodimeric partners of a multitude of other nuclear receptors. In addition, RXRs can regulate gene expression in a ligand-dependent (forming permissive heterodimeric complexes) or - independent (forming non-permissive heterodimeric complexes) manner. Given that ligand binding is a critical component of RXR function, this review will focus on the ligand dependent functions of RXR. The remarkably conserved ligand binding domain of RXR is a multi-functional structure that in addition to ligand binding, serves as a homo- and heterodimeric interface, and a region to bind coactivactor and corepressor molecules. RXRs have a small ligand binding pocket and therefore bind their ligands (such as 9-cis RA) with both high affinity and specificity. In the presence of ligand, permissive RXR heterodimers bind coactivators, but nonpermissive complexes can bind coactivators or corepressors depending on the activation of the RXRs heterodimeric partner. Physiologically, the temporal and tissue specific pattern of RXRs as well as the presence of phenotypic abnormalities in receptor knockout studies (most severe in RXRa -/- animals) demonstrate the important role for these receptors both during development (morphogenesis) and in adult differentiated tissues (cell proliferation, cell differentiation, cell death). These receptors also play an important regulatory role metabolic signaling pathways (glucose, fatty acid and cholesterol metabolism), including metabolic disorders such as type 2 diabetes, hyperlipidemia and atherosclerosis. RXRs function as master regulators producing diverse physiological effects through the activation of multiple nuclear receptor complexes. RXRs represent important targets for pharmacologic interventions and therapeutic applications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I395,I395)","v":12643171},{"$f":"(LEN($J395) - LEN(SUBSTITUTE(LOWER($J395),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J395) - LEN(SUBSTITUTE(LOWER($J395),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J395) - LEN(SUBSTITUTE(LOWER($J395),LOWER(D$3),\"\")))/LEN(D$3)","v":3},{"$f":"SUM(B395:D395)","v":3},2002,"Antioxidant vitamins and their influence in diabetes mellitus.","Hasanain",12643171,"Antioxidant vitamins and their influence in diabetes mellitus.    Abstract:   Diabetes mellitus is a chronic disease associated with serious complications. A number of studies have suggested that enhanced oxidation is the underlying abnormality responsible for some of the complications of diabetes. It is not known whether the ingestion of antioxidant vitamins could retard or perhaps reverse the oxidative damage. The information regarding the benefit of antioxidant vitamin supplementation is conflicting some trials have demonstrated adverse effects of excessive consumption of vitamin supplements. In this article, we review the available literature on the association of cardiovascular events and ingestion of vitamins with antioxidant properties. Given the lack of data to substantiate the benefit and safety of ingestion of antioxidant vitamins in excess of the recommended dietary allowance, physicians should avoid the recommendation of vitamin supplementation to their patients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I396,I396)","v":12570784},{"$f":"(LEN($J396) - LEN(SUBSTITUTE(LOWER($J396),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J396) - LEN(SUBSTITUTE(LOWER($J396),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J396) - LEN(SUBSTITUTE(LOWER($J396),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B396:D396)","v":3},2003,"Hormonal control of the neuropeptide Y system.","Magni",12570784,"Hormonal control of the neuropeptide Y system.    Abstract:   Neuropeptide Y (NPY) and the related receptors represent a widely diffused system that is involved in the regulation of multiple biological functions. NPY, a 36-aminoacid peptide expressed in several areas of the nervous system, is a pleiotropic factor participating to the control of some physiological processes, such as cognitive functions, eating behavior, circadian rhythms, neuroendocrine mechanisms, reproductive and cardiovascular functions. NPY acts through a series of G-protein-associated membrane receptors (NPY-Rs), characterized by different tissue distribution and affinity for the ligand. The expression and secretion of NPY and the expression of NPY-R isoforms are controlled by a very wide range of agents, acting in an endocrine and/or paracrine fashion. NPY and NPY-Rs appear to be strongly involved in the control of eating behavior; their expression is modulated by changes of food intake and energy balance and is disrupted in several animal models of obesity and diabetes. Moreover, the hypothalamic NPY system appears to integrate signals of energy balance in the modulation of the reproductive axis. Agents that stimulate their expression include activators of intracellular signalling pathways (protein kinase A and C), classical neurotransmitters, steroid and peptide hormones and growth factors, while other agents (leptin, insulin and retinoic acid) have been shown to be inhibitory. Interestingly, some agents, like retinoic acid, have been shown to modulate the expression of both NPY and NPY-Rs in the same direction, thus providing a fine mechanism for the tuning of the system. The regulation of NPY/NPY-R expression and function appears to be part of a complex system controlling multiple physiological functions, and its disruption might be relevant in the pathophysiology of disease states such as obesity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I397,I397)","v":12478728},{"$f":"(LEN($J397) - LEN(SUBSTITUTE(LOWER($J397),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J397) - LEN(SUBSTITUTE(LOWER($J397),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J397) - LEN(SUBSTITUTE(LOWER($J397),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B397:D397)","v":3},2002,"Selective RXR modulators for the treatment of type II diabetes.","Faul",12478728,"Selective RXR modulators for the treatment of type II diabetes.    Abstract:   Retinoid X receptor (RXR) modulators are being evaluated as a means for the treatment of non-insulin dependent (type II) diabetes mellitus, and substantial progress has been made in the preclinical evaluation of these compounds. To aid in this process, several structural classes of RXR modulators are now under investigation. The diverse structures and syntheses of these compounds will be discussed in this review."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I398,I398)","v":12455417},{"$f":"(LEN($J398) - LEN(SUBSTITUTE(LOWER($J398),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J398) - LEN(SUBSTITUTE(LOWER($J398),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J398) - LEN(SUBSTITUTE(LOWER($J398),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B398:D398)","v":3},2001,"Antifibrogenic therapies in chronic HCV infection.","Shimizu",12455417,"Antifibrogenic therapies in chronic HCV infection.    Abstract:   The most common cause of hepatic fibrosis is currently chronic HCV infection, the characteristic feature of which is hepatic steatosis. Hepatic steatosis leads to an increase in lipid peroxidation in hepatocytes, which in turn activates hepatic stellate cells (HSCs). HSCs are also regarded as the primary target cells for inflammatory stimuli, and produce extracellular matrix components. It should be noted that transforming growth factor beta (TGF-beta) is a potent fibrogenic cytokine produced by Kupffer cells and HSCs. There are several approaches to inhibit TGF-beta; use of decorin, soluble receptors, and gene therapy approaches. Hepatocyte growth factor (HGF) is a hepatotrophic factor for liver regeneration and seems to suppress hepatic fibrogenesis in animals. HOE 77, Safironil, and S 4682 are inhibitors of prolyl 4-hydroxylase, which is essential for thecollagen formation. Although HOE 77, Safironil, and S 4682 seem to work by inhibiting HSC activation, further studies will be required before their clinical application. alpha-Tocopherol, retinyl palmitate, and silybinin reduce lipid peroxidation and attenuate HSC activation in experimental models. Retinyl palmitate is the main storage type for retinoids in HSCs. Silymarin is extracted from milk thistle, the principle component of which is the silybinin. Unfortunately, they have had mixed effects in human liver diseases. A Japanese herbal medicine Sho-saiko-to functions as a potent antifibrosuppressant via the inhibition of oxidative stress in hepatocytes and HSCs. Its active components are baicalin and baicalein of flavonoids with chemical structures very similar to silybinin. Understanding the basic mechanisms underlying the HCV-mediated fibrogenesis provides valuable information on the search for effective antifibrogenic therapies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I399,I399)","v":12362775},{"$f":"(LEN($J399) - LEN(SUBSTITUTE(LOWER($J399),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J399) - LEN(SUBSTITUTE(LOWER($J399),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J399) - LEN(SUBSTITUTE(LOWER($J399),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B399:D399)","v":3},2002,"Application of isotope dilution technique in vitamin A nutrition.","Wasantwisut",12362775,"Application of isotope dilution technique in vitamin A nutrition.    Abstract:   The isotope dilution technique involving deuterated retinol has been developed to quantitatively estimate total body reserves of vitamin A in humans. The technique provided good estimates in comparison to hepatic vitamin A concentrations in Bangladeshi surgical patients. Kinetic studies in the United States, Bangladesh, and Guatemala indicated the mean equilibration time of 17 to 20 days irrespective of the size of hepatic reserves. Due to the controversy surrounding the efficacy of a carotene-rich diet on improvement of vitamin A status, the isotope dilution technique was proposed to pursue this research question further (IAEAs coordinated research program). In the Philippines, schoolchildren with low serum retinol concentrations showed significant improvement in total body vitamin A stores following intake of carotene-rich foods (orange fruits and vegetables), using a three-day deuterated-retinol-dilution procedure. When Chinese kindergarten children were fed green and yellow vegetables during the winter, their total body vitamin A stores were sustained as compared to a steady decline of vitamin A stores in the control children. Likewise, daily consumption of purified beta-carotene or diet rich in provitamin A carotenoids were shown to prevent a loss in total body vitamin A stores among Thai lactating women during the rice-planting season. These studies demonstrate potentials of the isotope dilution technique to evaluate the impact of provitamin A carotenoid intervention programs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I400,I400)","v":12148903},{"$f":"(LEN($J400) - LEN(SUBSTITUTE(LOWER($J400),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J400) - LEN(SUBSTITUTE(LOWER($J400),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J400) - LEN(SUBSTITUTE(LOWER($J400),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B400:D400)","v":3},2002,"Liposomal-all-trans-retinoic acid in treatment of acute promyelocytic leukemia.","Ozpolat",12148903,"Liposomal-all-trans-retinoic acid in treatment of acute promyelocytic leukemia.    Abstract:   Acute promyelocytic leukemia (APL) characterized by the translocation t(15;17) is uniquely sensitive to the differentiation-inducing effects of all-trans-retinoic acid (ATRA). All-trans-retinoic acid therapy induces complete clinical remissions (CRs) in most of patients with APL. However, chronic daily oral administration of ATRA results in accelerated metabolism of ATRA, leading to a progressive decline in plasma drug concentrations. These lower drug levels are associated with relapses and resistance to oral ATRA in patients with APL; thus the use of ATRA as a single agent is precluded. Liposomal ATRA (Lipo-ATRA) was designed to maintain high and stable plasma concentrations and to further improve the outcome of the APL disease by overcoming the development of ATRA resistance. Liposomal ATRA was shown to circumvent accelerated drug metabolism in the liver of rats in an animal model. In a phase I clinical study, intravenous (i.v.) administration of lipo-ATRA was shown to produce a significantly better pharmacokinetic profile than oral ATRA (non-liposomal) and to maintain higher and sustained plasma drug concentrations, with a similar side effects. More importantly, lipo-ATRA as a single agent induces PCR-negative molecular remissions in a high proportion of newly diagnosed patients with APL and maintain remissions up to 15-17 months or longer. In this review, we discuss the pharmacological features of lipo-ATRA and the molecular remissions induced by lipo-ATRA in newly diagnosed patients with APL or patients previously treated with ATRA or chemotherapy, and the possible impact of lipo-ATRA on the outcome of APL."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I401,I401)","v":11772294},{"$f":"(LEN($J401) - LEN(SUBSTITUTE(LOWER($J401),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J401) - LEN(SUBSTITUTE(LOWER($J401),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J401) - LEN(SUBSTITUTE(LOWER($J401),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B401:D401)","v":3},2001,"Novel agents for managing dyslipidaemia.","Best",11772294,"Novel agents for managing dyslipidaemia.    Abstract:   An elevated low-density lipoprotein (LDL) cholesterol level is a strong predictor of coronary heart disease (CHD) risk. Over the past seven years, equally strong evidence has accumulated that lowering LDL cholesterol with HMG-CoA reductase inhibitors or statins reduces CHD risk and there is now widespread use of these agents for the primary and secondary prevention of CHD. Treatment issues remain regarding the appropriate degree of LDL cholesterol reduction and whether, in people with very high levels, it would be preferable to achieve the LDL cholesterol goal with a powerful statin alone or combined with an agent that lowers LDL cholesterol by a different mechanism. The main focus in the development of novel agents is the patient with low high-density lipoprotein (HDL) cholesterol, usually associated with hypertriglyceridaemia. Already prevalent as a risk factor for CHD, this abnormality has been linked with insulin resistance, which is likely to increase greatly over the next decade, along with increasing obesity and diabetes. Agents that have potent HDL cholesterol raising capacity include cholesteryl ester transfer protein (CETP) inhibitors, retinoid X receptor (RXR) selective agonists, specific peroxisome proliferator-activated receptor (PPAR) agonists and oestrogen-like compounds. Another area of development involves agents that will lower both cholesterol and triglyceride levels, such as partial inhibitors of microsomal triglyceride transfer protein (MTP) and perhaps squalene synthase inhibitors and agonists of AMP kinase. Future emphasis will be on correcting all lipid abnormalities for the prevention of CHD, not just lowering LDL cholesterol."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I402,I402)","v":11422168},{"$f":"(LEN($J402) - LEN(SUBSTITUTE(LOWER($J402),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J402) - LEN(SUBSTITUTE(LOWER($J402),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J402) - LEN(SUBSTITUTE(LOWER($J402),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B402:D402)","v":3},2001,"Widespread biphasic amyloidosis: response to acitretin.","Hernández-Núñez",11422168,"Widespread biphasic amyloidosis: response to acitretin.    Abstract:   We report a patient who presented with an intensely pruritic rash, with hyperpigmentation of the whole back and multiple hyperpigmented and hyperkeratotic papules over his forearms and lower extremities. Histologically, he showed deposits of amyloid that reacted positively with monoclonal antibodies against cytokeratins. The lesions were resistant to antihistamines and corticosteroids. Treatment with oral acitretin was started and great improvement of the lesion was noted; the patient became asymptomatic. We review the literature on the effect of retinoids in cutaneous amyloidosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I403,I403)","v":11144017},{"$f":"(LEN($J403) - LEN(SUBSTITUTE(LOWER($J403),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J403) - LEN(SUBSTITUTE(LOWER($J403),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J403) - LEN(SUBSTITUTE(LOWER($J403),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B403:D403)","v":3},2000,"[Hepatocellular carcinoma. Part 2. Treatment].","Conte",11144017,"[Hepatocellular carcinoma. Part 2. Treatment].    Abstract:   Recent improvements on the therapeutical management of hepatocellular carcinoma are revised with special attention to evaluate the role of surgery for the disease. Considering that definitive surgical intervention is not feasible in most cases because of extreme tumor extension, multiplicity of tumor foci, and associated advanced liver cirrhosis at the time of diagnosis, others forms of treatment are listed, such as transcatheterarterial chemoembolization, percutaneous ethanol and acetic acid injections, and chemotherapy only to a small portion of patients with no indication for standard treatments. The emerging role of retinoic acid metabolism blocking agents, was examined and may offer a significant new potential treatment for cancer, inclusive the possibility of combining other anticancer drugs with exogenous retinoids or modulation of endogenous retinoids as a real opportunity to advance our ability to treat or prevent human cancer effectively Octreotide, nitrosamine and other drugs are analyzed and is concluded that improves survival and is a valuable alternative in the treatment of inoperable hepatocellular carcinoma. The potential role of intersticial laser coagulation for patients with irresectable hepatic tumors was investigated, and in terms of experience, it has now been developed sufficiently to study its effect on these patients survival. The homeostatic control of angiogenesis and its influences on the tumor growth and for migration of metastatic cells, was focused in this concise review, given that hepatocytes are the source of much of the precursor pool, regulation of angiogenesis may be regarded as a new liver function with important consequences for tissue repair and cancer. Early hepatocellular carcinoma and its recognition in routine clinical practice contributes to improved patients survival. Recombinant-Interferon-alpha therapy surely prevents, the development of cirrhosis or hepatocellular carcinoma in about one-third of patients, with chronic hepatitis C, with sustained response. Finally, in individuals with life-threatening liver disease, such as those with cirrhosis and hepatocellular carcinoma, the liver transplantation, must be considered, besides controversial, however, with increasing experience the results of the procedure in these patients have improved, and may offer a better long-term survival than liver resection."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I404,I404)","v":11017772},{"$f":"(LEN($J404) - LEN(SUBSTITUTE(LOWER($J404),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J404) - LEN(SUBSTITUTE(LOWER($J404),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J404) - LEN(SUBSTITUTE(LOWER($J404),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B404:D404)","v":3},2000,"Evolution of the thyroid hormone-binding protein, transthyretin.","Power",11017772,"Evolution of the thyroid hormone-binding protein, transthyretin.    Abstract:   Transthyretin (TTR) belongs to a group of proteins, which includes thyroxine-binding globulin and albumin, that bind to and transport thyroid hormones in the blood. TTR is also indirectly implicated in the carriage of vitamin A through the mediation of retinol-binding protein (RBP). It was first identified in 1942 in human serum and cerebrospinal fluid and was formerly called prealbumin for its ability to migrate faster than serum albumin on electrophoresis of whole plasma. It is a single polypeptide chain of 127 amino acids (14,000 Da) and is present in the plasma as a tetramer of noncovalently bound monomers. The major sites of synthesis of TTR in eutherian mammals, marsupials, and birds are the liver and choroid plexus but in reptiles it is synthesised only in the choroid plexus. The observation that TTR is strongly expressed in the choroid plexus but not in the liver of the stumpy-tailed lizard and the strong conservation of expression in the choroid plexus from reptiles to mammals have been taken as evidence to suggest that extrahepatic synthesis of TTR evolved first. The identification and cloning of TTR from the liver of an amphibian, Rana catesbeiana, and a teleost fish, Sparus aurata, and its absence from the choroid plexus of both species suggest an alternative model for its evolution. Protein modelling studies are presented that demonstrate differences in the electrostatic characteristics of the molecule in human, rat, chicken, and fish, which may explain why, in contrast to TTR from human and rat, TTR from fish and birds preferentially binds triiodo-l-thyronine."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I405,I405)","v":10968936},{"$f":"(LEN($J405) - LEN(SUBSTITUTE(LOWER($J405),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J405) - LEN(SUBSTITUTE(LOWER($J405),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J405) - LEN(SUBSTITUTE(LOWER($J405),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B405:D405)","v":3},2000,"Possible role of endogenous retinoid (Vitamin A) toxicity in the pathophysiology of primary biliary cirrhosis.","Erickson",10968936,"Possible role of endogenous retinoid (Vitamin A) toxicity in the pathophysiology of primary biliary cirrhosis.    Abstract:   Primary biliary cirrhosis (PBC) is a chronic, cholestatic disease of unknown etiology commonly affecting women. It is characterized by progressive destruction of the small intrahepatic bile ducts and portal inflammation, leading to fibrosis and cirrhosis. The major signs and symptoms of PBC, which include pruritus, lethargy, the sicca syndrome, and osteoporosis, closely resemble the manifestations of hypervitaminosis A. Based on a review of the literature and other observations connecting PBC with retinoid metabolism (vitamin A and its derivatives), the hypothesis is proposed that exposure to excess endogenous retinoids contributes to the pathogenesis of PBC and may be to the cause of some of the signs and symptoms associated with the disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I406,I406)","v":10762741},{"$f":"(LEN($J406) - LEN(SUBSTITUTE(LOWER($J406),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J406) - LEN(SUBSTITUTE(LOWER($J406),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J406) - LEN(SUBSTITUTE(LOWER($J406),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B406:D406)","v":3},2000,"Recent advances in cancer chemoprevention, with emphasis on breast and colorectal cancer.","Decensi",10762741,"Recent advances in cancer chemoprevention, with emphasis on breast and colorectal cancer.    Abstract:   Chemoprevention is a recently introduced and rapidly growing area of oncology that is identifying agents with a potentially preventive role in cancer. Several clinical trials have recently shown the feasibility of this approach in reducing the risk of major human cancers. In the USA, a large trial that demonstrated a reduction of approximately 50% in the risk of developing breast cancer led to Food and Drug Administration (FDA) approval of tamoxifen as a preventive agent in women at increased risk. Although the results could not be reproduced in two smaller European trials, further investigations into this agent are clearly warranted. Raloxifene, another selective oestrogen receptor modulator which has reduced the risk of breast cancer in a trial in women with osteoporosis, is being compared with tamoxifen in a large primary prevention trial in at-risk women. Retinoids are a group of compounds that have proved especially effective in reducing the occurrence of second primary tumours in subjects with skin, head and neck or liver cancer. Fenretinide, a synthetic retinoic acid derivative, has recently been shown to decrease the occurrence of a second breast malignancy in premenopausal women. Results with non-steroidal anti-inflammatory drugs (NSAIDs) have proved consistently encouraging in epidemiological studies in lowering the incidence of colorectal cancer. Clinical trials with selective cyclo-oxygenase inhibitors potentially devoid of gastrointestinal (GI) toxicity are currently underway in at-risk subjects. Calcium and selenium have also received much attention as chemopreventive agents. Originally investigated against skin cancer, selenium showed efficacy in reducing prostate, lung and colon cancer incidence. Similarly, vitamin E was effective in reducing prostate cancer incidence and mortality in a lung cancer prevention trial in heavy smokers. The challenges of conducting well-designed and unequivocal chemoprevention trials are considerable, but advances in techniques of identification of at-risk subjects and establishing surrogate endpoint biomarkers should contribute greatly to future studies. Current knowledge suggests that a pharmacological approach to preventing cancer, using natural or synthetic agents, could become an important way forward."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I407,I407)","v":10665336},{"$f":"(LEN($J407) - LEN(SUBSTITUTE(LOWER($J407),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J407) - LEN(SUBSTITUTE(LOWER($J407),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J407) - LEN(SUBSTITUTE(LOWER($J407),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B407:D407)","v":3},1999,"Human obesity and thinness, hyperlipidemia, hyperglycemia, and insulin resistance associated with HIV1 protease inhibitors. Prevention by alternating several antiproteases in short sequences.","Mathé",10665336,"Human obesity and thinness, hyperlipidemia, hyperglycemia, and insulin resistance associated with HIV1 protease inhibitors. Prevention by alternating several antiproteases in short sequences.    Abstract:   In 1997, and mainly in 1998 and 1999, a lipodystrophic syndrome with central obesity, peripheral fat loss, hyperlipidemia, hyperglycemia and insulin-resistant-diabetes II, was described as the most frequent manifestation of toxicity of HIV1 virostatic therapy, associated with protease inhibitors (PI) in 83% of the patients who used them for 10 months. Almost similar syndromes had been published before the latter, due, for example, to graft vs host reaction, or autoimmunity against insulin receptors, or to caloric excess in the presence of androgens (the mediator being hyperinsulinemia). Carr and Cooper have presented an original pathophysiological mechanism for the PI-associated syndrome, residing in 63% homology between HIV1-protease and the 3-low-density-lipoprotein-receptor-related protein (LRP), and in 53% homology between this virus enzyme and retinoid-binding-protein type 1 (CRAB1). The treatment should be more subtle than those of common obesity and/or type II diabetes. This HIV1-protease inhibitor toxicity can be prevented by alternating several antiproteases in short sequences of the different ones."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I408,I408)","v":10218665},{"$f":"(LEN($J408) - LEN(SUBSTITUTE(LOWER($J408),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J408) - LEN(SUBSTITUTE(LOWER($J408),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J408) - LEN(SUBSTITUTE(LOWER($J408),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B408:D408)","v":3},1999,"Antioxidant potentials of vitamin A and carotenoids and their relevance to heart disease.","Palace",10218665,"Antioxidant potentials of vitamin A and carotenoids and their relevance to heart disease.    Abstract:   Despite being one of the first vitamins to be discovered, the full range of biological activities for vitamin A remains to be defined. Structurally similar to vitamin A, carotenoids are a group of nearly 600 compounds. Only about 50 of these have provitamin A activity. Recent evidence has shown vitamin A, carotenoids and provitamin A carotenoids can be effective antioxidants for inhibiting the development of heart disease. Vitamin A must be obtained from the diet: green and yellow vegetables, dairy products, fruits and organ meats are some of the richest sources. Within the body, vitamin A can be found as retinol, retinal and retinoic acid. Because all of these forms are toxic at high concentrations, they are bound to proteins in the extracellular fluids and inside cells. Vitamin A is stored primarily as long chain fatty esters and as provitamin carotenoids in the liver, kidney and adipose tissue. The antioxidant activity of vitamin A and carotenoids is conferred by the hydrophobic chain of polyene units that can quench singlet oxygen , neutralize thiyl radicals and combine with and stabilize peroxyl radicals. In general, the longer the polyene chain, the greater the peroxyl radical stabilizing ability. Because of their structures, vitamin A and carotenoids can autoxidize when O2 tension increases, and thus are most effective antioxidants at low oxygen tensions that are typical of physiological levels found in tissues. Overall, the epidemiological evidence suggests that vitamin A and carotenoids are important dietary factors for reducing the incidence of heart disease. Although there is considerable discrepancy in the results from studies in humans regarding this relationship, carefully controlled experimental studies continue to indicate that these compounds are effective for mitigating and defending against many forms of cardiovascular disease. More work, especially concerning the relevance of how tissue concentrations, rather than plasma levels, relate to the progression of tissue damage in heart disease is required. This review assembles information regarding the basic structure and metabolism of vitamin A and carotenoids as related to their antioxidant activities. Epidemiological, intervention trials and experimental evidence about the effectiveness of vitamin A and carotenoids for reducing cardiovascular disease is also reviewed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I409,I409)","v":9857270},{"$f":"(LEN($J409) - LEN(SUBSTITUTE(LOWER($J409),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J409) - LEN(SUBSTITUTE(LOWER($J409),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J409) - LEN(SUBSTITUTE(LOWER($J409),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B409:D409)","v":3},1998,"Safety of vitamin A: recent results.","Wiegand",9857270,"Safety of vitamin A: recent results.    Abstract:   A still unresolved public health concern is that excessive vitamin A intake, like vitamin A deficiency, possibly causes birth defects not only in animals but also in man. Due to the low incidence of possibly vitamin A-related malformations in man, available data cannot convincingly define the upper safe limit of periconceptional vitamin A intake. Direct human intervention studies are not feasible for ethical reasons. Therefore, a novel approach in addressing this issue was chosen by combining teratogenicity data from a validated animal model with data on systemic exposure to vitamin A and its major metabolites in female volunteers. In a study in pregnant women endogenous plasma concentrations of vitamin A metabolites during early pregnancy ranged from 0.26 to 7.72 ng/ml. Since they did not cause any foetal malformations, retinoid plasma levels in this range can be considered non-teratogenic. Results of a trial in non-pregnant women document that daily oral vitamin A supplements of 4000, 10,000 and 30,000 IU given for 3 weeks were in the range or slightly above the range of endogenous plasma levels seen in early pregnancy. Even after a 3-week treatment with 30,000 IU/day, peak plasma levels of retinoic acid and isotretinoin were within or just slightly above the range of their physiological levels. In cynomolgus monkeys (average weight: 3-4 kg), a NOAEL (no observed adverse effect level) of 7500 IU per kg body weight and a LOAEL (lowest observed adverse effect level) for developmental toxicity of 20,000 IU/kg was found. Considering these results in the cynomolgus monkey, a dose of 30,000 IU/day should also be considered as non-teratogenic in man."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I410,I410)","v":9782470},{"$f":"(LEN($J410) - LEN(SUBSTITUTE(LOWER($J410),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J410) - LEN(SUBSTITUTE(LOWER($J410),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J410) - LEN(SUBSTITUTE(LOWER($J410),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B410:D410)","v":3},1998,"[Acute reversible night blindness caused by vitamin A deficiency in pancreatic carcinoma].","Schönherr",9782470,"[Acute reversible night blindness caused by vitamin A deficiency in pancreatic carcinoma].    Abstract:    BACKGROUND : Vitamin A deficiency is a leading cause of blindness in childhood in the developing countries. In developed countries xerophthalmia occurs mainly as secondary hypovitaminosis due to malabsorption in chronic alcoholism or intestinal disorders.  PATIENT AND METHODS : A 24-year-old female patient complained of night blindness since one week. There was a history of pancreas tail resection combined with radiation due to a papillary low grade cystic carcinoma at the age of 15. During a review period of 9 years of follow-up there was a slow disseminated metastatic spread including the liver. Despite a progressive tumor cachexia the patient was practising a profession. Visual acuity was 20/20 OU with normal visual fields. Dark adaptation was reduced to one log unit and scotopic electroretinography was extinguished. Serum vitamin A level was reduced to 75 ng/ml (normal range 400-700 ng/ml).  RESULTS : Under vitamin A substitution dark adaption and scotopic electroretinography normalized and night blindness disappeared within 7 days.  CONCLUSIONS : In malabsorption syndromes, especially in combination with liver manifestations, xerophthalmia should be considered as a potential complication. Vitamin A substitution should be administered if necessary. In cases of malignant tumors differential diagnosis includes the cancer associated retinopathy (CAR)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I411,I411)","v":9701158},{"$f":"(LEN($J411) - LEN(SUBSTITUTE(LOWER($J411),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J411) - LEN(SUBSTITUTE(LOWER($J411),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J411) - LEN(SUBSTITUTE(LOWER($J411),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B411:D411)","v":3},1998,"Interactions between zinc and vitamin A: an update.","Christian",9701158,"Interactions between zinc and vitamin A: an update.    Abstract:   Zinc status influences several aspects of vitamin A metabolism, including its absorption, transport, and utilization. Two common mechanisms postulated to explain this dependence relate to 1) the regulatory role of zinc in vitamin A transport mediated through protein synthesis, and 2) the oxidative conversion of retinol to retinal that requires the action of a zinc-dependent retinol dehydrogenase enzyme. However, evidence of an effect of zinc intake on vitamin A status from animal experiments is inconclusive, mainly because of the use of inadequate control groups. The higher weight gain of control animals as compared with the zinc-deficient ones in these experiments, even though pair fed, makes it difficult to isolate effects of zinc deficiency per se from those of generalized protein-energy malnutrition. A curvilinear relation has been suggested to describe an effect of plasma zinc on vitamin A transport. In humans, cross-sectional studies have more often than not shown a weak linkage between vitamin A and zinc status. Randomized trials have failed to show a consistent effect of zinc supplementation on vitamin A status. In disease states in which liver function is severely compromised and both zinc and vitamin A metabolism and transport are impaired, serum zinc and vitamin A concentrations tend to be positively correlated. In conclusion, clear evidence of synergy between these 2 micronutrients and its public health significance in humans is lacking. Research should focus on understanding this interaction in the context of coexisting moderate-to-severe zinc and vitamin A deficiencies in the population."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I412,I412)","v":9129249},{"$f":"(LEN($J412) - LEN(SUBSTITUTE(LOWER($J412),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J412) - LEN(SUBSTITUTE(LOWER($J412),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J412) - LEN(SUBSTITUTE(LOWER($J412),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B412:D412)","v":3},1997,"Vitamin A--functions, dietary requirements and safety in humans.","Gerster",9129249,"Vitamin A--functions, dietary requirements and safety in humans.    Abstract:   In recent years, new physiological functions of vitamin A have been identified in addition to its role in vision, namely its role in immune defence reducing morbidity of measles, of respiratory and possibly HIV infections, in gene regulation, in cell differentiation and morphogenesis. With the discovery of nuclear receptors for retinoic acid additional functions are likely to be found. The recommended dietary allowances (RDA) for vitamin A, including provitamin A carotenoids, vary greatly between countries. This may be explained by difficulties in establishing needs: Homeostatic mechanisms tightly control absorption, storage, release and transport of vitamin A to target tissue, and plasma concentrations do not reflect status unless there is vitamin A deficiency or excess. In the United States RDAs were established on the basis of vitamin A depletion-repletion studies with radio-labelled retinol. Intake requirements were calculated to amount to 1,000 micrograms retinol equivalents (RE) for men, 800 micrograms RE for non-pregnant as well as pregnant women and 1,300 micrograms RE for lactating women. Dietary intake studies in different countries have shown that it is in principle possible to obtain these values from the diet either as preformed vitamin A or in the form of provitamin A carotenoids or both. Risk groups for inadequate intakes include low-income groups and younger persons following weight-reducing and other unbalanced diets. Since experience with recommended intake values in the United States has been excellent, attempts at reducing these levels are unjustified and should be resisted. At intakes of up to three RDA values (approximately 3,000 micrograms RE) no unwanted side-effects are to be expected. Even higher doses, if not taken chronically, have been well tolerated, e.g. in deprived populations with low liver reserves. The suggestion derived from a case-control study that vitamin A taken at supplemental doses of 2,400 micrograms RE may be teratogenic have not been confirmed by several other studies. But it is judicious to follow the recommendations of the American Pediatric Society that women should not exceed a total daily intake of 3,000 micrograms RE. In developing countries where acute and chronic vitamin A deficiency is endemic causing xerophthalmia and blindness and increasing the prevalence of infectious diseases and death in children, special efforts are being made by WHO/UNICEF to provide programs for the eradication of vitamin A deficiency by immediate treatment and by long-term changes in dietary practices."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I413,I413)","v":8977664},{"$f":"(LEN($J413) - LEN(SUBSTITUTE(LOWER($J413),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J413) - LEN(SUBSTITUTE(LOWER($J413),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J413) - LEN(SUBSTITUTE(LOWER($J413),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B413:D413)","v":3},1996,"Acquired perforating dermatosis in a British dialysis population.","Morton",8977664,"Acquired perforating dermatosis in a British dialysis population.    Abstract:   A perforating disorder of the skin developing in association with chronic renal failure and often also diabetes, acquired perforating dermatosis (APD), affects up to 10% of patients receiving maintenance haemodialysis in North America. The prevalence of this condition in British dialysis patients has not yet been ascertained. We have undertaken a skin survey of our dialysis population (n = 80) to determine the prevalence and clinical presentation of APD, with subsequent assessment of disease management and outcome. Of 72 patients who participated in the survey, eight were found to have APD, seven of whom were also diabetic. Skin lesions had developed pre-dialysis in two patients, on commencement of dialysis in one, and after 1-3 years on dialysis in the remaining five. Patients typically presented with pruritic dome-shaped papules with central crusts arising on the trunk and extensor limb surfaces. Histological examination of biopsy specimens revealed two types of lesion, typified by either narrow or broad ulcer craters, each showing perforation of both collagen and elastic fibres. Topical/intradermal steroid or topical retinoid were effective therapies in certain of our patients. Clinical clearance was achieved after 3-12 months of treatment in five patients with improvement in the remaining two patients who received treatment. Of the four patients who were alive at 2-year review, three remained clear, while one patient continued to develop new lesions. We report an 11% prevalence of APD in our dialysis population, suggesting the disorder to be as prevalent in patients with chronic renal failure in Britain as in North America. An association of the disorder with long-standing diabetes was confirmed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I414,I414)","v":8823549},{"$f":"(LEN($J414) - LEN(SUBSTITUTE(LOWER($J414),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J414) - LEN(SUBSTITUTE(LOWER($J414),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J414) - LEN(SUBSTITUTE(LOWER($J414),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B414:D414)","v":3},1996,"Necrobiosis lipoidica treated with topical tretinoin.","Heymann",8823549,"Necrobiosis lipoidica treated with topical tretinoin.    Abstract:   Necrobiosis lipoidica is often resistant to therapeutic intervention. Lesions are atrophic and frequently ulcerate. A case is presented in which atrophy was diminished by the application of topical tretinoin. The practical and theoretical use of topical tretinoin in this disorder is reviewed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I415,I415)","v":8621054},{"$f":"(LEN($J415) - LEN(SUBSTITUTE(LOWER($J415),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J415) - LEN(SUBSTITUTE(LOWER($J415),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J415) - LEN(SUBSTITUTE(LOWER($J415),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B415:D415)","v":3},1996,"Absorption, metabolism, and transport of carotenoids.","Parker",8621054,"Absorption, metabolism, and transport of carotenoids.    Abstract:   Carotenoids are currently under intense scrutiny regarding their potential to modulate chronic disease risk and prevent vitamin A deficiency, and renewed emphasis has been placed on achieving a better understanding of the metabolic fate of these compounds in humans. The development of new animal models, and use of human metabolic studies and stable tracer methods have greatly improved our knowledge of how carotenoids are absorbed, metabolized, and transported to tissues; however, many important issues remain unresolved. For example, intestinal uptake of carotenoids occurs by passive diffusion, but the lumenal or intracellular factors limiting this process are obscure. The intestinal mucosa plays a key role in the metabolism of provitamin A carotenoids such as beta-carotene, thus greatly influencing their bioavailability. Most recent evidence supports a central oxidation mechanism of cleavage of beta-carotene to retinal in the intestinal mucosa, but the extent and site(s) of postabsorptive metabolism in the human is unknown. While the human and other species clearly absorb non-provitamin A carotenoids, little is known of the extent and pathways of their metabolism and elimination. The metabolic fate of cis isomers of beta-carotene is a subject of recent interest, since 9-cis retinoic acid can apparently be formed from 9-cis beta-carotene in vitro and in vivo. Substantial cis-trans isomerization of at least small oral doses of 9-cis beta-carotene occurs in the human, although the site of isomerization is not yet known. Carotenoids are transported in plasma exclusively by lipoproteins, with the distribution among lipoprotein classes determined in large part by the physical properties of the carotenoid. The consequences of differential distribution in terms of tissue uptake and retention are not clear at present. Improved knowledge of the metabolic fate of carotenoids will assist in the development and testing of hypotheses regarding their potential to influence biological processes in the human."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I416,I416)","v":8923025},{"$f":"(LEN($J416) - LEN(SUBSTITUTE(LOWER($J416),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J416) - LEN(SUBSTITUTE(LOWER($J416),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J416) - LEN(SUBSTITUTE(LOWER($J416),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B416:D416)","v":3},1996,"Adverse effects of preventive therapy in humans.","La Vecchia",8923025,"Adverse effects of preventive therapy in humans.    Abstract:   The main adverse effects of tamoxifen, aspirin, oral contraceptives (OCs) and retinoids used as chemopreventive agents in humans are reviewed and quantified here. With regard to tamoxifen, there are suggestions of some excess risk of liver, and perhaps gastrointestinal, cancers. The public health impact of such associations, if any, is still unclear. Tamoxifen use is associated with endometrial and myometrial hyperplasia. Data from five studies based on 174 cases indicate that the overall relative risk (RR) of endometrial cancer in ever tamoxifen users is 1.73 (95% confidence interval = 1.1-2.6). However, there is a significant difference between the results of American and European studies, so the relationship between tamoxifen and endometrial cancer remains open to debate. The major side-effect of aspirin is gastrointestinal lesions; the risk of these is increased two- to tenfold, depending on the dose. Aspirin is also associated with an increased risk of haemorrhagic stroke, although its protection against other types of stroke and against myocardial infarction leads to a favourable pattern of risk for all cardiovascular conditions. Short-term side-effects of OCs include vascular diseases and a moderately increased risk of breast cancer. The RR of cervical cancer and hepatocellular carcinoma are also increased in OC users, although the public health impact of such associations is small. Toxicity associated with retinoid treatment is rarely serious as most effects observed are reversible on stopping use. Side-effects include changes in the skin and mucous membranes (dry skin, hair loss, dry nose, conjunctivitis), musculoskeletal symptoms, ophthalmological effects, changes in transaminase activity, changes in clinical chemistry markers (increase in serum triglycerides and decrease in high-density lipoproteins) and, rarely, central nervous system effects. A serious toxicological aspect of retinoid treatment is teratogenesis; its use should therefore be avoided in women with childbearing potential, and, in cases of use, conception should be delayed for a long time after stopping treatment. Thus, when considering side-effects of chemoprevention, the major issues of concern are the rare long-term effects (chiefly neoplasms), and the need for more precise overall risk-and cost-benefit assessment, particularly for healthy people."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I417,I417)","v":8919126},{"$f":"(LEN($J417) - LEN(SUBSTITUTE(LOWER($J417),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J417) - LEN(SUBSTITUTE(LOWER($J417),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J417) - LEN(SUBSTITUTE(LOWER($J417),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B417:D417)","v":3},1996,"Hyperostotic and destructive osteoarthritis in a patient with vitamin A intoxication syndrome: a case report.","Romero",8919126,"Hyperostotic and destructive osteoarthritis in a patient with vitamin A intoxication syndrome: a case report.    Abstract:   The authors present a case report of a 59-year-old female suffering from hyperlipidemia who developed chronic vitamin A intoxication syndrome after ingestion of 30,000 IU retinol/daily over a period of six years. The patients main complaints included severe headaches, morning nausea, myalgias and disability around the hip, knee, and ankle joints. Radiologically, hyperostosis of the acetabular circumference and the spine was demonstrated. Because of rapidly increasing pain, total hip replacement was performed. Histology of cross sections from the femoral head revealed destructive osteoarthritis. Since no other causative reason was found, retinol may not only be responsible for hyperostotic bone and soft tissue formations but may perhaps also account for rapid progressing of degenerative joint disease. Despite the cessation of vitamin A intake the clinical symptoms persisted due to hyperlipidemia. The enlarged number of chylomicrons and the higher fraction of very low density lipoproteins may represent a second retinyl ester pool in case of overloaded fat storing Ito-cells in the liver. Therefore, rheumatological treatment reducing risk factors such as hyperlipidemia is mandatory."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I418,I418)","v":8767511},{"$f":"(LEN($J418) - LEN(SUBSTITUTE(LOWER($J418),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J418) - LEN(SUBSTITUTE(LOWER($J418),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J418) - LEN(SUBSTITUTE(LOWER($J418),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B418:D418)","v":3},1996,"Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action.","Köhrle",8767511,"Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action.    Abstract:   Development and tissue-specific deiodination of thyroid hormone leads to both activation of the prohormone thyroxine to the thyromimetically active T3 as well as to inactivation of T3 and its conjugates or inactivation of T4 to yield potential regulatory active rT3. At least three deiodinase isoenzymes have so far been characterized and cloned, and the deiodinase isozymes represent a new family of eukaryotic selenoproteins for which an enzyme function could be assigned. Selenium status apparently regulates the expression of these deiodinase isozymes to different extent indicating that a hierarchy of selenium incorporation exists for those enzymes. Currently, it appears that selenium deficiency does not affect expression of type II 5-deiodinase or 5-deiodinase to a marked extent in vivo whereas type I 5-deiodinase at least in liver and kidney is reduced in severe selenium deficiency. However, daily selenium intake in normal mideuropeans already saturates the requirement for the expression of the deiodinase isoenzymes. So far, only reduced expression of 5-D I and decreased T 3 production has been observed in specific diets such as for PKU or in cystic fibrosis, where transport of ions (iodide, selenite?) might be affected. Further alterations of T3 production by 5-D I activity are observed under the conditions of the low T3 syndrome, which comprise a broad spectrum of clinical disorders from carbohydrate withdrawal to intensive care patients. It is not yet clear if selenium supplementation or T3 treatment is beneficial to these patients. The marked tissue-specificity of expression of the deiodinases requires more detailed examinations on the relation between these enzymes and the expression of thyroid hormone action, which is mediated by the nuclear T3 receptor family or receptors and signal transduction molecules in the mitochondria, plasma membrane, or cytoskeleton. The location of the deiodinase enzymes either at the inner side of the plasma membrane or the cytosolic side of the endoplasmic reticulum positions these enzymes to a strategically important location enabling them to act as gate-keepers to the nuclear receptors. Similar to other enzymes involved in the activation or inactivation of compounds with hormone or signalling function, the deiodinases are key elements in the intracrine regulation of hormone activation in target tissues or inactivation in non-target tissues. Therefore, a detailed molecular, cell biological and physiological analysis of the function, regulation and gene structure of these enzymes is required before a development of tissue- or enzyme-specific pharmacological intervention is possible. Nevertheless, first data indicate that reduced 5-deiodinase type I expression in tumor tissues can be re-induced by treatment with retinoids at least in follicular thyroid carcinoma. Further studies are needed to prove that retinoids might be a useful therapeutic tool for re-differentiation therapy of thyroid carcinoma which are inaccessible to surgical intervention or lack radio-iodide uptake and storage. The important function and regio- and cell-specific expression of deiodinase isozymes in the central nervous system is far from being understood. Current first evidence suggests a close interaction between thyroid hormone deiodination, thyroid hormone concentration, and expression of thyroid hormone responsive genes in the adult brain as well as tight regulation and interaction between thyroid hormone metabolism and neurotransmitter synthesis release and action."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I419,I419)","v":7618499},{"$f":"(LEN($J419) - LEN(SUBSTITUTE(LOWER($J419),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J419) - LEN(SUBSTITUTE(LOWER($J419),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J419) - LEN(SUBSTITUTE(LOWER($J419),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B419:D419)","v":3},1995,"Vitamins as therapy in the 1990s.","Swain",7618499,"Vitamins as therapy in the 1990s.    Abstract:    BACKGROUND : At one time vitamins were considered as essential nutrients needed only in very small amounts to prevent deficiency syndromes. Many vitamins and their derivatives, however, are currently being used in the mainstream of medicine as therapeutic modalities.  METHODS : A MEDLINE literature search for clinical reviews and original studies on the use of vitamins in medicine was conducted along with a search of the obtained papers bibliographies. The primary years of search were 1990-1994. Research reports written before 1990 were used after cross-referencing from more recent articles.  RESULTS AND CONCLUSIONS : Based on the literature review, several recommendations for the use of vitamins for treatment and prevention are presented. They include topical vitamin A derivatives (tretinoin) for the treatment of acne and age-related skin damage, oral vitamin A derivatives for severe cystic acne (isotretinoin) and psoriasis (etretinate), vitamin D3 for the treatment and prevention of osteoporosis in postmenopausal females, topical vitamin D in psoriasis patients, and niacin for serum cholesterol reduction. Folate appears to decrease the incidence of neural tube defects if given in the preconception phase of pregnancy. Finally, recent preliminary evidence suggests the possible benefit of antioxidants (vitamins C, E, and beta-carotene) in the prevention of atherosclerosis and cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I420,I420)","v":7621297},{"$f":"(LEN($J420) - LEN(SUBSTITUTE(LOWER($J420),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J420) - LEN(SUBSTITUTE(LOWER($J420),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J420) - LEN(SUBSTITUTE(LOWER($J420),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B420:D420)","v":3},1994,"Postprandial lipoproteins and coronary heart disease.","Clifton",7621297,"Postprandial lipoproteins and coronary heart disease.    Abstract:   Postprandial lipaemia, whether measured using levels of triglyceride of retinyl palmitate, is more severe in patients with coronary heart disease; however, little improvement in the discrimination between individuals with and without coronary heart disease can be made using postprandial measurements rather than measuring levels of high-density-lipoprotein2 cholesterol of apolipoproteins B. Retinyl palmitate levels occasionally reveal differences not apparent from triglyceride measurements. Elevated fasting and postprandial triglyceride levels may produce clinical disease partly by enhancing coagulation and by interfering with fibrinolysis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I421,I421)","v":8100848},{"$f":"(LEN($J421) - LEN(SUBSTITUTE(LOWER($J421),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J421) - LEN(SUBSTITUTE(LOWER($J421),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J421) - LEN(SUBSTITUTE(LOWER($J421),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B421:D421)","v":3},1993,"Adhesion molecules and homeoproteins in the phenotypic determination of skin appendages.","Chuong",8100848,"Adhesion molecules and homeoproteins in the phenotypic determination of skin appendages.    Abstract:   We examined the roles of adhesion molecules and homeoproteins in the morphogenesis of skin appendages using feather as a model. The expression pattern of these molecules in different stages of feather development were very dynamic. For example, neural cell adhesion molecules are present first in the dermal condensations, then in distal bud epithelium, then in the dermal papilla, and finally in the marginal and axial plates. Tenascin is present first in the placode, then in the anterior bud epithelium and mesoderm, and then in the dermal papilla. The expression patterns suggest that the adhesion molecules are involved in forming the boundary of cell groups that interact to form skin appendages. Antibody perturbation of embryonic skin-explant cultures showed that liver cell adhesion molecules are involved in establishing the hexagonal pattern, neural cell adhesion molecules are involved in the formation of dermal condensations, tenascin appears to be involved in the growth of feather buds, and integrin is essential for epithelial-mesenchymal interactions. Using antibodies to XlHbox 1 (similar to Hox 3.3 or C6) and Hox 4.2 (or D4), we showed that there is a homeoprotein gradient within the feather buds, and that the expression pattern is position-specific. It is hypothesized that Hox codes, derived from the combined expression pattern of homeoproteins, determine the phenotypes and orientation of skin appendages. Experiments using retinoids in the media or retinoid-soaked beads to create a local retinoid gradient are consistent with this hypothesis. As demonstrated here, feather development provides an excellent opportunity to analyze the molecular cascade of skin-appendage morphogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I422,I422)","v":2068576},{"$f":"(LEN($J422) - LEN(SUBSTITUTE(LOWER($J422),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J422) - LEN(SUBSTITUTE(LOWER($J422),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J422) - LEN(SUBSTITUTE(LOWER($J422),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B422:D422)","v":3},1991,"Gout and vitamin A intoxication: is there a connection?","Mawson",2068576,"Gout and vitamin A intoxication: is there a connection?    Abstract:   Several lines of indirect evidence implicate vitamin A intoxication, associated mainly with impaired renal function, in the etiopathogenesis of gouty arthritis. The enzyme xanthine oxidase is involved not only in the conversion of xanthine to uric acid but also in that of retinol to its more toxic metabolite, retinoic acid. Retinoic acid should therefore be present in high concentration in hyperuricemic states."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I423,I423)","v":1845560},{"$f":"(LEN($J423) - LEN(SUBSTITUTE(LOWER($J423),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J423) - LEN(SUBSTITUTE(LOWER($J423),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J423) - LEN(SUBSTITUTE(LOWER($J423),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B423:D423)","v":3},1991,"Role of fat-storing cells in hepatic fibrogenesis. Retinoids as possible therapeutic agents.","De Bleser",1845560,"Role of fat-storing cells in hepatic fibrogenesis. Retinoids as possible therapeutic agents.    Abstract:   In normal liver, fat-storing cells are the main storage site of vitamin A derivatives, mainly of retinyl palmitate and oleate. During liver injury, the phenotype of fat-storing cells alters dramatically. The cells gradually lose their fat-droplets, proliferate and synthesize large amounts of connective tissue molecules. In the present paper, we summarize the characteristics of fat-storing cells, review the role of fat-storing cells in development of hepatic fibrosis, and describe how retinoids affect the protein synthesis and proliferation of these cells."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I424,I424)","v":2170809},{"$f":"(LEN($J424) - LEN(SUBSTITUTE(LOWER($J424),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J424) - LEN(SUBSTITUTE(LOWER($J424),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J424) - LEN(SUBSTITUTE(LOWER($J424),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B424:D424)","v":3},1990,"Hepatitis B virus as an insertional mutagene in a human hepatocellular carcinoma.","Dejean",2170809,"Hepatitis B virus as an insertional mutagene in a human hepatocellular carcinoma.    Abstract:   Chronic hepatitis B virus (HBV) infection is etiologically related to human hepatocellular carcinoma (HCC). Most HCCs contain integrated HBV DNA in the liver cellular DNA, suggesting that the integration may be involved in carcinogenesis. From a comparison of a single HBV integration site present in a hepatoma with the corresponding unoccupied site in the non-tumourous tissue of the same liver, we have shown that HBV DNA inserted in a putative cellular exon with striking similarity to the DNA-binding domain of the thyroid/steroid hormone receptors. The corresponding cDNA has been isolated (hap gene) and shown to encode the retinoic acid receptor. In the original patient, integration took place so that the first codons of the viral surface protein gene became fused in frame with most of the hap gene. Because retinoic acid is known to regulate the transcription of target genes crucial for cellular growth and differentiation, it is most probable that consequent to the HBV insertion, hap, usually transcribed at a very low level in normal hepatocytes, became inappropriately expressed as an altered chimaeric retinoic acid receptor, thus contributing to the cell transformation. These results strongly support the possibility that HBV may play a direct role in liver carcinogenesis by insertional mutagenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I425,I425)","v":2103414},{"$f":"(LEN($J425) - LEN(SUBSTITUTE(LOWER($J425),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J425) - LEN(SUBSTITUTE(LOWER($J425),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J425) - LEN(SUBSTITUTE(LOWER($J425),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B425:D425)","v":3},1990,"Hepatic toxicity of vitamin A and synthetic retinoids.","Fallon",2103414,"Hepatic toxicity of vitamin A and synthetic retinoids.    Abstract:   Vitamin A and synthetic retinoids have recently been used increasingly in a variety of health related concerns. Hepatic toxicity is an uncommon but serious side-effect of several Vitamin A derivatives which may lead to cirrhosis. This review will focus on the clinical and pathologic findings of hepatic involvement in chronic hypervitaminosis A and on the evidence concerning the potential hepatotoxicity of currently available synthetic retinoids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I426,I426)","v":3916047},{"$f":"(LEN($J426) - LEN(SUBSTITUTE(LOWER($J426),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J426) - LEN(SUBSTITUTE(LOWER($J426),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J426) - LEN(SUBSTITUTE(LOWER($J426),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B426:D426)","v":3},1985,"[Vitamin A and vitamin E in dermatology].","Menni",3916047,"[Vitamin A and vitamin E in dermatology].    Abstract:   Vitamin A is necessary to maintain the integrity and the differentiation of epithelia of the skin and adnexa. Evident deficiency of vitamin A in chronic diseases, malabsorption and liver affections may result in skin xerosis, follicular keratosis, and metaplasia of mucous membranes. The remarkable toxicity of vitamin A in high doses does not recommend its usage in dermatology. On the contrary the employ of retinoids, synthetic derivatives of vitamin A, brings to excellent results. These vitamin A compounds are much more effective, even if they show important side-effects. Etretinate and isotretinoin are widely used in psoriasis, keratinization disorders, and severe acne. Vitamin E functions in skin biology are not totally known. Vitamin E is used in the treatment of dermolytic recessive epidermolysis bullosa, with controversial results."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I427,I427)","v":6226726},{"$f":"(LEN($J427) - LEN(SUBSTITUTE(LOWER($J427),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J427) - LEN(SUBSTITUTE(LOWER($J427),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J427) - LEN(SUBSTITUTE(LOWER($J427),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B427:D427)","v":3},1983,"Isotretinoin treatment of acne and related disorders: an update.","Shalita",6226726,"Isotretinoin treatment of acne and related disorders: an update.    Abstract:   In the one year since isotretinoin has been available in the United States for the treatment of severe, recalcitrant, nodulocystic acne, there has been extensive clinical verification of the reports of its dramatic efficacy in the treatment of this troublesome disease. Proper selection of patients, as well as treatment with adequate doses of drug for 3 to 5 months, will most often result in significant clinical improvement or total clearing. Although dosages of less than 1 mg/kg/day may produce a nearly equivalent degree of improvement with somewhat fewer or less severe side effects, the recommended daily dose remains 1 mg/kg/day because lower dosages are associated with more frequent relapses. In severe cases, the daily dosage may be increased to 2 mg/kg/day. Teratogenicity, elevation of serum triglycerides, liver function abnormalities, pancreatitis, and pseudotumor cerebri may all be associated with isotretinoin therapy and require close monitoring of the patient."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I428,I428)","v":7039812},{"$f":"(LEN($J428) - LEN(SUBSTITUTE(LOWER($J428),LOWER(B$3),\"\")))/LEN(B$3)","v":3},{"$f":"(LEN($J428) - LEN(SUBSTITUTE(LOWER($J428),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J428) - LEN(SUBSTITUTE(LOWER($J428),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B428:D428)","v":3},1982,"Nutritional problems in cats: taurine deficiency and vitamin A excess.","Hayes",7039812,"Nutritional problems in cats: taurine deficiency and vitamin A excess.    Abstract:   Two nutritional problems of the cat are reviewed. One represents a deficiency of taurine, the other vitamin A toxicity. Taurine deficiency in cats is insidious because the progressive retinal degeneration induced may go unnoticed until the damage is advanced and irreversible. Both rods and cones undergo degeneration along with the underlying tapetum lucidum. The hyperreflective focal lesion is easily observed in the area centralis with an ophthalmoscope and has been previously identified as feline central retinal degeneration. This lesion is not reversed by taurine supplementation, even though the remaining retina may be saved from further degeneration. The cat requires dietary taurine, found in meat and fish, because it cannot synthesize enough to meet demands for bile acid conjugation and tissue metabolism, especially those of muscle and central nervous system. Vitamin A toxicity is not commonly observed in cats but may occur if cats are fed beef liver in which appreciable vitamin A is stored. Cats exhibit muscle soreness and hyperesthesia, especially along the neck and forelimbs where bony exostoses of cervical verterbrae and longbones are common. The diagnosis is readily made from radiographs. The response to removal of vitamin A from the diet is generally rapid and, unless the toxicity has been chronic in young kittens, recovery is generally satisfactory."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I429,I429)","v":349901},{"$f":"(LEN($J429) - LEN(SUBSTITUTE(LOWER($J429),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J429) - LEN(SUBSTITUTE(LOWER($J429),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J429) - LEN(SUBSTITUTE(LOWER($J429),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B429:D429)","v":3},1978,"[Metabolic studies under administration of oral contraceptives. A review].","Hauschildt",349901,"[Metabolic studies under administration of oral contraceptives. A review].    Abstract:   The use of oral contraceptives can produce changes in the metabolism of carbohydrates, lipids, proteins, vitamins, and minerals. Responsible for the alterations seems to be the used oestrogen- and gestagen derivative and not so much the type of the contraceptive. The most frequent findings are raised serum-glucose-, insulin-, and triglyceride levels; disturbances in protein-metabolism increase the risk of developing thrombosis and hypertonia. Little is known about the significance of oral contraceptives on the vitamin- and mineral metabolism--yet extreme deficiencies have not been observed so far. Oral contraceptives can become an extra risk factor when given to women with metabolic disturbances. A literature review of the effect of oral contraceptive (o.c.) use on various metabolic processes is presented. Several studies show an adverse effect of o.c. use on subclinical diabetes and on patients with manifest insulin-independent diabetes. Some researchers have found a beneficial effect of o.c. use on older diabetics. It has not been determined whether the estrogen or gestagen component of o.c.s is responsible for this decrease in glucose tolerance, nor has the mechanism for this effect been discovered. Changes in various plasma protein concentrations have been observed during o.c. use, which affect the blood coagulation and the blood pressure regulation systems. The estrogen component appears to be responsible for the increase in the serum triglyceride concentration during o.c. use; the mechanism is still unknown. Some studies indicate that o.c. use causes an increase in serum cholesterol levels, which could promote gall stone formation. An increase in Vitamin A concentration has been observed during o.c. use. Riboflavin, folic acid, vitamin B 12, and ascorbic acid levels have been shown to decrease during o.c. use. A decrease in pyridoxin levels during o.c. use indicates an increased metabolism of tryptophan to nicotinic acid robosyl-5-phosphate. This would cause a decrease in serotonin production, which could be a cause of the depression experienced by some o.c. users. An increase in the plasma copper and caeruloplasmin levels during o.c. use is apparently due to the estrogen component. An increase in transferrin and the serum iron levels have been observed during o.c. use. Contradictory findings are reported concerning the plasma concentration of zinc."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I430,I430)","v":27794419},{"$f":"(LEN($J430) - LEN(SUBSTITUTE(LOWER($J430),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J430) - LEN(SUBSTITUTE(LOWER($J430),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J430) - LEN(SUBSTITUTE(LOWER($J430),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B430:D430)","v":2},2016,"Mitochondria as a centrally positioned hub in the innate immune response.","Sandhir",27794419,"Mitochondria as a centrally positioned hub in the innate immune response.    Abstract:    NlmCategory=UNASSIGNEDMitochondria are vital organelles involved in numerous cellular functions ranging from energy metabolism to cell survival. Emerging evidence suggests that mitochondria provide a platform for signaling pathways involved in innate immune response. Mitochondrial ROS (mtROS) production, mitochondrial DNA (mtDNA) release, mitochondrial antiviral signaling protein (MAVS) are key triggers in the activation of innate immune response following variety of stress signals that include infection, tissue damage and metabolic dysregulation. The process is mediated through pattern recognition receptors (PRRs) that consist of retinoic acid inducible gene like receptors (RLRs), c-type lectin receptors (CLRs), toll type receptors (TLRs) and nuclear oligomerization-domain like receptors (NLRs). These signals converge to form a multiprotein complex called inflammasome that leads to caspase-1 activation to promote processing of precursor cytokines (pro-IL1β and pro-IL-18) to active cytokines (IL-1β and IL-18). It appears that mitochondria induced inflammasome activation contributes to inflammatory process in many diverse disorders. Therefore, strategies aimed at modulating mitochondria mediated inflammasome activation might be beneficial in many pathophysiological conditions. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I431,I431)","v":27447175},{"$f":"(LEN($J431) - LEN(SUBSTITUTE(LOWER($J431),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J431) - LEN(SUBSTITUTE(LOWER($J431),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J431) - LEN(SUBSTITUTE(LOWER($J431),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B431:D431)","v":2},2016,"Targeting the vitamin D endocrine system (VDES) for the management of inflammatory and malignant skin diseases: An historical view and outlook.","Reichrath",27447175,"Targeting the vitamin D endocrine system (VDES) for the management of inflammatory and malignant skin diseases: An historical view and outlook.    Abstract:    NlmCategory=UNASSIGNEDVitamin D represents one of the major driving factors for the development of life on earth and for human evolution. While up to 10-20 % of the human organisms requirements in vitamin D can be obtained by the diet (under most living conditions in the USA and Europe), approximately 90 % of all needed vitamin D has to be photosynthesized in the skin through the action of the sun (ultraviolet-B (UV-B)). The skin represents a key organ of the human bodys vitamin D endocrine system (VDES), being both the site of vitamin D synthesis and a target tissue for biologically active vitamin D metabolites. It was shown that human keratinocytes possess the enzymatic machinery (CYP27B1) for the synthesis of the biologically most active natural vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), representing an autonomous vitamin D3 pathway. Cutaneous production of 1,25(OH)2D3 may exert intracrine, autocrine, and paracrine effects on keratinocytes and on neighboring cells. Many skin cells (including keratinocytes, sebocytes, fibroblasts, melanocytes, and skin immune cells) express the vitamin D receptor (VDR), an absolute pre-requisite for the mediation of genomic effects of 1,25(OH)2D3 and analogs. VDR belongs to the superfamily of trans-acting transcriptional regulatory factors, which includes the steroid and thyroid hormone receptors as well as the retinoid X receptors (RXR) and retinoic acid receptors (RAR). Numerous studies, including cDNA microarray analyses of messenger RNAs (mRNAs), indicate that as many as 500-1000 genes may be regulated by VDR ligands that control various cellular functions including growth, differentiation, and apoptosis. The observation that 1,25(OH)2D3 is extremely effective in inducing the terminal differentiation and in inhibiting the proliferation of cultured human keratinocytes has resulted in the use of vitamin D analogs for the treatment of psoriasis. This review gives an historical view and summarizes our present knowledge about the relevance of the VDES for the management of inflammatory and malignant skin diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I432,I432)","v":27390265},{"$f":"(LEN($J432) - LEN(SUBSTITUTE(LOWER($J432),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J432) - LEN(SUBSTITUTE(LOWER($J432),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J432) - LEN(SUBSTITUTE(LOWER($J432),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B432:D432)","v":2},2016,"Molecular aspects of β, β-carotene-9, 10-oxygenase 2 in carotenoid metabolism and diseases.","Wu",27390265,"Molecular aspects of β, β-carotene-9, 10-oxygenase 2 in carotenoid metabolism and diseases.    Abstract:    NlmCategory=UNASSIGNEDCarotenoids, the carotenes and xanthophylls, are essential components in human nutrition. β, β-carotene-9, 10-oxygenase 2 (BCO2), also named as β, β-carotene-9, 10-dioxygenase 2 (BCDO2) catalyzes the asymmetrical cleavage of carotenoids, whereas β, β-carotene-15, 15-monooxygenase (BCMO1) conducts the symmetrical cleavage of pro-vitamin A carotenoids into retinoid. Unlike BCMO1, BCO2 has a broader substrate specificity and has been considered an alternative way to produce vitamin A. In contrast to BCMO1, a cytoplasmic protein, BCO2 is located in the inner mitochondrial membrane. The difference in cellular compartmentalization may reflect the different substrate specificity and physiological functions with respect to BCMO1 and BCO2. The BCO2 gene mutations are proven to be associated with yellow color of skin and fat tissue and milk in livestock. Mutation in intron 2 of BCO2 gene is also supposed to be related to the expression of IL-18, a pro-inflammatory cytokine associated with obesity, cardiovascular diseases, and type 2 diabetes. Further, BCO2 is associated with the development of mitochondrial oxidative stress, macular degeneration, anemia, and hepatic steatosis. This review of the literature will mostly address recent updates regarding the role of BCO2 in carotenoid metabolism, and discuss the potential impacts of BCO2 protein and the mutations in mammalian diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I433,I433)","v":27356935},{"$f":"(LEN($J433) - LEN(SUBSTITUTE(LOWER($J433),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J433) - LEN(SUBSTITUTE(LOWER($J433),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J433) - LEN(SUBSTITUTE(LOWER($J433),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B433:D433)","v":2},2016,"Nuclear Receptors in Hepatic Glucose and Lipid Metabolism during Neonatal and Adult Life.","Cai",27356935,"Nuclear Receptors in Hepatic Glucose and Lipid Metabolism during Neonatal and Adult Life.    Abstract:    NlmCategory=UNASSIGNEDResearch efforts focusing on metabolic diseases have established a close conjunction between glucolipid abnormalities and nuclear receptors, a large superfamily of receptors including classic peroxisome proliferation-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs) and glucocorticoid receptors (GRs) together with burgeoning retinoic acid receptor-related orphan receptors (RORs) and REV-ERBs. Nuclear receptors are identified to control a series of physiological and pathological processes of glucose and lipid metabolism and also implicated to mediate the long-term effects of early environmental and nutritional experiences on the formation of adult chronic metabolic disorders in human and animals. Thus, nuclear receptors play profound roles in fetal programming and adult regulation of glucolipid metabolism. In this review, we provide an overview on the recent advances in the field of nuclear receptors focusing on their roles in lipid and glucose metabolism during early and late life courses. We hope that this knowledge may shed new lights on identifying the novel target molecules or pathways for the prevention and treatment of metabolic disorders involving disrupted glucose and lipid homeostasis in human and animals."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I434,I434)","v":27162582},{"$f":"(LEN($J434) - LEN(SUBSTITUTE(LOWER($J434),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J434) - LEN(SUBSTITUTE(LOWER($J434),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J434) - LEN(SUBSTITUTE(LOWER($J434),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B434:D434)","v":2},2016,"Positive evidence for vitamin A role in prevention of type 1 diabetes.","Yosaee",27162582,"Positive evidence for vitamin A role in prevention of type 1 diabetes.    Abstract:   Type 1 diabetes mellitus (T1DM) as one of the most well-known autoimmune disease, results from the destruction of β-cells in pancreas by autoimmune process. T1DM is fatal without insulin treatment. The expansion of alternative treatment to insulin is a dream to be fulfilled. Currently autoimmunity is considered as main factor in development of T1DM. So manipulation of the immune system can be considered as alternative treatment to insulin. For the past decades, vitamin A has been implicated as an essential dietary micronutrient in regulator of immune function. Despite major advantage in the knowledge of vitamin A biology, patients who present T1DM are at risk for deficiency in vitamin A and carotenoids. Applying such evidences, vitamin A treatment may be the key approach in preventing T1DM."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I435,I435)","v":27057076},{"$f":"(LEN($J435) - LEN(SUBSTITUTE(LOWER($J435),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J435) - LEN(SUBSTITUTE(LOWER($J435),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J435) - LEN(SUBSTITUTE(LOWER($J435),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B435:D435)","v":2},2016,"Fat-Soluble Vitamins: Clinical Indications and Current Challenges for Chromatographic Measurement.","Albahrani",27057076,"Fat-Soluble Vitamins: Clinical Indications and Current Challenges for Chromatographic Measurement.    Abstract:   Fat-soluble vitamins, including vitamins A, D and E, are required for a wide variety of physiological functions. Over the past two decades, deficiencies of these vitamins have been associated with increased risk of cancer, type II diabetes mellitus and a number of immune system disorders. In addition, there is increasing evidence of interactions between these vitamins, especially between vitamins A and D. As a result of this enhanced clinical association with disease, translational clinical research and laboratory requests for vitamin measurements have significantly increased. These laboratory requests include measurement of 25-OHD (vitamin D), retinol (vitamin A) and α-tocopherol (vitamin E); the most accepted blood indicators for the assessment of body fat-soluble vitamin (FSV) status. There are significant obstacles to precise FSV measurement in blood. These obstacles include their physical and chemical properties, incomplete standardisation of measurement and limitations in the techniques that are currently used for quantification. The aim of this review is to briefly outline the metabolism and interactions of FSV as a prelude to identifying the current challenges for the quantification of blood vitamins A, D and E."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I436,I436)","v":27053491},{"$f":"(LEN($J436) - LEN(SUBSTITUTE(LOWER($J436),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J436) - LEN(SUBSTITUTE(LOWER($J436),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J436) - LEN(SUBSTITUTE(LOWER($J436),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B436:D436)","v":2},2016,"Current Capabilities and Limitations of Stable Isotope Techniques and Applied Mathematical Equations in Determining Whole-Body Vitamin A Status.","Lietz",27053491,"Current Capabilities and Limitations of Stable Isotope Techniques and Applied Mathematical Equations in Determining Whole-Body Vitamin A Status.    Abstract:    BACKGROUND : Retinol isotope dilution (RID) methodology provides a quantitative estimate of total body vitamin A (VA) stores and is the best method currently available for assessing VA status in adults and children. The methodology has also been used to test the efficacy of VA interventions in a number of low-income countries. Infections, micronutrient deficiencies (eg, iron and zinc), liver disease, physiological age, pregnancy, and lactation are known or hypothesized to influence the accuracy of estimating total body VA stores using the isotope dilution technique.  OBJECTIVE : Our objectives were to review the strengths and limitations of RID methods, to discuss what is known about the impact of various factors on results, and to summarize contributions of model-based compartmental analysis to assessing VA status.  METHODS : Relevant published literature is reviewed and discussed.  RESULTS : Various equations and compartmental modeling have been used to estimate the total body VA stores using stable isotopes, including a newer 3-day equation that provides an estimate of total body VA stores in healthy adults. At present, there is insufficient information on absorption of the isotope tracer, and there is a need to further investigate how various factors impact the application of RID techniques in field studies.  CONCLUSIONS : Isotope dilution methodology can provide useful estimates of total body VA stores in apparently healthy populations under controlled study conditions. However, more research is needed to determine whether the method is suitable for use in settings where there is a high prevalence of infection, iron deficiency, and/or liver disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I437,I437)","v":26962021},{"$f":"(LEN($J437) - LEN(SUBSTITUTE(LOWER($J437),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J437) - LEN(SUBSTITUTE(LOWER($J437),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J437) - LEN(SUBSTITUTE(LOWER($J437),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B437:D437)","v":2},2016,"Nuclear receptors and nonalcoholic fatty liver disease.","Cave",26962021,"Nuclear receptors and nonalcoholic fatty liver disease.    Abstract:   Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I438,I438)","v":26641242},{"$f":"(LEN($J438) - LEN(SUBSTITUTE(LOWER($J438),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J438) - LEN(SUBSTITUTE(LOWER($J438),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J438) - LEN(SUBSTITUTE(LOWER($J438),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B438:D438)","v":2},2015,"Therapy of Primary Sclerosing Cholangitis--Today and Tomorrow.","Halilbasic",26641242,"Therapy of Primary Sclerosing Cholangitis--Today and Tomorrow.    Abstract:   Primary sclerosing cholangitis (PSC) represents a fibro-obliterative bile duct disease with unpredictable individual clinical course that may progress to liver cirrhosis and malignancy. Due to our incomplete understanding of the etiology and pathogenesis of this disease, the therapeutic options are still rather limited. Bile acids play a key role in mediating cholangiocellular and hepatocellular injury in cholangiopathies such as PSC. Therefore, strategies targeting bile composition and homeostasis are valid approaches in PSC. Ursodeoxycholic acid (UDCA) is the paradigm therapeutic bile acid and its role in medical therapy of PSC is still under debate. Promising novel bile acid-based therapeutic options include 24-norursodeoxycholic acid (norUDCA), a side chain-shortened C23 homologue of UDCA, and bile acid receptor/farnesoid X receptor agonists (e.g. obeticholic acid). Other nuclear receptors such as fatty acid-activated peroxisome proliferator-activated receptors, vitamin D receptor and vitamin A receptors (retinoic acid receptor, retinoid X receptor) are also of potential interest and can be targeted by already available drugs. Furthermore, drugs targeting the gut-liver axis (e.g. intregrin blockers such as vedolizumab, antibiotics) appear promising, based on the close link of PSC to inflammatory bowel disease and the emerging relevance of the gut microbiome for the development of PSC. Finally, fibrosis represents a valid therapeutic target for anti-fibrotic drugs (e.g. simtuzumab) in PSC as paradigm fibro-obliterative disease. This review summarizes the current status and recent progress in the development of targeted therapeutic approaches based on increasing knowledge about the pathogenesis of this disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I439,I439)","v":26559678},{"$f":"(LEN($J439) - LEN(SUBSTITUTE(LOWER($J439),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J439) - LEN(SUBSTITUTE(LOWER($J439),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J439) - LEN(SUBSTITUTE(LOWER($J439),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B439:D439)","v":2},2016,"The Role of Retinoic Acid (RA) in Spermatogonial Differentiation.","Busada",26559678,"The Role of Retinoic Acid (RA) in Spermatogonial Differentiation.    Abstract:   Retinoic acid (RA) directs the sequential, but distinct, programs of spermatogonial differentiation and meiotic differentiation that are both essential for the generation of functional spermatozoa. These processes are functionally and temporally decoupled, as they occur in distinct cell types that arise over a week apart, both in the neonatal and adult testis. However, our understanding is limited in terms of what cellular and molecular changes occur downstream of RA exposure that prepare differentiating spermatogonia for meiotic initiation. In this review, we describe the process of spermatogonial differentiation and summarize the current state of knowledge regarding RA signaling in spermatogonia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I440,I440)","v":26487494},{"$f":"(LEN($J440) - LEN(SUBSTITUTE(LOWER($J440),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J440) - LEN(SUBSTITUTE(LOWER($J440),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J440) - LEN(SUBSTITUTE(LOWER($J440),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B440:D440)","v":2},2015,"[Granuloma annulare].","Butsch",26487494,"[Granuloma annulare].    Abstract:   Granuloma annulare is a benign, chronic inflammatory skin disease. Its pathogenesis is still unclear, but reports on infections as a trigger can be found. In addition, some authors reported an association with other systemic disease, e.g., cancer, trauma, and diabetes mellitus; however, these have not been verified. The clinical picture of granuloma annulare ranges from the localized form predominantly at the extremities to disseminated, subcutaneous, or perforating forms. Diagnosis is based on the typical clinical presentation which may be confirmed by a biopsy. Histologically, necrobiotic areas within granulomatous inflammation are typical. The prognosis of the disease is good with spontaneous resolution being frequently observed, especially in localized forms. Disseminated manifestations tend to persist longer, and recurrences are reported. When choosing between different therapeutic options, the benign disease character versus the individual degree of suffering and the potential therapy side effects must be considered. For local treatment, topical application of corticosteroids is most common. Disseminated forms can be treated systemically with corticosteroids for several weeks; alternatively, dapsone, hydroxychloroquine, retinoids, fumaric acid, cyclosporine, and anti-TNFα appear to be effective."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I441,I441)","v":26451809},{"$f":"(LEN($J441) - LEN(SUBSTITUTE(LOWER($J441),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J441) - LEN(SUBSTITUTE(LOWER($J441),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J441) - LEN(SUBSTITUTE(LOWER($J441),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B441:D441)","v":2},2016,"The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways.","Mellor",26451809,"The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways.    Abstract:   The development of adverse outcome pathways (AOPs) is becoming a key component of twenty-first century toxicology. AOPs provide a conceptual framework that links the molecular initiating event to an adverse outcome through organized toxicological knowledge, bridging the gap from chemistry to toxicological effect. As nuclear receptors (NRs) play essential roles for many physiological processes within the body, they are used regularly as drug targets for therapies to treat many diseases including diabetes, cancer and neurodegenerative diseases. Due to the heightened development of NR ligands, there is increased need for the identification of related AOPs to facilitate their risk assessment. Many NR ligands have been linked specifically to steatosis. This article reviews and summarizes the role of NR and their importance with links between NR examined to identify plausible putative AOPs. The following NRs are shown to induce hepatic steatosis upon ligand binding: aryl hydrocarbon receptor, constitutive androstane receptor, oestrogen receptor, glucocorticoid receptor, farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptor, pregnane X receptor and the retinoic acid receptor. A preliminary, putative AOP was formed for NR binding linked to hepatic steatosis as the adverse outcome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I442,I442)","v":26294335},{"$f":"(LEN($J442) - LEN(SUBSTITUTE(LOWER($J442),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J442) - LEN(SUBSTITUTE(LOWER($J442),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J442) - LEN(SUBSTITUTE(LOWER($J442),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B442:D442)","v":2},2015,"Beta Cell Function and the Nutritional State: Dietary Factors that Influence Insulin Secretion.","Moore",26294335,"Beta Cell Function and the Nutritional State: Dietary Factors that Influence Insulin Secretion.    Abstract:   Approximately 366 million people worldwide have been diagnosed with type-2 diabetes (T2D). Chronic insulin resistance, decreased functional β-cell mass, and elevated blood glucose are defining characteristics of T2D. Great advances have been made in understanding the pathogenesis of T2D with respect to the effects of dietary macronutrient composition and energy intake on β-cell physiology and glucose homeostasis. It has been further established that obesity is a leading pathogenic factor for developing insulin resistance. However, insulin resistance may not progress to T2D unless β-cells are unable to secret an adequate amount of insulin to compensate for decreased insulin sensitivity. Therefore, pancreatic β-cell dysfunction plays an important role in the development of overt diabetes. This paper reviews recent research findings on the effects of several micronutrients (zinc, vitamin D, iron, vitamin A), leucine, and the phytochemical, genistein on pancreatic β-cell physiology with emphasis on their effects on insulin secretion, specifically in the context of T2D."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I443,I443)","v":26029163},{"$f":"(LEN($J443) - LEN(SUBSTITUTE(LOWER($J443),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J443) - LEN(SUBSTITUTE(LOWER($J443),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J443) - LEN(SUBSTITUTE(LOWER($J443),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B443:D443)","v":2},2015,"Reporter Cell Lines for the Characterization of the Interactions between Human Nuclear Receptors and Endocrine Disruptors.","Grimaldi",26029163,"Reporter Cell Lines for the Characterization of the Interactions between Human Nuclear Receptors and Endocrine Disruptors.    Abstract:   Endocrine-disrupting chemicals (EDCs) are exogenous substances interfering with hormone biosynthesis, metabolism, or action, and consequently causing disturbances in the endocrine system. Various pathways are activated by EDCs, including interactions with nuclear receptors (NRs), which are primary targets of numerous environmental contaminants. The main NRs targeted by environmental contaminants are the estrogen (ER α, β) and the androgen (AR) receptors. ERs and AR have pleiotropic regulatory roles in a diverse range of tissues, notably in the mammary gland, the uterus, and the prostate. Thus, dysfunctional ERs and AR signaling due to inappropriate exposure to environmental pollutants may lead to hormonal cancers and infertility. The pregnane X receptor (PXR) is also recognized by many environmental molecules. PXR has a protective role of the body through its ability to regulate proteins involved in the metabolism, the conjugation, and the transport of many exogenous and endogenous compounds. However, the permanent activation of this receptor by xenobiotics may lead to premature drug metabolism, the formation, and accumulation of toxic metabolites and defects in hormones homeostasis. The activity of other NRs can also be affected by environmental molecules. Compounds capable of inhibiting or activating the estrogen related (ERRγ), the thyroid hormone (TRα, β), the retinoid X receptors (RXRα, β, γ), and peroxisome proliferator-activated (PPAR α, γ) receptors have been identified and are highly suspected to promote developmental, reproductive, neurological, or metabolic diseases in humans and wildlife. In this review, we provide an overview of reporter cell lines established to characterize the human NR activities of a large panel of EDCs including natural as well as industrial compounds such as pesticides, plasticizers, surfactants, flame retardants, and cosmetics."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I444,I444)","v":25925330},{"$f":"(LEN($J444) - LEN(SUBSTITUTE(LOWER($J444),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J444) - LEN(SUBSTITUTE(LOWER($J444),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J444) - LEN(SUBSTITUTE(LOWER($J444),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B444:D444)","v":2},2015,"Insights into the All-trans-Retinoic Acid and Arsenic Trioxide Combination Treatment for Acute Promyelocytic Leukemia: A Meta-Analysis.","Ma",25925330,"Insights into the All-trans-Retinoic Acid and Arsenic Trioxide Combination Treatment for Acute Promyelocytic Leukemia: A Meta-Analysis.    Abstract:    BACKGROUND : This study aimed to compare the curative effects of the combination therapy of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO, As₂O₃) with ATRA monotherapy on newly diagnosed acute promyelocytic leukemia (APL).  METHODS : The studies were retrieved from PubMed, EMBASE, Cochrane Library, ChinaInfo and China National Knowledge Infrastructure (CNKI) databases from the inception to June 20, 2014. Thereafter, the eligible studies were selected based on the predefined criteria, and the literature quality was assessed. The meta-analysis was conducted using Review Manager 5.2 software. The pooled effect size was relative risk (RR) and its 95% confidence interval (CI).  RESULTS : A total of 8 studies containing 480 cases were included, among which 264 were assigned to the ATRA + ATO group and the other 216 to the ATRA group. The meta-analysis showed that ATRA + ATO combination therapy significantly improved the complete remission (CR) rate (RR = 1.09, 95% CI = 1.03-1.16, p = 0.004), decreased the early mortality rate (RR = 0.42, 95% CI = 0.20-0.9, p = 0.03) and relapse rate (RR = 0.17, 95% CI = 0.07-0.42, p lt; 0.0001), but increased the high risk of liver dysfunction (RR = 2.43, 95% CI = 1.72-3.41, p lt; 0.00001), comparing with ATRA monotherapy.  CONCLUSIONS : The ATRA + ATO combination therapy may be more effective for newly diagnosed APL with a higher CR rate but lower early mortality rate and relapse rate. However, the risks of liver damage should be of concern."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I445,I445)","v":25920087},{"$f":"(LEN($J445) - LEN(SUBSTITUTE(LOWER($J445),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J445) - LEN(SUBSTITUTE(LOWER($J445),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J445) - LEN(SUBSTITUTE(LOWER($J445),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B445:D445)","v":2},2015,"New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.","Beuers",25920087,"New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond.    Abstract:   Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent norUDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I446,I446)","v":25858547},{"$f":"(LEN($J446) - LEN(SUBSTITUTE(LOWER($J446),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J446) - LEN(SUBSTITUTE(LOWER($J446),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J446) - LEN(SUBSTITUTE(LOWER($J446),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B446:D446)","v":2},2015,"Apolipoprotein M.","Ren",25858547,"Apolipoprotein M.    Abstract:   Apolipoprotein M (ApoM) is a novel apolipoprotein that was discovered in 1999 and is bound primarily to high-density lipoproteins (HDLs) in the plasma. Multiple factors may influence its expression at both the post-transcriptional and the transcriptional levels both in vivo and ex vivo as follows: hepatocyte nuclear factor-1α, 4α (HNF-1α, 4α), liver receptor homolog-1 (LRH-1), forkhead box A2 (Foxa2) and platelet activating factor (PAF) upregulate its expression; liver X receptor (LXR), retinoid X receptor (RXR), farnesoid X receptor (FXR), small heterodimer partner (SHP) and the majority of cytokines downregulate its expression. However, mechanisms underlying these processes remain unknown. Structurally, there exists a characterized hydrophobic binding pocket within the apoM protein, which enables it to bind functional lipids such as Sphingosine-1-Phosphate (S1P). Functionally, it facilitates the formation of preβ-HDL and enhances an avalanche of atheroprotective effects exerted by HDL. Moreover, in patients with diabetes, the levels of plasma apoM may decrease, whereas the augmentation of apoM decreases plasma glucose levels and magnifies the secretion of insulin. This article offers a panorama of the progress made in the research regarding the characteristics of apoM, particularly the regulation of its expression and its functions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I447,I447)","v":25722444},{"$f":"(LEN($J447) - LEN(SUBSTITUTE(LOWER($J447),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J447) - LEN(SUBSTITUTE(LOWER($J447),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J447) - LEN(SUBSTITUTE(LOWER($J447),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B447:D447)","v":2},2015,"Are there genetic paths common to obesity, cardiovascular disease outcomes, and cardiovascular risk factors?","Rankinen",25722444,"Are there genetic paths common to obesity, cardiovascular disease outcomes, and cardiovascular risk factors?    Abstract:   Clustering of obesity, coronary artery disease, and cardiovascular disease risk factors is observed in epidemiological studies and clinical settings. Twin and family studies have provided some supporting evidence for the clustering hypothesis. Loci nearest a lead single nucleotide polymorphism (SNP) showing genome-wide significant associations with coronary artery disease, body mass index, C-reactive protein, blood pressure, lipids, and type 2 diabetes mellitus were selected for pathway and network analyses. Eighty-seven autosomal regions (181 SNPs), mapping to 56 genes, were found to be pleiotropic. Most pleiotropic regions contained genes associated with coronary artery disease and plasma lipids, whereas some exhibited coaggregation between obesity and cardiovascular disease risk factors. We observed enrichment for liver X receptor (LXR)/retinoid X receptor (RXR) and farnesoid X receptor/RXR nuclear receptor signaling among pleiotropic genes and for signatures of coronary artery disease and hepatic steatosis. In the search for functionally interacting networks, we found that 43 pleiotropic genes were interacting in a network with an additional 24 linker genes. ENCODE (Encyclopedia of DNA Elements) data were queried for distribution of pleiotropic SNPs among regulatory elements and coding sequence variations. Of the 181 SNPs, 136 were annotated to ≥ 1 regulatory feature. An enrichment analysis found over-representation of enhancers and DNAse hypersensitive regions when compared against all SNPs of the 1000 Genomes pilot project. In summary, there are genomic regions exerting pleiotropic effects on cardiovascular disease risk factors, although only a few included obesity. Further studies are needed to resolve the clustering in terms of DNA variants, genes, pathways, and actionable targets."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I448,I448)","v":25683035},{"$f":"(LEN($J448) - LEN(SUBSTITUTE(LOWER($J448),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J448) - LEN(SUBSTITUTE(LOWER($J448),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J448) - LEN(SUBSTITUTE(LOWER($J448),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B448:D448)","v":2},2015,"Triorganotin compounds--ligands for quot;rexinoidquot; inducible transcription factors: biological effects.","Brtko",25683035,"Triorganotin compounds--ligands for quot;rexinoidquot; inducible transcription factors: biological effects.    Abstract:   We review trialkyltin and triaryltin compounds, representing a class of organometallic compounds that function as nuclear retinoid X receptors (RXR) agonists due to their capability to bind to the ligand-binding domain of RXR subtypes and function as transcriptional activators. RXRs act predominantly as heterodimers with other nuclear receptors as permissive heterodimers with peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptor, pregnane X receptor and constitutive androstan receptor or as non-permissive heterodimer with vitamin D receptor, and as conditional heterodimers with retinoid receptors, and thyroid hormone receptors. RXR - quot;partnerquot; receptor heterodimers are considered to be ligand-activated, DNA-binding, trans-acting, transcription-modulating proteins involved in a general molecular mechanism responsible for transcriptional responses in target genes. Tributyltin at even pico- or nanomolar concentrations may cause the superimposition of male genitalia on female in several aquatic organisms, since they are DNA-targeted, mitotic, and their actions are occurring through target gene(s)-mediated pathways. They may cause molecular interactions with reproductive system in mammals, and as potent environmental obesogens, they promote adipocyte differentiation. Organotin compounds become known also for their immunotoxicity, neurotoxicity, for their effects on reproduction and/or development. We also review effects of organotins with respect to levels and activities of hepatic P450s and aromatase activity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I449,I449)","v":25640656},{"$f":"(LEN($J449) - LEN(SUBSTITUTE(LOWER($J449),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J449) - LEN(SUBSTITUTE(LOWER($J449),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J449) - LEN(SUBSTITUTE(LOWER($J449),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B449:D449)","v":2},2015,"The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells.","Liu",25640656,"The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells.    Abstract:   Regulatory T (Treg) cells are necessary for immune system homeostasis and the prevention of autoimmune diseases. Foxp3 is specifically expressed in Treg cells and plays a key role in their differentiation and function. Foxp3(+) Treg cells are consisted of naturally occurring, thymus-derived Treg (nTreg) and peripheral-induced Treg (iTreg) cells that may have different functional characteristics or synergistic roles. All-trans retinoic acid (atRA), a vitamin A metabolite, regulates a wide range of biological processes, including cell differentiation and proliferation. Recent studies demonstrated that atRA also regulates the differentiation of T helper (Th) cells and Treg cells. Moreover, atRA also sustains nTreg stability under inflammatory conditions. In this review, we summarize the significant progress of our understanding of the role(s) and mechanisms of atRA in Treg biology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I450,I450)","v":25568859},{"$f":"(LEN($J450) - LEN(SUBSTITUTE(LOWER($J450),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J450) - LEN(SUBSTITUTE(LOWER($J450),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J450) - LEN(SUBSTITUTE(LOWER($J450),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B450:D450)","v":2},2014,"Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology.","Weiskirchen",25568859,"Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology.    Abstract:   The liver is a central immunological organ. Liver resident macrophages, Kupffer cells (KC), but also sinusoidal endothelial cells, dendritic cells (DC) and other immune cells are involved in balancing immunity and tolerance against pathogens, commensals or food antigens. Hepatic stellate cells (HSCs) have been primarily characterized as the main effector cells in liver fibrosis, due to their capacity to transdifferentiate into collagen-producing myofibroblasts (MFB). More recent studies elucidated the fundamental role of HSC in liver immunology. HSC are not only the major storage site for dietary vitamin A (Vit A) (retinol, retinoic acid), which is essential for proper function of the immune system. This pericyte further represents a versatile source of many soluble immunological active factors including cytokines [e.g., interleukin 17 (IL-17)] and chemokines [C-C motif chemokine (ligand) 2 (CCL2)], may act as an antigen presenting cell (APC), and has autophagy activity. Additionally, it responds to many immunological triggers via toll-like receptors (TLR) (e.g., TLR4, TLR9) and transduces signals through pathways and mediators traditionally found in immune cells, including the Hedgehog (Hh) pathway or inflammasome activation. Overall, HSC promote rather immune-suppressive responses in homeostasis, like induction of regulatory T cells (Treg), T cell apoptosis (via B7-H1, PDL-1) or inhibition of cytotoxic CD8 T cells. In conditions of liver injury, HSC are important sensors of altered tissue integrity and initiators of innate immune cell activation. Vice versa, several immune cell subtypes interact directly or via soluble mediators with HSC. Such interactions include the mutual activation of HSC (towards MFB) and macrophages or pro-apoptotic signals from natural killer (NK), natural killer T (NKT) and gamma-delta T cells (γδ T-cells) on activated HSC. Current directions of research investigate the immune-modulating functions of HSC in the environment of liver tumors, cellular heterogeneity or interactions promoting HSC deactivation during resolution of liver fibrosis. Understanding the role of HSC as central regulators of liver immunology may lead to novel therapeutic strategies for chronic liver diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I451,I451)","v":25526563},{"$f":"(LEN($J451) - LEN(SUBSTITUTE(LOWER($J451),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J451) - LEN(SUBSTITUTE(LOWER($J451),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J451) - LEN(SUBSTITUTE(LOWER($J451),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B451:D451)","v":2},2014,"Recent developments in β-cell differentiation of pluripotent stem cells induced by small and large molecules.","Kumar",25526563,"Recent developments in β-cell differentiation of pluripotent stem cells induced by small and large molecules.    Abstract:   Human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), hold promise as novel therapeutic tools for diabetes treatment because of their self-renewal capacity and ability to differentiate into beta (β)-cells. Small and large molecules play important roles in each stage of β-cell differentiation from both hESCs and hiPSCs. The small and large molecules that are described in this review have significantly advanced efforts to cure diabetic disease. Lately, effective protocols have been implemented to induce hESCs and human mesenchymal stem cells (hMSCs) to differentiate into functional β-cells. Several small molecules, proteins, and growth factors promote pancreatic differentiation from hESCs and hMSCs. These small molecules (e.g., cyclopamine, wortmannin, retinoic acid, and sodium butyrate) and large molecules (e.g. activin A, betacellulin, bone morphogentic protein (BMP4), epidermal growth factor (EGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), noggin, transforming growth factor (TGF-α), and WNT3A) are thought to contribute from the initial stages of definitive endoderm formation to the final stages of maturation of functional endocrine cells. We discuss the importance of such small and large molecules in uniquely optimized protocols of β-cell differentiation from stem cells. A global understanding of various small and large molecules and their functions will help to establish an efficient protocol for β-cell differentiation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I452,I452)","v":25427908},{"$f":"(LEN($J452) - LEN(SUBSTITUTE(LOWER($J452),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J452) - LEN(SUBSTITUTE(LOWER($J452),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J452) - LEN(SUBSTITUTE(LOWER($J452),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B452:D452)","v":2},2015,"Alcohol consumption, Wnt/β-catenin signaling, and hepatocarcinogenesis.","Mercer",25427908,"Alcohol consumption, Wnt/β-catenin signaling, and hepatocarcinogenesis.    Abstract:   Alcohol is a well-established risk factor for hepatocellular carcinoma, and the mechanisms by which alcohol liver cancer is complex. It has been suggested that ethanol (EtOH) metabolism may enhance tumor progression by increasing hepatocyte proliferation. To test this hypothesis, ethanol (EtOH) feeding of male mice began 7 weeks post-injection of the chemical carcinogen diethylnitrosamine (DEN), and continued for 16 weeks, with a final EtOH concentration of 28% of total calories. As expected, EtOH increased the total number of cancerous foci and liver tumors identified in situ fixed livers from the EtOH+DEN group compared to corresponding pair-fed (PF)+DEN and chow+DEN control groups. In the EtOH+DEN group, tumor multiplicity corresponded to a 3- to 4-fold increase in proliferation and immunohistochemical staining of β-catenin in non-tumorigenic hepatocytes when compared to the PF+DEN and chow+DEN groups, plt;0.05. Analysis of EtOH-treated livers from a previously published rat model of chronic liver disease revealed increases in hepatocyte proliferation accompanied by a hepatic depletion of retinol and retinoic acid stores (plt;0.05), nuclear accumulation of β-catenin (plt;0.05), increased cytosolic expression p-GSK3β (plt;0.05), significant upregulation of soluble Wnts, Wnt2, and Wnt7a, and increased expression of several β-catenin targets involved in tumor promotion and progression, cyclin D1, c-myc, WISP1, and MMP7 (plt;0.05). These data suggest that chronic EtOH consumption activates the Wnt/β-catenin signaling pathway, which increases hepatocyte proliferation thus promoting tumorigenesis following an initiating insult in the liver."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I453,I453)","v":25232244},{"$f":"(LEN($J453) - LEN(SUBSTITUTE(LOWER($J453),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J453) - LEN(SUBSTITUTE(LOWER($J453),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J453) - LEN(SUBSTITUTE(LOWER($J453),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B453:D453)","v":2},2014,"Nuclear receptors and pathogenesis of pancreatic cancer.","Polvani",25232244,"Nuclear receptors and pathogenesis of pancreatic cancer.    Abstract:   Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I454,I454)","v":25088698},{"$f":"(LEN($J454) - LEN(SUBSTITUTE(LOWER($J454),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J454) - LEN(SUBSTITUTE(LOWER($J454),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J454) - LEN(SUBSTITUTE(LOWER($J454),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B454:D454)","v":2},2015,"Role of TG-interacting factor (Tgif) in lipid metabolism.","Pramfalk",25088698,"Role of TG-interacting factor (Tgif) in lipid metabolism.    Abstract:   TG interacting factors (Tgifs) 1 and 2 are members of the TALE (three-amino-acid loop extension) superfamily of homeodomain proteins. These two proteins bind to the same DNA sequence and share a conserved C-terminal repression domain. Mutations in TGIF1 have been linked to holoprosencephaly, which is a human genetic disease that affects craniofacial development. As these proteins can interact with the ligand binding domain of retinoid X receptor α, a common heterodimeric partner of several nuclear receptors [e.g., liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs)], Tgif1 and Tgif2 might repress other transcriptional pathways activated by lipids. In line with this, Tgif1 interacts with LXRα and Tgif1 null mice have increased expression of the two Lxrα target genes apolipoproteins (Apo) c2 and a4. Also, we have recently identified Tgif1 to function as a transcriptional repressor of the cholesterol esterifying enzyme acyl-coenzyme A:cholesterol acyltransferase 2 (gene name SOAT2). As no studies yet have shown involvement of Tgif2 in the lipid metabolism, this review will focus on the role of Tgif1 in lipid and cholesterol metabolism. This article is part of a Special Issue entitled: Linking transcription to physiology in lipodomics."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I455,I455)","v":24618374},{"$f":"(LEN($J455) - LEN(SUBSTITUTE(LOWER($J455),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J455) - LEN(SUBSTITUTE(LOWER($J455),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J455) - LEN(SUBSTITUTE(LOWER($J455),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B455:D455)","v":2},2014,"The failure of cancer chemoprevention.","Potter",24618374,"The failure of cancer chemoprevention.    Abstract:   Chemoprevention is proposed as a clinical analogue of population prevention, aimed at reducing likelihood of disease progression, not across the population, but in identified high-risk individuals and not by behavioral or lifestyle modification, but by the use of pharmaceutical agents. Cardiovascular chemoprevention is successful via control of hyperlipidemias and hypertension. However, chemoprevention of cancer is an almost universal failure: not only are some results null; even more frequently, there is an excess of disease, including disease that the agents were chosen specifically to reduce. A brief introduction is followed by the evidence for a wide variety of agents and their largely deleterious, sometimes null, and in one case, largely beneficial, consequences as possible chemopreventives. The agents include (i) those that are food derived and their synthetic analogues: β-carotene, folic acid, retinol and retinoids, vitamin E, multivitamin supplements, vitamin C, calcium and selenium and (ii) agents targeted at metabolic and hormonal pathways: statins, estrogen and antagonists, 5α-reductase inhibitors. There are two agents for which there is good evidence of benefit when the strategy is focused on those at defined high risk but where wider application is much more problematic: aspirin and tamoxifen. The major problems with cancer chemoprevention are presented. This is followed by a hypothesis to explain the failure of cancer chemoprevention as an enterprise, arguing that the central tenets that underpin it are flawed and showing why, far from doing good, cancer chemoprevention causes harm."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I456,I456)","v":24577401},{"$f":"(LEN($J456) - LEN(SUBSTITUTE(LOWER($J456),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J456) - LEN(SUBSTITUTE(LOWER($J456),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J456) - LEN(SUBSTITUTE(LOWER($J456),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B456:D456)","v":2},2014,"REV-ERB and ROR nuclear receptors as drug targets.","Kojetin",24577401,"REV-ERB and ROR nuclear receptors as drug targets.    Abstract:   The nuclear receptors REV-ERB (consisting of REV-ERBα and REV-ERBβ) and retinoic acid receptor-related orphan receptors (RORs; consisting of RORα, RORβ and RORγ) are involved in many physiological processes, including regulation of metabolism, development and immunity as well as the circadian rhythm. The recent characterization of endogenous ligands for these former orphan nuclear receptors has stimulated the development of synthetic ligands and opened up the possibility of targeting these receptors to treat several diseases, including diabetes, atherosclerosis, autoimmunity and cancer. This Review focuses on the latest developments in ROR and REV-ERB pharmacology indicating that these nuclear receptors are druggable targets and that ligands targeting these receptors may be useful in the treatment of several disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I457,I457)","v":24502334},{"$f":"(LEN($J457) - LEN(SUBSTITUTE(LOWER($J457),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J457) - LEN(SUBSTITUTE(LOWER($J457),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J457) - LEN(SUBSTITUTE(LOWER($J457),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B457:D457)","v":2},2014,"Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc).","Fauber",24502334,"Modulators of the nuclear receptor retinoic acid receptor-related orphan receptor-γ (RORγ or RORc).    Abstract:   As the biology surrounding the nuclear receptor retinoic acid receptor-related orphan receptor-gamma (RORγ or RORc) continues to evolve, significant effort has been invested in discovering modulators of this potentially important target for the treatment of metabolic and immunological diseases. Several major pharmaceutical and biotechnology companies have disclosed RORc inhibitors or partnered with other players in the field. In this perspective, we discuss both the biology and the underlying structural biology of RORc, and summarize the RORc modulators disclosed in the scientific and patent literature."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I458,I458)","v":24485032},{"$f":"(LEN($J458) - LEN(SUBSTITUTE(LOWER($J458),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J458) - LEN(SUBSTITUTE(LOWER($J458),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J458) - LEN(SUBSTITUTE(LOWER($J458),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B458:D458)","v":2},2014,"Chaperone-mediated autophagy in the kidney: the road more traveled.","Franch",24485032,"Chaperone-mediated autophagy in the kidney: the road more traveled.    Abstract:   Chaperone-mediated autophagy (CMA) is a lysosomal proteolytic pathway in which cytosolic substrate proteins contain specific chaperone recognition sequences required for degradation and are translocated directly across the lysosomal membrane for destruction. CMA proteolytic activity has a reciprocal relationship with macroautophagy: CMA is most active in cells in which macroautophagy is least active. Normal renal proximal tubular cells have low levels of macroautophagy, but high basal levels of CMA activity. CMA activity is regulated by starvation, growth factors, oxidative stress, lipids, aging, and retinoic acid signaling. The physiological consequences of changes in CMA activity depend on the substrate proteins present in a given cell type. In the proximal tubule, increased CMA results from protein or calorie starvation and from oxidative stress. Overactivity of CMA can be associated with tubular lysosomal pathology and certain cancers. Reduced CMA activity contributes to protein accumulation in renal tubular hypertrophy, but may contribute to oxidative tissue damage in diabetes and aging. Although there are more questions than answers about the role of high basal CMA activity, this remarkable feature of tubular protein metabolism appears to influence a variety of chronic diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I459,I459)","v":26237385},{"$f":"(LEN($J459) - LEN(SUBSTITUTE(LOWER($J459),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J459) - LEN(SUBSTITUTE(LOWER($J459),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J459) - LEN(SUBSTITUTE(LOWER($J459),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B459:D459)","v":2},2014,"The Roles of Vitamin A in the Regulation of Carbohydrate, Lipid, and Protein Metabolism.","Chen",26237385,"The Roles of Vitamin A in the Regulation of Carbohydrate, Lipid, and Protein Metabolism.    Abstract:   Currently, two-thirds of American adults are overweight or obese. This high prevalence of overweight/obesity negatively affects the health of the population, as obese individuals tend to develop several chronic diseases, such as type 2 diabetes and cardiovascular diseases. Due to obesitys impact on health, medical costs, and longevity, the rise in the number of obese people has become a public health concern. Both genetic and environmental/dietary factors play a role in the development of metabolic diseases. Intuitively, it seems to be obvious to link over-nutrition to the development of obesity and other metabolic diseases. However, the underlying mechanisms are still unclear. Dietary nutrients not only provide energy derived from macronutrients, but also factors such as micronutrients with regulatory roles. How micronutrients, such as vitamin A (VA; retinol), regulate macronutrient homeostasis is still an ongoing research topic. As an essential micronutrient, VA plays a key role in the general health of an individual. This review summarizes recent research progress regarding VAs role in carbohydrate, lipid, and protein metabolism. Due to the large amount of information regarding VA functions, this review focusses on metabolism in metabolic active organs and tissues. Additionally, some perspectives for future studies will be provided."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I460,I460)","v":24269582},{"$f":"(LEN($J460) - LEN(SUBSTITUTE(LOWER($J460),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J460) - LEN(SUBSTITUTE(LOWER($J460),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J460) - LEN(SUBSTITUTE(LOWER($J460),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B460:D460)","v":2},2014,"Saffron and natural carotenoids: Biochemical activities and anti-tumor effects.","Bolhassani",24269582,"Saffron and natural carotenoids: Biochemical activities and anti-tumor effects.    Abstract:   Saffron, a spice derived from the flower of Crocus sativus, is rich in carotenoids. Two main natural carotenoids of saffron, crocin and crocetin, are responsible for its color. Preclinical studies have shown that dietary intake of some carotenoids have potent anti-tumor effects both in vitro and in vivo, suggesting their potential preventive and/or therapeutic roles in several tissues. The reports represent that the use of carotenoids without the potential for conversion to vitamin A may provide further protection and avoid toxicity. The mechanisms underlying cancer chemo-preventive activities of carotenoids include modulation of carcinogen metabolism, regulation of cell growth and cell cycle progression, inhibition of cell proliferation, anti-oxidant activity, immune modulation, enhancement of cell differentiation, stimulation of cell-to-cell gap junction communication, apoptosis and retinoid-dependent signaling. Taken together, different hypotheses for the antitumor actions of saffron and its components have been proposed such as a) the inhibitory effect on cellular DNA and RNA synthesis, but not on protein synthesis; b) the inhibitory effect on free radical chain reactions; c) the metabolic conversion of naturally occurring carotenoids to retinoids; d) the interaction of carotenoids with topoisomerase II, an enzyme involved in cellular DNA-protein interaction. Furthermore, the immunomodulatory activity of saffron was studied on driving toward Th1 and Th2 limbs of the immune system. In this mini-review, we briefly describe biochemical and immunological activities and chemo-preventive properties of saffron and natural carotenoids as an anticancer drug."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I461,I461)","v":24265236},{"$f":"(LEN($J461) - LEN(SUBSTITUTE(LOWER($J461),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J461) - LEN(SUBSTITUTE(LOWER($J461),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J461) - LEN(SUBSTITUTE(LOWER($J461),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B461:D461)","v":2},2013,"Hepatic stellate cells and liver fibrosis.","Puche",24265236,"Hepatic stellate cells and liver fibrosis.    Abstract:   Hepatic stellate cells are resident perisinusoidal cells distributed throughout the liver, with a remarkable range of functions in normal and injured liver. Derived embryologically from septum transversum mesenchyme, their precursors include submesothelial cells that invade the liver parenchyma from the hepatic capsule. In normal adult liver, their most characteristic feature is the presence of cytoplasmic perinuclear droplets that are laden with retinyl (vitamin A) esters. Normal stellate cells display several patterns of intermediate filaments expression (e.g., desmin, vimentin, and/or glial fibrillary acidic protein) suggesting that there are subpopulations within this parental cell type. In the normal liver, stellate cells participate in retinoid storage, vasoregulation through endothelial cell interactions, extracellular matrix homeostasis, drug detoxification, immunotolerance, and possibly the preservation of hepatocyte mass through secretion of mitogens including hepatocyte growth factor. During liver injury, stellate cells activate into alpha smooth muscle actin-expressing contractile myofibroblasts, which contribute to vascular distortion and increased vascular resistance, thereby promoting portal hypertension. Other features of stellate cell activation include mitogen-mediated proliferation, increased fibrogenesis driven by connective tissue growth factor, and transforming growth factor beta 1, amplified inflammation and immunoregulation, and altered matrix degradation. Evolving areas of interest in stellate cell biology seek to understand mechanisms of their clearance during fibrosis resolution by either apoptosis, senescence, or reversion, and their contribution to hepatic stem cell amplification, regeneration, and hepatocellular cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I462,I462)","v":24103914},{"$f":"(LEN($J462) - LEN(SUBSTITUTE(LOWER($J462),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J462) - LEN(SUBSTITUTE(LOWER($J462),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J462) - LEN(SUBSTITUTE(LOWER($J462),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B462:D462)","v":2},2013,"Understanding nuclear receptor form and function using structural biology.","Rastinejad",24103914,"Understanding nuclear receptor form and function using structural biology.    Abstract:   Nuclear receptors (NRs) are a major transcription factor family whose members selectively bind small-molecule lipophilic ligands and transduce those signals into specific changes in gene programs. For over two decades, structural biology efforts were focused exclusively on the individual ligand-binding domains (LBDs) or DNA-binding domains of NRs. These analyses revealed the basis for both ligand and DNA binding and also revealed receptor conformations representing both the activated and repressed states. Additionally, crystallographic studies explained how NR LBD surfaces recognize discrete portions of transcriptional coregulators. The many structural snapshots of LBDs have also guided the development of synthetic ligands with therapeutic potential. Yet, the exclusive structural focus on isolated NR domains has made it difficult to conceptualize how all the NR polypeptide segments are coordinated physically and functionally in the context of receptor quaternary architectures. Newly emerged crystal structures of the peroxisome proliferator-activated receptor-γ-retinoid X receptor α (PPARγ-RXRα) heterodimer and hepatocyte nuclear factor (HNF)-4α homodimer have recently revealed the higher order organizations of these receptor complexes on DNA, as well as the complexity and uniqueness of their domain-domain interfaces. These emerging structural advances promise to better explain how signals in one domain can be allosterically transmitted to distal receptor domains, also providing much better frameworks for guiding future drug discovery efforts."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I463,I463)","v":24010698},{"$f":"(LEN($J463) - LEN(SUBSTITUTE(LOWER($J463),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J463) - LEN(SUBSTITUTE(LOWER($J463),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J463) - LEN(SUBSTITUTE(LOWER($J463),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B463:D463)","v":2},2013,"[Suspicion of diabetes mellitus isotretinoin-induced].","Santos-Pérez",24010698,"[Suspicion of diabetes mellitus isotretinoin-induced].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I464,I464)","v":23967807},{"$f":"(LEN($J464) - LEN(SUBSTITUTE(LOWER($J464),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J464) - LEN(SUBSTITUTE(LOWER($J464),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J464) - LEN(SUBSTITUTE(LOWER($J464),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B464:D464)","v":2},2014,"Clinical profile, morbidity, and outcome of adult-onset generalized pustular psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, Malaysia.","Choon",23967807,"Clinical profile, morbidity, and outcome of adult-onset generalized pustular psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, Malaysia.    Abstract:    BACKGROUND : Generalized pustular psoriasis (GPP) is a severe but rare variant of psoriasis. Our objective is to review the clinical profile, comorbidities, and outcome of patients with GPP.  MATERIALS AND METHODS : A retrospective note review of all patients with adult-onset GPP.  RESULTS : A total of 102 patients with adult-onset GPP were diagnosed between 1989 and November 2011, with a female to male ratio of 2 : 1. The mean age at onset of GPP was 40.9 years (range: 21-81 years). Acute GPP was the most common variant seen (95 cases), followed by four localized variants of GPP and three with annular pustular psoriasis. Fever and painful skin were present in 89% of patients, arthritis in 34.7%, and leukocytosis in 78.4%. Common triggers were systemic steroids (45 cases), pregnancy (17 cases), and upper respiratory tract infections (16 cases). A positive family history of psoriasis and GPP was present in 29% and 11%, respectively. Comorbidities included obesity (42.9%), hypertension (25.7%), hyperlipidemia (25.7%), and diabetes mellitus (23.7%). The mean duration of admission and pustular flare for acute GPP was 10.3 days (range: 3-44 days) and 16 days (range: 7-60 days), respectively. Fifty-four patients responded to systemic retinoid, 21 to methotrexate, eight to cyclosporine, and one to adalimumab, but recurrences were common.  CONCLUSIONS : Our study confirms the poor response of GPP to currently available anti-psoriatic agents, with frequent flare-ups. There is a need for a more effective targeted therapy for this condition."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I465,I465)","v":23932496},{"$f":"(LEN($J465) - LEN(SUBSTITUTE(LOWER($J465),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J465) - LEN(SUBSTITUTE(LOWER($J465),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J465) - LEN(SUBSTITUTE(LOWER($J465),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B465:D465)","v":2},2013,"Macrophages engulfing apoptotic thymocytes produce retinoids to promote selection, differentiation, removal and replacement of double positive thymocytes.","Sarang",23932496,"Macrophages engulfing apoptotic thymocytes produce retinoids to promote selection, differentiation, removal and replacement of double positive thymocytes.    Abstract:   The thymus provides the microenvironment in which thymocytes develop into mature T-cells, and interactions with thymic stromal cells are thought to provide the necessary signals for thymocyte maturation. Recognition of self-MHC by T-cells is a basic requirement for mature T-cell functions, and those thymocytes that do not recognize or respond too strongly to the peptide-loaded self-MHC molecules found in the thymus undergo apoptosis. As a result, 95% of the thymocytes produced will die and be subsequently cleared by macrophages. This review describes a complex crosstalk between developing thymocytes and engulfing macrophages which is mediated by retinoids produced by engulfing macrophages. The interaction results in the harmonization of the rate of cell death of dying double positive cells with their clearance and replacement, and in promotion of the differentiation of the selected cells in the thymus."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I466,I466)","v":23905916},{"$f":"(LEN($J466) - LEN(SUBSTITUTE(LOWER($J466),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J466) - LEN(SUBSTITUTE(LOWER($J466),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J466) - LEN(SUBSTITUTE(LOWER($J466),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B466:D466)","v":2},2013,"The role of lipid-activated nuclear receptors in shaping macrophage and dendritic cell function: From physiology to pathology.","Kiss",23905916,"The role of lipid-activated nuclear receptors in shaping macrophage and dendritic cell function: From physiology to pathology.    Abstract:   Nuclear receptors are ligand-activated transcription factors linking lipid signaling to the expression of the genome. There is increasing appreciation of the involvement of this receptor network in the metabolic programming of macrophages and dendritic cells (DCs), essential members of the innate immune system. In this review we focus on the role of retinoid X receptor, retinoic acid receptor, peroxisome proliferator-associated receptor γ, liver X receptor, and vitamin D receptor in shaping the immune and metabolic functions of macrophages and DCs. We also provide an overview of the contribution of macrophage- and DC-expressed nuclear receptors to various immunopathologic conditions, such as rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, asthma, and some others. We suggest that systematic analyses of the roles of these receptors and their activating lipid ligands in immunopathologies combined with complementary and focused translational and clinical research will be crucial for the development of new therapies using the many molecules available to target nuclear receptors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I467,I467)","v":23630073},{"$f":"(LEN($J467) - LEN(SUBSTITUTE(LOWER($J467),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J467) - LEN(SUBSTITUTE(LOWER($J467),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J467) - LEN(SUBSTITUTE(LOWER($J467),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B467:D467)","v":2},2013,"Emerging roles of the corepressors NCoR1 and SMRT in homeostasis.","Mottis",23630073,"Emerging roles of the corepressors NCoR1 and SMRT in homeostasis.    Abstract:   Epigenetic regulation of gene expression is strongly influenced by the accessibility of nucleosomal DNA or the state of chromatin compaction. In this context, coregulators, including both coactivators and corepressors, are pivotal intermediates that bridge chromatin-modifying enzymes and transcription factors. NCoR1 (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) are among the best-characterized corepressors from a molecular point of view. These coregulators have conserved orthologs in lower organisms, which underscores their functional importance. Here we summarize the results from recent in vivo studies that reveal the wide-ranging roles of NCoR1 and SMRT in developmental as well as homeostatic processes, including metabolism, inflammation, and circadian rhythms. We also discuss the potential implications of NCoR1 and SMRT regulation of pathways ranging from genomic stability and carcinogenesis to metabolic diseases such as type 2 diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I468,I468)","v":23357530},{"$f":"(LEN($J468) - LEN(SUBSTITUTE(LOWER($J468),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J468) - LEN(SUBSTITUTE(LOWER($J468),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J468) - LEN(SUBSTITUTE(LOWER($J468),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B468:D468)","v":2},2013,"Cellular mechanisms regulating fuel metabolism in mammals: role of adipose tissue and lipids during prolonged food deprivation.","Viscarra",23357530,"Cellular mechanisms regulating fuel metabolism in mammals: role of adipose tissue and lipids during prolonged food deprivation.    Abstract:   Food deprivation in mammals results in profound changes in fuel metabolism and substrate regulation. Among these changes are decreased reliance on the counter-regulatory dynamics by insulin-glucagon due to reduced glucose utilization, and increased concentrations of lipid substrates in plasma to meet the energetic demands of peripheral tissues. As the primary storage site of lipid substrates, adipose tissue must then be a primary contributor to the regulation of metabolism in food deprived states. Through its regulation of lipolysis, adipose tissue influences the availability of carbohydrate, lipid, and protein substrates. Additionally, lipid substrates can act as ligands to various nuclear receptors (retinoid x receptor (RXR), liver x receptor (LXR), and peroxisome proliferator-activated receptor (PPAR)) and exhibit prominent regulatory capabilities over the expression of genes involved in substrate metabolism within various tissues. Therefore, through its control of lipolysis, adipose tissue also indirectly regulates the utilization of metabolic substrates within peripheral tissues. In this review, these processes are described in greater detail and the extent to which adipose tissue and lipid substrates regulate metabolism in food deprived mammals is explored with comments on future directions to better assess the contribution of adipose tissue to metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I469,I469)","v":23166024},{"$f":"(LEN($J469) - LEN(SUBSTITUTE(LOWER($J469),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J469) - LEN(SUBSTITUTE(LOWER($J469),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J469) - LEN(SUBSTITUTE(LOWER($J469),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B469:D469)","v":2},2012,"A laboratory course for teaching laboratory techniques, experimental design, statistical analysis, and peer review process to undergraduate science students.","Gliddon",23166024,"A laboratory course for teaching laboratory techniques, experimental design, statistical analysis, and peer review process to undergraduate science students.    Abstract:   This article describes a 13-week laboratory course called Human Toxicology taught at the University of Otago, New Zealand. This course used a guided inquiry based laboratory coupled with formative assessment and collaborative learning to develop in undergraduate students the skills of problem solving/critical thinking, data interpretation and written discussion of results. The laboratory practices were a guided inquiry based around retinols ability to potentiate acetaminophen-mediated hepatotoxicity. To induce critical thinking, students were given a choice as to which assay they could use to determine how retinol affected acetaminophen hepatotoxicity. Short summaries were handed in following each assay and formed the bases of the formative assessment. To complete the feedback loop, a summative assessment that consisted of all the graphs and concepts from the short summaries were combined into a manuscript. To give the students exposure to science communication, the manuscript had to be written in accordance to the submission guidelines for Toxicological Sciences. Evaluation of this course was determined by a student questionnaire using a Likert scale and students responses were very favorable. While the subject matter was toxicological centric, the content could be easily modified to suit another subject matter in biochemistry and molecular biology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I470,I470)","v":23085014},{"$f":"(LEN($J470) - LEN(SUBSTITUTE(LOWER($J470),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J470) - LEN(SUBSTITUTE(LOWER($J470),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J470) - LEN(SUBSTITUTE(LOWER($J470),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B470:D470)","v":2},2013,"Vitamin D: health panacea or false prophet?","Glade",23085014,"Vitamin D: health panacea or false prophet?    Abstract:   Vitamin D deficiency, diagnosed when the serum 25-hydroxyvitamin D (25-OHD(3)) concentration is less than 20 ng/mL, has joined vitamin A deficiency as two of the most common nutrition-responsive medical conditions worldwide. There have been more scientific articles published about vitamin D in the 21st century than about any other vitamin, reflecting the massive expansion of the field of vitamin D research. Adequate vitamin D status has been linked to decreased risks of developing specific cancers, including cancers of the esophagus, stomach, colon, rectum, gallbladder, pancreas, lung, breast, uterus, ovary, prostate, urinary bladder, kidney, skin, thyroid, and hematopoietic system (e.g., Hodgkins lymphoma, non-Hodgkins lymphoma, multiple myeloma); bacterial infections; rheumatoid arthritis; Crohns disease; periodontal disease; multiple sclerosis; asthma; type 2 diabetes; cardiovascular disease; stroke; peripheral artery disease; hypertension; chronic kidney disease; muscle weakness; cognitive impairment; Alzheimers disease; clinical depression; and premature death. On the other hand, inadequate vitamin D status during human pregnancy may be associated with increased risk for the development of type 1 diabetes in the offspring. However, this point of view may be excessively optimistic. There also is evidence that despite the current heavy reliance on serum 25-OHD(3) concentration for the diagnosis of an individuals vitamin D status, local tissue vitamin D intoxication may be present in individuals with much lower serum 25-OHD(3) concentrations than are currently appreciated. Only rarely are the symptoms of local tissue vitamin D intoxication associated with vitamin D status or intake. An individuals serum 25-OHD(3) concentration may appear to be quot;lowquot; for reasons totally independent of sunlight exposure or vitamin D intake. Serum 25-OHD(3) concentration is only poorly responsive to increases in vitamin D intake, and the prolonged routine consumption of thousands of international units of vitamin D may interfere with the regulation of phosphate homeostasis by fibroblast growth factor-23 (FGF23) and the Klotho gene product, with consequences that are detrimental to human health. In light of these counterbalancing observations, curbing excessive enthusiasm for universally increasing vitamin D intake recommendations may be in order."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I471,I471)","v":22782502},{"$f":"(LEN($J471) - LEN(SUBSTITUTE(LOWER($J471),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J471) - LEN(SUBSTITUTE(LOWER($J471),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J471) - LEN(SUBSTITUTE(LOWER($J471),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B471:D471)","v":2},2013,"Molecular mechanisms of vitamin D action.","Haussler",22782502,"Molecular mechanisms of vitamin D action.    Abstract:   The hormonal metabolite of vitamin D, 1α,25-dihydroxyvitamin D(3) (1,25D), initiates biological responses via binding to the vitamin D receptor (VDR). When occupied by 1,25D, VDR interacts with the retinoid X receptor (RXR) to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1,25D. By recruiting complexes of either coactivators or corepressors, ligand-activated VDR-RXR modulates the transcription of genes encoding proteins that promulgate the traditional functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. Thus, vitamin D action in a particular cell depends upon the metabolic production or delivery of sufficient concentrations of the 1,25D ligand, expression of adequate VDR and RXR coreceptor proteins, and cell-specific programming of transcriptional responses to regulate select genes that encode proteins that function in mediating the effects of vitamin D. For example, 1,25D induces RANKL, SPP1 (osteopontin), and BGP (osteocalcin) to govern bone mineral remodeling; TRPV6, CaBP(9k), and claudin 2 to promote intestinal calcium absorption; and TRPV5, klotho, and Npt2c to regulate renal calcium and phosphate reabsorption. VDR appears to function unliganded by 1,25D in keratinocytes to drive mammalian hair cycling via regulation of genes such as CASP14, S100A8, SOSTDC1, and others affecting Wnt signaling. Finally, alternative, low-affinity, non-vitamin D VDR ligands, e.g., lithocholic acid, docosahexaenoic acid, and curcumin, have been reported. Combined alternative VDR ligand(s) and 1,25D/VDR control of gene expression may delay chronic disorders of aging such as osteoporosis, type 2 diabetes, cardiovascular disease, and cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I472,I472)","v":22686165},{"$f":"(LEN($J472) - LEN(SUBSTITUTE(LOWER($J472),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J472) - LEN(SUBSTITUTE(LOWER($J472),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J472) - LEN(SUBSTITUTE(LOWER($J472),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B472:D472)","v":2},2012,"The interplay between retinoic acid receptor-related orphan receptors and human diseases.","Ranhotra",22686165,"The interplay between retinoic acid receptor-related orphan receptors and human diseases.    Abstract:   The retinoic acid receptor-related orphan receptors (RORs) are an important subfamily of transcriptional regulators of the nuclear receptors superfamily. Their discovery over a decade ago by gene cloning strategy have revealed three major isoforms of these orphan receptors in animals. Generation and analyses of isoform-specific ROR null mice have provided revealed-vital roles for the RORs in animals. The RORs undoubtedly participate in a host of biological functions such a metabolism, immunity, development and differentiation, angiogenesis, circadian clock, xenobiotic/drug metabolism and other tissue physiologies for optimal animal survival. Moreover, intense work in the last one decade also revealed a host of human diseases being modulated by the RORs. A number of diseases, such as cancer, autoimmune diseases, inflammation, osteoporosis, metabolic syndrome etc., strongly support the involvement of RORs in their onset and progression. By involving in such diseases, the RORs are indeed a critical factor for optimal cell function and are being intensely investigated as novel targets for drug interventions in the treatment of various diseases. This review focuses on the current knowledge and status about RORs in a number of human disease conditions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I473,I473)","v":22594656},{"$f":"(LEN($J473) - LEN(SUBSTITUTE(LOWER($J473),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J473) - LEN(SUBSTITUTE(LOWER($J473),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J473) - LEN(SUBSTITUTE(LOWER($J473),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B473:D473)","v":2},2012,"The effects of alcohol on the metabolism and toxicology of anti-psoriasis drugs.","Vena",22594656,"The effects of alcohol on the metabolism and toxicology of anti-psoriasis drugs.    Abstract:    INTRODUCTION : Alcohol has long been suspected to be a triggering and precipitating factor of psoriasis. Alcohol misuse is common in patients with moderate-to-severe psoriasis and appears to impair treatment outcome.  AREAS COVERED : In this article, the authors review the available data regarding the metabolic and toxicological interactions between anti-psoriasis systemic drugs and ethanol and/or alcoholic beverages. Special attention is given to the influence of alcohol consumption on the hepatotoxic risk of some anti-psoriasis drugs. The article was prepared using a MEDLINE literature search.  EXPERT OPINION : The available knowledge highlights the existence of a few significant pharmacological interactions, such as the reduced exposure to cyclosporine by red wine, the possible increase of cyclosporine levels following a heavy acute alcohol intake, and, especially, the conversion of acitretin to etretinate, in the presence of ethanol, with important implications in females of child-bearing potential. There are limited data on the contributing role of alcohol in the hepatotoxicity induced by some anti-psoriasis drugs and the existing information on this topic is still controversial. However, further investigation is needed to assess the relevance of interactions between alcohol consumption and drug therapy for psoriasis, under both pharmacological and toxicological perspectives. Long-term prospective studies on large cohorts of patients are warranted to disclose the actual significance of such potential interactions in clinical practice."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I474,I474)","v":22471982},{"$f":"(LEN($J474) - LEN(SUBSTITUTE(LOWER($J474),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J474) - LEN(SUBSTITUTE(LOWER($J474),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J474) - LEN(SUBSTITUTE(LOWER($J474),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B474:D474)","v":2},2012,"Transthyretin deposition in familial amyloidotic polyneuropathy.","Saraiva",22471982,"Transthyretin deposition in familial amyloidotic polyneuropathy.    Abstract:   The subject of the review is on hereditary transthyretin (TTR) amyloidosis which is a genetically transmitted disease that results from a mutation in the gene encoding the plasma TTR protein. TTR is a transport protein for thyroid hormones and vitamin A and is predominantly synthesised in the liver. Although originally regarded as a rare disease, it is now becoming clear that many kindreds exist worldwide. Current knowledge and hypotheses on the biology of TTR, mechanisms of TTR amyloid fibril formation, phenotypic consequences TTR amyloid deposition and pre-clinical models of the disease will be discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I475,I475)","v":22284354},{"$f":"(LEN($J475) - LEN(SUBSTITUTE(LOWER($J475),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J475) - LEN(SUBSTITUTE(LOWER($J475),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J475) - LEN(SUBSTITUTE(LOWER($J475),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B475:D475)","v":2},2012,"Targeting orphan nuclear receptors for treatment of metabolic diseases and autoimmunity.","Burris",22284354,"Targeting orphan nuclear receptors for treatment of metabolic diseases and autoimmunity.    Abstract:   The nuclear receptor (NR) superfamily is composed of 48 members in humans and includes receptors for steroid hormones, thyroid hormone, various lipids and oxysterols. This superfamily has been a rich source of drug targets for myriad diseases including inflammation, cancer, and metabolic disorders. Approximately half of the superfamily have well characterized natural ligands whereas the remaining receptors are considered orphan receptors and remain a focus of a number of investigators assessing their ability to be regulated by ligands. Here, we review recent discoveries that yield important insight into the druggability of three orphan nuclear receptors: the retinoic acid receptor-like orphan receptors (RORs), peroxisome proliferator-activated receptor γ (PPARγ), and liver receptor homolog-1 (LRH-1)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I476,I476)","v":22281155},{"$f":"(LEN($J476) - LEN(SUBSTITUTE(LOWER($J476),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J476) - LEN(SUBSTITUTE(LOWER($J476),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J476) - LEN(SUBSTITUTE(LOWER($J476),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B476:D476)","v":2},2012,"Adjuvant therapy options following curative treatment of hepatocellular carcinoma: a systematic review of randomized trials.","Zhong",22281155,"Adjuvant therapy options following curative treatment of hepatocellular carcinoma: a systematic review of randomized trials.    Abstract:    AIMS : Numerous postoperative therapies for preventing recurrence of hepatocellular carcinoma (HCC) have been reported, but their efficacy remains controversial and knowledge about adverse effects is limited. A systematic review of randomized controlled trials (RCTs) was performed to gain a comprehensive picture of the efficacy and risks of these therapies.  METHODS : MEDLINE, EMBASE and the Cochrane Library were systematically searched through July 2011. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated.  RESULTS : A total of 2989 patients from 28 RCTs involving 10 postoperative therapies were included. For interferon therapy, the estimated RR for the 2-year recurrence rate was 0.84 (95% CI 0.73-0.97, P = 0.02) and the overall survival (OS) was 1.15 (95% CI 1.07-1.22, P lt; 0.001). Postoperative therapy with the vitamin K2 analog did not lead to a significant reduction in the 1-year recurrence rate, with a pooled RR of 0.60 (95% CI 0.28-1.27, P = 0.18). However, it did slightly improve the 1-year OS, with a pooled RR of 1.03 (95% CI 1.00-1.05, P = 0.03). Transarterial chemotherapy with or without embolization, adoptive immunotherapy and heparanase inhibitor PI-88 therapy may delay tumor recurrence. The effects of acyclic retinoid, lipiodol-iodine-131 and tumor vaccine treatment were promising but require further study. All postoperative therapies except interferon administered intramuscularly were well tolerated by the majority of patients.  CONCLUSIONS : Use of adjuvant interferon is definitely associated with an increase in OS. Postoperative therapies involving acyclic retinoid, lipidol-iodine-131, or tumor vaccine may improve the OS of patients with HCC after curative treatment."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I477,I477)","v":27186126},{"$f":"(LEN($J477) - LEN(SUBSTITUTE(LOWER($J477),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J477) - LEN(SUBSTITUTE(LOWER($J477),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J477) - LEN(SUBSTITUTE(LOWER($J477),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B477:D477)","v":2},2012,"The therapeutic potential of RORγ modulators in the treatment of human disease.","Chang",27186126,"The therapeutic potential of RORγ modulators in the treatment of human disease.    Abstract:   Nuclear receptors (NR) are ligand-regulated transcription factors that bind DNA in proximity to their target genes and exert their effects as a result of binding by small molecule ligands such as sterols, lipids, fatty acids, retinoids, and steroid hormones. The retinoic acid receptor-related orphan receptors or RORs (NR1F1-NR1F3) are nuclear receptors that regulate multiple cellular processes, including metabolism, cellular differentiation, and apoptosis, in a range of tissues and organs. These receptors bind as monomers to ROR response elements commonly called ROREs present in promoter regions of target genes and tether chromatin remodeling enzymes, facilitating recruitment of transcription machinery. Several recent reports have highlighted the potential role for RORs in human disease, and more importantly, studies have demonstrated that these receptors can be modulated by exogenous synthetic ligands, paving the way for development of novel therapeutics. Here we review the current status of synthetic ligand development as well as the structural aspects governing modulation of ROR signaling pathways as they relate to metabolic diseases and autoimmune disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I478,I478)","v":21872797},{"$f":"(LEN($J478) - LEN(SUBSTITUTE(LOWER($J478),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J478) - LEN(SUBSTITUTE(LOWER($J478),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J478) - LEN(SUBSTITUTE(LOWER($J478),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B478:D478)","v":2},2011,"Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)₂vitamin D₃: genomic and non-genomic mechanisms.","Haussler",21872797,"Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)₂vitamin D₃: genomic and non-genomic mechanisms.    Abstract:   The conformationally flexible secosteroid, 1α,25(OH)₂vitamin D₃ (1α,25(OH)₂D₃) initiates biological responses via binding to the vitamin D receptor (VDR). The VDR contains two overlapping ligand binding sites, a genomic pocket (VDR-GP) and an alternative pocket (VDR-AP), that respectively bind a bowl-like ligand configuration (gene transcription) or a planar-like ligand shape (rapid responses). When occupied by 1α,25(OH)₂D₃, the VDR-GP interacts with the retinoid X receptor to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1α,25(OH)₂D₃. By recruiting complexes of either coactivators or corepressors, activated VDR modulates the transcription of genes encoding proteins that promulgate the traditional genomic functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. 1α,25(OH)₂D₃/VDR control of gene expression and rapid responses also delays chronic diseases of aging such as osteoporosis, cancer, type-1 and -2 diabetes, arteriosclerosis, vascular disease, and infection."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I479,I479)","v":21723946},{"$f":"(LEN($J479) - LEN(SUBSTITUTE(LOWER($J479),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J479) - LEN(SUBSTITUTE(LOWER($J479),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J479) - LEN(SUBSTITUTE(LOWER($J479),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B479:D479)","v":2},2012,"Retinoid-related orphan receptor alpha and the regulation of lipid homeostasis.","Fitzsimmons",21723946,"Retinoid-related orphan receptor alpha and the regulation of lipid homeostasis.    Abstract:   Many nuclear hormone receptors (NRs) control lipid, glucose and energy homeostasis in an organ specific manner. Concordantly, dysfunctional NR signalling results in metabolic disease. The Retinoic acid receptor-related orphan receptor alpha (RORα), a member of the NR1F subgroup, is expressed in metabolic tissues. Previous studies identified the role of this NR in dyslipidemia, apo-lipoprotein metabolism and atherosclerosis. Recent data is underscoring the significant role of this orphan NR in the regulation of phase I/II metabolism (bile acids, xenobiotics, steroids etc.), adiposity, insulin signalling, and glucose tolerance. Moreover, oxygenated sterols, have been demonstrated to function as native ligands and inverse agonists. This review focuses on the rapidly emerging and evolving role of RORα in the control of lipid and glucose homeostasis in major mass metabolic tissues. Article from the special issue orphan receptors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I480,I480)","v":21569862},{"$f":"(LEN($J480) - LEN(SUBSTITUTE(LOWER($J480),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J480) - LEN(SUBSTITUTE(LOWER($J480),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J480) - LEN(SUBSTITUTE(LOWER($J480),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B480:D480)","v":2},2012,"Mammalian carotenoid-oxygenases: key players for carotenoid function and homeostasis.","Lobo",21569862,"Mammalian carotenoid-oxygenases: key players for carotenoid function and homeostasis.    Abstract:   Humans depend on a dietary intake of lipids to maintain optimal health. Among various classes of dietary lipids, the physiological importance of carotenoids is still controversially discussed. On one hand, it is well established that carotenoids, such as β,β-carotene, are a major source for vitamin A that plays critical roles for vision and many aspects of cell physiology. On the other hand, large clinical trials have failed to show clear health benefits of carotenoids supplementation and even suggest adverse health effects in individuals at risk of disease. In recent years, key molecular players for carotenoid metabolism have been identified, including an evolutionarily well conserved family of carotenoid-oxygenases. Studies in knockout mouse models for these enzymes revealed that carotenoid metabolism is a highly regulated process and that this regulation already takes place at the level of intestinal absorption. These studies also provided evidence that β,β-carotene conversion can influence retinoid-dependent processes in the mouse embryo and in adult tissues. Moreover, these analyses provide an explanation for adverse health effects of carotenoids by showing that a pathological accumulation of these compounds can induce oxidative stress in mitochondria and cell signaling pathways related to disease. Advancing knowledge about carotenoid metabolism will contribute to a better understanding of the biochemical and physiological roles of these important micronutrients in health and disease. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I481,I481)","v":21529158},{"$f":"(LEN($J481) - LEN(SUBSTITUTE(LOWER($J481),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J481) - LEN(SUBSTITUTE(LOWER($J481),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J481) - LEN(SUBSTITUTE(LOWER($J481),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B481:D481)","v":2},2011,"Cytochrome P450s in the regulation of cellular retinoic acid metabolism.","Ross",21529158,"Cytochrome P450s in the regulation of cellular retinoic acid metabolism.    Abstract:   The active metabolite of vitamin A, retinoic acid (RA), is a powerful regulator of gene transcription. RA is also a therapeutic drug. The oxidative metabolism of RA by certain members of the cytochrome P450 (CYP) superfamily helps to maintain tissue RA concentrations within appropriate bounds. The CYP26 family--CYP26A1, CYP26B1, and CYP26C1--is distinguished by being both regulated by and active toward all-trans-RA (at-RA) while being expressed in different tissue-specific patterns. The CYP26A1 gene is regulated by multiple RA response elements. CYP26A1 is essential for embryonic development, whereas CYP26B1 is essential for postnatal survival as well as germ cell development. Enzyme kinetic studies have demonstrated that several CYP proteins are capable of metabolizing at-RA; however, it is likely that CYP26A1 plays a major role in RA clearance. Thus, pharmacological approaches to limiting the activity of CYP26 enzymes may extend the half-life of RA and could be useful clinically in the future."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I482,I482)","v":21488901},{"$f":"(LEN($J482) - LEN(SUBSTITUTE(LOWER($J482),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J482) - LEN(SUBSTITUTE(LOWER($J482),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J482) - LEN(SUBSTITUTE(LOWER($J482),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B482:D482)","v":2},2011,"Oral tolerance.","Weiner",21488901,"Oral tolerance.    Abstract:   The gut-associated lymphoid tissue is the largest immune organ in the body and is the primary route by which we are exposed to antigens. Tolerance induction is the default immune pathway in the gut, and the type of tolerance induced relates to the dose of antigen fed: anergy/deletion (high dose) or regulatory T-cell (Treg) induction (low dose). Conditioning of gut dendritic cells (DCs) by gut epithelial cells and the gut flora, which itself has a major influence on gut immunity, induces CD103(+) retinoic acid-dependent DC that induces Tregs. A number of Tregs are induced at mucosal surfaces. Th3 type Tregs are transforming growth factor-β dependent and express latency-associated peptide (LAP) on their surface and were discovered in the context of oral tolerance. Tr1 type Tregs (interleukin-10 dependent) are induced by nasal antigen and forkhead box protein 3(+) iTregs are induced by oral antigen and by oral administration of aryl hydrocarbon receptor ligands. Oral or nasal antigen ameliorates autoimmune and inflammatory diseases in animal models by inducing Tregs. Furthermore, anti-CD3 monoclonal antibody is active at mucosal surfaces and oral or nasal anti-CD3 monoclonal antibody induces LAP(+) Tregs that suppresses animal models (experimental autoimmune encephalitis, type 1 and type 2 diabetes, lupus, arthritis, atherosclerosis) and is being tested in humans. Although there is a large literature on treatment of animal models by mucosal tolerance and some positive results in humans, this approach has yet to be translated to the clinic. The successful translation will require defining responsive patient populations, validating biomarkers to measure immunologic effects, and using combination therapy and immune adjuvants to enhance Treg induction. A major avenue being investigated for the treatment of autoimmunity is the induction of Tregs and mucosal tolerance represents a non-toxic, physiologic approach to reach this goal."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I483,I483)","v":21428959},{"$f":"(LEN($J483) - LEN(SUBSTITUTE(LOWER($J483),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J483) - LEN(SUBSTITUTE(LOWER($J483),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J483) - LEN(SUBSTITUTE(LOWER($J483),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B483:D483)","v":2},2011,"Inflammasome activation: from inflammatory disease to infection.","Dunne",21428959,"Inflammasome activation: from inflammatory disease to infection.    Abstract:   The recognition of pathogen-derived molecules by the innate immune system is mediated by a number of receptors, including members of the TLR (Toll-like receptor), RLH [RIG (retinoic acid-inducible gene)-like helicase] and the NLR (NOD-like receptor) families. NLRs in particular are also involved in the recognition of host-derived danger-associated molecules which are produced under conditions of cellular stress or injury. Activation of these receptors leads to the assembly of high-molecular-mass complexes called inflammasomes which in turn leads to the generation of active caspase 1 and to the production of mature IL-1β (interleukin 1β). The discovery that NLRP3 (NLR-related protein 3) can recognize host-derived particulate matter such as uric acid and cholesterol crystals has led to this inflammasome being implicated in a number of inflammatory diseases, including gout, atherosclerosis and Type 2 diabetes. In addition, aberrant NLRP3 activation has also been observed in a number of heritable disorders now referred to as cryopyrinopathies. On the other hand, a number of studies have reported that recognition of both viral and bacterial products by NLRs is required for effective pathogen clearance. The present review discusses both aspects of NLR activation and will highlight the role of additional inflammasome complexes in sensing infection."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I484,I484)","v":21324803},{"$f":"(LEN($J484) - LEN(SUBSTITUTE(LOWER($J484),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J484) - LEN(SUBSTITUTE(LOWER($J484),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J484) - LEN(SUBSTITUTE(LOWER($J484),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B484:D484)","v":2},2011,"[Cod liver oil. A natural Vitamin D for preserving health].","Fehér",21324803,"[Cod liver oil. A natural Vitamin D for preserving health].    Abstract:   Vitamin D deficiency is pandemic in industrialized countries due to life-style changes. Recent studies suggest that besides bone-metabolism, vitamin D plays a central role in basic cell function like multiplication, differentiation and metabolism. This may explain that low vitamin D levels represent a risk factor for several apparently different diseases such as infective, autoimmune, neurodegenerative and cardiovascular diseases, as well as diabetes, osteoporosis and cancer. Accumulating evidences suggest that an adequate intake of vitamin D may significantly decrease prevalence and clinical outcome of these diseases. Estimated reduction of the economic burden might reach about 10 percent through normalizing vitamin D levels for these diseases. However, high doses of vitamin D monotherapy needs precaution for potential adverse effects and it should be substituted with the recommended doses of vitamin D in combination with synergistic vitamin A and omega 3 fatty acids, such as cod liver oil."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I485,I485)","v":21295138},{"$f":"(LEN($J485) - LEN(SUBSTITUTE(LOWER($J485),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J485) - LEN(SUBSTITUTE(LOWER($J485),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J485) - LEN(SUBSTITUTE(LOWER($J485),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B485:D485)","v":2},2011,"Nuclear receptor PXR, transcriptional circuits and metabolic relevance.","Ihunnah",21295138,"Nuclear receptor PXR, transcriptional circuits and metabolic relevance.    Abstract:   The pregnane X receptor (PXR, NR1I2) is a ligand activated transcription factor that belongs to the nuclear hormone receptor (NR) superfamily. PXR is highly expressed in the liver and intestine, but low levels of expression have also been found in many other tissues. PXR plays an integral role in xenobiotic and endobiotic metabolism by regulating the expression of drug-metabolizing enzymes and transporters, as well as genes implicated in the metabolism of endobiotics. PXR exerts its transcriptional regulation by binding to its DNA response elements as a heterodimer with the retinoid X receptor (RXR) and recruitment of a host of coactivators. The biological and physiological implications of PXR activation are broad, ranging from drug metabolism and drug-drug interactions to the homeostasis of numerous endobiotics, such as glucose, lipids, steroids, bile acids, bilirubin, retinoic acid, and bone minerals. The purpose of this article is to provide an overview on the transcriptional circuits and metabolic relevance controlled by PXR. This article is part of a Special Issue entitled: Translating Nuclear Receptors from Health to Disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I486,I486)","v":21163409},{"$f":"(LEN($J486) - LEN(SUBSTITUTE(LOWER($J486),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J486) - LEN(SUBSTITUTE(LOWER($J486),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J486) - LEN(SUBSTITUTE(LOWER($J486),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B486:D486)","v":2},2010,"Vitamin analogues in chemoprevention of hepatocellular carcinoma after resection or ablation--a systematic review and meta-analysis.","Chu",21163409,"Vitamin analogues in chemoprevention of hepatocellular carcinoma after resection or ablation--a systematic review and meta-analysis.    Abstract:    OBJECTIVE : While hepatic resection or local ablative therapy may provide a potentially curative treatment for hepatocellular carcinoma (HCC), more than half of these patients develop recurrent HCC within 5 years after treatment. Thus identification of any therapy which can decrease or delay the incidence of recurrence will improve the results of treatment. However, no chemopreventive agent has been approved for HCC.  METHODS : A MEDLINE database, Embase, Cancerlit (National Cancer Institute), and CBM (Chinese Biomedical Database) search from 1990 to 2009 was performed to identify relevant articles using the keywords quot;hepatocellular carcinoma,quot; quot;vitamin analogue,quot; and quot;chemoprevention.quot; Additional papers were identified by a manual search of the references from the key articles. The fixed effect model was used for a meta-analysis.  RESULTS : Oral administration of acyclic retinoids (vitamin A analogue), and menatetrenone (vitamin K2 analogue) have been tested as chemopreventive agents after hepatic resection or local ablative therapy for HCC. There were one and four randomised, controlled trials (RCTs) which evaluated the efficacy of polyprenoic acid and menatetrenone, respectively. All studies were conducted in Japan. One RCT showed the preventive effect of polyprenoic acid in lowering the incidence of HCC recurrence after hepatic resection or percutaneous ethanol injection, and this effect lasted up to 199 weeks after randomization (or 151 weeks after completion of retinoid administration). Four RCTs evaluated the preventive efficacy of menatetrenone on HCC recurrence after hepatic resection or local ablative therapy. The results of three studies, as well as the meta-analysis of all four studies, showed significantly better tumour recurrence-free survival. The beneficial effect on the overall survival was less definite.  CONCLUSION : There is evidence to suggest that chemopreventive therapy after partial hepatectomy or local ablative therapy is beneficial in prolonging disease-free survival, but the evidence is less for an effect on the overall survival. To confirm the beneficial role of vitamin A or K analogues in the chemoprevention of HCC further and larger randomised trials are now required."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I487,I487)","v":20579216},{"$f":"(LEN($J487) - LEN(SUBSTITUTE(LOWER($J487),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J487) - LEN(SUBSTITUTE(LOWER($J487),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J487) - LEN(SUBSTITUTE(LOWER($J487),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B487:D487)","v":2},2010,"Th17 cells: the emerging reciprocal partner of regulatory T cells in the liver.","Zhao",20579216,"Th17 cells: the emerging reciprocal partner of regulatory T cells in the liver.    Abstract:   T helper cells that produce interleukin-17 (IL-17) (Th17 cells) have recently been identified as the third distinct subset of effector T cells, the differentiation of which depends on specific transcription nuclear factor retinoic acid-related orphan nuclear receptor-gammat. Emerging data have suggested that Th17 cells play an important role in innate immunity, adaptive immunity and autoimmunity. Interestingly, there is a reciprocal relationship between Th17 cells and regulatory T cells (Treg), not only in development, but also in their effector function. Transforming growth factor (TGF)-beta induces Treg-specific transcription factor Forkhead box P3(FOXP3), while the addition of IL-6 to TGF-beta inhibits the generation of Treg cells and induces Th17 cells. It is proposed that the fine balance between Th17 and Treg cells is crucial for maintenance of immune homeostasis. In addition to IL-6, other factors such as retinoic acid, rapamycin, or cytokines (e.g., IL-2 and IL-27) could dictate the balance between Th17 and Treg cells. Since Treg cells play an important role in hepatic immunity with overregulation in chronic viral hepatitis and hepatic carcinoma, and inadequate inhibition in autoimmune liver diseases, graft rejection and acute liver failure, it is reasonable to assume that Th17 cells may play a reciprocal role in these diseases. Thus, future research on the Treg/Th17 balance may provide an opportunity to illustrate the pathogenesis of hepatic inflammation and to explore new therapeutic targets for immune-related liver diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I488,I488)","v":20536779},{"$f":"(LEN($J488) - LEN(SUBSTITUTE(LOWER($J488),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J488) - LEN(SUBSTITUTE(LOWER($J488),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J488) - LEN(SUBSTITUTE(LOWER($J488),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B488:D488)","v":2},2010,"Role of vitamins and minerals in prevention and management of type 2 diabetes mellitus.","Martini",20536779,"Role of vitamins and minerals in prevention and management of type 2 diabetes mellitus.    Abstract:   Vitamins and minerals play an important role in glucose metabolism, so understanding the impact of vitamin and mineral deficiencies and the potential utility of supplementation is relevant to the prevention and/or management of type 2 diabetes mellitus (DM). This review investigates current evidence for relationships between selected nutrients - vitamin B complex, antioxidants (vitamin A, C, E and carotenoids), calcium, vitamin D, vitamin K, magnesium, sodium, and potassium - and glucose metabolism. The investigation reveals current evidence is not strong enough for supplementation with minerals and vitamins to be recommended on a large scale for the prevention or management of DM. In order to prevent deficiencies and maintain health, the majority of diabetic individuals should receive daily vitamins and minerals within the ranges of recommended values from consumption of natural food sources and/or fortified foods. Further studies including large samples and longer follow-up periods are necessary to ascertain the benefits of mineral and vitamin supplementation to subsets of individuals who are at increased risk for DM or its complications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I489,I489)","v":20456381},{"$f":"(LEN($J489) - LEN(SUBSTITUTE(LOWER($J489),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J489) - LEN(SUBSTITUTE(LOWER($J489),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J489) - LEN(SUBSTITUTE(LOWER($J489),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B489:D489)","v":2},2010,"Differing obstetric outcomes of rosacea fulminans in pregnancy: report of three cases with review of pathogenesis and management.","Jarrett",20456381,"Differing obstetric outcomes of rosacea fulminans in pregnancy: report of three cases with review of pathogenesis and management.    Abstract:   Rosacea fulminans (RF) is a rare facial dermatosis characterized by the sudden onset of severe facial inflammation consisting of numerous pustules, cystic swellings and coalescing sinuses. The standard treatment is the retinoid drug isotretinoin in combination with systemic corticosteroids or with high-dose oral tetracycline antibiotics. We report three recent cases of RF in pregnancy with differing obstetric outcomes: an intrauterine death, a termination of pregnancy, and a normal vaginal delivery. The pathogenesis of RF is considered and therapeutic options in pregnancy are reviewed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I490,I490)","v":20402650},{"$f":"(LEN($J490) - LEN(SUBSTITUTE(LOWER($J490),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J490) - LEN(SUBSTITUTE(LOWER($J490),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J490) - LEN(SUBSTITUTE(LOWER($J490),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B490:D490)","v":2},2010,"Biliary innate immunity in the pathogenesis of biliary diseases.","Harada",20402650,"Biliary innate immunity in the pathogenesis of biliary diseases.    Abstract:   An innate immune response to bacterial and viral components is thought to be involved in the pathogenesis of cholangiopathies in case of primary biliary cirrhosis (PBC) and biliary atresia. Biliary epithelial cells possess the Toll-like receptor (TLR) family which recognizes pathogen-associated molecular patterns (PAMPs) and plays a pivotal role in the innate immune response. In PBC, disordered regulations of TLRs and a negative regulator of intracellular signaling, peroxisome proliferator-activated receptor-gamma (PPARgamma), with Th1-predominant cytokine milieu are involved in the pathogenesis of cholangitis such as chronic non-suppurative destructive cholangitis (CNSDC). Moreover, CD4-positive Th17 cells characterized by the secretion of IL-17, are implicated in the chronic inflammation of bile ducts in PBC and the induction of Th17 cells around bile ducts is causally associated with the biliary innate immune responses to PAMPs. In biliary atresia characterized by a progressive, inflammatory, and sclerosing cholangiopathy, dsRNA viruses could directly induce the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and apoptosis in biliary epithelial cells as a result of the biliary innate immune response via dsRNA-recognizing receptors such as TLR3 and retinoic acid inducible gene I (RIG-I). Moreover, as a mechanism behind the sclerosing cholangiopathy in biliary atresia, epithelial-mesenchymal transition (EMT) has been proposed and the biliary innate immune response to dsRNA viruses is demonstrated to induce biliary epithelial cells to undergo EMT. Biliary innate immunity is associated with the pathogenesis of various cholangiopathies in biliary diseases as well as biliary defense systems."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I491,I491)","v":21383957},{"$f":"(LEN($J491) - LEN(SUBSTITUTE(LOWER($J491),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J491) - LEN(SUBSTITUTE(LOWER($J491),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J491) - LEN(SUBSTITUTE(LOWER($J491),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B491:D491)","v":2},2010,"Deciphering the nuclear bile acid receptor FXR paradigm.","Modica",21383957,"Deciphering the nuclear bile acid receptor FXR paradigm.    Abstract:   Originally called retinoid X receptor interacting protein 14 (RIP14), the farnesoid X receptor (FXR) was renamed after the ability of its rat form to bind supra-physiological concentrations of farnesol. In 1999 FXR was de-orphanized since primary bile acids were identified as natural ligands. Strongly expressed in the liver and intestine, FXR has been shown to be the master transcriptional regulator of several entero-hepatic metabolic pathways with relevance to the pathophysiology of conditions such as cholestasis, fatty liver disease, cholesterol gallstone disease, intestinal inflammation and tumors. Furthermore, given the importance of FXR in the gut-liver axis feedbacks regulating lipid and glucose homeostasis, FXR modulation appears to have great input in diseases such as metabolic syndrome and diabetes. Exciting results from several cellular and animal models have provided the impetus to develop synthetic FXR ligands as novel pharmacological agents. Fourteen years from its discovery, FXR has gone from bench to bedside; a novel nuclear receptor ligand is going into clinical use."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I492,I492)","v":20015660},{"$f":"(LEN($J492) - LEN(SUBSTITUTE(LOWER($J492),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J492) - LEN(SUBSTITUTE(LOWER($J492),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J492) - LEN(SUBSTITUTE(LOWER($J492),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B492:D492)","v":2},2010,"Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation.","Liu",20015660,"Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation.    Abstract:   Thyroid hormone influences diverse metabolic pathways important in lipid and glucose metabolism, lipolysis and regulation of body weight. Recently, it has been recognized that thyroid hormone receptor interacts with transcription factors that predominantly respond to nutrient signals including the peroxisome proliferator-activated receptors, liver X receptor and others. Crosstalk between thyroid hormone signaling and these nutrient responsive factors occurs through a variety of mechanisms: competition for retinoid X receptor heterodimer partners, DNA binding sites and transcriptional cofactors. This review focuses on the mechanisms of interaction of thyroid hormone signaling with other metabolic pathways and the importance of understanding these interactions to develop therapeutic agents for treatment of metabolic disorders, such as dyslipidemias, obesity and diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I493,I493)","v":19912733},{"$f":"(LEN($J493) - LEN(SUBSTITUTE(LOWER($J493),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J493) - LEN(SUBSTITUTE(LOWER($J493),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J493) - LEN(SUBSTITUTE(LOWER($J493),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B493:D493)","v":2},2009,"[Arsenic trioxide in combination with all-trans retinoic acid for acute promyelocytic leukemia: a systematic review and meta-analysis].","Xu",19912733,"[Arsenic trioxide in combination with all-trans retinoic acid for acute promyelocytic leukemia: a systematic review and meta-analysis].    Abstract:    BACKGROUND : The studies have demonstrated that arsenic trioxide (ATO) in combination with all-trans retinoic acid (ATRA) takes effects in treatment of acute promyelocytic leukemia (APL) through different underlying mechanisms. This has established the molecular foundation of ATO plus ATRA therapy. Currently, ATO plus ATRA has also been widely used in clinical practice.  OBJECTIVE : To assess the efficacy and safety of ATO in combination with ATRA for APL.  SEARCH STRATEGY : The Cochrane Library (Issue 1, 2009), Cochrane Central Register of Controlled Trials (from 1970 to January 2009), MEDLINE (from 1978 to October 2008), EMBASE (from 1950 to March 2009), Chinese Biological Medical Literature Database (from 1978 to December 2008), CNKI (from 1994 to December 2008), China Medical Academic Conference Database (from 1994 to December 2008) were electronically searched. We also searched the Meta-Register of Controlled Trials, Conference Proceedings of American Society of Hematology (from 1946 to December 2008) and Conference Proceedings of American Society of Clinical Oncology (from 1946 to December 2008) on the internet for grey literature. The authors also hand-searched Chinese periodicals potentially related to the question including Chinese Journal of Hematology, Journal of Experimental Hematology and Journal of Clinical Hematology.  INCLUSION CRITERIA : All randomized controlled trials comparing ATO plus ATRA with other regimens for the treatment of APL were included. Intervention and comparison regimens include: 1) ATO plus ATRA vs ATO monotherapy; 2) ATO plus ATRA vs ATRA monotherapy; 3) ATO plus ATRA vs ATRA plus chemotherapy; 4) ATO plus ATRA vs ATO+ATRA+chemotherapy.  DATA EXTRACTION AND ANALYSIS : Related data concerning complete remission rate, overall survival rate, and disease free survival rate, time to complete remission, relapse rate, mortality and adverse reactions were extracted independently by two reviewers. The different statistical methods were applied according to different data type with RevMan 5.0 software.  RESULTS : After merging of the included trials, seven eligible randomized controlled trials with 392 cases were analyzed, among which 6 RCTs were methodologically graded as middle and one as of high risk of bias. The control therapies included ATO monotherapy, ATRA monotherapy and chemotherapy with ATO plus ATRA. Compared with ATO monotherapy, ATO plus ATRA could improve time to complete remission and relapse rate of newly diagnosed APL, but could not improve the complete remission rate, disease free survival rate, mortality and liver dysfunction of relapsed APL patients based on meta-analysis and sensitivity analysis. Compared with ATRA monotherapy, ATO plus ATRA shortened the time to complete remission, improved the disease free survival rate and relapse rate, but increased the incidence of edema during the treatment. Compared with chemotherapy with ATO plus ATRA, ATO plus ATRA could improve the complete remission rate, relapse rate, mortality and adverse reactions.  CONCLUSION : For newly diagnosed APL, ATO plus ATRA is superior to ATO monotherapy, ATRA monotherapy and chemotherapy with ATO plus ATRA, but due to the lack of data about comparison with the current standard treatment regimen (ATRA plus chemotherapy), it is not enough to recommend ATO plus ATRA as a frontline therapy. For relapsed APL, ATO plus ATRA is not superior to ATO monotherapy, and ATRA plus ATO is not a supportive therapy. Due to limitation of sample size and risk of bias from the included trials, the effects of ATO plus ATRA need to be confirmed by large and high-quality randomized controlled trials."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I494,I494)","v":19818218},{"$f":"(LEN($J494) - LEN(SUBSTITUTE(LOWER($J494),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J494) - LEN(SUBSTITUTE(LOWER($J494),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J494) - LEN(SUBSTITUTE(LOWER($J494),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B494:D494)","v":2},2009,"Vitamin D endocrine system and psoriasis vulgaris--review of the literature.","Rucević",19818218,"Vitamin D endocrine system and psoriasis vulgaris--review of the literature.    Abstract:   Vitamin D exerts its physiological functions on calcium and bone metabolism in humans through the active metabolite 1,25-dihydroxyvitamin D3(1,25(OH)2D3). The other spectrum of vitamin D activities includes important effects on cellular proliferation, differentiation and the immune system. These effects are mediated through the intracellularly located vitamin D receptor (VDR). VDR is a member of the steroid, estrogen and retinoid receptor gene family of proteins that mediate transcriptional activities of the respective ligands. The VDR complex binds in the nucleus to the vitamin D responsive element on the gene. Several polymorphisms of the vitamin D receptor (VDR) gene have been described including FokI in exon 2, BsmI and ApaI in intron 8 and TaqI in exon 9. Alterations in vitamin D-1,25 (OH)2D3 levels and polymorphisms of VDR gene have been shown to be associated with several malignant or autoimmune diseases such as sclerosis multiplex, breast cancer, diabetes mellitus, malignant melanoma, and psoriasis vulgaris. The effects of VDR gene polymorphisms including immunomodulation, stimulation of cellular differentiation and inhibition of proliferation make it a possible candidate for therapy of psoriasis as well as for the psoriasis gene modification. The objective of this article is to present the state-of-the-art in the VDR gene polymorphism research in psoriasis vulgaris."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I495,I495)","v":19760653},{"$f":"(LEN($J495) - LEN(SUBSTITUTE(LOWER($J495),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J495) - LEN(SUBSTITUTE(LOWER($J495),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J495) - LEN(SUBSTITUTE(LOWER($J495),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B495:D495)","v":2},2009,"Vitamin A deficiency in an infant with PAGOD syndrome.","Gavrilova",19760653,"Vitamin A deficiency in an infant with PAGOD syndrome.    Abstract:   PAGOD syndrome is a rare condition characterized by multiple congenital anomalies including pulmonary artery and lung hypoplasia, agonadism, diaphragmatic abnormalities, cardiac defects, omphalocele, and various genital anomalies. The etiology of this condition is unknown but the spectrum of birth defects is similar to the developmental anomalies observed in vitamin A deficiency animal models. We describe an infant with PAGOD syndrome phenotype. The patient had a normal male karyotype and no copy number changes were seen on chromosome genomic hybridization (CGH) microarray. Endocrine evaluation was consistent with primary hypogonadism. The testes and Müllerian structures were absent by imaging studies, raising the possibility of arrest of early gonadogenesis. The plasma free vitamin A was low, consistent with moderate to severe vitamin A deficiency; the maternal plasma vitamin A level was normal. During pregnancy maternal vitamin A is taken up by retinol binding protein 4 (RBP4) which is expressed in the embryonic visceral endoderm from pregastrulational stages. This transport is mediated via the specific membrane receptor for RBP, stimulated by retinoic acid 6 (STRA6). STRA6 is widely expressed in human organ systems including the placenta during embryonic development. Mutations in the STRA6 gene result in Matthew-Wood syndrome, which demonstrates significant phenotypic overlap with PAGOD syndrome. Sequencing of STRA6 coding regions in our patient, revealed no mutations. We present a case of PAGOD syndrome with a review of the literature, posing the hypothesis that a vitamin A metabolic defect, other than transport mediated by STRA6 receptor, might have an etiological role in the development of this multiple congenital anomalies syndrome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I496,I496)","v":19672026},{"$f":"(LEN($J496) - LEN(SUBSTITUTE(LOWER($J496),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J496) - LEN(SUBSTITUTE(LOWER($J496),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J496) - LEN(SUBSTITUTE(LOWER($J496),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B496:D496)","v":2},2009,"Retinoid X receptor heterodimer variants and cardiovascular risk factors.","Nohara",19672026,"Retinoid X receptor heterodimer variants and cardiovascular risk factors.    Abstract:   Nuclear receptors are transcription factors that can be activated by specific ligands. Recent progress has shown that retinoid X receptor (RXR) and its heterodimerization partners, including peroxisome proliferator-activated receptors, regulate many important genes involved in energy homeostasis and atherosclerosis, and should be promising therapeutic targets of metabolic syndrome. RXR heterodimers regulate a number of complex cellular processes, and genetic studies of RXR heterodimers have provided important clinical information in addition to knowledge gained from basic research. Genetic variants of RXR heterodimers were screened and investigated, and some variants were shown to have a considerable impact on metabolic disorders, including phenotypic components of familial combined hyperlipidemia. The combined efforts of basic and clinical science regarding nuclear receptors have achieved significant progress in unraveling the inextricably linked control system of energy expenditure, lipid and glucose homeostasis, inflammation, and atherosclerosis.This review summarizes the current understanding regarding RXR heterodimers based on their human genetic variants, which will provide new clues to uncover the background of multifactorial disease, such as metabolic syndrome or familial combined hyperlipidemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I497,I497)","v":19519282},{"$f":"(LEN($J497) - LEN(SUBSTITUTE(LOWER($J497),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J497) - LEN(SUBSTITUTE(LOWER($J497),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J497) - LEN(SUBSTITUTE(LOWER($J497),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B497:D497)","v":2},2009,"The role of CYP26 enzymes in retinoic acid clearance.","Thatcher",19519282,"The role of CYP26 enzymes in retinoic acid clearance.    Abstract:   Retinoic acid (RA) is a critical signaling molecule that regulates gene transcription and the cell cycle. Understanding of RA signaling has increased dramatically over the past decades, but the connection between whole body RA homeostasis and gene regulation in individual cells is still unclear. It has been proposed that cytochrome P450 family 26 (CYP26) enzymes have a role in determining the cellular exposure to RA by inactivating RA in cells that do not need RA. The CYP26 enzymes have been shown to metabolize RA efficiently and they are also inducible by RA in selected systems. However, their expression patterns in different cell types and a mechanistic understanding of their function is still lacking. Based on preliminary kinetic data and protein expression levels, one may predict that if CYP26A1 is expressed in the liver at even very low levels, it will be the major RA hydroxylase in this tissue. As such, it is an attractive pharmacological target for drug development when one aims to increase circulating or cellular RA concentrations. To further the understanding of how CYP26 enzymes contribute to the regulation of RA homeostasis, structural information of the CYP26s, commercially available recombinant enzymes and good specific and sensitive antibodies are needed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I498,I498)","v":19405812},{"$f":"(LEN($J498) - LEN(SUBSTITUTE(LOWER($J498),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J498) - LEN(SUBSTITUTE(LOWER($J498),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J498) - LEN(SUBSTITUTE(LOWER($J498),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B498:D498)","v":2},2009,"Age-associated decrease of high-density lipoprotein-mediated reverse cholesterol transport activity.","Berrougui",19405812,"Age-associated decrease of high-density lipoprotein-mediated reverse cholesterol transport activity.    Abstract:   High-density lipoproteins (HDL) are considered atheroprotective in contrast to low-density lipoproteins (LDL), which are atherogenic in their oxidized form. A growing body of evidence suggests that HDL exert part of their antiatherogenic effect by counteracting LDL oxidation as well as their proinflammatory effect. However, a number of studies, carried over the past 30 years, have shown that cholesterol efflux plays a major role in the atheroprotective effects of HDL and cholesterol homeostasis. These studies have further identified the scavenger receptor type B-I (SR-BI), the adenosine triphosphate (ATP)-binding cassette transporters ATP-binding cassette subfamily A1 (ABCA1), ATP-binding cassette subfamily G1 (ABCG1) and ABCG4, the liver X receptor/retinoid X receptor (LXR/RXR) and peroxisome proliferator-activated receptorgamma(PPAR gamma) transcription factors, the HDL components apolipoprotein A-I (apoA-I), lecithin-cholesterol acyltransferase (LCAT), and phospholipids as additional mediators of cholesterol transport. Cholesterol efflux occurs via three independent pathways: (1) aqueous diffusion, (2) nonspecific efflux via SR-BI receptors, and (3) specific efflux via cholesterol-responsive members of the ABC superfamily. Whereas aqueous diffusion and scavenger receptor class B, type I (SR-BI)-mediated efflux transport free cholesterol to a wide variety of cholesterol acceptors (particles containing phospholipids, HDL, and lipidated apo-lipoproteins; LDL, etc), the ABCA1 pathway mediates the transport of cholesterol in a unidirectional manner, mainly to lipid-poor apoA-I. In contrast, the ABCG1 pathway is responsible for the transport of cholesterol to all the subfamily members of HDL. Although HDL-mediated cholesterol efflux is apoA-I-dependent, recent studies have suggested an involvement of the enzyme paraoxonase 1 (PON1). Cholesterol efflux is carried on by a number of factors such as genetic mutations, smoking, stress, and high-fat diets. It is attenuated with aging due to changes in the composition and structure of HDL, especially the phosphatidylcholine/sphingomyelin ratio, the fluidity of the phospholipidic layer, the concentration of apoA-I, and the activity of PON1. This review summarizes the findings that cholesterol homeostasis is disrupted with aging as a consequence of dysfunctional cholesterol efflux and the impairment of physiological functions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I499,I499)","v":19374189},{"$f":"(LEN($J499) - LEN(SUBSTITUTE(LOWER($J499),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J499) - LEN(SUBSTITUTE(LOWER($J499),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J499) - LEN(SUBSTITUTE(LOWER($J499),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B499:D499)","v":2},2008,"[RIG-I mediated hepatic innate immune signaling that controls HCV infection].","Saito",19374189,"[RIG-I mediated hepatic innate immune signaling that controls HCV infection].    Abstract:   Hepatitis C virus (HCV) infection is one of the most serious public health problems in the world. HCV leads patients to develop hepatic cirrhosis and precipitates hepatocellular carcinoma. HCV establishes persistent infection by impairing host innate and adaptive immune responses. HCV infected hepatocytes sense the infection through Pathogen Associated Molecular Patterns (PAMPs). The sensor molecules, Pattern Recognition Receptors (PRRs) contain two distinct categories, toll like receptors (TLR) and cytoplasmic Retinoic Acid inducible Gene I (RIG-I) like helicases (RLHs). In the hepatocyte, the cytoplasmic PRR, Retinoic Acid inducible Gene I (RIG-I) plays the central role of HCV viral genome recognition, resulting in activation of signaling to induce type I interferon and proinflammatory cytokines. Type I IFN induces more than 300 effector molecules known as interferon stimulated genes (ISGs) that establish an antiviral state in infected cells and neighboring cells. The activation of innate immunity is also critical for the mounting of innate and adaptive immunity. However, a variety of viral strategies of HCV disrupt host innate immune signaling and ISG function, resulting in a dysfunctional immune response against HCV and poor responses to the current type I IFN based therapy. Many studies have reported immune dysfunction during HCV infection in cell culture, animal models and patients. This review article focuses on understanding how the hepatic innate immunity sensor, PRR, associates with HCV PAMPs, and how HCV escapes from host immunity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I500,I500)","v":19289545},{"$f":"(LEN($J500) - LEN(SUBSTITUTE(LOWER($J500),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J500) - LEN(SUBSTITUTE(LOWER($J500),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J500) - LEN(SUBSTITUTE(LOWER($J500),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B500:D500)","v":2},2009,"A role for nuclear receptors in mammalian hibernation.","Nelson",19289545,"A role for nuclear receptors in mammalian hibernation.    Abstract:   Hibernation is one of the most dramatic examples of phenotypic plasticity in mammals. During periods of food shortage and/or reduced ambient temperatures hibernating mammals become heterothermic, allowing their body temperature to decrease while entering an energy-conserving torpid state. In order to survive the multi-month hibernation season many species engage in hyperphagy, dramatically increasing adipose stores prior to the onset of hibernation. Nuclear receptors are a superfamily of transcription factors many of which bind lipophilic molecules as ligands. They regulate a variety of processes including energy homeostasis, carbohydrate and lipid metabolism, inflammation and circadian rhythm. Given that lipids are integral in the hibernation phenotype they may play important regulatory roles through their interactions with nuclear receptors. Here we review current knowledge and suggest possible roles in mammalian hibernation for peroxisome proliferator-activated receptors (PPARs), farnesoid X receptors (FXRs), liver X receptors (LXRs), retinoid-related orphan receptors (RORs) and Rev-ERBs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I501,I501)","v":19258656},{"$f":"(LEN($J501) - LEN(SUBSTITUTE(LOWER($J501),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J501) - LEN(SUBSTITUTE(LOWER($J501),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J501) - LEN(SUBSTITUTE(LOWER($J501),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B501:D501)","v":2},2008,"Biological role of liver X receptors.","Baranowski",19258656,"Biological role of liver X receptors.    Abstract:   Liver X receptors (LXRs) are ligand-activated transcription factors of the nuclear receptor superfamily. There are two LXR isoforms termed alpha and beta which upon activation form heterodimers with retinoid X receptor and bind to LXR response element found in the promoter region of the target genes. Their endogenous agonists include a variety of oxidized cholesterol derivatives referred to as oxysterols. In the recent years LXRs have been characterized as key transcriptional regulators of lipid and carbohydrate metabolism. LXRs were shown to function as sterol sensors protecting the cells from cholesterol overload by stimulating reverse cholesterol transport and activating its conversion to bile acids in the liver. This finding led to identification of LXR agonists as potent antiatherogenic agents in rodent models of atherosclerosis. However, first-generation LXR activators were also shown to stimulate lipogenesis via sterol regulatory element binding protein-1c leading to liver steatosis and hypertriglyceridemia. Despite their lipogenic action, LXR agonists possess antidiabetic properties. LXR activation normalizes glycemia and improves insulin sensitivity in rodent models of type 2 diabetes and insulin resistance. Antidiabetic action of LXR agonists is thought to result predominantly from suppression of hepatic gluconeogenesis. However, recent studies suggest that LXR activation may also enhance peripheral glucose uptake. The purpose of this review is to summarize the present state of knowledge on the physiological and pathophysiological implications of LXRs with the special consideration of their role in lipid and carbohydrate metabolism and associated diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I502,I502)","v":19204986},{"$f":"(LEN($J502) - LEN(SUBSTITUTE(LOWER($J502),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J502) - LEN(SUBSTITUTE(LOWER($J502),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J502) - LEN(SUBSTITUTE(LOWER($J502),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B502:D502)","v":2},2009,"On the diabetic menu: zebrafish as a model for pancreas development and function.","Kinkel",19204986,"On the diabetic menu: zebrafish as a model for pancreas development and function.    Abstract:   Development of the vertebrate pancreas is a complex stepwise process comprising regionalization, cell differentiation, and morphogenesis. Studies in zebrafish are contributing to an emerging picture of pancreas development in which extrinsic signaling molecules influence intrinsic transcriptional programs to allow ultimate differentiation of specific pancreatic cell types. Zebrafish experiments have revealed roles for several signaling molecules in aspects of this process; for example our own work has shown that retinoic acid signals specify the pre-pancreatic endoderm. Time-lapse imaging of live zebrafish embryos has started to provide detailed information about early pancreas morphogenesis. In addition to modeling embryonic development, the zebrafish has recently been used as a model for pancreas regeneration studies. Here, we review the significant progress in these areas and consider the future potential of zebrafish as a diabetes research model."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I503,I503)","v":19144126},{"$f":"(LEN($J503) - LEN(SUBSTITUTE(LOWER($J503),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J503) - LEN(SUBSTITUTE(LOWER($J503),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J503) - LEN(SUBSTITUTE(LOWER($J503),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B503:D503)","v":2},2009,"Tetralogy of Fallot.","Bailliard",19144126,"Tetralogy of Fallot.    Abstract:   Tetralogy of Fallot is a congenital cardiac malformation that consists of an interventricular communication, also known as a ventricular septal defect, obstruction of the right ventricular outflow tract, override of the ventricular septum by the aortic root, and right ventricular hypertrophy. This combination of lesions occurs in 3 of every 10,000 live births, and accounts for 7-10% of all congenital cardiac malformations. Patients nowadays usually present as neonates, with cyanosis of varying intensity based on the degree of obstruction to flow of blood to the lungs. The aetiology is multifactorial, but reported associations include untreated maternal diabetes, phenylketonuria, and intake of retinoic acid. Associated chromosomal anomalies can include trisomies 21, 18, and 13, but recent experience points to the much more frequent association of microdeletions of chromosome 22. The risk of recurrence in families is 3%. Useful diagnostic tests are the chest radiograph, electrocardiogram, and echocardiogram. The echocardiogram establishes the definitive diagnosis, and usually provides sufficient information for planning of treatment, which is surgical. Approximately half of patients are now diagnosed antenatally. Differential diagnosis includes primary pulmonary causes of cyanosis, along with other cyanotic heart lesions, such as critical pulmonary stenosis and transposed arterial trunks. Neonates who present with ductal-dependent flow to the lungs will receive prostaglandins to maintain ductal patency until surgical intervention is performed. Initial intervention may be palliative, such as surgical creation of a systemic-to-pulmonary arterial shunt, but the trend in centres of excellence is increasingly towards neonatal complete repair. Centres that undertake neonatal palliation will perform the complete repair at the age of 4 to 6 months. Follow-up in patients born 30 years ago shows a rate of survival greater than 85%. Chronic issues that now face such adults include pulmonary regurgitation, recurrence of pulmonary stenosis, and ventricular arrhythmias. As the strategies for surgical and medical management have progressed, the morbidity and mortality of those born with tetralogy of Fallot in the current era is expected to be significantly improved."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I504,I504)","v":18341851},{"$f":"(LEN($J504) - LEN(SUBSTITUTE(LOWER($J504),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J504) - LEN(SUBSTITUTE(LOWER($J504),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J504) - LEN(SUBSTITUTE(LOWER($J504),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B504:D504)","v":2},2008,"[Long-term control of psoriasis is necessary].","Sánchez Carazo",18341851,"[Long-term control of psoriasis is necessary].    Abstract:   Psoriasis is an immune mediated, inflammatory skin condition affecting approximately 1.43% of Spanish population. In clinical practice, physicians use PASI index to assess the severity. Psoriasis causes physical and mental disability comparable to other chronic diseases and affects seriously the patients quality of life. For treatment we have different options. Conventional systemic treatment such as methotrexate, cyclosporine and acitretin may be associated with relevant side effects, and organ toxicity that avoid long term therapy. Several psoriasis patients have other comorbid disorders like obesity, diabetes, dyslipemia, hypertension and an increased rate of cardiovascular disease and metabolic syndrome and these patients need safer treatments. The accumulating clinical experience with new therapies consistent on biological agents like efalizumab indicates that are effective therapies, with safety profile and no evidence of cumulative toxicity that allows a long term use. A better control of psoriasis improves patients quality of life."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I505,I505)","v":18850203},{"$f":"(LEN($J505) - LEN(SUBSTITUTE(LOWER($J505),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J505) - LEN(SUBSTITUTE(LOWER($J505),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J505) - LEN(SUBSTITUTE(LOWER($J505),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B505:D505)","v":2},2006,"Polyunsaturated fatty acids: From diet to binding to ppars and other nuclear receptors.","Bordoni",18850203,"Polyunsaturated fatty acids: From diet to binding to ppars and other nuclear receptors.    Abstract:   Dietary polyunsaturated fatty acids (PUFAs) function not only by altering membrane lipid composition, cellular metabolism, signal transduction, but possess also effects on gene expression by regulating the activity/abundance of different nuclear transcription factors: peroxisome proliferator activated receptors, retinoid X receptors, liver X receptors, hepatic nuclear factors-4a, and sterol regulatory binding proteins 1 and 2. PUFAs regulate the expression of genes in various tissues, including the liver, heart, adipose tissue, and brain, playing a major role in carbohydrate, fatty acid, triglyceride, and cholesterol metabolism. Before binding to transcription factors, PUFAs must be absorbed in the intestine and delivered to cells, and then they must enter the cell and the nucleus. PUFA concentration within the cell depends on many different factors, and regulate their possibility to act as transcription modulators. The aim of this review is to summarize recent knowledge about PUFAs destiny from dietto nuclear factors binding, examining the different variables which can modulate their interaction with nuclear factors themselves and therefore their effect on gene expression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I506,I506)","v":18653780},{"$f":"(LEN($J506) - LEN(SUBSTITUTE(LOWER($J506),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J506) - LEN(SUBSTITUTE(LOWER($J506),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J506) - LEN(SUBSTITUTE(LOWER($J506),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B506:D506)","v":2},2008,"The nuclear hormone receptor family round the clock.","Teboul",18653780,"The nuclear hormone receptor family round the clock.    Abstract:   Daily rhythms in behavior and physiology are observed in most organisms. These rhythms are controlled by internal self-sustained circadian ( approximately 24 h) clocks, which are present in virtually all cells. The 24-h oscillations are generated by a molecular mechanism entrained by external or internal time cues and which, in turn, regulate rhythmic outputs. In mammals, the circadian system comprises a master clock located in the hypothalamus that is directly entrained by the light-dark cycle and which coordinates the phases of local clocks in the periphery in order to ensure optimal timing of the physiology. Nuclear receptors (NRs) form a large family of transcription factors that include both ligand-inducible and orphan receptors. These NRs are key regulators of major biological processes such as reproduction, development, cell growth and death, inflammation, immunity, and metabolic homeostasis. Recent observations indicate that several NR signaling pathways play a critical role in central and peripheral circadian clocks. The REV-ERB/retinoid-related orphan receptor orphan NR subfamily regulates the expression of core clock genes and contributes to the robustness of the clock mechanism. Glucocorticoid and retinoic acid receptors are involved in the resetting of peripheral clocks. Several other NRs such as peroxisome proliferator-activated receptor-alpha, short heterodimer partner, and constitutive androstane receptor act as molecular links between clock genes and specific rhythmic metabolic outputs. The expanding functional links between NRs and circadian clocks open novel perspectives for understanding the hormonal regulation of the mammalian circadian system as well as for exploring the role of circadian clocks in the pathogenesis of NR-related diseases such as cancer and metabolic syndrome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I507,I507)","v":18508652},{"$f":"(LEN($J507) - LEN(SUBSTITUTE(LOWER($J507),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J507) - LEN(SUBSTITUTE(LOWER($J507),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J507) - LEN(SUBSTITUTE(LOWER($J507),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B507:D507)","v":2},2008,"Virus associated innate immunity in liver.","Kanto",18508652,"Virus associated innate immunity in liver.    Abstract:   Dendritic cells (DCs) sense virus via toll-like receptors (TLR) or retinoic acid inducible gene-I (RIG-I) and evoke a cascade of immune reactions. In myeloid DC (MDC) from hepatitis C virus (HCV)-infected patients, the levels of TLR/RIG-I-mediated IFN-beta or TNF-alfa induction are lower than those in uninfected donors, suggesting that their signal transduction in MDC is impaired. Dendritic cells in HCV infection are unresponsive to interferon (IFN)-alfa, thus failing to enhance MHC class-I related chain A/B and subsequent NK cell activation. Alternatively, NK cells from the patients down-regulate DC in the presence of HLA-E-expressing hepatocytes by secreting IL-10 and TGF-beta1. Such functional alteration of NK cells in HCV infection is ascribed to the enhanced expression of NKG2A/CD94. Activated NKT cells from the patients produce higher levels of IL-13 but comparable IFN-gamma with those from controls, showing their bias to Th2-type. In pegylated IFN-alfa/ribavirin therapy for chronic hepatitis C, improved DC function is related with successful HCV eradication. In conclusion, cross-talks among DCs and innate lymphocytes are critical in shaping immune response against HCV, either spontaneously or therapeutically."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I508,I508)","v":18456715},{"$f":"(LEN($J508) - LEN(SUBSTITUTE(LOWER($J508),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J508) - LEN(SUBSTITUTE(LOWER($J508),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J508) - LEN(SUBSTITUTE(LOWER($J508),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B508:D508)","v":2},2008,"Double outlet right ventricle: aetiologies and associations.","Obler",18456715,"Double outlet right ventricle: aetiologies and associations.    Abstract:    BACKGROUND : Double outlet right ventricle (DORV), a clinically significant congenital heart defect, occurs in 1-3% of individuals with congenital heart defects. In contrast to other major congenital heart defects, there are no systematic or comprehensive data regarding associations, aetiologies, and pathogenesis of DORV. We analysed reported cases in the medical literature to address these issues.  METHODS : We queried the PubMed database using key words quot;double outlet right ventriclequot; and quot;DORVquot; for case reports, epidemiologic analyses and animal studies with this cardiac anomaly. The anatomic subtype of DORV was classified according to criteria of Van Praagh.  RESULTS : Chromosomal abnormalities were present in 61 of the 149 cases of DORV. Trisomies 13 and 18, and del 22q11 were the most commonly associated cytogenetic lesions; different anatomic subtypes of DORV were noted in trisomies 13 and 18 versus del 22q11. DORV was reported in many uncommon or rare non-chromosomal syndromes. Mutations and non-synonymous sequence variants in the CFC1 and CSX genes were the most commonly reported monogenic loci associated with DORV in humans; numerous genes are reported in murine models of DORV. Animal studies implicate maternal diabetes and prenatal exposure to ethanol, retinoids, theophylline, and valproate in DORV teratogenesis.  CONCLUSIONS : The large number of genes associated with DORV in both humans and animal models and the different anatomic subtypes seen in specific aetiologies indicate the likelihood of several distinct pathogenetic mechanisms for DORV, including impairment of neural crest derivative migration and impairment of normal cardiac situs and looping."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I509,I509)","v":18375823},{"$f":"(LEN($J509) - LEN(SUBSTITUTE(LOWER($J509),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J509) - LEN(SUBSTITUTE(LOWER($J509),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J509) - LEN(SUBSTITUTE(LOWER($J509),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B509:D509)","v":2},2008,"Nuclear receptors and inflammatory diseases.","Wang",18375823,"Nuclear receptors and inflammatory diseases.    Abstract:   It is well known that the steroid hormone glucocorticoid and its nuclear receptor regulate the inflammatory process, a crucial component in the pathophysiological process related to human diseases that include atherosclerosis, obesity and type II diabetes, inflammatory bowel disease, Alzheimers disease, multiple sclerosis, and liver tumors. Growing evidence demonstrates that orphan and adopted orphan nuclear receptors, such as peroxisome proliferator-activated receptors, liver x receptors, the farnesoid x receptor, NR4As, retinoid x receptors, and the pregnane x receptor, regulate the inflammatory and metabolic profiles in a ligand-dependent or -independent manner in human and animal models. This review summarizes the regulatory roles of these nuclear receptors in the inflammatory process and the underlying mechanisms."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I510,I510)","v":18316956},{"$f":"(LEN($J510) - LEN(SUBSTITUTE(LOWER($J510),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J510) - LEN(SUBSTITUTE(LOWER($J510),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J510) - LEN(SUBSTITUTE(LOWER($J510),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B510:D510)","v":2},2008,"Glitazones and the cardiovascular system.","Devchand",18316956,"Glitazones and the cardiovascular system.    Abstract:    PURPOSE OF REVIEW : To chart recent progress on molecular mechanisms of rosiglitazone and pioglitazone in the cardiovascular system.  RECENT FINDINGS : Several classes of oral antidiabetic drugs are available to treat type 2 diabetes, but glitazones offer the unique promise of insulin-sensitizing ability coupled with potential to reverse cardiovascular abnormalities associated with insulin resistance. Currently the two drugs used are rosiglitazone and pioglitazone, marketed as Avandia and Actos. Recent results of different metaanalyses were inconclusive as to whether rosiglitazone caused real adverse effects of myocardial ischemia. Thus, the US Food and Drugs Administration placed a black box warning on Avandia to signal potential of myocardial infarction and heart-related deaths, as a precautionary measure until analyses of all available data provide clarity. Also unresolved is the extent to which the two compounds share modes of action.  SUMMARY : Type II diabetes affects more than 160 million people, approximately 5% of the worlds population (http://www.who.org). Recently, questions have been raised about the cardiovascular safety of glitazone antidiabetic drugs. Clearly, there is an urgency to define molecular mechanisms of rosiglitazone and pioglitazone and understand how these drugs may impact patients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I511,I511)","v":18281716},{"$f":"(LEN($J511) - LEN(SUBSTITUTE(LOWER($J511),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J511) - LEN(SUBSTITUTE(LOWER($J511),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J511) - LEN(SUBSTITUTE(LOWER($J511),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B511:D511)","v":2},2008,"Fifteen years after quot;Wingspreadquot;--environmental endocrine disrupters and human and wildlife health: where we are today and where we need to go.","Hotchkiss",18281716,"Fifteen years after quot;Wingspreadquot;--environmental endocrine disrupters and human and wildlife health: where we are today and where we need to go.    Abstract:   In 1991, a group of expert scientists at a Wingspread work session on endocrine-disrupting chemicals (EDCs) concluded that quot;Many compounds introduced into the environment by human activity are capable of disrupting the endocrine system of animals, including fish, wildlife, and humans. Endocrine disruption can be profound because of the crucial role hormones play in controlling development.quot; Since that time, there have been numerous documented examples of adverse effects of EDCs in invertebrates, fish, wildlife, domestic animals, and humans. Hormonal systems can be disrupted by numerous different anthropogenic chemicals including antiandrogens, androgens, estrogens, AhR agonists, inhibitors of steroid hormone synthesis, antithyroid substances, and retinoid agonists. In addition, pathways and targets for endocrine disruption extend beyond the traditional estrogen/androgen/thyroid receptor-mediated reproductive and developmental systems. For example, scientists have expressed concern about the potential role of EDCs in increasing trends in early puberty in girls, obesity and type II diabetes in the United States and other populations. New concerns include complex endocrine alterations induced by mixtures of chemicals, an issue broadened due to the growing awareness that EDCs present in the environment include a variety of potent human and veterinary pharmaceutical products, personal care products, nutraceuticals and phytosterols. In this review we (1) address what have we learned about the effects of EDCs on fish, wildlife, and human health, (2) discuss representative animal studies on (anti)androgens, estrogens and 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals, and (3) evaluate regulatory proposals being considered for screening and testing these chemicals."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I512,I512)","v":18068343},{"$f":"(LEN($J512) - LEN(SUBSTITUTE(LOWER($J512),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J512) - LEN(SUBSTITUTE(LOWER($J512),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J512) - LEN(SUBSTITUTE(LOWER($J512),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B512:D512)","v":2},2008,"Starring stellate cells in liver immunology.","Winau",18068343,"Starring stellate cells in liver immunology.    Abstract:   Stellate cells are star-shaped cells located in the liver and mediate a multitude of primarily non-immunological functions. They play a pivotal role in the metabolism of vitamin A and store 80% of total body retinol. Upon activation, stellate cells differentiate to myofibroblasts for production of extracellular matrix, leading to liver fibrosis. Moreover, activated stellate cells regulate liver blood flow through vasoconstriction implicated in portal hypertension. Earlier work demonstrated stellate cell derived secretion of chemokines and cytokines such as transforming growth factor beta (TGF-beta), suggesting an association with immunological processes. Indeed, recent evidence indicated that hepatic stellate cells perform potent APC function for stimulation of NKT cells as well as CD8 and CD4 T cells. Additionally, stellate cell mediated antigen presentation induced protective immunity against bacterial infection. Current experiments reveal that the presenting ability of stellate cells is the key to antigen-dependent T cell instruction by vitamin A derived retinoic acid. Finally, future studies will show whether in the firmament of immunology stellate cells will represent fixed or falling stars."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I513,I513)","v":17519397},{"$f":"(LEN($J513) - LEN(SUBSTITUTE(LOWER($J513),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J513) - LEN(SUBSTITUTE(LOWER($J513),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J513) - LEN(SUBSTITUTE(LOWER($J513),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B513:D513)","v":2},2007,"Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics.","Jenkins",17519397,"Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics.    Abstract:   Prevention of congenital cardiovascular defects has been hampered by a lack of information about modifiable risk factors for abnormalities in cardiac development. Over the past decade, there have been major breakthroughs in the understanding of inherited causes of congenital heart disease, including the identification of specific genetic abnormalities for some types of malformations. Although relatively less information has been available on noninherited modifiable factors that may have an adverse effect on the fetal heart, there is a growing body of epidemiological literature on this topic. This statement summarizes the currently available literature on potential fetal exposures that might alter risk for cardiovascular defects. Information is summarized for periconceptional multivitamin or folic acid intake, which may reduce the risk of cardiac disease in the fetus, and for additional types of potential exposures that may increase the risk, including maternal illnesses, maternal therapeutic and nontherapeutic drug exposures, environmental exposures, and paternal exposures. Information is highlighted regarding definitive risk factors such as maternal rubella; phenylketonuria; pregestational diabetes; exposure to thalidomide, vitamin A cogeners, or retinoids; and indomethacin tocolysis. Caveats regarding interpretation of possible exposure-outcome relationships from case-control studies are given because this type of study has provided most of the available information. Guidelines for prospective parents that could reduce the likelihood that their child will have a major cardiac malformation are given. Issues related to pregnancy monitoring are discussed. Knowledge gaps and future sources of new information on risk factors are described."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I514,I514)","v":17451793},{"$f":"(LEN($J514) - LEN(SUBSTITUTE(LOWER($J514),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J514) - LEN(SUBSTITUTE(LOWER($J514),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J514) - LEN(SUBSTITUTE(LOWER($J514),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B514:D514)","v":2},2007,"The relationship between nutrition and circadian rhythms in mammals.","Froy",17451793,"The relationship between nutrition and circadian rhythms in mammals.    Abstract:   The master clock located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus regulates circadian rhythms in mammals. The clock is an intracellular, transcriptional mechanism sharing the same molecular components in SCN neurons and in peripheral cells, such as the liver, intestine, and retina. The circadian clock controls food processing and energy homeostasis by regulating the expression and/or activity of enzymes involved in cholesterol, amino acid, lipid, glycogen, and glucose metabolism. In addition, many hormones involved in metabolism, such as insulin, glucagon, adiponectin, corticosterone, leptin, and ghrelin, exhibit circadian oscillation. Furthermore, disruption of circadian rhythms is involved in the development of cancer, metabolic syndrome, and obesity. Metabolism and food intake also feed back to influence the biological clock. Calorie restriction (CR) entrains the SCN clock, whereas timed meals entrain peripheral oscillators. Furthermore, the cellular redox state, dictated by food metabolism, and several nutrients, such as glucose, ethanol, adenosine, caffeine, thiamine, and retinoic acid, can phase-shift circadian rhythms. In conclusion, there is a large body of evidence that links feeding regimens, food components, and the biological clock."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I515,I515)","v":17368316},{"$f":"(LEN($J515) - LEN(SUBSTITUTE(LOWER($J515),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J515) - LEN(SUBSTITUTE(LOWER($J515),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J515) - LEN(SUBSTITUTE(LOWER($J515),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B515:D515)","v":2},2007,"Use of model-based compartmental analysis to study vitamin A kinetics and metabolism.","Cifelli",17368316,"Use of model-based compartmental analysis to study vitamin A kinetics and metabolism.    Abstract:   We discuss the use of mathematical modeling, and specifically model-based compartmental analysis, to analyze vitamin A kinetic data obtained in rat and human studies over the past 25 years. Following an overview of whole-body vitamin A metabolism, a review of early kinetic studies, and an introduction to the approach and terminology of compartmental analysis, we summarize studies done in this laboratory to develop models of whole-body vitamin A metabolism in rats at varying levels of vitamin A status. Highlights of the results of these studies include the extensive recycling of vitamin A among plasma and tissues before irreversible utilization and the existence of significant extrahepatic pools of the vitamin. Our studies also document important differences in vitamin A kinetics as a function of vitamin A status and the importance of plasma retinol pool size in vitamin A utilization rate. Later we describe vitamin A kinetics and models developed for specific organs including the liver, eyes, kidneys, small intestine, lungs, testes, adrenals, and remaining carcass, and we discuss the effects of various exogenous factors (e.g., 4-HPR, dioxin, iron deficiency, dietary retinoic acid, and inflammation) on vitamin A dynamics. We also briefly review the retrospective application of model-based compartmental analysis to human vitamin A kinetic data. Overall, we conclude that the application of model-based compartmental analysis to vitamin A kinetic data provides unique insights into both quantitative and descriptive aspects of vitamin A metabolism and homeostasis in the intact animal."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I516,I516)","v":17326005},{"$f":"(LEN($J516) - LEN(SUBSTITUTE(LOWER($J516),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J516) - LEN(SUBSTITUTE(LOWER($J516),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J516) - LEN(SUBSTITUTE(LOWER($J516),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B516:D516)","v":2},2007,"Nuclear hormone receptors in human skin.","Schmuth",17326005,"Nuclear hormone receptors in human skin.    Abstract:   Nuclear hormone receptors are of critical importance for skin homeostasis where they modulate cellular metabolism, proliferation, differentiation, cell death, and inflammation. The cutaneous role of the glucocorticoid, androgen, and estrogen receptors was explored initially. In recent years, sequence homology comparisons have uncovered the complete superfamily of related receptors, many of which are also implicated in cutaneous homeostasis. A subgroup of these receptors acts in concert with the retinoid X receptor by heterodimerization and has been successfully targeted for dermatologic therapy; i.e., the retinoic acid receptor and the vitamin D receptor. Ongoing research is aimed at delineating the cutaneous effects of additional members of this subgroup including the peroxisome proliferator-activated receptors and the liver X receptors. The various receptors exert differential effects in skin and can be rationally chosen as drug targets for the treatment of cutaneous pathologies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I517,I517)","v":17017903},{"$f":"(LEN($J517) - LEN(SUBSTITUTE(LOWER($J517),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J517) - LEN(SUBSTITUTE(LOWER($J517),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J517) - LEN(SUBSTITUTE(LOWER($J517),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B517:D517)","v":2},2006,"Novel agents to manage dyslipidemias and impact atherosclerosis.","Nachimuthu",17017903,"Novel agents to manage dyslipidemias and impact atherosclerosis.    Abstract:   Strong epidemiological evidence linked elevated levels of low-density lipoprotein cholesterol (LDL-C) to risk of atherosclerotic heart disease. As a consequence, LDL-C lowering has been the main goal of therapy to reduce cardiovascular risk for the past few decades and hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have become some of the most commonly prescribed drugs. In spite of the proven efficacy of these drugs, statins reduce cardiovascular events by only 30-40%. Epidemiological analyses clearly indicate that a significant portion of risk is linked to other particles such as low high-density lipoprotein cholesterol (HDL-C), high triglycerides and others. Furthermore, several quantitative coronary angiography studies showing regression of atherosclerosis and reduction in subsequent events utilized a combination of drugs effective on LDL-C as well as other lipoproteins. Hence, several new drugs are being investigated that affect more than the traditional LDL-C pathways. In this article, we review lipoprotein-modifying agents that have either been recently released, or are still in various phases of development. They include agents that reduce LDL-C levels by mechanisms other than HMG-CoA inhibition (such as cholesterol absorption inhibitors, Acyl-CoA cholesterol acyl transferase inhibitors, sterol-regulating binding protein cleavage activating protein ligands, microsomal triglyceride transfer protein inhibitors, LDL-C receptor activators and farnesoid X receptor antagonists) and agents that raise HDL-C cholesterol or improve cholesterol efflux (such as cholesterol ester transfer protein inhibitors, retinoid X receptor selective agonists, specific peroxisome proliferator-activated receptor (PPAR) agonists and estrogen like compounds)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I518,I518)","v":16915864},{"$f":"(LEN($J518) - LEN(SUBSTITUTE(LOWER($J518),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J518) - LEN(SUBSTITUTE(LOWER($J518),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J518) - LEN(SUBSTITUTE(LOWER($J518),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B518:D518)","v":2},2006,"Nuclear receptors: potential biomarkers for assessing physiological functions of soy proteins and phytoestrogens.","Xiao",16915864,"Nuclear receptors: potential biomarkers for assessing physiological functions of soy proteins and phytoestrogens.    Abstract:   Soy consumption is associated with decreased incidence of chronic diseases, including cardiovascular diseases, atherosclerosis, diabetes, osteoporosis, and certain types of cancers. However, consumption of high amounts of soy isoflavones may adversely influence endocrine functions, such as thyroid function and reproductive performance, because of their structural similarity to endogenous estrogens. Nuclear receptors are a group of transcription factors that play critical roles in the regulation of gene expression and physiological functions through direct interaction with target genes. Modulation of the abundance of these receptors, such as changing their gene expression, alters the sensitivity of the target cells or tissues to the stimulation of ligands, and eventually affects the relevant physiological functions, such as growth, development, osteogenesis, immune response, lipogenesis, reproductive process, and anticarcinogenesis. A number of studies have shown that the bioactive components in soy can modify the expression of these receptors in various tissues and cancer cells, which is believed to be a key intracellular mechanism by which soy components affect physiological functions. This review summarizes the current understanding of the modulation of nuclear receptors by soy proteins and isoflavones, and focuses especially on the receptors for estrogens, progesterone, androgen, vitamin D, retinoic acid, and thyroid hormones as well as the potential impact on physiological functions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I519,I519)","v":16819395},{"$f":"(LEN($J519) - LEN(SUBSTITUTE(LOWER($J519),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J519) - LEN(SUBSTITUTE(LOWER($J519),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J519) - LEN(SUBSTITUTE(LOWER($J519),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B519:D519)","v":2},2006,"Bile salt excretory pump: biology and pathobiology.","Suchy",16819395,"Bile salt excretory pump: biology and pathobiology.    Abstract:   Bile acids are the major determinant and driving force for the generation of bile flow. Bile acid transport across the canalicular membrane is primarily an ATP-dependent process. The predominant transporter is the bile salt excretory pump (BSEP, ABCB11), a member of the adenosine triphosphate-binding cassette (ABC) family of transporters. Regulatory mechanisms that can coordinate the genes encoding bile acid transport proteins are critically important to avoid hepatocyte damage from intracellar accumulation of bile acids. Bile salts are natural ligands for several nuclear hormone receptors expressed in liver and intestine. Nuclear receptors are transcription factors that bind specific ligands such as bile acids and regulate gene expression according to the metabolic requirements of the cell. In cloning of the BSEP gene, we found a binding site in the promoter for the farnesoid X receptor (FXR), a nuclear receptor for bile acids. FXR activity requires heterodimerization with the 9-cis retinoid receptor (RXR alpha), and when bound by bile acids and retinoic acid, the complex effectively activates the transcription of BSEP. There is a growing body of evidence for the activation of nuclear hormone receptors through the remodeling of chromatin by histone modification involving acetylation, in concert with methylation of H3 and H4 histones. We have recently demonstrated a role for the coactivator-associated arginine methyltransferase 1 (CARM1), as a coactivator of the FXR/RXR receptor and regulator of FXR responsive genes such as BSEP. Chromatin immunoprecipitation showed that the bile acid-dependent activation of the human BSEP is associated with a simultaneous increase of FXR and CARM1 occupation of the BSEP promoter. The increased occupation of the BSEP locus by CARM1 also corresponds with the increased deposition of Arg-17 methylation and Lys-9 acetylation of histone H3 within the FXR DNA-binding element of BSEP. Our work on the role of nuclear receptors in regulation of bile acid homeostasis has led to an increased understanding of the pathogenesis of the disorder, progressive familial intrahepatic cholestasis, type 1 (PFIC1) or Byler disease. The gene mutated in PFIC1 is called FIC1 and codes for a type IV P-type ATPase whose function is unknown. Increased ileal apical sodium-dependent bile acid transporter messenger RNA (mRNA) expression was detected in 3 patients with PFIC1. Ileal FXR and short heterodimer partner (an inhibitory nuclear receptor) messenger RNA levels were reduced in the same 3 patients. In studies of cells after antisense-mediated knock-down of endogenous FIC1, the activity of the ileal apical bile acid transporter promoter was enhanced, whereas the activities of the human FXR and BSEP promoters were reduced. Nuclear but not cytoplasmic localization of FXR is markedly decreased in FIC1-negative cells, indicating that FIC1 is necessary for posttranslational modifications necessary for the nuclear translocation of FXR. This defect leads to enhanced ileal bile salt uptake and impaired canalicular bile salt secretion by BSEP. In PFIC1, an increased load of bile acids is retained in the liver leading to cholestasis and progressive liver injury."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I520,I520)","v":16768108},{"$f":"(LEN($J520) - LEN(SUBSTITUTE(LOWER($J520),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J520) - LEN(SUBSTITUTE(LOWER($J520),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J520) - LEN(SUBSTITUTE(LOWER($J520),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B520:D520)","v":2},2006,"[Mouse NASH model using retinoic acid receptor alpha].","Shiota",16768108,"[Mouse NASH model using retinoic acid receptor alpha].    Abstract:   To explore the role of retinoic acid (RA) in the liver, we developed transgenic mice expressing RA receptor a-dominant negative form (RARE) in hepatocytes using albumin promoter and enhancer. The RARE m ice developed microvesicular steatosis andspotty focal necrosis. Mitochondrial beta-oxidation activity of fatty acids and related enzymes were down-regulated, while peroxisomal beta-oxidation and related enzymes were up-regulated. Expression of cytochrome p4504a10, cytochrome p4504a12, and cytochrome p4504a14 was increased. Formation of H2O2 and 8-OHdG was increased. With age, these mice developed liver tumor. Feeding on a high-RA diet reversed histological and biochemical abnormalities and inhibited the occurrence of liver tumors. These results suggest that hepatic loss of RA function leads to the development of steatohepatitis and liver tumors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I521,I521)","v":16628264},{"$f":"(LEN($J521) - LEN(SUBSTITUTE(LOWER($J521),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J521) - LEN(SUBSTITUTE(LOWER($J521),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J521) - LEN(SUBSTITUTE(LOWER($J521),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B521:D521)","v":2},2006,"Retinoic acid receptor-related orphan receptor alpha as a therapeutic target in the treatment of dyslipidemia and atherosclerosis.","Jakel",16628264,"Retinoic acid receptor-related orphan receptor alpha as a therapeutic target in the treatment of dyslipidemia and atherosclerosis.    Abstract:   Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor family. Recently, cholesterol (derivatives) has been identified as an RORalpha ligand and deorphanized this receptor. RORalpha is expressed in many tissues and is therefore a regulator of multiple biological processes. Studies of staggerer mice and in vitro assays indicate a beneficial modulatory role of RORalpha in the pathogenesis of dyslipidemia, inflammation and atherosclerosis. This paper provides an overview on the role of RORalpha in lipid metabolism and discusses its potential therapeutic option for treating lipid and inflammatory disorders leading to atherosclerosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I522,I522)","v":16606331},{"$f":"(LEN($J522) - LEN(SUBSTITUTE(LOWER($J522),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J522) - LEN(SUBSTITUTE(LOWER($J522),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J522) - LEN(SUBSTITUTE(LOWER($J522),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B522:D522)","v":2},2006,"Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress.","Seitz",16606331,"Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress.    Abstract:   Hepatocellular cancer is the fifth most frequent cancer in men and the eighth in women worldwide. Established risk factors are chronic hepatitis B and C infection, chronic heavy alcohol consumption, obesity and type 2 diabetes, tobacco use, use of oral contraceptives, and aflatoxin-contaminated food. Almost 90% of all hepatocellular carcinomas develop in cirrhotic livers. In Western countries, attributable risks are highest for cirrhosis due to chronic alcohol abuse and viral hepatitis B and C infection. Among those with alcoholic cirrhosis, the annual incidence of hepatocellular cancer is 1-2%. An important mechanism implicated in alcohol-related hepatocarcinogenesis is oxidative stress from alcohol metabolism, inflammation, and increased iron storage. Ethanol-induced cytochrome P-450 2E1 produces various reactive oxygen species, leading to the formation of lipid peroxides such as 4-hydroxy-nonenal. Furthermore, alcohol impairs the antioxidant defense system, resulting in mitochondrial damage and apoptosis. Chronic alcohol exposure elicits hepatocyte hyperregeneration due to the activation of survival factors and interference with retinoid metabolism. Direct DNA damage results from acetaldehyde, which can bind to DNA, inhibit DNA repair systems, and lead to the formation of carcinogenic exocyclic DNA etheno adducts. Finally, chronic alcohol abuse interferes with methyl group transfer and may thereby alter gene expression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I523,I523)","v":16469975},{"$f":"(LEN($J523) - LEN(SUBSTITUTE(LOWER($J523),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J523) - LEN(SUBSTITUTE(LOWER($J523),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J523) - LEN(SUBSTITUTE(LOWER($J523),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B523:D523)","v":2},2006,"The acute and chronic toxic effects of vitamin A.","Penniston",16469975,"The acute and chronic toxic effects of vitamin A.    Abstract:   The acute and chronic effects of vitamin A toxicity are well documented in the literature. Emerging evidence suggests that subtoxicity without clinical signs of toxicity may be a growing concern, because intake from preformed sources of vitamin A often exceeds the recommended dietary allowances (RDA) for adults, especially in developed countries. Osteoporosis and hip fracture are associated with preformed vitamin A intakes that are only twice the current RDA. Assessing vitamin A status in persons with subtoxicity or toxicity is complicated because serum retinol concentrations are nonsensitive indicators in this range of liver vitamin A reserves. The metabolism in well-nourished persons of preformed vitamin A, provided by either liver or supplements, has been studied by several research groups. To control vitamin A deficiency, large therapeutic doses are administered in developing countries to women and children, who often are undernourished. Nevertheless, little attention has been given to the short-term kinetics (ie, after absorption but before storage) of a large dose of vitamin A or to the short- and long-term effects of such a dose given to lactating women on serum and breast-milk concentrations of retinol and its metabolites. Moreover, appropriate dosing regimens have not been systematically evaluated to ascertain the quantitative improvement in vitamin A status of the women and children who receive these supplements. The known acute and chronic effects of vitamin A toxicity have been reported previously. However, further research is needed to ascertain the areas of the world in which subclinical toxicity exists and to evaluate its effects on overall health and well-being."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I524,I524)","v":16452829},{"$f":"(LEN($J524) - LEN(SUBSTITUTE(LOWER($J524),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J524) - LEN(SUBSTITUTE(LOWER($J524),LOWER(C$3),\"\")))/LEN(C$3)","v":2},{"$f":"(LEN($J524) - LEN(SUBSTITUTE(LOWER($J524),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B524:D524)","v":2},2005,"Fat paradox in liver disease.","Tsukamoto",16452829,"Fat paradox in liver disease.    Abstract:   Alcoholic liver disease (ALD) is characterized by accumulation of neutral lipids in hepatocytes leading to micro and macro-vesicular steatosis and balloon cell degeneration. Hypercaloric alimentation and resultant obesity also cause similar changes as evident in non-alcoholic fatty liver disease (NAFLD). Thus, accumulation of lipids in hepatocytes is a pathologic hallmark of ALD and NAFLD. In contrast, quiescent hepatic stellate cells (HSC) are characterized by the intracellular content of not only vitamin A but also triglycerides, and HSC activation is associated with depletion of these lipids. In fact, our recent work demonstrates that adipogenic/ lipogenic transcriptional regulation rendered by PPARgamma, LXRa, and SREBP-1c is essential for the maintenance of the fat-storing, quiescence phenotype of HSC. Expression of these adipogenic transcription factors is lost in activated HSC and the treatment of the cells with the adipocyte differentiation cocktail or ectopic expression of PPARgamma or SREBP-1c causes a reversal of activated cells to the quiescent phenotype. In steatotic livers from ALD and NAFLD mouse models, the expression of these adipogenic transcription factors is induced while the normal control livers lack such expression. Thus, adipogenic regulation is essential for HSC quiescence while it makes hepatocytes steatotic. Interestingly, under the adipogenic conditions of ALD and NAFLD, HSC are still activated to cause fibrosis. This fat paradox in hepatocytes and HSC highlights contrasted significance of fat in these two cell types that depend on each other for their homeostatic control. It further suggests, activated HSC in steatotic livers may have defective insulin signaling or lipogenic regulation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I525,I525)","v":16446877},{"$f":"(LEN($J525) - LEN(SUBSTITUTE(LOWER($J525),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J525) - LEN(SUBSTITUTE(LOWER($J525),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J525) - LEN(SUBSTITUTE(LOWER($J525),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B525:D525)","v":2},2005,"[New heterodimeric nuclear receptors: key metabolic regulators with relevance in the pathophysiology and therapy of dyslipidemias and diabetes mellitus].","Cortés",16446877,"[New heterodimeric nuclear receptors: key metabolic regulators with relevance in the pathophysiology and therapy of dyslipidemias and diabetes mellitus].    Abstract:   The regulation of gene expression is crucial for the normal development and the homeostatic maintenance of body tissues. Thus, its malfunction may determine a variety of human disease conditions. A growing body of evidence has shown the overwhelming relevance of a new class of gene expression regulators: the heterodimeric nuclear receptors, a family of structurally related proteins involved in multiple biological functions. In response to activating ligands, these molecules bind to specific genomic regulatory regions where they can coordinately modify the transcriptional activity of several genes involved in the main metabolic pathways of lipids and carbohydrates in cells. These functional properties have stimulated the study of the relationships between heterodimeric nuclear receptors and various disease conditions, such as dyslipidemias and diabetes mellitus. Here we review the experimental, clinical and epidemiological evidences that support the relevance of these transcriptional regulators in the pathophysiology of the most prevalent and lethal diseases in Western countries. We also explore the potential therapeutic impact of new strategies based in the pharmacological modulation of the heterodimeric nuclear receptors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I526,I526)","v":16433581},{"$f":"(LEN($J526) - LEN(SUBSTITUTE(LOWER($J526),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J526) - LEN(SUBSTITUTE(LOWER($J526),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J526) - LEN(SUBSTITUTE(LOWER($J526),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B526:D526)","v":2},2006,"Cost-effectiveness of moderate-to-severe psoriasis treatment.","Miller",16433581,"Cost-effectiveness of moderate-to-severe psoriasis treatment.    Abstract:   Psoriasis is a common, chronic inflammatory disease that can cause as much disability as cancer, diabetes or other major medical illnesses. Traditional therapies for treating moderate-to-severe psoriasis include phototherapy, methotrexate, oral retinoids and ciclosporin. New biological treatments provide further therapeutic options, but add to the already considerable cost of managing psoriasis. Expert panels have published guidelines for the use of biological agents in managing moderate-to-severe psoriasis; however, few if any of these guidelines appropriately consider the cost-effectiveness of treatment options. When considering cost-effectiveness in addition to safety and efficacy, ultraviolet Type B phototherapy seems to be the best first-line agent for the control of moderate-to-severe psoriasis, despite a small potential for cumulative toxicity. The biologics should be considered as second-line agents alongside the traditional systemic treatments when phototherapy proves to be ineffective or is otherwise contraindicated, such as in patients with psoriatic arthritis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I527,I527)","v":16154621},{"$f":"(LEN($J527) - LEN(SUBSTITUTE(LOWER($J527),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J527) - LEN(SUBSTITUTE(LOWER($J527),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J527) - LEN(SUBSTITUTE(LOWER($J527),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B527:D527)","v":2},2005,"An assessment of the toxicological significance of anthropogenic contaminants in Canadian arctic wildlife.","Fisk",16154621,"An assessment of the toxicological significance of anthropogenic contaminants in Canadian arctic wildlife.    Abstract:   Anthropogenic contaminants have been a concern in the Canadian arctic for over 30 years due to relatively high concentrations of bioaccumulating and biomagnifying organochlorine contaminants (OCs) and toxic metals found in some arctic biota and humans. However, few studies have addressed the potential effects of these contaminants in Canadian arctic wildlife. Prior to 1997, biological effects data were minimal and insufficient at any level of biological organization. The present review summarizes recent studies on biological effects related to contaminant exposure, and compares new tissue concentration data to threshold effects levels. Weak relationships between cadmium, mercury and selenium burdens and health biomarkers in common eider ducks (Somateria mollissima borealis) in Nunavut were found but it was concluded that metals were not influencing the health of these birds. Black guillemots (Cepphus grylle) examined near PCB-contaminated Saglek Bay, Labrador, had enlarged livers, elevated EROD and liver lipid levels and reduced retinol (vitamin A) and retinyl palmitate levels, which correlated to PCB levels in the birds. Circulating levels of thyroid hormones in polar bears (Ursus maritimus) were correlated to PCB and HO-PCB plasma concentrations, but the impact at the population level is unknown. High PCB and organochlorine pesticide concentrations were found to be strongly associated with impaired humoral and cell-mediated immune responses in polar bears, implying an increased infection risk that could impact the population. In beluga whale (Delphinapterus leucas), cytochromes P450 (phase I) and conjugating (phase II) enzymes have been extensively profiled (immunochemically and catalytically) in liver, demonstrating the importance of contaminants in relation to enzyme induction, metabolism and potential contaminant bioactivation and fate. Concentrations of OCs and metals in arctic terrestrial wildlife, fish and seabirds are generally below effects thresholds, with the possible exception of PCBs in burbot (Lota lota) in some Yukon lakes, Greenland shark (Somniosus microcephalus), glaucous and great black-backed gulls (Larus hyperboreus and L. marinus), and TEQs of dioxin-like chemicals in seabird eggs. PCB and DDT concentrations in several arctic marine mammal species exceed effects thresholds, although evidence of stress in these populations is lacking. There is little evidence that contaminants are having widespread effects on the health of Canadian arctic organisms, with the possible exception of polar bears. However, further research and better understanding of organohalogen exposure in arctic biota is needed considering factors such as tissue levels that exceed effects thresholds, exposure to quot;newquot; organohalogen contaminants of concern, contaminated regions, and climate change."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I528,I528)","v":15922648},{"$f":"(LEN($J528) - LEN(SUBSTITUTE(LOWER($J528),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J528) - LEN(SUBSTITUTE(LOWER($J528),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J528) - LEN(SUBSTITUTE(LOWER($J528),LOWER(D$3),\"\")))/LEN(D$3)","v":2},{"$f":"SUM(B528:D528)","v":2},2005,"Skeletal muscle and nuclear hormone receptors: implications for cardiovascular and metabolic disease.","Smith",15922648,"Skeletal muscle and nuclear hormone receptors: implications for cardiovascular and metabolic disease.    Abstract:   Skeletal muscle is a major mass peripheral tissue that accounts for approximately 40% of the total body mass and a major player in energy balance. It accounts for gt;30% of energy expenditure, is the primary tissue of insulin stimulated glucose uptake, disposal, and storage. Furthermore, it influences metabolism via modulation of circulating and stored lipid (and cholesterol) flux. Lipid catabolism supplies up to 70% of the energy requirements for resting muscle. However, initial aerobic exercise utilizes stored muscle glycogen but as exercise continues, glucose and stored muscle triglycerides become important energy substrates. Endurance exercise increasingly depends on fatty acid oxidation (and lipid mobilization from other tissues). This underscores the importance of lipid and glucose utilization as an energy source in muscle. Consequently skeletal muscle has a significant role in insulin sensitivity, the blood lipid profile, and obesity. Moreover, caloric excess, obesity and physical inactivity lead to skeletal muscle insulin resistance, a risk factor for the development of type II diabetes. In this context skeletal muscle is an important therapeutic target in the battle against cardiovascular disease, the worlds most serious public health threat. Major risk factors for cardiovascular disease include dyslipidemia, hypertension, obesity, sedentary lifestyle, and diabetes. These risk factors are directly influenced by diet, metabolism and physical activity. Metabolism is largely regulated by nuclear hormone receptors which function as hormone regulated transcription factors that bind DNA and mediate the patho-physiological regulation of gene expression. Metabolism and activity, which directly influence cardiovascular disease risk factors, are primarily driven by skeletal muscle. Recently, many nuclear receptors expressed in skeletal muscle have been shown to improve glucose tolerance, insulin resistance, and dyslipidemia. Skeletal muscle and nuclear receptors are rapidly emerging as critical targets in the battle against cardiovascular disease risk factors. Understanding the function of nuclear receptors in skeletal muscle has enormous pharmacological utility for the treatment of cardiovascular disease. This review focuses on the molecular regulation of metabolism by nuclear receptors in skeletal muscle in the context of dyslipidemia and cardiovascular disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I529,I529)","v":15857604},{"$f":"(LEN($J529) - LEN(SUBSTITUTE(LOWER($J529),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J529) - LEN(SUBSTITUTE(LOWER($J529),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J529) - LEN(SUBSTITUTE(LOWER($J529),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B529:D529)","v":2},2005,"Ah receptor- and TCDD-mediated liver tumor promotion: clonal selection and expansion of cells evading growth arrest and apoptosis.","Bock",15857604,"Ah receptor- and TCDD-mediated liver tumor promotion: clonal selection and expansion of cells evading growth arrest and apoptosis.    Abstract:   The Ah receptor (AhR) has been characterized as a ligand-activated transcription factor which belongs to the bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) family of chemosensors. Transgenic mouse models revealed adaptive and developmental functions of the AhR in the absence of exogenous ligands. Use of persistent agonists such as dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds demonstrated that the AhR mediates a plethora of species- and tissue-dependent toxicities, including chloracne, wasting, teratogenicity, immunotoxicity, liver tumor promotion and carcinogenicity. However, molecular mechanisms underlying most aspects of these toxic responses as well as biological functions of the AhR are currently unknown. Previous studies of liver tumor promotion in the two-stage hepatocarcinogenesis model indicated that TCDD mediates clonal expansion of initiated preneoplastic hepatocytes, identified as enzyme-altered foci (EAF) by inhibiting apoptosis and bypassing AhR-mediated growth arrest. In contrast, the Ah receptor has been shown in cell models to stimulate growth arrest and apoptosis. Possible underlying mechanisms of these AhR responses are discussed, including enhanced metabolism of retinoic acid which attenuates TGFbeta-mediated apoptosis and interaction of the Ah receptor with the hypophosphorylated retinoblastoma tumor suppressor protein. The discrepancy between in vivo findings in EAF and AhR functions may be solved by hypothesizing that sustained activation of the Ah receptor generates a strong selective pressure in liver treated with genotoxic carcinogens leading to selection and expansion of clones evading growth arrest and apoptosis. Models are discussed which may facilitate verification of this hypothesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I530,I530)","v":15733733},{"$f":"(LEN($J530) - LEN(SUBSTITUTE(LOWER($J530),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J530) - LEN(SUBSTITUTE(LOWER($J530),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J530) - LEN(SUBSTITUTE(LOWER($J530),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B530:D530)","v":2},2005,"Proposed involvement of adipocyte glyceroneogenesis and phosphoenolpyruvate carboxykinase in the metabolic syndrome.","Cadoudal",15733733,"Proposed involvement of adipocyte glyceroneogenesis and phosphoenolpyruvate carboxykinase in the metabolic syndrome.    Abstract:   Elevated concentration of plasma non-esterified fatty acids (NEFA) is now recognized as a key factor in the onset of insulin-resistance and type 2 diabetes mellitus. During fasting, circulating NEFAs arise from white adipose tissue (WAT) as a consequence of lipolysis from stored triacylglycerols. However, a significant part of these FAs (30-70%) is re-esterified within the adipocyte, so that a recycling occurs and net FA output is much less than lt; true gt; lipolysis. Indeed, a balance between two antagonistic processes, lipolysis and FA re-esterification, controls the rate of net FA release from WAT. During fasting, re-esterification requires glyceroneogenesis defined as the de novo synthesis of glycerol-3-P from pyruvate, lactate or certain amino acids. The key enzyme in this process is the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C; EC 4.1.1.32). Recent advance has stressed the role of glyceroneogenesis and of PEPCK-C in FA release from WAT. Results indicate that glyceroneogenesis is indeed important to lipid homeostasis and that a disregulation in this pathway may have profound pathophysiological effects. The present review focuses on the regulation of glyceroneogenesis and of PEPCK-C gene expression and activity by FAs, retinoic acids, glucocorticoids and the hypolipidemic class of drugs, thiazolidinediones."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I531,I531)","v":15543093},{"$f":"(LEN($J531) - LEN(SUBSTITUTE(LOWER($J531),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J531) - LEN(SUBSTITUTE(LOWER($J531),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J531) - LEN(SUBSTITUTE(LOWER($J531),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B531:D531)","v":2},2004,"Polar hysteria: an expression of hypervitaminosis A.","ODonnell",15543093,"Polar hysteria: an expression of hypervitaminosis A.    Abstract:   Isotretinoin (Accutane) is a drug closely related to the chemical structure of Vitamin A. The pharmacology and toxicology of these two retinoids is similar enough to warrant comparison. Accutane is a powerful drug which its manufacturer, Roche, indicates is limited for severe recalcitrant nodular acne. This potency is also reflected in Accutanes well-known ability to produce severe birth defects if taken during pregnancy. Less well-known is the risk of this lipid soluble chemical to affect the Central Nervous System. Reports of intracranial hypertension, depression, and suicidal indeation with Accutane use have prompted an examination of this serious and life threatening potential. Though Roche has added a warning to its product label for signs of depression and suicidal ideation, this product is being overprescribed for all forms of acne, including mild cases and moderate acne that have not been treated with alternative medications, which have a lesser risk of depression and suicide. There is no contesting that this drug is effective at clearing up the most severe forms of acne, but the public must be informed of its proper, limited indication for use; depression and suicide can follow in patients with no prior history of psychiatric symptoms or suicide attempts."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I532,I532)","v":15485588},{"$f":"(LEN($J532) - LEN(SUBSTITUTE(LOWER($J532),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J532) - LEN(SUBSTITUTE(LOWER($J532),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J532) - LEN(SUBSTITUTE(LOWER($J532),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B532:D532)","v":2},2004,"Diet, fatty acids, and regulation of genes important for heart disease.","Vanden Heuvel",15485588,"Diet, fatty acids, and regulation of genes important for heart disease.    Abstract:   Diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs), such as alpha-linoleic acid, eicosapentaenoic acid, and docosahexaenoic acid, are associated with decreased incidence and severity of coronary heart disease. Similarly, conjugated linoleic acids (CLAs), which are found in meat and dairy products, have beneficial effects against atherosclerosis, diabetes, and obesity. The effects of n3-PUFAs and CLAs are in contrast to fatty acids with virtually identical structures, such as linoleic acid and arachidonic acid (ie, n-6 PUFAs). This article discusses the possibility that cognate receptors exist for fatty acids or their metabolites that are able to regulate gene expression and coordinately affect metabolic or signaling pathways associated with coronary heart disease. Three nuclear receptors are emphasized as fatty acid receptors that respond to dietary and endogenous ligands: peroxisome proliferator activated receptors, retinoid X receptors, and liver X receptors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I533,I533)","v":15186199},{"$f":"(LEN($J533) - LEN(SUBSTITUTE(LOWER($J533),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J533) - LEN(SUBSTITUTE(LOWER($J533),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J533) - LEN(SUBSTITUTE(LOWER($J533),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B533:D533)","v":2},2004,"Acanthosis nigricans associated with insulin resistance : pathophysiology and management.","Hermanns-Lê",15186199,"Acanthosis nigricans associated with insulin resistance : pathophysiology and management.    Abstract:   The association of acanthosis nigricans, skin tags, diabetes mellitus due to insulin resistance, and obesity in adolescents and young adults represents a well defined syndrome. Hyperandrogenism may also be present. The endocrine origin of this condition is beyond doubt. Insulin and insulin-like growth factor-1, and their receptors on keratinocytes are obviously involved in the complex regulations leading to the peculiar epidermal hyperplasia. This condition is unrelated to other types of acanthosis nigricans, including the congenital and the paraneoplastic types. Control of obesity contributes largely to reverse the whole process, essentially by reducing both insulin resistance and compensatory hyperinsulinemia. Several drugs including metformin, octreotide, retinoids and topical colecalciferol (vitamin D(3)) analogs are also beneficial in clearing acanthosis nigricans."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I534,I534)","v":14987380},{"$f":"(LEN($J534) - LEN(SUBSTITUTE(LOWER($J534),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J534) - LEN(SUBSTITUTE(LOWER($J534),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J534) - LEN(SUBSTITUTE(LOWER($J534),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B534:D534)","v":2},2002,"Hereditary transthyretin amyloidosis: molecular basis and therapeutical strategies.","Saraiva",14987380,"Hereditary transthyretin amyloidosis: molecular basis and therapeutical strategies.    Abstract:   Transthyretin (TTR) is a transport protein for thyroid hormones and vitamin A and might have an important role in the nervous system. However, TTR can undergo a conformational change and form amyloid fibrils, in both acquired and hereditary forms of systemic amyloidosis. More than 80 TTR mutations have been associated with autosomal dominant amyloidosis, usually presenting with peripheral and autonomic neuropathy and/or cardiomyopathy. Major areas of research in TTR amyloidosis include: molecular mechanisms leading to fibril formation; mechanisms of fibril-induced cell death; modulators of phenotypic expression of the disease; and therapeutic strategies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I535,I535)","v":14750605},{"$f":"(LEN($J535) - LEN(SUBSTITUTE(LOWER($J535),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J535) - LEN(SUBSTITUTE(LOWER($J535),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J535) - LEN(SUBSTITUTE(LOWER($J535),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B535:D535)","v":2},2004,"Gene therapy for Leber congenital amaurosis.","Bennett",14750605,"Gene therapy for Leber congenital amaurosis.    Abstract:   Recent success in delivering vision to a canine model of a severe, early-onset blinding disease, Leber congenital amaurosis (LCA) (Acland et al 2001) demonstrates that adeno-associated virus serotype 2 (AAV2) is capable of delivering a corrective gene to the target retinal cells. Results of these studies indicate long-term rescue of vision as assessed by psychophysical, behavioural and molecular biological studies. Preliminary results of studies in progress are described and the implications of these results with respect to developing human clinical trials for LCA and for other retinal degenerative diseases are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I536,I536)","v":14631893},{"$f":"(LEN($J536) - LEN(SUBSTITUTE(LOWER($J536),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J536) - LEN(SUBSTITUTE(LOWER($J536),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J536) - LEN(SUBSTITUTE(LOWER($J536),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B536:D536)","v":2},2003,"[Population genetic correlation of vitamin D receptor polymorphisms with clinical disorders].","Gyórffy",14631893,"[Population genetic correlation of vitamin D receptor polymorphisms with clinical disorders].    Abstract:   Calcitriol, the active metabolite of Vitamin D (1,25(OH)2D3) has several major roles in the body: hormonal regulation of calcium and phosphate-homeostasis, regulation of parathormone synthesis and modulation of the immune and endocrine systems. Due to its antiproliferative effects it also plays a role in tumour development. The calcitriol can have these differential effects as it is modulating gene expression in the cell nucleus. The effects of vitamin D are mediated by the nuclear vitamin D receptor, which heterodimerizes with the retinoid X receptor and changes gene transcription. Until now 5 single nucleotide polymorphisms of the vitamin D receptor gene have been identified. This review summarizes the identified effects of vitamin D receptor polymorphisms on bone homeostasis, on the parathyroid function, on diversal tumours and on diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I537,I537)","v":14559106},{"$f":"(LEN($J537) - LEN(SUBSTITUTE(LOWER($J537),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J537) - LEN(SUBSTITUTE(LOWER($J537),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J537) - LEN(SUBSTITUTE(LOWER($J537),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B537:D537)","v":2},2003,"Role of nuclear receptors in the regulation of gene expression by dietary fatty acids (review).","Khan",14559106,"Role of nuclear receptors in the regulation of gene expression by dietary fatty acids (review).    Abstract:   Long chain fatty acids, derived either from endogenous metabolism or by nutritional sources play significant roles in important biological processes of membrane structure, production of biologically active compounds, and participation in cellular signaling processes. Recently, the structure of dietary fatty acids has become an important issue in human health because ingestion of saturated fats (containing triglycerides composed of saturated fatty acids) is considered harmful, while unsaturated fats are viewed as beneficial. It is important to note that the molecular reason for this dichotomy still remains elusive. Since fatty acids are important players in development of pathology of cardiovascular and endocrine system, understanding the key molecular targets of fatty acids, in particular those that discriminate between saturated and unsaturated fats, is much needed. Recently, insights have been gained on several fatty acid-activated nuclear receptors involved in gene expression. In other words, we can now envision long chain fatty acids as regulators of signal transduction processes and gene regulation, which in turn will dictate their roles in health and disease. In this review, we will discuss fatty acid-mediated regulation of nuclear receptors. We will focus on peroxisome proliferators-activated receptors (PPARs), liver X receptors (LXR), retinoid X receptors (RXRs), and Hepatocyte Nuclear Factor alpha (HNF-4alpha), all of which play pivotal roles in dietary fatty acid-mediated effects. Also, the regulation of gene expression by Conjugated Linoleic Acids (CLA), a family of dienoic fatty acids with a variety of beneficial effects, will be discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I538,I538)","v":14498827},{"$f":"(LEN($J538) - LEN(SUBSTITUTE(LOWER($J538),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J538) - LEN(SUBSTITUTE(LOWER($J538),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J538) - LEN(SUBSTITUTE(LOWER($J538),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B538:D538)","v":2},2003,"Modified fatty acids and their possible therapeutic targets in malignant diseases.","Tronstad",14498827,"Modified fatty acids and their possible therapeutic targets in malignant diseases.    Abstract:   Fatty acids and other lipids have multiple roles in the cell, functioning as structural components, participating in intracellular signalling and serving as metabolic fuel. Various compounds that influence cellular lipid metabolism can reduce the growth of malignant cells, and dietary as well as pharmacological strategies for modulating lipid metabolism have therefore been suggested as possible approaches for cancer prevention and treatment. By chemically modifying fatty acids (e.g., butyrates, retinoids), new potential anticancer agents have been produced that possess increased metabolic stability and more specific and potent biological activity compared to the natural fatty acids. Possible therapeutic targets for such modified fatty acids include: i) Histone deacetylase; ii) nuclear hormone receptors (retinoid receptors), peroxisome proliferator-activated receptors; iii) cyclooxygenase-2; iv) intracellular signalling involving protein farnesylation and Ras activation; and v) various mitochondrial functions. Although several fatty acid derivatives have been thoroughly investigated in experimental models, clinical data on toxicity and pharmacological interactions are not available for the majority of these agents. However, several promising novel compounds are now being evaluated in preclinical and early clinical studies, and future research will hopefully reveal new formulations and therapy schedules that will improve the outcome of patients with malignant disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I539,I539)","v":13679198},{"$f":"(LEN($J539) - LEN(SUBSTITUTE(LOWER($J539),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J539) - LEN(SUBSTITUTE(LOWER($J539),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J539) - LEN(SUBSTITUTE(LOWER($J539),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B539:D539)","v":2},2003,"Molecular based treatment of oral cancer.","Sudbø",13679198,"Molecular based treatment of oral cancer.    Abstract:   Given the increase in the age distribution of the population, an increase in cancer incidence rates are to be expected. Oral cancer is a disfiguring disease that continues to increase in incidence, particularly in the young, and to an extent that cannot be fully explained by increased exposure to known risk factors. Despite extensive research on treatment modalities towards oral cancer, the 5-year survival rate of this disease has not been improved over the last 4-5 decades. These facts strongly favour chemoprevention-systemic medication to revert, stop, or delay the carcinogenic process-as an approach to treating oral cancer. A chemopreventive approach to oral cancer most likely should encompass a combination of drugs targeting metabolic pathways relevant to oral carcinogenesis. Candidate drugs are retinoids and selective inhibitors of cyclooxygenase-2, epidermal growth factor receptor (EGFR), and peroxisome proliferator activated receptors (PPARs). Chemopreventive trials so far have used surrogate intermediate biomarkers as measurement of treatment effect. However, the efficiency of any drug for chemopreventive use should be assessed through a prospective randomized trial and evaluated by the only definitive end point for prevention of cancer, the incidence rates of new carcinomas."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I540,I540)","v":12704471},{"$f":"(LEN($J540) - LEN(SUBSTITUTE(LOWER($J540),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J540) - LEN(SUBSTITUTE(LOWER($J540),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J540) - LEN(SUBSTITUTE(LOWER($J540),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B540:D540)","v":2},2003,"The role of the enterohepatic circulation of bile salts and nuclear hormone receptors in the regulation of cholesterol homeostasis: Bile salts as ligands for nuclear hormone receptors.","Redinger",12704471,"The role of the enterohepatic circulation of bile salts and nuclear hormone receptors in the regulation of cholesterol homeostasis: Bile salts as ligands for nuclear hormone receptors.    Abstract:   The coordinated effect of lipid activated nuclear hormone receptors; liver X receptor (LXR), bound by oxysterol ligands and farnesoid X receptor (FXR), bound by bile acid ligands, act as genetic transcription factors to cause feed-forward cholesterol catabolism to bile acids and feedback repression of bile acid synthesis, respectively. It is the coordinated action of LXR and FXR, each dimerized to retinoid X receptor, that signal nuclear DNA response elements to encode proteins that prevent excessive cholesterol accumulation and bile salt toxicity, respectively. LXR helps prevent hypercholesterolemia by enhancing transporters for cholesterol efflux that enhance reverse cholesterol transport, while FXR enhances intestinal reabsorption and preservation of bile salts by increasing the ileal bile acid binding protein. FXR also targets sodium taurocholate cotransport peptide and bile salt export pump (protein) genes to limit bile salt uptake and enhance export, respectively, which prevents bile salt toxicity. Other nuclear hormone receptors such as pregnan X receptor, which share the obligate partner, retinoid X receptor, and vitamin D receptor also function as bile acid sensors to signal detoxification by hydroxylation of toxic bile acids. Pharmacologically targeted receptor agonists (or antagonists) may be developed that alter cholesterol and bile salt concentrations by modulating nuclear hormone receptors and/or their coactivators or corepressors to positively affect cholesterol homeostasis and bile salt metabolism. It is the coordinated transcription factor action of LXR, which responds to ligand binding of circulating oxysterols in both liver and peripheral tissues, and FXR responding to bile salts within the enterohepatic circulation that make possible the regulation of cholesterol and bile acid homeostasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I541,I541)","v":12679900},{"$f":"(LEN($J541) - LEN(SUBSTITUTE(LOWER($J541),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J541) - LEN(SUBSTITUTE(LOWER($J541),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J541) - LEN(SUBSTITUTE(LOWER($J541),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B541:D541)","v":2},2003,"Preventive treatments for recurrence after curative resection of hepatocellular carcinoma--a literature review of randomized control trials.","Sun",12679900,"Preventive treatments for recurrence after curative resection of hepatocellular carcinoma--a literature review of randomized control trials.    Abstract:   To review the inhibitory effect of preventive approaches on recurrence after operation in patients with hepatocellular carcinoma (HCC), we summarized all available publications reporting randomized control trial indexed in PubMed. The treatment approaches presented above included pre-operative transcatheter arterial chemoembolization (TACE), post-operative TACE, systemic or locoregional chemotherapy, immunotherapy, Interferons and acyclic retinoic acid. Although no standard treatment has been established, several approaches presented promising results, which were both effective and tolerable in post-operative patients. Pre-operative TACE was not effective on prolonging survivals, while post-operative TACE was shown with both disease-free survival and overall survival benefits in some papers, however, it was also questioned by others. Systemic chemotherapy was generally not effective on prolonging survival but also poorly tolerated for its significant toxicities. Adoptive immunotherapy using LAK cells was proved to be beneficial to patients survival in a recent paper. Interferon alpha and Interferon beta can inhibit recurrence in HCC patients with HCV infection background, though the mechanism is not fully understood. Acyclic retinoic acid was shown to decrease multi-centric recurrence after operation, which was reported by only one group. In conclusion, several adjuvant approaches have been studied for their efficacy on recurrence in HCC patients in randomized control trials; however, multi-centric randomized control trial is still needed for further evaluation on their efficacy and systemic or local toxicities; in addition, new adjuvant treatment should be investigated to provide more effective and tolerable methods for the patients with HCC after operation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I542,I542)","v":12514311},{"$f":"(LEN($J542) - LEN(SUBSTITUTE(LOWER($J542),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J542) - LEN(SUBSTITUTE(LOWER($J542),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J542) - LEN(SUBSTITUTE(LOWER($J542),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B542:D542)","v":2},2003,"Retinoids and alcohol-related carcinogenesis.","Wang",12514311,"Retinoids and alcohol-related carcinogenesis.    Abstract:   Chronic and excessive alcohol intake is associated with an increased incidence of a variety of cancers (e.g., liver, oral cavity, esophagus, colorectal and breast). Long-term alcohol intake results in impaired nutritional status of retinoic acid (RA), the most active derivative of vitamin A, which may provide a promoting environment for tumor formation. Recent studies demonstrate that chronic alcohol-induced hepatocellular proliferation, which may convert hepatocytes from a state of resistance to a carcinogen to a state of high susceptibility, is due to alcohol-impaired RA metabolism and signaling and crosstalk with the Jun N-terminal kinases-dependent signaling pathway. Further, the restoration of hepatic RA homeostasis by treatment with either RA supplementation or inhibitors of RA catabolism can suppress alcohol-induced hepatocyte hyperproliferation and restore alcohol-deregulated apoptosis, thereby reducing the risk of alcohol-promoted hepatocellular carcinogenesis. These studies indicate the importance of RA actions in the prevention and/or treatment of alcohol-related carcinogenic process in the liver and other organs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I543,I543)","v":12481554},{"$f":"(LEN($J543) - LEN(SUBSTITUTE(LOWER($J543),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J543) - LEN(SUBSTITUTE(LOWER($J543),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J543) - LEN(SUBSTITUTE(LOWER($J543),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B543:D543)","v":2},2002,"Vitamin D receptor and retinoid X receptor interactions in motion.","Barsony",12481554,"Vitamin D receptor and retinoid X receptor interactions in motion.    Abstract:   Vitamin D receptor (VDR) and retinoid X receptor (RXR) are members of the nuclear receptor superfamily and they bind target DNA sequences as heterodimers to regulate transcription. This article surveys the latest findings regarding the roles of dimerizing RXR in VDR function and emphasizes potential areas for future developments. We first highlight the importance of dimerization with RXR for both the ligand-independent (hair growth) and ligand-dependent functions of VDR (calcium homeostasis, bone development and mineralization, control of cell growth and differentiation). Emerging information regarding the regulatory control of dimerization based on biochemical, structural, and genetic studies is then presented. Finally, the main focus of this article is a new dynamic perspective of dimerization functions, based on recent research with fluorescent protein chimeras in living cells by microscopy. These studies revealed that both VDR and RXR constantly shuttle between the cytoplasm and the nucleus and between subnuclear compartments, and showed the transient nature of receptor--DNA and receptor--coregulator interactions. Because RXR dimerizes with most of the nuclear receptors, regulation of receptor dynamics by RXR has a broad significance."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I544,I544)","v":12476792},{"$f":"(LEN($J544) - LEN(SUBSTITUTE(LOWER($J544),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J544) - LEN(SUBSTITUTE(LOWER($J544),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J544) - LEN(SUBSTITUTE(LOWER($J544),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B544:D544)","v":2},2001,"Metastatic thyroid cancer unresponsive to conventional therapies: novel management approaches through translational clinical research.","Sarlis",12476792,"Metastatic thyroid cancer unresponsive to conventional therapies: novel management approaches through translational clinical research.    Abstract:   In this contribution, we review the limitations of the currently applied quot;standardquot; treatments for well-differentiated, non-medullary thyroid cancer (ThyrCa), and describe the molecular and cellular biologic basis of potential novel therapeutic modalities currently under study and/or development. Conventional therapy for ThyrCa consists of total/near-total thyroidectomy, radioiodine (RAI or 131I), and long-term thyroid hormone quot;suppressivequot; therapy (THST). RAI therapy remains the cornerstone of the quot;standardquot; management strategies for metastatic ThyrCa, and when administered under optimal conditions can achieve either eradication or long-term clinical quot;controlquot; of the disease. Despite increasing sophistication in the protocols using 131I over the last 30 years, no significant down-trend has been observed in the annual mortality rate for this disease, a fact reflecting the existence of a quot;corequot; population of patients with RAI-quot;resistantquot; disease. The molecular basis for this phenomenon is believed to be the progressive tumoral de-differentiation over time, with loss of (or marked decrease in) the expression of cellular components responsible for iodine uptake, organification and retention. Adjuvant methods to RAI, such as radiosensitizers and lithium carbonate, provide only marginal additional therapeutic effect. Further, the role of non-RAI-based modalities, such as secondary extensive metastatectomies with curative intent, external beam radiotherapy, and cytotoxic chemotherapy (mainly with doxorubicin-based regimens) has been unfortunately limited to highly selected cases. Palliative methods for acute clinical management of widely metastatic ThyrCa are also presented, along with anecdotal evidence for the potential therapeutic role for octreotide and its radiolabeled therapeutic peptide analogs, selective estrogen receptor modulators (SERMs), as well as bisphosphonates. Translational quot;bench-to-bedsidequot; research has recently led to the identification of the transcriptional machinery as a valid target for future therapeutic efforts in ThyrCa. Indeed, pre-clinical studies with a variety or agents that affect the rate of thyroid-specific gene transcription, i.e. retinoids, DNA methyltransferase inhibitors, and histone deacetylase inhibitors, have shown their potential for induction of re-differentiation, growth inhibition, promotion of apoptosis and cell cycle regulation. These concerted genomic effects of the above compounds will probably yield novel types of therapies in the clinical arena, especially for RAI-non-avid tumors. Retinoid analogs have already been used in pilot studies in ThyrCa patients with limited success. These re-differentiating agents have raised our expectations for a type of therapy for this malignancy based on a solid molecular rationale, while future progress in the domains of tissue-targeted gene therapy and anti-angiogenesis is eagerly awaited."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I545,I545)","v":11932986},{"$f":"(LEN($J545) - LEN(SUBSTITUTE(LOWER($J545),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J545) - LEN(SUBSTITUTE(LOWER($J545),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J545) - LEN(SUBSTITUTE(LOWER($J545),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B545:D545)","v":2},2002,"Teratogenesis of holoprosencephaly.","Cohen",11932986,"Teratogenesis of holoprosencephaly.    Abstract:   Teratogenic causes of holoprosencephaly are critically assessed. A brief general review of holoprosencephaly is followed by four tables summarizing etiologic factors. Subjects evaluated here include: 1) maternal diabetes; 2) ethyl alcohol; 3) retinoic acid; 4) mutated genes and teratogens involving the sonic hedgehog signaling network and cholesterol biosynthesis; and 5) cholesterol trafficking, sterol adducts, target tissue response, and sterol sensing domain."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I546,I546)","v":11606952},{"$f":"(LEN($J546) - LEN(SUBSTITUTE(LOWER($J546),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J546) - LEN(SUBSTITUTE(LOWER($J546),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J546) - LEN(SUBSTITUTE(LOWER($J546),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B546:D546)","v":2},2001,"Analysis of common side effects of isotretinoin.","McLane",11606952,"Analysis of common side effects of isotretinoin.    Abstract:   Patients with severe recalcitrant nodular acne that is unresponsive to conventional therapy (including topical and systemic antibiotics) have few alternative effective treatment modalities other than the use of oral isotretinoin (Accutane). The cause of acne vulgaris is multifactorial, but the pathogenesis of this disorder of the pilosebaceous follicles arises mainly from endogenous factors. It is usually, but not always, associated with the onset of puberty. Severe acne, defined by the prevalence of facial and truncal inflammatory lesions, is a disfiguring disease that can often result in significant permanent scarring after the healing of deep inflammatory lesions and other disorders, such as systemic bacterial infections. Topical treatments are considered as the first line of therapy for less severe forms of acne, although systemic treatments such as antibiotics or antiandrogen agents are effective for either mild or moderate forms and sometimes effective for severe acne. However, in many patients with large numbers of nodules, longer treatment periods with these agents are required to reduce the count of inflammatory lesions. It has become increasingly evident that (because topical agents and antibiotic or antiandrogenic therapy have a slow onset of action) even mild or moderate acne that is treated in this way can result in scarring. In addition, the excessive use of systemic antibiotics has led to the detection of increasing numbers of antibiotic-resistant bacteria on the skin of patients with acne.(1) Therefore, because of its relatively rapid onset of action and its high efficacy with reducing more than 90% of the most severe inflammatory lesions, Accutane has a role as an effective treatment in patients with severe acne that is recalcitrant to other therapies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I547,I547)","v":11586463},{"$f":"(LEN($J547) - LEN(SUBSTITUTE(LOWER($J547),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J547) - LEN(SUBSTITUTE(LOWER($J547),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J547) - LEN(SUBSTITUTE(LOWER($J547),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B547:D547)","v":2},2001,"History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells.","Geerts",11586463,"History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells.    Abstract:   In 1876, von Kupffer described liver Sternzellen (star-shaped cells). The functions of these cells remained enigmatic for 75 years until Ito observed lipid-containing perisinusoidal cells in human liver. In 1971, Wake demonstrated that the Sternzellen of von Kupffer and the fat-storing cells described by Ito were identical. Wake also established that these cells were important sites of vitamin A storage. Soon thereafter, Kent and Popper demonstrated that the stellate cells were intimately linked to the pathogenesis of hepatic fibrosis. Since then, these cells have been studied in detail. Quiescent stellate cells represent 5-8% of the total number of liver cells. They play a cardinal role in storage and controlled release of retinoids. They control extracellular matrix (ECM) turnover in the space of Disse by secreting the correct amounts of a limited number of ECM molecules, and by releasing matrix metalloproteinases and their inhibitors. By virtue of their long cytoplasmic processes, quiescent stellate cells presumably contribute to the control of blood flow through the sinusoidal capillaries. They are important sources of paracrine, autocrine, juxtacrine, and chemoattractant factors that maintain homeostasis in the microenvironment of the hepatic sinusoid."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I548,I548)","v":11413853},{"$f":"(LEN($J548) - LEN(SUBSTITUTE(LOWER($J548),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J548) - LEN(SUBSTITUTE(LOWER($J548),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J548) - LEN(SUBSTITUTE(LOWER($J548),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B548:D548)","v":2},2001,"[Blood lipid abnormalities during treatment with protease inhibitors].","Vergès",11413853,"[Blood lipid abnormalities during treatment with protease inhibitors].    Abstract:    UNLABELLEDHYPERLIPIDEMIA: HIV-1 protease-inhibitors therapy is associated with increased levels of triglycerides, LDL-cholesterol and Lp(a). But the understanding of hyperlipidaemia occurring in patients treated with HIV-1 protease-inhibitors is not easy since HIV infection itself is associated with lipid abnormalities and since HIV-1 protease-inhibitors therapy is also responsible for the development of a lipodystrophy syndrome (insulin resistance) which may influence lipid metabolism. However, many data indicate that HIV-1 protease-inhibitors therapy itself modifies significantly lipid metabolism.  UNDERLYING MECHANISMS NlmCategory=UNASSIGNEDThe mechanisms involved in HIV-1 protease-inhibitors induced hyperlipidaemia are still unclear. HIV-1 protease-inhibitors could bind to LRP (Low density lipoprotein receptor Related Protein), impairing hepatic chylomicron-remnants and VLDL uptake. They could interact with the retinoid X receptor (RXR), which functions as a heterodimer with PPAR (Peroxisome Proliferator Activator Receptor). HIV-1 protease-inhibitors could also modify lipoprotein metabolism through cytokines."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I549,I549)","v":11328624},{"$f":"(LEN($J549) - LEN(SUBSTITUTE(LOWER($J549),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J549) - LEN(SUBSTITUTE(LOWER($J549),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J549) - LEN(SUBSTITUTE(LOWER($J549),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B549:D549)","v":2},2001,"Current treatment of Cutaneous T-Cell Lymphoma.","Duvic",11328624,"Current treatment of Cutaneous T-Cell Lymphoma.    Abstract:   Cutaneous T-cell lymphomas are a heterogeneous group of cutaneous non-Hodgkins lymphomas. In the United States, the incidence of these diseases is rising faster than any other cancer. Environmental triggers may be important in the evolution of malignancy. Current therapy is reviewed with emphasis on a new retinoid, Targretin."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I550,I550)","v":11155466},{"$f":"(LEN($J550) - LEN(SUBSTITUTE(LOWER($J550),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J550) - LEN(SUBSTITUTE(LOWER($J550),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J550) - LEN(SUBSTITUTE(LOWER($J550),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B550:D550)","v":2},2000,"[Importance of chemoprevention in oncology].","Aragona",11155466,"[Importance of chemoprevention in oncology].    Abstract:   The therapeutic approach to cancer is generally limited to the advanced phases of disease. The preventive strategies aim at eliminating or reducing the exposition to known carcinogenes. We act with pharmacological and/or with an accurate dietary education to induce cellular differentiation phenomena, cytostasis and apoptosis. Chemoprevention acts both on the inductive phase (metabolic activation, DNA adducts), as well as on the promotion/proliferation of the long pre-clinical period of latency (antioxidants, anti-inflammatory, retinoids, carotenoids, vitamins and micronutrients, hormones and hormonal inhibitors, polyamine inhibitors, ditholetions, isothiocyanates, telomerase inhibitors, etc). Unanimous agreement has been reached on the preventive role of retinoids in head and neck tumors and of the cervical uterus, of hormonal inhibitors in breast and prostate cancer, and of anti-inflammatory in colorectal cancer. New and more accurate parameters for the evaluation of results and individual applications of chemopreventive strategies are linked to the biological research of high-risk subjects (genetic damage) or increased individual susceptibility. Caution, instead, should be applied in the clinical trial planning. An increased risk in developing and dying of lung tumor in smokers has been shown for the use vitamin A. Many clinical studies have been started in order to establish an efficient chemoprevention in oncology, and with the early diagnostic programs, and the evaluation of genotypic and phenotypic alterations, encouraging results will be reached for the next millennium."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I551,I551)","v":11126425},{"$f":"(LEN($J551) - LEN(SUBSTITUTE(LOWER($J551),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J551) - LEN(SUBSTITUTE(LOWER($J551),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J551) - LEN(SUBSTITUTE(LOWER($J551),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B551:D551)","v":2},2000,"Metabolic disorders among HIV-infected patients treated with protease inhibitors: a review.","Graham",11126425,"Metabolic disorders among HIV-infected patients treated with protease inhibitors: a review.    Abstract:   Currently available protease inhibitors are associated with development of a group of metabolic disorders. These include a peripheral lipodystrophy syndrome in which there is fat wasting in the face, arms, and legs; fat accumulation in the abdomen, dorsocervical region, and/or breasts (women only); as well as hyperlipidemia, hypercholesterolemia, and insulin resistance. A review of 15 observational studies and case reports shows that the incidence of the peripheral lipodystrophy syndrome increases with time of exposure to protease inhibitors, with a gt;60% incidence seen after 1 year of continuous treatment. Protease inhibitors are hypothesized to cause this syndrome by impairing conversion of retinoic acid to cis-9-retinoic acid (leading to impaired peripheral fat storage, sequestration of body fat to central adipocytes, and hyperlipidemia) and by inhibiting low-density lipoprotein receptor-related protein (LRP), thus preventing postprandial chylomicron clearance and further contributing to hyperlipidemia. Recent in vitro data suggest that more than one pathway contributes to the lipodystrophy syndrome and that pathways may differ among protease inhibitors. Although the central fat accumulation, hyperlipidemia, and insulin resistance components of this syndrome may reverse after discontinuation of protease inhibitor therapy, it is not known whether complete normalization of fast-wasted body regions is possible. Prospective controlled studies are needed to define whether protease inhibitors currently under development are less prone to produce the lipodystrophy syndrome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I552,I552)","v":11090943},{"$f":"(LEN($J552) - LEN(SUBSTITUTE(LOWER($J552),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J552) - LEN(SUBSTITUTE(LOWER($J552),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J552) - LEN(SUBSTITUTE(LOWER($J552),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B552:D552)","v":2},2000,"Use of the nuclear receptor PXR to predict drug interactions.","Moore",11090943,"Use of the nuclear receptor PXR to predict drug interactions.    Abstract:   We recently cloned the human, rabbit, rat, and mouse orthologs of a novel member of the steroid/retinoid/thyroid hormone receptor family, which we have named the Pregnane X Receptor (PXRs). The discovery and characterization of PXR has led to an increased understanding of the molecular basis of many drug-drug interactions as well as a better understanding of xenobiotic metabolism in general. The key insights into PXR action was the finding that this nuclear receptor is linked to regulation of the cytochrome P450 3A monooxygenase (CYP3A) genes. Several lines of evidence indicate that PXR mediates the induction of CYP3A gene transcription. First, PXR is selectively expressed in the liver and intestine, the same tissues in which CYP3A gene expression is induced. Second, PXR binds as a heterodimer with the retinoid X receptor (RXR) to xenobiotic response elements that have been identified in CYP3A gene promoters. Third, PXR is activated by the remarkable array of compounds that are known to induce CYP3A gene transcription. And finally, PXRs from different species are differentially activated by certain compounds such as rifampicin and pregnenolone 16alpha-carbonitrile (PCN) in a manner that correlates with species-specific induction of CYP3A gene expression. We are now employing high throughput PXR activation and binding assays to identify drug candidates that induce CYP3A gene expression so that these compounds can be removed from the drug development process."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I553,I553)","v":10860898},{"$f":"(LEN($J553) - LEN(SUBSTITUTE(LOWER($J553),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J553) - LEN(SUBSTITUTE(LOWER($J553),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J553) - LEN(SUBSTITUTE(LOWER($J553),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B553:D553)","v":2},2000,"HIV protease inhibitor-related lipodystrophy syndrome.","Carr",10860898,"HIV protease inhibitor-related lipodystrophy syndrome.    Abstract:   Human immunodeficiency virus (HIV) protease inhibitor (PI) therapy is frequently associated with a syndrome increasingly referred to as lipodystrophy syndrome, which is characterized by peripheral lipoatrophy, fat accumulation within the abdomen, in the breasts of women, and over the cervical vertebrae (quot;buffalo humpquot;), hyperlipidemia, and insulin resistance. In the largest study to date, peripheral lipoatrophy (an estimated 0.35-kg fat loss per month overall from the face, limbs, and upper trunk) was observed in association with all licensed PIs after a median 10 months of PI therapy. Diabetes mellitus type II appears to be a related, but less common, adverse effect. The lipodystrophy syndrome may be a result of the inhibition of 2 proteins involved in lipid metabolism that have significant homology to the catalytic site of HIV protease-namely, cytoplasmic retinoic acid binding protein type 1 and low density lipoprotein-receptor-related protein."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I554,I554)","v":10799410},{"$f":"(LEN($J554) - LEN(SUBSTITUTE(LOWER($J554),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J554) - LEN(SUBSTITUTE(LOWER($J554),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J554) - LEN(SUBSTITUTE(LOWER($J554),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B554:D554)","v":2},2000,"Vitamin A in pregnancy: requirements and safety limits.","Azaïs-Braesco",10799410,"Vitamin A in pregnancy: requirements and safety limits.    Abstract:   Most of the functions of vitamin A are mediated through the binding of retinoic acid to specific nuclear receptors that regulate genomic expression. Recent experimental work in transgenic mice showed clearly that normal embryonic development depends on the correct spatial and temporal expression of the receptors in the differentiating cells and on the binding of specific forms of retinoic acid. This implies that the parent compound, vitamin A, is available in adequate forms and quantities. Excessive dietary intake of vitamin A has been associated with teratogenicity in humans in lt;20 reported cases over 30 y. However, caution must be exercised to avoid unnecessary supplementation of women of childbearing age. Hypovitaminosis A affects millions of women and children worldwide. The main consequence of a poor vitamin A supply during pregnancy is a low vitamin A status at birth and in the next few months. Vitamin A deficiency is strongly associated with depressed immune function and higher morbidity and mortality due to infectious diseases such as diarrhea, measles, and respiratory infections. Vitamin A deficiency is often associated with an increased mother-to-child transmission of HIV-1. The initiation of vitamin A supplementation should be carefully examined in each case according to the risk-to-benefit ratio. The final decision should take into account the estimated vitamin A status of the woman, the availability of vitamin A-rich foods in her diet, and whether supplementation can be supervised."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I555,I555)","v":10779208},{"$f":"(LEN($J555) - LEN(SUBSTITUTE(LOWER($J555),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J555) - LEN(SUBSTITUTE(LOWER($J555),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J555) - LEN(SUBSTITUTE(LOWER($J555),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B555:D555)","v":2},2000,"Nutritional pharmacotherapy of chronic liver disease: from support of liver failure to prevention of liver cancer.","Moriwaki",10779208,"Nutritional pharmacotherapy of chronic liver disease: from support of liver failure to prevention of liver cancer.    Abstract:   Many patients with liver cirrhosis are in a state of protein and energy malnutrition and require careful nutritional support. Our research has revealed that approximately 30% of the patients have protein-energy malnutrition, 40% protein malnutrition, and 10% energy malnutrition; 20% are in a normal nutritional state. Supplementation with branched-chain amino acids alleviates chronic liver failure, improves the protein nutritional state, and subsequently prolongs survival. In contrast, therapeutic modalities for energy malnutrition have not yet been fully elucidated and await further studies. Improved survival of the cirrhotic patients essentially brings a higher incidence of hepatocellular carcinoma (HCC). A synthetic analogue of vitamin A (acyclic retinoid or 4,5-dehydrogeranyl geranoic acid) prevents at least the development of second primary tumors after curative treatment of preceding HCC. The mechanism of this cancer chemo-prevention is clonal deletion of premalignant and latent malignant cells by the retinoid. We describe our clinical experiences with these two nutritional pharmacotherapies of chronic liver diseases and review their basic mechanisms."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I556,I556)","v":10221899},{"$f":"(LEN($J556) - LEN(SUBSTITUTE(LOWER($J556),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J556) - LEN(SUBSTITUTE(LOWER($J556),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J556) - LEN(SUBSTITUTE(LOWER($J556),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B556:D556)","v":2},1999,"Orphan nuclear receptors: shifting endocrinology into reverse.","Kliewer",10221899,"Orphan nuclear receptors: shifting endocrinology into reverse.    Abstract:   Steroid and thyroid hormones and vitamin A metabolites (retinoids) regulate the expression of complex gene programs by binding to members of the nuclear receptor family of ligand-activated transcription factors. The nuclear receptor family also includes many quot;orphanquot; members that currently lack known ligands but that represent candidate receptors for new hormones. Recently, natural and synthetic ligands have been identified for several orphan receptors and used to dissect their biological roles. This quot;reverse endocrinologyquot; strategy has resulted in the discovery of unanticipated nuclear signaling pathways for retinoids, fatty acids, eicosanoids, and steroids with important physiological and pharmacological ramifications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I557,I557)","v":9865544},{"$f":"(LEN($J557) - LEN(SUBSTITUTE(LOWER($J557),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J557) - LEN(SUBSTITUTE(LOWER($J557),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J557) - LEN(SUBSTITUTE(LOWER($J557),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B557:D557)","v":2},1998,"Implications of the molecular characterization of the sodium-iodide symporter (NIS).","Schmutzler",9865544,"Implications of the molecular characterization of the sodium-iodide symporter (NIS).    Abstract:   The recently cloned sodium-iodide symporter (NIS) represents a key molecule for thyroid function by efficiently accumulating iodide from the circulation into the thyrocyte against an electrochemical gradient. This uptake requires energy, is coupled to the action of Na+/K+-ATPase, and stimulated by TSH, the main hormone regulating thyroid-specific functions. NIS mutations are found in congenital hypothyroidism, and potential defects in the NIS gene, its expression, or function of the NIS protein are currently under investigation in various thyroid diseases. Increased NIS expression has been found in autonomous adenoma and Graves disease, decreased levels of NIS protein and/or mRNA were observed in Hashimotos disease, cold nodules, most thyroid cancers and cell lines derived therefrom. Autoantibodies directed against NIS have been identified in autoimmune thyroid disease and blocking antibodies isolated from sera of patients with Hashimotos disease inhibit NIS function in NIS-transfected CHO cells. NIS mRNA expression can be up-regulated by retinoic acid in human thyroid carcinoma cell lines whereas retinoic acid treatment decreases NIS expression and function in differentiated rat thyroid FRTL-5 cells. Apart from thyrocytes, NIS is also expressed in other tissues known to transiently accumulate radioiodide, albeit at much lower levels, requiring RT-PCR for detection of the transcript. Diagnostic and therapeutic implications of the recent cloning of the human NIS gene such as development of NIS-directed drugs, ligands, antibodies, vaccines, gene therapeutic approaches combining NIS targeting and expression together with the long-established, efficient and safe method of radioiodide therapy are discussed both for application to thyroid related diseases and carcinoma, and non-thyroid benign and malignant diseases. Apart from these therapeutic and diagnostic perspectives the availability of the NIS gene will also open new opportunities to develop sensitive and homologous diagnostic test systems to identify factors involved in autoimmune thyroid disease, evolution of goitre, adenoma and thyroid cancer as well as NIS-directed new drugs. Advanced and sophisticated molecular diagnostic approaches (RT-PCR from fine needle aspirations, screening for mutations, analysis of gene defects) are already developed for NIS and will complement or overcome some established procedures in thyroid diagnostics."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I558,I558)","v":9860927},{"$f":"(LEN($J558) - LEN(SUBSTITUTE(LOWER($J558),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J558) - LEN(SUBSTITUTE(LOWER($J558),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J558) - LEN(SUBSTITUTE(LOWER($J558),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B558:D558)","v":2},1998,"The aryl hydrocarbon receptor: studies using the AHR-null mice.","Gonzalez",9860927,"The aryl hydrocarbon receptor: studies using the AHR-null mice.    Abstract:   The aryl hydrocarbon receptor (AHR) is believed to mediate the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyls, and polycyclic aromatic hydrocarbons. AHR is a member of the Per, ARNT, Sim/basic-helix-loop-helix superfamily of ligand-activated transcription factors that also harbors the transcription factors involved in the hypoxia response, development of the central nervous system, and day-night adaptations. To investigate the role of AHR in chemical toxicity and carcinogenesis and to determine any possible function in mammalian development and physiological homeostasis, AHR-null mice were developed. The AHR-null mice were resistant to the acute toxicity of TCDD and had an altered teratogenic response to this compound. These mice were found to have a number of abnormal phenotypes, thus confirming that AHR plays an important developmental and physiological role. Among the most consistent phenotypes was an altered liver pathology that was associated with accelerated rates of apoptosis. Evidence suggests that this may be related to an abnormal accumulation of levels of hepatic retinoic acid that cause an activation of transforming growth factor beta, resulting in stimulation of apoptosis. AHR may directly or indirectly control levels of a cytochrome P450 that is responsible for catabolizing retinoic acid."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I559,I559)","v":9787988},{"$f":"(LEN($J559) - LEN(SUBSTITUTE(LOWER($J559),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J559) - LEN(SUBSTITUTE(LOWER($J559),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J559) - LEN(SUBSTITUTE(LOWER($J559),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B559:D559)","v":2},1998,"Pharmacologic profile of tazarotene.","Duvic",9787988,"Pharmacologic profile of tazarotene.    Abstract:   The majority of patients with psoriasis exhibit a mild to moderate form of the disease. While topically applied agents represent the ideal therapeutic approach for these patients, our treatment options have been hampered by their inconsistent or limited efficacy, expense, and cosmetic properties. Furthermore, some of the topically applied preparations have the potential for systemic absorption and associated adverse events. Tazarotene is the first synthetically developed retinoid indicated for the topical treatment of patients with psoriasis. Pharmacologically, tazarotene affects the three primary abnormalities associated with psoriasis: it normalizes epidermal differentiation, it exhibits a potent antiproliferative effect, and it decreases epidermal inflammation. Following topical application, tazarotene is rapidly metabolized in the skin to tazarotenic acid, its primary and active metabolite. While tazarotenic acid achieves measurable levels in the systemic circulation, no drug-related hematologic, ophthalmologic, or metabolic adverse events have been observed. Only a minimal amount of tazarotene is absorbed into the circulation. While animal studies have found tazarotene to be nonmutagenic and nonteratogenic, women of child-bearing potential should be counseled regarding the potential risks of retinoid use during pregnancy. In summary, animal and clinical patient trials have found tazarotene to be effective, safe, and well-tolerated. The availability of such an agent in a topical formulation is a welcome treatment alternative for the management of patients with psoriasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I560,I560)","v":9740599},{"$f":"(LEN($J560) - LEN(SUBSTITUTE(LOWER($J560),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J560) - LEN(SUBSTITUTE(LOWER($J560),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J560) - LEN(SUBSTITUTE(LOWER($J560),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B560:D560)","v":2},1998,"Transcription-modulating drugs: a new frontier in the treatment of essential hypertension.","Kurtz",9740599,"Transcription-modulating drugs: a new frontier in the treatment of essential hypertension.    Abstract:   While the promises of gene therapy may be years away from realization, the therapeutic use of drugs that act by modifying gene transcription is a well-established practice in clinical medicine. Although transcription-modulating drugs are frequently used in many different specialties, the deliberate development and use of these agents in cardiovascular medicine has been comparatively limited. However, research advances in the area of gene transcription and in the molecular genetic regulation of blood pressure, insulin resistance, lipid metabolism, and cell growth are providing new opportunities for controlling the expression of genes that are relevant to the pathogenesis of cardiovascular disease and essential hypertension. These research advances are beginning to converge in the development of transcription-modulating drugs with the potential to attack genetically determined risk factors that often cluster in patients with essential hypertension. Ligand-activated transcription factors that serve as receptors for small lipophilic compounds such as the thiazolidinediones and retinoids represent examples of potential therapeutic targets with direct effects on the expression of genes relevant to the pathogenesis of essential hypertension and its complications. Mounting evidence suggesting that the superior cardiorenal protective properties of converting enzyme inhibitors are related in part to their ability to indirectly modify the expression of genes in the heart and vasculature provides provisional support for the clinical value of this therapeutic approach. Given the success of transcription-modulating drugs in the treatment of type II diabetes and many other clinical disorders, it is anticipated that these agents will be developed as tools for the prevention and treatment of hypertension and cardiovascular disease in the not too distant future."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I561,I561)","v":9379138},{"$f":"(LEN($J561) - LEN(SUBSTITUTE(LOWER($J561),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J561) - LEN(SUBSTITUTE(LOWER($J561),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J561) - LEN(SUBSTITUTE(LOWER($J561),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B561:D561)","v":2},1997,"The vitamin D hormone and its nuclear receptor: molecular actions and disease states.","Haussler",9379138,"The vitamin D hormone and its nuclear receptor: molecular actions and disease states.    Abstract:   Vitamin D plays a major role in bone mineral homeostasis by promoting the transport of calcium and phosphate to ensure that the blood levels of these ions are sufficient for the normal mineralization of type I collagen matrix in the skeleton. In contrast to classic vitamin D-deficiency rickets, a number of vitamin D-resistant rachitic syndromes are caused by acquired and hereditary defects in the metabolic activation of the vitamin to its hormonal form, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), or in the subsequent functions of the hormone in target cells. The actions of 1,25(OH)2D3 are mediated by the nuclear vitamin D receptor (VDR), a phosphoprotein which binds the hormone with-high affinity and regulates the expression of genes via zinc finger-mediated DNA binding and protein-protein interactions. In hereditary hypocalcemic vitamin D-resistant rickets (HVDRR), natural mutations in human VDR that confer patients with tissue insensitivity to 1,25(OH)2D3 are particularly instructive in revealing VDR structure function relationships. These mutations fall into three categories: (i) DNA binding/nuclear localization, (ii) hormone binding and (iii) heterodimerization with retinoid X receptors (RXRs). That all three classes of VDR mutations generate the HVDRR phenotype is consistent with a basic model of the active receptor as a DNA-bound, 1,25(OH)2D3-liganded heterodimer of VDR and RXR. Vitamin D responsive elements (VDREs) consisting of direct hexanucleotide repeats with a spacer of three nucleotides have been identified in the promoter regions of positively controlled genes expressed in bone, such as osteocalcin, osteopontin, beta 3-integrin and vitamin D 24-OHase. The 1,25(OH)2D3 ligand promotes VDR-RXR heterodimerization and specific, high affinity VDRE binding, whereas the ligand for RXR, 9-cis retinoic acid (9-cis RA), is capable of suppressing 1,25(OH)2D3-stimulated transcription by diverting RXR to form homodimers. However, initial 1,25(OH)2D3 liganding of a VDR monomer renders it competent not only to recruit RXR into a heterodimer but also to conformationally silence the ability of its RXR partner to bind 9-cis RA and dissociate the heterodimer. Additional probing of protein-protein interactions has revealed that VDR also binds to basal transcription factor IIB (TFIIB) and, in the presence of 1,25(OH)2D3, an RXR-VDR-TFIIB ternary complex can be created in solution. Moreover, for transcriptional activation by 1,25(OH)2D3, both VDR and RXR require an intact short amphipathic alpha-helix, known as AF-2, positioned at their extreme C-termini. Because the AF-2 domains participate neither in VDR-RXR heterodimerization nor in TFIIB association, it is hypothesized that they contact, in a ligand-dependent fashion, transcriptional coactivators such as those of the steroid receptor coactivator family, constituting yet a third protein-protein interaction for VDR. Therefore, in VDR-mediated transcriptional activation, 1,25(OH)2D3 binding to VDR alters the conformation of the ligand binding domain such that it: (i) engages in strong heterodimerization with RXR to facilitate VDRE binding, (ii) influences the RXR ligand binding domain such that it is resistant to the binding of 9-cis RA but active in recruiting coactivator to its AF-2 and (iii) presents the AF-2 region in VDR for coactivator association. The above events, including bridging by coactivators to the TATA binding protein and associated factors, may position VDR such that it is able to attract TFIIB and the balance of the RNA polymerase II transcription machinery, culminating in repeated transcriptional initiation of VDRE-containing, vitamin D target genes. Such a model would explain the action of 1,25(OH)2D3 to elicit bone remodeling by stimulating osteoblast and osteoclast precursor gene expression, while concomitantly triggering the termination of its hormonal signal by inducing the 24-OHase catabolizing enzyme."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I562,I562)","v":9086839},{"$f":"(LEN($J562) - LEN(SUBSTITUTE(LOWER($J562),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J562) - LEN(SUBSTITUTE(LOWER($J562),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J562) - LEN(SUBSTITUTE(LOWER($J562),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B562:D562)","v":2},1997,"[Regulation of tissue-associated fibrinolysis by retinoids: mechanism and consequence of retinoid-PA-TGF-beta system].","Kojima",9086839,"[Regulation of tissue-associated fibrinolysis by retinoids: mechanism and consequence of retinoid-PA-TGF-beta system].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I563,I563)","v":8668974},{"$f":"(LEN($J563) - LEN(SUBSTITUTE(LOWER($J563),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J563) - LEN(SUBSTITUTE(LOWER($J563),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J563) - LEN(SUBSTITUTE(LOWER($J563),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B563:D563)","v":2},1996,"[Vitamins and metals: possible hazards for humans].","Ballmer",8668974,"[Vitamins and metals: possible hazards for humans].    Abstract:   Administration of vitamins or metals may cause severe side effects. Retinoids (derivatives of vitamin A) used for the treatment of various skin disorders are teratogenic, hepatotoxic and may induce a substantial increase in serum lipids. A case report demonstrates that vitamin D supplementation in a patient under total parenteral nutrition can cause hypercalcemia. The isolated administration of vitamin B1, without concomitant vitamin B6 and nicotinamide may precipitate potentially life-threatening pellagra encephalopathy. Repeat blood transfusions may produce clinically overt organ hemosiderosis, e.g. cirrhosis of the liver, diabetes mellitus or myocardiopathy. The literature contains reports on a few cases of sarcoma associated with orthopedic metal implants. The controversial issue of the potential dangers of dental amalgams is briefly mentioned."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I564,I564)","v":8799026},{"$f":"(LEN($J564) - LEN(SUBSTITUTE(LOWER($J564),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J564) - LEN(SUBSTITUTE(LOWER($J564),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J564) - LEN(SUBSTITUTE(LOWER($J564),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B564:D564)","v":2},1996,"Fanconis anaemia and recurrent squamous cell carcinoma of the oral cavity: a case report.","Koo",8799026,"Fanconis anaemia and recurrent squamous cell carcinoma of the oral cavity: a case report.    Abstract:   Fanconis anaemia is a rare genetic disorder and majority of the patients die of haematologic complications in their second or third decades of life. Others who have mild or no cytopenias survive long enough to develop malignancies. This is a report of a 44-year-old woman who presented with recurrent oral squamous cell carcinoma during her adulthood, without clinical haematological problem. Despite treatment with cis-retinoic acid, she developed a third squamous cell carcinoma 6 months later. In a review of the literature, only in 1 reported case was the patient treated with low-dose retinoids but he developed recurrent anal cancer after 14 months."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I565,I565)","v":7621972},{"$f":"(LEN($J565) - LEN(SUBSTITUTE(LOWER($J565),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J565) - LEN(SUBSTITUTE(LOWER($J565),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J565) - LEN(SUBSTITUTE(LOWER($J565),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B565:D565)","v":2},1995,"Lipolysis-stimulated receptor: a newcomer on the lipoprotein research scene.","Bihain",7621972,"Lipolysis-stimulated receptor: a newcomer on the lipoprotein research scene.    Abstract:   It has been widely accepted that the remnants of the intestinally-derived lipoprotein chylomicrons, i.e., chylomicron remnants (CMR), are cleared from the circulation by a receptor genetically distinct from the well-known LDL-receptor. This second receptor was initially considered as a receptor specific for apo E, in contrast to the LDL-receptor, which binds both apo B and apoE. This article critically examines the current dogma of the putative CMR receptor, as well as both supporting and conflicting evidence for the recently-proposed identity of this receptor with the LDL-receptor related protein (LRP). Next, we introduce the lipolysis-stimulated receptor, LSR, which bears all the biochemical characteristics of the CMR receptor. In addition, the apparent number of LSR expressed in the liver is inversely correlated with nonfasting levels of plasma triglycerides. A change in LSR expression and parallel inverse change in plasma triglycerides is observed in rats treated with hyperlipidemic (retinoic acid) or hypolipidemic (fish oil in MaxEPA) agents, indicating that LSR represents a definite target for pharmacological management of hyperlipidemia. In support of this notion is the observation that MaxEPA, which causes an increase in LSR expression, also reduces both plasma triglyceride and cholesterol levels in the thus far intractable homozygous Watanabe heritable hyperlipidemic rabbit."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I566,I566)","v":7789356},{"$f":"(LEN($J566) - LEN(SUBSTITUTE(LOWER($J566),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J566) - LEN(SUBSTITUTE(LOWER($J566),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J566) - LEN(SUBSTITUTE(LOWER($J566),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B566:D566)","v":2},1995,"Influence of heredity on human sensitivity to environmental chemicals.","Weber",7789356,"Influence of heredity on human sensitivity to environmental chemicals.    Abstract:   Hereditary peculiarities in individual responses to environmental chemicals are a common occurrence in human populations. Genetic variation in glutathione S-transferase, CYP1A2, N-acetyltransferase, and paraoxonase exemplify the relationship of metabolic variation to individual susceptibility to cancer and other toxicants of environmental origin. Heritable receptor protein variants, a subset of proteins of enormous pharmacogenetic potential that have not thus far been extensively explored from the pharmacogenetic standpoint, are also considered. Examples of interest that are considered include receptor variants associated with retinoic acid resistance in acute promyelocytic leukemia, with paradoxical responses to antiandrogens in prostate cancer, and with retinitis pigmentosa. Additional heritable protein variants of pharmacogenetic interest that result in antibiotic-induced deafness, glucocorticoid-remediable aldosteronism and hypertension, the long-QT syndrome, and beryllium-induced lung disease are also discussed. These traits demonstrate how knowledge of the molecular basis and mechanism of the variant response may contribute to its prevention in sensitive persons as well as to improved therapy for genetically conditioned disorders that arise from environmental chemicals."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I567,I567)","v":7999471},{"$f":"(LEN($J567) - LEN(SUBSTITUTE(LOWER($J567),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J567) - LEN(SUBSTITUTE(LOWER($J567),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J567) - LEN(SUBSTITUTE(LOWER($J567),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B567:D567)","v":2},1994,"Prevention of breast cancer in premenopausal women.","Love",7999471,"Prevention of breast cancer in premenopausal women.    Abstract:   While all-inclusive complete models for breast cancer development are not available, four concepts are likely to be critical to creation of well-grounded breast cancer prevention efforts: 1) step-by-step progressive development, 2) involving multiple factors, 3) over several years, and 4) during a long period of which the process may be reversible. Interventions to prevent breast cancer must have a comprehensive biological rationale, an absence of serious toxic effects, and long-term acceptability by women. Prophylactic mastectomy may be beneficial in some women, but identification of individuals at very high risk for breast cancer remains elusive. At present, greater attention to four manipulable risk factors is appropriate: radiation, smoking, alcohol, and lactation. Clinical trials are in the process of studying a synthetic retinoid (4-hydroxyphenylretinamide), tamoxifen, and a low-fat diet. Other breast cancer prevention strategies in various phases of preclinical trial evaluation include: pseudopregnancy, an quot;idealquot; combination oral contraceptive, luteinizing hormone-releasing hormone (LHRH) agonist oophorectomy, modification of estrogen metabolism, suppression of ornithine decarboxylase induction, and manipulation of growth factors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I568,I568)","v":7979022},{"$f":"(LEN($J568) - LEN(SUBSTITUTE(LOWER($J568),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J568) - LEN(SUBSTITUTE(LOWER($J568),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J568) - LEN(SUBSTITUTE(LOWER($J568),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B568:D568)","v":2},1994,"[Cutis verticis gyrata and pachydermoperiostosis. Several cases in a same family. Initial results of the treatment of pachyderma with isotretinoin].","Beauregard",7979022,"[Cutis verticis gyrata and pachydermoperiostosis. Several cases in a same family. Initial results of the treatment of pachyderma with isotretinoin].    Abstract:   This is a case report of four patients of the same family with pachyderma. Their clinical findings are discussed in regard of a review of the literature. Also, because there are few data on effective treatment, their dramatic improvement with isotretinoin is of significant interest."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I569,I569)","v":7526405},{"$f":"(LEN($J569) - LEN(SUBSTITUTE(LOWER($J569),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J569) - LEN(SUBSTITUTE(LOWER($J569),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J569) - LEN(SUBSTITUTE(LOWER($J569),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B569:D569)","v":2},1994,"Mechanisms of chemical injury of thyroid gland.","Capen",7526405,"Mechanisms of chemical injury of thyroid gland.    Abstract:   Many goitrogenic xenobiotics that increase the incidence of thyroid tumors in rodents exert a direct effect on the thyroid gland to disrupt one of several steps in the biosynthesis and secretion of thyroid hormones. This includes 1) inhibition of the iodine-trapping mechanism (thiocyanate or perchlorate), 2) blockage of organic binding of iodine and coupling of iodothyronines to form thyroxine (T4) and triiodothyronine (T3) (e.g., sulfonamides, thiourea, methimazole, and aminotriazole, among others), and 3) inhibition of thyroid hormone secretion by an effect on proteolysis of active hormone from the colloid (lithium or an excess of iodide). Another large group of goitrogenic chemicals disrupts thyroid hormone economy by increasing the peripheral metabolism of thyroid hormones through an induction of hepatic microsomal enzymes. This group includes CNS-acting drugs (phenobarbital, benzodiazepines), calcium channel blockers (nicardipine, nifedipine), steroids (spironolactone), retinoids, chlorinated hydrocarbons (chlordane, DDT, TCDD), polyhalogenated biphenyls (PCB, PBB), and enzyme inducers. Thyroid hormone economy also can be disrupted by xenobiotics that inhibit the 5monodeiodinase, which converts T4 in peripheral sites (e.g., liver and kidney) to biologically active T3. Inhibition of this enzyme by FDamp;C Red No. 3, amiodarone, and iopanoic acid lowers circulating T3 levels, which results in a compensatory increased secretion of thyroid-stimulating hormone (TSH), follicular cell hypertrophy and hyperplasia, and an increased incidence of follicular cell tumors in 2-year or lifetime studies in rats. Physiologic perturbations alone such as the feeding of an iodine-deficient diet, partial thyroidectomy, natural goitrogens in certain foods, and transplantation of TSH-secreting pituitary tumors in rodents also can disrupt thyroid hormone economy and, if sustained, increase the development of thyroid tumors in rats. A consistent finding with all of these goitrogens, be they either physiologic perturbations or xenobiotic chemicals, is the chronic hypersecretion of TSH, which by receptor-mediated events places the rodent thyroid gland at greater risk of developing tumors through a secondary mechanism of thyroid oncogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I570,I570)","v":8377392},{"$f":"(LEN($J570) - LEN(SUBSTITUTE(LOWER($J570),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J570) - LEN(SUBSTITUTE(LOWER($J570),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J570) - LEN(SUBSTITUTE(LOWER($J570),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B570:D570)","v":2},1993,"[Oncology 1992. Association with ophthalmology and brief status evaluation].","Lohri",8377392,"[Oncology 1992. Association with ophthalmology and brief status evaluation].    Abstract:   Several clinical situations require the cooperation of ophthalmologist and medical oncologist. Systemic metastasis spreading from an ocular primary tumor may rarely pose a problem. Liver metastasis from an ocular melanoma can be treated with intrahepatic chemoembolization and local palliation can be achieved. Disseminated tumors such as breast cancer or leukemias may spread to the eye and require local therapy. Per continuitatem orbital infiltrations of i.e. nasopharyngeal carcinomas need a cooperative management. Ocular side effects from chemo/radiotherapy may be especially severe in high dose therapies such as preparative regimes for allogeneic bone marrow transplants (BMT). A Sjögren-type sicca syndrome, cataracts and a microvasculopathy with cotton wool spots are associated with total body irradiation and the immunosuppression needed in BMT. Cancer research over the past ten years was increasingly influenced by molecular biology which has added to our understanding of tumor biology. The retinoblastoma gene is a typical example of a tumor suppressor gene. It regulates cell growth in its normal physiological state. Deletions may occur, that lead to tumor formation. The detection of oncogenes helps in the diagnosis of leukemias or lymphomas. Growth factors such as the Granulocyte Colony Stimulating Factor (G-CSF) were introduced recently. The differentiation therapy with retinoids has brought a new dimension into the field of cancer treatment and probably also of cancer prophylaxis. Taxol, an alkaloid from the yew tree is a novel cytostatic compound with very promising activity in tumors such as refractory ovarian or breast cancer. High dose therapy with BMT today is an established treatment for certain leukemias.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I571,I571)","v":8509635},{"$f":"(LEN($J571) - LEN(SUBSTITUTE(LOWER($J571),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J571) - LEN(SUBSTITUTE(LOWER($J571),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J571) - LEN(SUBSTITUTE(LOWER($J571),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B571:D571)","v":2},1993,"Regulation of hepatitis B virus gene expression.","Huan",8509635,"Regulation of hepatitis B virus gene expression.    Abstract:   Human hepatitis B virus (HBV) mainly infects hepatocytes. HB viral gene expression has been demonstrated to be liver-specific using DNA transfection methods. This liver-specific gene expression is regulated by promoter/enhancer elements. HBV contains two enhancer elements. Enhancer element I has been studied in detail at the DNA-protein level. This is further substantiated by DNA transfections of liver and non-liver cell lines with expression plasmids containing enhancer elements controlling the transcription of reporter genes. Genetic analysis of the enhancer elements defined the minimal sequences which play a key role in the regulation of enhancer function. One of the factors binding in this region is RXR alpha. Using only the DNA binding domain of the liver-specific RXR alpha expressed in E. coli, we demonstrated binding of RXR alpha to the putative retinoic acid receptor response element (RARE) in the HBV enhancer. Our studies implicate a potentially important role of retinoic acid and its receptor in the liver-specific regulation of HBV gene expression and the disease pathogenesis associated with infection."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I572,I572)","v":1281935},{"$f":"(LEN($J572) - LEN(SUBSTITUTE(LOWER($J572),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J572) - LEN(SUBSTITUTE(LOWER($J572),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J572) - LEN(SUBSTITUTE(LOWER($J572),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B572:D572)","v":2},1992,"Pathophysiology of chemical injury of the thyroid gland.","Capen",1281935,"Pathophysiology of chemical injury of the thyroid gland.    Abstract:   Many goitrogenic xenobiotics that increase the incidence of thyroid tumors in rodents exert a direct effect on the thyroid gland to disrupt one of several possible steps in the biosynthesis and secretion of thyroid hormones. This includes: (1) inhibition of the iodine trapping mechanism (thiocyanate or perchlorate); (2) blockage of organic binding of iodine and coupling of iodothyronines to form thyroxine (T4) and triiodothyronine (T3) (e.g. sulfonamides, thiourea, methimazole, and aminotriazole, amongst others); (3) inhibition of thyroid hormone secretion by an effect on proteolysis of active hormone from the colloid (lithium or an excess of iodide). Another large group of goitrogenic chemicals disrupts thyroid hormone economy by increasing the peripheral metabolism of thyroid hormones through an induction of hepatic microsomal enzymes. This group includes CNS-acting drugs (phenobarbital, benzodiazepines), calcium channel blockers (nicardipine, nifedipine), steroids (spironolactone), retinoids, chlorinated hydrocarbons (chlordane, DDT, TCDD), polyhalogenated biphenyls (PCB, PBB), and enzyme inducers. Thyroid hormone economy also can be disrupted by xenobiotics that inhibit the 5-monodeiodinase which converts T4 in peripheral sites (e.g. liver and kidney) to biologically active T3. Inhibition of this enzyme by FDamp;C Red No. 3, amiodarone, and iopanoic acid lowers circulating T3 levels which results in a compensatory increased secretion of thyroid stimulating hormone (TSH), follicular cell hypertrophy and hyperplasia, and an increased incidence of follicular cell tumors in 2-year or lifetime studies in rats. Physiologic perturbations alone, such as the feeding of an iodine-deficient diet, partial thyroidectomy, natural goitrogens in certain foods, and transplantation of TSH-secreting pituitary tumors in rodents also can disrupt thyroid hormone economy and, if sustained, increase the development of thyroid tumors in rats. A consistent finding with all of these goitrogens, be they either physiologic perturbations or xenobiotics, is the chronic hypersecretion of TSH which places the rodent thyroid gland at greater risk to develop tumors through a secondary mechanism of thyroid oncogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I573,I573)","v":1389140},{"$f":"(LEN($J573) - LEN(SUBSTITUTE(LOWER($J573),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J573) - LEN(SUBSTITUTE(LOWER($J573),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J573) - LEN(SUBSTITUTE(LOWER($J573),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B573:D573)","v":2},1992,"Present challenges in the global prevention of blindness.","Thylefors",1389140,"Present challenges in the global prevention of blindness.    Abstract:   Cataract is responsible for 50% of world blindness, with at present an estimated backlog of 13.5 million cases in need of surgery. Low-cost cataract surgery must be made more available in developing countries, making use of alternative approaches for outpatient surgery and optimal management of available resources. Trachoma control needs to be targeted at the worst affected areas in endemic countries, with more emphasis on behavioural, educational and community aspects of the disease. Vitamin A deficiency and xerophthalmia control are becoming matters of maternal and child health care, with early intervention during infancy in view of the mortality issue. There are good prospects for the prevention of blindness from onchocerciasis, through the availability of ivermectin, but large-scale distribution schemes are still needed in most of the African countries concerned. The early detection and management of open-angle glaucoma still poses a major problem in developing countries, and further development of appropriate technology is needed in this field. Another area where more efforts are needed is ocular trauma, which is commonly the cause of unilateral loss of vision. General preventive measures must be enforced and better training provided to health personnel to deal competently with such cases, in order to prevent late complications. Diabetes, finally, is on the increase in many developing countries, giving rise to problems in dealing effectively with the ensuing retinopathy.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I574,I574)","v":1449018},{"$f":"(LEN($J574) - LEN(SUBSTITUTE(LOWER($J574),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J574) - LEN(SUBSTITUTE(LOWER($J574),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J574) - LEN(SUBSTITUTE(LOWER($J574),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B574:D574)","v":2},1992,"Hepatic fibrogenesis: the puzzle of interacting cells, fibrogenic cytokines, regulatory loops, and extracellular matrix molecules.","Gressner",1449018,"Hepatic fibrogenesis: the puzzle of interacting cells, fibrogenic cytokines, regulatory loops, and extracellular matrix molecules.    Abstract:   Fibrotic lesions affect a wide variety of organs but liver fibrosis is probably the most abundant form of organ fibrosis. Disturbances of the equilibrium between parenchyma and extracellular matrix (ECM) leading to a disproportionate increase and irregular deposition of newly formed connective tissue components (fibrosis) is a common and clinically most important sequelae of chronic active liver diseases. Significant progress has been made during the last years in the analysis of the structural composition of ECM in normal and fibrotic liver and in the dissection of the molecular and cellular mechanisms of exaggerated ECM-deposition in necroinflammatory areas using experimental models of hepatic fibrosis, isolated cells in mono- and coculture systems and the growing repertoire of molecular biological tools. Perisinusoidal, retinoid-storing cells (Ito cells, parasinusoidal lipocytes) transform under inflammatory stimuli to myofibroblast-like cells being qualitatively and quantitatively the most important connective tissue producing cell type in human and animal liver. Its activation and transformation is mediated by paracrine and autocrine loops involving transforming growth factor (TGF) beta as the main fibrogenic mediator secreted by activated liver macrophages, possibly also by endothelial cells and liberated by disintegrated thrombocytes. In advanced stages of retinoid-storing cell transformation additional growth factors like platelet derived growth factor (PDGF) become important indicating a sequential action of cytokines and fibrogenic mediators during the fibrogenic process. The molecular and cellular interactions in the course of liver fibrogenesis have gained model character for a number of other organ fibrotic processes, wound repair, and atherogenesis included.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I575,I575)","v":1734110},{"$f":"(LEN($J575) - LEN(SUBSTITUTE(LOWER($J575),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J575) - LEN(SUBSTITUTE(LOWER($J575),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J575) - LEN(SUBSTITUTE(LOWER($J575),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B575:D575)","v":2},1992,"Secondary dyslipidemia. Inadvertent effects of drugs in clinical practice.","Henkin",1734110,"Secondary dyslipidemia. Inadvertent effects of drugs in clinical practice.    Abstract:    OBJECTIVE : To examine the available literature on commonly prescribed drugs and their effects on blood lipid and lipoprotein levels.  DATA SOURCES : The review was based on searches of English-language articles from 1975 to 1990 by Medlars II and MEDLINE programs, the Index Medicus for 1980 to 1990, and references from identified articles. Relevant journals published within the last 6 months were also examined.  STUDY SELECTION : More than 500 articles were identified for inclusion. Articles were selected on the basis of appropriateness of design to demonstrate significant results, determined by consensus when necessary.  DATA EXTRACTION : Studies were classified according to type (observational or interventional), length of follow-up, and type of controls. Quanitative analysis of lipid, lipoprotein, and apoprotein changes induced by drugs was computed as the percentage of change observed during the course of the study (interventional) or compared with the controls at a given time (observational).  DATA SYNTHESIS : Steroid hormones that have strong progestogenic and androgenic properties, retinoids, cyclosporine A, and phenothiazines are potentially atherogenic. Steroid hormones with dominant estrogenic properties, several anticonvulsants, biguanides, high-dose ketoconazole, and aminosalicylic acid are potentially antiatherogenic. Corticosteroids appear to elevate all the lipoprotein cholesterol levels. Oral estrogens, retinoids, and corticosteroids also can elevate triglyceride levels. Other drugs with questionable effects on lipoprotein metabolism are reviewed.  CONCLUSION : Although the long-term implications of drug-induced lipoprotein changes are still undefined, physicians need to consider these effects in clinical practice."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I576,I576)","v":1609832},{"$f":"(LEN($J576) - LEN(SUBSTITUTE(LOWER($J576),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J576) - LEN(SUBSTITUTE(LOWER($J576),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J576) - LEN(SUBSTITUTE(LOWER($J576),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B576:D576)","v":2},1992,"Perspective of biochemical research in the neuronal ceroid-lipofuscinosis.","Rider",1609832,"Perspective of biochemical research in the neuronal ceroid-lipofuscinosis.    Abstract:   The search for biochemical abnormalities in the neuronal ceroid-lipofuscinoses (NCL) or Batten disease was initiated with the discovery of normal levels of gangliosides in juvenile amaurotic idiocy. The primary goal of most biochemical studies has been to discover the unique biochemical marker for carriers and at-risk individual. Ceroid, the singular pathomorphologic trait of NCL, was isolated and shown to differ from a similar but normal product of aged cells, lipofuscin. In spite of the availability of stored product, the chemical analysis of ceroid has not elucidated the unique biochemical defect in the NCL, as has been the case for other lysosomal storage disorders. The NCL were thought to be a result of lipid peroxidation because ceroid is also found in disorders of impaired vitamin E metabolism or results from a diet deficient in the antioxidant, vitamin E. In addition, tissue analysis indicated losses of polyunsaturated fatty acids in affecteds and carriers, as well as the presence of a secondary product of lipid peroxidation, 4-hydroxynonenal, in affected and carrier NCL dogs. With the exception of a fluorescent compound isolated from retinal ceroid, studies aimed at discovering the disease-specific fluorophores of ceroid have been largely inconclusive. The discovery of elevated dolichols in urine and brain tissue of NCL patients led to another hypothesis, that the basic biochemical defect in NCL involved the metabolism of dolichols and retinoids. However, the more recent view is that dolichol metabolism is secondary to the unknown NCL lesion.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I577,I577)","v":1315012},{"$f":"(LEN($J577) - LEN(SUBSTITUTE(LOWER($J577),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J577) - LEN(SUBSTITUTE(LOWER($J577),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J577) - LEN(SUBSTITUTE(LOWER($J577),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B577:D577)","v":2},1992,"Retinoic acid, bound to its nuclear receptor, enhances the expression of the gene for phosphoenolpyruvate carboxykinase.","Rider",1315012,"Retinoic acid, bound to its nuclear receptor, enhances the expression of the gene for phosphoenolpyruvate carboxykinase.    Abstract:   Over 30 years ago, whole-animal studies conclusively showed that liver glycogen depletion in vitamin A deficiency was caused by depressed gluconeogenesis. The techniques of modern cell and molecular biology have now been utilized to demonstrate the probable molecular pathogenesis of this defect associated with vitamin A deficiency. Retinoic acid, bound to its nuclear receptor, stimulates transcription of the gene for phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis, by binding to a short element of the promoter region of the PEPCK gene."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I578,I578)","v":1770192},{"$f":"(LEN($J578) - LEN(SUBSTITUTE(LOWER($J578),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J578) - LEN(SUBSTITUTE(LOWER($J578),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J578) - LEN(SUBSTITUTE(LOWER($J578),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B578:D578)","v":2},1991,"Alcohol, liver, and nutrition.","Lieber",1770192,"Alcohol, liver, and nutrition.    Abstract:   Until two decades ago, dietary deficiencies were considered to be the major reason why alcoholics developed liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary malnutrition. Direct hepatotoxic effects of ethanol were also established, some of which were linked to redox changes produced by reduced nicotinamide adenine dinucleotide (NADH) generated via the alcohol dehydrogenase (ADH) pathway. It was also determined that ethanol can be oxidized by a microsomal ethanol oxidizing system (MEOS) involving cytochrome P-450: the newly discovered ethanol-inducible cytochrome P-450 (P-450IIE1) contributes to ethanol metabolism, tolerance, energy wastage (with associated weight loss), and the selective hepatic perivenular toxicity of various xenobiotics. P-450 induction also explains depletion (and enhanced toxicity) of nutritional factors such as vitamin A. Even at the early fatty-liver stage, alcoholics commonly have a very low hepatic concentration of vitamin A. Ethanol administration in animals was found to depress hepatic levels of vitamin A, even when administered with diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration. The hepatic depletion of vitamin A was strikingly exacerbated when ethanol and other drugs were given together, mimicking a common clinical occurrence. Hepatic retinoid depletion was found to be associated with lysosomal lesions and decreased detoxification of chemical carcinogens. To alleviate these adverse effects, as well as to correct problems of night blindness and sexual inadequacies, the alcoholic patient should be provided with vitamin A supplementation. Such therapy, however, is complicated by the fact that in excessive amounts vitamin A is hepatotoxic, an effect exacerbated by long-term ethanol consumption. This results in striking morphologic and functional alterations of the mitochondria with leakage of mitochondrial enzymes, hepatic necrosis, and fibrosis. Thus, treatment with vitamin A and other nutritional factors (such as proteins) is beneficial but must take into account a narrowed therapeutic window in alcoholics who have increased needs for such nutrients, but also display an enhanced susceptibility to their adverse effects. Massive doses of choline also exerted some toxic effects and failed to prevent the development of alcoholic cirrhosis. Acetaldehyde (the metabolite produced from ethanol by either ADH or MEOS) impairs hepatic oxygen utilization and forms protein adducts, resulting in antibody production, enzyme inactivation, and decreased DNA repair. It also enhances pyridoxine and perhaps folate degradation and stimulates collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I579,I579)","v":1791218},{"$f":"(LEN($J579) - LEN(SUBSTITUTE(LOWER($J579),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J579) - LEN(SUBSTITUTE(LOWER($J579),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J579) - LEN(SUBSTITUTE(LOWER($J579),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B579:D579)","v":2},1991,"Lichen planus.","Boyd",1791218,"Lichen planus.    Abstract:   Lichen planus, a papulosquamous disease, in its classical presentation is characterized by pruritic violaceous papules most commonly on the extremities of middle-aged adults. It may or may not be accompanied by oral and genital mucous membrane involvement. Its course is generally self-limited for a period of several months to years, but it may last indefinitely. There are many clinical variants described, ranging from lichenoid drug eruptions to association with other diseases such as diabetes mellitus, autoimmune disease, and the graft-versus-host reaction. The relationship of these, if any, to classical lichen planus is questionable. Multiple therapeutic options exist including corticosteroids, retinoids, griseofulvin, PUVA, and cyclosporine."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I580,I580)","v":1882322},{"$f":"(LEN($J580) - LEN(SUBSTITUTE(LOWER($J580),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J580) - LEN(SUBSTITUTE(LOWER($J580),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J580) - LEN(SUBSTITUTE(LOWER($J580),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B580:D580)","v":2},1991,"Ocular teratology.","Strömland",1882322,"Ocular teratology.    Abstract:   The principles of teratology are described, and animal models for research in abnormal ocular development and clinical studies of human teratogens are surveyed. A review is made of presumed ocular teratogenic agents: radiation; external environmental teratogens; maternal conditions such as infections, diabetes, and epilepsy; alcohol and drugs such as thalidomide, retinoic acid, and coumarin anticoagulants; and other agents, such as cigarettes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I581,I581)","v":2109595},{"$f":"(LEN($J581) - LEN(SUBSTITUTE(LOWER($J581),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J581) - LEN(SUBSTITUTE(LOWER($J581),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J581) - LEN(SUBSTITUTE(LOWER($J581),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B581:D581)","v":2},1990,"Suppression of tumor promotion by inhibitors of poly(ADP)ribose formation.","Troll",2109595,"Suppression of tumor promotion by inhibitors of poly(ADP)ribose formation.    Abstract:   Tumor promoters, such as phorbol esters or hormones, cause many biological effects which may contribute to the expression of cancer. The mechanism of cancer expression may have a common theme. One method of learning about this common mechanism is the identification of chemicals that interfere with tumor development. That there is actually a common theme between very different substances, such as inflammatory skin tumor promoters and estradiol causing breast cancer, was shown by the fact that both skin and breast cancers are suppressed by the same agents, e.g., protease inhibitors and retinoids. In addition to skin and breast, protease inhibitors suppress colon, bladder, and liver cancers. The substances that crossed over in suppressing many varieties of cancer were found to inhibit oxygen radical formation by tumor promoter-activated neutrophils and ras oncogene expression in NIH 3T3 cells. Poly(ADP)ribose polymerase (PADPR polymerase) may serve as the connecting link between oxygen radicals that cause its activation and oncogene expression. PADPR polymerase is inhibited by retinoids, antioxidants, and some protease inhibitors. Benzamide, an inhibitor of PADPR polymerase, is also a chymotrypsin inhibitor which suppresses oxygen radical formation by tumor promoter-activated neutrophils. The inhibition of PADPR polymerase causes the expulsion of some oncogenes from NIH 3T3 cells at definite times after oncogene transfection. Further work is required to find what are the contributions of PADPR polymerase to tumor promotion and of its inhibitors to suppression of oncogene expression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I582,I582)","v":2698171},{"$f":"(LEN($J582) - LEN(SUBSTITUTE(LOWER($J582),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J582) - LEN(SUBSTITUTE(LOWER($J582),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J582) - LEN(SUBSTITUTE(LOWER($J582),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B582:D582)","v":2},1989,"[Vitamin A and the liver--current knowledge].","Körner",2698171,"[Vitamin A and the liver--current knowledge].    Abstract:   A short survey of metabolism and effects of vitamin A as well as of the role of Ito cells is presented. The Ito cells of the liver represent a special form of fibroblasts, about 80% of the vitamin A (VA) content of the normal liver is stored in these cells. Following to the absorption of VA in the intestine, VA (retinol) is transported in chylomicrons and their remnants, and taken up by hepatocytes through receptor-mediated endocytosis. Along with retinolbinding protein VA is transported from the hepatocytes to the Ito cells where is is being stored as lipid droplets. The VA content of the liver tissue in chronic, especially alcoholic liver disease is distinctly lowered. The VA deficiency of the chronic alcoholic liver disease is caused by an accelerated microsomal metabolism of VA. Furthermore, investigations elucidating the therapy of VA-deficiency in liver diseases are explained."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I583,I583)","v":3287781},{"$f":"(LEN($J583) - LEN(SUBSTITUTE(LOWER($J583),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J583) - LEN(SUBSTITUTE(LOWER($J583),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J583) - LEN(SUBSTITUTE(LOWER($J583),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B583:D583)","v":2},1988,"[Serum vitamin A determinations and their value in determining vitamin A status].","Gerlach",3287781,"[Serum vitamin A determinations and their value in determining vitamin A status].    Abstract:   As demonstrated in the literature on vitamin A metabolism and homeostasis of retinol in serum, the concentration of retinol in serum is regulated very exactly if the liver stores are within the physiological range (20-300 micrograms/g liver). Therefore, the serum level indicates the status of vitamin A storage only if there is an extreme depletion or overconsumption of vitamin A. At marginal depletion, however, there is damage to peripheral tissue before changes in the vitamin A level in serum occur. At the beginning of hypervitaminosis A, changes in the level of vitamin A in serum also occur later. Therefore, the determination of vitamin A in serum gives no information on the adequacy of liver reserves for judging the necessity of a substitution."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I584,I584)","v":3279077},{"$f":"(LEN($J584) - LEN(SUBSTITUTE(LOWER($J584),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J584) - LEN(SUBSTITUTE(LOWER($J584),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J584) - LEN(SUBSTITUTE(LOWER($J584),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B584:D584)","v":2},1988,"Amyloid and amyloidosis.","Breathnach",3279077,"Amyloid and amyloidosis.    Abstract:   Cutaneous lesions are present in up to 40% of patients with primary and myeloma-associated systemic amyloidosis and occur as a result of tissue deposition of immunoglobulin light chain material derived from a circulating paraprotein. The occurrence of waxy, purpuric mucocutaneous lesions provides a crucial early pointer to underlying occult plasma cell dyscrasia; the combination of the symptoms of the carpal tunnel syndrome, macroglossia, and specific mucocutaneous lesions is highly characteristic. Although secondary systemic (reactive) amyloidosis rarely gives rise to clinically evident cutaneous lesions, it may be etiologically related to a number of chronic dermatoses. Lesions of nodular primary localized cutaneous amyloidosis are indistinguishable from those of primary and myeloma-associated systemic amyloidosis, and they result from local plasma cell infiltration. Macular and papular (lichen amyloidosus) variants of primary localized cutaneous amyloidosis may have a familial or racial basis and are characterized by a tendency for keratinocytes to undergo filamentous degeneration and apoptosis. The prognosis of patients with plasma cell dyscrasia-related systemic amyloidosis remains poor, since there is little response to therapy with cytotoxic agents, colchicine, or dimethylsulfoxide. Colchicine is the drug of choice in the prevention and treatment of the renal amyloidosis associated with familial Mediterranean fever, and dimethylsulfoxide may be useful in the management of patients with secondary systemic amyloidosis. Macular amyloid and lichen amyloidosus generally follow a chronic course with intractable pruritus; there have been isolated reports of the beneficial effect of dermabrasion, topical dimethylsulfoxide, and therapy with the aromatic retinoid, etretinate."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I585,I585)","v":3516195},{"$f":"(LEN($J585) - LEN(SUBSTITUTE(LOWER($J585),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J585) - LEN(SUBSTITUTE(LOWER($J585),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J585) - LEN(SUBSTITUTE(LOWER($J585),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B585:D585)","v":2},1986,"Hyperlipidaemia due to isotretinoin and etretinate: possible mechanisms and consequences.","Marsden",3516195,"Hyperlipidaemia due to isotretinoin and etretinate: possible mechanisms and consequences.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I586,I586)","v":3936007},{"$f":"(LEN($J586) - LEN(SUBSTITUTE(LOWER($J586),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J586) - LEN(SUBSTITUTE(LOWER($J586),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J586) - LEN(SUBSTITUTE(LOWER($J586),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B586:D586)","v":2},1985,"[Prealbumin and retinol-binding protein].","di Costanzo-Dufetel",3936007,"[Prealbumin and retinol-binding protein].    Abstract:   Thyroxin binding prealbumin (TBPA) and retinol binding protein (RBP) are associated in a complex responsible for the transport of vitamin A and of about 10% of the thyroid hormones T3 and T4. Both are synthetized in the liver. RBP can be characterized by two essential points: its hepatic secretion depending on the nutritional vitamin A status explains the close relation noted between these two parameters; its catabolism located in the renal tubular cells indicates the important role played by kidney in its metabolism. The concentrations, in serum of normal healthy adults, of TBPA and RBP are respectively 323 mg/l and 63 mg/l for men, 283 mg/l and 52 mg/l for women. In these cases the variations of the two proteins are significantly correlated. In patients with liver diseases and with protein deficiency, there is a lack of synthesis of TBPA and RBP (deficiency in substrate and/or decrease in hepatic synthesis). In vitamin A deficiency and in renal failure, RBP alone is disturbed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I587,I587)","v":4076026},{"$f":"(LEN($J587) - LEN(SUBSTITUTE(LOWER($J587),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J587) - LEN(SUBSTITUTE(LOWER($J587),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J587) - LEN(SUBSTITUTE(LOWER($J587),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B587:D587)","v":2},1985,"Vitamin A status of pregnant and lactating women as assessed by serum levels in Machakos area, Kenya.","Kusin",4076026,"Vitamin A status of pregnant and lactating women as assessed by serum levels in Machakos area, Kenya.    Abstract:   In a sample of 100 pregnant and 106 lactating women, the serum levels of vitamin A, carotene, retinol-binding protein (RBP), and pre-albumin (PA) were analyzed. The study was in response to the problem of inadequate hepatic reserves and serum vitamin A levels of newborns. On the presumption that these levels are related to the Vitamin A status of mothers during pregnancy, and the Vitamin A content of breast milk during lactation, attention was given to the Vitamin A status of pregnant and lactating women in studies of maternal and child nutrition in Machakos. The women were selected at random from the total population of pregnant and lactating women with infants of 0-12 months. Blood was taken before the midday meal, centrifuged, and sera were deep frozen. Mean serum levels of the 4 biochemical parameters of vitamin A status were in the range for well-nourished population groups. Correlations of r=0.76-0.85 were found between RBP and PA, but between Vitamin A and RBP the correlation was r=0.32-0.40. Some seasonal variations reflected crop availability. A review of very little available literature shows that Vitamin A status of lactating women in Ethiopia is poorer among less privileged women. Dietary intake of retinol equivalents in West African countries being adequate, reported serum levels in these countries are also generally adequate. Xerophthalmia among young children in Machakos is rare, with the possible explanation that seasonal intake of carotene-rich foods is enough to replenish liver stores, and protein status (RBP and PA serum levels) is adequate as well."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I588,I588)","v":3916690},{"$f":"(LEN($J588) - LEN(SUBSTITUTE(LOWER($J588),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J588) - LEN(SUBSTITUTE(LOWER($J588),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J588) - LEN(SUBSTITUTE(LOWER($J588),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B588:D588)","v":2},1985,"Retinoids and retinoid-binding proteins.","Goodman",3916690,"Retinoids and retinoid-binding proteins.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I589,I589)","v":3916046},{"$f":"(LEN($J589) - LEN(SUBSTITUTE(LOWER($J589),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J589) - LEN(SUBSTITUTE(LOWER($J589),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J589) - LEN(SUBSTITUTE(LOWER($J589),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B589:D589)","v":2},1985,"The biochemical and physiological role of vitamins A and E and their interactions.","Hanck",3916046,"The biochemical and physiological role of vitamins A and E and their interactions.    Abstract:   The therapeutic applications of vitamin A and vitamin E are reviewed, with special references to their role in the retinal functions, epithelial differentiation and maintainance, deficiency due to liver diseases and malabsorption, antioxidant activity, membrane protection, and antiatherogenic function. The interference between the two vitamins and their synergism is discussed on the basis of the protective role of tocopherol on retinol. From experimental studies on chicken, a mathematical model linking the optimal plasma value of the two vitamins is obtained."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I590,I590)","v":2432054},{"$f":"(LEN($J590) - LEN(SUBSTITUTE(LOWER($J590),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J590) - LEN(SUBSTITUTE(LOWER($J590),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J590) - LEN(SUBSTITUTE(LOWER($J590),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B590:D590)","v":2},1985,"The role of nutrients in cancer causation.","Newberne",2432054,"The role of nutrients in cancer causation.    Abstract:   The role of nutrients in cancer causation has been a subject of considerable interest, research, and public discussion in recent years. Results from epidemiologic, clinical, and animal studies have suggested that: 1) a reduction in total calories decreases risk for a number of tumor types; 2) dietary protein is directly correlated with liver, prostate, and colon cancer, among others, with increasing dietary protein increasing the risk; 3) increased dietary fat is correlated with increased risk for breast cancer; the evidence for an effect of fat on colon cancer is equivocal in human and animal studies; 4) a deficiency of vitamin A may enhance lung and colon tumors in animal experiments but in human this is equivocal. Increasing vitamin A above normal levels, as an anticarcinogenic effect, has not been satisfactorily demonstrated in animal models. The synthetic retinoid, 13-cis retinoic acid, inhibits both colon and lung cancer in animal models; 5) zinc deficiency is associated with enhanced esophageal cancer in humans and markedly enhances animal tumors; selenium inhibits this form of neoplasia in animals, 6) diets low in lipotropes enhance liver cancer induced by a variety of hepatocarcinogens. Our data from studies in animal models agree in some cases with epidemiological observations, but disagree with others, particularly fat and colon cancer. Overall, some forms of cancer are enhanced by excessive calories, increased dietary protein and fat, and by deficiencies of vitamin A, selenium, zinc, and lipotropes. Decreasing total intake of calories, protein, and fat, and ensuring adequate dietary levels of vitamin A, selenium, zinc, and lipotropes decreases risk for some forms of cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I591,I591)","v":7010520},{"$f":"(LEN($J591) - LEN(SUBSTITUTE(LOWER($J591),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J591) - LEN(SUBSTITUTE(LOWER($J591),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J591) - LEN(SUBSTITUTE(LOWER($J591),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B591:D591)","v":2},1980,"The retinol-binding protein.","Rask",7010520,"The retinol-binding protein.    Abstract:   Vitamin A is transported from its storage site in the liver to the epithelial tissues by a carrier protein, the Retinol-binding protein (RBP). In plasma RBP forms a complex with thyroxine-binding prealbumin. The present article reviews available data on the RBP system. The complete primary structure of RBP has been determined. The plasma concentration of RBP is regulated by the vitamin A status so that in vitamin A deficiency RBP molecules are not secreted from the liver. RBP molecules interact with a cell membrane receptor, probably a protein component present on epithelial cells. Vitamin A is thereby delivered to the cells. The uptake of vitamin A by the cells causes a reduction of the affinity of RBP for prealbumin. The RBP molecules which no longer are able to interact efficiently with prealbumin are excreted through the kidney glomerulus and degraded."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I592,I592)","v":145940},{"$f":"(LEN($J592) - LEN(SUBSTITUTE(LOWER($J592),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J592) - LEN(SUBSTITUTE(LOWER($J592),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J592) - LEN(SUBSTITUTE(LOWER($J592),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B592:D592)","v":2},1977,"Vitamin A acid: a review of its pharmacological properties and therapeutic use in the topical treatment of acne vulgaris.","Heel",145940,"Vitamin A acid: a review of its pharmacological properties and therapeutic use in the topical treatment of acne vulgaris.    Abstract:   Vitamin A acid (retinoic acid: tretinoin) is a vitamin A derivative used in the topical treatment of acne. It acts by unseating comedones, improvement developing slowly over a period of 2 to 3 or more months, and is also said to prevent the formation of new lesions. About three-quarters of patients with acne vulgaris benefit from treatment. In controlled studies, results achieved after a 3 to 4 months course of treatment were superior to those with sulphur-resorcinol-salicylic acid. When compared with benzoyl peroxide, results were variable and appear to depend on the length of treatment, the types of formulations used, and the concentrations compared. Application of vitamin A acid should be continued until the patient has been free of new lesions for several months. Further continued application at a less frequent interval or using a less active dosage form may help to prevent exacerbations of acne. A systemic antibacterial agent such as tetracycline can be given as well as in patients with moderate to severe lesions. Vitamin A acid is used in conjunction with gentle washing (to remove surface oil) but should be applied to a dry skin to avoid unnecessary irritation. Patient education and encouragement are crucial during the initial phase of treatment when microcomedones may be converted to pustules prior to desquamation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I593,I593)","v":327356},{"$f":"(LEN($J593) - LEN(SUBSTITUTE(LOWER($J593),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J593) - LEN(SUBSTITUTE(LOWER($J593),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J593) - LEN(SUBSTITUTE(LOWER($J593),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B593:D593)","v":2},1977,"Cellular retinol and retinoic acid binding proteins.","Cohen",327356,"Cellular retinol and retinoic acid binding proteins.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I594,I594)","v":1213862},{"$f":"(LEN($J594) - LEN(SUBSTITUTE(LOWER($J594),LOWER(B$3),\"\")))/LEN(B$3)","v":2},{"$f":"(LEN($J594) - LEN(SUBSTITUTE(LOWER($J594),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J594) - LEN(SUBSTITUTE(LOWER($J594),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B594:D594)","v":2},1975,"New aspects of the tolerance of retinol in humans.","Körner",1213862,"New aspects of the tolerance of retinol in humans.    Abstract:   A review is given of the evaluation of 517 cases of acute vitamin A intoxication and chronic hypervitaminosis A. Whereas acute vitamin A intoxication has lost numerical importance during the past 15 years, chronic hypervitaminosis-A, especially that caused by self-medication, has provoked world-wide discussion concerning the safety of retinol intake. Evaluation of the 132 cases of chronic hypervitaminosis-A showed that approximately one quarter cannot be considered as genuine cases, whereas the rest is divided almost equally between vitamin A prescription and self-medication. A significant positive correlation could be shown between the dose administered and the duration of treatment. Moreover, with comparable doses the symptoms of chronic hypervitaminosis-A appear significantly earlier (by a factor of 6) after emulsified or equivalent preparations than after oily emulsions because of their better absorbability. As soon as the liver vitamin A storage capacity is exhausted, hypervitaminosis-A symptoms appear and the liver vitamin A concentration is at least 10-fold the normal. The calculated vitamin A concentration in the liver of the individual cases of hypervitaminosis-A is highly correlated with the daily intake of vitamin A per kg of body-weight and its duration."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I595,I595)","v":27757507},{"$f":"(LEN($J595) - LEN(SUBSTITUTE(LOWER($J595),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J595) - LEN(SUBSTITUTE(LOWER($J595),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J595) - LEN(SUBSTITUTE(LOWER($J595),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B595:D595)","v":1},2016,"The obesity-related pathology and Th17 cells.","Endo",27757507,"The obesity-related pathology and Th17 cells.    Abstract:    NlmCategory=UNASSIGNEDChronic inflammation associated with obesity plays a major role in the development of metabolic diseases, cancer, and autoimmune diseases. Among Th subsets, Th17 cells are involved in the pathogenesis of autoimmune disorders such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Accumulating data suggest that reciprocal interactions between the metabolic systems and immune system play pivotal roles in the pathogenesis of obesity-associated diseases. We herein outline the developing principles in the control of T cell differentiation and function via their cellular metabolism. Also discussed are recent findings that changes in the intracellular metabolism, including fatty acid metabolism, affect the Th17 cell function in obese individuals. Finally, we will also highlight the unique molecular mechanism involved in the activation of retinoid-related orphan receptor-gamma-t (RORγt) by intracellular metabolism and discuss a new therapeutic approach for treating autoimmune disorders through the inhibition of RORγt."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I596,I596)","v":27749919},{"$f":"(LEN($J596) - LEN(SUBSTITUTE(LOWER($J596),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J596) - LEN(SUBSTITUTE(LOWER($J596),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J596) - LEN(SUBSTITUTE(LOWER($J596),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B596:D596)","v":1},2016,"Effects of Ready-to-Eat-Cereals on Key Nutritional and Health Outcomes: A Systematic Review.","Priebe",27749919,"Effects of Ready-to-Eat-Cereals on Key Nutritional and Health Outcomes: A Systematic Review.    Abstract:    BACKGROUND : In many countries breakfast cereals are an important component of breakfast. This systematic review assesses the contribution of consumption of ready-to eat cereal (RTEC) to the recommended nutrient intake. Furthermore, the effects of RTEC consumption on key health parameters are investigated as well as health promoting properties of RTEC.  METHOD : The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and CINAHL have been searched up till 16th of June 2015. Randomized controlled trials were excluded if RTEC were used during hypocaloric diets, if RTEC were eaten at other times than breakfast and if breakfasts included other products than RTEC, milk and fruit. Observational studies were excluded when quot;breakfast cerealsquot; were not defined or their definition included cooked cereals. From cross-sectional studies only data concerning energy and nutrient intake as well as micronutrient status were used.  RESULTS : From 4727 identified citations 64 publications met the inclusion criteria of which 32 were cross-sectional studies, eight prospective studies and 24 randomized controlled trials. Consumption of RTEC is associated with a healthier dietary pattern, concerning intake of carbohydrates, dietary fiber, fat and micronutrients, however total sugar intake is higher. Persons consuming RTEC frequently (≥ 5 times/week) have a lower risk of inadequate micronutrient intake especially for vitamin A, calcium, folate, vitamin B 6, magnesium and zinc. Evidence from prospective studies suggests that whole grain RTEC may have beneficial effects on hypertension and type 2 diabetes. Consumption of RTEC with soluble fiber helps to reduce LDL cholesterol in hypercholesterolemic men and RTEC fortified with folate can reduce plasma homocysteine.  DISCUSSION : One of the reviews strengths is its thorough ex/inclusion of studies. Limitations are that results of observational studies were based on self-reported data and that many studies were funded by food-industry.  CONCLUSION : Consumption of RTEC, especially of fiber-rich or whole grain RTEC, is implicated with several beneficial nutritional and health outcomes. The effect on body weight, intestinal health and cognitive function needs further evaluation. Of concern is the higher total sugar intake associated with frequent RTEC consumption."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I597,I597)","v":27681502},{"$f":"(LEN($J597) - LEN(SUBSTITUTE(LOWER($J597),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J597) - LEN(SUBSTITUTE(LOWER($J597),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J597) - LEN(SUBSTITUTE(LOWER($J597),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B597:D597)","v":1},2016,"Deficiency of fat-soluble vitamins in chronic pancreatitis: A systematic review and meta-analysis.","Martínez-Moneo",27681502,"Deficiency of fat-soluble vitamins in chronic pancreatitis: A systematic review and meta-analysis.    Abstract:    BACKGROUND AND AIMS : Chronic pancreatitis (CP) patients are at risk for fat-soluble vitamins (A, D, E, K) deficiency, but available studies are small and heterogeneous. We conducted a systematic review and meta-analysis to determine the prevalence of fat-soluble vitamins deficiency in CP patients.  METHODS : Medline was searched up to January 2016 for case series and case-control studies reporting prevalence of fat-soluble vitamin deficiency in CP patients. The prevalent deficiency rate was pooled for included studies, and deficiency rate between CP and controls, with relative odds ratio (OR) and 95% confidence interval (CI) calculated for case-control studies.  RESULTS : Twelve studies including 548 patients included. With a random-effect model, the pooled prevalence rate of vitamin A, D and E deficiency were 16.8% (95%CI 6.9-35.7), 57.6% (95%CI 43.9-70.4) and 29.2% (95%CI 8.6-64.5) respectively, with considerable heterogeneity (I(2) = 75%, 87.1% and 92%). Only one study evaluated vitamin K deficiency. The pooled OR for vitamin D deficiency in CP cases compared with controls was 1.17 (95% CI 0.77-1.78). Sensitivity analyses showed lower prevalence of vitamin A and E, and higher prevalence of vitamin D deficiency in high-quality studies. The rate of pancreatic exocrine insufficiency did not seem affect the deficiency rates, while the use of different cut-offs influences results and heterogeneity for vitamin E, but not A.  CONCLUSIONS : Fat-soluble vitamins deficiency is frequent in CP patients, with considerable heterogeneity. There is, however, no apparent increased risk of vitamin D deficiency in CP compared to controls. Larger, high-quality studies are necessary to better estimate the prevalence of fat-soluble vitamins deficiency, including vitamin K."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I598,I598)","v":27544210},{"$f":"(LEN($J598) - LEN(SUBSTITUTE(LOWER($J598),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J598) - LEN(SUBSTITUTE(LOWER($J598),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J598) - LEN(SUBSTITUTE(LOWER($J598),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B598:D598)","v":1},2016,"Nuclear receptor function in skin health and disease: therapeutic opportunities in the orphan and adopted receptor classes.","Yin",27544210,"Nuclear receptor function in skin health and disease: therapeutic opportunities in the orphan and adopted receptor classes.    Abstract:   The skin forms a vital barrier between an organisms external environment, providing protection from pathogens and numerous physical and chemical threats. Moreover, the intact barrier is essential to prevent water and electrolyte loss without which terrestrial life could not be maintained. Accordingly, acute disruption of the skin through physical or chemical trauma needs to be repaired timely and efficiently as sustained skin pathologies ranging from mild irritations and inflammation through to malignancy impact considerably on morbidity and mortality. The Nuclear Hormone Receptor Family of transcriptional regulators has proven to be highly valuable targets for addressing a range of pathologies, including metabolic syndrome and cancer. Indeed members of the classic endocrine sub-group, such as the glucocorticoid, retinoid, and Vitamin D receptors, represent mainstay treatment strategies for numerous inflammatory skin disorders, though side effects from prolonged use are common. Emerging evidence has now highlighted important functional roles for nuclear receptors belonging to the adopted and orphan subgroups in skin physiology and patho-physiology. This review will focus on these subgroups and explore the current evidence that suggests these nuclear receptor hold great promise as future stand-alone or complementary drug targets in treating common skin diseases and maintaining skin homeostasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I599,I599)","v":27439768},{"$f":"(LEN($J599) - LEN(SUBSTITUTE(LOWER($J599),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J599) - LEN(SUBSTITUTE(LOWER($J599),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J599) - LEN(SUBSTITUTE(LOWER($J599),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B599:D599)","v":1},2016,"Is the Association between Vitamin D and Metabolic Syndrome Independent of Other Micronutrients.","Khosravi-Boroujeni",27439768,"Is the Association between Vitamin D and Metabolic Syndrome Independent of Other Micronutrients.    Abstract:    NlmCategory=UNASSIGNEDThe incidence of metabolic syndrome (MetS) has been increasing globally and it is recognized as a major public health problem because MetS is associated with increased risk of diabetes, stroke, cancer, and other chronic diseases. Recently, MetS has been linked to vitamin D deficiency. However, the evidence on the association between vitamin D deficiency and the risk of MetS remains inconclusive. This review therefore aims to depict the existing evidence related to MetS and vitamin D deficiency, and examined some of the possible confounders which may affect the association between vitamin D status and risk of MetS. Earlier studies on the association between vitamin D deficiency and MetS have adjusted for the effect of some confounders including, age, sex, body mass index, race, physical activity, smoking, alcohol consumption, and energy intake. However, these studies failed to consider other potential confounders. There is evidence that vitamin A, zinc (Zn), and magnesium (Mg) play important roles in the activation and function of vitamin D and interact with gene expression. Furthermore, these micronutrients are also related to several components of the MetS including glucose intolerance, dyslipidemia, and obesity. Thus, there could be an interaction between these micronutrients, vitamin D, and MetS. This review highlights the possible interactions of vitamin A, Zn, Mg, and vitamin D with MetS and its components. The findings reinforce the need for further well-designed studies that take into account all potential confounders, including other micronutrients such as vitamin A, Zn, and Mg status, to investigate the independent association of vitamin D status with MetS and its components, and also to scrutinize for possible interactions among other nutrients which may have similar confounding effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I600,I600)","v":27320331},{"$f":"(LEN($J600) - LEN(SUBSTITUTE(LOWER($J600),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J600) - LEN(SUBSTITUTE(LOWER($J600),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J600) - LEN(SUBSTITUTE(LOWER($J600),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B600:D600)","v":1},2016,"Recent progress in the design and discovery of RXR modulators targeting alternate binding sites of the receptor.","Su",27320331,"Recent progress in the design and discovery of RXR modulators targeting alternate binding sites of the receptor.    Abstract:    NlmCategory=UNASSIGNEDRetinoid X receptors (RXRs) occupy a central position within the nuclear receptor superfamily. They not only function as important transcriptional factors but also exhibit diverse nongenomic biological activities. The pleiotropic actions of RXRs under both physiological and pathophysiological conditions confer RXRs important drug targets for the treatment of cancer, and metabolic and neurodegenerative diseases. RXR modulators have been studied for the purpose of developing both drug molecules and chemical tools for biological investigation of RXR. Development of RXR modulators has focused on small molecules targeting the canonical ligand-binding pocket. However, accumulating results have demonstrated that there are other binding mechanisms by which small molecules interact with RXR to act as RXR modulators. This review discusses the recent development in the design and discovery of RXR modulators with a focus on those targeting novel binding sites on RXR."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I601,I601)","v":27200367},{"$f":"(LEN($J601) - LEN(SUBSTITUTE(LOWER($J601),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J601) - LEN(SUBSTITUTE(LOWER($J601),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J601) - LEN(SUBSTITUTE(LOWER($J601),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B601:D601)","v":1},2015,"Pan-cancer analyses of the nuclear receptor superfamily.","Long",27200367,"Pan-cancer analyses of the nuclear receptor superfamily.    Abstract:    NlmCategory=UNASSIGNEDNuclear receptors (NR) act as an integrated conduit for environmental and hormonal signals to govern genomic responses, which relate to cell fate decisions. We review how their integrated actions with each other, shared co-factors and other transcription factors are disrupted in cancer. Steroid hormone nuclear receptors are oncogenic drivers in breast and prostate cancer and blockade of signaling is a major therapeutic goal. By contrast to blockade of receptors, in other cancers enhanced receptor function is attractive, as illustrated initially with targeting of retinoic acid receptors in leukemia. In the post-genomic era large consortia, such as The Cancer Genome Atlas, have developed a remarkable volume of genomic data with which to examine multiple aspects of nuclear receptor status in a pan-cancer manner. Therefore to extend the review of NR function we have also undertaken bioinformatics analyses of NR expression in over 3000 tumors, spread across six different tumor types (bladder, breast, colon, head and neck, liver and prostate). Specifically, to ask how the NR expression was distorted (altered expression, mutation and CNV) we have applied bootstrapping approaches to simulate data for comparison, and also compared these NR findings to 12 other transcription factor families. Nuclear receptors were uniquely and uniformly downregulated across all six tumor types, more than predicted by chance. These approaches also revealed that each tumor type had a specific NR expression profile but these were most similar between breast and prostate cancer. Some NRs were down-regulated in at least five tumor types (e.g. NR3C2/MR and NR5A2/LRH-1)) whereas others were uniquely down-regulated in one tumor (e.g. NR1B3/RARG). The downregulation was not driven by copy number variation or mutation and epigenetic mechanisms maybe responsible for the altered nuclear receptor expression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I602,I602)","v":26819504},{"$f":"(LEN($J602) - LEN(SUBSTITUTE(LOWER($J602),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J602) - LEN(SUBSTITUTE(LOWER($J602),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J602) - LEN(SUBSTITUTE(LOWER($J602),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B602:D602)","v":1},2016,"Hepatic non-parenchymal cells: Master regulators of alcoholic liver disease?","Seo",26819504,"Hepatic non-parenchymal cells: Master regulators of alcoholic liver disease?    Abstract:   Chronic alcohol consumption is one of the most common causes of the progression of alcoholic liver disease (ALD). In the past, alcohol-mediated hepatocyte injury was assumed to be a significantly major cause of ALD. However, a huge number of recent and brilliant studies have demonstrated that hepatic non-parenchymal cells including Kupffer cells, hepatic stellate cells, liver sinusoidal endothelial cells and diverse types of lymphocytes play crucial roles in the pathogenesis of ALD by producing inflammatory mediators such as cytokines, oxidative stress, microRNA, and lipid-originated metabolites (retinoic acid and endocannabinoids) or by directly interacting with parenchymal cells (hepatocytes). Therefore, understanding the comprehensive roles of hepatic non-parenchymal cells during the development of ALD will provide new integrative directions for the treatment of ALD. This review will address the roles of non-parenchymal cells in alcoholic steatosis, inflammation, and liver fibrosis and might help us to discover possible therapeutic targets and treatments involving modulating the non-parenchymal cells in ALD."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I603,I603)","v":26755885},{"$f":"(LEN($J603) - LEN(SUBSTITUTE(LOWER($J603),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J603) - LEN(SUBSTITUTE(LOWER($J603),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J603) - LEN(SUBSTITUTE(LOWER($J603),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B603:D603)","v":1},2016,"Chemoprevention of obesity-related liver carcinogenesis by using pharmaceutical and nutraceutical agents.","Sakai",26755885,"Chemoprevention of obesity-related liver carcinogenesis by using pharmaceutical and nutraceutical agents.    Abstract:   Obesity and its related metabolic disorders are serious health problems worldwide, and lead to various health-related complications, including cancer. Among human cancers, hepatocellular carcinoma (HCC) is one of the most common malignancies affected by obesity. Therefore, obesity and its related disorders might be a key target for the prevention of HCC. Recently, new research indicates that the molecular abnormalities associated with obesity, including insulin resistance/hyperinsulinemia, chronic inflammation, adipokine imbalance, and oxidative stress, are possible molecular mechanisms underlying the pathogenesis of obesity-related hepatocarcinogenesis. Green tea catechins and branched-chain amino acids, both of which are classified as nutraceutical agents, have been reported to prevent obesity-related HCC development by improving metabolic abnormalities. The administration of acyclic retinoid, a pharmaceutical agent, reduced the incidence of HCC in obese and diabetic mice, and was also associated with improvements in insulin resistance and chronic inflammation. In this article, we review the detailed molecular mechanisms that link obesity to the development of HCC in obese individuals. We also summarize recent evidence from experimental and clinical studies using either nutraceutical or pharmaceutical agents, and suggest that nutraceutical and pharmaceutical approaches targeting metabolic abnormalities might be a promising strategy to prevent the development of obesity-related HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I604,I604)","v":26688184},{"$f":"(LEN($J604) - LEN(SUBSTITUTE(LOWER($J604),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J604) - LEN(SUBSTITUTE(LOWER($J604),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J604) - LEN(SUBSTITUTE(LOWER($J604),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B604:D604)","v":1},2016,"[Thyroid and lipidic dysfunction associated with bexarotene in cutaneous T-cell lymphoma].","Rodriguez Suarez",26688184,"[Thyroid and lipidic dysfunction associated with bexarotene in cutaneous T-cell lymphoma].    Abstract:    BACKGROUND AND OBJECTIVE : Bexarotene is a synthetic selective X receptor rexinoide approved for the systemic treatment of cutaneous T-cell lymphoma. During treatment is very frequent the occurrence of hypothyroidism and severe mixed hyperlipidemia, both are reversibles and dose-dependent adverse events. Increase of triglycerides and LDL-cholesterol level (up to even higher levels have been associated with pancreatitis in some cases) is widely described (as is the case with other retinoids) but decrease in HDL-cholesterol is poored know. We review our experience with the use of bexarotene.  MATERIAL AND METHODS : We present a serie of 3 clinical report of patients treated with bexarotene in whose, in addition to these well-known adverse event, a serious lowering of HDL-cholesterol was observed.  RESULTS : The 3 patients studied had metabolic complications like central hypothyroidism and severe mixed hyperlipidemia; with special emphasis on the sharp fall (mean decreasegt;83%) in the HDL-cholesterol level. Cholesterol lowering medication and substitutive hormonal replacement with levotiroxine resulted in an improvement of the biochimical parameters without reaching the correct goals.  CONCLUSIONS : Bexarotene produce as predictable side effects severe mixed hyperlipidemia with marked decrease in HDL-cholesterol levels and central hypothyroidism, being the both reversible and dose-dependent. A reflection on the possible aetiological mechanisms and implications of this phenomenon are included."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I605,I605)","v":26687281},{"$f":"(LEN($J605) - LEN(SUBSTITUTE(LOWER($J605),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J605) - LEN(SUBSTITUTE(LOWER($J605),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J605) - LEN(SUBSTITUTE(LOWER($J605),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B605:D605)","v":1},2016,"Current standard treatment of adult acute promyelocytic leukaemia.","Lo-Coco",26687281,"Current standard treatment of adult acute promyelocytic leukaemia.    Abstract:   The outcome of patients with acute promyelocytic leukaemia (APL) has dramatically improved over the last two decades, due to the introduction of combined all-trans retinoic acid (ATRA) and chemotherapy regimens and, more recently, to the advent of arsenic trioxide (ATO). ATRA and anthracycline-based chemotherapy remains a widely used strategy, providing cure rates above 80%, but it is associated with risk of severe infections and occurrence of secondary leukaemias. ATO is the most effective single agent in APL and, used alone or in combination with ATRA or ATRA and reduced-intensity chemotherapy, results in greater efficacy with considerably less haematological toxicity. The toxic profile of ATO includes frequent, but manageable, QTc prolongation and increase of liver enzymes. Two large randomized studies have shown that ATRA + ATO is superior to ATRA + chemotherapy for newly diagnosed low-risk APL resulting in 2-4 year event-free survival rates above 90% and very few relapses. According to real world data, the spectacular progress in APL outcomes reported in clinical trials has not been paralleled by a significant improvement in early death rates, this remains the most challenging issue for the final cure of the disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I606,I606)","v":26673411},{"$f":"(LEN($J606) - LEN(SUBSTITUTE(LOWER($J606),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J606) - LEN(SUBSTITUTE(LOWER($J606),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J606) - LEN(SUBSTITUTE(LOWER($J606),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B606:D606)","v":1},2016,"Role of co-regulators in metabolic and transcriptional actions of thyroid hormone.","Astapova",26673411,"Role of co-regulators in metabolic and transcriptional actions of thyroid hormone.    Abstract:   Thyroid hormone (TH) controls a wide range of physiological processes through TH receptor (TR) isoforms. Classically, TRs are proposed to function as tri-iodothyronine (T3)-dependent transcription factors: on positively regulated target genes, unliganded TRs mediate transcriptional repression through recruitment of co-repressor complexes, while T3 binding leads to dismissal of co-repressors and recruitment of co-activators to activate transcription. Co-repressors and co-activators were proposed to play opposite roles in the regulation of negative T3 target genes and hypothalamic-pituitary-thyroid axis, but exact mechanisms of the negative regulation by TH have remained elusive. Important insights into the roles of co-repressors and co-activators in different physiological processes have been obtained using animal models with disrupted co-regulator function. At the same time, recent studies interrogating genome-wide TR binding have generated compelling new data regarding effects of T3, local chromatin structure, and specific response element configuration on TR recruitment and function leading to the proposal of new models of transcriptional regulation by TRs. This review discusses data obtained in various mouse models with manipulated function of nuclear receptor co-repressor (NCoR or NCOR1) and silencing mediator of retinoic acid receptor and thyroid hormone receptor (SMRT or NCOR2), and family of steroid receptor co-activators (SRCs also known as NCOAs) in the context of TH action, as well as insights into the function of co-regulators that may emerge from the genome-wide TR recruitment analysis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I607,I607)","v":26610729},{"$f":"(LEN($J607) - LEN(SUBSTITUTE(LOWER($J607),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J607) - LEN(SUBSTITUTE(LOWER($J607),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J607) - LEN(SUBSTITUTE(LOWER($J607),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B607:D607)","v":1},2016,"Dietary regulation of adiponectin by direct and indirect lipid activators of nuclear hormone receptors.","Rühl",26610729,"Dietary regulation of adiponectin by direct and indirect lipid activators of nuclear hormone receptors.    Abstract:   Adiponectin is an adipokine mainly secreted by adipocytes that presents antidiabetic, anti-inflammatory, and antiatherogenic functions. Therefore, modulation of adiponectin expression represents a promising target for prevention or treatment of several diseases including insulin resistance and type II diabetes. Pharmacological agents such as the nuclear hormone receptor synthetic agonists like peroxisome proliferator activated receptor γ agonists are of particular interest in therapeutic strategies due to their ability to increase the plasma adiponectin concentration. Nutritional approaches are also of particular interest, especially in primary prevention, since some active compounds of our diet (notably vitamins, carotenoids, or other essential nutrients) are direct or indirect lipid-activators of nuclear hormone receptors and are modifiers of adiponectin expression and secretion. The aim of the present review is to summarize current knowledge about the nutritional regulation of adiponectin by derivatives of active compounds naturally present in the diet acting as indirect or direct activators of nuclear hormone receptors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I608,I608)","v":26596315},{"$f":"(LEN($J608) - LEN(SUBSTITUTE(LOWER($J608),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J608) - LEN(SUBSTITUTE(LOWER($J608),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J608) - LEN(SUBSTITUTE(LOWER($J608),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B608:D608)","v":1},2016,"Hypercalcemia. Pathophysiological aspects.","Žofková",26596315,"Hypercalcemia. Pathophysiological aspects.    Abstract:   The metabolic pathways that contribute to maintain serum calcium concentration in narrow physiological range include the bone remodeling process, intestinal absorption and renal tubule resorption. Dysbalance in these regulations may lead to hyper- or hypocalcemia. Hypercalcemia is a potentionally life-threatening and relatively common clinical problem, which is mostly associated with hyperparathyroidism and/or malignant diseases (90 %). Scarce causes of hypercalcemia involve renal failure, kidney transplantation, endocrinopathies, granulomatous diseases, and the long-term treatment with some pharmaceuticals (vitamin D, retinoic acid, lithium). Genetic causes of hypercalcemia involve familial hypocalciuric hypercalcemia associated with an inactivation mutation in the calcium sensing receptor gene and/or a mutation in the CYP24A1 gene. Furthermore, hypercalcemia accompanying primary hyperparathyroidism, which develops as part of multiple endocrine neoplasia (MEN1 and MEN2), is also genetically determined. In this review mechanisms of hypercalcemia are discussed. The objective of this article is a review of hypercalcemia obtained from a Medline bibliographic search."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I609,I609)","v":26579442},{"$f":"(LEN($J609) - LEN(SUBSTITUTE(LOWER($J609),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J609) - LEN(SUBSTITUTE(LOWER($J609),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J609) - LEN(SUBSTITUTE(LOWER($J609),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B609:D609)","v":1},2015,"Role of farnesoid X receptor and bile acids in alcoholic liver disease.","Manley",26579442,"Role of farnesoid X receptor and bile acids in alcoholic liver disease.    Abstract:   Alcoholic liver disease (ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a) and PPARα (peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I610,I610)","v":26579436},{"$f":"(LEN($J610) - LEN(SUBSTITUTE(LOWER($J610),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J610) - LEN(SUBSTITUTE(LOWER($J610),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J610) - LEN(SUBSTITUTE(LOWER($J610),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B610:D610)","v":1},2015,"Circadian rhythms in liver metabolism and disease.","Ferrell",26579436,"Circadian rhythms in liver metabolism and disease.    Abstract:   Mounting research evidence demonstrates a significant negative impact of circadian disruption on human health. Shift work, chronic jet lag and sleep disturbances are associated with increased incidence of metabolic syndrome, and consequently result in obesity, type 2 diabetes and dyslipidemia. Here, these associations are reviewed with respect to liver metabolism and disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I611,I611)","v":26576089},{"$f":"(LEN($J611) - LEN(SUBSTITUTE(LOWER($J611),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J611) - LEN(SUBSTITUTE(LOWER($J611),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J611) - LEN(SUBSTITUTE(LOWER($J611),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B611:D611)","v":1},2015,"Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma.","Varshosaz",26576089,"Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma.    Abstract:   Hepatocellular carcinoma (HCC) is the 5(th) most common malignancy which is responsible for more than half million annual mortalities; also, it is the third leading cause of cancer related death. Unfavorable systemic side-effects of chemotherapeutic agents and susceptibility to the degradation of small interfering RNAs (siRNAs), which can knock down a specific gene involved in the disease, have hampered their clinical application. So, it could be beneficial to develop an efficient carrier for the stabilization and specific delivery of drugs and siRNA to cells. Targeted nanoparticles have gained considerable attention as an efficient drug and gene delivery system, which is due to their capability in achieving the highest accumulation of cytotoxic agents in tumor tissue, modifiable drug pharmacokinetic- and bio-distribution, improved effectiveness of treatment, and limited side-effects. Recent studies have shed more light on the advantages of novel drug loaded carrier systems vs free drugs. Most of the animal studies have reported improvement in treatment efficacy and survival rate using novel carrier systems. Targeted delivery may be achieved passively or actively. In passive targeting, no ligand as homing device is used, while targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. However, in active targeting, the therapeutic agent or carrier system is conjugated to a tissue or cell-specific receptor which is over-expressed in a special malignancy using a ligand called a homing device. This review covers a broad spectrum of targeted nanoparticles as therapeutic and non-viral siRNA delivery systems, which are developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and their characteristics and opportunities for the clinical applications of drugs and therapeutic siRNA are discussed in this article. Asialoglycoprotein receptors, low-density lipoprotein, ganglioside GM1 cell surface ligand, epidermal growth factor receptor receptors, monoclonal antibodies, retinoic acid receptors, integrin receptors targeted by Arg-Gly-Asp peptide, folate, and transferrin receptors are the most widely studied cell surface receptors which are used for the site specific delivery of drugs and siRNA-based therapeutics in HCC and discussed in detail in this article."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I612,I612)","v":26469117},{"$f":"(LEN($J612) - LEN(SUBSTITUTE(LOWER($J612),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J612) - LEN(SUBSTITUTE(LOWER($J612),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J612) - LEN(SUBSTITUTE(LOWER($J612),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B612:D612)","v":1},2015,"Brdt Bromodomains Inhibitors and Other Modern Means of Male Contraception.","Zdrojewicz",26469117,"Brdt Bromodomains Inhibitors and Other Modern Means of Male Contraception.    Abstract:   Compared to efficient and secure female contraception, a vasectomy and condoms are the only options for men. The choice of male contraceptive methods is limited, so contraception mainly rests on the shoulders of women. Several concepts are considered: testosterone administration--inhibiting pituitary secretion of lutropin (LH) and follicle stimulating hormone (FSH), progestogen--affecting the secretion of gonadotropin and gonadoliberin (GnRH) antagonists. New potential targets for non-hormonal male contraception were discovered: glyceraldehyde-3-phosphate-dehydrogenase (GAPDHS)--specific to male germ cells and voltage-gated cation channel (CatSper). Both are responsible for sperm motility. Drugs such as thioridazine used in schizophrenia treatment and phenoxybenzamine (antihypertensive activity) exhibit a contraceptive effect. Similar action exhibits an analogue of lonidamine--adjudin and an antagonist of retinoic acid receptors (BMS-189453). Researchers are working on a contraceptive vaccine, whose active ingredient is epididymal protease inhibitor (Eppin). Another promising method acts by blocking Bromodomain testis-specific proteins (Brdt) involved in the process of spermatogenesis. JQ1-the Brdt inhibitor causes reversible infertility without affecting the endocrine signaling pathways. A recent discovery of Juno as the binding partner for Izumo1 identifies these proteins as the cell-surface receptor pair, essential for gamete recognition and this interaction can be inhibited by an anti-Juno monoclonal antibody. Our review shows that the situation of men can change and investigators are close to the optimal solution. In the near future men will be able to choose the best contraceptive suited to their needs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I613,I613)","v":26419362},{"$f":"(LEN($J613) - LEN(SUBSTITUTE(LOWER($J613),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J613) - LEN(SUBSTITUTE(LOWER($J613),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J613) - LEN(SUBSTITUTE(LOWER($J613),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B613:D613)","v":1},2015,"Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms.","Ellis",26419362,"Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms.    Abstract:   Tylosis (hyperkeratosis palmaris et plantaris) is characterised by focal thickening of the skin of the hands and feet and is associated with a very high lifetime risk of developing squamous cell carcinoma of the oesophagus. This risk has been calculated to be 95% at the age of 65 in one large family, however the frequency of the disorder in the general population is not known and is likely to be less than one in 1,000,000. Oesophageal lesions appear as small (2-5 mm), white, polyploid lesions dotted throughout the oesophagus and oral leukokeratosis has also been described. Although symptoms of oesophageal cancer can include dysphagia, odynophagia, anorexia and weight loss, there may be an absence of symptoms in early disease, highlighting the importance of endoscopic surveillance in these patients. Oesophageal cancer associated with tylosis usually presents in middle to late life (from mid-fifties onwards) and shows no earlier development than the sporadic form of the disease. Tylosis with oesophageal cancer is inherited as an autosomal dominant trait with complete penetrance of the cutaneous features, usually by 7 to 8 years of age but can present as late as puberty. Mutations in RHBDF2 located on 17q25.1 have recently been found to be causative. A diagnosis of tylosis with oesophageal cancer is made on the basis of a positive family history, characteristic clinical features, including cutaneous and oesophageal lesions, and genetic analysis for mutations in RHBDF2. The key management goal is surveillance for early detection and treatment of oesophageal dysplasia. Surveillance includes annual gastroscopy with biopsy of any suspicious lesion together with quadratic biopsies from the upper, middle and lower oesophagus. This is coupled with dietary and lifestyle modification advice and symptom education. Symptomatic management of the palmoplantar keratoderma includes regular application of emollients, specialist footwear and early treatment of fissures and super-added infection, particularly tinea pedis. More specific treatment for the thick skin is available in the form of oral retinoids, which are very effective but commonly produce side effects, including nasal excoriation and bleeding, hypercholesterolaemia, and abnormal liver function tests. Genetic counselling can be offered to patients and family members once a family history has been established. The prognosis of tylosis with oesophageal cancer is difficult to determine due to the limited number of affected individuals. In the last 40 years of surveillance, five out of six cases of squamous oesophageal cancer in the Liverpool family were detected endoscopically and were surgically removed. Four of five patients had stage 1 disease at presentation and remain alive and well more than 8 years later. This suggests that the presence of a screening program improves prognosis for these patients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I614,I614)","v":26416507},{"$f":"(LEN($J614) - LEN(SUBSTITUTE(LOWER($J614),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J614) - LEN(SUBSTITUTE(LOWER($J614),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J614) - LEN(SUBSTITUTE(LOWER($J614),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B614:D614)","v":1},2015,"Mitochondrial regulation of macrophage cholesterol homeostasis.","Graham",26416507,"Mitochondrial regulation of macrophage cholesterol homeostasis.    Abstract:   This review explores the relationship between mitochondrial structure and function in the regulation of macrophage cholesterol metabolism and proposes that mitochondrial dysfunction contributes to loss of the elegant homeostatic mechanisms which normally maintain cellular sterol levels within defined limits. Mitochondrial sterol 27-hydroxylase (CYP27A1) can generate oxysterol activators of liver X receptors which heterodimerise with retinoid X receptors, enhancing the transcription of ATP binding cassette transporters (ABCA1, ABCG1, and ABCG4), that can remove excess cholesterol via efflux to apolipoproteins A-1, E, and high density lipoprotein, and inhibit inflammation. The activity of CYP27A1 is regulated by the rate of supply of cholesterol substrate to the inner mitochondrial membrane, mediated by a complex of proteins. The precise identity of this dynamic complex remains controversial, even in steroidogenic tissues, but may include steroidogenic acute regulatory protein and the 18 kDa translocator protein, together with voltage-dependent anion channels, ATPase AAA domain containing protein 3A, and optic atrophy type 1 proteins. Certainly, overexpression of StAR and TSPO proteins can enhance macrophage cholesterol efflux to apoA-I and/or HDL, while perturbations in mitochondrial function, or changes in the expression of mitochondrial fusion proteins, alter the efficiency of cholesterol efflux. Molecules which can sustain or improve mitochondrial function or increase the activity of the protein complex involved in cholesterol transfer may have utility in resolving the problem of dysregulated macrophage cholesterol homeostasis, a condition which may contribute to inflammation, atherosclerosis, nonalcoholic steatohepatitis, osteoblastic bone resorption, and some disorders of the central nervous system."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I615,I615)","v":26159903},{"$f":"(LEN($J615) - LEN(SUBSTITUTE(LOWER($J615),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J615) - LEN(SUBSTITUTE(LOWER($J615),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J615) - LEN(SUBSTITUTE(LOWER($J615),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B615:D615)","v":1},2016,"Dietary intake and nutritional status of micronutrients in adults with cystic fibrosis in relation to current recommendations.","Li",26159903,"Dietary intake and nutritional status of micronutrients in adults with cystic fibrosis in relation to current recommendations.    Abstract:   An increased prevalence of cystic fibrosis (CF) related complications such as impaired bone health and diabetes has accompanied increased survival of patients with CF. This review was conducted to determine the extent to which adults with CF are meeting current nutrition recommendations for micronutrients in association with CF-related complications management. Although dietary intake and nutritional status in CF has improved significantly in recent decades, micronutrient status seems to have diverged. While vitamin A and E intakes appear adequate, frequent vitamin D and K deficiency/insufficiency and compromised bone health in CF, occurs despite supplementation. Although deficiency of water-soluble vitamins and minerals is uncommon, ongoing surveillance will enhance overall health outcomes, particularly in cases of CF-related liver disease and deteriorated lung function and bone health. Salt and fluid status in CF may also need attention due to diminished thirst sensation and voluntary rehydration. Further investigation in micronutrient status optimisation in CF will inform the development of more effective and targeted nutrition therapies to enable integration of more refined recommendations for micronutrient intakes in CF based on individual needs and disease progression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I616,I616)","v":26143416},{"$f":"(LEN($J616) - LEN(SUBSTITUTE(LOWER($J616),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J616) - LEN(SUBSTITUTE(LOWER($J616),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J616) - LEN(SUBSTITUTE(LOWER($J616),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B616:D616)","v":1},2015,"Granuloma Annulare.","Keimig",26143416,"Granuloma Annulare.    Abstract:   Granuloma annulare (GA) is a noninfectious granulomatous skin condition that can present with a variety of cutaneous morphologies. It is characterized by collagen degeneration, mucin deposition, and palisaded or interstitial histiocytes. Although the mechanism underlying development of GA is unknown, studies point to a cell-mediated hypersensitivity reaction to an as-yet undetermined antigen. Systemic associations with diabetes, thyroid disorders, lipid abnormalities, malignancy, and infection are described in atypical GA. Treatment is divided into localized skin-directed therapies and systemic immunomodulatory or immunosuppressive therapies. The selected treatment modality should be based on disease severity, comorbid conditions, consideration of potential side effects, and patient preference."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I617,I617)","v":26015696},{"$f":"(LEN($J617) - LEN(SUBSTITUTE(LOWER($J617),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J617) - LEN(SUBSTITUTE(LOWER($J617),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J617) - LEN(SUBSTITUTE(LOWER($J617),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B617:D617)","v":1},2015,"Oral lichen planus: An overview.","Krupaa",26015696,"Oral lichen planus: An overview.    Abstract:   Lichen planus is an immunologically mediated mucocutaneous disease that is triggered by varied etiological agents. The oral lichenoid reaction is considered a variant of the disease that needs to be clearly diagnosed as a separate entity from oral lichen planus and treated. They follow a strict cause-effector relationship, protocols that suggest the differentiation. Lichen planus has varied clinical forms in the oral mucosa and cutaneously that has different prognosis. This condition also arises in association with various other systemic conditions such as hypertension, diabetes mellitus. There have been cases reported in the esophagus, larynx, scalp, nail, cutaneous areas, especially arms and wrists, trunk. There is reported malignant transformation that essentiates careful examination, treatment protocol and regular follow-up sessions. This article throws light on the disease condition of oral lichen planus and oral lichenoid reaction that is essential for the differentiation and treatment."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I618,I618)","v":25938935},{"$f":"(LEN($J618) - LEN(SUBSTITUTE(LOWER($J618),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J618) - LEN(SUBSTITUTE(LOWER($J618),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J618) - LEN(SUBSTITUTE(LOWER($J618),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B618:D618)","v":1},2015,"Circadian clock-coupled lung cellular and molecular functions in chronic airway diseases.","Sundar",25938935,"Circadian clock-coupled lung cellular and molecular functions in chronic airway diseases.    Abstract:   Airway diseases are associated with abnormal circadian rhythms of lung function, reflected in daily changes of airway caliber, airway resistance, respiratory symptoms, and abnormal immune-inflammatory responses. Circadian rhythms are generated at the cellular level by an autoregulatory feedback loop of interlocked transcription factors collectively referred to as clock genes. The molecular clock is altered by cigarette smoke, LPS, and bacterial and viral infections in mouse and human lungs and in patients with chronic airway diseases. Stress-mediated post-translational modification of molecular clock proteins, brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) and PERIOD 2, is associated with a reduction in the activity/level of the deacetylase sirtuin 1 (SIRT1). Similarly, the levels of the nuclear receptor REV-ERBα and retinoic acid receptor-related orphan receptor α (ROR α), critical regulators of Bmal1 expression, are altered by environmental stresses. Molecular clock dysfunction is implicated in immune and inflammatory responses, DNA damage response, and cellular senescence. The molecular clock in the lung also regulates the timing of glucocorticoid sensitivity and phasic responsiveness to inflammation. Herein, we review our current understanding of clock-controlled cellular and molecular functions in the lungs, the impact of clock dysfunction in chronic airway disease, and the response of the pulmonary clock to different environmental perturbations. Furthermore, we discuss the evidence for candidate signaling pathways, such as the SIRT1-BMAL1-REV-ERBα axis, as novel targets for chronopharmacological management of chronic airway diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I619,I619)","v":25766659},{"$f":"(LEN($J619) - LEN(SUBSTITUTE(LOWER($J619),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J619) - LEN(SUBSTITUTE(LOWER($J619),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J619) - LEN(SUBSTITUTE(LOWER($J619),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B619:D619)","v":1},2015,"Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma.","Liu",25766659,"Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma.    Abstract:   Alcohol drinking is a major etiological factor of oro-esophageal squamous cell carcinoma (OESCC). Both local and systemic effects of ethanol may promote carcinogenesis, especially among chronic alcoholics. However, molecular mechanisms of ethanol-associated OESCC are still not well understood. In this review, we summarize current understandings and propose three mechanisms of ethanol-associated OESCC: (1) Disturbance of systemic metabolism of nutrients: during ethanol metabolism in the liver, systemic metabolism of retinoids, zinc, iron and methyl groups is altered. These nutrients are known to be associated with the development of OESCC. (2) Disturbance of redox metabolism in squamous epithelial cells: when ethanol is metabolized in oro-esophageal squamous epithelial cells, reactive oxygen species are generated and produce oxidative damage. Meanwhile, ethanol may also disturb fatty-acid metabolism in these cells. (3) Disturbance of signaling pathways in squamous epithelial cells: due to its physico-chemical properties, ethanol changes cell membrane fluidity and shape, and may thus impact multiple signaling pathways. Advanced molecular techniques in genomics, epigenomics, metabolomics and microbiomics will help us elucidate how ethanol promotes OESCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I620,I620)","v":25764675},{"$f":"(LEN($J620) - LEN(SUBSTITUTE(LOWER($J620),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J620) - LEN(SUBSTITUTE(LOWER($J620),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J620) - LEN(SUBSTITUTE(LOWER($J620),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B620:D620)","v":1},2015,"[Recognition mechanism of hepatitis C viral infection].","Dansako",25764675,"[Recognition mechanism of hepatitis C viral infection].    Abstract:   In the viral reproduction, hepatitis C virus(HCV) produces double-stranded RNA (dsRNA) as a replication intermediate. RIG-I(retinoic acid inducible protein I) recognizes the intracellular HCV dsRNA as a quot;non selfquot; molecule, and triggers the induction of interferon (IFN)-β and then numerous IFN-stimulated genes(ISGs). On the other hand, one of toll-like receptors, TLR3 also recognizes the extracellular HCV dsRNA, and subsequently triggers the induction of IFN-β and ISGs. We recently reported class A scavenger receptor (MSR1) was required for TLR3-mediated recognition of the extracellular HCV dsRNA. In this review, we summarize current knowledge about RIG-I- and TLR3/MSR1-mediated recognition mechanisms of HCV infection."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I621,I621)","v":25665393},{"$f":"(LEN($J621) - LEN(SUBSTITUTE(LOWER($J621),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J621) - LEN(SUBSTITUTE(LOWER($J621),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J621) - LEN(SUBSTITUTE(LOWER($J621),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B621:D621)","v":1},2014,"[Role of thyroid system in adaptation to cold].","Maslov",25665393,"[Role of thyroid system in adaptation to cold].    Abstract:   Adaptation to cold promotes an increase in blood T3 and T4 levels in men and animals. The long-term cold exposure can induce a decrease in concentration of serum total and free T3 in human due to an enhancement of this hormone clearance. Endogenous catecholamines during adaptation to cold raise iodothyronine deiodinase D2 activity in brown fat due to α1-adrenergic receptor stimulation. Triiodothyronine is an inductor of iodothyronine deiodinase expression in brown fat, liver and kidney. Iodothyronine deiodinase D2 plays an important role in adaptation of organism to cold contributing to the high adrenergic reactivity of brown fat. At adaptation to cold T3 interacts with T3Rβ, it is formed T3Rβ-RXR complex, which binds to DNA with following transcription of UCP-1 and UCP-3 genes and UCP-1 and UCP-3 protein synthesis and uncoupling oxidative phosphorylation and an increase in heat production, where T3Rβ is T3-receptor-β, RXR is retinoid X-receptor, UCP is uncoupling protein. Triiodothyronine contributes to normal response to adrenergic agents of brown fat due to T3Rα activation. Sympatho-adrenomedullary and thyroid systems act as synergists in adaptation to cold."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I622,I622)","v":25659870},{"$f":"(LEN($J622) - LEN(SUBSTITUTE(LOWER($J622),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J622) - LEN(SUBSTITUTE(LOWER($J622),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J622) - LEN(SUBSTITUTE(LOWER($J622),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B622:D622)","v":1},2015,"Nuclear receptors and cholesterol metabolism in the intestine.","Moschetta",25659870,"Nuclear receptors and cholesterol metabolism in the intestine.    Abstract:   Nuclear receptors are involved in many important function and mediate signaling by factors including hormones, vitamins and a number of endogenous ligands and xenobiotics, several of which are involved in lipid metabolism. This review focuses on the liver X receptor (LXR), which is an important regulator of whole-body cholesterol, fatty acid, and glucose homeostasis that binds to LXR response elements as a heterodimer with retinoid X receptors, and the farnesoid X receptor (FXR), which is a bile acid receptor involved in feedback inhibition of bile acid synthesis, and thus cholesterol catabolism. These nuclear receptors regulate gene programs that control intestinal and hepatic lipid homeostasis through their effects on cholesterol transport and catabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I623,I623)","v":25657097},{"$f":"(LEN($J623) - LEN(SUBSTITUTE(LOWER($J623),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J623) - LEN(SUBSTITUTE(LOWER($J623),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J623) - LEN(SUBSTITUTE(LOWER($J623),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B623:D623)","v":1},2015,"Endogenous molecular-cellular hierarchical modeling of prostate carcinogenesis uncovers robust structure.","Zhu",25657097,"Endogenous molecular-cellular hierarchical modeling of prostate carcinogenesis uncovers robust structure.    Abstract:   We explored endogenous molecular-cellular network hypothesis for prostate cancer by constructing relevant endogenous interaction network model and analyzing its dynamical properties. Molecular regulations involved in cell proliferation, apoptosis, differentiation and metabolism are included in a hierarchical mathematical modeling scheme. This dynamical network organizes into multiple robust functional states, including physiological and pathological ones. Some states have characteristics of cancer: elevated metabolic and immune activities, high concentration of growth factors and different proliferative, apoptotic and adhesive behaviors. The molecular profile of calculated cancer state agrees with existing experiments. The modeling results have additional predictions which may be validated by further experiment: 1) Prostate supports both stem cell like and liver style proliferation; 2) While prostate supports multiple cell types, including basal, luminal and endocrine cell type differentiated from its stem cell, luminal cell is most likely to be transformed malignantly into androgen independent type cancer; 3) Retinoic acid pathway and C/EBPα are possible therapeutic targets."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I624,I624)","v":25618772},{"$f":"(LEN($J624) - LEN(SUBSTITUTE(LOWER($J624),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J624) - LEN(SUBSTITUTE(LOWER($J624),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J624) - LEN(SUBSTITUTE(LOWER($J624),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B624:D624)","v":1},2016,"Interactions of vitamin D and the proximal tubule.","Chesney",25618772,"Interactions of vitamin D and the proximal tubule.    Abstract:   Severe vitamin D deficiency (reduction in serum 25(OH)D concentration) in infants and children can cause features of the Fanconi syndrome, including phosphaturia, glycosuria, aminoaciduria, and renal tubular acidosis. This indicates that vitamin D and its metabolites influence proximal tubule function. Filtered 25(OH)D bound to vitamin D binding protein (DBP) is endocytosed by megalin-cubilin in the apical membrane. Intracellular 25(OH)D is metabolized to 1,25(OH)2D or calcitroic acid by 1-α-hydroxylase or 24-hydroxylase in tubule cell mitochondria. Bone-produced fibroblast growth factor 23 (FGF23) bound to Klotho in tubule cells and intracellular phosphate concentrations are regulators of 1-α-hydroxylase activity and cause proximal tubule phosphaturia. Aminoaciduria occurs when amino acid transporter synthesis is deficient, and 1,25(OH)2D along with retinoic acid up-regulate transporter synthesis by a vitamin D response element in the promoter region of the transporter gene. This review discusses evidence gained from studies in animals or cell lines, as well as from human disorders, that provide insight into vitamin D-proximal tubule interactions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I625,I625)","v":25553772},{"$f":"(LEN($J625) - LEN(SUBSTITUTE(LOWER($J625),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J625) - LEN(SUBSTITUTE(LOWER($J625),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J625) - LEN(SUBSTITUTE(LOWER($J625),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B625:D625)","v":1},2015,"Farnesoid x receptor in human metabolism and disease: the interplay between gene polymorphisms, clinical phenotypes and disease susceptibility.","Koutsounas",25553772,"Farnesoid x receptor in human metabolism and disease: the interplay between gene polymorphisms, clinical phenotypes and disease susceptibility.    Abstract:    INTRODUCTION : Farnesoid x receptor (FXR) belongs to the group of nuclear receptors (NRs), which regulate the expression of various genes by binding to DNA either as a monomer or a heterodimer with retinoid x receptor.  AREAS COVERED : FXR affects several metabolic pathways through its specific target genes, regulating bile acid (BA) synthesis and homeostasis, glucose and lipid metabolism, also exhibiting a crucial role in intestinal bacterial growth and liver regeneration. Additionally, FXR is involved in the pathogenesis of different cholestatic diseases, as well as non-alcoholic fatty liver disease, inflammatory bowel disease (IBD) and primary idiopathic BA malabsorption.  EXPERT OPINION : Analyses of certain FXR polymorphisms revealed associations with clinical phenotypes and susceptibility to various human diseases. FXR single-nucleotide polymorphisms seem to be correlated with differences in glucose homeostasis, gallstone formation, intrahepatic cholestasis of pregnancy, IBD and therapeutic response to hypolipidemic therapy, among studied populations. Unfortunately, little data are still available and more studies remain to be done to determine the contribution of FXR polymorphisms in estimating risk factors and clinical outcomes for several diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I626,I626)","v":25540141},{"$f":"(LEN($J626) - LEN(SUBSTITUTE(LOWER($J626),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J626) - LEN(SUBSTITUTE(LOWER($J626),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J626) - LEN(SUBSTITUTE(LOWER($J626),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B626:D626)","v":1},2015,"NOD-like receptors: versatile cytosolic sentinels.","Motta",25540141,"NOD-like receptors: versatile cytosolic sentinels.    Abstract:   Nucleotide binding oligomerization domain (NOD)-like receptors are cytoplasmic pattern-recognition receptors that together with RIG-I-like receptor (retinoic acid-inducible gene 1), Toll-like receptor (TLR), and C-type lectin families make up the innate pathogen pattern recognition system. There are 22 members of NLRs in humans, 34 in mice, and even a larger number in some invertebrates like sea urchins, which contain more than 200 receptors. Although initially described to respond to intracellular pathogens, NLRs have been shown to play important roles in distinct biological processes ranging from regulation of antigen presentation, sensing metabolic changes in the cell, modulation of inflammation, embryo development, cell death, and differentiation of the adaptive immune response. The diversity among NLR receptors is derived from ligand specificity conferred by the leucine-rich repeats and an NH2-terminal effector domain that triggers the activation of different biological pathways. Here, we describe NLR genes associated with different biological processes and the molecular mechanisms underlying their function. Furthermore, we discuss mutations in NLR genes that have been associated with human diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I627,I627)","v":25488886},{"$f":"(LEN($J627) - LEN(SUBSTITUTE(LOWER($J627),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J627) - LEN(SUBSTITUTE(LOWER($J627),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J627) - LEN(SUBSTITUTE(LOWER($J627),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B627:D627)","v":1},2014,"A successful spontaneous pregnancy in abetalipoproteinemia: Amsterdam or the art of vitamin replacement?","Ferreira",25488886,"A successful spontaneous pregnancy in abetalipoproteinemia: Amsterdam or the art of vitamin replacement?    Abstract:   Abetalipoproteinemia is a rare metabolic disorder that causes disturbed lipid absorption with consequent hypocholesterolaemia and liposoluble avitaminosis. The broad spectrum of presentations includes malabsorption, failure to thrive and acanthocytosis in children, while later in life expected manifestations include coagulopathy, myopathy, retinitis pigmentosa, peripheral neuropathy, hyporeflexia and ataxia. These neurological complications stem from demyelination secondary to vitamin E deficiency. Another complication is reduced fertility in women. In the event of a successful conception, issues arise in vitamin supplementation, the mainstay of treatment of abetalipoproteinemia. The skilful clinician must master the delicate balance between the teratogenic effects on the fetus of over as well as under replacement of vitamins, pregnancy complications such as premature rupture of membranes and eclampsia, and, finally, maternal complications such as corneal ulcers. We describe the management of a patient ranging from pubertal growth to bearing a successful spontaneous pregnancy with an outcome of a completely healthy mother and child."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I628,I628)","v":25455729},{"$f":"(LEN($J628) - LEN(SUBSTITUTE(LOWER($J628),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J628) - LEN(SUBSTITUTE(LOWER($J628),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J628) - LEN(SUBSTITUTE(LOWER($J628),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B628:D628)","v":1},2014,"Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers.","Roshan-Moniri",25455729,"Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers.    Abstract:   Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B-like receptors, and ‘‘dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1’’ (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I629,I629)","v":25427904},{"$f":"(LEN($J629) - LEN(SUBSTITUTE(LOWER($J629),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J629) - LEN(SUBSTITUTE(LOWER($J629),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J629) - LEN(SUBSTITUTE(LOWER($J629),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B629:D629)","v":1},2015,"Alcoholic cirrhosis and hepatocellular carcinoma.","Stickel",25427904,"Alcoholic cirrhosis and hepatocellular carcinoma.    Abstract:   Hepatocellular carcinoma shows a rising incidence worldwide, and the largest burden of disease in Western countries derives from patients with alcoholic liver disease (ALD) and cirrhosis, the latter being the premier premalignant factor for HCC. The present chapter addresses key issues including the epidemiology of alcohol-associated HCC, and its link to other coexisting non-alcoholic liver diseases, and additional host and environmental risk factors including the underlying genetics. Also discussed are molecular mechanisms of alcohol-associated liver cancer evolution involving the mediators of alcohol toxicity and carcinogenicity, acetaldehyde and reactive oxygen species, as well as the recently described mutagenic adducts which these mediators form with DNA. Specifically, interference of alcohol with retinoids and cofactors of transmethylation processes are outlined. Information presented in this chapter illustrates that the development of HCC in the context of ALD is multifaceted and suggests several molecular targets for prevention and markers for the screening of risk groups."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I630,I630)","v":25427901},{"$f":"(LEN($J630) - LEN(SUBSTITUTE(LOWER($J630),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J630) - LEN(SUBSTITUTE(LOWER($J630),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J630) - LEN(SUBSTITUTE(LOWER($J630),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B630:D630)","v":1},2015,"Alcohol and cancer: an overview with special emphasis on the role of acetaldehyde and cytochrome P450 2E1.","Seitz",25427901,"Alcohol and cancer: an overview with special emphasis on the role of acetaldehyde and cytochrome P450 2E1.    Abstract:   The mechanisms by which chronic alcohol consumption enhances carcinogenesis include acetaldehyde (AA) generated by alcohol dehydrogenase and reactive oxygen species (ROS) generated predominantly by cytochrome P450 2E1 (CYP2E1), but also by other factors during inflammation. In addition, ethanol also alters epigenetics by changing DNA and histone methylation and acetylation. A loss of retinoic acid due to a CYP2E1-related enhanced degradation results in enhanced cellular proliferation and decreased cell differentiation. Changes in cancer genes and in signaling pathways (MAPK, RAS, Rb, TGFβ, p53, PTEN, ECM, osteopontin, Wnt) may also contribute to ethanol-mediated mechanisms in carcinogenesis. Finally, immunosuppression may facilitate tumor spread. In the present review major emphasis is led on AA and ROS. While AA binds to proteins and DNA generating carcinogenic DNA adducts and inhibiting DNA repair and DNA methylation, ROS results in lipid peroxidation with the generation of lipid peroxidation products such as 4-hydoxynonenal which binds to DNA-forming highly carcinogenic exocyclic DNA adducts. ROS production correlates significantly with CYP2E1 in the liver but also in the esophagus, and its generation can be significantly reduced by the specific CYP2E1 inhibitor clomethiazole. Finally, CMZ also inhibits alcohol-mediated nitrosamine-induced hepatocarcinogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I631,I631)","v":25412782},{"$f":"(LEN($J631) - LEN(SUBSTITUTE(LOWER($J631),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J631) - LEN(SUBSTITUTE(LOWER($J631),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J631) - LEN(SUBSTITUTE(LOWER($J631),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B631:D631)","v":1},2015,"Psoriasis is a systemic disease with multiple cardiovascular and metabolic comorbidities.","Ryan",25412782,"Psoriasis is a systemic disease with multiple cardiovascular and metabolic comorbidities.    Abstract:   There is evidence that patients with moderate to severe psoriasis have an increased risk of conditions such as cardiovascular disease, obesity, diabetes mellitus, and metabolic syndrome. The precise mechanisms underlying the observed increase in cardiovascular disease in psoriasis remain to be defined but inflammatory pathways mutual to both conditions are probably involved. Suppression of systemic inflammation in psoriasis could help reduce cardiovascular inflammation but robust evidence is still lacking evidence is lacking. This article summarizes the current literature on cardiovascular and metabolic comorbidities in psoriasis, identifies research gaps, and suggests management strategies to reduce cardiovascular risk in patients with moderate to severe psoriasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I632,I632)","v":25369304},{"$f":"(LEN($J632) - LEN(SUBSTITUTE(LOWER($J632),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J632) - LEN(SUBSTITUTE(LOWER($J632),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J632) - LEN(SUBSTITUTE(LOWER($J632),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B632:D632)","v":1},2014,"Recent advances in the prevention of hepatocellular carcinoma recurrence.","Lu",25369304,"Recent advances in the prevention of hepatocellular carcinoma recurrence.    Abstract:   Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Early-stage HCC can be curatively treated, but the recurrence rate remains high. To date, adjuvant treatments have not proven effective in preventing HCC recurrence after curative treatment. Although early studies explored the potential of vitamin K2, retinoid, chemotherapy, and recently, sorafenib, none of the studies reported successful outcomes. Several new lines of evidence have emerged to support the use of novel antiviral agents for preventing the recurrence of virus-related HCC after curative treatment. In this review, the authors provide a thorough overview of the various adjuvant treatments that have been attempted or are being considered for trial."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I633,I633)","v":25333772},{"$f":"(LEN($J633) - LEN(SUBSTITUTE(LOWER($J633),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J633) - LEN(SUBSTITUTE(LOWER($J633),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J633) - LEN(SUBSTITUTE(LOWER($J633),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B633:D633)","v":1},2014,"IGF axis and other factors in HPV-related and HPV-unrelated carcinogenesis (review).","Durzyńska",25333772,"IGF axis and other factors in HPV-related and HPV-unrelated carcinogenesis (review).    Abstract:   The insulin-like growth factor (IGF) axis promotes the growth of cells, tissues and organs. IGF-1 is mainly produced in the liver but is also secreted from local tissues. In the circulation, IGF-1 is bound to insulin-like binding proteins (IGFBPs), and when released it activates the insulin-like growth factor receptor (IGF-1R). The signal is further transmitted by intracellular signaling pathways leading to gene expression that regulates, among others, cell proliferation and survival. This review presents the IGF axis in the context of cell transformation and cancer development. Aspects involving IGF-1 deficiency and protection from cancer are also briefly described. Furthermore, human papillomaviruses (HPVs) interplaying with IGF axis components in cervical cancer development are described. These small dsDNA viruses are divided into low-risk and high-risk HPVs with regard to the potency of their oncogenic actions; they mainly infect epithelial or mucosal cells. Special attention is drawn to expression of two major HPV oncogenes (E6 and E7) initiating and maintaining cervical carcinogenesis, which is a multistep and multifactorial process; therefore, involvement of additional factors such as mitochondrial DNA changes, sex hormones, retinoic and folic acids are also discussed. Finally, IGF axis components and HPV oncogenes as targets in anticancer treatment are presented which include IGF-1R downregulation, RNA interference and anti-HPV therapeutic vaccines. The review concludes that despite an enormous advancement in research on IGF and HPV-related cancers, more molecular studies and clinical trials are needed before commercialized therapies are widely available for oncology patients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I634,I634)","v":24953623},{"$f":"(LEN($J634) - LEN(SUBSTITUTE(LOWER($J634),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J634) - LEN(SUBSTITUTE(LOWER($J634),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J634) - LEN(SUBSTITUTE(LOWER($J634),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B634:D634)","v":1},2014,"[Management of chronic hand eczema].","Lahfa",24953623,"[Management of chronic hand eczema].    Abstract:   The management of hand eczema, more readily called chronic hand dermatitis, is complex. This heaviness is related not only to the disease itself by its different clinical forms but also the multiplicity and diversity of etiological factors, triggering / maintaining or aggravating factors. The repeated therapeutic failures are ransom of incorrect information about the disease and its environment, a lack of clarity in the prescription and duration of treatment in general too short. The reference treatment is high potency topical steroids with or without occlusion for 4-8 weeks followed by alitretinoin 30 mg / day for at least 3-6 months with a monthly lipid and liver monitoring and mandatory monthly pregnancy test in women of childbearing. Associated measures and patient education are the cornerstones of successful treatment. Other alternative treatments such as phototherapy, methotrexate, cyclosporin, mycophenolate mofetil etc. can be considered in case of resistance or for clearing followed by topical treatments."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I635,I635)","v":24872274},{"$f":"(LEN($J635) - LEN(SUBSTITUTE(LOWER($J635),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J635) - LEN(SUBSTITUTE(LOWER($J635),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J635) - LEN(SUBSTITUTE(LOWER($J635),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B635:D635)","v":1},2014,"Xeroderma pigmentosum in Ghanaians: a report of three cases and review of literature.","Adu",24872274,"Xeroderma pigmentosum in Ghanaians: a report of three cases and review of literature.    Abstract:    BACKGROUND : Xeroderma pigmentosum is an autosomal recessive disease with sun sensitivity, photophobia, early onset of freckling, and subsequent neoplastic changes on sun-exposed surfaces. There is cellular hypersensitivity to UV radiation and to certain chemicals in association with abnormal DNA repair. Patients with defective DNA nucleotide excision repair (NER) have defects in one of seven NER genes; xeroderma pigmentosum variants have normal NER and a defect in a polymerase gene.  STUDY DESIGN : This is a case presentation of three patients with the features of xeroderma pigmentosum, aged 48, 15, and 14 years. The latter two patients were females. Each presented with areas of hyper-and hypo-pigmentation over sun exposed body surfaces. Each patient had a minimum of two cutaneous malignancies, distributed on the upper chest, face or scalp.  RESULTS : The first and third patients had their lesions surgically excised and the defects were skin grafted. The second patient was treated with radiotherapy. All the lesions presented were confirmed histologically as squamous cell carcinoma. No recurrence of the malignancies has been noticed.  CONCLUSION : Xeroderma pigmentosum is not rare in Ghana. Early recognition of the disease is necessary to avoid morbidity and mortality from malignant complications. The use of other treatment modalities such as sunscreens, oral retinoids, and chemical therapy with 5-fluorouracil is discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I636,I636)","v":24864105},{"$f":"(LEN($J636) - LEN(SUBSTITUTE(LOWER($J636),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J636) - LEN(SUBSTITUTE(LOWER($J636),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J636) - LEN(SUBSTITUTE(LOWER($J636),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B636:D636)","v":1},2014,"[Role of the RIG-I-like receptors in antiviral response].","Jabłońska",24864105,"[Role of the RIG-I-like receptors in antiviral response].    Abstract:   The innate nonspecific immunity is the first line of defense against viral infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are two main receptor families detecting viral nucleic acid. So far, three RLR family members were characterized: RIG-I, MDA5 and LGP2. RLR constitute a family of cytoplasmic helicases, which recognized intracellular single-stranded and double-stranded RNA that is introduced to cytosol during viral infection and replication. In this work we review the current knowledge about the mechanisms of viral recognition by RIG-I-like receptors and their signaling pathways for the activation of type I interferons and pro-inflammatory cytokines synthesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I637,I637)","v":24844148},{"$f":"(LEN($J637) - LEN(SUBSTITUTE(LOWER($J637),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J637) - LEN(SUBSTITUTE(LOWER($J637),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J637) - LEN(SUBSTITUTE(LOWER($J637),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B637:D637)","v":1},2014,"ATP-binding cassette transporter A1: from metabolism to neurodegeneration.","Koldamova",24844148,"ATP-binding cassette transporter A1: from metabolism to neurodegeneration.    Abstract:   ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoprotein A-I (apoA-I) and apolipoprotein E (apoE). ABCA1 is an essential regulator of high density lipoproteins (HDL) and reverse cholesterol transport - a role that determines its importance for atherosclerosis. Over the last 10 years studies have provided convincing evidence that ABCA1, via its control of apoE lipidation, also has a role in Alzheimers disease (AD). A series of reports have revealed a significant impact of ABCA1 on Aβ deposition and clearance in AD model mice, as well as an association of common and rare ABCA1 gene variants with the risk for AD. Since APOE is the major genetic risk factor for late onset AD, the regulation of apoE level or its functionality by ABCA1 may prove significant for AD pathogenesis. ABCA1 is transcriptionally regulated by Liver X Receptors (LXR) and Retinoic X Receptors (RXR) which provides a starting point for drug discovery and development of synthetic LXR and RXR agonists for treatment of metabolic and neurodegenerative disorders. This review summarizes the recent results of research on ABCA1, particularly relevant to atherosclerosis and AD."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I638,I638)","v":24716523},{"$f":"(LEN($J638) - LEN(SUBSTITUTE(LOWER($J638),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J638) - LEN(SUBSTITUTE(LOWER($J638),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J638) - LEN(SUBSTITUTE(LOWER($J638),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B638:D638)","v":1},2014,"Postoperative therapy options for hepatocellular carcinoma.","Zhong",24716523,"Postoperative therapy options for hepatocellular carcinoma.    Abstract:   Hepatocellular carcinoma (HCC) is associated with poor prognosis and often recurs even after curative hepatic resection (HR) or radiofrequency ablation (RFA). In fact, recurrence is the most frequent cause of postoperative death in patients with HCC; it can arise through intrahepatic metastasis by the primary tumor or through the emergence of de novo tumors. Even though studies have examined numerous adjuvant therapies and chemotherapies for their ability to prevent recurrence, no consensus recommendations exist about their clinical application. To gain a comprehensive picture of clinical options, we identified 39 randomized controlled trials, involving 4113 participants, which explore the efficacy of adjuvant or chemotherapies to prevent HCC recurrence after potentially curative HR or RFA. The available evidence suggests a significant improvement in recurrence-free survival and overall survival when transarterial chemoembolization is used for patients who are at high risk for recurrence, lamivudine for patients with hepatitis B virus (HBV)-related HCC (gt;500 copies of HBV DNA/ml), and interferon-α for patients with hepatitis C virus (HCV)-infected HCC. In contrast, available evidence does not definitively establish clinical benefits of interferon-β for patients with HCV-related HCC, interferon-α for patients with HBV-related HCC, or any of the following therapies for patients with HCC: iodine-125 brachytherapy, autologous tumor vaccination, adoptive immunotherapy, or therapy involving acyclic retinoid, vitamin K2 analog, iodine-131-labeled lipiodol, sorafenib, heparanase inhibitor PI-88, or capecitabine. Though the findings of our review should be interpreted with caution because of clinical heterogeneity and small sample size in the included trials, they highlight gaps in the evidence base, and therefore, may guide future research."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I639,I639)","v":24350319},{"$f":"(LEN($J639) - LEN(SUBSTITUTE(LOWER($J639),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J639) - LEN(SUBSTITUTE(LOWER($J639),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J639) - LEN(SUBSTITUTE(LOWER($J639),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B639:D639)","v":1},2013,"Psoriasis.","Burfield",24350319,"Psoriasis.    Abstract:   Psoriasis is a chronic, immune-mediated inflammatory skin disease affecting 1.3-2.2% of the UK population.1 Most commonly, psoriasis is characterised by well-demarcated, red plaques with adherent scale with a predilection for the scalp and extensor surfaces of the limbs. However, the effects of psoriasis go far beyond a patients skin and may result in a degree of disability and impaired quality of life similar to that of other major medical conditions, such as cancer and heart disease. First-line therapies for most patients are topical treatments such as topical corticosteroids and vitamin D analogues. For those with more severe or treatment-resistant disease, second- or third-line therapies include phototherapy, systemic therapies such as methotrexate and more recently biologic therapies such as tumour necrosis factor (TNF) inhibitors. These therapeutic modalities are proven to be highly effective; however, the potential for long-term toxicity needs to be considered. Aside from the visible skin disease, psoriasis is also increasingly recognised to have important systemic manifestations. Psoriatic arthritis has long been established as an associated condition and, more recently, it has emerged that psoriasis is also associated with an increased risk of inflammatory bowel disease, cardiovascular disease and the metabolic syndrome. Both National Institute for Health and Care Excellence (NICE)2 and Scottish Intercollegiate Guidelines Network (SIGN)3 have recently published guidelines for the assessment and management of psoriasis which highlight the need for regular assessment in order to detect the development of arthritis and the presence of other co-morbidities such as obesity, diabetes, dyslipidaemia and hypertension."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I640,I640)","v":24334113},{"$f":"(LEN($J640) - LEN(SUBSTITUTE(LOWER($J640),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J640) - LEN(SUBSTITUTE(LOWER($J640),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J640) - LEN(SUBSTITUTE(LOWER($J640),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B640:D640)","v":1},2014,"Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: the influence of LCPUFA on neural development, aging, and neurodegeneration.","Janssen",24334113,"Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: the influence of LCPUFA on neural development, aging, and neurodegeneration.    Abstract:   Many clinical and animal studies demonstrate the importance of long-chain polyunsaturated fatty acids (LCPUFA) in neural development and neurodegeneration. This review will focus on involvement of LCPUFA from genesis to senescence. The LCPUFA docosahexaenoic acid and arachidonic acid are important components of neuronal membranes, while eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid also affect cardiovascular health and inflammation. In neural development, LCPUFA deficiency can lead to severe disorders like schizophrenia and attention deficit hyperactivity disorder. Perinatal LCPUFA supplementation demonstrated beneficial effects in neural development in humans and rodents resulting in improved cognition and sensorimotor integration. In normal aging, the effect of LCPUFA on prevention of cognitive impairment will be discussed. LCPUFA are important for neuronal membrane integrity and function, and also contribute in prevention of brain hypoperfusion. Cerebral perfusion can be compromised as result of obesity, cerebrovascular disease, hypertension, or diabetes mellitus type 2. Last, we will focus on the role of LCPUFA in most common neurodegenerative diseases like Alzheimers disease and Parkinsons disease. These disorders are characterized by impaired cognition and connectivity and both clinical and animal supplementation studies have shown the potential of LCPUFA to decrease neurodegeneration and inflammation. This review shows that LCPUFA are essential throughout life."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I641,I641)","v":24308533},{"$f":"(LEN($J641) - LEN(SUBSTITUTE(LOWER($J641),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J641) - LEN(SUBSTITUTE(LOWER($J641),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J641) - LEN(SUBSTITUTE(LOWER($J641),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B641:D641)","v":1},2014,"Retinoic acid actions through mammalian nuclear receptors.","Huang",24308533,"Retinoic acid actions through mammalian nuclear receptors.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I642,I642)","v":24300092},{"$f":"(LEN($J642) - LEN(SUBSTITUTE(LOWER($J642),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J642) - LEN(SUBSTITUTE(LOWER($J642),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J642) - LEN(SUBSTITUTE(LOWER($J642),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B642:D642)","v":1},2014,"Action mechanisms of Liver X Receptors.","Gabbi",24300092,"Action mechanisms of Liver X Receptors.    Abstract:   The two Liver X Receptors, LXRα and LXRβ, are nuclear receptors belonging to the superfamily of ligand-activated transcription factors. They share more than 78% homology in amino acid sequence, a common profile of oxysterol ligands and the same heterodimerization partner, Retinoid X Receptor. LXRs play crucial roles in several metabolic pathways: lipid metabolism, in particular in preventing cellular cholesterol accumulation; glucose homeostasis; inflammation; central nervous system functions and water transport. As with all nuclear receptors, the transcriptional activity of LXR is the result of an orchestration of numerous cellular factors including ligand bioavailability, presence of corepressors and coactivators and cellular context i.e., what other pathways are activated in the cell at the time the receptor recognizes its ligand. In this mini-review we summarize the factors regulating the transcriptional activity and the mechanisms of action of these two receptors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I643,I643)","v":24279858},{"$f":"(LEN($J643) - LEN(SUBSTITUTE(LOWER($J643),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J643) - LEN(SUBSTITUTE(LOWER($J643),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J643) - LEN(SUBSTITUTE(LOWER($J643),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B643:D643)","v":1},2013,"Pharmacogenetics of the nuclear hormone receptors: the missing link between environment and drug effects?","De Mattia",24279858,"Pharmacogenetics of the nuclear hormone receptors: the missing link between environment and drug effects?    Abstract:   In the last decade, genetic variations in ABC/SLC transporters and phase I/II enzymes have raised pharmacogenetic markers as being predictive to the attention of researchers in the field of personalized medicine in oncology. However, it is becoming evident that the sequence variations in these genes cannot address by themselves the sharp interindividual variability in drug effects. Recently, nuclear receptors (NRs), including pregnane X receptor, constitutive androstane receptor, retinoid X receptor, farnesoid X receptor, liver X receptor, vitamin D receptor, peroxisome proliferator-activated receptors and HNF4A, have demonstrated key roles in regulating transporter and metabolic gene expression in response to xeno/endobiotics, as well as antineoplastic drugs. These findings attracted interest to the genetics of the NRs for their possible role in influencing the metabolism and pharmacological profiles of chemotherapeutics. In this review, we aim to summarize the most recent findings in the innovative field of NR pharmacogenetics and findings in how they could integrate with more traditional markers in order to improve drug treatment personalization."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I644,I644)","v":24266866},{"$f":"(LEN($J644) - LEN(SUBSTITUTE(LOWER($J644),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J644) - LEN(SUBSTITUTE(LOWER($J644),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J644) - LEN(SUBSTITUTE(LOWER($J644),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B644:D644)","v":1},2014,"Functions, therapeutic applications, and synthesis of retinoids and carotenoids.","Álvarez",24266866,"Functions, therapeutic applications, and synthesis of retinoids and carotenoids.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I645,I645)","v":24184141},{"$f":"(LEN($J645) - LEN(SUBSTITUTE(LOWER($J645),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J645) - LEN(SUBSTITUTE(LOWER($J645),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J645) - LEN(SUBSTITUTE(LOWER($J645),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B645:D645)","v":1},2014,"From the Medical Board of the National Psoriasis Foundation: The risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies.","Hugh",24184141,"From the Medical Board of the National Psoriasis Foundation: The risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies.    Abstract:    BACKGROUND : Many studies have identified cardiovascular risk factors in patients with psoriasis. Some psoriasis therapies may increase cardiovascular disease (CVD) and others may decrease CVD.  OBJECTIVE : We reviewed the literature to define the impact of common psoriasis therapies on cardiovascular measures and outcomes.  RESULTS : Phototherapy has no major cardiovascular impact and may reduce levels of proinflammatory cytokines. Acitretin increases serum lipids and triglycerides, but has not been shown to increase cardiovascular risk. Cyclosporine A increases blood pressure, serum triglycerides, and total cholesterol. Methotrexate is associated with a decreased risk of CVD morbidity and mortality. Among the biologics, data for tumor necrosis factor inhibitors suggest an overall reduction in cardiovascular events. Most data on short-term ustekinumab use suggest no effect on major adverse cardiovascular events, however some authorities remain concerned. Nevertheless, ustekinumab use over a 4-year period shows a decrease in major adverse cardiovascular events when compared both with the general US population and with psoriatics in Great Britain.  LIMITATIONS : Most studies lack the power and randomization of large clinical trials and long-term follow-up periods. In addition, the increased risk of CVD associated with psoriasis itself is a confounding factor.  CONCLUSION : Some therapies for moderate to severe psoriasis, including methotrexate and tumor necrosis factor inhibitors, may reduce cardiovascular events in psoriatic patients. Ustekinumab appears to be neutral but there may be a long-term benefit. Appropriate patient counseling and selection and clinical follow-up are necessary to maximize safety with these agents. Further long-term study is necessary to quantify the benefits and risks associated with biologic therapies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I646,I646)","v":23965907},{"$f":"(LEN($J646) - LEN(SUBSTITUTE(LOWER($J646),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J646) - LEN(SUBSTITUTE(LOWER($J646),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J646) - LEN(SUBSTITUTE(LOWER($J646),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B646:D646)","v":1},2014,"Effect of the vegetarian diet on non-communicable diseases.","Li",23965907,"Effect of the vegetarian diet on non-communicable diseases.    Abstract:   A vegetarian diet generally includes plenty of vegetables and fruits, which are rich in phytochemicals, antioxidants, fiber, magnesium, vitamins C and E, Fe³⁺, folic acid and n-6 polyunsaturated fatty acid (PUFA), and is low in cholesterol, total fat and saturated fatty acid, sodium, Fe²⁺, zinc, vitamin A, B₁₂ and D, and especially n-3 PUFA. Mortality from all-cause, ischemic heart disease, and circulatory and cerebrovascular diseases was significantly lower in vegetarians than in omnivorous populations. Compared with omnivores, the incidence of cancer and type 2 diabetes was also significantly lower in vegetarians. However, vegetarians have a number of increased risk factors for non-communicable diseases such as increased plasma homocysteine, mean platelet volume and platelet aggregability compared with omnivores, which are associated with low intake of vitamin B₁₂ and n-3 PUFA. Based on the present data, it would seem appropriate for vegetarians to carefully design their diet, specifically focusing on increasing their intake of vitamin B₁₂ and n-3 PUFA to further reduce already low mortality and morbidity from non-communicable diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I647,I647)","v":23878812},{"$f":"(LEN($J647) - LEN(SUBSTITUTE(LOWER($J647),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J647) - LEN(SUBSTITUTE(LOWER($J647),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J647) - LEN(SUBSTITUTE(LOWER($J647),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B647:D647)","v":1},2013,"Molecular functions of thyroid hormones and their clinical significance in liver-related diseases.","Chi",23878812,"Molecular functions of thyroid hormones and their clinical significance in liver-related diseases.    Abstract:   Thyroid hormones (THs) are potent mediators of several physiological processes, including embryonic development, cellular differentiation, metabolism, and cell growth. Triiodothyronine (T3) is the most biologically active TH form. Thyroid hormone receptors (TRs) belong to the nuclear receptor superfamily and mediate the biological functions of T3 via transcriptional regulation. TRs generally form heterodimers with the retinoid X receptor (RXR) and regulate target genes upon T3 stimulation. Research over the past few decades has revealed that disruption of cellular TH signaling triggers chronic liver diseases, including alcoholic or nonalcoholic fatty liver disease and hepatocellular carcinoma (HCC). Animal model experiments and epidemiologic studies to date imply close associations between high TH levels and prevention of liver disease. Moreover, several investigations spanning four decades have reported the therapeutic potential of T3 analogs in lowering lipids, preventing chronic liver disease, and as anticancer agents. Thus, elucidating downstream genes/signaling pathways and molecular mechanisms of TH actions is critical for the treatment of significant public health issues. Here, we have reviewed recent studies focusing on the roles of THs and TRs in several disorders, in particular, liver diseases. We also discuss the potential therapeutic applications of THs and underlying molecular mechanisms."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I648,I648)","v":23855305},{"$f":"(LEN($J648) - LEN(SUBSTITUTE(LOWER($J648),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J648) - LEN(SUBSTITUTE(LOWER($J648),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J648) - LEN(SUBSTITUTE(LOWER($J648),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B648:D648)","v":1},2013,"Hepatic stellate cells, liver innate immunity, and hepatitis C virus.","Wang",23855305,"Hepatic stellate cells, liver innate immunity, and hepatitis C virus.    Abstract:   Chronic hepatitis C virus (HCV) infection can cause liver damage, ranging from mild to more severe conditions, such as fibrosis and cirrhosis. Hepatic stellate cell (HSC) activation is a key event in HCV-induced liver fibrosis. HSCs express several HCV coreceptors that interact with HCV proteins, promoting liver fibrogenesis. In addition, HSCs have the ability to engulf apoptotic bodies of hepatocytes induced by HCV and trigger a profibrogenic response. Recent studies have suggested that HSCs may play a novel role in the liver innate immunity. HSCs enhanced differentiation and accumulation of regulatory T cells. HSCs-activated natural killer cells could produce γ-interferon that inhibits HCV replication. Importantly, HSCs possess functional Toll-like receptor-3 and retinoic acid-inducible gene I that can be activated by their ligands (poly I :C, 5ppp-dsRNA), leading to the induction of interferon and inhibition of HCV replication in hepatocytes. These new observations highlight the importance of HSCs in liver immunity against HCV, which is the focus of this review paper."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I649,I649)","v":23807605},{"$f":"(LEN($J649) - LEN(SUBSTITUTE(LOWER($J649),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J649) - LEN(SUBSTITUTE(LOWER($J649),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J649) - LEN(SUBSTITUTE(LOWER($J649),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B649:D649)","v":1},2013,"Update in the medical therapy of Cushings disease.","Nieman",23807605,"Update in the medical therapy of Cushings disease.    Abstract:    PURPOSE OF REVIEW : Recently developed agents treat Cushings disease by inhibiting ACTH secretion from corticotrope tumors or antagonizing cortisol action.  RECENT FINDINGS : The dopamine agonist cabergoline and the somatostatin agonist pasireotide target ACTH secretion. Each has low rates of normalization of urine-free cortisol (UFC), about 40% at doses of 1-7 mg weekly and 20% at doses of 600 or 900 μg twice daily, respectively. Cabergoline, an oral agent, has a relatively benign side-effect profile, primarily asthenia. Small trials suggest that combination therapy with ketoconazole increases effectiveness. Pasireotide, a parenteral agent, is associated with types and rates of adverse events similar to those seen with other somatostatin agonists (diarrhea, nausea, cholelithiasis), except for glucose intolerance, which occurs more frequently (∼75%). It may be most effective when UFC is less than two-fold normal. A few case reports suggest that pasireotide or cabergoline may control tumor size and ACTH secretion from macroadenomas. Retinoic acid must be evaluated further. The glucocorticoid antagonist mifepristone ameliorates glucose intolerance but may not normalize other Cushingoid features.  SUMMARY : These novel approaches provide options for treatment of patients in whom surgery has failed or is not possible, and those who decline adrenalectomy or radiation therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I650,I650)","v":23746772},{"$f":"(LEN($J650) - LEN(SUBSTITUTE(LOWER($J650),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J650) - LEN(SUBSTITUTE(LOWER($J650),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J650) - LEN(SUBSTITUTE(LOWER($J650),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B650:D650)","v":1},2013,"Maternal and child undernutrition and overweight in low-income and middle-income countries.","Black",23746772,"Maternal and child undernutrition and overweight in low-income and middle-income countries.    Abstract:   Maternal and child malnutrition in low-income and middle-income countries encompasses both undernutrition and a growing problem with overweight and obesity. Low body-mass index, indicative of maternal undernutrition, has declined somewhat in the past two decades but continues to be prevalent in Asia and Africa. Prevalence of maternal overweight has had a steady increase since 1980 and exceeds that of underweight in all regions. Prevalence of stunting of linear growth of children younger than 5 years has decreased during the past two decades, but is higher in south Asia and sub-Saharan Africa than elsewhere and globally affected at least 165 million children in 2011; wasting affected at least 52 million children. Deficiencies of vitamin A and zinc result in deaths; deficiencies of iodine and iron, together with stunting, can contribute to children not reaching their developmental potential. Maternal undernutrition contributes to fetal growth restriction, which increases the risk of neonatal deaths and, for survivors, of stunting by 2 years of age. Suboptimum breastfeeding results in an increased risk for mortality in the first 2 years of life. We estimate that undernutrition in the aggregate--including fetal growth restriction, stunting, wasting, and deficiencies of vitamin A and zinc along with suboptimum breastfeeding--is a cause of 3·1 million child deaths annually or 45% of all child deaths in 2011. Maternal overweight and obesity result in increased maternal morbidity and infant mortality. Childhood overweight is becoming an increasingly important contributor to adult obesity, diabetes, and non-communicable diseases. The high present and future disease burden caused by malnutrition in women of reproductive age, pregnancy, and children in the first 2 years of life should lead to interventions focused on these groups."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I651,I651)","v":23736028},{"$f":"(LEN($J651) - LEN(SUBSTITUTE(LOWER($J651),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J651) - LEN(SUBSTITUTE(LOWER($J651),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J651) - LEN(SUBSTITUTE(LOWER($J651),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B651:D651)","v":1},2013,"Functional and cancer genomics of ASXL family members.","Katoh",23736028,"Functional and cancer genomics of ASXL family members.    Abstract:   Additional sex combs-like (ASXL)1, ASXL2 and ASXL3 are human homologues of the Drosophila Asx gene that are involved in the regulation or recruitment of the Polycomb-group repressor complex (PRC) and trithorax-group (trxG) activator complex. ASXL proteins consist of ASXN, ASXH, ASXM1, ASXM2 and PHD domains. ASXL1 directly interacts with BAP1, KDM1A (LSD1), NCOA1 and nuclear hormone receptors (NHRs), such as retinoic acid receptors, oestrogen receptor and androgen receptor. ASXL family members are epigenetic scaffolding proteins that assemble epigenetic regulators and transcription factors to specific genomic loci with histone modifications. ASXL1 is involved in transcriptional repression through an interaction with PRC2 and also contributes to transcriptional regulation through interactions with BAP1 and/or NHR complexes. Germ-line mutations of human ASXL1 and ASXL3 occur in Bohring-Opitz and related syndromes. Amplification and overexpression of ASXL1 occur in cervical cancer. Truncation mutations of ASXL1 occur in colorectal cancers with microsatellite instability (MSI), malignant myeloid diseases, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma, and liver, prostate and breast cancers; those of ASXL2 occur in prostate cancer, pancreatic cancer and breast cancer and those of ASXL3 are observed in melanoma. EPC1-ASXL2 gene fusion occurs in adult T-cell leukaemia/lymphoma. The prognosis of myeloid malignancies with misregulating truncation mutations of ASXL1 is poor. ASXL family members are assumed to be tumour suppressive or oncogenic in a context-dependent manner."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I652,I652)","v":23731645},{"$f":"(LEN($J652) - LEN(SUBSTITUTE(LOWER($J652),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J652) - LEN(SUBSTITUTE(LOWER($J652),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J652) - LEN(SUBSTITUTE(LOWER($J652),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B652:D652)","v":1},2013,"Pathogenesis of hyperostosis: a key role for mesenchymatous cells?","Berthelot",23731645,"Pathogenesis of hyperostosis: a key role for mesenchymatous cells?    Abstract:   The similarities between diffuse idiopathic skeletal hyperostosis (DISH) and some forms of ankylosing spondylitis suggest shared pathogenic mechanisms. Entheseal ossification progresses at the same rate in the two conditions, and spondyloarthritis was the first diagnosis considered in several families with genetically determined early-onset DISH. However, DISH may be a heterogeneous condition, as the presence of peripheral calcifications in some families suggests pathogenic similarities with several animal models combining entheseal ossification and peripheral calcifications, as well as with X-linked familial hypophosphatemia and dentin-matrix-protein mutations. In the far more common presentation of hyperostosis without calcifications, entheseal ossification may be related to abnormal osteoblastic differentiation of mesenchymatous stem cells normally found around the intervertebral disks, in the vertebral periosteum, and in the anterior and posterior longitudinal ligaments. The many factors suspected of promoting this abnormal differentiation include bone morphogenetic proteins (BMPs), retinoids, and various hormonal factors; in addition, adipokines such as leptin are the focus of growing interest based on the well-documented association between DISH and obesity. Confirmation of the role for mesenchymatous cells in DISH should encourage investigations of mesenchymatous cells as possible pathogenic contributors to the entheseal abnormalities seen in spondyloarthritis. These cells normally exert immunosuppressive effects, which may be subverted in spondyloarthritis, notably by a T-cell population that homes specifically to the entheses."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I653,I653)","v":23718268},{"$f":"(LEN($J653) - LEN(SUBSTITUTE(LOWER($J653),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J653) - LEN(SUBSTITUTE(LOWER($J653),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J653) - LEN(SUBSTITUTE(LOWER($J653),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B653:D653)","v":1},2013,"Acquired reactive perforating dermatosis.","Wagner",23718268,"Acquired reactive perforating dermatosis.    Abstract:   Acquired reactive perforating dermatosis is characterized by umbilicated erythematous papules and plaques with firmly adherent crusts. Histopathological examination shows a typical cup-shaped ulceration in the epidermis containing cellular debris and collagen. There is transepidermal elimination of degenerated material with basophilic collagen bundles. The etiology and pathogenesis of acquired reactive perforating dermatosis are unclear. Metabolic disorders and malignancies are associated with this dermatosis. Associated pruritus is regarded as a key pathogenic factor. Constant scratching may cause a repetitive trauma to the skin. This pathogenesis may involve a genetic predisposition. The trauma may lead to degeneration of the collagen bundles. Treatment of acquired reactive perforating dermatosis follows a multimodal approach. Apart from the treating any underlying disease, treatment of pruritus is a major goal. Systemic steroids and retinoids, as well as UVB phototherapy are well-established treatment options. Some patients may also benefit from oral allopurinol."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I654,I654)","v":23619224},{"$f":"(LEN($J654) - LEN(SUBSTITUTE(LOWER($J654),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J654) - LEN(SUBSTITUTE(LOWER($J654),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J654) - LEN(SUBSTITUTE(LOWER($J654),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B654:D654)","v":1},2013,"[Nutrigenomics--bioactive dietary components].","Gętek",23619224,"[Nutrigenomics--bioactive dietary components].    Abstract:   Nutrigenomics analyzes relations between diet and genes, and identifies mechanisms in which food and nutrition affect health and lifestyles and noncommunicable diseases (R. Chadwick, 2004). Bioactive dietary components are signal molecules that carry information from the external environment and affect in terms of quantity and quality in the process of gene expression. The biological effect of bioactive dietary components depends on various of physiological processes that can occur within a few genes. Polymorphism of genes can change their function and physiological response of the body for nutrients. Bioactive dietary components work on at least two levels of the expression of genes as factors regulating chromatin structure and as factors directly regulate the activity of nuclear receptors. The processes of synthesis and DNA repair are regulated by some of vitamins, macro-and micro-elements. They provide, among others, cofactors of enzymes that catalyze the replication of DNA methylation and its repair. DNA methylation profile may change under the influence of diet, single nucleotide polymorphisms and environmental factors. Bioactive dietary components may directly affect the process of gene expression by acting as ligands for nuclear receptors. Sensitive to dietary group of nuclear receptors are sensory receptors. This group includes, among others receptor PPAR (peroxisome proliferator activated), responsible for energy metabolism and receptors LXR (liver X receptor), FXR (farnesoid X receptor) and RXR, which is responsible for the metabolism of cholesterol."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I655,I655)","v":23413096},{"$f":"(LEN($J655) - LEN(SUBSTITUTE(LOWER($J655),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J655) - LEN(SUBSTITUTE(LOWER($J655),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J655) - LEN(SUBSTITUTE(LOWER($J655),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B655:D655)","v":1},2013,"Pregnane X receptor and human malignancy.","Koutsounas",23413096,"Pregnane X receptor and human malignancy.    Abstract:   Pregnane X Receptor (PXR) is a member of the nuclear receptor superfamily, expressed in liver, intestine and other tissues. PXR exerts transcriptional regulation by binding to its DNA response elements as an heterodimer with Retinoid X Receptor (RXR). This nuclear receptor is implicated in the homeostasis of numerous endobiotics, such as glucose, lipids, steroids and bile acids. Additionally, the activation of PXR induces expression of drug metabolizing enzymes (DMEs) and transporters, including multidrug resistance protein 1 (MDR1), leading to regulation of xenobiotic metabolism and drug-drug interactions. New roles for PXR have been established in inflammatory bowel disease, bone homeostasis, liver steatosis, antifibrogenesis and oxidative stress. PXR has, additionally, a multifactorial impact on cancer, either by directly affecting cell proliferation and apoptosis or by inducing chemotherapy resistance, in colon, breast, prostate, and endometrial cancer, and in osteosarcoma. PXR polymorphisms may also have clinical significance in certain types of cancer and their treatment. Further studies are needed in order to clarify the mechanisms involved in PXR-regulated carcinogenesis. PXR down-regulation could be considered as a novel therapeutic approach to overcome chemoresistance, while future research should be mainly focused on modulating PXR status in order to increase chemotherapy effectiveness and finally improve cancer patient prognosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I656,I656)","v":23386905},{"$f":"(LEN($J656) - LEN(SUBSTITUTE(LOWER($J656),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J656) - LEN(SUBSTITUTE(LOWER($J656),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J656) - LEN(SUBSTITUTE(LOWER($J656),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B656:D656)","v":1},2013,"IL-22: An Evolutionary Missing-Link Authenticating the Role of the Immune System in Tissue Regeneration.","Kumar",23386905,"IL-22: An Evolutionary Missing-Link Authenticating the Role of the Immune System in Tissue Regeneration.    Abstract:   Tissue regeneration is a critical component of organ maintenance. The ability of lymphocytes to kill pathogen-infected cells has been well-studied. However, the necessity for lymphocytes to participate in reconstruction of destroyed tissues has not been explored until recently. Interleukin (IL)-22, a newly defined cytokine exclusively produced by subsets of lymphocytes, provides the strongest proof yet for the tissue regenerative potentials of the immune system. IL-22 plays an obligatory role in epithelial homeostasis in the gut, liver and lung. The receptor for IL-22 (IL-22R1 and IL-10R2) is predominantly expressed by epithelial cells. While the pro-inflammatory effect is questioned, the pro-constructive potential of IL-22 is well established. It is evident from the response to IL-22, that epithelial cells not only produce anti-microbial peptides but also actively proliferate. Aryl hydrocarbon receptor (AhR) and retinoic acid-related orphan receptor (RORγt) transcription factor are required for IL-22 generation from Lymphoid Tissue inducer cells LTi, Th22 and NK-like cells. However, IL-22 production from conventional NK cells is independent of AhR and RORγt. In this review, we present a case for a paradigm shift in how we define the function of the immune system. This would include tissue regeneration as a legitimate immune function."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I657,I657)","v":23330539},{"$f":"(LEN($J657) - LEN(SUBSTITUTE(LOWER($J657),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J657) - LEN(SUBSTITUTE(LOWER($J657),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J657) - LEN(SUBSTITUTE(LOWER($J657),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B657:D657)","v":1},2013,"Regulation of the cytosolic sulfotransferases by nuclear receptors.","Runge-Morris",23330539,"Regulation of the cytosolic sulfotransferases by nuclear receptors.    Abstract:   The cytosolic sulfotransferases (SULTs) are a multigene family of enzymes that catalyze the transfer of a sulfonate group from the physiologic sulfate donor, 3-phosphoadenosine-5-phosphosulfate, to a nucleophilic substrate to generate a polar product that is more amenable to elimination from the body. As catalysts of both xenobiotic and endogenous metabolism, the SULTs are major points of contact between the external and physiological environments, and modulation of SULT-catalyzed metabolism can not only affect xenobiotic disposition, but it can also alter endogenous metabolic processes. Therefore, it is not surprising that SULT expression is regulated by numerous members of the nuclear receptor (NR) superfamily that function as sensors of xenobiotics as well as endogenous molecules, such as fatty acids, bile acids, and oxysterols. These NRs include the peroxisome proliferator-activated receptors, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, liver X receptors, farnesoid X receptor, retinoid-related orphan receptors, and estrogen-related receptors. This review summarizes current information about NR regulation of SULT expression. Because species differences in SULT subfamily composition and tissue-, sex-, development-, and inducer-dependent regulation are prominent, these differences will be emphasized throughout the review. In addition, because of the central role of the SULTs in cellular physiology, the effect of NR-mediated SULT regulation on physiological and pathophysiological processes will be discussed. Gaps in current knowledge that require further investigation are also highlighted."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I658,I658)","v":23297354},{"$f":"(LEN($J658) - LEN(SUBSTITUTE(LOWER($J658),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J658) - LEN(SUBSTITUTE(LOWER($J658),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J658) - LEN(SUBSTITUTE(LOWER($J658),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B658:D658)","v":1},2013,"Human cytochromes P450 in health and disease.","Nebert",23297354,"Human cytochromes P450 in health and disease.    Abstract:   There are 18 mammalian cytochrome P450 (CYP) families, which encode 57 genes in the human genome. CYP2, CYP3 and CYP4 families contain far more genes than the other 15 families; these three families are also the ones that are dramatically larger in rodent genomes. Most (if not all) genes in the CYP1, CYP2, CYP3 and CYP4 families encode enzymes involved in eicosanoid metabolism and are inducible by various environmental stimuli (i.e. diet, chemical inducers, drugs, pheromones, etc.), whereas the other 14 gene families often have only a single member, and are rarely if ever inducible or redundant. Although the CYP2 and CYP3 families can be regarded as largely redundant and promiscuous, mutations or other defects in one or more genes of the remaining 16 gene families are primarily the ones responsible for P450-specific diseases-confirming these genes are not superfluous or promiscuous but rather are more directly involved in critical life functions. P450-mediated diseases comprise those caused by: aberrant steroidogenesis; defects in fatty acid, cholesterol and bile acid pathways; vitamin D dysregulation and retinoid (as well as putative eicosanoid) dysregulation during fertilization, implantation, embryogenesis, foetogenesis and neonatal development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I659,I659)","v":23257291},{"$f":"(LEN($J659) - LEN(SUBSTITUTE(LOWER($J659),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J659) - LEN(SUBSTITUTE(LOWER($J659),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J659) - LEN(SUBSTITUTE(LOWER($J659),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B659:D659)","v":1},2013,"SREBP: a novel therapeutic target.","Xiao",23257291,"SREBP: a novel therapeutic target.    Abstract:   Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the biosynthesis of cholesterol, fatty acid, and triglyceride. They control the expression of crucial genes involved in lipogenesis and uptake. In this review, we summarize the processing of SREBPs and their regulation by insulin, cAMP, and vitamin A, and the relationship between miRNA and lipid metabolism. We also discuss the recent functional studies on SREBPs. These discoveries suggest that inhibition of SREBP can be a novel strategy to treat metabolic diseases, such as type II diabetes, insulin resistance, fatty liver, and atherosclerosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I660,I660)","v":23198448},{"$f":"(LEN($J660) - LEN(SUBSTITUTE(LOWER($J660),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J660) - LEN(SUBSTITUTE(LOWER($J660),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J660) - LEN(SUBSTITUTE(LOWER($J660),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B660:D660)","v":1},2012,"[The mechanism of HBV disruption on RIG-I signaling pathway].","Yan",23198448,"[The mechanism of HBV disruption on RIG-I signaling pathway].    Abstract:   Hepatitis B virus (HBV) infection disrupt the innate immunity response, which may play an important role in the chronic mechanism, while retinoic acid-induced gene I (RIG-I) mediated signaling pathway is one of the most important channel in the innate immunity. HBx and HBV polymerase may disrupt RIG-I mediated signaling pathway. The recent advances about HBV and RIG-I are reviewed in this article."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I661,I661)","v":23053550},{"$f":"(LEN($J661) - LEN(SUBSTITUTE(LOWER($J661),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J661) - LEN(SUBSTITUTE(LOWER($J661),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J661) - LEN(SUBSTITUTE(LOWER($J661),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B661:D661)","v":1},2012,"The role of lycopene and its derivatives in the regulation of transcription systems: implications for cancer prevention.","Sharoni",23053550,"The role of lycopene and its derivatives in the regulation of transcription systems: implications for cancer prevention.    Abstract:   Evidence from epidemiologic studies has suggested that carotenoids, and lycopene in particular, decrease the risk of cancer: however, not all studies support this view. To gain insight into the molecular mechanisms whereby lycopene and other carotenoids may exert their chemoprotective effects, we and others performed a series of studies that used a large panel of cancer cell lines of different lineages and animal models of human cancer. In this review we address some of the mechanisms proposed for the cancer-preventive activity of tomato lycopene, focusing on the induction of the antioxidant response element transcription system and the inhibition of the transcriptional activity of sex hormones, such as estrogens and androgens, and the activity of growth factors, such as insulin-like growth factor. We also considered the modulation by lycopene of the transcription factors peroxisome proliferator-activated receptor, retinoid X receptor, liver X receptor, and activating protein-1. The ligands and the phytonutrient regulators of these transcription systems contain electrophilic active groups, whereas lycopene and nonxanthophylic carotenoids are devoid of them. Thus, we suggest that at least some of the cellular effects of carotenoids are mediated through their derivatives formed either by chemical oxidation or by enzymatic cleavage inside the cells. This review highlights findings that pertain to this exciting avenue of research, which is currently under intense scrutiny in several laboratories worldwide."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I662,I662)","v":22955376},{"$f":"(LEN($J662) - LEN(SUBSTITUTE(LOWER($J662),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J662) - LEN(SUBSTITUTE(LOWER($J662),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J662) - LEN(SUBSTITUTE(LOWER($J662),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B662:D662)","v":1},2013,"Thyroid hormone actions in liver cancer.","Wu",22955376,"Thyroid hormone actions in liver cancer.    Abstract:   The thyroid hormone 3,3,5-triiodo-L-thyronine (T3) mediates several physiological processes, including embryonic development, cellular differentiation, metabolism, and the regulation of cell proliferation. Thyroid hormone receptors (TRs) generally act as heterodimers with the retinoid X receptor (RXR) to regulate target genes. In addition to their developmental and metabolic functions, TRs have been shown to play a tumor suppressor role, suggesting that their aberrant expression can lead to tumor transformation. Conversely, recent reports have shown an association between overexpression of wild-type TRs and tumor metastasis. Signaling crosstalk between T3/TR and other pathways or specific TR coregulators appear to affect tumor development. Since TR actions are complex as well as cell context-, tissue- and time-specific, aberrant expression of the various TR isoforms has different effects during diverse tumorigenesis. Therefore, elucidation of the T3/TR signaling mechanisms in cancers should facilitate the identification of novel therapeutic targets. This review provides a summary of recent studies focusing on the role of TRs in hepatocellular carcinomas (HCCs)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I663,I663)","v":22949321},{"$f":"(LEN($J663) - LEN(SUBSTITUTE(LOWER($J663),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J663) - LEN(SUBSTITUTE(LOWER($J663),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J663) - LEN(SUBSTITUTE(LOWER($J663),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B663:D663)","v":1},2012,"Small molecule inhibitors of RORγt: targeting Th17 cells and other applications.","Huh",22949321,"Small molecule inhibitors of RORγt: targeting Th17 cells and other applications.    Abstract:   Nuclear hormone receptors (NHRs) form a family of transcription factors that are composed of modular protein structures with DNA- and ligand-binding domains (DBDs and LBDs). The DBDs confer gene target site specificity, whereas LBDs serve as control switches for NHR function. For many NHRs, both endogenous and synthetic small molecule ligands bind to small pockets within the LBDs, resulting in conformational changes that regulate transcriptional activity. This property of NHRs has been exploited by the pharmaceutical industry for therapeutic targeting of a wide variety of diseases, ranging from inflammatory diseases and cancer to endocrine and metabolic diseases. Th17 cells are CD4(+) T helper effector cells that express several pro-inflammatory cytokines, including IL-17A, and the actions of these cells have been linked to multiple human autoimmune diseases. Our laboratory previously identified the NHR RORγt, an immune cell-specific isoform of RORγ (retinoic acid receptor-related orphan nuclear receptor gamma), as a key transcription factor for the development of Th17 cells both in human and mouse. Although endogenous ligands for RORγt have not yet been reported, it is thought that RORγt activity and Th17-cell development can be modulated with highly specific small molecules that bind to the RORγt LBD and displace its endogenous ligands. Recent studies from multiple groups have reported the activities of such inhibitors. In this mini review, we describe how RORγt inhibitors were identified and how they may contribute to our understanding about RORγt and its biology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I664,I664)","v":22916806},{"$f":"(LEN($J664) - LEN(SUBSTITUTE(LOWER($J664),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J664) - LEN(SUBSTITUTE(LOWER($J664),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J664) - LEN(SUBSTITUTE(LOWER($J664),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B664:D664)","v":1},2012,"Nutritional quality and health benefits of chickpea (Cicer arietinum L.): a review.","Jukanti",22916806,"Nutritional quality and health benefits of chickpea (Cicer arietinum L.): a review.    Abstract:   Chickpea (Cicer arietinum L.) is an important pulse crop grown and consumed all over the world, especially in the Afro-Asian countries. It is a good source of carbohydrates and protein, and protein quality is considered to be better than other pulses. Chickpea has significant amounts of all the essential amino acids except sulphur-containing amino acids, which can be complemented by adding cereals to the daily diet. Starch is the major storage carbohydrate followed by dietary fibre, oligosaccharides and simple sugars such as glucose and sucrose. Although lipids are present in low amounts, chickpea is rich in nutritionally important unsaturated fatty acids such as linoleic and oleic acids. β-Sitosterol, campesterol and stigmasterol are important sterols present in chickpea oil. Ca, Mg, P and, especially, K are also present in chickpea seeds. Chickpea is a good source of important vitamins such as riboflavin, niacin, thiamin, folate and the vitamin A precursor β-carotene. As with other pulses, chickpea seeds also contain anti-nutritional factors which can be reduced or eliminated by different cooking techniques. Chickpea has several potential health benefits, and, in combination with other pulses and cereals, it could have beneficial effects on some of the important human diseases such as CVD, type 2 diabetes, digestive diseases and some cancers. Overall, chickpea is an important pulse crop with a diverse array of potential nutritional and health benefits."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I665,I665)","v":22873216},{"$f":"(LEN($J665) - LEN(SUBSTITUTE(LOWER($J665),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J665) - LEN(SUBSTITUTE(LOWER($J665),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J665) - LEN(SUBSTITUTE(LOWER($J665),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B665:D665)","v":1},2012,"Chemoprevention of hepatocarcinogenesis with dietary isoprenic derivatives: cellular and molecular aspects.","Ong",22873216,"Chemoprevention of hepatocarcinogenesis with dietary isoprenic derivatives: cellular and molecular aspects.    Abstract:   Bioactive food components (BFACs) represent promising candidates for liver cancer chemoprevention. Among them, isoprenic derivatives (carotenoids, retinoids, perillyl alcohol, limonene, geraniol, farnesol, geranylgeraniol and β- ionone) can be highlighted. The relevance of animal models for the investigation of chemopreventive agents is supported by comparative functional genomic studies that reinforce the similarities between rodent and human hepatocarcinogenesis. Thus, characterization of BFACs in animal models as blocking and/or suppressing agents allows the establishment of the theoretical basis for the development of chemoprevention strategies. Dietary isoprenic derivatives actions on hepatocarcinogenesis may involve a block in carcinogen activation, induction of phase 2 enzymes and an antioxidant activity, as well as interference with cellular processes including cell communication, proliferation, apoptosis, differentiation and remodeling of preneoplastic lesions. Dietary isoprenic derivatives modulate molecular targets including HMG-CoA-reductase, Rho, nuclear receptors, c-myc, connexin 43, NF-κB and Nrf2. Several networks related to these targets are altered in early phases of hepatocarcinogenesis. This emphasizes the importance of such agents for the chemoprevention of hepatocellular carcinoma. Combinations of isoprenic derivatives or of these substances with other BFACs classes should be further investigated. Also, toxicity and bioavailability and pharmacokinetic aspects of these derivatives represent relevant issues in their development as chemopreventive agents. One major current limitation of the adoption of dietary isoprenic derivatives for liver cancer chemoprevention is the challenge in overcoming the initial preclinical phase in agent development. Dietary isoprenic derivatives that present liver cancer chemopreventive properties should be further explored in clinical trials, begining with the phase 0 approach."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I666,I666)","v":22789990},{"$f":"(LEN($J666) - LEN(SUBSTITUTE(LOWER($J666),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J666) - LEN(SUBSTITUTE(LOWER($J666),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J666) - LEN(SUBSTITUTE(LOWER($J666),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B666:D666)","v":1},2012,"Action of RORs and their ligands in (patho)physiology.","Solt",22789990,"Action of RORs and their ligands in (patho)physiology.    Abstract:   The retinoic-acid-receptor-related orphan receptors (RORs) are members of the nuclear receptor (NR) superfamily whose activity has been implicated in several physiological and pathological processes. The RORs, specifically RORα and RORγ, are considered to be master regulators of T(H)17 cells, a recently described subset of CD4(+) T helper cells that have been demonstrated to have a pathological role in autoimmune disease. As with most members of the NR superfamily, RORs are ligand-regulated, suggesting that their activity can be modulated by synthetic ligands. Recent advances in the field have established that selective inhibition of the RORs is a viable therapeutic approach for not only the treatment of autoimmune disorders but also ROR-mediated metabolic disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I667,I667)","v":22733267},{"$f":"(LEN($J667) - LEN(SUBSTITUTE(LOWER($J667),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J667) - LEN(SUBSTITUTE(LOWER($J667),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J667) - LEN(SUBSTITUTE(LOWER($J667),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B667:D667)","v":1},2012,"Nuclear receptor coregulators: modulators of pathology and therapeutic targets.","Lonard",22733267,"Nuclear receptor coregulators: modulators of pathology and therapeutic targets.    Abstract:   The nuclear receptor superfamily includes transcription factors that transduce steroid, thyroid and retinoid hormones and other ligands in conjunction with coregulators. To date, over 350 coregulators have been reported in the literature, and advances in proteomic analyses of coregulator protein complexes have revealed that a far greater number of coregulator-interacting proteins also exist. Coregulator dysfunction has been implicated in diverse pathological states, genetic syndromes and cancer. A hallmark of disease related to the disruption of normal coregulator function is the pleiotropic effect on animal physiology, which is frequently manifested as the dysregulation of metabolic and neurological systems. Coregulators have broad physiological and pathological functions that make them promising new drug targets for diseases such as hormone-dependent cancers. Advances in proteomics, genomics and transcriptomics have provided novel insights into the biology of coregulators at a system-wide level and will lead the way to a new understanding of how coregulators can be evaluated in the context of complex and multifaceted genetic factors, hormones, diet, the environment and stress. Ultimately, better knowledge of the associations that exist between coregulator function and human diseases is expected to expand the indications for the use of future coregulator-targeted drugs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I668,I668)","v":22696047},{"$f":"(LEN($J668) - LEN(SUBSTITUTE(LOWER($J668),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J668) - LEN(SUBSTITUTE(LOWER($J668),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J668) - LEN(SUBSTITUTE(LOWER($J668),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B668:D668)","v":1},2012,"Biological roles of liver X receptors in immune cells.","Pascual-García",22696047,"Biological roles of liver X receptors in immune cells.    Abstract:   Liver X receptors (LXRs) are members of the nuclear receptor superfamily that are activated by specific oxysterols. LXRs heterodimerize with retinoid X receptors to regulate positively the expression of a variety of target genes, many of which are involved in lipid and glucose metabolism. In the last few years, new targets of LXR activation have been identified with roles in the modulation of immune responses. Moreover, LXRs mediate repression of inflammatory pathways through mechanisms collectively known as transrepression. Here, we revise recent findings on the impact of LXR activation on immune responses, with an emphasis on advances in the understanding of the molecular mechanisms that mediate these effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I669,I669)","v":22656374},{"$f":"(LEN($J669) - LEN(SUBSTITUTE(LOWER($J669),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J669) - LEN(SUBSTITUTE(LOWER($J669),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J669) - LEN(SUBSTITUTE(LOWER($J669),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B669:D669)","v":1},2012,"Nutrigenomics and nutrigenetics of ω3 polyunsaturated fatty acids.","Vanden Heuvel",22656374,"Nutrigenomics and nutrigenetics of ω3 polyunsaturated fatty acids.    Abstract:   Diets rich in ω3 polyunsaturated fatty acids (ω3-PUFAs) such as alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid are associated with decreased incidence and severity of several chronic diseases including cardiovascular disease (CVD) and cancer. At least some of the beneficial effects of these dietary fatty acids are via metabolites such as prostaglandins, leukotrienes, thromboxanes, and resolvins. The effects of ω3-PUFAs are in contrast to those of fatty acids with virtually identical structures, such as the ω6-PUFAs linoleic acid and arachidonic acid, and their corresponding metabolites. The purpose of this chapter is to discuss both the nutrigenomics (nutrient-gene interactions) and nutrigenetics (genetic variation in nutrition) of dietary fatty acids with a focus on the ω3-PUFAs (Gebauer et al., 2007(1)). Important in the biological response for these fatty acids or their metabolites are cognate receptors that are able to regulate gene expression and coordinately affect metabolic or signaling pathways associated with CVD and cancer. Four nuclear receptor (NR) subfamilies will be emphasized as receptors that respond to dietary and endogenous ligands: (1) peroxisome proliferator-activated receptors, (2) retinoid X receptors, (3) liver X receptors, and (4) farnesoid X receptor. In addition to the different responses elicited by varying structures of fatty acids, responses may vary because of genetic variation in enzymes that metabolize ω3- and ω6 fatty acids or that respond to them. In particular, polymorphisms in the fatty acid desaturases and the aforementioned NRs contribute to the complexity of nutritional effects seen with ω3-PUFAs. Following a brief introduction to the health benefits of ω3-PUFAs, the regulation of gene expression by these dietary fatty acids via NRs will be characterized. Subsequently, the effects of single-nucleotide polymorphisms (SNPs) in key enzymes involved in the metabolism and response to ω3-PUFAs will be described. An outline of the events to be explored is shown in Fig. 1. Understanding the nutrigenomics and nutrigenetics of dietary fatty acids is key to understanding the etiology, as well as prevention, of critically important human diseases including CVD and cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I670,I670)","v":22595346},{"$f":"(LEN($J670) - LEN(SUBSTITUTE(LOWER($J670),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J670) - LEN(SUBSTITUTE(LOWER($J670),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J670) - LEN(SUBSTITUTE(LOWER($J670),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B670:D670)","v":1},2012,"The neural crest in cardiac congenital anomalies.","Keyte",22595346,"The neural crest in cardiac congenital anomalies.    Abstract:   This review discusses the function of neural crest as they relate to cardiovascular defects. The cardiac neural crest cells are a subpopulation of cranial neural crest discovered nearly 30 years ago by ablation of premigratory neural crest. The cardiac neural crest cells are necessary for normal cardiovascular development. We begin with a description of the crest cells in normal development, including their function in remodeling the pharyngeal arch arteries, outflow tract septation, valvulogenesis, and development of the cardiac conduction system. The cells are also responsible for modulating signaling in the caudal pharynx, including the second heart field. Many of the molecular pathways that are known to influence specification, migration, patterning and final targeting of the cardiac neural crest cells are reviewed. The cardiac neural crest cells play a critical role in the pathogenesis of various human cardiocraniofacial syndromes such as DiGeorge, Velocardiofacial, CHARGE, Fetal Alcohol, Alagille, LEOPARD, and Noonan syndromes, as well as Retinoic Acid Embryopathy. The loss of neural crest cells or their dysfunction may not always directly cause abnormal cardiovascular development, but are involved secondarily because crest cells represent a major component in the complex tissue interactions in the head, pharynx and outflow tract. Thus many of the human syndromes linking defects in the heart, face and brain can be better understood when considered within the context of a single cardiocraniofacial developmental module with the neural crest being a key cell type that interconnects the regions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I671,I671)","v":22419222},{"$f":"(LEN($J671) - LEN(SUBSTITUTE(LOWER($J671),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J671) - LEN(SUBSTITUTE(LOWER($J671),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J671) - LEN(SUBSTITUTE(LOWER($J671),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B671:D671)","v":1},2012,"Liver X receptors, atherosclerosis and inflammation.","Michael",22419222,"Liver X receptors, atherosclerosis and inflammation.    Abstract:   Liver X receptors (LXRs) belong to the nuclear receptor superfamily of ligand-dependent transcription factors. LXRs are activated by oxysterols, metabolites of cholesterol, and therefore act as intracellular sensors of this lipid. There are two LXR genes (α and β) that display distinct tissue/cell expression profiles. LXRs interact with regulatory sequences in target genes as heterodimers with retinoid X receptor. Such direct targets of LXR actions include important genes implicated in the control of lipid homeostasis, particularly reverse cholesterol transport. In addition, LXRs attenuate the transcription of genes associated with the inflammatory response indirectly by transrepression. In this review, we describe recent evidence that both highlights the key roles of LXRs in atherosclerosis and inflammation and provides novel insights into the mechanisms underlying their actions. In addition, we discuss the major limitations of LXRs as therapeutic targets for the treatment of atherosclerosis and how these are being addressed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I672,I672)","v":22342903},{"$f":"(LEN($J672) - LEN(SUBSTITUTE(LOWER($J672),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J672) - LEN(SUBSTITUTE(LOWER($J672),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J672) - LEN(SUBSTITUTE(LOWER($J672),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B672:D672)","v":1},2012,"Up- and down-regulation of adiponectin expression and multimerization: mechanisms and therapeutic implication.","Liu",22342903,"Up- and down-regulation of adiponectin expression and multimerization: mechanisms and therapeutic implication.    Abstract:   Adiponectin has been receiving a great deal of attention due to its potential therapeutic use for metabolic and cardiovascular disorders. Adiponectin expression levels and multimerization are down-regulated in obesity and up-regulated by insulin sensitizers such as thiazolidinediones (TZDs), metformin, sulfonylurea and resveratrol (RSV). The precise mechanisms underlying adiponectin up- and down-regulation remain largely unknown, but recent studies indicate that the cellular and plasma levels of adiponectin could be regulated at both transcriptional and post-transcriptional levels. At the post-translational level, TZDs and resveratrol promote adiponectin levels and multimerization via up-regulation of disulfide-bond-A oxidoreductase-like protein (DsbA-L). Adiponectin levels are also stimulated by FOXO1 and AMP-activated protein kinase (AMPK), and are suppressed by PKA or silencing mediator of retinoid and thyroid hormone receptors (SMRT). Since multimerization is important not only for adiponectin function but also for stability, increasing adiponectin multimerization has become a promising drug target for the treatment of metabolic diseases and other related disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I673,I673)","v":24279770},{"$f":"(LEN($J673) - LEN(SUBSTITUTE(LOWER($J673),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J673) - LEN(SUBSTITUTE(LOWER($J673),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J673) - LEN(SUBSTITUTE(LOWER($J673),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B673:D673)","v":1},2012,"The potential of rice to offer solutions for malnutrition and chronic diseases.","Dipti",24279770,"The potential of rice to offer solutions for malnutrition and chronic diseases.    Abstract:   It is internationally accepted that malnutrition and chronic diseases in developing countries are key limitations to achieving the Millennium Development Goals. In many developing countries, rice is the primary source of nutrition. In those countries, the major forms of malnutrition are Fe-induced anaemia, Zn deficiency and Vitamin A deficiency, whereas the major chronic disease challenges are Type II diabetes, cardiovascular disease and some cancers. There is a growing corpus of evidence regarding both limitations and opportunities as to how rice could be an effective vehicle by which to tackle key nutrition and health related problems in countries with limited resources. Rice breeding programs are able to focus on developing new varieties carrying enhanced amounts of either Fe, Zn or beta-carotene because of large public investment, and the intuitive link between providing a mineral/vitamin to cure a deficiency in that mineral/vitamin. By contrast, there has been little investment in progressing the development of particular varieties for potential impact on chronic diseases. In this review article we focus on the broad battery of evidence linking rice-related nutritional limitations to their impact on a variety of human health issues. We discuss how rice might offer sometimes even simple solutions to rectifying key problems through targeted biofortification strategies and finally, we draw attention to how recent technological (-omics) developments may facilitate untold new opportunities for more rapidly generating improved rice varieties specifically designed to meet the current and future nutritional needs of a rapidly expanding global population."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I674,I674)","v":22205187},{"$f":"(LEN($J674) - LEN(SUBSTITUTE(LOWER($J674),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J674) - LEN(SUBSTITUTE(LOWER($J674),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J674) - LEN(SUBSTITUTE(LOWER($J674),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B674:D674)","v":1},2012,"Pregnancy after bariatric surgery: a current view of maternal, obstetrical and perinatal challenges.","Magdaleno",22205187,"Pregnancy after bariatric surgery: a current view of maternal, obstetrical and perinatal challenges.    Abstract:    UNLABELLEDWith the increase in the number of bariatric surgeries being performed in women of childbearing age, physicians must have concerns regarding the safety of pregnancy after bariatric surgery. The aim of this review is to summarize the literature reporting on maternal, obstetrical and perinatal implications of pregnancy following BS.  METHODS : English, Spanish and Portuguese-language articles were identified in a PUBMED search from 2005 to February 2011 using the keywords for pregnancy and bariatric surgery or gastric bypass or gastric banding.  RESULTS : The studies show improved fertility and a reduced risk of gestational diabetes, pregnancy-induced hypertension and pre-eclampsia, macrosomia in pregnant women after bariatric surgery. The incidence of intrauterine growth restriction and small for gestational age are increased. No conclusions can be drawn concerning the risk for cesarean delivery and the best surgery-to-conception interval. Deficiencies in iron, vitamin A, vitamin B12, vitamin K, folate and calcium can result in maternal and fetal complications.  CONCLUSIONS : Pregnancy outcome of women who delivered after BS, as compared to obese populations, is better and safer and comparable to the general population. Close supervision before, during and after pregnancy following bariatric surgery and nutrient supplementation adapted to the patients individual requirements can prevent nutrition-related complications and improve maternal and fetal health."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I675,I675)","v":22167840},{"$f":"(LEN($J675) - LEN(SUBSTITUTE(LOWER($J675),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J675) - LEN(SUBSTITUTE(LOWER($J675),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J675) - LEN(SUBSTITUTE(LOWER($J675),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B675:D675)","v":1},2011,"[Matrix Gla-protein and its role in vascular wall calcification].","Harbuzova",22167840,"[Matrix Gla-protein and its role in vascular wall calcification].    Abstract:   Data on the structure of matrix Gla-protein (MGP), its chemical characteristics, regulation of synthesis and post-translational modifications are described. The information on the structure of the MGP gene, its well distributed polymorphisms are presented. Factors that regulate expression and activity of MGP include vitamin D, retinoic acid, extracellular calcium ions, cytokines, and some hormones. It is emphasized that MGP is an important inhibitor of calcification of soft tissues. These properties of this protein are associated with the presence of residues of gamma-carboxiglutamic acid of its molecule. Four possible mechanisms of anticalcinogenic action of MGP are described: binding with calcium ions and crystals of hydroxyapatite, binding to extracellular matrix components, interaction with bone morphogenetic protein (BMP-2) and elimination the effects of the latter, participation in the regulation of apoptosis. It is emphasized that the study of allelic variants of the MGP gene is important in the context of their possible association with the development of cardiovascular and other diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I676,I676)","v":22130718},{"$f":"(LEN($J676) - LEN(SUBSTITUTE(LOWER($J676),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J676) - LEN(SUBSTITUTE(LOWER($J676),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J676) - LEN(SUBSTITUTE(LOWER($J676),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B676:D676)","v":1},2012,"Endogenous inhibitory mechanisms and the regulation of platelet function.","Jones",22130718,"Endogenous inhibitory mechanisms and the regulation of platelet function.    Abstract:   The response of platelets to changes in the immediate environment is always a balance between activatory and inhibitory signals, the cumulative effect of which is either activation or quiescence. This is true of platelets in free flowing blood and of their regulation of haemostasis and thrombosis. In this review, we consider the endogenous inhibitory mechanisms that combine to regulate platelet activation. These include those derived from the endothelium (nitric oxide, prostacyclin, CD39), inhibitory receptors on the surface of platelets (platelet endothelial cell adhesion molecule-1, carcinoembryonic antigen cell adhesion molecule 1, G6b-B - including evidence for the role of Ig-ITIM superfamily members in the negative regulation of ITAM-associated GPVI platelet-collagen interactions and GPCR-mediated signalling and in positive regulation of quot;outside-inquot; integrin α(IIb)β(3)-mediated signalling), intracellular inhibitory receptors (retinoic X receptor, glucocorticoid receptor, peroxisome proliferator-activated receptors, liver X receptor), and emerging inhibitory pathways (canonical Wnt signalling, Semaphorin 3A, endothelial cell specific adhesion molecule, and junctional adhesion molecule-A)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I677,I677)","v":22055893},{"$f":"(LEN($J677) - LEN(SUBSTITUTE(LOWER($J677),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J677) - LEN(SUBSTITUTE(LOWER($J677),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J677) - LEN(SUBSTITUTE(LOWER($J677),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B677:D677)","v":1},2012,"Diet and risk of inflammatory bowel disease.","Andersen",22055893,"Diet and risk of inflammatory bowel disease.    Abstract:    BACKGROUND : A better understanding of the environmental factors leading to inflammatory bowel disease should help to prevent occurrence of the disease and its relapses.  AIM : To review current knowledge on dietary risk factors for inflammatory bowel disease.  METHODS : The PubMed, Medline and Cochrane Library were searched for studies on diet and risk of inflammatory bowel disease.  RESULTS : Established non-diet risk factors include family predisposition, smoking, appendectomy, and antibiotics. Retrospective case-control studies are encumbered with methodological problems. Prospective studies on European cohorts, mainly including middle-aged adults, suggest that a diet high in protein from meat and fish is associated with a higher risk of inflammatory bowel disease. Intake of the n-6 polyunsaturated fatty acid linoleic acid may confer risk of ulcerative colitis, whereas n-3 polyunsaturated fatty acids may be protective. No effect was found of intake of dietary fibres, sugar, macronutrients, total energy, vitamin C, D, E, Carotene, or Retinol (vitamin A) on risk of ulcerative colitis. No prospective data was found on risk related to intake of fruits, vegetables or food microparticles (titanium dioxide and aluminium silicate).  CONCLUSIONS : A diet high in protein, particular animal protein, may be associated with increased risk of inflammatory bowel disease and relapses. N-6 polyunsaturated fatty acids may predispose to ulcerative colitis whilst n-3 polyunsaturated fatty acid may protect. These results should be confirmed in other countries and in younger subjects before dietary counselling is recommended in high risk subjects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I678,I678)","v":21908933},{"$f":"(LEN($J678) - LEN(SUBSTITUTE(LOWER($J678),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J678) - LEN(SUBSTITUTE(LOWER($J678),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J678) - LEN(SUBSTITUTE(LOWER($J678),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B678:D678)","v":1},2011,"Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond [Review].","Hashimoto",21908933,"Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond [Review].    Abstract:   Thyroid hormone receptors (TRs) and liver X receptors (LXRs) are members of the nuclear receptor superfamily. Although LXRs and TRs belong to two distinct receptor subgroups with respect to ligand-binding affinity, the two receptor systems show similarity with respect to molecular mechanism, target genes, and physiological roles. Since both TRs and LXRs play an important role in metabolic regulation, form heterodimers with retinoid X receptors (RXRs), and bind to direct repeat-4 (DR-4) with identical geometry and polarity, crosstalk between these two receptors has been reported, especially on lipid metabolism-related genes. Recently, several types of crosstalk between TRs and LXRs have been identified and crosstalk has also been observed in other physiological systems such as central nervous system rather than lipid metabolism. In this review, recent advances in elucidating the molecular mechanisms of the crosstalk between these two nuclear receptors are discussed, with the aim of finding a perspective on unknown roles of TRs and LXRs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I679,I679)","v":26189518},{"$f":"(LEN($J679) - LEN(SUBSTITUTE(LOWER($J679),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J679) - LEN(SUBSTITUTE(LOWER($J679),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J679) - LEN(SUBSTITUTE(LOWER($J679),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B679:D679)","v":1},2011,"Chemoprevention against hepatocellular carcinoma.","Okano",26189518,"Chemoprevention against hepatocellular carcinoma.    Abstract:   Since the majority of hepatocellular carcinoma (HCC) arises from a background of chronic liver diseases caused by infection with hepatitis C virus (HCV) and hepatitis B virus (HBV), chemoprevention targeting patients at high risk of HCC is feasible. In this review article, we summarize current knowledge of chemoprevention against HCC mostly using phytochemicals which have less toxicity than pharmaceutical agents. We describe in vivo and in vitro evidence and proposed mechanisms of beneficial effects of several compounds on the liver, including acyclic retinoid (ACR), angiotensin-converting enzyme inhibitors (ACEIs), caffeine, capsaicin, cepharanthine (CEP), cinnamaldehyde, curcumin, diallyl sulfide (DAS), eicosapentaenoic acid (EPA), epigallocatechin-3-gallate (EGCG), genistein, lycopene, resveratrol, silymarin, sulforaphane (SFN), and xanthohumol (XN). Because antihepatocarcinogenic effects by these compounds are mostly based on experimental studies, clinical evidence is urgently necessary."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I680,I680)","v":21763723},{"$f":"(LEN($J680) - LEN(SUBSTITUTE(LOWER($J680),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J680) - LEN(SUBSTITUTE(LOWER($J680),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J680) - LEN(SUBSTITUTE(LOWER($J680),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B680:D680)","v":1},2011,"Proteins involved in uptake, intracellular transport and basolateral secretion of fat-soluble vitamins and carotenoids by mammalian enterocytes.","Reboul",21763723,"Proteins involved in uptake, intracellular transport and basolateral secretion of fat-soluble vitamins and carotenoids by mammalian enterocytes.    Abstract:   Our understanding of the molecular mechanisms responsible for fat-soluble vitamin uptake and transport at the intestinal level has advanced considerably over the past decade. On one hand, it has long been considered that vitamin D and E as well as β-carotene (the main provitamin A carotenoid in human diet) were absorbed by a passive diffusion process, although this could not explain the broad inter-individual variability in the absorption efficiency of these molecules. On the other hand, it was assumed that preformed vitamin A (retinol) and vitamin K1 (phylloquinone) absorption occurred via energy-dependent processes, but the transporters involved have not yet been identified. The recent discovery of intestinal proteins able to facilitate vitamin E and carotenoid uptake and secretion by the enterocyte has spurred renewed interest in studying the fundamental mechanisms involved in the absorption of these micronutrients. The proteins identified so far are cholesterol transporters such as SR-BI (scavenger receptor class B type I), CD36 (cluster determinant 36), NPC1L1 (Niemann-Pick C1-like 1) or ABCA1 (ATP-Binding Cassette A1) displaying a broad substrate specificity, but it is likely that other membrane proteins are also involved. After overviewing the metabolism of fat-soluble vitamins and carotenoids in the human upper gastrointestinal lumen, we will focus on the putative or identified proteins participating in the intestinal uptake, intracellular transport and basolateral secretion of these fat-soluble vitamins and carotenoids, and outline the uncertainties that need to be explored in the future. Identifying the proteins involved in intestinal uptake and transport of fat-soluble vitamins and carotenoids across the enterocyte is of great importance, especially as some of them are already targets for the development of drugs able to slow cholesterol absorption. Indeed, these drugs may also interfere with lipid vitamin uptake. A better understanding of the molecular mechanisms involved in fat-soluble vitamin and carotenoid absorption is a priority to better optimize their bioavailability."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I681,I681)","v":21526899},{"$f":"(LEN($J681) - LEN(SUBSTITUTE(LOWER($J681),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J681) - LEN(SUBSTITUTE(LOWER($J681),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J681) - LEN(SUBSTITUTE(LOWER($J681),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B681:D681)","v":1},2011,"The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis.","Solt",21526899,"The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis.    Abstract:   Research efforts spanning the past two decades have established a clear link between nuclear receptor function, regulation of the circadian clock and lipid homeostasis. As such, this family of receptors represents an important area of research. Recent advances in the field have identified two nuclear receptor subfamilies, the REV-ERBs and the retinoic acid receptor-related orphan receptors (RORs), as critical regulators of the circadian clock with significant roles in lipid homeostasis. In this review, the latest information garnered from cutting-edge research on these two nuclear receptor subfamilies will be discussed. Through direct targeting of the REV-ERBs and RORs with synthetic ligands, generation of novel tools aimed at characterizing their function in vivo have been developed, which may lead to novel therapeutics for the treatment of metabolic disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I682,I682)","v":21457433},{"$f":"(LEN($J682) - LEN(SUBSTITUTE(LOWER($J682),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J682) - LEN(SUBSTITUTE(LOWER($J682),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J682) - LEN(SUBSTITUTE(LOWER($J682),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B682:D682)","v":1},2011,"Review of liver injury associated with dietary supplements.","Stickel",21457433,"Review of liver injury associated with dietary supplements.    Abstract:   Dietary supplements (DS) are easily available and increasingly used, and adverse hepatic reactions have been reported following their intake. To critically review the literature on liver injury because of DSs, delineating patterns and mechanisms of injury and to increase the awareness towards this cause of acute and chronic liver damage. Studies and case reports on liver injury specifically because of DSs published between 1990 and 2010 were searched in the PubMed and EMBASE data bases using the terms dietary/nutritional supplements, adverse hepatic reactions, liver injury; hepatitis, liver failure, vitamin A and retinoids, and reviewed for yet unidentified publications. Significant liver injury was reported after intake of Herbalife and Hydroxycut products, tea extracts from Camellia sinensis, products containing usnic acid and high contents of vitamin A, anabolic steroids and others. No uniform pattern of hepatotoxicity has been identified and severity may range from asymptomatic elevations of serum liver enzymes to hepatic failure and death. Exact estimates on how frequent adverse hepatic reactions occur as a result of DSs cannot be provided. Liver injury from DSs mimicking other liver diseases is increasingly recognized. Measures to reduce risk include tighter regulation of their production and distribution and increased awareness of users and professionals of the potential risks."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I683,I683)","v":21392258},{"$f":"(LEN($J683) - LEN(SUBSTITUTE(LOWER($J683),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J683) - LEN(SUBSTITUTE(LOWER($J683),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J683) - LEN(SUBSTITUTE(LOWER($J683),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B683:D683)","v":1},2011,"The impact of oral vitamin A derivatives on lipid metabolism - What recommendations can be derived for dealing with this issue in the daily dermatological practice?","Klör",21392258,"The impact of oral vitamin A derivatives on lipid metabolism - What recommendations can be derived for dealing with this issue in the daily dermatological practice?    Abstract:   Retinoids and vitamin A derivatives have been widely used topically and systemically in the treatment of hyper- and parakeratotic skin diseases, genodermatoses, severe acne, autoimmune diseases (i. e. lupus erythematosus) or cutaneous T-cell lymphoma for more than 30 years. In addition to the desired proliferation-inhibiting, differentiation-inducing and antiinflammatory or sebo-suppressive effects, vitamin A derivatives also affect lipid metabolism. This is shown primarily by an increase of transaminases, triglycerides or cholesterol levels which vary in intensity from patient to patient. The degree of impact on the different parameters of lipid metabolism depends on the nature of the vitamin A derivative on the one hand due to different receptor specific binding interactions (RAR/RXR), while on the other hand posttranslational processes also play a major role. This review paper gives a brief, concise overview of the vitamin A derivatives and possible effects on lipid metabolism that can be expected. Additionally it contains a recommendation for secure handling of abnormal laboratory values before, during and after oral therapy with vitamin A derivatives. The aim of this article is to provide practical help and confidence in dealing with vitamin A derivatives in daily clinical practice. The publication was created in cooperation with the Deutsche Dermatologische Gesellschaft (DDG) and Deutsche Gesellschaft zur Bekämpfung von Fettstoffwechselstörungen und ihren Folgeerkrankungen (DGFF [Lipid-Liga] e. V.)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I684,I684)","v":21348819},{"$f":"(LEN($J684) - LEN(SUBSTITUTE(LOWER($J684),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J684) - LEN(SUBSTITUTE(LOWER($J684),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J684) - LEN(SUBSTITUTE(LOWER($J684),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B684:D684)","v":1},2011,"Application of innate immune molecules for a new class of drugs: infection, inflammation and beyond.","Kimura",21348819,"Application of innate immune molecules for a new class of drugs: infection, inflammation and beyond.    Abstract:   The innate immune system plays an important role systemically and locally in infectious and inflammatory diseases. Vaccines, vaccine adjuvants and anti-inflammatory drugs were developed by understanding mechanisms of the innate immune system and causative factors of infection and inflammatory diseases. Pattern-recognition receptors, such as Toll-like receptors, retinoic acid-inducible gene I (RIG-I)-like helicases and nucleotide-binding oligomerization domain(NOD)-like receptors, and their downstream signals have great potential as targets of therapeutics because they are involved in numerous diseases. Furthermore, proteolytic systems such as autophagy and immunoproteasomes play important roles in the innate immune system, making them potential therapeutic targets also. By taking advantage of the immune system, humankind has made a great effort to develop new therapeutic and preventive medicines. Accordingly, we have reported several studies on the development of vaccines and adjuvants based on novel mechanistic strategies. Additionally, we have elucidated the mechanism underlying an interaction between innate immunity and the endocrine system. This review introduces the possible use of innate immune molecules for the development of immunomodulatory drugs and the involvement of the immune system in endocrine metabolic diseases to discuss future applications of innate immune molecules to therapeutics of various inflammatory diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I685,I685)","v":21253791},{"$f":"(LEN($J685) - LEN(SUBSTITUTE(LOWER($J685),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J685) - LEN(SUBSTITUTE(LOWER($J685),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J685) - LEN(SUBSTITUTE(LOWER($J685),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B685:D685)","v":1},2011,"Chemoprevention of hepatocellular carcinoma in chronic hepatitis C.","Morgan",21253791,"Chemoprevention of hepatocellular carcinoma in chronic hepatitis C.    Abstract:   Hepatitis C virus (HCV) infection causes chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma (HCC). The incidence of hepatocellular carcinoma in the United States tripled between 1975 and 2005, and is expected to increase further, and to remain elevated for more than 20 years. Curing hepatitis C infection in patients with cirrhosis through treatment with peginterferon and ribavirin reduces the risk of developing hepatocellular carcinoma. Several noncurative treatments also appear to reduce the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Prospective studies report a reduced incidence of hepatocellular carcinoma among patients treated with a mixture of carotenoids with or without myo-inositol, with vitamin K₂, or with polyprenoic acid (an acyclic retinoid). Uncontrolled and/or retrospective studies have reported beneficial effects of treatment with Sho-saiko-to, glycyrrhizin and ursodeoxycholic acid on hepatocellular carcinoma incidence. Meta-analyses of epidemiologic studies show a reduced risk of hepatocellular carcinoma among liver disease patients who drink two or more cups of coffee per day. Numerous agents prevent or reduce hepatocarcinogenesis in animal models. An ongoing Phase II clinical trial is evaluating S-adenosylmethionine (SAMe) as a potential chemopreventive agent in hepatitis C cirrhosis. Overall, these data suggest that chemoprevention of hepatocellular carcinoma in patients with chronic hepatitis C is an achievable objective."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I686,I686)","v":21242240},{"$f":"(LEN($J686) - LEN(SUBSTITUTE(LOWER($J686),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J686) - LEN(SUBSTITUTE(LOWER($J686),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J686) - LEN(SUBSTITUTE(LOWER($J686),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B686:D686)","v":1},2011,"Vitamin A provision for preterm infants: are we meeting current guidelines?","Mactier",21242240,"Vitamin A provision for preterm infants: are we meeting current guidelines?    Abstract:    BACKGROUND : Preterm infants have reduced liver stores of vitamin A at birth compared to term born infants. Current guidelines recommend an intake of 700-1500 IU/kg/day vitamin A, and there is evidence to support higher doses for infants with significant lung disease. The importance of appropriate early nutrition for preterm infants is increasingly becoming apparent.  OBJECTIVES : To examine whether preterm infants admitted to a UK neonatal unit received the currently recommended amounts of vitamin A during the first 4 weeks of life, and to identify the feeding patterns associated with optimal vitamin A intake.  DESIGN : Retrospective case note review.  SETTING : UK tertiary neonatal unit.  POPULATION : 36 preterm infants with a median gestation of 30 weeks (range 26-33 weeks) and median birth weight of 1305 g (range 880-1800 g).  MAIN OUTCOME MEASURE : Mean daily total intake of vitamin A in each of the first 4 weeks of life.  RESULTS : Despite a policy of introducing intravenous lipid supplemented with fat soluble vitamins on day 2, only four infants (11%) consistently met the recommended daily intake of vitamin A during the first 2 weeks of life. Adequacy of vitamin A intake in the first 2 weeks of life was not predicted by gestation or pattern of feeding.  CONCLUSION : Recommendations for intravenous vitamin A supplementation in parenterally fed preterm infants require revision. Intravenous lipid with added fat soluble vitamins should be started as soon as possible after birth, and consideration given to early oral vitamin A supplementation in those infants tolerant of enteral feeds."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I687,I687)","v":21241729},{"$f":"(LEN($J687) - LEN(SUBSTITUTE(LOWER($J687),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J687) - LEN(SUBSTITUTE(LOWER($J687),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J687) - LEN(SUBSTITUTE(LOWER($J687),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B687:D687)","v":1},2011,"Sensing disease and danger: a survey of vertebrate PRRs and their origins.","Hansen",21241729,"Sensing disease and danger: a survey of vertebrate PRRs and their origins.    Abstract:   A key facet of the innate immune response lays in its ability to recognize and respond to invading microorganisms and cellular disturbances. Through the use of germ-line encoded PRRs, the innate immune system is capable of detecting invariant pathogen motifs termed pathogen-associated molecular patterns (PAMPS) that are distinct from host encoded proteins or products released from dying cells, which are known as damage-associated molecular patterns (DAMPs). PAMPs and DAMPs include both protein and nucleic acids for the detection and response to pathogens and metabolic quot;dangerquot; signals. This is by far one of the most active areas of research as recent studies have shown retinoic acid inducible gene 1 (RIG1)-like receptors (RLRs), the nucleotide-binding domain, leucine-rich repeat containing proteins (NLRs) and Toll-like receptors (TLRs) and the recently described AIM-like receptors (ALRs) are responsible for initiating interferon production or the assembly and activation of the inflammasome, ultimately resulting in the release of bioactive IL-1 family members. Overall, the vertebrate PRR recognition machinery consists of seven domains (e.g., Death, NACHT, CARD, TIR, LRR, PYD, helicase), most of which can be traced to the very origins of the deuterostomes. This review is intended to provide an overview of the basic components that are used by vertebrates to detect and respond to pathogens, with an emphasis on these receptors in fish as well as a brief note on their likely origins."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I688,I688)","v":21137622},{"$f":"(LEN($J688) - LEN(SUBSTITUTE(LOWER($J688),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J688) - LEN(SUBSTITUTE(LOWER($J688),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J688) - LEN(SUBSTITUTE(LOWER($J688),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B688:D688)","v":1},2010,"Diagnosis and treatment of Acanthosis nigricans.","Kapoor",21137622,"Diagnosis and treatment of Acanthosis nigricans.    Abstract:   Acanthosis nigricans is a dermatologic condition commonly seen in diabetics and obese individuals. Histologically, it is characterized by the proliferation of epidermal keratinocytes and fibroblasts. Clinically, the lesions appear as dark-brown thickened plaques. The neck and the axillas are the most commonly affected sites. Treatment involves management of the underlying disorder. Topical tretinoin and calcipotriol have also been used with some limited success. Other treatment options include laser and surgical excision."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I689,I689)","v":21067523},{"$f":"(LEN($J689) - LEN(SUBSTITUTE(LOWER($J689),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J689) - LEN(SUBSTITUTE(LOWER($J689),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J689) - LEN(SUBSTITUTE(LOWER($J689),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B689:D689)","v":1},2010,"Hepatic stellate cell (vitamin A-storing cell) and its relative--past, present and future.","Senoo",21067523,"Hepatic stellate cell (vitamin A-storing cell) and its relative--past, present and future.    Abstract:   HSCs (hepatic stellate cells) (also called vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells or Ito cells) exist in the space between parenchymal cells and liver sinusoidal endothelial cells of the hepatic lobule and store 50-80% of vitamin A in the whole body as retinyl palmitate in lipid droplets in the cytoplasm. In physiological conditions, these cells play pivotal roles in the regulation of vitamin A homoeostasis. In pathological conditions, such as hepatic fibrosis or liver cirrhosis, HSCs lose vitamin A and synthesize a large amount of extracellular matrix components including collagen, proteoglycan, glycosaminoglycan and adhesive glycoproteins. Morphology of these cells also changes from the star-shaped SCs (stellate cells) to that of fibroblasts or myofibroblasts. The hepatic SCs are now considered to be targets of therapy of hepatic fibrosis or liver cirrhosis. HSCs are activated by adhering to the parenchymal cells and lose stored vitamin A during hepatic regeneration. Vitamin A-storing cells exist in extrahepatic organs such as the pancreas, lungs, kidneys and intestines. Vitamin A-storing cells in the liver and extrahepatic organs form a cellular system. The research of the vitamin A-storing cells has developed and expanded vigorously. The past, present and future of the research of the vitamin A-storing cells (SCs) will be summarized and discussed in this review."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I690,I690)","v":21054565},{"$f":"(LEN($J690) - LEN(SUBSTITUTE(LOWER($J690),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J690) - LEN(SUBSTITUTE(LOWER($J690),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J690) - LEN(SUBSTITUTE(LOWER($J690),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B690:D690)","v":1},2011,"Depigmentation therapies for normal skin in vitiligo universalis.","AlGhamdi",21054565,"Depigmentation therapies for normal skin in vitiligo universalis.    Abstract:   If vitiligo involves most of the body, it might be easier to depigment the normal remaining skin rather than to attempt repigmentation. We reviewed the literature to date regarding available therapies for depigmenting the normal skin in vitiligo universalis. Our review revealed that the threshold regarding what percentage of body surface area qualifies as depigmentation is variable among practitioners. Monobenzyl ether of hydroquinone (MBEH) is the most widely used depigmenting agent and has few side-effects. Tretinoin in combination with MBEH is able to speed depigmentation of the skin. Monomethylether of hydroquinone has also been used successfully for depigmentation. Eighty-eight per cent phenol is also effective in depigmenting the skin but its application on large areas is toxic for liver and kidney. Different types of lasers are also available to destruct the melanocytes selectively, but this technique can be painful and expensive. Cryotherapy is a cheap depigmenting therapy but, because of scarring risk, it should only be used by experienced dermatologists. No trials have compared the efficacy of the above-mentioned well-established depigmentation agents/techniques. Certain drugs such as imatinib, imiquimod and diphencyprone, which are used to treat other diseases, caused depigmentation as a side-effect. Some depigmentation agents used for branding cattle can also serve as topical depigmentation agents. In conclusion, comparative clinical trials are needed to compare the efficacy of various depigmentation agents/techniques. In particular, topical imatinib, imiquimod and diphencyprone may be considered as potential depigmenting agents, which require further investigation. This review revealed that MBEH is safe and effective depigmenting agent."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I691,I691)","v":20960547},{"$f":"(LEN($J691) - LEN(SUBSTITUTE(LOWER($J691),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J691) - LEN(SUBSTITUTE(LOWER($J691),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J691) - LEN(SUBSTITUTE(LOWER($J691),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B691:D691)","v":1},2010,"Metabolic management following bariatric surgery.","Strohmayer",20960547,"Metabolic management following bariatric surgery.    Abstract:   Bariatric surgery is an effective treatment option for obesity. Commonly utilized procedures are either restrictive, malabsorptive, or both. Substantial weight loss can be achieved. Postoperatively, patients experience nutritional, metabolic, and hormonal changes that have important clinical implications. The postoperative diet should be advanced carefully, according to protocol. Micronutrient deficiencies such as vitamin C, vitamin A, and zinc deficiencies are common, especially following malabsorptive procedures. Bone metabolism is greatly affected, in part due to vitamin D deficiency, decreased calcium absorption, and secondary hyperparathyroidism. Diabetes improves acutely in malabsorptive procedures and in sequence with weight loss in restrictive procedures. Polycystic ovarian syndrome improves in nearly all women with this condition who undergo bariatric surgery. Testosterone levels in men also improve after surgery. Consideration of these nutritional, metabolic, and hormonal changes allows for optimal medical management following bariatric surgery."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I692,I692)","v":20957457},{"$f":"(LEN($J692) - LEN(SUBSTITUTE(LOWER($J692),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J692) - LEN(SUBSTITUTE(LOWER($J692),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J692) - LEN(SUBSTITUTE(LOWER($J692),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B692:D692)","v":1},2011,"Metabolic syndrome: from the genetics to the pathophysiology.","Sookoian",20957457,"Metabolic syndrome: from the genetics to the pathophysiology.    Abstract:   The metabolic syndrome (MS) constitutes a combination of underlying risk factors for an adverse outcome, cardiovascular disease. Thus, the clinical behavior of the MS can be regarded as a whole. Nevertheless, from a pathogenic point of view, understanding of the underlying mechanisms of each MS intermediate phenotype is far beyond their understanding as an integrative process. Systems biology introduces a new concept for revealing the pathogenesis of human disorders and suggests the presence of common physiologic processes and molecular networks influencing the risk of a disease. This paper shows a model of this concept to explain the genetic determinants of MS-associated phenotypes. Based on the hypothesis that common physiologic processes and molecular networks may influence the risk of MS disease components, we propose two systems-biology approaches: a gene enrichment analysis and the use of a protein-protein interaction network. Our results show that a network driven by many members of the nuclear receptor superfamily of proteins, including retinoid X receptor and farnesoid X receptor (FXR), may be implicated in the pathogenesis of the MS by its interactions at multiple levels of complexity with genes associated with metabolism, cell differentiation, and oxidative stress. In addition, we review two alternative genetic mechanisms that are gaining acceptance in the physiopathology of the MS: the regulation of transcriptional and post-transcriptional gene expression by microRNAs and epigenetic modifications such as DNA methylation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I693,I693)","v":20940115},{"$f":"(LEN($J693) - LEN(SUBSTITUTE(LOWER($J693),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J693) - LEN(SUBSTITUTE(LOWER($J693),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J693) - LEN(SUBSTITUTE(LOWER($J693),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B693:D693)","v":1},2010,"[New possibilities of targeted therapy in the treatment of hepatocellular carcinoma with the help of molecular biology].","Hagymási",20940115,"[New possibilities of targeted therapy in the treatment of hepatocellular carcinoma with the help of molecular biology].    Abstract:   Hepatocellular carcinoma (HCC) has a poor prognosis. Approximately 85% of patients are not candidates for curative treatments at the time of diagnosis; hence palliative modalities (transcatheter arterial chemoembolisation, radiofrequency ablation, systemic chemotherapy) are used. Systemic chemotherapies have disappointing results. The increasing knowledge in the molecular biology of HCC will increase the possibilities of targeted therapy. The multi-tyrosine kinase inhibitor sorafenib is the only drug which has approved. The VEGF-inhibitors (bevacizumab, sunitinib), EGFR-blocker agents (erlotinib), as well as the inhibition of mTOR (rapamycin) are promising. Combination of sorafenib or other anti-angiogenic agents with local ablative procedure (transcatheter arterial chemoembolisation, radiofrequency ablation), or with curative hepatectomy also can be favorable. Alteration of Wnt pathway, retinoid compounds, inhibition of the cell cycle as well as the proteosome, and epigenetic therapy can be other potential promising targets in HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I694,I694)","v":20926935},{"$f":"(LEN($J694) - LEN(SUBSTITUTE(LOWER($J694),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J694) - LEN(SUBSTITUTE(LOWER($J694),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J694) - LEN(SUBSTITUTE(LOWER($J694),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B694:D694)","v":1},2010,"Liver x receptors: a potential therapeutic target for modulating the atherosclerotic process.","Parikh",20926935,"Liver x receptors: a potential therapeutic target for modulating the atherosclerotic process.    Abstract:   Liver X receptors (LXRs) are nuclear receptors that play a major role in the expression of genes which are involved in lipid metabolism. LXRs are part of the superfamily of steroid receptors that work to deliver metabolic signals on the transcriptional level to either suppress or activate target genes. LXRs, once ligand-activated, work by forming heterodimers with the retinoid X receptor, after which they act as transcription factors by binding to the promoter region of deoxyribonucleic acid sequences, thereby affecting gene expression. Specifically, LXR has been shown to be involved with genes that help in the modulation of lipid metabolism, therein having a significant effect on the development or propagation of atherosclerosis. This review paper will discuss the overall function of LXRs and their role in lipid metabolism, and will help identify possible therapeutic modulators of LXRs that can be used for the prevention and treatment of atherosclerosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I695,I695)","v":20659512},{"$f":"(LEN($J695) - LEN(SUBSTITUTE(LOWER($J695),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J695) - LEN(SUBSTITUTE(LOWER($J695),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J695) - LEN(SUBSTITUTE(LOWER($J695),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B695:D695)","v":1},2010,"Functional crosstalk of CAR-LXR and ROR-LXR in drug metabolism and lipid metabolism.","Xiao",20659512,"Functional crosstalk of CAR-LXR and ROR-LXR in drug metabolism and lipid metabolism.    Abstract:   Nuclear receptor crosstalk represents an important mechanism to expand the functions of individual receptors. The liver X receptors (LXR, NR1H2/3), both the α and β isoforms, are nuclear receptors that can be activated by the endogenous oxysterols and other synthetic agonists. LXRs function as cholesterol sensors, which protect mammals from cholesterol overload. LXRs have been shown to regulate the expression of a battery of metabolic genes, especially those involved in lipid metabolism. LXRs have recently been suggested to play a novel role in the regulation of drug metabolism. The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic receptor that regulates the expression of drug-metabolizing enzymes and transporters. Disruption of CAR alters sensitivity to toxins, increasing or decreasing it depending on the compounds. More recently, additional roles for CAR have been discovered. These include the involvement of CAR in lipid metabolism. Mechanistically, CAR forms an intricate regulatory network with other members of the nuclear receptor superfamily, foremost the LXRs, in exerting its effect on lipid metabolism. Retinoid-related orphan receptors (RORs, NR1F1/2/3) have three isoforms, α, β and γ. Recent reports have shown that loss of RORα and/or RORγ can positively or negatively influence the expression of multiple drug-metabolizing enzymes and transporters in the liver. The effects of RORs on expression of drug-metabolizing enzymes were reasoned to be, at least in part, due to the crosstalk with LXR. This review focuses on the CAR-LXR and ROR-LXR crosstalk, and the implications of this crosstalk in drug metabolism and lipid metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I696,I696)","v":20615451},{"$f":"(LEN($J696) - LEN(SUBSTITUTE(LOWER($J696),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J696) - LEN(SUBSTITUTE(LOWER($J696),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J696) - LEN(SUBSTITUTE(LOWER($J696),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B696:D696)","v":1},2011,"Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR.","Krasowski",20615451,"Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR.    Abstract:   Nuclear hormone receptors (NHRs) are transcription factors that work in concert with co-activators and co-repressors to regulate gene expression. Some examples of ligands for NHRs include endogenous compounds such as bile acids, retinoids, steroid hormones, thyroid hormone, and vitamin D. This review describes the evolution of liver X receptors α and β (NR1H3 and 1H2, respectively), farnesoid X receptor (NR1H4), vitamin D receptor (NR1I1), pregnane X receptor (NR1I2), and constitutive androstane receptor (NR1I3). These NHRs participate in complex, overlapping transcriptional regulation networks involving cholesterol homeostasis and energy metabolism. Some of these receptors, particularly PXR and CAR, are promiscuous with respect to the structurally wide range of ligands that act as agonists. A combination of functional and computational analyses has shed light on the evolutionary changes of NR1H and NR1I receptors across vertebrates, and how these receptors may have diverged from ancestral receptors that first appeared in invertebrates."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I697,I697)","v":20596911},{"$f":"(LEN($J697) - LEN(SUBSTITUTE(LOWER($J697),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J697) - LEN(SUBSTITUTE(LOWER($J697),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J697) - LEN(SUBSTITUTE(LOWER($J697),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B697:D697)","v":1},2010,"The role of mesodermal signals during liver organogenesis in zebrafish.","Niu",20596911,"The role of mesodermal signals during liver organogenesis in zebrafish.    Abstract:   Three germ cell layers, the ectoderm, mesoderm and endoderm, are established during the gastrulation stage. All cell types in different organs and tissues are derived from these 3 germ cell layers at later stages. For example, skin epithelial cells and neuronal cells are derived from the ectoderm, while endothelial cells and muscle cells from the mesoderm and lung, and intestine epithelial cells from the endoderm. While in a normal situation different germ cells are destined to specific cell fates in different organs and tissues, each type of germ cells or its derivatives also produce extracellular signaling molecules to direct and facilitate the specification and differentiation of other germ cells during organogenesis. Liver is derived from the endoderm, but completion of liver organogenesis is regulated at different levels. While the pan-endoderm factors (e.g. FoxA and Gata families) and liver specific factors (e.g. Prox1 and Hhex) are essential intrinsic factors for endoderm cells to be differentiated into hepatoblasts, the role of signals produced by neighboring mesoderm cells for liver organogenesis is equally important. This review summarizes recent progress in studying the role of Bone morphogenetic proteins (Bmp), Fibroblast growth factors (Fgf), retinoic acid (RA) and Wingless and Int (Wnt), the 4 types of signaling molecules produced by the mesoderm cells, in liver organogenesis in zebrafish."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I698,I698)","v":20576803},{"$f":"(LEN($J698) - LEN(SUBSTITUTE(LOWER($J698),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J698) - LEN(SUBSTITUTE(LOWER($J698),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J698) - LEN(SUBSTITUTE(LOWER($J698),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B698:D698)","v":1},2010,"Orphan nuclear receptors in breast cancer pathogenesis and therapeutic response.","Riggins",20576803,"Orphan nuclear receptors in breast cancer pathogenesis and therapeutic response.    Abstract:   Nuclear receptors comprise a large family of highly conserved transcription factors that regulate many key processes in normal and neoplastic tissues. Most nuclear receptors share a common, highly conserved domain structure that includes a carboxy-terminal ligand-binding domain. However, a subgroup of this gene family is known as the orphan nuclear receptors because to date there are no known natural ligands that regulate their activity. Many of the 25 nuclear receptors classified as orphan play critical roles in embryonic development, metabolism, and the regulation of circadian rhythm. Here, we review the emerging role(s) of orphan nuclear receptors in breast cancer, with a particular focus on two of the estrogen-related receptors (ERRalpha and ERRgamma) and several others implicated in clinical outcome and response or resistance to cytotoxic or endocrine therapies, including the chicken ovalbumin upstream promoter transcription factors, nerve growth factor-induced B, DAX-1, liver receptor homolog-1, and retinoic acid-related orphan receptor alpha. We also propose that a clearer understanding of the function of orphan nuclear receptors in mammary gland development and normal mammary tissues could significantly improve our ability to diagnose, treat, and prevent breast cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I699,I699)","v":20547315},{"$f":"(LEN($J699) - LEN(SUBSTITUTE(LOWER($J699),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J699) - LEN(SUBSTITUTE(LOWER($J699),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J699) - LEN(SUBSTITUTE(LOWER($J699),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B699:D699)","v":1},2010,"Does chemotherapy prevent HCV-related hepatocellular carcinoma? Pros.","Masuzaki",20547315,"Does chemotherapy prevent HCV-related hepatocellular carcinoma? Pros.    Abstract:   Hepatitis C virus (HCV) infection, which seems to have spread worldwide recently, is now the leading cause of hepatocellular carcinoma (HCC) development in various geographic areas. The primary prevention of HCV-related HCC includes strategies for the prevention of HCV infection and those for viral eradication. Even after HCC development, short-term prognosis of patients has been much improved recently due to advances in early diagnosis and treatment. However, long-term prognosis is as yet far from satisfactory due to frequent recurrence of HCC even after apparently curative treatment, either local ablation or surgical resection. At least theoretically, strategies similar to those of primary prevention may be applicable to HCC recurrence. In this review, we summarized the reported favorable effects of chemotherapy on primary and tertiary prevention of HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I700,I700)","v":20492886},{"$f":"(LEN($J700) - LEN(SUBSTITUTE(LOWER($J700),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J700) - LEN(SUBSTITUTE(LOWER($J700),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J700) - LEN(SUBSTITUTE(LOWER($J700),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B700:D700)","v":1},2010,"[Etanercept and chronic infection by HCV and HBV].","Bordas",20492886,"[Etanercept and chronic infection by HCV and HBV].    Abstract:   Both psoriasis and chronic infections by HBV and HCV have high prevalence. Thus, it is relatively easy for them to coincide in the same patient. If the psoriasis requires systemic treatment, the dermatologist should consider the hepatic comorbidity when selecting an appropriate treatment. Cyclosporine, in addition to other well-known side effects, is an immunosuppressant that may condition worse evolution of the viral hepatitis. On the other hand, retinoids, psoralens and, above all, methotrexate may worsen the liver function. The anti-TNF-|A biological agents are not hepatotoxic and their theoretical contraindication in this context would be because of their action on the immune response and risk of reactivation of the hepatic infection. However, several studies have demonstrated that neither the viral load nor the hepatic inflammation parameters are generally modified negatively when they are used in hepatitis due to HCV. Their use in this context, with correct monitoring, seems, therefore, very reasonable. On the contrary, in chronic hepatitis B virus, there are cases of worsening, even with fatal outcome in some cases, and the use of these biological agents should be reserved for cases having greater need, and always be associated to antiviral treatment and strict monitoring. The review of the recent literature seems to allow the conclusion that the concomitant use of lamivudine would greatly reduce the risk of viral reactivation and, with this condition, the use of etanercept in some HBV+ patients may also be contemplated."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I701,I701)","v":20506379},{"$f":"(LEN($J701) - LEN(SUBSTITUTE(LOWER($J701),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J701) - LEN(SUBSTITUTE(LOWER($J701),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J701) - LEN(SUBSTITUTE(LOWER($J701),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B701:D701)","v":1},2010,"The biology and pathology of vitamin D control in bone.","Bell",20506379,"The biology and pathology of vitamin D control in bone.    Abstract:   Vitamin D is a steroid pro-hormone, whose active metabolite binds the vitamin D receptor (VDR) which, in turn, binds to DNA sequences on target genes as a heterodimer with the retinoid-X receptor, resulting in regulation of gene expression. The vitamin D pro-hormone can be synthesized in the skin, in response to ultraviolet radiation; however, dietary sources have become increasingly important as a result of cultural changes over the past few centuries. Based on its initial discovery as an anti-rachitic factor, studies of the role of vitamin D and its receptor have largely focused on the skeleton. Investigations into the pathophysiologic basis and therapeutic responses of skeletal disorders associated with impaired vitamin D action have led to the identification of the molecular pathways involved in hormone activation and regulation of gene expression by the liganded VDR. These studies have also demonstrated that the skeletal actions of the VDR and its ligand are largely redundant if normal mineral ion homeostasis can be maintained by other means. However, investigations in animal models with tissue-specific ablation of the VDR or the enzyme required for hormone activation have demonstrated novel actions in skeletal tissues. The active vitamin D metabolite has been shown to have both paracrine and endocrine actions in other tissues as well."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I702,I702)","v":20478364},{"$f":"(LEN($J702) - LEN(SUBSTITUTE(LOWER($J702),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J702) - LEN(SUBSTITUTE(LOWER($J702),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J702) - LEN(SUBSTITUTE(LOWER($J702),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B702:D702)","v":1},2010,"Crosstalk and DC-SCRIPT: expanding nuclear receptor modulation.","Ansems",20478364,"Crosstalk and DC-SCRIPT: expanding nuclear receptor modulation.    Abstract:   Nuclear receptors (NR) are intracellular receptors that execute a transcriptional program upon binding to hormones, vitamins and metabolic products. They are key regulators of distinct physiological processes, including growth and differentiation, metabolism, and immunity. The impact of NR activation on a given cell can differ from proliferation induction to programmed cell death. NR malfunction is associated with different diseases, such as diabetes, chronic inflammatory diseases and cancer. Much progress has been made towards understanding the transcriptional regulation by individual NR at the molecular level. However, essentially every cell expresses multiple NR and will encounter complex mixtures of NR ligands during its life cycle. In this review, we will focus on novel insights in balancing NR activity via NR crosstalk and DC-SCRIPT/ZNF366, a bi-functional NR coregulator. The impact on breast cancer development and prognosis will be discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I703,I703)","v":20463294},{"$f":"(LEN($J703) - LEN(SUBSTITUTE(LOWER($J703),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J703) - LEN(SUBSTITUTE(LOWER($J703),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J703) - LEN(SUBSTITUTE(LOWER($J703),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B703:D703)","v":1},2010,"Pathogenesis of alcoholic liver disease: the role of nuclear receptors.","Gyamfi",20463294,"Pathogenesis of alcoholic liver disease: the role of nuclear receptors.    Abstract:   Ethanol consumption causes fatty liver, which can lead to inflammation, fibrosis, cirrhosis and even liver cancer. The molecular mechanisms by which ethanol exerts its damaging effects are extensively studied, but not fully understood. It is now evident that nuclear receptors (NRs), including retinoid x receptor alpha and peroxisome proliferator-activated receptors, play key roles in the regulation of lipid homeostasis and inflammation during the pathogenesis of alcoholic liver disease (ALD). Given their pivotal roles in physiological processes, NRs represent potential therapeutic targets for the treatment and prevention of numerous metabolic and lipid-related diseases including ALD. This review summarizes the factors that contribute to ALD and the molecular mechanisms of ALD with a focus on the role of NRs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I704,I704)","v":20417372},{"$f":"(LEN($J704) - LEN(SUBSTITUTE(LOWER($J704),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J704) - LEN(SUBSTITUTE(LOWER($J704),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J704) - LEN(SUBSTITUTE(LOWER($J704),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B704:D704)","v":1},2010,"[Alitretinoin: Toctino].","Berbis",20417372,"[Alitretinoin: Toctino].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I705,I705)","v":20202584},{"$f":"(LEN($J705) - LEN(SUBSTITUTE(LOWER($J705),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J705) - LEN(SUBSTITUTE(LOWER($J705),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J705) - LEN(SUBSTITUTE(LOWER($J705),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B705:D705)","v":1},2010,"Postoperative metabolic and nutritional complications of bariatric surgery.","Koch",20202584,"Postoperative metabolic and nutritional complications of bariatric surgery.    Abstract:   Bariatric surgery has become an increasingly important method for management of medically complicated obesity. In patients who have undergone bariatric surgery, up to 87% with type 2 diabetes mellitus develop improvement or resolution of their disease postoperatively. Bariatric surgery can reduce the number of absorbed calories through performance of either a restrictive or a malabsorptive procedure. Patients who have undergone bariatric surgery require indefinite, regular follow-up care by physicians who need to follow laboratory parameters of macronutrient as well as micronutrient malnutrition. Physicians who care for patients after bariatric surgery need to be familiar with common postoperative syndromes that result from specific nutrient deficiencies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I706,I706)","v":20167001},{"$f":"(LEN($J706) - LEN(SUBSTITUTE(LOWER($J706),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J706) - LEN(SUBSTITUTE(LOWER($J706),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J706) - LEN(SUBSTITUTE(LOWER($J706),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B706:D706)","v":1},2009,"New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I.","Mo",20167001,"New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I.    Abstract:   CYP2C9 is one of the most abundant CYP enzymes in the human liver ( approximately 20% of hepatic total CYP content). CYP2C9 metabolizes approximately 20% clinical drugs (gt;120 drugs), including a number of drugs with narrow therapeutic ranges. Some natural compounds are also metabolized, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Typical substrates of CYP2C9 such as celecoxib, ibuprofen, flurbiprofen, and diclofenac are relatively small, lipophilic and contain acidic groupings with pK(a) values in the range 3.8-8.1 which will be ionized at physiological pH. The carboxylate groups of tienilic acid and diclofenac have been shown to be responsible for substrate preference and orientation in the active site of CYP2C9. Therefore, a typical CYP2C9 substrate should contain an anionic site and a hydrophobic site. However, neutral or positively charged compounds may also be substrates of CYP2C9. CYP2C9 is subject to inhibition by a number of drugs and other compounds and this may provide an explanation for some clinical drug-drug interactions. With regard to prodrugs that need CYP2C9 for activation, inhibition of CYP2C9 may cause a decrease in the amount of the active metabolite, leading to therapeutic failure. Pharmacophore models have revealed that hydrogen bonding, ion-pair interactions, and probably hydrophobic interactions play a major role in determining the substrate specificity and inhibitor selectivity of CYP2C9. A number of structure-activity relationship studies have identified the structural determinants of compounds for their binding affinity to CYP2C9 and inhibitory potency for CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates and/or inhibitors of CYP2C9 in drug development and drugs with minimal interactions with this enzyme should be chosen for further development. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I707,I707)","v":20080321},{"$f":"(LEN($J707) - LEN(SUBSTITUTE(LOWER($J707),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J707) - LEN(SUBSTITUTE(LOWER($J707),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J707) - LEN(SUBSTITUTE(LOWER($J707),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B707:D707)","v":1},2010,"X-linked ichthyosis: an oculocutaneous genodermatosis.","Fernandes",20080321,"X-linked ichthyosis: an oculocutaneous genodermatosis.    Abstract:   X-linked ichthyosis (XLI) is an X-linked recessive disorder of cutaneous keratinization with possible extracutaneous manifestations. It was first described as a distinct type of ichthyosis in 1965. XLI is caused by a deficiency in steroid sulfatase activity, which results in abnormal desquamation and a retention hyperkeratosis. XLI is usually evident during the first few weeks of life as polygonal, loosely adherent translucent scales in a generalized distribution that desquamate widely. These are quickly replaced by large, dark brown, tightly adherent scales occurring primarily symmetrically on the extensor surfaces and the side of the trunk. In addition, extracutaneous manifestations such as corneal opacities, cryptorchidism, and abnormalities related to contiguous gene syndromes may be observed. Diagnosis of XLI is usually made clinically, as the histopathology is nonspecific, but confirmation may be obtained through either biochemical or genetic analysis. Treatment should focus on cutaneous hydration, lubrication, and keratolysis and includes topical moisturizers and topical retinoids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I708,I708)","v":21525755},{"$f":"(LEN($J708) - LEN(SUBSTITUTE(LOWER($J708),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J708) - LEN(SUBSTITUTE(LOWER($J708),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J708) - LEN(SUBSTITUTE(LOWER($J708),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B708:D708)","v":1},2010,"Induction of cross-linking and silencing of Sp1 by transglutaminase during liver injury in ASH and NASH via different ER stress pathways.","Kojima",21525755,"Induction of cross-linking and silencing of Sp1 by transglutaminase during liver injury in ASH and NASH via different ER stress pathways.    Abstract:   Alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) share many histological similarities, but the molecular mechanisms responsible for hepatic apoptosis remain unclear. We previously reported that transglutaminase 2 (TG2), a protein cross-linking enzyme, is induced in the nucleus of ethanol-treated hepatocytes, and cross-links and inactivates a general transcription factor Sp1, which eventually leads to reduced expression of c-Met and caspase-independent hepatic apoptosis [Tatsukawa et al., Gastroenterology 2009;136:1783-1795]. In this study, we investigated if a similar change might be observed also in NASH and if yes how TG2 and cross-linked Sp1 (CLSp1) would be induced in NASH and ASH. We obtained elevated nuclear TG2 and CLSp1 formation in NASH patients, as well as in HepG2 cells treated with free fatty acids (FFAs). Biochemical analyses on this culture model revealed that both ethanol and FFAs provoked fat accumulation, endoplasmic reticulum (ER) stress, increased nuclear factor-κB (NFκB) and nuclear TG2, but the synergistic effect was not obvious between FFA and ethanol. Salubrinal, a selective inhibitor against dephosphorylation of eukaryotic initiation factor-2α in ER stress-induced pancreatic ER kinase (PERK) signal pathway, inhibited NFκB activation, nuclear TG2 expression and apoptosis only induced by FFAs, but not those induced by ethanol, while retinoid antagonist blocks ethanol induction of NFκB and TG2. These results suggest that FFA and ethanol may increase ER stress and lead to nuclear NFκB activation and TG2 induction through respectively distinctive pathways, leading to TG2-mediated apoptosis via cross-linking and inactivation of Sp1 and reduction in c-Met."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I709,I709)","v":19852886},{"$f":"(LEN($J709) - LEN(SUBSTITUTE(LOWER($J709),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J709) - LEN(SUBSTITUTE(LOWER($J709),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J709) - LEN(SUBSTITUTE(LOWER($J709),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B709:D709)","v":1},2009,"Cardiovascular disease-related genes and regulation by diet.","Vanden Heuvel",19852886,"Cardiovascular disease-related genes and regulation by diet.    Abstract:   Diets rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) such as alpha-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid are associated with decreased incidence and severity of cardiovascular disease (CVD). At least some of the beneficial effects of these dietary fatty acids are mediated by metabolites such as prostaglandins, leukotrienes, thromboxanes, and resolvins. The effects of n-3 PUFAs often differ from those of other fatty acids with very similar structures, such as linoleic acid and arachidonic acid (n-6 PUFAs) and their corresponding metabolites. This article reviews the evidence that specific receptors exist for fatty acids or their metabolites that are able to regulate gene expression and coordinately affect metabolic or signaling pathways associated with CVD. Four nuclear receptor subfamilies that respond to dietary and endogenous ligands and have implications for CVD are emphasized in this article: peroxisome proliferator-activated receptors, retinoid X receptors, liver X receptors, and the farnesoid X receptor."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I710,I710)","v":19837721},{"$f":"(LEN($J710) - LEN(SUBSTITUTE(LOWER($J710),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J710) - LEN(SUBSTITUTE(LOWER($J710),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J710) - LEN(SUBSTITUTE(LOWER($J710),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B710:D710)","v":1},2010,"Liver X receptor in cholesterol metabolism.","Zhao",19837721,"Liver X receptor in cholesterol metabolism.    Abstract:   The liver X receptors (LXRs) are nuclear receptors that are activated by endogenous oxysterols, oxidized derivatives of cholesterol. There are two isoforms of LXR, LXRalpha (NR1H3) and LXRbeta (NR1H2). Both LXRalpha and LXRbeta regulate gene expression by binding to DNA sequences associated with target genes as heterodimers with isoforms of the retinoid X receptor (RXR), RXRalpha (NR2B1), RXRbeta (NR2B2), and RXRgamma (NR2B3). LXRs act as cholesterol sensors: when cellular oxysterols accumulate as a result of increasing concentrations of cholesterol, LXR induces the transcription of genes that protect cells from cholesterol overload. In this review, we summarize the roles of LXRs in controlling cholesterol homeostasis, including their roles in bile acid synthesis and metabolism/excretion, reverse cholesterol transport, cholesterol biosynthesis and uptake, and cholesterol absorption/excretion in the intestine. The overlapping and distinct roles of the LXRalpha and LXRbeta isoforms, and the potential use of LXRs as attractive targets for treatment of cardiovascular disease are also discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I711,I711)","v":19702528},{"$f":"(LEN($J711) - LEN(SUBSTITUTE(LOWER($J711),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J711) - LEN(SUBSTITUTE(LOWER($J711),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J711) - LEN(SUBSTITUTE(LOWER($J711),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B711:D711)","v":1},2009,"Structure, function, regulation and polymorphism of human cytochrome P450 2A6.","Di",19702528,"Structure, function, regulation and polymorphism of human cytochrome P450 2A6.    Abstract:   The CYP2A6 gene spans a region of approximately 6 kb pairs consisting of 9 exons and has been mapped to the long arm of chromosome 19 (between 19q12 and 19q13.2). The CYP2A6 protein has 494 amino acids and is an important hepatic Phase I enzyme that metabolizes approximately 3% of therapeutic drugs (n gt; 30; e.g. valproic acid, pilocarpine, tegafur, fadrozole, ifosfamide, cyclophosphamide, nicotine, tamoxifen, promazine, propofol, and cisapride), environmental toxicants (e.g. gasoline additives), and many procarcinogens such as nitrosamines and aflatoxin B(1). This enzyme also participates in the biotransformation of several endogenous compounds such as retinoid acids and steroids. Because CYP2A6 is responsible for 70-80% of the initial metabolism of nicotine, CYP2A6 has been proposed to be a novel target for smoking cessation. Site-directed mutagenesis and homology modeling studies have identified a number of amino acids (e.g. F300, A301, S208, S369, and L370) that play a role in substrate recognition and binding. CYP2A6 shows a crystal structure with a compact, hydrophobic active site with Asn297 serving as one hydrogen bond donor and orienting substrates for regio-selective oxidation. CYP2A6 contains the second smallest active site cavity among the human CYPs with known structures. The regulation mechanism of CYP2A6 expression is not fully understood, but available data suggest that several nuclear receptors including constitutive androstane receptor, pregnane X receptor and glucocorticoid receptor are involved in its regulation. Pilocarpine and tranylcypromine are commonly used as selective competitive inhibitors of CYP2A6. Selegiline, methoxsalen, (R)-(+) menthofuran and decursinol angelate are mechanism-based inhibitors of CYP2A6. Both in vitro and in vivo studies have demonstrated a wide (20- to gt;100-fold) interindividual variation in CYP2A6 expression and activity, which is due primarily to genetic polymorphisms in the CYP2A6 gene, but CYP2A6 activity is also modified by certain drugs and pathological and environmental factors. To date, more than 36 variant alleles (*1B through *37) of the CYP2A6 gene have been identified. There have been 278 SNPs found in the CYP2A6 upstream sequence, 8 introns and 9 exons in NCBI dbSNP. Polymorphism of CYP2A6 has been associated with smoking behavior, drug clearance and lung cancer risk. Further studies are warranted to explore the role of CYP2A6 in clinical practice, drug development and toxicology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I712,I712)","v":19615405},{"$f":"(LEN($J712) - LEN(SUBSTITUTE(LOWER($J712),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J712) - LEN(SUBSTITUTE(LOWER($J712),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J712) - LEN(SUBSTITUTE(LOWER($J712),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B712:D712)","v":1},2009,"Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: key regulators of innate immunity.","Barral",19615405,"Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: key regulators of innate immunity.    Abstract:   The innate immune system responds within minutes of infection to produce type I interferons and pro-inflammatory cytokines. Interferons induce the synthesis of cell proteins with antiviral activity, and also shape the adaptive immune response by priming T cells. Despite the discovery of interferons over 50 years ago, only recently have we begun to understand how cells sense the presence of a virus infection. Two families of pattern recognition receptors have been shown to distinguish unique molecules present in pathogens, such as bacterial and fungal cell wall components, viral RNA and DNA, and lipoproteins. The first family includes the membrane-bound toll-like receptors (TLRs). Studies of the signaling pathways that lead from pattern recognition to cytokine induction have revealed extensive and overlapping cascades that involve protein-protein interactions and phosphorylation, and culminate in activation of transcription proteins that control the transcription of genes encoding interferons and other cytokines. A second family of pattern recognition receptors has recently been identified, which comprises the cytoplasmic sensors of viral nucleic acids, including MDA-5, RIG-I, and LGP2. In this review we summarize the discovery of these cytoplasmic sensors, how they recognize nucleic acids, the signaling pathways leading to cytokine synthesis, and viral countermeasures that have evolved to antagonize the functions of these proteins. We also consider the function of these cytoplasmic sensors in apoptosis, development and differentiation, and diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I713,I713)","v":19530969},{"$f":"(LEN($J713) - LEN(SUBSTITUTE(LOWER($J713),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J713) - LEN(SUBSTITUTE(LOWER($J713),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J713) - LEN(SUBSTITUTE(LOWER($J713),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B713:D713)","v":1},2009,"Statin regulation of CYP3A4 and CYP3A5 expression.","Willrich",19530969,"Statin regulation of CYP3A4 and CYP3A5 expression.    Abstract:   CYP3A4 and CYP3A5 are cytochrome P450 enzymes that are highly expressed in the liver and gut and metabolize endogenous compounds and xenobiotics. Statins are cholesterol-lowering drugs that are extensively metabolized by CYP3A4 and CYP3A5. The bioavailability of statins is affected by CYP3A4 and CYP3A5 and glucuronidases metabolism as well as uptake and efflux transporters that affect drug disposition. CYP3A4 and CYP3A5 variants have been demonstrated to influence the pharmacokinetics, efficacy and safety of statins. Inducers and inhibitors of CYP3A4 and CYP3A5 play an important role in reducing statin efficacy and increase the risk of adverse effects, respectively. Statins have been demonstrated to increase CYP3A expression in vitro, most likely because they are ligands to nuclear receptors (pregnane X receptor and constitutive androsterone receptor) that form heterodimers with retinoid X receptors and bind to responsive elements in the CYP3A4 and CYP3A5 promoter regions. This special report outlines the earlier studies on variability of response to statins owing to CYP3A variants and highlights findings on the induction of CYP3A4 and CYP3A5 expression by statins."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I714,I714)","v":19522700},{"$f":"(LEN($J714) - LEN(SUBSTITUTE(LOWER($J714),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J714) - LEN(SUBSTITUTE(LOWER($J714),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J714) - LEN(SUBSTITUTE(LOWER($J714),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B714:D714)","v":1},2009,"Aldo-keto reductase family 1 member B1 inhibitors: old drugs with new perspectives.","Liu",19522700,"Aldo-keto reductase family 1 member B1 inhibitors: old drugs with new perspectives.    Abstract:   Aldo-keto reductase 1 member B1 (AKR1B1) is pathogenically involved in diabetic complications by driving glucose flux through polyol pathway; a variety of AKR1B1 inhibitors has been developed for the treatment of diabetic complications and a body of invaluable preclinical and clinical data have been collected through decades efforts. Recent studies have shown that some AKR1B1 inhibitors demonstrate strong inhibitory activity to aldo-keto reductase family 1 member B10 (AKR1B10), a protein identical to AKR1B1, in vitro and in cancer cells. AKR1B1 and AKR1B10 are overexpressed in human tumors, such as liver, breast, and lung cancer, and may play a critical role in the development and progression of cancer through carbonyl detoxification, retinoic acid homeostatic regulation, and lipid metabolic control, as well as the activation of tobacco smoke carcinogens. Therefore, AKR1B1 inhibitors may represent a novel class of antitumor agents; and the clinical data assembled in diabetic clinics would greatly assist the transition of these inhibitors to cancer clinics. This article summaries the current understanding of the expression and function of AKR1B1 and AKR1B10 in human cancers and reviews the patents and papers of AKR1B1 inhibitors. Authors opinions concerning the current and future development of AKR1B1 and/or AKR1B10-specific inhibitors are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I715,I715)","v":19515014},{"$f":"(LEN($J715) - LEN(SUBSTITUTE(LOWER($J715),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J715) - LEN(SUBSTITUTE(LOWER($J715),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J715) - LEN(SUBSTITUTE(LOWER($J715),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B715:D715)","v":1},2009,"Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development.","Zhou",19515014,"Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development.    Abstract:   Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I716,I716)","v":19334283},{"$f":"(LEN($J716) - LEN(SUBSTITUTE(LOWER($J716),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J716) - LEN(SUBSTITUTE(LOWER($J716),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J716) - LEN(SUBSTITUTE(LOWER($J716),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B716:D716)","v":1},2009,"Xenopus pancreas development.","Pearl",19334283,"Xenopus pancreas development.    Abstract:   Understanding how the pancreas develops is vital to finding new treatments for a range of pancreatic diseases, including diabetes and pancreatic cancer. Xenopus is a relatively new model organism for the elucidation of pancreas development, and has already made contributions to the field. Recent studies have shown benefits of using Xenopus for understanding both early patterning and lineage specification aspects of pancreas organogenesis. This review focuses specifically on Xenopus pancreas development, and covers events from the end of gastrulation, when regional specification of the endoderm is occurring, right through metamorphosis, when the mature pancreas is fully formed. We have attempted to cover pancreas development in Xenopus comprehensively enough to assist newcomers to the field and also to enable those studying pancreas development in other model organisms to better place the results from Xenopus research into the context of the field in general and their studies specifically. Developmental Dynamics 238:1271-1286, 2009. (c) 2009 Wiley-Liss, Inc."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I717,I717)","v":19276889},{"$f":"(LEN($J717) - LEN(SUBSTITUTE(LOWER($J717),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J717) - LEN(SUBSTITUTE(LOWER($J717),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J717) - LEN(SUBSTITUTE(LOWER($J717),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B717:D717)","v":1},2009,"A network approach to micronutrient genetics: interactions with lipid metabolism.","Lietz",19276889,"A network approach to micronutrient genetics: interactions with lipid metabolism.    Abstract:    PURPOSE OF REVIEW : Although interactions between fat soluble micronutrients and lipid metabolism in relation to absorption, status and body composition have been well described, there is new evidence to suggest that key genes have profound effects on how micronutrients and lipids are handled in a range of cells and organs. This review highlights the importance of genetic variation in folate, selenium, zinc and carotenoid metabolism and the recent findings of micro-macro nutrient interactions.  RECENT FINDINGS : Although the methylenetetrahydrofolate reductase gene has been linked to CVD for some time, recent findings indicate that single-nucleotide polymorphisms (SNPs) in this gene are also linked to diabetes and may influence the pathogenesis of this disease through elevated alanine amino transferase concentrations. A recent selenium supplementation trial showed that SNPs can affect responses of GPx4, GPx1 and GPx3 protein expression or activity in response to Se supplementation or withdrawal. There is convincing evidence to suggest that the high variability of plasma carotenoids seen in human populations is at least partly caused by multiple genetic variations in genes involved in lipoprotein metabolism and lipid transfer. The most striking evidence of an interaction between carotenoid and lipid metabolism, however, comes from the observation that BCMO1 mice develop liver steatosis independent of the vitamin A content of the diet, and the discovery of common SNPs in this gene indicates that this interaction might be of clinical significance.  SUMMARY : Knowledge of genetic variants that affect micronutrient metabolism and responses to micronutrient supplementation were until recently largely limited to methylenetetrahydrofolate reductase. However, identification of novel functional SNPs in BCMO1, the critical enzyme of beta-carotene metabolism, and in several key selenoproteins indicates the potential importance of micronutrient-gene interactions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I718,I718)","v":19275452},{"$f":"(LEN($J718) - LEN(SUBSTITUTE(LOWER($J718),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J718) - LEN(SUBSTITUTE(LOWER($J718),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J718) - LEN(SUBSTITUTE(LOWER($J718),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B718:D718)","v":1},2009,"Spontaneous fracture: multiple causes.","Wick",19275452,"Spontaneous fracture: multiple causes.    Abstract:   Spontaneous fractures occur in seemingly normal bone with no apparent blunt-force trauma. Spontaneous fracture occurs primarily in two distinct groups of patients: the very active young and the elderly. Researchers and clinicians have used several terms interchangeably for spontaneous fracture, including pathologic fracture, fragility fracture, compression fracture, or fatigue or insufficiency fracture. Among the most common causes of spontaneous fracture are osteoporosis (calcium deficiency and corticosteroid-induced), malignancy, overexposure to vitamin A, periprosthetic weakening, Brucellosis, cerebral palsy (especially in children), and osteodystrophy because of chronic renal failure. Preliminary research observations indicate that spontaneous fracture may be a rare adverse outcome associated with bisphosphonates."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I719,I719)","v":19250188},{"$f":"(LEN($J719) - LEN(SUBSTITUTE(LOWER($J719),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J719) - LEN(SUBSTITUTE(LOWER($J719),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J719) - LEN(SUBSTITUTE(LOWER($J719),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B719:D719)","v":1},2009,"Perspectives in understanding the role of human 17beta-hydroxysteroid dehydrogenases in health and disease.","Meier",19250188,"Perspectives in understanding the role of human 17beta-hydroxysteroid dehydrogenases in health and disease.    Abstract:   Steroid signaling involves specific receptors that mediate genomic effects and many further proteins responsible for fast nongenomic activities. Metabolism at the position 17 of the steroid scaffold plays a pivotal role in the final regulation of the biological potency of steroid hormones. Enzymes responsible for that, the 17beta-hydroxysteroid dehydrogenases (17beta-HSD), act as carbonyl reductases and require cofactors for their catalytic activity. There is a substantial amount of evidence that human 17beta-HSDs are as well involved in the metabolic pathways of retinoids and fatty acid beyond that which has so far been anticipated. At present fourteen 17beta-HSDs have been annotated and characterized, and more might follow. Many of 17beta-HSDs have been shown to be involved in the pathogenesis of human disorders and are targets for therapeutic intervention. Strategies on deciphering the physiological role of the 17beta-HSD and the genetic predisposition for associated diseases will be presented involving analyses of animal models."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I720,I720)","v":19136457},{"$f":"(LEN($J720) - LEN(SUBSTITUTE(LOWER($J720),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J720) - LEN(SUBSTITUTE(LOWER($J720),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J720) - LEN(SUBSTITUTE(LOWER($J720),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B720:D720)","v":1},2009,"Reproductive outcome after bariatric surgery: a critical review.","Guelinckx",19136457,"Reproductive outcome after bariatric surgery: a critical review.    Abstract:    BACKGROUND : After many cycles of weight loss and weight gain, more and more morbidly obese patients undergo bariatric surgery, like gastric banding or gastric bypass, as the ultimate treatment for their obesity-problem. Since women of reproductive age are candidates for bariatric surgery, concerns arise regarding the potential impact on future pregnancy.  METHODS : English-language articles were identified in a PUBMED search from 1982 to January 2008 using the keywords for pregnancy and bariatric surgery or gastric bypass or gastric banding.  RESULTS : The few reported case-control and cohort studies clearly show improved fertility and a reduced risk in obstetrical complications, including gestational diabetes, macrosomia and hypertensive disorders of pregnancy, in women after operatively induced weight loss when compared with morbidly obesity women. The incidence of intrauterine growth restriction (IUGR) appears to be increased, however. No conclusions can be drawn concerning the risk for preterm labour and miscarriage, although these risks are probably increased compared with controls matched for body mass index. Operative complications are not uncommon with bariatric surgery and several cases have pointed to the increased risk for intestinal hernias and nutritional deficiencies in subsequent pregnancy. Deficiencies in iron, vitamin A, vitamin B(12), vitamin K, folate and calcium can result in both maternal complications, such as severe anaemia, and fetal complications, such as congenital abnormalities, IUGR and failure to thrive.  CONCLUSIONS : Close supervision before, during and after pregnancy following bariatric surgery and nutrient supplementation adapted to the patients individual requirements can help to prevent nutrition-related complications and improve maternal and fetal health, in this high-risk obstetric population."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I721,I721)","v":19035881},{"$f":"(LEN($J721) - LEN(SUBSTITUTE(LOWER($J721),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J721) - LEN(SUBSTITUTE(LOWER($J721),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J721) - LEN(SUBSTITUTE(LOWER($J721),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B721:D721)","v":1},2008,"Liver X receptors (LXR) as therapeutic targets in dyslipidemia.","Bełtowski",19035881,"Liver X receptors (LXR) as therapeutic targets in dyslipidemia.    Abstract:   Liver X receptors (LXR) alpha and beta belong to a family of nuclear receptors which form heterodimers with the retinoid X receptor (RXR) and, upon ligand binding, stimulate the expression of target genes. LXR were initially described as orphan receptors and later oxidized cholesterol derivatives (oxysterols) were identified as their natural ligands. In addition, several synthetic LXR agonists such as T0901317 and GW3965 were synthesized. Oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore LXR operate as cholesterol sensors which protect from cholesterol overload by inhibiting intestinal cholesterol absorption, stimulating cholesterol efflux from cells to high-density lipoproteins (HDL), its transport to the liver, conversion to bile acids, and biliary excretion. In addition, LXR agonists activate fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and liver steatosis. Lipogenic effect seems is the most important negative feature of LXR agonists considered as potential hypolipidemic drugs. Some of currently used drugs also affect LXR signaling. For example, statins may impair LXR signaling by inhibiting oxysterol synthesis, whereas fibrates and thiazolidinediones increase LXR expression and activity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I722,I722)","v":18806735},{"$f":"(LEN($J722) - LEN(SUBSTITUTE(LOWER($J722),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J722) - LEN(SUBSTITUTE(LOWER($J722),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J722) - LEN(SUBSTITUTE(LOWER($J722),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B722:D722)","v":1},2008,"[Selected mechanisms of the therapeutic effect of arsenic trioxide in cancer treatment].","Izdebska",18806735,"[Selected mechanisms of the therapeutic effect of arsenic trioxide in cancer treatment].    Abstract:   The properties of arsenic trioxide (arsenic) have been known for centuries. This compound has been used, among others, in the industrial production of paints and glass and also for the conservation of leather and wood. Although arsenic trioxide is highly toxic, this compound was shown to have a therapeutic potential as early as the fifteenth century. The period between the seventeenth and nineteenth centuries resulted in the development of new arsenic-based drugs which were applied for the treatment of skin diseases and acute promyelocytic leukemia. The mechanism of action of arsenic trioxide is mainly related to the induction of apoptosis (programmed cell death) in cancer cells. In particular it involves effects on the activities of JNK kinases, NF-kB transcription factor, glutathione, caspases, as well as pro- and anti-apoptotic proteins. Experiments investigating the effect of arsenic trioxide on cell lines such as glioma and prostate, breast, stomach, liver, and ovarian cancer are in progress. There are also clinical trials underway aimed at the use of arsenic trioxide with ascorbic acid, retinoid acid, and growth factors in combined therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I723,I723)","v":18781947},{"$f":"(LEN($J723) - LEN(SUBSTITUTE(LOWER($J723),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J723) - LEN(SUBSTITUTE(LOWER($J723),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J723) - LEN(SUBSTITUTE(LOWER($J723),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B723:D723)","v":1},2008,"Expression and function of cytochrome p450-dependent enzymes in human skin cells.","Baron",18781947,"Expression and function of cytochrome p450-dependent enzymes in human skin cells.    Abstract:   Scientific interest in defining the human bodys ability to limit the effects of administered drugs and xenobiotics dates from the mid-19th century when developing knowledge and techniques in the field of organic chemistry first made such studies possible. The first experimental evidence documenting the existence of cytochrome p450 (CYP) dates to the year 1955, when an enzyme system capable of oxidizing xenobiotic compounds was identified in the endoplasmic reticulum of liver homogenates. From these days on several studies analyzed the expression and function of metabolizing phase I enzymes in liver cells. Due to the unique structural features of human skin, little was known about the expression and function of CYP enzymes in this tissue and their role in uptake, metabolism and elimination of xenobiotics as well as endogenous substrates. Lasting recent years it has become clear that human skin cells express various CYP enzymes, including CYP26AI which is responsible for the metabolism of retinoic acid in skin cells. It has been also shown that CYP enzyme expression patterns are cell type and tissue specific and that in skin cells this differs significantly from its expression in other environmental interfaces such as the liver, lung and gastrointestinal tract. Therefore knowledge of skin-specific CYP expression and function is a prerequisite for pharmacological studies of the skin."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I724,I724)","v":18611256},{"$f":"(LEN($J724) - LEN(SUBSTITUTE(LOWER($J724),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J724) - LEN(SUBSTITUTE(LOWER($J724),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J724) - LEN(SUBSTITUTE(LOWER($J724),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B724:D724)","v":1},2008,"Abetalipoproteinemia: two case reports and literature review.","Zamel",18611256,"Abetalipoproteinemia: two case reports and literature review.    Abstract:   Abetalipoproteinemia (ABL, OMIM 200100) is a rare, autosomal recessive disorder, characterized by fat malabsorption, acanthocytosis and hypocholesterolemia in infancy. Later in life, deficiency of fat-soluble vitamins is associated with development of atypical retinitis pigmentosa, coagulopathy, posterior column neuropathy and myopathy. ABL results from mutations in the gene encoding the large subunit of microsomal triglyceride transfer protein (MTP; OMIM 157147). To date at least 33 MTP mutations have been identified in 43 ABL patients. We describe the clinical progress of two patients, both currently in the fifth decade of life, who were diagnosed with ABL as children and were treated with high oral doses of fat soluble vitamins, including vitamin E over the last three decades. Treatment appears to have been associated with arrest of the neuropathy and other complications in both patients. Because pharmacologic inhibition of MTP is being developed as a novel approach to reduce plasma cholesterol for prevention of cardiovascular disease, defining the long-term clinical features of patients with a natural deficiency in MTP might provide some insight into the possible effects of such treatments. We review the range of clinical, biochemical and molecular perturbations in ABL."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I725,I725)","v":18600385},{"$f":"(LEN($J725) - LEN(SUBSTITUTE(LOWER($J725),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J725) - LEN(SUBSTITUTE(LOWER($J725),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J725) - LEN(SUBSTITUTE(LOWER($J725),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B725:D725)","v":1},2008,"Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies.","Li",18600385,"Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies.    Abstract:   Activation of hepatic stellate cells (HSCs) is the dominant event in liver fibrosis. The early events in the organization of HSC activation have been termed initiation. Initiation encompasses rapid changes in gene expression and phenotype that render the cells responsive to cytokines and other local stimuli. Cellular responses following initiation are termed perpetuation, which encompasses those cellular events that amplify the activated phenotype through enhanced growth factor expression and responsiveness. Multiple cells and cytokines play a part in the regulation of HSC activation. HSC activation consists of discrete phenotype responses, mainly proliferation, contractility, fibrogenesis, matrix degradation, chemotaxis and retinoid loss. Currently, antifibrotic therapeutic strategies include inhibition of HSC proliferation or stimulation of HSC apoptosis, downregulation of collagen production or promotion of its degradation, administration of cytokines, and infusion of mesenchymal stem cells. In this review, we summarize the latest advances in our understanding of the mechanisms of HSC activation and possible antifibrotic therapeutic strategies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I726,I726)","v":18535165},{"$f":"(LEN($J726) - LEN(SUBSTITUTE(LOWER($J726),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J726) - LEN(SUBSTITUTE(LOWER($J726),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J726) - LEN(SUBSTITUTE(LOWER($J726),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B726:D726)","v":1},2008,"The emerging role of nuclear receptor RORalpha and its crosstalk with LXR in xeno- and endobiotic gene regulation.","Wada",18535165,"The emerging role of nuclear receptor RORalpha and its crosstalk with LXR in xeno- and endobiotic gene regulation.    Abstract:   Retinoid-related orphan receptors (RORs), including the alpha, beta and gamma isoforms (NR1F1-3), are orphan nuclear receptors that have been implicated in tissue development, immune responses, and circadian rhythm. Although RORalpha and RORgamma have been shown to be expressed in the liver, the hepatic function of these two RORs remains unknown. We have recently shown that loss of RORalpha and/or RORgamma can positively or negatively influence the expression of multiple Phase I and Phase II drug metabolizing enzymes and transporters in the liver. Among ROR responsive genes, we identified oxysterol 7alpha-hydroxylase (Cyp7b1), which plays a critical role in the homeostasis of cholesterol, as a RORalpha target gene. We showed that RORalpha is both necessary and sufficient for Cyp7b1 activation. Studies of mice deficient of RORalpha or liver X receptors (LXRs) revealed an interesting and potentially important functional crosstalk between RORalpha and LXR. The respective activation of LXR target genes and ROR target genes in RORalpha null mice and LXR null mice led to our hypothesis that these two receptors are mutually suppressive in vivo. LXRs have been shown to regulate a battery of metabolic genes. We conclude that RORs participate in the xeno- and endobiotic regulatory network by regulating gene expression directly or through crosstalk with LXR, which may have broad implications in metabolic homeostasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I727,I727)","v":18525185},{"$f":"(LEN($J727) - LEN(SUBSTITUTE(LOWER($J727),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J727) - LEN(SUBSTITUTE(LOWER($J727),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J727) - LEN(SUBSTITUTE(LOWER($J727),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B727:D727)","v":1},2008,"[Chemoprevention of hepatocellular carcinoma by acyclic retinoid].","Nagaki",18525185,"[Chemoprevention of hepatocellular carcinoma by acyclic retinoid].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I728,I728)","v":18505683},{"$f":"(LEN($J728) - LEN(SUBSTITUTE(LOWER($J728),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J728) - LEN(SUBSTITUTE(LOWER($J728),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J728) - LEN(SUBSTITUTE(LOWER($J728),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B728:D728)","v":1},2008,"Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the cancer diseases.","Jelski",18505683,"Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the cancer diseases.    Abstract:   Epidemiological data have identified chronic alcohol consumption as a significant risk factor for cancer in humans. The exact mechanism of ethanol-associated carcinogenesis has remained unknown. The metabolism of ethanol leads to generation of acetaldehyde (AA), which is highly toxic and carcinogenic. The amount of acetaldehyde to which cells or tissues are exposed after alcohol ingestion may be of great importance and may, among others, affects carcinogenesis. Ethanol is metabolized to acetaldehyde by alcohol dehydrogenase (ADH). The enzyme responsible for oxidation of acetaldehyde is aldehyde dehydrogenase (ALDH). Both formation and degradation of acetaldehyde depends on the activity of these enzymes. The total alcohol dehydrogenase activity is significantly higher in cancer tissues than in this healthy organs (e.g. liver, stomach, esophagus, colorectum). Moreover the activity of ADH is much higher than the activity of ALDH. This suggests that cancer cells have a greater capability for ethanol oxidation but less ability to remove acetaldehyde than normal tissues. In addition significant differences of ADH isoenzymes activities between cancer tissues and healthy organs may be a factor intensifying carcinogenesis by the increased ability to acetaldehyde formation from ethanol and disorders in metabolism of some biologically important substances (e.g. retinoic acid). The changes in activity of particular ADH isoenzymes in the sera of patients with different cancers, seem to be caused by release of these isoenzymes from cancer cells, and may be useful for diagnostics of this cancer. The particular isoenzymes of ADH present in the serum may indicate the cancer localization."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I729,I729)","v":18369680},{"$f":"(LEN($J729) - LEN(SUBSTITUTE(LOWER($J729),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J729) - LEN(SUBSTITUTE(LOWER($J729),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J729) - LEN(SUBSTITUTE(LOWER($J729),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B729:D729)","v":1},2008,"Prevention of vitamin and mineral deficiencies after bariatric surgery: evidence and algorithms.","Schweitzer",18369680,"Prevention of vitamin and mineral deficiencies after bariatric surgery: evidence and algorithms.    Abstract:   Bariatric surgery is widely accepted as first-choice treatment of morbid obesity and has also shown promising results in the treatment of diabetes and the metabolic syndrome. The number of operations each year is increasing, as well as, consequently, the urgent need for a coordinated nutritional approach, as micronutrient deficiencies occur frequently in these patients. Official guidelines on chronic use of multivitamins and minerals are, yet, unavailable in bariatric medicine. The current review provides an algorithm that supports bariatric teams to guarantee adequate nutrition after the operation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I730,I730)","v":18318655},{"$f":"(LEN($J730) - LEN(SUBSTITUTE(LOWER($J730),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J730) - LEN(SUBSTITUTE(LOWER($J730),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J730) - LEN(SUBSTITUTE(LOWER($J730),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B730:D730)","v":1},2008,"Nanodisks: hydrophobic drug delivery vehicles.","Ryan",18318655,"Nanodisks: hydrophobic drug delivery vehicles.    Abstract:   Members of the class of exchangeable apolipoproteins possess the unique capacity to transform phospholipid vesicle substrates into nanoscale disk-shaped bilayers. This reaction can proceed in the presence of exogenous hydrophobic biomolecules, resulting in the formation of novel transport vehicles termed nanodisks (NDs). The objective of this study is to describe the structural organization of NDs and evaluate the utility of these complexes as hydrophobic biomolecule transport vehicles. The topics presented focus on two distinct water insoluble drugs, amphotericin B (AMB) and all trans retinoic acid (ATRA). In vitro and in vivo studies reveal that AMB-ND display potent anti-fungal and anti-protozoal activity, while ATRA-ND show promise in the treatment of cancer. The versatility conferred by the presence of a polypeptide component provides opportunities for targeted delivery of ND to cells."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I731,I731)","v":18291307},{"$f":"(LEN($J731) - LEN(SUBSTITUTE(LOWER($J731),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J731) - LEN(SUBSTITUTE(LOWER($J731),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J731) - LEN(SUBSTITUTE(LOWER($J731),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B731:D731)","v":1},2008,"Nutritargeting.","Biesalski",18291307,"Nutritargeting.    Abstract:   The term quot;nutritargetingquot; in analogy to the term quot;drug targetingquot; means targeting nutrients to specific quot;targetquot; tissues. What is the rationale for this idea? Some tissues obviously are able to accumulate micronutrients selectively and to use them predominantly for specific functions. It has, for instance, been known for a long time that the accumulation of beta-carotene in the skin does not only provide a quot;golden-yellowquot; color but considerable antioxidative protection as well. Yet beta-carotene is only one of many antioxidants, which can be detected in the skin. Other carotenoids, for example, lutein and zeaxanthine, are preferentially found in the macula lutea, the so-called yellow spot in the eye. Here, carotenoids are subject to a metabolism typical for that tissue, which cannot be found in other tissues (e.g., formation of meso-zeaxanthine). In addition, they can specifically be absorbed into the macula. In the macula, they protect the retinal pigment epithelial cells against oxidative damage from UV light. Indeed, these two carotenoids can be protective against age-dependent macula degeneration. Another example is the tissues that are particularly rich in vitamin C, for example, the cortex of the suprarenal gland or the lens: here, vitamin C fulfills both antioxidative functions and metabolic ones as it helps in the formation of collagen structures. Approximately 40% of the bodys ascorbate is stored in skeletal muscle because this tissue is relatively abundant and its cellular concentration is tenfold higher than the plasma level. Similarly, the intracellular ascorbate concentration in the brain (3 mM) greatly exceeds the level in the extracellular fluid (200-400 muM). The majority of ascorbate is stored in the astroglial cells that are capable of reducing great quantities of DHAA to ascorbate, which then becomes available for release back into the extracellular fluid. Thus, the accumulation of vitamins respectively micronutrients in single tissues is not limited to a pure storage process like the storage of vitamin A in the liver, but is often connected with important and tissue-specific metabolic functions. When single micronutrients are applied for prevention or even intervention in diseases of organs or tissues, they are usually administered in higher doses for a longer period of time. The hope is to accumulate it this way sufficiently in the tissue and to thus be able to ensure the therapeutic success. This procedure, however, leads to a quot;floodingquot; of the whole organism with micronutrients and their potential enrichment in tissues which would usually not accumulate the respective micronutrient. Thus, unexpected side effects may occur. An attractive solution to these problems in the future could be to wrap up or apply micronutrients in such a way that they can selectively reach the targeted tissue. For this approach, called quot;drug targetingquot; by pharmacologists, one could introduce the analogous expression quot;nutritargetingquot; with respect to micronutrients. For such a nutritargeting there are already a lot of examples and developments which show that it is possible to accumulate micronutrients in target tissues while simultaneously circumventing or protecting other tissues. A substantial requirement for the development of quot;carriersquot; for nutritargeting is the availability of procedures or specific carriers, which allow the selected nutrients to bypass the main barriers that are encountered when, for example, circumventing the enteral route in the targeting process. The entrance areas for such a targeting are the nasal mucosa, the oral mucosa, the cornea, the skin, or the lung. In the case of enteral application of proteins, the packaging has to resist gastric digestion and the body must be able to absorb the particles through the intestinal mucosa without hydrolyzing the proteins in order for them to reach the systemic circulation. Another field in which nutritargeting may play an important role is the diseases where either systemic absorption is not possible (e.g., malabsorption/maldigestion) or where local deficits occur, which may not or only inadequately be supplied by systemic application."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I732,I732)","v":18283793},{"$f":"(LEN($J732) - LEN(SUBSTITUTE(LOWER($J732),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J732) - LEN(SUBSTITUTE(LOWER($J732),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J732) - LEN(SUBSTITUTE(LOWER($J732),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B732:D732)","v":1},2008,"Rare T-cell lymphomas.","Molina",18283793,"Rare T-cell lymphomas.    Abstract:   The evolving classification systems in lymphoma have been driven by advances in the pathologic characterization of lymphoid malignancies. As evidenced by the detailed pathology descriptions earlier, subdividing heterogenous diseases results in an increasing number of distinct subtypes. This has allowed pathologists to provide more accurate diagnoses and begin to shed light on the molecular mechanisms that underlie these disorders. However, clinical information on these rare subtypes has lagged. Standard staging studies are less useful for these primarily extranodal diseases, although newer technologies such as PET scanning might be useful in detecting and following sites of disease. Optimal management remains undefined. Although these lymphomas are often aggressive, particularly in the case of ETCL, HSTCL, and GD-TCL, standard combination-chemotherapy regimens have only rarely provided durable remissions. Highdose therapy strategies have shown early promise, particularly for HSTCL, although conclusive data to support its routine use is lacking. Other strategies such as biologic therapies as with retinoids for SPTCL have provided durable benefit for some patients with less toxicity. Ultimately, it will take larger series with these rare but increasingly recognized entities to better define a preferred management approach."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I733,I733)","v":18258684},{"$f":"(LEN($J733) - LEN(SUBSTITUTE(LOWER($J733),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J733) - LEN(SUBSTITUTE(LOWER($J733),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J733) - LEN(SUBSTITUTE(LOWER($J733),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B733:D733)","v":1},2008,"Adopting new orphans into the family of metabolic regulators.","Hummasti",18258684,"Adopting new orphans into the family of metabolic regulators.    Abstract:   The importance of the adopted metabolite receptors, such as peroxisome proliferator-activated receptor, liver X receptor, and farnesoid X receptor, in transcriptional control of metabolic pathways has been appreciated for many years. However, it is becoming increasingly clear that the number of nuclear receptors with roles in metabolism is much larger than initially suspected. Recent years have brought an intense effort to define the biological functions of the most enigmatic group of the nuclear receptor superfamily, the true orphan receptors, including nuclear receptor 4As, estrogen-related receptors, retinoid-related orphan receptors, and Rev-erbs. Unexpectedly, several of these receptors also turn out to have important functions in various aspects of metabolic control."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I734,I734)","v":18221121},{"$f":"(LEN($J734) - LEN(SUBSTITUTE(LOWER($J734),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J734) - LEN(SUBSTITUTE(LOWER($J734),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J734) - LEN(SUBSTITUTE(LOWER($J734),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B734:D734)","v":1},2007,"HDL elevation and lipid lowering therapy: current scenario and future perspectives.","Chhabria",18221121,"HDL elevation and lipid lowering therapy: current scenario and future perspectives.    Abstract:   High density lipoprotein (HDL) has proven its role in reverse cholesterol transport and cellular cholesterol efflux thus acting as a protective factor against atherogenic cardiovascular diseases. The article focuses primarily on structure and function of genes influencing HDL metabolism. Various novel targets involve liver X receptor, retinoid X receptor, peroxisome proliferators activated receptor agonists and apoA-I mimetics. New molecules targeting these nuclear receptors are described. Phospholipid transfer protein and scavenger receptor B1 are also attractive targets in HDL metabolism. ATP-Binding Cassette transporter A1 and several lipases also play a crucial role in HDL metabolism and are very useful target for atherogenic dyslipidemia. Cholesteryl ester transfer protein inhibitors have shown great promise as possible drug candidates of future. Notably, JTT-705 (Japan Tobacco, Roche) is of great interest in spite of withdrawal of torcetrapib. Considering modest effect of currently available therapeutic options on HDL, these novel HDL elevating targets are doubtlessly the target for future atherosclerotic intervention."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I735,I735)","v":18221072},{"$f":"(LEN($J735) - LEN(SUBSTITUTE(LOWER($J735),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J735) - LEN(SUBSTITUTE(LOWER($J735),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J735) - LEN(SUBSTITUTE(LOWER($J735),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B735:D735)","v":1},2006,"Non-steroidal LXR agonists; an emerging therapeutic strategy for the treatment of atherosclerosis.","Bennett",18221072,"Non-steroidal LXR agonists; an emerging therapeutic strategy for the treatment of atherosclerosis.    Abstract:   The Liver X Receptor (LXR) alpha and beta isoforms are members of the type II nuclear receptor family which function as obligate heterodimers with the Retinoid X Receptor (RXR). Upon agonist binding, the DNA Binding Domain (DBD) of LXR interacts with LXR response elements on target genes to initiate transcription. A number of genes have been shown to be modulated by LXR function, including the ATP-binding cassette transporter A1 (ABCA1). ABCA1 is involved in the process of reverse cholesterol transport (RCT) from macrophages in atherosclerotic plaques to high-density lipoproteins (HDL) in the plasma. Both homozygous and heterozygous mutations in ABCA1 result in conditions characterised by decreased levels of HDL and an earlier onset of atherosclerosis. A number of other genes are upregulated by LXR activation which would be expected to have either pro- or anti-atherogenic effects. One such target gene is sterol regulatory element binding protein-1c (SREBP-1c), which is involved in the process of lipogenesis leading to increased levels of triglycerides which are pro-atherogenic. The complexity of LXR responses, however, makes it difficult to extrapolate the positive or negative effects of each target gene in isolation to a conclusion as to the outcome in humans when all target genes are being modulated in concert. This review will cover the structural features and associated biological data of non-steroidal LXR modulators claimed for the treatment of cardiovascular disease, as well as highlighting preferred compounds where this information can be discerned. In addition to this patent information a précis of literature data relevant to the utility of specific compounds in the treatment of cardiovascular disease will be given where available."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I736,I736)","v":18220775},{"$f":"(LEN($J736) - LEN(SUBSTITUTE(LOWER($J736),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J736) - LEN(SUBSTITUTE(LOWER($J736),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J736) - LEN(SUBSTITUTE(LOWER($J736),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B736:D736)","v":1},2008,"Design, structure activity relationships and X-Ray co-crystallography of non-steroidal LXR agonists.","Bennett",18220775,"Design, structure activity relationships and X-Ray co-crystallography of non-steroidal LXR agonists.    Abstract:   The Liver X Receptor (LXR) alpha and beta isoforms are members of the type II nuclear receptor family which function as a heterodimer with the Retinoid X Receptor (RXR). Upon agonist binding, the formation of the LXR/RXR heterodimer takes place and ultimately the regulation of a number of genes begins. The LXR isoforms share 77% sequence homology, with LXRalpha having highest expression in liver, intestine, adipose tissue, and macrophages and LXRbeta being ubiquitously expressed. The aim of this article is to review the reported medicinal chemistry strategies towards the optimisation of novel non-steroidal chemotypes as LXR agonists. An analysis of the structural features important for LXR ligand binding will be given, utilising both structural activity relationship data obtained from LXR assays as well as X-ray co-crystallographic data obtained with LXR ligands and the LXR ligand binding domain (LBD). The X-ray co-crystallographic data analysis will detail the key structural interactions required for LXR binding/agonist activity and reveal the differences observed between chemotype classes. It has been postulated that a LXRbeta selective compound may have a beneficial outcome on the lipid profile for a ligand by dissociating the favourable and unfavourable effects of LXR agonists. Whilst there have been a few examples of compounds showing a modest level of LXRalpha selectivity, obtaining a potent LXRbeta selective compound has been more challenging. Analysis of the SAR and X-ray co-crystallographic data suggests that the rational design of a LXRbeta selective compound will not be trivial."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I737,I737)","v":18195085},{"$f":"(LEN($J737) - LEN(SUBSTITUTE(LOWER($J737),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J737) - LEN(SUBSTITUTE(LOWER($J737),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J737) - LEN(SUBSTITUTE(LOWER($J737),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B737:D737)","v":1},2008,"Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.","Friedman",18195085,"Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.    Abstract:   The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cells functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I738,I738)","v":18063918},{"$f":"(LEN($J738) - LEN(SUBSTITUTE(LOWER($J738),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J738) - LEN(SUBSTITUTE(LOWER($J738),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J738) - LEN(SUBSTITUTE(LOWER($J738),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B738:D738)","v":1},2007,"Liver X receptors (LXRs). Part I: structure, function, regulation of activity, and role in lipid metabolism.","Wójcicka",18063918,"Liver X receptors (LXRs). Part I: structure, function, regulation of activity, and role in lipid metabolism.    Abstract:   Liver X receptors (LXRs) alpha and ss belong to a family of nuclear receptors which form heterodimers with the retinoid X receptor and, upon ligand binding, stimulate the expression of target genes. LXRs were initially described as orphan receptors and oxidized cholesterol derivatives (oxysterols) were later identified as their natural ligands. In addition, several synthetic LXR agonists such as T0901317 and GW3965 were synthesized. Oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore the LXRs operate as cholesterol sensors which protect from cholesterol overload by: 1) inhibiting intestinal cholesterol absorption, 2) stimulating cholesterol efflux from cells to high-density lipoproteins through the ATP-binding cassette transporters ABCA1 and ABCG1, 3) activating the conversion of cholesterol to bile acids in the liver, and (4) activating biliary cholesterol and bile acid excretion. In addition, LXR agonists activate de novo fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and liver steatosis. Here we describe the structure and function of the LXRs, their endo- and exogenous agonists and antagonists, the regulation of LXR expression and activity, and their role in the regulation of cholesterol and lipid metabolism. In the accompanying article we characterize other effects of LXRs, alterations in LXR expression, and changes in the level of their endogenous agonists in pathological conditions as well as therapeutic implications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I739,I739)","v":17665093},{"$f":"(LEN($J739) - LEN(SUBSTITUTE(LOWER($J739),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J739) - LEN(SUBSTITUTE(LOWER($J739),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J739) - LEN(SUBSTITUTE(LOWER($J739),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B739:D739)","v":1},2007,"The importance of beta-carotene as a source of vitamin A with special regard to pregnant and breastfeeding women.","Strobel",17665093,"The importance of beta-carotene as a source of vitamin A with special regard to pregnant and breastfeeding women.    Abstract:   Vitamin A is essential for growth and differentiation of a number of cells and tissues. Notably during pregnancy and throughout the breastfeeding period, vitamin A has an important role in the healthy development of the fetus and the newborn, with lung development and maturation being particularly important. The German Nutrition Society (DGE) recommends a 40% increase in vitamin A intake for pregnant women and a 90% increase for breastfeeding women. However, pregnant women or those considering becoming pregnant are generally advised to avoid the intake of vitamin A rich liver and liver foods, based upon unsupported scientific findings. As a result, the provitamin A carotenoid beta-carotene remains their essential source of vitamin A. Basic sources of provitamin A are orange and dark green vegetables, followed by fortified beverages which represent between 20% and 40% of the daily supply. The average intake of beta-carotene in Germany is about 1.5-2 mg a day. Assuming a vitamin A conversion rate for beta-carotene for juices of 4:1, and fruit and vegetables between 12:1 and 26:1; the total vitamin A contribution from beta-carotene intake represents 10-15% of the RDA. The American Pediatrics Association cites vitamin A as one of the most critical vitamins during pregnancy and the breastfeeding period, especially in terms of lung function and maturation. If the vitamin A supply of the mother is inadequate, her supply to the fetus will also be inadequate, as will later be her milk. These inadequacies cannot be compensated by postnatal supplementation. A clinical study in pregnant women with short birth intervals or multiple births showed that almost 1/3 of the women had plasma retinol levels below 1.4 micromol/l corresponding to a borderline deficiency. Despite the fact that vitamin A and beta-carotene rich food is generally available, risk groups for low vitamin A supply exist in the western world. It is therefore highly critical to restrict the beta-carotene supply from diet, particularly from sources of beta-carotene with high consumer acceptance such as fortified juices (e.g. quot;ACE juicesquot;) or dietary supplements (e.g. multivitamins for pregnant women). For the part of the population unable to meet vitamin A requirements according to the DACH recommendations, sufficient intake of beta-carotene may be crucial to help improve and maintain adequate vitamin A status and prevention of developmental disorders. At this time it has to be urgently advised against restricting the beta-carotene supply or putting warning labels on beta-carotene fortified products. It is, however, highly recommended to improve the available data on nutrient intakes in Germany, especially for pregnant and breastfeeding women. For them, recommendations to be aware of potential nutrient intake inadequacies might prove useful."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I740,I740)","v":17981741},{"$f":"(LEN($J740) - LEN(SUBSTITUTE(LOWER($J740),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J740) - LEN(SUBSTITUTE(LOWER($J740),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J740) - LEN(SUBSTITUTE(LOWER($J740),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B740:D740)","v":1},2008,"Effect of soy proteins and isoflavones on lipid metabolism and involved gene expression.","Xiao",17981741,"Effect of soy proteins and isoflavones on lipid metabolism and involved gene expression.    Abstract:   Clinical trials and animal studies showed that ingestion of soy proteins improves blood lipid profiles including lowering triglyceride, total and LDL cholesterol levels and increasing HDL cholesterol content. However, the effective components in the soy and the mechanisms involved in the hypolipidemic actions are not fully understood. Increasing evidence from animal studies have suggested that soy components may regulate lipid metabolism by modulating the activities of key transcription factors and thereby changing the downstream gene expression involved in lipogenesis or lipolysis. It has been shown that intake of soy proteins alters the expression of genes for sterol regulatory element binding protein, peroxisomal proliferator activated receptor, and liver X receptor. Dietary soy proteins suppress the DNA binding activities of hepatic nuclear receptors for thyroid hormones and retinoic acid, and alter the activities of key enzymes including cholesterol 7alpha hydroxylase and ATPase/ATP synthase through post-translational protein modifications. This paper reviews the current understanding of the cellular and molecular events by which soy components affect lipid levels, especially focusing on modulation of transcription factors and regulation of gene expression involved in lipid metabolism by soy proteins and associated isoflavones."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I741,I741)","v":17972437},{"$f":"(LEN($J741) - LEN(SUBSTITUTE(LOWER($J741),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J741) - LEN(SUBSTITUTE(LOWER($J741),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J741) - LEN(SUBSTITUTE(LOWER($J741),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B741:D741)","v":1},2007,"Vitamin A: is it a risk factor for osteoporosis and bone fracture?","Ribaya-Mercado",17972437,"Vitamin A: is it a risk factor for osteoporosis and bone fracture?    Abstract:   Results from observational studies of the association between vitamin A intake or serum concentration and bone mineral density or fracture are mixed. The inconsistencies may be due, in part, to difficulties in obtaining an accurate assessment of vitamin A intake or status. Serum retinol is a poor measure of vitamin A status because it is subject to homeostatic control. Stable-isotope-dilution methodology gives a validated assessment of the total-body and liver vitamin A stores and is recommended in future studies on vitamin A status and osteoporosis. The potential for exacerbating an already serious public health problem with intakes of vitamin A currently considered safe indicates further research into this matter is warranted."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I742,I742)","v":19072444},{"$f":"(LEN($J742) - LEN(SUBSTITUTE(LOWER($J742),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J742) - LEN(SUBSTITUTE(LOWER($J742),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J742) - LEN(SUBSTITUTE(LOWER($J742),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B742:D742)","v":1},2007,"Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis.","Gao",19072444,"Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis.    Abstract:   Liver lymphocytes are enriched in natural killer (NK) cells, which are involved in innate immune defenses against viral infection and tumor transformation in the liver. Recent evidence indicates that NK cell activation by IFN-alpha, IFN-gamma or dsRNA attenuates liver fibrosis through the direct killing of activated hepatic stellate cells (HSCs). Interestingly, NK cells do not kill quiescent or fully activated HSCs, but only early-activated HSCs, as only these cells express elevated levels of the NK cell-activating ligand retinoic acid-induced early transcript (RAE)-1 and TNF-related apoptosis-inducing ligand receptors, in addition to downregulated levels of the NK-cell inhibitory ligand, MHC-I. Inhibition of liver fibrosis by NK cells can also be achieved through production of IFN-gamma, which induces HSC cell cycle arrest and apoptosis in a STAT1-dependent manner. Clinically, it has also been observed that NK cell activity is negatively correlated with liver fibrosis in patients with chronic hepatitis C infection. Therefore, since NK cells inhibit liver fibrosis, stimulating NK activity could potentially be a novel strategy to treat liver fibrosis. Clinical studies will be required to confirm whether stimulating NK cell activity is effective and safe in treating human liver fibrosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I743,I743)","v":17894159},{"$f":"(LEN($J743) - LEN(SUBSTITUTE(LOWER($J743),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J743) - LEN(SUBSTITUTE(LOWER($J743),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J743) - LEN(SUBSTITUTE(LOWER($J743),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B743:D743)","v":1},2007,"Nutritional status of vitamin A in morbid obesity before and after Roux-en-Y gastric bypass.","Chaves",17894159,"Nutritional status of vitamin A in morbid obesity before and after Roux-en-Y gastric bypass.    Abstract:   The objective of the present study was to identify the factors which contribute to the appearance and/or aggravation of Vitamin A Deficiency (VAD) in individuals with morbid obesity in the pre- and postoperative stages of Roux-en-Y gastric bypass (RYGBP). Bibliography searches were done in the data-bases of Medline and Lilacs, published in the last 35 years, priorizing the studies which assessed VAD through serum levels of retinol. The principal factors identified as contributors to VAD were oxidative stress, deficiency of other nutrients, lipid malabsorption in the postoperative stage, insufficient intake of lipids and food sources of Vitamin A, and presence of nonalcoholic fatty liver disease. The investigation of the nutritional status of Vitamin A in those individuals may foment intervention strategies easily incorporated in already established routine procedures, aiming to reduce VAD rates, which will reflect upon those individuals quality of life."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I744,I744)","v":17646865},{"$f":"(LEN($J744) - LEN(SUBSTITUTE(LOWER($J744),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J744) - LEN(SUBSTITUTE(LOWER($J744),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J744) - LEN(SUBSTITUTE(LOWER($J744),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B744:D744)","v":1},2007,"Molecular mechanisms of alcohol-mediated carcinogenesis.","Seitz",17646865,"Molecular mechanisms of alcohol-mediated carcinogenesis.    Abstract:   Approximately 3.6% of cancers worldwide derive from chronic alcohol drinking, including those of the upper aerodigestive tract, the liver, the colorectum and the breast. Although the mechanisms for alcohol-associated carcinogenesis are not completely understood, most recent research has focused on acetaldehyde, the first and most toxic ethanol metabolite, as a cancer-causing agent. Ethanol may also stimulate carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. Alcohol-related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I745,I745)","v":17645377},{"$f":"(LEN($J745) - LEN(SUBSTITUTE(LOWER($J745),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J745) - LEN(SUBSTITUTE(LOWER($J745),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J745) - LEN(SUBSTITUTE(LOWER($J745),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B745:D745)","v":1},2007,"Dermatologic adverse effects of antiretroviral therapy: recognition and management.","Luther",17645377,"Dermatologic adverse effects of antiretroviral therapy: recognition and management.    Abstract:   Despite the decrease in opportunistic infections associated with HIV in the highly active antiretroviral treatment (HAART) era, a significant number of patients still present with skin pathology, some of which can be attributed directly or indirectly to antiretroviral therapy. The non-nucleoside reverse transcriptase inhibitors exhibit a class effect with regard to skin adverse manifestations, and the spectrum of disease can vary from a mild morbilliform rash to Stevens-Johnson syndrome. Certain protease inhibitors are associated with rash, and indinavir causes retinoid-like manifestations such as paronychia, alopecia, ingrown toe-nails, and curling of straight hair. Abacavir, a nucleoside reverse transcriptase inhibitor, is notorious for causing a hypersensitivity reaction in select patients. The fusion inhibitor enfuvirtide causes injection-site reactions in the overwhelming majority of patients, although a new method of delivery has decreased the rate and severity of these reactions. A syndrome of lipoatrophy with or without lipohypertrophy, often termed lipodystrophy, has been described in patients receiving HAART. Potential management of lipoatrophy includes switching antiretrovirals and surgical treatment with facial fillers. Lastly, skin manifestations of the immune reconstitution inflammatory syndrome, including herpes zoster and warts, must be recognized and treated accordingly. In the evaluation of the individual HIV-infected patient receiving antiretroviral therapy who presents with a skin disorder, clinicians should consider the CD4 cell count as a marker of the degree of immunodeficiency, the specific antiretrovirals used, and the timing of the initiation of antiretroviral therapy in order to formulate a rational differential diagnosis. Management should be individualized based on the specific drug that is implicated and the severity of the reaction."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I746,I746)","v":17634721},{"$f":"(LEN($J746) - LEN(SUBSTITUTE(LOWER($J746),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J746) - LEN(SUBSTITUTE(LOWER($J746),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J746) - LEN(SUBSTITUTE(LOWER($J746),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B746:D746)","v":1},2007,"Oral lichen planus and lichenoid reactions: etiopathogenesis, diagnosis, management and malignant transformation.","Ismail",17634721,"Oral lichen planus and lichenoid reactions: etiopathogenesis, diagnosis, management and malignant transformation.    Abstract:   Lichen planus, a chronic autoimmune, mucocutaneous disease affects the oral mucosa (oral lichen planus or OLP) besides the skin, genital mucosa, scalp and nails. An immune mediated pathogenesis is recognized in lichen planus although the exact etiology is unknown. The disease most commonly affects middle-aged females. Oral lichenoid reactions (OLR) which are considered variants of OLP, may be regarded as a disease by itself or as an exacerbation of an existing OLP, by the presence of medication (lichenoid drug reactions) or dental materials (contact hypersensitivity). OLP usually presents as white striations (Wickhams striae), white papules, white plaque, erythema, erosions or blisters. Diagnosis of OLP is established either by clinical examination only or by clinical examination with histopathologic confirmation. Direct immunofluorescence examination is only used as an adjunct to the above method of diagnosis and to rule out specific autoimmune diseases such as pemphigus and pemphigoid. Histopathologic features of OLP and OLR are similar with suggestions of certain discriminatory features by some authors. Topical corticosteroids are the treatment of choice for OLP although several other medications have been studied including retinoids, tacrolimus, cyclosporine and photodynamic therapy. Certain OLP undergo malignant transformation and the exact incidence and mechanisms are still controversial. In this paper, etiopathogenesis, diagnosis, management and malignant transformation of OLP and OLR have been reviewed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I747,I747)","v":17627554},{"$f":"(LEN($J747) - LEN(SUBSTITUTE(LOWER($J747),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J747) - LEN(SUBSTITUTE(LOWER($J747),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J747) - LEN(SUBSTITUTE(LOWER($J747),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B747:D747)","v":1},2007,"Visceral fat as target of highly active antiretroviral therapy-associated metabolic syndrome.","Barbaro",17627554,"Visceral fat as target of highly active antiretroviral therapy-associated metabolic syndrome.    Abstract:   HIV-associated lipodystrophy or lipoatrophy, unreported before the introduction of highly active antiretroviral therapy (HAART), was first described in 1998, and has a prevalence ranging from 18% to 83%. As in genetic lipodystrophy syndromes, fat redistribution may precede the development of metabolic complications (dyslipidemia, insulin resistance) in HIV-infected patients receiving HAART. The pathogenesis of HAART-associated lipodystrophy and metabolic syndrome is complex and a number of factors are involved, including direct effects of HAART on lipid metabolism, endothelial and adipocyte cell function, and mitochondria. Protease inhibitors are responsible for a decrease in cytoplasmic retinoic-acid protein-1, in low density lipoprotein-receptor-related protein and in peroxisome proliferator activated receptor type-gamma. Nucleoside reverse transcriptase inhibitors, and thymidine analogues, are responsible for mitochondrial dysfunction as demonstrated by a decrease in subcutaneous adipose tissue mitochondrial DNA content. Both phenomena are responsible for a decreased differentiation of adipocytes, increased levels of free fatty acids and lipoatrophy. The increased levels of proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-6 may further contribute in development of lipodystrophy. TNF-alfa activates 11-beta-hydroxysteroid dehydrogenase type-1, which converts inactive cortisone to active cortisol, resulting in increased lipid accumulation in adipocytes and insulin resistance. HAART drugs and inflammatory cytokines are associated with a decrease in adiponectin. The levels of adiponectin and adiponectin-to-leptin ratio correlate positively with insulin resistance in HIV-infected patients with lipodystrophy. HAART-associated metabolic syndrome is an increasingly recognized clinical entity. The atherogenic profile of this syndrome may increase the risk of cardiovascular disease even in young HIV-infected patients. A better understanding of the molecular mechanisms responsible for this syndrome will lead to the discovery of new drugs that will reduce the incidence of lipodystrophy and related metabolic complications in HIV-infected patients receiving HAART."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I748,I748)","v":17539885},{"$f":"(LEN($J748) - LEN(SUBSTITUTE(LOWER($J748),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J748) - LEN(SUBSTITUTE(LOWER($J748),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J748) - LEN(SUBSTITUTE(LOWER($J748),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B748:D748)","v":1},2007,"Does birth spacing affect maternal or child nutritional status? A systematic literature review.","Dewey",17539885,"Does birth spacing affect maternal or child nutritional status? A systematic literature review.    Abstract:   This review addresses the question of whether a short birth interval is associated with adverse nutritional outcomes for the mother or the child. Indices of anthropometric status (maternal weight or body mass index; child growth) and micronutrient status (e.g. iron or vitamin A) were included as outcomes. A computerized search of all relevant papers published since 1966 was completed, and the snowball method was used to identify additional relevant published or unpublished papers. In total, 57 papers were found to contain data regarding the relationship between birth spacing and nutritional outcomes (35 for child nutrition, 11 for maternal anthropometric status, and 11 for maternal anaemia or micronutrient status). Of these, 23 papers were excluded from further consideration because they did not include any multivariate analysis, leaving 34 papers that met the criteria for the review (22 for child nutrition, eight for maternal anthropometric status, and four for maternal anaemia or micronutrient status). The studies on child nutrition outcomes indicate that a longer birth interval is associated with a lower risk of malnutrition in some populations, but not all. In those countries in which the relationship was significant, the reduction in stunting associated with a previous birth interval gt;or=36 months ranged from approximately 10% to 50%. Some of this reduction may be due to residual confounding, i.e. to factors not included in the analysis (such as breastfeeding and maternal height). The studies on maternal anthropometric outcomes yielded mixed results. Because the nutritional burden on the mother between pregnancies depends on the extent of breastfeeding, the interpregnancy interval is not the best measure of whether the mother has had a chance to recover from the pregnancy, in terms of repleting her nutritional status. Therefore, some studies examined the recuperative interval (duration of the non-pregnant, non-lactating interval) instead. Taken as a whole, the studies do not provide clear evidence of a link between interpregnancy or recuperative interval and maternal anthropometric status. This may be due, in part, to changes in the hormonal regulation of nutrient partitioning between the mother and the fetus when a mother is malnourished. Only four papers were identified that related to micronutrient status, three of which examined maternal anaemia. One study showed an increased risk for maternal anaemia when the interpregnancy interval was lt;6 months, but the analysis did not control for iron supplementation during pregnancy. The other two studies did not show a significant association between interpregnancy interval and maternal anaemia. One study of micronutrient status indicated no significant relationship between interpregnancy interval and maternal serum zinc, copper, magnesium, ferritin, folate or thyroid-stimulating hormone. Important methodological limitations were apparent in most of the studies. Thus, further research with more comprehensive control of potentially confounding variables is needed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I749,I749)","v":17464165},{"$f":"(LEN($J749) - LEN(SUBSTITUTE(LOWER($J749),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J749) - LEN(SUBSTITUTE(LOWER($J749),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J749) - LEN(SUBSTITUTE(LOWER($J749),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B749:D749)","v":1},2007,"[Prevention of hepatocellular carcinoma].","Song",17464165,"[Prevention of hepatocellular carcinoma].    Abstract:   Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and has the third highest mortality rate among malignancies in South Korea. Despite the continuing efforts for the early detection of HCC, the mortality rate and prognosis have not been improved yet. Its clinical behavior is quite different from other cancers. High recurrence rate after curative treatment might be the reason for poor prognosis. Several methods including chemoprevention, blocking the development of HCC, have been under investigations. The vaccine for hepatitis, in the form of primary prevention, is considered to be the most effective one inhibiting the development of liver disease. Furthermore, keeping away from hepatotoxic agents is another way for preventing liver cell injuries. Secondary prevention is to stop the development of HCC in chronic liver diseases. Since the level of DNA in hepatitis B virus (HBV) hepatitis patients is closely related with the development of HCC, it is helpful to lower the DNA level using anti-viral agents. In addition, IFN, one of the anti-viral agents, can inhibit HCV hepatitis from tumorigenesis. Cyclo-oxygenase (COX)-2 inhibitors are also alleged to have a function in interrupting the development of HCC. Tertiary prevention means the prevention of recurrence of HCC after successful treatment. Because of high recurrence rate, the prevention of recurrence should be one of the important factors affecting the prognosis of HCC. Up to now, COX inhibitors, retinoic acids, vitamin K2, glycyrrhizin epigallocatechin-3-gallate (EGCG), and ginseng had been reported to be effective for the chemoprevention of HCC. Further studies are required for an advancement in the prevention of HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I750,I750)","v":17434893},{"$f":"(LEN($J750) - LEN(SUBSTITUTE(LOWER($J750),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J750) - LEN(SUBSTITUTE(LOWER($J750),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J750) - LEN(SUBSTITUTE(LOWER($J750),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B750:D750)","v":1},2007,"Targeted therapy in nuclear medicine--current status and future prospects.","Oyen",17434893,"Targeted therapy in nuclear medicine--current status and future prospects.    Abstract:   In recent years, a number of new developments in targeted therapies using radiolabeled compounds have emerged. New developments and insights in radioiodine treatment of thyroid cancer, treatment of lymphoma and solid tumors with radiolabeled monoclonal antibodies (mAbs), the developments in the application of radiolabeled small receptor-specific molecules such as meta-iodobenzylguanidine and peptides and the position of locoregional treatment in malignant involvement of the liver are reviewed. The introduction of recombinant human thyroid-stimulating hormone and the possibility to enhance iodine uptake with retinoids has changed the radioiodine treatment protocol of patients with thyroid cancer. Introduction of radiolabeled mAbs has provided additional treatment options in patients with malignant lymphoma, while a similar approach proves to be cumbersome in patients with solid tumors. With radiolabeled small molecules that target specific receptors on tumor cells, high radiation doses can be directed to tumors in patients with disseminated disease. Radiolabeled somatostatin derivatives for the treatment of neuroendocrine tumors are the role model for this approach. Locoregional treatment with radiopharmaceuticals of patients with hepatocellular carcinoma or metastases to the liver may be used in inoperable cases, but may also be of benefit in a neo-adjuvant or adjuvant setting. Significant developments in the application of targeted radionuclide therapy have taken place. New treatment modalities have been introduced in the clinic. The concept of combining therapeutic radiopharmaceuticals with other treatment modalities is more extensively explored."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I751,I751)","v":17402795},{"$f":"(LEN($J751) - LEN(SUBSTITUTE(LOWER($J751),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J751) - LEN(SUBSTITUTE(LOWER($J751),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J751) - LEN(SUBSTITUTE(LOWER($J751),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B751:D751)","v":1},2007,"Classification and predictive modeling of liver X receptor response elements.","Varga",17402795,"Classification and predictive modeling of liver X receptor response elements.    Abstract:    BACKGROUND : The liver X receptor (LXR), a transcription factor that forms a heterodimer with the retinoid X receptor, plays a key role in the transcriptional regulation of many important genes implicated in prevalent metabolic diseases. In spite of numerous studies, a complete list of LXR direct target genes remains elusive. To complement experimental approaches, computational prediction can be used to help build such a list because all LXR target genes are expected to carry the response elements (LXREs) in their promoter or enhancer regions. In practice, however, such a prediction has been hampered by the inaccuracies of currently available predictive models of LXREs. We report on a novel computational application for the highly accurate prediction of LXREs in DNA sequences.  METHODS : We first conducted a comprehensive review of experimentally determined LXR target genes and collected all known LXREs. Subsequently, all such sites were classified using various computational methods based on sequence similarity to identify multiple subtypes. A library of Hidden Markov Models (LXRE.HMM) was developed to represent all subtypes and to enable the promoter scanning of LXR target genes.  RESULTS AND CONCLUSION : Our model outperformed the widely used LXRE model in MatInspector in identifying the LXREs for all known LXR direct target genes at the experimentally verified positions. As a result, this new approach will make the genomewide prediction of LXR target genes feasible."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I752,I752)","v":17368322},{"$f":"(LEN($J752) - LEN(SUBSTITUTE(LOWER($J752),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J752) - LEN(SUBSTITUTE(LOWER($J752),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J752) - LEN(SUBSTITUTE(LOWER($J752),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B752:D752)","v":1},2007,"Effects of vitamins, including vitamin A, on HIV/AIDS patients.","Mehta",17368322,"Effects of vitamins, including vitamin A, on HIV/AIDS patients.    Abstract:   An estimated 25 million lives have been lost to acquired immune-deficiency syndrome (AIDS) since the immunodeficiency syndrome was first described in 1981. The progress made in the field of treatment in the form of antiretroviral therapy (ART) for HIV disease/AIDS has prolonged as well as improved the quality of life of HIV-infected individuals. However, access to such treatment remains a major concern in most parts of the world, especially in the developing countries. Hence, there is a constant need to find low-cost interventions to complement the role of ART in prevention of HIV infection and slowing clinical disease progression. Nutritional interventions, particularly vitamin supplementation, have the potential to be a low-cost method for being such an intervention by virtue of their modulation of the immune system. Among all the vitamins, the role of vitamin A has been studied most extensively; most observational studies have found that low vitamin A levels are associated with increased risk of transmission of HIV from mother to child. This finding has not been supported by large randomized trials of vitamin A supplementation; on the contrary, these trials have found that vitamin A supplementation increases the risk of mother-to-child transmission (MTCT). There are a number of potential mechanisms that might explain these contradictory findings. One is the issue of reverse causality in observational studies-for instance, advanced HIV disease may suppress release of vitamin A from the liver. This would lead to low levels of vitamin A in the plasma despite the body having enough vitamin A liver stores. Further, advanced HIV disease is likely to increase the risk of MTCT, and hence it would appear that low serum vitamin A levels are associated with increased MTCT. The HIV genome also has a retinoic acid receptor element-hence, vitamin A may increase HIV replication via interacting with this element, thus increasing risk of MTCT. Finally, vitamin A is known to increase lymphoid cell differentiation, which leads to an increase in CCR5 receptors. These receptors are essential for attachment of HIV to the lymphocytes and therefore, an increase in their number is likely to increase HIV replication. Vitamin A supplementation in HIV-infected children, on the other hand, has been associated with protective effects against mortality and morbidity, similar to that seen in HIV-negative children. The risk for lower respiratory tract infection and severe watery diarrhea has been shown to be lower in HIV-infected children supplemented with vitamin A. All-cause mortality and AIDS-related deaths have also been found to be lower in vitamin A-supplemented HIV-infected children. The benefits of multivitamin supplementation, particularly vitamins B, C, and E, have been more consistent across studies. Multivitamin supplementation in HIV-infected pregnant mothers has been shown to reduce the incidence of adverse pregnancy outcomes such as fetal loss and low birth weight. It also has been shown to decrease rates of MTCT among women who have poor nutritional or immunologic status. Further, multivitamin supplementation reduces the rate of HIV disease progression among patients in early stage of disease, thus delaying the need for ART by prolonging the pre-ART stage. In brief, there is no evidence to recommend vitamin A supplementation of HIV-infected pregnant women; however, periodic vitamin A supplementation of HIV-infected infants and children is beneficial in reducing all-cause mortality and morbidity and is recommended. Similarly, multivitamin supplementation of people infected with HIV, particularly pregnant women, is strongly suggested."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I753,I753)","v":17349800},{"$f":"(LEN($J753) - LEN(SUBSTITUTE(LOWER($J753),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J753) - LEN(SUBSTITUTE(LOWER($J753),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J753) - LEN(SUBSTITUTE(LOWER($J753),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B753:D753)","v":1},2007,"Carotenoids and human health.","Rao",17349800,"Carotenoids and human health.    Abstract:   Oxidative stress is an important contributor to the risk of chronic diseases. Dietary guidelines recommend increased consumption of fruits and vegetables to combat the incidence of human diseases such as cancer, cardiovascular disease, osteoporosis and diabetes. Fruits and vegetables are good sources of antioxidant phytochemicals that mitigate the damaging effect of oxidative stress. Carotenoids are a group of phytochemicals that are responsible for different colors of the foods. They are recognized as playing an important role in the prevention of human diseases and maintaining good health. In addition to being potent antioxidants some carotenoids also contribute to dietary vitamin A. There is scientific evidence in support of the beneficial role of phytochemicals in the prevention of several chronic diseases. Although the chemistry of carotenoids has been studied extensively, their bioavailability, metabolism and biological functions are only now beginning to be investigated. Recent interest in carotenoids has focused on the role of lycopene in human health. Unlike some other carotenoids, lycopene does not have pro-vitamin A properties. Because of the unsaturated nature of lycopene it is considered to be a potent antioxidant and a singlet oxygen quencher. This article will review carotenoids in general and lycopene in particular for their role in human health."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I754,I754)","v":17311876},{"$f":"(LEN($J754) - LEN(SUBSTITUTE(LOWER($J754),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J754) - LEN(SUBSTITUTE(LOWER($J754),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J754) - LEN(SUBSTITUTE(LOWER($J754),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B754:D754)","v":1},2007,"Antioxidant vitamin supplementation in cardiovascular diseases.","Riccioni",17311876,"Antioxidant vitamin supplementation in cardiovascular diseases.    Abstract:   Cardiovascular disease is the most important adult health problem in wealthy countries, where biological factors such as obesity, hypertension, dyslipidemia, diabetes, inappropriate diet, cigarette smoking, and sedentary life-style have contributed to its dissemination. Research concerning nutritional regimens has shown that persons who consume large amounts of fruit and vegetables have lower incidences of cardiovascular diseases, stroke, and tumors, although the precise mechanisms for this protective effect are elusive. Possible explanations include (a) increased consumption of dietary fiber, (b) reduced consumption of dietary cholesterol and other lipids, and (c) increased intake of the antioxidant vitamins (A, C, and E). Numerous studies have raised the question whether vitamin supplements help to prevent cardiovascular diseases. Results of randomized controlled trials of antioxidant vitamin supplements in large numbers of participants has been ambiguous or contradictory. This minireview examines the relevant clinical reports on dietary supplements of vitamins A, C, and E to determine whether they support the premise that patients at risk of cardiovascular disease may be candidates for this therapeutic option."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I755,I755)","v":17168675},{"$f":"(LEN($J755) - LEN(SUBSTITUTE(LOWER($J755),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J755) - LEN(SUBSTITUTE(LOWER($J755),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J755) - LEN(SUBSTITUTE(LOWER($J755),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B755:D755)","v":1},2006,"Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets.","Narayanan",17168675,"Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets.    Abstract:   Chemoprevention has the potential to be a major component of colon, breast, prostate and lung cancer control. Epidemiological, experimental, and clinical studies provide evidence that antioxidants, anti-inflammatory agents, n-3 polyunsaturated fatty acids and several other phytochemicals possess unique modes of action against cancer growth. However, the mode of action of several of these agents at the gene transcription level is not completely understood. Completion of the human genome sequence and the advent of DNA microarrays using cDNAs enhanced the detection and identification of hundreds of differentially expressed genes in response to anticancer drugs or chemopreventive agents. In this review, we are presenting an extensive analysis of the key findings from studies using potential chemopreventive agents on global gene expression patterns, which lead to the identification of cancer drug targets. The summary of the study reports discussed in this review explains the extent of gene alterations mediated by more than 20 compounds including antioxidants, fatty acids, NSAIDs, phytochemicals, retinoids, selenium, vitamins, aromatase inhibitor, lovastatin, oltipraz, salvicine, and zinc. The findings from these studies further reveal the utility of DNA microarray in characterizing and quantifying the differentially expressed genes that are possibly reprogrammed by the above agents against colon, breast, prostate, lung, liver, pancreatic and other cancer types. Phenolic antioxidant resveratrol found in berries and grapes inhibits the formation of prostate tumors by acting on the regulatory genes such as p53 while activating a cascade of genes involved in cell cycle and apoptosis including p300, Apaf-1, cdk inhibitor p21, p57 (KIP2), p53 induced Pig 7, Pig 8, Pig 10, cyclin D, DNA fragmentation factor 45. The group of genes significantly altered by selenium includes cyclin D1, cdk5, cdk4, cdk2, cdc25A and GADD 153. Vitamine D shows impact on p21(Waf1/Cip1) p27 cyclin B and cyclin A1. Genomic expression profile with vitamin D indicated differential expression of gene targets such as c-JUN, JUNB, JUND, FREAC-1/FoxF1, ZNF-44/KOX7, plectin, filamin, and keratin-13, involved in antiproliferative, differentiation pathways. The agent UBEIL has a remarkable effect on cyclin D1. Curcumin mediated NrF2 pathway significantly altered p21(Waf1/Cip1) levels. Aromatase inhibitors affected the expression of cyclin D1. Interestingly, few dietary compounds listed in this review also have effect on APC, cdk inhibitors p21(Waf1/Cip1) and p27. Tea polyphenol EGCG has a significant effect on TGF-beta expression, while several other earlier studies have shown its effect on cell cycle regulatory proteins. This review article reveals potential chemoprevention drug targets, which are mainly centered on cell cycle regulatory pathway genes in cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I756,I756)","v":17109512},{"$f":"(LEN($J756) - LEN(SUBSTITUTE(LOWER($J756),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J756) - LEN(SUBSTITUTE(LOWER($J756),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J756) - LEN(SUBSTITUTE(LOWER($J756),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B756:D756)","v":1},2006,"Role of ethanol in the regulation of hepatic stellate cell function.","Wang",17109512,"Role of ethanol in the regulation of hepatic stellate cell function.    Abstract:   Evidence has accumulated to suggest an important role of ethanol and/or its metabolites in the pathogenesis of alcohol-related liver disease. In this review, the fibrogenic effects of ethanol and its metabolites on hepatic stellate cells (HSCs) are discussed. In brief, ethanol interferes with retinoid metabolism and its signaling, induces the release of fibrogenic cytokines such as transforming growth factor beta-1 (TGFbeta-1) from HSCs, up-regulates the gene expression of collagen I and enhances type I collagen protein production by HSCs. Ethanol further perpetuates an activated HSC phenotype through extracellular matrix remodeling. The underlying pathophysiologic mechanisms by which ethanol exerts these pro-fibrogenic effects on HSCs are reviewed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I757,I757)","v":17014561},{"$f":"(LEN($J757) - LEN(SUBSTITUTE(LOWER($J757),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J757) - LEN(SUBSTITUTE(LOWER($J757),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J757) - LEN(SUBSTITUTE(LOWER($J757),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B757:D757)","v":1},2006,"Molecular mechanisms mediating vascular calcification: role of matrix Gla protein.","Proudfoot",17014561,"Molecular mechanisms mediating vascular calcification: role of matrix Gla protein.    Abstract:   Patients with chronic kidney disease (CKD) have a higher incidence of vascular calcification and a greatly increased risk of cardiovascular death. The mechanisms involved in the accelerated vascular calcification observed in CKD have recently become clearer, leading to the hypothesis that a lack of natural inhibitors of calcification may trigger calcium deposition. One of these inhibitory factors, matrix Gla protein (MGP), is the focus of the present review. MGP, originally isolated from bone, is a vitamin K-dependent protein that is also highly expressed by vascular smooth muscle cells. MGP has been confirmed as a calcification-inhibitor in numerous studies; however, its mechanism of action is not completely understood. It potentially acts in several ways to regulate calcium deposition including: (i) binding calcium ions and crystals; (ii) antagonizing bone morphogenetic protein and altering cell differentiation; (iii) binding to extracellular matrix components; and (iv) regulating apoptosis. Its expression is regulated by several factors including retinoic acid, vitamin D and extracellular calcium ions, and a reduced form of vitamin K (KH2) is important in maintaining MGP in an active form. Therefore, strategies aimed at increasing its expression and activity may be beneficial in tipping the balance in favour of inhibition of calcification in CKD."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I758,I758)","v":16950593},{"$f":"(LEN($J758) - LEN(SUBSTITUTE(LOWER($J758),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J758) - LEN(SUBSTITUTE(LOWER($J758),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J758) - LEN(SUBSTITUTE(LOWER($J758),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B758:D758)","v":1},2006,"Metastatic breast cancer: an updating.","Nicolini",16950593,"Metastatic breast cancer: an updating.    Abstract:    UNLABELLEDThis article reports on recent advances on metastatic breast cancer. Detection, prognostic factors, predictors of response to therapy and therapy, with particular regard to targeted therapies, were examined.  DETECTION NlmCategory=UNASSIGNEDUnlike current guidelines that yet do not routinely recommend intensive clinical-instrumental post-operative follow-up of breast cancer patients, relatively large data collected in the last decades have shown that an intensive post-operative follow-up with dynamic evaluation of a suitable tumour marker panel precedes a few months as average the clinical and/or instrumental sign of a pending relapse in most relapsed patients and largely limits the use of the common instrumental examinations.  PROGNOSIS AND THERAPY PREDICTORS NlmCategory=UNASSIGNEDDisease-free interval (DFI)lt;or=24 months, adjuvant chemotherapy, liver and distant soft tissue involvement or DFIgt;24 months and disease confined to bony skeleton are prognostic factors more often correlated with relatively poor or prolonged survival, respectively. Estrogen receptor (ER) expression in primary tumour and at the relapse correlates strongly with response to salvage hormone therapy and data from large trials showed that 38-59% of ER and/or PR+ post-menopausal patients had clinical benefit from first line tamoxifen or aromatase inhibitors. An inverse correlation of ER with epidermal growth factor receptor (EGFR) has been found. The co-expression of HER-2/neu and/or elevated serum HER-2/neu protein level were associated with a low rate and shorter duration of response of ER+ patients to first line hormone therapy. Accordingly, ER-EGFR- compared with ER-EGFR+ tumours are usually more responsive to endocrine therapy. High class III beta-tubulin expression or fall in insulin-like growth factor binding protein-3 (IGFBP-3) from baseline levels have been found to significantly predict resistance to chemotherapeutic agents.  THERAPY : Liposomes as carrier of doxorubicin (Caelix, Evacet, Myocet) is one approach to decrease the anthracycline-related cardiac toxicity. Weekly paclitaxel or docetaxel and oral formulation of vinorelbine and 5-fluorouracil (5-FU) (capecitabine) provide new effective and well tolerated options that reach greater dose intensity and cumulative dose than with the conventional schedules. As to the so called tailored or targeted therapies, the more potent and highly selective third generation of aromatase inhibitors (letrozole, anastrozole, exemestane) targeting ER+ tumours by estrogen deprivation, challenge tamoxifen as current standard first line therapy in postmenopausals. One pilot study showed that stimulation of cellular immunity by the addition of beta-interferon-interleukin-2 sequence in patients on clinical benefit on first line tamoxifen significantly prolonged median overall survival (OS) and duration of response compared to that observed in similar patients only treated with tamoxifen. Trastuzumab, a humanised monoclonal antibody to extracellular domain of HER-2, plus conventional chemotherapy has become a standard of care for women with overexpressing HER-2 tumours. Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor (VEGF) that in refractory metastatic breast cancer doubled the response rate of capecitabine although it did not affect survival. Finally, the so called oligometastatic and a few stage IV diseases are conditions amenable to be rendered with no evidence of disease (NED) after local surgery and/or radiation. In both, as well as in complete responders to chemotherapy, minimal residual disease (m.r.d.) likely continues to be present. Recent data suggest that biological therapy (immunomodulators and/or retinoids with or without hormone therapy), might be suitable to be successfully tested in these patients as maintenance treatment given soon after local intervention or chemotherapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I759,I759)","v":16886661},{"$f":"(LEN($J759) - LEN(SUBSTITUTE(LOWER($J759),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J759) - LEN(SUBSTITUTE(LOWER($J759),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J759) - LEN(SUBSTITUTE(LOWER($J759),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B759:D759)","v":1},2006,"Vitamin D compounds: activity against microbes and cancer.","Gombart",16886661,"Vitamin D compounds: activity against microbes and cancer.    Abstract:   Vitamin D3 is produced in skin and is sequentially metabolized by the liver and kidney to the biologically active form 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. It is a seco-steroid hormone that regulates calcium homeostasis within the body. The genomic actions of 1,25(OH)2D3 are modulated through the vitamin D receptor (VDR). VDR belongs to a superfamily of nuclear receptors that transduce hormonal signals from the immediate environment and transactivate genes in response to these signals. Target genes contain hormone response elements (VDREs) in their promoters to which heterodimers of VDR and retinoid X receptors (RXR) can bind and transactivate expression of the target genes. The VDR is expressed in at least 30 different target tissues including bone, kidney, blood, breast, prostate, gut, activated B- and T- lymphocytes, monocytes and keratinocytes). Most dividing cell types, normal and malignant, can express VDR and respond to 1,25(OH)2D3. Although 1,25(OH)2D3 and its analogs (termed deltanoids) are important regulators of calcium and bone metabolism, their non-calciotropic activities that include inhibition of cell proliferation, promotion of cell differentiation and modulation of immune cell function have spurred interest in therapeutic applications in a wide variety of diseases. In this report, the anticancer and newly discovered antimicrobial actions of 1,25(OH)2D3 and deltanoids are reviewed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I760,I760)","v":16882161},{"$f":"(LEN($J760) - LEN(SUBSTITUTE(LOWER($J760),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J760) - LEN(SUBSTITUTE(LOWER($J760),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J760) - LEN(SUBSTITUTE(LOWER($J760),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B760:D760)","v":1},2006,"Minimizing adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert opinion.","Assaf",16882161,"Minimizing adverse side-effects of oral bexarotene in cutaneous T-cell lymphoma: an expert opinion.    Abstract:   Bexarotene is an oral retinoid therapy that is effective for the treatment of early and advanced-stage cutaneous T-cell lymphoma (CTCL) in patients who have failed on other therapies. However, bexarotene treatment is associated with unavoidable side-effects, in particular hypertriglyceridaemia and hypothyroidism, which are manageable with adequate concomitant medications and are reversible on cessation of treatment. A pragmatic strategy for minimizing bexarotene-associated hypertriglyceridaemia and hypothyroidism is suggested, based on data from the studies with bexarotene in CTCL and on day-to-day experience with this agent in the clinical setting. The strategy anticipates that these common adverse events are likely to occur and recommends the early use of preventive therapy to lower triglycerides and elevate thyroid hormone levels in the blood, followed by subsequent monitoring, dose adjustment during bexarotene treatment, and titration of the daily bexarotene dose from 150 to 300 mg m(-2), which is optimal for most patients. When further information becomes available on how bexarotene interacts with lipid metabolism and thyroid function, the management approach suggested here may need to be changed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I761,I761)","v":16772153},{"$f":"(LEN($J761) - LEN(SUBSTITUTE(LOWER($J761),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J761) - LEN(SUBSTITUTE(LOWER($J761),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J761) - LEN(SUBSTITUTE(LOWER($J761),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B761:D761)","v":1},2006,"Treatment of hirsutism and acne in hyperandrogenism.","Moghetti",16772153,"Treatment of hirsutism and acne in hyperandrogenism.    Abstract:   Hirsutism and acne are common and highly distressing complaints in women with polycystic ovary syndrome (PCOS). Drugs are only partially effective on terminalized hairs, and removal of these hairs is usually required. Therefore, management of hirsutism is generally based upon a dual approach: a pharmacological therapy to reduce androgen secretion and/or androgen action, and removal of terminal hair already present. Ovarian suppression of androgen secretion with oral contraceptives is widely used in these women, but its efficacy appears limited. The most effective medical therapy for hirsutism is by anti-androgen drugs. Electrolysis and laser photothermolysis are considered the most effective cosmetic procedures, although the effects of these methods should not be considered permanent. Acne may be treated with different tools, according to the severity of the condition and other characteristics of the patient. These tools include topical and systemic retinoids and antibiotics, topical antibacterial agents, androgen suppression by oral contraceptives, and anti-androgen drugs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I762,I762)","v":16690801},{"$f":"(LEN($J762) - LEN(SUBSTITUTE(LOWER($J762),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J762) - LEN(SUBSTITUTE(LOWER($J762),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J762) - LEN(SUBSTITUTE(LOWER($J762),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B762:D762)","v":1},2006,"Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling.","Grün",16690801,"Environmental obesogens: organotins and endocrine disruption via nuclear receptor signaling.    Abstract:   Over the last two decades, the incidence of obesity and associated metabolic syndrome diseases has risen dramatically, becoming a global health crisis. Increased caloric intake and decreased physical activity are believed to represent the root causes of this dramatic rise. However, recent findings highlight the possible involvement of environmental obesogens, xenobiotic chemicals that can disrupt the normal developmental and homeostatic controls over adipogenesis and energy balance. Environmental estrogens, i.e. chemicals with estrogenic potential, have been reported to perturb adipogenic mechanisms using in vitro model systems, but other classes of endocrine-disrupting chemicals are now coming under scrutiny as well. Organotins represent one class of widespread persistent organic pollutants with potent endocrine-disrupting properties in both invertebrates and vertebrates. New data identify tributyltin chloride and triphenyltin chloride as nanomolar agonist ligands for retinoid X receptor (RXR alpha, RXR beta, and RXR gamma) and peroxisome proliferator-activated receptor gamma, nuclear receptors that play pivotal roles in lipid homeostasis and adipogenesis. The environmental obesogen hypothesis predicts that inappropriate receptor activation by organotins will lead directly to adipocyte differentiation and a predisposition to obesity and/or will sensitize exposed individuals to obesity and related metabolic disorders under the influence of the typical high-calorie, high-fat Western diet. The linking of organotin exposure to adipocyte differentiation and obesity opens an important new area of research into potential environmental influences on human health and disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I763,I763)","v":16566124},{"$f":"(LEN($J763) - LEN(SUBSTITUTE(LOWER($J763),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J763) - LEN(SUBSTITUTE(LOWER($J763),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J763) - LEN(SUBSTITUTE(LOWER($J763),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B763:D763)","v":1},2005,"[Alpha-lipoic--dihydrolipoic acids--active bioantioxidant and bioregulatory system].","Baraboĭ",16566124,"[Alpha-lipoic--dihydrolipoic acids--active bioantioxidant and bioregulatory system].    Abstract:   alpha-Lipoic (LA) acid (thioctic acid) is an intramolecular disulfide that may be simply endogenically turned into dithiol. Dihydrolipoic acid (DHLA)/ LA and DHLA are bioantioxidants. They are synthesized in the body and taken with diet. Water- and lipide-soluble LA is highly-effective against the reactive oxygen species. LA (DHLA) protect the biomembranes, mitochondria from oxidative stresses of various kinds. LA, DHLA and lipoamide function as cofactors of polyenzyme mitochondrial complexes of 2-oxoacid dehydrogenases, of glycin decarboxylases and of some other enzymes. LA (DHLA) is ubiquinone reactivator and synergist by vitamin A, C, E. LA optimizes glucose metabolism, it is effective in insulin-resistant diabetes and its complications, in neutopathies and neurodegenerative diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I764,I764)","v":16508294},{"$f":"(LEN($J764) - LEN(SUBSTITUTE(LOWER($J764),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J764) - LEN(SUBSTITUTE(LOWER($J764),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J764) - LEN(SUBSTITUTE(LOWER($J764),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B764:D764)","v":1},2005,"Alcohol consumption and cancer of the gastrointestinal tract.","Seitz",16508294,"Alcohol consumption and cancer of the gastrointestinal tract.    Abstract:   Epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper gastrointestinal cancer (oropharynx, hypopharynx, esophagus) and colorectal cancer. Pathophysiological mechanisms include generation of acetaldehyde (AA) and reactive oxygen species (ROS), induction of cytochrome P 4502E1 (CYP2E1), and local and nutritional factors. Genetic polymorphisms of alcohol-metabolizing enzymes may individually influence the risk of carcinogenesis. AA, the first and major metabolite of ethanol, has proven to be the most carcinogenic and mutagenic agent in alcohol-associated cancer. Gastrointestinal bacteria as well as various isozymes of alcohol dehydrogenase (ADH) are capable of metabolizing ethanol to AA thus leading to an increased cell turnover of the gastrointestinal mucosa after chronic alcohol consumption. In Caucasians, ADH1C polymorphism is most important, for the ADH1C*1 transcription results in an ADH isoenzyme 2.5 times more active than that from ADH1C*2, which is associated with an increase in AA production. Additionally, oxidative stress due to an induction of CYP2E1 in the gastrointestinal mucosa of alcoholics should be considered as another key factor in alcohol-induced carcinogenesis. Nutritional deficiencies, i.e. lack of folic and retinoic acid, as well as malnutrition itself may also contribute to the development of gastrointestinal cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I765,I765)","v":16454693},{"$f":"(LEN($J765) - LEN(SUBSTITUTE(LOWER($J765),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J765) - LEN(SUBSTITUTE(LOWER($J765),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J765) - LEN(SUBSTITUTE(LOWER($J765),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B765:D765)","v":1},2006,"Altered CYP expression and function in response to dietary factors: potential roles in disease pathogenesis.","Murray",16454693,"Altered CYP expression and function in response to dietary factors: potential roles in disease pathogenesis.    Abstract:   Increasing evidence implicates dietary factors in the progression of diseases, including certain cancers, diabetes and obesity. Diet also regulates the expression and function of CYP genes, which impacts on drug elimination and may also significantly affect disease pathogenesis. Upregulation of CYPs 2E1 and 4A occurs after feeding of experimental diets that are high in fats or carbohydrates; these diets also promote hepatic lipid infiltration, which is a component of the metabolic syndrome that characterises obesity. Increased availability of lipid substrates for CYPs can enhance free radical production and exacerbate tissue injury. Similar processes may also occur in other models of experimental disease states that exhibit a component of altered nutrient utilization. Food-derived chemicals, including constituents of cruciferous vegetables and fruits, modulate CYP expression and the expression of genes that encode cytoprotective phase II enzymes. Certain dietary indoles and flavonoids activate CYP1A expression either by direct ligand interaction with the aryl hydrocarbon receptor (AhR) or by augmenting the interaction of the AhR with xenobiotic response elements in CYP1A1 and other target genes. Other dietary chemicals, including methylenedioxyphenyl (MDP) compounds and isothiocyanates also modulate CYP gene expression. Apart from altered CYP regulation, a number of dietary agents also inhibit CYP enzyme activity, leading to pharmacokinetic interactions with coadministered drugs. A well described example is that of grapefruit juice, which contains psoralens and possibly other chemicals, that inactivate intestinal CYP3A4. Decreased presystemic oxidation by this CYP increases the systemic bioavailability of drug substrates and the likelihood of drug toxicity. Dietary interactions may complicate drug therapy but inhibition of certain CYP reactions may also protect the individual against toxic metabolites and free radicals generated by CYPs. Chemicals in teas and cruciferous vegetables may also inhibit human CYP enzymes that have been implicated in the bioactivation of chemical carcinogens. Thus, food constituents modulate CYP expression and function by a range of mechanisms, with the potential for both deleterious and beneficial outcomes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I766,I766)","v":16448612},{"$f":"(LEN($J766) - LEN(SUBSTITUTE(LOWER($J766),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J766) - LEN(SUBSTITUTE(LOWER($J766),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J766) - LEN(SUBSTITUTE(LOWER($J766),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B766:D766)","v":1},2006,"[Hepatic stellate cells: its role in normal and pathological conditions].","Sarem",16448612,"[Hepatic stellate cells: its role in normal and pathological conditions].    Abstract:   Hepatic fibrosis is a dynamic and sophisticatedly regulated wound healing response to chronic hepatocellular injury. This fibrotic process results from the accumulation of extracellular matrix (ECM) including collagen, proteoglycan, and adhesive glycoproteins which are principally produced by hepatic stellate cells (HSC), a mesenchymal cell type located between parenchymal cell plates and sinusoidal endothelial cells in the space of Disse. In physiological conditions, quiescent HSCs play important roles in the regulation of retinoid homeostasis and ECM remodeling by producing ECM components as well as metalloproteases and its inhibitor. However during hepatic fibrogenesis, HSCs are known to be activated or quot;transdifferentiatedquot; to myofibroblast-like cells which play a pivotal role in ECM remodeling and hepatic blood flow regulation. Activation of HSC is now well established as the key process involved in the development of hepatic fibrosis. Both basic morphology and functions of HSCs in normal conditions and its role in pathological fibrosis will be discussed in this review."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I767,I767)","v":16430309},{"$f":"(LEN($J767) - LEN(SUBSTITUTE(LOWER($J767),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J767) - LEN(SUBSTITUTE(LOWER($J767),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J767) - LEN(SUBSTITUTE(LOWER($J767),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B767:D767)","v":1},2006,"Significance of the minor cytochrome P450 3A isoforms.","Daly",16430309,"Significance of the minor cytochrome P450 3A isoforms.    Abstract:   Cytochrome P450 (CYP) 3A4 is responsible for most CYP3A-mediated drug metabolism but the minor isoforms CYP3A5, CYP3A7 and CYP3A43 also contribute. CYP3A5 is the best studied of the minor CYP3A isoforms. It is well established that only approximately 20% of livers express CYP3A5. The most common reason for the absence of expression is a splice site mutation. The frequency of variant alleles shows interethnic differences, with the wild-type CYP3A5*1 allele more common in Africans than Caucasians and Asians. In individuals who express CYP3A5, the percentage contributed to total hepatic CYP3A by this isoform is still unclear, with estimates ranging from 17% to 50%. CYP3A5 is also expressed in a range of extrahepatic tissues. Only limited information is available on the regulation of CYP3A5 expression but it appears to be inducible via the glucocorticoid receptor, pregnane X receptor and constitutive androstane receptor-beta, as for CYP3A4. Although information on the substrate specificity of CYP3A5 is limited compared with CYP3A4, there have been a number of recent pharmacokinetic studies on a small range of substrates in individuals of known genotype to investigate the contribution of CYP3A5. In the case of midazolam, ciclosporin, nifedipine and docetaxel, clearance by individuals with a CYP3A5-expressing genotype did not differ from that for nonexpressors, but in the case of tacrolimus, eight independent studies have demonstrated faster clearance by those carrying one or two CYP3A5*1 alleles. This may reflect faster turnover of tacrolimus by CYP3A5 than the other substrates. CYP3A5 genotype may affect cancer susceptibility. Certain combined CYP3A4/CYP3A5 haplotypes show differential susceptibility to prostate cancer and there is a nonsignificant increase in the risk of small-cell lung cancer for a CYP3A5*1/*1 genotype. Females positive for CYP3A5*1 appear to reach puberty earlier, which may affect breast cancer risk. CYP3A5*1 homozygotes may have higher systolic blood pressure.CYP3A7 is predominantly expressed in fetal liver but is also found in some adult livers and extrahepatically. The molecular basis for expression in adult liver relates to upstream polymorphisms, which appear to increase homology to CYP3A4 and make regulation of expression more similar. CYP3A7 has a specific role in hydroxylation of retinoic acid and 16alpha-hydroxylation of steroids, and is therefore of relevance both to normal development and carcinogenesis.CYP3A43 is the most recently discovered CYP3A isoform. In addition to a low level of expression in liver, it is expressed in prostate and testis. Its substrate specificity is currently unclear. Polymorphisms predicting absence of active enzyme have been identified."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I768,I768)","v":16424607},{"$f":"(LEN($J768) - LEN(SUBSTITUTE(LOWER($J768),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J768) - LEN(SUBSTITUTE(LOWER($J768),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J768) - LEN(SUBSTITUTE(LOWER($J768),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B768:D768)","v":1},2006,"The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism.","Chmurzyńska",16424607,"The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism.    Abstract:   Fatty acid-binding proteins (FABPs) are members of the superfamily of lipid-binding proteins (LBP). So far 9 different FABPs, with tissue-specific distribution, have been identified: L (liver), I (intestinal), H (muscle and heart), A (adipocyte), E (epidermal), Il (ileal), B (brain), M (myelin) and T (testis). The primary role of all the FABP family members is regulation of fatty acid uptake and intracellular transport. The structure of all FABPs is similar - the basic motif characterizing these proteins is beta-barrel, and a single ligand (e.g. a fatty acid, cholesterol, or retinoid) is bound in its internal water-filled cavity. Despite the wide variance in the protein sequence, the gene structure is identical. The FABP genes consist of 4 exons and 3 introns and a few of them are located in the same chromosomal region. For example, A-FABP, E-FABP and M-FABP create a gene cluster. Because of their physiological properties some FABP genes were tested in order to identify mutations altering lipid metabolism. Furthermore, the porcine A-FABP and H-FABP were studied as candidate genes with major effect on fatness traits."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I769,I769)","v":16406653},{"$f":"(LEN($J769) - LEN(SUBSTITUTE(LOWER($J769),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J769) - LEN(SUBSTITUTE(LOWER($J769),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J769) - LEN(SUBSTITUTE(LOWER($J769),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B769:D769)","v":1},2006,"Vitamin D signaling is modulated on multiple levels in health and disease.","Ebert",16406653,"Vitamin D signaling is modulated on multiple levels in health and disease.    Abstract:   Vitamin D signaling is dependent on the availability and turnover of the active Vitamin D receptor (VDR) ligand 1,25-dihydroxycholecalciferol and on the efficiency of VDR transactivation. Activating and inactivating secosteroid metabolizing p450 enzymes, e.g. 25-hydroxylases, 1alpha-hydroxylase and 24-hydroxylase, are responsible for ligand availability on the basis of substrate production in the skin and of nutritional intake of precursors. Net availability of active hormone depends on the delivery of substrate and the balance of activating and inactivating enzymes. 1Alpha-hydroxylase is the critical activating enzyme. It is expressed in the kidney for systemic supply and in target tissues for local secosteroid activation. It is upregulated in the kidney by low calcium intake and parathyroid hormone, downregulated by phosphatonins and proinflammatory signal transduction. Transactivation of VDR depends on the correct molecule structure, effective nuclear translocation and the presence of the unliganded heterodimer partner retinoid X-receptor (RXR) and other nuclear cofactors. Rapid Vitamin D-dependent membrane associated effects and consecutive second messenger activation exert an own pattern of gene regulation. A membrane receptor for these effects is hypothesized but not yet identified. Rickets is the long known clinical syndrome of impaired Vitamin D signaling due to Vitamin D3 deficiency. It can be caused by inherited defects of the cascade, nutritional deficits, lack of sunlight exposure, malabsorption and underlying diseases like chronic inflammation. It has been shown during the last decades that many modifiers of Vitamin D signaling are targets of disease in terms of inherited and acquired syndromes and that Vitamin D signaling is modulated at multiple levels and is more complex than mere mechanistic ligand/receptor/DNA interaction."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I770,I770)","v":16399347},{"$f":"(LEN($J770) - LEN(SUBSTITUTE(LOWER($J770),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J770) - LEN(SUBSTITUTE(LOWER($J770),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J770) - LEN(SUBSTITUTE(LOWER($J770),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B770:D770)","v":1},2005,"Structure of UDP-glucuronosyltransferases in membranes.","Radominska-Pandya",16399347,"Structure of UDP-glucuronosyltransferases in membranes.    Abstract:   This chapter presents the most recent experimental approaches to the investigation of UDP-glucuronosyltransferase (UGTs) in membranes. The first topic described is the subcellular localization of UGTs with special emphasis on the association of these proteins with the endoplasmic reticulum (ER). Experimental methods include subfractionation of tissue for microsome preparation, evaluation of the purity of the membrane fraction obtained, and measurement of UGT activity in the presence of detergents. Next, the recently demonstrated formation of UGT homo- and heterodimer formation and its functional relevance is discussed and the appropriate methods used to characterize such interactions are given (radiation inactivation, size exclusion chromatography, immunopurification, cross-linking, two-hybrid system). The structural determinants of UGTs in relation to membrane association, residency, and enzymatic activity are the next topic, supplemented by a description of the appropriate methods, including the design and expression of chimeric proteins, membrane insertion, and subcellular localization by immunofluorescence. Also presented is new information on the structure and function of UGTs obtained by molecular modeling, bioinformatics (sequence alignment), and comparison with selected crystallized glycosyltransferases. Finally, we discuss the important, and still not fully developed, issue of UGT active site architecture and organization within the ER. This is addressed from two perspectives: (1) chemical modification of UGT active sites by amino acid-specific probes and (2) photoaffinity labeling of UGTs. The detailed synthesis of a photoaffinity probe for an aglycon-binding site is provided and the use of this probe and direct photoaffinity labeling with retinoids is discussed. The application of proteomics techniques, including proteolytic digestion and protein sequencing by liquid chromatography/tandem mass spectrometry and matrix-assisted laser desorption ionization/time of flight, to the identification of crucial amino acids of the active sites, and subsequent site-directed mutagenesis of identified amino acids, is discussed in detail."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I771,I771)","v":16333837},{"$f":"(LEN($J771) - LEN(SUBSTITUTE(LOWER($J771),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J771) - LEN(SUBSTITUTE(LOWER($J771),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J771) - LEN(SUBSTITUTE(LOWER($J771),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B771:D771)","v":1},2007,"Favorable histology, MYCN-amplified 4S neonatal neuroblastoma.","Chan",16333837,"Favorable histology, MYCN-amplified 4S neonatal neuroblastoma.    Abstract:   We report a neonate with 4S neuroblastoma and MYCN amplification, but favorable Shimada histology, successfully treated with chemotherapy and 13-cis-retinoic acid without stem cell transplantation. MYCN amplification in neuroblastoma is usually associated with unfavorable Shimada histology; the presence of these features in infants with 4S disease confers a poor prognosis. A small number of infants with 4S neuroblastoma and MYCN amplification have favorable Shimada histology. In this subgroup of infants, histopathology may be equally important in predicting outcome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I772,I772)","v":16263076},{"$f":"(LEN($J772) - LEN(SUBSTITUTE(LOWER($J772),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J772) - LEN(SUBSTITUTE(LOWER($J772),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J772) - LEN(SUBSTITUTE(LOWER($J772),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B772:D772)","v":1},2005,"Connexins as targets for cancer chemoprevention and chemotherapy.","King",16263076,"Connexins as targets for cancer chemoprevention and chemotherapy.    Abstract:   Cells within a tissue continuously interact to coordinate normal tissue functions and maintain homeostasis. Gap junctional communication (GJC), mediated by the connexin protein family, allows this type of intercellular crosstalk resulting in synchronized and cooperative tissue behavior such as cardiac contraction. In cancer, loss of these types of cell:cell interactions has been shown to facilitate tumorigenesis and enable the autonomous cell behavior associated with transformed cells. Indeed, many human tumor lines demonstrate deficient or aberrant GJC and/or loss of connexin expression. Restoration of exogenous connexin expression/GJC function is correlated with increased cell growth control both in vitro and in vivo. In support of this growth regulatory hypothesis, decreased connexin expression has been observed in situ in early human neoplasia of various organs. Additionally, genetically engineered mice lacking particular connexins (Connexins 32 or 43) exhibit increased susceptibility to radiation and chemically-induced liver and/or lung tumorigenesis. These studies strongly suggest that connexins and GJC serve a tumor suppressor role. Consistent with this proposed role, in a model cell culture system, retinoids and carotenoids up-regulate Connexin43 (Cx43) expression in direct proportion to their ability to suppress carcinogen-induced neoplastic transformation. Here, we discuss the important role of connexins and GJC in tumorigenesis and suggest the possibility of connexins as potential anti-oncogenic targets for chemoprevention and/or chemotherapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I773,I773)","v":16208627},{"$f":"(LEN($J773) - LEN(SUBSTITUTE(LOWER($J773),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J773) - LEN(SUBSTITUTE(LOWER($J773),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J773) - LEN(SUBSTITUTE(LOWER($J773),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B773:D773)","v":1},2005,"Roles for lipid-activated transcription factors in atherosclerosis.","Nagy",16208627,"Roles for lipid-activated transcription factors in atherosclerosis.    Abstract:   The initial cellular event in atherosclerosis is the recruitment of monocytes to the vessel wall, and the formation of foam cells by the uptake of modified lipoproteins. The role of macrophages in this process is the uptake and processing of lipoproteins ultimately leading to foam cell formation. These cells also sustain a chronic inflammatory reaction believed to participate in disease progression. We have been interested in identifying regulatory processes contributing to these events. Some members of a distinct class of transcription factors, nuclear hormone receptors, are expressed in macrophages and are likely to have roles in the initiation of atherosclerosis. We review here the identification of interrelated nuclear receptor-regulated pathways involving peroxisome proliferator-activated receptor, liver X receptor, and retinoid receptors, and contributing to lipid uptake and efflux in macrophages."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I774,I774)","v":16178789},{"$f":"(LEN($J774) - LEN(SUBSTITUTE(LOWER($J774),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J774) - LEN(SUBSTITUTE(LOWER($J774),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J774) - LEN(SUBSTITUTE(LOWER($J774),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B774:D774)","v":1},2005,"Role of FXR in regulating bile acid homeostasis and relevance for human diseases.","Rizzo",16178789,"Role of FXR in regulating bile acid homeostasis and relevance for human diseases.    Abstract:   Recent studies reveal that bile acids are signalling molecules that activate several nuclear receptors and regulate many physiological pathways and processes to maintain bile acid and cholesterol homeostasis. Analysis of orphan receptor expression patterns in enterohepatic tissues identified bile acids as ligands for farnesoid X receptor (FXR). The primary bile acid chenodeoxycholic acid (CDCA) was shown to be the most potent FXR ligand in vitro at an EC50 of 10-50 microM. FXR can also be activated by the secondary bile acids lithocholic acid (LCA) and deoxycholic acid (DCA). Upon activation FXR heterodimerises with 9-cis retinoic X receptor (RXR) and regulates a cohort of genes involved in cholesterol catabolism and bile acids biosynthesis. Thus bile acid-activated FXR directly induces expression of Small Heterodimer Partner (SHP), a nuclear receptor that suppresses bile acid biosynthesis down-regulates the Na+ taurocholate cotransport peptide (NTCP), a pump depicted to transport bile acids from the lumen into hepatocyte, and induces expression of bile salt export pump (BSEP), the principal bile acid efflux transporter in the liver. As demonstrated by the Fxr null mice, FXR defends the liver against cholestasis. The 6-ethyl derivative of CDCA (6-ECDCA) is approximately 100 fold more potent than CDCA in activating FXR in vitro. In vivo administration of 6-ECDCA protects against cholestasis induced by estrogen and LCA in rats providing evidence that development of potent FXR agonists might represent a new approach for the treatment of cholestastic disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I775,I775)","v":16107759},{"$f":"(LEN($J775) - LEN(SUBSTITUTE(LOWER($J775),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J775) - LEN(SUBSTITUTE(LOWER($J775),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J775) - LEN(SUBSTITUTE(LOWER($J775),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B775:D775)","v":1},2005,"Regulation of mast cell development.","Shiohara",16107759,"Regulation of mast cell development.    Abstract:   Human mast cells originated from multipotential hematopoietic progenitors in bone marrow (BM). A large proportion of these progenitors were CD34+CD38-c-kit+ cells and CD34+CD38+c-kit+ cells. Cloning of stem cell factor (SCF) contributed to the development of culture systems of human mast cells from different sources including BM mononuclear cells, CD34+ cord blood (CB) cells, and fetal liver cells. SCF could support mast cell development from CD34+ CB cells in the serum-deprived culture system. The cumulative mast cell number reached 10(10)-fold the input quantity at 50 weeks of SCF-containing serumdeprived culture. CB-derived mast cells expressed tryptase, chymase, and histamine similar to mast cells residing in tissues. The surface expression of FcepsilonRI, however, was very low on fetal liver- or CB-derived mast cells. Factors that had effects on SCF-dependent human mast cell development were divided into four types: (1) factors that stimulated both proliferation and maturation: SCF; (2) factors that stimulated only proliferation: thrombopoietin, interleukin (IL)-9; (3) factors that inhibited proliferation, but stimulated maturation: IL-4, IL-6, and (4) factors that inhibited proliferation and maturation: retinoids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I776,I776)","v":16101412},{"$f":"(LEN($J776) - LEN(SUBSTITUTE(LOWER($J776),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J776) - LEN(SUBSTITUTE(LOWER($J776),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J776) - LEN(SUBSTITUTE(LOWER($J776),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B776:D776)","v":1},2005,"Vitamin D receptor modulators for inflammation and cancer.","Yee",16101412,"Vitamin D receptor modulators for inflammation and cancer.    Abstract:   1alpha, 25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the biologically active form of vitamin D, is an important hormone that is critically required for the maintenance of mineral homeostasis and structural integrity of bones. 1,25-(OH)2D3 accomplishes this by facilitating calcium absorption from the gut and by a direct action on osteoblasts, the bone forming cells. Apart form its classical actions on the gut and bone, 1,25-(OH)2D3 and its synthetic analogs also possess potent anti-proliferative, differentiative and immunomodulatory activities. 1,25-(OH)2D3 exerts these effects through vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the superfamily of steroid/thyroid hormone/retinoid nuclear receptors. The presence of VDR in various tissues other than gut and bone, along with their ability to exert differentiation, growth inhibitory and anti-inflammatory action, has set the stage for therapeutic exploitation of VDR ligands for the treatment of various inflammatory indications and cancer. However, the use of VDR ligands in clinic is limited by their major dose-related side effect, namely hypercalcemia/hypercalciuria. Efforts are being undertaken to develop vitamin D receptor modulators (VDRMs) that are tissue-selective and/or gene-selective in their action and these ligands may exhibit increased therapeutic indices. This review explores the recent advances in VDR biology, non-secosteroidal VDR ligands and the current and potential clinical applications of VDR ligands in inflammation and cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I777,I777)","v":16093469},{"$f":"(LEN($J777) - LEN(SUBSTITUTE(LOWER($J777),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J777) - LEN(SUBSTITUTE(LOWER($J777),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J777) - LEN(SUBSTITUTE(LOWER($J777),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B777:D777)","v":1},2005,"Retinoid x receptor heterodimers in the metabolic syndrome.","Shulman",16093469,"Retinoid x receptor heterodimers in the metabolic syndrome.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I778,I778)","v":15995809},{"$f":"(LEN($J778) - LEN(SUBSTITUTE(LOWER($J778),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J778) - LEN(SUBSTITUTE(LOWER($J778),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J778) - LEN(SUBSTITUTE(LOWER($J778),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B778:D778)","v":1},2005,"Pancreatic differentiation.","Mehta",15995809,"Pancreatic differentiation.    Abstract:   Over the last decade, with the advent of new techniques and technologies in modern molecular biology, our understanding of the underlying mechanisms responsible for organ differentiation has developed rapidly. Despite this, our knowledge of these signaling pathways is still far from complete. Some of these advances, such as the creation of transgenic mouse models, have given us new tools to help us understand the interactions of the various transcription factors that are responsible for the creation of various cell types from a single cell type during embryogenesis. This knowledge then gives rise to the concept of creating new ways to manipulate stem cells in order to correct the deficiencies present in various disease processes. Here, we present work that focuses specifically on pancreatic development. The ultimate goal of our research in studying the mechanisms of the basic differentiation of pancreatic precursor cells is to gain the knowledge necessary to be able to engineer stem cells specifically into beta-cells in the treatment of diabetes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I779,I779)","v":15987645},{"$f":"(LEN($J779) - LEN(SUBSTITUTE(LOWER($J779),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J779) - LEN(SUBSTITUTE(LOWER($J779),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J779) - LEN(SUBSTITUTE(LOWER($J779),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B779:D779)","v":1},2005,"Novel extrahepatic cytochrome P450s.","Karlgren",15987645,"Novel extrahepatic cytochrome P450s.    Abstract:   The cytochrome P450 enzymes are highly expressed in the liver and are involved in the metabolism of xenobiotics. Because of the initiatives associated with the Human Genome Project, a great progress has recently been seen in the identification and characterization of novel extrahepatic P450s, including CYP2S1, CYP2R1, CYP2U1 and CYP2W1. Like the hepatic enzymes, these P450s may play a role in the tissue-specific metabolism of foreign compounds, but they may also have important endogenous functions. CYP2S1 has been shown to metabolize all-trans retinoic acid and CYP2R1 is a major vitamin D 25-hydroxylase. Regarding their metabolism of xenobiotics, much remains to be established, but CYP2S1 metabolizes naphthalene and it is likely that these P450s are responsible for metabolic activation of several different kinds of xenobiotic chemicals and contribute to extrahepatic toxicity and carcinogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I780,I780)","v":15929630},{"$f":"(LEN($J780) - LEN(SUBSTITUTE(LOWER($J780),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J780) - LEN(SUBSTITUTE(LOWER($J780),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J780) - LEN(SUBSTITUTE(LOWER($J780),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B780:D780)","v":1},2005,"Relationship between dementia and nutrition-related factors and disorders: an overview.","Salerno-Kennedy",15929630,"Relationship between dementia and nutrition-related factors and disorders: an overview.    Abstract:   This review gives a brief overview of the main types of dementia and summarizes current thinking on the relationship between nutritional-related factors and disorders, and dementia. Dementia is a multi-factor pathological condition, and nutrition is one factor that may play a role on its onset and progression. An optimal intake of nutrients doesnt protect people from dementia. However, studies in this area show that inadequate dietary habits, which are of particular concern in elderly populations, may increase the risk of developing a number of age-related diseases, including disorders of impaired cognitive function. They show that a deficiency in essential nutrients, such as certain B complex vitamins, can result in hyperhomocysteinemia, a well-known risk factor for atherosclerosis and recently associated with cognitive impairment in old age. A deficiency of antioxidants such as vitamins C and E, and beta-carotene, as well as nutrition-related disorders like hypercholesterolemia, hypertension, and diabetes, may also have some role in cognitive impairment. These factors can be present for a long time before cognitive impairment becomes evident, therefore they could be potentially detected and corrected in a timely manner."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I781,I781)","v":15918144},{"$f":"(LEN($J781) - LEN(SUBSTITUTE(LOWER($J781),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J781) - LEN(SUBSTITUTE(LOWER($J781),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J781) - LEN(SUBSTITUTE(LOWER($J781),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B781:D781)","v":1},2005,"Prevention of hepatocellular carcinoma.","Colombo",15918144,"Prevention of hepatocellular carcinoma.    Abstract:   Prevention is the only realistic approach for reducing mortality rates associated with hepatocellular carcinoma (HCC) worldwide. Vaccination against hepatitis B and screening of blood donations are effective measures of primary prevention. Screening of blood donations has led to a substantial reduction in viral hepatitis transmission among the general population, and in Taiwan vaccination against hepatitis B caused a significant reduction in HCC incidence among infants. Primary prevention also includes approaches that alter epigenetic and genetic changes in hepatocytes, known to increase susceptibility to HCC, as well as treatments slowing progression to cirrhosis. The only evidence that chemoprevention reduces HCC risk is a multicenter randomized prospective study in Asian patients with advanced hepatitis B who received the oral nucleoside analogue lamivudine. Circumstantial evidence suggests that HCC risk is also reduced in patients with chronic hepatitis C who have had a sustained virological response to interferon therapy. HCC is not substantially reduced in patients with hepatitis B treated with interferon and patients with hepatitis C who did not respond to interferon. Secondary prevention, that is, prevention of tumor recurrence after hepatic resection or local ablative therapies, has been pursued with different approaches. Retinoids, hepatic embolization with (131)I lipiodol, and adoptive adjuvant immunotherapy have yielded encouraging results. Other approaches, including those based on interferon alfa or beta, provided inconclusive evidence for secondary prophylaxis of HCC, mainly because of the poor methodologies and scientific background of the studies. Dietary interventions and antiaflatoxin agents might help to prevent HCC in susceptible individuals, but the real efficacy of these approaches is far from being demonstrated."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I782,I782)","v":15802212},{"$f":"(LEN($J782) - LEN(SUBSTITUTE(LOWER($J782),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J782) - LEN(SUBSTITUTE(LOWER($J782),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J782) - LEN(SUBSTITUTE(LOWER($J782),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B782:D782)","v":1},2005,"The life-threatening complications of dermatologic therapies.","Orion",15802212,"The life-threatening complications of dermatologic therapies.    Abstract:   Dermatologists use a variety of systemic drugs, some of which can cause severe adverse reactions and even fatalities. Ivermectin, a well-tolerated drug, can cause severe neurological side effects, whereas metronidazole, in high cumulative doses, has been associated with convulsions and rarely with hepatotoxicity. Dapsone is associated with frequent hematologic side effects, such as methemoglobinemia, hemolysis, and anemia. Although hepatotoxicity is rare and usually mild and reversible with the new antifungal agents, severe cutaneous reactions (such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and anaphylaxis) have been reported. Even a relatively safe drug such as acyclovir has been reported to be the cause of renal failure and neurotoxicity. Retinoids can cause not so benign quot;benignquot; intracranial hypertension. Methotrexate can cause not only liver toxicity, but also myelosuppression and pancytopenia, which may be acute and life threatening. Nephrotoxicity is a well-recognized side effect of cyclosporine, whereas thrombotic thrombocytopenic purpura, which is associated with high morbidity and mortality, is less well known. Dermatologists should be familiar with these and other severe adverse reactions of the most popular and most used systemic medications of our trade."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I783,I783)","v":15771974},{"$f":"(LEN($J783) - LEN(SUBSTITUTE(LOWER($J783),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J783) - LEN(SUBSTITUTE(LOWER($J783),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J783) - LEN(SUBSTITUTE(LOWER($J783),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B783:D783)","v":1},2005,"[Recent knowledge about intestinal absorption and cleavage of carotenoids].","Borel",15771974,"[Recent knowledge about intestinal absorption and cleavage of carotenoids].    Abstract:   Our knowledge about intestinal absorption and cleavage of carotenoids has rapidly grown during the last years. New facts about carotenoid absorption have emerged while some controversies about cleavage are close to end. The knowledge of the absorption and conversion processes is indispensable to understand and interpret the perturbations that can occur in the metabolism of carotenoids and vitamin A. Recently, it has been shown that the absorption of certain carotenoids is not passive - as believed for a long time - but is a facilitated process that requires, at least for lutein, the class B-type 1 scavenger receptor (SR-B1). Various epidemiological and clinical studies have shown wide variations in carotenoid absorption from one subject to another, such differences are now explained by the structure of the concerned carotenoid, by the nature of the food that is absorbed with the carotenoid, by diverse exogenous factors like the intake of medicines or interfering components, by diet factors, by genetic factors, and by the nutritional status of the subject. Recently, the precise mechanism of beta-carotene cleavage by betabeta-carotene 15,15 monooxygenase (EC 1.14.99.36) - formerly called beta-carotene 15,15 dioxygenase (ex EC 1.13.11.21) - has been discovered, and a second enzyme which cleaves asymmetrically the beta-carotene molecule has been found. beta-carotene 15,15 monooxygenase only acts on the 15,15 bond, thus forming two molecules of retinal from one molecule of beta-carotene by central cleavage. Even though the betabeta-carotene 15,15 monooxygenase is much more active on the beta-carotene molecule, a study has shown that it can act on all carotenoids. Searchers now agree that other enzymes that can catalyse an eccentric cleavage of carotenoids probably exist, but under physiological conditions the betabeta-carotene 15,15 monooxygenase is by far the most active, and it is mainly effective in the small bowel mucosa and in the liver. However the conversion of provitamin A carotenoids into vitamin A is only partial, and requires a satisfactory protein status."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I784,I784)","v":15763234},{"$f":"(LEN($J784) - LEN(SUBSTITUTE(LOWER($J784),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J784) - LEN(SUBSTITUTE(LOWER($J784),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J784) - LEN(SUBSTITUTE(LOWER($J784),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B784:D784)","v":1},2005,"Alcohol in hepatocellular cancer.","Voigt",15763234,"Alcohol in hepatocellular cancer.    Abstract:   Hepatocellular cancer accounts for almost half a million cancer deaths a year, with an escalating incidence in the Western world. Alcohol has long been recognized as a major risk factor for cancer of the liver and of other organs including oropharynx, larynx, esophagus, and possibly the breast and colon. There is compelling epidemiologic data confirming the increased risk of cancer associated with alcohol consumption, which is supported by animal experiments. Cancer of the liver associated with alcohol usually occurs in the setting of cirrhosis. Alcohol may act as a cocarcinogen, and has strong synergistic effects with other carcinogens including hepatitis B and C, aflatoxin, vinyl chloride, obesity, and diabetes mellitus. Acetaldehyde, the main metabolite of alcohol, causes hepatocellular injury, and is an important factor in causing increased oxidant stress, which damages DNA. Alcohol affects nutrition and vitamin metabolism, causing abnormalities of DNA methylation. Abnormalities of DNA methylation, a key pathway of epigenetic gene control, lead to cancer. Other nutritional and metabolic effects, for example on vitamin A metabolism, also play a key role in hepatocarcinogenesis. Alcohol enhances the effects of environmental carcinogens directly and by contributing to nutritional deficiency and impairing immunological tumor surveillance. This review summarizes the epidemiologic evidence for the role of alcohol in hepatocellular cancer, and discusses the mechanisms involved in the promotion of cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I785,I785)","v":15658282},{"$f":"(LEN($J785) - LEN(SUBSTITUTE(LOWER($J785),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J785) - LEN(SUBSTITUTE(LOWER($J785),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J785) - LEN(SUBSTITUTE(LOWER($J785),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B785:D785)","v":1},2004,"[Vitamin A (retinoids)].","Okuno",15658282,"[Vitamin A (retinoids)].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I786,I786)","v":15633140},{"$f":"(LEN($J786) - LEN(SUBSTITUTE(LOWER($J786),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J786) - LEN(SUBSTITUTE(LOWER($J786),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J786) - LEN(SUBSTITUTE(LOWER($J786),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B786:D786)","v":1},2005,"Suppression of FGF signaling: a putative mechanism for the chemopreventive effects of acyclic retinoid in hepatocellular carcinoma.","Wang",15633140,"Suppression of FGF signaling: a putative mechanism for the chemopreventive effects of acyclic retinoid in hepatocellular carcinoma.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I787,I787)","v":15545507},{"$f":"(LEN($J787) - LEN(SUBSTITUTE(LOWER($J787),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J787) - LEN(SUBSTITUTE(LOWER($J787),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J787) - LEN(SUBSTITUTE(LOWER($J787),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B787:D787)","v":1},2005,"Transcriptional regulation of renin: an update.","Pan",15545507,"Transcriptional regulation of renin: an update.    Abstract:   Renin, as a component of the renin-angiotensin system, plays important roles in the regulation of blood pressure, electrolyte homeostasis, and mammalian renal development. Transcription of renin genes is subject to complex developmental and tissue-specific regulation. Progress has been made recently in elucidating the molecular mechanisms involved in renin gene expression. Using mouse As4.1 cells, which have many features characteristic of the renin-expressing juxtaglomerular cells of kidney, a proximal promoter region (-197 to -50 bp) and an enhancer (-2866 to -2625 bp) have been identified in the mouse renin gene, Ren-1(c), that are critical for its expression. The proximal promoter region contains at least 7 transcription factor-binding sites, including a binding site for the products of Hox, developmental control genes. The enhancer consists of at least 11 transcription factor-binding sites and is responsive to various signal transduction pathways, including cAMP, retinoic acid, endothelin-1, and cytokines, to alter renin mRNA levels. Sequence highly homologous to the mouse enhancer is also found in the human and rat renin genes. How these regulatory regions function in vivo will be the focus of future study."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I788,I788)","v":15543094},{"$f":"(LEN($J788) - LEN(SUBSTITUTE(LOWER($J788),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J788) - LEN(SUBSTITUTE(LOWER($J788),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J788) - LEN(SUBSTITUTE(LOWER($J788),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B788:D788)","v":1},2004,"Possible pathomechanisms of sudden infant death syndrome: key role of chronic hypoxia, infection/inflammation states, cytokine irregularities, and metabolic trauma in genetically predisposed infants.","Prandota",15543094,"Possible pathomechanisms of sudden infant death syndrome: key role of chronic hypoxia, infection/inflammation states, cytokine irregularities, and metabolic trauma in genetically predisposed infants.    Abstract:   Chronic hypoxia, viral infections/bacterial toxins, inflammation states, biochemical disorders, and genetic abnormalities are the most likely trigger of sudden infant death syndrome (SIDS). Autopsy studies have shown increased pulmonary density of macrophages and markedly more eosinophils in the lungs accompanied by increased T and B lymphocytes. The elevated levels of immunoglobulins, about 20% more muscle in the pulmonary arteries, increased airway smooth muscle cells, and increased fetal hemoglobin and erythropoietin are evidence of chronic hypoxia before death. Other abnormal findings included mucosal immune stimulation of the tracheal wall, duodenal mucosa, and palatine tonsils, and circulating interferon. Low normal or higher blood levels of cortisol often with petechiae on intrathoracic organs, depleted maternal IgG antibodies to endotoxin core (EndoCAb) and early IgM EndoCAb triggered, partial deletions of the C4 gene, and frequent IL-10-592*A polymorphism in SIDS victims as well as possible hypoxia-induced decreased production of antiinflammatory, antiimmune, and antifibrotic cytokine IL-10, may be responsible for the excessive reactions to otherwise harmless infections. In SIDS infants, during chronic hypoxia and times of infection/inflammation, several proinflammatory cytokines are released in large quantities, sometimes also representing a potential source of tissue damage if their production is not sufficiently well controlled, eg, by pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP). These proinflammatory cytokines down-regulate gene expression of major cytochrome P-450 and/or other enzymes with the specific effects on mRNA levels, protein expression, and enzyme activity, thus affecting metabolism of several endogenous lipophilic substances, such as steroids, lipid-soluble vitamins, prostaglandins, leukotrienes, thromboxanes, and exogenous substances. In SIDS victims, chronic hypoxia, TNF-alpha and other inflammatory cytokines, and arachidonic acid (AA) as well as n-3 polyunsaturated fatty acids (FA), stimulated and/or augmented superoxide generation by polymorphonuclear leukocytes, which contributed to tissue damage. Chronic hypoxia, increased amounts of nonheme iron in the liver and adrenals of these infants, enhanced activity of CYP2C9 regarded as the functional source of reactive oxygen species (ROS) in some endothelial cells, and nicotine accumulation in tissues also intensified production of ROS. These increased quantities of proinflammatory cytokines, ROS, AA, and nitric oxide (NO) also resulted in suppression of many CYP450 and other enzymes, eg, phosphoenolpyruvate carboxykinase (PEPCK), an enzyme important in the metabolism of FA during gluconeogenesis and glyceroneogenesis. PEPCK deficit found in SIDS infants (caused also by vitamin A deficiency) and eventually enhanced by PACAP lipolysis of adipocyte triglycerides resulted in an increased FA level in blood because of their impaired reesterification to triacylglycerol in adipocytes. In turn, the overproduction and release of FA into the blood of SIDS victims could lead to the metabolic syndrome and an early phase of type 2 diabetes. This is probably the reason for the secondary overexpression of the hepatic CYP2C8/9 content and activity reported in SIDS infants, which intensified AA metabolism. Pulmonary edema and petechial hemorrhages often present in SIDS victims may be the result of the vascular leak syndrome caused by IL-2 and IFN-alpha. Chronic hypoxia with the release of proinflammatory mediators IL-1alpha, IL-1beta and IL-6, and overloading of the cardiovascular and respiratory systems due to the narrowing airways and small pulmonary arteries of these children could also contribute to the development of these abnormalities. Moreover, chronic hypoxia of SIDS infants induced also production of hypoxia-inducible factor 1alpha (HIF-1alpha), which stimulated synthesis and release of different growth factors by vascular endothelial cells and intensified subclinical inflammatory reactions in the central nervous system, perhaps potentiated also by PACAP and VIP gene mutations. These processes could lead to the development of brainstem gliosis and disorders in the release of neuromediators important for physiologic sleep regulation. All these changes as well as eventual PACAP abnormalities could result in disturbed homeostatic control of the cardiovascular and respiratory responses of SIDS victims, which, combined with the nicotine effects and metabolic trauma, finally lead to death in these often genetically predisposed children."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I789,I789)","v":15523539},{"$f":"(LEN($J789) - LEN(SUBSTITUTE(LOWER($J789),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J789) - LEN(SUBSTITUTE(LOWER($J789),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J789) - LEN(SUBSTITUTE(LOWER($J789),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B789:D789)","v":1},2004,"Aromatic hydrocarbon receptor status in the metabolism of xenobiotics under normal and pathophysiological conditions.","Vrzal",15523539,"Aromatic hydrocarbon receptor status in the metabolism of xenobiotics under normal and pathophysiological conditions.    Abstract:   The aryl hydrocarbon receptor (AhR), a cytosolic protein belonging to the family of nuclear receptors, controls transcription of a wide range of structurally unrelated genes. To date, the most potent AhR ligand is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Exposure to TCDD leads to a number of toxic effects, in particular to tumor promotion and immunosuppression. The function of AhR in cells and living organisms therefore seems to be of paramount importance. Its absence in AhR null mice, results in severe phenotypic abnormalities, such as liver half size with fibrosis, accumulation of retinoic acid and immune system insufficiency. An important role of AhR inheres in its transcriptional control of several biotransformation enzymes (CYP1A1/2,1B1). Hence AhR is the crucial factor in the regulation of xenobiotic metabolism. Under pathophysiological conditions, such as inflammation, the level and activity of the AhR target gene CYP1A is decreased. Thus it is likely, that mediators and/or products of inflammation affect AhR function. This review deals with the role of AhR in xenobiotic metabolism under normal and pathophysiological conditions, with respect to inflammation in particular."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I790,I790)","v":15508108},{"$f":"(LEN($J790) - LEN(SUBSTITUTE(LOWER($J790),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J790) - LEN(SUBSTITUTE(LOWER($J790),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J790) - LEN(SUBSTITUTE(LOWER($J790),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B790:D790)","v":1},2004,"Alcohol and hepatocellular carcinoma.","Morgan",15508108,"Alcohol and hepatocellular carcinoma.    Abstract:   More than 18 million adults in the United States abuse alcohol, a prevalence 5 times higher than that of hepatitis C. Chronic alcohol use of greater than 80 g/day for more than 10 years increases the risk for hepatocellular carcinoma (HCC) approximately 5-fold; alcohol use of less than 80 g/day is associated with a nonsignificant increased risk for HCC. The risk for HCC in decompensated alcohol induced cirrhosis approaches 1% per year. The risk does not decrease with abstinence, and HCC can occur in a noncirrhotic liver. Alcohol use in chronic hepatitis C doubles the risk for HCC as compared with the risk in hepatitis C alone. Furthermore, there may be synergism between alcohol and hepatitis C in the development of HCC, and in these patients HCC may occur at an earlier age and the HCC may be histologically more advanced. Studies in the United States and Italy suggest that alcohol is the most common cause of HCC (accounting for 32%-45% of HCC). The mechanisms by which alcohol causes HCC are incompletely understood, but may include chromosomal loss, oxidative stress, a decreased retinoic acid level in the liver, altered DNA methylation, and genetic susceptibility. Alcohol use is increasing in many countries, suggesting that alcohol will continue to be a common cause of HCC throughout the world."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I791,I791)","v":15332354},{"$f":"(LEN($J791) - LEN(SUBSTITUTE(LOWER($J791),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J791) - LEN(SUBSTITUTE(LOWER($J791),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J791) - LEN(SUBSTITUTE(LOWER($J791),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B791:D791)","v":1},2004,"[Role of black bean Phaseolus vulgaris on the nutritional status of Guatemalan population].","Serrano",15332354,"[Role of black bean Phaseolus vulgaris on the nutritional status of Guatemalan population].    Abstract:   Guatemala provides an example of epidemiological superposition, in which health problems typical of developed countries and developing countries are both observed. Nutritional deficiencies in some micronutrients like vitamin A and iron coexist alongside chronic diseases such as diabetes type II and cardiovascular diseases. The importance of black beans in the normal Guatemala diet is well known:70g per capita of black beans are consumed daily. Black beans are an important sources of protein and energy in the diet. They contain quot;lentequot; digestion carbohydrates and a high proportion of non-digested carbohydrates that may be fermented in the large intestine. Theses types of carbohydrates are associated with a low glycemic response, low serum cholesterol levels, and a decrease of colon cancer risk factors. These physiological effects may be related to colonic fermentation end products (propionic and butyric acids). Black beans also contain several antinutritional compounds (enzymatic inhibitors, haemaglutenins, saponins and phytic acid, etc.), some of them thermolabiles that are partially eliminated during culinary processes and may modify the nutritional quality of beans. Black beans play a crucial role in the etiology of several diseases in Guatemala."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I792,I792)","v":15225593},{"$f":"(LEN($J792) - LEN(SUBSTITUTE(LOWER($J792),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J792) - LEN(SUBSTITUTE(LOWER($J792),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J792) - LEN(SUBSTITUTE(LOWER($J792),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B792:D792)","v":1},2004,"Molecular imaging of the transcription factor NF-kappaB, a primary regulator of stress response.","Carlsen",15225593,"Molecular imaging of the transcription factor NF-kappaB, a primary regulator of stress response.    Abstract:   A wide range of environmental stress and human disorders involves inappropriate regulation of NF-kappaB, including cancers and numerous inflammatory conditions. We have developed transgenic mice that express luciferase under the control of NF-kappaB, enabling real-time non-invasive imaging of NF-kappaB activity in intact animals. We show that, in the absence of stimulation, strong, intrinsic luminescence is evident in lymph nodes in the neck region, thymus, and Peyers patches. Treating mice with stressors, such as TNF-alpha, IL-1alpha, or lipopolysaccharide (LPS) increases the luminescence in a tissue-specific manner, with the strongest activity observable in the skin, lungs, spleen, Peyers patches, and the wall of the small intestine. Liver, kidney, heart, muscle, and adipose tissue exhibit less intense activities. Exposure of the skin to a low dose of UV-B radiation increases luminescence in the exposed areas. In ocular experiments, LPS- and TNF-alpha injected NF-kappaB-luciferase transgenic mice exhibit a 20-40-fold increase in lens NF-kappaB activity, similar to other LPS- and TNF-alpha-responsive organs. Peak NF-kappaB activity occurs 6h after injection of TNF-alpha and 12h after injection of LPS. Peak activities occur, respectively, 3 and 6h later than that in other tissues. Mice exposed to 360J/m(2) of UV-B exhibit a 16-fold increase in NF-kappaB activity 6h after exposure, characteristically similar to TNF-alpha-exposed mice. Thus, in NF-kappaB-luciferase transgenic mice, NF-kappaB activity also occurs in lens epithelial tissue and is activated when the intact mouse is exposed to classical stressors. Furthermore, as revealed by real-time non-invasive imaging, induction of chronic inflammation resembling rheumatoid arthritis produces strong NF-kappaB activity in the affected joints. Finally, we have used the model to demonstrate NF-kappaB regulation by manipulating the Vitamin A status in mice. NF-kappaB activity is elevated in mice fed a Vitamin A deficient (VAD) diet, and suppressed by surplus doses of retinoic acid (RA). We thus demonstrate the development and use of a versatile model for monitoring NF-kappaB activation both in tissue homogenates and in intact animals after the use of classical activators, during disease progression and after dietary intervention."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I793,I793)","v":15206159},{"$f":"(LEN($J793) - LEN(SUBSTITUTE(LOWER($J793),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J793) - LEN(SUBSTITUTE(LOWER($J793),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J793) - LEN(SUBSTITUTE(LOWER($J793),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B793:D793)","v":1},2004,"[Angptl3(angiopoietin-like 3)].","Shimizugawa",15206159,"[Angptl3(angiopoietin-like 3)].    Abstract:   Angiopoietin-like 3(Angptl3)-deficiency results in abnormally low lipid levels in mice. Angptl3-deficient mice showed enhanced very low density lipoprotein(VLDL) clearance compared with wild-type mice. Recombinant human ANGPTL3 protein inhibited lipoprotein lipase(LPL) activity in vitro, suggesting that Angptl3 affects VLDL triglyceride clearance by interfering with LPL activity. Liver X receptor(LXR) ligands and LXR-retinoid X receptor complex increased the promoter activity of Angptl3 gene. LXR ligand treatment did not increased plasma triglyceride levels in Angptl3-deficient mice at all, suggesting that hypertriglyceridemia associated with LXR ligand treatment is due to overproduction of Angptl3. Angptl3-deficiency decreases both plasma lipid levels and aorta atherogenic lesions in apoE-deficient mice, suggesting that repression of ANGPTL3 could decrease plasma lipid levels and could be protective against atherosclerosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I794,I794)","v":15180492},{"$f":"(LEN($J794) - LEN(SUBSTITUTE(LOWER($J794),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J794) - LEN(SUBSTITUTE(LOWER($J794),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J794) - LEN(SUBSTITUTE(LOWER($J794),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B794:D794)","v":1},2004,"Cytochrome P450 in neurological disease.","Liu",15180492,"Cytochrome P450 in neurological disease.    Abstract:   Advances in a multitude of disciplines support an emerging role for cytochrome P450 enzymes and their metabolic substrates and end-products in the pathogenesis and treatment of central nervous system disorders, including acute cerebrovascular injury, such as stroke, chronic neurodegenerative disease, such as Alzheimers and Parkinsons disease, as well as epilepsy, multiple sclerosis and psychiatric disorders, including anxiety and depression. The neural tissue contains its own unique set of P450 genes that are regulated in a manner that is distinct from their molecular regulation in peripheral tissue. Furthermore, brain P450s catalyze the formation of important brain signaling molecules, such as neurosteroids and eicosanoids, and metabolize substrates as diverse as vitamins A and D, cholesterol, bile acids, as well as centrally acting drugs, anesthetics and environmental neurotoxins. These unique characteristics allow this family of proteins and their metabolites to perform such vital functions in brain as neurotrophic support, neuroprotection, control of cerebral blood flow, temperature control, neuropeptide release, maintenance of brain cholesterol homoeostasis, elimination of retinoids from CNS, regulation of neurotransmitter levels and other functions important in brain physiology, development and disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I795,I795)","v":15153273},{"$f":"(LEN($J795) - LEN(SUBSTITUTE(LOWER($J795),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J795) - LEN(SUBSTITUTE(LOWER($J795),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J795) - LEN(SUBSTITUTE(LOWER($J795),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B795:D795)","v":1},2004,"Factors to consider in Micronesian food-based interventions: a case study of preventing vitamin A deficiency.","Englberger",15153273,"Factors to consider in Micronesian food-based interventions: a case study of preventing vitamin A deficiency.    Abstract:    BACKGROUND : Many factors need to be considered in a food-based intervention. Vitamin A deficiency and chronic diseases, such as diabetes, heart disease and cancer, have become serious problems in the Federated States of Micronesia (FSM) following the decreased production and consumption of locally grown foods. However, agricultural and social conditions are still favourable for local food production.  AIM : To identify key factors to consider in a Micronesian food-based intervention focusing on increased production and consumption of four major Micronesian staple foods: banana, breadfruit, giant swamp taro and pandanus.  METHODS : Ethnographic methods including key informant interviews and a literature review.  RESULTS : Pacific and Micronesian values, concepts of food and disease, and food classifications differ sharply from Western concepts. There are few FSM professionals with nutrition expertise. Traditional foods and food cultivars vary in nutrient content, consumption level, cost, availability, status, convenience in growing, storing and cooking, and organoleptic factors.  CONCLUSIONS : A systematic consideration of the factors that relate to a food-based intervention is critical to its success. The evaluation of which food and cultivar of that food that might be most effectively promoted is also critical. Regional differences, for example FSM inter-island differences between the staple foods and cultivars, must be considered carefully. The evaluation framework presented here may be relevant to Pacific Island and other countries with similar foods where food-based interventions are being planned. An ethnographic approach was found to be essential in understanding the cultural context and in data collection and analysis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I796,I796)","v":15103938},{"$f":"(LEN($J796) - LEN(SUBSTITUTE(LOWER($J796),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J796) - LEN(SUBSTITUTE(LOWER($J796),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J796) - LEN(SUBSTITUTE(LOWER($J796),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B796:D796)","v":1},2004,"[Acute promyelocytic leukemia after living donor partial orthotopic liver transplantation].","Sato",15103938,"[Acute promyelocytic leukemia after living donor partial orthotopic liver transplantation].    Abstract:   We encountered a 12-year-old girl with acute promyelocytic leukemia (APL) that occurred 21 months after a living donor partial orthotopic liver transplantation from her father for ornithine transcarbamylase deficiency. FK-506 had been administered for prophylaxis against graft-versus-host reaction. The bone marrow specimen revealed a massive infiltration of promyelocytic blasts (M3 by FAB classification) with chromosome 46, XX, t (15; 17) (q22; q12), being the recipient origin. A PML/RAR alpha chimeric gene was detected by RT-PCR. The patient was diagnosed as having APL and successfully induced to complete remission by chemotherapy including daunorubicin (DNR), cytarabine (araC), and all-trans retinoic acid (ATRA). She has been in continuous remission for 12 months after the treatment. Leukemia after liver transplantation is generally taken as a rare complication. However, recent advances in the survival rate of patients who have undergone liver transplantation will lead to an increase of such cases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I797,I797)","v":15102878},{"$f":"(LEN($J797) - LEN(SUBSTITUTE(LOWER($J797),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J797) - LEN(SUBSTITUTE(LOWER($J797),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J797) - LEN(SUBSTITUTE(LOWER($J797),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B797:D797)","v":1},2004,"Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.","Khovidhunkit",15102878,"Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host.    Abstract:   Infection and inflammation induce the acute-phase response (APR), leading to multiple alterations in lipid and lipoprotein metabolism. Plasma triglyceride levels increase from increased VLDL secretion as a result of adipose tissue lipolysis, increased de novo hepatic fatty acid synthesis, and suppression of fatty acid oxidation. With more severe infection, VLDL clearance decreases secondary to decreased lipoprotein lipase and apolipoprotein E in VLDL. In rodents, hypercholesterolemia occurs attributable to increased hepatic cholesterol synthesis and decreased LDL clearance, conversion of cholesterol to bile acids, and secretion of cholesterol into the bile. Marked alterations in proteins important in HDL metabolism lead to decreased reverse cholesterol transport and increased cholesterol delivery to immune cells. Oxidation of LDL and VLDL increases, whereas HDL becomes a proinflammatory molecule. Lipoproteins become enriched in ceramide, glucosylceramide, and sphingomyelin, enhancing uptake by macrophages. Thus, many of the changes in lipoproteins are proatherogenic. The molecular mechanisms underlying the decrease in many of the proteins during the APR involve coordinated decreases in several nuclear hormone receptors, including peroxisome proliferator-activated receptor, liver X receptor, farnesoid X receptor, and retinoid X receptor. APR-induced alterations initially protect the host from the harmful effects of bacteria, viruses, and parasites. However, if prolonged, these changes in the structure and function of lipoproteins will contribute to atherogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I798,I798)","v":15083599},{"$f":"(LEN($J798) - LEN(SUBSTITUTE(LOWER($J798),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J798) - LEN(SUBSTITUTE(LOWER($J798),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J798) - LEN(SUBSTITUTE(LOWER($J798),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B798:D798)","v":1},2004,"Vitamin D analogs as therapeutic agents: a clinical study update.","Wu-Wong",15083599,"Vitamin D analogs as therapeutic agents: a clinical study update.    Abstract:   Vitamin D3 is modified by vitamin D3-25-hydroxylase in the liver and 25-hydroxyvitamin D3-1 alpha-hydroxylase in the kidney to form the active metabolite 1 alpha,25-dihydroxyvitamin D3. The binding of 1 alpha,25-dihydroxyvitamin D3 to the vitamin D receptor (VDR), a nuclear receptor, activates VDR to interact with retinoid X receptor (RXR) and form the VDR/RXR/co-factor complex, which binds to vitamin D response elements in the promoter region of target genes to regulate gene transcription. 1 alpha,25-dihydroxyvitamin D3 regulates the homeostasis of calcium and phosphorus, and also controls the expression of parathyroid hormone. Chronic renal disease is characterized by reduced synthesis of 1 alpha,25-dihydroxyvitamin D3, inadequate renal phosphate clearance and calcium imbalance, over-stimulation of the parathyroid gland, and increased parathyroid hormone synthesis. This secondary hyperparathyroidism (HPT) can cause renal osteodystrophy unless treated. Several vitamin D analogs are currently available or under investigation for the treatment of secondary HPT, psoriasis and osteoporosis. Additional clinical studies are being conducted for a variety of indications, including bone diseases, cell proliferation disorders and autoimmune diseases. Different vitamin D analogs seem to exhibit differential effects as exemplified by the survival benefit provided by paricalcitol over 1 alpha,25-dihydroxyvitamin D3 for end-stage renal disease patients on hemodialysis. Elucidation of the mechanism of action for the different vitamin D analogs will enhance our understanding of the vitamin D pathway and improve therapeutic uses of these analogs. This review discusses recent progress on the use of vitamin D and its analogs in the management of HPT secondary to chronic renal disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I799,I799)","v":15070439},{"$f":"(LEN($J799) - LEN(SUBSTITUTE(LOWER($J799),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J799) - LEN(SUBSTITUTE(LOWER($J799),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J799) - LEN(SUBSTITUTE(LOWER($J799),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B799:D799)","v":1},2004,"Alcohol and cancer: genetic and nutritional aspects.","Pöschl",15070439,"Alcohol and cancer: genetic and nutritional aspects.    Abstract:   Chronic alcohol consumption is a major risk factor for cancer of upper aero-digestive tract (oro-pharynx, hypopharynx, larynx and oesophagus), the liver, the colo-rectum and the breast. Evidence has accumulated that acetaldehyde is predominantly responsible for alcohol-associated carcinogenesis. Acetaldehyde is carcinogenic and mutagenic, binds to DNA and protein, destroys the folate molecule and results in secondary cellular hyper-regeneration. Acetaldehyde is produced by mucosal and cellular alcohol dehydrogenase, cytochrome P450 2E1 and through bacterial oxidation. Its generation and/or its metabolism is modulated as a result of polymorphisms or mutations of the genes responsible for these enzymes. Acetaldehyde can also be produced by oral bacteria. Smoking, which changes the oral bacterial flora, also increases salivary acetaldehyde. Cigarette smoke and some alcoholic beverages, such as Calvados, contain acetaldehyde. In addition, chronic alcohol consumption induces cytochrome P450 2E1 enxyme activity in mucosal cells, resulting in an increased generation of reactive oxygen species and in an increased activation of various dietary and environmental carcinogens. Deficiencies of riboflavin, Zn, folate and possibly retinoic acid may further enhance alcohol-associated carcinogenesis. Finally, methyl deficiency as a result of multiple alcohol-induced changes leads to DNA hypomethylation. A depletion of lipotropes, including methionine, choline, betaine and S-adenosylmethionine, as well as folate, results in the hypomethylation of oncogenes and may lead to DNA strand breaks, all of which are associated with increased carcinogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I800,I800)","v":15067580},{"$f":"(LEN($J800) - LEN(SUBSTITUTE(LOWER($J800),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J800) - LEN(SUBSTITUTE(LOWER($J800),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J800) - LEN(SUBSTITUTE(LOWER($J800),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B800:D800)","v":1},2004,"[What is the role of endothelin system?].","Pinet",15067580,"[What is the role of endothelin system?].    Abstract:   Endothelins are a family of three peptides of 21 amino acids with strong vasoconstrictor effects. The three peptides are encoded by three different genes and derived from precursors (quot; big endothelinsquot;) which are cleaved by metalloproteases, named endothelin-converting enzyme. Two receptors have been cloned, ET-A and ET-B which bind the three endothelins with various affinities. The diverse expression pattern of the endothelin system (ET) components is associated with a complex pharmacology and its counteracting physiological actions. New modulators of the ET system have been described : retinoic acid, leptin, prostaglandins, hypoxia. Endothelins can be considered as regulators working in paracrine and autocrine fashion in a variety of organs in different cellular types. The ET system has beneficial and detrimental roles in mammals. The different components have been shown to be essential for a normal embryonic and neonatal development, for renal homeostasis and maintenance of basal vascular tone. They are involved in physiological and tumoral angiogenesis. They affect the physiology and pathophysiology of the liver, muscle, skin, adipose tissue and reproductive tract. The endothelin system participates in the development of atherosclerosis as well as pulmonary hypertension, and mediates cardiac remodeling in heart failure. Elaboration of new animal models (knock-out, pathophysiological models em leader ) will allow the clear genetic dissection of physiological and pathophysiological roles of the endothelin system."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I801,I801)","v":15066229},{"$f":"(LEN($J801) - LEN(SUBSTITUTE(LOWER($J801),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J801) - LEN(SUBSTITUTE(LOWER($J801),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J801) - LEN(SUBSTITUTE(LOWER($J801),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B801:D801)","v":1},2004,"Treatment of hepatocarcinoma.","Gerard",15066229,"Treatment of hepatocarcinoma.    Abstract:   This article reviews the current developments and significant trends in the treatment of hepatocarcinoma (HCC). Prevention programs should be based on large vaccination campaigns and the use of immunologic or biologic molecules to delay the onset of HCC in already cirrhotic patients. Surgery remains the therapy of choice in patients with a small and limited number of tumor nodules. To date, no preoperative treatment has been proven useful. Adjuvant treatments involving systemic chemotherapy, intra-arterial infusion, or chemoembolization failed to improve survival, whereas immune therapy, retinoids, radiolabeled isotopes, and antiangiogenic agents seem promising. Such local treatments as percutaneous ethanol injection, cryotherapy, and radiofrequency are proposed for patients with limited hepatic function and should be combined with other treatment modalities to optimize their efficacy and limit their toxicity. Regional therapy should take a selective, subsegmental approach at intervals depending on tumor response and possibly combined with other treatment modalities. Systemic therapy with cytotoxic agents remains disappointing. Hormonal therapy with tamoxifen or antiandrogens has shown no efficacy and might even be detrimental. Further progress may be expected from targeted therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I802,I802)","v":15053163},{"$f":"(LEN($J802) - LEN(SUBSTITUTE(LOWER($J802),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J802) - LEN(SUBSTITUTE(LOWER($J802),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J802) - LEN(SUBSTITUTE(LOWER($J802),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B802:D802)","v":1},2004,"Lipid lowering activity of drugs affecting cholesterol absorption.","Norata",15053163,"Lipid lowering activity of drugs affecting cholesterol absorption.    Abstract:    AIM : Dietary cholesterol absorption, endogenous cholesterol synthesis and biliary cholesterol excretion regulate whole body cholesterol balance as a result of biotransformation into bile acids or direct cholesterol excretion. Recent studies have significantly advanced our understanding of intestinal sterol absorption at molecular level. This review concentrates on two major issues: the mechanisms of sterol absorption, and the currently available or experimental drugs that affect this pathway.  DATA SYNTHESIS : Nuclear hormone receptors, such as the liver X, farnesoid X and retinoid X receptors, regulate the absorption of dietary sterols by modulating the transcription of several genes involved in cholesterol metabolism, The ABC proteins transport dietary cholesterol from enterocytes back to the intestinal lumen, thus limiting the amount of absorbed cholesterol. By means of the same mechanism, ABC transporters also provide an efficient barrier against the absorption of plant sterols. Phytosterols, bile acid sequestrants, ezetimibe and ACAT inhibitors are possible means of affecting these pathways.  CONCLUSION : In addition to providing an insight into the molecular mechanisms of sterol absorption, these recent findings may lead to new therapeutic options for the treatment of hypercholesterolemia. This is particularly true in the case of patients at high risk of coronary artery disease requiring aggressive lipid-lowering therapy combining a statin with drugs affecting cholesterol absorption in order to ensure the optimal management of dyslipidemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I803,I803)","v":15034284},{"$f":"(LEN($J803) - LEN(SUBSTITUTE(LOWER($J803),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J803) - LEN(SUBSTITUTE(LOWER($J803),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J803) - LEN(SUBSTITUTE(LOWER($J803),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B803:D803)","v":1},2004,"[Reverse cholesterol transport in cultured gallbladder epithelial cells].","Lee",15034284,"[Reverse cholesterol transport in cultured gallbladder epithelial cells].    Abstract:   Bile is the major route of cholesterol excretion from the body. It is concentrated in the gallbladder, and often results in supersaturation of cholesterol. The high levels of cholesterol in gallbladder bile has clinical implications with respect to cholesterol gallstone formation and cholesterolosis of the gallbladder wall. Gallbladder epithelial cells (GBEC) are exposed to high cholesterol concentrations on their apical surfaces. Therefore, GBEC are uniquely positioned to play an important role in modulating biliary cholesterol concentrations. Recently, it has been documented that the key-transporter for polarized cholesterol and phospholipid efflux in GBEC is ATP-binding cassette transporter A1 (ABCA1) and Liver X receptor (LXR) and retinoid X receptor (RXR) in the nucleus of GBEC have a role that regulates ABCA1 expression. In addition, GBEC synthesize apolipoprotein A-I and E as cholesterol acceptors. These results indicate that GBEC has a perfect system for reverse cholesterol transport. We introduce the roles and mechanisms of ABCA1, scavenger receptor class B-I, LXR and RXR related to reverse cholesterol transport in GBEC with a review of our study experience and related literature."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I804,I804)","v":14989258},{"$f":"(LEN($J804) - LEN(SUBSTITUTE(LOWER($J804),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J804) - LEN(SUBSTITUTE(LOWER($J804),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J804) - LEN(SUBSTITUTE(LOWER($J804),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B804:D804)","v":1},2004,"Vitamin E, nuclear receptors and xenobiotic metabolism.","Traber",14989258,"Vitamin E, nuclear receptors and xenobiotic metabolism.    Abstract:   Supplemental vitamin E (alpha-tocopherol) is taken daily by more than 35 million people in the US. Following absorption and liver uptake, the fate of vitamin E is largely unknown. Of potential importance are recent clinical studies that have reported adverse effects of vitamin E that may be directly related to its hepatic metabolism. In an in vitro system, both vitamin E and rifampicin, a known stimulator of xenobiotic metabolism, activated the pregnane X receptor (PXR), an orphan nuclear receptor. PXR as a heterodimer with the retinoid X receptor (RXR), binds to specific cis-elements in the promoter regions of genes. PXR/RXR regulates a constellation of genes involved in xenobiotic detoxification, including oxidation, conjugation, and transporters. Importantly, PXR/RXR regulates the cytochrome P450 (CYP), CYP3A, involved in the hepatic detoxification of more than 50% of prescription drugs. Vitamin E acting as a PXR ligand could alter these PXR-mediated reactions. Unfortunately, the extent to which pharmacologic doses of vitamin E modulate these pathways in vivo has not been determined."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I805,I805)","v":14870618},{"$f":"(LEN($J805) - LEN(SUBSTITUTE(LOWER($J805),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J805) - LEN(SUBSTITUTE(LOWER($J805),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J805) - LEN(SUBSTITUTE(LOWER($J805),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B805:D805)","v":1},2003,"Carotenoid-rich bananas: a potential food source for alleviating vitamin A deficiency.","Englberger",14870618,"Carotenoid-rich bananas: a potential food source for alleviating vitamin A deficiency.    Abstract:   This review article points out that bananas are an important food for many people in the world. Thus, banana cultivars rich in provitamin A carotenoids may offer a potential food source for alleviating vitamin A deficiency, particularly in developing countries. Many factors are associated with the presently known food sources of vitamin A that limit their effectiveness in improving vitamin A status. Acceptable carotenoid-rich banana cultivars have been identified in Micronesia, and some carotenoid-rich bananas have been identified elsewhere. Bananas are an ideal food for young children and families for many regions of the world, because of their sweetness, texture, portion size, familiarity, availability, convenience, versatility, and cost. Foods containing high levels of carotenoids have been shown to protect against chronic disease, including certain cancers, cardiovascular disease, and diabetes. Because the coloration of the edible flesh of the banana appears to be a good indicator of likely carotenoid content, it may be possible to develop a simple method for selecting carotenoid-rich banana cultivars in the community. Research is needed on the identification of carotenoid-rich cultivars, targeting those areas of the world where bananas are a major staple food; investigating factors affecting production, consumption, and acceptability; and determining the impact that carotenoid-rich bananas may have on improving vitamin A status. Based on these results, interventions should be undertaken for initiating or increasing homestead and commercial production."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I806,I806)","v":14695916},{"$f":"(LEN($J806) - LEN(SUBSTITUTE(LOWER($J806),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J806) - LEN(SUBSTITUTE(LOWER($J806),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J806) - LEN(SUBSTITUTE(LOWER($J806),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B806:D806)","v":1},2003,"Regulation of coenzyme Q biosynthesis and breakdown.","Dallner",14695916,"Regulation of coenzyme Q biosynthesis and breakdown.    Abstract:   All animal cells synthesize sufficient amounts of coenzyme Q (CoQ) and the cells also possess the capacity to metabolize the lipid. The main product of the metabolism is an intact ring with a short carboxylated side chain which glucuronidated in the liver and excreted mainly into the bile (Nakamura et al., Biofactors 9 (1999), 111-119). In other cells CoQ is phosphorylated, transferred into the blood and excreted through the urine. The biosynthesis of this lipid is regulated by nuclear receptors. PPARalpha is not required for the biosynthesis, or induction upon cold exposure, but it is necessary for the elevated CoQ synthesis during peroxisomal induction. RXRalpha is involved in the basal synthesis of CoQ and also in the increased synthesis upon cold treatment but is not required for peroxisomal induction. Dietary CoQ in human appear in the blood and it is taken up by mononuclear but not polynuclear cells. The former cells display a specific phospholipid modification, an increase of arachidonic acid content. In monocytes the CoQ administration leads to a significant decrease of the beta2-integrin CD11b and the complement receptor CD35. CD11b is one of the adhesion factors regulating the entry of these cells into the arterial wall which demonstrates that the anti-atherogenic effect of CoQ is mediated by other mechanisms beside its antioxidant protection."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I807,I807)","v":14608448},{"$f":"(LEN($J807) - LEN(SUBSTITUTE(LOWER($J807),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J807) - LEN(SUBSTITUTE(LOWER($J807),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J807) - LEN(SUBSTITUTE(LOWER($J807),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B807:D807)","v":1},2003,"The use of folic acid for the prevention of neural tube defects and other congenital anomalies.","Wilson",14608448,"The use of folic acid for the prevention of neural tube defects and other congenital anomalies.    Abstract:    OBJECTIVE : To provide information regarding the use of folic acid for the prevention of neural tube defects (NTDs) and other congenital anomalies, in order that physicians, midwives, nurses, and other health-care workers can assist in the education of women in the preconception phase of their health care. OPTION: Folic acid supplementation is problematic, since 50% of pregnancies are unplanned and the health status of women may not be optimal.  OUTCOMES : Folic acid supplementation has been proven to decrease or minimize specific birth defects.  EVIDENCE : A systematic review of the literature, including review and peer-reviewed articles, government publications, the previous Society of Obstetricians and Gynaecologists of Canada (SOGC) Policy Statement of March 1993, and statements from the American College of Obstetrics and Gynecology, was used to develop a new clinical practice guideline for the SOGC.  VALUES : Peer-review process within the committee structure.  BENEFITS, HARMS, AND COSTS : The benefit is reduced lethal and severe morbidity birth defects and the harm is minimal. The personal cost is of vitamin supplementation on a daily basis and eating a healthy diet.  RECOMMENDATIONS : 1. Women in the reproductive age group should be advised about the benefits of folic acid supplementation during wellness visits (birth control renewal, Pap testing, yearly examination), especially if pregnancy is contemplated. (III-A) 2. Women should be advised to maintain a healthy nutritional diet, as recommended in Canadas Food Guide to Healthy Eating (good or excellent sources of folic acid: broccoli, spinach, peas, Brussels sprouts, corn, beans, lentils, oranges). (III-A) 3. Women who could become pregnant should be advised to take a multivitamin containing 0.4 mg to 1.0 mg of folic acid daily. (II-1A) 4. Women taking a multivitamin with folic acid supplement should be advised not to take more than 1 daily dose of vitamin supplement, as indicated on the product label. (II-2A) 5. Women in intermediate- to high-risk categories for NTDs (NTD-affected previous pregnancy, family history, insulin-dependent diabetes, epilepsy treatment with valproic acid or carbamazepine) should be advised that high-dose folic acid (4.0 mg-5.0 mg daily) supplementation is recommended. This should be taken as folic acid alone, not in a multivitamin format, due to risk of excessive intake of other vitamins such as vitamin A. (I-A) 6. The choice of a 5 mg folic acid daily dose for women considering a pregnancy should be made under medical supervision after minimizing the risk of undiagnosed vitamin B12 deficiency (hypersegmentation of polymorphonuclear cells, macrocystic indices, large ovalocytes, leukopenia, thrombocytopenia, markedly elevated lactate dehydrogenase level, confirmed red blood cell folate level). (II-2A) 7. Signs or symptoms of vitamin B12 deficiency should be considered before initiating folic acid supplementation of doses greater than 1.0 mg. (III-A) 8. A three-generation pedigree on the families of both the pregnant woman and the biological father should be obtained to identify increased risk for congenital birth defects (i.e., NTD, cardiac, chromosomal, genetic). (III-A) 9. Women who become pregnant should be advised of the availability of noninvasive screening tests and invasive diagnostic tests for congenital birth defects (including NTDs): maternal serum quot;triple marker screenquot; at 15 to 20 weeks, ultrasound at 16 to 20 weeks, and amniocentesis after 15 weeks of pregnancy if a positive screening test is present. (I-A) VALIDATION: This is a revision of a previous guideline and information from other consensus reviews from medical and government publications has been used."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I808,I808)","v":13677624},{"$f":"(LEN($J808) - LEN(SUBSTITUTE(LOWER($J808),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J808) - LEN(SUBSTITUTE(LOWER($J808),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J808) - LEN(SUBSTITUTE(LOWER($J808),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B808:D808)","v":1},2002,"Oxidant-antioxidant system: role and significance in human body.","Irshad",13677624,"Oxidant-antioxidant system: role and significance in human body.    Abstract:   Present article gives a holistic view of the causes, role and conrol of oxidative stress in the development and progression of various human diseases. Several types of reactive species are generated in the body as a result of metabolic reactions in the form of free radicals or non-radicals. These species may be either oxygen derived or nitrogen derived and called prooxidants. They attack macromolecules including protein, DNA and lipid etc. causing cellular/tissue damage. To counter their effect, the body is endowed with another category of compounds called antioxidants. These antioxidants are produced either endogenously or received from exogenous sources and include enzymes like superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, minerals like Se, Mn, Cu and Zn, and vitamins like vitamin A, C and E. Other compounds with antioxidant activity include glutathione, flavonoids, bilirubin and uric acid etc.. In a healthy body, prooxidants and antioxidants maintain a ratio and a shift in this ratio towards prooxidants gives rise to oxidative stress. This oxidative stress may be either mild or severe depending on the extent of shift and remains the cause of several diseases such as cardiovascular diseases, neurological diseases, malignancies, renal diseases, diabetes, inflammatory problems, skin diseases, aging, respiratory diseases, liver diseases and different types of viral infections. As more and more reports are pouring in, a lot of information is being unfolded about oxidative stress in relation to several other diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I809,I809)","v":12675072},{"$f":"(LEN($J809) - LEN(SUBSTITUTE(LOWER($J809),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J809) - LEN(SUBSTITUTE(LOWER($J809),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J809) - LEN(SUBSTITUTE(LOWER($J809),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B809:D809)","v":1},1998,"A review of vitamins A, C, and E and their relationship to cardiovascular disease.","Brown",12675072,"A review of vitamins A, C, and E and their relationship to cardiovascular disease.    Abstract:   Cardiovascular disease (CVD), particularly in the form of coronary artery disease, is the leading cause of death in the United States. Research in the past 10 years links pathogenic low-density lipoprotein (LDL) modification to oxidation damage by free radicals. This review summarizes the major findings of CVD-related epidemiologic research and clinical trials conducted in the past 5 years on vitamins A, C, and E. Vitamin supplementation behaviors are discussed. In prospective studies, the intake of vitamins A, C, and E has been correlated with lower mortality rates. When recent clinical trials and oxidation studies are analyzed, the weight of evidence suggests that 100-400 IU of daily vitamin E over 2 years or more may be most efficacious in reducing low-density lipoprotein oxidation and positively influencing mortality rates from CVD in primary care. Research also supports vitamin E supplementation in patients with known CAD or a history of transient ischemic attacks. Persons with diabetes or hypertension as well as smokers may benefit from supplemental vitamin C intake. Targeted antioxidant vitamin intake should be included in CVD risk assessment and primary preventive counseling efforts."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I810,I810)","v":12638266},{"$f":"(LEN($J810) - LEN(SUBSTITUTE(LOWER($J810),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J810) - LEN(SUBSTITUTE(LOWER($J810),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J810) - LEN(SUBSTITUTE(LOWER($J810),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B810:D810)","v":1},2002,"[New data about ITO cells].","Stanciu",12638266,"[New data about ITO cells].    Abstract:   Ito cells (the fat-storing cells) are stellate cells located in the space of Disse. They can be selectively stained with gold chloride, but their distinguishing feature in routine histological preparations is the presence of multiple lipid droplets in their cytoplasm. Ito cells have the capacity to accumulate exogenously administered vitamin A as retinyl esters in lipid droplets. The quantity of vitamin A, which is stuck into Ito cells, decreases progressively in liver injury, like chronic alcohol intake. Also, the fat-storing cells are the principal cellular source of collagen and other extracellular substances in normal as well as fibrotic liver. Liver injury is followed by an increase in the number of the fat-storing cells."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I811,I811)","v":12636232},{"$f":"(LEN($J811) - LEN(SUBSTITUTE(LOWER($J811),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J811) - LEN(SUBSTITUTE(LOWER($J811),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J811) - LEN(SUBSTITUTE(LOWER($J811),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B811:D811)","v":1},2003,"Pleiotropic functions of erythropoietin.","Sasaki",12636232,"Pleiotropic functions of erythropoietin.    Abstract:   Erythropoietin (EPO) produced by the fetal liver and adult kidney is an essential stimulator of erythropoiesis. EPO production is regulated through hypoxic activation of gene transcription and possibly hypoxia-induced stabilization of its mRNA. In the liver of early embryos in which EPO production poorly responds to hypoxia, retinoic acid may be an important stimulator. In this decade, new sites of EPO production have been found: central nervous system and reproductive organs. These tissues have a paracrine and/or autocrine system of EPO, which is independent of the endocrine system (kidney/bone marrow) in adult erythropoiesis. In the central nervous system, astrocytes are the main producers of EPO, while EPO receptor is expressed in neurons. EPO protects neurons from a various types of damage. The uterine EPO is likely involved in the estrogen-dependent angiogenesis of the endometrial layer. The possible functions of EPO in other tissues and tissue-characteristic regulation of EPO production are also discussed in this review."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I812,I812)","v":12573484},{"$f":"(LEN($J812) - LEN(SUBSTITUTE(LOWER($J812),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J812) - LEN(SUBSTITUTE(LOWER($J812),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J812) - LEN(SUBSTITUTE(LOWER($J812),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B812:D812)","v":1},2003,"The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors.","Pascussi",12573484,"The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors.    Abstract:   Numerous chemicals increase the metabolic capability of organisms by their ability to activate genes encoding various xenochemical-metabolizing enzymes, such as cytochromes P450 (CYPs), transferases and transporters. For example, natural and synthetic glucocorticoids (agonists and antagonists) as well as other clinically important drugs induce the hepatic CYP2B, CYP2C and CYP3A subfamilies in man, and these inductions might lead to clinically important drug-drug interactions. Only recently, the key cellular receptors that mediate such inductions have been identified. They include nuclear receptors, such as the constitutive androstane receptor (CAR, NR1I3), the retinoid X receptor (RXR, NR2B1), the pregnane X receptor (PXR, NR1I2), and the vitamin D receptor (VDR, NR1I1) and steroid receptors such as the glucocorticoid receptor (GR, NR3C1). There is a wide promiscuity of these receptors in the induction of CYPs in response to xenobiotics. Indeed, this adaptive system appears now as a tangle of networks, where receptors share partners, ligands, DNA response elements and target genes. Moreover, they influence mutually their relative expression. This review is focused on these different pathways controlling human CYP2B6, CYP2C9 and CYP3A4 gene expression, and the cross-talk between these pathways."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I813,I813)","v":12573483},{"$f":"(LEN($J813) - LEN(SUBSTITUTE(LOWER($J813),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J813) - LEN(SUBSTITUTE(LOWER($J813),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J813) - LEN(SUBSTITUTE(LOWER($J813),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B813:D813)","v":1},2003,"Phenobarbital induction of drug/steroid-metabolizing enzymes and nuclear receptor CAR.","Kakizaki",12573483,"Phenobarbital induction of drug/steroid-metabolizing enzymes and nuclear receptor CAR.    Abstract:   Phenobarbital (PB) increases hepatic drug/steroid-metabolic capability by coordinately activating transcription of the genes encoding various metabolizing enzymes. The nuclear receptor CAR was first implicated as a transcription factor that activates the cytochrome P450 Cyp2b10 gene. In response to PB, CAR forms a heterodimer with the retinoid X receptor (RXR), binds to a PB response element (typified by DR-4 motif), and activates transcription of the gene. In the CAR-null mouse, PB does not only induce the Cyp2b10 gene, but also induces genes encoding various metabolizing enzymes. Thus, CAR is a general nuclear receptor that is essential for PB induction of drug/steroid metabolizing enzymes. PB also induces amino levulinate synthase 1 (ALAS-1), the rate-limiting enzyme in heme biosynthesis, to increase heme supply. However, PB induction of the synthase occurs in CAR-null mice, suggesting that CAR does not coordinate the heme synthesis for the induction of drug/steroid metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I814,I814)","v":12559450},{"$f":"(LEN($J814) - LEN(SUBSTITUTE(LOWER($J814),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J814) - LEN(SUBSTITUTE(LOWER($J814),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J814) - LEN(SUBSTITUTE(LOWER($J814),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B814:D814)","v":1},2003,"The coming of age of our understanding of the enterohepatic circulation of bile salts.","Redinger",12559450,"The coming of age of our understanding of the enterohepatic circulation of bile salts.    Abstract:   Recent advances in molecular biology have greatly accelerated knowledge relating to the significance of the enterohepatic circulation of bile salts. This review highlights the role that both oxysterols and bile salts play as ligands which, when bound to nuclear hormone receptors, activate transcription factors that set into play feed-forward catabolism of cholesterol to bile salts and feedback control of bile acid synthesis. The nuclear hormone receptors, liver X receptor (LXR) and farnesoid X receptor (FXR) both combined as heterodimers with retinoid X receptor and with oxysterols and bile salts, respectively as their ligands, initiate powerful genetic controls over cholesterol and bile acid homeostatic mechanisms. LXR/RXR signals molecular control of feed-forward catabolism of cholesterol to bile acids while FXR/RXR initiates feedback control of bile acid synthesis. An additional nuclear hormone receptor, small heterodimer partner (SHP), is required to inhibit the competence factor, liver receptor homolog-1 to achieve repression of bile acid synthesis in the liver and in so doing SHP autoregulates its own function. Additionally, while bile acid synthesis is repressed, pool size is preserved by the action of FXR/RXR at both hepatic and intestinal levels, which genetically signals enhanced hepatocyte bile salt transport by the bile salt export pump (BSEP) and the ileal bile acid binding protein (IBABP) for ileal reabsorption. During activation of cholesterol catabolism, LXR/RXR enhances reverse cholesterol transport by increasing cholesterol efflux via the ABC-1 transporter from extrahepatic cells. This cholesterol is then taken up by high-density lipoprotein (HDL) and transported back to the liver for further cholesterol catabolism and elimination in bile. The genetic coordination of nuclear hormone receptor function within the territory of the enterohepatic of bile salts allows for normal cholesterol and bile acid homeostasis thereby preventing atherosclerosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I815,I815)","v":12479579},{"$f":"(LEN($J815) - LEN(SUBSTITUTE(LOWER($J815),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J815) - LEN(SUBSTITUTE(LOWER($J815),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J815) - LEN(SUBSTITUTE(LOWER($J815),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B815:D815)","v":1},2002,"New insights into the fatty acid-binding protein (FABP) family in the small intestine.","Besnard",12479579,"New insights into the fatty acid-binding protein (FABP) family in the small intestine.    Abstract:   The fatty acid-binding protein (FABP) superfamily is constituted by 14-15 kDa soluble proteins which bind with a high affinity either long-chain fatty acids (LCFAs), bile acids (BAs) or retinoids. In the small intestine, three different FABP isoforms exhibiting a high affinity for LCFAs and/or BAs are expressed: the intestinal and the liver-type (I-FABP and L-FABP) and the ileal bile acid-binding protein (I-BABP). Despite of extensive investigations, their respective physiological function(s) are not clearly established. In contrast to the I-FABP, L-FABP and I-BABP share several common structural features (shape, size and volume of the hydrophobic pocket). Moreover, L-FABP and I-BABP genes are also specifically regulated by their respective preferential ligands through a very similar molecular mechanism. Although, they exhibit differences in their binding specificities and location along the small intestine supporting a specialization, it is likely that L-FABP and I-BABP genes exert the same type of basic function(s) in the enterocyte, in contrast to I-FABP."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I816,I816)","v":12479567},{"$f":"(LEN($J816) - LEN(SUBSTITUTE(LOWER($J816),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J816) - LEN(SUBSTITUTE(LOWER($J816),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J816) - LEN(SUBSTITUTE(LOWER($J816),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B816:D816)","v":1},2002,"Insights into binding of fatty acids by fatty acid binding proteins.","Hanhoff",12479567,"Insights into binding of fatty acids by fatty acid binding proteins.    Abstract:   Members of the phylogenetically related intracellular lipid binding protein (iLBP) are characterized by a highly conserved tertiary structure, but reveal distinct binding preferences with regard to ligand structure and conformation, when binding is assessed by the Lipidex method (removal of unbound ligand by hydrophobic polymer) or by isothermal titration calorimetry, a true equilibrium method. Subfamily proteins bind retinoids, subfamily II proteins bind bulky ligands, examples are intestinal bile acid binding protein (I-BABP) and liver fatty acid binding protein (L-FABP) which binds 2 ligand molecules, preferably monounsaturated and n-3 fatty acids. Subfamily III intestinal fatty acid binding protein (I-FABP) binds fatty acid in a bent conformation. The fatty acid bound by subfamily IV FABPs has a U-shaped conformation; here heart (H-) FABP preferably binds n-6, brain (B-) FABP n-3 fatty acids. The ADIFAB-method is a fluorescent test for fatty acid in equilibrium with iLBP and reveals some correlation of binding affinity to fatty acid solubility in the aqueous phase; these data are often at variance with those obtained by the other methods. Thus, in this review published binding data are critically discussed, taking into account on the one hand binding increments calculated for fatty acid double bonds on the basis of the solubility hypothesis, on the other hand the interpretation of calorimetric data on the basis of crystallographic and solution structures of iLBPs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I817,I817)","v":12449021},{"$f":"(LEN($J817) - LEN(SUBSTITUTE(LOWER($J817),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J817) - LEN(SUBSTITUTE(LOWER($J817),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J817) - LEN(SUBSTITUTE(LOWER($J817),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B817:D817)","v":1},2002,"LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis.","Edwards",12449021,"LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis.    Abstract:   The Liver X Receptors (LXR alpha, NR1H3; LXR beta, NR1H2) encode highly homologous transcription factors that are members of the nuclear receptor superfamily of proteins. Both LXR alpha and LXR beta form heterodimers with the obligate partner 9-cis retinoic acid receptor alpha (RXR alpha; NR2B1). LXR/RXR heterodimers function as sensors for cellular oxysterols and, when activated by these agonists, increase the expression of genes that control sterol and fatty acid metabolism/homeostasis. These conclusions are based on studies that: (i) identified oxysterols as the natural ligands for both LXR alpha and LXR beta; (ii) identified target genes that are activated by LXR/RXR; (iii) generated mice that were deficient in LXR alpha, LXR beta or both LXR alpha and LXR beta; (iv) identified synthetic LXR ligands that were extremely potent in vivo; and (v) demonstrated significant alterations in cholesterol and fatty acid homeostasis in animals in which LXR had been either activated or deleted. These findings suggest that synthetic LXR ligands may prove useful in the treatment of certain dyslipidemias. In this review, we summarize the current status of this rapidly moving area with a special emphasis on the potential for pharmacological intervention."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I818,I818)","v":12387968},{"$f":"(LEN($J818) - LEN(SUBSTITUTE(LOWER($J818),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J818) - LEN(SUBSTITUTE(LOWER($J818),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J818) - LEN(SUBSTITUTE(LOWER($J818),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B818:D818)","v":1},2002,"Clinical importance of the cytochromes P450.","Nebert",12387968,"Clinical importance of the cytochromes P450.    Abstract:   The human cytochrome P450 (CYP) superfamily comprises 57 genes. These genes code for enzymes that can have a role in: metabolism of drugs, foreign chemicals, arachidonic acid and eicosanoids; cholesterol metabolism and bile-acid biosynthesis; steroid synthesis and metabolism; vitamin D(3) synthesis and metabolism; retinoic acid hydroxylation; and those of still unknown function. Cytochrome P450 was once believed to be mainly a hepatic drug detoxication system, but is now understood to include a myriad of enzymic reactions implicated in important life processes. Mutations in many CYP genes cause inborn errors of metabolism and contribute to many clinically relevant diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I819,I819)","v":12387089},{"$f":"(LEN($J819) - LEN(SUBSTITUTE(LOWER($J819),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J819) - LEN(SUBSTITUTE(LOWER($J819),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J819) - LEN(SUBSTITUTE(LOWER($J819),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B819:D819)","v":1},2002,"[Lipodystrophic diabetes].","Sakaue",12387089,"[Lipodystrophic diabetes].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I820,I820)","v":12383393},{"$f":"(LEN($J820) - LEN(SUBSTITUTE(LOWER($J820),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J820) - LEN(SUBSTITUTE(LOWER($J820),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J820) - LEN(SUBSTITUTE(LOWER($J820),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B820:D820)","v":1},2002,"[The epicardium and epicardial-derived cells: multiple functions in cardiac development].","Muñoz-Chápuli",12383393,"[The epicardium and epicardial-derived cells: multiple functions in cardiac development].    Abstract:   The epicardium develops from an extracardiac primordium, the proepicardium, which is constituted by a cluster of mesothelial cells located on the cephalic and ventral surface of the liver-sinus venosus limit (avian embryos) or on the pericardial side of the septum transversum (mammalian embryos). The proepicardium contacts the myocardial surface and gives rise to a mesothelium, which grows and progressively lines the myocardium. The epicardium generates, through a process of epithelial-mesenchymal transition, a population of epicardial-derived cells (EPDC). EPDC contribute to the development of cardiac connective tissue, fibroblasts, and the smooth muscle of cardiac vessels. Recent data suggest that EPDC can also differentiate into endothelial cells of the primary subepicardial vascular plexus. If this is confirmed, EPDC would show the same developmental properties that characterize the stem-cell-derived bipotential vascular progenitors recently described, whose differentiation into endothelium and smooth muscle is regulated by exposure to VEGF and PDGF-BB, respectively. Aside from their function in the development of cardiac connective and vascular tissue, EPDC also play an essential modulating role in the differentiation of the compact ventricular layer of the myocardium, a role which might be regulated by the transcription factor WT1 and the production of retinoic acid."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I821,I821)","v":12361782},{"$f":"(LEN($J821) - LEN(SUBSTITUTE(LOWER($J821),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J821) - LEN(SUBSTITUTE(LOWER($J821),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J821) - LEN(SUBSTITUTE(LOWER($J821),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B821:D821)","v":1},2002,"Free radicals, antioxidants, and nutrition.","Fang",12361782,"Free radicals, antioxidants, and nutrition.    Abstract:   Radiation hazards in outer space present an enormous challenge for the biological safety of astronauts. A deleterious effect of radiation is the production of reactive oxygen species, which result in damage to biomolecules (e.g., lipid, protein, amino acids, and DNA). Understanding free radical biology is necessary for designing an optimal nutritional countermeasure against space radiation-induced cytotoxicity. Free radicals (e.g., superoxide, nitric oxide, and hydroxyl radicals) and other reactive species (e.g., hydrogen peroxide, peroxynitrite, and hypochlorous acid) are produced in the body, primarily as a result of aerobic metabolism. Antioxidants (e.g., glutathione, arginine, citrulline, taurine, creatine, selenium, zinc, vitamin E, vitamin C, vitamin A, and tea polyphenols) and antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidases) exert synergistic actions in scavenging free radicals. There has been growing evidence over the past three decades showing that malnutrition (e.g., dietary deficiencies of protein, selenium, and zinc) or excess of certain nutrients (e.g., iron and vitamin C) gives rise to the oxidation of biomolecules and cell injury. A large body of the literature supports the notion that dietary antioxidants are useful radioprotectors and play an important role in preventing many human diseases (e.g., cancer, atherosclerosis, stroke, rheumatoid arthritis, neurodegeneration, and diabetes). The knowledge of enzymatic and non-enzymatic oxidative defense mechanisms will serve as a guiding principle for establishing the most effective nutrition support to ensure the biological safety of manned space missions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I822,I822)","v":12354357},{"$f":"(LEN($J822) - LEN(SUBSTITUTE(LOWER($J822),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J822) - LEN(SUBSTITUTE(LOWER($J822),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J822) - LEN(SUBSTITUTE(LOWER($J822),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B822:D822)","v":1},2002,"Prevention of liver cancer.","Guyton",12354357,"Prevention of liver cancer.    Abstract:   Hepatocellular carcinoma (HCC) is among the most prevalent and deadly cancers worldwide. Prominent risk factors for HCC include viral hepatitis infection; dietary exposure to hepatotoxic contaminants such as aflatoxins; alcoholism; smoking; and male gender. This review highlights ongoing efforts in HCC prevention. Strategies include vaccination against, and treatment of, viral hepatitis infection. In addition to interferon alpha, an acyclic retinoid (all-trans-3,7,11, 15-tetramethyl-2,4,6,10,14-hexadecapentanoic acid), glycyrrhizin and ginseng are currently under clinical investigation for HCC prevention in Japanese hepatitis C patients. Several recent clinical studies in a Chinese region of pervasive aflatoxin contamination also support the approach of favorably altering aflatoxin metabolism and excretion using the chemopreventive agents oltipraz or chlorophyllin. Agents exhibiting chemopreventive efficacy in preclinical HCC models include vitamins A, D, and E, herbal extracts, a 5alpha-reductase inhibitor, green tea, and D-limonene. Efforts to elucidate the molecular lesions and processes underlying HCC development have identified several putative molecular targets for preventive interventions. These include genes and gene products controlling viral replication, carcinogen metabolism, signal transduction, cell-cycle arrest, apoptosis, proliferation, and oxidative stress."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I823,I823)","v":12218915},{"$f":"(LEN($J823) - LEN(SUBSTITUTE(LOWER($J823),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J823) - LEN(SUBSTITUTE(LOWER($J823),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J823) - LEN(SUBSTITUTE(LOWER($J823),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B823:D823)","v":1},2002,"[Doxycycline].","Bonnetblanc",12218915,"[Doxycycline].    Abstract:   Doxycyclin is a semi-synthetic structural isomer of the tetracycline family. It exhibits good intra-cellular penetration, with bacteriostatic activity on many bacteria. Different types or bacterial resistance are known. Acquired resistance has a ribosomal or a plasmidic mechanism. Resistance of Propionibacterium acnes is secondary to a mutation of ARNr. Doxycyclin also has an anti-inflammatory activity, via numerous pathways. Doxycyclin is rapidly and almost completely absorbed by the digestive tract. Food has no incidence on the absorption. It has a high but labile affinity for proteins with 90 p. 100 of the molecule linked. It rapidly diffuses in the extravascular compartment and in most of the tissues. Bile excretion is the main excretion route. It occurs more slowly by the kidney with tubular reabsorption. The main dermatological indication is acne with daily dose varing between 50 mg and 100 mg. Although good assays are lacking, a large professional consensus has validated its use. It is also active at the same dosage in rosacea. Chlamydial and mycoplasma urethritis may be treated by doxycyclin, and this antibiotic is presently used as second choice. Many other diseases may be treated as a primary or secondary choice, such as treponematoses, brucellosis, pasteurellosis, borreliosis, rickettsioses and cholera. Some non infectious diseases have been occasionally treated by doxycycline. Digestive side effects are the more frequent. Esophageal toxicity has been reduced with tablets and sufficient concomitant water ingestion. Phototoxicity is dose-dependent. Various cutaneous side effects have been described, some of them severe. Systemic toxicity is rare. Pregnancy is a contra-indication, and as other tetracyclines, it should not be given to children and during lactation. Doxycycline is commercialized as tablets. No reduction of the dose is necessary in renal failure. Association with retinoids is not recommended. Anticoagulants are potentialized. Didanosin, iron, and mineral salts lower its activity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I824,I824)","v":12149777},{"$f":"(LEN($J824) - LEN(SUBSTITUTE(LOWER($J824),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J824) - LEN(SUBSTITUTE(LOWER($J824),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J824) - LEN(SUBSTITUTE(LOWER($J824),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B824:D824)","v":1},2002,"[The Ito cells in ontogenesis and liver regeneration].","Kiiasov",12149777,"[The Ito cells in ontogenesis and liver regeneration].    Abstract:   This review regards the Ito cells, which constitute one of the four types of liver sinusoidal cells. These cells synthesize many cytokines and extracellular matrix proteins. The Ito cells make an important link in retinoid metabolism. The role played by the Ito cells in liver hemopoiesis and differentiation of liver epithelium in prenatal ontogenesis is emphasized. The importance of the Ito cells in reparative liver regeneration is also discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I825,I825)","v":12113033},{"$f":"(LEN($J825) - LEN(SUBSTITUTE(LOWER($J825),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J825) - LEN(SUBSTITUTE(LOWER($J825),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J825) - LEN(SUBSTITUTE(LOWER($J825),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B825:D825)","v":1},2001,"Management of hepatocellular carcinoma: advances in diagnosis, treatment and prevention.","Shiratori",12113033,"Management of hepatocellular carcinoma: advances in diagnosis, treatment and prevention.    Abstract:   Since the major causes of hepatocellular carcinoma are hepatitis viruses, the difference and similarity of clinical features in relation to the causative virus may indicate that persistent inflammation of the liver is a major role in hepatocellular carcinoma development in both HBV and HCV infection. However, there is a variety of molecular products of virus-inducing mutagenesis, especially in HBV. An advance in the diagnosis of hepatocellular carcinoma is imaging modality to detect hemodynamics of hepatocellular carcinoma with noninvasive methods of ultrasonography and tumor markers. Chemoprevention using synthetic retinoid is another important issue for the prevention of hepatocellular carcinoma development, as well as viral eradication and suppression of inflammation in the liver using interferon and other drugs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I826,I826)","v":12083993},{"$f":"(LEN($J826) - LEN(SUBSTITUTE(LOWER($J826),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J826) - LEN(SUBSTITUTE(LOWER($J826),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J826) - LEN(SUBSTITUTE(LOWER($J826),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B826:D826)","v":1},2002,"Recurrent and/or metastatic thyroid cancer: therapeutic options.","Karavitaki",12083993,"Recurrent and/or metastatic thyroid cancer: therapeutic options.    Abstract:   Thyroid cancer is relatively rare, accounting for 0.5 - 10 cases per 100,000 individuals per year. Despite their generally favourable prognosis, patients with differentiated thyroid cancer are at risk of tumour recurrence for decades after diagnosis. The optimal management remains controversial even in the low-risk patients because of the high cure rates, long natural history and rarity of these tumours. Therapeutic interventions in recurrent and metastatic differentiated thyroid cancer depend on the type of initial treatment, the site and the extent of disease. Surgical excision of the amenable-to-surgery lesions and radioiodine administration remain the first approach. External radiotherapy may be given to patients with inoperable lesions or those not concentrating radioiodine. Chemotherapy has not provided consistently successful results. Various therapeutic approaches for anaplastic carcinoma give poor results, making the development of novel treatments necessary. Innovative strategies, including recombinant human thyroid stimulating hormone, retinoic acid redifferentiation therapy and gene therapy, may lead to further improvement in the management of thyroid cancer arising from follicular cells."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I827,I827)","v":12061140},{"$f":"(LEN($J827) - LEN(SUBSTITUTE(LOWER($J827),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J827) - LEN(SUBSTITUTE(LOWER($J827),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J827) - LEN(SUBSTITUTE(LOWER($J827),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B827:D827)","v":1},2002,"[Function and regulation of production of hepatocyte growth factor (HGF)].","Gohda",12061140,"[Function and regulation of production of hepatocyte growth factor (HGF)].    Abstract:   Hepatocyte growth factor (HGF) was purified as a potent mitogen for rat hepatocytes in primary culture and is believed to be the most physiological hepatotrophic factor that triggers liver regeneration. HGF is one of the largest disulfide-linked cytokines, consisting of a 60-kDa heavy chain and a 35-kDa light chain. Human HGF is synthesized as a single polypeptide chain precursor of 728 amino acid residues that has an appreciable homology with plasminogen, and it is processed proteolytically to release an N-terminal signal peptide of 31 amino acids and to generate an active heterodimer after secretion. The novel serine protease HGF activator and urokinase-type plasminogen activator (u-PA) are responsible for the latter extracellular processing. HGF stimulates the proliferation of rat hepatocytes in primary culture at concentrations as low as 10 pM. It also stimulates the growth of various epithelial cells, endothelial cells, and some kinds of mesenchymal cells. HGF inhibits the proliferation of several tumor cell lines and induces apoptosis of some of them. It also has motogenic, morphogenic, anti-apoptotic, angiogenic, and immunoregulatory activities. The receptor of HGF is the product of c-met proto-oncogene with tyrosine kinase activity that mediates the transduction of multiple biological signals of HGF. During liver regeneration, HGF gene expression in the liver, spleen, and lung and HGF levels in the blood and liver increase prior to the induction of liver DNA synthesis. Liver regeneration is markedly inhibited by continuous administration of a neutralizing anti-HGF antibody. HGF production in cultured cells is induced by PKC-activating agents, cAMP-elevating agents, PKA-activating agents, growth factors, and inflammatory cytokines; and it is inhibited by TGF-beta, glucocorticoids, 1,25-dihydroxyvitamin D3, and retinoic acid. There are many reports on potential application of HGF as a therapeutic agent for organ diseases that are difficult to cure such as liver cirrhosis, chronic renal failure, pulmonary fibrosis, myocardial infarction, and arteriosclerosis obliterans utilizing its potent growth-stimulating activity for a wide variety of cells. ELISA kits for assays of serum and plasma HGF levels are clinically used to prognosticate the development of fulminant hepatic failure."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I828,I828)","v":12002680},{"$f":"(LEN($J828) - LEN(SUBSTITUTE(LOWER($J828),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J828) - LEN(SUBSTITUTE(LOWER($J828),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J828) - LEN(SUBSTITUTE(LOWER($J828),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B828:D828)","v":1},2002,"Influence of dietary fat on beta-carotene absorption and bioconversion into vitamin A.","Ribaya-Mercado",12002680,"Influence of dietary fat on beta-carotene absorption and bioconversion into vitamin A.    Abstract:   Dietary fat facilitates the utilization of carotenoids and, based on serum beta-carotene or retinol responses following ingestion of meals containing carotene and fat sources, it has been reported that the amount of fat required in a meal may be minimal (approximately 3-5 g). However, the dietary fat requirement for optimal carotene utilization in humans cannot be fully ascertained without longer-term dose-response studies that measure the changes in vitamin A body stores in response to varying levels of dietary fat. In humans, vitamin A body stores can be determined by use of stable isotope-dilution methods. Animal studies have shown that although the level of dietary fat has no effect on serum vitamin A concentrations of animals fed beta-carotene, higher liver vitamin A concentrations were found in those that ingested higher fat levels. Other factors that might influence the relationship of fat intake and beta-carotene utilization include the type of fat ingested, physicochemical properties of the carotenoid source, amount of carotene ingested, whether fat and beta-carotene sources are provided in the same meal, the presence of helminthic infections, age, and vitamin A status."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I829,I829)","v":11960770},{"$f":"(LEN($J829) - LEN(SUBSTITUTE(LOWER($J829),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J829) - LEN(SUBSTITUTE(LOWER($J829),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J829) - LEN(SUBSTITUTE(LOWER($J829),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B829:D829)","v":1},2002,"Nuclear receptors. II. Intestinal corticosteroid receptors.","Sheppard",11960770,"Nuclear receptors. II. Intestinal corticosteroid receptors.    Abstract:   Two corticosteroid receptors have been cloned; they are the glucocorticoid receptor and the mineralocorticoid receptor. These receptors are members of the steroid/thyroid/retinoid receptor family of nuclear transactivating factors, which are characterized by two highly conserved zinc fingers in the central DNA binding domain, a COOH-terminal domain that encompasses the ligand binding site, and a variable NH(2)-terminal domain. In addition to these cloned receptors, other corticosteroid receptors have recently been identified in intestine. Steroid binding studies have identified two novel putative corticosteroid receptors in intestinal epithelia, and molecular cloning studies have detected two low-affinity receptors in small intestine that are activated by corticosteroids and induce CYP3A gene expression. This article focuses on the identification of these novel corticosteroid receptors and the potential role they may play in intestinal physiology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I830,I830)","v":11800161},{"$f":"(LEN($J830) - LEN(SUBSTITUTE(LOWER($J830),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J830) - LEN(SUBSTITUTE(LOWER($J830),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J830) - LEN(SUBSTITUTE(LOWER($J830),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B830:D830)","v":1},2001,"Protein coregulators that mediate estrogen receptor function.","Ratajczak",11800161,"Protein coregulators that mediate estrogen receptor function.    Abstract:   The recent discovery of estrogen receptor beta as a biological partner with estrogen receptor alpha in mediating the estrogen response has come at precisely the same time as intensive research is revealing the role played by downstream coregulator proteins in linking nuclear hormone receptor activity to general transcription machinery involved in gene transcriptional activation. In what is a rapidly evolving area of research, findings to date have led to a proposed model of hormonal action, in which a receptor activated by estrogen or cell-membrane-derived phosphorylation-dependent signaling pathways promotes recruitment of selected members of the multifunctional steroid receptor coactivator family and the cointegrators, p300/CBP and P/CAF. The intrinsic histone acetylase activity mediated by these coactivator and cointegrator proteins, alters chromatin structure giving rise to increased transcriptional efficiency. On the other hand, antiestrogen-bound receptors favour the assembly of receptor-corepressor complexes containing the sequence-related corepressors N-CoR (nuclear receptor corepressor) or SMRT (silencing mediator of retinoid and thyroid hormone receptors), localizing histone deacetylase activity to the promoter and leading to transcriptional repression. The model predicts that a change in the balance between corepressor and coactivator expression in favour of coactivators, might result in antiestrogen resistance. Together with available crystal structure data for estrogen- and antiestrogen-bound receptors, these studies have provided valuable insights into events that occur subsequent to receptor interaction with specific DNA sequences and have helped define the molecular basis of estrogen and antiestrogen activity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I831,I831)","v":11762053},{"$f":"(LEN($J831) - LEN(SUBSTITUTE(LOWER($J831),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J831) - LEN(SUBSTITUTE(LOWER($J831),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J831) - LEN(SUBSTITUTE(LOWER($J831),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B831:D831)","v":1},2001,"[Retinoid].","Moriwaki",11762053,"[Retinoid].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I832,I832)","v":11739886},{"$f":"(LEN($J832) - LEN(SUBSTITUTE(LOWER($J832),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J832) - LEN(SUBSTITUTE(LOWER($J832),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J832) - LEN(SUBSTITUTE(LOWER($J832),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B832:D832)","v":1},2001,"Can lack of improvement in vitamin A status indicators be explained by little or no overall change in vitamin A status of humans?","Tanumihardjo",11739886,"Can lack of improvement in vitamin A status indicators be explained by little or no overall change in vitamin A status of humans?    Abstract:   Changes in vitamin A status using conventional indicators, i.e., serum and breast milk retinol concentrations and the modified relative dose response test, following a vitamin A intervention have not always been shown. A simplified model to predict calculated changes in vitamin A status after intervention is described. The model shows that changes in indicator values cannot be expected if the change in vitamin A status is only marginal. A critical review of several papers using vitamin A status assessment indicators was undertaken. Assumptions that included current knowledge concerning vitamin A absorption and metabolism were made and applied to the data. Based on current recommended daily allowances for women and children, one cannot necessarily expect a change in indicators if an overall change in vitamin A status was not achieved. Thus, when designing vitamin A intervention studies, the following parameters should be considered if applicable to the population to be enrolled in the study: average body weight, estimated liver weight, amount of vitamin A administered, estimated loss in breast milk and study duration."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I833,I833)","v":11726824},{"$f":"(LEN($J833) - LEN(SUBSTITUTE(LOWER($J833),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J833) - LEN(SUBSTITUTE(LOWER($J833),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J833) - LEN(SUBSTITUTE(LOWER($J833),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B833:D833)","v":1},2001,"Leukemia after liver transplant.","Doti",11726824,"Leukemia after liver transplant.    Abstract:    INTRODUCTION : Acute leukemia is rare after solid organ transplantation.  METHODS : Review of data on 3 patients with acute leukemia identified among 1365 who underwent liver transplantation at our center, and a review of the literature.  RESULTS : In patient 1, AML-M4 developed 19 months after transplant for cryptogenic cirrhosis. In patient 2, B cell acute lymphoid leukemia was diagnosed 10 months after liver transplant for fulminant hepatitis. Both patients had normal cytogenetics, and achieved complete remission with chemotherapy. In patient 3, acute monocytic leukemia-M3 with t(15;17) arose 18 months after transplant for hepatitis C cirrhosis. This patient received treatment with retinoic acid and chemotherapy, but developed a disseminated intravascular coagulation and died before completing therapy. No patient presented with chromosomal abnormalities commonly seen in secondary leukemia. The latency period to diagnosis after transplant was 10-19 months.  CONCLUSIONS : Acute leukemia, although rare after liver transplantation, should be considered in the differential diagnosis of hematological complications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I834,I834)","v":11702302},{"$f":"(LEN($J834) - LEN(SUBSTITUTE(LOWER($J834),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J834) - LEN(SUBSTITUTE(LOWER($J834),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J834) - LEN(SUBSTITUTE(LOWER($J834),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B834:D834)","v":1},2000,"Risk-benefit assessment of methotrexate in the treatment of severe psoriasis.","Kuijpers",11702302,"Risk-benefit assessment of methotrexate in the treatment of severe psoriasis.    Abstract:   Methotrexate is an established and highly effective systemic treatment for severe psoriasis, including the pustular and erythrodermic forms. It has been widely used during the last 3 decades. For this reason, the long term adverse effects of methotrexate are well known, in contrast to other relatively new systemic treatments like cyclosporin and retinoids. The most frequent adverse effects occurring during methotrexate therapy are abnormal liver function tests, nausea and gastric complaints. The most feared adverse effects are myelosuppression and hepatotoxicity. Because hepatotoxicity is related to a high cumulative dose of methotrexate, rotational therapy or an intermittent instead of a continuous treatment schedule are advised. The histological assessment of liver biopsies, according to the international guidelines, remains the gold standard for detection of liver damage until equally reliable noninvasive screening methods for liver damage--tentatively dynamic hepatic scintigraphy (DHS) or measurement of levels of serum aminoterminal propeptide of type III procollagen--are well evaluated. Low dose methotrexate therapy is relatively well tolerated, provided that there is careful patient selection and regular monitoring for adverse effects and drug interactions during methotrexate therapy is carried out. The long term clinical efficacy and relative safety of methotrexate remain impressive."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I835,I835)","v":11593936},{"$f":"(LEN($J835) - LEN(SUBSTITUTE(LOWER($J835),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J835) - LEN(SUBSTITUTE(LOWER($J835),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J835) - LEN(SUBSTITUTE(LOWER($J835),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B835:D835)","v":1},2001,"Maintaining corneal integrity how the quot;windowquot; stays clear.","Kurpakus-Wheater",11593936,"Maintaining corneal integrity how the quot;windowquot; stays clear.    Abstract:   The anterior surface of the eye is composed of the cornea, conjunctiva, and the zone between the two called the limbus. The cornea must maintain optical clarity to retain good vision. However, the ocular surface is vulnerable to trauma, microbial infection, and exposure to environmental toxins. This places the cornea, especially, at risk for disruptions of the epithelial barrier and subsequent immunopathological events. Cell-cell and cell-matrix attachment junctions incorporating adhesion molecules ensure that the epithelial barrier remains intact. Protein components of the basement membrane, including laminins, are vital to the adhesion of corneal epithelial cells to the underlying stroma and function to enhance the strength of the bond between epithelium and connective tissue. Epithelial cells also play an early and crucial role in the initiation of ocular surface responses should a potentially antigenic molecule enter into deeper corneal tissues. For example, epithelial cells may produce and release cytokines such as interleukin-1 (IL-1). The delicate balance between the matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are central to mechanisms regulating dissolution of the extracellular matrix that may be a consequence of infection or wound healing. Adhesion molecules, cytokines and chemokines, and MMPs and TIMPs thus participate in the corneal response to immunologic challenge or wounding. They may also be involved in corneal pathologies associated with genetic diseases, diabetes, and vitamin A deficiency. In addition these molecules are components of cellular pathways underlying the clinical complications often observed with contact lens wear and refractive surgeries used to improve visual acuity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I836,I836)","v":11584078},{"$f":"(LEN($J836) - LEN(SUBSTITUTE(LOWER($J836),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J836) - LEN(SUBSTITUTE(LOWER($J836),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J836) - LEN(SUBSTITUTE(LOWER($J836),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B836:D836)","v":1},2001,"Molecular mechanisms of sterol absorption.","Chen",11584078,"Molecular mechanisms of sterol absorption.    Abstract:   Recent studies have significantly advanced our understanding of intestinal sterol absorption at the molecular level. Nuclear hormone receptors (such as liver X receptor, farnesoid X receptor and retinoid X receptor) regulate the absorption of dietary sterols by modulating the transcription of several important genes involved in cholesterol metabolism. One of these genes encodes a molecule [adenosine triphosphate-binding cassette (ABC) transporter] that transports dietary cholesterol from enterocytes back out to the intestinal lumen, thereby limiting the amount of cholesterol absorbed. ABC transporters also provide an efficient barrier against the absorption of plant sterols. Another key process that affects intestinal sterol absorption is the synthesis of cholesterol esters. Mice lacking the enzyme for cholesterol esterification in the small intestine have a reduced capacity to absorb dietary cholesterol and are protected against diet-induced hypercholesterolemia and gallstone formation. In addition to elucidating some of the molecular mechanisms of sterol absorption, these recent findings may lead to new therapeutic options to treat hypercholesterolemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I837,I837)","v":11562285},{"$f":"(LEN($J837) - LEN(SUBSTITUTE(LOWER($J837),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J837) - LEN(SUBSTITUTE(LOWER($J837),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J837) - LEN(SUBSTITUTE(LOWER($J837),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B837:D837)","v":1},2001,"Vitamin D analogs: mechanism of action and therapeutic applications.","Nagpal",11562285,"Vitamin D analogs: mechanism of action and therapeutic applications.    Abstract:   The physiological VDR ligand, 1 alpha,25-dihydroxyvitamin D3, acts upon a wide variety of tissues and cells, both related to and unrelated to calcium and phosphate homeostasis. The noncalcemic actions of natural and synthetic VDR ligands are exemplified by their potent anti-proliferative, prodifferentiative and immunomodulatory activities. As a result, a VDR ligand is an approved drug for the topical treatment of psoriasis. A plethora of actions of 1 alpha,25-dihydroxyvitamin D3 in various systems have suggested wide clinical applications of VDR ligands in such diverse disease states as inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, photoaging and skin rejuvenation), osteoporosis, cancers (breast, prostate, colon, leukemia and myelodysplastic syndrome) and autoimmune diseases (multiple sclerosis, type I diabetes and systemic lupus erythematosus). VDR ligands have shown therapeutic potential in limited human clinical trials as well as in animal models of these diseases. Some of the VDR ligands have shown not only potent preventive but also therapeutic anabolic activities in animal models of osteoporosis. However, the use of VDR in above mentioned indications as well as in oral therapy for psoriasis and even topical therapy for severe psoriasis is hampered by its associated toxicity, namely hypercalcemia. New VDR ligands have been synthesized which exhibit greater specificity by retaining desirable properties, but with reduced calcemic potential. The discovery of novel vitamin D3 analogs along with an increased understanding of the biological functions and mechanisms of action of VDR are likely to result in improved treatments for responsive indications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I838,I838)","v":11513329},{"$f":"(LEN($J838) - LEN(SUBSTITUTE(LOWER($J838),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J838) - LEN(SUBSTITUTE(LOWER($J838),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J838) - LEN(SUBSTITUTE(LOWER($J838),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B838:D838)","v":1},2001,"Cytochrome P450 in the brain; a review.","Hedlund",11513329,"Cytochrome P450 in the brain; a review.    Abstract:   After many frustrating decades of unsuccessful attempts to characterize the isoforms of P450 in the brain, several scientific breakthroughs in the 80s and 90s have resulted in major advances in our understanding of cytochromes P450 (CYP) in brain. We now know that classical CYP inducers, e.g. phenobarbital and pregnenolone 16alpha-carbonitrile, which regulate drug-metabolizing enzymes in the liver, are specific ligands for ligand-activated transcription factors, and that the brain content of many of these transcription factors is low. This explains why these inducers have little effect on brain CYP content. The most effective inducers of brain P450 are some of the CNS active drugs and solvents. The level of CYPs in brain, approximately 0.5-2% of that in liver, is too low to significantly influence the overall pharmacokinetics of drugs and hormones in the body. Instead CYPs appear to have specific functions in brain, e.g. regulation of the levels of endogenous GABAA receptor agonists maintenance of brain cholesterol homeostasis and elimination of retinoids The novel CYPs which catalyse these reactions have recently been characterized. They are abundantly expressed in the brain confirming what has been previously found, i.e. that the major hepatic, adrenal and gonadal CYP isozymes contribute very little to the overall content of CYP in brain. It is not clear what fraction of brain CYP has been characterized, although a complete characterization of constitutive and induced CYPs in brain is essential for understanding the role of these enzymes in brain physiology as well as in age-related and xenobiotic-induced neurotoxicity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I839,I839)","v":11509110},{"$f":"(LEN($J839) - LEN(SUBSTITUTE(LOWER($J839),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J839) - LEN(SUBSTITUTE(LOWER($J839),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J839) - LEN(SUBSTITUTE(LOWER($J839),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B839:D839)","v":1},2001,"Micronutrients in pregnancy.","Black",11509110,"Micronutrients in pregnancy.    Abstract:   Vitamins and minerals, referred to collectively as micronutrients, have important influences on the health of pregnant women and the growing fetus. Iron deficiency results in anemia which may increase the risk of death from hemorrhage during delivery, but its effects on fetal development and birth outcomes is still unclear. Folic acid deficiency can lead to hematological consequences, pregnancy complications and congenital malformations, but again the association with other birth outcomes is equivocal. Zinc deficiency has been associated in some, but not all studies with complications of pregnancy and delivery, as well as with growth retardation, congenital abnormalities and retarded neurobehavioral and immunological development in the fetus. Iodine deficiency during pregnancy results in cretinism and possible fetal wastage and preterm delivery. Deficiency of other minerals such as magnesium, selenium, copper, and calcium have also been associated with complications of pregnancy, childbirth or fetal development. Deficiencies of vitamins other than folate may likewise be related to such complications; and vitamin A or beta-carotene supplements in pregnancy reduced maternal mortality by 50 % in a controlled trial in Nepal. Additional research is need on the prevalence of such deficiencies and their consequences and on cost-effective public health interventions for their control."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I840,I840)","v":11506816},{"$f":"(LEN($J840) - LEN(SUBSTITUTE(LOWER($J840),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J840) - LEN(SUBSTITUTE(LOWER($J840),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J840) - LEN(SUBSTITUTE(LOWER($J840),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B840:D840)","v":1},2001,"Mechanism of up-regulated gap junctional intercellular communication during chemoprevention and chemotherapy of cancer.","Trosko",11506816,"Mechanism of up-regulated gap junctional intercellular communication during chemoprevention and chemotherapy of cancer.    Abstract:   To develop a strategy for efficacious intervention in order to prevent or treat various cancers, one must understand the basic mechanism(s) by which various anticancer dietary factors prevent or reverse the tumor promotion or progression phases. Carcinogenesis is a multistage, multimechanism process, involving the irreversible alteration of a stem cell (the quot;initiationquot; phase), followed by the clonal proliferation of the initiated stem cell (the quot;promotionquot; phase), from which the acquisition of the invasive and metastatic phenotypes are generated (the quot;progressionquot; phase). While intervention to prevent or treat cancer could occur at each step, the objective of this presentation will focus on the rate limiting step, the promotion phase.Gap junctional intercellular communication (GJIC) has been hypothesized to regulate growth control, differentiation and apoptosis. Most normal, contact-inhibited cells have functional GJIC, while most, if not all, tumor cells have dysfunctional homologous or heterologous GJIC. Cancer cells are characterized by the lack of growth control, by the inability to terminally differentiate and by resistance to apoptosis. Chemical tumor promoters (phorbol esters, DDT, phenobarbital, unsaturated fatty acids, saccharin, etc.) inhibit GJIC in a reversible fashion and at doses above particular chemical thresholds. Various oncogenes (e.g. ras, raf, neu, src, mos) down-regulate GJIC while several tumor suppressor genes can up-regulate GJIC. Antitumor promoters (retinoids, carotenoids, green tea components) and antioncogene drugs (i.e. lovastatin) can up-regulate GJIC. Transfection of gap junction genes (quot;connexinsquot;) into GJIC-deficient tumor cells can restore GJIC, growth control and reduce tumorigenicity. On the other hand, antisense gap junction genes can convert the phenotype of a non-tumorigenic cell to that of a tumorigenic one. Recently, a specific connexin knockout mouse was shown to have a higher frequency of spontaneous and induced liver cancers. Evidence from these studies clearly suggests that dietary factors can modulate GJIC by inducing various signal transducing systems. The modulation can either down-regulate GJIC and lead to tumor promotion or it can up-regulate GJIC and lead to suppression of the initiated cells. Multiple mechanisms of up- or down-regulation of GJIC exist, as well as multiple types of pre-malignant and malignant tumor cells that are unable able to have functional GJIC. GJIC can be down-regulated by mutations and by epigenetic means. Alteration of gene expression at the transcriptional, translational or post-translational levels would require specific dietary prevention or treatment of cancer. In conclusion, if dietary prevention or treatment of cancer is to occur, it must ameliorate the growth-stimulatory effects, above threshold levels, of chemicals, growth factors or hormones, that trigger various mitogenic/antiapoptotic signal transducing systems that block GJIC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I841,I841)","v":11478382},{"$f":"(LEN($J841) - LEN(SUBSTITUTE(LOWER($J841),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J841) - LEN(SUBSTITUTE(LOWER($J841),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J841) - LEN(SUBSTITUTE(LOWER($J841),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B841:D841)","v":1},2001,"Polyunsaturated fatty acid regulation of gene expression.","Ntambi",11478382,"Polyunsaturated fatty acid regulation of gene expression.    Abstract:   Polyunsaturated fatty acids (PUFAs), specifically the n-3 and n-6 series, play a key role in the progression or prevention of human diseases such as obesity, diabetes, cancer, neurological and heart disease, mainly by affecting cellular membrane lipid composition, metabolism, signal-transduction pathways, and by direct control of gene expression. PUFAs show regulation of gene expression in several tissues, including brain, liver, heart, and adipose. Most recently, research has focused on identifying the mechanisms by which PUFAs regulate lipogenic gene expression. Research to date indicates that PUFA-mediated regulation of the genetic expression and proteolytic maturation of a group of transcription factors termed sterol regulatory element binding proteins (SREBPs) accounts for the suppression of hepatic lipogenic gene expression. However, our recent studies on the transcriptional regulation of the stearoyl-coenzyme A (CoA) desaturase gene, encoding a key enzyme in the cellular synthesis of monounsaturated fatty acids from saturated fatty acids indicates that PUFA can suppress gene transcription by a mechanism independent of SREBP maturation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I842,I842)","v":11450594},{"$f":"(LEN($J842) - LEN(SUBSTITUTE(LOWER($J842),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J842) - LEN(SUBSTITUTE(LOWER($J842),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J842) - LEN(SUBSTITUTE(LOWER($J842),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B842:D842)","v":1},2001,"Professor Toshio Ito: a clairvoyant in pericyte biology.","Suematsu",11450594,"Professor Toshio Ito: a clairvoyant in pericyte biology.    Abstract:   Ito cells are liver-specific pericytes which were first described as Fett Speicherung Zellen, the fat-storing cells encircling outside sinusoidal endothelial cells, in 1951 by the late professor Toshio Ito. His pioneering approaches for morphological characterization of the cells stimulate investigators to further examine their functional roles in liver homeostasis: a body of evidence has been accumulated in recent years showing that the cells play a crucial role in storage and delivery of vitamin A, regulation of sinusoidal tone and local blood supply, and tissue repair and fibrosis. It is now widely accepted that microvascular pericytes including Ito cells serve as a key player that controls angiogenesis. Furthermore, recent studies support a concept that Ito cells constitutes a bridging apparatus mediating bidirectional metabolic interactions between sinusoids and hepatocytes, utilizing prostanoids and/or gaseous mediators such as nitric oxide and carbon monoxide as signaling molecules. This article reviews researches on this liver-specific pericyte and its leading roles in recent development of pericyte biology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I843,I843)","v":11445441},{"$f":"(LEN($J843) - LEN(SUBSTITUTE(LOWER($J843),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J843) - LEN(SUBSTITUTE(LOWER($J843),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J843) - LEN(SUBSTITUTE(LOWER($J843),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B843:D843)","v":1},2001,"Physiological function of the orphans GCNF and COUP-TF.","Cooney",11445441,"Physiological function of the orphans GCNF and COUP-TF.    Abstract:   Orphan nuclear receptors are members of the nuclear receptor superfamily of ligand-activated transcription factors for which ligands and functions have not been identified. Since the cloning of the original orphans, ligands have been identified for several orphan receptors that heterodimerize with the retinoid X receptor and are no longer classified as orphan receptors. Considering the central role that nuclear receptors play in differentiation, development, metabolic regulation, homeostasis and disease, it is crucial that we understand the roles of the remaining orphans. However, the identification of ligands for those orphans that form homodimers has proven more difficult. Thus, to gain greater insight into the functions of orphan receptors, gene targeting has been used to knock out these factors and study mouse development in their absence. Here we will review the progress made in understanding the roles of the orphans GCNF and the COUP-TFs with the use of gene knockouts."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I844,I844)","v":11391068},{"$f":"(LEN($J844) - LEN(SUBSTITUTE(LOWER($J844),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J844) - LEN(SUBSTITUTE(LOWER($J844),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J844) - LEN(SUBSTITUTE(LOWER($J844),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B844:D844)","v":1},2001,"How is the liver primed or sensitized for alcoholic liver disease?","Tsukamoto",11391068,"How is the liver primed or sensitized for alcoholic liver disease?    Abstract:   This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Hidekazu Tsukamoto and Yoshiyuki Takei. The presentations were (1) Tribute to Professor Rajendar K. Chawla, by Craig J. McClain; (2) Dysregulated TNF signaling in alcoholic liver disease, by Craig J. McClain, S. Joshi-Barve, D. Hill, J Schmidt, I. Deaciuc, and S. Barve; (3) The role of mitochondria in ethanol-mediated sensitization of the liver, by Anna Colell, Carmen Garcia-Ruiz, Neil Kaplowitz, and Jose C. Fernandez-Checa; (4) A peroxisome proliferator (bezafibrate) can prevent superoxide anion release into hepatic sinusoid after acute ethanol administration, by Hirokazu Yokoyama, Yukishige Okamura, Yuji Nakamura, and Hiromasa Ishii; (5) S-adenosylmethionine affects tumor necrosis factor-alpha gene expression in macrophages, by Rajendar K. Chawla, S. Barve, S. Joshi-Barve, W. Watson, W. Nelson, and C. McClain; (6) Iron, retinoic acid and hepatic macrophage TNFalpha gene expression in ALD, by Hidekazu Tsukamoto, Min Lin, Mitsuru Ohata, and Kenta Motomura; and (7) Role of Kupffer cells and gut-derived endotoxin in alcoholic liver injury, by N. Enomoto, K. Ikejima, T. Kitamura, H. Oide, Y. Takei, M. Hirose, B. U. Bradford, C. A. Rivera, H. Kono, S. Peter, S. Yamashina, A. Konno, M. Ishikawa, H. Shimizu, N. Sato, and R. Thurman."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I845,I845)","v":11385973},{"$f":"(LEN($J845) - LEN(SUBSTITUTE(LOWER($J845),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J845) - LEN(SUBSTITUTE(LOWER($J845),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J845) - LEN(SUBSTITUTE(LOWER($J845),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B845:D845)","v":1},2001,"Liver cancer.","Aguayo",11385973,"Liver cancer.    Abstract:   The prognosis of patients with HCC remains dismal. Even in the subgroups of patients who have the most favorable characteristics and are eligible for surgical resection, the 5-year survival rate is less than 25%. For patients with more advanced disease, the median survival time is less than 1 year. The good news in HCC research is that the disease can be prevented. In Taiwan, the rate of HCC in children aged 6 to 9 years decreased from 5.2 per million population before the neonatal vaccination program began in 1984 to 1.3 per million population in the first vaccinated cohort. Treatment of viral hepatitis with IFN may decrease the rates of long-term development of HCC. Other agents that may prevent second primary tumors following resection of HCC, such as polyprenoic acid and acylic retinoid, are also being investigated."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I846,I846)","v":11340622},{"$f":"(LEN($J846) - LEN(SUBSTITUTE(LOWER($J846),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J846) - LEN(SUBSTITUTE(LOWER($J846),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J846) - LEN(SUBSTITUTE(LOWER($J846),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B846:D846)","v":1},2001,"Studies of vitamin A metabolism in mouse model systems.","Gottesman",11340622,"Studies of vitamin A metabolism in mouse model systems.    Abstract:   Over the past several years, discoveries from mouse genetics have had direct impact on our understanding of vitamin A metabolism. Although the metabolism of vitamin A in the mouse does have some special features (for example very large stores of liver and pulmonary retinyl esters), the ability to construct knockout and transgenic mouse models has yielded an impressive amount of information directly relevant to understanding the general principles of vitamin A transport, storage and degradation. We discuss below the metabolism of vitamin A through a number of genetically engineered mouse strains with alterations in genes that affect this metabolism. The novelty of this experimental approach is evidenced by the fact that the oldest of these strains was first reported only eight years ago.1)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I847,I847)","v":11338401},{"$f":"(LEN($J847) - LEN(SUBSTITUTE(LOWER($J847),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J847) - LEN(SUBSTITUTE(LOWER($J847),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J847) - LEN(SUBSTITUTE(LOWER($J847),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B847:D847)","v":1},2001,"Xeroderma pigmentosum--bridging a gap between clinic and laboratory.","Moriwaki",11338401,"Xeroderma pigmentosum--bridging a gap between clinic and laboratory.    Abstract:   Xeroderma pigmentosum (XP) is an autosomal recessive photosensitive disorder with an extremely high incidence of UV-related skin cancers associated with impaired ability to repair UV-induced DNA damage. There are seven nucleotide excision repair (NER) complementation groups (A through G) and an NER proficient form (XP variant). XPA, B, D and G patients may also develop XP neurological disease. The laboratory diagnosis of XP can be performed by autoradiography. Recently, the isolation and characterization of the genes responsible for XP have made it possible to use molecular biological techniques to diagnose XP patients, for carrier detection and for prenatal diagnosis, especially in Japanese XPA patients. These techniques include polymerase chain reaction (PCR) and plasmid host cell reactivation assays with cloned XP genes. DNA damage is not repaired by the NER system equally throughout the genome. There are two DNA repair pathways: 1) transcription-coupled repair, and 2) global genome repair. Many factors involved in these pathways are related to the pathogenesis of XP and a related photosensitive disease, Cockayne syndrome. Clinical management consists of early diagnosis followed by a rigorous program of sun protection including avoidance of unnecessary UV exposure, wearing UV blocking clothing, and use of sunblocks on the skin. Although there is no cure for XP, the efficacy of oral retinoids for the prevention of new skin cancers, local injection of interferon, and the external use of a prokaryotic DNA repair enzyme have been reported."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I848,I848)","v":11264984},{"$f":"(LEN($J848) - LEN(SUBSTITUTE(LOWER($J848),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J848) - LEN(SUBSTITUTE(LOWER($J848),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J848) - LEN(SUBSTITUTE(LOWER($J848),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B848:D848)","v":1},2001,"Structure, function and regulation of the ABC1 gene product.","Schmitz",11264984,"Structure, function and regulation of the ABC1 gene product.    Abstract:   The role of the ATP-binding cassette transporter 1 (ABCA1) in cellular lipid efflux and high density lipoprotein metabolism has been recently documented by mutations in genetic HDL deficiency syndromes such as classical Tangier disease. Analysis of ABCA1 knockout mice and overexpression studies have established the importance of ABCA1 as a major determinant of HDL cholesterol in plasma. These studies also indicate that ABCA1 is critically involved in cellular trafficking of cholesterol and choline-phospholipids and in total body lipid homeostasis, such as intestinal cholesterol and fat-soluble vitamin absorption and in the modulation of steroidogenesis. First insights into the upregulation of ABCA1 gene expression by cellular cholesterol and cAMP have identified critical ABCA1 promoter elements, which bind the transcription factors liver X receptor, retinoid X receptor, Sp1 and E-box proteins. The finding that a lipid sensitive subgroup of ABC transporters is able to translocate cholesterol and phospholipids supports the concept that in ABCA1 deficiency, compensatory mechanisms possibly involving MDR1, MDR3 and MRP-family members could be active. This suggests that a network of ABC transporters involved in cellular lipid transport exists, which is under the tight control of energy pathways directly linked to high density lipoprotein metabolism and atherogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I849,I849)","v":11264453},{"$f":"(LEN($J849) - LEN(SUBSTITUTE(LOWER($J849),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J849) - LEN(SUBSTITUTE(LOWER($J849),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J849) - LEN(SUBSTITUTE(LOWER($J849),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B849:D849)","v":1},2001,"Phenobarbital response elements of cytochrome P450 genes and nuclear receptors.","Sueyoshi",11264453,"Phenobarbital response elements of cytochrome P450 genes and nuclear receptors.    Abstract:   Phenobarbital (PB) response elements are composed of various nuclear receptor (NR)-binding sites. A 51-bp distal element PB-responsive enhancer module (PBREM) conserved in the PB-inducible CYP2B genes contains two NR-binding direct repeat (DR)-4 motifs. Responding to PB exposure in liver, the NR constitutive active receptor (CAR) translocates to the nucleus, forms a dimer with the retinoid X receptor (RXR), and activates PBREM via binding to DR-4 motifs. For CYP3A genes, a common NR site [DR-3 or everted repeat (ER)-6] is present in proximal promoter regions. In addition, the distal element called the xenobiotic responsive module (XREM) is found in human CYP3A4 genes, which contain both DR-3 and ER-6 motifs. Pregnane X receptor (PXR) could bind to all of these sites and, upon PB induction, a PXR:RXR heterodimer could transactivate XREM. These response elements and NRs are functionally versatile, and capable of responding to distinct but overlapping groups of xenochemicals."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I850,I850)","v":11200465},{"$f":"(LEN($J850) - LEN(SUBSTITUTE(LOWER($J850),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J850) - LEN(SUBSTITUTE(LOWER($J850),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J850) - LEN(SUBSTITUTE(LOWER($J850),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B850:D850)","v":1},2000,"[Transport and metabolism of vitamin A].","Chetyrkin",11200465,"[Transport and metabolism of vitamin A].    Abstract:   The present paper is a review of up-to-date findings on vitamin A transport from intestines to target-cell and metabolism of this fat-soluble vitamin. The hypotheses of possible enzymes participation in the process of etherification/hydrolysis and oxidation/reduction of vitamin A are discussed. Furthermore, possible roles of cellular retinoid-binding proteins in the process of vitamin A transport and metabolism are reviewed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I851,I851)","v":11194782},{"$f":"(LEN($J851) - LEN(SUBSTITUTE(LOWER($J851),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J851) - LEN(SUBSTITUTE(LOWER($J851),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J851) - LEN(SUBSTITUTE(LOWER($J851),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B851:D851)","v":1},2000,"Update on pharmacologic therapy for chronic obstructive pulmonary disease.","Ferguson",11194782,"Update on pharmacologic therapy for chronic obstructive pulmonary disease.    Abstract:   As described throughout this article, significant improvements continue to occur in the pharmacologic management of COPD. These improvements range from improved medication targeting to better understanding of mechanisms of action, to better delivery of medications, to lower side effects. New areas of pharmacologic intervention, if not ready for use today, hold great promise for the not-too-distant future. In addition to the many agents described here, multiple mediator antagonists and anti-inflammatory agents are also under investigation for use in COPD. Interestingly, repair of alveolar tissue may be possible. Indeed, preliminary animal studies suggest that retinoic acid may be able to induce regeneration of lung alveoli. Overall, more effort is needed to broaden awareness and provide for the appropriate diagnosis of COPD, better explain pharmacologic therapies for COPD, simplify and disseminate guidelines, and highlight key differences between asthma and COPD, including their treatment strategies. As interest in COPD continues to grow, future updates on COPD management will continue to add new pharmacologic options for this devastating and preventable disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I852,I852)","v":11172537},{"$f":"(LEN($J852) - LEN(SUBSTITUTE(LOWER($J852),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J852) - LEN(SUBSTITUTE(LOWER($J852),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J852) - LEN(SUBSTITUTE(LOWER($J852),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B852:D852)","v":1},2001,"Treatment of acute promyelocytic leukemia with arsenic compounds: in vitro and in vivo studies.","Chen",11172537,"Treatment of acute promyelocytic leukemia with arsenic compounds: in vitro and in vivo studies.    Abstract:   Arsenic compounds, Including arsenic trioxide (As2O3) and arsenic sulfide (As4S4), have recently been shown to be effective in the treatment of acute promyelocytic leukemia (APL). In vitro, As2O3 exerts a dose-dependent dual effect: it triggers apoptosis at relatively high concentrations (0.5 to 2.0 micromol/L) and induces partial differentiation at low concentrations (0.1 to 0.5 micromol/L). The apoptosis-inducing effect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the retinoic acid signaling is required for APL cell differentiation. As2O3 over a wide range of concentrations (0.1 to 2.0 micromol/L) Induces degradation of PML-RARalpha as well as the wild-type PML and enhances the acetylation of histone, a process important for the transcriptional activation of genes. In vivo, As2O3 induces a high complete remission (CR) rate in patients with both primary and relapsed APL (around 85% to 90%). Side effects, such as skin reaction, gastrointestinal symptoms, electrocardiographic (EKG) changes, neuropathy, and liver dysfunction, are mild to moderate in relapsed patients, and severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As2O3 as postremission therapy has yielded better survival than treatment with As2O3 alone. This is in line with the observation that remission induction with As2O3 is not sufficient in most cases to obtain a molecular remission as Judged by reverse-transcriptase polymerase chain reaction for PML-RARalpha fusion transcripts. The in vivo effect of As2O3 seems to be related to the expression of APL-specific PML-RARalpha oncoprotein, and a synergistic effect between As2O3 and ATRA has been shown in the APL mouse model. Besides As2O3, other arsenic compounds such as As4S4 also show a therapeutic effect in APL. Because the toxic effects of arsenic treatment in primary APL need to be investigated further, we propose use of ATRA as a first-line drug for remission induction in primary APL, whereas As2O3 can be incorporated into multidrug postremission therapy or used as rescue for relapsed APL patients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I853,I853)","v":10891663},{"$f":"(LEN($J853) - LEN(SUBSTITUTE(LOWER($J853),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J853) - LEN(SUBSTITUTE(LOWER($J853),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J853) - LEN(SUBSTITUTE(LOWER($J853),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B853:D853)","v":1},2000,"[Microsomal triglyceride transfer protein and abetalipoproteinemia].","Berriot-Varoqueaux",10891663,"[Microsomal triglyceride transfer protein and abetalipoproteinemia].    Abstract:   Microsomal triglyceride transfer protein (MTP) is a dimeric protein complex consisting of protein disulfide isomerase and a unique 97 kDa subunit. In vitro, MTP accelerates the transport of triglyceride, cholesteryl ester, and phospholipid between vesicles. It was recently demonstrated that abetalipoproteinemia, a disease characterized as an inability to produce chylomicrons and very low density lipoproteins in the intestine and liver, respectively, is the result of a genetic absence of MTP. Downstream effects resulting from this defect, include very low plasma cholesterol and triglyceride levels, absence of plasma apolipoprotein B and a lipid malabsorption syndrome, leading to lipo-soluble vitamin deficiencies. A low fat diet is instituted to eliminate the diarrhea. In addition, a therapy with vitamins A and E is essential to prevent patients from developing secondary effects such as neuropathy, muscle weakness, and retinopathy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I854,I854)","v":10830735},{"$f":"(LEN($J854) - LEN(SUBSTITUTE(LOWER($J854),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J854) - LEN(SUBSTITUTE(LOWER($J854),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J854) - LEN(SUBSTITUTE(LOWER($J854),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B854:D854)","v":1},2000,"Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: an useful salvage therapy.","Huan",10830735,"Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: an useful salvage therapy.    Abstract:   Arsenic trioxide (As2O3) was recently identified as a very potent agent against acute promyelocytic leukemia (APL). Intravenous infusion of 10 mg As2O3 daily for one to two months can induce significant complete remission (CR) of APL, and there is no cross drug-resistance between As2O3 and other antileukemic agents, including all-trans retinoic acid (ATRA). The CR rate of relapsed and/or refractory APL patients who received As2O3 treatment ranged from 52.3% to 93.3%. The median duration to CR ranged from 38 to 51 days, with accumulative As2O3 dosage of 340-430 mg. Although most adverse reactions of As2O3 treatment were tolerable, certain infrequent but severe toxicities related to As2O3 were observed, including renal failure, hepatic damage, cardiac arrhythmia and chronic neuromuscular degeneration, which should be monitored carefully. As2O3 can induce partial differentiation and subsequent apoptosis of APL cells through degradation of wild type PML and PML/RAR alpha chimeric proteins and possible anti-mitochondrial effects. Like the treatment of ATRA in APL, early relapses from As2O3 treatment within a few months were not infrequently seen, indicating that rapid emerging resistance to As2O3 can occur. Nevertheless, the PML/RAR alpha fusion protein was reported to disappear in some APL patients who received As2O3, and who might earn long-survival. However, the follow-up is still too short to draw the conclusion. Intriguingly, it has been shown that As2O3 can also induce apoptosis of other non-APL tumor cells with clinical achievable concentrations. However, the detailed molecular mechanisms are not yet fully understood. Further studies regarding to the pharmacological characters, clinical efficacies, toxicities, apoptogenic mechanisms, and spectrum of anti-tumor activity of As2O3 are warranted."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I855,I855)","v":10789492},{"$f":"(LEN($J855) - LEN(SUBSTITUTE(LOWER($J855),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J855) - LEN(SUBSTITUTE(LOWER($J855),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J855) - LEN(SUBSTITUTE(LOWER($J855),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B855:D855)","v":1},2000,"Prevention of lung cancer.","Goodman",10789492,"Prevention of lung cancer.    Abstract:   Lung cancer is the major cause of death in industrialized western societies. Its link to tobacco abuse is well established and efforts should be made to eliminate this potent environmental carcinogen. The concept of chemoprevention, the use of agents to inhibit and reverse lung cancer carcinogenesis, has great appeal. The CARET study, conducted in 18,000 high-risk smokers in the US, found that a combination of beta-carotene and retinyl palmitate resulted in a 28% increase in the incidence of lung cancer. A similar study conducted in Finland, the ATBC trial utilizing alpha tocopherol and beta-carotene, had similar findings for the group taking beta-carotene. These two trials have caused a rethinking of the use of natural compounds as chemoprevention agents. These agents should no longer be regarded as harmless, but as having potential toxicities. A new approach in the chemoprevention of cancer has been the concept of surrogate endpoints, biological changes that are on the pathway to cancer. Trials are underway to determine what are appropriate surrogate endpoints for lung cancer chemoprevention trials."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I856,I856)","v":10748653},{"$f":"(LEN($J856) - LEN(SUBSTITUTE(LOWER($J856),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J856) - LEN(SUBSTITUTE(LOWER($J856),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J856) - LEN(SUBSTITUTE(LOWER($J856),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B856:D856)","v":1},2000,"[Dysmetabolic syndrome related to HIV-1 protease inhibitors. Review of the literature and personal data].","Urso",10748653,"[Dysmetabolic syndrome related to HIV-1 protease inhibitors. Review of the literature and personal data].    Abstract:   HIV-positive patients receiving antiretroviral therapy with HIV-1 protease-inhibitors (PI) frequently show insulin-resistance, impaired glucose tolerance, hypertriglyceridaemia and lipodystrophy (LD). LD has often been reported only after the beginning of PI therapy. Some authors link LD to HIV chronic infection, some others suggest that PIs increase pre-existent disturb. Preliminary data of an observational study drawn in IV day-hospital of Spallanzani Institute in Rome showed hypertriglyceridaemia in 36.4% and hyperglycaemia in 11.2% of patients treated with PI. Carr suggests that such drugs should have this lipid-increasing effect because of their inhibition of low density lipoprotein-receptor-related protein, cytoplasmic retinoic-acid binding protein type 1 and P450 3A cytochrome. This theory doesnt explain why both untreated patients and treated with only reverse transcriptase inhibitors show sometimes the same disorders. According to another hypothesis Tumor necrosis factor-alpha, through inhibition of lipoprotein-lipase, would determine high fat-storage in the adipose tissue. Cardiovascular risk factors have always to be assessed before starting a therapy with PI. Glycaemia, triglyceridaemia, cholesterolaemia have to be performed every three months during the treatment and, if necessary, C-Peptide and insulinaemia too. A treatment with lipid-lowering drugs is always recommended in patients with hypertriglyceridaemia gt; 500 mg/dl and/or hypercholesterolaemia LDL gt; 190 mg/dl in two following checks. Fibrates have proven to be effective in reducing hypertriglyceridaemia, but there is no certainty that such therapies could have good effects on the LD itself too."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I857,I857)","v":10728792},{"$f":"(LEN($J857) - LEN(SUBSTITUTE(LOWER($J857),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J857) - LEN(SUBSTITUTE(LOWER($J857),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J857) - LEN(SUBSTITUTE(LOWER($J857),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B857:D857)","v":1},2000,"New aspects of hepatic fibrosis.","Brenner",10728792,"New aspects of hepatic fibrosis.    Abstract:   Hepatic stellate cells are the major source of extracellular matrix proteins in hepatic fibrosis, including Type I collagen. In response to liver injury, the hepatic stellate cells change from a quiescent to an activated phenotype. This activation process includes a phenotypic change to a myofibroblast-like cell, increased proliferation rate, loss of retinoid stores, increased production of extracellular matrix proteins, chemokines, and cytokines, and contractility. Ongoing studies are characterizing the genes that are differentially expressed in the quiescent and activated hepatic stellate cells. We have also investigated the regulation of Type I collagen expression, the cleavage of collagen propeptides, and the formation of collagen cross-links. Understanding these pathways may provide new insights into the molecular pathogenesis of hepatic fibrosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I858,I858)","v":10652499},{"$f":"(LEN($J858) - LEN(SUBSTITUTE(LOWER($J858),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J858) - LEN(SUBSTITUTE(LOWER($J858),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J858) - LEN(SUBSTITUTE(LOWER($J858),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B858:D858)","v":1},2000,"Transcriptional repression by nuclear hormone receptors.","Hu",10652499,"Transcriptional repression by nuclear hormone receptors.    Abstract:   Repression by nuclear receptors plays important roles in acute promyelocytic leukemia and other diseases. Nuclear receptor corepressor (N-CoR) and SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) are corepressor proteins whose modular structure facilitates receptor interaction as well as transduction of repression signals involving histone deacetylation, alterations in chromatin structure and direct interactions with the basal transcription machinery. Interactions between nuclear receptors and corepressor complexes have multiple determinants. This allows regulation, and potentially therapeutic manipulation, of receptor, corepressor, cell-type and target-gene specificity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I859,I859)","v":10540889},{"$f":"(LEN($J859) - LEN(SUBSTITUTE(LOWER($J859),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J859) - LEN(SUBSTITUTE(LOWER($J859),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J859) - LEN(SUBSTITUTE(LOWER($J859),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B859:D859)","v":1},1999,"[Hepatobiliary and pancreatic disorders as risk factors for fat-soluble vitamin deficiencies].","Shirahata",10540889,"[Hepatobiliary and pancreatic disorders as risk factors for fat-soluble vitamin deficiencies].    Abstract:   The aim of this article is to describe the fat-soluble vitamin status in patients with hepatobiliary and pancreatic diseases, and the contribution of these vitamin deficiency or excess to hepatic injury. A considerable number of patients with advanced liver disease and cholestasis might actually be fat-soluble vitamin deficient, although clinical signs of deficiency are uncommonly seen in patients with vitamin A and E deficiency. Increased bone resorption may be the predominant cause of hepatic osteodystrophy. On the other hand, the possible causes of vitamin K deficiency seen in patients with hepatobiliary disease are the decrease of vitamin K absorption from intestine, the disturbance of vitamin K cycle and the decrease of pool area for vitamin K storage. The intake of vitamin A may be associated with the risk of liver cirrhosis in lifetime teetotalers, although the retinyl palmitate reduces hepatic fibrosis in rats."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I860,I860)","v":10572559},{"$f":"(LEN($J860) - LEN(SUBSTITUTE(LOWER($J860),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J860) - LEN(SUBSTITUTE(LOWER($J860),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J860) - LEN(SUBSTITUTE(LOWER($J860),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B860:D860)","v":1},1999,"Chemoprevention of breast cancer.","Osborne",10572559,"Chemoprevention of breast cancer.    Abstract:   A critical question is, why do the European studies fail to confirm the US study? Clearly, the answers are complex and uncertain. Differences in power, age, risk, compliance, the use of ERT, and follow-up in the European studies may all be relevant. The efficacy of tamoxifen in BRCA 1 or 2 carriers is an important issue; recent data have shown a DNA repair defect in those with BRCA 1 gene alterations. This finding, coupled with the potential genotoxicity of tamoxifen, is of concern, but the NSABP study did show a significant reduction in breast cancer risk in those with first-degree relatives with breast cancer, including those likely to have a hereditary-predisposition gene. The issue will be clarified when the BRCA 1 or 2 status of these individuals is determined from the stored DNA samples of all participants in the NSABP study. The duration of use of an antiestrogen for prevention is uncertain; the adjuvant trial data for up to 5 years of tamoxifen use showed an effect on contralateral breast cancer prevention extending beyond 5 years, but experimental data show that stopping tamoxifen therapy results in the appearance of new tumors. The long-term use of tamoxifen for prevention carries significant risks. If raloxifene can be given long term, then continuing the prevention of tumors may be possible if raloxifene is proven safe. Should tamoxifen be used outside of a clinical trial? The FDA has approved its use to quot;delayquot; breast cancer so it can be prescribed for any patient at increased risk for breast cancer. The word prevention has been the subject of polemics. Every day that breast cancer is delayed is a day that it is prevented. Risk reduction is technically a more accurate phrase but lacks meaning to many women. Novel approaches to chemoprevention are being explored. Naturally occurring compounds or their analogues are being assessed. Based on experimental studies, the vitamin A analogue 4-hydroxyphenyl retinamide (4-HPR) was shown to delay and reduce carcinogen-induced breast cancer. A randomized clinical trial of 4-HPR is being tested in women in Italy to reduce contralateral breast cancer, but no results are available. New approaches using substances derived from plants, such as vegetables, are being pursued. Based on epidemiologic studies, investigators have proposed that an estrogen metabolite, C16 alpha-hydroxyesterone (16 alpha-OHE1), may have estrogen-stimulating and DNA-damaging properties of mammary epithelial cells. Strategies to reduce 16 alpha-OHE1 have been explored. Indole-3-carbinol, found in high concentration in cruciferous vegetables (i.e., cabbage, cauliflower, broccoli, rabe, brussels sprouts, kale, and bok choi), has been shown to reduce mammary cancer in rodent models and induces a metabolic pathway competing with 16 alpha-OHE1, which increases C-2 hydroxyesterone and thereby reduces substrate available for the 16 alpha-OHE1 pathway. Indole-3-carbinol has a good short-term safety profile. The minimum effective dose that favorably perturbs the ratio between 16 alpha-OHE1 and 2-OHE1 has been determined, and a pilot feasibility trial is in progress in women at risk for breast cancer at Strang Cancer Prevention Center. Future research will identify single or a combination of agents that may significantly reduce the risk for breast cancer without toxicity. A better understanding of the steps involved in the progression of normal breast cells toward cancer will permit the development of strategies to reduce the incidence of and mortality from breast cancer, with the ultimate goal of prevention."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I861,I861)","v":10475022},{"$f":"(LEN($J861) - LEN(SUBSTITUTE(LOWER($J861),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J861) - LEN(SUBSTITUTE(LOWER($J861),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J861) - LEN(SUBSTITUTE(LOWER($J861),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B861:D861)","v":1},1999,"[Prevention of hepatic carcinogenesis by retinoids].","Moriwaki",10475022,"[Prevention of hepatic carcinogenesis by retinoids].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I862,I862)","v":10422196},{"$f":"(LEN($J862) - LEN(SUBSTITUTE(LOWER($J862),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J862) - LEN(SUBSTITUTE(LOWER($J862),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J862) - LEN(SUBSTITUTE(LOWER($J862),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B862:D862)","v":1},1999,"Cytokines and fibrogenesis.","Friedman",10422196,"Cytokines and fibrogenesis.    Abstract:   Cytokines play a major role in the development of hepatic fibrosis, the wound-healing response of the liver to chronic injury. Major concepts in defining the role of cytokines in fibrogenesis include (1) Cytokines may be pro- or antifibrogenic; (2) autocrine, paracrine, and matrix-bound sources of cytokines are the most important; and (3) multiple mechanisms of cytokine regulation are essential to fine-tune their effects. The hepatic stellate cell is the key effector of the fibrotic response and both a principal source and target of cytokines. Activation of stellate cells connotes the conversion of a resting vitamin A-rich cell to one which is proliferative, contractile, fibrogenic, and devoid of vitamin A. The features of stellate cell activation provide a framework in which to understand how cytokines drive fibrosis. These features include (1) proliferation; (2) contractility; (3) fibrogenesis; (4) extracellular matrix degradation; (5) chemotaxis; (6) cytokine release; and (7) retinoid loss. The insights gained from illuminating the role of stellate cells has engendered realistic hopes for treating hepatic fibrosis through modulation of cytokine actions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I863,I863)","v":9932514},{"$f":"(LEN($J863) - LEN(SUBSTITUTE(LOWER($J863),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J863) - LEN(SUBSTITUTE(LOWER($J863),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J863) - LEN(SUBSTITUTE(LOWER($J863),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B863:D863)","v":1},1998,"The bioconversion of beta-carotene into retinoids.","Wang",9932514,"The bioconversion of beta-carotene into retinoids.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I864,I864)","v":9800111},{"$f":"(LEN($J864) - LEN(SUBSTITUTE(LOWER($J864),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J864) - LEN(SUBSTITUTE(LOWER($J864),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J864) - LEN(SUBSTITUTE(LOWER($J864),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B864:D864)","v":1},1998,"Emerging treatments for epidemic (AIDS-related) Kaposis sarcoma.","McGarvey",9800111,"Emerging treatments for epidemic (AIDS-related) Kaposis sarcoma.    Abstract:   Kaposis sarcoma (KS) is an opportunistic tumor that develops with increased frequency (100,000-fold) after HIV infection. KS causes significant morbidity from mucocutaneous involvement and mortality from complications of visceral sites of disease such as the lungs, gastrointestinal tract, and the liver. Progressive unraveling of the KS pathogenesis has lead to the development of novel therapeutic approaches. Newest therapies are first evaluated in patients with limited tumor burden. These include: 1) inhibitors of angiogenesis such as vascular endothelial growth factor signaling inhibitor (SU 5416), and several other inhibitors of angiogenesis such as the dipeptide IM 862, TNP-470, Col-3, and thalidomide; 2) topical and systemic retinoids; 3) antiviral agents specific for Kaposis sarcoma herpesvirus and human herpesvirus-8, or HIV; and 4) pregnancy-related factors. Patients with advanced disease such as widespread mucocutaneous disease, lymphedema, and visceral disease are treated most effectively with cytotoxic agents. The most active agents include liposomal anthracyclines, paclitaxel, vinca alkaloids, and bleomycin. The combination of liposomal anthracyclines and paclitaxel, with and without the most promising biologicals, should now be studied to further reduce the toxicity, and enhance the antitumor effects. Furthermore, identification of risk factors for KS should serve to explore prophylactic therapies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I865,I865)","v":9785060},{"$f":"(LEN($J865) - LEN(SUBSTITUTE(LOWER($J865),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J865) - LEN(SUBSTITUTE(LOWER($J865),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J865) - LEN(SUBSTITUTE(LOWER($J865),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B865:D865)","v":1},1998,"Drugs causing dyslipoproteinemia.","Donahoo",9785060,"Drugs causing dyslipoproteinemia.    Abstract:   Diuretics and beta-blockers have a strong tendency to affect serum lipids adversely, whereas the peripherally acting alpha-blocking agents consistently result in beneficial effects. Most of the other antihypertensive agents (calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists, and drugs that act centrally) are lipid neutral. The effect of steroid hormones varies with the drug, dose, and route of administration. In general, androgens lower HDL-C and have a variable effect on LDL-C. The effects of progestins vary greatly depending on their androgenicity, and estrogens are beneficial except when hypertriglyceridemia occurs with oral estrogens. Glucocorticoids raise HDL-C and may also increase triglycerides and LDL-C. Retinoids increase triglycerides and LDL-C and also reduce HDL-C. Interferons can cause hypertriglyceridemia. Following organ transplantation, a dyslipidemia often ensues. This is caused in part by the medications used to prevent rejection (glucocorticoids, cyclosporine, and FK-506) and requires close attention and, in some patients, drug therapy to prevent coronary artery disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I866,I866)","v":9782379},{"$f":"(LEN($J866) - LEN(SUBSTITUTE(LOWER($J866),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J866) - LEN(SUBSTITUTE(LOWER($J866),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J866) - LEN(SUBSTITUTE(LOWER($J866),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B866:D866)","v":1},1998,"Biomedical applications of maghemite ferrofluid.","Halbreich",9782379,"Biomedical applications of maghemite ferrofluid.    Abstract:   The use of cell-targeted ferrofluid in the characterization of modifications of cell membranes is reviewed. Maghemite ferrofluid was synthesized by the Massart method, complexed with dimercaptosuccinic acid (FF). Cell targeting by FF was developed by coupling FF to various biological effectors such as antibodies, lectins, etc, which enabled magnetic cell sorting. Modifications in erythrocyte membranes were studied using FF bound to recombinant human annexin V (AnxFF) which is very sensitive, compared to other Anx-based reagents, in the early detection of phosphatidylserine (PS) exposition on the outer leaflet of the plasma membrane. Thus PS exposition on mouse RBC was detected already after a 24-h storage at 4 degrees C and, transiently, 24 h after their infection by Plasmodium parasites, at which time the parasites are still confined to the liver, thus leading to the recruitment of young RBC and the accumulation of a species, intermediate between reticulocytes and erythrocytes, and the actual RBC target of plasmodial invasion. AnxFF revealed PS exposition on RBC from sickle cell anemia patients, following various inflammations and already after 20 days of human blood storage under blood bank conditions. Such a sensitive detection should be similar to that of macrophages which recognize exposed PS on cells and bring about the latters elimination from the circulation. AnxFF binding determination was combined with that of cell electrophoretic mobility, glycerol resistance and filterability to characterize RBC membrane modifications in Alzheimers disease patients which suggested a continuous damage and regeneration in RBC of these patients. A logistic analysis suggested that several three-parameter combinations could permit diagnosis of Alzheimers disease with up to 95% accuracy. THP1 cells and macrophages, derived themselves by incubation with retinoic acid, were bound to FF and placed in a radio frequency alternating magnetic field. Magnetocytolysis was associated with FF attachment to the cells without damage to non-bound cells and without heating of the surrounding solution."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I867,I867)","v":9751941},{"$f":"(LEN($J867) - LEN(SUBSTITUTE(LOWER($J867),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J867) - LEN(SUBSTITUTE(LOWER($J867),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J867) - LEN(SUBSTITUTE(LOWER($J867),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B867:D867)","v":1},1998,"Metabolism of ethanol and some associated adverse effects on the liver and the stomach.","Lieber",9751941,"Metabolism of ethanol and some associated adverse effects on the liver and the stomach.    Abstract:   Current knowledge of alcohol oxidation and its effects on hepatic metabolism and its toxicity are summarized. This includes an evaluation of the relationship of the level of consumption to its interaction with nutrients (especially retinoids, carotenoids, and folate) and the development of various stages of liver disease. Ethanol metabolism in the stomach and its link to pathology and Helicobacter pylori is reviewed. Promising therapeutic approaches evolving from newly gained insight in the pathogenesis of medical complications of alcoholism are outlined. At present, the established approach for the prevention and treatment of alcoholism are outlined. At present, the established approach for the prevention and treatment of alcoholic liver injury is to control alcohol abuse, with the judicial application of selective antioxidant therapy, instituted at early stages, prior to the social or medical disintegration of the patient, and associated with antiinflammatory agents at the acute phase of alcoholic hepatitis. In addition, effective antifibrotic therapy may soon become available."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I868,I868)","v":9718434},{"$f":"(LEN($J868) - LEN(SUBSTITUTE(LOWER($J868),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J868) - LEN(SUBSTITUTE(LOWER($J868),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J868) - LEN(SUBSTITUTE(LOWER($J868),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B868:D868)","v":1},1998,"Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma.","Muto",9718434,"Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I869,I869)","v":9717061},{"$f":"(LEN($J869) - LEN(SUBSTITUTE(LOWER($J869),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J869) - LEN(SUBSTITUTE(LOWER($J869),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J869) - LEN(SUBSTITUTE(LOWER($J869),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B869:D869)","v":1},1998,"Metabolic basis for hypertriglyceridaemia in familial combined hyperlipidaemia.","Erkelens",9717061,"Metabolic basis for hypertriglyceridaemia in familial combined hyperlipidaemia.    Abstract:   Familial combined hyperlipidaemia (FCH) is not a single entity with a clearly defined cause but can occur through an increased fatty acid flux from adipose cells, lipoprotein lipase dysfunction or apolipoprotein CIII abnormalities. A dynamic model of the metabolic processes of FCH has been used to describe how lipolysis of adipose cells may ultimately contribute to the formation of atherosclerotic plaques. Elevated circulating levels of chylomicrons are broken down to produce atherogenic remnants. One of the roles of lipoprotein lipase is in the low density lipoprotein (LDL) receptor-like protein-mediated uptake of lipoprotein remnants in the liver and up to 20% of FCH patients show a genetic abnormality of this enzyme. Vitamin A loading and measurement of chylomicron retinyl palmitate levels has further demonstrated impaired chylomicron remnant metabolism in these patients. Macrophages located in the vascular walls engulf remnants but are unable to metabolize their cholesterol. These cells contribute to atherosclerotic plaques. In terms of atherogenic potential, triglyceride levels are found to be higher and the hypertriglyceridaemia more severe in fed than in fasted patients. A case study of a patient with abetalipoproteinaemia suggests that the hypertriglyceridaemia seen in patients with FCH may be the result of an abnormality in microsomal triglyceride transport protein function. Studies also suggest a direct relationship between the post-prandial triglyceride levels and LDL cholesterol levels in the fasting state of patients with FCH and sporadic hypercholesterolaemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I870,I870)","v":9642691},{"$f":"(LEN($J870) - LEN(SUBSTITUTE(LOWER($J870),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J870) - LEN(SUBSTITUTE(LOWER($J870),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J870) - LEN(SUBSTITUTE(LOWER($J870),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B870:D870)","v":1},1998,"[Pre- and/or postoperative adjuvant therapy for hepatocellular carcinoma].","Imaoka",9642691,"[Pre- and/or postoperative adjuvant therapy for hepatocellular carcinoma].    Abstract:   Pre- and/or postoperative adjuvant therapy for hepatocellular carcinoma (HCC) is discussed. There is a high recurrence rate of HCC of up to 50% or more within three years after hepatectomy. More than 80% of those recurrences are in the form of intrahepatic metastases. Therefore it is extremely important to administer successful adjuvant therapy to prevent intrahepatic recurrence. There are two types of intrahepatic recurrence: simple dissemination from the primary focus of HCC; and newly developed HCC in the remnant liver. TAE is one option for preoperative adjuvant therapy to prevent intrahepatic recurrence. Postoperative adjuvant chemotherapy via the hepatic artery has occasionally been administered, but it is not yet established as an effective adjuvant therapy. However, a report by Muto et al showed that retinoid administration can prevent intrahepatic recurrence of newly developed HCC after hepatectomy. On the other hand, adjuvant therapy must not be tooaggressive, because: 1) HCC develops mainly in cirrhotic liver (with poor liver function); and 2) locoregional therapy for intrahepatic recurrence results in good survival rats even after detection of an established recurrence."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I871,I871)","v":9604458},{"$f":"(LEN($J871) - LEN(SUBSTITUTE(LOWER($J871),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J871) - LEN(SUBSTITUTE(LOWER($J871),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J871) - LEN(SUBSTITUTE(LOWER($J871),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B871:D871)","v":1},1997,"Acquired perforating dermatosis and diabetic nephropathy--a case report and review of the literature.","Maurice",9604458,"Acquired perforating dermatosis and diabetic nephropathy--a case report and review of the literature.    Abstract:   A case of acquired perforating dermatosis associated with diabetic nephropathy is described. The case is unusual in that the dermatosis first developed approximately 1 year after renal transplantation rather than at a time when renal function was more severely impaired or during haemodialysis. There was a partial response to treatment with isotretinoin but the use of this drug was limited by the development of hyperlipidaemia. The relevant literature is reviewed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I872,I872)","v":9504139},{"$f":"(LEN($J872) - LEN(SUBSTITUTE(LOWER($J872),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J872) - LEN(SUBSTITUTE(LOWER($J872),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J872) - LEN(SUBSTITUTE(LOWER($J872),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B872:D872)","v":1},1997,"Carotenoids: biology and treatment.","Rock",9504139,"Carotenoids: biology and treatment.    Abstract:   Carotenoids are pigments found in plants and microorganisms, but not synthesized in animals. Fewer than 10% of the carotenoids can function as vitamin A precursors in mammals. Carotenoids and retinoids have chemical and metabolic similarities and differences, and some overlap in biological activities. Carotenoids in tissues reflect food choices. Carotenoids exhibit biological activities as antioxidants, affect cell growth regulation, and modulate gene expression and immune response. Epidemiologic evidence links higher carotenoid intakes and tissue concentrations with reduced cancer and cardiovascular disease risk, although results from clinical trials do not support beta-carotene supplementation as a strategy to reduce risk. Continued research in this area is likely to stimulate better intervention strategies with clinical and public health applications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I873,I873)","v":9498311},{"$f":"(LEN($J873) - LEN(SUBSTITUTE(LOWER($J873),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J873) - LEN(SUBSTITUTE(LOWER($J873),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J873) - LEN(SUBSTITUTE(LOWER($J873),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B873:D873)","v":1},1998,"Hepatic and other medical disorders of alcoholism: from pathogenesis to treatment.","Lieber",9498311,"Hepatic and other medical disorders of alcoholism: from pathogenesis to treatment.    Abstract:   The medical risks of moderate and excessive alcohol consumption are reviewed. Current knowledge of metabolism of alcohol, including effects of moderate amounts, on hepatic metabolism and toxicity is summarized, with an evaluation of the relationship between the level of consumption and its effects on nutrients (including retinoids, carotenoids and folate), liver disease and other medical complications of alcoholism, including cardiovascular diseases and cancer. Putative benefits are also considered. Promising therapeutic approaches evolving from newly gained insight in the pathogenesis of medical complications of alcoholism are outlined."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I874,I874)","v":9394678},{"$f":"(LEN($J874) - LEN(SUBSTITUTE(LOWER($J874),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J874) - LEN(SUBSTITUTE(LOWER($J874),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J874) - LEN(SUBSTITUTE(LOWER($J874),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B874:D874)","v":1},1997,"Retinoids and alcoholic liver disease.","Mezey",9394678,"Retinoids and alcoholic liver disease.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I875,I875)","v":9302568},{"$f":"(LEN($J875) - LEN(SUBSTITUTE(LOWER($J875),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J875) - LEN(SUBSTITUTE(LOWER($J875),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J875) - LEN(SUBSTITUTE(LOWER($J875),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B875:D875)","v":1},1997,"The hepatic perisinusoidal stellate cell.","Kawada",9302568,"The hepatic perisinusoidal stellate cell.    Abstract:   Hepatic stellate cell (also referred to as Ito cell, fat-storing cell, perisinusoidal cell, lipocyte) is one of the sinusoid-constituent cells that play multiple roles in liver pathophysiology. Although identification of the stellate cell had taken about 100 years because of the misconception caused by the discoverer von Kupffer, Wake made a great contribution to the quot;requot; discovery of the cell in 1971. Establishment of the isolation of hepatic non-parenchymal cells from rats by Knook has made it possible to uncover the metabolic function of individual cells. Now, the stellate cell function is expanding from a retinol (fat)-storing site to a center of extracellular matrix metabolism and mediator production in the liver. Function as a liver specific pericyte has also been elucidated. Transition of the stellate cells from the vitamin A-storing phenotype to quot;activatedquot; or quot;myofibroblasticquot; cells that produce a large amount of type I collagen and transforming growth factor beta triggers the progress of liver fibrosis in the course of hepatic inflammation. Communication of the stellate cells with the other hepatic constituent cells and invading inflammatory cells is also an important factor that regulates the local pathological reaction. Analysis of cellular and molecular aspects of the stellate cell activation would lead to the establishment of a novel therapeutic strategy against the progress of liver fibrosis in human liver disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I876,I876)","v":9028626},{"$f":"(LEN($J876) - LEN(SUBSTITUTE(LOWER($J876),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J876) - LEN(SUBSTITUTE(LOWER($J876),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J876) - LEN(SUBSTITUTE(LOWER($J876),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B876:D876)","v":1},1997,"Ethanol metabolism, cirrhosis and alcoholism.","Lieber",9028626,"Ethanol metabolism, cirrhosis and alcoholism.    Abstract:   Alcohol-induced tissue damage results from associated nutritional deficiencies as well as some direct toxic effects, which have now been linked to the metabolism of ethanol. The main pathway involves liver alcohol dehydrogenase which catalyzes the oxidation of ethanol to acetaldehyde, with a shift to a more reduced state, and results in metabolic disturbances, such as hyperlactacidemia, acidosis, hyperglycemia, hyperuricemia and fatty liver. More severe toxic manifestations are produced by an accessory pathway, the microsomal ethanol oxidizing system involving an ethanol-inducible cytochrome P450 (2E1). After chronic ethanol consumption, there is a 4- to 10-fold induction of 2E1, associated not only with increased acetaldehyde generation but also with production of oxygen radicals that promote lipid peroxidation. Most importantly, 2E1 activates many xenobiotics to toxic metabolites. These include solvents commonly used in industry, anaesthetic agents, medications such as isoniazid, over the counter analgesics (acetaminophen), illicit drugs (cocaine), chemical carcinogens, and even vitamin A and its precursor beta-carotene. Furthermore, enhanced microsomal degradation of retinoids (together with increased hepatic mobilization) promotes their depletion and associated pathology. Induction of 2E1 also yields increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, impaired utilization of oxygen, glutathione depletion, free radical-mediated toxicity, lipid peroxidation, and increased collagen synthesis. New therapies include adenosyl-L-methionine which, in baboons, replenishes glutathione, and attenuates mitochondrial lesions. In addition, polyenylphosphatidylcholine (PPC) fully prevents ethanol-induced septal fibrosis and cirrhosis, opposes ethanol-induced hepatic phospholipid depletion, decreased phosphatidylethanolamine methyltransferase activity and activation of hepatic lipocytes, whereas its dilinoleoyl species increases collagenase activity. Current clinical trials with PPC are targeted on susceptible populations, namely heavy drinkers at precirrhotic stages."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I877,I877)","v":9076940},{"$f":"(LEN($J877) - LEN(SUBSTITUTE(LOWER($J877),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J877) - LEN(SUBSTITUTE(LOWER($J877),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J877) - LEN(SUBSTITUTE(LOWER($J877),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B877:D877)","v":1},1997,"Tissue inhibitors of metalloproteinases in liver fibrosis.","Iredale",9076940,"Tissue inhibitors of metalloproteinases in liver fibrosis.    Abstract:   Liver fibrosis and its end stage sequelae cirrhosis represent a major worldwide health problem. By definition progressive fibrosis occurs when the rate of matrix synthesis exceeds matrix degradation. Considerable evidence suggests that the hepatic stellate cell is central to the fibrotic process. During liver injury these cells transform from a quiescent retinoid filled phenotype to a proliferative myofibroblast like cell. In this activated phenotype the HSC is the major source of the interstitial collagens, which characterize fibrosis. Recent work suggests that the HSCs are also a source of matrix degrading metalloproteinase (MMPs), indicating that, together with other cells, hepatic stellate cells (HSC) could participate in matrix remodelling. However, HSC activation in tissue culture models and in vivo is also associated with expression of the powerful MMP inhibitors: tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and TIMP-2). TIMP expression has also been demonstrated in fibrotic human liver disease and animal models of liver fibrosis. TIMPs 1 and 2 may therefore promote progression of hepatic fibrosis through inhibition of matrix degradation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I878,I878)","v":9167333},{"$f":"(LEN($J878) - LEN(SUBSTITUTE(LOWER($J878),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J878) - LEN(SUBSTITUTE(LOWER($J878),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J878) - LEN(SUBSTITUTE(LOWER($J878),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B878:D878)","v":1},1996,"Methotrexate for psoriasis.","Boffa",9167333,"Methotrexate for psoriasis.    Abstract:   Methotrexate is an effective antipsoriatic agent and has been widely used to treat severe psoriasis since the 1960s. It is especially useful in acute generalized pustular psoriasis, psoriatic erythroderma, psoriatic arthritis and for extensive chronic plaque psoriasis in patients who are inadequately controlled by topical therapy alone. It has not, however, been formally compared with other systemic treatments for severe psoriasis such as cyclosporin, retinoids or photochemotherapy with psoralen and UVA (PUVA), but in comparison with these other therapies it is inexpensive, with correct use, its safety profile is favourable. In summary, therefore, it can be used as a short-term option to gain control of unstable psoriasis such as pustular psoriasis or erythroderma before returning to other modes of treatment, or more often, as long-term maintenance treatment. The most important potential side-effect is acute myelosuppression, which is the cause of most of the rare deaths attributable to this therapy for psoriasis. Myelosuppression is more likely in the elderly, in patients with renal impairment and/or folate depletion, and with overdose or drug interactions. Long-term therapy carries with it a risk of liver fibrosis which is related to the dosage regimen employed, and is increased by exposure to other hepatic toxins, particularly alcohol. The correlation between the risk of development of liver fibrosis, cumulative lifetime dose and duration of treatment with methotrexate is not clear-cut, but may have been overstated in some studies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I879,I879)","v":9031080},{"$f":"(LEN($J879) - LEN(SUBSTITUTE(LOWER($J879),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J879) - LEN(SUBSTITUTE(LOWER($J879),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J879) - LEN(SUBSTITUTE(LOWER($J879),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B879:D879)","v":1},1996,"Leukocyte alkaline phosphatase a specific marker for the post-mitotic neutrophilic granulocyte: regulation in acute promyelocytic leukemia.","Garattini",9031080,"Leukocyte alkaline phosphatase a specific marker for the post-mitotic neutrophilic granulocyte: regulation in acute promyelocytic leukemia.    Abstract:   Leukocyte alkaline phosphatase (LAP) is the product of the gene coding for the liver/bone/kidney-type alkaline phosphatase. In the normal hematopoietic system, the only cell type expressing LAP in basal conditions is the post-mitotic neutrophilic granulocyte. Thus LAP represents a specific and restrictive marker for the terminal maturation of the neutrophilic granulocyte. The study of the factors and the molecular mechanisms responsible for the expression of LAP in cells undergoing granulocytic maturation may shed light on this complex biological process. Acute promyelocytic leukemia (APL) represents a unique biological model in which it is possible to investigate neutrophilic differentiation. APL blasts undergo rapid and irreversible maturation towards cells morphologically and biochemically resembling normal mature granulocytes upon in vivo and in vitro challenge with all-trans retinoic acid (ATRA). In this cellular context, we studied the endogenous factors involved in the expression of LAP. The phosphatase is not synthesized in undifferentiated APL blasts and it is expressed only upon treatment with combinations between ATRA and a second cyto-differentiating signal. The second signal may be given by G-CSF, cAMP analogs, IL-6 and to a lesser extent by IL-1 beta. The molecular mechanisms underlying the induction of LAP by combinations of ATRA and G-CSF or cAMP analogs were studied in detail and are the object of this review."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I880,I880)","v":9026696},{"$f":"(LEN($J880) - LEN(SUBSTITUTE(LOWER($J880),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J880) - LEN(SUBSTITUTE(LOWER($J880),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J880) - LEN(SUBSTITUTE(LOWER($J880),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B880:D880)","v":1},1996,"[Oral lichen planus (OLP). Therapeutic guidelines and clinical experience with 71 patients].","Vescovi",9026696,"[Oral lichen planus (OLP). Therapeutic guidelines and clinical experience with 71 patients].    Abstract:   The authors report the results of a study performed in 71 patients suffering from lichen planus of the mucous membranes and skin. They discuss dermatological and stomatological clinical data in relation to possible basal diseases (hepatopathies, dermopathies, diabetes, hypertension, gastrointestinal diseases, etc.) and other anamnestic data (psychological aspects, drug taking, working activity, etc.). Moreover, they report the results of the clinical protocol used (betamethasone in a gel and vitamin A base) with a follow-up of 5 years and examine the other therapeutic possibilities reported in the literature."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I881,I881)","v":8886320},{"$f":"(LEN($J881) - LEN(SUBSTITUTE(LOWER($J881),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J881) - LEN(SUBSTITUTE(LOWER($J881),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J881) - LEN(SUBSTITUTE(LOWER($J881),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B881:D881)","v":1},1996,"Current food and nutrition situation in south Asian and south-east Asian countries.","Gopalan",8886320,"Current food and nutrition situation in south Asian and south-east Asian countries.    Abstract:   Food production in the countries of South and South-East Asia has shown a general upward trend during the last decade. Despite the considerable increase in population in many of these countries, food production per capita in 1988-90 was significantly higher as compared to 1979-81 figures, the increase being specially marked in such countries as Vietnam, Cambodia, Indonesia, and Malaysia. Available daily calorie supply was adequate to meet the requirement. The overall pattern of food production however has shown little change, with cereal production continuing to account for a predominant part of food production. There is no evidence of a significant uptrend with respect to production of pulses, milk, horticultural products, poultry or meat production in most countries. A unique and unfortunate feature of the nutrition situation in South-Asian countries is that the incidence of low birth weight deliveries is as high as 34% (1990), ranging from 25% in Sri Lanka to 50% in Bangladesh (as against less than 7% in the countries of Europe and North America). Even in countries of Africa where the overall food and nutrition situation is worse than in South Asia, the incidence is well below 20%. This is a reflection of the poor state of maternal nutrition in pregnancy. Florid nutritional deficiency diseases have shown a steep decline over the last two decades, but goitre and iron deficiency anaemia continue to be major public health problems, though some headway has been made with regard to the control of the former. Severe forms of growth retardation in children have declined but the majority suffer from mild and moderate forms of growth retardation. Countries of the Region are in varying stages of developmental transition. Among the burgeoning middle classes in some of these countries there are evidences of escalation of degenerative diseases such as diabetes and coronary heart disease. With increasing life expectancy, geriatric nutritional problems will demand increasing attention. This article discusses the Human Development Index levels in southern and southeastern Asia, food production and availability, soil and water erosion and fishery depletion, undernutrition, anemia, child mortality, and low birth weight. Urbanization is rapidly increasing. There is a growing affluent middle class. Public health is being threatened by new diseases such as AIDS. An estimated 33% of populations in South and Southeast Asia will be living in urban areas. Urbanization influences are expected to change life styles and patterns of food consumption. It is argued that the future will pose challenges to food resource allocation. Nutrition will be an emerging issue on the national agenda. South Asians and Southeast Asians now comprise about 56% of Asias total population and about 33% of total world population. Most South and Southeast Asian countries rank in the medium and low levels of the Human Development Index. Only Singapore, Thailand, and Malaysia are ranked high. Proper management of Asias land and water resources suggest the ability to feed their growing populations. In 1992 cereal and pulse production kept pace with population growth. However, the estimated per capita daily food availability barely met estimated requirements, and food availability was deficient in some countries. The Green Revolution emphasized the production of wheat and rice at the expense of legumes and pulses. Fruits and vegetables were sufficiently available but seasonally unequally distributed due to storage and refrigeration problems. Soil quality and fish stocks declined during the Green Revolution. Many programs are working to increase nutrition among low-income groups. The widespread health problems include growth retardation, anemia, iodine deficiency, and vitamin A deficiency. Other measures of health, such as prevalence of low birth weight, are based on old studies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I882,I882)","v":8836870},{"$f":"(LEN($J882) - LEN(SUBSTITUTE(LOWER($J882),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J882) - LEN(SUBSTITUTE(LOWER($J882),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J882) - LEN(SUBSTITUTE(LOWER($J882),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B882:D882)","v":1},1996,"Expression of bone-specific genes by hypertrophic chondrocytes: implication of the complex functions of the hypertrophic chondrocyte during endochondral bone development.","Gerstenfeld",8836870,"Expression of bone-specific genes by hypertrophic chondrocytes: implication of the complex functions of the hypertrophic chondrocyte during endochondral bone development.    Abstract:   Endochondral bone formation is one of the most extensively examined developmental sequences within vertebrates. This process involves the coordinated temporal/spatial differentiation of three separate tissues (cartilage, bone, and the vasculature) into a variety of complex structures. The differentiation of chondrocytes during this process is characterized by a progressive morphological change associated with the eventual hypertrophy of these cells. These cellular morphological changes are coordinated with proliferation, a columnar orientation of the cells, and the expression of unique phenotypic properties including type X collagen, high levels of bone, liver, and kidney alkaline phosphatase, and mineralization of the cartilage matrix. Several studies indicate that hypertrophic chondrocytes also express osteocalcin, osteopontin, and bone sialoprotein, three proteins which until very recently were widely believed to be restricted in their expression to osteoblasts. Recent studies suggest that the hypertrophic chondrocytes are regulated by the calcitropic hormones, morphogenic steroids, and local tissue factors. These considerations are based on the regulation by 1,25 (OH)2D3 and retinoids of the cartilage specific genes as well as osteopontin and osteocalcin expression in hypertrophic chondrocytes. They are also based on the effects on growth plate development caused by 1) transgenic ablation of autocrine/paracrine regulators such as PTHrP and of the transcriptional regulator c-fos and 2) naturally occurring genetic mutations of the FGF receptor. These studies further suggest that specific transcriptional factors mediate exogenous regulatory signals in a coordinated manner with the development of bone. While it has been widely demonstrated that the majority of hypertrophic chondrocytes undergo apoptosis during terminal stages of the developmental sequence, their response to specific exogenous regulatory signals and their expression of bone-specific proteins give rise to questions about whether all growth chondrocytes have the same developmental fates and have identical functions. Furthermore, specific questions arise as to whether there are similar mechanisms of regulation for commonly expressed genes found in both cartilage and bone or whether these genes have unique regulatory mechanisms in these different tissues. These recent findings suggest that hypertrophic chondrocytes are functionally coupled during endochondral bone formation to the recruitment of osteoblasts, vascular cells, and osteoclasts."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I883,I883)","v":8796989},{"$f":"(LEN($J883) - LEN(SUBSTITUTE(LOWER($J883),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J883) - LEN(SUBSTITUTE(LOWER($J883),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J883) - LEN(SUBSTITUTE(LOWER($J883),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B883:D883)","v":1},1996,"Miscellaneous metabolic diseases.","Van Linthoudt",8796989,"Miscellaneous metabolic diseases.    Abstract:   Musculoskeletal manifestations are commonly observed in metabolic disorders. Here we review the recent literature on several metabolic arthropathies. Hemochromatosis should be suspected in patients with the sign of the quot;iron salutequot;. Screening for this disorder by routine measurement of transferrin saturation appears to be a cost-effective procedure in white men aged 30 years or older. In dialysis arthropathy, radiologic lesions of the hand joints increased in size and frequency with the duration of dialysis. However, destructive arthropathy of the fingers is not necessarily related to amyloid deposition. In patients with dialysis-related beta 2-microglobulin amyloid deposition, renal transplantation improved clinical rheumatologic manifestations but did not prevent progression of destructive arthropathies nor dissolution of amyloid deposits. In ochronotic arthropathy, spinal changes may resemble those seen in ankylosing spondylitis and can lead to cord compression. The presence of brownish-blackish rods in the synovial fluid is an unusual but useful diagnostic tool. Metabolic factors are likely to play a role in the pathogenesis of diffuse idiopathic skeletal hyperostosis, and recent studies have demonstrated elevated insulin and growth hormone but normal insulin-like growth factor-1 levels in these patients. Other metabolites that may play a role in this condition include retinoids and bone morphogenetic protein-2."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I884,I884)","v":8731193},{"$f":"(LEN($J884) - LEN(SUBSTITUTE(LOWER($J884),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J884) - LEN(SUBSTITUTE(LOWER($J884),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J884) - LEN(SUBSTITUTE(LOWER($J884),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B884:D884)","v":1},1996,"Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis.","Gressner",8731193,"Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis.    Abstract:   Hepatic stellate cells (HSC) are the major source of extracellular matrix components (ECM), if these precursor cells are activated in areas of necroinflammation to proliferate and to transdifferentiate from the retinoid storing to the ECM-producing phenotype termed myofibroblast (MFB). The mechanisms of HSC activation are crucial for the understanding of liver fibrogenesis. Activation is promoted by cytokines from Kupffer cells (KC) and platelets, of which TGF-beta is of great importance. It stimulates in HSC gene expression of ECM molecules but inhibits proliferation and induces phenotypic transdifferentiation. Latent TGF-beta is activated in cooperation with endothelial cells. TGF-alpha, also secreted by KC, stimulates HSC proliferation. In addition, hepatocytes (PC) enhance proliferation of HSC but ECM production is not affected. The mitogenic effect is mediated by TGF-alpha, IGF-1 and other cytokines. The paracrine signals of PC are increased by PC damage. During transdifferentiation MFB increasingly express TGF-beta and TGF-alpha, which are suspected to be involved in autocrine stimulation of MFB and paracrine activation of still untransformed HSC. A three-step cascade model of HSC activation is suggested. A preinflammatory phase initiates HSC activation by discharge of mitogenic cytokines (TGF-alpha, IGF-1) from damaged PC followed by the inflammatory phase based on cytokines (TGF-beta, etc.) from activated KC. In the postinflammatory phase MFB are stimulated by autocrine mechanisms contributing potentially to a perpetuation of the fibrogenic process even after cessation of the primary event (PC damage)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I885,I885)","v":9077255},{"$f":"(LEN($J885) - LEN(SUBSTITUTE(LOWER($J885),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J885) - LEN(SUBSTITUTE(LOWER($J885),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J885) - LEN(SUBSTITUTE(LOWER($J885),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B885:D885)","v":1},1996,"Fish and healthy pregnancy: more than just a red herring!","Rice",9077255,"Fish and healthy pregnancy: more than just a red herring!    Abstract:   In modern Western diets we eat predominantly omega-6 essential fatty acids from vegetable oils, and too little omega-3. The Department of Health recommends doubling the amount of omega-3s we eat. Omega-3 essential fatty acids (EFAs) are derived mainly from fish oils. Omega-3s are believed to help reduce the risks of cardiovascular disease. Among the main materials required for fetal brain and CNS growth in late pregnancy are omega-3s (mainly docosahexaenoic acid [DHA]) and omega-6 EFAs (mainly arachidonic acid [AA]). These come from the mothers diet. Several formulae for preterm infants now contain DHA and AA to aid optimum brain, nerve and retinal development. One manufacturer has begun to include DHA and AA in formulae for term babies. Breast milk contains DHA and AA, derived from the mothers diet. Eating oily fish in pregnancy has been found to have a slight beneficial effect on birthweight and length of gestation. Eating fresh or canned oil-rich fish (e.g. kippers, herring, mackerel, salmon, sardine, pilchards, tuna) twice or three times a week can be encouraged as part of a healthy balanced diet, in pregnancy and for all the family. As well as containing omega-3 polyunsaturates, oily fish is a good source of protein and vitamins A and D. Alternatively, a fish-oil supplement may be taken. Cod liver oil is best avoided during pregnancy, because of concerns over the possible teratogenicity of vitamin A."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I886,I886)","v":8783579},{"$f":"(LEN($J886) - LEN(SUBSTITUTE(LOWER($J886),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J886) - LEN(SUBSTITUTE(LOWER($J886),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J886) - LEN(SUBSTITUTE(LOWER($J886),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B886:D886)","v":1},1996,"Retinoids in the management of non-melanoma skin cancer and melanoma.","Craven",8783579,"Retinoids in the management of non-melanoma skin cancer and melanoma.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I887,I887)","v":8727369},{"$f":"(LEN($J887) - LEN(SUBSTITUTE(LOWER($J887),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J887) - LEN(SUBSTITUTE(LOWER($J887),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J887) - LEN(SUBSTITUTE(LOWER($J887),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B887:D887)","v":1},1996,"[Genetic diagnosis of colorectal cancer].","Itoh",8727369,"[Genetic diagnosis of colorectal cancer].    Abstract:   Accumulating evidences that carcinogenesis requires multiple gene alterations of oncogenes and tumor suppressor genes have recently emerged. In addition, genes related to invasion and metastasis are also important in understanding development of colorectal cancer. In this study, clinical significance and application of tumor suppressor genes and invasion related genes such as APC (adenomatous polyposis coli), DCC (deleted in colorectal carcinoma) tumor suppressor genes and invasion related gene, matrilysin were studied. In the mouse tumor induced by mutagen contained in cooked food, PhIP (2-amino-1-methyl-6- phenylimidazo [4,5-b] pyridine), nonsense mutations of APC gene that is similar to human colorectal cancer have been observed. These results suggested the quite interesting issue of mutagen contained in daily food having etiological role of colorectal cancer. DCC gene alteration, decreased expression of DCC mRNA was detected in 60% of advanced colorectal cancer. In all cases with liver metastasis, DCC expression was absent or markedly decreased, a finding that detection of DCC expression have an clinical importance that predicts metastatic potential of colorectal cancer. Matrilysin, the member of MMPs (matrix metalloproteinases) which degrade matrix components such as type IV collagen, laminin or fibronectin. In most of colorectal cancer, matrilysin was overexpressed in tumor cells. Matrilysin-transfected colorectal cancer cells showed more invasive ability in vitro and gained metastatic potential in SCID mice. Suppression of matrilysin expression by treated with all-trans retinoic acid (ATRA) or introduction of anti-sense matrilysin decreased the invasive ability in vitro. This result suggests that matrilysin plays an important role in invasion and metastasis and have a possibility of new anti-invasion therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I888,I888)","v":8586927},{"$f":"(LEN($J888) - LEN(SUBSTITUTE(LOWER($J888),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J888) - LEN(SUBSTITUTE(LOWER($J888),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J888) - LEN(SUBSTITUTE(LOWER($J888),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B888:D888)","v":1},1995,"[Preventive use of retinoids for occurrence of liver neoplasm].","Muto",8586927,"[Preventive use of retinoids for occurrence of liver neoplasm].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I889,I889)","v":8600672},{"$f":"(LEN($J889) - LEN(SUBSTITUTE(LOWER($J889),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J889) - LEN(SUBSTITUTE(LOWER($J889),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J889) - LEN(SUBSTITUTE(LOWER($J889),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B889:D889)","v":1},1995,"A cascade-mechanism of fat storing cell activation forms the basis of the fibrogenic reaction of the liver.","Gressner",8600672,"A cascade-mechanism of fat storing cell activation forms the basis of the fibrogenic reaction of the liver.    Abstract:   Evidence has been provided that fat storing cells (FSC) are the major source of extracellular matrix components (ECM), if these precursor cells are activated in areas of necroinflammation to proliferate and to switch from the retinoid storing to the ECM-producing phenotype termed myofibroblast (MFB). The mechanisms of FSC activation, which are crucial to fibrogenesis, have been studied under cell culture conditions. FSC are strongly activated by cytokines from Kupffer cells (KC) and platelets, of which TGF-beta is of great importance. It stimulates ECM gene expression but inhibits FSC proliferation and stimulates phenotypic transformation. It is activated in cooperation with endothelial cells. TGF-alpha, also secreted by KC, stimulates FSC proliferation. In addition, hepatocytes (PC) also stimulate proliferation of FSC but ECM production is not affected. The mitogenic effect is mediated by TGF-alpha, IGF-1 and other cytokines. The paracrine signals of PC are increased by PC damage. During transformation MFB increasingly express TGF-beta and TGF-alpha, which are involved in autocrine stimulation of myofibroblasts and paracrine activation of still untransformed FSC. Cellular crosstalk let us suggest a three-step cascade model of FSC activation. A preinflammatory phase initiates FSC activation by discharge of mitogenic cytokines (TGF-alpha, IGF-1) from damaged PC followed by the inflammatory phase based on cytokines (TGF-beta etc.) from activated KC. In the post-inflammatory phase MFB are stimulated by autocrine mechanisms contributing potentially to a perpetuation of the fibrogenic process even after cessation of the primary event (PC damage)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I890,I890)","v":8549875},{"$f":"(LEN($J890) - LEN(SUBSTITUTE(LOWER($J890),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J890) - LEN(SUBSTITUTE(LOWER($J890),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J890) - LEN(SUBSTITUTE(LOWER($J890),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B890:D890)","v":1},1995,"Molecular mechanisms of liver fibrogenesis--a homage to the role of activated fat-storing cells.","Gressner",8549875,"Molecular mechanisms of liver fibrogenesis--a homage to the role of activated fat-storing cells.    Abstract:   During the last few years, considerable progress has been made in the dissection of cellular and molecular mechanisms of hepatic fibrogenesis. The disease, initiated by hepatocellular damage and perpetuated by inflammatory reactions, results not only in an overall increase in extracellular matrix (ECM) but also in molecular and histological rearrangement of virtually all matrix molecules including collagens, structural glycoproteins, proteoglycans and hyaluronan. These alterations of ECM cause severe clinical (e.g. hemodynamic) complications and further metabolic changes in the whole organ. Perisinusoidal fat (retinoid)-storing cells have been identified as the (precursor) cell type mainly responsible for matrix production in the diseased liver. However, these cells have to be activated, i.e. stimulated to proliferate, to transform phenotypically to myofibroblasts and to express matrix genes before full competency for fibrogenesis is reached. Multiple cell interactions with Kupffer cells, platelets, endothelial cells and hepatocytes mediated by various cytokines and growth factors (e.g. TGF-beta 1, TGF-alpha, PDGF, FGF, IGF-1) are involved in the mechanism of fat-storing cell activation which is the common and central pathogenetic mechanism in fibrogenesis. A three-step cascade model of fat-storing cell activation is proposed, which offers target mechanisms for possible anti-fibrotic interventions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I891,I891)","v":8525763},{"$f":"(LEN($J891) - LEN(SUBSTITUTE(LOWER($J891),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J891) - LEN(SUBSTITUTE(LOWER($J891),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J891) - LEN(SUBSTITUTE(LOWER($J891),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B891:D891)","v":1},1995,"[New suggestions for the management of alcoholic liver diseases].","Jmelnitzky",8525763,"[New suggestions for the management of alcoholic liver diseases].    Abstract:   Some recent proposals in management of alcoholic liver disease are discussed focusing on early diagnosis and treatment of alcohol abuse itself, alcoholic hepatitis early mortality, clinical meaning of nutritional therapy, serological approach and treatment of hepatic fibrosis, and problems in liver transplantation for end stage alcoholic liver cirrhosis. CAGE or similar systematized brief questionnaires, and desialylated transferrin/total transferrin ratio as serological marker, seems to be interesting contributions to quot;hiddenquot; alcohol abuse diagnosis and abstinence control while psycho-social support and voluntary incorporation to self-aid groups are the best weapons to reach persistent abstinence. Corticosteroids seems to improve survival in a selected group of patients with severe alcoholic hepatitis, specially in those presenting encephalopathy but free of GI bleeding, decompensated diabetes, active infections, pancreatitis, and other contraindications or adverse effects of these drugs. Relationship between direct toxicity and nutritional deficiencies in pathogenesis of alcoholic liver injury are not clear enough, but malnutrition is generally present in patients requiring hospitalization, and related to clinical severity; oral, enteral or parenteral nutritional supplementation in this order of preference according to patients condition, associated or not with steroid anabolics, are useful in cases with moderate to severe alcoholic hepatitis or decompensated cirrhosis to eliminate the catabolic state, reaching a better nitrogen balance and liver function tests, without special adverse effects. A special role on liver regeneration is discussed. Antioxidants and supernutrients are special quot;modernquot; aspects of nutritional therapy in alcoholic liver disease generally related to the MEOS activation in chronic alcoholism, the excessive production of free radicals, and the depletion of glutathione, membrane phospholipids (specially phosphatidycholine), and vitamin A, E, and C. Natural supplements as soybean polyunsaturated lecithin, with high concentration of phosphatidycholine, or oral supplementation with natural metabolic products depleted from the liver of chronic heavy drinkers, such SAMe, have an interesting rationale based on experimental and clinical findings besides availability and costs. Carotenoids and tocopherols supplementation seems to be an useful tool, but are limited in the case of vitamin A because its special toxicity in chronic alcoholism. Serological markers of metabolism of liver connective tissue are clearly involved in fibrogenesis process and other inflammatory connected events; standardization of laboratory methods surely will result in new possibilities of non-invasive valuation of liver injury, evolution and therapeutic response; special histological damage such as sinusoidal quot;cappilarizationquot; (type i.v. collagen and laminin), endothelial sinusoidal cell function (seric hyaluronate), or collagenase activity (TIMP-1 or tissue inhibitor of metalloproteinases-1) seems to be valuable by these new technologies.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I892,I892)","v":7718307},{"$f":"(LEN($J892) - LEN(SUBSTITUTE(LOWER($J892),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J892) - LEN(SUBSTITUTE(LOWER($J892),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J892) - LEN(SUBSTITUTE(LOWER($J892),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B892:D892)","v":1},1994,"Biotransformation and toxicity of halogenated benzenes.","den Besten",7718307,"Biotransformation and toxicity of halogenated benzenes.    Abstract:   1. Multiple potentially harmful metabolites can be distinguished in the metabolic activation of halogenated benzenes: epoxides, phenols, benzoquinones and benzoquinone-derived glutathione conjugates. 2. The role of these (re-) active metabolites in the toxic effects induced by halogenated benzenes such as hepatotoxicity, nephrotoxicity, porphyria and thyroid toxicity is discussed. 3. Evidence is presented suggesting that the formation of reactive benzoquinone metabolites rather than the traditional epoxides is linked to halogenated benzene-induced hepatotoxicity. 4. A crucial role for the benzoquinone-derived glutathione adducts in halogenated benzene-induced nephrotoxicity is clearly established. 5. Although metabolic activation appears to be involved in porphyria, the nature of the ultimate porphyrinogenic metabolite has not been elucidated yet. 6. Disturbances in thyroid hormone (and retinoid) homeostasis can be (at least partially) explained by the formation of halogenated phenol metabolites. 7. In conclusion, for a relevant prediction of the ultimate fate of a compound in a living organism, one should know the chemical characteristics and reactivity of the parent compound and its metabolites, together with insight into the formation mechanism of each of the suspected metabolites, and an understanding of the interaction between a specific chemical (reactive) structure and its target molecule."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I893,I893)","v":7971835},{"$f":"(LEN($J893) - LEN(SUBSTITUTE(LOWER($J893),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J893) - LEN(SUBSTITUTE(LOWER($J893),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J893) - LEN(SUBSTITUTE(LOWER($J893),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B893:D893)","v":1},1994,"[Iatrogenic hypertriglyceridemia].","Turpin",7971835,"[Iatrogenic hypertriglyceridemia].    Abstract:   Several recent studies have confirmed the pathogenic effect of endogenous hypertriglyceridaemia (type IV) on atherosclerosis and thrombosis. Our understanding of the pathophysiological mechanism involved in these hypertriglyceridaemias is constantly improving. Iatrogenic hypertriglyceridaemia can be caused by several classes of drugs including synthetic oestrogens, especially the oestrogen-progesterone contraceptives, and to a lesser extent natural oestrogens taken orally as replacement treatment during menopause, certain hypotensive drugs (non-cardioselective beta-blockers and thiazidic diuretics), corticosteroids, retinoids, cyclosporine, enzyme inductors and iodine produces (by iodine-induced hypothyroidism). All these situations should be recognized and when high lipid levels are observed treatment protocols should be modified or interrupted. Whether associated with a rise or a fall in cholesterol-LDL, such conditions should always taken into consideration due to the increased risk of atherosclerosis, thrombosis or even acute or subacute pancreatitis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I894,I894)","v":7968931},{"$f":"(LEN($J894) - LEN(SUBSTITUTE(LOWER($J894),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J894) - LEN(SUBSTITUTE(LOWER($J894),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J894) - LEN(SUBSTITUTE(LOWER($J894),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B894:D894)","v":1},1994,"[Nutritional principles for the pregnant diabetic].","Strata",7968931,"[Nutritional principles for the pregnant diabetic].    Abstract:   After a short account on alimentation in pregnant women, the authors examine in detail the correct alimentation in pregnant women affected by different types of diabetes. As general lines for a correct nutritional approach, a total caloric intake of 2200-2500 kcal daily (9196-10450 Kj) (which enclose 35-40 kcal/pro/kg ideal weight and a caloric surplus for pregnancy) is recommended. In over-weight women the caloric intake will be reduced till 1500 kcal (6270 Kj) checking constantly metabolic situation (increase of weight should be for the first ten weeks of 100 g weekly, than of 300 g weekly). Altogether weight increase should be from 9 to 12 kg. 15-20% of caloric intake should be represented for proteins, very important for pregnancy and good growth of fetus. Carbohydrate intake should be 55-60% of caloric intake represented for 75-80% by complex glucides and for 20-25% simple glucides to support a suitable amount of dietary fibres (25-30%). The lipid intake recommended should be 25-30% of the daily calories with a third of monounsaturated fat acids, a third of polyunsaturated fat acids and a third of saturated fat acids, with a cholesterol amount under 300 mg/die. In additional the nutritional plan should consist of a adequate amount of quot;non energetic nutrientsquot; (minerals and vitamins), particularly the calcium intake must be 1200 mg/die and 18 mg/die that of iron and folic acid, vitamin A, D and B intake must be increased. Finally, the authors advise against alcoholic beverages and recommend a regular subdivision of the meals.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I895,I895)","v":7955929},{"$f":"(LEN($J895) - LEN(SUBSTITUTE(LOWER($J895),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J895) - LEN(SUBSTITUTE(LOWER($J895),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J895) - LEN(SUBSTITUTE(LOWER($J895),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B895:D895)","v":1},1994,"Life-threatening hepatic toxicity caused by all-trans-retinoic acid in a patient with acute promyelocytic leukaemia.","Shibata",7955929,"Life-threatening hepatic toxicity caused by all-trans-retinoic acid in a patient with acute promyelocytic leukaemia.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I896,I896)","v":8177978},{"$f":"(LEN($J896) - LEN(SUBSTITUTE(LOWER($J896),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J896) - LEN(SUBSTITUTE(LOWER($J896),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J896) - LEN(SUBSTITUTE(LOWER($J896),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B896:D896)","v":1},1994,"New insight into the structure and functions of the vitamin D receptor.","MacDonald",8177978,"New insight into the structure and functions of the vitamin D receptor.    Abstract:   The past 5 years has witnessed marked progress toward a higher understanding of the vitamin D endocrine system. Presently, we have a more complete picture of the VDR itself, the DNA sequences to which it binds, and the other coreceptors with which it interacts. This last feature is perhaps the most startling recent development in the vitamin D endocrine system. It clearly suggests a potential role for retinoids and their vitamin A-derived ligands in the mechanism of vitamin D action. These two fat-soluble vitamins not only have quite discrete functionalities, but they may also play requisite roles in the pathway of each other. This is particularly intriguing because the actions of vitamin D were attributed originally to vitamin A. Only later were these two vitamins functionally dissected. Now, approximately 75 years later, the emerging data suggest that selected actions of these two fat-soluble vitamins may indeed be linked."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I897,I897)","v":8283927},{"$f":"(LEN($J897) - LEN(SUBSTITUTE(LOWER($J897),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J897) - LEN(SUBSTITUTE(LOWER($J897),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J897) - LEN(SUBSTITUTE(LOWER($J897),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B897:D897)","v":1},1994,"Secondary causes of hyperlipidemia.","Stone",8283927,"Secondary causes of hyperlipidemia.    Abstract:   Secondary causes of hyperlipidemia are important to recognize. In fact, hyperlipidemia may be a clue to the presence of an underlying systemic disorder. It may greatly heighten the risk of atherosclerosis with a raised LDL-c, triglyceride-rich lipoprotein excess, and increased lipoprotein(a) as well as lowered HDL-c. The search for secondary causes may provide a clue as to why patients with primary lipid disorders suddenly develop worsening lipid profiles. The point is a crucial one because some acquired causes of hyperlipidemia, such as alcohol, estrogens, steroids, or pregnancy, when superimposed on a primary familial form of hypertriglyceridemia can result in a saturated removal system and a buildup of chylomicrons, which can lead to life-threatening pancreatitis. A convenient way to remember secondary causes is to think of the four Ds of diet, drugs, disorders of metabolism, and diseases. Although diets rich in saturated fats and cholesterol are a common cause of the mild hypercholesterolemia seen in our society, alcohol excess and weight gain can explain much of the tendency toward hypertriglyceridemia. Interestingly anorexia nervosa has long been associated with severe but reversible hypercholesterolemia. Several classes of drugs need to be considered as common causes of altered lipid profiles. Glucocorticoids and estrogens elevate triglycerides and raise levels of HDL-c. Anabolic steroids taken orally markedly reduce levels of HDL-c in contrast to injectable testosterone, which does not adversely affect the LDL-to-HDL ratio. Oral contraceptives affect atherosclerotic risk depending on the kind and doses of progestin/estrogen. In those with an underlying primary hypertriglyceridemia and associated obesity, estrogenic medications can depress triglyceride removal mechanisms, leading to the chylomicronemia syndrome and pancreatitis. Antihypertensives have variable effects on lipids and lipoproteins. Although short-term thiazide usage raises cholesterol, triglycerides, and LDL-c, long-term usage is not necessarily associated with significant alterations in lipid levels. Alpha blockers may cause an increase in HDL-c, whereas beta blockers raise triglycerides and lower HDL-c. Sympatholytics, angiotensin converting enzyme inhibitors, and calcium channel blockers are essentially lipid neutral. Retinoids can be associated with increased LDL-to-HDL ratios and occasionally striking elevations in triglycerides. Cyclosporine raises LDL-c and lipoprotein(a). Classes of drugs that may raise HDL-c include cimetidine, antiepileptic drugs, and tamoxifen, but the effect may be seen primarily in women. Hypothyroidism is the most common secondary cause of hyperlipidemia after dietary causes are considered. A thyroxine and TSH level should be obtained on all new cases of clinically important hyperlipidemia.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I898,I898)","v":7632008},{"$f":"(LEN($J898) - LEN(SUBSTITUTE(LOWER($J898),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J898) - LEN(SUBSTITUTE(LOWER($J898),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J898) - LEN(SUBSTITUTE(LOWER($J898),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B898:D898)","v":1},1994,"[Multifocal epithelioid hemangioendothelioma with partial remission after interferon alfa-2a treatment].","Roudier-Pujol",7632008,"[Multifocal epithelioid hemangioendothelioma with partial remission after interferon alfa-2a treatment].    Abstract:    INTRODUCTION : Epithelioid hemangioendothelioma (EHE) is a rare vascular tumour of the soft tissue having an intermediate malignancy. Cutaneous presentations have exceptionally been reported.  OBSERVATION : A young woman, initially affected by an EHE with cutaneous and bone involvement, then with pulmonary and hepatic localizations, was in partial remission after one year of treatment with alpha 2a interferon.  DISCUSSION : In a critical review of the literature, we describe the main features of this tumour and the difficulties to classify this entity in the vascular tumors spectrum. Histologically, epithelioid hemangioendothelioma has a very characteristic appearance and is clearly different from other vascular tumors as angiolymphoid hyperplasia with eosinophilia and Kimuras disease. The assumption of a multicentric or a metastatic origin when multiple tumor deposits are found, is still not elucidated. Different therapeutic approaches are proposed: surgery, interferon, interleukin-2, retinoids. Randomized studies would be necessary to confirm our results with alpha 2a interferon but are probably difficult to realize because of the lack of cases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I899,I899)","v":8399348},{"$f":"(LEN($J899) - LEN(SUBSTITUTE(LOWER($J899),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J899) - LEN(SUBSTITUTE(LOWER($J899),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J899) - LEN(SUBSTITUTE(LOWER($J899),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B899:D899)","v":1},1993,"Enzymes catalyzing the hydrolysis of retinyl esters.","Harrison",8399348,"Enzymes catalyzing the hydrolysis of retinyl esters.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I900,I900)","v":8237856},{"$f":"(LEN($J900) - LEN(SUBSTITUTE(LOWER($J900),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J900) - LEN(SUBSTITUTE(LOWER($J900),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J900) - LEN(SUBSTITUTE(LOWER($J900),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B900:D900)","v":1},1993,"Herman Award Lecture, 1993: a personal perspective on alcohol, nutrition, and the liver.","Lieber",8237856,"Herman Award Lecture, 1993: a personal perspective on alcohol, nutrition, and the liver.    Abstract:   Alcohol causes primary malnutrition by displacing nutrients in the diet and secondary malnutrition via malabsorption and cellular injury through direct cytotoxicity. Hepatotoxicity results from metabolic disturbances associated with the oxidation of ethanol via liver alcohol dehydrogenase (ADH) and the redox changes produced by the generated NADH (the reduced form of nicotinamide adenine dinucleotide), which in turn affects the metabolism of lipids, carbohydrates, proteins, and purines. Ethanol is also oxidized in liver microsomes by an ethanol-inducible cytochrome P450, which contributes to the alcoholics tolerance and his increased vulnerability to the toxicity of industrial solvents, anesthetics, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens, and retinoids. Increased acetaldehyde generation, with formation of protein adducts, results in antibody production, enzyme inactivation, decreased DNA repair, impaired utilization of oxygen, glutathione depletion, free radical-mediated toxicity, lipid peroxidation, and increased collagen synthesis. Therapy may eventually improve with the use of supernutrients such as S-adenosyl-L-methionine, which replenishes glutathione, restores methylation, and attenuates liver injury, as well as dilinoleoylphosphatidylcholine, which prevents cirrhosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I901,I901)","v":8512248},{"$f":"(LEN($J901) - LEN(SUBSTITUTE(LOWER($J901),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J901) - LEN(SUBSTITUTE(LOWER($J901),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J901) - LEN(SUBSTITUTE(LOWER($J901),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B901:D901)","v":1},1993,"Carcinogen-induced tissue vitamin A depletion. Potential protective advantages of beta-carotene.","Edes",8512248,"Carcinogen-induced tissue vitamin A depletion. Potential protective advantages of beta-carotene.    Abstract:   Exposure to benzopyrene, an enzyme-inducing PAH carcinogen, promotes vitamin A depletion in exposed tissues. This effect is evident while on a vitamin A sufficient diet and without a decline in serum retinol. The finding of local tissue vitamin depletion without systemic depletion may have considerable implications in maintaining tissue health. While the described studies involved dietary exposure to benzopyrene, it is reasonable to extrapolate that inhalation exposure via cigarette smoke would have a similar effect in the lungs and perhaps stomach and bladder. Higher MFO enzyme activity in the lungs may have detrimental effects. Kellermanns early work identifying a higher incidence of lung cancer in those with genetically greater aryl hydrocarbon hydroxylase activity was interpreted as due to the greater formation of a reactive intermediate in the process of carcinogen metabolism. As an alternative hypothesis I suggest that those with higher enzyme inducibility may have greater carcinogen-induced vitamin A depletion. If poor tissue vitamin A nutriture potentiates the carcinogenicity of compounds such as benzopyrene, dietary or pharmacologic interventions which improve tissue nutriture could be important. The demonstrated effect of dietary beta-carotene on preventing carcinogen-induced tissue vitamin A depletion suggests one mechanism by which beta-carotene may be cancer protective. Further investigations are warranted, particularly with inhalation exposure to carcinogens and the effect of dietary beta-carotene on lung tissue nutriture."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I902,I902)","v":8483280},{"$f":"(LEN($J902) - LEN(SUBSTITUTE(LOWER($J902),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J902) - LEN(SUBSTITUTE(LOWER($J902),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J902) - LEN(SUBSTITUTE(LOWER($J902),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B902:D902)","v":1},1993,"[Vitamin A and E deficiency in children, including the marginal deficiency].","Mino",8483280,"[Vitamin A and E deficiency in children, including the marginal deficiency].    Abstract:   1. Vitamin A: There are very few reports on vitamin A deficiency in Japan because of the rising national status of nutrition, while vitamin A deficiency is still an important nutritional problem in developing and poorly developed countries. In the pediatric field, relationship between vitamin A nutrition and the mechanism for development of bronchopulmonary dysplasia have been discussed, since vitamin A acts as a protector from the keratinization of epithelial cells in the mucosal layer and the skin. The changes in the lung tissues with inadequately supplied vitamin A, probably cause the chronic lung disease resulting from mechanical ventilation in neonates, in whom the plasma vitamin A and retinol binding protein levels are usually low. 2. Vitamin E: In keeping with the view that newborn infants and especially premature infants suffer from vitamin E deficiency. On the basis of recent findings of the vitamin E content in the neonatal cells, the previous concept would agree, as an existing marginal deficiency in neonates. The neurologic deficits manifested in a beta-lipoproteinemia is confirmed to be vitamin deficiency in humans. It has also become clear that similar neurologic impairment occurs in other chronic fat malabsorptive states, such as cholestatic liver diseases, extensive resection of the gut. More recently several patients with spinocerebellar degeneration from vitamin E deficiency without other evidence of malabsorption in whom progression of the diseases is terminated by the vitamin E therapy (isolated vitamin E deficiency) have been reported. The above items are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I903,I903)","v":8483278},{"$f":"(LEN($J903) - LEN(SUBSTITUTE(LOWER($J903),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J903) - LEN(SUBSTITUTE(LOWER($J903),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J903) - LEN(SUBSTITUTE(LOWER($J903),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B903:D903)","v":1},1993,"[Recommended dietary allowances of fat-soluble vitamins].","Yasuda",8483278,"[Recommended dietary allowances of fat-soluble vitamins].    Abstract:   In Japan the recommended dietary allowances (RDAs) of vitamin A for adult male is calculated at 600 micrograms RE, on the data in a human vitamin A depletion-repletion study that minimum requirement for maintenance of a adequate retinol storage at liver is 6.6 micrograms/kg body weight/day. By contrast, it is estimated at 1,000 micrograms RE in U.S., on the basis of a study that minimum requirement for prevention of follicular hyperkeratosis, not impaired dark adaptation, is 910 micrograms RE/day in most adult men. On fourth edition of Japanese RDAs in 1989, the estimated safe and adequate daily dietary intake of vitamin E for adult male was established at 8 mg alpha TE, on the data that the average of unsaturated fatty acid intake was 14.3 g/day and a desirable [vitamin E (mg) to PUFA (g)] ratio of 0.4, whereas the 8-10th editions of U.S. RDAs of vitamin E for adult male had been estimated at 10 mg alpha TE. And the RDAs of other fat-soluble vitamins were discussed on the differences between Japan and other countries."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I904,I904)","v":8388706},{"$f":"(LEN($J904) - LEN(SUBSTITUTE(LOWER($J904),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J904) - LEN(SUBSTITUTE(LOWER($J904),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J904) - LEN(SUBSTITUTE(LOWER($J904),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B904:D904)","v":1},1993,"The nuclear retinoid receptors.","Rowe",8388706,"The nuclear retinoid receptors.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I905,I905)","v":8464160},{"$f":"(LEN($J905) - LEN(SUBSTITUTE(LOWER($J905),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J905) - LEN(SUBSTITUTE(LOWER($J905),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J905) - LEN(SUBSTITUTE(LOWER($J905),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B905:D905)","v":1},1993,"[Recent studies on Ito cells with molecular biology].","Enzan",8464160,"[Recent studies on Ito cells with molecular biology].    Abstract:   By Northern blot analysis of total RNA, extracted from normal human and rat Ito cells, either freshly isolated or in culture, recent studies demonstrated the expression of mRNA for collagen type I, III, IV, fibronectin, laminin, transforming growth factor-beta (TGF-beta), hepatocyte growth factor, nuclear retinoic acid receptor-beta and alpha-smooth m muscle actin. Moreover, Ito cells isolated from experimentally induced fibrotic livers exhibited a marked increase in mRNA for collagen type I, associated with a moderate increase in mRNA of collagen type III and TGF-beta. Although endothelial cells from the same liver also showed moderate increase in mRNA for collagen type I alone, hepatocytes showed no changes. From these results it is concluded that Ito cells are the most important cells in hepatic fibrogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I906,I906)","v":8471092},{"$f":"(LEN($J906) - LEN(SUBSTITUTE(LOWER($J906),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J906) - LEN(SUBSTITUTE(LOWER($J906),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J906) - LEN(SUBSTITUTE(LOWER($J906),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B906:D906)","v":1},1993,"Nutrition in the pathogenesis of alcoholic liver disease.","French",8471092,"Nutrition in the pathogenesis of alcoholic liver disease.    Abstract:   The data and experimental results reviewed here allow the construction of the following hypothesis: alcohol-induced liver disease results from a combination of two phenomena. The first is the induction of the maximum activity of CYP 2E1 by several dietary factors, i.e. (1) low carbohydrate-high fat diet; and (2) the dietary fats composed of PUFA (Yang et al., 1992). The second is the production of lipid peroxidation induced by CYP 2E1 oxidation of ethanol maintained at high blood alcohol levels (gt; 200 mg %) with the availability of PUFA as substrate (Ekstrom and Ingelman-Sundberg, 1988; Koop, 1992). Thus, lipid peroxidation may be the final common pathway which supports the induction of ALD. Further, it may provide the common denominator which links ALD pathogenesis to non-alcoholic steato-hepatitis (NASH) (French et al., 1989b), where CYP 2E1 is induced by high fat diet and/or diabetes (Dong et al., 1988)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I907,I907)","v":8427885},{"$f":"(LEN($J907) - LEN(SUBSTITUTE(LOWER($J907),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J907) - LEN(SUBSTITUTE(LOWER($J907),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J907) - LEN(SUBSTITUTE(LOWER($J907),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B907:D907)","v":1},1993,"Preclinical aspects and therapeutic perspectives of acute and chronic leukemias.","Hiddemann",8427885,"Preclinical aspects and therapeutic perspectives of acute and chronic leukemias.    Abstract:   Increasing understanding of the processes regulating cell growth, differentiation, and the process of malignant transformation as well as the identification of immunologic defense mechanisms against leukemic cells and a better knowledge of the pharmacokinetics of cytostatic drugs, provide the basis for novel therapeutic approaches being explored in preclinical investigations and early clinical trials. These approaches include antileukemic therapy at the molecular level by attempts to block the translation of central oncogenes by antisense oligonucleotides or the interference with abnormal signal transduction by modulation of key enzyme systems, eg, tyrosine kinases or protein kinase C. Reversion of the neoplastic phenotype may be obtained by transfection of tumor cells with wild-type tumor-suppressor genes or restoration of cellular differentiation, ie, by retinoic acid in acute promyelocytic leukemia. Antisense oligonucleotides may also be applied to abrogate abnormal expression of hematopoietic growth factors. Growth factors are also being used clinically to sensitize leukemic cells prior to cytostatic treatment or for a more rapid recovery of normal hematopoiesis after intensive chemotherapy. Immunologic approaches against leukemic cells are based on the identification of disease-specific markers, providing the target for antibody therapy with monoclonal antibodies coupled to immunotoxins or allowing the augmentation of cell-mediated immunity by cytokine stimulation, ie, with interleukin-2 or retroviral transfer of genes, eg, the tumor necrosis factor-alpha gene into effector cells. New perspectives also arise from a more detailed knowledge of cytostatic drug pharmacokinetics and the detection of metabolic differences between leukemic cells and their normal hematopoietic counterparts, allowing the design of more specific and tumor-directed drug scheduling. This review highlights some examples of recent preclinical findings that may translate into a better understanding of leukemia biology and ultimately improved therapy for these diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I908,I908)","v":8179244},{"$f":"(LEN($J908) - LEN(SUBSTITUTE(LOWER($J908),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J908) - LEN(SUBSTITUTE(LOWER($J908),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J908) - LEN(SUBSTITUTE(LOWER($J908),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B908:D908)","v":1},1993,"[Interferons. Interferons alpha and gamma: indications in systemic diseases].","Blétry",8179244,"[Interferons. Interferons alpha and gamma: indications in systemic diseases].    Abstract:   Interferon alpha (INF-alpha)--In systemic diseases, most indications for INF-alpha result from its effect on haematological or hepatological manifestations. The spectacular effect of INF-alpha in chronic myeloid leukemia has led to its use for the treatment of hypereosinophilia syndrome and systemic mastocytosis. Over the last 6 years, we have treated 7 patients with the hypereosinophilia syndrome who were resistant to corticotherapy and had markers of myeloproliferation. Although both hydroxyurea and INF-alpha can be effective alone, their combination led to a decrease in the eosinophilia count to 1,000/ml, a decrease which was long-lasting in most cases. INF-alpha is also used in histiocytosis X alone or in combination with retinoids or with etoposide and has been found effective in several observations. In carcinoid syndromes whether treated priorly or not with a 5-fluoro-uracil-streptozoticin combination, INF-alpha leads to an objective response in two-thirds of the patients. Several multicentric protocols are currently assessing the efficacity of INF-alpha in mixed cryoglobulinaemias. In most observations these cryoglobulinaemias are seen in patients with markers of hepatitis C (mainly HCV) and the early results are encouraging. Temporary improvement has been reported in discoid or subacute lupus in 8 out of 10 cases. Haemangiomas of the infant, when life-threatening and corticoresistant, may be a good indication for INF-alpha. Thus 20 newborns or infants (including 4 with Kasabach-Merrit syndrome) have been treated with good results in 18. Interferon gamma (INF-gamma).(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I909,I909)","v":7693404},{"$f":"(LEN($J909) - LEN(SUBSTITUTE(LOWER($J909),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J909) - LEN(SUBSTITUTE(LOWER($J909),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J909) - LEN(SUBSTITUTE(LOWER($J909),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B909:D909)","v":1},1993,"Food quality and human nutrition.","James",7693404,"Food quality and human nutrition.    Abstract:   New nutritional analyses suggest that current trends in the production of food are inappropriate for the health of most of the worlds populations. Four deficiency problems now dominate analyses of the nutritional disorders of developing countries: the risks from iodine, vitamin A and iron deficiencies and protein energy malnutrition now affect over two billion children and adults. Chronic energy deficiency affects half of Indian adults, with similar rates in Pakistan and Ethiopia. India will need to increase food production two- to three-fold by 2020 to cope with the predicted population explosion and desirable increases in food consumption. As erosion, salination and environmental degradation further limit land availability, current problems will overwhelm agricultural demand. Societies increase their meat, milk and fat consumption as they become affluent, and suffer from heart disease, diabetes, obesity, cancers and a variety of other Western public health problems. Agricultural production is then regeared inappropriately. The Second World has an agriculture system geared to 1940s Western concepts of high animal production. Russia now vies with Scotland and Northern Ireland for the highest heart disease rates in the world and has the fattest adults in Europe. Most major non-infective public health issues throughout the world are nutritionally related. Global warming will exacerbate these problems, but effective dietary change with less animal production could release land which could be used more efficiently."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I910,I910)","v":1337119},{"$f":"(LEN($J910) - LEN(SUBSTITUTE(LOWER($J910),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J910) - LEN(SUBSTITUTE(LOWER($J910),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J910) - LEN(SUBSTITUTE(LOWER($J910),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B910:D910)","v":1},1992,"[Vitamin D3].","Inaba",1337119,"[Vitamin D3].    Abstract:   With the application of biochemical technique came the discovery that vitamin D is metabolized sequentially to 25-hydroxyvitamin D in liver and then to 1.25-dihydroxyvitamin D (1.25D), the hormonal form of vitamin D, in kidney. The latter process is strictly controlled with the demand of calcium and phosphorus. The produced 1.25D binds its specific receptor probably located in the nuclei. With the application of modern tools of molecular biology came the discovery that vitamin D receptor (VDR), which belongs to steroid receptor family, acquires increased affinity for DNA when it binds to 1.25D and then VDR complexes bind to DNA with its two zinc-finger projections. VDR complexes recognize vitamin D responsive element on DNA, two tandemly repeated hexanucleotide sequences separated by three base pairs. Furthermore, to interact with the VDRE, VDR complexes require nuclear accessory factor, which might be retinoid X receptor (RXR). As above, molecular biology helps us to extend our knowledge in the field of vitamin D."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I911,I911)","v":1409729},{"$f":"(LEN($J911) - LEN(SUBSTITUTE(LOWER($J911),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J911) - LEN(SUBSTITUTE(LOWER($J911),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J911) - LEN(SUBSTITUTE(LOWER($J911),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B911:D911)","v":1},1992,"Vitamin A homeostasis endangered by environmental pollutants.","Zile",1409729,"Vitamin A homeostasis endangered by environmental pollutants.    Abstract:   Normal vitamin A function depends on adequate stores of the vitamin, a finely regulated supply of the vitamin to target tissues, and an ability of cells to generate functionally active forms of the vitamin. Both endogenous and exogenous factors can adversely affect vitamin A homeostasis. Polyhalogenated aromatic hydrocarbons are ubiquitous environmental pollutants and cause severe disturbances in vitamin A metabolism, manifested by an accelerated metabolism and breakdown of vitamin A and its metabolites and a depletion of vitamin A from the body; this sequence of events accounts for the vitamin A deficiency-like symptoms associated with PHAH intoxication. The mechanism(s) responsible for these events most likely includes altered activities of enzymes that are either directly or indirectly involved in critical vitamin A metabolic pathways. Human populations that continue to be exposed to environmental pollutants, may accumulate critical levels of polyhalogenated aromatic hydrocarbons and will be at risk for inadequate vitamin A function as well as for other health impairments that have been difficult to link to any specific causes. Therefore, it is important to seriously evaluate the similarities in physiological disturbances across species that have become apparent in studies with wildlife inhabiting polluted environments similar to ours; the relevance to human health is evident."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I912,I912)","v":1596431},{"$f":"(LEN($J912) - LEN(SUBSTITUTE(LOWER($J912),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J912) - LEN(SUBSTITUTE(LOWER($J912),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J912) - LEN(SUBSTITUTE(LOWER($J912),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B912:D912)","v":1},1992,"Contraception for midlife women.","Root",1596431,"Contraception for midlife women.    Abstract:   Women wish to continue to be sexually active long after their desire to bear children. The risks associated with unintended pregnancy easily can be avoided by providing women with information about, and access to, contraceptives that are safe and effective. Because fertility naturally declines with age, different contraceptives may be more suitable for women toward the end of their reproductive years than were appropriate at periods of peak fertility. This article discusses the risks and benefits of various contraceptives for midlife women and the implications of this information on nursing practice. For women beyond the desire for childbearing, the contraceptive options are discussed as appropriate for the age and in light of risks and benefits. Reeducation and careful history taking are important. A pregnancy for a woman 40 years places a woman at greater risk for an elective abortion and greater risk of maternal mortality from abortion; low dose contraceptive use can have beneficial effects for menopausal women. Methods are grouped as contraceptive steroids (combination pills, progestin-only pills, oral preparations, implants, and injections), IUDs, barrier methods (diaphragms, cervical caps, vaginal sponges, spermicides, and contraceptive film), condoms, sterilization, and natural family planning. Empowering women means providing current scientific information and urging women to examine their lives, and to review how and why contraceptive choices were made, and the consequences of the choices. Sexually transmitted disease counseling is appropriate for women in new relationships. A positive attitude toward menopause needs to be conveyed. Combination pills at the lowest dose possible are recommended for women 35 years who are healthy, nonsmoking (or smoking 15 cigarettes/day), blood group O, and able to derive benefits from the pill. Benefits include a 30% reduction in uterine fibroids and protection against endometrial cancer, and decreased risk of ectopic pregnancy, pelvic inflammatory disease (PID), and iron deficiency anemia. Multivitamin use with the pill is recommended due to reduced liver stores of vitamin A. Women 40 years with a parent dying of cardiac disease 50 years or with a history of hypertension, diabetes, or hyperlipidemia are not suitable candidates. 35 mcg preparations are recommended for women 35-45 years, and 20 mcg for women over 45 years. Progestin-only pills are recommended for those with contraindication to estrogen, but have a higher pregnancy rate. IUD use among older women may be difficult due to cervical or pelvic surgery; there is a higher incidence of PID and ectopic pregnancy with IUD use. Barrier methods are more successful for older women due to the changing vaginal anatomy. Vasectomy is the safest sterilization procedure."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I913,I913)","v":1338446},{"$f":"(LEN($J913) - LEN(SUBSTITUTE(LOWER($J913),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J913) - LEN(SUBSTITUTE(LOWER($J913),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J913) - LEN(SUBSTITUTE(LOWER($J913),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B913:D913)","v":1},1992,"Retinoids and cancer chemoprevention.","Moriwaki",1338446,"Retinoids and cancer chemoprevention.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I914,I914)","v":1928631},{"$f":"(LEN($J914) - LEN(SUBSTITUTE(LOWER($J914),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J914) - LEN(SUBSTITUTE(LOWER($J914),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J914) - LEN(SUBSTITUTE(LOWER($J914),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B914:D914)","v":1},1991,"Hepatic, metabolic and toxic effects of ethanol: 1991 update.","Lieber",1928631,"Hepatic, metabolic and toxic effects of ethanol: 1991 update.    Abstract:   Until two decades ago, dietary deficiencies were considered to be the only reason for alcoholics to develop liver disease. As the overall nutrition of the population improved, more emphasis was placed on secondary malnutrition and direct hepatotoxic effects of ethanol were established. Ethanol is hepatotoxic through redox changes produced by the NADH generated in its oxidation via the alcohol dehydrogenase pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins, and purines. Ethanol is also oxidized in liver microsomes by an ethanol-inducible cytochrome P-450 (P-450IIE1) that contributes to ethanol metabolism and tolerance, and activates xenobiotics to toxic radicals thereby explaining increased vulnerability of the heavy drinker to industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens, and even nutritional factors such as vitamin A. In addition, ethanol depresses hepatic levels of vitamin A, even when administered with diets containing large amounts of the vitamin, reflecting, in part, accelerated microsomal degradation through newly discovered microsomal pathways of retinol metabolism, inducible by either ethanol or drug administration. The hepatic depletion of vitamin A is strikingly exacerbated when ethanol and other drugs were given together, mimicking a common clinical occurrence. Microsomal induction also results in increased production of acetaldehyde. Acetaldehyde, in turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and alterations in microtubules, plasma membranes and mitochondria with a striking impairment of oxygen utilization. Acetaldehyde also causes glutathione depletion and lipid peroxidation, and stimulates hepatic collagen production by the vitamin A storing cells (lipocytes) and myofibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I915,I915)","v":1918456},{"$f":"(LEN($J915) - LEN(SUBSTITUTE(LOWER($J915),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J915) - LEN(SUBSTITUTE(LOWER($J915),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J915) - LEN(SUBSTITUTE(LOWER($J915),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B915:D915)","v":1},1991,"Skin and bones. I.","Orlow",1918456,"Skin and bones. I.    Abstract:   Skin disorders in which a radiograph may detect associated bony changes or abnormalities of calcification are discussed. They are grouped into eight categories: (1) inherited diseases (e.g., alkaptonuria, neurofibromatosis); (2) congenital disorders (e.g., Sturge-Weber and Proteus syndromes); (3) inflammatory conditions (e.g., dermatomyositis, sarcoidosis); (4) infections (e.g., dental sinus, syphilis); (5) neoplasias (e.g., histiocytosis, mastocytosis); (6) drug- and environment-induced (e.g., acroosteolysis, retinoid toxicity); (7) calcinosis cutis; and (8) osteoma cutis. Part I of our review discusses the first two categories."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I916,I916)","v":1821298},{"$f":"(LEN($J916) - LEN(SUBSTITUTE(LOWER($J916),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J916) - LEN(SUBSTITUTE(LOWER($J916),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J916) - LEN(SUBSTITUTE(LOWER($J916),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B916:D916)","v":1},1991,"Etiopathogenesis of craniosynostosis.","Cohen",1821298,"Etiopathogenesis of craniosynostosis.    Abstract:   Craniosynostosis is both etiologically and pathogenetically heterogeneous. Known causes include monogenic and chromosomal disorders, fetal head constraint, teratogens (aminopterin, diphenylhydantoin, retinoic acid, valproic acid), metabolic diseases (hyperthyroidism, rickets, mucopolysaccharidoses, mucolipidoses), hematologic disorders (thalassemias, sickle cell anemia, congenital hemolytic icterus, polycythemia vera), and malformations (microcephaly, encephalocele, shunted hydrocephaly, holoprosencephaly)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I917,I917)","v":1759070},{"$f":"(LEN($J917) - LEN(SUBSTITUTE(LOWER($J917),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J917) - LEN(SUBSTITUTE(LOWER($J917),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J917) - LEN(SUBSTITUTE(LOWER($J917),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B917:D917)","v":1},1991,"[Portal hypertension and hypervitaminosis A. Apropos of 2 cases and review of the literature].","Dubois",1759070,"[Portal hypertension and hypervitaminosis A. Apropos of 2 cases and review of the literature].    Abstract:   Portal hypertension consecutive to hypervitaminosis A has seldom been well documented. Two cases are reported here. The first case concerns a 39-year old woman who had taken meladinine (8-methoxypsoralen) for the purpose of tanning. In the second case, a 43-year old woman had absorbed Plethoryl (a combination of tiratricol, cyclovalone and retinol) in order to lose weight. Both patients had histological hepatic lesions, such as hypertrophic Ito cells, perisinusoidal cirrhosis and spontaneous autofluorescence, suggestive of vitamin A overload, associated with a hepatic vein pressure gradient of 10 mmHg or more and high liver concentrations of vitamin A. The responsibility of Plethoryl in case 2 is beyond any doubt, but the mechanism of hypervitaminosis in case 1 is controverted. A review of the literature has provided detailed information on the signs of vitamin A overload, the frequency of which is probably underestimated. Patients with portal hypertension of unknown origin should be investigated for hypervitaminosis A."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I918,I918)","v":1892952},{"$f":"(LEN($J918) - LEN(SUBSTITUTE(LOWER($J918),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J918) - LEN(SUBSTITUTE(LOWER($J918),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J918) - LEN(SUBSTITUTE(LOWER($J918),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B918:D918)","v":1},1991,"Liver fibrosis: perspectives in pathobiochemical research and clinical outlook.","Gressner",1892952,"Liver fibrosis: perspectives in pathobiochemical research and clinical outlook.    Abstract:   Disturbances of the equilibrium between parenchyma and extracellular matrix, leading to a disproportionate increase in and an irregular deposition of newly formed connective tissue components (fibrosis), is a common sequel of chronic active liver diseases with serious clinical consequences. Significant progress has been made in recent years in the analysis of the structural composition of extracellular matrix in normal and fibrotic liver and in the dissection of the molecular and cellular mechanisms of exaggerated extracellular matrix deposition in necroinflammatory areas. Under the influence of inflammatory stimuli, perisinusoidal, retinoid-storing cells (Ito cells, parasinusoidal lipocytes), which are qualitatively and quantitatively the most important connective tissue-producing cell type in human and animal liver, transform to myofibroblast-like cells. Activation and transformation of perisinusoidal cells are mediated by paracrine and autocrine loops involving transforming growth factor beta as the main fibrogenic mediator, which is secreted by activated liver macrophages, possibly also by endothelial cells, and liberated by disintegrated thrombocytes. The molecular and cellular interactions during liver fibrogenesis have become a model for a number of other organ fibrotic processes, wound repair and even atherogenesis. Therapeutic interference with the early steps of fibrogenesis seems feasible but a breakthrough has not yet been achieved. For clinical-chemical, non-invasive diagnosis and monitoring of ongoing fibrogenesis, a rather limited repertoire of more or less organ- and disease-unspecific parameters is available. Split products of the extracellular maturation pathway of the procollagen types, laminin and hyaluronan, can be assayed but the clinical interpretation of the results has to be made with caution. Strategies and major topics of future pathobiochemical and clinically oriented research are highlightened."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I919,I919)","v":2060847},{"$f":"(LEN($J919) - LEN(SUBSTITUTE(LOWER($J919),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J919) - LEN(SUBSTITUTE(LOWER($J919),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J919) - LEN(SUBSTITUTE(LOWER($J919),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B919:D919)","v":1},1991,"Prevention of cancer by agents that suppress oxygen radical formation.","Troll",2060847,"Prevention of cancer by agents that suppress oxygen radical formation.    Abstract:   The prevention of cancer by agents in our diet has led to the concept that oxygen radicals are a necessary component of a variety of human cancers including breast, colon and prostatic cancer. These cancers are putatively promoted by estradiol, bile acids and androgens. Epidemiological studies have shown that these cancers are suppressed in vegetarian populations. Vegetable components that may be responsible for this cancer prevention are Vitamin A, retinoids and protease inhibitors (PIs). These agents have been shown to suppress the formation of hydrogen peroxide in promoter-induced neutrophils. They also have been shown to block two-stage carcinogenesis and breast cancer when fed to animals. PIs also suppress experimentally-induced colon cancer and spontaneous liver cancer. Moreover, a new series of cancer-preventive agents, Sarcophytols (isolated by Fujiki and co-workers), are capable of suppressing two-stage carcinogenesis, breast and colon cancers in rodents when given in low concentrations. Sarcophytols were also active suppressors of H2O2 formation of 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced neutrophils. These observations point to an essential role of oxygen radicals in carcinogenesis. Suppression of the oxygen radical response of neutrophils in relation to cancer preventive agents is a facile assay of these important substances. The mechanism of action of oxygen radicals in promoting carcinogenesis is a multiple one, including: (1) activation of oncogenes, (2) modification of DNA bases, and (3) formation of single-strand breaks leading to poly(ADP)ribose polymerase activation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I920,I920)","v":1935221},{"$f":"(LEN($J920) - LEN(SUBSTITUTE(LOWER($J920),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J920) - LEN(SUBSTITUTE(LOWER($J920),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J920) - LEN(SUBSTITUTE(LOWER($J920),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B920:D920)","v":1},1991,"Effects of retinoids on lipoprotein metabolism.","Vahlquist",1935221,"Effects of retinoids on lipoprotein metabolism.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I921,I921)","v":1803172},{"$f":"(LEN($J921) - LEN(SUBSTITUTE(LOWER($J921),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J921) - LEN(SUBSTITUTE(LOWER($J921),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J921) - LEN(SUBSTITUTE(LOWER($J921),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B921:D921)","v":1},1991,"Free radicals as carcinogens and their quenchers as anticarcinogens.","Santamaria",1803172,"Free radicals as carcinogens and their quenchers as anticarcinogens.    Abstract:   An oxygen dependent signal was detected, late in the 1950s by electron spin resonance (ESR) in a saline solution of hematoporphyrin (Hp) excited by light. This signal expressed a free radical consisting of some kind of an association between Hp and oxygen, that Smaller et al. called oxyradical (HpOO.). It soon opened a new level of understanding in carcinogenesis triggered by photodynamic substances, including Hp itself, polycyclic hydrocarbons (PCHs), as well as any carcinogen involving molecular species activated by radiation and/or metabolic reaction. Early in the 1960s, this prompted the discovery of benzo(a)pyrene (BP) photocarcinogenic enhancement (BP-PCE) in mice, probably due to an increase in free oxygen radical generation following correct light exposure. This assumption was confirmed in 1980 by the fact that mice orally loaded with antioxidants and radical quenchers, such as beta-carotene (BC) and cantaxanthin (CX), were protected against BP-PCE at 100% and against total BP carcinogenicity at more than 60%. These achievements were presented as the bases of the current explosion of interest in biology and medicine in building up the new field of chemoprevention against cancer and other chronic diseases by supplementation with antioxidant vitamins, retinoids and especially carotenoids and their synergistic association. The relevant findings of this research obtained in the last decade in in vitro and in vivo experiments as well as human interventions are reported and discussed with personal contributions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I922,I922)","v":2226349},{"$f":"(LEN($J922) - LEN(SUBSTITUTE(LOWER($J922),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J922) - LEN(SUBSTITUTE(LOWER($J922),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J922) - LEN(SUBSTITUTE(LOWER($J922),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B922:D922)","v":1},1990,"Metabolism and effects of epidermal growth factor and related growth factors in mammals.","Fisher",2226349,"Metabolism and effects of epidermal growth factor and related growth factors in mammals.    Abstract:   The initial observations of Stanley Cohen in the 1960s established that EGF induced in vivo effects such as precocious eyelid opening and tooth eruption. Subsequently the actions of EGF have been extensively explored in cell culture systems. The receptor for EGF was characterized as a prototype model for other growth factors and the now extensive in vitro data indicate multiple functions for EGF. Moreover, EGF and EGF receptors have been characterized in many tissues, and EGF has been identified in most body fluids of several mammalian species. Interestingly, neither EGF antibody administration to newborn animals nor passive immunization of pregnant rodents against EGF has caused major deleterious effects (except the delay in epidermal maturation events), as might be expected from the in vitro studies. This is in contrast to the effects of nerve growth factor antiserum in developing rodents. Also, to date, no pathological EGF deficiency disorder has been characterized. However, the EGF family of growth factors appears to be important in mammalian development and function, although the precise roles and significance are not yet clear. Members of the family may have a role in embryogenesis and fetal growth since receptors have been identified in fetal tissues. Available evidence suggests that TGF alpha subserves the growth factor family roles in fetal development. In the developing postnatal animal pro-EGF mRNA, immunoreactive EGF, immunoreactive TGF alpha, and EGF receptors are present in many tissues. EGF also is produced and secreted by the maternal mammary gland, and mammary derived EGF appears to be important in gut development in the neonatal rodent. There is now extensive data to indicate important hormone-EGF interactions. In the postnatal period, thyroid and steroid hormones including retinoic acid have been shown to modulate EGF and/or EGF receptors in several tissues. GH increases EGF binding in liver and increases urine EGF concentrations. Moreover, EGF stimulates secretion of several hypothalamic and pituitary hormones, increases placental production of hCG and human chorionic somatomammotropin, increases adrenal cortisol production, and inhibits testicular, ovarian, and thyroid hormone secretions. As summarized in this review EGF has been implicated in a number of developmental events including palate and skin differentiation, growth of hair follicles, eye opening and tooth eruption, lung maturation, gut and liver growth, and differentiation of neurons. These EGF actions probably are mediated via autocrine, paracrine, and endocrine routes. A role for salivary and urine EGF in the maintenance of adult stomal, gut, and urinary epithelial surface integrity seems likely, although not yet proven.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I923,I923)","v":2134673},{"$f":"(LEN($J923) - LEN(SUBSTITUTE(LOWER($J923),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J923) - LEN(SUBSTITUTE(LOWER($J923),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J923) - LEN(SUBSTITUTE(LOWER($J923),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B923:D923)","v":1},1990,"Structure-function aspects of the glucocorticoid receptor.","Gustafsson",2134673,"Structure-function aspects of the glucocorticoid receptor.    Abstract:   The glucocorticoid receptor belongs to a family of ligand activated nuclear receptors. In addition to steroid hormone receptors, this family also includes receptors for thyroid hormone, retinoic acid and 1,25-dihydroxyvitamin D3 as well as some receptors with as yet unknown ligands, the so called orphan receptors. It is possible that the dioxin receptor is a member of this family as well although this cannot be definitely assessed until the receptor has been cloned. Interestingly, the clofibrate receptor, believed to be involved in clofibrate induction of certain isozymes of cytochrome P-450, has recently been shown to be a member of the steroid receptor supergene family and it is conceivable that other P-450 inducers might act via as yet uncharacterized receptors belonging to the same gene family. Therefore, we should learn significantly about principles of P-450 regulation by considering basic mechanisms of glucocorticoid action; the glucocorticoid receptor probably represents the most extensively studied member of the nuclear receptor family. Our laboratory has been particularly interested in structural aspects of this receptor and has used gene technology to overexpress its different domains, particularly the DNA-binding domain, the structure of which has been resolved using NMR."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I924,I924)","v":2081478},{"$f":"(LEN($J924) - LEN(SUBSTITUTE(LOWER($J924),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J924) - LEN(SUBSTITUTE(LOWER($J924),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J924) - LEN(SUBSTITUTE(LOWER($J924),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B924:D924)","v":1},1990,"Interaction of alcohol with other drugs and nutrients. Implication for the therapy of alcoholic liver disease.","Lieber",2081478,"Interaction of alcohol with other drugs and nutrients. Implication for the therapy of alcoholic liver disease.    Abstract:   Two decades of research in ethanol metabolism have culminated in the molecular elucidation of an ethanol-inducible cytochrome P450 (P450IIE1) which is not only involved with ethanol metabolism and ethanol tolerance, but also with the activation of a number of xenobiotics. The unique ability of P450IIE1 to activate xenobiotic agents now appears to be responsible for the increased susceptibility of the heavy drinker to hepatotoxic industrial solvents, commonly used drugs, over-the-counter medications and chemical carcinogens. It also explains some of the interaction of ethanol with nutritional factors, such as hepatic vitamin A: enhanced microsomal degradation of retinoids (together with hepatic mobilisation) promotes depletion. Treatment, however, is complicated by the fact that ethanol also enhances the toxicity of excess vitamin A. All pathways of ethanol metabolism result in the production of acetaldehyde, the toxicity of which has been reviewed (Lieber 1982). New aspects discussed here include the formation of acetaldehyde-protein adducts and an associated immune response that may play a pathogenic role. Also discussed are the implications of ethanol-induced alterations in microtubules, mitochondria and plasma membranes, as they relate, in part, to accompanying acetaldehyde-induced toxicity, to the production of free radicals or to lipid peroxidation-mediated injury associated with glutathione depletion. There is also depletion of S-adenosyl-L-methionine (SAMe). Administration of synthetic SAMe results in a partial correction of the SAMe depletion and a consequent restoration of glutathione levels. Other beneficial effects of SAMe include a significant attenuation of the increase in plasma aspartate transaminase and glutamate dehydrogenase activities. Mitochondrial damage, including giant forms, documented by light and electron microscopy, is also attenuated by SAMe. Thus, the new understanding of the pathophysiology of alcohol-induced liver damage has led to more successful therapy with drugs and nutritional factors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I925,I925)","v":2550213},{"$f":"(LEN($J925) - LEN(SUBSTITUTE(LOWER($J925),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J925) - LEN(SUBSTITUTE(LOWER($J925),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J925) - LEN(SUBSTITUTE(LOWER($J925),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B925:D925)","v":1},1989,"Retinol-binding protein: the serum transport protein for vitamin A.","Blaner",2550213,"Retinol-binding protein: the serum transport protein for vitamin A.    Abstract:   The information available regarding the chemical structure of RBP, the structure of the RBP gene, and the expression of the RBP gene has expanded dramatically in recent years. Still many questions concerning RBP remain to be answered. The longstanding and important questions concerning the possible existence and the biochemical characteristics of the RBP cell surface receptor are in need of resolution. The factors that regulate RBP secretion from the liver still remain to be fully elucidated. Additional information concerning the physiological role of RBP synthesis in extrahepatic tissues is needed. Considering what is now known, it is clear that in the future much intense research will be required before the many important questions regarding the structure, synthesis, secretion, and physiological roles of RBP can be answered."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I926,I926)","v":2542706},{"$f":"(LEN($J926) - LEN(SUBSTITUTE(LOWER($J926),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J926) - LEN(SUBSTITUTE(LOWER($J926),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J926) - LEN(SUBSTITUTE(LOWER($J926),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B926:D926)","v":1},1989,"Hepatocellular carcinoma: molecular biology of its growth and relationship to hepatitis B virus infection.","Di Bisceglie",2542706,"Hepatocellular carcinoma: molecular biology of its growth and relationship to hepatitis B virus infection.    Abstract:   Hepatocellular carcinoma is a very common tumor worldwide and is associated with high mortality rates. Evidence that the development of hepatocellular carcinoma is related to chronic HBV infection has accumulated from epidemiologic studies, information from animal and cell culture models, and molecular biologic evidence that HBV components can be found within hepatocellular carcinoma tissue. Integration of HBV DNA within host liver cell chromosomes may be a crucial step in the development of hepatocellular carcinoma. Integration is associated with disruption of both structure and function of DNA at the site of integration. The study of individual examples of HBV DNA integration in hepatocellular carcinoma tissue illustrates possible mechanisms of hepatocarcinogenesis by HBV. In many cases, activation of various growth factors has been found in association with HBV DNA integration including IGF II, oncogenes such as c-myc, and novel growth factors such as the retinoic acid receptor. A clearer understanding of the mechanisms involved may allow for possible therapeutic interventions in the future, or perhaps even the prevention of hepatocellular carcinoma."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I927,I927)","v":2660707},{"$f":"(LEN($J927) - LEN(SUBSTITUTE(LOWER($J927),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J927) - LEN(SUBSTITUTE(LOWER($J927),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J927) - LEN(SUBSTITUTE(LOWER($J927),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B927:D927)","v":1},1989,"[Ossification of the antibrachial interosseous membrane caused by etretinate].","Zabarino",2660707,"[Ossification of the antibrachial interosseous membrane caused by etretinate].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I928,I928)","v":2645591},{"$f":"(LEN($J928) - LEN(SUBSTITUTE(LOWER($J928),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J928) - LEN(SUBSTITUTE(LOWER($J928),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J928) - LEN(SUBSTITUTE(LOWER($J928),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B928:D928)","v":1},1989,"Lipid metabolism and retinoid therapy.","Marsden",2645591,"Lipid metabolism and retinoid therapy.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I929,I929)","v":2645589},{"$f":"(LEN($J929) - LEN(SUBSTITUTE(LOWER($J929),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J929) - LEN(SUBSTITUTE(LOWER($J929),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J929) - LEN(SUBSTITUTE(LOWER($J929),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B929:D929)","v":1},1989,"Retinoids: toxicology and teratogenicity to date.","Teelmann",2645589,"Retinoids: toxicology and teratogenicity to date.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I930,I930)","v":2645587},{"$f":"(LEN($J930) - LEN(SUBSTITUTE(LOWER($J930),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J930) - LEN(SUBSTITUTE(LOWER($J930),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J930) - LEN(SUBSTITUTE(LOWER($J930),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B930:D930)","v":1},1989,"Liver toxicity of retinoid therapy.","Roenigk",2645587,"Liver toxicity of retinoid therapy.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I931,I931)","v":3054577},{"$f":"(LEN($J931) - LEN(SUBSTITUTE(LOWER($J931),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J931) - LEN(SUBSTITUTE(LOWER($J931),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J931) - LEN(SUBSTITUTE(LOWER($J931),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B931:D931)","v":1},1988,"[Skeletal abnormalities caused by etretinate].","de Groot",3054577,"[Skeletal abnormalities caused by etretinate].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I932,I932)","v":2971690},{"$f":"(LEN($J932) - LEN(SUBSTITUTE(LOWER($J932),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J932) - LEN(SUBSTITUTE(LOWER($J932),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J932) - LEN(SUBSTITUTE(LOWER($J932),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B932:D932)","v":1},1988,"Use of oral and topical agents for acne in pregnancy.","Rothman",2971690,"Use of oral and topical agents for acne in pregnancy.    Abstract:   Dermatologists frequently are consulted by a pregnant patient or a woman of childbearing age who desires acne therapy. Because there are no published studies in which women took acne medications throughout pregnancy, information about safety must be obtained indirectly from studies in which the agents were taken for another indication during some portion of pregnancy. Oral tetracycline is associated with maternal liver toxicity and deciduous tooth staining in the infant, and tetracycline occasionally has been associated with other congenital anomalies. Maternal isotretinoin ingestion is associated with major craniofacial and cardiac deformities, as well as other congenital anomalies. Erythromycin, however, appears to be safe. Topical acne medications never have been implicated as a cause of fetal deformities in human beings. Dermatologists should be aware of potential toxic and teratogenic effects of acne medicines before prescribing them to women of childbearing age. Prompt reporting of adverse effects is encouraged."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I933,I933)","v":3315935},{"$f":"(LEN($J933) - LEN(SUBSTITUTE(LOWER($J933),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J933) - LEN(SUBSTITUTE(LOWER($J933),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J933) - LEN(SUBSTITUTE(LOWER($J933),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B933:D933)","v":1},1987,"The role of hepatic fat-storing (stellate) cells in retinoid metabolism.","Hendriks",3315935,"The role of hepatic fat-storing (stellate) cells in retinoid metabolism.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I934,I934)","v":3331726},{"$f":"(LEN($J934) - LEN(SUBSTITUTE(LOWER($J934),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J934) - LEN(SUBSTITUTE(LOWER($J934),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J934) - LEN(SUBSTITUTE(LOWER($J934),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B934:D934)","v":1},1987,"Hepatic retinol metabolism: role of the various cell types.","Blomhoff",3331726,"Hepatic retinol metabolism: role of the various cell types.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I935,I935)","v":3106031},{"$f":"(LEN($J935) - LEN(SUBSTITUTE(LOWER($J935),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J935) - LEN(SUBSTITUTE(LOWER($J935),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J935) - LEN(SUBSTITUTE(LOWER($J935),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B935:D935)","v":1},1987,"Microsomal ethanol-oxidizing system.","Lieber",3106031,"Microsomal ethanol-oxidizing system.    Abstract:   Advances in our knowledge of the microsomal metabolism of ethanol enable us to understand a number of complications that develop in the alcoholic. After chronic ethanol consumption, microsomal ethanol-oxidizing system (MEOS) activity increases with an associated rise in microsomal cytochrome P-450, including a form different from that induced by phenobarbital and methylcholanthrene and which has a high affinity for ethanol, as shown in reconstituted systems. The role of this MEOS in vivo and its increase after chronic ethanol consumption was most conclusively shown in alcohol dehydrogenase-negative deer mice. Microsomal induction is also associated with enhanced metabolism of other drugs, resulting in metabolic drug tolerance. Furthermore, there is increased conversion to toxic metabolites of known hepatotoxic agents (such as CCl4), which may explain the enhanced susceptibility of alcoholics to the toxicity of industrial solvents. Furthermore, the ethanol-induced form of cytochrome P-450 has a high capacity for the conversion to toxic metabolites of some commonly used drugs, such as acetaminophen, and also carcinogens, such as dimethylnitrosamine which is activated at concentrations much lower than those required for other microsomal inducers. Moreover, catabolism of retinol is accelerated through a newly discovered microsomal pathway, thereby contributing to hepatic vitamin A depletion and possibly vitamin A toxicity. There is also induction of microsomal enzymes involved in lipoprotein production, resulting in hyperlipemia. Contrasting with the chronic effects of ethanol consumption, acutely, ethanol inhibits the metabolism of other drugs through competition for an at least partially shared microsomal detoxification pathway."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I936,I936)","v":3540970},{"$f":"(LEN($J936) - LEN(SUBSTITUTE(LOWER($J936),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J936) - LEN(SUBSTITUTE(LOWER($J936),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J936) - LEN(SUBSTITUTE(LOWER($J936),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B936:D936)","v":1},1986,"Update on the effects of vitamins A, C, and E and selenium on carcinogenesis.","Birt",3540970,"Update on the effects of vitamins A, C, and E and selenium on carcinogenesis.    Abstract:   The effects of vitamins A, C, and E and of selenium on carcinogenesis are briefly summarized and updated. These vitamins and minerals were selected because they have been studied extensively in recent years with a variety of carcinogenesis models. The consumption of vitamin A and its precursors (carotenoids) has been negatively correlated with cancer at a number of sites, particularly the lung. Animal investigations on vitamin A involvement in carcinogenesis have generally been of three types: those assessing the effect of vitamin A deficiency, the effect of excess vitamin A, or the effect of supplementation with synthetic analogs of vitamin A. Vitamin A deficiency had no effect on salivary gland carcinogenesis, enhanced urinary bladder, lung, and liver carcinogenesis, and inhibited colon carcinogenesis. Excess of various forms of vitamin A enhanced or inhibited skin tumorigenesis, inhibited mammary carcinogenesis in rats (but not in mice), and carcinogenesis of the forestomach, liver, and urinary bladder (with one model, but not with another), or enhanced or did not influence lung carcinogenesis. Vitamin A analogs have enhanced or inhibited skin tumorigenesis, inhibited salivary gland, mammary, and urinary bladder carcinogenesis, enhanced tracheal and liver carcinogenesis, and either enhanced or inhibited pancreas carcinogenesis, depending upon the model employed. Although retinoids have been shown to inhibit carcinogenesis at many sites, numerous negative studies have been reported and some reports have indicated enhanced carcinogenesis. The most convincing evidence for the involvement of vitamin C in cancer prevention is the ability of ascorbic acid to prevent formation of nitrosamine and of other N-nitroso compounds. In addition vitamin C supplementation was shown to inhibit skin, nose, tracheal, lung, and kidney carcinogenesis, to either not influence or enhance skin, mammary gland, and colon carcinogenesis, and to enhance urinary bladder carcinogenesis, when given as sodium ascorbate, but not when given as ascorbic acid. Like vitamin C, vitamin E can inhibit nitrosation. Vitamin E was shown to inhibit skin, cheek pouch, and forestomach carcinogenesis, to enhance or inhibit colon carcinogenesis, and to have no effect on or to inhibit mammary gland carcinogenesis, depending upon the method of vitamin E administration or the level of dietary selenium or dietary fat. Selenium effects on carcinogenesis have been recently reviewed and the present discussion only updates this area by indicating that enhancement of carcinogenesis by dietary selenium supplements has been observed in the liver, pancreas, and skin.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I937,I937)","v":3772906},{"$f":"(LEN($J937) - LEN(SUBSTITUTE(LOWER($J937),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J937) - LEN(SUBSTITUTE(LOWER($J937),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J937) - LEN(SUBSTITUTE(LOWER($J937),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B937:D937)","v":1},1986,"Contraceptive steroid effects on nonreproductive organ systems.","Corson",3772906,"Contraceptive steroid effects on nonreproductive organ systems.    Abstract:   Oral contraceptives affect many organ systems in addition to the reproductive tract. In some cases the alteration is just a clinical laboratory test result value; in others it represents a true alteration in metabolism, with the induction of increased enzyme activity. Even with the markedly reduced steroid content of todays oral contraceptives, the practitioner must continue to be aware of these potential and real effects on nonreproductive organ systems. How oral contraceptives (OCs) affect the nonreproductive organ systems depends on both the dose and choice of the estrogenic and progestational components and the interaction between the 2. Several animal model systems have been used to measure the potencies of these agents and their estrogenic-androgenic metabolic effects. These test results have been combined with human data from delay-of-menses tests and gonadotropin-suppression studies to differentiate between commercially available combinations. There has been a tendency to place less importance on animal studies because the data correlate poorly with human experience. Ongoing studies provide particularly valuable information. In a study conducted at the Northwest Lipid Research Clinic at the University of Washington, Seattle, the clinical chemistries of women using OCs and replacement estrogen were compared with those of nonusers. OC users and those on estrogen replacement therapy had lower levels of alkaline phosphates than nonusers when adjusted age-specific values were compared. Mean SGOT and bilirubin levels were statistically lower than in OC users. Knopp, with the same group, also investigated the effects of pregnancy and OC use on clinical serum chemistry. OC users and women who were 36 weeks pregnant were compared with nonpregnant women who did not use OCs. Total plasma bilirubin concentration was lower in OC users (29%) and pregnant women (32%). Plasma glucose levels showed a wider variation: 3% lower in OC users and 17% lower in pregnant women as compared with the controls. Discordancy was noted for SGOT levels, with a 9% decrease in OC users but a 27% increase in pregnancy. Commonly used biochemical indexes are influenced differently by the estrogen and progestin components of the pill. Yet, even recently published longitudinal studies evaluated doses no longer commonly used. Because some of these changes seem to be dose related in part, it is necessary to continue to study the newer preparations. In 1975, Wynn reviewed the issue of OC use and vitamins. He noted that vitamin A was increased 30-80% in OC users as a consequence of an estrogen-mediated increase in retinol-binding protein. Thiamine (B1) and pyridoxine (B6) were decreased; vitamin C was decreased by 30-40% in OC users but not enough to reach deficiency ranges. In 1966 Shearman called attention to post-pill amenorrhea. 9 of 86 patients with secondary amenorrhea had experienced the onset after cessation of OC use. Conversely, in 1977 Jacobs et al. analyzed 131 consecutive cases of secondary amenorrhea and concluded that OC use did not cause that disorder. Dickey and Berger discussed the incidence of post-pill amenorrhea over various time periods and reported an estimated 2-2.6% at 6 months after cessation of OCs. Bennion et al. demonstrated the effect of OCs on bile composition in 22 women; OCs increased gall bladder bile cholesterol saturation. Because OCs markedly decrease the ovarian production of androgens, decrease adrenal production of the precursors, and increase sex-binding globulin, its therapeutic effect is broad based."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I938,I938)","v":3537868},{"$f":"(LEN($J938) - LEN(SUBSTITUTE(LOWER($J938),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J938) - LEN(SUBSTITUTE(LOWER($J938),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J938) - LEN(SUBSTITUTE(LOWER($J938),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B938:D938)","v":1},1986,"The enzymes and kinetics of hepatic retinol metabolism.","Corson",3537868,"The enzymes and kinetics of hepatic retinol metabolism.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I939,I939)","v":3535154},{"$f":"(LEN($J939) - LEN(SUBSTITUTE(LOWER($J939),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J939) - LEN(SUBSTITUTE(LOWER($J939),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J939) - LEN(SUBSTITUTE(LOWER($J939),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B939:D939)","v":1},1986,"[Etretinate and the prevention of skin cancers].","Verret",3535154,"[Etretinate and the prevention of skin cancers].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I940,I940)","v":3515480},{"$f":"(LEN($J940) - LEN(SUBSTITUTE(LOWER($J940),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J940) - LEN(SUBSTITUTE(LOWER($J940),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J940) - LEN(SUBSTITUTE(LOWER($J940),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B940:D940)","v":1},1986,"[Retinoids in dermatology].","Quevrin",3515480,"[Retinoids in dermatology].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I941,I941)","v":2871933},{"$f":"(LEN($J941) - LEN(SUBSTITUTE(LOWER($J941),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J941) - LEN(SUBSTITUTE(LOWER($J941),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J941) - LEN(SUBSTITUTE(LOWER($J941),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B941:D941)","v":1},1986,"Risks for hyperlipidemia.","Nestruck",2871933,"Risks for hyperlipidemia.    Abstract:   The predisposition for the development of hyperlipidemia rests almost equally on genetic and environmental factors and their interplay. Because one of the least understood factors is the duration of exposure to risk, the authors have chosen to review here some of the genetic factors and some of the relatively long-term environmental factors, such as diet and drug therapies, that are known to increase the risk of hyperlipidemia and likely the predisposition to cardiovascular disease. Some of the genetic factors and environmental factors such as diet and drug therapies that are known to increase the risk of hyperlipidemia and possibly the predisposition to cardiovascular disease are reviewed. The cholesterol associated with the low-density lipoproteins (LDL), accounting for 60-75% of the plasma levels, is responsible for the powerful and direct relationship which exists between plasma cholesterol and coronary heart disease. Also, the cholesterol that accumulates in atheromatous lesions is derived primarily from plasma LDL. Hyperlipidemia is defined by elevated levels of the plasma levels; the risk for atherosclerosis is associated with the classification types IIa, IIb, III, and possibly IV, a classification system based on phenotypic manifestations of increased lipoprotein fractions. The Lipid Research Clinics Program reports data on plasma lipid and lipoprotein cholesterol distributions of a large-scale screening of white men and women (both with and without sex hormone usage) aged 20-59 years in the US. They found age-related trends for rising triglycerides and cholesterol with differences between the sexes clearly demonstrated. It has been established that normolipemic individuals are not immune to the development of atherosclerosis. The recent focus on the apolipoprotein moieties has revealed a number of normolipemic dyslipoproteinemias associated with tissue lipid infiltration. Multifactorial population studies provide a strong case for the powerful role of the environment, i.e., predominantly dietary intake of total fat, saturated fat, saturated fats, and calories, in hyperlipidemia. According to the Seven Countries Study, populations with higher levels of cholesterol and LDL cholesterol (and increased atherosclerosis) have saturated fat intakes of 10% or more of calories. Migration studies of Japanese populations in Japan and in the US also show the influence of diet. As was shown early on, oral contraceptive (OC) use predisposes to the development of hyperlipidemia. OCs also predispose to other cardiovascular risk factors that, when combined with smoking, bring about a greatly magnified risk for myocardial infarction. Also reviewed in terms of their effect on the lipoprotein profile are antihypertensive therapies, retinoids, and hypolipidemic agents. Regarding genetic predisposition, single-gene mutations in apoproteins, lipoproteins, and some of the enzymes involved in lipoprotein may underlie disorders of hyperlipoproteinemia or hypolipoproteinemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I942,I942)","v":4031157},{"$f":"(LEN($J942) - LEN(SUBSTITUTE(LOWER($J942),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J942) - LEN(SUBSTITUTE(LOWER($J942),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J942) - LEN(SUBSTITUTE(LOWER($J942),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B942:D942)","v":1},1985,"Nethertons syndrome. Report of a case and review of the literature.","Greene",4031157,"Nethertons syndrome. Report of a case and review of the literature.    Abstract:   A patient with Nethertons syndrome who was followed since birth had previously been diagnosed as having Leiners disease and acrodermatitis enteropathica; the disorder was recognized clinically when the patient was 20 years of age. Therapy with 13-cis-retinoic acid significantly aggravated the ichthyosis and induced increased fragility of the skin. This patient also had an intermittent aminoaciduria with clinical investigations that showed normal renal function. Furthermore, the aminoaciduria resolved spontaneously after the discontinuance of topically applied corticosteroids. The normal results of clinical studies and a review of the literature suggest that the aminoaciduria may have been artifactual because excess absorption of topically applied corticosteroids directly affects the renal tubules and impairs renal reabsorption or enhances the free excretion of amino acids. We review forty-two other cases of Nethertons syndrome in the literature and reaffirm the significance of associated ichthyosis, atopy, trichorrhexis invaginata, and other findings in this unique syndrome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I943,I943)","v":2995886},{"$f":"(LEN($J943) - LEN(SUBSTITUTE(LOWER($J943),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J943) - LEN(SUBSTITUTE(LOWER($J943),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J943) - LEN(SUBSTITUTE(LOWER($J943),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B943:D943)","v":1},1985,"Effect of vitamin A status on retinoid-binding protein levels in rat tissues.","Warnes",2995886,"Effect of vitamin A status on retinoid-binding protein levels in rat tissues.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I944,I944)","v":3881285},{"$f":"(LEN($J944) - LEN(SUBSTITUTE(LOWER($J944),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J944) - LEN(SUBSTITUTE(LOWER($J944),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J944) - LEN(SUBSTITUTE(LOWER($J944),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B944:D944)","v":1},1985,"Metabolic effects of alcohol.","Mezey",3881285,"Metabolic effects of alcohol.    Abstract:   The metabolic effects of ethanol are due to a direct action of ethanol or its metabolites, changes in the redox state occurring during its metabolism, and modifications of the effects of ethanol by nutritional factors. Ethanol causes hyperglycemia or hypoglycemia depending on whether glycogen stores are adequate, inhibits protein synthesis, and results in fatty liver and in elevations in serum triglyceride levels. Increases in high-density lipoprotein cholesterol after ethanol ingestion may explain the lower risk of myocardial infarction and death from coronary disease after moderate drinking. Increases in serum lactate, resulting from the increased NADH/NAD+ ratio, and hyperuricemia, most likely the result of increased turnover of adenine nucleotides, are common transient effects of ethanol ingestion. Causes of vitamin deficiencies in alcoholism are decreased dietary intake, decreased intestinal absorption, and alterations in vitamin metabolism. Ethanol decreases thiamine absorption and decreases the enterohepatic circulation of folate. Acetaldehyde increases the degradation of pyridoxal 5-phosphate by displacing it from its binding protein and making it susceptible to hydrolysis by membrane-bound alkaline phosphatase. Ethanol decreases hepatic vitamin A concentration and its conversion to active retinal, and modifies renal metabolism of vitamin D."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I945,I945)","v":2865858},{"$f":"(LEN($J945) - LEN(SUBSTITUTE(LOWER($J945),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J945) - LEN(SUBSTITUTE(LOWER($J945),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J945) - LEN(SUBSTITUTE(LOWER($J945),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B945:D945)","v":1},1985,"[Metabolic aspects of alcoholic liver damage: 1984/1985 update. 2: Microsomal enzyme induction and hypermetabolism].","Seitz",2865858,"[Metabolic aspects of alcoholic liver damage: 1984/1985 update. 2: Microsomal enzyme induction and hypermetabolism].    Abstract:   In the second part of this review, the effect of ethanol on hepatic microsomal enzymes is primarily discussed. Since ethanol is metabolized via a cytochrome P-450 dependent biotransformation system (MEOS) in hepatic microsomes, the microsomal enzyme induction in the smooth endoplasmic reticulum has to be considered as an adaptive response. This enzyme induction results in an accelerated metabolism of ethanol. However, subsequently, the negative consequences of such a microsomal enzyme induction are predominant. Acetaldehyde production increases and oxygen consumption is enhanced leading to pericentral (perivenular) hypoxia. In addition, microsomal enzyme induction results in an enhanced metabolism of drugs, xenobiotics and hepatotoxins and thus to an increased production of toxic intermediates. Also procarcinogens are activated to a higher degree in microsomes following chronic ethanol consumption. Subsequently, an enhanced microsomal metabolism of vitamin A may explain the low serum concentrations of this vitamin in the alcoholic and may lead to toxic metabolites of retinol. The quantitative role of an enhanced reoxidation of NADH responsible for an increased oxidation of alcohol following chronic ethanol ingestion has still to be determined. However, according to recent investigations, a thyroid hormone induced hypermetabolism seems unlikely."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I946,I946)","v":6369133},{"$f":"(LEN($J946) - LEN(SUBSTITUTE(LOWER($J946),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J946) - LEN(SUBSTITUTE(LOWER($J946),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J946) - LEN(SUBSTITUTE(LOWER($J946),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B946:D946)","v":1},1984,"Vitamin A and retinoids in health and disease.","Goodman",6369133,"Vitamin A and retinoids in health and disease.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I947,I947)","v":6428773},{"$f":"(LEN($J947) - LEN(SUBSTITUTE(LOWER($J947),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J947) - LEN(SUBSTITUTE(LOWER($J947),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J947) - LEN(SUBSTITUTE(LOWER($J947),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B947:D947)","v":1},1984,"Implications of nutritional status on human biochemistry, physiology, and health.","Sauberlich",6428773,"Implications of nutritional status on human biochemistry, physiology, and health.    Abstract:   Optimum nutrition is the level of intake that should promote the highest level of health. Although excess caloric intake will lead to obesity, a deficit in nutrition may result in a tissue depletion of essential nutrients that can lead to biochemical changes and eventually to clinical signs and symptoms. Nutrition requirements may differ according to sex, age, activity, or physiological state and can be influenced by drugs, smoking, alcohol, and other factors. With ever-increasing sedentary life styles and less physically demanding jobs, the resulting reduced caloric requirements have made it more difficult to make nutritionally sound food choices. Nutrition is the single most important component of preventive health care. Diet has been associated with cancer, heart disease, diabetes, stroke and hypertension, arteriosclerosis, and cirrhosis of the liver. The ability of the human to respond to stresses, such as altitude, heat, trauma, surgery, and infection can be influenced by nutritional status. Nutritional status is reflected in a variety of metabolic processes that provide the basis for a number of methods for its assessment."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I948,I948)","v":6380538},{"$f":"(LEN($J948) - LEN(SUBSTITUTE(LOWER($J948),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J948) - LEN(SUBSTITUTE(LOWER($J948),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J948) - LEN(SUBSTITUTE(LOWER($J948),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B948:D948)","v":1},1984,"The function and metabolism of vitamin K.","Olson",6380538,"The function and metabolism of vitamin K.    Abstract:   Since the discovery of gamma-carboxyglutamic acid a decade ago, great progress has been made in advancing our knowledge of the function and metabolism of vitamin K. The distribution of this new amino acid in proteins of diverse origin and the presence of the vitamin K-dependent carboxylase in diverse tissues have emphasized the widespread significance in biology of a new triad: vitamin K, Gla, and calcium. New knowledge has been obtained on the importance of the utilization and reutilization of vitamin K, whose body pools are extremely low for a fat-soluble vitamin, for the posttranslational carboxylation of peptide-bound glutamate residues in the vitamin K-dependent proteins. The regulation of the activation of the vitamin K-vitamin K-epoxide cycle by drugs and nutrients appears to be the key to controlling the synthesis of vitamin K-dependent proteins, eight of which are involved in blood coagulation. The purification of the vitamin K-dependent gamma-glutamyl carboxylase has turned out to be a more formidable task than anyone had imagined. Many of the questions about its complicated mechanism, utilizing as it does four substrates (KH2, O2, CO2, and a Glu-containing peptide), cannot be answered until the enzyme is homogeneous. Basically, the vitamin K-dependent carboxylase system consists of a specialized microsomal electron transport system coupled to a carbon dioxide fixation. The reaction does not require ATP but apparently utilizes the energy of vitamin KH2 oxidation to perform the chemical work required in Gla synthesis. Why a quinone is employed in this system when other mechanisms exist for CO2 fixation is still mysterious unless the whole process goes by one electron transport. Whether the final CO2 addition to the gamma-methylene group of glutamic acid is a radical reaction is unsettled. Since this enzyme is an intrinsic membrane-bound protein, the scientific attack on its structure and function is at one of the present frontiers of molecular biology. A view of the synthesis of vitamin K-dependent proteins in the RER is shown in Figure 9. Finally, the nutritional requirements for vitamin K in humans are unknown. An unknown fraction of vitamin K in humans is derived from menaquinone biosynthesis in the intestinal flora. Contributions from diet and biosynthesis have not yet been quantitated. Sensitive HPLC methods for measuring plasma phylloquinone are now available, and related methods for measuring long-chain menaquinones can be developed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I949,I949)","v":6364354},{"$f":"(LEN($J949) - LEN(SUBSTITUTE(LOWER($J949),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J949) - LEN(SUBSTITUTE(LOWER($J949),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J949) - LEN(SUBSTITUTE(LOWER($J949),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B949:D949)","v":1},1983,"Adverse effects of large doses of vitamin A and retinoids.","Olson",6364354,"Adverse effects of large doses of vitamin A and retinoids.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I950,I950)","v":6355574},{"$f":"(LEN($J950) - LEN(SUBSTITUTE(LOWER($J950),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J950) - LEN(SUBSTITUTE(LOWER($J950),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J950) - LEN(SUBSTITUTE(LOWER($J950),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B950:D950)","v":1},1983,"[Retinol-binding protein (RBP)].","Kanai",6355574,"[Retinol-binding protein (RBP)].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I951,I951)","v":6347683},{"$f":"(LEN($J951) - LEN(SUBSTITUTE(LOWER($J951),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J951) - LEN(SUBSTITUTE(LOWER($J951),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J951) - LEN(SUBSTITUTE(LOWER($J951),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B951:D951)","v":1},1983,"Overview of tumor promotion in animals.","Slaga",6347683,"Overview of tumor promotion in animals.    Abstract:   Our present understanding of two-stage carcinogenesis encompasses almost four decades of research. Evidence for chemical promotion or cocarcinogenesis was first provided by Berenblum, who reported that a regimen of croton oil (weak or noncarcinogenic) applied alternately with small doses of benzo(a)pyrene (BP) to mouse skin induced a larger number of tumors than BP alone. Subsequently, Moltram found that a single subcarcinogenic dose of BP followed by multiple applications of croton oil could induce a large number of skin tumors. These investigations as well as a number of others, such as Boutwell, Van Duuren and Hecker, were responsible in defining many important aspects of the initiation and promotion of two-stage carcinogenesis. The initiation stage in mouse skin requires only a single application of either a direct-acting carcinogen or a procarcinogen and is essentially an irreversible step which as data suggests probably involves a somatic cell mutation. The promotion stage in mouse skin can be accomplished by a wide variety of weak or noncarcinogenic agents and is initially reversible later becoming irreversible. Current information suggests that skin tumor promoters are not mutagenic but bring about a number of important epigenetic changes, such as epidermal hyperplasia, and an increase in polyamines, prostaglandins and dark basal keratinocytes as well as other embryonic conditions. Recently, tumor promotion in mouse skin was shown to consist of at least two stages, in which each stage can be accomplished by either a known promoter or a weak or nonpromoting agent. Some of the important characteristics of the first stage of promotion are: (1) only one application of a first-stage promoter, such as phorbol ester tumor promoters, calcium ionophore A23187, hydrogen peroxide and wounding is needed; (2) the action is partially irreversible; (3) an increase in dark basal keratinocytes and prostaglandins is important; and (4) such an increase can be inhibited by antiinflammatory steroids and protease inhibitors. The second stage of promotion is initially reversible but later becomes irreversible. Polyamines and epidermal cell proliferation are important events in the second stage of promotion. A number of weak or nonpromoting agents, such as mezerein, are effective second-stage promoters which can be counteracted by retinoic acid, antiinflammatory steroids and polyamine synthesis inhibitors. Although skin tumor promotion has been extensively studied in mice, not all strains and stocks of mice are susceptible to phorbol ester tumor promoters. In this regard, the C57BL/6 mice appear to be fairly resistant to phorbol ester tumor promoters. In addition, not all species are equally susceptible to phorbol ester tumor promotion. Recently the generality of the two-stage system of inducing tumors has been shown to exist in a number of experimental carcinogenesis systems, such as the liver, bladder, lung, colon, esophagus, stomach, mammary gland, pancreas and cells in culture. In these systems, a wide variety of promoting agents such as diet, bile acids, hormones, saccharin, tryptophan, phenobarbital, polychlorinated biphenyls, polybrominated biphenyls and butylated hydroxytoluene have been used to accomplish the tumor promotion stage. It is not presently known if other experimental carcinogenesis systems and the induction of human cancer involves a series of stages similar to that in the mouse skin."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I952,I952)","v":6179019},{"$f":"(LEN($J952) - LEN(SUBSTITUTE(LOWER($J952),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J952) - LEN(SUBSTITUTE(LOWER($J952),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J952) - LEN(SUBSTITUTE(LOWER($J952),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B952:D952)","v":1},1982,"Intracellular retinol-binding protein and keratin messenger-RNA: evidence for a nuclear function of vitamin A.","Hemken",6179019,"Intracellular retinol-binding protein and keratin messenger-RNA: evidence for a nuclear function of vitamin A.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I953,I953)","v":6764592},{"$f":"(LEN($J953) - LEN(SUBSTITUTE(LOWER($J953),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J953) - LEN(SUBSTITUTE(LOWER($J953),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J953) - LEN(SUBSTITUTE(LOWER($J953),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B953:D953)","v":1},1982,"[Iatrogenic pathology of the optic nerve].","Hamard",6764592,"[Iatrogenic pathology of the optic nerve].    Abstract:   Iatrogenic pathology of the optic nerve is examined according to a framework which distinguishes direct and indirect effects on the optic nerve. Direct effects due to toxic drugs should be suspected when unexplained, usually bilateral loss of visual acuity occurs. The 3 clinical stages of classical optic toxic neuropathy are 1) anomalies of color vision, 2) loss of visual acuity and narrowing field of vision, and 3) papillary palor corresponding to irreversible optic atrophy. Usually only the 1st stages are reversible, but the reversibility may be incomplete. The list of drugs which can cause such effects is lengthy and includes antiinfectious drugs such as sulfamides and derivatives of hydroxyquinoleins, chloramphenicol especially when used to treat cystic fibrosis of the pancreas in children, the antituberculins ethambutol in high doses and isoniazide, which occasion particular risks when combined; antiparasitics such as quinine and its derivatives chloroquine and hydroxychloroquine, which cause optic neuropathy through their effect on the retina; arsenic pentavalents such as tryparsamide, quinacrine, trecator and mystatin; drugs affecting the central nervous system such as monoamineoxydase inhibitors, laroxyl, phenothiazine and the barbituates; anticonvulsants such as phenytoin; antimitotics such as vincristine; digitalics, disulfiram; penicillamines, and pexid. The action of lasers on the optic nerve can have a similar effect. The optic nerve may be indirectly damaged during surgical procedures leading to hypotonia, acute ischemia of the head of the optic nerve or embolic accident after a local or regional injection. Damage may also be caused by radiotherapy of intracranial tumors and certain drugs which cause isolated papillary edema or edema associated with headaches, such as Tetracycline, large doses of vitamin A or D, corticoids, and oral contraceptive (OC) pills, which may cause papillary edema through cerebral pseudo-tumors that regress with discontinuation of treatment. This condition has been observed in women with uncontrolled hyperlipidemia. It is probable that an alteration ofaxonal transport is at the basis of the neuropathic mechanisms. The 1st step in therapy is the suppression of the toxin, or at least its discontinuation. Some success has been obtained with vitamin B therapy, corticotherapy, zinc, or isaxonine, depending on the specific condition."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I954,I954)","v":7449242},{"$f":"(LEN($J954) - LEN(SUBSTITUTE(LOWER($J954),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J954) - LEN(SUBSTITUTE(LOWER($J954),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J954) - LEN(SUBSTITUTE(LOWER($J954),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B954:D954)","v":1},1981,"Carotenemia. A review.","Lascari",7449242,"Carotenemia. A review.    Abstract:   Awareness of carotenemia is important to avoid confusion with jaundice and unnecessary diagnostic studies. It is surprising how little information can be found about this relatively common condition in the standard pediatric textbooks. Ingestion of excessive amounts of carrots is the usual cause of carotenemia, but it can also be associated with ingestion of many other yellow vegetables, as well as some green vegetables. Mothers may unknowingly be giving their infants large amounts of carrots in the form of commercial infant food combinations. Carotenemia is a benign condition; vitamin A poisoning does not occur despite massive doses of carotene because the conversion of carotene to vitamin A is slow. Hypothyroidism, diabetes mellitus, hepatic and renal diseases may be associated with carotenemia, but are not caused by ingestion of carotene. The absence of yellow pigment in the sclera and oral cavities distinguishes carotenemia from jaundice. A similar disorder, lycopenemia, is associated with an orange-yellow skin pigmentation as a result of ingestion of large amounts of tomatoes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I955,I955)","v":7009064},{"$f":"(LEN($J955) - LEN(SUBSTITUTE(LOWER($J955),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J955) - LEN(SUBSTITUTE(LOWER($J955),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J955) - LEN(SUBSTITUTE(LOWER($J955),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B955:D955)","v":1},1981,"The nutrition significance of sucrose consumption, 1970-1980.","Lee",7009064,"The nutrition significance of sucrose consumption, 1970-1980.    Abstract:   Sucrose consumption is a controversial issue. Part of the difficulty arises because of inadequate knowledge about the actual consumption of populations, as well as individuals within a population. Data on the sucrose content of foods are lacking. This review presents information published in the 1970s on these topics as well as current research and thinking about possible relationships of sucrose consumption to dental caries, cardiovascular disease, diabetes, obesity, and other disease conditions. Current attitudes toward recommendations concerning sugar consumption in the U.S. Dietary Goals are examined, as are data on the use of sugar as a fortification vehicle."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I956,I956)","v":7001892},{"$f":"(LEN($J956) - LEN(SUBSTITUTE(LOWER($J956),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J956) - LEN(SUBSTITUTE(LOWER($J956),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J956) - LEN(SUBSTITUTE(LOWER($J956),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B956:D956)","v":1},1980,"Vitamin A and zinc metabolism in alcoholism.","Russell",7001892,"Vitamin A and zinc metabolism in alcoholism.    Abstract:   Vitamin A and zinc metabolism are affected both by ethanol and by hepatic cirrhosis. Ethanol causes abnormal dark adaptation by acting as a competitive inhibitor with retinol for alcohol dehydrogenase in the eye. In animals oral ethanol intake results in increased losses of zinc by the urinary and fecal routes. Vitamin A malnutrition in cirrhotics may be caused by poor diet, malabsorption, decreased hepatic vitamin A uptake, and decreased hepatic storage capacity for vitamin A. In some cirrhotic patients zinc deficiency and or protein deficiency may limit the ability to respond to vitamin A. Combined vitamin A and zinc deficiencies are common in cirrhotics and either may result in abnormal dark adaptation or impaired taste and smell. The interaction of these two micro-nutrients must be kept in mind by the clinician caring for alcoholic or alcoholic cirrhotic patients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I957,I957)","v":333319},{"$f":"(LEN($J957) - LEN(SUBSTITUTE(LOWER($J957),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J957) - LEN(SUBSTITUTE(LOWER($J957),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J957) - LEN(SUBSTITUTE(LOWER($J957),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B957:D957)","v":1},1977,"Retinol binding protein in man and rat.","Bazyka",333319,"Retinol binding protein in man and rat.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I958,I958)","v":325439},{"$f":"(LEN($J958) - LEN(SUBSTITUTE(LOWER($J958),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J958) - LEN(SUBSTITUTE(LOWER($J958),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J958) - LEN(SUBSTITUTE(LOWER($J958),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B958:D958)","v":1},1977,"Retinol-linked sugars in glycoprotein synthesis.","Wolf",325439,"Retinol-linked sugars in glycoprotein synthesis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I959,I959)","v":323066},{"$f":"(LEN($J959) - LEN(SUBSTITUTE(LOWER($J959),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J959) - LEN(SUBSTITUTE(LOWER($J959),LOWER(C$3),\"\")))/LEN(C$3)","v":1},{"$f":"(LEN($J959) - LEN(SUBSTITUTE(LOWER($J959),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B959:D959)","v":1},1977,"Interrelationships of mycotoxins with nutrition.","Hamilton",323066,"Interrelationships of mycotoxins with nutrition.    Abstract:   Mycotoxins interact with lipid, protein, carbohydrate, and vitamin nutrition. Diets high in lipid have a mortality-sparing effect against aflatoxicosis and, if high in unsaturated fatty acids, a growth-sparing effect. Aflatoxicosis causes a lipid malabsorption syndrome coupled with decreased digestive enzymes and bile salt excretion, a decreased synthesis of fatty acids, and impaired transport. Deficiencies of vitamins A, D, or riboflavin make animals more sensitive to aflatoxin while a thiamin deficiency has the opposite effect. Interaction with vitamins E and K has not been clearly demonstrated as yet. Mycotoxins increase the protein requirements of animals and apparently alter the enzymes that regulate glycogen catabolism and neogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I960,I960)","v":787995},{"$f":"(LEN($J960) - LEN(SUBSTITUTE(LOWER($J960),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J960) - LEN(SUBSTITUTE(LOWER($J960),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J960) - LEN(SUBSTITUTE(LOWER($J960),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B960:D960)","v":1},1976,"Retinol-binding protein, prealbumin, and vitamin A transport.","Goodman",787995,"Retinol-binding protein, prealbumin, and vitamin A transport.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I961,I961)","v":4610746},{"$f":"(LEN($J961) - LEN(SUBSTITUTE(LOWER($J961),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J961) - LEN(SUBSTITUTE(LOWER($J961),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J961) - LEN(SUBSTITUTE(LOWER($J961),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B961:D961)","v":1},1974,"Diabetes and skin-a review.","Haroon",4610746,"Diabetes and skin-a review.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I962,I962)","v":4617402},{"$f":"(LEN($J962) - LEN(SUBSTITUTE(LOWER($J962),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J962) - LEN(SUBSTITUTE(LOWER($J962),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J962) - LEN(SUBSTITUTE(LOWER($J962),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B962:D962)","v":1},1974,"Vitamin A metabolism and requirements in the human studied with the use of labeled retinol.","Sauberlich",4617402,"Vitamin A metabolism and requirements in the human studied with the use of labeled retinol.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I963,I963)","v":4617400},{"$f":"(LEN($J963) - LEN(SUBSTITUTE(LOWER($J963),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J963) - LEN(SUBSTITUTE(LOWER($J963),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J963) - LEN(SUBSTITUTE(LOWER($J963),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B963:D963)","v":1},1974,"Distribution of retinol-binding protein in tissues.","Glover",4617400,"Distribution of retinol-binding protein in tissues.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I964,I964)","v":4617398},{"$f":"(LEN($J964) - LEN(SUBSTITUTE(LOWER($J964),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J964) - LEN(SUBSTITUTE(LOWER($J964),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J964) - LEN(SUBSTITUTE(LOWER($J964),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B964:D964)","v":1},1974,"Vitamin A transport and retinol-binding protein metabolism.","Goodman",4617398,"Vitamin A transport and retinol-binding protein metabolism.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I965,I965)","v":4257143},{"$f":"(LEN($J965) - LEN(SUBSTITUTE(LOWER($J965),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J965) - LEN(SUBSTITUTE(LOWER($J965),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J965) - LEN(SUBSTITUTE(LOWER($J965),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B965:D965)","v":1},1971,"Retinoic acid.","Ashton",4257143,"Retinoic acid.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I966,I966)","v":4986874},{"$f":"(LEN($J966) - LEN(SUBSTITUTE(LOWER($J966),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J966) - LEN(SUBSTITUTE(LOWER($J966),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J966) - LEN(SUBSTITUTE(LOWER($J966),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B966:D966)","v":1},1970,"Inhibition of alcohol dehydrogenase by aminophenoxyalkanes: a possible mechanism of their retinotoxicity.","Nimmo-Smith",4986874,"Inhibition of alcohol dehydrogenase by aminophenoxyalkanes: a possible mechanism of their retinotoxicity.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I967,I967)","v":4904797},{"$f":"(LEN($J967) - LEN(SUBSTITUTE(LOWER($J967),LOWER(B$3),\"\")))/LEN(B$3)","v":1},{"$f":"(LEN($J967) - LEN(SUBSTITUTE(LOWER($J967),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J967) - LEN(SUBSTITUTE(LOWER($J967),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B967:D967)","v":1},1969,"[Current methods of the treatment of diabetic retinopathy. (Literature review)].","Mazovetskiĭ",4904797,"[Current methods of the treatment of diabetic retinopathy. (Literature review)].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I968,I968)","v":14124248},{"$f":"(LEN($J968) - LEN(SUBSTITUTE(LOWER($J968),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J968) - LEN(SUBSTITUTE(LOWER($J968),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J968) - LEN(SUBSTITUTE(LOWER($J968),LOWER(D$3),\"\")))/LEN(D$3)","v":1},{"$f":"SUM(B968:D968)","v":1},1963,"NUTRITION IN DIABETES.","STOWERS",14124248,"NUTRITION IN DIABETES.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I969,I969)","v":27498574},{"$f":"(LEN($J969) - LEN(SUBSTITUTE(LOWER($J969),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J969) - LEN(SUBSTITUTE(LOWER($J969),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J969) - LEN(SUBSTITUTE(LOWER($J969),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B969:D969)","v":0},2016,"Dietary supplementation in patients with alcoholic liver disease: a review on current evidence.","Ghorbani",27498574,"Dietary supplementation in patients with alcoholic liver disease: a review on current evidence.    Abstract:    BACKGROUND : Alcoholic liver disease (ALD) is one of the main causes of liver disease worldwide. Although the pathogenesis of ALD has not yet been well elucidated, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species play a pivotal role in the clinical and pathological spectrum of the disease. This review summarizes the existing evidences on dietary supplements considered to have antioxidant, and/or anti-inflammatory properties, and their role in the management of ALD and the proposed mechanisms.  DATA SOURCES : The present study reviewed all studies published in PubMed, ScienceDirect and Scopus, from 1959 to 2015, indicating the role of different dietary supplementation in attenuation of many pathophysiological processes involved in development and progression of ALD. Full-texts of citations were used except for those that were published in languages other than English.  RESULTS : Significant progress has been made to understand the key events and molecular players for the onset and progression of ALD from both experimental and clinical studies; however, there is no successful treatment currently available. The present review discussed the role of a variety of dietary supplements (e.g. vitamin A, carotenoids, vitamins B3, C and E, in addition to antioxidants and anti-inflammatory agents) in treating ALD. It has been shown that supplementation with some carotenoids, vitamin B3, vitamin C, silymarin, curcumin, probiotics, zinc, S-adenosylmethionine and garlic may have potential beneficial effects in animal models of ALD; however, the number of clinical studies is very limited. In addition, supplementation should be accompanied with alcohol cessation.  CONCLUSIONS : Since oxidative stress and inflammation are involved in the pathogenesis of ALD, dietary supplements that can modulate these pathologies could be useful in the treatment of ALD. In addition to alcohol cessation, these supplements have shown beneficial effects on animal models of ALD. Clinical trials are needed to validate the beneficiary role of these supplements in patients with ALD."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I970,I970)","v":27402097},{"$f":"(LEN($J970) - LEN(SUBSTITUTE(LOWER($J970),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J970) - LEN(SUBSTITUTE(LOWER($J970),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J970) - LEN(SUBSTITUTE(LOWER($J970),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B970:D970)","v":0},2016,"Liver toxicity related to herbs and dietary supplements: Online table of case reports. Part 3 of 6.","Brown",27402097,"Liver toxicity related to herbs and dietary supplements: Online table of case reports. Part 3 of 6.    Abstract:    BACKGROUND : No current list of potentially life-threatening, hepatotoxic herbs and dietary supplements based on PubMed case studies exists in a summarized tabular form.  METHODS : Documented case reports of herbs or dietary supplements appearing to contribute to liver injury were used to create a quot;Harmful Herb and Dietary Supplement Listquot; of potentially hepatotoxic herbs and dietary supplements (PubMed, 1966 to May, 2015, and cross-referencing). The spectrum of herbal induced liver injuries (HDSILI) researched included elevated liver enzymes, hepatitis, steatosis, cholestasis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, veno-occlusive disease, acute liver failure requiring a liver transplant, and death.  RESULTS : Over the past 50 years, approximately 19 herbs (minus germander and usnic acid that are no longer sold) and 13 dietary supplements (minus the six no longer sold and vitamin A amp; niacin due to excess) posed a possible risk for liver injures in certain individuals. The top three herbs with the most number of reported publications (but not cases studies) in descending order, were germander, black cohosh, kava extract, and green tea extract.  CONCLUSION : These online tables will contribute to continued Phase IV post marketing surveillance to detect possible liver toxicity cases and serve to forewarn consumers, clinicians, and corporations."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I971,I971)","v":27355911},{"$f":"(LEN($J971) - LEN(SUBSTITUTE(LOWER($J971),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J971) - LEN(SUBSTITUTE(LOWER($J971),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J971) - LEN(SUBSTITUTE(LOWER($J971),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B971:D971)","v":0},2016,"Nutritional supplements for people being treated for active tuberculosis.","Grobler",27355911,"Nutritional supplements for people being treated for active tuberculosis.    Abstract:    BACKGROUND : Tuberculosis and malnutrition are linked in a complex relationship. Tuberculosis may cause undernutrition through increased metabolic demands and decreased intake, and nutritional deficiencies may worsen the disease, or delay recovery by depressing important immune functions. At present, there is no evidence-based nutritional guidance for adults and children being treated for tuberculosis.  OBJECTIVES : To assess the effects of oral nutritional supplements in people being treated with antituberculous drug therapy for active tuberculosis.  SEARCH METHODS : We searched the Cochrane Infectious Disease Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL; Issue 1, 2016), MEDLINE (from 1946 to 4 February 2016), EMBASE (from 1980 to 4 February 2016), LILACS (from 1982 to 4 February 2016), the metaRegister of Controlled Trials (mRCT), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the Indian Journal of Tuberculosis up to 4 February 2016, and checked the reference lists of all included studies.  SELECTION CRITERIA : Randomized controlled trials that compared any oral nutritional supplement given for at least four weeks with no nutritional intervention, placebo, or dietary advice only for people being treated for active tuberculosis. The primary outcomes of interest were all-cause death, and cure at six and 12 months.  DATA COLLECTION AND ANALYSIS : Two review authors independently selected trials for inclusion, and extracted data and assessed the risk of bias in the included trials. We presented the results as risk ratios (RR) for dichotomous variables, and mean differences (MD) for continuous variables, with 95% confidence intervals (CIs). Where appropriate, we pooled data from trials with similar interventions and outcomes. We assessed the quality of the evidence using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach.  MAIN RESULTS : Thirty-five trials, including 8283 participants, met the inclusion criteria of this review. Macronutrient supplementationSix trials assessed the provision of free food, or high-energy supplements. Only two trials measured total dietary intake, and in both trials the intervention increased calorie consumption compared to controls.The available trials were too small to reliably prove or exclude clinically important benefits on mortality (RR 0.34, 95% CI 0.10 to 1.20; four trials, 567 participants, very low quality evidence), cure (RR 0.91, 95% CI 0.59 to 1.41; one trial, 102 participants, very low quality evidence), or treatment completion (data not pooled; two trials, 365 participants, very low quality evidence).Supplementation probably produces a modest increase in weight gain during treatment for active tuberculosis, although this was not seen consistently across all trials (data not pooled; five trials, 883 participants, moderate quality evidence). Two small studies provide some evidence that quality of life may also be improved but the trials were too small to have much confidence in the result (data not pooled; two trials, 134 participants, low quality evidence). Micronutrient supplementationSix trials assessed multi-micronutrient supplementation in doses up to 10 times the dietary reference intake, and 18 trials assessed single or dual micronutrient supplementation.Routine multi-micronutrient supplementation may have little or no effect on mortality in HIV-negative people with tuberculosis (RR 0.86, 95% CI 0.46 to 1.6; four trials, 1219 participants, low quality evidence), or HIV-positive people who are not taking antiretroviral therapy (RR 0.92, 95% CI 0.69 to 1.23; three trials, 1429 participants, moderate quality evidence). There is insufficient evidence to know if supplementation improves cure (no trials), treatment completion (RR 0.99, 95% CI 0.95 to 1.04; one trial, 302 participants, very low quality evidence), or the proportion of people who remain sputum positive during the first eight weeks (RR 0.92, 95% CI 0.63 to 1.35; two trials, 1020 participants, very low quality evidence). However, supplementation may have little or no effect on weight gain during treatment (data not pooled; five trials, 2940 participants, low quality evidence), and no studies have assessed the effect on quality of life.Plasma levels of vitamin A appear to increase following initiation of tuberculosis treatment regardless of supplementation. In contrast, supplementation probably does improve plasma levels of zinc, vitamin D, vitamin E, and selenium, but this has not been shown to have clinically important benefits. Of note, despite multiple studies of vitamin D supplementation in different doses, statistically significant benefits on sputum conversion have not been demonstrated.  AUTHORS CONCLUSIONS : There is currently insufficient research to know whether routinely providing free food, or energy supplements improves tuberculosis treatment outcomes, but it probably improves weight gain in some settings.Although blood levels of some vitamins may be low in people starting treatment for active tuberculosis, there is currently no reliable evidence that routinely supplementing above recommended daily amounts has clinical benefits."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I972,I972)","v":27294593},{"$f":"(LEN($J972) - LEN(SUBSTITUTE(LOWER($J972),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J972) - LEN(SUBSTITUTE(LOWER($J972),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J972) - LEN(SUBSTITUTE(LOWER($J972),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B972:D972)","v":0},2016,"Hidradenitis suppurativa/Acne inversa: an endocrine skin disorder?","Karagiannidis",27294593,"Hidradenitis suppurativa/Acne inversa: an endocrine skin disorder?    Abstract:    NlmCategory=UNASSIGNEDHidradenitis suppurativa / acne inversa (HS) is a chronic inflammatory, debilitating skin disorder with a largely unknown etiology. However, many observations such as the typical onset of the disease after puberty, the female predominance, the pre-menstrual flare ups and the improvement during pregnancy suggest a contribution of endocrinological factors to the emergence of the disease. In addition, the reported efficacy of anti-androgen treatment on HS indicates a possible involvement of androgens in the pathogenesis. Furthermore, the common comorbidity with metabolic syndrome points to possible interactions between endocrinological and metabolic alterations in the development of HS. Taking into account the endocrine functions of the human skin, several studies investigated the effects of hormones and the behavior of the pilosebaceous unit in the skin of patients with HS. In this review we describe the current view on the hormonal dysregulation and metabolic syndrome and their role in HS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I973,I973)","v":27272974},{"$f":"(LEN($J973) - LEN(SUBSTITUTE(LOWER($J973),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J973) - LEN(SUBSTITUTE(LOWER($J973),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J973) - LEN(SUBSTITUTE(LOWER($J973),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B973:D973)","v":0},2016,"Vitamin A toxicity presenting as bone pain.","Baineni",27272974,"Vitamin A toxicity presenting as bone pain.    Abstract:    NlmCategory=UNASSIGNEDA 4-year-old boy presented with severe bone pains, refusal to walk, diffuse bony swelling of forelimbs, skin changes and abdominal pain, with symptoms evolving over 6 weeks. Blood screening tests were normal except for raised aspartate aminotransferase (AST). Radiographs revealed thickened periosteum, widening of the diaphyses of long bones and lifted periosteum in mid-shaft of ulnae and right femur. Skeletal scintigraphy showed a high uptake of radionuclide at clinically affected and unaffected sites, suggestive of multifocal osteoblastic skeletal lesions. After repeated enquiries, his parents admitted to giving him massive doses of preformed vitamin A for over 3 months as health tablets. Surprisingly, he did not have overt liver disease typically found with much smaller doses, although the dermal changes and musculoskeletal pathology were florid. He made a full clinical recovery within 2 months of cessation of vitamin A."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I974,I974)","v":27225642},{"$f":"(LEN($J974) - LEN(SUBSTITUTE(LOWER($J974),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J974) - LEN(SUBSTITUTE(LOWER($J974),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J974) - LEN(SUBSTITUTE(LOWER($J974),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B974:D974)","v":0},2016,"Circadian regulation of lipid metabolism.","Gooley",27225642,"Circadian regulation of lipid metabolism.    Abstract:    NlmCategory=UNASSIGNEDThe circadian system temporally coordinates daily rhythms in feeding behaviour and energy metabolism. The objective of the present paper is to review the mechanisms that underlie circadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). The SCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including the liver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated at the cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation are rhythmically activated and repressed by clock proteins, hence providing a direct mechanism for circadian regulation of lipids. Disruption of clock gene function results in abnormal metabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phase associated with dysregulation of lipid metabolism. Recent studies using metabolomics and lipidomics platforms have shown that hundreds of lipid species are circadian-regulated in human plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterol lipids and sphingolipids. In future work, these lipid profiling approaches can be used to understand better the interaction between diet, mealtimes and circadian rhythms on lipid metabolism and risk for obesity and metabolic diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I975,I975)","v":27152175},{"$f":"(LEN($J975) - LEN(SUBSTITUTE(LOWER($J975),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J975) - LEN(SUBSTITUTE(LOWER($J975),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J975) - LEN(SUBSTITUTE(LOWER($J975),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B975:D975)","v":0},2015,"Non-sympathetic control of brown adipose tissue.","Cereijo",27152175,"Non-sympathetic control of brown adipose tissue.    Abstract:   The thermogenic activity of brown adipose tissue (BAT) in the organism is tightly regulated through different processes, from short-term induction of uncoupling protein-1-mediated mitochondrial proton conductance to complex processes of BAT recruitment, and appearance of the beige/brite adipocytes in white adipose tissue (WAT), the so-called browning process. The sympathetic nervous system is classically recognized as the main mediator of BAT activation. However, novel factors capable of activating BAT through non-sympathetic mechanisms have been recently identified. Among them are members of the bone morphogenetic protein family, with likely autocrine actions, and activators of nuclear hormone receptors, especially vitamin A derivatives. Multiple endocrine factors released by peripheral tissues that act on BAT have also been identified. Some are natriuretic peptides of cardiac origin, whereas others include irisin, originating in skeletal muscle, and fibroblast growth factor-21, mainly produced in the liver. These factors have cell-autonomous effects in brown adipocytes, but indirect effects in vivo that modulate sympathetic activity toward BAT cannot be excluded. Moreover, these factors can affect to different extents such as the activation of existing BAT, the induction of browning in WAT or both. The identification of non-sympathetic controllers of BAT activity is of special biomedical interest as a prerequisite for developing pharmacological tools that influence BAT activity without the side effects of sympathomimetics."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I976,I976)","v":27087396},{"$f":"(LEN($J976) - LEN(SUBSTITUTE(LOWER($J976),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J976) - LEN(SUBSTITUTE(LOWER($J976),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J976) - LEN(SUBSTITUTE(LOWER($J976),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B976:D976)","v":0},2016,"Daily iron supplementation for improving anaemia, iron status and health in menstruating women.","Low",27087396,"Daily iron supplementation for improving anaemia, iron status and health in menstruating women.    Abstract:    BACKGROUND : Iron-deficiency anaemia is highly prevalent among non-pregnant women of reproductive age (menstruating women) worldwide, although the prevalence is highest in lower-income settings. Iron-deficiency anaemia has been associated with a range of adverse health outcomes, which restitution of iron stores using iron supplementation has been considered likely to resolve. Although there have been many trials reporting effects of iron in non-pregnant women, these trials have never been synthesised in a systematic review.  OBJECTIVES : To establish the evidence for effects of daily supplementation with iron on anaemia and iron status, as well as on physical, psychological and neurocognitive health, in menstruating women.  SEARCH METHODS : In November 2015 we searched CENTRAL, Ovid MEDLINE, EMBASE, and nine other databases, as well as four digital thesis repositories. In addition, we searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and reference lists of relevant reviews.  SELECTION CRITERIA : We included randomised controlled trials (RCTs) and quasi-RCTs comparing daily oral iron supplementation with or without a cointervention (folic acid or vitamin C), for at least five days per week at any dose, to control or placebo using either individual- or cluster-randomisation. Inclusion criteria were menstruating women (or women aged 12 to 50 years) reporting on predefined primary (anaemia, haemoglobin concentration, iron deficiency, iron-deficiency anaemia, all-cause mortality, adverse effects, and cognitive function) or secondary (iron status measured by iron indices, physical exercise performance, psychological health, adherence, anthropometric measures, serum/plasma zinc levels, vitamin A status, and red cell folate) outcomes.  DATA COLLECTION AND ANALYSIS : We used the standard methodological procedures of Cochrane.  MAIN RESULTS : The search strategy identified 31,767 records; after screening, 90 full-text reports were assessed for eligibility. We included 67 trials (from 76 reports), recruiting 8506 women; the number of women included in analyses varied greatly between outcomes, with endpoint haemoglobin concentration being the outcome with the largest number of participants analysed (6861 women). Only 10 studies were considered at low overall risk of bias, with most studies presenting insufficient details about trial quality.Women receiving iron were significantly less likely to be anaemic at the end of intervention compared to women receiving control (risk ratio (RR) 0.39 (95% confidence interval (CI) 0.25 to 0.60, 10 studies, 3273 women, moderate quality evidence). Women receiving iron had a higher haemoglobin concentration at the end of intervention compared to women receiving control (mean difference (MD) 5.30, 95% CI 4.14 to 6.45, 51 studies, 6861 women, high quality evidence). Women receiving iron had a reduced risk of iron deficiency compared to women receiving control (RR 0.62, 95% CI 0.50 to 0.76, 7 studies, 1088 women, moderate quality evidence). Only one study (55 women) specifically reported iron-deficiency anaemia and no studies reported mortality. Seven trials recruiting 901 women reported on any side effect and did not identify an overall increased prevalence of side effects from iron supplements (RR 2.14, 95% CI 0.94 to 4.86, low quality evidence). Five studies recruiting 521 women identified an increased prevalence of gastrointestinal side effects in women taking iron (RR 1.99, 95% CI 1.26 to 3.12, low quality evidence). Six studies recruiting 604 women identified an increased prevalence of loose stools/diarrhoea (RR 2.13, 95% CI 1.10, 4.11, high quality evidence); eight studies recruiting 1036 women identified an increased prevalence of hard stools/constipation (RR 2.07, 95% CI 1.35 to 3.17, high quality evidence). Seven studies recruiting 1190 women identified evidence of an increased prevalence of abdominal pain among women randomised to iron (RR 1.55, 95% CI 0.99 to 2.41, low quality evidence). Eight studies recruiting 1214 women did not find any evidence of an increased prevalence of nausea among women randomised to iron (RR 1.19, 95% CI 0.78 to 1.82). Evidence that iron supplementation improves cognitive performance in women is uncertain, as studies could not be meta-analysed and individual studies reported conflicting results. Iron supplementation improved maximal and submaximal exercise performance, and appears to reduce symptomatic fatigue. Although adherence could not be formally meta-analysed due to differences in reporting, there was no evident difference in adherence between women randomised to iron and control.  AUTHORS CONCLUSIONS : Daily iron supplementation effectively reduces the prevalence of anaemia and iron deficiency, raises haemoglobin and iron stores, improves exercise performance and reduces symptomatic fatigue. These benefits come at the expense of increased gastrointestinal symptomatic side effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I977,I977)","v":27070596},{"$f":"(LEN($J977) - LEN(SUBSTITUTE(LOWER($J977),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J977) - LEN(SUBSTITUTE(LOWER($J977),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J977) - LEN(SUBSTITUTE(LOWER($J977),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B977:D977)","v":0},2016,"Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics.","García-Cortés",27070596,"Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics.    Abstract:   Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I978,I978)","v":26881492},{"$f":"(LEN($J978) - LEN(SUBSTITUTE(LOWER($J978),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J978) - LEN(SUBSTITUTE(LOWER($J978),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J978) - LEN(SUBSTITUTE(LOWER($J978),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B978:D978)","v":0},2016,"Nutritional strategies to enhance adaptation in intestinal failure.","Lamprecht",26881492,"Nutritional strategies to enhance adaptation in intestinal failure.    Abstract:    PURPOSE OF REVIEW : This article summarizes the current and potential future nutritional approaches to stimulate adaptation in intestinal failure. Adaptation in this context usually refers to intestinal adaptation but also involves changes in whole body physiology as well as in eating/drinking behavior.  RECENT FINDINGS : Adaptation largely depends on residual functional anatomy. Luminal exposure to complex nutrients is the most important trigger for intestinal adaptation. Enteral fat as well as enteral or parenteral short chain fatty acids have a specific stimulatory effect. Zinc and vitamin A status need to be optimized for adaptation to proceed and be maintained. In the context of maintaining sodium and water homeostasis, flushing the remnant intestine because of uncontrolled thirst/drinking must be avoided. Complications of nutritional care such as malnutrition, intestinal failure-associated liver disease, and recurrent line sepsis also need optimal management.  SUMMARY : Stimulation by luminal nutrients as well as prophylaxis against and treatment of (nutritional) complications are the cornerstones of adaptation to the short bowel situation. Based on ample data from animal studies but only limited evidence in humans specific nutritional stimulators need to be studied more rigorously. As long as such data are missing they can be tried on an individual basis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I979,I979)","v":26818403},{"$f":"(LEN($J979) - LEN(SUBSTITUTE(LOWER($J979),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J979) - LEN(SUBSTITUTE(LOWER($J979),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J979) - LEN(SUBSTITUTE(LOWER($J979),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B979:D979)","v":0},2016,"The effectiveness and safety of treatments used for acute diarrhea and acute gastroenteritis in children: protocol for a systematic review and network meta-analysis.","Florez",26818403,"The effectiveness and safety of treatments used for acute diarrhea and acute gastroenteritis in children: protocol for a systematic review and network meta-analysis.    Abstract:    BACKGROUND : Acute diarrhea and acute gastroenteritis (AD/AGE) are common among children in low- and middle-income countries (LMIC) and high-income countries (HIC). Supportive therapy including maintaining feeding, prevention of dehydration, and use of oral rehydration solution (ORS), is the mainstay of treatment in all children. Several additional treatments aiming to reduce the episode duration have been compared to placebo, but the differences in effectiveness among them are unknown.  METHODS AND ANALYSIS : We will conduct a systematic review of all randomized controlled trials evaluating the use of zinc, vitamin A, probiotics, prebiotics, synbiotics, racecadotril, smectite, and fermented and lactose-free milk/formula for AD/AGE treatment in children. The primary outcomes are diarrhea duration and mortality. Secondary outcomes are diarrhea lasting 3 or 7 days, stool frequency, treatment failure, hospitalizations, and adverse events. We will search MEDLINE, Ovid EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL), and LILACS through Ovid, as well as grey literature resources. Two reviewers will independently screen titles and abstracts, review full texts, extract information, and assess the risk of bias (ROB) and the confidence in the estimate (with the grading of recommendations, assessment, development, and evaluation [GRADE] approach). Results will be summarized narratively and statistically. Subgroup analysis according to HIC vs. LMIC, age, nutrition status, and ROB is planned. We will perform a Bayesian network meta-analysis to combine the pooled direct and indirect treatment effect estimates for each outcome, if adequate data is available.  DISCUSSION : This is the first systematic review and network meta-analysis that aims to determine the relative effectiveness of pharmacological and nutritional treatments for reducing the duration of AD/AGE in children. The results will help to reduce the uncertainty of the effectiveness of the interventions, find knowledge gaps, and/or encourage further research for other therapeutic options.  SYSTEMATIC REVIEW REGISTRATION : PROSPERO registration number: CRD42015023778."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I980,I980)","v":26579440},{"$f":"(LEN($J980) - LEN(SUBSTITUTE(LOWER($J980),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J980) - LEN(SUBSTITUTE(LOWER($J980),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J980) - LEN(SUBSTITUTE(LOWER($J980),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B980:D980)","v":0},2015,"Emerging role of microRNAs in lipid metabolism.","Yang",26579440,"Emerging role of microRNAs in lipid metabolism.    Abstract:   microRNAs (miRNAs or miRs) are small non-coding RNAs that are involved in post-transcriptional regulation of their target genes in a sequence-specific manner. Emerging evidence demonstrates that miRNAs are critical regulators of lipid synthesis, fatty acid oxidation and lipoprotein formation and secretion. Dysregulation of miRNAs disrupts gene regulatory network, leading to metabolic syndrome and its related diseases. In this review, we introduced epigenetic and transcriptional regulation of miRNAs expression. We emphasized on several representative miRNAs that are functionally involved into lipid metabolism, including miR-33/33(⁎), miR122, miR27a/b, miR378/378(⁎), miR-34a and miR-21. Understanding the function of miRNAs in lipid homeostasis may provide potential therapeutic strategies for fatty liver disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I981,I981)","v":26041952},{"$f":"(LEN($J981) - LEN(SUBSTITUTE(LOWER($J981),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J981) - LEN(SUBSTITUTE(LOWER($J981),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J981) - LEN(SUBSTITUTE(LOWER($J981),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B981:D981)","v":0},2015,"Reprint of: Nutrition in the Management of Cirrhosis and its Neurological Complications.","Bémeur",26041952,"Reprint of: Nutrition in the Management of Cirrhosis and its Neurological Complications.    Abstract:   Malnutrition is a common feature of chronic liver diseases that is often associated with a poor prognosis including worsening of clinical outcome, neuropsychiatric complications as well as outcome following liver transplantation. Nutritional assessment in patients with cirrhosis is challenging owing to confounding factors related to liver failure. The objectives of nutritional intervention in cirrhotic patients are the support of liver regeneration, the prevention or correction of specific nutritional deficiencies and the prevention and/or treatment of the complications of liver disease per se and of liver transplantation. Nutritional recommendations target the optimal supply of adequate substrates related to requirements linked to energy, protein, carbohydrates, lipids, vitamins and minerals. Some issues relating to malnutrition in chronic liver disease remain to be addressed including the development of an appropriate well-validated nutritional assessment tool, the identification of mechanistic targets or therapy for sarcopenia, the development of nutritional recommendations for obese cirrhotic patients and liver-transplant recipients and the elucidation of the roles of vitamin A hepatotoxicity, as well as the impact of deficiencies in riboflavin and zinc on clinical outcomes. Early identification and treatment of malnutrition in chronic liver disease has the potential to lead to better disease outcome as well as prevention of the complications of chronic liver disease and improved transplant outcomes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I982,I982)","v":25808650},{"$f":"(LEN($J982) - LEN(SUBSTITUTE(LOWER($J982),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J982) - LEN(SUBSTITUTE(LOWER($J982),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J982) - LEN(SUBSTITUTE(LOWER($J982),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B982:D982)","v":0},2015,"The link between Hepatic Vitamin A Metabolism and Nonalcoholic Fatty Liver Disease.","Chen",25808650,"The link between Hepatic Vitamin A Metabolism and Nonalcoholic Fatty Liver Disease.    Abstract:   The liver is essential for the control of glucose and lipid metabolism. Excessive accumulation of fat in the liver disturbs its function and leads to the development of fatty liver diseases. The nonalcoholic fatty liver disease (NAFLD) is a common type of fatty liver disease found in patients who have not consumed significant amount of alcohol. Multiple factors and cell types contribute to the development and progression of NAFLD. Diets contain macronutrients with energy and micronutrients with regulatory roles. As an essential micronutrient, vitamin A (VA), plays critical roles in various physiological functions including the regulation of glucose and lipid homeostasis in the liver. The bodys VA is mainly stored in quiescent hepatic stellate cells (HSCs) in the liver. Hepatocytes actively metabolize VA, and change glucose and lipid metabolism in response to VA metabolites. Interestingly, the activated HSCs lose their VA content and contribute to the NAFLD progression. Significant number of studies have been conducted to investigate the link between VA metabolism and NAFLD development. This review is to summarize current literatures that discuss the changes of VA metabolism occurring locally between hepatocytes and HSCs, and intracellularly in hepatocytes during the course of NAFLD development. It appears that factors derived from HSCs and hepatocytes mutually affect each other, which contributes to NAFLD development. Additionally, this review discusses the potential mechanism by which excessive VA metabolism increases lipogenesis and contributes to fat accumulation in hepatocytes. It offers potential future directions for the study of the role of VA metabolism in the NAFLD development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I983,I983)","v":25774260},{"$f":"(LEN($J983) - LEN(SUBSTITUTE(LOWER($J983),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J983) - LEN(SUBSTITUTE(LOWER($J983),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J983) - LEN(SUBSTITUTE(LOWER($J983),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B983:D983)","v":0},2014,"Night blindness and ancient remedy.","Al Binali",25774260,"Night blindness and ancient remedy.    Abstract:   The aim of this article is to briefly review the history of night blindness and its treatment from ancient times until the present. The old Egyptians, the Babylonians, the Greeks and the Arabs used animal liver for treatment and successfully cured the disease. The author had the opportunity to observe the application of the old remedy to a patient. Now we know what the ancients did not know, that night blindness is caused by Vitamin A deficiency and the animal liver is the store house for Vitamin A."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I984,I984)","v":25755550},{"$f":"(LEN($J984) - LEN(SUBSTITUTE(LOWER($J984),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J984) - LEN(SUBSTITUTE(LOWER($J984),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J984) - LEN(SUBSTITUTE(LOWER($J984),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B984:D984)","v":0},2014,"Nutrition in the management of cirrhosis and its neurological complications.","Bémeur",25755550,"Nutrition in the management of cirrhosis and its neurological complications.    Abstract:   Malnutrition is a common feature of chronic liver diseases that is often associated with a poor prognosis including worsening of clinical outcome, neuropsychiatric complications as well as outcome following liver transplantation. Nutritional assessment in patients with cirrhosis is challenging owing to confounding factors related to liver failure. The objectives of nutritional intervention in cirrhotic patients are the support of liver regeneration, the prevention or correction of specific nutritional deficiencies and the prevention and/or treatment of the complications of liver disease per se and of liver transplantation. Nutritional recommendations target the optimal supply of adequate substrates related to requirements linked to energy, protein, carbohydrates, lipids, vitamins and minerals. Some issues relating to malnutrition in chronic liver disease remain to be addressed including the development of an appropriate well-validated nutritional assessment tool, the identification of mechanistic targets or therapy for sarcopenia, the development of nutritional recommendations for obese cirrhotic patients and liver-transplant recipients and the elucidation of the roles of vitamin A hepatotoxicity, as well as the impact of deficiencies in riboflavin and zinc on clinical outcomes. Early identification and treatment of malnutrition in chronic liver disease has the potential to lead to better disease outcome as well as prevention of the complications of chronic liver disease and improved transplant outcomes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I985,I985)","v":25742431},{"$f":"(LEN($J985) - LEN(SUBSTITUTE(LOWER($J985),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J985) - LEN(SUBSTITUTE(LOWER($J985),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J985) - LEN(SUBSTITUTE(LOWER($J985),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B985:D985)","v":0},2015,"Nutritional status in children with Shwachman-diamond syndrome.","Pichler",25742431,"Nutritional status in children with Shwachman-diamond syndrome.    Abstract:    OBJECTIVE : In Shwachman-Diamond syndrome (SDS), pancreatic insufficiency can lead to malabsorption of fat-soluble vitamins and trace elements. The aim of this study was to assess the serum concentrations of vitamins A and E, zinc, copper, and selenium and their deficiencies.  METHODS : This retrospective review was performed in 21 children (12 were male; median age, 7.8 years) with genetically confirmed SDS at a tertiary pediatric hospital. Pancreatic enzyme replacement therapy (PERT) and vitamin or trace elements supplements were documented.  RESULTS : Twenty patients (95%) had pancreatic insufficiency receiving PERT, 10 (47%) had a combined vitamin and trace element deficiency, 6 (29%) had an isolated vitamin deficiency, and 4 (19%) had an isolated trace element deficiency. Vitamins A and E deficiency occurred in 16 (76%) and 4 (19%) of 21, respectively. Low serum selenium was found in 10 (47%), zinc deficiency in 7 (33%), and copper deficiency in 5 (24%). Eleven patients (52%) were on multivitamin supplementation, and 2 (10%) on zinc and selenium supplements. No statistical differences were found between repeated measurements for all micronutrients.  CONCLUSIONS : More than 50% of the children had vitamin A and selenium deficiencies despite adequate supplementation of PERT and supplements. Micronutrients should be routinely measured in SDS patients to prevent significant complications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I986,I986)","v":25483623},{"$f":"(LEN($J986) - LEN(SUBSTITUTE(LOWER($J986),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J986) - LEN(SUBSTITUTE(LOWER($J986),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J986) - LEN(SUBSTITUTE(LOWER($J986),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B986:D986)","v":0},2015,"The emerging roles of lipids in circadian control.","Adamovich",25483623,"The emerging roles of lipids in circadian control.    Abstract:   Lipids play vital roles in a wide variety of cellular functions. They act as structural components in cell membranes, serve as a major form of energy storage, and function as key signaling molecules. Mounting evidence points towards a tight interplay between lipids and circadian clocks. In mammals, circadian clocks regulate the daily physiology and metabolism, and disruption of circadian rhythmicity is associated with altered lipid homeostasis and pathologies such as fatty liver and obesity. Concomitantly, emerging evidence suggest that lipids are embedded within the core clock circuitry and participate in circadian control. Recent advances in lipidomics methodologies and their application in chronobiology studies have shed new light on the cross talk between circadian clocks and lipid homeostasis. We review herein the latest literature related to the involvement of lipids in circadian clocks function and highlight the contribution of circadian lipidomics studies to our understanding of circadian rhythmicity and lipid homeostasis. This article is part of a Special Issue entitled Brain Lipids."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I987,I987)","v":25398733},{"$f":"(LEN($J987) - LEN(SUBSTITUTE(LOWER($J987),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J987) - LEN(SUBSTITUTE(LOWER($J987),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J987) - LEN(SUBSTITUTE(LOWER($J987),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B987:D987)","v":0},2014,"Undernutrition, the acute phase response to infection, and its effects on micronutrient status indicators.","Bresnahan",25398733,"Undernutrition, the acute phase response to infection, and its effects on micronutrient status indicators.    Abstract:   Infection and undernutrition are prevalent in developing countries and demonstrate a synergistic relation. Undernutrition increases infection-related morbidity and mortality. The acute phase response (APR) is an innate, systemic inflammatory reaction to a wide array of disruptions in a hosts homeostasis, including infection. Released from immune cells in response to deleterious stimuli, proinflammatory cytokines act on distant tissues to induce behavioral (e.g., anorexia, weakness, and fatigue) and systemic effects of the APR. Cytokines act to increase energy and protein requirements to manifest fever and support hepatic acute phase protein (APP) production. Blood concentrations of glucose and lipid are augmented to provide energy to immune cells in response to cytokines. Additionally, infection decreases intestinal absorption of nutrients and can cause direct loss of micronutrients. Traditional indicators of iron, zinc, and vitamin A status are altered during the APR, leading to inaccurate estimations of deficiency in populations with a high or unknown prevalence of infection. Blood concentrations of APPs can be measured in nutrition interventions to assess the time stage and severity of infection and correct for the APR; however, standardized cutoffs for nutrition applications are needed. Protein-energy malnutrition leads to increased gut permeability to pathogens, abnormal immune cell populations, and impaired APP response. Micronutrient deficiencies cause specific immune impairments that affect both innate and adaptive responses. This review describes the antagonistic interaction between the APR and nutritional status and emphasizes the need for integrated interventions to address undernutrition and to reduce disease burden in developing countries."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I988,I988)","v":25345007},{"$f":"(LEN($J988) - LEN(SUBSTITUTE(LOWER($J988),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J988) - LEN(SUBSTITUTE(LOWER($J988),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J988) - LEN(SUBSTITUTE(LOWER($J988),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B988:D988)","v":0},2014,"[Update on isolation and functional research of hepatic stellate cells].","Li",25345007,"[Update on isolation and functional research of hepatic stellate cells].    Abstract:   Hepatic stellate cells (HSCs), also called Ito cells or lipocytes, are one of inherent liver nonparenchymal cell types located in the Dissé space between hepatocytes and sinusoidal endothelial cells, and account for up to 50%-80% of vitamin A in the form of lipid drops. The methods of primary HSCs isolation mainly focus on density gradient centrifugation combined with centrifugal elutriation, side scatter-activated cell sorting, UV-excited autofluorescence or antibody-based flow cytometry, etc., and will provide solid foundation for the research on physiological and pathological HSCs function. The research of this vitamin A-storing cells has developed and expanded vigorously. In physiological conditions, HSCs are quiescent and play pivotal roles in the synthesis of extracellular matrix (ECM) to maintain its stability with broad uptake and storage of vitamin A, and also regulate liver regeneration. But in pathological conditions, HSCs are activated by constant stimulations or liver injury, then with activated proliferation, reduced lipid drops, and increased ECM synthesis. Morphology of these cells also changes from the star-shaped stellate cells to that of fibroblasts or myofibroblasts with obvious contractibility and secretion of cytokines and chemokines including a variety of proinflammatory factors and adhesion molecules, suggesting that the activation of HSCs is one of the key events in the development of liver fibrosis. Study on the isolation and function of HSCs is always one of the hot topics for liver biology. In this review, we systematically summarize and discuss the recent advances in our understanding of the isolation methods and improvements of HSCs, and functional research of HSCs biology in health and disease, as well as potential directions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I989,I989)","v":25296396},{"$f":"(LEN($J989) - LEN(SUBSTITUTE(LOWER($J989),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J989) - LEN(SUBSTITUTE(LOWER($J989),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J989) - LEN(SUBSTITUTE(LOWER($J989),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B989:D989)","v":0},2014,"Nutrition and health in amphibian husbandry.","Ferrie",25296396,"Nutrition and health in amphibian husbandry.    Abstract:   Amphibian biology is intricate, and there are many inter-related factors that need to be understood before establishing successful Conservation Breeding Programs (CBPs). Nutritional needs of amphibians are highly integrated with disease and their husbandry needs, and the diversity of developmental stages, natural habitats, and feeding strategies result in many different recommendations for proper care and feeding. This review identifies several areas where there is substantial room for improvement in maintaining healthy ex situ amphibian populations specifically in the areas of obtaining and utilizing natural history data for both amphibians and their dietary items, achieving more appropriate environmental parameters, understanding stress and hormone production, and promoting better physical and population health. Using a scientific or research framework to answer questions about disease, nutrition, husbandry, genetics, and endocrinology of ex situ amphibians will improve specialists understanding of the needs of these species. In general, there is a lack of baseline data and comparative information for most basic aspects of amphibian biology as well as standardized laboratory approaches. Instituting a formalized research approach in multiple scientific disciplines will be beneficial not only to the management of current ex situ populations, but also in moving forward with future conservation and reintroduction projects. This overview of gaps in knowledge concerning ex situ amphibian care should serve as a foundation for much needed future research in these areas."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I990,I990)","v":25248458},{"$f":"(LEN($J990) - LEN(SUBSTITUTE(LOWER($J990),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J990) - LEN(SUBSTITUTE(LOWER($J990),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J990) - LEN(SUBSTITUTE(LOWER($J990),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B990:D990)","v":0},2014,"The phenomenon of micronutrient deficiency among children in China: a systematic review of the literature.","Wong",25248458,"The phenomenon of micronutrient deficiency among children in China: a systematic review of the literature.    Abstract:    OBJECTIVE : The present study aimed to review the literature on micronutrient deficiency and other factors influencing a deficiency status among children living in China.  DESIGN : A systematic review was performed to analyse the literature.  SETTING : Studies were identified through a search of PubMed and secondary references.  SUBJECTS : Children living in China aged less than 18 years.  RESULTS : Sixty-one articles were included. The prevalence of vitamin A deficiency decreased to approximately 10 % in 1995-2009. It increased with age but no significant difference was found between genders. The prevalence of thiamin and vitamin B12 deficiency was 10·5 % in Yunnan and 4·5 % in Chongqing provinces, respectively. Higher vitamin D deficiency rates were seen in spring and winter. The incidence of bleeding due to vitamin K deficiency was 3·3 % in 1998-2001 and more prevalent in rural areas. Both iodine deficiency and excess iodine intake were observed. Goitre rates were reported in Tibet, Jiangxi, Gansu and Hong Kong (3·5-46 %). Anaemia rates ranged from 20 % to 40 % in 2007-2011. High Se deficiency rates were found in Tibet, Shaanxi and Jiangsu. High Zn deficiency rates were also found (50-70 %) in 1995-2006. Few studies reported Ca deficiency rates (19·6-34·3 %). The degrees of deficiency for vitamin A, vitamin B12, Fe and Zn were more substantial in rural areas compared with urban areas.  CONCLUSIONS : The prevalence of micronutrient deficiency rates varied. Socio-economic status, environmental factors and the Chinese diet may influence micronutrient deficiency. Public health policies should consider implementing programmes of supplementation, food fortification and nutrition education to address these deficiencies among Chinese children."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I991,I991)","v":25220021},{"$f":"(LEN($J991) - LEN(SUBSTITUTE(LOWER($J991),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J991) - LEN(SUBSTITUTE(LOWER($J991),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J991) - LEN(SUBSTITUTE(LOWER($J991),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B991:D991)","v":0},2015,"Forty years of research on xeroderma pigmentosum at the US National Institutes of Health.","Kraemer",25220021,"Forty years of research on xeroderma pigmentosum at the US National Institutes of Health.    Abstract:   In 1968, Dr. James Cleaver reported defective DNA repair in cultured cells from patients with xeroderma pigmentosum. This link between clinical disease and molecular pathophysiology has sparked interest in understanding not only the clinical characteristics of sun sensitivity, damage and cancer that occurred in XP patients but also the mechanisms underlying the damage and repair. While affected patients are rare, their exaggerated UV damage provides a window into the workings of DNA repair. These studies have clarified the importance of a functioning DNA repair system to the maintenance of skin and neurologic health in the general population. Understanding the role of damage in causing cancer, neurologic degeneration, hearing loss and internal cancers provides an opportunity for prevention and treatment. Characterizing complementation groups pointed to the importance of different underlying genes. Studying differences in cancer age of onset and underlying molecular signatures in cancers occurring either in XP patients or the general population has led to insights into differences in carcinogenic mechanisms. The accelerated development of cancers in XP has been used as a model to discover new cancer chemopreventive agents. An astute insight can be a quot;tipping pointquot; triggering decades of productive inquiry."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I992,I992)","v":25188737},{"$f":"(LEN($J992) - LEN(SUBSTITUTE(LOWER($J992),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J992) - LEN(SUBSTITUTE(LOWER($J992),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J992) - LEN(SUBSTITUTE(LOWER($J992),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B992:D992)","v":0},2014,"Hypervitaminosis A causing hypercalcemia in cystic fibrosis. Case report and focused review.","Safi",25188737,"Hypervitaminosis A causing hypercalcemia in cystic fibrosis. Case report and focused review.    Abstract:   Hypercalcemia is a rare complication of hypervitaminosis A. We report a pediatric patient with cystic fibrosis (CF) and pancreatic insufficiency who was found to have hypervitaminosis A causing hypercalcemia, complicated by nephrocalcinosis and renal impairment. The patient is a 4-year-old girl with pancreatic-insufficient CF, gastroesophageal reflux, oral aversion, and failure to thrive requiring gastrostomy tube placement. She was prescribed Source CF vitamins, but rarely received the full dose, due to emesis and intolerance. She had routine annual labs that revealed hypercalcemia with elevated blood urea nitrogen and creatinine, which were not present in her previous annual labs. Upon further questioning, her mother reported that she seemed more fatigued for a few weeks, had abdominal pain, and was urinating more frequently. Upon admission to the hospital, laboratory results revealed elevated HCO3, while serum levels of potassium, phosphorus, and albumin were within normal limits. Vitamin D (25-hydroxy) level was low, and vitamin A level was elevated. Extensive metabolic and hormonal workup for the etiology of the hypercalcemia revealed evidence of chronic renal insufficiency and elevated vitamin A levels. She had a renal ultrasound that revealed bilateral nephrocalciosis. Diagnosis of chronic hypervitaminosis A complicated by hypercalcemia was made and was managed by holding vitamin A supplements, aggressive diuresis, and prednisolone. This case emphasizes the importance of regular vitamin A monitoring in patients with CF. There is a wide variability for the lowest intake required to cause toxicity, and the lower limit to cause toxicity has not been determined."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I993,I993)","v":25101554},{"$f":"(LEN($J993) - LEN(SUBSTITUTE(LOWER($J993),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J993) - LEN(SUBSTITUTE(LOWER($J993),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J993) - LEN(SUBSTITUTE(LOWER($J993),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B993:D993)","v":0},2014,"Global burden of childhood diarrhea and interventions.","Das",25101554,"Global burden of childhood diarrhea and interventions.    Abstract:    PURPOSE OF REVIEW : Diarrhea is a leading cause of morbidity and mortality among children under 5 years in low-income and middle-income countries. Over the past 2 decades under-five mortality has decreased substantially, but reductions have been uneven and unsatisfactory in resource-poor regions.  RECENT FINDINGS : There are known interventions which can prevent diarrhea or manage children who suffer from it. Interventions with proven effectiveness at the prevention level include water, sanitation, and hygiene interventions, breastfeeding, complementary feeding, vitamin A and zinc supplementation, and vaccines for diarrhea (rotavirus and cholera). Oral rehydration solution, zinc treatment, continued feeding, and antibiotic treatment for certain strains of diarrhea (cholera, Shigella, and cryptosporidiosis) are effective strategies for treatment of diarrhea. The recent Lancet series using the Lives Saved tool suggested that if these identified interventions were scaled up to a global coverage to at least 80%, and immunizations to at least 90%; almost all deaths due to diarrhea could be averted.  SUMMARY : The current childhood mortality burden highlights the need of a focused global diarrhea action plan. The findings suggest that with proper packaging of interventions and delivery platforms, the burden of childhood diarrhea can be reduced to a greater extent. All that is required is greater attention and steps toward right direction."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I994,I994)","v":24874548},{"$f":"(LEN($J994) - LEN(SUBSTITUTE(LOWER($J994),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J994) - LEN(SUBSTITUTE(LOWER($J994),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J994) - LEN(SUBSTITUTE(LOWER($J994),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B994:D994)","v":0},2014,"Nuclear receptors in neurodegenerative diseases.","Skerrett",24874548,"Nuclear receptors in neurodegenerative diseases.    Abstract:   Nuclear receptors have generated substantial interest in the past decade as potential therapeutic targets for the treatment of neurodegenerative disorders. Despite years of effort, effective treatments for progressive neurodegenerative diseases such as Alzheimers disease, Parkinsons disease, Huntingtons disease and ALS remain elusive, making non-classical drug targets such as nuclear receptors an attractive alternative. A substantial literature in mouse models of disease and several clinical trials have investigated the role of nuclear receptors in various neurodegenerative disorders, most prominently AD. These studies have met with mixed results, yet the majority of studies in mouse models report positive outcomes. The mechanisms by which nuclear receptor agonists affect disease pathology remain unclear. Deciphering the complex signaling underlying nuclear receptor action in neurodegenerative diseases is essential for understanding this variability in preclinical studies, and for the successful translation of nuclear receptor agonists into clinical therapies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I995,I995)","v":24792485},{"$f":"(LEN($J995) - LEN(SUBSTITUTE(LOWER($J995),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J995) - LEN(SUBSTITUTE(LOWER($J995),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J995) - LEN(SUBSTITUTE(LOWER($J995),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B995:D995)","v":0},2014,"Perspectives of drug-based neuroprotection targeting mitochondria.","Procaccio",24792485,"Perspectives of drug-based neuroprotection targeting mitochondria.    Abstract:   Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I996,I996)","v":24781598},{"$f":"(LEN($J996) - LEN(SUBSTITUTE(LOWER($J996),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J996) - LEN(SUBSTITUTE(LOWER($J996),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J996) - LEN(SUBSTITUTE(LOWER($J996),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B996:D996)","v":0},2014,"Update on primary hypobetalipoproteinemia.","Hooper",24781598,"Update on primary hypobetalipoproteinemia.    Abstract:   quot;Primary hypobetalipoproteinemiaquot; refers to an eclectic group of inherited lipoprotein disorders characterized by low concentrations of or absence of low-density lipoprotein cholesterol and apolipoprotein B in plasma. Abetalipoproteinemia and homozygous familial hypobetalipoproteinemia, although caused by mutations in different genes, are clinically indistinguishable. A framework for the clinical follow-up and management of these two disorders has been proposed recently, focusing on monitoring of growth in children and preventing complications by providing specialized dietary advice and fat-soluble vitamin therapeutic regimens. Other recent publications on familial combined hypolipidemia suggest that although a reduction of angiopoietin-like 3 activity may improve insulin sensitivity, complete deficiency also reduces serum cholesterol efflux capacity and increases the risk of early vascular atherosclerotic changes, despite low low-density lipoprotein cholesterol levels. Specialist laboratories offer exon-by-exon sequence analysis for the molecular diagnosis of primary hypobetalipoproteinemia. In the future, massively parallel sequencing of panels of genes involved in dyslipidemia may play a greater role in the diagnosis of these conditions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I997,I997)","v":24625968},{"$f":"(LEN($J997) - LEN(SUBSTITUTE(LOWER($J997),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J997) - LEN(SUBSTITUTE(LOWER($J997),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J997) - LEN(SUBSTITUTE(LOWER($J997),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B997:D997)","v":0},2014,"Is it necessary to assess for fat-soluble vitamin deficiencies in pediatric patients with newly diagnosed celiac disease?","Imam",24625968,"Is it necessary to assess for fat-soluble vitamin deficiencies in pediatric patients with newly diagnosed celiac disease?    Abstract:    BACKGROUND : The purpose of this study was to identify the frequency of fat-soluble vitamin deficiencies in children with celiac disease (CD) and to determine the value of routine testing for these deficiencies.  METHODS : We conducted a retrospective medical record review of patients with a confirmed diagnosis of CD and fat-soluble vitamin levels measured at diagnosis between 1995 and 2012 at Mayo Clinic. Patients demographics, fat-soluble vitamin levels, and pertinent clinical factors at the time of diagnosis were collected.  RESULTS : Eighty-three patients were included in the final analysis: 51 girls and 32 boys, with an average age at diagnosis of 12.8 years in girls and 13.0 years in boys. The most commonly reported symptoms were abdominal pain in 49 patients and diarrhea in 30 patients. Family history of CD was reported in 32 patients. Average vitamin levels for vitamin E, 25-hydroxyvitamin D (25 (OH) D), and vitamin A were 7.5 mg/L, 32.8 ng/mL, and 334.5 μg/dL, respectively. No patients had vitamin A deficiency, 2 patients had vitamin E deficiency, and 9 patients had mild-to-moderate vitamin D deficiency (none had severe deficiency). Both patients with vitamin E deficiency were symptomatic and had complete villous atrophy. Thirty-one patients had insufficiency of 25 (OH) D, which was less than the reported frequency of vitamin D insufficiency in the general pediatric population in the United States in 2004. None of the patients were receiving vitamin supplements at the time of diagnosis.  CONCLUSIONS : Fat-soluble vitamin deficiencies are uncommon in children with new diagnosis of CD. Routine measuring of fat-soluble vitamins levels may not be necessary."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I998,I998)","v":24307779},{"$f":"(LEN($J998) - LEN(SUBSTITUTE(LOWER($J998),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J998) - LEN(SUBSTITUTE(LOWER($J998),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J998) - LEN(SUBSTITUTE(LOWER($J998),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B998:D998)","v":0},2013,"Between Scylla and Charybdis: the role of the human immune system in the pathogenesis of hepatitis C.","Spengler",24307779,"Between Scylla and Charybdis: the role of the human immune system in the pathogenesis of hepatitis C.    Abstract:   Hepatitis C virus (HCV) frequently elicits only mild immune responses so that it can often establish chronic infection. In this case HCV antigens persist and continue to stimulate the immune system. Antigen persistence then leads to profound changes in the infected hosts immune responsiveness, and eventually contributes to the pathology of chronic hepatitis. This topic highlight summarizes changes associated with chronic hepatitis C concerning innate immunity (interferons, natural killer cells), adaptive immune responses (immunoglobulins, T cells, and mechanisms of immune regulation (regulatory T cells). Our overview clarifies that a strong anti-HCV immune response is frequently associated with acute severe tissue damage. In chronic hepatitis C, however, the effector arms of the immune system either become refractory to activation or take over regulatory functions. Taken together these changes in immunity may lead to persistent liver damage and cirrhosis. Consequently, effector arms of the immune system will not only be considered with respect to antiviral defence but also as pivotal mechanisms of inflammation, necrosis and progression to cirrhosis. Thus, avoiding Scylla - a strong, sustained antiviral immune response with inital tissue damage - takes the infected host to virus-triggered immunopathology, which ultimately leads to cirrhosis and liver cancer - the realm of Charybdis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I999,I999)","v":24212089},{"$f":"(LEN($J999) - LEN(SUBSTITUTE(LOWER($J999),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J999) - LEN(SUBSTITUTE(LOWER($J999),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J999) - LEN(SUBSTITUTE(LOWER($J999),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B999:D999)","v":0},2013,"The influence of vitamin A supplementation on iron status.","Michelazzo",24212089,"The influence of vitamin A supplementation on iron status.    Abstract:   Vitamin A (VA) and iron deficiencies are important nutritional problems, affecting particularly preschool children, as well as pregnant and lactating women. A PubMed (National Library of Medicine, National Institutes of Health, Bethesda, MD, USA) literature review was carried out to search for clinical trials published from 1992 to 2013 that assessed the influence of vitamin A supplementation on iron status. Simultaneous use of iron and vitamin A supplements seemed to be more effective to prevent iron deficiency anemia than the use of these micronutrients alone. Some studies did not include a placebo group and only a few of them assessed vitamin A status of the individuals at baseline. Moreover, the studies did not consider any inflammatory marker and a reasonable number of iron parameters. Another important limitation was the lack of assessment of hemoglobin variants, especially in regions with a high prevalence of anemia. Assessment of hemoglobin variants, inflammatory markers and anemia of chronic inflammation would be important to the studies investigated. Studies involving different populations are necessary to elucidate the interaction between the two micronutrients, especially regarding iron absorption and modulation of erythropoiesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1000,I1000)","v":24139874},{"$f":"(LEN($J1000) - LEN(SUBSTITUTE(LOWER($J1000),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1000) - LEN(SUBSTITUTE(LOWER($J1000),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1000) - LEN(SUBSTITUTE(LOWER($J1000),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1000:D1000)","v":0},2014,"Multifunctional and potent roles of the 3-hydroxypropoxy group provide eldecalcitols benefit in osteoporosis treatment.","Ono",24139874,"Multifunctional and potent roles of the 3-hydroxypropoxy group provide eldecalcitols benefit in osteoporosis treatment.    Abstract:   Eldecalcitol (1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3, [developing code: ED-71]), a new osteoporosis treatment drug that was recently approved in Japan, is a best-in-class drug in the class of calcitriol (1α,25-dihydroxyvitamin D3) and its prodrug alfacalcidol (1α-hydroxyvitamin D3), which have been used to treat osteoporosis for 30 years. In a comparative Phase III clinical study with alfacalcidol in osteoporosis patients, eldecalcitol demonstrated superior efficacy in the endpoints of increment of bone mineral density and reduction of bone fracture with equivalent safety to alfacalcidol. Eldecalcitol was discovered by searching synthetic analogs of calcitriol and alfacalcidol, and its main structural characteristic is having the 3-hydroxypropoxy group at the 2β-position. This review discusses why introducing the group leads to excellent efficacy and safety in osteoporosis treatment and elucidates the functional roles of the 3-hydroxypropoxy group. Briefly, the functional roles of the group are, first, realizing the metabolism switching in which eldecalcitol shows resistance to CYP24A1 and is metabolized in the liver; second, increasing the affinity to the serum carrier protein and prolonging the half-life to 53h; and third, stabilizing the eldecalcitol-receptor complex. Taken together, these functional roles of the 3-hydroxypropoxy group are beneficial in osteoporosis treatment. This review attempts to give a detailed account of the mode of action of eldecalcitol by clarifying these multifunctional roles of the 3-hydroxypropoxy group from the medicinal chemists perspective."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1001,I1001)","v":24011318},{"$f":"(LEN($J1001) - LEN(SUBSTITUTE(LOWER($J1001),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1001) - LEN(SUBSTITUTE(LOWER($J1001),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1001) - LEN(SUBSTITUTE(LOWER($J1001),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1001:D1001)","v":0},2013,"Secondary bilateral striopallidodentate calcinosis associated with generalized pustular psoriasis (Von Zumbusch).","Pacheco",24011318,"Secondary bilateral striopallidodentate calcinosis associated with generalized pustular psoriasis (Von Zumbusch).    Abstract:   Bilateral striopallidodentate calcinosis (BSPDC) mentioned in the literature as Fahrs disease (a misnomer), is characterized by symmetrical and bilateral intracerebral calcifications located in the basal ganglia with or without deposits in the dentate nucleus, thalamus, and white matter. This entity is usually asymptomatic but may be manifested by neurological symptoms. Idiopathic BSPDC can occur either as sporadic or autosomal dominant familial forms. Secondary presentations of BSPDC are associated with infections, neoplastic diseases, toxicological or traumatic factors, and metabolic disorders. We describe a case of generalized pustular psoriasis associated with secondary BSPDC owing to pseudohypoparathyroidism. Laboratory tests revealed hypocalcemia, hyperphosphatemia, and a normal serum level of parathormone. The correction of the phosphorus-calcium metabolism disorder produced clinical improvement."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1002,I1002)","v":23977452},{"$f":"(LEN($J1002) - LEN(SUBSTITUTE(LOWER($J1002),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1002) - LEN(SUBSTITUTE(LOWER($J1002),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1002) - LEN(SUBSTITUTE(LOWER($J1002),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1002:D1002)","v":0},2013,"Liver Injury and the Activation of the Hepatic Myofibroblasts.","Jiang",23977452,"Liver Injury and the Activation of the Hepatic Myofibroblasts.    Abstract:   Liver fibrosis is a wound healing process, the end result of chronic liver injury elicited by different noxious stimuli. Activated hepatic stellate cells or myofibroblasts and portal myofibroblasts are considered as the main producers of the extracellular matrix in the liver. Upon liver injury the quiescent stellate cells transdifferentiate into myofibroblasts a process highlighted by the loss of vitamin A stores, upregulation of interstitial type collagens, smooth muscle α actin, matrix metalloproteinases, proteoglycans, and the induction of cell survival pathways. Activation of hepatic stellate cells is a result of a complex interplay between the parenchymal cells, immune cells, extracellular matrix mechanics and extrahepatic milieu such as the gut microbiome. In this review we will focus on the pathomechanism of stellate cell activation following chronic liver injury; with the aim of identifying possible treatment targets for anti-fibrogenic agents."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1003,I1003)","v":23878126},{"$f":"(LEN($J1003) - LEN(SUBSTITUTE(LOWER($J1003),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1003) - LEN(SUBSTITUTE(LOWER($J1003),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1003) - LEN(SUBSTITUTE(LOWER($J1003),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1003:D1003)","v":0},2013,"Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age (Review).","De-Regil",23878126,"Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age (Review).    Abstract:    BACKGROUND : Vitamin and mineral deficiencies, particularly those of iron, vitamin A and zinc, affect more than two billion people worldwide. Young children are highly vulnerable because of rapid growth and inadequate dietary practices. Micronutrient powders (MNP) are single-dose packets containing multiple vitamins and minerals in powder form that can be sprinkled onto any semi-solid food.The use of MNP for home or point-of-use fortification of complementary foods has been proposed as an intervention for improving micronutrient intake in children under two years of age.  OBJECTIVES : To assess the effects and safety of home (point-of-use) fortification of foods with multiple micronutrient powders on nutritional, health and developmental outcomes in children under two years of age.  SEARCH METHODS : We searched the following databases in February 2011: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (1948 to week 2 February 2011), EMBASE (1980 to Week 6 2011), CINAHL (1937 to current), CPCI-S (1990 to 19 February 2011), Science Citation Index (1970 to 19 February 2011), African Index Medicus (searched 23 February 2011), POPLINE (searched 21 February 2011), ClinicalTrials.gov (searched 23 February 2011), mRCT (searched 23 February 2011), and World Health Organization International Clinical Trials Registry Platform (ICTRP) (searched 23 February 2011). We also contacted relevant organisations (25 January 2011) for the identification of ongoing and unpublished studies.  SELECTION CRITERIA : We included randomised and quasi-randomised trials with either individual or cluster randomisation. Participants were children under the age of two years at the time of intervention, with no specific health problems. The intervention was consumption of food fortified at the point of use with multiple micronutrient powders formulated with at least iron, zinc and vitamin A compared with placebo, no intervention or the use of iron containing supplements, which is the standard practice.  DATA COLLECTION AND ANALYSIS : Two review authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies and assessed the risk of bias of the included studies.  MAIN RESULTS : We included eight trials (3748 participants) conducted in low income countries in Asia, Africa and the Caribbean, where anaemia is a public health problem. The interventions lasted between two and 12 months and the powder formulations contained between five and 15 nutrients. Six trials compared the use of MNP versus no intervention or a placebo and the other two compared the use of MNP versus daily iron drops. Most of the included trials were assessed as at low risk of bias. Home fortification with MNP reduced anaemia by 31% (six trials, RR 0.69; 95% CI 0.60 to 0.78) and iron deficiency by 51% (four trials, RR 0.49; 95% CI 0.35 to 0.67) in infants and young children when compared with no intervention or placebo, but we did not find an effect on growth. In comparison with daily iron supplementation, the use of MNP produced similar results on anaemia (one trial, RR 0.89; 95% CI 0.58 to 1.39) and haemoglobin concentrations (two trials, MD -2.36 g/L; 95% CI -10.30 to 5.58); however, given the limited amount of data these results should be interpreted cautiously. No deaths were reported in the trials and information on side effects and morbidity, including malaria, was scarce. It seems that the use of MNP is efficacious among infants and young children six to 23 months of age living in settings with different prevalences of anaemia and malaria endemicity, regardless of whether the intervention lasts two, six or 12 months or whether recipients are male or female.  AUTHORS CONCLUSIONS : Home fortification of foods with multiple micronutrient powders is an effective intervention to reduce anaemia and iron deficiency in children six months to 23 months of age. The provision of MNP is better than no intervention or placebo and possibly comparable to commonly used daily iron supplementation. The benefits of this intervention as a child survival strategy or on developmental outcomes are unclear. Data on effects on malaria outcomes are lacking and further investigation of morbidity outcomes is needed. The micronutrient powders containing multiple nutrients are well accepted but adherence is variable and in some cases comparable to that achieved in infants and young children receiving standard iron supplements as drops or syrups."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1004,I1004)","v":23851159},{"$f":"(LEN($J1004) - LEN(SUBSTITUTE(LOWER($J1004),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1004) - LEN(SUBSTITUTE(LOWER($J1004),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1004) - LEN(SUBSTITUTE(LOWER($J1004),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1004:D1004)","v":0},2013,"Impairment of autophagy: from hereditary disorder to drug intoxication.","Aki",23851159,"Impairment of autophagy: from hereditary disorder to drug intoxication.    Abstract:   At first, the molecular mechanism of autophagy was unveiled in a unicellular organism Saccharomyces cerevisiae (budding yeast), followed by the discovery that the basic mechanism of autophagy is conserved in multicellular organisms including mammals. Although autophagy was considered to be a non-selective bulk protein degradation system to recycle amino acids during periods of nutrient starvation, it is also believed to be an essential mechanism for the selective elimination of proteins/organelles that are damaged under pathological conditions. Research advances made using autophagy-deficient animals have revealed that impairments of autophagy often underlie the pathogenesis of hereditary disorders such as Danon, Parkinsons, Alzheimers, and Huntingtons diseases, and amyotrophic lateral sclerosis. On the other hand, there are many reports that drugs and toxicants, including arsenic, cadmium, paraquat, methamphetamine, and ethanol, induce autophagy during the development of their toxicity on many organs including heart, brain, lung, kidney, and liver. Although the question as to whether autophagic machinery is involved in the execution of cell death or not remains controversial, the current view of the role of autophagy during cell/tissue injury is that it is an important, often essential, cytoprotective reaction; disturbances in cytoprotective autophagy aggravate cell/tissue injuries. The purpose of this review is to provide (1) a gross summarization of autophagy processes, which are becoming more important in the field of toxicology, and (2) examples of important studies reporting the involvement of perturbations in autophagy in cell/tissue injuries caused by acute as well as chronic intoxication."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1005,I1005)","v":23791055},{"$f":"(LEN($J1005) - LEN(SUBSTITUTE(LOWER($J1005),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1005) - LEN(SUBSTITUTE(LOWER($J1005),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1005) - LEN(SUBSTITUTE(LOWER($J1005),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1005:D1005)","v":0},2013,"[Prevalence and prevention of common nutritional risks in children after earthquake].","Fan",23791055,"[Prevalence and prevention of common nutritional risks in children after earthquake].    Abstract:   Children have been identified as the most nutritionally vulnerable group when disaster happens. The most common nutritional risks include protein-energy malnutrition, iron-deficiency anemia, and trace element deficiency in children after earthquake. During the disaster relief, effective nutritional interventions should be performed according to the nutritional conditions of children in the affected area, so as to prevent the common nutritional risks. Timely diagnosis and treatment should be provided for children at a high risk of malnutrition."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1006,I1006)","v":23782937},{"$f":"(LEN($J1006) - LEN(SUBSTITUTE(LOWER($J1006),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1006) - LEN(SUBSTITUTE(LOWER($J1006),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1006) - LEN(SUBSTITUTE(LOWER($J1006),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1006:D1006)","v":0},2013,"Foam cells in atherosclerosis.","Yu",23782937,"Foam cells in atherosclerosis.    Abstract:   Atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima. Macrophage foam cells play a critical role in the occurrence and development of atherosclerosis. The generation of these cells is associated with imbalance of cholesterol influx, esterification and efflux. CD36 and scavenger receptor class A (SR-A) are mainly responsible for uptake of lipoprotein-derived cholesterol by macrophages. Acyl coenzyme A:cholesterol acyltransferase-1 (ACAT1) and neutral cholesteryl ester hydrolase (nCEH) regulate cholesterol esterification. ATP-binding cassette transporters A1(ABCA1), ABCG1 and scavenger receptor BI (SR-BI) play crucial roles in macrophage cholesterol export. When inflow and esterification of cholesterol increase and/or its outflow decrease, the macrophages are ultimately transformed into lipid-laden foam cells, the prototypical cells in the atherosclerotic plaque. The aim of this review is to describe what is known about the mechanisms of cholesterol uptake, esterification and release in macrophages. An increased understanding of the process of macrophage foam cell formation will help to develop novel therapeutic interventions for atherosclerosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1007,I1007)","v":23748105},{"$f":"(LEN($J1007) - LEN(SUBSTITUTE(LOWER($J1007),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1007) - LEN(SUBSTITUTE(LOWER($J1007),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1007) - LEN(SUBSTITUTE(LOWER($J1007),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1007:D1007)","v":0},2013,"Targeting long non-coding RNAs in cancers: progress and prospects.","Li",23748105,"Targeting long non-coding RNAs in cancers: progress and prospects.    Abstract:   Pervasive transcription occurs in the human genome to generate thousands of RNA transcripts, and accumulating evidence suggested that the RNA molecules, without protein coding ability, have important roles in diverse biological functions. Long non-coding RNA (lncRNA), with size larger than 200 nt, is a new class of the non-coding RNA that contributes to cancer development and progression. Roles for several lncRNAs in cancers have been characterized and strategies targeting them have inhibitory effects to malignant cells in vitro and in vivo. These findings point to the potential of lncRNAs as prospective novel therapeutic targets in cancers. Recent advance in biological drugs, led by nucleic acid drugs (i.e. siRNAs, antisense oligonucleotides), suggest directions for the development of cancer therapies targeting lncRNAs. Here, we discuss the characteristics of lncRNAs regarding their synthesis, stability and functional role in cells, and emphasize their unique properties that determine their molecular functions. We then discuss the association of lncRNAs with cancers, and illustrate the anticancer effects induced upon modulating the level and function of lncRNAs. We also revisit established methods for targeting RNA molecules and discuss new agents and strategies to attenuate lncRNAs in cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1008,I1008)","v":23720419},{"$f":"(LEN($J1008) - LEN(SUBSTITUTE(LOWER($J1008),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1008) - LEN(SUBSTITUTE(LOWER($J1008),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1008) - LEN(SUBSTITUTE(LOWER($J1008),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1008:D1008)","v":0},2013,"Embryonic cardiac chamber maturation: Trabeculation, conduction, and cardiomyocyte proliferation.","Samsa",23720419,"Embryonic cardiac chamber maturation: Trabeculation, conduction, and cardiomyocyte proliferation.    Abstract:   Congenital heart diseases are some of the most common human birth defects. Though some congenital heart defects can be surgically corrected, treatment options for other congenital heart diseases are very limited. In many congenital heart diseases, genetic defects lead to impaired embryonic heart development or growth. One of the key development processes in cardiac development is chamber maturation, and alterations in this maturation process can manifest as a variety of congenital defects including non-compaction, systolic dysfunction, diastolic dysfunction, and arrhythmia. During development, to meet the increasing metabolic demands of the developing embryo, the myocardial wall undergoes extensive remodeling characterized by the formation of muscular luminal protrusions called cardiac trabeculae, increased cardiomyocyte mass, and development of the ventricular conduction system. Though the basic morphological and cytological changes involved in early heart development are clear, much remains unknown about the complex biomolecular mechanisms governing chamber maturation. In this review, we highlight evidence suggesting that a wide variety of basic signaling pathways and biomechanical forces are involved in cardiac wall maturation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1009,I1009)","v":23580402},{"$f":"(LEN($J1009) - LEN(SUBSTITUTE(LOWER($J1009),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1009) - LEN(SUBSTITUTE(LOWER($J1009),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1009) - LEN(SUBSTITUTE(LOWER($J1009),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1009:D1009)","v":0},2013,"Age-related macular degeneration.","Cheung",23580402,"Age-related macular degeneration.    Abstract:   Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, and the prevalence of the disease increases exponentially with every decade after age 50 years. It is a multifactorial disease involving a complex interplay of genetic, environmental, metabolic, and functional factors. Besides smoking, hypertension, obesity, and certain dietary habits, a growing body of evidence indicates that inflammation and the immune system may play a key role in the development of the disease. AMD may progress from the early form to the intermediate form and then to the advanced form, where two subtypes exist: the nonneovascular (dry) type and the neovascular (wet) type. The results from the Age-Related Eye Disease Study have shown that for the nonneovascular type of AMD, supplementation with high-dose antioxidants (vitamin C, vitamin E, and β-carotene) and zinc is recommended for those with the intermediate form of AMD in one or both eyes or with advanced AMD or vision loss due to AMD in one eye. As for the neovascular type of the advanced AMD, the current standard of therapy is intravitreal injections of vascular endothelial growth factor inhibitors. In addition, lifestyle and dietary modifications including improved physical activity, reduced daily sodium intake, and reduced intake of solid fats, added sugars, cholesterol, and refined grain foods are recommended. To date, no study has demonstrated that AMD can be cured or effectively prevented. Clearly, more research is needed to fully understand the pathophysiology as well as to develop prevention and treatment strategies for this devastating disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1010,I1010)","v":23558789},{"$f":"(LEN($J1010) - LEN(SUBSTITUTE(LOWER($J1010),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1010) - LEN(SUBSTITUTE(LOWER($J1010),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1010) - LEN(SUBSTITUTE(LOWER($J1010),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1010:D1010)","v":0},2013,"Pharmacotherapy prevention and management of nutritional deficiencies post Roux-en-Y gastric bypass.","Levinson",23558789,"Pharmacotherapy prevention and management of nutritional deficiencies post Roux-en-Y gastric bypass.    Abstract:   Roux-en-Y gastric bypass is the most commonly performed bariatric procedure. It is associated with nutritional deficiencies due to gastric reduction, intestinal bypass, reduced caloric intake, avoidance of nutrient-rich foods, noncompliance with supplementation and poor food tolerability. Although there are multiple publications on this topic, there is a lack of consistent guidance for the healthcare practitioner caring for the bariatric patient. This article will encompass literature reviewing the pharmacotherapy approach to prevention and management of nutritional deficiencies since the American Society of Metabolic and Bariatric Surgery guidelines were published in 2008."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1011,I1011)","v":23369858},{"$f":"(LEN($J1011) - LEN(SUBSTITUTE(LOWER($J1011),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1011) - LEN(SUBSTITUTE(LOWER($J1011),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1011) - LEN(SUBSTITUTE(LOWER($J1011),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1011:D1011)","v":0},2013,"What role (if any) does the highly conserved CSB-PGBD3 fusion protein play in Cockayne syndrome?","Weiner",23369858,"What role (if any) does the highly conserved CSB-PGBD3 fusion protein play in Cockayne syndrome?    Abstract:   The PGBD3 piggyBac transposon inserted into CSB intron 5 early in the primate lineage. As a result of alternative splicing, the human CSB gene now encodes three proteins: CSB, a CSB-PGBD3 fusion protein that joins the N-terminal CSB domain to the C-terminal PGBD3 transposase domain, and PGBD3 transposase. The fusion protein is as highly conserved as CSB, suggesting that it is advantageous in health; however, expression of the fusion protein in CSB-null cells induces a constitutive interferon (IFN) response. The fusion protein binds in vivo to PGBD3-related MER85 elements, but is also tethered to c-Jun, TEAD1, and CTCF motifs by interactions with the cognate transcription factors. The fusion protein regulates nearby genes from the c-Jun (and to a lesser extent TEAD1 and CTCF) motifs, but not from MER85 elements. We speculate that the fusion protein interferes with CSB-dependent chromatin remodeling, generating double-stranded RNA (dsRNA) that induces an IFN response through endosomal TLR or cytoplasmic RIG-I and/or MDA5 RNA sensors. We suggest that the fusion protein was fixed in primates because an elevated IFN response may help to fight viral infection. We also speculate that an inappropriate IFN response may contribute to the clinical presentation of CS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1012,I1012)","v":23353605},{"$f":"(LEN($J1012) - LEN(SUBSTITUTE(LOWER($J1012),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1012) - LEN(SUBSTITUTE(LOWER($J1012),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1012) - LEN(SUBSTITUTE(LOWER($J1012),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1012:D1012)","v":0},2013,"Thailand nutrition in transition: situation and challenges of maternal and child nutrition.","Winichagoon",23353605,"Thailand nutrition in transition: situation and challenges of maternal and child nutrition.    Abstract:   Double burden of malnutrition (DBMN), the coexistence of under- and overnutrition in the same population, is an emerging public health concern in developing countries, including Thailand. This paper aims to review the maternal and child nutrition situation and trends as the country moved from a low-income to a middle-income country, using data from large scale national surveys. Protein-energy malnutrition and micronutrient deficiencies predominantly affected mothers and children prior to the 1980s. The situation greatly improved during the 1980s- 1990s, with the implementation of multi-sectoral policies and programs focusing on poverty alleviation and primary health care. Economic development, improved access to health services and effective community-based nutrition programs contributed to these positive trends. However, the prevalence of low birth weight remained at 8- 10%, while stunting and underweight declined to about 10% by the 1990s, with small change thereafter. The prevalence of anemia among pregnant women and children decreased by half and vitamin A deficiency is no longer a public health problem. Iodine deficiency, especially during pregnancy is still a major concern. As the country progressed in terms of economic and social development, overnutrition among women and children affected all socio-economic levels. Changes in lifestyles, food access and eating patterns are observed both in urban and rural areas. Although efforts have been made to address these challenges, harmonized policy and strategic programs that address DBMN in the complex social and economic environment are urgently needed. Early life undernutrition should be considered along with measures to address obesity and chronic diseases in children."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1013,I1013)","v":23292551},{"$f":"(LEN($J1013) - LEN(SUBSTITUTE(LOWER($J1013),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1013) - LEN(SUBSTITUTE(LOWER($J1013),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1013) - LEN(SUBSTITUTE(LOWER($J1013),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1013:D1013)","v":0},2013,"Hepatic stellate cells--the pericytes in the liver.","Hellerbrand",23292551,"Hepatic stellate cells--the pericytes in the liver.    Abstract:   Hepatic stellate cells (HSCs) are pericytes of liver in the space between parenchymal cells and sinusoidal endothelial cells of the hepatic lobule. HSCs comprise specialized functions such as vitamin A storage, hemodynamic functions, support of liver regeneration, and immunoregulation. In pathological conditions, HSCs transform to an activated myofibroblasts-like phenotype, start to proliferate, and de novo express several proinflammatory and profibrogenic genes. These processes are particularly important in the development of cirrhosis, portal hypertension, and hepatocellular cancer. This review highlights recent findings in understanding the biology of HSCs and discusses the physiological functions of HSCs and the role of activated HSCs in pathophysiology and disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1014,I1014)","v":23277707},{"$f":"(LEN($J1014) - LEN(SUBSTITUTE(LOWER($J1014),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1014) - LEN(SUBSTITUTE(LOWER($J1014),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1014) - LEN(SUBSTITUTE(LOWER($J1014),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1014:D1014)","v":0},2012,"A rethinking on the benefits and drawbacks of common antioxidants and a proposal to look for the antioxidants in allium products as ideal agents: a review.","Augusti",23277707,"A rethinking on the benefits and drawbacks of common antioxidants and a proposal to look for the antioxidants in allium products as ideal agents: a review.    Abstract:   This review article on the beneficial uses of Allium antioxidants tries to give some answers to the recent doubts raised by Singh et al. (Ind J Clin Biochem 25(3):225-243, 2010) against the claim of some researchers that Antioxidants (AOs) are miraculous molecules. Many people still believe that vitamins like A, C and E are the only true AOs that play important role in the corrections of metabolic derangements in life style diseases and hence all their faults are attributed to the failures of AOs as a class. This is quite unfair as there are many other natural AOs that do equal or even better AO action than the vitamins. Such is the case with the Allium S-alkyl sulfoxide aminoacids and their breakdown products viz, the various poly sulfides and their oxides e.g. allicin and ajoene type compounds which trap electrons mainly. It is true that antioxidant vitamins and β-carotene a precursor of Vitamin A bring about problems as prooxidant or as agents that block some metabolic pathways and gene expression. Again the argument that AOs cannot improve the level of antioxidant enzymes like SOD, catalase and glutathione Px is also not universal. Actually allium AOs can even spare the use of antioxidant vitamins in the body and enhance the action of antioxidant enzymes and supply of ATP and other nutrients to the tissues as the former are good vasodialators and promoters of membrane permeability. The use of AOs should be selective and moderate. Allium AOs satisfy the role of ideal AOs based on many of their invivo and invitro actions reported by the author and others. Their metabolits can regenerate them and recycle them for a sufficient time in the body. They have non antioxidant effects also such as antiplatelet, fibrinolytic, antiinflammatory, immunomodulatory, antiageing actions etc. Plant derived AOs may be more beneficial and better tolerated in their partially purified forms rather than in their absolutely purified forms as the accompanying principles have some protective and regulatory effects in general. This and other aspects of allium AOs are discussed in the paper."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1015,I1015)","v":23277047},{"$f":"(LEN($J1015) - LEN(SUBSTITUTE(LOWER($J1015),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1015) - LEN(SUBSTITUTE(LOWER($J1015),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1015) - LEN(SUBSTITUTE(LOWER($J1015),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1015:D1015)","v":0},2013,"Cellular basis of hepatic fibrosis and its role in inflammation and cancer.","Kocabayoglu",23277047,"Cellular basis of hepatic fibrosis and its role in inflammation and cancer.    Abstract:   Multiple etiologies of liver injury can lead to fibrosis, which results from an imbalance between production and resorption of extracellular matrix. Hepatic stellate cells (HSCs), resident vitamin A storing cells, play a vital role in the response to injury. Upon activation, HSCs orchestrate the responsiveness of the liver to different types of injury, leading to deposition of excessive scar matrix into the interstitium as a wound-healing response. Quantitatively and qualitatively, the altered extracellular matrix (ECM) provides a permissive milieu for the development of cellular dysplasia and ultimately hepatocellular carcinoma (HCC). There is a range of underlying mechanisms that contribute to progression of fibrosis to HCC. As the functional complexity of HSC activation and its roles in inflammation, immune responses, angiogenesis, and proliferation are being clarified, new advances in therapeutic options for patients with chronic liver disease are emerging."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1016,I1016)","v":23232823},{"$f":"(LEN($J1016) - LEN(SUBSTITUTE(LOWER($J1016),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1016) - LEN(SUBSTITUTE(LOWER($J1016),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1016) - LEN(SUBSTITUTE(LOWER($J1016),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1016:D1016)","v":0},2013,"Vitamin a deficiency in pregnancy: perspectives after bariatric surgery.","Chagas",23232823,"Vitamin a deficiency in pregnancy: perspectives after bariatric surgery.    Abstract:   This study aims to describe the clinical consequences of vitamin A deficiency (VAD) in pregnant women after bariatric surgery. Included are studies on VAD during pregnancy and after bariatric surgery conducted in humans from 1993 to 2011. There are few investigations on the relationship between pregnancy and bariatric surgery and on the damage to the binomial mother-child resulting from VAD in this relationship. The high percentage of VAD in the postoperative period is a cause for concern, especially considering the function of this vitamin in certain biological moments and in moments of intense nutritional demand. This vitamin serum evaluation is recommended during the prenatal period."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1017,I1017)","v":23201837},{"$f":"(LEN($J1017) - LEN(SUBSTITUTE(LOWER($J1017),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1017) - LEN(SUBSTITUTE(LOWER($J1017),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1017) - LEN(SUBSTITUTE(LOWER($J1017),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1017:D1017)","v":0},2012,"Lipophilic micronutrients and adipose tissue biology.","Landrier",23201837,"Lipophilic micronutrients and adipose tissue biology.    Abstract:   Lipophilic micronutrients (LM) constitute a large family of molecules including several vitamins (A, D, E, K) and carotenoids. Their ability to regulate gene expression is becoming increasingly clear and constitutes an important part of nutrigenomics. Interestingly, adipose tissue is not only a main storage site for these molecules within the body, but it is also subjected to the regulatory effects of LM. Indeed, several gene regulations have been described in adipose tissue that could strongly impact its biology with respect to the modulation of adipogenesis, inflammatory status, or energy homeostasis and metabolism, among others. The repercussions in terms of health effects of such regulations in the context of obesity and associated pathologies represent an exciting and emerging field of research. The present review will focus on the regulatory effects of vitamin A, D, E and K as well as carotenoids on adipose tissue biology and physiology, notably in the context of obesity and associated disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1018,I1018)","v":23178453},{"$f":"(LEN($J1018) - LEN(SUBSTITUTE(LOWER($J1018),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1018) - LEN(SUBSTITUTE(LOWER($J1018),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1018) - LEN(SUBSTITUTE(LOWER($J1018),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1018:D1018)","v":0},2013,"Integration of toxicological approaches with quot;omicquot; and related technologies to elucidate mechanisms of carcinogenic action: propiconazole, an example.","Nesnow",23178453,"Integration of toxicological approaches with quot;omicquot; and related technologies to elucidate mechanisms of carcinogenic action: propiconazole, an example.    Abstract:   The field of mechanistic chemical carcinogenesis has evolved with the advent and advances in genomic, proteomic and metabolomic technologies. These advances allow mechanistic events along the process of exposure to frank tumors to be studied in great detail. Herein is reviewed an example of this approach using, propiconazole, a triazole-containing antifungal agent that is a mouse hepatocarcinogen. This review will highlight those toxicological, genomic, proteomic and metabolomic findings in mice that were used to describe a set of linked events that lead to propiconazole-induced hepatocarcinogenesis. Independent experimental proof of many of these events is presented that solidified this proposed mechanism of carcinogenic action for propiconazole."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1019,I1019)","v":23044345},{"$f":"(LEN($J1019) - LEN(SUBSTITUTE(LOWER($J1019),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1019) - LEN(SUBSTITUTE(LOWER($J1019),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1019) - LEN(SUBSTITUTE(LOWER($J1019),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1019:D1019)","v":0},2013,"The role of nuclear receptors in controlling the fine balance between proliferation and differentiation of neural stem cells.","Stergiopoulos",23044345,"The role of nuclear receptors in controlling the fine balance between proliferation and differentiation of neural stem cells.    Abstract:   In the central nervous system (CNS) of vertebrates a large variety of cell types are specified from a pool of highly plastic neural stem/progenitor cells (NSCs) via a combined action of extrinsic morphogenetic cues and intrinsic transcriptional regulatory networks. Nuclear receptors and their ligands are key regulators of fate decisions in NSCs during development and adulthood, through their ability to control transcription of downstream genes. In the last few years considerable progress has been made towards the understanding of the actions of nuclear receptors in NSCs as well as elucidating the mechanistic basis for these actions. Here we summarize recent progress in the role of nuclear receptors in the biology of NSCs. These studies highlight the importance of this family of transcriptional regulators in CNS development and function in health and disease. Furthermore, they raise the intriguing possibility of using nuclear receptors as therapeutic targets for nervous system related diseases and traumas."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1020,I1020)","v":23008041},{"$f":"(LEN($J1020) - LEN(SUBSTITUTE(LOWER($J1020),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1020) - LEN(SUBSTITUTE(LOWER($J1020),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1020) - LEN(SUBSTITUTE(LOWER($J1020),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1020:D1020)","v":0},2012,"Interaction of vitamin A and other micronutrients.","McLaren",23008041,"Interaction of vitamin A and other micronutrients.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1021,I1021)","v":23008037},{"$f":"(LEN($J1021) - LEN(SUBSTITUTE(LOWER($J1021),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1021) - LEN(SUBSTITUTE(LOWER($J1021),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1021) - LEN(SUBSTITUTE(LOWER($J1021),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1021:D1021)","v":0},2012,"Assessment of vitamin A status.","McLaren",23008037,"Assessment of vitamin A status.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1022,I1022)","v":23008036},{"$f":"(LEN($J1022) - LEN(SUBSTITUTE(LOWER($J1022),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1022) - LEN(SUBSTITUTE(LOWER($J1022),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1022) - LEN(SUBSTITUTE(LOWER($J1022),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1022:D1022)","v":0},2012,"Vitamin A in health.","McLaren",23008036,"Vitamin A in health.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1023,I1023)","v":23008034},{"$f":"(LEN($J1023) - LEN(SUBSTITUTE(LOWER($J1023),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1023) - LEN(SUBSTITUTE(LOWER($J1023),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1023) - LEN(SUBSTITUTE(LOWER($J1023),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1023:D1023)","v":0},2012,"Food sources.","McLaren",23008034,"Food sources.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1024,I1024)","v":22868377},{"$f":"(LEN($J1024) - LEN(SUBSTITUTE(LOWER($J1024),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1024) - LEN(SUBSTITUTE(LOWER($J1024),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1024) - LEN(SUBSTITUTE(LOWER($J1024),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1024:D1024)","v":0},2013,"Innate immune responses in hepatitis C virus infection.","Li",22868377,"Innate immune responses in hepatitis C virus infection.    Abstract:   Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis and hepatocellular carcinoma worldwide and thus poses a significant public health threat. A hallmark of HCV infection is the extraordinary ability of the virus to persist in a majority of infected people. Innate immune responses represent the front line of defense of the human body against HCV immediately after infection. They also play a crucial role in orchestrating subsequent HCV-specific adaptive immunity that is pivotal for viral clearance. Accumulating evidence suggests that the host has evolved multifaceted innate immune mechanisms to sense HCV infection and elicit defense responses, while HCV has developed elaborate strategies to circumvent many of these. Defining the interplay of HCV with host innate immunity reveals mechanistic insights into hepatitis C pathogenesis and informs approaches to therapy. In this review, we summarize recent advances in understanding innate immune responses to HCV infection, focusing on induction and effector mechanisms of the interferon antiviral response as well as the evasion strategies of HCV."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1025,I1025)","v":22488437},{"$f":"(LEN($J1025) - LEN(SUBSTITUTE(LOWER($J1025),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1025) - LEN(SUBSTITUTE(LOWER($J1025),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1025) - LEN(SUBSTITUTE(LOWER($J1025),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1025:D1025)","v":0},2012,"Pathway engineering strategies for production of beneficial carotenoids in microbial hosts.","Ye",22488437,"Pathway engineering strategies for production of beneficial carotenoids in microbial hosts.    Abstract:   Carotenoids, such as lycopene, β-carotene, zeaxanthin, canthaxanthin and astaxanthin have many benefits for human health. In addition to the functional role of carotenoids as vitamin A precursors, adequate consumption of carotenoids prevents the development of a variety of serious diseases. Biosynthesis of carotenoids is a complex process and it starts with the common isoprene precursors. Condensation of these precursors and subsequent modifications, by introducing hydroxyl- and keto-groups, leads to the generation of diversified carotenoid structures. To improve carotenoid production, metabolic engineering has been explored in bacteria, yeast, and algae. The success of the pathway engineering effort depends on the host metabolism, specific enzymes used, the enzyme expression levels, and the strategies employed. Despite the difficulty of pathway engineering for carotenoid production, great progress has been made over the past decade. We review metabolic engineering approaches used in a variety of microbial hosts for carotenoid biosynthesis. These advances will greatly expedite our efforts to bring the health benefits of carotenoids and other nutritional compounds to our diet."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1026,I1026)","v":22363988},{"$f":"(LEN($J1026) - LEN(SUBSTITUTE(LOWER($J1026),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1026) - LEN(SUBSTITUTE(LOWER($J1026),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1026) - LEN(SUBSTITUTE(LOWER($J1026),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1026:D1026)","v":0},2011,"[The relationship between LXR/RXR and ABCA1 transmembrane-transport system with Alzheimers disease].","Gao",22363988,"[The relationship between LXR/RXR and ABCA1 transmembrane-transport system with Alzheimers disease].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1027,I1027)","v":22157539},{"$f":"(LEN($J1027) - LEN(SUBSTITUTE(LOWER($J1027),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1027) - LEN(SUBSTITUTE(LOWER($J1027),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1027) - LEN(SUBSTITUTE(LOWER($J1027),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1027:D1027)","v":0},2012,"The historical evolution of thought regarding multiple micronutrient nutrition.","Semba",22157539,"The historical evolution of thought regarding multiple micronutrient nutrition.    Abstract:   Multiple micronutrient nutrition is an idea that originated in the 1940s and exemplifies the iterative nutritional paradigm. In the first four decades of the 20th century, scientists sought to separate and characterize the vitamins that were responsible for xerophthalmia, rickets, pellagra, scurvy, and beriberi. The dietary requirements of the different micronutrients began to be established in the early 1940s. Surveys showed that multiple micronutrient deficiencies were widespread in industrialized countries, and the problem was addressed by use of cod-liver oil, iodized salt, fortified margarine, and flour fortification with multiple micronutrients, and, with rising living standards, the increased availability and consumption of animal source foods. After World War II, surveys showed that multiple micronutrient deficiencies were widespread in developing countries. Approaches to the elimination of multiple micronutrient deficiencies include periodic vitamin A supplementation, iodized salt, targeted iron/folate supplementation, fortified flour, other fortified foods, home fortification with micronutrient powders, and homestead food production. The prevention of multiple micronutrient malnutrition is a key factor in achieving the Millennium Development Goals, given the important effects of micronutrients on health and survival."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1028,I1028)","v":22149583},{"$f":"(LEN($J1028) - LEN(SUBSTITUTE(LOWER($J1028),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1028) - LEN(SUBSTITUTE(LOWER($J1028),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1028) - LEN(SUBSTITUTE(LOWER($J1028),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1028:D1028)","v":0},2012,"Update on hepatic stellate cells: pathogenic role in liver fibrosis and novel isolation techniques.","Tacke",22149583,"Update on hepatic stellate cells: pathogenic role in liver fibrosis and novel isolation techniques.    Abstract:   Hepatic stellate cells (HSCs), also called Ito cells or lipocytes, are vitamin A-storing cells located in the Dissé space between hepatocytes and sinusoidal endothelial cells. Upon liver injury, these cells transdifferentiate into extracellular matrix-producing, highly proliferative myofibroblasts that promote hepatic fibrogenesis. Other possible collagen-producing cells in liver fibrosis include portal fibroblasts, bone marrow-derived cells (mesenchymal stem cells, fibrocytes and hematopoietic cells) and parenchymal cells undergoing epithelial-to-mesenchymal transition. Important factors and signaling pathways for HSC activation, as well as different functions of HSC during homeostasis and fibrosis, such as collagen production, secretion of cytokines and chemokines, immune modulation and changes in contractile features, as well as vitamin A storage capacity, have been identified in vitro and in vivo. Novel isolation techniques, specifically HSC sorting by FACS via autofluorescence and antibodies, will provide us with further opportunities to advance our understanding of HSC biology in health and disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1029,I1029)","v":22123644},{"$f":"(LEN($J1029) - LEN(SUBSTITUTE(LOWER($J1029),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1029) - LEN(SUBSTITUTE(LOWER($J1029),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1029) - LEN(SUBSTITUTE(LOWER($J1029),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1029:D1029)","v":0},2012,"Advances in coeliac disease.","Armstrong",22123644,"Advances in coeliac disease.    Abstract:    PURPOSE OF REVIEW : This article critically summarizes the recent scientific and clinical advances in coeliac disease.  RECENT FINDINGS : Epidemiological studies have shown that coeliac disease is as common in parts of Asia, Africa and Eastern Europe as in the western world. Genome-wide association studies continue to identify genetic susceptibilities that are both unique to coeliac disease and overlap with other autoimmune diseases. Human leukocyte antigen genotyping offers additional sensitivity in detecting coeliac disease in individuals who have self-prescribed gluten-free diets (GFD) or have atypical presentations. Immunological advances have highlighted the potential proinflammatory pitfalls of vitamin A supplementation in active coeliac disease and have enabled identification of oat and barley subsets that may be safely incorporated into coeliac diets. Large population-based studies have expanded our knowledge of the long-term risks of coeliac disease, in addition to excluding infertility as a cause for concern once a GFD has been established.  SUMMARY : The long-term implications of active coeliac disease emphasize the need for early detection and strict adherence to GFD, which remains the cornerstone of management. Technological advances in food modulation and immuno-therapies offer promise, but remain in the translational phases of clinical trials at present."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1030,I1030)","v":22071828},{"$f":"(LEN($J1030) - LEN(SUBSTITUTE(LOWER($J1030),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1030) - LEN(SUBSTITUTE(LOWER($J1030),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1030) - LEN(SUBSTITUTE(LOWER($J1030),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1030:D1030)","v":0},2011,"Nutritional supplements for people being treated for active tuberculosis.","Sinclair",22071828,"Nutritional supplements for people being treated for active tuberculosis.    Abstract:    BACKGROUND : Tuberculosis and malnutrition are linked in a complex relationship. The infection may cause undernutrition through increased metabolic demands and decreased intake, and nutritional deficiencies may worsen the disease, or delay recovery by depressing important immune functions. At present, there are no evidence-based nutritional guidance for adults and children being treated for tuberculosis.  OBJECTIVES : To assess the effects of oral nutritional supplements (food, protein/energy supplements or micronutrients) on tuberculosis treatment outcomes and recovery in people on antituberculous drug therapy for active tuberculosis.  SEARCH METHODS : We searched the Cochrane Infectious Disease Group Specialized Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, LILACS, mRCT, and the Indian Journal of Tuberculosis to July 2011, and checked the reference lists of all included studies.  SELECTION CRITERIA : Randomized controlled trials comparing any oral nutritional supplement given for at least four weeks with no nutritional intervention, placebo, or dietary advice only for people being treated for active tuberculosis.  DATA COLLECTION AND ANALYSIS : Two authors independently selected trials, extracted data, and assessed the risk of bias. Results are presented as risk ratios (RR) for dichotomous variables, and mean differences (MD) for continuous variables, with 95% confidence intervals (CI). Where appropriate, data from trials with similar interventions and outcomes have been pooled. The quality of evidence was assessed using the GRADE methods.  MAIN RESULTS : Twenty-three trials, with 6842 participants, were included. Macronutrient supplementation Five trials assessed the provision of free food, or high energy supplements, although none were shown to provide a total daily kilocalorie intake above the current daily recommended intake for the non-infected population.The available trials were too small to reliably prove or exclude clinically important benefits on mortality, cure, or treatment completion. One small trial from India did find a statistically significant benefit on treatment completion, and clearance of the bacteria from the sputum, but these findings have not been confirmed in larger trials elsewhere (VERY LOW quality evidence).The provision of free food or high-energy nutritional products probably does produce a modest increase in weight gain during treatment for active tuberculosis (MODERATE quality evidence). Two small studies provide some evidence that physical function and quality of life may also be improved but the trials were too small to have much confidence in the result (LOW quality evidence). These effects were not seen in the one trial which included only human immunodeficiency virus (HIV)-positive patients.Micronutrient supplementation Five trials assessed multi-micronutrient supplementation in doses up to ten times the dietary reference intake, and 12 trials assessed single or dual micronutrient supplementation.There is insufficient evidence to judge whether multi-micronutrients have a beneficial effect on mortality in HIV- negative patients with tuberculosis (VERY LOW quality evidence), but the available studies show that multi-micronutrients probably have little or no effect on mortality in HIV-positive patients with tuberculosis (MODERATE quality evidence). No studies have assessed the effects of multi-micronutrients on cure, or treatment completion.Multi-micronutrient supplements may have little or no effect on the proportion of tuberculosis patients remaining sputum positive during the first eight weeks (LOW quality evidence), and probably have no effect on weight gain during treatment (MODERATE quality evidence). No studies have assessed quality of life.Plasma levels of vitamin A appear to increase following initiation of tuberculosis treatment regardless of supplementation. In contrast, plasma levels of zinc, vitamin D and E, and selenium may be improved by supplementation during the early stages of tuberculosis treatment, but a consistent benefit on tuberculosis treatment outcomes or nutritional recovery has not been demonstrated.  AUTHORS CONCLUSIONS : There is insufficient research to know whether routinely providing free food or energy supplements results in better tuberculosis treatment outcomes, or improved quality of life. Further trials, particularly from food insecure settings, should have adequate sample sizes to identify, or exclude, clinically important benefits.Although blood levels of some vitamins may be low in patients starting treatment for active tuberculosis, there is currently no reliable evidence that routinely supplementing at or above recommended daily amounts has clinical benefits."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1031,I1031)","v":21932165},{"$f":"(LEN($J1031) - LEN(SUBSTITUTE(LOWER($J1031),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1031) - LEN(SUBSTITUTE(LOWER($J1031),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1031) - LEN(SUBSTITUTE(LOWER($J1031),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1031:D1031)","v":0},2012,"The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis.","Haussler",21932165,"The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis.    Abstract:   1,25-dihydroxyvitamin D (1,25D), through association with the nuclear vitamin D receptor (VDR), exerts control over a novel endocrine axis consisting of the bone-derived hormone FGF23, and the kidney-expressed klotho, CYP27B1, and CYP24A1 genes, which together prevent hyperphosphatemia/ectopic calcification and govern the levels of 1,25D to maintain bone mineral integrity while promoting optimal function of other vital tissues. When occupied by 1,25D, VDR interacts with RXR to form a heterodimer that binds to VDREs in the region of genes directly controlled by 1,25D (e.g., FGF23, klotho, Npt2c, CYP27B1 and CYP24A1). By recruiting complexes of comodulators, activated VDR initiates a series of events that induces or represses the transcription of genes encoding proteins such as: the osteocyte-derived hormone, FGF23; the renal anti-senescence factor and protein co-receptor for FGF23, klotho; other mediators of phosphate transport including Npt2a/c; and vitamin D hormone metabolic enzymes, CYP27B1 and CYP24A1. The mechanism whereby osteocytes are triggered to release FGF23 is yet to be fully defined, but 1,25D, phosphate, and leptin appear to play major roles. The kidney responds to FGF23 to elicit CYP24A1-catalyzed detoxification of the 1,25D hormone while also repressing both Npt2a/c to mediate phosphate elimination and CYP27B1 to limit de novo 1,25D synthesis. Comprehension of these skeletal and renal actions of 1,25D should facilitate the development of novel mimetics to prevent ectopic calcification, chronic renal and vascular disease, and promote healthful aging."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1032,I1032)","v":21901727},{"$f":"(LEN($J1032) - LEN(SUBSTITUTE(LOWER($J1032),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1032) - LEN(SUBSTITUTE(LOWER($J1032),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1032) - LEN(SUBSTITUTE(LOWER($J1032),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1032:D1032)","v":0},2011,"Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age.","De-Regil",21901727,"Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age.    Abstract:    BACKGROUND : Vitamin and mineral deficiencies, particularly those of iron, vitamin A and zinc, affect more than two billion people worldwide. Young children are highly vulnerable because of rapid growth and inadequate dietary practices. Micronutrient powders (MNP) are single-dose packets containing multiple vitamins and minerals in powder form that can be sprinkled onto any semi-solid food.The use of MNP for home or point-of-use fortification of complementary foods has been proposed as an intervention for improving micronutrient intake in children under two years of age.  OBJECTIVES : To assess the effects and safety of home (point-of-use) fortification of foods with multiple micronutrient powders on nutritional, health and developmental outcomes in children under two years of age.  SEARCH STRATEGY : We searched the following databases in February 2011: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (1948 to week 2 February 2011), EMBASE (1980 to Week 6 2011), CINAHL (1937 to current), CPCI-S (1990 to 19 February 2011), Science Citation Index (1970 to 19 February 2011), African Index Medicus (searched 23 February 2011), POPLINE (searched 21 February 2011), ClinicalTrials.gov (searched 23 February 2011), mRCT (searched 23 February 2011), and World Health Organization International Clinical Trials Registry Platform (ICTRP) (searched 23 February 2011). We also contacted relevant organisations (25 January 2011) for the identification of ongoing and unpublished studies.  SELECTION CRITERIA : We included randomised and quasi-randomised trials with either individual or cluster randomisation. Participants were children under the age of two years at the time of intervention, with no specific health problems. The intervention was consumption of food fortified at the point of use with multiple micronutrient powders formulated with at least iron, zinc and vitamin A compared with placebo, no intervention or the use of iron containing supplements, which is the standard practice.  DATA COLLECTION AND ANALYSIS : Two review authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies and assessed the risk of bias of the included studies.  MAIN RESULTS : We included eight trials (3748 participants) conducted in low income countries in Asia, Africa and the Caribbean, where anaemia is a public health problem. The interventions lasted between two and 12 months and the powder formulations contained between five and 15 nutrients. Six trials compared the use of MNP versus no intervention or a placebo and the other two compared the use of MNP versus daily iron drops. Most of the included trials were assessed as at low risk of bias.Home fortification with MNP reduced anaemia by 31% (six trials, RR 0.69; 95% CI 0.60 to 0.78) and iron deficiency by 51% (four trials, RR 0.49; 95% CI 0.35 to 0.67) in infants and young children when compared with no intervention or placebo, but we did not find an effect on growth.In comparison with daily iron supplementation, the use of MNP produced similar results on anaemia (one trial, RR 0.89; 95% CI 0.58 to 1.39) and haemoglobin concentrations (two trials, MD -2.36 g/L; 95% CI -10.30 to 5.58); however, given the limited amount of data these results should be interpreted cautiously.No deaths were reported in the trials and information on side effects and morbidity, including malaria, was scarce.It seems that the use of MNP is efficacious among infants and young children six to 23 months of age living in settings with different prevalences of anaemia and malaria endemicity, regardless of whether the intervention lasts two, six or 12 months or whether recipients are male or female.  AUTHORS CONCLUSIONS : Home fortification of foods with multiple micronutrient powders is an effective intervention to reduce anaemia and iron deficiency in children six months to 23 months of age. The provision of MNP is better than no intervention or placebo and possibly comparable to commonly used daily iron supplementation. The benefits of this intervention as a child survival strategy or on developmental outcomes are unclear. Data on effects on malaria outcomes are lacking and further investigation of morbidity outcomes is needed. The micronutrient powders containing multiple nutrients are well accepted but adherence is variable and in some cases comparable to that achieved in infants and young children receiving standard iron supplements as drops or syrups."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1033,I1033)","v":21896442},{"$f":"(LEN($J1033) - LEN(SUBSTITUTE(LOWER($J1033),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1033) - LEN(SUBSTITUTE(LOWER($J1033),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1033) - LEN(SUBSTITUTE(LOWER($J1033),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1033:D1033)","v":0},2011,"[Fatty liver and hepatitis C virus infection].","Lakatos",21896442,"[Fatty liver and hepatitis C virus infection].    Abstract:   Hepatitis C virus infection is a common liver disease worldwide, leading to the development of steatosis, cirrhosis and hepatocellular carcinoma. In patients with chronic hepatitis C virus infection the prevalence of steatosis has been estimated to be about 55%. Development of steatosis is due to both viral and metabolic factors. Hepatitis C virus proteins moderate a number of intracellular pathways, however, further studies are required to understand these mechanisms. Obesity and insulin resistance may allow the virus to resist antiviral treatment. This review discusses the relationship among steatosis, insulin resistance and the response to antiviral therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1034,I1034)","v":21717915},{"$f":"(LEN($J1034) - LEN(SUBSTITUTE(LOWER($J1034),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1034) - LEN(SUBSTITUTE(LOWER($J1034),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1034) - LEN(SUBSTITUTE(LOWER($J1034),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1034:D1034)","v":0},2011,"Bioavailability of micronutrients: stable isotope techniques to develop effective food-based strategies to combat micronutrient deficiencies.","Davidsson",21717915,"Bioavailability of micronutrients: stable isotope techniques to develop effective food-based strategies to combat micronutrient deficiencies.    Abstract:    BACKGROUND : The prevalence of micronutrient deficiencies, in particular those of iron, vitamin A, iodine, and zinc, is unacceptably high, especially among infants, children, and women of childbearing age in developing countries. Effective food-based strategies to combat these public health problems are therefore urgently needed.  OBJECTIVE : As only a fraction of dietary iron, zinc, and provitamin A carotenoids is absorbed and utilized, i.e., bioavailable, access to information on micronutrient bioavailability is crucial in the development of food fortification strategies and interventions based on dietary diversification.  METHODS : Review of literature.  RESULTS AND CONCLUSIONS : This overview highlights the usefulness of stable isotope techniques to assess the bioavailability of nonheme iron and provitamin A carotenoids and the importance of generating data on micronutrient bioavailability to move the agenda forward."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1035,I1035)","v":21677119},{"$f":"(LEN($J1035) - LEN(SUBSTITUTE(LOWER($J1035),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1035) - LEN(SUBSTITUTE(LOWER($J1035),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1035) - LEN(SUBSTITUTE(LOWER($J1035),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1035:D1035)","v":0},2010,"Cod liver oil, young children, and upper respiratory tract infections.","Linday",21677119,"Cod liver oil, young children, and upper respiratory tract infections.    Abstract:   Cod liver oil contains long-chain omega-3 fatty acids, as well as vitamins D and A. It was a traditional source of vitamin D in the United States and was used to prevent and treat rickets. In our clinical research, we used liquid cod liver oil of adequate purity and acceptable taste for infants and young children, as well as a childrens multivitamin/mineral supplement with selenium and other trace metals. In a cluster-randomized study of pediatric visits for upper respiratory illness during the winter and early spring, these nutritional supplements decreased mean visits/subject/month by 36%-58%. Cod liver oil is culturally valued and has been used as a folk remedy by many low-income minorities in the United States. Nutritional supplements cannot be purchased with SNAP benefits (formerly called food stamps). Inclusion of cod liver oil in state Medicaid formularies would make it available to low-income children, whose families may not be able to pay for it out-of-pocket."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1036,I1036)","v":21666984},{"$f":"(LEN($J1036) - LEN(SUBSTITUTE(LOWER($J1036),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1036) - LEN(SUBSTITUTE(LOWER($J1036),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1036) - LEN(SUBSTITUTE(LOWER($J1036),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1036:D1036)","v":0},2011,"[Phrynoderma secondary to vitamin A deficiency in a patient with biliopancreatic diversion].","Ocón Bretón",21666984,"[Phrynoderma secondary to vitamin A deficiency in a patient with biliopancreatic diversion].    Abstract:   Biliopancreatic diversion (BPD) is a malabsorptivebariatric procedure can lead to the development of several nutritional complications, including fat-soluble vitamins deficiencies. Routine supplementation with vitamins and trace elements and a close follow-up long-term can prevent these nutritional risks. Vitamin A participates in ocular metabolism, epithelial differentiation, growth, and embryogenesis. Have been described several cases of ophthalmological and fetal complications associated with vitamin A deficiency in patients who have undergone BPD. Few information exists in literature about dermatologic manifestations that may occur in these patients. Phrynoderma is a type of follicular hyperkeratosis located on the extensor surfaces of the extremities whose main cause is vitamin A deficiency. We report an exceptional case of severe cutaneous and ocular complications in a patient who had undergone BPD with poor adherence to treatment and postoperative follow-up. Our patient presented simultaneously the characteristic skin lesions of phrynoderma with nytalopia and xerophthalmia in a setting of low serum levels of vitamin A. Treatment with high doses vitamin A obtained the resolution of both processes. We review and discuss the relationship between phrynoderma, malnutrition and vitamin A deficiency."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1037,I1037)","v":21570926},{"$f":"(LEN($J1037) - LEN(SUBSTITUTE(LOWER($J1037),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1037) - LEN(SUBSTITUTE(LOWER($J1037),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1037) - LEN(SUBSTITUTE(LOWER($J1037),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1037:D1037)","v":0},2011,"Xeroderma pigmentosum family support group: Helping families and promoting clinical initiatives.","Milota",21570926,"Xeroderma pigmentosum family support group: Helping families and promoting clinical initiatives.    Abstract:   The past two decades of research into Xeroderma pigmentosum (XP), an autosomal recessive disease, has been marked by significant progress in understanding the molecular basis of this rare disease. More importantly, especially from the perspective of the affected families, is that this knowledge has been applied to diagnose the condition both in utero as well as in the very early days of life. The eight known XP genes and their different phenotypes present a number of challenges that the XP Workshop sponsored by the NIH in 2010 has highlighted. There is little current treatment specifically designed for any of the XP types other than standard dermatological and neurological evaluations and care. The Xeroderma Pigmentosum Family Support Group (XPFSG) is dedicated to serving families with children and adults with all forms of XP and to help them better understand the condition, to identify practical measures which can be taken by the XP patients and their families to mitigate the effects of the disease, and to serve as patient advocates to help families discuss issues with their physicians. We summarize our efforts in terms of outreach within the US and abroad to affected families and discuss XPFSG-sponsored clinical initiatives that include molecular diagnoses, treatment, and initial proof-of-concept studies that can, if successful, improve the lives of XP patients in the near term."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1038,I1038)","v":21554208},{"$f":"(LEN($J1038) - LEN(SUBSTITUTE(LOWER($J1038),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1038) - LEN(SUBSTITUTE(LOWER($J1038),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1038) - LEN(SUBSTITUTE(LOWER($J1038),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1038:D1038)","v":0},2011,"Role of Class II nuclear receptors in liver carcinogenesis.","Li",21554208,"Role of Class II nuclear receptors in liver carcinogenesis.    Abstract:   Nuclear receptors (NRs) are ligand-activated transcription factors that are important to life by regulating a wide variety of physiological and pathological functions. There are three classes of NRs defined by ligands and heterodimer partners. The Class II NRs are involved in a broad range of pathophysiological functions in the liver, including cholesterol and bile acid homeostasis; lipid and glucose metabolism; inflammation; liver regeneration and hepatocellular carcinogenesis. Due to highly complicated molecular mechanisms in the development and progression of hepatocellular carcinoma (HCC), HCC is still one of the most common malignancies in the world. Given the pivotal functions of the Class II NRs in the liver, the roles of these NRs in hepatocellular carcinogenesis are emerging. This review summarizes the roles of Class II NRs in liver carcinogenesis and their potential application in the prevention and treatment of HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1039,I1039)","v":21419276},{"$f":"(LEN($J1039) - LEN(SUBSTITUTE(LOWER($J1039),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1039) - LEN(SUBSTITUTE(LOWER($J1039),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1039) - LEN(SUBSTITUTE(LOWER($J1039),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1039:D1039)","v":0},2011,"Key roles of vitamins A, C, and E in aflatoxin B1-induced oxidative stress.","Alpsoy",21419276,"Key roles of vitamins A, C, and E in aflatoxin B1-induced oxidative stress.    Abstract:   Aflatoxins (Aspergillus flavus toxins) are one of the natural toxic molecules which are produced by a group of fungi called Aspergillus. Foods and drinks contaminated with aflatoxins cause global health and environmental problems. Today in many developing countries, these toxins are leading cause of some liver cancers and serious gastrointestinal problems. Aflatoxins, which are well known to be mutagenic, carcinogenic, hepatotoxic, and immunosuppressive, exert inhibitory effects on biological processes including DNA synthesis, DNA-dependent RNA synthesis, DNA repair, and protein synthesis. Aflatoxins B(1) (AFB(1)) is the most widespread oxidative agent of the aflatoxins. Numerous diverse compounds and extracts have been reported to reduce the aflatoxins induced oxidative stress in the body. Most of these inhibitors including phenylpropanoids, terpenoids, alkaloids, and vitamins are originally derived from plants. Among these, being essential biomolecules, vitamins are used as coenzymes in very significant biological reactions. They also function as nonenzymatic antioxidative agents protecting the cells from oxidative stress-induced toxicity and transformation. This chapter reviews the mechanism of AFB(1)-induced oxidative stress and focuses on the protective effects of vitamins A, C, and E on reducing this stress."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1040,I1040)","v":21412909},{"$f":"(LEN($J1040) - LEN(SUBSTITUTE(LOWER($J1040),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1040) - LEN(SUBSTITUTE(LOWER($J1040),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1040) - LEN(SUBSTITUTE(LOWER($J1040),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1040:D1040)","v":0},2011,"Antioxidant supplements for liver diseases.","Bjelakovic",21412909,"Antioxidant supplements for liver diseases.    Abstract:    BACKGROUND : Several liver diseases have been associated with oxidative stress. Accordingly, antioxidants have been suggested as potential therapeutics for various liver diseases. The evidence supporting these suggestions is equivocal.  OBJECTIVES : To assess the benefits and harms of antioxidant supplements for patients with liver diseases.  SEARCH STRATEGY : We searched The Cochrane Library, MEDLINE, EMBASE, LILACS, the Science Citation Index Expanded, and Conference Proceedings Citation Index-Science to January 2011. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials.  SELECTION CRITERIA : We considered for inclusion randomised trials that compared antioxidant supplements (beta-carotene, vitamin A, C, E, and selenium) versus placebo or no intervention for autoimmune liver diseases, viral hepatitis, alcoholic liver disease, and cirrhosis (any aetiology).  DATA COLLECTION AND ANALYSIS : Four authors independently selected trials for inclusion and extracted data. Outcome measures were all-cause mortality, liver-related mortality, liver-related morbidity, biochemical indices at maximum follow-up in the individual trials as well as adverse events, quality-of-life measures, and cost-effectiveness. For patients with hepatitis B or C we also considered end of treatment and sustained virological response. We conducted random-effects and fixed-effect meta-analyses. Results were presented as relative risks (RR) or mean differences (MD), both with 95% confidence intervals (CI).  MAIN RESULTS : Twenty randomised trials with 1225 participants were included. The trials assessed beta-carotene (3 trials), vitamin A (2 trials), vitamin C (9 trials), vitamin E (15 trials), and selenium (8 trials). The majority of the trials had high risk of bias and showed heterogeneity. Overall, the assessed antioxidant supplements had no significant effect on all-cause mortality (relative risk [RR] 0.84, 95% confidence interval [CI] 0.60 to 1.19, I(2) = 0%), or liver-related mortality (RR 0.89, 95% CI 0.39 to 2.05, I(2) = 37%). Stratification according to the type of liver disease did not affect noticeably the results. Antioxidant supplements significantly increased activity of gamma glutamyl transpeptidase (MD 24.21 IU/l, 95% CI 6.67 to 41.75, I(2) = 0%).  AUTHORS CONCLUSIONS : We found no evidence to support or refute antioxidant supplements in patients with liver disease. Antioxidant supplements may increase liver enzyme activity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1041,I1041)","v":20871833},{"$f":"(LEN($J1041) - LEN(SUBSTITUTE(LOWER($J1041),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1041) - LEN(SUBSTITUTE(LOWER($J1041),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1041) - LEN(SUBSTITUTE(LOWER($J1041),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1041:D1041)","v":0},2011,"Vitamin a deficiency after gastric bypass surgery: an underreported postoperative complication.","Zalesin",20871833,"Vitamin a deficiency after gastric bypass surgery: an underreported postoperative complication.    Abstract:   Introduction. Few data are available on vitamin A deficiency in the gastric bypass population. Methods. We performed a retrospective chart review of gastric bypass patients (n = 69, 74% female). The relationship between serum vitamin A concentration and markers of protein metabolism at 6-weeks and 1-year post-operative were assessed. Results. The average weight loss at 6-weeks and 1-year following surgery was 20.1 ± 9.1 kg and 44.1 ± 17.1 kg, respectively. At 6 weeks and 1 year after surgery, 35% and 18% of patients were vitamin A deficient, (lt;325 mcg/L). Similarly, 34% and 19% had low pre-albumin levels (lt;18 mg/dL), at these time intervals. Vitamin A directly correlated with pre-albumin levels at 6 weeks (r = 0.67, P lt; 0.001) and 1-year (r = 0.67,  P lt; 0.0001). There was no correlation between the roux limb length measurement and pre-albumin or vitamin A serum concentrations at these post-operative follow-ups. Vitamin A levels and markers of liver function testing were also unrelated. Conclusion. Vitamin A deficiency is common after bariatric surgery and is associated with a low serum concentration of pre-albumin. This fat-soluble vitamin should be measured in patients who have undergone gastric bypass surgery and deficiency should be suspected in those with evidence of protein-calorie malnutrition."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1042,I1042)","v":20702838},{"$f":"(LEN($J1042) - LEN(SUBSTITUTE(LOWER($J1042),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1042) - LEN(SUBSTITUTE(LOWER($J1042),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1042) - LEN(SUBSTITUTE(LOWER($J1042),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1042:D1042)","v":0},2010,"Update in pediatrics: focus on fat-soluble vitamins.","Sathe",20702838,"Update in pediatrics: focus on fat-soluble vitamins.    Abstract:   This article provides an update on fat-soluble vitamins (A, D, E, and K) in the healthy pediatric population and in children with chronic disease states that commonly cause deficiencies, specifically cystic fibrosis and cholestatic liver disease. For each fat-soluble vitamin, the biological function, nutrition availability, absorption, deficiency, toxic states, and monitoring parameters are defined."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1043,I1043)","v":20689419},{"$f":"(LEN($J1043) - LEN(SUBSTITUTE(LOWER($J1043),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1043) - LEN(SUBSTITUTE(LOWER($J1043),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1043) - LEN(SUBSTITUTE(LOWER($J1043),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1043:D1043)","v":0},2010,"Obesogens.","Grün",20689419,"Obesogens.    Abstract:    PURPOSE OF REVIEW : The environmental obesogen hypothesis postulates chemical pollutants that are able to promote obesity by altering homeostatic metabolic set-points, disrupting appetite controls, perturbing lipid homeostasis to promote adipocyte hypertrophy, or stimulating adipogenic pathways that enhance adipocyte hyperplasia during development or in adults. This review focuses on recent experimental advances for candidate obesogens that target nuclear hormone receptors when a direct link between exposure, modulation of transcriptional networks and adipogenic phenotypes can be rationalized.  RECENT FINDINGS : Various endocrine disrupting chemicals can disrupt hormonal signaling relevant to adipose tissue biology. In this review, progress on one identified obesogen, the organotin tributyltin, will be outlined to highlight principles and novel insights into its high-affinity nuclear hormone receptor-mediated mechanism, its effects on adipocyte biology, its potential to promote long-term obesogenic changes and its epidemiological relevance. When appropriate, important results for other suspected obesogenic ligands, including bisphenol A, phthalates, polybrominated diphenyl ethers and perfluoro-compounds, will highlight corroborating principles.  SUMMARY : These examples serve to provide perspective on the potential harm that man-made obesogenic pollutants pose to human health, focus attention on areas in which knowledge remains inadequate and prompt a re-evaluation of the causative risk factors driving the current changes in obesity rates."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1044,I1044)","v":20594533},{"$f":"(LEN($J1044) - LEN(SUBSTITUTE(LOWER($J1044),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1044) - LEN(SUBSTITUTE(LOWER($J1044),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1044) - LEN(SUBSTITUTE(LOWER($J1044),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1044:D1044)","v":0},2010,"Chemoprevention of colorectal cancer: systematic review and economic evaluation.","Cooper",20594533,"Chemoprevention of colorectal cancer: systematic review and economic evaluation.    Abstract:    BACKGROUND : Colorectal cancer (CRC) is the third most common cancer in the UK: incidence increases with age, median age at diagnosis being over 70 years. Approximately 25% of cases occur in individuals with a family history of CRC, including 5% caused by familial adenomatous polyposis (FAP) or hereditary non-polyposis CRC (HNPCC). Most develop from adenomatous polyps arising from the intestine lining. Individuals with these polyps undergo polypectomy and are invited for endoscopic surveillance. Screening via faecal occult blood testing has been rolled out across the UK.  OBJECTIVES : To evaluate the clinical effectiveness and cost-effectiveness of drug and micronutrient interventions for the prevention of CRC and/or adenomatous polyps. Interventions considered include: non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclo-oxygenase-2 (COX-2) inhibitors; folic acid; calcium; vitamin D and antioxidants (including vitamin A, vitamin C, vitamin E, selenium and beta-carotene). Chemoprevention was assessed in the general population, in individuals at increased risk of CRC, and in individuals with FAP or HNPCC.  DATA SOURCES : A systematic review identified randomised controlled trials (RCTs) assessing drug and nutritional agents for the prevention of CRC or adenomatous polyps. A separate search identified qualitative studies relating to individuals views, attitudes and beliefs about chemoprevention. MEDLINE, MEDLINE In-Process amp; Other Non-Indexed Citations, EMBASE, CINAHL, the Cochrane Database of Systematic Reviews, Cochrane CENTRAL Register of Controlled Trials, DARE, NHS-EED (NHS Economic Evaluation Database), HTA database, Science Citation Index, BIOSIS previews and the Current Controlled Trials research register were searched in June 2008. Data were extracted by one reviewer and checked by a second.  REVIEW METHODS : The synthesis methods used were systematic review and meta-analysis for RCTs and qualitative framework synthesis for qualitative studies. A health economic model was developed to assess the cost-effectiveness of chemoprevention for two populations with different levels of risk of developing CRC: the general population and an intermediate-risk population.  RESULTS : The search identified 44 relevant RCTs and six ongoing studies. A small study of aspirin in FAP patients produced no statistically significant reduction in polyp number but a possible reduction in polyp size. There was a statistically significant 21% reduction in risk of adenoma recurrence [relative risk (RR) 0.79, 95% confidence interval (CI) 0.68 to 0.92] in an analysis of aspirin versus no aspirin in individuals with a history of adenomas or CRC. In the general population, a significant 26% reduction in CRC incidence was demonstrated in studies with a 23-year follow-up (RR 0.74, 95% CI 0.57 to 0.97). Non-aspirin NSAID use in FAP individuals produced a non-statistically significant reduction in adenoma incidence after 4 years of treatment and follow-up and reductions in polyp number and size. In individuals with a history of adenomas there was a statistically significant 34% reduction in adenoma recurrence risk (RR 0.66, 95% CI 0.60 to 0.72) and a statistically significant 55% reduction in advanced adenoma incidence (RR 0.45, 95% CI 0.35 to 0.58). No studies assessed the effect of non-aspirin NSAIDs in the general population. There were no studies of folic acid in individuals with FAP or HNPCC. There was no significant effect of folic acid versus placebo on adenoma recurrence (RR 1.16, 95% CI 0.97 to 1.39) or advanced adenoma incidence in individuals with a history of adenomas. In the general population there was no significant effect of folic acid on risk of CRC (RR 1.13, 95% CI 0.77 to 1.64), although studies were of relatively short duration. Calcium use by FAP patients produced no significant reduction in polyp number or disease progression. In individuals with a history of adenomas there was a statistically significant 18% reduction in risk of adenoma recurrence (RR 0.82, 95% CI 0.69 to 0.98) and a non-significant reduction in risk of advanced adenomas (RR 0.77, 95% CI 0.50 to 1.17). In the general population there was no significant effect of calcium on risk of CRC (RR 1.08, 95% CI 0.87 to 1.34), although studies were of relatively short duration. There were no studies of antioxidant use in individuals with FAP or HNPCC, and in individuals with a history of adenomas no statistically significant differences in relative risk of adenoma recurrence were found. In the general population there was no difference in incidence of CRC (RR 1.00, 95% CI 0.88 to 1.13) with antioxidant use compared with no antioxidant use. Twenty studies reported qualitative findings concerning chemoprevention. People are more likely to use NSAIDs if there is a strong perceived need. Perceptions of risk and benefit also influence decision-making and use. People have fewer concerns about using antioxidants or other supplements, but their perception of the benefits of these agents is less well-defined. The model analysis suggested that the most cost-effective age-range policy in the general population would be to provide chemoprevention to all individuals within the general population from age 50 to 60 years. The use of aspirin in addition to screening within the general population is likely to result in a discounted cost per life-year gained of around 10,000 pounds and a discounted cost per quality-adjusted life-year (QALY) gained of around 23,000 pounds compared with screening alone. In the intermediate-risk group the most economically viable age-range policy would be to provide chemoprevention to individuals following polypectomy aged 61 to 70 years. Calcium is likely to have a discounted cost per QALY gained of around 8000 pounds compared with screening alone. Although aspirin in addition to screening should be more effective and less costly than screening alone, under the current assumptions of benefits to harms of aspirin and calcium, aspirin is expected to be extendedly dominated by calcium.  LIMITATIONS : Whilst a number of studies were included in the review, the duration of follow-up was generally insufficient to detect an effect on cancer incidence. Given the uncertainties and ambiguities in the evidence base, the results of the health economic analysis should be interpreted with caution.  CONCLUSIONS : Aspirin and celecoxib may reduce recurrence of adenomas and incidence of advanced adenomas in individuals with an increased risk of CRC and calcium may reduce recurrence of adenomas in this group. COX-2 inhibitors may decrease polyp number in patients with FAP. There is some evidence for aspirin reducing the incidence of CRC in the general population. Both aspirin and NSAIDs are associated with adverse effects so it will be important to consider the risk-benefit ratio before recommending these agents for chemoprevention. The economic analysis suggests that chemoprevention has the potential to represent a cost-effective intervention, particularly when targeted at intermediate-risk populations following polypectomy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1045,I1045)","v":20580500},{"$f":"(LEN($J1045) - LEN(SUBSTITUTE(LOWER($J1045),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1045) - LEN(SUBSTITUTE(LOWER($J1045),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1045) - LEN(SUBSTITUTE(LOWER($J1045),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1045:D1045)","v":0},2010,"A review of select vitamins and minerals used by postmenopausal women.","Dennehy",20580500,"A review of select vitamins and minerals used by postmenopausal women.    Abstract:    OBJECTIVES : The purpose of this review is to summarize the effectiveness of select vitamins, minerals and trace elements in postmenopausal women for their effects on bone health, cardiovascular health, breast cancer, cognition and vasomotor symptoms.  METHODS : Review of the relevant literature and results from recent clinical studies, as well as critical analyses of published systematic reviews and meta-analyses were obtained from PubMed and Cochrane Library of Reviews. Vitamin A, the B vitamins, vitamin C, calcium, vitamin D, vitamin E, vitamin K, magnesium, selenium and zinc were selected for review. In circumstances where the vitamin, mineral or trace element has not been studied for a given condition, no information was provided.  RESULTS AND DISCUSSION : All vitamins, minerals and trace elements play an important role in maintaining health and wellbeing among menopausal women. Adequate dietary intake is essential and supplementation should be considered in women with documented malabsorption syndromes or deficiencies. Based on a review of the literature, supplementation with vitamin C, D, K and calcium can also be recommended for proper maintenance of bone health. The only supplement studied for vasomotor symptoms was vitamin E and this vitamin lacked clinical support. Supplementation in healthy postmenopausal women with vitamins and minerals in diet or pill forms cannot be recommended currently for any other indications."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1046,I1046)","v":20422498},{"$f":"(LEN($J1046) - LEN(SUBSTITUTE(LOWER($J1046),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1046) - LEN(SUBSTITUTE(LOWER($J1046),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1046) - LEN(SUBSTITUTE(LOWER($J1046),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1046:D1046)","v":0},2010,"Nuclear receptor regulation of the adaptive response of bile acid transporters in cholestasis.","Wagner",20422498,"Nuclear receptor regulation of the adaptive response of bile acid transporters in cholestasis.    Abstract:   Although hereditary or acquired defects in hepatobiliary transporter systems cause or predispose to cholestasis, adaptive bile acid transporter changes can counteract cholestasis by reducing hepatocellular and systemic concentrations of retained cholephiles. An important level in the regulation of adaptive bile acid transporters and overflow pathways is mediated at the transcriptional level by nuclear hormone receptors. Moreover, therapeutic approaches targeting nuclear receptors in cholestasis may stimulate these adaptive changes and open a new perspective for the treatment of cholestatic liver diseases. This review gives a comprehensive overview on bile acid transporters in the enterohepatic circulation and their adaptive changes in response to cholestasis as well as the regulatory networks underlying these adaptive mechanisms."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1047,I1047)","v":20388054},{"$f":"(LEN($J1047) - LEN(SUBSTITUTE(LOWER($J1047),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1047) - LEN(SUBSTITUTE(LOWER($J1047),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1047) - LEN(SUBSTITUTE(LOWER($J1047),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1047:D1047)","v":0},2011,"Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part II--vitamin D, vitamin A, iron, zinc, iodine, essential fatty acids.","Simpson",20388054,"Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part II--vitamin D, vitamin A, iron, zinc, iodine, essential fatty acids.    Abstract:   Part II of this review considers additional micronutrients. Vitamin D is a fat soluble vitamin found in foods of animal origins (fatty fish, liver oil) or fortified products (milk, cheese). Vitamin D deficiency is common in African-American women living in northern latitudes. Vitamin D supplementation may be needed to reach desired 25-(OH)D3 concentrations of gt;50 nmol/L. In foods of animal origin, preformed Vitamin A is present; in plants (fruits and vegetables) vitamin A precursors (β-carotenoids) are present. Vitamin A supplementation is usually not warranted, and in developing countries should not exceed 3000 μg (10,000 IU)/day. Iron in the form of haem-iron is found in meat, fish and poultry; non-haem (inorganic) iron is found in vegetables, fruits and grains. Iron supplementation may be necessary in the third trimester, earlier in pregnancy or in non-pregnant states if serum ferritin is lt;20 μg/L or haemoglobin lt;10.9 g/dL. Zinc is available in red meat, seafood including oysters and unpolished grains; supplementation is not necessary. To assure adequate iodine, food is fortified worldwide with iodated salt. If urinary iodine levels are low, supplementation is needed. Essential fatty acids requirements can be met by one to two portions of fish per week."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1048,I1048)","v":20363593},{"$f":"(LEN($J1048) - LEN(SUBSTITUTE(LOWER($J1048),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1048) - LEN(SUBSTITUTE(LOWER($J1048),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1048) - LEN(SUBSTITUTE(LOWER($J1048),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1048:D1048)","v":0},2010,"Micronutrient deficiencies after bariatric surgery.","Shankar",20363593,"Micronutrient deficiencies after bariatric surgery.    Abstract:   It has been estimated that approximately 220,000 people with morbid obesity underwent bariatric surgery in 2008. Modification of the gastrointestinal tract affects absorption and health care professionals counseling bariatric patients need to be aware of possible micronutrient deficiencies and their symptoms. A systematic review of several databases and bariatric surgery center websites on the Internet was conducted from January 1980 to July 2009 to identify literature related to micronutrient deficiencies occurring after bariatric surgery. Keywords used individually or in combination were bariatric surgery, obesity, vitamin/mineral deficiencies, altered gastrointestinal function, nutrient absorption, nutrient supplementation, and metabolic complications, and were variously combined in the search list. Based on this review, all patients scheduled for bariatric surgery should receive daily multivitamin and multitrace mineral supplements. The literature suggests that bariatric surgery patients are at risk for deficiency of the following nutrients after surgery: vitamins B(12), B(1), C, folate, A, D, and K, along with the trace minerals iron, selenium, zinc, and copper. Over-the-counter multivitamin and mineral supplements do not provide adequate amounts of certain nutrients such as vitamin B(12), iron, or fat-soluble vitamins and patients will require additional doses of prophylactic supplementation life-long to maintain optimal micronutrient status. In addition, preconception care for adequate prenatal supplementation is critical for pregnant women who have undergone bariatric surgery, as iron, vitamin A, vitamin B(12), vitamin K, and folate deficiencies are associated with maternal and fetal complications, including severe anemia, congenital abnormalities, low birth weight, and failure to thrive. All bariatric surgery patients would be best served by receiving regular monitoring of serum nutrient levels starting at 3 mo after surgery and periodically thereafter."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1049,I1049)","v":20172476},{"$f":"(LEN($J1049) - LEN(SUBSTITUTE(LOWER($J1049),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1049) - LEN(SUBSTITUTE(LOWER($J1049),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1049) - LEN(SUBSTITUTE(LOWER($J1049),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1049:D1049)","v":0},2010,"The impact of common micronutrient deficiencies on iodine and thyroid metabolism: the evidence from human studies.","Hess",20172476,"The impact of common micronutrient deficiencies on iodine and thyroid metabolism: the evidence from human studies.    Abstract:   Deficiencies of micronutrients are highly prevalent in low-income countries. Inadequate intake of iodine impairs thyroid function and results in a spectrum of disorders. Other common deficiencies of micronutrients such as iron, selenium, vitamin A, and possibly zinc may interact with iodine nutrition and thyroid function. Randomised controlled intervention trials in iodine- and iron-deficient populations have shown that providing iron along with iodine results in greater improvements in thyroid function and volume than providing iodine alone. Vitamin A supplementation given alone or in combination with iodised salt can have a beneficial impact on thyroid function and thyroid size. Despite numerous studies of the effect of selenium on iodine and thyroid metabolism in animals, most published randomised controlled intervention trials in human populations failed to confirm an impact of selenium supplementation on thyroid metabolism. Little evidence is available on interactions between iodine and zinc metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1050,I1050)","v":20095133},{"$f":"(LEN($J1050) - LEN(SUBSTITUTE(LOWER($J1050),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1050) - LEN(SUBSTITUTE(LOWER($J1050),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1050) - LEN(SUBSTITUTE(LOWER($J1050),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1050:D1050)","v":0},2009,"Red palm oil: nutritional, physiological and therapeutic roles in improving human wellbeing and quality of life.","Oguntibeju",20095133,"Red palm oil: nutritional, physiological and therapeutic roles in improving human wellbeing and quality of life.    Abstract:   The link between dietary fats and cardiovascular disease has created a growing interest in dietary red palm oil research. Also, the link between nutrition and health, oxidative stress and the severity or progression of disease has stimulated further interest in the potential role of red palm oil (a natural antioxidant product) to improve oxidative status by reducing oxidative stress in patients with cardiovascular disease, cancer and other chronic diseases. In spite of its level of saturated fatty acid content (50%), red palm oil has not been found to promote atherosclerosis and/or arterial thrombosis. This is probably due to the ratio of its saturated fatty acid to unsaturated fatty acid content and its high concentration of antioxidants such as beta-carotene, tocotrienols, tocopherols and vitamin E. It has also been reported that the consumption of red palm oil reduces the level of endogenous cholesterol, and this seems to be due to the presence of the tocotrienols and the peculiar isomeric position of its fatty acids. The benefits of red palm oil to health include a reduction in the risk of arterial thrombosis and/or atherosclerosis, inhibition of endogenous cholesterol biosynthesis, platelet aggregation, a reduction in oxidative stress and a reduction in blood pressure. It has also been shown that dietary red palm oil, taken in moderation in animals and humans, promotes the efficient utilisation of nutrients, activates hepatic drug metabolising enzymes, facilitates the haemoglobinisation of red blood cells and improves immune function. This review provides a comprehensive overview of the nutritional, physiological and biochemical roles of red palm oil in improving wellbeing and quality of life."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1051,I1051)","v":19942154},{"$f":"(LEN($J1051) - LEN(SUBSTITUTE(LOWER($J1051),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1051) - LEN(SUBSTITUTE(LOWER($J1051),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1051) - LEN(SUBSTITUTE(LOWER($J1051),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1051:D1051)","v":0},2009,"Drugs that suppress TSH or cause central hypothyroidism.","Haugen",19942154,"Drugs that suppress TSH or cause central hypothyroidism.    Abstract:   Many different drugs affect thyroid function. Most of these drugs act at the level of the thyroid in patients with normal thyroid function, or at the level of thyroid hormone absorption or metabolism in patients requiring exogenous levothyroxine. A small subset of medications including glucocorticoids, dopamine agonists, somatostatin analogues and rexinoids affect thyroid function through suppression of TSH in the thyrotrope or hypothalamus. Fortunately, most of these medications do not cause clinically evident central hypothyroidism. A newer class of nuclear hormone receptors agonists, called rexinoids, cause clinically significant central hypothyroidism in most patients and dopamine agonists may exacerbate hypothyroidism in patients with non-thyroidal illness. In this review, we explore mechanisms governing TSH suppression of these drugs and the clinical relevance of these effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1052,I1052)","v":19931062},{"$f":"(LEN($J1052) - LEN(SUBSTITUTE(LOWER($J1052),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1052) - LEN(SUBSTITUTE(LOWER($J1052),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1052) - LEN(SUBSTITUTE(LOWER($J1052),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1052:D1052)","v":0},2009,"Nutritional deficiencies during normal growth.","Suskind",19931062,"Nutritional deficiencies during normal growth.    Abstract:   Nutritional deficiencies have always been a major consideration in pediatrics. Although the classic forms of many of the well-documented nutritional deficiencies are memorized during training as a physician, nutritional deficiencies that can occur in otherwise asymptomatic normally growing children are often overlooked. The two most common deficiencies seen in children who are growing normally are iron and vitamin D deficiencies. These deficiencies are surprisingly common and can have a significant impact on the overall health of a child. This article reviews these nutritional deficiencies and other less commonly seen deficiencies in children who are otherwise growing normally."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1053,I1053)","v":19803427},{"$f":"(LEN($J1053) - LEN(SUBSTITUTE(LOWER($J1053),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1053) - LEN(SUBSTITUTE(LOWER($J1053),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1053) - LEN(SUBSTITUTE(LOWER($J1053),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1053:D1053)","v":0},2009,"[The research progress of ATP binding cassette transporter G1].","Liu",19803427,"[The research progress of ATP binding cassette transporter G1].    Abstract:   ATP binding cassette transporter G1 (ABCG1) is a membrane half-transporter which is the member of ATP-binding cassette (ABC) transporter super-family, it has an important role of regulating the cholesterol and phospholipids effluence. ABCG1 and ABCA1 synergize to mediate cholesterol effluence to HDL (high density lipoprotein). The expression of ABCG1 is mainly regulated by the liver X receptor/the lactochrome receptor system (LXR/RXR). Although the ABCG1 plays an important role in balancing the lipids, its role in cardiovascular disease (CVD) in the animal studies is still controversial. The issue focuses the ABCG1 on the structure, the function, the regulation and the contribution to CVD."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1054,I1054)","v":19793845},{"$f":"(LEN($J1054) - LEN(SUBSTITUTE(LOWER($J1054),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1054) - LEN(SUBSTITUTE(LOWER($J1054),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1054) - LEN(SUBSTITUTE(LOWER($J1054),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1054:D1054)","v":0},2009,"Landscape analysis of interactions between nutrition and vaccine responses in children.","Savy",19793845,"Landscape analysis of interactions between nutrition and vaccine responses in children.    Abstract:   The worlds poorest children are likely to be malnourished when receiving their childhood vaccines. It is uncertain whether this affects vaccine efficacy and whether the coadministration of nutrient supplements with vaccines has beneficial or detrimental effects. More recently, a detrimental interaction between vitamin A (VA) supplementation (VAS) and the killed diphtheria-tetanus-pertussis vaccine given in early childhood has been suggested. This report provides a critical review of the published interactions between nutritional status and/or supplementation and vaccine responses in children. Due to an absence of evidence for most nutrients, this analysis focused on protein-energy, vitamins A and D, and iron and zinc. All vaccines were considered. Both observational studies and clinical trials that led to peer-reviewed publications in English or French were included. These criteria led to a pool of 58 studies for protein-energy malnutrition, 43 for VA, 4 for vitamin D, 10 for iron, and 22 for zinc. Our analysis indicates that malnutrition has surprisingly little or no effect on vaccine responses. Evidence for definitive adjunctive effects of micronutrient supplementation at the time of vaccination is also weak. Overall, the paucity, poor quality, and heterogeneity of data make it difficult to draw firm conclusions. The use of simple endpoints that may not correlate strongly with disease protection adds uncertainty. A detailed examination of the immunological mechanisms involved in potential interactions, employing modern methodologies, is therefore required. This would also help us understand the proposed, but still unproven, negative interactions between VAS and vaccine safety, a resolution of which is urgently required."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1055,I1055)","v":19715393},{"$f":"(LEN($J1055) - LEN(SUBSTITUTE(LOWER($J1055),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1055) - LEN(SUBSTITUTE(LOWER($J1055),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1055) - LEN(SUBSTITUTE(LOWER($J1055),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1055:D1055)","v":0},2009,"Pathway enrichment based on text mining and its validation on carotenoid and vitamin A metabolism.","Waagmeester",19715393,"Pathway enrichment based on text mining and its validation on carotenoid and vitamin A metabolism.    Abstract:   Carotenoid metabolism is relevant to the prevention of various diseases. Although the main actors in this metabolic pathway are known, our understanding of the pathway is still incomplete. The information on the carotenoids is scattered in the large and growing body of scientific literature. We designed a text-mining work flow to enrich existing pathways. It has been validated on the vitamin A pathway, which is a well-studied part of the carotenoid metabolism. In this study we used the vitamin A metabolism pathway as it has been described by an expert team on carotenoid metabolism from the European network of excellence in Nutrigenomics (NuGO). This work flow uses an initial set of publications cited in a review paper (1,191 publications), enlarges this corpus with Medline abstracts (13,579 documents), and then extracts the key terminology from all relevant publications. Domain experts validated the intermediate and final results of our text-mining work flow. With our approach we were able to enrich the pathway representing vitamin A metabolism. We found 37 new and relevant terms from a total of 89,086 terms, which have been qualified for inclusion in the analyzed pathway. These 37 terms have been assessed manually and as a result 13 new terms were then added as entities to the pathway. Another 14 entities belonged to other pathways, which could form the link of these pathways with the vitamin A pathway. The remaining 10 terms were classified as biomarkers or nutrients. Automatic literature analysis improves the enrichment of pathways with entities already described in the scientific literature."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1056,I1056)","v":19708811},{"$f":"(LEN($J1056) - LEN(SUBSTITUTE(LOWER($J1056),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1056) - LEN(SUBSTITUTE(LOWER($J1056),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1056) - LEN(SUBSTITUTE(LOWER($J1056),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1056:D1056)","v":0},2009,"Intracellular innate immune cascades and interferon defenses that control hepatitis C virus.","Horner",19708811,"Intracellular innate immune cascades and interferon defenses that control hepatitis C virus.    Abstract:   Hepatitis C virus (HCV) is a global public health problem that mediates a persistent infection in nearly 200 million people. HCV is efficient in establishing chronicity due in part to the inefficiency of the host immune system in controlling and counteracting HCV-mediated evasion strategies. HCV persistence is linked to the ability of the virus to suppress the RIG-I pathway and interferon production from infected hepatocytes, thus evading innate immune defenses within the infected cell. This review describes the virus and host processes that regulate the RIG-I pathway during HCV infection. An understanding of these HCV-host interactions could lead to more effective therapies for HCV designed to reactivate the host immune response following HCV infection."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1057,I1057)","v":19642878},{"$f":"(LEN($J1057) - LEN(SUBSTITUTE(LOWER($J1057),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1057) - LEN(SUBSTITUTE(LOWER($J1057),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1057) - LEN(SUBSTITUTE(LOWER($J1057),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1057:D1057)","v":0},2009,"Hepatic and pancreatic stellate cells in focus.","Kordes",19642878,"Hepatic and pancreatic stellate cells in focus.    Abstract:   Stellate cells are vitamin A-storing cells of liver and pancreas and have been described in all vertebrates ranging from lampreys (primitive fish) to humans, demonstrating their major importance. This cell type is thought to contribute to fibrosis, a condition characterized by an excess deposition of extracellular matrix proteins. Recently, the expression of stem/progenitor cell markers, such as CD133 (prominin-1) and Oct4, was discovered in hepatic stellate cells (HSCs) of rats. Moreover, HSCs possess signaling pathways important for maintenance of stemness and cell differentiation, such as hedgehog, beta-catenin-dependent Wnt, and Notch signaling, and are resistant to CD95-mediated apoptosis. In analogy to a stem cell niche, some characteristics of quiescent HSC are maintained by aid of a special microenvironment located in the space of Dissé. Finally, stellate cells display a differentiation potential as investigated in vitro and in vivo. Collectively all these properties are congruently found in stem/progenitor cells and support the concept that stellate cells are undifferentiated cells, which might play an important role in liver regeneration. The present review highlights findings related to this novel aspect of stellate cell biology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1058,I1058)","v":19594417},{"$f":"(LEN($J1058) - LEN(SUBSTITUTE(LOWER($J1058),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1058) - LEN(SUBSTITUTE(LOWER($J1058),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1058) - LEN(SUBSTITUTE(LOWER($J1058),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1058:D1058)","v":0},2009,"Role of iodine, selenium and other micronutrients in thyroid function and disorders.","Triggiani",19594417,"Role of iodine, selenium and other micronutrients in thyroid function and disorders.    Abstract:   Micronutrients, mostly iodine and selenium, are required for thyroid hormone synthesis and function. Iodine is an essential component of thyroid hormones and its deficiency is considered as the most common cause of preventable brain damage in the world. Nowadays about 800 million people are affected by iodine deficiency disorders that include goiter, hypothyroidism, mental retardation, and a wide spectrum of other growth and developmental abnormalities. Iodine supplementation, under form of iodized salt and iodized vegetable oil, produced dramatic improvements in many areas, even though iodine deficiency is still a problem not only for developing countries. In fact, certain subpopulations like vegetarians may not reach an adequate iodine intake even in countries considered iodine-sufficient. A reduction in dietary iodine content could also be related to increased adherence to dietary recommendations to reduce salt intake for preventing hypertension. Furthermore, iodine intakes are declining in many countries where, after endemic goiter eradication, the lack of monitoring of iodine nutrition can lead to a reappearance of goiter and other iodine deficiency disorders. Three different selenium-dependent iodothyronine deiodinases (types I, II, and III) can both activate and inactivate thyroid hormones, making selenium an essential micronutrient for normal development, growth, and metabolism. Furthermore, selenium is found as selenocysteine in the catalytic center of enzymes protecting the thyroid from free radicals damage. In this way, selenium deficiency can exacerbate the effects of iodine deficiency and the same is true for vitamin A or iron deficiency. Substances introduced with food, such as thiocyanate and isoflavones or certain herbal preparations, can interfere with micronutrients and influence thyroid function. Aim of this paper is to review the role of micronutrients in thyroid function and diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1059,I1059)","v":19453674},{"$f":"(LEN($J1059) - LEN(SUBSTITUTE(LOWER($J1059),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1059) - LEN(SUBSTITUTE(LOWER($J1059),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1059) - LEN(SUBSTITUTE(LOWER($J1059),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1059:D1059)","v":0},2009,"Achievements, challenges, and promising new approaches in vitamin and mineral deficiency control.","Boy",19453674,"Achievements, challenges, and promising new approaches in vitamin and mineral deficiency control.    Abstract:   Micronutrient deficiencies (MNDs) contribute significantly to the worlds disease and mortality burden. Global efforts addressing MNDs have achieved significant yet heterogeneous progress across and within regions and countries. For vitamin A and iodine interventions, enhancing achievements in coverage require further political and financial commitment and targeting of hard-to-reach populations. Anemia control must focus on prevention among preschoolers and adolescent women and on integrated public health programs. Current international guidelines on iron supplementation and cut-off values for anemia need revision. For zinc, advocacy to accelerate the application of revised diarrhea management guidelines is critical, as are efficacy studies on food-based interventions and preventive supplementation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1060,I1060)","v":19438091},{"$f":"(LEN($J1060) - LEN(SUBSTITUTE(LOWER($J1060),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1060) - LEN(SUBSTITUTE(LOWER($J1060),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1060) - LEN(SUBSTITUTE(LOWER($J1060),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1060:D1060)","v":0},2009,"[Disseminated cutaneous granulomatosis].","Lapointe",19438091,"[Disseminated cutaneous granulomatosis].    Abstract:   The disseminated cutaneous granulomatosis (DCG) are heterogeneous cutaneous diseases histologically characterized by a granulomatous infiltrate. The most frequent cutaneous granulomatosis is sarcoidosis, but many other causes can be found, because DCG are probably a skin granulomatous reaction to different stimuli: infectious, inflammatory, neoplastic, metabolic or chemical. The histopathological examination is useful for the diagnosis of DCG, but gives rarely an etiological diagnosis. In this article, we will propose a strategy for the etiological diagnosis of DCG, and propose therapeutic recommendations based on recent data from the literature."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1061,I1061)","v":19412668},{"$f":"(LEN($J1061) - LEN(SUBSTITUTE(LOWER($J1061),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1061) - LEN(SUBSTITUTE(LOWER($J1061),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1061) - LEN(SUBSTITUTE(LOWER($J1061),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1061:D1061)","v":0},2009,"Skeletal sequelae of cancer and cancer treatment.","Stava",19412668,"Skeletal sequelae of cancer and cancer treatment.    Abstract:    INTRODUCTION : Survivors of cancer may experience lingering adverse skeletal effects such as osteoporosis and osteomalacia. Skeletal disorders are often associated with advancing age, but these effects can be exacerbated by exposure to cancer and its treatment. This review will explore the cancer and cancer treatment-related causes of skeletal disorders.  METHODS : We performed a comprehensive search, using various Internet-based medical search engines such as PubMed, Medline Plus, Scopus, and Google Scholar, for published articles on the skeletal effects of cancer and cancer therapies.  RESULTS : One-hundred-forty-two publications, including journal articles, books, and book chapters, met the inclusion criteria. They included case reports, literature reviews, systematic analyses, and cohort reports. Skeletal effects resulting from cancer and cancer therapies, including hypogonadism, androgen deprivation therapy, estrogen suppression, glucocorticoids/corticosteroids, methotrexate, megestrol acetate, platinum compounds, cyclophosphamide, doxorubicin, interferon-alpha, valproic acid, cyclosporine, vitamin A, NSAIDS, estramustine, ifosfamide, radiotherapy, and combined chemotherapeutic regimens, were identified and described. Skeletal effects of hyperparathyroidism, vitamin D deficiency, gastrectomy, hypophosphatemia, and hyperprolactinemia resulting from cancer therapies were also described.  DISCUSSION/CONCLUSIONS : The publications researched during this review both highlight and emphasize the association between cancer therapies, including chemotherapy and radiotherapy, and skeletal dysfunction.  IMPLICATIONS FOR CANCER SURVIVORS : These studies confirm that cancer survivors experience a more rapid acceleration of bone loss than their age-matched peers who were never diagnosed with cancer. Further studies are needed to better address the skeletal needs of cancer survivors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1062,I1062)","v":19393271},{"$f":"(LEN($J1062) - LEN(SUBSTITUTE(LOWER($J1062),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1062) - LEN(SUBSTITUTE(LOWER($J1062),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1062) - LEN(SUBSTITUTE(LOWER($J1062),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1062:D1062)","v":0},2009,"Transcriptional regulation of hepatic stellate cells.","Mann",19393271,"Transcriptional regulation of hepatic stellate cells.    Abstract:   Hepatic stellate cell (HSC) activation is a process of cellular transdifferentiation in which, upon liver injury, the quiescent vitamin A storing perisinusoidal HSC is converted into a wound-healing myofibroblast and acquires potent pro-inflammatory and pro-fibrogenic activities. This remarkable phenotypic transformation is underpinned by changes in the expression of a vast number of genes. In this review we survey current knowledge of the transcription factors that either control HSC activation or which regulate specific fibrogenic functions of the activated HSC such as collagen expression, proliferation and resistance to apoptosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1063,I1063)","v":19169201},{"$f":"(LEN($J1063) - LEN(SUBSTITUTE(LOWER($J1063),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1063) - LEN(SUBSTITUTE(LOWER($J1063),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1063) - LEN(SUBSTITUTE(LOWER($J1063),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1063:D1063)","v":0},2009,"Biological and pharmacological activities of squalene and related compounds: potential uses in cosmetic dermatology.","Huang",19169201,"Biological and pharmacological activities of squalene and related compounds: potential uses in cosmetic dermatology.    Abstract:   Squalene is a triterpene that is an intermediate in the cholesterol biosynthesis pathway. It was so named because of its occurrence in shark liver oil, which contains large quantities and is considered its richest source. However, it is widely distributed in nature, with reasonable amounts found in olive oil, palm oil, wheat-germ oil, amaranth oil, and rice bran oil. Squalene, the main component of skin surface polyunsaturated lipids, shows some advantages for the skin as an emollient and antioxidant, and for hydration and its antitumor activities. It is also used as a material in topically applied vehicles such as lipid emulsions and nanostructured lipid carriers (NLCs). Substances related to squalene, including beta-carotene, coenzyme Q10 (ubiquinone) and vitamins A, E, and K, are also included in this review article to introduce their benefits to skin physiology. We summarize investigations performed in previous reports from both in vitro and in vivo models."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1064,I1064)","v":19102134},{"$f":"(LEN($J1064) - LEN(SUBSTITUTE(LOWER($J1064),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1064) - LEN(SUBSTITUTE(LOWER($J1064),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1064) - LEN(SUBSTITUTE(LOWER($J1064),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1064:D1064)","v":0},2008,"Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic.","Cannell",19102134,"Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1065,I1065)","v":19061584},{"$f":"(LEN($J1065) - LEN(SUBSTITUTE(LOWER($J1065),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1065) - LEN(SUBSTITUTE(LOWER($J1065),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1065) - LEN(SUBSTITUTE(LOWER($J1065),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1065:D1065)","v":0},2008,"Acanthosis nigricans: a practical approach to evaluation and management.","Higgins",19061584,"Acanthosis nigricans: a practical approach to evaluation and management.    Abstract:   Acanthosis nigricans is a dermatosis characterized by thickened, hyperpigmented plaques, typically of the intertriginous surfaces and neck. Common in some populations, its prevalence depends on race. Clinicians should recognize acanthosis nigricans; it heralds disorders ranging from endocrinologic disturbances to malignancy. In this review, we discuss the pathogenesis of acanthosis nigricans and its clinical implications and management."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1066,I1066)","v":19018724},{"$f":"(LEN($J1066) - LEN(SUBSTITUTE(LOWER($J1066),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1066) - LEN(SUBSTITUTE(LOWER($J1066),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1066) - LEN(SUBSTITUTE(LOWER($J1066),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1066:D1066)","v":0},2008,"PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics.","Zhang",19018724,"PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics.    Abstract:   The pregnane X receptor (PXR; NR1I2), a member of the nuclear receptor superfamily, regulates the expression of drug-metabolic enzymes and transporters involved in the responses of mammals to their chemical environment. The same enzyme and transporter systems are also involved in the homeostasis of numerous endogenous chemicals. The regulatory function of PXR is implicated in normal physiology and diseases, such as drug-drug interactions, hepatic steatosis, vitamin D homeostasis, bile acids homeostasis, steroid hormones homeostasis and inflammatory bowel diseases. As such, any genetic variations of this receptor could potentially have widespread effects on the disposition of xenobiotics and endobiotics. Knowledge concerning the genetic polymorphisms of PXR may help to understand the variations in human drug response and ensure safe drug use. The correlation of PXR genetic polymorphisms with several disease conditions also suggests that this receptor may represent a valid therapeutic for hepato-intestinal disorders such as inflammatory bowel disease and primary sclerosing cholangitis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1067,I1067)","v":18972075},{"$f":"(LEN($J1067) - LEN(SUBSTITUTE(LOWER($J1067),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1067) - LEN(SUBSTITUTE(LOWER($J1067),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1067) - LEN(SUBSTITUTE(LOWER($J1067),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1067:D1067)","v":0},2008,"Systemic therapy of hepatocellular carcinoma: are we making progress?","Roxburgh",18972075,"Systemic therapy of hepatocellular carcinoma: are we making progress?    Abstract:   Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer deaths. Surgical resection, with or without transplantation, can result in long-term survival. However, surgery can only be performed in about 15% of patients with HCC and the 5-year survival rate is only approximately 33%-50% after potentially curative resection. Percutaneous ethanol injection, radiofrequency ablation, and transarterial chemoembolization are invasive techniques that have shown efficacy in reducing tumor bulk. Similarly, systemic chemotherapy may induce tumor responses, but a survival benefit has not been clearly demonstrated. In addition, the lack of efficacy of antiandrogens, tamoxifen, and single-agent interferon has now been confirmed.Sorafenib is a multikinase inhibitor with antiangiogenic, proapoptotic, and Raf kinase inhibitory activity. In a large, multicenter, randomized, phase 3 trial there was a significant improvement in both time to disease progression and overall survival with sorafenib compared with placebo. Sorafenib is the first agent to demonstrate a consistent improvement in overall survival for patients with advanced HCC. Further studies are required to determine the role of other molecular-targeted therapies, either alone or in combination with sorafenib in patients with advanced HCC. Further studies are also required to determine the role of sorafenib in combination with locoregional therapies (eg, transarterial chemoembolization), and the role of sorafenib as adjuvant therapy following surgery."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1068,I1068)","v":18831229},{"$f":"(LEN($J1068) - LEN(SUBSTITUTE(LOWER($J1068),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1068) - LEN(SUBSTITUTE(LOWER($J1068),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1068) - LEN(SUBSTITUTE(LOWER($J1068),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1068:D1068)","v":0},2008,"Micronutrients and anaemia.","Jamil",18831229,"Micronutrients and anaemia.    Abstract:   Micronutrient deficiencies and anaemia remain as major health concerns for children in Bangladesh. Among the micronutrient interventions, supplementation with vitamin A to children aged less than five years has been the most successful, especially after distribution of vitamin A was combined with National Immunization Days. Although salt sold in Bangladesh is intended to contain iodine, much of the salt does not contain iodine, and iodine deficiency continues to be common. Anaemia similarly is common among all population groups and has shown no sign of improvement even when iron-supplementation programmes have been attempted. It appears that many other causes contribute to anaemia in addition to iron deficiency. Zinc deficiency is a key micronutrient deficiency and is covered in a separate paper because of its importance among new child-health interventions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1069,I1069)","v":18784430},{"$f":"(LEN($J1069) - LEN(SUBSTITUTE(LOWER($J1069),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1069) - LEN(SUBSTITUTE(LOWER($J1069),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1069) - LEN(SUBSTITUTE(LOWER($J1069),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1069:D1069)","v":0},2008,"Maternal abetalipoproteinemia resulting in multiple fetal anomalies.","Seckeler",18784430,"Maternal abetalipoproteinemia resulting in multiple fetal anomalies.    Abstract:   Abetalipoproteinemia is a rare genetic condition that results in an inability of the body to absorb dietary fats, including fat-soluble vitamins. Deficiencies of these vitamins are known to cause a wide range of clinical effects ranging from blindness to coagulopathy and neuropathy. We present the case of a child with multisystem anomalies born to a mother with abetalipoproteinemia and provide a brief review of the literature about vitamin A and fetal development. Mothers at high risk for vitamin deficiencies should be screened and counseled on the potential benefits, and risks, of vitamin supplementation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1070,I1070)","v":18677777},{"$f":"(LEN($J1070) - LEN(SUBSTITUTE(LOWER($J1070),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1070) - LEN(SUBSTITUTE(LOWER($J1070),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1070) - LEN(SUBSTITUTE(LOWER($J1070),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1070:D1070)","v":0},2008,"Antioxidant supplements for preventing gastrointestinal cancers.","Bjelakovic",18677777,"Antioxidant supplements for preventing gastrointestinal cancers.    Abstract:    BACKGROUND : Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory.  OBJECTIVES : To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers.  SEARCH STRATEGY : We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2007), MEDLINE, EMBASE, LILACS, SCI-EXPANDED, and The Chinese Biomedical Database from inception to October 2007. We scanned reference lists and contacted pharmaceutical companies.  SELECTION CRITERIA : Randomised trials comparing antioxidant supplements to placebo/no intervention examining occurrence of gastrointestinal cancers.  DATA COLLECTION AND ANALYSIS : Two authors (GB and DN) independently selected trials for inclusion and extracted data. Outcome measures were gastrointestinal cancers, overall mortality, and adverse effects. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on random-effects and fixed-effect model meta-analysis. Meta-regression assessed the effect of covariates across the trials.  MAIN RESULTS : We identified 20 randomised trials (211,818 participants), assessing beta-carotene (12 trials), vitamin A (4 trials), vitamin C (8 trials), vitamin E (10 trials), and selenium (9 trials). Trials quality was generally high. Heterogeneity was low to moderate. Antioxidant supplements were without significant effects on gastrointestinal cancers (RR 0.94, 95% CI 0.83 to 1.06). However, there was significant heterogeneity (I(2) = 54.0%, P = 0.003). The heterogeneity may have been explained by bias risk (low-bias risk trials RR 1.04, 95% CI 0.96 to 1.13 compared to high-bias risk trials RR 0.59, 95% CI 0.43 to 0.80; test of interaction P lt; 0.0005), and type of antioxidant supplement (beta-carotene potentially increasing and selenium potentially decreasing cancer risk). The antioxidant supplements had no significant effects on mortality in a random-effects model meta-analysis (RR 1.02, 95% CI 0.97 to 1.07, I(2) = 53.5%), but significantly increased mortality in a fixed-effect model meta-analysis (RR 1.04, 95% CI 1.02 to 1.07). Beta-carotene in combination with vitamin A (RR 1.16, 95% CI 1.09 to 1.23) and vitamin E (RR 1.06, 95% CI 1.02 to 1.11) significantly increased mortality. Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In five trials (four with high risk of bias), selenium seemed to show significant beneficial effect on gastrointestinal cancer occurrence (RR 0.59, 95% CI 0.46 to 0.75, I(2) = 0%).  AUTHORS CONCLUSIONS : We could not find convincing evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, antioxidant supplements seem to increase overall mortality. The potential cancer preventive effect of selenium should be tested in adequately conducted randomised trials."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1071,I1071)","v":18622197},{"$f":"(LEN($J1071) - LEN(SUBSTITUTE(LOWER($J1071),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1071) - LEN(SUBSTITUTE(LOWER($J1071),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1071) - LEN(SUBSTITUTE(LOWER($J1071),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1071:D1071)","v":0},2008,"New insights and therapies for teenage psoriasis.","Belazarian",18622197,"New insights and therapies for teenage psoriasis.    Abstract:    PURPOSE OF REVIEW : Psoriasis is an important disorder in the adolescent population and has a tremendous physical and psychological impact on patients. It is important to understand the genetics, various clinical presentations, comorbidities, and treatment options associated with psoriasis.  RECENT FINDINGS : The human leukocyte antigen-C gene likely contains a susceptibility locus for psoriasis. Cytokines interleukin-12 and interleukin-23 have been implicated in the pathogenesis of psoriasis as well. Psoriasis is likely associated with an increased risk of myocardial infarction, metabolic syndrome, Crohns disease, and depression; it is difficult to assess the implications in the adolescent population.  SUMMARY : Psoriasis is not rare in the adolescent population. It is important for physicians to be aware of the different clinical presentations as well as the spectrum of treatment options that are available."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1072,I1072)","v":18525183},{"$f":"(LEN($J1072) - LEN(SUBSTITUTE(LOWER($J1072),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1072) - LEN(SUBSTITUTE(LOWER($J1072),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1072) - LEN(SUBSTITUTE(LOWER($J1072),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1072:D1072)","v":0},2008,"[Adjuvant therapy after treatment of hepatocellular carcinoma].","Kasai",18525183,"[Adjuvant therapy after treatment of hepatocellular carcinoma].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1073,I1073)","v":18484612},{"$f":"(LEN($J1073) - LEN(SUBSTITUTE(LOWER($J1073),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1073) - LEN(SUBSTITUTE(LOWER($J1073),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1073) - LEN(SUBSTITUTE(LOWER($J1073),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1073:D1073)","v":0},2008,"The hepatic microvascular system in health and its response to toxicants.","McCuskey",18484612,"The hepatic microvascular system in health and its response to toxicants.    Abstract:   This review briefly summarizes what is known about the dynamic morphology of the hepatic microvascular system that includes all vessels in the liver with a diameter less than 300 microm and various morphological sites within these vessels that regulate the distribution of blood flow. The latter include the various segments of the afferent portal venules and hepatic arterioles, the sinusoids, and central and hepatic venules. Sinusoids are unique exchange vessels lined by fenestrated endothelial cells which have important endocytotic functions and phagocytic Kupffer cells which are important for host defense. These are encircled by extraluminal stellate cells that are specialized pericytes containing fat droplets that store vitamin A. The principle sites for regulating blood flow are in the sinusoidal network with stellate and endothelial cells playing a major role in regulating the diameters of sinusoids and the distribution of blood flow in individual sinusoids, lobules, or segments of lobules. The sinusoidal endothelial cells are a sensitive and early target for several toxicants. For example, as early as 30 minutes after the administration of acetaminophen, the endothelial cells become swollen and begin to lose the ability to endocytose ligands. Within 2 hr, gaps through the cytoplasm appear formed by the destruction and/or coalescence of fenestrae which permit red blood cells to penetrate into the space of Disse. Subsequently, the sinusoid may collapse or disintegrate reducing blood flow."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1074,I1074)","v":18454812},{"$f":"(LEN($J1074) - LEN(SUBSTITUTE(LOWER($J1074),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1074) - LEN(SUBSTITUTE(LOWER($J1074),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1074) - LEN(SUBSTITUTE(LOWER($J1074),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1074:D1074)","v":0},2008,"The paradox of anemia with high meat intake: a review of the multifactorial etiology of anemia in the Inuit of North America.","Jamieson",18454812,"The paradox of anemia with high meat intake: a review of the multifactorial etiology of anemia in the Inuit of North America.    Abstract:   Anemia is a serious concern among indigenous populations in North America, and it appears to be widespread among the Inuit despite abundant intakes of heme iron. It is therefore hypothesized that anemia for the Inuit involves other dietary factors not usually associated with animal foods, such as low intakes of vitamin A and/or folate, riboflavin, and vitamin C. Also, Helicobacter pylori infection and/or parasitosis may result in gastrointestinal blood loss and/or functional iron deficiency. This review aims to describe factors that may cause anemia in Inuit populations despite high meat intakes, abundant bioavailable iron, and other important hematological nutrients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1075,I1075)","v":18430567},{"$f":"(LEN($J1075) - LEN(SUBSTITUTE(LOWER($J1075),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1075) - LEN(SUBSTITUTE(LOWER($J1075),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1075) - LEN(SUBSTITUTE(LOWER($J1075),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1075:D1075)","v":0},2008,"Steroid binding sites in liver membranes: interplay between glucocorticoids, sex steroids, and pituitary hormones.","Fernández-Pérez",18430567,"Steroid binding sites in liver membranes: interplay between glucocorticoids, sex steroids, and pituitary hormones.    Abstract:   Steroid hormones activate target cells through specific receptors that discriminate among ligands based upon recognition of distinct structural features. For most known steroids, membrane and nuclear receptors co-exist in many target cells. However, while the structure of the nuclear receptors and their function as transcriptional activators of specific target genes is generally well understood, the identity of the membrane receptors remains elusive. Using pharmacological and biochemical approaches, we are beginning to characterize receptors for glucocorticoids and anabolic-androgenic steroids in male rat liver membranes. Male rat liver endoplasmic reticulum contains two steroid binding sites which are functionally related and associated with a 90-134 kDa oligomeric protein: (1) the low-affinity glucocorticoid binding site (LAGS), composed at least in part of two peptides (37 and 53 kDa) that bind glucocorticoids and (2) the stanozolol binding protein (STBP), composed at least in part of three peptides (22, 31, and 55 kDa) that bind the synthetic androgen stanozolol. These steroid binding proteins have many properties different from those of classical nuclear receptors, with the salient differences being a failure to recognize quot;classicalquot; ligands for nuclear receptors together with marked differences in biochemical properties and physiological regulation. The mechanism of interaction of glucocorticoids with the LAGS can be clearly distinguished from that with STBP. Moreover, STBP shows an extremely narrow pharmacological profile, being selective for ST and its analog, danazol, among more than 100 steroids and non-steroidal compounds that were assayed, including those that are able to displace glucocorticoids from the LAGS. The level of LAGS activity undergoes dramatic variations following changes from the physiological serum levels of thyroid hormones, glucocorticoids, GH, vitamin A, and E2. However, neither thyroid hormones nor GH have a critical role on STBP activity. The STBP is functionally related to LAGS. We have suggested a novel mechanism for STBP whereby membrane-associated glucocorticoid binding activity is targeted by stanozolol (and 16beta-hydroxylated stanozolol): stanozolol modulates glucocorticoid activity in the liver through negative allosteric modulation of the LAGS resulting in an effective increase in classical GR-signaling by increasing glucocorticoid availability to the cytosolic GR."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1076,I1076)","v":18423260},{"$f":"(LEN($J1076) - LEN(SUBSTITUTE(LOWER($J1076),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1076) - LEN(SUBSTITUTE(LOWER($J1076),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1076) - LEN(SUBSTITUTE(LOWER($J1076),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1076:D1076)","v":0},2008,"Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics.","Menter",18423260,"Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics.    Abstract:   Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this first of 5 sections of the guidelines of care for psoriasis, we discuss the classification of psoriasis; associated comorbidities including autoimmune diseases, cardiovascular risk, psychiatric/psychologic issues, and cancer risk; along with assessment tools for skin disease and quality-of-life issues. Finally, we will discuss the safety and efficacy of the biologic treatments used to treat patients with psoriasis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1077,I1077)","v":22443565},{"$f":"(LEN($J1077) - LEN(SUBSTITUTE(LOWER($J1077),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1077) - LEN(SUBSTITUTE(LOWER($J1077),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1077) - LEN(SUBSTITUTE(LOWER($J1077),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1077:D1077)","v":0},2008,"The potential for improving physiological, behavioural and immunological responses in the neonatal lamb by trace element and vitamin supplementation of the ewe.","Rooke",22443565,"The potential for improving physiological, behavioural and immunological responses in the neonatal lamb by trace element and vitamin supplementation of the ewe.    Abstract:   Neonatal lamb mortality represents both a welfare issue (due to the considerable suffering and distress) and an important production inefficiency. In lambs, approximately 80% of mortality can be attributed to the starvation-mismothering-exposure complex and occurs in the first 3 days after birth. It was the object of this review to determine the micronutrient(s) most likely to have a positive effect on neonatal lamb survival when included above the requirement for that micronutrient. Micronutrients discussed were Co, Cu, I, Fe, Mn, Se, Zn, vitamins A and E and n-3 fatty acids. For Co, Fe, Mn and Zn, there was no evidence of positive responses to supplementation. Cu and I had toxicity thresholds that were sufficiently close to requirement that supplementing above requirement presented a risk of inducing toxicity. In the case of vitamin A, while serum concentrations indicated that sub-optimal status did exist, long-term buffering from liver stores (from grazing) makes experimentation difficult and practical benefits to supplementation unlikely. Therefore, the most likely candidates for supplementation were Se, vitamin E and fatty acids. Fatty acid supplementation with fish oils or docosahexaenoic acid-containing algal biomass consistently improved lamb vigour but it is unlikely that supplementation will be economic. Positive responses to Se supplementation throughout gestation were recorded. However, in many studies the Se status of control ewes was marginal and there is a need for more studies where control ewes are clearly adequate in Se. Positive responses to vitamin E supplementation above requirement in the last-third of gestation were observed but the optimum dietary inclusion of vitamin E and period of feeding during pregnancy still require clarification."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1078,I1078)","v":18343198},{"$f":"(LEN($J1078) - LEN(SUBSTITUTE(LOWER($J1078),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1078) - LEN(SUBSTITUTE(LOWER($J1078),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1078) - LEN(SUBSTITUTE(LOWER($J1078),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1078:D1078)","v":0},2008,"Nuclear receptors: doubling up in the lung.","Farrow",18343198,"Nuclear receptors: doubling up in the lung.    Abstract:   Inhaled corticosteroids are highly effective in the treatment of asthma and also show efficacy in chronic obstructive pulmonary disease (COPD). Considerable effort continues to be focused on improvement of their pharmacology and pharmacokinetic properties. Corticosteroids act through the glucocorticoid receptor, one of a family of ligand activated transcription factors. These proteins are highly tractable to drug discovery, and are targeted by a number of existing therapeutic agents. The possibility that family members other than the glucocorticoid receptor might have therapeutic benefit in lung disease has received increasing attention. Recent studies using ligands for the vitamin D3 receptor, the peroxisome proliferator-activated receptors, and the liver X receptor have demonstrated significant potential for these novel targets in the treatment of lung disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1079,I1079)","v":18299830},{"$f":"(LEN($J1079) - LEN(SUBSTITUTE(LOWER($J1079),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1079) - LEN(SUBSTITUTE(LOWER($J1079),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1079) - LEN(SUBSTITUTE(LOWER($J1079),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1079:D1079)","v":0},2008,"Two cases of post-liver transplant acute myeloid leukemia in Korean adults: review of bibliographies and comparison with post-renal transplant acute myeloid leukemia.","Cho",18299830,"Two cases of post-liver transplant acute myeloid leukemia in Korean adults: review of bibliographies and comparison with post-renal transplant acute myeloid leukemia.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1080,I1080)","v":18297887},{"$f":"(LEN($J1080) - LEN(SUBSTITUTE(LOWER($J1080),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1080) - LEN(SUBSTITUTE(LOWER($J1080),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1080) - LEN(SUBSTITUTE(LOWER($J1080),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1080:D1080)","v":0},2007,"Iron metabolism in infants and children.","Lönnerdal",18297887,"Iron metabolism in infants and children.    Abstract:   Meeting the iron requirements of infants and children is difficult, and supplementation or fortification of food with iron is often recommended. Although iron supplementation of infants and children with iron deficiency and iron-deficiency anemia may be beneficial, recent studies suggest that this may not be the case for those with adequate iron status, and adverse effects have been noted. The recent discoveries of proteins and peptides regulating iron absorption have enhanced our knowledge of iron metabolism in infants and children. Iron is taken up in the small intestine by divalent metal transporter-1 and is either stored by ferritin inside the mucosal cell or transported to the systemic circulation by ferroportin, while being oxidized by hephaestin to be incorporated into transferrin. Hepcidin, a small peptide synthesized by the liver, can sense iron stores and regulates iron transport by inhibition of ferroportin. However, regulation of iron transporters is immature in infants, possibly explaining the adverse effects of iron supplementation. Interactions among iron, vitamin A, zinc, and copper need to be considered when evaluating the effects of iron supplementation on infants and children."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1081,I1081)","v":18222560},{"$f":"(LEN($J1081) - LEN(SUBSTITUTE(LOWER($J1081),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1081) - LEN(SUBSTITUTE(LOWER($J1081),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1081) - LEN(SUBSTITUTE(LOWER($J1081),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1081:D1081)","v":0},2008,"Metabolic engineering of carotenoid biosynthesis in plants.","Giuliano",18222560,"Metabolic engineering of carotenoid biosynthesis in plants.    Abstract:   Carotenoids are one of the most diverse classes of natural compounds. Plant carotenoids are composed of a C40 isoprenoid skeleton with or without epoxy, hydroxy and keto groups. They have fundamental roles in human nutrition as antioxidants and vitamin A precursors and their consumption is increasingly associated with protection from a range of diseases. They are also used commercially as safe food, feed and cosmetic colorants and they protect plants from photooxidative stress. In the past six years many metabolic engineering efforts have been undertaken in plants aiming to improve the nutritional value of staple crops, to enable the use of plants as cell factories for producing specialty carotenoids and to improve plant resistance to abiotic stress."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1082,I1082)","v":18214023},{"$f":"(LEN($J1082) - LEN(SUBSTITUTE(LOWER($J1082),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1082) - LEN(SUBSTITUTE(LOWER($J1082),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1082) - LEN(SUBSTITUTE(LOWER($J1082),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1082:D1082)","v":0},2007,"Influence of infection/inflammation, thalassemia and nutritional status on iron absorption.","Lynch",18214023,"Influence of infection/inflammation, thalassemia and nutritional status on iron absorption.    Abstract:   Iron balance in human beings is maintained by the control of absorption. Recent observations have demonstrated that a peptide hormone, hepcidin, is the principal regulator of iron homeostasis. It is produced in the liver in response to increasing iron stores. It is also induced by interleukin-6 (IL-6) in infectious and inflammatory diseases. Hepcidin restricts both iron absorption and iron release from stores. Disorders that affect the duodenum or stomach directly, particularly gluten enteropathy and H. pylori infections, also impair iron absorption by damaging enterocytes or reducing gastric acid output. Hepcidin secretion is suppressed by accelerated erythropoiesis even when iron stores are increased. This appears to account for the contribution that excessive absorption makes to the iron overload seen in patients with iron-loading anemias such as thalassemia major. There is some evidence suggesting that two nutritional deficiency disorders (deficiencies of vitamin A and riboflavin) lead to impaired iron absorption or utilization, but further research is needed to reconcile conflicting experimental observations."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1083,I1083)","v":18207566},{"$f":"(LEN($J1083) - LEN(SUBSTITUTE(LOWER($J1083),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1083) - LEN(SUBSTITUTE(LOWER($J1083),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1083) - LEN(SUBSTITUTE(LOWER($J1083),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1083:D1083)","v":0},2008,"Maternal and child undernutrition: global and regional exposures and health consequences.","Black",18207566,"Maternal and child undernutrition: global and regional exposures and health consequences.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1084,I1084)","v":17726308},{"$f":"(LEN($J1084) - LEN(SUBSTITUTE(LOWER($J1084),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1084) - LEN(SUBSTITUTE(LOWER($J1084),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1084) - LEN(SUBSTITUTE(LOWER($J1084),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1084:D1084)","v":0},2007,"Contribution of selected vitamins and trace elements to immune function.","Wintergerst",17726308,"Contribution of selected vitamins and trace elements to immune function.    Abstract:   Adequate intakes of vitamins and trace elements are required for the immune system to function efficiently. Micronutrient deficiency suppresses immune functions by affecting the innate T-cell-mediated immune response and adaptive antibody response, and leads to dysregulation of the balanced host response. This increases the susceptibility to infections, with increased morbidity and mortality. In turn, infections aggravate micronutrient deficiencies by reducing nutrient intake, increasing losses, and interfering with utilization by altering metabolic pathways. Insufficient intake of micronutrients occurs in people with eating disorders, in smokers (both active and passive), in individuals with chronic alcohol abuse, in patients with certain diseases, during pregnancy and lactation, and in the elderly. With aging a variety of changes are observed in the immune system, which translate into less effective innate and adaptive immune responses and increased susceptibility to infections. Antioxidant vitamins and trace elements (vitamins C, E, selenium, copper, and zinc) counteract potential damage caused by reactive oxygen species to cellular tissues and modulate immune cell function through regulation of redox-sensitive transcription factors and affect production of cytokines and prostaglandins. Adequate intake of vitamins B(6), folate, B(12), C, E, and of selenium, zinc, copper, and iron supports a Th1 cytokine-mediated immune response with sufficient production of proinflammatory cytokines, which maintains an effective immune response and avoids a shift to an anti-inflammatory Th2 cell-mediated immune response and an increased risk of extracellular infections. Supplementation with these micronutrients reverses the Th2 cell-mediated immune response to a proinflammatory Th1 cytokine-regulated response with enhanced innate immunity. Vitamins A and D play important roles in both cell-mediated and humoral antibody response and support a Th2-mediated anti-inflammatory cytokine profile. Vitamin A deficiency impairs both innate immunity (mucosal epithelial regeneration) and adaptive immune response to infection resulting in an impaired ability to counteract extracellular pathogens. Vitamin D deficiency is correlated with a higher susceptibility to infections due to impaired localized innate immunity and defects in antigen-specific cellular immune response. Overall, inadequate intake and status of these vitamins and minerals may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1085,I1085)","v":17483773},{"$f":"(LEN($J1085) - LEN(SUBSTITUTE(LOWER($J1085),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1085) - LEN(SUBSTITUTE(LOWER($J1085),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1085) - LEN(SUBSTITUTE(LOWER($J1085),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1085:D1085)","v":0},2007,"[Nutritional deficiencies associated with bariatric surgery].","Folope",17483773,"[Nutritional deficiencies associated with bariatric surgery].    Abstract:   Morbidly obese patients often have nutritional deficiencies, particularly in fat-soluble vitamins, folic acid and zinc. After bariatric surgery, these deficiencies may increase and others can appear, especially because of the limitation of food intake in gastric reduction surgery and of malabsorption in by-pass procedures. The latter result in more important weight loss but also increase the risk of more severe deficiencies. The protein deficiency associated with a decrease in the fat-free mass has been described in both procedures. It can sometimes require an enteral or parenteral support. Anemia can be secondary to iron deficiency, folic acid deficiency and even to vitamin B12 deficiency. Neurological disorders such as Gayet-Wernicke encephalopathy due to thiamine deficiency, or peripheral neuropathies may also be observed. Malabsorption of fat-soluble vitamins and other nutrients, especially if diagnosed after by-pass surgery, rarely cause clinical symptoms. However, some complications have been reported such as bone demineralization due to vitamin D deficiency, hair loss secondary to zinc deficiency or hemeralopia from vitamin A deficiency. A careful nutritional follow-up should be performed during pregnancy after obesity surgery, because possible deficiencies can affect the health of both the mother and child. In conclusion, increased awareness of the risk of deficiency and the systematic dosage of micronutrients are needed in the pre- and postoperative period in obese patients undergoing bariatric surgery. The case by case correction of these deficiencies is mandatory, and their systematic prevention should be evaluated."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1086,I1086)","v":17475465},{"$f":"(LEN($J1086) - LEN(SUBSTITUTE(LOWER($J1086),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1086) - LEN(SUBSTITUTE(LOWER($J1086),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1086) - LEN(SUBSTITUTE(LOWER($J1086),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1086:D1086)","v":0},2007,"Is metabolic syndrome X a disorder of the brain with the initiation of low-grade systemic inflammatory events during the perinatal period?","Das",17475465,"Is metabolic syndrome X a disorder of the brain with the initiation of low-grade systemic inflammatory events during the perinatal period?    Abstract:   An imbalance between pro- and anti-inflammatory molecules occurs in metabolic syndrome X. High-energy diet, saturated fats and trans-fats during perinatal period could suppress Delta(6) and Delta(5) desaturases both in the maternal and fetal tissues, resulting in a decrease in the concentrations of long-chain polyunsaturated fatty acids (LCPUFAs): arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that have a negative feedback control on inflammation. EPA, DHA and AA augment endothelial nitric oxide synthesis, potentiate insulin action both in the peripheral tissues and brain and alter leptin production. LCPUFAs are essential for brain growth and development and synaptogenesis and modulate the action of several neurotransmitters and hypothalamic peptides. This suggests that metabolic syndrome X could be a disorder of the brain due to suboptimal LCPUFAs during perinatal period that triggers low-grade systemic inflammation, implying that perinatal strategies are needed to prevent its development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1087,I1087)","v":17314330},{"$f":"(LEN($J1087) - LEN(SUBSTITUTE(LOWER($J1087),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1087) - LEN(SUBSTITUTE(LOWER($J1087),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1087) - LEN(SUBSTITUTE(LOWER($J1087),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1087:D1087)","v":0},2007,"Innate immune system regulation of nuclear hormone receptors in metabolic diseases.","Chow",17314330,"Innate immune system regulation of nuclear hormone receptors in metabolic diseases.    Abstract:   The immune system modulates a number of biological processes to properly defend against pathogens. Here, we review how crosstalk between nuclear hormone receptors and the innate immune system may influence multiple biological functions during an immune response. Although nuclear hormone receptor repression of innate immune responses and inflammation has been well studied, a number of new studies have identified repression of nuclear hormone receptor signaling by various innate immune responses. IFN regulatory factor 3, a key transcription factor involved in the induction of antiviral genes, may play a role in mediating such crosstalk between the innate immune response and nuclear receptor-regulated metabolism. This crosstalk mechanism is now implicated in the pathogenesis of atherosclerosis and Reyes syndrome and could provide an explanation for other pathogen-associated metabolic and developmental disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1088,I1088)","v":17151585},{"$f":"(LEN($J1088) - LEN(SUBSTITUTE(LOWER($J1088),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1088) - LEN(SUBSTITUTE(LOWER($J1088),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1088) - LEN(SUBSTITUTE(LOWER($J1088),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1088:D1088)","v":0},2006,"Vitamin A toxicity in a physical culturist patient: a case report and review of the literature.","Castaño",17151585,"Vitamin A toxicity in a physical culturist patient: a case report and review of the literature.    Abstract:   Excessive intake of vitamin A may produce acute or chronic toxicity. Vitamin A can be consumed in foods, fortified products and supplements. We present a case of a young physical culturist man who was referred to our Unit because of chronic liver disease of unknown origin. The patient had a history of increased vitamin A intake from natural source with the addition of high dose of vitamin A supplements with the purpose of improving his muscular development. Our patient showed chronic liver disease with severe fibrosis, signs of portal hypertension and marked hyperplasia of Ito cells. In conclusion, chronic vitamin A toxicity may produce severe liver damage and should be recognized in the differential diagnosis of chronic liver diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1089,I1089)","v":17022912},{"$f":"(LEN($J1089) - LEN(SUBSTITUTE(LOWER($J1089),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1089) - LEN(SUBSTITUTE(LOWER($J1089),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1089) - LEN(SUBSTITUTE(LOWER($J1089),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1089:D1089)","v":0},2006,"Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.","Gaudet",17022912,"Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.    Abstract:    BACKGROUND : Abetalipoproteinemia (ABL) is a metabolic disorder resulting in poor absorption of fat-soluble vitamins.  CASE : Two pregnancies in a woman with ABL are reported, contrasting outcomes with subtherapeutic and normal vitamin levels.  CONCLUSION : Fat-soluble vitamin levels in pregnancy are critical for many aspects of fetal development. This report details a congenital ophthalmologic finding that may be associated with vitamin A deficiency."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1090,I1090)","v":17016948},{"$f":"(LEN($J1090) - LEN(SUBSTITUTE(LOWER($J1090),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1090) - LEN(SUBSTITUTE(LOWER($J1090),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1090) - LEN(SUBSTITUTE(LOWER($J1090),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1090:D1090)","v":0},2003,"Combating hidden hunger: the role of international agencies.","Dalmiya",17016948,"Combating hidden hunger: the role of international agencies.    Abstract:   The importance of micronutrient deficiencies or quot;hidden hungerquot; was clearly emphasized by the inclusion of specific goals on iron, vitamin A, and iodine deficiency at the 1990 World Summit for Children and other major international nutrition conferences. Significant progress has since been made toward eliminating vitamin A and iodine deficiencies, with less progress made toward reducing the burden of iron-deficiency anemia. The role of international agencies, such as the World Health Organization, United Nations Childrens Fund, Food and Agricultural Organization, and World Bank in assisting countries to make progress toward the World Summit for Children goals has been very important. International agencies have played a critical role in advocating for and raising awareness of these issues at the international, regional, and national levels among policymakers and the general population. Using a rights-based approach, UNICEF and other agencies have been instrumental in elevating to the highest political level the discussion of every childs right to adequate nutrition. International agencies have also been very supportive at the national level in providing technical guidance for programs, including monitoring and evaluation. These agencies have played a critical role in engaging the cooperation of other partners, including bilateral donors, non-governmental organizations, and the private sector for micronutrient programs. Furthermore, international agencies provide financial and material support for micronutrient programs. In the future, such agencies must continue to be heavily involved in programs to achieve the newly confirmed goals for 2010. The present paper focuses on the role of international agencies in combating micronutrient deficiencies, drawing on the lessons learned over the last decade. The first section of the paper summarizes the progress achieved since 1990, and the second section describes the specific role of international agencies in contributing to that progress."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1091,I1091)","v":17013515},{"$f":"(LEN($J1091) - LEN(SUBSTITUTE(LOWER($J1091),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1091) - LEN(SUBSTITUTE(LOWER($J1091),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1091) - LEN(SUBSTITUTE(LOWER($J1091),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1091:D1091)","v":0},2006,"Liver cirrhosis and hepatic stellate cells.","Brandão",17013515,"Liver cirrhosis and hepatic stellate cells.    Abstract:   The cirrhosis represents the final stage of several chronic hepatic diseases and it is characterized by the presence of fibrosis and morphologic conversion from the normal hepatic architecture into structurally abnormal nodules. In the evolution of the disease there is loss of the normal vascular relationship and portal hypertension. There are also regenerative hepatocellular alterations that become more prominent with the progression of the disease. The liver transplantation continues to be the only therapeutic option in cases of disease in terminal phase. The hepatic stellate cells (HSC) are perisinusoidal cells that store vitamin A and produce growth factors, citocins, prostaglandins and other bioactive substances. They can suffer an activation process that convert them to cells with a phenotype similar to myofibroblasts. When activated, they present increased capacity of proliferation, mobility, contractility and synthesis of collagen and other components of extracellular matrix. They possess cytoplasmic processes adhered to sinusoids and can affect the sinusoidal blood flow. HSC are important in pathogenesis of fibrosis and portal hypertension."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1092,I1092)","v":16972684},{"$f":"(LEN($J1092) - LEN(SUBSTITUTE(LOWER($J1092),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1092) - LEN(SUBSTITUTE(LOWER($J1092),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1092) - LEN(SUBSTITUTE(LOWER($J1092),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1092:D1092)","v":0},2006,"[Nutrition-related bone disease].","Hirota",16972684,"[Nutrition-related bone disease].    Abstract:   Bone disorders clearly related to nutrition are osteomalacia and osteoporosis. Osteomalacia is caused by a deficiency of vitamin D or a disturbance of its metabolism. Dietary deficiency of phosphate or excess of aluminum or cadmium will also cause osteomalacia. Osteoporosis is associated with low intake of calcium and other nutrients. Dietary copper deficiency might stimulate bone metabolism and increase in hip fractures. Excess vitamin A intake was also associated with lower bone mineral density and higher risk of hip fractures. Excess vitamin D sometimes causes mental simplicity, congenital heart disease and calcification of soft tissue. Therefore not only diet but also drugs and supplements of nutrients should be carefully observed in older women."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1093,I1093)","v":16958682},{"$f":"(LEN($J1093) - LEN(SUBSTITUTE(LOWER($J1093),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1093) - LEN(SUBSTITUTE(LOWER($J1093),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1093) - LEN(SUBSTITUTE(LOWER($J1093),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1093:D1093)","v":0},2006,"Matrix metalloproteinases, the pros and cons, in liver fibrosis.","Han",16958682,"Matrix metalloproteinases, the pros and cons, in liver fibrosis.    Abstract:   Residing in the space of Disse within loose extracellular matrix (ECM) resembling that in basement membranes, the hepatic stellate cells (HSC) remain in quiescence as vitamin A storage cells. In response to liver injury HSC undergo morphologic and functional trans-differentiation, converting from vitamin A-storing, star-like cells into contractile myofibroblastic cells, a process called activation. Accompanying cellular activation, the ECM components in the space of Disse switch from matrices rich in type-IV collagen and laminin, into condensed interstitial ECM, indicating that proteolytic degradation may occur to change the microenvironment in sinusoids as well as the fate of HSC. Indeed, matrix metalloproteinases (MMP), a family of ECM degradative enzymes, are promptly expressed by HSC in response to diverse hepatic toxins. In vitro experiments also demonstrated the role of MMP in activation of HSC cultured in 3-D ECM. Conversely, MMP may also contribute to regression of liver fibrosis through cleavage of the fibrillar ECM and promotion of apoptosis among the activated HSC. Thus, MMP play dual roles both bad and good in liver fibrosis, depending on the timing."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1094,I1094)","v":16858612},{"$f":"(LEN($J1094) - LEN(SUBSTITUTE(LOWER($J1094),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1094) - LEN(SUBSTITUTE(LOWER($J1094),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1094) - LEN(SUBSTITUTE(LOWER($J1094),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1094:D1094)","v":0},2007,"ABCA1, from pathology to membrane function.","Zarubica",16858612,"ABCA1, from pathology to membrane function.    Abstract:   The ABCA1 transporter is the prototype of the A class of mammalian adenosine triphosphate binding cassette transporters and one of the largest members of this family. ABCA1 has been originally identified as an engulfment receptor on macrophages and, more recently, it has been shown to play an essential role in the handling of cellular lipids. Indeed by promoting the effluxes of membrane phospholipids and cholesterol to lipid-poor apoprotein acceptors, ABCA1 controls the formation of high-density lipoproteins and thus the whole process of reverse cholesterol transport. A number of additional phenotypes have been found in the mouse model of invalidation of the ABCA1 gene. In spite of their clinical diversity, they all are extremely sensitive to variations in the physicochemical properties of the cell membrane, which ABCA1 controls as a lipid translocator."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1095,I1095)","v":16817375},{"$f":"(LEN($J1095) - LEN(SUBSTITUTE(LOWER($J1095),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1095) - LEN(SUBSTITUTE(LOWER($J1095),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1095) - LEN(SUBSTITUTE(LOWER($J1095),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1095:D1095)","v":0},2006,"[Iatrogenic hypercalcemia].","Akatsu",16817375,"[Iatrogenic hypercalcemia].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1096,I1096)","v":16688120},{"$f":"(LEN($J1096) - LEN(SUBSTITUTE(LOWER($J1096),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1096) - LEN(SUBSTITUTE(LOWER($J1096),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1096) - LEN(SUBSTITUTE(LOWER($J1096),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1096:D1096)","v":0},2006,"The podocytes response to injury: role in proteinuria and glomerulosclerosis.","Shankland",16688120,"The podocytes response to injury: role in proteinuria and glomerulosclerosis.    Abstract:   The terminally differentiated podocyte, also called glomerular visceral epithelial cell, are highly specialized cells. They function as a critical size and charge barrier to prevent proteinuria. Podocytes are injured in diabetic and non-diabetic renal diseases. The clinical signature of podocyte injury is proteinuria, with or without loss of renal function owing to glomerulosclerosis. There is an exciting and expanding literature showing that hereditary, congenital, or acquired abnormalities in the molecular anatomy of podocytes leads to proteinuria, and at times, glomerulosclerosis. The change in podocyte shape, called effacement, is not simply a passive process following injury, but is owing to a complex interplay of proteins that comprise the molecular anatomy of the different protein domains of podocytes. These will be discussed in this review. Recent studies have also highlighted that a reduction in podocyte number directly causes proteinuria and glomerulosclerosis. This is owing to several factors, including the relative inability for these cells to proliferate, detachment, and apoptosis. The mechanisms of these events are being elucidated, and are discussed in this review. It is the hope that by delineating the events following injury to podocytes, therapies might be developed to reduce the burden of proteinuric renal diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1097,I1097)","v":16452274},{"$f":"(LEN($J1097) - LEN(SUBSTITUTE(LOWER($J1097),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1097) - LEN(SUBSTITUTE(LOWER($J1097),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1097) - LEN(SUBSTITUTE(LOWER($J1097),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1097:D1097)","v":0},2006,"Vitamins.","Sethuraman",16452274,"Vitamins.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1098,I1098)","v":16397353},{"$f":"(LEN($J1098) - LEN(SUBSTITUTE(LOWER($J1098),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1098) - LEN(SUBSTITUTE(LOWER($J1098),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1098) - LEN(SUBSTITUTE(LOWER($J1098),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1098:D1098)","v":0},2006,"[Drug-induced hypercalcemia].","Sato",16397353,"[Drug-induced hypercalcemia].    Abstract:   Drug-induced hypercalcemia is caused by increased bone resorption (vitamin D and vitamin A intoxication), increased calcium absorption in the gastrointestinal tract (vitamin D intoxication, excessive intake of calcium) or increased calcium reabsorption in the renal tubules (thiazide diuretics). When vitamin D (D(2) or D(3)) intoxication develops, the hypercalcemia persists for more than several months. Therefore, short-acting active vitamin D (1alpha-OHD(3), 1,25- (OH) (2)D(3)) are clinically used. Recently, various analogs of 1,25- (OH) (2)D(3) with potent differentiation stimulating activity on keratinocytes but insufficient calcium-movilizing activity have been developed (tacalcitol, calcipotriol, 22-oxacalcitriol). However, severe hypercalcemia may develop when these ointments were abundantly applied to patients with psoriasis since the agents can be easily absorbed through the skin lesions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1099,I1099)","v":16363067},{"$f":"(LEN($J1099) - LEN(SUBSTITUTE(LOWER($J1099),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1099) - LEN(SUBSTITUTE(LOWER($J1099),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1099) - LEN(SUBSTITUTE(LOWER($J1099),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1099:D1099)","v":0},2005,"Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years.","Lieber",16363067,"Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years.    Abstract:   Fifty years ago the dogma prevailed that alcohol was not toxic to the liver and that alcoholic liver disease was exclusively a consequence of nutritional deficiencies. We showed, however, that liver pathology developed even in the absence of malnutrition. This toxicity of alcohol was linked to its metabolism via alcohol dehydrogenase which converts nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide-reduced form (NADH) which contributes to hyperuricemia, hypoglycemia and hepatic steatosis by inhibiting lipid oxidation and promoting lipogenesis. We also discovered a new pathway of ethanol metabolism, the microsomal ethanol oxidizing system (MEOS). The activity of its main enzyme, cytochrome P4502E1 (CYP2E1), and its gene are increased by chronic consumption, resulting in metabolic tolerance to ethanol. CYP2E1 also detoxifies many drugs but occasionally toxic and even carcinogenic metabolites are produced. This activity is also associated with the generation of free radicals with resulting lipid peroxidation and membrane damage as well as depletion of mitochondrial reduced glutathione (GSH) and its ultimate precursor, namely methionine activated to S-adenosylmethionine (SAMe). Its repletion restores liver functions. Administration of polyenylphosphatidylcholine (PPC), a mixture of unsaturated phosphatidylcholines (PC) extracted from soybeans, restores the structure of the membranes and the function of the corresponding enzymes. Ethanol impairs the conversion of beta-carotene to vitamin A and depletes hepatic vitamin A and, when it is given together with vitamin A or beta-carotene, hepatotoxicity is potentiated. Our present therapeutic approach is to reduce excess alcohol consumption by the Brief Intervention technique found to be very successful. We correct hepatic SAMe depletion and supplementation with PPC has some favorable effects on parameters of liver damage which continue to be evaluated. Similarly dilinoleoylphosphatidylcholine (DLPC), PPCs main component, also partially opposes the increase in CYP2E1 by ethanol. Hence, therapy with SAMe +DLPC is now being considered."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1100,I1100)","v":16335761},{"$f":"(LEN($J1100) - LEN(SUBSTITUTE(LOWER($J1100),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1100) - LEN(SUBSTITUTE(LOWER($J1100),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1100) - LEN(SUBSTITUTE(LOWER($J1100),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1100:D1100)","v":0},2004,"Iron deficiency anaemia--an old enemy.","Bagchi",16335761,"Iron deficiency anaemia--an old enemy.    Abstract:   Anaemia has remained a widespread public health problem in countries of the Eastern Mediterranean Region. Prevalence figures vary from a low of 17% to a high of over 70% among preschool children; from 14% to 42% among adolescents and from 11% to over 40% among women of childbearing age. Although the prevalence of anaemia has often been used as a proxy indicator for iron deficiency anaemia, this approach is not valid in settings where the etiology of anaemia is complex or unknown or where other micronutrient deficiencies of folate, vitamin B12 and vitamin A can co-exist. An integrated, multifactorial and multisectoral approach has to be adopted comprising targeted interventions to provide iron supplements to especially vulnerable segments of the population, in particular pregnant women; food-based approaches to increase iron intake through food fortification and dietary diversification; and other measures combined with iron interventions where other causes of anaemia are prevalent."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1101,I1101)","v":16275119},{"$f":"(LEN($J1101) - LEN(SUBSTITUTE(LOWER($J1101),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1101) - LEN(SUBSTITUTE(LOWER($J1101),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1101) - LEN(SUBSTITUTE(LOWER($J1101),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1101:D1101)","v":0},2005,"Genetic analysis of adrenal absence: agenesis and aplasia.","Else",16275119,"Genetic analysis of adrenal absence: agenesis and aplasia.    Abstract:   The adrenal cortex shares a common embryological heritage with the gonad and kidney: all are derived from components of the urogenital ridge. Adrenocortical specification from this embryonic structure and the ultimate organogenesis of the adrenal gland are directed by the sequential expression of transcriptional regulators, with later development being additionally mediated by endocrine hormones that regulate organ maintenance and tissue differentiation. Recent advancements in the field of human and mouse genetics have accumulated evidence for a host of novel factors involved in these processes, such as the hedgehog signaling network and peptides derived from proopiomelanocortin."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1102,I1102)","v":16182194},{"$f":"(LEN($J1102) - LEN(SUBSTITUTE(LOWER($J1102),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1102) - LEN(SUBSTITUTE(LOWER($J1102),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1102) - LEN(SUBSTITUTE(LOWER($J1102),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1102:D1102)","v":0},2005,"Emerging role of high-density lipoprotein in the prevention of cardiovascular disease.","Brousseau",16182194,"Emerging role of high-density lipoprotein in the prevention of cardiovascular disease.    Abstract:   In major statin trials, the relative risk reduction is typically in the range 25-35%, thus indicating that the majority of cardiac events continues to occur despite statin therapy. Hence, there is a considerable interest in identifying novel therapies capable of further reducing cardiovascular disease risk. One such potential therapeutic target is a low level of high-density lipoprotein (HDL) cholesterol. Emerging targets involved in HDL metabolism are: (i) liver X receptor and peroxisome proliferator-activated receptor agonists; (ii) cholesteryl ester transfer protein inhibitors; (iii) HDL mimetics (ETC-216); (iv) apolipoprotein A-I synthetic peptides; and (v) HDL delipidation and reinfusion. Although they are at various stages of development, each of these therapies has promise for the treatment of cardiovascular disease in humans."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1103,I1103)","v":16164019},{"$f":"(LEN($J1103) - LEN(SUBSTITUTE(LOWER($J1103),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1103) - LEN(SUBSTITUTE(LOWER($J1103),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1103) - LEN(SUBSTITUTE(LOWER($J1103),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1103:D1103)","v":0},2005,"The innate immune response under the control of the LXR pathway.","Valledor",16164019,"The innate immune response under the control of the LXR pathway.    Abstract:   Macrophages play essential roles in infection and resolution of inflammation. This review summarizes recent findings that suggest a relevant role for the nuclear receptor liver X receptor (LXR) in the evolution of immune responses. By exerting both positive and negative regulation of specific macrophage gene expression networks, LXRs display anti-inflammatory activities and promote macrophage survival in bacterial infection settings. Agonists that activate the LXR pathway may be used to enhance innate immunity to highly virulent pathogens that otherwise induce macrophage apoptosis as a means to subvert host immune defense."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1104,I1104)","v":16121828},{"$f":"(LEN($J1104) - LEN(SUBSTITUTE(LOWER($J1104),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1104) - LEN(SUBSTITUTE(LOWER($J1104),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1104) - LEN(SUBSTITUTE(LOWER($J1104),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1104:D1104)","v":0},2005,"Ophthaproblem. Vitamin A and vitamin E.","Segal",16121828,"Ophthaproblem. Vitamin A and vitamin E.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1105,I1105)","v":16101408},{"$f":"(LEN($J1105) - LEN(SUBSTITUTE(LOWER($J1105),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1105) - LEN(SUBSTITUTE(LOWER($J1105),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1105) - LEN(SUBSTITUTE(LOWER($J1105),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1105:D1105)","v":0},2005,"FXR, a therapeutic target for bile acid and lipid disorders.","Westin",16101408,"FXR, a therapeutic target for bile acid and lipid disorders.    Abstract:   The farnesoid X receptor (FXR) is a nuclear receptor expressed in tissues exposed to high concentrations of bile acids such as the liver, kidney and intestine and functions as a bile acid sensor. FXR regulates the expression of various transport proteins and biosynthetic enzymes crucial to the physiological maintenance of lipids, cholesterol and bile acid homeostasis. The concept of reverse endocrinology, whereby the receptor is identified first, followed by the identification of ligands and the sequential elucidation of the physiological role of the receptor has been widely used for a number of orphan nuclear receptors. The design of synthetic high affinity ligands acting via these receptors not only helps to decipher the function of the receptor, but also should lead to the development of novel and highly specific drugs. The bile acid receptor FXR is a perfect example where this strategy helped with understanding the role of this receptor in cholesterol and bile acid homeostasis. Regulation of FXR through small-molecule drugs represents a promising therapy for diseases resulting from lipid, cholesterol and bile acid abnormalities."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1106,I1106)","v":16048032},{"$f":"(LEN($J1106) - LEN(SUBSTITUTE(LOWER($J1106),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1106) - LEN(SUBSTITUTE(LOWER($J1106),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1106) - LEN(SUBSTITUTE(LOWER($J1106),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1106:D1106)","v":0},2005,"[Diet, nutrition and rheumatoid arthritis].","Miggiano",16048032,"[Diet, nutrition and rheumatoid arthritis].    Abstract:   Rheumatoid Arthritis (RA) is a chronic inflammatory disease resulting in diarthrodial joints inflammation (particularly joints of hands, wrists, feet, knees, cubitus, ankles, shoulder, etc.) that is manifested by swelling and functional impairment. The associated complications, osteoporosis and cardiovascular disease, make RA important in public health terms. During the active phase of disease, elevated plasma concentrations of inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and acute-phase proteins, lead to reduction of fat free body mass (FFM) with a loss mean of 15% of cell body mass (CM) and consequent reduction of muscle strength. The pharmacological therapy (non steroidal anti inflammatory drugs (NSAIDs), slow acting antirheumatic drugs and corticosteroids), have the potential to cause side-effects, such as gastrointestinal bleeding, bone loss beyond to increase the requirement of some nutrients and reduce their absorption. The diet may play role in the management of RA, particularly in alleviating the symptoms of the disease, combating the side-effects of therapy and reducing the risk of complications. The increase of the caloric and proteic intake is not sufficient to offset a increased metabolic rhythm and important proteic catabolism but a diet balanced may warrant an adequate intake of nutrients. The carbohydrates of the diet provide 55-60% of the caloric intake, the diet is normo-proteinic or hyper-proteinic in the active phase of disease, and lipids represent 25-30% of the caloric intake (saturated, monounsaturated, polyunsaturated fatty acids in the ratio 1:1:1). omega-3 fatty acids supplementation, in combination with reduction of fatty acids omega-6 and adequate intake of monounsaturated fatty acids induce improvement in symptoms and sometimes a reduction in NSAIDs usage. Proper antioxidant nutrients (Vitamin A, Vitamin C, selenium) may provide an important defence against the increased oxidant stress and a supplementation of folate and vitamin B12, in patients treated with methotrexate (MTX), reduce the incidence of side effects and offset the elevation in plasma homocysteine frequent in these patients. Calcium and vitamin D, in patients treated with corticosteroids, reduce the bone loss, while a supplementation with iron may prevent anaemia. Finally, elimination diets may be feasible therapy only in patients with positive skin prick test."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1107,I1107)","v":16040282},{"$f":"(LEN($J1107) - LEN(SUBSTITUTE(LOWER($J1107),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1107) - LEN(SUBSTITUTE(LOWER($J1107),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1107) - LEN(SUBSTITUTE(LOWER($J1107),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1107:D1107)","v":0},2005,"Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases.","de Grey",16040282,"Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases.    Abstract:   Several major diseases of old age, including atherosclerosis, macular degeneration and neurodegenerative diseases are associated with the intracellular accumulation of substances that impair cellular function and viability. Moreover, the accumulation of lipofuscin, a substance that may have similarly deleterious effects, is one of the most universal markers of aging in postmitotic cells. Reversing this accumulation may thus be valuable, but has proven challenging, doubtless because substances resistant to cellular catabolism are inherently hard to degrade. We suggest a radically new approach: augmenting humans natural catabolic machinery with microbial enzymes. Many recalcitrant organic molecules are naturally degraded in the soil. Since the soil in certain environments - graveyards, for example - is enriched in human remains but does not accumulate these substances, it presumably harbours microbes that degrade them. The enzymes responsible could be identified and engineered to metabolise these substances in vivo. Here, we survey a range of such substances, their putative roles in age-related diseases and the possible benefits of their removal. We discuss how microbes capable of degrading them can be isolated, characterised and their relevant enzymes engineered for this purpose and ways to avoid potential side-effects."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1108,I1108)","v":15994105},{"$f":"(LEN($J1108) - LEN(SUBSTITUTE(LOWER($J1108),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1108) - LEN(SUBSTITUTE(LOWER($J1108),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1108) - LEN(SUBSTITUTE(LOWER($J1108),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1108:D1108)","v":0},2005,"Hypervitaminosis A in the cat: a case report and review of the literature.","Polizopoulou",15994105,"Hypervitaminosis A in the cat: a case report and review of the literature.    Abstract:   A case of hypervitaminosis A with secondary entrapment and compression of the left brachial plexus nerve roots is described. A 9-year-old male castrated domestic shorthair, fed a home-made diet based on raw pork liver, was submitted for examination for a left forelimb lameness that evolved to paralysis over a 2-month period. Clinical examination revealed a flaccid paralysis and atrophy of all left forelimb muscles. An ipsilateral Horners syndrome was also noted. Radiological examination of the cervical and thoracic spine showed massive new bone formation at the ventral aspect of the second cervical to sixth thoracic vertebra. The diagnosis of hypervitaminosis A was made, based on the clinical and radiographic findings, as well as the determination of serum vitamin A concentration, which was 630 microg/dl, three times above the upper normal limit for this species. Despite the unfavourable initial prognosis, the cat progressively regained function of the affected limb approximately 6 months after the diet was changed to a commercial canned food."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1109,I1109)","v":15988384},{"$f":"(LEN($J1109) - LEN(SUBSTITUTE(LOWER($J1109),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1109) - LEN(SUBSTITUTE(LOWER($J1109),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1109) - LEN(SUBSTITUTE(LOWER($J1109),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1109:D1109)","v":0},2005,"The role of SF1/DAX1 in adrenal and reproductive function.","Achermann",15988384,"The role of SF1/DAX1 in adrenal and reproductive function.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1110,I1110)","v":15969329},{"$f":"(LEN($J1110) - LEN(SUBSTITUTE(LOWER($J1110),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1110) - LEN(SUBSTITUTE(LOWER($J1110),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1110) - LEN(SUBSTITUTE(LOWER($J1110),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1110:D1110)","v":0},2004,"Dietary antioxidant compounds and liver health.","Vitaglione",15969329,"Dietary antioxidant compounds and liver health.    Abstract:   Chronic liver damage is a widespread pathology characterized by a progressive evolution from steatosis to chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. As the oxidative stress plays a central role in liver diseases pathogenesis and progression, the use of antioxidants have been proposed as therapeutic agents, as well as drug coadjuvants, to counteract liver damage. In this work in vitro and in vivo studies, with emphasis on humans and animals experiments, have been considered and reviewed according to antioxidant typologies. Great differences emerge as far as ingested doses, bioavailability and liver ability to accumulate the various compounds. Results available up to now suggest that lycopene-rich foods could be proposed in therapeutic treatment of some liver pathologies. On the other hand contradictory results have been obtained with alpha-tocopherol, beta-carotene and trans-resveratrol. Quercetin, silymarin, esculetin and thyme and rosemary among phenolic compounds need further studies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1111,I1111)","v":15949683},{"$f":"(LEN($J1111) - LEN(SUBSTITUTE(LOWER($J1111),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1111) - LEN(SUBSTITUTE(LOWER($J1111),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1111) - LEN(SUBSTITUTE(LOWER($J1111),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1111:D1111)","v":0},2005,"Induction of PXR-mediated metabolism by beta-carotene.","Rühl",15949683,"Induction of PXR-mediated metabolism by beta-carotene.    Abstract:   beta-carotene is the major carotenoid occurring in the human diet and in the human organism. Besides its function as pro-vitamin A, beta-carotene has been shown to be an activator of the human pregnan X receptor (PXR). PXR is mainly expressed in the liver/intestine and an inducer of enzymes involved in phase I, II and III metabolism. This review is focused on the evaluation of physiological and nutritional relevance of beta-carotene as an inducer of phase I enzymes in the human organism via PXR-mediated mechanisms. Beneficial and detrimental effects of beta-carotene on xenobiotica metabolism and metabolism of various other derivatives will be discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1112,I1112)","v":15948399},{"$f":"(LEN($J1112) - LEN(SUBSTITUTE(LOWER($J1112),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1112) - LEN(SUBSTITUTE(LOWER($J1112),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1112) - LEN(SUBSTITUTE(LOWER($J1112),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1112:D1112)","v":0},2005,"[Motor neuron disease up-to date].","Yamamoto",15948399,"[Motor neuron disease up-to date].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1113,I1113)","v":15885783},{"$f":"(LEN($J1113) - LEN(SUBSTITUTE(LOWER($J1113),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1113) - LEN(SUBSTITUTE(LOWER($J1113),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1113) - LEN(SUBSTITUTE(LOWER($J1113),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1113:D1113)","v":0},2005,"Ocular complications of hypovitaminosis a after bariatric surgery.","Lee",15885783,"Ocular complications of hypovitaminosis a after bariatric surgery.    Abstract:    PURPOSE : To report the ocular complications of xerophthalmia, nyctalopia, and visual deterioration to legal blindness as a result of inadequate vitamin A supplementation after malabsorptive bariatric surgery.  DESIGN : Observational case report and literature review.  PARTICIPANT : A 39-year-old woman with xerophthalmia and nyctalopia occurring 3 years after gastric bypass surgery.  RESULTS : We report a patient with a rare finding of xerophthalmia and visual deterioration after gastric bypass surgery as a result of vitamin A deficiency. The patient was referred for decreased vision associated with chronic dry eyes, bilateral diffuse punctate keratitis, and corneal scarring of unknown cause after several ophthalmologic examinations. The medical history, ophthalmic findings, and clinical course are discussed.  CONCLUSIONS : Gastric bypass procedures can cause vitamin A deficiency leading to serious ocular complications, including xerophthalmia, nyctalopia, and ultimate blindness. The increasing incidence of obesity and gastric bypass procedures warrants patient and physician education regarding strict adherence to vitamin supplementation. Education is imperative to avoid detrimental ophthalmic complications resulting from hypovitaminosis A and to prevent a potential epidemic of iatrogenic xerophthalmia and blindness."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1114,I1114)","v":15883453},{"$f":"(LEN($J1114) - LEN(SUBSTITUTE(LOWER($J1114),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1114) - LEN(SUBSTITUTE(LOWER($J1114),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1114) - LEN(SUBSTITUTE(LOWER($J1114),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1114:D1114)","v":0},2005,"Multiple micronutrients in pregnancy and lactation: an overview.","Allen",15883453,"Multiple micronutrients in pregnancy and lactation: an overview.    Abstract:   This overview of multiple micronutrients during pregnancy and lactation emphasizes 2 relatively neglected issues. The first is that maternal micronutrient status in the periconceptional period, and throughout pregnancy and lactation, should be viewed as a continuum; too often these 3 stages are treated and discussed separately from both a scientific and a public health perspective. Iron and vitamin B-12 are included as examples to stress how status at conception affects maternal, fetal, and infant status and health until the child is weaned. The second issue is that while most attention has been focused on a few micronutrients, for example iron and folate as discussed elsewhere in this Supplement, multiple micronutrient deficiencies occur simultaneously when diets are poor. Some of these deserve more attention as causes of poor pregnancy outcome, including other B vitamin deficiencies that result in homocysteinemia, antioxidants, vitamin D, and iodine. In lactation, maternal status or intake of the B vitamins (except folate), vitamin A, selenium and iodine strongly affect the amount of these nutrients secreted in breast milk. This can result in the infant consuming substantially less than the recommended amounts and further depleting stores that were low at birth. While the optimal mode of meeting recommended micronutrient intakes is an adequate diet, in some situations supplementation is also important. Unfortunately, information is lacking on the optimal formulation of micronutrient supplements for pregnant women, and the need to continue these supplements during lactation is not recognized in many situations where maternal and infant health could benefit."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1115,I1115)","v":15883451},{"$f":"(LEN($J1115) - LEN(SUBSTITUTE(LOWER($J1115),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1115) - LEN(SUBSTITUTE(LOWER($J1115),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1115) - LEN(SUBSTITUTE(LOWER($J1115),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1115:D1115)","v":0},2005,"Dietary Reference Intakes: development and uses for assessment of micronutrient status of women--a global perspective.","Kennedy",15883451,"Dietary Reference Intakes: development and uses for assessment of micronutrient status of women--a global perspective.    Abstract:   This paper reviews the process of developing the Dietary Reference Intakes (DRIs) and provides a synopsis of the micronutrient status of women worldwide. At a 1993 symposium held by the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM), it was decided that the Recommended Dietary Allowances (RDAs) would be replaced by the DRIs, which would address several issues that the RDAs did not, including chronic disease risk reduction, upper levels for nutrients where toxicity data existed, and the possible health benefits of some food components that did not meet the traditional definition of a nutrient. Another important distinction is that because the DRIs are comprised of 4 reference values -the Estimated Average Requirement (EAR), RDA, Adequate Intake (AI), and a tolerable Upper Level (UL) -and not a single reference value like the previous RDAs, they could be used to differentiate planning from diagnosis or assessment. The latest DRIs and nutrient intakes are shown for iron, zinc, calcium, Vitamin A and folate status in women in the United States. Data on the micronutrient status of women globally are much more limited. Summary statistics on iron deficiency anemia, night blindness, and risk of zinc deficiency are summarized."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1116,I1116)","v":15854063},{"$f":"(LEN($J1116) - LEN(SUBSTITUTE(LOWER($J1116),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1116) - LEN(SUBSTITUTE(LOWER($J1116),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1116) - LEN(SUBSTITUTE(LOWER($J1116),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1116:D1116)","v":0},2005,"Possible contraindications and adverse reactions associated with the use of ocular nutritional supplements.","Bartlett",15854063,"Possible contraindications and adverse reactions associated with the use of ocular nutritional supplements.    Abstract:   The role of oxidation in the development of age-related eye disease has prompted interest in the use of nutritional supplementation for prevention of onset and progression. Our aim is to highlight possible contraindications and adverse reactions of isolated or high dose ocular nutritional supplements. Web of Science and PubMed database searches were carried out, followed by a manual search of the bibliographies of retrieved articles. Vitamin A should be avoided in women who may become pregnant, in those with liver disease, and in people who drink heavily. Relationships have been found between vitamin A and reduced bone mineral density, and beta-carotene and increased risk of lung cancer in smoking males. Vitamin E and Ginkgo biloba have anticoagulant and anti-platelet effects respectively, and high doses are contraindicated in those being treated for vascular disorders. Those patients with contraindications or who are considered at risk of adverse reactions should be advised to seek specialist dietary advice via their medical practitioner."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1117,I1117)","v":15823436},{"$f":"(LEN($J1117) - LEN(SUBSTITUTE(LOWER($J1117),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1117) - LEN(SUBSTITUTE(LOWER($J1117),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1117) - LEN(SUBSTITUTE(LOWER($J1117),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1117:D1117)","v":0},2005,"Metabolic complications of bariatric surgery: diagnosis and management issues.","Mason",15823436,"Metabolic complications of bariatric surgery: diagnosis and management issues.    Abstract:   Acute complications after bariatric surgery include rhabdomyolysis and immobilization hypercalcemia. The most common long-term metabolic complications following bariatric surgery are anemia and metabolic bone disease. Neuropathy, acute Wemickes encephalopathy and vitamin A deficiency also occur. Prevention, diagnosis,and treatment of these disorders are necessary parts of lifelong care after bariatric surgery."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1118,I1118)","v":15810801},{"$f":"(LEN($J1118) - LEN(SUBSTITUTE(LOWER($J1118),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1118) - LEN(SUBSTITUTE(LOWER($J1118),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1118) - LEN(SUBSTITUTE(LOWER($J1118),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1118:D1118)","v":0},2005,"Recent trends in malnutrition in developing regions: vitamin A deficiency, anemia, iodine deficiency, and child underweight.","Mason",15810801,"Recent trends in malnutrition in developing regions: vitamin A deficiency, anemia, iodine deficiency, and child underweight.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1119,I1119)","v":15806901},{"$f":"(LEN($J1119) - LEN(SUBSTITUTE(LOWER($J1119),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1119) - LEN(SUBSTITUTE(LOWER($J1119),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1119) - LEN(SUBSTITUTE(LOWER($J1119),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1119:D1119)","v":0},2003,"Multiple approaches to micronutrient deficiency in developing countries.","Nagati",15806901,"Multiple approaches to micronutrient deficiency in developing countries.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1120,I1120)","v":15758665},{"$f":"(LEN($J1120) - LEN(SUBSTITUTE(LOWER($J1120),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1120) - LEN(SUBSTITUTE(LOWER($J1120),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1120) - LEN(SUBSTITUTE(LOWER($J1120),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1120:D1120)","v":0},2005,"Drug-induced hepatotoxicity: 2005.","Maddrey",15758665,"Drug-induced hepatotoxicity: 2005.    Abstract:   The removal from the marketplace of several widely prescribed drugs due to hepatotoxicity has attracted considerable attention. Now under extensive review are means by which we can better identify hepatic risk prior to federal approval. Assessment of risk-to-benefit ratios regarding a novel agent with hepatotoxicity issues (especially one for a life-threatening condition) requires considerable judgment and education on the part of prescribers and patients. The spectrum of drug-induced liver injury is broad with simulation of almost all unknown liver disorders. Drug-induced liver injuries often have a somewhat characteristic signature, as regards type of injury (hepatocellular vs cholestatic) and time of onset. The diagnosis of drug-induced liver injury is often one of exclusion with initial suspicion based on circumstantial evidence. Factors affecting susceptibility to drug-induced injury include age, sex, concomitant use of other drugs, and genetic polymorphism in metabolic pathways involved in activation or disposition of therapeutic drugs. Drug-drug interactions present particular problems in patients, often elderly, who are receiving several drugs simultaneously. Mechanisms of drug-induced liver injury are many and varied. With many drugs, intermediary products produced during metabolism are highly reactive and toxic. In these situations, the balance between the rate of production of the metabolite and the effectiveness of the drug may determine whether or not hepatic injury occurs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1121,I1121)","v":15733744},{"$f":"(LEN($J1121) - LEN(SUBSTITUTE(LOWER($J1121),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1121) - LEN(SUBSTITUTE(LOWER($J1121),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1121) - LEN(SUBSTITUTE(LOWER($J1121),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1121:D1121)","v":0},2005,"Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.","Gual",15733744,"Positive and negative regulation of insulin signaling through IRS-1 phosphorylation.    Abstract:   This review will provide insight on the current understanding of the regulation of insulin signaling in both physiological and pathological conditions through modulations that occur with regards to the functions of the insulin receptor substrate 1 (IRS1). While the phosphorylation of IRS1 on tyrosine residue is required for insulin-stimulated responses, the phosphorylation of IRS1 on serine residues has a dual role, either to enhance or to terminate the insulin effects. The activation of PKB in response to insulin propagates insulin signaling and promotes the phosphorylation of IRS1 on serine residue in turn generating a positive-feedback loop for insulin action. Insulin also activates several kinases and these kinases act to induce the phosphorylation of IRS1 on specific sites and inhibit its functions. This is part of the negative-feedback control mechanism induced by insulin that leads to termination of its action. Agents such as free fatty acids, cytokines, angiotensin II, endothelin-1, amino acids, cellular stress and hyperinsulinemia, which induce insulin resistance, lead to both activation of several serine/threonine kinases and phosphorylation of IRS1. These agents negatively regulate the IRS1 functions by phosphorylation but also via others molecular mechanisms (SOCS expression, IRS degradation, O-linked glycosylation) as summarized in this review. Understanding how these agents inhibit IRS1 functions as well as identification of kinases involved in these inhibitory effects may provide novel targets for development of strategies to prevent insulin resistance."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1122,I1122)","v":15724031},{"$f":"(LEN($J1122) - LEN(SUBSTITUTE(LOWER($J1122),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1122) - LEN(SUBSTITUTE(LOWER($J1122),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1122) - LEN(SUBSTITUTE(LOWER($J1122),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1122:D1122)","v":0},2005,"Vitamin A and preterm infants: what we know, what we dont know, and what we need to know.","Mactier",15724031,"Vitamin A and preterm infants: what we know, what we dont know, and what we need to know.    Abstract:   Vitamin A is essential for optimal growth and development. In the developing world, vitamin A supplementation of the newborn infant reduces mortality. In the developed world, extremely preterm infants are born with low body stores of vitamin A and are at high risk of vitamin A deficiency. Optimal vitamin A supplementation for this population is not clearly defined, however, and, despite evidence of benefit, early vitamin A supplementation of extremely preterm infants is not uniformly practised in the United Kingdom. There is an urgent need for studies in preterm infants that include quantification of hepatic stores and functional assessment of vitamin A status as well as long term outcome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1123,I1123)","v":15715367},{"$f":"(LEN($J1123) - LEN(SUBSTITUTE(LOWER($J1123),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1123) - LEN(SUBSTITUTE(LOWER($J1123),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1123) - LEN(SUBSTITUTE(LOWER($J1123),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1123:D1123)","v":0},2005,"[Liver fibrosis: pathophysiology, diagnosis and treatment].","Pár",15715367,"[Liver fibrosis: pathophysiology, diagnosis and treatment].    Abstract:   The extracellular matrix deposition in the liver parenchyma is a major component of cirrhosis. A great deal of knowledge has been gathered in the past two decades regarding the regulation and dynamics of fibrogenesis, and based on these advances, a review is delivered on the pathophysiology, diagnosis and therapy of liver fibrosis. The key event in fibrogenesis is the activation of hepatic stellate cells, and in its mechanism, inflammation, oxidative stress, steatosis, cytokines, growth factors, enzymes and enzyme inhibitors play a pivotal role. The phenotypic response of activated stellate cells comprises proliferation, fibrogenesis, contractility, loss of vitamin A and matrix degradation. In the diagnosis of liver fibrosis, besides liver biopsy--as quot;golden standardquot;--recently non-invasive methods, such as imaging techniques, and mainly serum fibrosis markers and indices have widely been studied. Experimental and clinical data have proved the reversibility of fibrosis, and suggested that an effective antifibrotic treatment in the future may serve even for the prevention of cirrhosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1124,I1124)","v":15696852},{"$f":"(LEN($J1124) - LEN(SUBSTITUTE(LOWER($J1124),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1124) - LEN(SUBSTITUTE(LOWER($J1124),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1124) - LEN(SUBSTITUTE(LOWER($J1124),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1124:D1124)","v":0},2004,"Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease.","vanBerge-Henegouwen",15696852,"Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease.    Abstract:   In the formation of cholesterol gallstones, cholesterol hypersecretion into bile causing cholesterol supersaturation and crystallization appears to be the primary factor, with disturbed gallbladder and intestinal motility as secondary factors. Although intestinal uptake mechanisms have not yet been fully elucidated, the HDL receptor scavenger receptor B1 (SRB1) may be involved. Since HDL-cholesterol, both from the intestine and peripheral sources, is the preferred type of cholesterol for biliary secretion, increased HDL transport to the liver can also cause cholesterol hypersecretion in bile. In the hepatocyte, bile formation is regulated by several transmembrane proteins, all belonging to the ABC family. A change in the activity in one of these proteins can have a profound impact on biliary lipid secretion. The bile salt export pump (BSEP or ABCB11) regulates the excretion of bile salts into bile and mutations cause severe cholestasis. The second ABC transporter, ABCB4 (MDR3) regulates the secretion in bile of phosphatidylcholine (PC), while ABCG5/G8 is active in the excretion of cholesterol and sterols into bile. These transporters also facilitate transport of sterols back into the intestinal lumen. Mutations in either of these genes cause sitosterolaemia with increased absorption of plant sterols and cholesterol. Until now, evidence for a genetic background of human gallstone disease is mostly indirect and based on ethnic differences. Only two single gene defects are associated with gallstones. One is an ABCB4 mutation which causes a deficiency in biliary PC secretion and the other is a CYP7A1 mutation, the rate-limiting enzyme in the synthesis of bile salts from cholesterol in the liver. Recently, several common DNA polymorphisms in the ABCG8 gene were discovered that are associated with variations in plasma sterols, which could also influence biliary cholesterol secretion, but there is still a paucity of human studies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1125,I1125)","v":15682880},{"$f":"(LEN($J1125) - LEN(SUBSTITUTE(LOWER($J1125),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1125) - LEN(SUBSTITUTE(LOWER($J1125),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1125) - LEN(SUBSTITUTE(LOWER($J1125),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1125:D1125)","v":0},2004,"Diffuse idiopathic skeletal hyperostosis: Forestiers disease.","Childs",15682880,"Diffuse idiopathic skeletal hyperostosis: Forestiers disease.    Abstract:   Diffuse idiopathic skeletal hyperostosis (DISH) or Forestiers disease is characterized by calcification and ossification of soft tissue entheses of ligaments and tendons. DISH is believed to be a variant of osteoarthritis (OA) without the degenerative intervertebral disc and joint degenerative qualities seen in classic OA. The likely pathoetiologic causes of DISH are presented."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1126,I1126)","v":15658253},{"$f":"(LEN($J1126) - LEN(SUBSTITUTE(LOWER($J1126),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1126) - LEN(SUBSTITUTE(LOWER($J1126),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1126) - LEN(SUBSTITUTE(LOWER($J1126),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1126:D1126)","v":0},2004,"[Clinical significance of remnant-lipoprotein].","Nakamura",15658253,"[Clinical significance of remnant-lipoprotein].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1127,I1127)","v":15629904},{"$f":"(LEN($J1127) - LEN(SUBSTITUTE(LOWER($J1127),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1127) - LEN(SUBSTITUTE(LOWER($J1127),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1127) - LEN(SUBSTITUTE(LOWER($J1127),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1127:D1127)","v":0},2005,"Index of suspicion.","Duong",15629904,"Index of suspicion.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1128,I1128)","v":15611656},{"$f":"(LEN($J1128) - LEN(SUBSTITUTE(LOWER($J1128),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1128) - LEN(SUBSTITUTE(LOWER($J1128),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1128) - LEN(SUBSTITUTE(LOWER($J1128),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1128:D1128)","v":0},2005,"Tuberous sclerosis and insulin resistance. Unlikely bedfellows reveal a TORrid affair.","Shah",15611656,"Tuberous sclerosis and insulin resistance. Unlikely bedfellows reveal a TORrid affair.    Abstract:   The TSC1-TSC2 tumor suppressor complex serves as an interface between insulin and nutrient signaling pathways and the cell growth machinery. Recent work has indicated that the TSC1-TSC2 complex plays a role in the pathobiology of a number of tumor predisposition syndromes, including tuberous sclerosis (TSC1/2), Peutz-Jeghers syndrome (LKB1), and Cowdens syndrome (PTEN), in which the TSC/Rheb/mTOR axis is inappropriately active secondary to loss of tumor suppressor function. Recent work has demonstrated that TSC deficiency imposes a negative autoregulatory loop that suppresses insulin signaling at the post-receptor level, effectively resulting in cell autonomous insulin resistance. Exploitation of this insulin signaling deficiency may hold promise among tailored clinical therapies designed to manage tuberous sclerosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1129,I1129)","v":15560038},{"$f":"(LEN($J1129) - LEN(SUBSTITUTE(LOWER($J1129),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1129) - LEN(SUBSTITUTE(LOWER($J1129),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1129) - LEN(SUBSTITUTE(LOWER($J1129),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1129:D1129)","v":0},1998,"Lipids and lipid-activated vitamins in chronic cholestatic diseases.","Kowdley",15560038,"Lipids and lipid-activated vitamins in chronic cholestatic diseases.    Abstract:   Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune cholangiopathy are cholestatic liver diseases of unknown cause. Destruction of small to medium bile ducts (in primary biliary cirrhosis and autoimmune cholangiopathy) and large bile ducts (in primary sclerosing cholangitis) leads to progressive cholestasis, liver failure and end-stage liver disease. A variety of abnormalities in lipid metabolism have been described in primary biliary cirrhosis, and range from alterations in serum lipid levels and lipoprotein subsets to deranged metabolism of cholesterol. Progressive cholestasis and, consequently, decreased small intestinal bile acid concentrations in these cholestatic liver disease can also lead to impaired absorption of fats and fat-soluble vitamins, resulting in steatorrhea and deficiencies in vitamins A, D, E, and K. This article focuses on abnormalities in lipid metabolism in primary biliary cirrhosis and primary sclerosing cholangitis, and on lipid-activated vitamin deficiencies in these disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1130,I1130)","v":15559182},{"$f":"(LEN($J1130) - LEN(SUBSTITUTE(LOWER($J1130),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1130) - LEN(SUBSTITUTE(LOWER($J1130),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1130) - LEN(SUBSTITUTE(LOWER($J1130),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1130:D1130)","v":0},2004,"Intestinal parasitic infections and micronutrient deficiency: a review.","Hesham",15559182,"Intestinal parasitic infections and micronutrient deficiency: a review.    Abstract:   Malnutrition including vitamin A and iron deficiency and parasitic diseases have a strikingly similar geographical distribution with the same people experiencing both insults together for much of their lives. Parasitic infections are thought to contribute to child malnutrition and micronutrient deficiency through subtle reduction in digestion and absorption, chronic inflammation and loss of nutrients. Parasites may affect the intake of food; its subsequent digestion and absorption, metabolism and the maintenance of nutrient pools. The most important parasites related to nutritional status are intestinal parasites especially soil transmitted helminthes, Giardia duodenalis, Entamoeba histolytica, followed by other parasites such as the coccidia, Schistosoma sp. and malarial parasites."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1131,I1131)","v":15535450},{"$f":"(LEN($J1131) - LEN(SUBSTITUTE(LOWER($J1131),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1131) - LEN(SUBSTITUTE(LOWER($J1131),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1131) - LEN(SUBSTITUTE(LOWER($J1131),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1131:D1131)","v":0},2003,"Relationships between nutrition, alcohol use, and liver disease.","Lieber",15535450,"Relationships between nutrition, alcohol use, and liver disease.    Abstract:   Many alcoholics are malnourished, either because they ingest too little of essential nutrients (e.g., carbohydrates, proteins, and vitamins) or because alcohol and its metabolism prevent the body from properly absorbing, digesting, and using those nutrients. As a result, alcoholics frequently experience deficiencies in proteins and vitamins, particularly vitamin A, which may contribute to liver disease and other serious alcohol-related disorders. Furthermore, alcohol breakdown in the liver, both by the enzyme alcohol dehydrogenase and by an enzyme system called the microsomal ethanol-oxidizing system (MEOS), generates toxic products such as acetaldehyde and highly reactive, and potentially damaging, oxygen-containing molecules. These products can interfere with the normal metabolism of other nutrients, particularly lipids, and contribute to liver cell damage. Nutritional approaches can help prevent or ameliorate alcoholic liver disease. For example, a complete balanced diet can compensate for general malnutrition. Administration of antioxidants (e.g., precursors of the endogenous antioxidant glutathione) can help the body eliminate reactive oxygen molecules and other reactive molecules generated from abnormal lipid breakdown. New agents currently are being studied as promising nutritional supplements for alcoholics with liver disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1132,I1132)","v":15495084},{"$f":"(LEN($J1132) - LEN(SUBSTITUTE(LOWER($J1132),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1132) - LEN(SUBSTITUTE(LOWER($J1132),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1132) - LEN(SUBSTITUTE(LOWER($J1132),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1132:D1132)","v":0},2004,"Antioxidant supplements for preventing gastrointestinal cancers.","Bjelakovic",15495084,"Antioxidant supplements for preventing gastrointestinal cancers.    Abstract:    BACKGROUND : Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory.  OBJECTIVES : To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers.  SEARCH STRATEGY : We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 1, 2003), MEDLINE, EMBASE, LILACS, and SCI-EXPANDED from inception to February 2003, and The Chinese Biomedical Database (March 2003). We scanned reference lists and contacted pharmaceutical companies.  SELECTION CRITERIA : Randomised trials comparing antioxidant supplements to placebo/no intervention examining the incidence of gastrointestinal cancers.  DATA COLLECTION AND ANALYSIS : Two reviewers independently selected trials for inclusion and extracted data. The outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse events. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on fixed and random effects meta-analyses.  MAIN RESULTS : We identified 14 randomised trials (170,525 participants), assessing beta-carotene (9 trials), vitamin A (4 trials), vitamin C (4 trials), vitamin E (5 trials), and selenium (6 trials). Trial quality was generally high. Heterogeneity was low to moderate. Neither the fixed effect (RR 0.96, 95% CI 0.88 to 1.04) nor random effects meta-analyses (RR 0.90, 95% CI 0.77 to 1.05) showed significant effects of supplementation with antioxidants on the incidences of gastrointestinal cancers. Among the seven high-quality trials reporting on mortality (131,727 participants), the fixed effect (RR 1.06, 95% CI 1.02 to 1.10) unlike the random effects meta-analysis (RR 1.06, 95% CI 0.98 to 1.15) showed that antioxidant supplements significantly increased mortality. Two low-quality trials (32,302 participants) found no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high- and low-quality trials was significant by test of interaction (z = 2.10, P = 0.04). Beta-carotene and vitamin A (RR 1.29, 95% CI 1.14 to 1.45) and beta-carotene and vitamin E (RR 1.10, 95% CI 1.01 to 1.20) significantly increased mortality, while beta-carotene alone only tended to do so (RR 1.05, 95% CI 0.99 to 1.11). Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In four trials (three with unclear/inadequate methodology), selenium showed significant beneficial effect on gastrointestinal cancer incidences.  REVIEWERS CONCLUSIONS : We could not find evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, they seem to increase overall mortality. The potential cancer preventive effect of selenium should be studied in adequately conducted randomised trials."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1133,I1133)","v":15464421},{"$f":"(LEN($J1133) - LEN(SUBSTITUTE(LOWER($J1133),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1133) - LEN(SUBSTITUTE(LOWER($J1133),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1133) - LEN(SUBSTITUTE(LOWER($J1133),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1133:D1133)","v":0},2004,"Molecular mechanisms of DAX1 action.","Iyer",15464421,"Molecular mechanisms of DAX1 action.    Abstract:   DAX1 (dosage sensitive sex reversal (DSS), adrenal hypoplasia congenita (AHC) critical region on the X chromosome, gene 1) encoded by the gene NR0B1, is an unusual orphan nuclear receptor that when mutated causes AHC with associated hypogonadotropic hypogonadism (HH), and when duplicated causes DSS. DAX1 expression has been shown in all regions of the hypothalamic-pituitary-adrenal-gonadal (HPAG) axis during development and in adult tissues, suggesting a critical role for DAX1 in the normal development and function of this axis. Steroidogenic factor 1 (SF1, NR5A1) knockout mice show similar developmental defects as AHC and HH patients, but paradoxically, DAX1 is a negative coregulator of SF1 transactivation. The function of DAX1 as an antagonist of SF1 in gonadal development is consistent with the fact that in humans, duplication of the region of the X chromosome containing DAX1 causes a similar phenotype as mutations in SF1. However, how disruption of DAX1 leads to adrenal, hypothalamic, and pituitary developmental defects similar to SF1 disruption remains to be clarified. The exact mechanism of DAX1 action in each of these tissues during adulthood and critical stages of development are not fully understood. Recent evidence suggests a broader functional role for DAX1 as a negative coregulator of estrogen receptor (ER, NR3A1-2), liver receptor homologue-1 (LRH-1, NR5A2), androgen receptor (AR, NR3C4), and progesterone receptor (PR, NR3C3), each by distinct repression mechanisms. DAX1 may have pleiotropic roles in addition to its function as a negative regulator of steroidogenesis during the development and adult function of the HPAG axis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1134,I1134)","v":15464182},{"$f":"(LEN($J1134) - LEN(SUBSTITUTE(LOWER($J1134),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1134) - LEN(SUBSTITUTE(LOWER($J1134),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1134) - LEN(SUBSTITUTE(LOWER($J1134),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1134:D1134)","v":0},2004,"Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis.","Bjelakovic",15464182,"Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis.    Abstract:    BACKGROUND : Oxidative stress can cause cancer. Our aim was to establish whether antioxidant supplements reduce the incidence of gastrointestinal cancer and mortality.  METHODS : With the Cochrane Collaboration methodology, we reviewed all randomised trials comparing antioxidant supplements with placebo for prevention of gastrointestinal cancers. We searched electronic databases and reference lists (February, 2003). Outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse effects. Outcomes were analysed with fixed-effect and random-effects model meta-analyses and were reported as relative risk with 95% CIs.  FINDINGS : We identified 14 randomised trials (n=170,525). Trial quality was generally high. Heterogeneity of results was low to moderate. Neither the fixed-effect (relative risk 0.96, 95% CI 0.88-1.04) nor random-effects meta-analyses (0.90, 0.77-1.05) showed significant effects of supplementation with beta-carotene, vitamins A, C, E, and selenium (alone or in combination) versus placebo on oesophageal, gastric, colorectal, pancreatic, and liver cancer incidences. In seven high-quality trials (n=131727), the fixed-effect model showed that antioxidant significantly increased mortality (1.06, 1.02-1.10), unlike the random-effects meta-analysis (1.06, 0.98-1.15). Low-quality trials showed no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high-quality and low-quality trials was significant (Z=2.10, p=0.04 by test of interaction). beta-carotene and vitamin A (1.29, 1.14-1.45) and beta-carotene and vitamin E (1.10, 1.01-1.20) significantly increased mortality, whereas beta-carotene alone only tended to increase mortality (1.05, 0.99-1.11). In four trials (three with unclear or inadequate methodology), selenium showed significant beneficial effect on the incidence of gastrointestinal cancer.  INTERPRETATION : We could not find evidence that antioxidant supplements can prevent gastrointestinal cancers; on the contrary, they seem to increase overall mortality. The potential preventive effect of selenium should be studied in adequate randomised trials."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1135,I1135)","v":15349806},{"$f":"(LEN($J1135) - LEN(SUBSTITUTE(LOWER($J1135),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1135) - LEN(SUBSTITUTE(LOWER($J1135),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1135) - LEN(SUBSTITUTE(LOWER($J1135),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1135:D1135)","v":0},2004,"Nutrition and alcoholic liver disease.","Halsted",15349806,"Nutrition and alcoholic liver disease.    Abstract:   Malnutrition is a common finding in chronic alcoholics, and protein calorie malnutrition (PCM) is universal and predictive of survival in patients with established alcoholic liver disease (ALD). These patients also demonstrate frequent deficiencies of folate, thiamine, pyridoxine, and vitamin A, which enhance the likelihood of anemia, altered cognitive states, and night blindness. The etiologies of malnutrition in ALD patients are multiple and interactive and include anorexia with inadequate dietary intake, abnormal digestion of macronutrients and absorption of several micronutrients, increased skeletal and visceral protein catabolism, and abnormal interactions of ethanol and lipid metabolism. Numerous, and mostly inadequately controlled, studies have evaluated the potential efficacies of oral, enteral, and parenteral nutrition approaches to treatment of ALD, with mixed results on liver function, clinical improvements, and short- or long-term survival. Targeted metabolic treatments include supplementation with S-adenosylmethionine (SAM) or phosphatidylcholine derivatives, each with promising experimental bases but inconclusive clinical trials."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1136,I1136)","v":15331819},{"$f":"(LEN($J1136) - LEN(SUBSTITUTE(LOWER($J1136),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1136) - LEN(SUBSTITUTE(LOWER($J1136),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1136) - LEN(SUBSTITUTE(LOWER($J1136),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1136:D1136)","v":0},2004,"Undernutrition as an underlying cause of malaria morbidity and mortality in children less than five years old.","Caulfield",15331819,"Undernutrition as an underlying cause of malaria morbidity and mortality in children less than five years old.    Abstract:   Undernutrition is highly prevalent in many areas in which morbidity and mortality from malaria is unacceptably high. That undernutrition exacerbates diarrhea and respiratory infections is widely demonstrated; however, research suggests that it may exacerbate, palliate, or have little effect on malaria outcomes. This review examines the global burden of malaria associated with various nutrient deficiencies as well as underweight status in children 0-4 years of age. Although the association is complex and requires additional research, improved nutritional status lessens the severity of malaria episodes and results in fewer deaths due to malaria. Deficiencies in vitamin A, zinc, iron, folate, as well as other micronutrients are responsible for a substantial proportion of malaria morbidity and mortality. It is recommended that nutrition programs be integrated into existing malaria intervention programs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1137,I1137)","v":15320484},{"$f":"(LEN($J1137) - LEN(SUBSTITUTE(LOWER($J1137),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1137) - LEN(SUBSTITUTE(LOWER($J1137),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1137) - LEN(SUBSTITUTE(LOWER($J1137),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1137:D1137)","v":0},2004,"[Antioxidants in liver protection].","Hagymási",15320484,"[Antioxidants in liver protection].    Abstract:   Great importance has been attributed to antioxidants in the prevention and treatment of conditions associated with oxidative stress for many years. At the same time the antioxidants are free radicals themselves, and they can exert prooxidant activity depending on the concentration. They influence the cell redox homeostasis by their prooxidant and antioxidant activity as well. Drugs of chronic liver diseases should be considered, because free radicals are generated during the activity of the monooxygenase system, which affect the tissue oxidised status. Combined antioxidant treatment is more favourable compared with monotherapy, because antioxidants have scavenger-, compartment- and tissue-specificity and they regenerate each other directly, too. Beside their antioxidant property they may also directly regulate many important processes, e.g. cell cycle. We have some favourable results with regard combined antioxidant therapy of liver disease of different etiology."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1138,I1138)","v":15291398},{"$f":"(LEN($J1138) - LEN(SUBSTITUTE(LOWER($J1138),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1138) - LEN(SUBSTITUTE(LOWER($J1138),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1138) - LEN(SUBSTITUTE(LOWER($J1138),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1138:D1138)","v":0},2004,"Exploiting micronutrient interaction to optimize biofortification programs: the case for inclusion of selenium and iodine in the HarvestPlus program.","Lyons",15291398,"Exploiting micronutrient interaction to optimize biofortification programs: the case for inclusion of selenium and iodine in the HarvestPlus program.    Abstract:   Biofortification of staple food crops with micronutrients by either breeding for higher uptake efficiency or fertilization can be an effective strategy to address widespread dietary deficiency in human populations. Selenium and iodine deficiencies affect a large proportion of the population in countries targeted for biofortification of staple crops with Zn, Fe, and vitamin A, and inclusion of Se and I would be likely to enhance the success of these programs. Interactions between Se and I in the thyroid gland are well established. Moreover, Se appears to have a normalizing effect on certain nutrients in the body. For example, it increases the concentration of Zn and Fe at key sites such as erythrocytes when these elements are deficient, and reduces potentially harmful high Fe concentration in the liver during infection. An important mechanism in Se/Zn interaction is selenoenzyme regulation of Zn delivery from metallothionein to Zn enzymes. More research is needed to determine whether sufficient genetic variability exists within staple crops to enable selection for Se and I uptake efficiency. In addition, bioavailability trials with animals and humans are needed, using varying dietary concentrations of Se, I, Zn, Fe, and vitamin A to elucidate important interactions in order to optimize delivery in biofortification programs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1139,I1139)","v":15289752},{"$f":"(LEN($J1139) - LEN(SUBSTITUTE(LOWER($J1139),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1139) - LEN(SUBSTITUTE(LOWER($J1139),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1139) - LEN(SUBSTITUTE(LOWER($J1139),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1139:D1139)","v":0},2004,"[Celiac disease and its endocrine and nutritional implications on male reproduction].","Stazi",15289752,"[Celiac disease and its endocrine and nutritional implications on male reproduction].    Abstract:   The problem of the interference of celiac disease (CD) with the male reproductive system is made evident both by the recognized adverse effects on female reproduction and by the multifactorial nature of the disease. It is important to consider CD as a multifactorial condition since its diverse effects can be modulated, besides gluten, by different concurrent genetic and environmental factors. The male CD patient has a greater risk of infertility and other reproductive disturbances, as well as a greater incidence of hypoandrogenism. In this paper the problems of CD associated to endocrine disorders and to deficiencies of micronutrients are discussed. Affected males show a picture of tissue resistance to androgens. Moreover, attention should be paid to increases of FSH and prolactin; these are not associated to infertility and/or impotence, but they may indicate an imbalance at hypothalamus-pituitary level, with general effects on health: an example is the increased risk of male osteoporosis in CD patients. Hormone alterations are reversible upon start of the gluten-free diet, emphasizing the importance of early diagnosis; this should be performed in the case of clinical suspicion, e.g., unexplained hypoandrogenism. As regards nutritional aspects, the folic acid deficiency of CD can affect rapidly proliferating tissues, such as the embryo and the seminiferous epithelium. More attention should be paid to deficiencies of fat-soluble vitamins, such as A and E, observed in CD. Vitamin A is important for Sertoli cell function as well as for early spermatogenetic phases. Vitamin E supports the correct differentiation and function of epidydimal epithelium, spermatid maturation and secretion of proteins by the prostate. Therefore, CD male patients should be considered as vulnerable subjects; thus, the detection of early biomarkers of andrological or endocrinological dysfunctions should trigger timely strategies for prevention and treatment."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1140,I1140)","v":15222487},{"$f":"(LEN($J1140) - LEN(SUBSTITUTE(LOWER($J1140),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1140) - LEN(SUBSTITUTE(LOWER($J1140),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1140) - LEN(SUBSTITUTE(LOWER($J1140),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1140:D1140)","v":0},2004,"Recombinant human lactoferrin treatment for global health issues: iron deficiency and acute diarrhea.","Bethell",15222487,"Recombinant human lactoferrin treatment for global health issues: iron deficiency and acute diarrhea.    Abstract:   Iron deficiency and diarrhea are two of the most significant issues for global health. Iron deficiency anemia is the most common nutritional deficiency in the world, affecting nearly 25% of the world population (UNICEF/WHO 1999). The prevalence of iron deficiency in developing countries is illustrated by comparison with other deficiencies: iron deficiency affects 3.5 billion people, while vitamin A and iodine deficiency affect 0.3 billion people and 0.8 billion people, respectively. The prevalence is highest among young children and women of childbearing age (particularly pregnant women). It is estimated that national productivity levels could be raised as much as 20% by correcting iron deficiency in developing countries. Recombinant human lactoferrin (rhLF), expressed and extracted from rice seed, is being evaluated by Ventria Bioscience for use as a dietary supplement to treat iron deficiency and/or iron deficiency anemia. Diarrhea is also a major world health issue. Sixty percent of children who die under age five die of pneumonia, diarrhea or measles. World Health Organization oral rehydration solution (WHO-ORS) is one of the major medical advances in the past 50 years, saving the lives of 1 to 2 million children annually. Many studies have demonstrated similar efficacy of rice-based ORS. There are studies documenting the reduced frequency of diarrhea in breast-fed children and this health improvement is attributed to the antimicrobial action of the human milk proteins lactoferrin and lysozyme. In vitro data document the growth inhibition of the diarrheal associated organisms: rotavirus, ETEC, cholera, salmonella, and shigella by human lactoferrin (hLF) and human lysozyme. Using Ventrias ExpressTec system, we have expressed human lactoferrin and human lysozyme in rice. In a rice-based ORS formulation, these proteins have the potential to provide not only the benefits of reduced stool volume and improved weight gain, but also shorten the course of diarrheal episodes via antimicrobial activity against the causative agent."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1141,I1141)","v":15195890},{"$f":"(LEN($J1141) - LEN(SUBSTITUTE(LOWER($J1141),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1141) - LEN(SUBSTITUTE(LOWER($J1141),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1141) - LEN(SUBSTITUTE(LOWER($J1141),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1141:D1141)","v":0},2004,"Systemic treatment of hepatocellular carcinoma.","Ganne-Carrié",15195890,"Systemic treatment of hepatocellular carcinoma.    Abstract:   The results of systemic treatments for hepatocellular carcinoma are currently disappointing. In patients with advanced disease, none of the tested treatments (particularly systemic chemotherapy or hormonal treatment, such as tamoxifen) demonstrated an unequivocal benefit in terms of survival, and the trials including the largest numbers of patients have constantly been negative. After successful treatment of a first tumour, the most promising adjuvant strategy seems to be the use of interferon to treat patients who have hepatitis C infection. Nevertheless, only a few small randomized controlled trials have been performed and this result should be confirmed. Methodological improvement of clinical trials is needed, as major bias has often hampered the interpretation of the results. As recommended at a recent international conference in Barcelona, the most reliable methods for assessing the clinical outcome of a treatment in hepatocellular carcinoma are large randomized trials that each include a control arm of untreated patients, with overall survival as the primary endpoint, and an intention-to-treat analysis. New therapeutic strategies should be developed. Drugs such as vitamin D or vitamin A derivatives and inhibitors of COX-2 or angiogenesis could have a favourable influence on tumour growth. Some of these drugs are currently being tested in preliminary studies or even large randomized trials."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1142,I1142)","v":15180293},{"$f":"(LEN($J1142) - LEN(SUBSTITUTE(LOWER($J1142),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1142) - LEN(SUBSTITUTE(LOWER($J1142),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1142) - LEN(SUBSTITUTE(LOWER($J1142),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1142:D1142)","v":0},2003,"Gene therapy for Leber congenital amaurosis.","Dejneka",15180293,"Gene therapy for Leber congenital amaurosis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1143,I1143)","v":15130269},{"$f":"(LEN($J1143) - LEN(SUBSTITUTE(LOWER($J1143),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1143) - LEN(SUBSTITUTE(LOWER($J1143),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1143) - LEN(SUBSTITUTE(LOWER($J1143),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1143:D1143)","v":0},2004,"Novel systemic therapy options for hepatocellular carcinoma.","Cusnir",15130269,"Novel systemic therapy options for hepatocellular carcinoma.    Abstract:   Hepatocellular carcinoma, a common malignancy globally, has been increasing in incidence in the United States, mostly due to the rising incidence of Hepatitis C viral (HCV) infection. The prognosis of patients with this cancer has been poor and even tumor resection has rarely been curative. However, orthotopic liver transplantation (OLT) has been associated with long-term survival benefit and cures, provided rigorous patient-selection criteria were adhered to. Liver cirrhosis is the most common precursor for HCC, and attempts have been made to prevent the progression from liver cirrhosis to HCC. Post resection adjuvant therapies have included interferon, polyprenoic acid, and adoptive immunotherapy. Finding effective systemic treatments for non-resectable HCC has been challenging and quite frustrating. The presence of liver cirrhosis and the associated volume expansion, electrolyte imbalances, decreased liver synthetic and metabolic reserve, and portal hypertension has made the design of systemic therapy for HCC a major challenge. Additionally staging of HCC using the Tumor Node Metastases (TNM) system, but ignoring the underlying liver disease made it extremely difficult to compare results of different trials. However by and large it would seem, that the more aggressive chemotherapy agents and combinations were associated with median survival times of 3-5 months. Considering the vascular nature of HCC it may be reasonable to combine tolerable chemotherapy with newly released agents with angiogenesis inhibiting properties. Thus, systemic therapy of HCC is a work in progress that calls for additional trials of tolerable newer agents and combinations."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1144,I1144)","v":15117174},{"$f":"(LEN($J1144) - LEN(SUBSTITUTE(LOWER($J1144),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1144) - LEN(SUBSTITUTE(LOWER($J1144),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1144) - LEN(SUBSTITUTE(LOWER($J1144),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1144:D1144)","v":0},2004,"Recent trials of antioxidant therapy: what should we be telling our patients?","Hasnain",15117174,"Recent trials of antioxidant therapy: what should we be telling our patients?    Abstract:   The current evidence does not support the indiscriminate use of vitamins A, C, or E or beta carotene to prevent or reduce cardiovascular disease. Despite a plausible theory that antioxidants can prevent diseases caused by oxidative damage, trials thus far have not proven this. In fact, some studies found antioxidants may be harmful in some people. We review important studies of the effects of four antioxidants (vitamins A, C, and E, and beta carotene) and analyze whether the current evidence supports or confirms or rejects the presumed protective role."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1145,I1145)","v":15032131},{"$f":"(LEN($J1145) - LEN(SUBSTITUTE(LOWER($J1145),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1145) - LEN(SUBSTITUTE(LOWER($J1145),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1145) - LEN(SUBSTITUTE(LOWER($J1145),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1145:D1145)","v":0},2004,"The use of nutraceuticals in cancer therapy.","Roudebush",15032131,"The use of nutraceuticals in cancer therapy.    Abstract:   The high prevalence of nutraceutical use among human patients with cancer suggests that the use of nutraceuticals in pet animals with cancer is probably common. Dogs with a wide variety of malignant diseases have significant alterations in carbohydrate, protein, and fat metabolism. These metabolic alterations may be ameliorated by using functional foods relatively low in soluble carbohydrate, moderate amounts of protein that includes sources of arginine, and moderate amounts of fat supplemented with omega-3 long-chain polyunsaturated fatty acids. Well-controlled clinical studies in a variety of species with cancer, including rodents, people, and dogs, have documented that increased dietary and serum levels of omega-3 fatty acids are associated with a number of health benefits, including improved disease-free interval, survival time, and quality of life. Other nutraceuticals of interest in patients with cancer include antioxidant vitamins, trace minerals, glutamine, protease inhibitors, garlic, tea polyphenols, vitamin A, and shark cartilage."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1146,I1146)","v":15024783},{"$f":"(LEN($J1146) - LEN(SUBSTITUTE(LOWER($J1146),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1146) - LEN(SUBSTITUTE(LOWER($J1146),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1146) - LEN(SUBSTITUTE(LOWER($J1146),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1146:D1146)","v":0},2003,"Update on the prevalence of malnutrition among children in Asia.","Khor",15024783,"Update on the prevalence of malnutrition among children in Asia.    Abstract:   Approximately 70.0% of the worlds malnourished children live in Asia, resulting in the region having the highest concentration of childhood malnutrition. About half of the preschool children are malnourished ranging from 16.0% in the Peoples Republic of China to 64.0% in Bangladesh. Prevalence of stunting and underweight are high especially in South Asia where one in every two preschool children is stunted. Besides protein-energy malnutrition, Asian children also suffer from micronutrient deficiency. Iron deficiency anaemia affects 40.0-50.0% of preschool and primary school children. Nearly half of all vitamin A deficiency and xeropthalmia in the world occurs in South and Southeast Asia, with large numbers of cases in India (35.3 million), Indonesia (12.6 million) and China (11.4 million). Another major micronutrient problem in the region is iodine deficiency disorders, which result in high goiter rates as manifested in India, Pakistan and parts of Indonesia. While under-nutrition problem persists, overweight problem in children has emerged in Asia, including Taiwan, Singapore and urban China and Malaysia. The etiology of childhood malnutrition is complex involving interactions of multiple determinants that include biological, cultural and socio-economic influences. Protein-energy malnutrition and micronutrient deficiency leading to early growth failure often can be traced to poor maternal nutritional and health care before and during pregnancy, resulting in intrauterine growth retardation and children born with low birth weight. While significant progress has been achieved over the past 30 years in reducing the proportion of malnourished children in developing countries, nonetheless, malnutrition persists affecting large numbers of children. The socio-economic cost of the malnutrition burden to the individual, family and country is high resulting in lower cognitive outcomes in children and lower adult productivity. Interventions that are cost-effective and culturally appropriate for the elimination of childhood malnutrition deserve the support of all."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1147,I1147)","v":15000734},{"$f":"(LEN($J1147) - LEN(SUBSTITUTE(LOWER($J1147),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1147) - LEN(SUBSTITUTE(LOWER($J1147),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1147) - LEN(SUBSTITUTE(LOWER($J1147),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1147:D1147)","v":0},2004,"Haematological profiles of the people of rural southern Malawi: an overview.","Brabin",15000734,"Haematological profiles of the people of rural southern Malawi: an overview.    Abstract:   An integrative review of the results of two published and two unpublished studies of anaemia in children, adolescent females, pregnant women and adults living in southern Malawi is presented. Anaemia was universally present in all age-groups, with the higher prevalences in infants (100%) and adolescent primigravidae (93.8%). Nutritional deficits of iron and vitamin A were major contributory factors but chronic malarial haemolysis also significantly contributed to the anaemia. Among boys, anaemia was more common among those with glucose-6-phosphate-dehydrogenase (G6PD) deficiency than in those without this deficiency (Plt;0.002). This enzymopathy, which occurred in 23.5% [95% confidence interval (CI)=16.7%-30.1%] of the male and 30% (CI=17.3%-42.7%) of the female infants examined, was also associated with neonatal jaundice. The overall prevalences of the-alpha(3.7)/alphaalpha and -alpha(3.7)/-alpha(3.7) thalassaemia genotypes were estimated at 41.0% (CI=28.3%-53.7%) and 8.7% (CI=1.5%-15.9%), respectively. Haemoglobin AS was present in 18.1% (CI=12.8%-23.4%) of the infants and haemoglobin SS in 2.5% (CI=1.4%-3.6%). As the prevalence of infection with Plasmodium falciparum was significantly higher in infants with haemoglobin AS than in those with AA (21.4% v. 6.7%; Plt;0.001), an increased risk of early-onset moderate parasitaemias in young infants probably stimulates the development of immunity, protecting older heterozygotes from severe malarial infection. Innovative community approaches are required to break the cycle of ill health that anaemia supports in those living in rural areas of southern Malawi. Interventions in adolescent girls could be of particular importance, as they could break the cycle in both pregnant women and their infants."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1148,I1148)","v":14980129},{"$f":"(LEN($J1148) - LEN(SUBSTITUTE(LOWER($J1148),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1148) - LEN(SUBSTITUTE(LOWER($J1148),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1148) - LEN(SUBSTITUTE(LOWER($J1148),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1148:D1148)","v":0},2004,"[Some factors on hepatic stellate cells activation].","Yang",14980129,"[Some factors on hepatic stellate cells activation].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1149,I1149)","v":14711761},{"$f":"(LEN($J1149) - LEN(SUBSTITUTE(LOWER($J1149),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1149) - LEN(SUBSTITUTE(LOWER($J1149),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1149) - LEN(SUBSTITUTE(LOWER($J1149),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1149:D1149)","v":0},2003,"Anaemia and micronutrient deficiencies.","van den Broek",14711761,"Anaemia and micronutrient deficiencies.    Abstract:   Anaemia in pregnancy is a common and worldwide problem that deserves more attention. For many developing countries, prevalence rates of up to 75% are reported. Anaemia is frequently severe in these situations and can be expected to contribute significantly to maternal mortality and morbidity. After a discussion of definitions, screening for anaemia and prevalence, the relationship between anaemia and maternal mortality and morbidity will be reviewed. Micronutrient deficiency and especially iron deficiency is believed to be the main underlying cause for anaemia. More recently the role of vitamin A deficiency as a contributing factor to anaemia has also been examined. The difficulties of assessment of micronutrient sufficiency or deficiency in pregnancy are described, as is the interaction between infection and micronutrient deficiency states."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1150,I1150)","v":14642860},{"$f":"(LEN($J1150) - LEN(SUBSTITUTE(LOWER($J1150),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1150) - LEN(SUBSTITUTE(LOWER($J1150),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1150) - LEN(SUBSTITUTE(LOWER($J1150),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1150:D1150)","v":0},2003,"Intestinal absorption in health and disease: micronutrients.","Basu",14642860,"Intestinal absorption in health and disease: micronutrients.    Abstract:   The main theme of this chapter concerns the precise biochemical mechanisms involved in stages up to, and including, gastrointestinal absorption of vitamins and certain selected minerals. Essential data regarding sequential events, immediately following absorption of these micronutrients, are also included. There is reference to water-soluble vitamins that are, in general, either coenzymes in various metabolic reactions or carriers of certain biochemical groupings. In contrast, fat-soluble vitamins frequently function as integral components of cell membranes; they, too, receive ample attention. It is appropriate, nevertheless, to recognize that some minerals required in very small amounts are closely allied biochemically with particular vitamins; these specific associations are apportioned emphasis at relevant places in the text. Although predominant discussion centres on the physiological state, clinical reference is necessarily made to gastrointestinal disorders in which imbalance of vitamins and minerals consequently results in an additional detrimental impact on health."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1151,I1151)","v":14617432},{"$f":"(LEN($J1151) - LEN(SUBSTITUTE(LOWER($J1151),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1151) - LEN(SUBSTITUTE(LOWER($J1151),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1151) - LEN(SUBSTITUTE(LOWER($J1151),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1151:D1151)","v":0},2003,"Safety assessment of Salicylic Acid, Butyloctyl Salicylate, Calcium Salicylate, C12-15 Alkyl Salicylate, Capryloyl Salicylic Acid, Hexyldodecyl Salicylate, Isocetyl Salicylate, Isodecyl Salicylate, Magnesium Salicylate, MEA-Salicylate, Ethylhexyl Salicylate, Potassium Salicylate, Methyl Salicylate, Myristyl Salicylate, Sodium Salicylate, TEA-Salicylate, and Tridecyl Salicylate.","Gyórffy",14617432,"Safety assessment of Salicylic Acid, Butyloctyl Salicylate, Calcium Salicylate, C12-15 Alkyl Salicylate, Capryloyl Salicylic Acid, Hexyldodecyl Salicylate, Isocetyl Salicylate, Isodecyl Salicylate, Magnesium Salicylate, MEA-Salicylate, Ethylhexyl Salicylate, Potassium Salicylate, Methyl Salicylate, Myristyl Salicylate, Sodium Salicylate, TEA-Salicylate, and Tridecyl Salicylate.    Abstract:   Salicylic Acid is an aromatic acid used in cosmetic formulations as a denaturant, hair-conditioning agent, and skin-conditioning agent--miscellaneous in a wide range of cosmetic products at concentrations ranging from 0.0008% to 3%. The Calcium, Magnesium, and MEA salts are preservatives, and Potassium Salicylate is a cosmetic biocide and preservative, not currently in use. Sodium Salicylate is used as a denaturant and preservative (0.09% to 2%). The TEA salt of Salicylic Acid is used as an ultraviolet (UV) light absorber (0.0001% to 0.75%). Several Salicylic Acid esters are used as skin conditioning agents--miscellaneous (Capryloyl, 0.1% to 1%; C12-15 Alkyl, no current use; Isocetyl, 3% to 5%; Isodecyl, no current use; and Tridecyl, no current use). Butyloctyl Salicylate (0.5% to 5%) and Hexyldodecyl Salicylate (no current use) are hair-conditioning agents and skin-conditioning agents--miscellaneous. Ethylhexyl Salicylate (formerly known as Octyl Salicylate) is used as a fragrance ingredient, sunscreen agent, and UV light absorber (0.001% to 8%), and Methyl Salicylate is used as a denaturant and flavoring agent (0.0001% to 0.6%). Myristyl Salicylate has no reported function. Isodecyl Salicylate is used in three formulations, but no concentration of use information was reported. Salicylates are absorbed percutaneously. Around 10% of applied salicylates can remain in the skin. Salicylic Acid is reported to enhance percutaneous penetration of some agents (e.g., vitamin A), but not others (e.g., hydrocortisone). Little acute toxicity (LD(50) in rats; gt;2 g/kg) via a dermal exposure route is seen for Salicylic Acid, Methyl Salicylate, Tridecyl Salicylate, and Butyloctyl Salicylate. Short-term oral, inhalation, and parenteral exposures to salicylates sufficient to produce high blood concentrations are associated primarily with liver and kidney damage. Subchronic dermal exposures to undiluted Methyl Salicylate were associated with kidney damage. Chronic oral exposure to Methyl Salicylate produced bone lesions as a function of the level of exposure in 2-year rat studies; liver damage was seen in dogs exposed to 0.15 g/kg/day in one study; kidney and liver weight increases in another study at the same exposure; but no liver or kidney abnormalities in a study at 0.167 g/kg/day. Applications of Isodecyl, Tridecyl, and Butyloctyl Salicylate were not irritating to rabbit skin, whereas undiluted Ethylhexyl Salicylate produced minimal to mild irritation. Methyl Salicylate at a 1% concentration with a 70% ethanol vehicle were irritating, whereas a 6% concentration in polyethylene glycol produced little or no irritation. Isodecyl Salicylate, Methyl Salicylate, Ethylhexyl (Octyl) Salicylate, Tridecyl Salicylate, and Butyloctyl Salicylate were not ocular irritants. Although Salicylic Acid at a concentration of 20% in acetone was positive in the local lymph node assay, a concentration of 20% in acetone/olive oil was not. Methyl Salicylate was negative at concentrations up to 25% in this assay, independent of vehicle. Maximization tests of Methyl Salicylate, Ethylhexyl Salicylate, and Butyloctyl Salicylate produced no sensitization in guinea pigs. Neither Salicylic Acid nor Tridecyl Salicylate were photosensitizers. Salicylic Acid, produced when aspirin is rapidly hydrolyzed after absorption from the gut, was reported to be the causative agent in aspirin teratogenesis in animals. Dermal exposures to Methyl Salicylate, oral exposures to Salicylic Acid, Sodium Salicylate, and Methyl Salicylate, and parenteral exposures to Salicylic Acid, Sodium Salicylate, and Methyl Salicylate are all associated with reproductive and developmental toxicity as a function of blood levels reached as a result of exposure. An exposure assessment of a representative cosmetic product used on a daily basis estimated that the exposure from the cosmetic product would be only 20% of the level seen with ingestion of a quot;babyquot; aspirin (81 mg) on a daily basis. Studies of the genotoxic potential of Salicylic Acid, Sodium Salicylate, Isodecyl Salicylate, Methyl Salicylate, cosmetic product would be only 20% of the level seen with ingestion of a quot;babyquot; aspirin (81 mg) on a daily basis. Studies of the genotoxic potential of Salicylic Acid, Sodium Salicylate, Isodecyl Salicylate, Methyl Salicylate, Ethylhexyl (Octyl) Salicylate, Tridecyl Salicylate, and Butyloctyl Salicylate were generally negative. Methyl Salicylate, in a mouse skin-painting study, did not induce neoplasms. Likewise, Methyl Salicylate was negative in a mouse pulmonary tumor system. In clinical tests, Salicylic Acid (2%) produced minimal cumulative irritation and slight or no irritation(1.5%); TEA-Salicylate (8%) produced no irritation; Methyl Salicylate (gt;12%) produced pain and erythema, a 1% aerosol produced erythema, but an 8% solution was not irritating; Ethylhexyl Salicylate (4%) and undiluted Tridecyl Salicylate produced no irritation. In atopic patients, Methyl Salicylate caused irritation as a function of concentration (no irritation at concentrations of 15% or less). In normal skin, Salicylic Acid, Methyl Salicylate, and Ethylhexyl (Octyl) Salicylate are not sensitizers. Salicylic Acid is not a photosensitizer, nor is it phototoxic. Salicylic Acid and Ethylhexyl Salicylate are low-level photoprotective agents. Salicylic Acid is well-documented to have keratolytic action on normal human skin. Because of the possible use of these ingredients as exfoliating agents, a concern exists that repeated use may effectively increase exposure of the dermis and epidermis to UV radiation. It was concluded that the prudent course of action would be to advise the cosmetics industry that there is a risk of increased UV radiation damage with the use of any exfoliant, including Salicylic Acid and the listed salicylates, and that steps need to be taken to formulate cosmetic products with these ingredients as exfoliating agents so as not to increase sun sensitivity, or when increased sun sensitivity would be expected, to include directions for the daily use of sun protection. The available data were not sufficient to establish a limit on concentration of these ingredients, or to identify the minimum pH of formulations containing these ingredients, such that no skin irritation would occur, but it was recognized that it is possible to formulate cosmetic products in a way such that significant irritation would not be likely, and it was concluded that the cosmetics industry should formulate products containing these ingredients so as to be nonirritating. Although simultaneous use of several products containing Salicylic Acid could produce exposures greater than would be seen with use of baby aspirin (an exposure generally considered to not present a reproductive or developmental toxicity risk), it was not considered likely that consumers would simultaneously use multiple cosmetic products containing Salicylic Acid. Based on the available information, the Cosmetic Ingredient Review Expert Panel reached the conclusion that these ingredients are safe as used when formulated to avoid skin irritation and when formulated to avoid increasing the skins sun sensitivity, or, when increased sun sensitivity would be expected, directions for use include the daily use of sun protection."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1152,I1152)","v":14559961},{"$f":"(LEN($J1152) - LEN(SUBSTITUTE(LOWER($J1152),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1152) - LEN(SUBSTITUTE(LOWER($J1152),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1152) - LEN(SUBSTITUTE(LOWER($J1152),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1152:D1152)","v":0},2003,"Important causes of visual impairment in the world today.","Congdon",14559961,"Important causes of visual impairment in the world today.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1153,I1153)","v":12927947},{"$f":"(LEN($J1153) - LEN(SUBSTITUTE(LOWER($J1153),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1153) - LEN(SUBSTITUTE(LOWER($J1153),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1153) - LEN(SUBSTITUTE(LOWER($J1153),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1153:D1153)","v":0},2003,"Hyperlipidaemia in patients with HIV-1 infection receiving highly active antiretroviral therapy: epidemiology, pathogenesis, clinical course and management.","Calza",12927947,"Hyperlipidaemia in patients with HIV-1 infection receiving highly active antiretroviral therapy: epidemiology, pathogenesis, clinical course and management.    Abstract:   A wide range of abnormalities of lipid metabolism have been recently described in HIV-infected patients receiving a protease inhibitor (PI)-based highly active antiretroviral therapy, including hypertriglyceridaemia and hypercholesterolaemia. The increase of plasma lipid concentrations may involve up to 70-80% of HIV-positive subjects treated with a PI-containing regimen and are frequently (but not always) associated with the fat redistribution or the lipodystrophy syndrome. Multiple pathogenetic mechanisms by which antiretroviral agents lead to dyslipidaemia have been hypothesized, but they are still controversial. The potential clinicopathological consequences of HIV-associated hyperlipidaemia are not completely known, but several anecdotal observations report an increased risk of premature coronary artery diseases in young HIV-positive individuals receiving PIs, besides peripheral atherosclerosis and acute pancreatitis. A limited-to-significant improvement of increased triglyceride and cholesterol plasma levels was described in patients who replaced PIs with nevirapine, efavirenz or abacavir, but the risks of long-term toxicity and virological relapse of this treatment switching are not completely defined. A hypolipidaemic diet and regular physical exercise may act favorably on dyslipidaemia, but pharmacological therapy becomes necessary when hyperlipidaemia is severe or persists for a long time. The choice of hypolipidaemic drugs is problematic because of potential pharmacological interactions with antiretroviral compounds and other antimicrobial agents, associated with an increased risk of toxicity and intolerance. Statins are considered the first-line therapy for the PI-related hypercholesterolaemia, while fibrates are the cornerstone of drug therapy when predominant hypertriglyceridaemia is of concern."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1154,I1154)","v":12901271},{"$f":"(LEN($J1154) - LEN(SUBSTITUTE(LOWER($J1154),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1154) - LEN(SUBSTITUTE(LOWER($J1154),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1154) - LEN(SUBSTITUTE(LOWER($J1154),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1154:D1154)","v":0},2003,"[Alcoholic liver disease].","Waluga",12901271,"[Alcoholic liver disease].    Abstract:   Ethanol toxicity on liver is a function of duration of alcoholism, amount of daily intake of alcohol and patients nutrition. The threshold of alcohol toxicity on the liver is about 40 g of ethanol daily in men and 20-30 g in women, however liver cirrhosis develops in no more than 8-20% of patients exceeding this values. Ethanol is oxidized in the liver to acetaldehyde--a compound considerably more toxic than ethanol itself. Despite small amount of alcohol dehydrogenase (ADH) found in gastric mucosa, the metabolism of ethanol in this site may have an important hepatoprotective effect. The oxidation of ethanol is associated with a change of hepatocyte redox homeostasis, which leads to a number of metabolic disorders such as lactic acidosis, hyperlipidaemia and hyperuricaemia. Chronic ethanol consumption does not influence ADH activity, but has a profound stimulatory effect on microsomal enzymes, in particular cytochrome CYP2E1. This fact is responsible for development in alcoholic liver associated with rise of oxygen consumption, excessive production of free radicals and increased metabolism of ethanol, vitamin A and testosterone. Ethanol and acetaldehyde have a deleterious effect, both the direct and indirect, on hepatocytes e.g., generating radical oxygen species and damaging intestinal mucosal barrier. Cellular oxidative stress that is caused by both an excess of free radicals and the antioxidatives deficiency (glutathion, vitamin E, phosphatidylcholine), may be the principal factor responsible for progression of alcoholic liver disease. Among other factors accelerating alcohol-related liver lesion there are certain drugs, high fat diet, infection with HCV and genetic factors (female sex, enzymatic polymorphic forms of ADH and ALDH, hemochromatosis). Great importance in pathogenesis of necrotic and inflammatory hepatic events is being attributed to portal endotoxaemia and cytokines induced within the liver, in particular TNF-alpha and interleukin 8. These cytokines play a key role in development of alcoholic hepatitis, which clinical severity ranges from subclinical to fatal forms. Apart from abstinence, the treatment of alcohol liver disease is based on hyperalimentation, since alcoholism is generally associated with protein malnutrition. In severe forms of alcohol hepatitis corticosteroids are recommended."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1155,I1155)","v":12858562},{"$f":"(LEN($J1155) - LEN(SUBSTITUTE(LOWER($J1155),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1155) - LEN(SUBSTITUTE(LOWER($J1155),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1155) - LEN(SUBSTITUTE(LOWER($J1155),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1155:D1155)","v":0},2002,"Regulatory networks controlling mitochondrial energy production in the developing, hypertrophied, and diabetic heart.","Finck",12858562,"Regulatory networks controlling mitochondrial energy production in the developing, hypertrophied, and diabetic heart.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1156,I1156)","v":12842416},{"$f":"(LEN($J1156) - LEN(SUBSTITUTE(LOWER($J1156),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1156) - LEN(SUBSTITUTE(LOWER($J1156),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1156) - LEN(SUBSTITUTE(LOWER($J1156),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1156:D1156)","v":0},2003,"Programming the cardiovascular system, kidney and the brain--a review.","Wintour",12842416,"Programming the cardiovascular system, kidney and the brain--a review.    Abstract:   The concept that life before birth or the first environment is important in determining subsequent risk for the development of cardiovascular/metabolic disease is now gaining acceptance. There are substantial data from animal experiments that complement and enhance the epidemiological data from human studies. We argue that any factor which disrupts nephrogenesis, and lowers nephron number, during the period of active nephrogenesis, will induce malapadaptive changes in the future functioning of that kidney and predispose to the onset of adult hypertension. Such factors include exposure of the mother, to a particular low-protein diet, excess synthetic or natural glucocorticoid at certain critical periods, mild vitamin A deficiency, elevated blood glucose, unilateral nephrectomy during the period of nephrogenesis, as well as the deletion of one allele of a gene (GDNF) involved in normal metanephric development. All of these stresses are associated with a reduction (20-40 per cent) in total nephron number in the adult, and the development of hypertension. In some hypertensive models, (rats) there is evidence of alterations in the components of the hippocampal/hypothalamic/pituitary/adrenal axis, whereas in others (sheep) there are alterations in the expression of angiotensinogen (hypothalamus) and angiotensin II receptor type I (AT(1)) in the medulla oblongata. The surprising finding is that the period when the kidney and brain are most vulnerable is very early in development, when both organs are in an extremely primitive state of development."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1157,I1157)","v":12808230},{"$f":"(LEN($J1157) - LEN(SUBSTITUTE(LOWER($J1157),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1157) - LEN(SUBSTITUTE(LOWER($J1157),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1157) - LEN(SUBSTITUTE(LOWER($J1157),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1157:D1157)","v":0},2003,"Hepatic stellate cells: unique characteristics in cell biology and phenotype.","Sato",12808230,"Hepatic stellate cells: unique characteristics in cell biology and phenotype.    Abstract:   Hepatic stellate cells (HSCs), a mesenchymal cell type in hepatic parenchyma, have unique features with respect to their cellular origin, morphology, and function. Normal, quiescent HSCs function as major vitamin A-storing cells containing over 80% of total vitamin A in the body to maintain vitamin A homeostasis. HSCs are located between parenchymal cell plates and sinusoidal endothelial cells, and extend well-developed, long processes surrounding sinusoids in vivo as pericytes. However, HSCs are known to be activated or transdifferentiated to myofibroblast-like phenotype lacking cytoplasmic lipid droplets and long processes in pathological conditions such as liver fibrosis and cirrhosis, as well as merely during cell culture after isolation. HSCs are the predominant cell type producing extracellular matrix (ECM) components as well as ECM degrading metalloproteases in hepatic parenchyma, indicating that they play a pivotal role in ECM remodeling in both normal and pathological conditions. Recent findings have suggested that HSCs have a neural crest origin from their gene expression pattern similar to neural cell type and/or smooth muscle cells and myofibroblasts. The morphology and function of HSCs are regulated by ECM components as well as by cytokines and growth factors in vivo and in vitro. Liver regeneration after partial hepatectomy might be an invaluable model to clarify the HSC function in elaborate organization of liver tissue by cell-cell and cell-ECM interaction and by growth factor and cytokine regulation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1158,I1158)","v":12775766},{"$f":"(LEN($J1158) - LEN(SUBSTITUTE(LOWER($J1158),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1158) - LEN(SUBSTITUTE(LOWER($J1158),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1158) - LEN(SUBSTITUTE(LOWER($J1158),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1158:D1158)","v":0},2003,"DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation.","Lalli",12775766,"DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation.    Abstract:   The unusual orphan member of the nuclear hormone receptor superfamily DAX-1 (NR0B1) owes its name to its double role in human pathology. On one side, duplications in Xp21, containing the DAX-1 gene, cause phenotypic sex reversal in XY individuals. On the other side, DAX-1 gene mutations are responsible for adrenal hypoplasia congenita, invariably associated with hypogonadotropic hypogonadism. DAX-1 functions as a global negative regulator of steroid hormone production by repressing the expression of multiple genes involved in the steroidogenic pathway. Here we review the mechanism of DAX-1 function in adrenal and gonadal differentiation, with special emphasis on recent results showing the critical role of DAX-1 protein misfolding in the pathogenesis of adrenal hypoplasia congenita."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1159,I1159)","v":12730490},{"$f":"(LEN($J1159) - LEN(SUBSTITUTE(LOWER($J1159),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1159) - LEN(SUBSTITUTE(LOWER($J1159),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1159) - LEN(SUBSTITUTE(LOWER($J1159),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1159:D1159)","v":0},2003,"Cigarette smoking, alcohol use and adverse pregnancy outcomes: implications for micronutrient supplementation.","Cogswell",12730490,"Cigarette smoking, alcohol use and adverse pregnancy outcomes: implications for micronutrient supplementation.    Abstract:   This literature review examines whether smoking or alcohol use during pregnancy increases maternal micronutrient requirements and whether smoking or alcohol use interacts with micronutrient deficiencies to affect pregnancy outcomes. Studies suggest that vitamin C requirements increase for pregnant smokers. Studies also indicate that beta-carotene, vitamin B-12, vitamin B-6 and folate concentrations appear lower in pregnant smokers than in pregnant nonsmokers, although it is unclear whether lower serum concentrations are due to increased requirements, lower dietary or supplement intakes or other factors. Experimental animal studies suggest that iron supplementation partially ameliorates impaired fetal growth caused by cadmium, a heavy metal inhaled from cigarette smoke, but studies in humans have not substantiated cadmiums effect on fetal growth. Animal studies also suggest chronic alcohol consumption at levels of 20-50% of energy intake during pregnancy may mobilize fetal vitamin A concentration from the liver and result in increases in vitamin A in fetal organs and subsequent defects. Evidence is lacking, however, on whether zinc metabolism is altered by alcohol intake during pregnancy. Health care practitioners should consider increasing nutrient levels in pregnant women who do not meet the Recommended Dietary Allowances through their diet. Future studies that examine the nutrient levels of women exposed to cigarette smoke and alcohol should control for dietary intake. In addition, randomized controlled studies of the health impact of micronutrient supplementation in pregnant women should consider stratification by exposure to cigarette smoke and alcohol use."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1160,I1160)","v":12653010},{"$f":"(LEN($J1160) - LEN(SUBSTITUTE(LOWER($J1160),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1160) - LEN(SUBSTITUTE(LOWER($J1160),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1160) - LEN(SUBSTITUTE(LOWER($J1160),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1160:D1160)","v":0},2002,"Nutrition.","Patel",12653010,"Nutrition.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1161,I1161)","v":12602939},{"$f":"(LEN($J1161) - LEN(SUBSTITUTE(LOWER($J1161),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1161) - LEN(SUBSTITUTE(LOWER($J1161),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1161) - LEN(SUBSTITUTE(LOWER($J1161),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1161:D1161)","v":0},2002,"Palm oil: biochemical, physiological, nutritional, hematological, and toxicological aspects: a review.","Edem",12602939,"Palm oil: biochemical, physiological, nutritional, hematological, and toxicological aspects: a review.    Abstract:   The link between dietary fats and cardiovascular diseases has necessitated a growing research interest in palm oil, the second largest consumed vegetable oil in the world. Palm oil, obtained from a tropical plant, Elaeis guineensis contains 50% saturated fatty acids, yet it does not promote atherosclerosis and arterial thrombosis. The saturated fatty acid to unsaturated fatty acid ratio of palm oil is close to unity and it contains a high amount of the antioxidants, beta-carotene, and vitamin E. Although palm oil-based diets induce a higher blood cholesterol level than do corn, soybean, safflower seed, and sunflower oils, the consumption of palm oil causes the endogenous cholesterol level to drop. This phenomenon seems to arise from the presence of the tocotrienols and the peculiar isomeric position of its fatty acids. The benefits of palm oil to health include reduction in risk of arterial thrombosis and atherosclerosis, inhibition of endogenous cholesterol biosynthesis, platelet aggregation, and reduction in blood pressure. Palm oil has been used in the fresh state and/or at various levels of oxidation. Oxidation is a result of processing the oil for various culinary purposes. However, a considerable amount of the commonly used palm oil is in the oxidized state, which poses potential dangers to the biochemical and physiological functions of the body. Unlike fresh palm oil, oxidized palm oil induces an adverse lipid profile, reproductive toxicity and toxicity of the kidney, lung, liver, and heart. This may be as a result of the generation of toxicants brought on by oxidation. In contrast to oxidized palm oil, red or refined palm oil at moderate levels in the diet of experimental animals promotes efficient utilization of nutrients, favorable body weight gains, induction of hepatic drug metabolizing enzymes, adequate hemoglobinization of red cells and improvement of immune function. Howerer, high palm oil levels in the diet induce toxicity to the liver as shown by loss of cellular radial architecture and cell size reductions which are corroborated by alanine transaminase to asparate transaminase ratios which are higher than unity. The consumtion of moderate amounts of palm oil and reduction in the level of oxidation may reduce the health risk believed to be associated with the consumption of palm oil. Red palm oil, by virtue of its beta-carotene content, may protect against vitamin A deficiency and certain forms of cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1162,I1162)","v":12553849},{"$f":"(LEN($J1162) - LEN(SUBSTITUTE(LOWER($J1162),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1162) - LEN(SUBSTITUTE(LOWER($J1162),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1162) - LEN(SUBSTITUTE(LOWER($J1162),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1162:D1162)","v":0},2003,"Ichthyosis: etiology, diagnosis, and management.","DiGiovanna",12553849,"Ichthyosis: etiology, diagnosis, and management.    Abstract:   The ichthyoses are a heterogeneous group of disorders with both inherited and acquired forms. Clinical presentation, pattern of inheritance, and laboratory evaluation may establish a precise diagnosis, which can assist in prognosis and genetic counseling. Congenital autosomal recessive ichthyosis (CARI) usually presents at birth, often as a collodion baby. CARI can progress into any one of a spectrum of disorders. Lamellar ichthyosis is characterized by dark, plate (armor)-like scale. This disease is often caused by mutations in the gene encoding the enzyme transglutaminase 1. Congenital ichthyosiform erythroderma is another phenotype within CARI, marked by generalized redness and fine white scale. Epidermolytic hyperkeratosis is an autosomal dominant disorder characterized by hyperkeratosis and blistering, and at least six clinical phenotypes have been described. It may be due to mutations in the gene encoding the intermediate filament proteins keratin 1 and 10. Ichthyosis vulgaris is the most common ichthyosis, and is inherited in an autosomal dominant pattern. Involvement is generally mild and may vary greatly with climate and humidity. X-linked ichthyosis, due to a defect in the enzyme steroid sulfatase, affects males with generalized scaling that usually begins soon after birth. There may be associated corneal opacities that do not affect vision. Sjögren-Larsson syndrome is an autosomal recessive ichthyosis associated with progressive spastic paralysis and mental retardation. This condition is caused by mutations in the gene for fatty aldehyde dehydrogenase. Refsums disease, due to accumulation of phytanic acid, results in ichthyosis and progressive neurologic dysfunction. The erythrokeratodermas are characterized by hyperkeratosis and localized erythema. Erythrokeratodermia variabilis is autosomal dominant and characterized by generalized or localized hyperkeratosis and migratory red patches. Mutations in the genes encoding the gap junction proteins, connexins, underlie this disorder. Nethertons syndrome is an autosomal recessive disorder characterized by ichthyosis, a hair shaft abnormality and atopy. The ichthyosis may present at birth with erythroderma or in some cases a collodion presentation. However, a frequent characteristic skin manifestation is ichthyosis linearis circumflexa. Nethertons syndrome has been found to be due to an abnormality in a serum protease inhibitor. Acquired ichthyosis can have a variety of underlying causes including neoplastic, infectious, drugs, endocrine, metabolic, autoimmune, malabsorptive states, and hereditary. Topical, and in more severe cases, systemic, therapy are useful in managing this array of disorders of cornification."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1163,I1163)","v":12542546},{"$f":"(LEN($J1163) - LEN(SUBSTITUTE(LOWER($J1163),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1163) - LEN(SUBSTITUTE(LOWER($J1163),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1163) - LEN(SUBSTITUTE(LOWER($J1163),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1163:D1163)","v":0},2003,"An orphan meets family members in skin.","Nagpal",12542546,"An orphan meets family members in skin.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1164,I1164)","v":12526094},{"$f":"(LEN($J1164) - LEN(SUBSTITUTE(LOWER($J1164),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1164) - LEN(SUBSTITUTE(LOWER($J1164),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1164) - LEN(SUBSTITUTE(LOWER($J1164),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1164:D1164)","v":0},2002,"Prevention of liver cancer: basic and clinical aspects.","Moriwaki",12526094,"Prevention of liver cancer: basic and clinical aspects.    Abstract:   Cancer prevention is a challenging project both in the basic and clinical medicine. In particular, prevention of liver cancer is the most urgent task in countries where the incidence of hepatitis virus- related liver cancer is rising. As reviewed in this article, liver cancer is going to be the first cancer that will be actually prevented by primary and secondary interventions. Even the improvement of absolute survival of the patients can be expected by successful prevention, as already demonstrated in a few clinical trials. Thus, prevention of liver cancer is promising to provide not only cost-effectiveness by morbidity reduction but also cost-benefit by mortality improvement."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1165,I1165)","v":12510986},{"$f":"(LEN($J1165) - LEN(SUBSTITUTE(LOWER($J1165),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1165) - LEN(SUBSTITUTE(LOWER($J1165),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1165) - LEN(SUBSTITUTE(LOWER($J1165),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1165:D1165)","v":0},2002,"Advances in the understanding of the genetic basis of adrenal insufficiency.","Storr",12510986,"Advances in the understanding of the genetic basis of adrenal insufficiency.    Abstract:   Primary adrenal failure in a pediatric population most frequently results from autoimmune destruction of the gland. Recent discoveries regarding the genetic factors underlying this and other inherited causes of adrenocortical failure provide valuable insights into the molecular basis of adrenal development and function. Among these are the clinical syndromes resulting from defects in DAX-1 and SF-1 and the functional defects caused by mutations in the ACTH receptor and the StAR protein. Adrenoleukodystrophy and the triple A syndrome result from the degenerative effects induced by failure of very long chain fatty acid metabolism in the former case and the unknown effects of a novel protein that is mutated in the latter case. This review summarizes these recent findings and briefly describes the possible pathogenetic mechanisms that they reveal."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1166,I1166)","v":12456552},{"$f":"(LEN($J1166) - LEN(SUBSTITUTE(LOWER($J1166),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1166) - LEN(SUBSTITUTE(LOWER($J1166),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1166) - LEN(SUBSTITUTE(LOWER($J1166),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1166:D1166)","v":0},2002,"Are annual blood tests in preschool cystic fibrosis patients worthwhile?","Jaffé",12456552,"Are annual blood tests in preschool cystic fibrosis patients worthwhile?    Abstract:    AIM : To investigate whether routine annual assessment blood tests in cystic fibrosis (CF) patients under 5 years influence management.  METHODS : Retrospective review of the results of the first annual assessment blood tests of patients with CF less than 5 years of age during a four year period (1995-99). Management changes were identified from a follow up letter to the general practitioner or local paediatrician.  RESULTS : A total of 169 patients (100 female), median age 2.2 years (range 0.3-4.9) were identified. Venepuncture was successful in 93% of patients. Of the 32 individual blood parameters measured, the overall success rate in obtaining a result was 81%. Eleven per cent of patients underwent subsequent management changes, including liver ultrasound, fasting glucose, and a short course of iron. Of particular importance, vitamin A and E concentrations were low in 9% of patients, which prompted an increase in prescribed dose.  CONCLUSIONS : These results support the recommendations for routine blood tests at annual review in preschool CF children. The results may help to rationalise which tests are performed and thus reduce laboratory costs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1167,I1167)","v":12408446},{"$f":"(LEN($J1167) - LEN(SUBSTITUTE(LOWER($J1167),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1167) - LEN(SUBSTITUTE(LOWER($J1167),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1167) - LEN(SUBSTITUTE(LOWER($J1167),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1167:D1167)","v":0},2002,"Consequences of Helicobacter pylori infection on the absorption of micronutrients.","Annibale",12408446,"Consequences of Helicobacter pylori infection on the absorption of micronutrients.    Abstract:   Recent studies have suggested a relationship between Helicobacter pylori infection and various important micronutrients, including iron and vitamin B12, suggesting likely biological factors in the association between Helicobacter pylori and microcytic or macrocytic anaemia. There is some evidence that direct or indirect consequences of Helicobacter pylori gastritis on acid secretion account for the role of the bacterium in the absorption process of iron and Vitamin B12. The plasma, intragastric and mucosal concentration of different antioxidant compounds such as ascorbic acid, a-tocopherol and beta-carotene is also affected by Helicobacter pylori gastritis supporting the possible role of Helicobacter pylori in the multistep cascade leading to gastric carcinogenesis. The relationship between Helicobacter pylori infection and micronutrients is, therefore, a promising and, until now, poorly investigated field of research."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1168,I1168)","v":12359125},{"$f":"(LEN($J1168) - LEN(SUBSTITUTE(LOWER($J1168),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1168) - LEN(SUBSTITUTE(LOWER($J1168),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1168) - LEN(SUBSTITUTE(LOWER($J1168),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1168:D1168)","v":0},2002,"Genetic disorders associated with ATP binding cassette cholesterol transporters.","Burris",12359125,"Genetic disorders associated with ATP binding cassette cholesterol transporters.    Abstract:   Coronary artery disease is the most prevalent form of mortality and morbidity in Western countries. Studies in the last several decades have identified high LDL cholesterol and low HDL cholesterol as major risk factors leading to the disease. Human genetic studies have provided significant insight into the regulation of lipoprotein metabolism. In the last several years, the genes associated with several rare genetic diseases of lipid metabolism have been revealed. These landmark discoveries that identified mutant ABC cholesterol transporters as the underlying causes of these genetic disorders have paved the way for better understanding of the cellular cholesterol transport process and HDL biogenesis. This summary provides an overview and discussion of the most recent progress that includes molecular mechanism and regulation of cholesterol transport mediated by these ABC transporters."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1169,I1169)","v":12296961},{"$f":"(LEN($J1169) - LEN(SUBSTITUTE(LOWER($J1169),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1169) - LEN(SUBSTITUTE(LOWER($J1169),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1169) - LEN(SUBSTITUTE(LOWER($J1169),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1169:D1169)","v":0},2002,"Mesenchymal cells in the liver--one cell type or two?","Ramadori",12296961,"Mesenchymal cells in the liver--one cell type or two?    Abstract:   The wall of the liver sinusoid is made of highly specialized cells, the hepatic stellate cells (HSC) which together with the sinusoidal endothelial cells represent a loose barrier to the corpusculate part of the blood flowing through the liver. Quiescent stellate cells (quiescent HSC) store Vitamin A; quot;activatedquot; stellate cells become involved in the reaction to acute or chronic noxae damaging the liver parenchyma. Activated HSC show increased protein synthesis capacity, increased DNA-synthesis and acquire a myofibroblast-like phenotype. Under similar conditions liver myofibroblasts (MF) of the portal field and of the pericentral area may also become quot;activatedquot; by increasing protein synthesis, DNA synthesis and cell division. They express the fibulin-2 gene and produce large amounts of IL-6. In contrast to quot;activatedquot; HSC they do not undergo spontaneous apoptosis in vitro and do not express the CD95-ligand gene. So far no definite prove has been found for a quot;transdifferentiationquot; of HSC to myofibroblasts. On the contrary an increasing amount of data support the conviction that HSC and MF represent two similar but not identical cell populations the latter being comparable to those of other organs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1170,I1170)","v":12243697},{"$f":"(LEN($J1170) - LEN(SUBSTITUTE(LOWER($J1170),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1170) - LEN(SUBSTITUTE(LOWER($J1170),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1170) - LEN(SUBSTITUTE(LOWER($J1170),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1170:D1170)","v":0},2002,"[Hypovitaminosis A in Brazil: a public health problem].","Ramalho",12243697,"[Hypovitaminosis A in Brazil: a public health problem].    Abstract:   Vitamin A deficiency is considered one of the most important of the easily preventable public health problems in a number of countries, including Brazil. The objective of this study was to review the scientific literature in the MEDLINE and LILACS databases that was published between 1970 and 2000 concerning vitamin A deficiency, and to assess the occurrence of hypovitaminosis A in Latin America, especially Brazil. Our research showed that until around 1980 the public health concerns focused mainly on the importance of vitamin A in ensuring good vision. In the second half of the 1980s, epidemiological studies suggested that, on a population level, subclinical vitamin A deficiency could also have a negative effect on metabolic functions, with a great impact on childhood morbidity and mortality. Marginal vitamin A deficiency has been reported in all the regions of Brazil for which there are data available, with high prevalences in various age groups. This situation is inexcusable, given the health care technology and resources that are now available. There must be a commitment to reducing vitamin A deficiency in order to ensure the adequate development of future generations."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1171,I1171)","v":12230796},{"$f":"(LEN($J1171) - LEN(SUBSTITUTE(LOWER($J1171),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1171) - LEN(SUBSTITUTE(LOWER($J1171),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1171) - LEN(SUBSTITUTE(LOWER($J1171),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1171:D1171)","v":0},2002,"Effects of fatty acids on gene expression: role of peroxisome proliferator-activated receptor alpha, liver X receptor alpha and sterol regulatory element-binding protein-1c.","Kersten",12230796,"Effects of fatty acids on gene expression: role of peroxisome proliferator-activated receptor alpha, liver X receptor alpha and sterol regulatory element-binding protein-1c.    Abstract:   Dietary fatty acids have numerous effects on cellular function, many of which are achieved by altering the expression of genes. The present paper reviews recent data on the mechanisms by which fatty acids influence DNA transcription, and focus specifically on the importance of three transcription factors: peroxisome proliferator-activated receptor alpha; liver X receptor alpha; sterol regulatory element-binding protein 1c. These data indicate that fatty acids induce or inhibit the mRNA expression of a variety of different genes by acting both as agonists and as antagonists for nuclear hormone receptors."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1172,I1172)","v":12185666},{"$f":"(LEN($J1172) - LEN(SUBSTITUTE(LOWER($J1172),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1172) - LEN(SUBSTITUTE(LOWER($J1172),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1172) - LEN(SUBSTITUTE(LOWER($J1172),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1172:D1172)","v":0},2002,"Recent insights into organogenesis of the adrenal cortex.","Keegan",12185666,"Recent insights into organogenesis of the adrenal cortex.    Abstract:   The primary endocrine organs responsible for steroid hormone biosynthesis--the adrenal cortex and gonads--are derived from the urogenital ridge. Several recent discoveries in human and mouse genetics have begun to unravel the complex genetic cascade that dictates adrenocortical cell lineage, proliferation and differentiation. The factors that regulate adrenocortical organogenesis and the maintenance of growth promote or block a cascade of transcription factors that differentially coordinate the proliferation and differentiation of the gland. Here, we outline the developmental milestones of the adrenal cortex with recent contributions to the field, focusing on factors that have been shown to play a role in vivo in humans and mice."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1173,I1173)","v":12109342},{"$f":"(LEN($J1173) - LEN(SUBSTITUTE(LOWER($J1173),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1173) - LEN(SUBSTITUTE(LOWER($J1173),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1173) - LEN(SUBSTITUTE(LOWER($J1173),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1173:D1173)","v":0},2002,"Chemoprevention of bladder cancer.","Kamat",12109342,"Chemoprevention of bladder cancer.    Abstract:   The data presented herein, although highly supportive for a protective role of various nutrients against bladder cancer, are far from definitive. Many authorities question the validity of current recommendations for nutritional chemoprevention against bladder cancer. The reason for the wide variations reported in epidemiologic studies lies in the nature of observational studies. Dietary studies are limited in their conclusions because the protection afforded by the consumption of a particular nutrient may be multifactorial, with different components of the food exerting potential chemopreventive effects. Furthermore, measuring levels of nutrients in the food intake of populations is confounded by factors that might affect these levels and also the incidence of cancer. For example, vitamin A can come from animal or vegetarian sources. Because animal fat has been identified as a potential carcinogen in man, depending on the source of the vitamin, varying levels of protection might be deduced. In addition, chemoprevention studies using dietary supplements are expected to have mild effects, and large studies would be required to confirm statistical significance. Even with agents such as intravesical chemotherapy, only half the studies achieve statistical significance [29]. Prospective randomized trials with a large sample size, longer follow-up, and an extended duration of treatment are needed to clarify the association between micronutrients and cancer protection. With these caveats in mind, several recommendations can be made. Simple measures, such as drinking more fluids (especially water), can have a profound impact on the incidence of bladder cancer. Vitamins are being extensively studied in chemopreventive trials for different cancers. There is strong evidence for a chemoprotective effect of vitamin A in bladder cancer. The authors recommend 32,000 IU/day of vitamin A initially, with lower doses (24,000 IU) for persons less than 50 kg. Because liver toxicity is a possibility with long-term administration, the dose should be decreased to 16,000 IU after 3 years. High doses of beta-carotene should be avoided based on a large clinical trial reporting a 25% increase in the number of cases of prostate cancer and a statistically significant increase in the incidence of lung cancer. Vitamin B6 has been studied in several clinical trials in bladder cancer. The US-based Veterans Administration cooperative study found benefit for vitamin B6 when given as a single agent. Data for vitamins C and E are insufficient to recommend either agent as stand-alone treatment. Nonetheless, each of these vitamins is known to have beneficial effects, including improved function of the immune system. It is possible that only a small percentage of patients with bladder cancer respond to vitamins B6, C, or E, yet each is safe, nontoxic, and inexpensive. In an effort to pool the efficacy of individual agents and to increase the power of study, the authors evaluated the combination of vitamins A, B6, C, and E in a double-blind trial. The observed 50% 5-year reduction in tumor recurrence was highly significant and greater than would be expected for any of the individual ingredients and suggests that combinations of nutritional agents may be most appropriate. A large-volume study along similar lines is being conducted. Among the numerous other compounds and dietary substances purported to have chemopreventive effect, soybeans, garlic, and green tea stand out as having the greatest promise and can freely be recommended to patients. For synthetically synthesized agents such as celecoxib, piroxicam, or DFMO, recommendations must be deferred until the results of clinical trials are conclusively in favor of their use. Many of the dietary factors found to be protective against bladder cancer are being investigated in other cancers and are beneficial to general health. Although naturally occurring nutrients are ideal, especially because the delicate balance of various micronutrients might be impossible to synthesize in the laboratory, the general population finds it easier to take vitamin supplements. Unfortunately, dietary changes such as decreasing fat and increasing fruit and vegetable intake are more difficult to initiate. There is a mistaken notion that simply because an agent is naturally occurring, it cannot be as beneficial as taking a substance synthesized in the laboratory. Even in a high-risk group such as nuclear-bomb survivors in Japan, high consumption of vegetables and fruit is protective against bladder cancer [44]. Encouraging patients to follow an essentially healthy food habit lifestyle will be a significant contribution in the fight against cancer."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1174,I1174)","v":12077107},{"$f":"(LEN($J1174) - LEN(SUBSTITUTE(LOWER($J1174),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1174) - LEN(SUBSTITUTE(LOWER($J1174),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1174) - LEN(SUBSTITUTE(LOWER($J1174),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1174:D1174)","v":0},2002,"Cocarcinogenic effects of alcohol in hepatocarcinogenesis.","Stickel",12077107,"Cocarcinogenic effects of alcohol in hepatocarcinogenesis.    Abstract:   Alcohol is a major aetiological factor in hepatocarcinogenesis but our understanding of its importance as a modulating factor is just beginning to emerge. In the present review, a number of possible cofactors and mechanisms are discussed by which alcohol may enhance the development of hepatoma. These include dietary or environmental carcinogens ingested along with alcoholic beverages, alcoholic cirrhosis as a precancerous condition, and the effects of alcohol metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1175,I1175)","v":12035866},{"$f":"(LEN($J1175) - LEN(SUBSTITUTE(LOWER($J1175),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1175) - LEN(SUBSTITUTE(LOWER($J1175),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1175) - LEN(SUBSTITUTE(LOWER($J1175),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1175:D1175)","v":0},2002,"Adverse effects of poor micronutrient status during childhood and adolescence.","Kapil",12035866,"Adverse effects of poor micronutrient status during childhood and adolescence.    Abstract:   Despite Indias substantial progress in human development since its independence in 1947, 5-7% of its children have vitamin A deficiency disorders in selected geographic areas, 53% have iron deficiency anemia, and 9% have goiter. Three micronutrients--vitamin A, iron, and iodine--are among the most important of all the nutrients needed by the body because they are vital for developing normal learning and cognitive functions, immunity, work capacity, and reproductive health. The body cannot synthesize them, so they must be made available through the diet. Deficiencies of these three micronutrients are known to have devastating effects on health."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1176,I1176)","v":12035848},{"$f":"(LEN($J1176) - LEN(SUBSTITUTE(LOWER($J1176),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1176) - LEN(SUBSTITUTE(LOWER($J1176),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1176) - LEN(SUBSTITUTE(LOWER($J1176),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1176:D1176)","v":0},2002,"Intervention strategies for improving iron status of young children and adolescents in India.","Ahluwalia",12035848,"Intervention strategies for improving iron status of young children and adolescents in India.    Abstract:   Despite advances in scientific knowledge regarding multiple etiology, treatment, and potential strategies for combating iron deficiency and deficiencies of other micronutrients, iron deficiency anemia, vitamin A deficiency, and iodine deficiency remain significant public health challenges for growing children and adolescents. The short-term efficient supplementation approach, although technically feasible, has not been successful due to problems with delivery and compliance. Evidence is building that preventive supplementation coupled with nutrition education may be a more effective strategy associated with better compliance and improvement in iron status. Long-term, effective approaches include fortification, dietary modification, public health and disease control measures, and income generation programs. Food fortification can be a cost-effective intervention strategy if technologically feasible, nutritionally sound, culturally acceptable and economically viable food vehicle(s) and fortificant(s) can be identifed. Foods such as wheat, rice, and salt are commonly consumed in India; research is underway to evaluate various fortificants for these foods. Doubly fortified salt with iodine and iron may be particularly promising in the Indian situation as it is affordable, culturally acceptable, and may enhance iron absorption from Indian dietaries containing inhibitors of iron absorption. Feasibility studies are underway to evalute the stability and storage issues as well as bioavailability of fortificant iron. Dietary modification involves increased iron intake, by increasing total food intake and consumption of locally available iron-rich foods, and dietary practices favoring iron absorption. Blood loss associated with worm infestation can be controlled by periodic deworming and reducing reinfestation. Coordinating these major intervention approaches by building partnerships between the community, existing nutrition and health programs, government, industry, and academic institutions is critical for success of these programs. Nutrition education must be integral to all of these strategies discusssed. Primary health care system and school infrastructure and staff, along with school children and community members, can be powerful resources for addressing malnutrition in children and adolescents."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1177,I1177)","v":11989264},{"$f":"(LEN($J1177) - LEN(SUBSTITUTE(LOWER($J1177),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1177) - LEN(SUBSTITUTE(LOWER($J1177),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1177) - LEN(SUBSTITUTE(LOWER($J1177),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1177:D1177)","v":0},2002,"[Prevention of liver neoplasms].","Moriwaki",11989264,"[Prevention of liver neoplasms].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1178,I1178)","v":11983160},{"$f":"(LEN($J1178) - LEN(SUBSTITUTE(LOWER($J1178),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1178) - LEN(SUBSTITUTE(LOWER($J1178),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1178) - LEN(SUBSTITUTE(LOWER($J1178),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1178:D1178)","v":0},2002,"Linking activators and basals in transcription: it is all in one family.","Timmers",11983160,"Linking activators and basals in transcription: it is all in one family.    Abstract:   Analysis of nuclear hormone receptor function in cells derived from xeroderma pigmentosum patients reveals novel links between DNA repair and transcription and points to novel mechanisms of regulating transcriptional regulators."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1179,I1179)","v":11965516},{"$f":"(LEN($J1179) - LEN(SUBSTITUTE(LOWER($J1179),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1179) - LEN(SUBSTITUTE(LOWER($J1179),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1179) - LEN(SUBSTITUTE(LOWER($J1179),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1179:D1179)","v":0},2002,"Meat and cancer: meat as a component of a healthy diet.","Biesalski",11965516,"Meat and cancer: meat as a component of a healthy diet.    Abstract:   Based on epidemiological studies it is assumed that meat, especially red meat, enhances risk for cancer, particularly of the colon, breast and prostate. Meat and meat products are important sources of protein, some micronutrients and fat. High fat intake has been blamed for correlation with different diseases, including cancer. Meat protein is reported to contribute to cancer formation. However, meat, including liver, is not only composed of fat and protein, it contains essential nutrients which appear exclusively in meat (vitamin A, vitamin B12) and micronutrients for which meat is the major source because of either high concentrations or better bioavailability (folate, selenium, zinc). In particular, vitamin A, folate and selenium are reported to be cancer-preventive, with respect to colon, breast and prostate cancer. Taken together, meat consists of a few, not clearly defined cancer-promoting and a lot of cancer-protecting factors. The latter can be optimized by a diet containing fruit and vegetables, which contain hundreds of more or less proven bioactive constituents, many of them showing antioxidative and anticarcinogenic effects in vitro."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1180,I1180)","v":11962754},{"$f":"(LEN($J1180) - LEN(SUBSTITUTE(LOWER($J1180),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1180) - LEN(SUBSTITUTE(LOWER($J1180),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1180) - LEN(SUBSTITUTE(LOWER($J1180),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1180:D1180)","v":0},2002,"The hepatic stellate cell in the post-genomic era.","Okuyama",11962754,"The hepatic stellate cell in the post-genomic era.    Abstract:   The draft human genome sequence was published on February 15, 2001, which will provide a huge amount of information on human genetics, human disease, and human cell biology. Now, medical scientists and cell biologists are turning their attention to illustrating gene expression pattern using gene microarray and to identifying the functions and the expression patterns of proteins encoded by the genes. Hepatic stellate cell is one of the sinusoid-constituent cells that play multiple roles in the liver pathophysiology. Transformation of stellate cells from the vitamin A-storing phenotype to the quot;myofibroblasticquot; one closely correlates to hepatic fibrosis during chronic liver trauma. Analyses of the molecular mechanisms of stellate cell activation have made a great progress, in particular, in the field of intracellular signal transduction of transforming growth factor-beta and platelet-derived growth factor, integrin signaling related to cell-adhesion, and cell motility-associated Rho and focal-adhesion kinase. Accumulation of the information on the stellate cell activation would shed light on the establishment of a novel therapeutic strategy against fibrosis of human liver disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1181,I1181)","v":11950566},{"$f":"(LEN($J1181) - LEN(SUBSTITUTE(LOWER($J1181),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1181) - LEN(SUBSTITUTE(LOWER($J1181),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1181) - LEN(SUBSTITUTE(LOWER($J1181),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1181:D1181)","v":0},2002,"Improving iron, zinc and vitamin A nutrition through plant biotechnology.","Zimmermann",11950566,"Improving iron, zinc and vitamin A nutrition through plant biotechnology.    Abstract:   Recent understanding of plant metabolism has made it possible to increase the iron, zinc and beta-carotene (provitamin A) content in staple foods by both conventional plant breeding and genetic engineering. Improving the micronutrient composition of plant foods may become a sustainable strategy to combat deficiencies in human populations, replacing or complementing other strategies such as food fortification or nutrient supplementation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1182,I1182)","v":11942046},{"$f":"(LEN($J1182) - LEN(SUBSTITUTE(LOWER($J1182),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1182) - LEN(SUBSTITUTE(LOWER($J1182),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1182) - LEN(SUBSTITUTE(LOWER($J1182),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1182:D1182)","v":0},2002,"Prevention of liver cancer: current strategies and future perspectives.","Moriwaki",11942046,"Prevention of liver cancer: current strategies and future perspectives.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1183,I1183)","v":11925487},{"$f":"(LEN($J1183) - LEN(SUBSTITUTE(LOWER($J1183),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1183) - LEN(SUBSTITUTE(LOWER($J1183),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1183) - LEN(SUBSTITUTE(LOWER($J1183),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1183:D1183)","v":0},2002,"Iron supplements: scientific issues concerning efficacy and implications for research and programs.","Allen",11925487,"Iron supplements: scientific issues concerning efficacy and implications for research and programs.    Abstract:   Iron supplementation remains an important strategy for the prevention and treatment of iron deficiency anemia and can produce substantial improvements in the functional performance of iron deficient individuals and populations. Many potential benefits of iron supplementation require further exploration, including its effect on vitamin A and iodine metabolism. There is strong evidence that vitamin A and riboflavin deficiencies affect iron utilization from supplements and are important on a global scale, but little evidence that folate and vitamin B-12 deficiencies play a major causal role in the global burden of anemia. The efficacy of multiple micronutrient supplements for the prevention and treatment of anemia must be further evaluated. Because weekly supplementation with iron is effective at improving iron status, this option should be thoroughly explored and evaluated in the context of programs for the prevention and the treatment of iron deficiency and anemia. More conformation is warranted concerning the number of tablets that must be consumed in different situations, and the efficacy of supplying other micronutrients weekly with iron. Weekly supplementation programs may improve the logistical and economic constraints that currently limit the provision of supplements to the many target population groups for whom they are recommended, but usually fail to reach. Further work is required to clarify the purpose, delivery and outcomes of iron supplementation programs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1184,I1184)","v":11907135},{"$f":"(LEN($J1184) - LEN(SUBSTITUTE(LOWER($J1184),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1184) - LEN(SUBSTITUTE(LOWER($J1184),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1184) - LEN(SUBSTITUTE(LOWER($J1184),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1184:D1184)","v":0},2002,"Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP.","Davis",11907135,"Regulation of cholesterol-7alpha-hydroxylase: BAREly missing a SHP.    Abstract:   Cholesterol-7alpha-hydroxylase (CYP7A1) regulates the pathway through which cholesterol is converted into bile acids. The unique detergent properties of bile acids are essential for the digestion and intestinal absorption of hydrophobic nutrients. Bile acids have potent toxic properties (e.g., membrane disruption) and there are a plethora of mechanisms to limit their accumulation in blood and tissues. The discovery of farnesoid X receptor (FXR), the nuclear receptor activated specifically by bile acids, has opened new insights into these mechanisms. Bile acid activation of FXR has been shown to repress the expression of CYP7A1 via increasing the expression of small heterodimer partner (SHP), a non-DNA binding protein. The increased abundance of SHP causes it to associate with liver receptor homolog (LRH)-1, an obligate factor required for transcription of CYP7A1. Recent studies show there is an quot;FXR/SHP-independentquot; mechanism that also represses CYP7A1 expression. This quot;FXR/SHP-independentquot; pathway involves the interaction of bile acids with liver macrophages (i.e., Kupffer cells), which induces the expression, and secretion of cytokines. These inflammatory cytokines, which include tumor necrosis factor alpha and interleukin-1beta, act upon liver parenchymal cells causing a rapid repression of the CYP7A1 gene."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1185,I1185)","v":11897564},{"$f":"(LEN($J1185) - LEN(SUBSTITUTE(LOWER($J1185),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1185) - LEN(SUBSTITUTE(LOWER($J1185),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1185) - LEN(SUBSTITUTE(LOWER($J1185),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1185:D1185)","v":0},2002,"Activation of hepatic stellate cells--a key issue in liver fibrosis.","Reeves",11897564,"Activation of hepatic stellate cells--a key issue in liver fibrosis.    Abstract:   Hepatic fibrosis describes the presence of excess collagen due to new fiber formation, laid down as part of the tissue repair response to chronic liver injury. The causes of injury include toxins, disorders of the immune system, viral and parasitic infections, as well as rarer liver diseases such as haemochromatosis, Wilsons disease and galactosaemia. Whatever the cause of injury, the cells and soluble factors contributing to this wound healing response are similar. The principal effector of hepatic fibrogenesis is now widely recognized as the hepatic stellate cell. Stellate cells are usually quiescent cells, but in response to liver injury they undergo an activation process in which they become highly proliferative and synthesize a fibrotic matrix rich in type I collagen. Initiation of stellate cell activation is largely due to paracrine stimulation, whereas perpetuation of activation involves autocrine as well as paracrine loops, and is dependent on a number of functional changes. The principal paracrine and autocrine factors currently thought to be involved in these processes are discussed in this review, as are the roles of the extracellular matrix, the nuclear receptor superfamily, non-peptide ligands, and oxidative stress."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1186,I1186)","v":11868781},{"$f":"(LEN($J1186) - LEN(SUBSTITUTE(LOWER($J1186),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1186) - LEN(SUBSTITUTE(LOWER($J1186),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1186) - LEN(SUBSTITUTE(LOWER($J1186),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1186:D1186)","v":0},2002,"Current strategies for chemoprevention of hepatocellular carcinoma.","Okita",11868781,"Current strategies for chemoprevention of hepatocellular carcinoma.    Abstract:   Hepatocellular carcinoma (HCC) develops frequently in the liver of patients with chronic hepatitis and cirrhosis caused by persistent infection with hepatitis B virus or hepatitis C virus in Asia. Several studies including ours have revealed that the risk of HCC increases in parallel with the progression of hepatic fibrosis associated with chronic hepatitis and liver cirrhosis. It may be delineated reasonably, therefore, that suppression of fibrosis by chemical (or biological) agents would be able to decrease the risk of HCC. We have demonstrated that antifibrotic agents, such as HOE 077, TJ-9 and interferon, can reduce the risk of HCC. Accordingly, antifibrotic agents are promising candidates for chemoprevention of HCC. The results of our study are discussed within the scope of the current state of the art as regards chemopreventing HCC."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1187,I1187)","v":11857932},{"$f":"(LEN($J1187) - LEN(SUBSTITUTE(LOWER($J1187),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1187) - LEN(SUBSTITUTE(LOWER($J1187),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1187) - LEN(SUBSTITUTE(LOWER($J1187),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1187:D1187)","v":0},2002,"[DAX-1 abnormality].","Kinoshita",11857932,"[DAX-1 abnormality].    Abstract:   DAX-1 is an orphan nuclear receptor that plays a key role in the development and function of the adrenal gland and hypothalamic-pituitary-gonadal axis. Absence of DAX-1 results in X-linked adrenal hypoplasia congenita, a human inherited disorder characterized by adrenal insufficiency and hypogonadotropic hypogonadism. The DAX-1 gene may be responsible for a male-to-female sex reversal syndrome, referred to as dosage sensitive sex reversal(DSS), due to the duplication of a small region of human chromosome Xp21. Dax-1 and Sry have been shown to act antagonistically in the mouse system, where over-expression of Dax-1 leads to female development and increasing activity of Sry to male development. Although these data strongly implicate Dax-1 in sex determination, there is no evidence that DAX-1 is equivalent to DSS in human."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1188,I1188)","v":11813818},{"$f":"(LEN($J1188) - LEN(SUBSTITUTE(LOWER($J1188),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1188) - LEN(SUBSTITUTE(LOWER($J1188),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1188) - LEN(SUBSTITUTE(LOWER($J1188),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1188:D1188)","v":0},2002,"CT of emphysema.","Newell",11813818,"CT of emphysema.    Abstract:   This article focuses on three main topics: (1) the importance of emphysema as a serious respiratory disease, (2) qualitative assessment of emphysema using CT, and (3) the emerging importance of quantitative CT in the evaluation of patients with emphysema for surgery and drug therapy. CT also can identify the major anatomic subtypes of emphysema. CT is critical in the assessment of patients with the potential for lung volume reduction surgery. CT may well be superior to pulmonary function tests in the longitudinal assessment of current and proposed drug therapies for the treatment of emphysema."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1189,I1189)","v":11761989},{"$f":"(LEN($J1189) - LEN(SUBSTITUTE(LOWER($J1189),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1189) - LEN(SUBSTITUTE(LOWER($J1189),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1189) - LEN(SUBSTITUTE(LOWER($J1189),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1189:D1189)","v":0},2001,"[Hepatitis C virus-related hepatocellular carcinoma].","Sumi",11761989,"[Hepatitis C virus-related hepatocellular carcinoma].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1190,I1190)","v":11755917},{"$f":"(LEN($J1190) - LEN(SUBSTITUTE(LOWER($J1190),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1190) - LEN(SUBSTITUTE(LOWER($J1190),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1190) - LEN(SUBSTITUTE(LOWER($J1190),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1190:D1190)","v":0},2002,"Is there a genetic basis for resistance to atherosclerosis?","Stein",11755917,"Is there a genetic basis for resistance to atherosclerosis?    Abstract:   Atherosclerosis and its major clinical manifestation, coronary heart disease, is and will remain the main cause of mortality. Reviews on this subject dealt with factors that enhance development of atherosclerosis. This review deals with a new facet, that some individuals are less prone to develop atherosclerosis: (1) despite high cholesterol intake or (2) despite hypercholesterolemia with elevated low-density lipoprotein cholesterol (LDL-C) levels. The variability of response of plasma cholesterol to dietary intake was shown to be regulated by liver x receptor (LXR) that determines the rate of intestinal cholesterol absorption through the ATP-binding cassette (ABC) gene family. Other gene products, such as apolipoprotein-E (apo-E), scavenger receptor-B1 (SR-B1) and acyl coenzyme: cholesterol acyltransferase-2 (ACAT-2) affect cholesterol absorption also. The role of a genetic background for relative resistance to atherosclerosis is highlighted by subjects with familial hypercholesterolemia in whom high plasma cholesterol levels has not curtailed their expected life span. Studies in animals have shown that resistance to atherosclerosis in spite of hypercholesterolemia is affected by factors such as high-density lipoprotein (HDL) phospholipids that enhance reverse cholesterol transport, non-responsiveness to induction or lack of monocyte chemotactic protein-1 (MCP-1), C-C chemokine receptor 2 (CCR2), macrophage colony stimulating factor (MCSF), or vascular cell adhesion molecule-1 (VCAM-1). Since macrophages have been regarded as pro- or anti-atherogenic, evidence was collated that the high activity of scavenger receptors may contribute towards resistance to atherosclerosis if accompanied by adequate amounts of apo-E for cholesterol removal."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1191,I1191)","v":11729302},{"$f":"(LEN($J1191) - LEN(SUBSTITUTE(LOWER($J1191),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1191) - LEN(SUBSTITUTE(LOWER($J1191),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1191) - LEN(SUBSTITUTE(LOWER($J1191),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1191:D1191)","v":0},2001,"Nuclear receptors and lipid physiology: opening the X-files.","Chawla",11729302,"Nuclear receptors and lipid physiology: opening the X-files.    Abstract:   Cholesterol, fatty acids, fat-soluble vitamins, and other lipids present in our diets are not only nutritionally important but serve as precursors for ligands that bind to receptors in the nucleus. To become biologically active, these lipids must first be absorbed by the intestine and transformed by metabolic enzymes before they are delivered to their sites of action in the body. Ultimately, the lipids must be eliminated to maintain a normal physiological state. The need to coordinate this entire lipid-based metabolic signaling cascade raises important questions regarding the mechanisms that govern these pathways. Specifically, what is the nature of communication between these bioactive lipids and their receptors, binding proteins, transporters, and metabolizing enzymes that links them physiologically and speaks to a higher level of metabolic control? Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1192,I1192)","v":11718960},{"$f":"(LEN($J1192) - LEN(SUBSTITUTE(LOWER($J1192),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1192) - LEN(SUBSTITUTE(LOWER($J1192),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1192) - LEN(SUBSTITUTE(LOWER($J1192),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1192:D1192)","v":0},2001,"Concurrent inflammation as a determinant of susceptibility to toxicity from xenobiotic agents.","Ganey",11718960,"Concurrent inflammation as a determinant of susceptibility to toxicity from xenobiotic agents.    Abstract:   Sensitivity to the toxic effects of xenobiotic agents is influenced by a number of factors. Recent evidence derived from studies using experimental animals suggests that inflammation is one of these factors. For example, induction of inflammation by coexposure to bacterial endotoxin, vitamin A or Corynebacterium parvum increases injury in response to a number of xenobiotic agents that target liver. These agents are diverse in chemical nature and in mechanism of hepatotoxic action. Factors critical to the augmentation of liver injury by inflammation include Kupffer cells, neutrophils, cytokines such as tumor necrosis factor-alpha (TNF-alpha) and lipid mediators such as prostaglandins, but these may vary depending on the xenobiotic agent and the mechanisms by which it alters hepatocellular homeostasis. In addition, the timing of inflammagen exposure can qualitatively alter the toxic response to chemicals. Inflammation-induced increases in susceptibility to toxicity are not limited to liver. Concurrent inflammation also sensitizes animals to the toxic effects of agents that damage the respiratory tract, kidney and lymphoid tissue. It is concluded that inflammation should be considered as a determinant of susceptibility to intoxication by xenobiotic exposure."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1193,I1193)","v":11712405},{"$f":"(LEN($J1193) - LEN(SUBSTITUTE(LOWER($J1193),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1193) - LEN(SUBSTITUTE(LOWER($J1193),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1193) - LEN(SUBSTITUTE(LOWER($J1193),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1193:D1193)","v":0},2001,"[A trend of insulin sensitizer which is under development].","Kadowaki",11712405,"[A trend of insulin sensitizer which is under development].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1194,I1194)","v":11569705},{"$f":"(LEN($J1194) - LEN(SUBSTITUTE(LOWER($J1194),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1194) - LEN(SUBSTITUTE(LOWER($J1194),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1194) - LEN(SUBSTITUTE(LOWER($J1194),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1194:D1194)","v":0},2001,"Fat-soluble vitamin levels in patients with primary biliary cirrhosis.","Phillips",11569705,"Fat-soluble vitamin levels in patients with primary biliary cirrhosis.    Abstract:    OBJECTIVE : To determine the occurrence of fat-soluble vitamin deficiencies and to identify clinical factors that may predict vitamin deficiency in patients with primary biliary cirrhosis (PBC).  METHODS : Review of our data from a randomized, placebo-controlled trial that evaluated the efficacy of UDCA in 180 patients with PBC. We use the first available measurements of vitamin levels in each study participant. Vitamin levels for A, D, and E were measured in serum. The prothrombin time (PT) was used as a surrogate marker for vitamin K.  RESULTS : The proportion of patients with fat-soluble vitamin deficiencies in the treatment and placebo groups was similar and the data sets were combined. The proportion with vitamin A, D, E or K deficiency was 33.5%, 13.2%, 1.9%, and 7.8%, respectively. In multivariate analysis, the Mayo risk score, advanced histological stage, and total cholesterol were independently associated with vitamin A deficiency whereas serum albumin levels was independently associated with vitamin D deficiency. No factors were associated with vitamin E or K deficiency in multivariate analysis owing to the few vitamin E and K deficient patients. Factors predictive of vitamin K deficiency by univariate analysis included Mayo risk score, advanced histological stage, HDL, total bilirubin, AST, and albumin. The cut-off value of the Mayo risk score with the highest sensitivity and specificity for vitamin A deficiency was 5.0.  CONCLUSION : Other than deficiency of vitamin A, deficiency of fat-soluble vitamins occurs uncommonly in patients with PBC. A Mayo risk score gt; or = 5 helps in selecting patients with PBC for surveillance for vitamin A deficiency."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1195,I1195)","v":11509093},{"$f":"(LEN($J1195) - LEN(SUBSTITUTE(LOWER($J1195),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1195) - LEN(SUBSTITUTE(LOWER($J1195),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1195) - LEN(SUBSTITUTE(LOWER($J1195),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1195:D1195)","v":0},2001,"Immunobiology of mild micronutrient deficiencies.","Bhaskaram",11509093,"Immunobiology of mild micronutrient deficiencies.    Abstract:   Nutrition is a critical determinant of the outcome of host microbe interactions through a modulation of the immune response. Besides macronutrient malnutrition, deficiencies of several macronutrients also influence immune homeostasis and thus affect infection-related morbidity and mortality. Deficiencies of micronutrients like vitamin A, iron and zinc are widely prevalent among populations living in developing countries. Besides their severe deficiencies, subclinical deficiencies are known to impair biological functions in the host, immune function being one of them. The effects of these micronutrients on various immune mechanisms are briefly reviewed in this article."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1196,I1196)","v":11466240},{"$f":"(LEN($J1196) - LEN(SUBSTITUTE(LOWER($J1196),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1196) - LEN(SUBSTITUTE(LOWER($J1196),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1196) - LEN(SUBSTITUTE(LOWER($J1196),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1196:D1196)","v":0},2001,"Blindness in Africa: present situation and future needs.","Lewallen",11466240,"Blindness in Africa: present situation and future needs.    Abstract:    AIM : To review the prevalence and causes of blindness in sub-Saharan Africa, the existing services and limitations, and the Vision 2020 goals for the future.  METHODS : Methodologically sound population based surveys published in the past 20 years are reviewed and results for prevalence and causes of blindness are tabulated. The current resources and needs according to recent publications and international working groups are described.  CONCLUSIONS : Blindness prevalence rates vary widely but the evidence suggests that approximately 1% of Africans are blind. The major cause is cataract; trachoma and glaucoma are also important causes of blindness. The bulk of blindness in the region is preventable or curable. Efforts should focus on eye problems which are universally present and for which there are cost effective remedies, such as cataract and refractive problems and on those problems which occur focally and can be prevented by primary healthcare measures, such as trachoma, onchocerciasis, and vitamin A deficiency. Major development of staffing levels, infrastructure, and community programmes will be necessary to achieve Vision 2020 goals."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1197,I1197)","v":11459853},{"$f":"(LEN($J1197) - LEN(SUBSTITUTE(LOWER($J1197),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1197) - LEN(SUBSTITUTE(LOWER($J1197),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1197) - LEN(SUBSTITUTE(LOWER($J1197),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1197:D1197)","v":0},2001,"Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism.","Lu",11459853,"Orphan nuclear receptors as eLiXiRs and FiXeRs of sterol metabolism.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1198,I1198)","v":11411262},{"$f":"(LEN($J1198) - LEN(SUBSTITUTE(LOWER($J1198),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1198) - LEN(SUBSTITUTE(LOWER($J1198),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1198) - LEN(SUBSTITUTE(LOWER($J1198),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1198:D1198)","v":0},2000,"Micronutrient deficiency conditions in the Middle East region: an overview.","Galal",11411262,"Micronutrient deficiency conditions in the Middle East region: an overview.    Abstract:   The Middle East is perhaps the worlds best laboratory for learning more about iron and zinc deficiencies, and their widespread prevalence contributes much to constraining the quality of life for a large share of the population. Always, in the context of endemic IDD, countries in the region need to make sure that the programs are in place to consign this still-serious problem to the history books. Research is not required so much in relation to IDD, but clearly applications need to be monitored. Vitamin A deficiency is probably widespread at mild to moderate levels, and should be addressed by a combination of appropriate case management for infectious disease, breastfeeding promotion, and dietary diversification/nutrition education. Iron deficiency is the most prevalent, and so far the most intractable, micronutrient problem. It probably will not yield to less than a multipronged strategy including fortification of the food supply with iron. Several other micronutrient deficiencies require our eventual attention as well, and looking forward to their solution should be part of the research agenda."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1199,I1199)","v":11391922},{"$f":"(LEN($J1199) - LEN(SUBSTITUTE(LOWER($J1199),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1199) - LEN(SUBSTITUTE(LOWER($J1199),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1199) - LEN(SUBSTITUTE(LOWER($J1199),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1199:D1199)","v":0},2001,"[Liver fibrosis--the forefront of the study on stellate cells].","Kawada",11391922,"[Liver fibrosis--the forefront of the study on stellate cells].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1200,I1200)","v":11391063},{"$f":"(LEN($J1200) - LEN(SUBSTITUTE(LOWER($J1200),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1200) - LEN(SUBSTITUTE(LOWER($J1200),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1200) - LEN(SUBSTITUTE(LOWER($J1200),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1200:D1200)","v":0},2001,"Alcohol and cancer.","Seitz",11391063,"Alcohol and cancer.    Abstract:   This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Helmut K. Seitz and Shohei Matsuzaki. The presentations were (1) Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotype and cancer risk for upper aerodigestive tract in Japanese alcoholics, by Akira Yokoyama; (2) The role of acetaldehyde in alcohol-associated carcinogenesis, by Nils Homann; (3) High salivary acetaldehyde levels after a moderate dose of alcohol in ALDH2-deficient subjects, by Satu Väkeväinen; (4) Alcohol and vitamin A interactions, by Xian Dong Wang; and (5) Alcohol and colorectal cancer, by Helmut K. Seitz."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1201,I1201)","v":11389365},{"$f":"(LEN($J1201) - LEN(SUBSTITUTE(LOWER($J1201),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1201) - LEN(SUBSTITUTE(LOWER($J1201),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1201) - LEN(SUBSTITUTE(LOWER($J1201),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1201:D1201)","v":0},2001,"Updates in pediatric nutrition.","Oken",11389365,"Updates in pediatric nutrition.    Abstract:   Ongoing research in several areas of pediatric nutrition has new practical applications for community-based pediatricians. For example, a fresh understanding of risk factors for rickets persuades pediatricians to recognize and treat this disease, which was thought to be nearly extinct in the modern industrialized world. Similarly, an expanded awareness of the antibacterial components of breast milk encourages a more complete dialogue between pediatricians and new mothers about the potential benefits of breast-feeding. For those infants with feeding intolerance, new data help to refine the indications for hypoallergenic formulas, which are increasingly recommended for children with a variety of symptoms. The past year also has seen breakthroughs in our understanding of supplemental nutrition for children. Vitamin A may provide direct benefits for the most vulnerable of children, namely premature infants at high risk for lung disease. At the other end of the pediatric spectrum, adolescent athletes seeking to enhance their performance are consuming poorly studied sports supplements that may not be beneficial and may even be toxic. Finally, a greater appreciation for the epidemic of obesity that is sweeping the United States and other countries suggests that children at high risk may represent a far more diverse population than had been recognized previously."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1202,I1202)","v":11352180},{"$f":"(LEN($J1202) - LEN(SUBSTITUTE(LOWER($J1202),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1202) - LEN(SUBSTITUTE(LOWER($J1202),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1202) - LEN(SUBSTITUTE(LOWER($J1202),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1202:D1202)","v":0},2001,"Pathogenesis of anemia during human immunodeficiency virus infection.","Semba",11352180,"Pathogenesis of anemia during human immunodeficiency virus infection.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1203,I1203)","v":11347073},{"$f":"(LEN($J1203) - LEN(SUBSTITUTE(LOWER($J1203),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1203) - LEN(SUBSTITUTE(LOWER($J1203),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1203) - LEN(SUBSTITUTE(LOWER($J1203),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1203:D1203)","v":0},2001,"[Andersons disease/chylomicron retention disease].","Ohashi",11347073,"[Andersons disease/chylomicron retention disease].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1204,I1204)","v":11302779},{"$f":"(LEN($J1204) - LEN(SUBSTITUTE(LOWER($J1204),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1204) - LEN(SUBSTITUTE(LOWER($J1204),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1204) - LEN(SUBSTITUTE(LOWER($J1204),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1204:D1204)","v":0},2001,"Natural therapies for ocular disorders, part two: cataracts and glaucoma.","Head",11302779,"Natural therapies for ocular disorders, part two: cataracts and glaucoma.    Abstract:   Pathophysiological mechanisms of cataract formation include deficient glutathione levels contributing to a faulty antioxidant defense system within the lens of the eye. Nutrients to increase glutathione levels and activity include lipoic acid, vitamins E and C, and selenium. Cataract patients also tend to be deficient in vitamin A and the carotenes, lutein and zeaxanthin. The B vitamin riboflavin appears to play an essential role as a precursor to flavin adenine dinucleotide (FAD), a co-factor for glutathione reductase activity. Other nutrients and botanicals, which may benefit cataract patients or help prevent cataracts, include pantethine, folic acid, melatonin, and bilberry. Diabetic cataracts are caused by an elevation of polyols within the lens of the eye catalyzed by the enzyme aldose reductase. Flavonoids, particularly quercetin and its derivatives, are potent inhibitors of aldose reductase. Glaucoma is characterized by increased intraocular pressure (IOP) in some but not all cases. Some patients with glaucoma have normal IOP but poor circulation, resulting in damage to the optic nerve. Faulty glycosaminoglycan (GAG) synthesis or breakdown in the trabecular meshwork associated with aqueous outflow has also been implicated. Similar to patients with cataracts, those with glaucoma typically have compromised antioxidant defense systems as well. Nutrients that can impact GAGs such as vitamin C and glucosamine sulfate may hold promise for glaucoma treatment. Vitamin C in high doses has been found to lower IOP via its osmotic effect. Other nutrients holding some potential benefit for glaucoma include lipoic acid, vitamin B12, magnesium, and melatonin. Botanicals may offer some therapeutic potential. Ginkgo biloba increases circulation to the optic nerve; forskolin (an extract from Coleus forskohlii) has been used successfully as a topical agent to lower IOP; and intramuscular injections of Salvia miltiorrhiza have shown benefit in improving visual acuity and peripheral vision in people with glaucoma."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1205,I1205)","v":11291787},{"$f":"(LEN($J1205) - LEN(SUBSTITUTE(LOWER($J1205),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1205) - LEN(SUBSTITUTE(LOWER($J1205),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1205) - LEN(SUBSTITUTE(LOWER($J1205),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1205:D1205)","v":0},2000,"Micronutrient malnutrition--present status and future remedies.","Chakravarty",11291787,"Micronutrient malnutrition--present status and future remedies.    Abstract:   Micronutrient deficiency is a serious public health concern in most of the developing countries which leads to malnutrition syndromes. The micronutient deficiencies which are of greatest public health significance include iron deficiency, vitamin A deficiency and iodine deficiency disorder. National Pilot Programme on Control of Micronutrient Malnutrition was launched in 1995 and the department of biochemistry and nutrition of the All India Institute of Hygiene and Public Health, Calcutta was entrusted to co-ordinate the activities. It presently covers five eastern and north-eastern states. Baseline situation analysis was conducted mainly on iron deficiency anaemia, iodine deficiency disorder and vitamin A deficiency. Comparing with WHO cut off figures, point prevalence of anaemia in various age groups was found to be high. Bitots spot was mainly noted in the age group of 6-71 months. Nightblindness was found in the children of the age group of 24-71 months. High prevalence of nightblindness in pregnant women is a point of concern. Action needed to control micronutrient deficiency includes: Intervention strategies, extensive nutrition and health education, to support the problem specific programmes, to stregthen various state government programmes and strengthen role of NGOs."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1206,I1206)","v":11268819},{"$f":"(LEN($J1206) - LEN(SUBSTITUTE(LOWER($J1206),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1206) - LEN(SUBSTITUTE(LOWER($J1206),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1206) - LEN(SUBSTITUTE(LOWER($J1206),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1206:D1206)","v":0},2001,"Liver diseases by alcohol and hepatitis C: early detection and new insights in pathogenesis lead to improved treatment.","Lieber",11268819,"Liver diseases by alcohol and hepatitis C: early detection and new insights in pathogenesis lead to improved treatment.    Abstract:   Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of treatment. Therapy must include correction of nutritional deficiencies, while taking into account changes of nutritional requirements. Methionine is normally activated to S-adenosylmethionine (SAMe). However, in liver disease, the corresponding enzyme is depressed. The resulting deficiencies can be attenuated by the administration of SAMe but not by methionine. Similarly, phosphatidylethanolamine methyltransferase activity is depressed, but the lacking phosphatidylcholine (PC) can be administrated as polyenylphosphatidylcholine (PPC). Chronic ethanol consumption increases CYP2E1, resulting in increased generation of toxic acetaldehyde and free radicals, tolerance to ethanol and other drugs, and multiple ethanol-drug interactions. Experimentally, PPC opposes CYP2E1 induction and fibrosis. Alcoholism and hepatitis C infection commonly co-exist, with acceleration of fibrosis, cirrhosis, and hepatocellular carcinoma. PPC is being tested clinically as a corresponding antifibrotic agent. Available antiviral agents are contraindicated in the alcoholic. Anti-inflammatory agents, such as steroids, may be selectively useful. Finally, anticraving agents, such as naltrexone or acamprosate, should be part of therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1207,I1207)","v":11243083},{"$f":"(LEN($J1207) - LEN(SUBSTITUTE(LOWER($J1207),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1207) - LEN(SUBSTITUTE(LOWER($J1207),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1207) - LEN(SUBSTITUTE(LOWER($J1207),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1207:D1207)","v":0},1999,"Integrated Child Development Services scheme (ICDS) and its impact on nutritional status of children in India and recent initiatives.","Kapil",11243083,"Integrated Child Development Services scheme (ICDS) and its impact on nutritional status of children in India and recent initiatives.    Abstract:   Integrated Child Development Services (ICDS) scheme is the largest national programme for the promotion of the mother and child health and their development in the world. The beneficiaries include children below 6 years, pregnant and lactating mothers, and other women in the age group of 15 to 44 years. The package of services provided by the ICDS scheme includes supplementary nutrition, immunization, health check-up, referral services, nutrition and health education, and pre-school education. The distribution of iron and folic acid tablets and megadose of vitamin A is also undertaken, to prevent iron deficiency anaemia and xerophthalmia respectively. The scheme services are rendered essentially through the Anganwadi worker (AWW) at a village centre called quot;Anganwadiquot;. The ICDS had led to (i) reduction in prevalence of severe grades of malnutrition and (ii) better utilization of services of national nutritional anaemia prophylaxis programme and the national programme for prevention of nutritional blindness due to vitamin A deficiency by ICDS beneficiaries. The ICDS scheme is being modified continuously to strengthen the programme. This article presents the impact of Integrated Child Development Services (ICDS) on the nutritional status of mothers and of children under 6 years old in India. ICDS is the first and probably the only program in the country that aims at the holistic development of an individual. The reduction in prevalence of severe malnutrition is comparatively more significant in ICDS scheme population than in other population groups. There has been an extensive improvement in the nutritional status of children living in rural, urban and tribal areas and in those belonging to depressed sections of the community. The new initiative schemes for supplementary nutrition include: (a) improved monitoring mechanisms, (b) increased and improved norms of nutrition, (c) improved acceptability of supplementary recipes, (d) care of the severely malnourished, (e) the formation of a state level committee of experts, (f) inspection of quality, and (g) the introduction of community growth charts for malnourished children. The distribution of iron and folic tablets together with megadoses of vitamin A has also been undertaken for iron deficiency anemia and xerophthalmia prevention. Professionals, administrators, and politicians should feel obliged to continue making their contributions to the effective implementation of ICDS."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1208,I1208)","v":11111081},{"$f":"(LEN($J1208) - LEN(SUBSTITUTE(LOWER($J1208),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1208) - LEN(SUBSTITUTE(LOWER($J1208),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1208) - LEN(SUBSTITUTE(LOWER($J1208),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1208:D1208)","v":0},2000,"Sterols and gene expression: control of affluence.","Schoonjans",11111081,"Sterols and gene expression: control of affluence.    Abstract:   Intracellular and extracellular cholesterol levels are tightly maintained within a narrow concentration range by an intricate transcriptional control mechanism. Excess cholesterol can be converted into oxysterols, signaling molecules, which modulate the activity of a number of transcription factors, as to limit accumulation of excess of cholesterol. Two key regulatory pathways are affected by oxysterols. The first pathway involves the uptake and de novo synthesis of cholesterol and is controlled by the family of sterol response element binding proteins, whose activity is regulated by a sterol-dependent feedback mechanism. The second pathway, which only recently has become a topic of interest, involves the activation by a feedforward mechanism of cholesterol utilization for either bile acid or steroid hormone synthesis by oxysterol-activated nuclear receptors, such as liver X receptor and steroidogenic factor-1. Furthermore, biosynthesis and enterohepatic reabsorption of bile acids are regulated by the farnesol X receptor, a receptor activated by bile acids. Both the feedback inhibition of cholesterol uptake and production and the stimulation of cholesterol utilization will ultimately result in a lowering of the intracellular cholesterol concentration and allow for a fine-tuned regulation of the cholesterol concentration."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1209,I1209)","v":11058998},{"$f":"(LEN($J1209) - LEN(SUBSTITUTE(LOWER($J1209),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1209) - LEN(SUBSTITUTE(LOWER($J1209),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1209) - LEN(SUBSTITUTE(LOWER($J1209),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1209:D1209)","v":0},2000,"[Heterodimeric nuclear receptors. II. Fatty acid and steroid metabolism regulation].","Kwiatkowska-Korczak",11058998,"[Heterodimeric nuclear receptors. II. Fatty acid and steroid metabolism regulation].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1210,I1210)","v":11029010},{"$f":"(LEN($J1210) - LEN(SUBSTITUTE(LOWER($J1210),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1210) - LEN(SUBSTITUTE(LOWER($J1210),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1210) - LEN(SUBSTITUTE(LOWER($J1210),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1210:D1210)","v":0},2000,"Effect of tea and other dietary factors on iron absorption.","Zijp",11029010,"Effect of tea and other dietary factors on iron absorption.    Abstract:   Iron deficiency is a major world health problem, that is, to a great extent, caused by poor iron absorption from the diet. Several dietary factors can influence this absorption. Absorption enhancing factors are ascorbic acid and meat, fish and poultry; inhibiting factors are plant components in vegetables, tea and coffee (e.g., polyphenols, phytates), and calcium. After identifying these factors their individual impact on iron absorption is described. Specific attention was paid to the effects of tea on iron absorption. We propose a calculation model that predicts iron absorption from a meal. Using this model we calculated the iron absorption from daily menus with varying amounts of enhancers and inhibitors. From these calculations we conclude that the presence of sufficient amounts of iron absorption enhancers (ascorbic acid, meat, fish, poultry, as present in most industrialized countries) overcomes inhibition of iron absorption from even large amounts of tea. In individuals with low intakes of heme iron, low intakes of enhancing factors and/or high intakes of inhibitors, iron absorption may be an issue. Depletion of iron stores enhances iron absorption, but this effect is not adequate to compensate for the inhibition of iron absorption in such an inadequate dietary situation. For subjects at risk of iron deficiency, the following recommendations are made. Increase heme-iron intake (this form of dietary iron present in meat fish and poultry is hardly influenced by other dietary factors with respect to its absorption); increase meal-time ascorbic acid intake; fortify foods with iron. Recommendations with respect to tea consumption (when in a critical group) include: consume tea between meals instead of during the meal; simultaneously consume ascorbic acid and/or meat, fish and poultry."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1211,I1211)","v":10948381},{"$f":"(LEN($J1211) - LEN(SUBSTITUTE(LOWER($J1211),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1211) - LEN(SUBSTITUTE(LOWER($J1211),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1211) - LEN(SUBSTITUTE(LOWER($J1211),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1211:D1211)","v":0},2000,"The role of vitamins in the prevention and control of anaemia.","Fishman",10948381,"The role of vitamins in the prevention and control of anaemia.    Abstract:    OBJECTIVE : While iron deficiency is regarded as the major cause of nutritional anaemia, changes in vitamins A, B12, C and E, folic acid and riboflavin status have also been linked to its development and control. This paper provides a systematic review of vitamin supplementation trials relating to the control of nutritional anaemia.  METHODS : A MEDLINE search was used to find reports of vitamin supplementation trials that reported changes in anaemia or iron status.  RESULTS : Vitamin A can improve haematological indicators and enhance the efficacy of iron supplementation. Both folate and vitamin B12 can cure and prevent megaloblastic anaemia. Riboflavin enhances the haematological response to iron, and its deficiency may account for a significant proportion of anaemia in many populations. Vitamin C enhances the absorption of dietary iron, although population-based data showing its efficacy in reducing anaemia or iron deficiency are lacking. Vitamin E supplementation given to preterm infants has not reduced the severity of the anaemia of prematurity. Vitamin B6 effectively treats sideroblastic anaemia. Multivitamin supplementation may raise haemoglobin (Hb) concentration, but few studies have isolated the effect of multivitamins from iron on haematological status.  CONCLUSIONS : In general, the public health impact of vitamin supplementation in controlling anaemia is not clear. Neither are the complex interactions involving multiple vitamins in haematopoiesis sufficiently understood to explain the observed variability in haematological responses to vitamins by age, population, vitamin mixture and dosages. Further research is needed to understand the roles of individual and combined vitamin deficiencies on anaemia to design appropriate micronutrient interventions to prevent anaemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1212,I1212)","v":10803632},{"$f":"(LEN($J1212) - LEN(SUBSTITUTE(LOWER($J1212),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1212) - LEN(SUBSTITUTE(LOWER($J1212),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1212) - LEN(SUBSTITUTE(LOWER($J1212),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1212:D1212)","v":0},2000,"Hepatic fibrogenesis and hepatitis C.","Rockey",10803632,"Hepatic fibrogenesis and hepatitis C.    Abstract:   Hepatitis C virus (HCV) infection is currently the most common cause of fibrosing liver disease and represents a major clinical challenge. In patients with HCV infection, inflammation and injury lead to fibrosis and cirrhosis in a significant proportion of patients; cirrhosis in turn has multiple clinical sequelae. Therefore, understanding the pathological basis of fibrogenesis in hepatitis C infection is critical. This review will highlight fundamental issues underlying the fibrogenic response to injury and in addition will focus on potential points of intervention."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1213,I1213)","v":10746344},{"$f":"(LEN($J1213) - LEN(SUBSTITUTE(LOWER($J1213),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1213) - LEN(SUBSTITUTE(LOWER($J1213),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1213) - LEN(SUBSTITUTE(LOWER($J1213),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1213:D1213)","v":0},1999,"Anaemia and iron deficiency disease in children.","Olivares",10746344,"Anaemia and iron deficiency disease in children.    Abstract:   Iron deficiency is the single most common nutritional disorder world-wide and the main cause of anaemia in infancy, childhood and pregnancy. It is prevalent in most of the developing world and it is probably the only nutritional deficiency of consideration in industrialised countries. In the developing world the prevalence of iron deficiency is high, and is due mainly to a low intake of bioavailable iron. However, in this setting, iron deficiency often co-exists with other conditions such as, malnutrition, vitamin A deficiency, folate deficiency, and infection. In tropical regions, parasitic infestation and haemoglobinopathies are also a common cause of anaemia. In the developed world iron deficiency is mainly a single nutritional problem. The conditions previously mentioned might contribute to the development of iron deficiency or they present difficulties in the laboratory diagnosis of iron deficiency."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1214,I1214)","v":10685461},{"$f":"(LEN($J1214) - LEN(SUBSTITUTE(LOWER($J1214),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1214) - LEN(SUBSTITUTE(LOWER($J1214),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1214) - LEN(SUBSTITUTE(LOWER($J1214),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1214:D1214)","v":0},2000,"[Olfactory disorders and general pathology. Analysis and review of the literature].","Norès",10685461,"[Olfactory disorders and general pathology. Analysis and review of the literature].    Abstract:    INTRODUCTION : Disturbances of the sense of smell have been documented in many general pathologies. The actual etiology of such impairments is often difficult to determine. The aim of the authors is to review the literature on olfactory disorders in general diseases.  CURRENT KNOWLEDGE AND KEY POINTS : Acute and chronic liver disorders are frequently associated with hyposmia, which can be improved by vitamin A intake. Renal insufficiency could induce hyposmia according to the severity of the renal disease. Olfactory disorders seem to regress after transplantation but not after dialysis. Patients with AIDS--especially neurological forms--often present with taste and smell impairments. Smell alteration can also be noted in hypothyroidism and pseudohypoparathyroidism. In addition, taste and smell impairments have been described in patients with adrenal insufficiency or Cushings disease. Subsequent to glucocorticoid therapy, adrenal insufficiency can induce regressive olfactory hypersensitivity. Olfactory impairments in diabetic patients can be associated with diabetic macrovascular manifestations due to ischemic alterations in the olfactory neuroepithelium. Impairment of the sense of smell has been described in many systemic diseases such as Hortons arteritis and Sjögrens syndrome.  FUTURE PROSPECTS AND PROJECTS : Olfactory disorders should be investigated in patients presenting one of the above-mentioned diseases."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1215,I1215)","v":10586628},{"$f":"(LEN($J1215) - LEN(SUBSTITUTE(LOWER($J1215),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1215) - LEN(SUBSTITUTE(LOWER($J1215),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1215) - LEN(SUBSTITUTE(LOWER($J1215),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1215:D1215)","v":0},1999,"[A case of various neurological deficits caused by multi-vitamin deficiency associated with malabsorption syndrome after pancreatomy and small bowel resection].","Fujimori",10586628,"[A case of various neurological deficits caused by multi-vitamin deficiency associated with malabsorption syndrome after pancreatomy and small bowel resection].    Abstract:   A 34-year-old woman presented with walking difficulty and pain in the legs 3 years after several abdominal operations for pancreatic cancer and intestinal obstruction thereafter. Corneal erosion, loss of deep sensation in the legs, polyneuropathy, myopathy, and memory disturbance were recognized. Deficiency of multiple vitamins (A, B1, B6, D, E, K) was found. The diagnoses were vitamin A-deficient corneal erosion, vitamin K-deficient bleeding abnormality (asymptomatic), and the neurological deficits caused by vitamin E, B1, B6 and D deficiency. Although the vitamin supplement started 2 years after the onset of the neurological disease, both clinical and electrophysiological recovery was seen. She was unable to walk on admission, but became able to walk after vitamin E supplement. To our knowledge, this is the first report showing multi-vitamin deficiency causing extensive neurological, ophthalmological, and hematological deficits. Recognition of this condition would prevent the progression of potentially irreversible neurological disorders in patients with malabsorption syndrome after extensive abdominal surgery."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1216,I1216)","v":10569233},{"$f":"(LEN($J1216) - LEN(SUBSTITUTE(LOWER($J1216),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1216) - LEN(SUBSTITUTE(LOWER($J1216),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1216) - LEN(SUBSTITUTE(LOWER($J1216),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1216:D1216)","v":0},1999,"Nutritional effects and management of diarrhoea in infancy.","Gracey",10569233,"Nutritional effects and management of diarrhoea in infancy.    Abstract:   The interactions between diarrhoeal disease and nutritional status are complex and synergistic. These are serious issues globally because they affect hundreds of millions of young children and annually cause gt; 3 million deaths in children aged under 5 y. Despite intensive field-based and laboratory studies over three decades, many questions remain unanswered about the causes, pathophysiology and best approaches to management and prevention of this quot;diarrhoea-malnutritionquot; syndrome. Oral rehydration therapy (ORT) has been a major advance and has saved many lives from acute diarrhoea. However, persistent diarrhoea is now a major problem and is very significant because of its strong negative impacts on nutritional status and because persistent diarrhoea and dysentery are now major causes of infant and young child deaths. ORT provides clear and practical methods for replacement of fluid and electrolyte losses during diarrhoea. Rehydration salts can be made available as (i) a simple, easy-to-use package, complete with user instructions; (ii) cereal-based formulae based on widely available ingredients that can be prepared domestically or commercially; and (iii) home-made mixtures of sugar and salt which should be simple to prepare but are risky because of inadequate understanding about their preparation at home and the chance of mixing the ingredients inaccurately and giving them wrongly. Continuation and encouragement of breastfeeding is an important strategy to prevent and control diarrhoea and as part of its management. Early refeeding during diarrhoea is another important principle to help to reduce its duration, severity and its nutritional impacts. Supplementation with specific dietary ingredients, such as vitamin A, zinc and folate, is rather contentious and drug therapy is of little value unless specifically indicated. Some patients may require enteral nutrition or parenteral nutrition but these require specialized equipment and skills that are usually beyond the reach of developing countries and infants and children who live in remote areas."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1217,I1217)","v":10535323},{"$f":"(LEN($J1217) - LEN(SUBSTITUTE(LOWER($J1217),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1217) - LEN(SUBSTITUTE(LOWER($J1217),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1217) - LEN(SUBSTITUTE(LOWER($J1217),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1217:D1217)","v":0},1999,"Influence of fetal environment on kidney development.","Merlet-Bénichou",10535323,"Influence of fetal environment on kidney development.    Abstract:   Several lines of evidence, mostly derived from animal studies, indicate that changes in fetal environment may affect renal development. Besides maternal hyperglycemia or drug exposure, that were recently found to alter nephrogenesis, changes in vitamin A supply to the fetus may prove to be responsible for most of the variations in nephron number found in the population. A low vitamin A status in the fetus may be a major cause of inborn nephron deficit, either as a feature of intrauterine growth retardation or independently of growth retardation. The possibility that vitamin A status may also influence renal vascular development is raised. We suggest that low vitamin A supply to the fetus plays a role in the intrauterine programming of chronic renal disease and hypertension."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1218,I1218)","v":10517280},{"$f":"(LEN($J1218) - LEN(SUBSTITUTE(LOWER($J1218),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1218) - LEN(SUBSTITUTE(LOWER($J1218),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1218) - LEN(SUBSTITUTE(LOWER($J1218),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1218:D1218)","v":0},1999,"Influence of palm oil (Elaesis guineensis) on health.","Ebong",10517280,"Influence of palm oil (Elaesis guineensis) on health.    Abstract:   In recent times there has been a growing research interest in palm oil, one of the major edible plant oils in the tropical countries, because of the link between dietary fats and coronary heart disease. Obtained from a tropical plant, Elaesis guineensis, it has a polyunsaturated fatty acid/saturated fatty acid ratio close to unity and a high amount of antioxidant vitamin A precursors and vitamin E. Palm oil is consumed in the fresh state and/or at various levels of oxidation. Feeding experiments in various animal species and humans have highlighted the beneficial role of fresh palm oil to health. These benefits include reduction in the risk of arterial thrombosis and atherosclerosis, inhibition of cholesterol biosynthesis and platelet aggregation, and reduction in blood pressure. However, a considerable amount of the commonly used palm oil is in the oxidized state which possesses potential dangers to the physiological and biochemical functions of the body. Oxidation is as a result of processing the oil for various culinary purposes. Studies have revealed that relative to fresh palm oil, oxidized palm oil induces an adverse plasma lipid profile, free fatty acids, phospholipids and cerebrosides. Additionally, oxidized palm oil induces reproductive toxicity and organotoxicity particularly of the kidneys, lungs, liver and heart. Available evidence suggests that at least part of the oxidized oil impact on health reflects generation of toxicants due to oxidation. The reduction of the dietary level of oxidized oil and/or the level of oxidation may reduce the health risk associated with consumption of oxidized fats."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1219,I1219)","v":10440206},{"$f":"(LEN($J1219) - LEN(SUBSTITUTE(LOWER($J1219),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1219) - LEN(SUBSTITUTE(LOWER($J1219),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1219) - LEN(SUBSTITUTE(LOWER($J1219),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1219:D1219)","v":0},1999,"Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy.","Li",10440206,"Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy.    Abstract:   Hepatic fibrosis is a wound-healing response to chronic liver injury, which if persistent leads to cirrhosis and liver failure. Exciting progress has been made in understanding the mechanisms of hepatic fibrosis. Major advances include: (i) characterization of the components of extracellular matrix (ECM) in normal and fibrotic liver; (ii) identification of hepatic stellate cells as the primary source of ECM in liver fibrosis; (iii) elucidation of key cytokines, their cellular sources, modes of regulation, and signalling pathways involved in liver fibrogenesis; (iv) characterization of key matrix proteases and their inhibitors; (v) identification of apoptotic mediators in stellate cells and exploration of their roles during the resolution of liver injury. These advances have helped delineate a more comprehensive picture of liver fibrosis in which the central event is the activation of stellate cells, a transformation from quiescent vitamin A-rich cells to proliferative, fibrogenic and contractile myofibroblasts. The progress in understanding fibrogenic mechanisms brings the development of effective therapies closer to reality. In the future, targeting of stellate cells and fibrogenic mediators will be a mainstay of antifibrotic therapy. Points of therapeutic intervention may include: (i) removing the injurious stimuli; (ii) suppressing hepatic inflammation; (iii) down-regulating stellate cell activation; and (iv) promoting matrix degradation. The future prospects for effective antifibrotic treatment are more promising than ever for the millions of patients with chronic liver disease worldwide."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1220,I1220)","v":10377659},{"$f":"(LEN($J1220) - LEN(SUBSTITUTE(LOWER($J1220),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1220) - LEN(SUBSTITUTE(LOWER($J1220),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1220) - LEN(SUBSTITUTE(LOWER($J1220),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1220:D1220)","v":0},1999,"[The AD-drops can be replaced by D-drops].","Axelsson",10377659,"[The AD-drops can be replaced by D-drops].    Abstract:   Since 1932, when vitamin A and D supplementation, in the form of cod liver oil, was introduced in Sweden, rickets has been a rare diagnosis among Swedish infants. In 1978, the National Board of Health and Welfare issued recommendations of daily supplementation with 300 micrograms (1000 IU) of vitamin A and 10 micrograms (400 IU) of vitamin D. This has recently been under review by the Paediatric Committee on Nutrition and Health, of the Swedish Paediatric Association and the National Food Administration, who concluded that there is no reason to retain vitamin A supplementation, but that vitamin D supplementation should continue to be recommended at the same daily dose (400 IU)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1221,I1221)","v":10372835},{"$f":"(LEN($J1221) - LEN(SUBSTITUTE(LOWER($J1221),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1221) - LEN(SUBSTITUTE(LOWER($J1221),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1221) - LEN(SUBSTITUTE(LOWER($J1221),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1221:D1221)","v":0},1999,"Vitamin D and the parathyroid.","Beckerman",10372835,"Vitamin D and the parathyroid.    Abstract:   Vitamin Ds biologically active metabolite, 1,25(OH)2D3, has important effects upon the parathyroid cell that are relevant to both the physiology of mineral metabolism and the regulation of the secondary hyperparathyroidism of chronic renal failure. 1,25(OH)2D3 markedly decreases parathyroid hormone (PTH) gene transcription and thus PTH synthesis and secretion. It also acts to decrease parathyroid cell proliferation. Nonhypercalemic analogs of 1,25(OH)2D3 are being developed that may have a wider therapeutic window than 1,25(OH)2D3 itself. In the situations of chronic hypocalcemia and hypophosphatemia, there are interesting interrelationships between 1,25(OH)2D3 and the post-transcriptional regulation of the PTH gene. In nodular secondary hyperparathyroidism, there is down-regulation of the vitamin D receptor in the parathyroid. Different vitamin D receptor genotypes may be associated with higher levels of serum PTH and a predisposition to autonomous hyperplasia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1222,I1222)","v":10371413},{"$f":"(LEN($J1222) - LEN(SUBSTITUTE(LOWER($J1222),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1222) - LEN(SUBSTITUTE(LOWER($J1222),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1222) - LEN(SUBSTITUTE(LOWER($J1222),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1222:D1222)","v":0},1999,"Cytokine regulation of hepatic stellate cells in liver fibrosis.","Tsukamoto",10371413,"Cytokine regulation of hepatic stellate cells in liver fibrosis.    Abstract:   Cytokines constitute a major class of mediators responsible for quot;activationquot; of hepatic stellate cells (HSCs) in vitro and in vivo. They are largely divided into mitogenic (transforming growth factor-alpha, platelet-derived growth factor, interleukin-1, tumor necrosis factor-alpha, and insulin-like growth factor) and fibrogenic (transforming growth factor-beta and interleukin-6) cytokines. In addition to their mitogenic (stimulation of cell proliferation) and fibrogenic (induction of matrix proteins) properties, they are also shown to confer in vitro unique cellular changes known to be the key features of HSC quot;activation,quot; including loss of vitamin A, stimulation of migration, enhanced cellular contractility, and matrix metalloproteinase and tissue inhibitor of metalloproteinase induction. Potential cellular sources of the cytokines consist of hepatic macrophages, endothelial cells, biliary epithelial cells, lymphocytes, platelets, hepatocytes, and activated HSCs. To better understand the mode of actions and the pathogenetic significance of cytokines/chemokines involved in quot;activationquot; of HSCs, the following four questions need to be addressed: (1) What other cytokines are expressed by HSCs to establish critical autocrine stimulation? (2) What are endogenous or exogenous priming factors for HSC stimulation? (3) What is the mechanism of activation for transforming growth factor-beta, the pivotal fibrogenic cytokine? (4) How important are HSC-derived proinflammatory mediators in liver fibrosis? This review will discuss these questions, along with the current understanding of the role of cytokines in HSC activation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1223,I1223)","v":10371412},{"$f":"(LEN($J1223) - LEN(SUBSTITUTE(LOWER($J1223),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1223) - LEN(SUBSTITUTE(LOWER($J1223),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1223) - LEN(SUBSTITUTE(LOWER($J1223),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1223:D1223)","v":0},1999,"Stellate cell activation in alcoholic fibrosis--an overview.","Friedman",10371412,"Stellate cell activation in alcoholic fibrosis--an overview.    Abstract:   There has been remarkable progress in our understanding of how chronic alcohol ingestion may lead to hepatic injury and scarring, or fibrosis. Hepatic fibrosis represents the livers wound healing response and is characterized by accumulation of interstitial matrix, or scar. Fibrosis in the liver results from the activation of stellate cells, or resident mesenchymal cells. Stellate cell activation is a dramatic phenotype transition whose net effect is the replacement of normal liver matrix by scar. Features of stellate cell activation include increased cell accumulation from proliferation and directed migration, increased matrix production, enhanced contractility, accelerated degradation of the normal liver matrix, release of profibrogenic cytokines, and loss of cellular vitamin A. Alcohol may enhance fibrogenesis through stimulation of stellate cells by hypoxia, generation of lipid peroxides from damaged hepatocytes, production of acetaldehyde that may have direct fibrogenic activity, and through activation of Kupffer cells or resident macrophages. Unanswered questions remain to be studied, but the clarification of underlying mechanisms of fibrosis portends continued progress in our ability to treat alcoholic liver fibrosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1224,I1224)","v":10363203},{"$f":"(LEN($J1224) - LEN(SUBSTITUTE(LOWER($J1224),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1224) - LEN(SUBSTITUTE(LOWER($J1224),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1224) - LEN(SUBSTITUTE(LOWER($J1224),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1224:D1224)","v":0},1999,"Gene regulation in hepatic stellate cell.","Lang",10363203,"Gene regulation in hepatic stellate cell.    Abstract:   Hepatic stellate cells are now recognized as the major source of extracellular matrix in hepatic fibrosis. Following liver injury the hepatic stellate cell changes from a quiescent to an activated cell. The activation process includes an increased proliferation rate, a phenotypic change to a myofibroblast-like cell, loss of vitamin A stores, increased extra-cellular matrix protein synthesis and contractility. Furthermore, hepatic stellate cells have been implicated in hepatic inflammation through their ability to secrete cytokines and chemokines. Here, we review the literature on the molecular pathogenesis of hepatic stellate cells activation with emphasis on the most recent findings. The reviewed topics include transcriptional and post-transcriptional regulation of the genes encoding type I collagen in hepatic stellate cells; the role of the transcription factor nuclear factor Kappa B in the hepatic stellate cell activation; focal adhesion kinase and integrin-mediated signal transduction in hepatic stellate cell, and apoptosis in hepatic stellate cells. New insight into hepatic stellate cell activation and death may lead to the development of novel therapies for hepatic fibrosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1225,I1225)","v":10216946},{"$f":"(LEN($J1225) - LEN(SUBSTITUTE(LOWER($J1225),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1225) - LEN(SUBSTITUTE(LOWER($J1225),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1225) - LEN(SUBSTITUTE(LOWER($J1225),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1225:D1225)","v":0},1999,"The role of the 5 untranslated region of an mRNA in translation regulation during development.","van der Velden",10216946,"The role of the 5 untranslated region of an mRNA in translation regulation during development.    Abstract:   Cap-dependent ribosomal scanning occurs on the majority of cellular 5 UTRs. This process is severely hampered on long 5 UTRs, containing AUGs and secondary structure. These characteristics are often found in mRNAs encoding regulatory proteins like proto-oncogenes, growth factors, their receptors, and homeodomain proteins. A number of these mRNAs use an alternative mechanism of translation initiation, involving an internal ribosomal entry site (IRES). Cellular mRNAs containing a complex 5 UTR or an IRES share an intriguing characteristic: their translational efficiency can be very specifically regulated by their 5 UTR, providing post-transcriptional regulation. During embryonic development, the 5 UTRs of Antp. Ubx RAR beta 2 c-mos and c-myc regulate protein expression in a spatio-temporal manner. Translation initiation on a number of growth factor RNAs (IGFII, PDGF2, TGF beta, FGF-2, and VEGF) is specifically regulated during differentiation, growth, and stress. Furthermore, 5 UTR activity, mutations in the 5 UTR, or the occurrence of alternative 5 UTRs have been implicated in the progression of various forms of cancer. The mechanisms involved in 5 UTR mediated control are not well understood. Binding of trans-acting factors could mediate translation stimulation or repression. Furthermore, the precise localization of upstream AUGs and the activity of the cap-binding initiation factor 4E are suggested to be important for translation regulation of these mRNAs. This review focuses on 5 UTRs whose activity is regulated, the processes during which this regulation occurs, and as far as known the mechanisms involved."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1226,I1226)","v":10210743},{"$f":"(LEN($J1226) - LEN(SUBSTITUTE(LOWER($J1226),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1226) - LEN(SUBSTITUTE(LOWER($J1226),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1226) - LEN(SUBSTITUTE(LOWER($J1226),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1226:D1226)","v":0},1999,"[Carotenoids: 1. Metabolism and physiology].","Faure",10210743,"[Carotenoids: 1. Metabolism and physiology].    Abstract:   Carotenoids are a family of pigments with at least 600 members. They derive from lycopene after steps of cyclisation, dehydrogenation and oxidation. It is their chemical structure that determines their physiochemical properties and, in part, their biological activities. About 50 carotenoids can be found in human diet and about 20 of them have been found in plasma and tissues. There is no RDA (Recommended Daily Allowance) for carotenoids. Quantities of carotenoids in diet are difficult to estimate, partly because methods used for the establishment of food composition tables were not specific and sensitive enough. Also, given values do not always take into account variations due to season and region of culture. Absorption of beta-carotene in humans has been the subject of numerous studies but only very little is known about other carotenoids. In general, absorption depends on bioavailability from the food matrix and solubility in micelles. After absorption through passive diffusion, carotenoids follow the chylomicrons metabolism. They are taken up by the liver and released in the blood stream in lipoproteins (VLDL). Carotenoids with no-substituted beta-ionone cycles (alpha and beta-carotene and beta-cryptoxanthin) have provitamin A activity. Highest activity has been found for all-trans beta-carotene. Not all steps of vitamin A biosynthesis and metabolism of other carotenoids have been clarified yet. Besides their provitamin A activity, carotenoids have numerous biological functions. They are efficient scavengers of free radicals, particularly of 1O2. In vitro they have been shown to protect LDL. However, results in vivo are inconsistent. Other functions include enhancement of gap junctions, immunomodulation and regulation of enzyme activity involved in carcinogenesis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1227,I1227)","v":10203551},{"$f":"(LEN($J1227) - LEN(SUBSTITUTE(LOWER($J1227),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1227) - LEN(SUBSTITUTE(LOWER($J1227),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1227) - LEN(SUBSTITUTE(LOWER($J1227),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1227:D1227)","v":0},1999,"Vitamin A as quot;anti-infectivequot; therapy, 1920-1940.","Semba",10203551,"Vitamin A as quot;anti-infectivequot; therapy, 1920-1940.    Abstract:   In the last fifteen years, a large series of controlled clinical trials showed that vitamin A supplementation reduces morbidity and mortality of children in developing countries. It is less well known that vitamin A underwent two decades of intense clinical investigation prior to World War II. In the 1920s, a theory emerged that vitamin A could be used in quot;anti-infectivequot; therapy. This idea, largely championed by Edward Mellanby, led to a series of at least 30 trials to determine whether vitamin A--usually supplied in the form of cod-liver oil--could reduce the morbidity and mortality of respiratory disease, measles, puerperal sepsis, and other infections. The early studies generally lacked such innovations known to the modern controlled clinical trial such as randomization, masking, sample size and power calculations, and placebo controls. Results of the early trials were mixed, but the pharmaceutical industry emphasized the positive results in their advertising to the public. With the advent of the sulfa antibiotics for treatment of infections, scientific interest in vitamin A as quot;anti-infectivequot; therapy waned. Recent controlled clinical trials of vitamin A from the last 15 y follow a tradition of investigation that began largely in the 1920s."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1228,I1228)","v":10193589},{"$f":"(LEN($J1228) - LEN(SUBSTITUTE(LOWER($J1228),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1228) - LEN(SUBSTITUTE(LOWER($J1228),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1228) - LEN(SUBSTITUTE(LOWER($J1228),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1228:D1228)","v":0},1999,"Primary prevention of CHD: nine ways to reduce risk.","Havranek",10193589,"Primary prevention of CHD: nine ways to reduce risk.    Abstract:   Lowering cholesterol can reduce the incidence of coronary heart disease. Treating hypertension reduces overall mortality and is most effective in reducing the risk of coronary heart disease in older patients. Smoking cessation reduces the level of risk to that of nonsmokers within about three years of cessation. Aspirin is likely to be an effective means of primary prevention, but a group in whom treatment is appropriate has yet to be defined. Evidence that supplementation with vitamin A or C reduces the risk of coronary heart disease is inadequate; the data for use of vitamin E are inconclusive. Epidemiologic evidence is sufficient to recommend that most persons increase their levels of physical activity. Lowering homocysteine levels through increased folate intake is a promising but unproven primary prevention strategy. Hormone replacement therapy was associated with reduced incidence of coronary heart disease in epidemiologic studies but was not effective in a secondary prevention trial."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1229,I1229)","v":9929897},{"$f":"(LEN($J1229) - LEN(SUBSTITUTE(LOWER($J1229),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1229) - LEN(SUBSTITUTE(LOWER($J1229),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1229) - LEN(SUBSTITUTE(LOWER($J1229),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1229:D1229)","v":0},1999,"[Nutrition-related problems in pet birds].","Schoemaker",9929897,"[Nutrition-related problems in pet birds].    Abstract:   The detection and correction of dietary errors plays an important role in avian medicine. Examples of diseases caused in part by a deficiency or abundance of a nutrient include hypovitaminosis A in birds of the parrot (Psittacidae) family, hypocalcemia in the African grey parrot, goitre in budgerigars, and iron storage diseases in the minah and toucan. Hypovitaminosis A can lead to metaplasia of mucous membranes, which in turn can lead to chronic rhinitis and respiratory fungal infections. Vitamin A deficiency is caused by feeding a seed based diet. Seed mixtures are often deficient in calcium, and nutritional secondary hyperparathyroidism can develop if an additional source of calcium, in the form of ground shells, is not provided. Tetanic symptoms as a result of hypocalcemia are only seen in the African grey parrot and the timneh parrot. Over supplementation of vitamin D gives rise to poisoning with polyuria and polydipsia as common initial symptoms. The exact cause of iron storage diseases in toucans and minahs is not known. A diet low in iron and vitamin C is advised as therapy. Goitre can develop in budgerigars as a result of iodine-deficient drinking water and provision of a seed mixture based on millet. An unbalanced or multideficient diet can give rise to reproductive disorders, abnormal feathers, or infections as a result of diminished resistance. It is usually not possible to relate the cause of these diseases in a simple way to the composition of the diet. Obesity, which occurs in the galah, Amazon parrot, and budgerigars, can lead to fatty liver and lipoma. A gradual reduction in weight, by means of calorie restriction, is recommended. Commercially available nutritionally balanced bird food is often effective."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1230,I1230)","v":9873118},{"$f":"(LEN($J1230) - LEN(SUBSTITUTE(LOWER($J1230),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1230) - LEN(SUBSTITUTE(LOWER($J1230),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1230) - LEN(SUBSTITUTE(LOWER($J1230),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1230:D1230)","v":0},1998,"Side effects of acne therapy and their management.","Miller",9873118,"Side effects of acne therapy and their management.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1231,I1231)","v":9794827},{"$f":"(LEN($J1231) - LEN(SUBSTITUTE(LOWER($J1231),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1231) - LEN(SUBSTITUTE(LOWER($J1231),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1231) - LEN(SUBSTITUTE(LOWER($J1231),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1231:D1231)","v":0},1998,"The LXRs: a new class of oxysterol receptors.","Peet",9794827,"The LXRs: a new class of oxysterol receptors.    Abstract:   The liver X receptors (LXRs) are a family of transcription factors that were first identified as orphan members of the nuclear receptor superfamily. The identification of a specific class of oxidized derivatives of cholesterol as ligands for the LXRs has been crucial to helping understand the function of these receptors in vivo and first suggested their role in the regulation of lipid metabolism. Confirmation of this role has come from the recent analysis of LXR-deficient mice, which has demonstrated the essential function of one of these receptors in the liver as a major sensor of dietary cholesterol."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1232,I1232)","v":9751943},{"$f":"(LEN($J1232) - LEN(SUBSTITUTE(LOWER($J1232),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1232) - LEN(SUBSTITUTE(LOWER($J1232),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1232) - LEN(SUBSTITUTE(LOWER($J1232),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1232:D1232)","v":0},1998,"Alcohol and cancer.","Seitz",9751943,"Alcohol and cancer.    Abstract:   A great number of epidemiological data have identified chronic alcohol consumption as a significant risk factor for upper alimentary tract cancer, including cancer of the oropharynx, larynx, and the esophagus, and for the liver. In contrast to those organs, the risk by which alcohol consumption increases cancer in the large intestine and in the breast is much smaller. However, although the risk is lower, carcinogenesis can be enhanced with relatively low daily doses of ethanol. Considering the high prevalence of these tumors, even a small increase in cancer risk is of great importance, especially in those individuals who exhibit a higher risk for other reasons. The epidemiological data on alcohol and other organ cancers are controversial and there is at present not enough evidence for a significant association. Although the exact mechanisms by which chronic alcohol ingestion stimulates carcinogenesis are not known, experimental studies in animals support the concept that ethanol is not a carcinogen, but under certain experimental conditions is a cocarcinogen and/or (especially in the liver) a tumor promoter. The metabolism of ethanol leads to the generation of acetaldehyde and free radicals. These highly reactive compounds bind rapidly to cell constituents and possibly to DNA. Acetaldehyde decreases DNA repair mechanisms and the methylation of cytosine in DNA. It also traps glutathione, an important peptide in detoxification. Furthermore, it leads to chromosomal aberrations and seems to be associated with tissue damage and secondary compensatory hyperregeneration. More recently, the finding of considerable production of acetaldehyde by gastrointestinal bacteria was reported. Other mechanisms by which alcohol stimulates carcinogenesis include the induction of cytochrome P4502E1, associated with an enhanced activation of various procarcinogens present in alcoholic beverages, in association with tobacco smoke and in diets, a change in the metabolism and distribution of carcinogens, alterations in cell cycle behavior such as cell cycle duration leading to hyperregeneration, nutritional deficiencies such as methyl, vitamin A, folate, pyrridoxalphosphate, zinc and selenium deficiency, and alterations of the immune system, eventually resulting in an increased susceptibility to certain viral infections such as hepatitis B virus and hepatitis C virus. In addition, local mechanisms in the upper gastrointestinal tract and in the rectum may be of particular importance. Such mechanisms lead to tissue injury such as cirrhosis of the liver, a major prerequisite for hepatocellular carcinoma. Thus, all these mechanisms, functioning in concert, actively modulate carcinogenesis, leading to its stimulation."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1233,I1233)","v":9742500},{"$f":"(LEN($J1233) - LEN(SUBSTITUTE(LOWER($J1233),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1233) - LEN(SUBSTITUTE(LOWER($J1233),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1233) - LEN(SUBSTITUTE(LOWER($J1233),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1233:D1233)","v":0},1998,"Treatment of hepatocellular carcinoma: medical options.","Fried",9742500,"Treatment of hepatocellular carcinoma: medical options.    Abstract:   Nonsurgical therapy provides some benefit to patients with advanced hepatocellular carcinoma, although surgical options, including transplantation, remain the only chance for cure. Careful patient selection is required; patients with small nodular tumors may be considered for PEI therapy, whereas patients with larger tumors may be considered for TACE. Regardless of the treatment modality, the likelihood of survival is usually directly associated with the degree of hepatic dysfunction. Randomized, controlled trials of these treatment modalities are limited in number and design; therefore, it is difficult to assess their true impact on patient survival and quality of life. Secondary chemoprophylaxis against recurrent disease with vitamin A analogues is a promising adjunctive measure to both surgical and nonsurgical treatments for hepatocellular carcinoma."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1234,I1234)","v":9721514},{"$f":"(LEN($J1234) - LEN(SUBSTITUTE(LOWER($J1234),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1234) - LEN(SUBSTITUTE(LOWER($J1234),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1234) - LEN(SUBSTITUTE(LOWER($J1234),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1234:D1234)","v":0},1998,"[Liver fibrogenesis and cytokines].","Okuno",9721514,"[Liver fibrogenesis and cytokines].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1235,I1235)","v":9693214},{"$f":"(LEN($J1235) - LEN(SUBSTITUTE(LOWER($J1235),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1235) - LEN(SUBSTITUTE(LOWER($J1235),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1235) - LEN(SUBSTITUTE(LOWER($J1235),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1235:D1235)","v":0},1998,"Hepatic fibrosis - therapeutic strategies.","Schuppan",9693214,"Hepatic fibrosis - therapeutic strategies.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1236,I1236)","v":9669730},{"$f":"(LEN($J1236) - LEN(SUBSTITUTE(LOWER($J1236),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1236) - LEN(SUBSTITUTE(LOWER($J1236),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1236) - LEN(SUBSTITUTE(LOWER($J1236),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1236:D1236)","v":0},1998,"Mechanisms of hepatic fibrosis.","Benyon",9669730,"Mechanisms of hepatic fibrosis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1237,I1237)","v":9645003},{"$f":"(LEN($J1237) - LEN(SUBSTITUTE(LOWER($J1237),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1237) - LEN(SUBSTITUTE(LOWER($J1237),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1237) - LEN(SUBSTITUTE(LOWER($J1237),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1237:D1237)","v":0},1998,"[Hypo beta-lipoproteinemia with selective deletion of apo B-48].","Tohdoh",9645003,"[Hypo beta-lipoproteinemia with selective deletion of apo B-48].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1238,I1238)","v":9645000},{"$f":"(LEN($J1238) - LEN(SUBSTITUTE(LOWER($J1238),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1238) - LEN(SUBSTITUTE(LOWER($J1238),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1238) - LEN(SUBSTITUTE(LOWER($J1238),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1238:D1238)","v":0},1998,"[Familial hypo beta-lipoproteinemia].","Tohdoh",9645000,"[Familial hypo beta-lipoproteinemia].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1239,I1239)","v":9571719},{"$f":"(LEN($J1239) - LEN(SUBSTITUTE(LOWER($J1239),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1239) - LEN(SUBSTITUTE(LOWER($J1239),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1239) - LEN(SUBSTITUTE(LOWER($J1239),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1239:D1239)","v":0},1998,"Combating micronutrient deficiencies: problems and perspectives.","Alnwick",9571719,"Combating micronutrient deficiencies: problems and perspectives.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1240,I1240)","v":9537797},{"$f":"(LEN($J1240) - LEN(SUBSTITUTE(LOWER($J1240),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1240) - LEN(SUBSTITUTE(LOWER($J1240),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1240) - LEN(SUBSTITUTE(LOWER($J1240),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1240:D1240)","v":0},1998,"Xerophthalmia and vitamin A status.","Sommer",9537797,"Xerophthalmia and vitamin A status.    Abstract:   The existence of fat-soluble A has been known for over 80 years. But until recently clinicians were almost wholly absorbed by the ocular changes accompanying deficiency (xerophthalmia), and scientists with the vitamins metabolic role in the rhodopsin cycle. The past two decades have witnessed a revolution in clinical and scientific concerns. Xerophthalmia is now recognized as a late manifestation of severe deficiency rather than of early, mild deficiency; as the mechanism responsible for half or more of all measles-associated blindness; and as the cause of half a million or more cases of pediatric blindness worldwide. Milder deficiency increases the severity of infectious morbidity, exacerbates iron deficiency anemia, retards growth, and is responsible for one to three million childhood deaths each year. Scientists are now busy unraveling vitamin A-dependent gene regulation to explain the myriad manifestations accompanying deficiency, while clinicians are designing and supervising programs to improve vitamin A status in over 60 countries, up from only three countries two decades ago. Control of vitamin A deficiency is now a major health challenge and goal of both UNICEF and the World Health Organization (WHO). Reaching that goal requires better parameters for assessing vitamin A status, increased understanding of metabolic pathways responsible for corneal dissolution (keratomalacia) and the molecular and cellular basis by which vitamin A status mediates resistance to infection. These issues are detailed elsewhere (Sommer and West, 1996)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1241,I1241)","v":9465190},{"$f":"(LEN($J1241) - LEN(SUBSTITUTE(LOWER($J1241),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1241) - LEN(SUBSTITUTE(LOWER($J1241),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1241) - LEN(SUBSTITUTE(LOWER($J1241),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1241:D1241)","v":0},1997,"Nutrition. From whither to wither micronutrient malnutrition?","West",9465190,"Nutrition. From whither to wither micronutrient malnutrition?    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1242,I1242)","v":9407544},{"$f":"(LEN($J1242) - LEN(SUBSTITUTE(LOWER($J1242),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1242) - LEN(SUBSTITUTE(LOWER($J1242),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1242) - LEN(SUBSTITUTE(LOWER($J1242),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1242:D1242)","v":0},1997,"Development of hepatic sinusoidal structure with special reference to the Ito cells.","Enzan",9407544,"Development of hepatic sinusoidal structure with special reference to the Ito cells.    Abstract:   To elucidate sinusoidal cell structure and function under normal conditions and their behavior in diseased settings, an understanding of their developmental aspects is needed. At day 10 of gestation in mice and rats or at 5 weeks of gestation in humans, the hepatic cords grow into the mesenchymal tissue of the septum transversum, and the primitive sinusoidlike structure is simultaneously observed between the liver cell cords. In the margin of the growing liver primordium, mesenchymal cells in the septum transversum are trapped in the subendothelial space. These subendothelial cells are at the early stages of organogenesis and become progenitors of the Ito cells. By days 12-14 of gestation in mice and rats or 8 weeks of gestation in humans, the basic structure of the sinusoids has developed. Embryonic hepatic sinusoids are usually lined by a continuous endothelium without basement membranes, and an incompletely fenestrated sinusoid appears at the middle gestational stage. In the late gestational stages, the Ito cells exhibit myofibroblastlike features in humans, mice, and rats. In association with this event, perisinusoidal reticular networks are gradually intensified. After birth until days 4-5 in mice and rats, the sinusoidal and perisinusoidal structures are almost completely formed, although slight morphological differences from those in adult livers still exist. What happens to sinusoidal endothelial cells and Ito cells in hepatic fibrosis-cirrhosis of the adult may be a deviated or uncontrolled occurrence of what goes on during the fetal period, i.e., a continuous nonfenestrated sinusoidal lining in the early embryonic stage and a myofibroblastlike transformation of Ito cells in late fetal life."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1243,I1243)","v":9410960},{"$f":"(LEN($J1243) - LEN(SUBSTITUTE(LOWER($J1243),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1243) - LEN(SUBSTITUTE(LOWER($J1243),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1243) - LEN(SUBSTITUTE(LOWER($J1243),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1243:D1243)","v":0},1997,"[Liver diseases and nutritional therapy].","Muto",9410960,"[Liver diseases and nutritional therapy].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1244,I1244)","v":9396207},{"$f":"(LEN($J1244) - LEN(SUBSTITUTE(LOWER($J1244),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1244) - LEN(SUBSTITUTE(LOWER($J1244),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1244) - LEN(SUBSTITUTE(LOWER($J1244),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1244:D1244)","v":0},1997,"[One hundred years of sinusoidal cells in the liver].","Wake",9396207,"[One hundred years of sinusoidal cells in the liver].    Abstract:   Kupffer (1898) reported that the stellate cells were phagocytic endothelial cells, retracting his earlier view that these cells were perivascular cells. His new concept stimulated studies on the vital staining and the RES theory, while it ensued several controversies in liver histology. The original stellate cells were rediscovered in 1971, and were proved to be identical with several perisinusoidal cells reported previously. For this cell the term hepatic stellate cell has recently been adopted as the standardized name. The space of Disse is newly defined as the space between the endothelial cell-stellate cell complex and the parenchymal cells. The stellate cells display vitamin A-storage, collagen synthesis and may contract to regulate the sinusoidal blood flow and the fluid-exchange between the sinusoidal lumen and the space of Disse. The sinusoidal endothelial cells uptake injected lithium carmine and macromolecules by coated vesicles. Kupffer cells clear endotoxin, bacteria and apoptotic neutrophils and release various cytokines. The pit cells are the liver-associated NK cells and are activated by the administration of biological response modifiers, preventing tumor metastasis. Extrathymic pathways of T cell differentiation exist in the hepatic sinusoid. The dendritic cells differentiate in the sinusoid and translocate to the Glissons sheath. Intralobular heterogeneity of sinusoidal cells have been observed. The sinusoidal cells communicate each other with autocrine and paracrine mechanisms to regulate various functions of the liver."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1245,I1245)","v":9287481},{"$f":"(LEN($J1245) - LEN(SUBSTITUTE(LOWER($J1245),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1245) - LEN(SUBSTITUTE(LOWER($J1245),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1245) - LEN(SUBSTITUTE(LOWER($J1245),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1245:D1245)","v":0},1997,"Importance of adequate vitamin A status during iron supplementation.","Ribaya-Mercado",9287481,"Importance of adequate vitamin A status during iron supplementation.    Abstract:   Nutritional deficiencies, including iron deficiency, may promote infection by lowering the bodys resistance to infectious diseases. However, it has been shown that administration of iron in developing countries can result in increased morbidity, because pathogenic bacteria may compete effectively for iron in the circulation, resulting in an exacerbation of existing infections. Improved vitamin A status may protect against this potentially harmful effect of iron supplementation in environments where infections are highly prevalent."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1246,I1246)","v":9099976},{"$f":"(LEN($J1246) - LEN(SUBSTITUTE(LOWER($J1246),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1246) - LEN(SUBSTITUTE(LOWER($J1246),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1246) - LEN(SUBSTITUTE(LOWER($J1246),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1246:D1246)","v":0},1997,"The hepatic stellate (Ito) cell: its role in human liver disease.","Hautekeete",9099976,"The hepatic stellate (Ito) cell: its role in human liver disease.    Abstract:   The hepatic stellate (Ito) cell lies within the space of Disse and has a variety of functions. Stellate cells store vitamin A in characteristic lipid droplets. In the normal human liver, the cells can be identified by the presence of these lipid droplets; in addition, many stellate cells in the normal liver express alpha-smooth muscle actin. In acute liver injury, there is an expansion of the stellate cell population with increased alpha-smooth muscle actin expression; stellate cells appear to play a role in extracellular matrix remodelling after recovery from injury. In chronic liver injury, the stellate cell differentiates into a myofibroblast-like cell with marked expression of alpha-smooth muscle actin and occasional expression of desmin. Myofibroblast-like cells have a high fibrogenic capacity in the chronically diseased liver and are also involved in matrix degradation. In vitamin A intoxication, hypertrophy and proliferation of the stellate and myofibroblast-like cells may lead to non-cirrhotic portal hypertension, fibrosis and cirrhosis. In liver tumours, myofibroblast-like cells are involved in the capsule formation around the tumour and in the production of extracellular matrix within it. The transition of stellate cells into myofibroblast-like cells is regulated by an intricate network of intercellular communication between stellate cells and activated Kupffer cells, damaged hepatocytes, platelets, endothelial and inflammatory cells, involving cytokines and nonpeptide mediators such as reactive oxygen species, eicosanoids and acetaldehyde. The findings suggest that the stellate cell plays an active role in a number of human liver diseases, with a particular reactivity pattern in fibrotic liver disorders."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1247,I1247)","v":9097604},{"$f":"(LEN($J1247) - LEN(SUBSTITUTE(LOWER($J1247),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1247) - LEN(SUBSTITUTE(LOWER($J1247),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1247) - LEN(SUBSTITUTE(LOWER($J1247),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1247:D1247)","v":0},1997,"[Triglyceride turnover and its evaluation].","Oikawa",9097604,"[Triglyceride turnover and its evaluation].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1248,I1248)","v":9155218},{"$f":"(LEN($J1248) - LEN(SUBSTITUTE(LOWER($J1248),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1248) - LEN(SUBSTITUTE(LOWER($J1248),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1248) - LEN(SUBSTITUTE(LOWER($J1248),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1248:D1248)","v":0},1997,"The impact of disease states as a modifying factor for nutrition toxicity.","Russell",9155218,"The impact of disease states as a modifying factor for nutrition toxicity.    Abstract:   Acquired kidney and liver diseases are relatively common diseases that can raise the potential for nutrient intoxication. For example, high-protein diets increase glomerular blood flow and the blood pressure gradient across the glomerular capillary wall in the kidney, which can result in injury to membranes. Likewise, the liver can increase nutrient intoxication because it is involved in the intermediary metabolism of many nutrients, serves as the storage organ for many nutrients, and is important in the biotransformation and excretion of nutrients. In this paper, vitamin A serves as an example to illustrate how kidney disease and liver disease can increase a single nutrients toxicity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1249,I1249)","v":9078734},{"$f":"(LEN($J1249) - LEN(SUBSTITUTE(LOWER($J1249),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1249) - LEN(SUBSTITUTE(LOWER($J1249),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1249) - LEN(SUBSTITUTE(LOWER($J1249),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1249:D1249)","v":0},1997,"[Disorder of vitamin metabolism in alcoholics].","Hashizume",9078734,"[Disorder of vitamin metabolism in alcoholics].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1250,I1250)","v":23899212},{"$f":"(LEN($J1250) - LEN(SUBSTITUTE(LOWER($J1250),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1250) - LEN(SUBSTITUTE(LOWER($J1250),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1250) - LEN(SUBSTITUTE(LOWER($J1250),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1250:D1250)","v":0},1997,"The use of non destructive biomarkers in the study of marine mammals.","M Cristina Fossi And Letizia Marsili",23899212,"The use of non destructive biomarkers in the study of marine mammals.    Abstract:   Marine mammals have been subject to heavy anthropogenic pressure by direct killing and chemical pollution all over the world. Most studies of contamination and biomarker responses in marine mammals have been conducted using animals killed by hunting out of a total of 12 cetacean species studied, 45 of the specimens were obtained by sacrificing the animal; out of a total of eight pinniped species studied, 40 of the specimens were obtained by killing. The development of a series of non destructive techniques to evaluate biomarker responses and residue levels is recommended for the hazard assessment and conservation of endangered species of marine mammals. Here we review the current status of the non destructive biomarker approach in marine mammals, describing the biological materials available for non destructive tests in stranded brain, liver, blood, skin, subcutaneous blubber, muscle and fur and free ranging animals blood, skin biopsy, fur and faeces and the respective biomarker techniques mixed function oxidase activity and DNA damage in skin biopsy samples; porphyrins in faeces and fur; esterases, porphyrins, clinical biochemical parameter, vitamin A and micronuclei in blood samples. Residue analysis can be carried out in the various biological materials. We also report the results of applying this methodological approach to cetaceans minke whale Balaenoptera acutorostrata, fin whale-- Balaenoptera physalus, beluga whale-- Delphinapterus leucas, short finned pilot whale-- Globicephala macrorhynchus, harbour porpoise -- Phocoena phocoena, Rissos dolphin-- Risso s Grampus griseus, Dall s porpoise-- Phocoenoides dalli dalli, melon headed whale-- Peponocephala electra, bottlenose dolphin -- Tursiops truncatus, striped dolphin-- Stenella coeruleoalba, spinner dolphin-- Stenella longirostris, killer whale-- Orcinus orca and pinnipeds northern fur seal- Callorhinus ursinus, hooded seal-- Cystophora cristata, grey seal-- Halichoerus grypus, harbour seal-- Phoca vitulina, ringed seal-- Phoca hispida, harp seal-- Phoca groenlandica, ribbon seal-- Phoca fasciata, largha seal- Phoca largha, southern sea lion-- Otaria flavescens in field studies for prognostic and diagnostic purposes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1251,I1251)","v":15706741},{"$f":"(LEN($J1251) - LEN(SUBSTITUTE(LOWER($J1251),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1251) - LEN(SUBSTITUTE(LOWER($J1251),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1251) - LEN(SUBSTITUTE(LOWER($J1251),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1251:D1251)","v":0},1997,"Scarring in alcoholic liver disease: new insights and emerging therapies.","Friedman",15706741,"Scarring in alcoholic liver disease: new insights and emerging therapies.    Abstract:   Like other organs, the liver responds to injury (e.g., from chronic alcohol ingestion) with scar formation (i.e., fibrosis). Specialized cells known as stellate cells play a major role in the development of liver fibrosis. Normally these cells serve as important storage depots for vitamin A, but during alcoholic injury, a collection of cellular and molecular mediators cause stellate cells to undergo a process of activation that results in dramatic changes in their structure and function. Activated stellate cells then become primary producers of scar tissue. In turn, accumulated scar provokes a series of events that contributes to deteriorated liver function. An improved understanding of the factors that trigger stellate cell activation has led to new therapeutic approaches for reversing or preventing liver fibrosis more effectively."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1252,I1252)","v":9401406},{"$f":"(LEN($J1252) - LEN(SUBSTITUTE(LOWER($J1252),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1252) - LEN(SUBSTITUTE(LOWER($J1252),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1252) - LEN(SUBSTITUTE(LOWER($J1252),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1252:D1252)","v":0},1997,"Role of Ito cells in the liver function.","Flisiak",9401406,"Role of Ito cells in the liver function.    Abstract:   Ito cells (perisinusoidal fat-storing cells, stellate cells, lipocytes) of the liver are mesenchymal cells located in the space of Disse. They are the main place of vitamin A storage in characteristic lipid droplets. Moreover, they demonstrate synthetic activity of collagens and other extracellular matrix proteins involved in hepatic fibrosis. Their long, contractile cytoplasmic processes encompass the sinusoids and can affect sinusoidal blood flow. Because of their location in the space of Disse and connection with other sinusoidal and parenchymal cells, they are probably involved in local neurotransmission and paracrine regulation of numerous liver functions. As a source of cytokines, prostaglandins and other bioactive substances, produced in the response to noxious agents, they play a crucial role in the mechanisms of liver injury, regeneration and fibrosis. This article is a review of the current state of knowledge on Ito cells structure and function."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1253,I1253)","v":9350470},{"$f":"(LEN($J1253) - LEN(SUBSTITUTE(LOWER($J1253),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1253) - LEN(SUBSTITUTE(LOWER($J1253),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1253) - LEN(SUBSTITUTE(LOWER($J1253),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1253:D1253)","v":0},1997,"Antioxidative vitamins in prevention of ischemia/reperfusion injury.","Nagel",9350470,"Antioxidative vitamins in prevention of ischemia/reperfusion injury.    Abstract:   Involvement of oxygen free radicals in ischemia-/reperfusion injury is based on measurement of increased products of lipid peroxidation after organ ischemia and restoration of blood flow during surgical operations and reperfusion of organ transplants. In cardiology inverse epidemiological correlations between plasma vitamin E levels and mortality due to ischemic heart disease, as well as beneficial effects of vitamin E on experimentally induced oxidative damage to the heart support the hypothesis, that vitamin E might have a protective role against myocardial ischemia-/reperfusion injury. In abdominal surgery efficiency of free radical scavengers has been intensively studied on animal models of hepatic ischemia and reperfusion. Examination of free radical scavengers and adenosine metabolites in liver tissue during hepatic ischemia revealed that vitamin E and glutathione levels as well as hepatic adenosine triphosphate levels are decreased during hepatic ischemia and reperfusion. The beneficial effects of alpha-tocopherol on hepatic viability and survival rate after ischemia and reperfusion demonstrated in these studies will be of great importance concerning further studies in organ preservation. In clinical kidney transplantation prevention of lipid peroxidation and improvement in kidney viability and function was demonstrated after infusion of a multivitamin cocktail in a prospective randomised study."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1254,I1254)","v":9276994},{"$f":"(LEN($J1254) - LEN(SUBSTITUTE(LOWER($J1254),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1254) - LEN(SUBSTITUTE(LOWER($J1254),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1254) - LEN(SUBSTITUTE(LOWER($J1254),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1254:D1254)","v":0},1997,"Nutritional metabolic diseases of poultry and disorders of the biological antioxidant defence system.","Mézes",9276994,"Nutritional metabolic diseases of poultry and disorders of the biological antioxidant defence system.    Abstract:   Deficiencies or disturbances of nutrition cause a variety of diseases and can arise in different ways. The amount of a particular nutrient in the diet may be insufficient to meet the requirements, the diet may contain substances that inactivate the nutrient or inhibit its absorption/utilisation, or metabolism may be upset by the interaction of dietary and environmental factors. Peroxidation of lipids or oxygen free radical generation in general is a physiological process important for cell metabolism, division and differentiation and also for the biosynthesis of hormones and prostaglandins. Free radicals generated through these processes are effectively scavenged by the antioxidant defence system. Uncontrolled lipid oxidation caused by disturbances of that system may play a crucial role in some important poultry diseases and toxicoses. The first route of lipid peroxide loading of the organism is via the feed, such as through oxidised lipids. Oxidised fatty acids are absorbed from the intestine mainly in the form of unsaturated keto compounds and initiate lipid peroxidation in the tissues. The second problem is the insufficient amount of antioxidants in the feed, e.g. vitamin E deficiency. Nutritional encephalomalacia is a problem in poultry production which depends both on the actual vitamin E supply and the dietary amount of polyunsaturated fatty acids. In young birds the primary target of vitamin E deficiency is the brain because it contains low amounts of vitamin E, and the vitamin E content of the liver acting as store decreases rapidly during the first week of life. Besides vitamin E, other components of the antioxidant system, e.g. the antioxidant enzymes (catalase and glutathione peroxidase) also have low activity in the brain as compared to other major tissues. The brain is highly susceptible to oxidative stress because of the accumulation of polyunsaturated fatty acids. The third source of free radical generation is the toxic level of different feed ingredients, e.g. toxicoses caused by vitamin A, selenium, and ionophore antibiotics. Other important aspects of antioxidants (e.g. vitamin E and selenium) in poultry are stimulation of the immune response (e.g. in the case of vaccination) and reduction of the risks of free radical formation as a result of macrophage function."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1255,I1255)","v":9034713},{"$f":"(LEN($J1255) - LEN(SUBSTITUTE(LOWER($J1255),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1255) - LEN(SUBSTITUTE(LOWER($J1255),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1255) - LEN(SUBSTITUTE(LOWER($J1255),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1255:D1255)","v":0},1997,"Regulation and activities of alpha-fetoprotein.","Chen",9034713,"Regulation and activities of alpha-fetoprotein.    Abstract:   alpha-Fetoprotein (AFP) is one of the major serum proteins in the early life of mammals. The function of this protein is not yet fully understood. AFP is an oncodevelopmental gene product which is expressed at high levels in the embryonic yolk sac and fetal liver. The synthesis of AFP decreases dramatically after birth. Only trace amounts of AFP are synthesized in the adult liver. However, expression of the AFP gene is reactivated in the adult during liver regeneration and hepatocarcinogenesis. AFP is an excellent model system for studying the temporal and tissue-specific regulation of oncodevelopmental gene expression. Experiments with transgenic mice and DNA transfection studies have revealed several transcriptional control regions and cis-acting elements in the AFP gene. A large number of trans-acting protein factors interacting with these cis-acting elements have also been identified. Recent studies demonstrated that expression of AFP is regulated by at least two major signal transduction pathways in response to extracellular stimuli. The interactions between steroid hormone receptors and transcriptional factors which respond to separate signal transduction pathways result in transcriptional regulation of AFP gene expression. Trans-acting protein factors or steroid receptors complexed with given response elements can display different activities in different cell types due to cross-talk among both local protein-protein interactions within the DNA-binding domain, and distal protein-protein interactions. However, the detailed mechanisms of AFP gene expression are still not completely understood."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1256,I1256)","v":8855579},{"$f":"(LEN($J1256) - LEN(SUBSTITUTE(LOWER($J1256),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1256) - LEN(SUBSTITUTE(LOWER($J1256),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1256) - LEN(SUBSTITUTE(LOWER($J1256),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1256:D1256)","v":0},1996,"Oral rehydration therapy.","Sachdev",8855579,"Oral rehydration therapy.    Abstract:   Oral rehydration solution (ORS), the best treatment of dehydration due to acute diarrhea, is the most important medical advance of this century since it is key to reducing infant and child morbidity and mortality. Pathogens responsible for acute diarrhea include those which produce enterotoxin at the intestinal mucosal surface, inducing secretion but are not invasive (e.g., Vibrio cholerae); those which invade and disrupt the mucosal lining (e.g., shigella species); and rotavirus. The World Health Organization (WHO)/UNICEF ORS is considered a universal ORS. Much research has been done on the ideal composition of an ORS. An ORS must have sufficient sodium to replace losses on a volume to volume basis, a glucose concentration that matches that of sodium to ensure its delivery to the ileum, sufficient amounts of potassium and base (e.g., sodium bicarbonate or trisodium citrate dihydrate) to correct acidosis and to enhance sodium absorption, and sufficient amounts of liquid. The risk of hypernatremia with use of the WHO/UNICEF ORS is a concern since infants and young children have an immature renal concentrating capacity, increased insensible water losses, and an impaired natriuretic response. Neonates and young infants may be prone to relatively slow correction of acidosis. It appears that the potassium content (20 mmol/l) of WHO-ORS should be higher to promote a net positive potassium retention. Too much glucose in the ORS will induce reverse osmosis of water into the gut, effectively making the ORS a dehydrating solution rather than a hydrating solution. Some carbohydrates other than glucose have proven effective glucose substitutes (e.g., sucrose, rice starch and powder, other cereals). Cereals have higher acceptability levels in developing countries. Research is investigating the nutritional benefits of supplementing ORS with micronutrients (e.g., vitamin A, folic acid, and zinc). ORS use with early refeeding has a beneficial effect on nutritional status after an acute diarrhea episode."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1257,I1257)","v":8841766},{"$f":"(LEN($J1257) - LEN(SUBSTITUTE(LOWER($J1257),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1257) - LEN(SUBSTITUTE(LOWER($J1257),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1257) - LEN(SUBSTITUTE(LOWER($J1257),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1257:D1257)","v":0},1996,"Vitamin A intake and status.","van den Berg",8841766,"Vitamin A intake and status.    Abstract:    OBJECTIVE : To review the methodology for vitamin A intake and status assessment and to discuss available data on vitamin A intake and status in the Netherlands.  CONCLUSIONS : For diagnosis of a deficient vitamin A status, a number of valid biochemical and functional tests and criteria for interpretation are available. However, the sensitivity and specificity of most tests for assessment of the vitamin A status in the suboptimal and/or marginal range seem troublesome. The average vitamin A intake in the Netherlands (adult men 830 RE; adult women 650 RE) is slightly below the Dutch RDA (men 1000 RE; women 800 RE. In particular, individuals avoiding liver and liver products have lower intakes and might have limited stores. The functional significance of these findings remains to be established."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1258,I1258)","v":8801165},{"$f":"(LEN($J1258) - LEN(SUBSTITUTE(LOWER($J1258),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1258) - LEN(SUBSTITUTE(LOWER($J1258),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1258) - LEN(SUBSTITUTE(LOWER($J1258),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1258:D1258)","v":0},1996,"The contribution of vitamin A to public health.","Underwood",8801165,"The contribution of vitamin A to public health.    Abstract:   Vitamin A deficiency among children in developing countries remains the leading cause of preventable severe visual impairment and blindness, and is a significant contributor to severe infections and death, particularly from diarrhea and measles. Vitamin A deficiency is also likely to increase vulnerability to other illnesses in both women and children, such as iron-deficiency anemia, and may be an important factor contributing to poor maternal performance during pregnancy and lactation and to growth deficits in children. Benefits to public health can be expected by improving the vitamin A status of deficient populations through an appropriate mix of acceptable, affordable, and available programs including promotion of breast-feeding, control of infections, dietary diversification, food fortification, and supplementation. Benefits include not only improved health and welfare for individuals and their families, but also improved chances of survival for an estimated 254 million children."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1259,I1259)","v":8678014},{"$f":"(LEN($J1259) - LEN(SUBSTITUTE(LOWER($J1259),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1259) - LEN(SUBSTITUTE(LOWER($J1259),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1259) - LEN(SUBSTITUTE(LOWER($J1259),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1259:D1259)","v":0},1996,"Small bowel intussusception and brown bowel syndrome in association with severe malnutrition.","Drake",8678014,"Small bowel intussusception and brown bowel syndrome in association with severe malnutrition.    Abstract:   Brown bowel syndrome is a rare condition characterized by deposition of lipofuscin in the smooth muscle cells of the gastrointestinal tract. The number of reported cases is small, but all are associated with malabsorptive states. Despite these small numbers, there is considerable evidence that vitamin E deficiency is important etiologically. We report here the case of a severely malnourished [body mass index 11.7 kg/m (2): normal range 20-25 kg/m (2)] 31-yr-old black male with a longstanding history of alcohol abuse, who was on anti-tuberculosis therapy. The patient presented with an acute abdomen and was found, at operation, to have a mid-ileal intussusception. Histological examination of the resected specimen demonstrated lipofuscin accumulation consistent with brown bowel syndrome, but no tumor. Subsequent investigations revealed no significant quantities of vitamin E in the blood and pancreatic steatorrhea. However, deficiency of other fat-soluble (vitamin A and D) and water-soluble vitamins (vitamin C and thiamine) also were detected. This report supports the association of brown bowel syndrome with vitamin E deficiency but cannot exclude the compounding effects of protein calorie malnutrition, multiple vitamin deficiencies, and chronic alcohol toxicity."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1260,I1260)","v":8624173},{"$f":"(LEN($J1260) - LEN(SUBSTITUTE(LOWER($J1260),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1260) - LEN(SUBSTITUTE(LOWER($J1260),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1260) - LEN(SUBSTITUTE(LOWER($J1260),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1260:D1260)","v":0},1996,"Safety of antioxidant vitamins.","Meyers",8624173,"Safety of antioxidant vitamins.    Abstract:   As a result of the many scientific and popular press reports of the benefits of antioxidant vitamins (vitamin A, beta-carotene, vitamin E, and ascorbic acid), it is estimated that 40% of the US population is consuming vitamin supplements. The efficacy of these supplements is not yet proved, and some have questioned their safety. Approximately 10 to 15 cases of vitamin A toxic reactions are reported per year in the United States, usually at doses greater than 100,000 IU/d. No adverse effects have been reported for beta-carotene. The frequency of vitamin E toxic reactions is not well delineated, but case reports are few at dosages less than 3200 mg/d. Ascorbic acid toxic reactions are rare at dosages less than 4 g/d. Despite a lack of clinical trial data, it seems that antioxidant vitamins are safe, although prudence might dictate their avoidance by women of childbearing potential, persons with liver disease or renal dysfunction, and those taking certain medications or undergoing specific laboratory tests."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1261,I1261)","v":8934754},{"$f":"(LEN($J1261) - LEN(SUBSTITUTE(LOWER($J1261),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1261) - LEN(SUBSTITUTE(LOWER($J1261),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1261) - LEN(SUBSTITUTE(LOWER($J1261),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1261:D1261)","v":0},1996,"Lessons learned from xeroderma pigmentosum.","Kraemer",8934754,"Lessons learned from xeroderma pigmentosum.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1262,I1262)","v":9055576},{"$f":"(LEN($J1262) - LEN(SUBSTITUTE(LOWER($J1262),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1262) - LEN(SUBSTITUTE(LOWER($J1262),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1262) - LEN(SUBSTITUTE(LOWER($J1262),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1262:D1262)","v":0},1996,"Hepatic stellate cells.","Friedman",9055576,"Hepatic stellate cells.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1263,I1263)","v":8858804},{"$f":"(LEN($J1263) - LEN(SUBSTITUTE(LOWER($J1263),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1263) - LEN(SUBSTITUTE(LOWER($J1263),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1263) - LEN(SUBSTITUTE(LOWER($J1263),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1263:D1263)","v":0},1996,"Quantitative and conceptual contributions of mathematical modeling to current views on vitamin A metabolism, biochemistry, and nutrition.","Green",8858804,"Quantitative and conceptual contributions of mathematical modeling to current views on vitamin A metabolism, biochemistry, and nutrition.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1264,I1264)","v":8839287},{"$f":"(LEN($J1264) - LEN(SUBSTITUTE(LOWER($J1264),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1264) - LEN(SUBSTITUTE(LOWER($J1264),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1264) - LEN(SUBSTITUTE(LOWER($J1264),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1264:D1264)","v":0},1996,"Structure and function of sinusoidal lining cells in the liver.","Wisse",8839287,"Structure and function of sinusoidal lining cells in the liver.    Abstract:   The hepatic sinusoid harbors 4 different cells: endothelial cells (100, 101), Kupffer cells (96, 102, 103), fat-storing cells (34, 51, 93), and pit cells (14, 107, 108). Each cell type has its own specific morphology and functions, and no transitional stages exist between the cells. These cells have the potential to proliferate locally, either in normal or in special conditions, that is, experiments or disease. Sinusoidal cells from a functional unit together with the parenchymal cells. Isolation protocols exist for all sinusoidal cells. Endothelial cells filter the fluids, exchanged between the sinusoid and the space of Disse through fenestrae (100), which measure 175 nm in diameter and are grouped in sieve plates. Fenestrae occupy 6-8% of the surface (106). No intact basal lamina is present under these cells (100). Various factors change the number and diameter of fenestrae [pressure, alcohol, serotonin, and nicotin; for a review, see Fraser et al (32)]. These changes mainly affect the passage of lipoproteins, which contain cholesterol and vitamin A among other components. Fat-storing cells are pericytes, located in the space of Disse, with long, contractile processes, which probably influence liver (sinusoidal) blood flow. Fat-storing cells possess characteristic fat droplets, which contain a large part of the bodys depot of vitamin A (91, 93). These cells play a major role in the synthesis of extracellular matrix (ECM) (34, 39-41). Strongly reduced levels of vitamin A occur in alcoholic livers developing fibrosis (56). Vitamin A deficiency transforms fat-storing cells into myofibroblast-like cells with enhanced ECM production (38). Kupffer cells accumulate in periportal areas. They specifically endocytose endotoxin (70), which activates these macrophages. Lipopolysaccharide, together with interferon gamma, belongs to the most potent activators of Kupffer cells (28). As a result of activation, these cells secrete oxygen radicals, tumor necrosis factor, interleukin 1, interleukin 6, and a series of eicosanoids (28) and become cytotoxic against tumor cells [e.g., colon carcinoma cells (19, 22, 48)]. Toxic secretory products can cause necrosis of the liver parenchyma, which constitutes a crucial factor in liver transplantation (55). Pit cells possess characteristic azurophylic granules and display a high level of spontaneous cytolytic activity against various tumor cells, identifying themselves as natural killer cells (10). The number and cytotoxicity of pit cells can be considerably enhanced with biological response modifiers, such as Zymosan or interleukin 2 (8). Pit cell proliferation occurs within the liver, but recent evidence indicates that blood large granular lymphocytes develop into pit cells in 2 steps involving high- and low-density pit cells (88). Kupffer cells control the motility, adherence, viability, and cytotoxicity of pit cells (89), whereas cytotoxicity against tumor cells is synergistically enhanced (80, 81)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1265,I1265)","v":8778447},{"$f":"(LEN($J1265) - LEN(SUBSTITUTE(LOWER($J1265),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1265) - LEN(SUBSTITUTE(LOWER($J1265),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1265) - LEN(SUBSTITUTE(LOWER($J1265),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1265:D1265)","v":0},1996,"Annual review or continuous assessment?","Carr",8778447,"Annual review or continuous assessment?    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1266,I1266)","v":8682490},{"$f":"(LEN($J1266) - LEN(SUBSTITUTE(LOWER($J1266),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1266) - LEN(SUBSTITUTE(LOWER($J1266),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1266) - LEN(SUBSTITUTE(LOWER($J1266),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1266:D1266)","v":0},1996,"Pathobiology of hepatic stellate cells.","Mathew",8682490,"Pathobiology of hepatic stellate cells.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1267,I1267)","v":8682445},{"$f":"(LEN($J1267) - LEN(SUBSTITUTE(LOWER($J1267),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1267) - LEN(SUBSTITUTE(LOWER($J1267),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1267) - LEN(SUBSTITUTE(LOWER($J1267),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1267:D1267)","v":0},1996,"Is necroinflammation a prerequisite for fibrogenesis?","Day",8682445,"Is necroinflammation a prerequisite for fibrogenesis?    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1268,I1268)","v":7588030},{"$f":"(LEN($J1268) - LEN(SUBSTITUTE(LOWER($J1268),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1268) - LEN(SUBSTITUTE(LOWER($J1268),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1268) - LEN(SUBSTITUTE(LOWER($J1268),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1268:D1268)","v":0},1995,"[Endemic sprue: its first diagnosis based on bleeding complications].","Heidinger",7588030,"[Endemic sprue: its first diagnosis based on bleeding complications].    Abstract:    HISTORY AND CLINICAL FINDINGS : A 47-year-old man without previously known illness was admitted to hospital because of acute haematomas in the legs: the history revealed no cause. The pale-looking patient reported having large and foul-smelling stools once or twice daily. There were large haematomas and swellings on both legs. His general and nutritional state was reduced. quot;Bleeding of unknown originquot; was suspected at this time.  INVESTIGATIONS : Haemoglobin concentration was 5.6 g/dl, while iron was normal and ferritin reduced. Quick value was below 5%, activated partial thromboplastin time prolonged to 180 s. Vitamin A and E concentrations were reduced; coumarin derivatives were not demonstrated in blood. Abdominal ultrasonography showed clearly thickened intestinal walls.  TREATMENT AND COURSE : Four units of erythrocyte concentrate were immediately administered, together with 2000 IU factors II, VII, X and anti-haemophilic factor B (PPSB), and 10 mg vitamin K intravenously. As intestinal malabsorption was suspected, a vitamin A absorption test was performed: it indicated malabsorption. Upper intestinal endoscopy showed coeliac disease, as did a biopsy. The patients state quickly improved after he had been given vitamins A, D, E and K and put on a gluten-free diet.  CONCLUSION : Coeliac disease can take a clinically unremarkable course for a long time and may finally become manifest through an isolated abnormality, such as bleeding."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1269,I1269)","v":8675241},{"$f":"(LEN($J1269) - LEN(SUBSTITUTE(LOWER($J1269),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1269) - LEN(SUBSTITUTE(LOWER($J1269),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1269) - LEN(SUBSTITUTE(LOWER($J1269),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1269:D1269)","v":0},1995,"Strategies for control of micronutrient malnutrition.","Vijayaraghavan",8675241,"Strategies for control of micronutrient malnutrition.    Abstract:   Micronutrient malnutrition, particularly vitamin A deficiency (VAD), iron deficiency anaemia (IDA) and iodine deficiency disorders (IDD), poses a serious threat to the health of vulnerable segments of population. Dietary Inadequacy is the primary cause of VAD and IDA, while poor iodine content of soil and water due to environmental iodine deficiency is the main determinant of IDD. Three major intervention strategies are available for the control of micronutrient malnutrition: supplementation of the specific micronutrients; fortification of foods with micronutrients; and horticulture intervention to increase production and nutrition education to ensure regular consumption of micronutrient rich foods. In India currently the national nutrition programmes being implemented for preventing these deficiencies are based on short term supplementation like periodic mega dosing of vitamin A, distribution of iron and folic acid tablets, and salt iodisation. Though these have been in operation for over two decades, there has been no perceptible biological impact on the prevalence of micronutrient malnutrition. Among the constraints, the most important are: lack of coordination, shortage of resources and manpower, inadequate and irregular supplies, lack of proper orientation and training to the functionaries, poor monitoring and supervision and absence of nutrition education. Integrated and multi-sectoral approaches are required to achieve the goals set under the National Nutrition Policy. These should include community-friendly nutrition education to increase awareness and motivation; active peoples participation; food fortification; nutrient supplementation; nutrition oriented horticulture programmes; orientation of functionaries, and establishment of integrated micronutrient surveillance. Concerted and focussed efforts are needed to combat micronutrient malnutrition by the 2000 AD."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1270,I1270)","v":7585282},{"$f":"(LEN($J1270) - LEN(SUBSTITUTE(LOWER($J1270),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1270) - LEN(SUBSTITUTE(LOWER($J1270),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1270) - LEN(SUBSTITUTE(LOWER($J1270),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1270:D1270)","v":0},1995,"Antioxidants in the Mediterranean diet.","Mancini",7585282,"Antioxidants in the Mediterranean diet.    Abstract:   It has been suggested that antioxidant vitamins or other antioxidants might inhibit the oxidation of low density lipoproteins into a particularly atherogenic form and preserve endothelial function. Antioxidants in the Mediterranean diet have been evaluated in relation to cardiovascular disease protection in this area. Observational epidemiologic data obtained from case-control, cohort or cross-cultural studies have consistently suggested that persons, such as those living in the Mediterranean area, who consume large amounts of antioxidant vitamins have a lower than average risk of cardiovascular disease. In another cross-cultural comparison, dietary intake, antioxidant status and plasma lipid peroxidation were compared in healthy young persons in Naples (Southern Italy) who consumed typical regional foods, and in Bristol (UK). The Naples group consumed more tomatoes and tomato juice, a higher proportion of monounsaturated fatty acids (from olive oil) and had a higher level of lipid antioxidant vitamin E (P = 0.005) and of beta carotene (P lt; 0.001) than the Bristol group. The intake of vitamin C, fresh fruit and vegetables, plasma vitamin A, serum selenium and copper levels did not differ. Several indices of plasma lipid peroxidation were significantly lower in the Naples group: conjugated dienes (P lt; 0.001), diene conjugation index (P = 0.019), lipid peroxides (P lt; 0.001). Dietary habits leading to relatively low levels of oxidized lipoproteins might contribute to the lower risk of coronary artery disease in Southern Italy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1271,I1271)","v":7549031},{"$f":"(LEN($J1271) - LEN(SUBSTITUTE(LOWER($J1271),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1271) - LEN(SUBSTITUTE(LOWER($J1271),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1271) - LEN(SUBSTITUTE(LOWER($J1271),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1271:D1271)","v":0},1995,"The major complications of coeliac disease.","Wright",7549031,"The major complications of coeliac disease.    Abstract:   Neoplasms constitute the major complication of coeliac disease, and high-grade T-cell lymphoma of the small intestine (enteropathy-associated T-cell lymphoma) is the most common neoplasm in this category. HLA genotyping indicates that in patients with enteropathy-associated T-cell lymphoma have the coeliac disease associated DQA1*0501, DQB1*0201 phenotype, although additional HLA-DR/DQ alleles may represent risk factors for lymphoma development. Molecular biological and immunohistochemical studies have shown that the intestinal mucosa distant from the tumour contains clonal populations of small T cells, often of the same clone as the high-grade T-cell lymphoma. These findings suggest that enteropathy-associated T-cell lymphoma arises in the setting of coeliac disease and evolves from reactive intraepithelial lymphocytes through a low-grade lymphocytic neoplasm to a high-grade tumour, which is usually the cause of the presenting symptoms. Most cases of chronic ulcerative enteropathy (ulcerative jejunitis) are probably part of the same disease process. If the ulceration occurs at a time when the neoplastic T-cells are of a low grade, morphological recognition of tumour cells in the ulcers may be impossible. Carcinoma of the pharynx and oesophagus, and adenocarcinoma of the small intestine, are increased in frequency in patients with coeliac disease. The increased risk of carcinoma of the oesophagus may be related to vitamin A deficiency. A number of reports have indicated an increased prevalence of various types of chronic hepatitis in patients with coeliac disease, but no coherent view of the cause of this association has emerged. Similarly, patients with coeliac disease have been reported to have various forms of fibrosing lung disease of uncertain causation. In recent years, there have been several reports, mainly from Italy, of a syndrome of epilepsy and bilateral brain calcification occurring in coeliac patients. The pathogenesis of this condition is not known and its prevalence in other communities is uncertain. Splenic atrophy occurs frequently in patients with coeliac disease and is related to the severity of the disease and degree of dietary control. Splenic atrophy predisposes to infection with capsulated bacteria, although mortality studies indicate that infection with these organisms is not a major cause of death in patients with coeliac disease."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1272,I1272)","v":7672435},{"$f":"(LEN($J1272) - LEN(SUBSTITUTE(LOWER($J1272),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1272) - LEN(SUBSTITUTE(LOWER($J1272),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1272) - LEN(SUBSTITUTE(LOWER($J1272),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1272:D1272)","v":0},1995,"Peroxisome proliferation in response to xenobiotics.","DePierre",7672435,"Peroxisome proliferation in response to xenobiotics.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1273,I1273)","v":7847365},{"$f":"(LEN($J1273) - LEN(SUBSTITUTE(LOWER($J1273),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1273) - LEN(SUBSTITUTE(LOWER($J1273),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1273) - LEN(SUBSTITUTE(LOWER($J1273),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1273:D1273)","v":0},1995,"Hypervitaminosis A in two hemodialysis patients.","Fishbane",7847365,"Hypervitaminosis A in two hemodialysis patients.    Abstract:   We present two cases of hemodialysis patients developing vitamin A toxicity related to excessive consumption of nutritional supplements containing large quantities of vitamin A. In one patient, severe hypercalcemia was the lone presenting sign; in the other, hypercalcemia was associated with unusual neurologic manifestations. We will discuss the reason why hemodialysis patients are at special risk for the development of hypervitaminosis A and review the mechanism leading to the associated hypercalcemia."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1274,I1274)","v":7731628},{"$f":"(LEN($J1274) - LEN(SUBSTITUTE(LOWER($J1274),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1274) - LEN(SUBSTITUTE(LOWER($J1274),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1274) - LEN(SUBSTITUTE(LOWER($J1274),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1274:D1274)","v":0},1995,"Treatment of vulvar lichen sclerosus in the elderly: an update.","Elchalal",7731628,"Treatment of vulvar lichen sclerosus in the elderly: an update.    Abstract:   Lichen sclerosus et atrophicus is a disorder of the skin that can occur anywhere on the body and in all age groups but mainly affects middle-aged and elderly women in the vulvoperineal area. It consists of ivory or pink papules or macules that eventually coalesce into thin, gray, parchment-like areas. Clinically, the main symptoms are severe and intractable itching and vaginal soreness with dyspareunia. Although it has been described to be associated with an increased risk for epithelial malignancy this, in fact, very rarely occurs. The exact nature of LSA is still unknown. The accumulation of evidence does little to clarify its pathogenesis and etiology. The different reports indicate at least three general possibilities; autoimmune, metabolic, and more recently infectious etiology. The coexistence of such diverse findings in one disease entity may indicate one of the two; either we are facing a group of very similar conditions, which will be separated in the future into several closely related clinical entities, each with its own etiology, or that all findings represent a complex multi-step single pathogenetic mechanism. The latter possibility seems more probable because it has previously been suggested that B. burgdorferi, a recent prime suspect in the pathogenesis of LSA, may induce both metabolic and autoimmune abnormalities in the course of infection. New therapeutic options and attitudes emerge that dramatically improved the conservative treatment of this disease (Table 5).(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1275,I1275)","v":7985711},{"$f":"(LEN($J1275) - LEN(SUBSTITUTE(LOWER($J1275),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1275) - LEN(SUBSTITUTE(LOWER($J1275),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1275) - LEN(SUBSTITUTE(LOWER($J1275),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1275:D1275)","v":0},1994,"Vitamin A hepatotoxicity: a cautionary note regarding 25,000 IU supplements.","Kowalski",7985711,"Vitamin A hepatotoxicity: a cautionary note regarding 25,000 IU supplements.    Abstract:   Vitamin A hepatotoxicity has been reported at doses exceeding 50,000 IU/day. At 25,000 IU vitamin A per day, although elevated liver enzymes may be seen, hepatotoxicity is rare. We report a case of severe hepatotoxicity associated with the habitual daily ingestion of 25,000 IU of vitamin A bought as an over-the-counter dietary supplement. With the general availability of high-dose supplements and recent literature emphasizing the importance of vitamin A adequacy, the potential for vitamin A hepatotoxicity may increase. Health professionals should remain aware of the potential for vitamin A hepatotoxicity and elicit a vitamin A history in all patients being evaluated for liver dysfunction."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1276,I1276)","v":7698827},{"$f":"(LEN($J1276) - LEN(SUBSTITUTE(LOWER($J1276),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1276) - LEN(SUBSTITUTE(LOWER($J1276),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1276) - LEN(SUBSTITUTE(LOWER($J1276),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1276:D1276)","v":0},1994,"Fat-soluble vitamins and their importance in patients with cholestatic liver diseases.","Sokol",7698827,"Fat-soluble vitamins and their importance in patients with cholestatic liver diseases.    Abstract:   A substantial effort has been made over the past decade to characterize the metabolism of the fat-soluble vitamins in chronic cholestasis to both improve the clinical care of affected patients and to understand the pathophysiology of the vitamin deficiency states. Cholestatic liver disease is a unique cause of fat malabsorption in which standard indices to evaluate vitamin status may be inaccurate. Thus, specific approaches to define vitamin status are being developed. Using the treatment modalities outlined in this review, fat-soluble vitamin deficiency should be a manageable problem and not lead to significant morbidity in patients with chronic cholestasis. The most subtle consequences of deficiency of each vitamin remains to be discovered."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1277,I1277)","v":7974494},{"$f":"(LEN($J1277) - LEN(SUBSTITUTE(LOWER($J1277),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1277) - LEN(SUBSTITUTE(LOWER($J1277),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1277) - LEN(SUBSTITUTE(LOWER($J1277),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1277:D1277)","v":0},1994,"Kupffer cell stimulation with Corynebacterium parvum reduces some cytochrome P450-dependent activities and diminishes acetaminophen and carbon tetrachloride-induced liver injury in the rat.","Raiford",7974494,"Kupffer cell stimulation with Corynebacterium parvum reduces some cytochrome P450-dependent activities and diminishes acetaminophen and carbon tetrachloride-induced liver injury in the rat.    Abstract:   Chemical activation of Kupffer cells in vivo by vitamin A or latex beads is associated with a worsening of hepatic injury induced by the P450-dependent hepatotoxins acetaminophen (ACET) and carbon tetrachloride (CCl4) and by the P450-independent toxin galactosamine (GLN). Immunostimulants such as Corynebacterium parvum (CP) also activate Kupffer cells, but do so while prompting release of soluble mediators which depress microsomal oxidative activities in cultured hepatocytes. Therefore, we sought to characterize the effects of CP on hepatic injury in vivo due to ACET and CCl4 while employing GLN as a control. Hepatic microsomal oxidative activity and glutathione (GSH) disposition were examined since each influences susceptibility to injury from ACET or CCl4. Rats were given CP 28 mg/kg i.v. 5 days before challenge with hepatotoxicant. Hepatic injury was assessed 24 hr after hepatotoxicant administration by measurement of serum alanine aminotransferase (ALT) activity and review of histological sections. Livers from parallel groups of rats were used to prepare microsomal and cytosolic fractions, to measure tissue GSH, or for perfusion to assess GSH efflux. Significant reductions in injury due to ACET or CCl4 were observed while injury due to GLN was potentiated. Serum ALT levels after ACET were 3000 +/- 620 in controls vs 170 +/- 45 IU/liter in the CP-treated group and ALT levels after CCl4 were 3100 +/- 500 in controls vs 1700 + 450 IU/liter in the CP-treated group. In contrast, serum ALT levels after GLN were 920 +/- 230 in controls vs 1700 +/- 370 in the CP-treated group. Patterns of hepatic injury observed on histological sections were those characteristic for each toxin and the severity of injury correlated well with alterations in serum ALT levels for each agent. Hepatic microsomal fractions from rats pretreated with CP showed significantly diminished total cytochrome P450 content as well as reduced activity for two P450IIE1 substrates, p-nitrophenol and 7-ethoxycoumarin. While sinusoidal efflux of GSH increased by 40% in rats pretreated with CP and cytosolic glutathione-S-transferase activity fell slightly, tissue GSH levels were unaffected. These data demonstrate that CP decreases microsomal cytochrome P450 content, reduces biotransformation of two P450IIE1 substrates, and diminishes ACET- and CCl4-induced hepatic injury. In contrast, hepatic injury due to the P450-independent toxin GLN was enhanced. Thus, chemical and immune stimulation of Kupffer cells may result in divergent effects on susceptibility to injury from individual hepatotoxins."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1278,I1278)","v":7927269},{"$f":"(LEN($J1278) - LEN(SUBSTITUTE(LOWER($J1278),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1278) - LEN(SUBSTITUTE(LOWER($J1278),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1278) - LEN(SUBSTITUTE(LOWER($J1278),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1278:D1278)","v":0},1994,"The Mallory body: theories on development and pathological significance (Part 2 of a literature survey).","Jensen",7927269,"The Mallory body: theories on development and pathological significance (Part 2 of a literature survey).    Abstract:   Drawing on data from a previously published literature survey on the clinical and experimental epidemiology of the Mallory body, we discuss current theories on its development in a pro et contra manner. Conclusions have been largely left open to the interpretations of the reader because many are still speculative. The main results of this study characterize Mallory bodies as stereotypical histological byproducts to diverse hepatic injuries (mostly alcohol associated) of questionable pathogenic importance. The temporal characteristics of Mallory bodies cast doubt on their role in hepatic neoplasia both as a disease marker and a causative agent, and prognosis studies suggest that they may be considered preterminal markers in some nonalcoholic liver diseases but remain prognostically unimportant in most studies on alcoholic patients. By similar line of inquiry, no consistent relationships may be found with disease severity or duration in alcoholic liver diseases. The roles of vitamin A deficiency and protein-calorie malnutrition are circumstantial. Drugs known to have calcium-antagonist properties and the physiological characteristics of the stress-response protein ubiquitin support the concept of defective protein systems in Mallory body pathogenesis. Disproportionate hepatic copper accumulation seems both epidemiologically and topographically associated with Mallory bodies, but these connections are largely unsupported by exposure studies. Many arguments still downplay the importance of uncoordinated changes in hepatic oxygen delivery and consumption, but ischemia-reperfusion studies suggest a role of oxygen-derived free radicals in the liver injuries under scrutiny. Finally, the role of Mallory bodies in the control system of hepatocyte function is addressed, and indirect evidence lends credence to a cybernetic approach in future study designs. It is reasonable to assume that different elements of a multifactorial setting operate with varying intensity over time as this may account for some of the controversies that exist. In conclusion, the biological significance of Mallory bodies is still mystery. It is not known whether Mallory bodies represent an epiphenomenon or play a role themselves in the initiation and continuation of liver damage."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1279,I1279)","v":7826592},{"$f":"(LEN($J1279) - LEN(SUBSTITUTE(LOWER($J1279),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1279) - LEN(SUBSTITUTE(LOWER($J1279),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1279) - LEN(SUBSTITUTE(LOWER($J1279),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1279:D1279)","v":0},1994,"Hepatic and metabolic effects of ethanol: pathogenesis and prevention.","Lieber",7826592,"Hepatic and metabolic effects of ethanol: pathogenesis and prevention.    Abstract:   Mechanisms of the hepatotoxicity of ethanol are reviewed, including effects resulting from alcohol dehydrogenase (ADH) mediated excessive hepatic generation of NADH and acetaldehyde. Gastric ADH explains first-pass metabolism by ethanol; its activity is low in alcoholics and in females and is decreased by some commonly used drugs. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last 25 years have culiminated in the molecular elucidation of the ethanol-inducible cytochrome P-450 (2E1) which causes metabolic tolerance to ethanol and to various commonly used medications, enhanced degradation of testosterone and vitamin A (with vitamin A depletion) and selective hepatic perivenular toxicity. The latter results from free radical generation and activation of various xenobiotics, causing increased vulnerability of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens and even nutritional factors such as vitamin A and beta-carotene. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation which promotes GSH depletion and lipid peroxidation and other toxic effects. Nutritional deficits may affect the toxicity of ethanol and acetaldehyde, as illustrated by the depletion in glutathione, ameliorated by S-adenosyl-L-methionine. Other supernutrients include polyenylphosphatidylcholine, shown to correct the alcohol-induced hepatic phosphatidylcholine depletion and to prevent alcoholic cirrhosis in non-human primates."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1280,I1280)","v":7802623},{"$f":"(LEN($J1280) - LEN(SUBSTITUTE(LOWER($J1280),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1280) - LEN(SUBSTITUTE(LOWER($J1280),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1280) - LEN(SUBSTITUTE(LOWER($J1280),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1280:D1280)","v":0},1994,"[The problem of a high content of vitamin A in the liver of calves, cattle, sheep and swine for the consumer. Amount of accumulation and mechanism of teratogenic effect (review article)].","Kolb",7802623,"[The problem of a high content of vitamin A in the liver of calves, cattle, sheep and swine for the consumer. Amount of accumulation and mechanism of teratogenic effect (review article)].    Abstract:   Cases of hypervitaminosis A in men--especially in pregnant women, with development of malformations--are reported. The existence of withdrawal times to slaughter after the application of vitamin-A-containing preparations with a content of 10,000 to 10(6) international units and more is described. The content of vitamin A in the liver of monogastric animals is closely related to that in the feed. In ruminants about 40 to 70% of the vitamin A of the feed is decomposed by the microorganisms in the forestomachs. The amount of vitamin A stored in the liver after a therapeutic application is dependent of the initial content. The velocity of the depletion of the stores at a carotene- and vitamin-A-poor feeding is described. In ruminants and pigs in the account of the properties of the placenta no embryotoxicity of a therapeutic dose of vitamin A is to be expected. The mechanism of the teratogenesis by vitamin A in mice is described."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1281,I1281)","v":7739873},{"$f":"(LEN($J1281) - LEN(SUBSTITUTE(LOWER($J1281),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1281) - LEN(SUBSTITUTE(LOWER($J1281),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1281) - LEN(SUBSTITUTE(LOWER($J1281),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1281:D1281)","v":0},1994,"[Perisinusoidal stellate cells or Ito cells and their role in hepatic fibrosis].","Casu",7739873,"[Perisinusoidal stellate cells or Ito cells and their role in hepatic fibrosis].    Abstract:   In this review on stellate cells, discovered by Kupffer more than 100 years ago, morphological and ultrastructural aspects, origin and differentiation are described through also a comparative analysis in some animal species. Many methods used from different laboratories for isolation, identification and in vitro culture of these heterogeneous cells are reported and discussed regarding advantages and disadvantages. The normal Ito cells functions, that are metabolism and storage of vitamin A, extracellular matrix (ECM) synthesis under cytokines control, and sinusoidal tonus through its reversible contraction are discussed. Then an update description is reported about fibrogenesis and all the factors involved in liver fibrosis, from cytokines to the adhesion molecules. Stellate cells being the main source of ECM in chronic liver injury, can play different and primary roles by shifting its functions toward fibrosis. The role of metalloproteinases and their inhibitors on the balance of the ECM synthesis and degradation are also evaluated. When liver is injured, Ito cells became activated and change their phenotype from fat-storing cells to cells to cell devoid of retonoid droplets. They express the smooth muscle-like features, including a-SM-actin. The role of vitamin A in liver fibrosis is not yet clear: current data and hypothesis about this topic are discussed. Contractile behaviour of the perisinusoidal stellate cells seems also important in influencing portal blood pressure during fibrosis and cirrhosis. Diagnostic methods for hepatic fibrosis and Ito cells activation are also briefly reported. The review is supplied with more than three hundred references updated to August 1994."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1282,I1282)","v":8085583},{"$f":"(LEN($J1282) - LEN(SUBSTITUTE(LOWER($J1282),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1282) - LEN(SUBSTITUTE(LOWER($J1282),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1282) - LEN(SUBSTITUTE(LOWER($J1282),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1282:D1282)","v":0},1994,"Antioxidant vitamins and cancer.","Hennekens",8085583,"Antioxidant vitamins and cancer.    Abstract:   Cancer is the second leading cause of death in the United States as well as most developed countries. Although advances in treatment have afforded tremendous benefits to large numbers of patients, effective primary prevention measures could, in theory, have an even greater public health impact. Diet has been postulated to account for as much as 35% of all human cancers, raising the possibility that specific constituents of diet with cancer chemopreventive effects could be identified. Risk reductions of even 20-30%, which is the most likely magnitude of any protective effect of nutritional agents, could have a significant public health impact on so common and serious a disease. Antioxidant vitamins are among the constituents of diet hypothesized to exert chemopreventive effects. Antioxidant vitamins, which include beta-carotene (pro-vitamin A), vitamin E, and vitamin C, are hypothesized to decrease cancer risk by preventing tissue damage by trapping organic free radicals and/or deactivating excited oxygen molecules, a by-product of many metabolic functions. Over 100 observational epidemiologic studies have assessed the relationship of dietary antioxidant intake or blood nutrient levels with cancer risk. Such studies are not entirely consistent but provide support for the hypothesis that antioxidant vitamin intake may decrease cancer risk. However, the chief limitation of such observational studies is their inability to control for all factors associated with vitamin intake that might independently affect cancer risk. Such unknown or unmeasured confounding variables could account for all or part of any observed associations. For this reason, definitive data on the role of antioxidant vitamins and cancer can derive only from properly conducted large-scale randomized trials of sufficient sample size, dose, and duration of treatment and follow-up. Two large-scale trials have been completed, and several are currently ongoing among well-nourished populations at high risk for cancer as well as among individuals at usual risk. Over the next several years, these trials should provide clear evidence concerning the role of antioxidant vitamins in the prevention of cancer. Such data are crucial for both individual clinical decision making as well as rational public health policy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1283,I1283)","v":7965695},{"$f":"(LEN($J1283) - LEN(SUBSTITUTE(LOWER($J1283),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1283) - LEN(SUBSTITUTE(LOWER($J1283),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1283) - LEN(SUBSTITUTE(LOWER($J1283),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1283:D1283)","v":0},1994,"Nutrition and wound healing.","Mazzotta",7965695,"Nutrition and wound healing.    Abstract:   Proper nutrition in presurgical patients can enhance wound healing and potentially decrease the cost of postsurgical medical care. Therefore, to combat increasing health care costs, it is important that the health care professional have a solid understanding of the role of essential nutrients in the healing process. The author reviews the role of the following in wound healing: protein, vitamin A, zinc, vitamin C, vitamin E, and iron."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1284,I1284)","v":8029686},{"$f":"(LEN($J1284) - LEN(SUBSTITUTE(LOWER($J1284),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1284) - LEN(SUBSTITUTE(LOWER($J1284),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1284) - LEN(SUBSTITUTE(LOWER($J1284),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1284:D1284)","v":0},1994,"[Hypercalcemia].","Schmid",8029686,"[Hypercalcemia].    Abstract:   Severe hypercalcemia is mainly caused by inappropriately high concentrations of compounds which promote bone resorption, in particular PTH, PTHrP, or 1,25 (OH)2D3. The major consequences are impaired central nervous system and kidney function (polyuria/dehydration); the latter, in turn, aggravate hypercalcemia via decreased fluid intake, mobility, and renal calcium clearance. The most common causes of hypercalcemia are primary hyperparathyroidism and tumors, drugs (in particular thiazides, lithium, vitamin D and vitamin A and their derivatives), granulomatous and infectious diseases. The patient with mild hypercalcemia should be controlled (and if necessary operated on for adenoma of the parathyroid glands), while the patient with acute severe hypercalcemia needs to be treated immediately by (1.) 0.9% NaCl i.v. to restore plasma volume, (2.) bisphophonates i.v. to block bone resorption, and (3.) therapy for the underlying disorder."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1285,I1285)","v":8143977},{"$f":"(LEN($J1285) - LEN(SUBSTITUTE(LOWER($J1285),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1285) - LEN(SUBSTITUTE(LOWER($J1285),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1285) - LEN(SUBSTITUTE(LOWER($J1285),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1285:D1285)","v":0},1994,"Alcohol and the liver: 1994 update.","Lieber",8143977,"Alcohol and the liver: 1994 update.    Abstract:   This article reviews current concepts on the pathogenesis and treatment of alcoholic liver disease. It has been known that the hepatotoxicity of ethanol results from alcohol dehydrogenase-mediated excessive generation of hepatic nicotinamide adenine dinucleotide, reduced form, and acetaldehyde. It is now recognized that acetaldehyde is also produced by an accessory (but inducible) microsomal pathway that additionally generates oxygen radicals and activates many xenobiotics to toxic metabolites, thereby explaining the increased vulnerability of heavy drinkers to industrial solvents, anesthetics, commonly used drugs, over-the-counter medications, and carcinogens. The contribution of gastric alcohol dehydrogenase to the first-pass metabolism of ethanol and alcohol-drug interactions is discussed. Roles for hepatitis C, cytokines, sex, genetics, and age are now emerging. Alcohol also alters the degradation of key nutrients, thereby promoting deficiencies as well as toxic interactions with vitamin A and beta carotene. Conversely, nutritional deficits may affect the toxicity of ethanol and acetaldehyde, as illustrated by the depletion in glutathione, ameliorated by S-adenosyl-L-methionine. Other quot;supernutrientsquot; include polyunsaturated lecithin, shown to correct the alcohol-induced hepatic phosphatidylcholine depletion and to prevent alcoholic cirrhosis in nonhuman primates. Thus, a better understanding of the pathology induced by ethanol is now generating improved prospects for therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1286,I1286)","v":8072308},{"$f":"(LEN($J1286) - LEN(SUBSTITUTE(LOWER($J1286),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1286) - LEN(SUBSTITUTE(LOWER($J1286),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1286) - LEN(SUBSTITUTE(LOWER($J1286),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1286:D1286)","v":0},1994,"Amrita Bindu--a salt-spice-herbal health food supplement for the prevention of nitrosamine induced depletion of antioxidants.","Shanmugasundaram",8072308,"Amrita Bindu--a salt-spice-herbal health food supplement for the prevention of nitrosamine induced depletion of antioxidants.    Abstract:   Ayurveda, practised in India, identified a large number of plant components to be used in the diet for the prevention or the delayed development of degenerative disorders. They include some of the commonly used spices, namely pepper and ginger. The Materia Medica includes both naturally occurring and artificially produced salts, as a partial substitute for common salt. Health promoting herbs and spices which are classified pharmacologically as rejuvenating, nourishing, invigorating, cleansing, wound-healing, etc., are used as food additives. Amrita Bindu is a salt-spice-herbal mixture based on these principles and was tested for its effect in maintaining antioxidant defense systems in blood and liver when exposed to a carcinogenic nitrosamine, N-methyl-N-nitro-N-nitrosoguanidine (MNNG). Amrita Bindu supplementation prevented MNNG induced depletion of the antioxidant enzymes and the scavenger antioxidants glutathione and vitamins A, C and E. Amrita Bindu provides protection against free radical and reactive oxygen species induced tissue lipid peroxidation and the resultant tissue degeneration."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1287,I1287)","v":8974351},{"$f":"(LEN($J1287) - LEN(SUBSTITUTE(LOWER($J1287),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1287) - LEN(SUBSTITUTE(LOWER($J1287),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1287) - LEN(SUBSTITUTE(LOWER($J1287),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1287:D1287)","v":0},1994,"Susceptibility to alcohol-related liver injury.","Lieber",8974351,"Susceptibility to alcohol-related liver injury.    Abstract:   Alcohol affects the liver through metabolic disturbances associated with its oxidation. Redox changes produced by the hepatic alcohol dehydrogenase pathway affect lipid, carbohydrate and protein metabolism. Ethanol is also oxidized in liver microsomes by the ethanol-inducible cytochrome P4502E1, resulting in ethanol tolerance and selective hepatic perivenular damage. Furthermore, P4502E1 activates various xenobiotics, explaining the increased susceptibility of the heavy drinker to the toxicity of anesthetics, commonly used medications (i.e. isoniazid), analgesics (i.e. acetaminophen), and chemical carcinogens. Induction of microsomal enzymes also contributes to vitamin A depletion, enhances its hepatotoxicity and results in increased acetaldehyde generation from ethanol, with formation of protein adducts, glutathione depletion, free-radical-mediated toxicity, and lipid peroxidation. Chronic ethanol consumption strikingly enhances the number of hepatic collagen-producing activated lipocytes. Both in vivo (in our baboon model of alcoholic cirrhosis) and in vitro (in cultured myofibroblasts and activated lipocytes) ethanol and/or its metabolite acetaldehyde increase collagen accumulation and mRNA for collagen. Gender differences are related, in part, to lower gastric ADH activity (with consequent reduction of first pass ethanol metabolism) in young women, decreased hepatic fatty acid binding protein and increased free-fatty acid levels as well as lesser omega-hydroxylation, all of which result in increased vulnerability to ethanol. Elucidation of the biochemical effects of ethanol are now resulting in improved therapy: in baboons, S-adenosyl-L-methionine attenuates the ethanol-induced glutathione depletion and associated mitochondrial lesions, and polyenylphosphatidylcholine opposes the ethanol-induced hepatic phospholipid depletion, the decrease in phosphatidylethanolamine methyltransferase activity and the activation of hepatic lipocytes, with full prevention of ethanol-induced septal fibrosis and cirrhosis; its dilinoleoyl species also increases collagenase activity in lipocytes. The efficacy of this compound in man is now being studied in randomized multicenter clinical trials."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1288,I1288)","v":8172982},{"$f":"(LEN($J1288) - LEN(SUBSTITUTE(LOWER($J1288),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1288) - LEN(SUBSTITUTE(LOWER($J1288),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1288) - LEN(SUBSTITUTE(LOWER($J1288),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1288:D1288)","v":0},1994,"[Bacterial translocation from the nutritional perspective].","de Oca",8172982,"[Bacterial translocation from the nutritional perspective].    Abstract:   A variety of situations involving loss of the physical integrity of the gastrointestinal barrier, excess intraluminal bacterial growth or immunological compromise of the host, have been shown experimentally to predispose to bacterial translocation. While colonization of the mesenteric ganglia is a mechanism which stimulates local immune defenses, distant colonization of other organs causes these defences to fail. In general, in the latter situation, a variety of factors must combine, notably the nutritional state or nutritional therapy. Protein malnutrition states do not alone generate bacterial translocation, but they do facilitate the distant dissemination of germs in situations such as endotoxemia. Bacterial translocation is objectivized after the prolonged use of total parenteral nutrition or of chemically defined non-fiber diets. The addition of fiber restores the architecture and physiology of the intestinal microvilli and prevents bacterial translocation in animals with a variety of morphological lesions of the intestinal barrier. While the results of the clinical studies are as yet not very conclusive, there is a clear link between bacteremia of intestinal origin and multiple organ failures. Nutritional support of patients with an acute metabolic compromise must, at least as inferred from the experimental studies, take account of the following factors: in the first place, the use of a preparation with a qualitatively and quantitatively suitable fiber content, to prevent atrophy of the intestinal villi; in the second place, the use of quot;scavengerquot; agents or physiological sweepers of the free radicals of oxygen, such as vitamin A, E or C or selenium; and, finally, day by day there is an increasing interest in the therapeutic use of substrates with immunomodulatory capacity, such as glutamine or arginine. On the other hand, the use must be questioned of substances such as Omega 3 series polyunsaturated fatty acids which are on their own able to increase lipidic peroxidation induced by free oxygen radicals."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1289,I1289)","v":8031675},{"$f":"(LEN($J1289) - LEN(SUBSTITUTE(LOWER($J1289),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1289) - LEN(SUBSTITUTE(LOWER($J1289),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1289) - LEN(SUBSTITUTE(LOWER($J1289),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1289:D1289)","v":0},1994,"Miscellaneous neurologic, cardiac, pulmonary, and metabolic disorders with rheumatic manifestations.","Larkin",8031675,"Miscellaneous neurologic, cardiac, pulmonary, and metabolic disorders with rheumatic manifestations.    Abstract:   The First International Workshop on Hypertrophic Osteoarthropathy crystallized the current knowledge of this puzzling syndrome. Cytokine release by large thrombocytes in the periphery is the favored etiology, although specific therapy remains unavailable. An article on the rheumatologic consequences of alcohol is reviewed, along with a number of case reports of joint problems in rare skin and metabolic diseases. Understanding the mechanisms of rarities, including rheumatic fever, interleukin-2-induced arthritis, and a unique quot;menstrual arthritisquot; might give insight into the etiology of more common arthropathies."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1290,I1290)","v":7972256},{"$f":"(LEN($J1290) - LEN(SUBSTITUTE(LOWER($J1290),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1290) - LEN(SUBSTITUTE(LOWER($J1290),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1290) - LEN(SUBSTITUTE(LOWER($J1290),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1290:D1290)","v":0},1994,"Delineating peroxisome proliferator action to improve human risk assessment.","Green",7972256,"Delineating peroxisome proliferator action to improve human risk assessment.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1291,I1291)","v":7966525},{"$f":"(LEN($J1291) - LEN(SUBSTITUTE(LOWER($J1291),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1291) - LEN(SUBSTITUTE(LOWER($J1291),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1291) - LEN(SUBSTITUTE(LOWER($J1291),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1291:D1291)","v":0},1994,"Mechanisms of ethanol-drug-nutrition interactions.","Lieber",7966525,"Mechanisms of ethanol-drug-nutrition interactions.    Abstract:   Mechanisms of the toxicologic manifestations of ethanol abuse are reviewed. Hepatotoxicity of ethanol results from alcohol dehydrogenase-mediated excessive hepatic generation of nicotinamide adenine dinucleotide and acetaldehyde. It is now recognized that acetaldehyde is also produced by an accessory (but inducible) pathway, the microsomal ethanol-oxidizing system, which involves a specific cytochrome P450. It generates oxygen radicals and activates many xenobiotics to toxic metabolites, thereby explaining the increased vulnerability of heavy drinkers to industrial solvents, anesthetics, commonly used drugs, over-the-counter medications and carcinogens. The contribution of gastric alcohol dehydrogenase to the first pass metabolism of ethanol and alcohol-drug interactions is now recognized. Alcohol also alters the degradation of key nutrients, thereby promoting deficiencies as well as toxic interactions with vitamin A and beta-carotene. Conversely, nutritional deficits may affect the toxicity of ethanol and acetaldehyde, as illustrated by the depletion in glutathione, ameliorated by S-adenosyl-L-methionine. Other supernutrients include polyenylphosphatidylcholine, shown to correct the alcohol-induced hepatic phosphatidylcholine depletion and to prevent alcoholic cirrhosis in non-human primates. Thus, a better understanding of the pathology induced by ethanol has now generated improved prospects for therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1292,I1292)","v":8219401},{"$f":"(LEN($J1292) - LEN(SUBSTITUTE(LOWER($J1292),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1292) - LEN(SUBSTITUTE(LOWER($J1292),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1292) - LEN(SUBSTITUTE(LOWER($J1292),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1292:D1292)","v":0},1993,"Aetiology and pathogenesis of alcoholic liver disease.","Lieber",8219401,"Aetiology and pathogenesis of alcoholic liver disease.    Abstract:   Until the 1960s, liver disease of the alcoholic patient was attributed exclusively to dietary deficiencies. Since then, however, our understanding of the impact of alcoholism on nutritional status has undergone a progressive evolution. Alcohol, because of its high energy content, was at first perceived to act exclusively as empty calories displacing other nutrients in the diet, and causing primary malnutrition through decreased intake of essential nutrients. With improvement in the overall nutrition of the population, the role of primary malnutrition waned and secondary malnutrition was emphasized as a result of a better understanding of maldigestion and malabsorption caused by chronic alcohol consumption and various diseases associated with chronic alcoholism. At the same time, the concept of the direct toxicity of alcohol came to the forefront as an explanation for the widespread cellular injury. Some of the hepatotoxicity was found to result from the metabolic disturbances associated with the oxidation of ethanol via the liver alcohol dehydrogenase (ADH) pathway and the redox changes produced by the generated NADH, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Exaggeration of the redox change by the relative hypoxia which prevails physiologically in the perivenular zone contributes to the exacerbation of the ethanol-induced lesions in zone 3. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last twenty years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450IIE1 (CYP2E1) which contributes not only to ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various xenobiotics. Their activation by CYP2E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, over the counter analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation and decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize oxygen. Moreover, acetaldehyde promotes glutathione depletion, free-radical mediated toxicity and lipid peroxidation. In addition, acetaldehyde affects hepatic collagen synthesis: both in vivo and in vitro (in cultured myofibroblasts and lipocytes), ethanol and its metabolite acetaldehyde were found to increase collagen accumulation and mRNA levels for collagen. This new understanding of the pathogenesis of alcoholic liver disease may eventually improve therapy with drugs and nutrients."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1293,I1293)","v":8374671},{"$f":"(LEN($J1293) - LEN(SUBSTITUTE(LOWER($J1293),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1293) - LEN(SUBSTITUTE(LOWER($J1293),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1293) - LEN(SUBSTITUTE(LOWER($J1293),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1293:D1293)","v":0},1993,"Cutaneous findings of nutritional deficiencies in children.","Goskowicz",8374671,"Cutaneous findings of nutritional deficiencies in children.    Abstract:   Nutritional deficiencies may be associated with a variety of cutaneous findings in children. This review emphasizes new developments relating to cutaneous findings of nutritional deficiencies. Zinc deficiency, acrodermatitis enteropathica, and acrodermatitis enteropathica-like eruptions are seen with a variety of conditions including cystic fibrosis, anorexia nervosa, and breastfeeding. Similar cutaneous findings not related to zinc deficiency may also occur with such metabolic disorders as methylmalonic aciduria, multiple carboxylase deficiency, essential fatty acid deficiency and other amino acid deficiencies. Vitamin K deficiency is associated with hemorrhagic disease of the newborn and coagulopathy. Vitamin A deficiency presents with a variety of systemic findings and distinctive dermatologic findings. Acute vitamin A deficiency may be seen in children infected with measles and is associated with more severe disease. The systemic and cutaneous findings of vitamin C deficiency, scurvy, are discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1294,I1294)","v":8243382},{"$f":"(LEN($J1294) - LEN(SUBSTITUTE(LOWER($J1294),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1294) - LEN(SUBSTITUTE(LOWER($J1294),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1294) - LEN(SUBSTITUTE(LOWER($J1294),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1294:D1294)","v":0},1993,"Impact of the environment on reproduction from conception to parturition.","Sullivan",8243382,"Impact of the environment on reproduction from conception to parturition.    Abstract:   Consideration of environmental influences on human reproduction must include an investigation of the socioeconomic factors that play an important role in embryo-fetal development. Nutritional factors are of prime importance, and modern methods of food production and supply have led to new hazards for pregnant women. For example, pregnant women have been advised in a number of European countries not to eat liver due to the very high concentration (frequently exceeding 100,000 IU per 100 g) of vitamin A. The clear demonstration that periconceptional vitamin supplementation can dramatically reduce the recurrence rate of neural tube defects suggests that folic acid deficiency may be common even in otherwise well-nourished women. Modern methods of food production manufacture and sale have increased the risks of Salmonella and Listeria infections in pregnancy. The dangers of social drug use, especially alcohol and tobacco, are discussed. The types of adverse effect that can result from chemical exposure during the different stages of pregnancy is reviewed with a discussion of some of the problems of epidemiological studies in attempting to identify toxic chemicals. The extent of the ignorance concerning the reproductive toxicity of industrial and environmental chemicals is emphasized by the fact that data are available on only a small percentage of even the high-production volume (1000 tons/year) chemicals. The evidence of reproductive toxicity from exposure to lead, methyl mercury, polychlorinated biphenyls, polychlorinated dibenzofurans, and hexachlorobenzene are briefly reviewed. Some areas of research needs are discussed with emphasis on nutrition, food production, preparation, and storage and the new problems that may be introduced by genetic manipulation.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1295,I1295)","v":8337602},{"$f":"(LEN($J1295) - LEN(SUBSTITUTE(LOWER($J1295),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1295) - LEN(SUBSTITUTE(LOWER($J1295),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1295) - LEN(SUBSTITUTE(LOWER($J1295),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1295:D1295)","v":0},1993,"Biochemical factors in alcoholic liver disease.","Lieber",8337602,"Biochemical factors in alcoholic liver disease.    Abstract:   Three decades of research in ethanol metabolism have established that alcohol is hepatotoxic not only because of secondary malnutrition, but also through metabolic disturbances associated with the oxidation of ethanol. Some of these alterations are due to redox changes produced by the NADH generated via the liver ADH pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins, and purines. Exaggeration of the redox change by the relative hypoxia, which prevails physiologically in the perivenular zone, contributes to the exacerbation of the ethanol-induced lesions in zone III. Gastric ADH also explains first-pass metabolism by ethanol; its activity is low in alcoholics and in females and is decreased by some H2 blockers. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last 20 years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450 (P4502E1) which contributes not only to ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various xenobiotics. Their activation by P4502E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens, and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion, but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize oxygen. Moreover, acetaldehyde promotes GSH depletion, free-radical-mediated toxicity, and lipid peroxidation. In addition, acetaldehyde affects hepatic collagen synthesis; both in vivo (in our baboon model of alcoholic cirrhosis) and in vitro (in cultured myofibroblasts and lipocytes); ethanol and its metabolite acetaldehyde were found to increase collagen accumulation and mRNA levels for collagen. This new understanding may eventually improve therapy with drugs and nutrients. Encouraging results have been obtained with some quot;superquot; nutrients. On the one hand, SAMe, the active form of methionine, was found to attenuate the ethanol-induced depletion in SAMe and GSH and associated mitochondrial lesions. On the other hand, phosphatidylcholine, purified from polyunsaturated lecithin, was discovered to oppose the ethanol-induced fibrosis by decreasing the activation of lipocytes to transitional cells, and possibly also by stimulating collagenase activity, an effect for which dilinoleoylphosphatidylcholine, its major phospholipid species, was found to be responsible."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1296,I1296)","v":8383356},{"$f":"(LEN($J1296) - LEN(SUBSTITUTE(LOWER($J1296),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1296) - LEN(SUBSTITUTE(LOWER($J1296),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1296) - LEN(SUBSTITUTE(LOWER($J1296),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1296:D1296)","v":0},1993,"Fat-storing cells: hyper- and hypovitaminosis A and the relationships with liver fibrosis.","Hendriks",8383356,"Fat-storing cells: hyper- and hypovitaminosis A and the relationships with liver fibrosis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1297,I1297)","v":8243915},{"$f":"(LEN($J1297) - LEN(SUBSTITUTE(LOWER($J1297),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1297) - LEN(SUBSTITUTE(LOWER($J1297),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1297) - LEN(SUBSTITUTE(LOWER($J1297),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1297:D1297)","v":0},1993,"[Drug-induced chronic hepatitis and cirrhosis].","Dhumeaux",8243915,"[Drug-induced chronic hepatitis and cirrhosis].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1298,I1298)","v":8212979},{"$f":"(LEN($J1298) - LEN(SUBSTITUTE(LOWER($J1298),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1298) - LEN(SUBSTITUTE(LOWER($J1298),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1298) - LEN(SUBSTITUTE(LOWER($J1298),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1298:D1298)","v":0},1993,"[Alcohol, liver cirrhosis and disorders in sex hormone metabolism].","Van Steenbergen",8212979,"[Alcohol, liver cirrhosis and disorders in sex hormone metabolism].    Abstract:   Abnormalities in the metabolism of sex hormones are frequently observed in cirrhotic patients, especially in chronic alcoholics. Signs of hypogonadism with disturbed reproductive and endocrine gonadal functions are found in men as well as in women. Primary hypogonadism as well as hypothalamic-pituitary inhibition seem to play a role. Primary gonadal insufficiency is the result of a direct toxic effect of ethanol and of acetaldehyde on the gonads with inhibition of LH binding to the Leydig cells, with inhibition of the enzymes responsible for the formation of sex hormones, and with inhibition of the intratesticular activation of vitamin A. Hypothalamic-pituitary hypogonadism also results from a direct toxic effect of ethanol as well as from the increasing concentrations of oestrogens in the plasma. Men with alcoholic cirrhosis may also be characterized by signs of feminization, which mainly result from an increased peripheral conversion of androgens. In men who abstain from alcohol, a spontaneous recovery of sexual functions can occur, especially when no testicular atrophy is found and when the response of gonadotrophins after stimulation with LH-RH is normal. Therapeutically, only the administration of non-aromatizable androgens in high doses seems to lead to recovery of potency."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1299,I1299)","v":1461639},{"$f":"(LEN($J1299) - LEN(SUBSTITUTE(LOWER($J1299),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1299) - LEN(SUBSTITUTE(LOWER($J1299),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1299) - LEN(SUBSTITUTE(LOWER($J1299),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1299:D1299)","v":0},1992,"[Alcohol and the liver: ethanol metabolism and the pathomechanism of alcoholic liver damage].","Seitz",1461639,"[Alcohol and the liver: ethanol metabolism and the pathomechanism of alcoholic liver damage].    Abstract:   Ethanol is oxidized in the liver by three different enzyme systems, namely by alcohol dehidrogenase (ADH), the microsomal ethanol oxidizing system and catalase. Alcohol also undergoes a first pass metabolism in the gastric mucosa due to alcohol dehydrogenase. This first pass metabolism of ethanol is decreased in the alcoholic, in the fasted state, in the elderly and during cimetidine therapy leading to elevated alcohol blood-concentrations. Ethanol toxicity is closely related to its metabolism in the liver. Ethanol oxidation by ADH generates reducing equivalents (NADH) and acetaldehyde (AA). The elevated NADH/NAD ratio results in alterations of the intermediary metabolism of lipids, carbohydrates, proteins, purines, hormones and porphyrins. Furthermore, NADH flavours free radical production. The ethanol-associated redox changes are pronounced in the perivenular zone, since this is the area of low oxygen tension and of high ADH activity. In addition to NADH, AA exerts striking toxic effects on the hepatocyte. AA binds to cellular proteins and membranes including the mitochondria, microtubules, glutathion and various enzymes. In addition, AA and lactate stimulate collagen production in fibroblasts. AA-adducts stimulate the production of antibodies against AA-epitopes and could thus aggravate the liver injury. Chronic ethanol consumption results also in the microsomal induction of a specific ethanol-inducible form of cytochrome P--450, the cytochrome P--450IIE1 with high affinity not only to ethanol but also to some drugs (acetaminophen), procarcinogens (nitrosamines) and industrial agents (carbon tetrachloride). The interaction between ethanol metabolism and the metabolism of these compounds including vitamin A may also contribute to hepatic toxicity, since the susceptibility of the alcoholic toward those compounds is enhanced."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1300,I1300)","v":1419509},{"$f":"(LEN($J1300) - LEN(SUBSTITUTE(LOWER($J1300),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1300) - LEN(SUBSTITUTE(LOWER($J1300),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1300) - LEN(SUBSTITUTE(LOWER($J1300),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1300:D1300)","v":0},1992,"Musculoskeletal signs of metabolic and systemic diseases in childhood.","Miller",1419509,"Musculoskeletal signs of metabolic and systemic diseases in childhood.    Abstract:   Many metabolic and systemic disorders affect the musculoskeletal system in growing children. This review surveys some of the recent literature in several diverse areas, including new radiologic methods to determine bone mineralization and their use in children with juvenile arthritis and other systemic diseases, bone disorders in childhood, and the association of endocrinopathies and musculoskeletal symptoms."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1301,I1301)","v":1339084},{"$f":"(LEN($J1301) - LEN(SUBSTITUTE(LOWER($J1301),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1301) - LEN(SUBSTITUTE(LOWER($J1301),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1301) - LEN(SUBSTITUTE(LOWER($J1301),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1301:D1301)","v":0},1992,"Regulation of human alcohol dehydrogenase genes.","Edenberg",1339084,"Regulation of human alcohol dehydrogenase genes.    Abstract:   This review focuses upon the regulation of the three human class I alcohol dehydrogenase genes, ADH1, ADH2 and ADH3. These closely related genes are expressed at high levels in liver, and at different levels in other tissues. Multiple cis-acting sequences to which nuclear proteins bind have been mapped, and transcription factors that can bind to these sequences have been identified; these include C/EBP alpha, Sp1, USF, HNF1, CTF/NF1, the glucocorticoid receptor, and RAR alpha. There are interesting but often subtle differences in the binding to these three closely related genes, that presumably account for the differences in patterns of their expression."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1302,I1302)","v":1593206},{"$f":"(LEN($J1302) - LEN(SUBSTITUTE(LOWER($J1302),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1302) - LEN(SUBSTITUTE(LOWER($J1302),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1302) - LEN(SUBSTITUTE(LOWER($J1302),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1302:D1302)","v":0},1992,"Vitamin A and liver fibrosis: cure or villain?","Schuppan",1593206,"Vitamin A and liver fibrosis: cure or villain?    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1303,I1303)","v":1341862},{"$f":"(LEN($J1303) - LEN(SUBSTITUTE(LOWER($J1303),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1303) - LEN(SUBSTITUTE(LOWER($J1303),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1303) - LEN(SUBSTITUTE(LOWER($J1303),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1303:D1303)","v":0},1992,"[Vitamin A in the treatment of measles].","Porcelli",1341862,"[Vitamin A in the treatment of measles].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1304,I1304)","v":1550720},{"$f":"(LEN($J1304) - LEN(SUBSTITUTE(LOWER($J1304),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1304) - LEN(SUBSTITUTE(LOWER($J1304),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1304) - LEN(SUBSTITUTE(LOWER($J1304),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1304:D1304)","v":0},1992,"Skin signs of nutritional disorders.","Prendiville",1550720,"Skin signs of nutritional disorders.    Abstract:   Children, especially infants, require adequate calories and nutrients to meet the high demands of normal growth and development; protein, essential fatty acids, vitamins and minerals are all important in achieving this goal. Malnutrition results from deficiency in one or more of these basic nutrients. It may be caused by (1) insufficient dietary intake, (2) malabsorption, (3) poor utilization of nutrients, and (4) increased catabolism. A range of clinical and metabolic changes occurs as a result of profound and generalized abnormalities at a cellular level. Mucocutaneous changes constitute one of the variable and multisystemic clinical manifestations of malnutrition. Although some signs are characteristic of a specific nutrient deficiency, an overlap of skin manifestations is observed in multiple deficiency states. The periorificial glazed erythema and hair loss of zinc deficiency also may be seen in patients with essential fatty acid deficiency, biotinidase deficiency, and even kwashiorkor. Mucous membrane changes associated with deficiency of many water-soluble vitamins may likewise be difficult to distinguish."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1305,I1305)","v":1516146},{"$f":"(LEN($J1305) - LEN(SUBSTITUTE(LOWER($J1305),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1305) - LEN(SUBSTITUTE(LOWER($J1305),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1305) - LEN(SUBSTITUTE(LOWER($J1305),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1305:D1305)","v":0},1992,"Cytoskeleton of liver perisinusoidal cells (lipocytes) in normal and pathological conditions.","Rockey",1516146,"Cytoskeleton of liver perisinusoidal cells (lipocytes) in normal and pathological conditions.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1306,I1306)","v":1503811},{"$f":"(LEN($J1306) - LEN(SUBSTITUTE(LOWER($J1306),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1306) - LEN(SUBSTITUTE(LOWER($J1306),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1306) - LEN(SUBSTITUTE(LOWER($J1306),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1306:D1306)","v":0},1992,"Vitamin A: physiological and biochemical processing.","Blomhoff",1503811,"Vitamin A: physiological and biochemical processing.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1307,I1307)","v":1495238},{"$f":"(LEN($J1307) - LEN(SUBSTITUTE(LOWER($J1307),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1307) - LEN(SUBSTITUTE(LOWER($J1307),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1307) - LEN(SUBSTITUTE(LOWER($J1307),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1307:D1307)","v":0},1992,"[Clinical biochemistry of alcohol and its metabolic and hepatic effects].","Lieber",1495238,"[Clinical biochemistry of alcohol and its metabolic and hepatic effects].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1308,I1308)","v":1368195},{"$f":"(LEN($J1308) - LEN(SUBSTITUTE(LOWER($J1308),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1308) - LEN(SUBSTITUTE(LOWER($J1308),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1308) - LEN(SUBSTITUTE(LOWER($J1308),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1308:D1308)","v":0},1992,"Production of vitamins, coenzymes and related biochemicals by biotechnological processes.","Vandamme",1368195,"Production of vitamins, coenzymes and related biochemicals by biotechnological processes.    Abstract:   Vitamins and related biofactors belong to those few chemicals with a direct positive appeal to people. There is indeed a large need for extra vitamins, other than those derived from plant and animal food sources, due to unbalanced food habits or processing, food shortage or disease. Added vitamins are now either prepared chemically or biotechnologically via fermentation or bioconversion processes. Several vitamins and related biofactors are now only or mainly produced chemically (vitamin A, cholecalciferol (D3), tocopherol (E), vitamin K2, thiamine (B1), niacin (PP or B3), pantothenic acid (B5), pyridoxine (B6), biotin (H or B8), folic acid (B9) or via extraction processes (beta-carotene or provitamin A, provitamin D3, tocopherol, vitamin F-group). However, for several of these compounds microbiological or algal methods also exist or are rapidly emerging. Others are produced practically exclusively via fermentation (ergosterol or provitamin D2, riboflavin (B2), cyanocobalamin (B12), orotic acid (B13), vitamin F-group, ATP, nucleosides, coenzymes, etc. or via microalgal culture (beta-carotene, E, F). Both chemical and microbial processes are run industrially for vitamin B2 while vitamin C (ascorbic acid) is produced via a combination of chemical reactions and fermentation processes. A survey is given here of the current state of vitamin production, with emphasis on developments and strategies for improved biotechnological production and its significance, as compared to existing chemical processes. The screening or construction of vitamin hyperproducing microbial strains is a difficult task; pathway elucidation and metabolic (de)regulation need further study; r-DNA technology has only recently been introduced; improved fermentation processes and immobilised biocatalysts bioconversions for the synthesis of chiral vitamin compounds or intermediates or derivatives are gaining importance; the recovery and purification of these vitamin compounds from their fermentation broths remains equally complex."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1309,I1309)","v":1289080},{"$f":"(LEN($J1309) - LEN(SUBSTITUTE(LOWER($J1309),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1309) - LEN(SUBSTITUTE(LOWER($J1309),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1309) - LEN(SUBSTITUTE(LOWER($J1309),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1309:D1309)","v":0},1992,"Liver cell heterogeneity: functions of non-parenchymal cells.","Bouwens",1289080,"Liver cell heterogeneity: functions of non-parenchymal cells.    Abstract:   The normal hepatic sinusoid is formed or lined by four different cell types, each with its specific phenotypic characteristics, functions and topography. Endothelial cells constitute the closed lining or wall of the capillary. They contain small fenestrations to allow the free diffusion of substances, but not of particles like chylomicrons, between the blood and the hepatocyte surface. This filtering effect regulates the fat uptake by the liver. Sinusoidal endothelial cells also have a pronounced endocytotic capacity which makes them an important part of the reticuloendothelial system. They are also active in the secretion of bioactive factors and extracellular matrix components of the liver. Recently, a zonal heterogeneity of the endothelial lining has been reported with regard to its filtering capacity (fenestration) and binding capacity for lectins and cells. Kupffer cells are intrasinusoidally located tissue macrophages with a pronounced endocytotic capacity. They are potent mediators of the inflammatory response by the secretion of a variety of bioactive factors and play an important part in the immune defense. A zonal heterogeneity has been established with regard to the endocytotic capacity and cytotoxic function. Pit cells are now known to represent a liver-associated population of large granular lymphocytes. They have the capacity to kill tumor cells and probably also play a role in the antiviral defense of the liver. In addition, pit cells may have a growth-regulatory function of the liver. They are known to be numerically more prominent in the periportal region, as is also the case for Kupffer cells. Fat-storing or Ito cells are present in the perisinusoidal space of Disse and are thought to represent the main hepatic source of extracellular matrix components. They are also the main site of vitamin-A storage. Fat-storing cells are more numerous in the periportal region than in the central region of the hepatic acinus. The periportal cells also store higher amounts of vitamin A. Sinusoidal cells may be considered to represent a functional unit at the border line between the hepatocytes or parenchymal cells and the blood. They participate in various liver functions and liver pathologies and our knowledge about this is growing. The heterogeneity of these cell types and possible cooperations between them and the hepatocytes may add to our understanding of liver functions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1310,I1310)","v":1924551},{"$f":"(LEN($J1310) - LEN(SUBSTITUTE(LOWER($J1310),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1310) - LEN(SUBSTITUTE(LOWER($J1310),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1310) - LEN(SUBSTITUTE(LOWER($J1310),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1310:D1310)","v":0},1991,"Vitamin A metabolism: new perspectives on absorption, transport, and storage.","Blomhoff",1924551,"Vitamin A metabolism: new perspectives on absorption, transport, and storage.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1311,I1311)","v":1749529},{"$f":"(LEN($J1311) - LEN(SUBSTITUTE(LOWER($J1311),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1311) - LEN(SUBSTITUTE(LOWER($J1311),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1311) - LEN(SUBSTITUTE(LOWER($J1311),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1311:D1311)","v":0},1991,"Iatrogenic liver disease from vitamin A.","Boyd",1749529,"Iatrogenic liver disease from vitamin A.    Abstract:   In a retrospective case series, 41 patients developed severe liver disease after prolonged administration of vitamin A originally recommended for the treatment of medically benign conditions, mostly dermatologic. Six patients died of liver failure during follow-up."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1312,I1312)","v":1868937},{"$f":"(LEN($J1312) - LEN(SUBSTITUTE(LOWER($J1312),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1312) - LEN(SUBSTITUTE(LOWER($J1312),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1312) - LEN(SUBSTITUTE(LOWER($J1312),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1312:D1312)","v":0},1991,"Evaluation of risk factors in human cataractogenesis.","Lerman",1868937,"Evaluation of risk factors in human cataractogenesis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1313,I1313)","v":1845551},{"$f":"(LEN($J1313) - LEN(SUBSTITUTE(LOWER($J1313),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1313) - LEN(SUBSTITUTE(LOWER($J1313),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1313) - LEN(SUBSTITUTE(LOWER($J1313),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1313:D1313)","v":0},1991,"Biochemical mechanisms of alcohol-induced hepatic injury.","Lieber",1845551,"Biochemical mechanisms of alcohol-induced hepatic injury.    Abstract:   Three decades of research in ethanol metabolism have established that alcohol is hepatotoxic not only because of secondary malnutrition but also through metabolic disturbances associated with the oxidation of ethanol. Some of these alterations are due to redox changes produced by the NADH generated via the alcohol dehydrogenase (ADH) pathway which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Exaggeration of the redox change by the relative hypoxia which prevails physiologically in the perivenular zone explains the exacerbation of the ethanol-induced lesions in zone III. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last twenty years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450 (P450IIE1) which contributes not only to ethanol metabolism and tolerance, but also to the toxicity of various xenobiotics. Their activation by P450IIE1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion but it also enhances its hepatoxicity. Furthermore, induction of the microsomal pathway results in increased acetaldehyde production. Acetaldehyde, in turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and is associated with a striking impairment of the capacity of the liver to utilize oxygen. Acetaldehyde also promotes glutathione depletion, free-radical mediated toxicity, lipid peroxidation and hepatic collagen synthesis. This new understanding may eventually improve drug and nutritional therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1314,I1314)","v":1685276},{"$f":"(LEN($J1314) - LEN(SUBSTITUTE(LOWER($J1314),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1314) - LEN(SUBSTITUTE(LOWER($J1314),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1314) - LEN(SUBSTITUTE(LOWER($J1314),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1314:D1314)","v":0},1991,"The stellate cell (Ito-cell, fat-storing cell, lipocyte, perisinusoidal cell) of the liver. New insights into pathophysiology of an intriguing cell.","Ramadori",1685276,"The stellate cell (Ito-cell, fat-storing cell, lipocyte, perisinusoidal cell) of the liver. New insights into pathophysiology of an intriguing cell.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1315,I1315)","v":2243288},{"$f":"(LEN($J1315) - LEN(SUBSTITUTE(LOWER($J1315),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1315) - LEN(SUBSTITUTE(LOWER($J1315),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1315) - LEN(SUBSTITUTE(LOWER($J1315),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1315:D1315)","v":0},1990,"Methods for assessment of vitamin A status.","Underwood",2243288,"Methods for assessment of vitamin A status.    Abstract:   Assessment of the relative level of vitamin A nutriture in human populations when clinical signs and symptoms of deficiency or of toxicity are absent has presented methodological difficulties. Commonly used indicators include dietary intakes of the vitamin, serum levels, and dark adaptation, all of which have limitations in their precision, especially when applied to individuals and to young children. New and developing nonclinical indicators include the relative dose response (RDR) test or a modification (MRDR) of it, conjunctival impression cytology (CIC), and isotope dilution to estimate total body reserves. These methods, all of which are promising, require additional work to verify their sensitivity, specificity, and predictive power as indicators of relative states of vitamin A depletion for individuals and populations under the many varied conditions commonly associated with an inadequate vitamin status. Currently, the most reliable assessment of vitamin A nutriture is likely when a combination of methods is used."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1316,I1316)","v":2127745},{"$f":"(LEN($J1316) - LEN(SUBSTITUTE(LOWER($J1316),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1316) - LEN(SUBSTITUTE(LOWER($J1316),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1316) - LEN(SUBSTITUTE(LOWER($J1316),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1316:D1316)","v":0},1990,"Scientifically-based strategies for nutrition of the high-risk low birth weight infant.","Neu",2127745,"Scientifically-based strategies for nutrition of the high-risk low birth weight infant.    Abstract:   Technological advances in the intensive care of low birth weight (LBW) infants have resulted in major increases in their survival. New challenges in meeting their nutritional needs have emerged. Very low birth (VLBW) weight infants have very little body fat or glycogen reserves at birth, making them susceptible to starvation. If fed enterally, they require at least 120 calories/kg per day for growth. Numerous immaturities in the gastrointestinal tract and liver limit protein digestion, absorption, and metabolism. Several amino acids not considered essential to the older child or adult are essential to the VLBW infant. Supplying a high protein load with an inappropriate amino acid composition may lead to metabolic imbalances. The digestion and absorption of fats differs from the older child or adult. Lingual and gastric lipases are important, and the lack of bile acids limits fat absorption. Lipoprotein lipase deficiency causes problems when too much fat or fat of incorrect composition is provided. There are controversies regarding the most appropriate carbohydrate source, but research shows that lactose remains an important carbohydrate source for most of these infants. Calcium, magnesium, and phosphorus requirements pose questions in both enterally and parenterally nourished infants. Studies of iron usage suggest that VLBW infants fed either human milk or formula should receive iron supplements. Vitamin E may be helpful in preventing oxygen toxicity. Vitamin D deficiency contributes to bone demineralization and rickets. Controversy exists regarding the correlation between vitamin A nutrition and development of chronic lung disease. Guidelines have been developed for recommended intakes, but much needs to be learned to provide a sound scientific basis upon which to provide optimal nourishment for the high risk, LBW infant."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1317,I1317)","v":2197848},{"$f":"(LEN($J1317) - LEN(SUBSTITUTE(LOWER($J1317),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1317) - LEN(SUBSTITUTE(LOWER($J1317),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1317) - LEN(SUBSTITUTE(LOWER($J1317),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1317:D1317)","v":0},1990,"Evaluation of vitamin A toxicity.","Hathcock",2197848,"Evaluation of vitamin A toxicity.    Abstract:   Toxicity has been associated with abuse of vitamin A supplements and with diets extremely high in preformed vitamin A. Consumption of 25,000-50,000 IU/d for periods of several months or more can produce multiple adverse effects. The lowest reported intakes causing toxicity have occurred in persons with liver function compromised by drugs, viral hepatitis, or protein-energy malnutrition. Certain drugs or other chemicals may markedly potentiate vitamin A toxicity in animals. Especially vulnerable groups include children, with adverse effects occurring with intakes as low as 1,500 IU.kg-1.d-1, and pregnant women, with birth defects being associated with maternal intakes as low as approximately 25,000 IU/d. The maternal dose threshold for birth defects cannot be identified from present data. An identifiable fraction of the population surveyed consumes vitamin A supplements at 25,000 IU/d and a few individuals consume much more. beta-Carotene is much less toxic than vitamin A."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1318,I1318)","v":2198038},{"$f":"(LEN($J1318) - LEN(SUBSTITUTE(LOWER($J1318),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1318) - LEN(SUBSTITUTE(LOWER($J1318),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1318) - LEN(SUBSTITUTE(LOWER($J1318),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1318:D1318)","v":0},1990,"Ethanol-induced lipid peroxidation and oxidative stress in extrahepatic tissues.","Nordmann",2198038,"Ethanol-induced lipid peroxidation and oxidative stress in extrahepatic tissues.    Abstract:   An ethanol-induced oxidative stress is not restricted to the liver, where ethanol is actively oxidized, but can affect various extrahepatic tissues as shown by experimental data obtained in the rat during acute or chronic ethanol intoxication. Most of these data concern the central nervous system, the heart and the testes. An acute ethanol load has been reported to enhance lipid peroxidation in the cerebellum. This is accompanied by an increase in the cytosolic concentration of low-molecular-weight iron derivatives which may contribute to the generation of aggressive free radicals. The ethanol-induced decrease in the main antioxidant systems (superoxide dismutase, alpha-tocopherol, ascorbate and selenium) is a likely contributor to the cerebellar oxidative stress. Most of these disturbances can be prevented by allopurinol administration. Some experimental data support also the occurrence of pro- and anti-oxidant disturbances in the cerebellum and in other regions of the central nervous system after chronic ethanol administration. Chronic ethanol administration enhances lipid peroxidation in the heart. The increased conversion of xanthine dehydrogenase into xanthine oxidase as well as the activation of peroxisomal acyl CoA-oxidase linked to ethanol administration could contribute to the oxidative stress. Chronic ethanol administration elicits in the testes an enhancement in mitochondrial lipid peroxidation and a decrease in the glutathione level, which appear to be correlated to the gross testicular atrophy observed. Vitamin A supplementation attenuates the changes in lipid peroxidation, glutathione and testicular morphology. Whether the reported disturbances are involved in the pathogenesis of the tissue disorders observed in alcoholic patients remains unanswered.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1319,I1319)","v":2181486},{"$f":"(LEN($J1319) - LEN(SUBSTITUTE(LOWER($J1319),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1319) - LEN(SUBSTITUTE(LOWER($J1319),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1319) - LEN(SUBSTITUTE(LOWER($J1319),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1319:D1319)","v":0},1990,"Mechanism of ethanol induced hepatic injury.","Lieber",2181486,"Mechanism of ethanol induced hepatic injury.    Abstract:   Ethanol is hepatotoxic through redox changes produced by the NADH generated in its oxidation via the alcohol dehydrogenase pathway, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Ethanol is also oxidized in liver microsomes by an ethanol-inducible cytochrome P-450 (P-450IIE1) which contributes to ethanol metabolism and tolerance, and activates xenobiotics to toxic radicals thereby explaining increased vulnerability of the heavy drinker to industrial solvents, anesthetic agents, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Induction also results in energy wastage and increased production of acetaldehyde. Acetaldehyde, in turn, causes injury through the formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, and alterations in microtubules, plasma membranes and mitochondria with a striking impairment of oxygen utilization. Acetaldehyde also causes glutathione depletion and lipid peroxidation, and stimulates hepatic collagen synthesis, thereby promoting fibrosis."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1320,I1320)","v":2671546},{"$f":"(LEN($J1320) - LEN(SUBSTITUTE(LOWER($J1320),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1320) - LEN(SUBSTITUTE(LOWER($J1320),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1320) - LEN(SUBSTITUTE(LOWER($J1320),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1320:D1320)","v":0},1989,"Cutaneous reactions to drugs used for rheumatologic disorders.","Roth",2671546,"Cutaneous reactions to drugs used for rheumatologic disorders.    Abstract:   Cutaneous reactions to medications probably represent the most common manifestation of drug reactions. The diversity of cutaneous eruptions produced by drugs provide a challenge in searching for the mechanisms producing the reaction. Many eruptions are due to a form of allergic hypersensitivity, while others may be idiosyncratic, due to a metabolic abnormality, or represent a cumulative phenomenon. This article discusses the diagnosis of drug-induced cutaneous reactions by reviewing specific drugs commonly used in rheumatologic therapy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1321,I1321)","v":2663408},{"$f":"(LEN($J1321) - LEN(SUBSTITUTE(LOWER($J1321),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1321) - LEN(SUBSTITUTE(LOWER($J1321),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1321) - LEN(SUBSTITUTE(LOWER($J1321),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1321:D1321)","v":0},1989,"A critical view of the mechanism(s) of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Implications for human safety assessment.","Rozman",2663408,"A critical view of the mechanism(s) of toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Implications for human safety assessment.    Abstract:   2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been an important issue in occupational and environmental health for nearly two decades. During this period scientists have studied its possible impacts on exposed human populations. At the same time enormous efforts were made to elucidate the mechanism of TCDD action in various biological models. This paper provides a critical view of the advances made towards understanding the mechanism of TCDD action. Major topics discussed include the Ah-receptor hypothesis, TCDD as a thyroid hormone agonist, TCDD and vitamin A deficiency, TCDDs effect on receptor regulation, and its effect on intermediary metabolism including related hormonal responses. Although the exact mechanism of TCDD action is not yet known, more information is available on the toxicity of this compound than perhaps on that of any other substance. This wealth of information allows important conclusions regarding the assessment of acute, as well as of chronic, toxicities of TCDD for humans. There is no documented case of human death as a result of exposure to TCDD. It appears that humans are acutely less sensitive to TCDD than some animal species. The cause of TCDD-induced lethality in rats is a progressive lethal hypoglycemia due to inhibition of gluconeogenesis. Regulation of this metabolic pathway is quite different amongst species, although primates share great similarities. The assumption that the cause of TCDD-induced death in primates, in analogy to rats, is inhibition of gluconeogenesis would suggest that the acute toxicity of TCDD in humans would be in the range seen in rhesus monkeys (70-300 micrograms/kg). These values are about midway between the most (guinea pig) and least (hamster) sensitive species. TCDD is not a genotoxic agent and not an initiator, but promoter of tumor formation. There is considerable evidence that promotion of cancer, like any other chronic end point of toxicity, is a threshold-type biological process. Therefore, a linear extrapolation of the dose-response is an unnecessarily conservative approach in the safety assessment of TCDD. This paper, based on several studies with different end points of toxicity, supports the notion that 10 pg/kg/day of TCDD represent a safe lifetime exposure level for humans with regard to promotion of cancer, porphyria and chloracne."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1322,I1322)","v":2654771},{"$f":"(LEN($J1322) - LEN(SUBSTITUTE(LOWER($J1322),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1322) - LEN(SUBSTITUTE(LOWER($J1322),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1322) - LEN(SUBSTITUTE(LOWER($J1322),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1322:D1322)","v":0},1989,"Effect of vitamin A deficiency in rats on glycosylation of glycoproteins.","Rozman",2654771,"Effect of vitamin A deficiency in rats on glycosylation of glycoproteins.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1323,I1323)","v":2661927},{"$f":"(LEN($J1323) - LEN(SUBSTITUTE(LOWER($J1323),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1323) - LEN(SUBSTITUTE(LOWER($J1323),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1323) - LEN(SUBSTITUTE(LOWER($J1323),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1323:D1323)","v":0},1989,"Effects of the intake of selected vitamins and minerals on cancer prevention.","Birt",2661927,"Effects of the intake of selected vitamins and minerals on cancer prevention.    Abstract:   This paper provides an overview of our knowledge on the involvement in cancer of vitamins A, C and E and of calcium, selenium and zinc. This work is a background for studies on dietary magnesiums effects on cancer. Consumption of vitamin A and its dietary precursors has been associated with reduced cancer at several sites in human and animal studies. Carcinogenesis studies using several models of cancer have been conducted on the influence of vitamin A deficiency, vitamin A excess and supplementation of vitamin A analogues. Vitamins C and E are effective in the prevention of N-nitroso compound (nitrosamine) formation. Vitamin C is effective in aqueous and vitamin E is effective in non-aqueous media. Both of these vitamins also have inhibited carcinogenesis by preformed carcinogens at several sites, but enhancement has been observed at some sites when excess vitamin treatment was studied. The potential role of calcium in the prevention of colon cancer is being pursed. Few experimental studies have been conducted but data support an effect of calcium on colonic epithelial proliferation. Epidemiological and especially experimental results suggest an inhibition of cancer by dietary selenium. In animal studies, selenium supplementation has been particularly effective in inhibiting colon and mammary carcinogenesis, but enhanced carcinogenesis was observed in some studies on skin, liver and pancreas cancer. Data suggest that zinc deficiency may be a factor in esophageal cancer; however, studies on tumor growth have demonstrated retarded tumor growth in zinc-deficient animals."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1324,I1324)","v":2507705},{"$f":"(LEN($J1324) - LEN(SUBSTITUTE(LOWER($J1324),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1324) - LEN(SUBSTITUTE(LOWER($J1324),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1324) - LEN(SUBSTITUTE(LOWER($J1324),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1324:D1324)","v":0},1989,"Large dose vitamin A to control vitamin A deficiency.","Sommer",2507705,"Large dose vitamin A to control vitamin A deficiency.    Abstract:   Vitamin A deficiency is a serious problem throughout the developing world. An estimated 25-50 million children may well suffer the physiologic consequences of vitamin A deficiency; 5 million develop xerophthalmia, of whom 250,000 to 500,000 go blind every year; and untold numbers are at increased risk of diarrhea, respiratory disease, and death. Even mild vitamin A deficiency has been associated with a 14- to 10-fold increase in mortality, and controlled field trials have demonstrated vitamin A supplementation can reduce childhood death rates by 30%-70%. Three general intervention strategies exist for improving vitamin A status of high-risk, rural, economically deprived populations. These include nutrition education leading to increased dietary intake; vitamin A fortification of centrally processed, widely consumed dietary items; and periodic administration of large doses of vitamin A. At present, the latter is far and away the most widely employed intervention activity, because of its immediate impact, and because it can be implemented through the existing (and specialized) health care infrastructure. Vitamin A is a fat-soluble vitamin stored in the liver, so that a large dose of 200,000 IU (100,000 IU for children under 1 year of age) every 6 months reduces mortality, stimulates growth, and prevents xerophthalmia and nutritional blindness. Recent data suggest more frequent administration, every 3 to 4 months, may be desirable. Side effects have been minimal, with mild nausea, vomiting, and headaches in less than 1% to 4% of recipients. Care should be taken, however, that doses above 10,000 IU not be administered to women during the first trimester of pregnancy because of potential teratogenic effects.(ABSTRACT TRUNCATED AT 250 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1325,I1325)","v":3064890},{"$f":"(LEN($J1325) - LEN(SUBSTITUTE(LOWER($J1325),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1325) - LEN(SUBSTITUTE(LOWER($J1325),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1325) - LEN(SUBSTITUTE(LOWER($J1325),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1325:D1325)","v":0},1988,"The role of vitamins in modulating disease resistance.","Nockels",3064890,"The role of vitamins in modulating disease resistance.    Abstract:   Many of the metabolic incursions resulting from stress and oxidative damage are detrimental to disease resistance. Vitamins A, E, and C and carotenoids are able to protect cells from free radical oxidation, reduce the detrimental effects of certain eicosanoids, and enhance humoral and cellular immune responses in disease. The regulation of cell differentiation by vitamin A in maintaining an epithelial barrier to pathogen entry and the differentiation of precursor cells to functional lymphocytes by 1,25-dihydroxycholecalciferol are essential to disease resistance. Nutritionists must redefine the levels of vitamins necessary to maximize health-supportive systems. The animals metabolism must constantly be adjusting to its environmental stress or disease and may require increased vitamins."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1326,I1326)","v":3049495},{"$f":"(LEN($J1326) - LEN(SUBSTITUTE(LOWER($J1326),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1326) - LEN(SUBSTITUTE(LOWER($J1326),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1326) - LEN(SUBSTITUTE(LOWER($J1326),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1326:D1326)","v":0},1988,"Toxicity and metabolism of pyrrolizidine alkaloids.","Cheeke",3049495,"Toxicity and metabolism of pyrrolizidine alkaloids.    Abstract:   Pyrrolizidine alkaloids (PA) are found mainly in plants of three families: boraginaceae, Compositae and Leguminosae. In North America, PA poisoning of livestock is caused primarily by consumption of Senecio and Crotalaria spp. The PA of Senecio spp. cause irreversible hepatic damage; toxicity signs are a consequence of impaired liver function. Crotalaria intoxication leads to pulmonary damage as a primary effect; hepatic effects are less prominent. Large species differences exist in susceptibility to PA toxicosis. Small herbivores such as sheep, goats, rabbits, guinea pigs and other herbivorous laboratory animals are highly resistant to PA toxicity, associated with a low rate of hepatic production of reactive metabolites (pyrroles) and(or) a high rate of activity of detoxifying enzymes. Diester PA common to Heliotropium and Echium spp. are metabolized in the ovine rumen to 1-methyl metabolites, whereas the macrocyclic ester PA of Senecio spp. are not. Exposure to PA results in high concentrations of liver Cu, reduced liver Zn, and abnormal Fe metabolism with hematopoiesis markedly impaired. Pyrrolizidine alkaloid toxicity alters vitamin A metabolism in rats, depressing plasma and liver levels of vitamin A. Synthetic antioxidants in the diet confer protective activity in laboratory animals (e.g., rats, mice) against PA toxicoses. The PA and their metabolites are secreted in the milk of lactating animals, but this probably does not represent a significant human health hazard."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1327,I1327)","v":3291739},{"$f":"(LEN($J1327) - LEN(SUBSTITUTE(LOWER($J1327),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1327) - LEN(SUBSTITUTE(LOWER($J1327),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1327) - LEN(SUBSTITUTE(LOWER($J1327),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1327:D1327)","v":0},1988,"The effect of ethanol and its metabolites on carbohydrate, protein, and lipid metabolism.","Forman",3291739,"The effect of ethanol and its metabolites on carbohydrate, protein, and lipid metabolism.    Abstract:   The metabolic effects of ethanol are due to a direct action of ethanol or its metabolites, changes in the redox state occurring during its metabolism, and modifications of the effects of ethanol by several nutritional factors. Ethanol causes hyperglycemia or hypoglycemia depending whether or not glycogen stores are adequate, inhibits protein synthesis, and results in a fatty liver and elevations in serum triglyceride levels. Increases in serum lactate, results from the increased reduced nicotinamide-adenine dinucleotide/nicotinamide-adenine dinucleotide + (NADH/NAD+) ratio, and hyperuricemia probably occurs owing to the increased turnover of adenine nucleotides after ethanol ingestion. Ethanol decreases thiamine absorption and decreases the enterohepatic circulation of folate. Acetaldehyde, the major metabolite of ethanol, increases the degradation of pyridoxal 5-phosphate by displacing it from its binding protein and making it susceptible to hydrolysis by membrane-bound alkaline phosphatase. Chronic ethanol administration also results in decreased vitamin A stores and reduced bone mass and blood levels of 25-hydroxyvitamin D. The mechanism whereby ethanol affects these vitamins and their associated enzymes is unknown."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1328,I1328)","v":3285252},{"$f":"(LEN($J1328) - LEN(SUBSTITUTE(LOWER($J1328),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1328) - LEN(SUBSTITUTE(LOWER($J1328),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1328) - LEN(SUBSTITUTE(LOWER($J1328),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1328:D1328)","v":0},1988,"Vitamin A controls fibronectin gene expression.","Forman",3285252,"Vitamin A controls fibronectin gene expression.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1329,I1329)","v":3053038},{"$f":"(LEN($J1329) - LEN(SUBSTITUTE(LOWER($J1329),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1329) - LEN(SUBSTITUTE(LOWER($J1329),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1329) - LEN(SUBSTITUTE(LOWER($J1329),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1329:D1329)","v":0},1988,"Factors modifying the secretion and action of parathyroid hormone in renal failure.","Cundy",3053038,"Factors modifying the secretion and action of parathyroid hormone in renal failure.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1330,I1330)","v":3317083},{"$f":"(LEN($J1330) - LEN(SUBSTITUTE(LOWER($J1330),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1330) - LEN(SUBSTITUTE(LOWER($J1330),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1330) - LEN(SUBSTITUTE(LOWER($J1330),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1330:D1330)","v":0},1987,"Recent insights into the function of hepatic sinusoidal cells.","Bouwens",3317083,"Recent insights into the function of hepatic sinusoidal cells.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1331,I1331)","v":3331730},{"$f":"(LEN($J1331) - LEN(SUBSTITUTE(LOWER($J1331),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1331) - LEN(SUBSTITUTE(LOWER($J1331),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1331) - LEN(SUBSTITUTE(LOWER($J1331),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1331:D1331)","v":0},1987,"Effect of xenobiotics on hepatic vitamin A storage.","Yob",3331730,"Effect of xenobiotics on hepatic vitamin A storage.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1332,I1332)","v":3106606},{"$f":"(LEN($J1332) - LEN(SUBSTITUTE(LOWER($J1332),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1332) - LEN(SUBSTITUTE(LOWER($J1332),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1332) - LEN(SUBSTITUTE(LOWER($J1332),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1332:D1332)","v":0},1987,"Nutritional support for the infant with extrahepatic biliary atresia.","Kaufman",3106606,"Nutritional support for the infant with extrahepatic biliary atresia.    Abstract:   Some infants with biliary atresia obtain dramatic improvement for prolonged periods after the performance of hepatic portoenterostomy. Such infants may have life styles not substantially different from those of normal children. In others, the benefit from this operation, if any, is short lived. These infants are very vulnerable to the debilitating effects of severe, prolonged malabsorption and ultimately require orthotopic liver transplantation to sustain life. The physician caring for infants awaiting liver transplantation can do much, not only to prolong survival but to maintain satisfactory growth and development. The key consideration is to provide adequate nitrogen and nonnitrogen calories, liberally utilizing modern methods of enteral alimentation when necessary. In addition, attention must be directed toward several vitamin and mineral deficiencies, particularly those of the fat-soluble vitamins, that inevitably accompany severe malabsorption in children. Management of extrahepatic biliary atresia in infants is difficult and requires meticulous attention to details. Nevertheless, the long-term cure of this disorder provided by liver transplantation makes their care a rewarding experience."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1333,I1333)","v":3607655},{"$f":"(LEN($J1333) - LEN(SUBSTITUTE(LOWER($J1333),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1333) - LEN(SUBSTITUTE(LOWER($J1333),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1333) - LEN(SUBSTITUTE(LOWER($J1333),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1333:D1333)","v":0},1987,"Pathogenesis of neurological signs associated with bovine enteric coccidiosis: a prospective study and review.","Isler",3607655,"Pathogenesis of neurological signs associated with bovine enteric coccidiosis: a prospective study and review.    Abstract:   Various hypotheses have been proposed for the pathogenesis of the neurological signs associated with bovine enteric coccidiosis. We undertook a prospective study of cases of bovine enteric coccidiosis with and without nervous signs to test the validity of these hypotheses and explore other possible pathophysiological mechanisms. Clinical, pathological and toxicological data from 12 calves with, and 15 calves without, neurological signs were compared. Calves with neurological signs had a lower liver Cu concentration (p less than 0.01) and a higher plasma glucose concentration (p less than 0.05) than did calves without neurological signs. Hyperglycemia and Cu deficiency may increase the susceptibility to central nervous system damage, but are not likely to account for the onset of neurological signs in calves with enteric coccidiosis. The results of the study suggest that the following are not involved in the pathogenesis of quot;nervous coccidiosisquot;: disturbance of serum Na, K, Ca, P, or Mg concentration, vitamin A deficiency, thiamine deficiency, anemia, lead intoxication, uremia, Haemophilus somnus meningoencephalitis, severity of coccidial infection, gross alterations in intestinal bacterial flora and hepatopathy."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1334,I1334)","v":3327704},{"$f":"(LEN($J1334) - LEN(SUBSTITUTE(LOWER($J1334),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1334) - LEN(SUBSTITUTE(LOWER($J1334),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1334) - LEN(SUBSTITUTE(LOWER($J1334),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1334:D1334)","v":0},1987,"The concept of the quot;perisinusoidal functional unitquot; of the liver--importance to pathological processes.","David",3327704,"The concept of the quot;perisinusoidal functional unitquot; of the liver--importance to pathological processes.    Abstract:   Non-hepatocytes account for 30 per cent of cells in the liver, with sinusoid-coating endothelial and Kupffer cells being the most common types. In addition, there are some scattered pit cells in the wall. Ito cells (perisinusoidal cells, lipocytes) are located in the Disse space. In this paper a review is given of structural and functional changes of cells in response to pathological conditions with reference to the importance of such changes due to diseases of the liver and the organism in large. Cooperation and interaction among non-hepatocytes, the vascular pole of hepatocytes, and Disse space as the site of reaction are summarised under the concept of the quot;Perisinusoidal Functional Unitquot;, and the concept is explained in greater detail by examples (lipoprotein catabolism, processes of phagocytosis, vitamin A storage, virus infections, accumulation of pathological substances, fibrosis, and capillarization)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1335,I1335)","v":3311705},{"$f":"(LEN($J1335) - LEN(SUBSTITUTE(LOWER($J1335),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1335) - LEN(SUBSTITUTE(LOWER($J1335),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1335) - LEN(SUBSTITUTE(LOWER($J1335),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1335:D1335)","v":0},1987,"[Pathogenesis of hyperoxalurias and calcium oxalate calculi in intestinal diseases].","Müller",3311705,"[Pathogenesis of hyperoxalurias and calcium oxalate calculi in intestinal diseases].    Abstract:   Hyperoxaluria and calcium oxalate lithiasis have a multifactorial genesis in bowel diseases. The augmented synthesis of oxalic acid in the liver is of minor importance. A diminished bacterial degradation is to asses up to day only hardly. The increasing absorption is of highest importance by deficient production of calcium oxalate in the intestinal tract and by increasing permeability of colonic mucosa above all in steatorrhoea or in patients with augmented calcium absorption. The crystallization of calcium oxalate in the urine is promoted by shortage of vitamin A, citrate, zinc or magnesium."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1336,I1336)","v":3544907},{"$f":"(LEN($J1336) - LEN(SUBSTITUTE(LOWER($J1336),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1336) - LEN(SUBSTITUTE(LOWER($J1336),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1336) - LEN(SUBSTITUTE(LOWER($J1336),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1336:D1336)","v":0},1986,"Mechanisms of vitamin deficiencies in alcoholism.","Hoyumpa",3544907,"Mechanisms of vitamin deficiencies in alcoholism.    Abstract:   Chronic alcoholic patients are frequently deficient in one or more vitamins. The deficiencies commonly involve folate, vitamin B6, thiamine, and vitamin A. Although inadequate dietary intake is a major cause of the vitamin deficiency, other possible mechanisms may also be involved. Alcoholism can affect the absorption, storage, metabolism, and activation of many of these vitamins. Possible factors which cause alterations in the absorption, storage, and metabolism of these vitamins are discussed. Suggestions for management of vitamin deficiencies in chronic alcoholics are also discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1337,I1337)","v":3542861},{"$f":"(LEN($J1337) - LEN(SUBSTITUTE(LOWER($J1337),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1337) - LEN(SUBSTITUTE(LOWER($J1337),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1337) - LEN(SUBSTITUTE(LOWER($J1337),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1337:D1337)","v":0},1986,"Xeroderma pigmentosum.","Jung",3542861,"Xeroderma pigmentosum.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1338,I1338)","v":2941237},{"$f":"(LEN($J1338) - LEN(SUBSTITUTE(LOWER($J1338),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1338) - LEN(SUBSTITUTE(LOWER($J1338),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1338) - LEN(SUBSTITUTE(LOWER($J1338),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1338:D1338)","v":0},1986,"Soft tissue mineralization: roentgen analysis.","Feldman",2941237,"Soft tissue mineralization: roentgen analysis.    Abstract:   Numerous, incompletely understood, and undetermined physiologic factors may exert further but unappreciated influences on the development of ectopic calcification and ossification. In the former instance, in addition to serum calcium and phosphorous ion concentrations, tissue pH, blood supply, hormones, i.e., vitamin D, vitamin A, and various enzymes (e.g., alkaline phosphatase and pyrophosphatase) may all play significant, ancillary, time-dependent, but as yet undetermined roles. Ossification, like calcification, may occur in association with many types of disorders and under a variety of circumstances, some of which, such as trauma, have been reduplicated in the laboratory. However, experimental conditions that produce ectopic bone, as well as the species that are predilected do not always coincide with clinical observations in man. Not only are there differences between species in regard to susceptibility to ectopic bone production under particular circumstances, i.e., rabbits are the most susceptible and mice the least to mechanical injury, but there are differences between individuals. Individual variability in susceptibility to soft tissue ossification suggests either a personal or familial predilection. If such liability is inherited, this would be an example of an ecogenetic condition, in which someone is susceptible to an environmental agent by virtue of genetic constitution. Histocompatibility (HLS) antigens have provided substantiation of this concept. In the case of soft tissue ossification, causative environmental agents could include trauma, burns, hip replacement, and immobility secondary to neurological insults. In the case of soft tissue calcification, trauma, infections, or repeated injections could constitute the triggering environmental event. Not only do individuals at risk develop bone, but those that do tend to do so in characteristic places. Therefore, there is an additional differential susceptibility at various sites in the same individual. In cases with neurological conditions, thigh muscles are more susceptible than paraspinal muscles. The underlying condition is a further moderator, i.e., in paraplegics, thigh muscles are most apt to be involved. Elbows are most commonly affected after burns regardless of the site of the burn. Ectopic ossification also has a further predilection for distribution. Not only are muscle groups unequal in risk in terms of site, but the type of muscle affected is relevant, since skeletal muscles are involved in these same conditions to the exclusion of smooth muscles.(ABSTRACT TRUNCATED AT 400 WORDS)"]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1339,I1339)","v":3538647},{"$f":"(LEN($J1339) - LEN(SUBSTITUTE(LOWER($J1339),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1339) - LEN(SUBSTITUTE(LOWER($J1339),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1339) - LEN(SUBSTITUTE(LOWER($J1339),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1339:D1339)","v":0},1986,"Genetic defects in vitamin utilization. Part I: General aspects and fat-solumbe vitamins.","Elsas",3538647,"Genetic defects in vitamin utilization. Part I: General aspects and fat-solumbe vitamins.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1340,I1340)","v":3524618},{"$f":"(LEN($J1340) - LEN(SUBSTITUTE(LOWER($J1340),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1340) - LEN(SUBSTITUTE(LOWER($J1340),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1340) - LEN(SUBSTITUTE(LOWER($J1340),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1340:D1340)","v":0},1986,"Regulation of cholesterol biosynthesis.","Rudney",3524618,"Regulation of cholesterol biosynthesis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1341,I1341)","v":3523400},{"$f":"(LEN($J1341) - LEN(SUBSTITUTE(LOWER($J1341),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1341) - LEN(SUBSTITUTE(LOWER($J1341),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1341) - LEN(SUBSTITUTE(LOWER($J1341),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1341:D1341)","v":0},1986,"The liver sinusoidal cells. Their role in disorders of the liver, lipoprotein metabolism and atherogenesis.","Fraser",3523400,"The liver sinusoidal cells. Their role in disorders of the liver, lipoprotein metabolism and atherogenesis.    Abstract:   A review of the morphological and metabolic interactions between hepatocytes, the various sinusoidal cells and sinusoidal blood is presented. This field of investigation is rapidly expanding, with widespread implications in the regulation of physiological processes and diseases in the liver and other organs. Although most of the review is of already published work, some areas incorporate personal speculations of the probable role of sinusoidal cells in disease processes."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1342,I1342)","v":3520661},{"$f":"(LEN($J1342) - LEN(SUBSTITUTE(LOWER($J1342),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1342) - LEN(SUBSTITUTE(LOWER($J1342),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1342) - LEN(SUBSTITUTE(LOWER($J1342),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1342:D1342)","v":0},1986,"Interaction of alcohol and nutritional factors with hepatic fibrosis.","Lieber",3520661,"Interaction of alcohol and nutritional factors with hepatic fibrosis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1343,I1343)","v":3299887},{"$f":"(LEN($J1343) - LEN(SUBSTITUTE(LOWER($J1343),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1343) - LEN(SUBSTITUTE(LOWER($J1343),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1343) - LEN(SUBSTITUTE(LOWER($J1343),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1343:D1343)","v":0},1986,"Nutritional aspects of infection.","Crompton",3299887,"Nutritional aspects of infection.    Abstract:   Current knowledge is examined about the means whereby ascariasis, hookworm disease, strongyloidiasis and trichuriasis may contribute to the aetiology of human malnutrition. Results from experiments with related parasites in the laboratory have demonstrated the role of gastrointestinal helminthiases in animal malnutrition. Some evidence shows that in children, infection with the intestinal stages of Ascaris lumbricoides is associated with reduced growth rate, disturbed nitrogen balance, malabsorption of vitamin A, abnormal fat digestion, lactose maldigestion and an increased intestinal transit time. The main impact of hookworm infection is its relationship with iron-deficiency anaemia which may have effects at the community level as regards work and productivity in adults and learning and school performance in children. More research is needed to extend knowledge of the nutritional impact of ascariasis and hookworm disease in order to establish their public health significance. Research is needed also to identify the range of nutritional effects on man that occur as a result of trichuriasis and strongyloidiasis. The significance of less prevalent and more localized gastrointestinal helminthiases should not be ignored."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1344,I1344)","v":3083708},{"$f":"(LEN($J1344) - LEN(SUBSTITUTE(LOWER($J1344),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1344) - LEN(SUBSTITUTE(LOWER($J1344),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1344) - LEN(SUBSTITUTE(LOWER($J1344),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1344:D1344)","v":0},1986,"Effects of alcohol on other hepatotoxins.","Zimmerman",3083708,"Effects of alcohol on other hepatotoxins.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1345,I1345)","v":3012644},{"$f":"(LEN($J1345) - LEN(SUBSTITUTE(LOWER($J1345),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1345) - LEN(SUBSTITUTE(LOWER($J1345),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1345) - LEN(SUBSTITUTE(LOWER($J1345),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1345:D1345)","v":0},1986,"Vitamin A and the liver.","De Luca",3012644,"Vitamin A and the liver.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1346,I1346)","v":3911189},{"$f":"(LEN($J1346) - LEN(SUBSTITUTE(LOWER($J1346),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1346) - LEN(SUBSTITUTE(LOWER($J1346),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1346) - LEN(SUBSTITUTE(LOWER($J1346),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1346:D1346)","v":0},1985,"[Role of vitamin A in the body].","Janczewska",3911189,"[Role of vitamin A in the body].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1347,I1347)","v":3905268},{"$f":"(LEN($J1347) - LEN(SUBSTITUTE(LOWER($J1347),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1347) - LEN(SUBSTITUTE(LOWER($J1347),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1347) - LEN(SUBSTITUTE(LOWER($J1347),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1347:D1347)","v":0},1985,"Parathyroid tumors.","Granberg",3905268,"Parathyroid tumors.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1348,I1348)","v":3901272},{"$f":"(LEN($J1348) - LEN(SUBSTITUTE(LOWER($J1348),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1348) - LEN(SUBSTITUTE(LOWER($J1348),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1348) - LEN(SUBSTITUTE(LOWER($J1348),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1348:D1348)","v":0},1985,"Treatment of primary biliary cirrhosis.","Warnes",3901272,"Treatment of primary biliary cirrhosis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1349,I1349)","v":2408489},{"$f":"(LEN($J1349) - LEN(SUBSTITUTE(LOWER($J1349),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1349) - LEN(SUBSTITUTE(LOWER($J1349),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1349) - LEN(SUBSTITUTE(LOWER($J1349),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1349:D1349)","v":0},1985,"Regulation of gap junctional conductance.","Spray",2408489,"Regulation of gap junctional conductance.    Abstract:   Gap junctional conductance is regulated by the number of channels between coupled cells (the balance between formation and loss of these channels) and by the fraction of these channels that are open (gating mechanisms). A variety of treatments are known to affect junction formation. Adenosine 3,5-cyclic monophosphate (cAMP) is involved in some cases, and protein synthesis may be required but precursor molecules can also exist. Junction removal occurs both by dispersion of particles and by internalization of junctional membrane. Factors promoting removal are not well understood. A variety of gating mechanisms exist. Coupling may be controlled by changes in conductance of nonjunctional membranes. Several kinds of voltage dependence of junctional conductance are known, but rat ventricular junctions at least are electrically linear. Cytoplasmic acidification decreases conductance of most gap junctions. Sensitivity in rat ventricular myocytes allows modulation of coupling by moderate changes near normal internal pH. Increasing intracellular Ca also decreases junctional conductance, but in the better studied cases sensitivity is much lower to Ca than H. A few data support low sensitivity to Ca in cardiac cells, but quantitative studies are lacking. Higher alcohols such as octanol block junctional conductance in a wide range of tissues including rat ventricular myocytes. An antibody to liver gap junctions blocks junctions between rat ventricular myocytes. Cross reactivity indicates at least partial homology between many gap junctions. Although differences among gap junctions are known, a general physiology is being developed, which may have considerable relevance to normal cardiac function and also to conduction disorders of that tissue."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1350,I1350)","v":3890798},{"$f":"(LEN($J1350) - LEN(SUBSTITUTE(LOWER($J1350),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1350) - LEN(SUBSTITUTE(LOWER($J1350),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1350) - LEN(SUBSTITUTE(LOWER($J1350),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1350:D1350)","v":0},1985,"[Metabolism and function of vitamin A].","Amédée-Manesme",3890798,"[Metabolism and function of vitamin A].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1351,I1351)","v":3888764},{"$f":"(LEN($J1351) - LEN(SUBSTITUTE(LOWER($J1351),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1351) - LEN(SUBSTITUTE(LOWER($J1351),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1351) - LEN(SUBSTITUTE(LOWER($J1351),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1351:D1351)","v":0},1985,"[The perisinusoidal cell (or Ito cell)].","Bioulac-Sage",3888764,"[The perisinusoidal cell (or Ito cell)].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1352,I1352)","v":3907770},{"$f":"(LEN($J1352) - LEN(SUBSTITUTE(LOWER($J1352),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1352) - LEN(SUBSTITUTE(LOWER($J1352),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1352) - LEN(SUBSTITUTE(LOWER($J1352),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1352:D1352)","v":0},1985,"Nutritional factors of lameness and metabolic bone disease in cattle.","Smart",3907770,"Nutritional factors of lameness and metabolic bone disease in cattle.    Abstract:   Lameness in cattle has numerous causes, and many factors interact to interfere with normal locomotion. The nutrients that have been implicated are protein, energy, calcium, phosphorus, copper, manganese, selenium, zinc, and vitamins A, D, and E. The fact that several nutrients may be involved with the problem should not be overlooked. There may also be factors in the diet that interact with the nutrient (particularly with trace minerals) that must be considered. When congenital skeletal deformities are being investigated, the veterinarian should not overlook the nutrition of the dam during pregnancy. When recommending dietary changes, a veterinarian should be careful that new imbalances have not been created and that the producer is not adding nutrients to the diet other than those suggested."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1353,I1353)","v":3891492},{"$f":"(LEN($J1353) - LEN(SUBSTITUTE(LOWER($J1353),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1353) - LEN(SUBSTITUTE(LOWER($J1353),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1353) - LEN(SUBSTITUTE(LOWER($J1353),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1353:D1353)","v":0},1985,"[The liver and vitamin A].","Rosenbaum",3891492,"[The liver and vitamin A].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1354,I1354)","v":3911268},{"$f":"(LEN($J1354) - LEN(SUBSTITUTE(LOWER($J1354),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1354) - LEN(SUBSTITUTE(LOWER($J1354),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1354) - LEN(SUBSTITUTE(LOWER($J1354),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1354:D1354)","v":0},1985,"Functional consequences of zinc deficiency.","McClain",3911268,"Functional consequences of zinc deficiency.    Abstract:   Zinc is an essential trace element necessary for over 200 zinc metalloenzymes and required for normal nucleic acid, protein, and membrane metabolism. During the past two decades there has been a rapid expansion of knowledge concerning zinc metabolism in both normal and disease situations, including mechanisms for zinc absorption, excretion and internal redistribution of zinc after stress or trauma. Acrodermatitis enteropathica has been recognized to be a disease of impaired zinc absorption in man. A host of disease processes now are recognized to be complicated by zinc deficiency including alcoholic liver disease, sickle cell anemia, protein calorie malnutrition, and a variety of intestinal diseases including Crohns disease, sprue, short bowel syndrome and after jejunal ileal bypass. Zinc has proved to be an extremely interesting mineral to nutritionists and physicians because of its importance in normal physiology and biochemistry and because of the diverse presenting features of zinc deficiency. This paper reviews ten functional consequences of zinc deficiency and emphasizes certain consequences in which there have been new discoveries concerning their mechanism (e.g., anorexia) or their clinical importance (e.g., immune dysfunction)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1355,I1355)","v":3887776},{"$f":"(LEN($J1355) - LEN(SUBSTITUTE(LOWER($J1355),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1355) - LEN(SUBSTITUTE(LOWER($J1355),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1355) - LEN(SUBSTITUTE(LOWER($J1355),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1355:D1355)","v":0},1985,"Mechanism of conversion of beta-carotene into vitamin A--central cleavage versus random cleavage.","Ganguly",3887776,"Mechanism of conversion of beta-carotene into vitamin A--central cleavage versus random cleavage.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1356,I1356)","v":2983288},{"$f":"(LEN($J1356) - LEN(SUBSTITUTE(LOWER($J1356),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1356) - LEN(SUBSTITUTE(LOWER($J1356),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1356) - LEN(SUBSTITUTE(LOWER($J1356),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1356:D1356)","v":0},1985,"[Lipid peroxidation and free radicals. Role in cellular biology and pathology].","Clavel",2983288,"[Lipid peroxidation and free radicals. Role in cellular biology and pathology].    Abstract:   Membrane phospholipids attack by oxygen free radicals, i.e. lipidoperoxidation, occurs in normal cellular life. This free radicals attack is controlled by a protective system, both enzymatic (superoxide dismutase, catalase, glutahione peroxidase) and non enzymatic (vitamine E). Imbalance between attack and defense can explain many pathological events. In these events, the oxidation products of unsaturated fatty acids are of fundamental importance, in particular those derived from arachidonic acid (prostaglandins, prostacyclins, thromboxanes and leukotrienes)."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1357,I1357)","v":2418640},{"$f":"(LEN($J1357) - LEN(SUBSTITUTE(LOWER($J1357),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1357) - LEN(SUBSTITUTE(LOWER($J1357),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1357) - LEN(SUBSTITUTE(LOWER($J1357),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1357:D1357)","v":0},1985,"Alcohol and the liver: metabolism of ethanol, metabolic effects and pathogenesis of injury.","Lieber",2418640,"Alcohol and the liver: metabolism of ethanol, metabolic effects and pathogenesis of injury.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1358,I1358)","v":6098078},{"$f":"(LEN($J1358) - LEN(SUBSTITUTE(LOWER($J1358),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1358) - LEN(SUBSTITUTE(LOWER($J1358),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1358) - LEN(SUBSTITUTE(LOWER($J1358),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1358:D1358)","v":0},1984,"A review of the aetiology and pathogenesis of hypercalcaemia.","Choo-Kang",6098078,"A review of the aetiology and pathogenesis of hypercalcaemia.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1359,I1359)","v":6389304},{"$f":"(LEN($J1359) - LEN(SUBSTITUTE(LOWER($J1359),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1359) - LEN(SUBSTITUTE(LOWER($J1359),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1359) - LEN(SUBSTITUTE(LOWER($J1359),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1359:D1359)","v":0},1984,"Alcohol and the liver: 1984 update.","Lieber",6389304,"Alcohol and the liver: 1984 update.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1360,I1360)","v":6435918},{"$f":"(LEN($J1360) - LEN(SUBSTITUTE(LOWER($J1360),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1360) - LEN(SUBSTITUTE(LOWER($J1360),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1360) - LEN(SUBSTITUTE(LOWER($J1360),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1360:D1360)","v":0},1984,"Therapy of exocrine and endocrine pancreatic insufficiency.","Lankisch",6435918,"Therapy of exocrine and endocrine pancreatic insufficiency.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1361,I1361)","v":6100131},{"$f":"(LEN($J1361) - LEN(SUBSTITUTE(LOWER($J1361),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1361) - LEN(SUBSTITUTE(LOWER($J1361),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1361) - LEN(SUBSTITUTE(LOWER($J1361),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1361:D1361)","v":0},1984,"[Zinc and chronic enteropathies].","Giorgi",6100131,"[Zinc and chronic enteropathies].    Abstract:   In recent years the nutritional importance of zinc has been well established; its deficiency and its symptoms have also been recognized in humans. Furthermore, Acrodermatitis Enteropathica has been isolated, a rare but severe disease, of which skin lesions, chronic diarrhoea and recurring infections are the main symptoms. The disease is related to the malfunctioning of intestinal absorption of zinc and can be treated by administering pharmacological doses of zinc orally. Good dietary sources of zinc are meat, fish and, to a less extent, human milk. The amount of zinc absorbed in the small intestine is influenced by other nutrients: some compounds inhibit this process (dietary fiber, phytate) while others (picolinic acid, citric acid), referred to as Zn-binding ligands (ZnBL) facilitate it. Citric acid is thought to be the ligand which accounts for the high level of bioavailability of zinc in human milk. zinc absorption occurs throughout the small intestine, not only in the prossimal tract (duodenum and jejunum) but also in the distal tract (ileum). Diarrhoea is one of the clinical manifestations of zinc deficiency, thus many illnesses distinguished by chronic diarrhoea entail a bad absorption of zinc. In fact, in some cases of chronic enteropathies in infants, like coeliac disease and seldom cystic fibrosis, a deficiency of zinc has been isolated. Some of the symptoms of Crohns disease, like retarded growth and hypogonadism, have been related to hypozinchemia which is present in this illness. Finally, it is possible that some of the dietary treatments frequently used for persistent post-enteritis diarrhoea (i.e. cows milk exclusion, abuse and misuse of dietary fiber like carrot and carub powder, use of soy formula) can constitute a scarce supply of zinc and therefore could promote the persistency of diarrhoea itself."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1362,I1362)","v":6397187},{"$f":"(LEN($J1362) - LEN(SUBSTITUTE(LOWER($J1362),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1362) - LEN(SUBSTITUTE(LOWER($J1362),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1362) - LEN(SUBSTITUTE(LOWER($J1362),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1362:D1362)","v":0},1984,"Whats new in paediatric dermatology.","Rasmussen",6397187,"Whats new in paediatric dermatology.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1363,I1363)","v":6385273},{"$f":"(LEN($J1363) - LEN(SUBSTITUTE(LOWER($J1363),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1363) - LEN(SUBSTITUTE(LOWER($J1363),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1363) - LEN(SUBSTITUTE(LOWER($J1363),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1363:D1363)","v":0},1984,"Other trace elements and the liver.","Linder",6385273,"Other trace elements and the liver.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1364,I1364)","v":6382655},{"$f":"(LEN($J1364) - LEN(SUBSTITUTE(LOWER($J1364),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1364) - LEN(SUBSTITUTE(LOWER($J1364),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1364) - LEN(SUBSTITUTE(LOWER($J1364),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1364:D1364)","v":0},1984,"Biology of wound healing.","Carrico",6382655,"Biology of wound healing.    Abstract:   A clear understanding of wound healing is vital to a rational surgical approach. This article describes the major biologic processes of tissue repair and the factors influencing the healing processes, and it discusses specific wound-healing problems and recommends management regimens."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1365,I1365)","v":6390952},{"$f":"(LEN($J1365) - LEN(SUBSTITUTE(LOWER($J1365),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1365) - LEN(SUBSTITUTE(LOWER($J1365),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1365) - LEN(SUBSTITUTE(LOWER($J1365),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1365:D1365)","v":0},1984,"[Inhibitors of gluconeogenesis (review)].","Kendysh",6390952,"[Inhibitors of gluconeogenesis (review)].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1366,I1366)","v":6087458},{"$f":"(LEN($J1366) - LEN(SUBSTITUTE(LOWER($J1366),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1366) - LEN(SUBSTITUTE(LOWER($J1366),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1366) - LEN(SUBSTITUTE(LOWER($J1366),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1366:D1366)","v":0},1984,"Chemical carcinogenesis: mycotoxins and other chemicals to which humans are exposed.","Newberne",6087458,"Chemical carcinogenesis: mycotoxins and other chemicals to which humans are exposed.    Abstract:   HCC occurs in a higher incidence in some subsets of human populations residing in specific geographic areas around the world. These include black populations residing south of the Sahara, particularly in South and East Africa; in populations of Southeast Asia and the Western Pacific; in India, China, and in some other circumscribed areas. These epidemiologic observations strongly suggest that environmental factors are involved in the etiology of HCC. Evidence from human and animal data point toward a multicausal etiology, including dietary or environmental contamination with mycotoxin carcinogens, acting in concert with hepatitis B viral infection and, in some areas, with malnutrition. Dietary factors that appear to influence susceptibility to HCC include fat, protein and amino acids, vitamin A, selenium, and zinc. In addition, alcohol consumption, environmental chemicals that are natural or man made, and genetic predisposition must also be considered. It seems likely that identification of etiologic agents (hepatitis B infection, aflatoxin, malnutrition) and correction or prevention of these are the most promising means for controlling HCC in man."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1367,I1367)","v":6093676},{"$f":"(LEN($J1367) - LEN(SUBSTITUTE(LOWER($J1367),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1367) - LEN(SUBSTITUTE(LOWER($J1367),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1367) - LEN(SUBSTITUTE(LOWER($J1367),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1367:D1367)","v":0},1984,"Prevention of cancer: practical prospects.","Doll",6093676,"Prevention of cancer: practical prospects.    Abstract:   The discovery of some 40 specific factors that have caused cancer in humans has demonstrated conclusively that many fatal cancers are capable of being prevented. These known factors are responsible for less than half all fatal cancers in all countries and much less in most; but there is good evidence, derived from the variation in the incidence of cancer in different communities, in different countries, and at different times that in many countries it may be possible to prevent 80% of all cancers or even more. The practical problems facing each country are different. Not only are the types of cancer different that need most urgently to be prevented, but so are the social and economic conditions that permit or constrain the introduction of preventive measures. Well-understood measures are summarized and the prospects for others that are less established or as yet untried are discussed, including the use of low-tar cigarettes, dietary modification, and anti-viral vaccines."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1368,I1368)","v":6399449},{"$f":"(LEN($J1368) - LEN(SUBSTITUTE(LOWER($J1368),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1368) - LEN(SUBSTITUTE(LOWER($J1368),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1368) - LEN(SUBSTITUTE(LOWER($J1368),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1368:D1368)","v":0},1984,"Alcohol-nutrition interaction: 1984 update.","Lieber",6399449,"Alcohol-nutrition interaction: 1984 update.    Abstract:   Alcohol remains a prevailing cause of malnutrition resulting in a variety of deficiency states secondary to decreased intake of nutrients. In addition to various well described primary malnutrition syndromes, secondary malnutrition may result from the interaction of ethanol with nutrient digestion, absorption or utilization. Some of the latter alcohol-nutrient interactions have been recently defined and their pathogenesis is discussed in this review. Included are interactions with thiamine, folic acid, vitamin A and disorders secondary to amino acid imbalances. The rationale for various forms of therapy is reviewed, including the treatment aimed at correcting the quot;hypermetabolic statequot; in alcoholics ad the pitfalls of excess nutrient administration (particularly as it pertains to pyridoxine, vitamin A and amino acids). The desirability of recognizing early precirrhotic stages of alcoholic fibrosis is emphasized, in order to start therapy prior to the medical and/or social disintegration of the alcoholic."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1369,I1369)","v":6230219},{"$f":"(LEN($J1369) - LEN(SUBSTITUTE(LOWER($J1369),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1369) - LEN(SUBSTITUTE(LOWER($J1369),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1369) - LEN(SUBSTITUTE(LOWER($J1369),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1369:D1369)","v":0},1984,"Vitamin therapy in the absence of obvious deficiency. What is the evidence?","Ovesen",6230219,"Vitamin therapy in the absence of obvious deficiency. What is the evidence?    Abstract:   Vitamins are a group of organic compounds occurring naturally in food and are necessary for good health. Lack of a vitamin may lead to a specific deficiency syndrome, which may be primary (due to inadequate diet) or secondary (due to malabsorption or to increased metabolic need), and it is rational to use high-dose vitamin supplementation in situations where these clinical conditions exist. However, pharmacological doses of vitamins are claimed to be of value in a wide variety of conditions which have no, or only a superficial, resemblance to the classic vitamin deficiency syndromes. The enormous literature on which these claims are based consists mainly of uncontrolled clinical trials or anecdotal reports. Only a few studies have made use of the techniques of randomisation and double-blinding. Evidence from such studies reveals a beneficial therapeutic effect of vitamin E in intermittent claudication and fibrocystic breast disease and of vitamin C in pressure sores, but the use of vitamin A in acne vulgaris, vitamin E in angina pectoris, hyperlipidaemia and enhancement of athletic capacity, of vitamin C in advanced cancer, and niacin in schizophrenia has been rejected. Evidence is conflicting or inconclusive as to the use of vitamin C in the common cold, asthma and enhancement of athletic capacity, of pantothenic acid in osteoarthritis, and folic acid (folacin) in neural tube defects. Most of the vitamins have been reported to cause adverse effects when ingested in excessive doses. It is therefore worthwhile to consider the risk-benefit ratio before embarking upon the use of high-dose vitamin supplementation for disorders were proof of efficacy is lacking."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1370,I1370)","v":6391114},{"$f":"(LEN($J1370) - LEN(SUBSTITUTE(LOWER($J1370),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1370) - LEN(SUBSTITUTE(LOWER($J1370),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1370) - LEN(SUBSTITUTE(LOWER($J1370),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1370:D1370)","v":0},1984,"Epidemiologic studies on vitamin A and cancer.","Mettlin",6391114,"Epidemiologic studies on vitamin A and cancer.    Abstract:   Data derived from epidemiologic studies on human populations are consistent with the protection from cancer afforded by vitamin A seen in animal studies. The populations studied are diverse, including groups living in India, Singapore, Norway, the United Kingdom, and the United States. The methodologies brought to bear on the question have been equally varied. Although there are inconsistencies in findings, and instances in which an association has not been observed, the weight of evidence suggests that the intake of vitamin A from dietary or other sources may inhibit the onset of lung cancer and possibly other cancers. However, the evidence from human populations is not experimental and it is conceivable that the associations observed are not causal. Additional epidemiologic research is needed to determine what sites of cancer may be inhibited by vitamin A and whether cancer growth at any other site is enhanced by high vitamin A intakes. It is also important that controlled trials using vitamin A as a chemopreventive agent be considered as a means of determining whether the epidemiologic findings are of clinical significance."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1371,I1371)","v":6380542},{"$f":"(LEN($J1371) - LEN(SUBSTITUTE(LOWER($J1371),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1371) - LEN(SUBSTITUTE(LOWER($J1371),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1371) - LEN(SUBSTITUTE(LOWER($J1371),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1371:D1371)","v":0},1984,"Nutrition of the domestic cat, a mammalian carnivore.","MacDonald",6380542,"Nutrition of the domestic cat, a mammalian carnivore.    Abstract:   From the foregoing discussion of the nutritional requirements and some of the metabolic anomalies of the cat, it is clear that the cat is adapted to eating a carnivorous diet. It may, however, have less capability than omnivores and herbivores to adapt to wide ranges in dietary composition. For example, the lack of ability to synthesize sufficient vitamin A from carotene, ornithine from glutamic acid, arachidonate from linoleate, and taurine from cysteine results from a complete deletion or severe limitation of the enzyme or pathway that makes each nutrient. Other nutrient requirements, such as the absolute requirement for niacin and the high protein requirement, appear to result from the high activity of one or more enzymes and the fact that these enzymes are not adaptive in the cat. For example, the cat cannot decrease picolinic carboxylase in order to force tryptophan toward the niacin-synthetic pathway (244) nor can it decrease the urea cycle enzymes when dietary protein is decreased in the diet in order to conserve nitrogen (209). Indeed, the cat appears to have less capability to adapt to most changes in dietary composition because it cannot change the quantities of enzymes involved in the metabolic pathways (209). This evolutionary development has resulted in more stringent nutritional requirements for cats than for omnivores such as the rat, dog, and man. What little evidence exists for other carnivore species leads us to suggest that this pattern may well be common among other strict carnivores. The metabolic differences between the cat and omnivores provide the researcher with a useful animal model for studying the biochemical basis of some nutrient requirements. For example, because there is no significant conversion of linoleate to arachidonate in cat liver (101, 150, 231), the physiological functions of linoleate can be determined independent of it having a role as a precursor of arachidonate (150). This has not been possible with other species. It is anticipated that further studies of the nutrition of the cat will increase our understanding of metabolic adaptation and nutrient functions."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1372,I1372)","v":6361415},{"$f":"(LEN($J1372) - LEN(SUBSTITUTE(LOWER($J1372),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1372) - LEN(SUBSTITUTE(LOWER($J1372),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1372) - LEN(SUBSTITUTE(LOWER($J1372),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1372:D1372)","v":0},1984,"Metabolism and metabolic effects of alcohol.","Lieber",6361415,"Metabolism and metabolic effects of alcohol.    Abstract:   The author provides an excellent overview of the three major pathways for the metabolism of ethanol. Many of the toxic effects of ethanol can be attributed to two specific products, hydrogen and acetaldehyde, and these effects are explored in detail."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1373,I1373)","v":6235826},{"$f":"(LEN($J1373) - LEN(SUBSTITUTE(LOWER($J1373),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1373) - LEN(SUBSTITUTE(LOWER($J1373),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1373) - LEN(SUBSTITUTE(LOWER($J1373),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1373:D1373)","v":0},1984,"Adverse effects of excessive consumption of amino acids.","Benevenga",6235826,"Adverse effects of excessive consumption of amino acids.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1374,I1374)","v":6416916},{"$f":"(LEN($J1374) - LEN(SUBSTITUTE(LOWER($J1374),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1374) - LEN(SUBSTITUTE(LOWER($J1374),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1374) - LEN(SUBSTITUTE(LOWER($J1374),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1374:D1374)","v":0},1983,"Selenium interactions with carcinogens.","Whanger",6416916,"Selenium interactions with carcinogens.    Abstract:   Although selenium was once considered to be a toxic, undesirable and carcinogenic element, it is now recognized as an essential element with anticarcinogenic properties. Epidemiological studies in the United States have shown an inverse relationship between selenium intake and certain forms of cancer in humans, but other factors must be considered since cancer is not higher in people living in selenium-deficient areas of the world (Finland, New Zealand, and Keshan disease area, China). Under most dietary conditions, selenium has been shown to reduce the spontaneous mammary tumor incidence in an inbred strain of mice. In general, selenium will counteract to various degrees, the chemical carcinogens used to produce lesions of the skin [coal tar, 3-methylcholanthrene, alpha-pyrene, and 7,12 dimethylbenz(a) anthracene (DMBA)], liver (3-methyl-4-dimethyl-aminoazobenzene, aflatoxin B1, and 2-acetylaminofluorene), mammary gland (DMBA and N-methyl-N-nitrosurea), and intestinal tract [1,2-dimethylhydrazine, bis(2-oxopropyl)nitrosamine, and azoxymethane]. Dietary factors, such as fat, will modify the protective effects of selenium. High dietary unsaturated fats, for example, markedly increase the mammary tumors in rats treated with DMBA, and selenium will reduce the tumor incidence but not to the level of rats fed a low fat diet. Other factors known to affect the anticarcinogenic effects of selenium include synthetic antioxidants, vitamin E, vitamin A and ascorbic acid. The mechanisms of selenium counteraction of carcinogens remain unknown."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1375,I1375)","v":6354899},{"$f":"(LEN($J1375) - LEN(SUBSTITUTE(LOWER($J1375),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1375) - LEN(SUBSTITUTE(LOWER($J1375),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1375) - LEN(SUBSTITUTE(LOWER($J1375),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1375:D1375)","v":0},1983,"Zinc and vitamin A deficiency in liver cirrhosis.","Schölmerich",6354899,"Zinc and vitamin A deficiency in liver cirrhosis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1376,I1376)","v":6353294},{"$f":"(LEN($J1376) - LEN(SUBSTITUTE(LOWER($J1376),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1376) - LEN(SUBSTITUTE(LOWER($J1376),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1376) - LEN(SUBSTITUTE(LOWER($J1376),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1376:D1376)","v":0},1983,"Hypervitaminosis A enhances hepatotoxicity of ethanol in rats.","Schölmerich",6353294,"Hypervitaminosis A enhances hepatotoxicity of ethanol in rats.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1377,I1377)","v":6149527},{"$f":"(LEN($J1377) - LEN(SUBSTITUTE(LOWER($J1377),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1377) - LEN(SUBSTITUTE(LOWER($J1377),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1377) - LEN(SUBSTITUTE(LOWER($J1377),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1377:D1377)","v":0},1983,"Tyrosinemia II: lessons in molecular pathophysiology.","Goldsmith",6149527,"Tyrosinemia II: lessons in molecular pathophysiology.    Abstract:   Tyrosinemia II is caused by a deficiency of hepatic tyrosine aminotransferase. With the deficiency of this key enzyme of tyrosine catabolism there is an increase in plasma tyrosine and then an increase in tyrosine metabolites in the urine. The increased plasma tyrosine causes tyrosine to crystallize in the cornea, producing corneal ulcerations and sometimes proliferation of corneal epithelium. In the epidermis of the palms and soles, tyrosine leads to erosions, crusting, and then hyperkeratosis. The human disease is due to an autosomal recessive gene, and similar genetic diseases have been found in mink and in dogs. A nutritional model for the disease, in which a high-tyrosine low-protein diet is fed to rats, produces almost identical features. The features of this disorder and some of the implications of this disease for the study of other genetic diseases is discussed in this review."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1378,I1378)","v":6409470},{"$f":"(LEN($J1378) - LEN(SUBSTITUTE(LOWER($J1378),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1378) - LEN(SUBSTITUTE(LOWER($J1378),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1378) - LEN(SUBSTITUTE(LOWER($J1378),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1378:D1378)","v":0},1983,"Parasites and malabsorption.","Brasitus",6409470,"Parasites and malabsorption.    Abstract:   In summary, it appears that giardiasis, coccidiosis, cryptosporidiosis, strongyloidiasis, capillariasis and perhaps P. falciparum malaria are the only parasitic diseases which cause malabsorption of many nutrients. D. latum and A. lumbricoides interfere with vitamin B12 and vitamin A absorption, respectively. In view of the increasing use of immunosuppressive therapy, it is likely that malabsorption caused by intestinal parasites may become even more evident in the future."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1379,I1379)","v":6192609},{"$f":"(LEN($J1379) - LEN(SUBSTITUTE(LOWER($J1379),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1379) - LEN(SUBSTITUTE(LOWER($J1379),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1379) - LEN(SUBSTITUTE(LOWER($J1379),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1379:D1379)","v":0},1983,"[Newer aspects of clinical experimental cirrhosis research].","Gerok",6192609,"[Newer aspects of clinical experimental cirrhosis research].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1380,I1380)","v":6300952},{"$f":"(LEN($J1380) - LEN(SUBSTITUTE(LOWER($J1380),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1380) - LEN(SUBSTITUTE(LOWER($J1380),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1380) - LEN(SUBSTITUTE(LOWER($J1380),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1380:D1380)","v":0},1983,"Anorexia nervosa and bulimia.","Halmi",6300952,"Anorexia nervosa and bulimia.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1381,I1381)","v":6403949},{"$f":"(LEN($J1381) - LEN(SUBSTITUTE(LOWER($J1381),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1381) - LEN(SUBSTITUTE(LOWER($J1381),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1381) - LEN(SUBSTITUTE(LOWER($J1381),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1381:D1381)","v":0},1983,"Factors affecting vitamin A transport in animals and man.","Glover",6403949,"Factors affecting vitamin A transport in animals and man.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1382,I1382)","v":6355942},{"$f":"(LEN($J1382) - LEN(SUBSTITUTE(LOWER($J1382),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1382) - LEN(SUBSTITUTE(LOWER($J1382),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1382) - LEN(SUBSTITUTE(LOWER($J1382),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1382:D1382)","v":0},1983,"[Vitamin A in the treatment of eye diseases].","Mozherenkov",6355942,"[Vitamin A in the treatment of eye diseases].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1383,I1383)","v":6342974},{"$f":"(LEN($J1383) - LEN(SUBSTITUTE(LOWER($J1383),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1383) - LEN(SUBSTITUTE(LOWER($J1383),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1383) - LEN(SUBSTITUTE(LOWER($J1383),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1383:D1383)","v":0},1983,"Alcohol, protein nutrition, and liver injury.","Lieber",6342974,"Alcohol, protein nutrition, and liver injury.    Abstract:   Ther are several main mechanisms that allow us to understand a number of the hepatic and metabolic effects of ethanol. Ethanol is oxidized in the liver to two products (hydrogen and acetaldehyde), to which many of the effects of ethanol can be attributed. The hydrogen generated alters the redox state, and though this effect is attenuated after chronic ethanol consumption, it may still be sufficient to explain alterations in lipid metabolism, possibly increased collagen deposition, and, under special circumstances, depression of protein synthesis. Acetaldehyde impairs microtubules, decreases protein secretion, and causes protein retention and ballooning of the hepatocyte. Acetaldehyde exerts toxicity also with regard to other key cellular functions, particularly in the mitochondria, and it may promote peroxidation of the cellular membranes. It is noteworthy that after chronic consumption of ethanol, there is increased acetaldehyde, in part because of decreased disposition in the mitochondria and partly because of induction of an alternative pathway of ethanol metabolism, namely the microsomal ethanol-oxidizing system. Indeed, this MEOS increases in activity after chronic ethanol consumption, with cross induction and acceleration of the metabolism of other drugs and increased lipoprotein production with hyperlipemia. There is also increased microsomal activation of hepatotoxic compounds (including drugs and possibly vitamin A). Fibrosis and cirrhosis can develop despite an associated adequate diet and even in the absence of alcoholic hepatitis. They are preceded by myofibroblasts and fibroblast proliferation. What eventually causes the increased number of myofibroblasts and promotes fibrosis is unclear, nor do we know the relative role of hepatocytes or mesenchymal cells in the process of fibroplasis. Possibly selective roles in this process of specific nutritional factors remain to be elucidated."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1384,I1384)","v":6342343},{"$f":"(LEN($J1384) - LEN(SUBSTITUTE(LOWER($J1384),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1384) - LEN(SUBSTITUTE(LOWER($J1384),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1384) - LEN(SUBSTITUTE(LOWER($J1384),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1384:D1384)","v":0},1983,"Nutrition and 3-methylindole-induced lung injury.","Carlson",6342343,"Nutrition and 3-methylindole-induced lung injury.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1385,I1385)","v":6317601},{"$f":"(LEN($J1385) - LEN(SUBSTITUTE(LOWER($J1385),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1385) - LEN(SUBSTITUTE(LOWER($J1385),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1385) - LEN(SUBSTITUTE(LOWER($J1385),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1385:D1385)","v":0},1983,"Absorption of fat-soluble vitamins.","Weber",6317601,"Absorption of fat-soluble vitamins.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1386,I1386)","v":7050193},{"$f":"(LEN($J1386) - LEN(SUBSTITUTE(LOWER($J1386),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1386) - LEN(SUBSTITUTE(LOWER($J1386),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1386) - LEN(SUBSTITUTE(LOWER($J1386),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1386:D1386)","v":0},1982,"Possible role of beta-carotene in improving fertility in dairy cattle.","Hemken",7050193,"Possible role of beta-carotene in improving fertility in dairy cattle.    Abstract:   Recent interest in beta-carotene has been stimulated by reports that reproductive performance in cattle was improved with dietary supplementation of beta-carotene even when the diet was supplemented with vitamin A. Vitamin A requirements for cattle are based on studies with beta-carotene as the vitamin A source and with studies with vitamin A in the ester or alcohol form. Most of the studies with cattle that demonstrate the need for vitamin A for optimum reproduction were when beta-carotene was the source of vitamin A. Recent German reports show an improvement in conception rate, intensity of estrus, and changes in luteinizing hormone patterns when cattle received beta-carotene supplementation of low carotene diets. These diets were supplemented with vitamin A. A similar study from Israel did not detect benefits of beta-carotene. The active form of vitamin A for reproduction in rats and other species has not been determined; however, vitamin A does meet the reproductive requirements. The ruminant animal does have differences in carotene metabolism from the rat. Before the role of beta-carotene for reproduction in cattle can be clarified, the specific function of carotene or the specific form of vitamin A for reproduction needs to be determined."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1387,I1387)","v":6279485},{"$f":"(LEN($J1387) - LEN(SUBSTITUTE(LOWER($J1387),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1387) - LEN(SUBSTITUTE(LOWER($J1387),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1387) - LEN(SUBSTITUTE(LOWER($J1387),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1387:D1387)","v":0},1982,"Liver and cellular vitamin A binding proteins.","Chytil",6279485,"Liver and cellular vitamin A binding proteins.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1388,I1388)","v":6751049},{"$f":"(LEN($J1388) - LEN(SUBSTITUTE(LOWER($J1388),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1388) - LEN(SUBSTITUTE(LOWER($J1388),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1388) - LEN(SUBSTITUTE(LOWER($J1388),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1388:D1388)","v":0},1982,"Vitamins E and A in vascular diseases.","Butturini",6751049,"Vitamins E and A in vascular diseases.    Abstract:   The major pathogenetic factors of the atherosclerotic diseases are: a) vasal endothelium distress; b) rheological disturbs; c) alterations in plasma lipid pattern; d) dietary intake of saturated and polyunsaturated fatty acids; e) alteration of mitochondrial and microsomal membranes; f) vascular injury induced by immune complexes; g) increased lipid peroxidations. Many well documented reports state a positive effect of vitamins A and E on some of the factors previously considered. Vitamins A and E have an endothelium-protective activity and an antiperoxidative effect; they act as antiaggregant factors, affect O2 transport and utilization processes, increase HDL-cholesterol, potentiate the hypolipidemic action of the nicotinic acid."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1389,I1389)","v":6292757},{"$f":"(LEN($J1389) - LEN(SUBSTITUTE(LOWER($J1389),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1389) - LEN(SUBSTITUTE(LOWER($J1389),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1389) - LEN(SUBSTITUTE(LOWER($J1389),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1389:D1389)","v":0},1982,"[Does 24,25 dihydroxycholecalciferol have a physiological and pathophysiological role?].","Sebert",6292757,"[Does 24,25 dihydroxycholecalciferol have a physiological and pathophysiological role?].    Abstract:   The authors review recent experimental and human data concerning the potential physiological and pathophysiological role of 24,25 (OH)2D3, the dihydroxylated metabolite of vitamin D which is synthetisized with preference over 1,25 (OH)2D3 in organisms that have been replenished with vitamin D. For the major known effects of vitamin D such as stimulation of intestinal absorption and bone resorption of calcium and phosphorus, 24,25 (OH)2D3 is less effective than the 1,25 (OH)2D3 metabolite and consequently of lesser physiological importance. Some recent in vitro experiments have shown, however, that 24,25 (OH)2D3 intervenes in the stimulation of proteoglycan synthesis, inhibition of PTH, vitamin A and heparin induced resorption, whereas 1,25 (OH)2D3 does not. Although there is controversy as to its direct inhibitory effect on secretion of PTH, it seems to act with 1,25 (OH)2D3 to prevent hyperplasia of parathyroids in vitamin D deficient chicken. From a pathophysiological point, the presence of 24,25 (OH)2D3 seems vital to allow normal bone formation and mineralisation and possibly to counteract excessive bone resorption."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1390,I1390)","v":6177111},{"$f":"(LEN($J1390) - LEN(SUBSTITUTE(LOWER($J1390),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1390) - LEN(SUBSTITUTE(LOWER($J1390),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1390) - LEN(SUBSTITUTE(LOWER($J1390),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1390:D1390)","v":0},1981,"[Recent findings on the importance of vitamin A and its metabolism in man and laboratory animals].","Kolb",6177111,"[Recent findings on the importance of vitamin A and its metabolism in man and laboratory animals].    Abstract:   A survey is given concerning recent realizations of importance and metabolism of vitamin A in man and experimental animals. The transport of vitamin A from the small intestine takes place in form of esters by inclusion in chylomicrons and lipoproteins. A higher content in the blood plasma over a longer period evokes toxic effects. In the liver one part of the vitamin A in form of an ester with binding to lipoproteins is accumulated, one part is - according to the need - associated with a vitamin-A-binding protein, which forms complexes with prealbumin molecules and transports the vitamin to the various places of effect. With the help of the receptor proteins the vitamin A is included in the cells, in which it is effective and is transported into the vitamin-A-aldehyde and the vitamin-A-acid. The vitamin A and the vitamin-A-acid are transported into the cell nuclei with the help of receptor-proteins and play a role in the differentiation of the tissues and in the regulation of the synthesis of RNA. When a deficit or an abundance of vitamin A is present in the early phase of pregnancy malformations in the fetuses appear. The vitamin A and structure-similar connections have an inhibiting effect on the development of tumours."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1391,I1391)","v":6170219},{"$f":"(LEN($J1391) - LEN(SUBSTITUTE(LOWER($J1391),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1391) - LEN(SUBSTITUTE(LOWER($J1391),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1391) - LEN(SUBSTITUTE(LOWER($J1391),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1391:D1391)","v":0},1981,"Biochemical controls of liver cholesterol biosynthesis.","Ott",6170219,"Biochemical controls of liver cholesterol biosynthesis.    Abstract:   Major endogenous regulatory controls of cholesterol synthesis including dietary-feedback inhibition, circadian rhythms, feeding/fasting fluctuations, and enterohepatic bile acid circulation are discussed in terms of biochemical control mechanisms of liver cholesterol biosynthesis. Other likely control mechanisms such as cofactors, enzyme levels, and enzyme activities are noted. The current state of the biochemical knowledge is very dependent upon integrated data from one experimental animal - the rat. Inferences and implications in the human are thus limited."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1392,I1392)","v":7051303},{"$f":"(LEN($J1392) - LEN(SUBSTITUTE(LOWER($J1392),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1392) - LEN(SUBSTITUTE(LOWER($J1392),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1392) - LEN(SUBSTITUTE(LOWER($J1392),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1392:D1392)","v":0},1981,"Nature, pathogenesis and significance of the Mallory body.","French",7051303,"Nature, pathogenesis and significance of the Mallory body.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1393,I1393)","v":7017738},{"$f":"(LEN($J1393) - LEN(SUBSTITUTE(LOWER($J1393),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1393) - LEN(SUBSTITUTE(LOWER($J1393),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1393) - LEN(SUBSTITUTE(LOWER($J1393),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1393:D1393)","v":0},1981,"The assessment of vitamin A status.","Pitt",7017738,"The assessment of vitamin A status.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1394,I1394)","v":7044701},{"$f":"(LEN($J1394) - LEN(SUBSTITUTE(LOWER($J1394),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1394) - LEN(SUBSTITUTE(LOWER($J1394),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1394) - LEN(SUBSTITUTE(LOWER($J1394),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1394:D1394)","v":0},1981,"Hypogonadism and feminization in alcoholic men: the past, present and future.","Van Thiel",7044701,"Hypogonadism and feminization in alcoholic men: the past, present and future.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1395,I1395)","v":7026480},{"$f":"(LEN($J1395) - LEN(SUBSTITUTE(LOWER($J1395),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1395) - LEN(SUBSTITUTE(LOWER($J1395),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1395) - LEN(SUBSTITUTE(LOWER($J1395),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1395:D1395)","v":0},1981,"Vitamin and alcoholism. IX. Vitamin A.","Bonjour",7026480,"Vitamin and alcoholism. IX. Vitamin A.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1396,I1396)","v":6269976},{"$f":"(LEN($J1396) - LEN(SUBSTITUTE(LOWER($J1396),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1396) - LEN(SUBSTITUTE(LOWER($J1396),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1396) - LEN(SUBSTITUTE(LOWER($J1396),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1396:D1396)","v":0},1981,"The Mallory body: structure, composition, and pathogenesis.","French",6269976,"The Mallory body: structure, composition, and pathogenesis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1397,I1397)","v":7425890},{"$f":"(LEN($J1397) - LEN(SUBSTITUTE(LOWER($J1397),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1397) - LEN(SUBSTITUTE(LOWER($J1397),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1397) - LEN(SUBSTITUTE(LOWER($J1397),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1397:D1397)","v":0},1980,"Abetalipoproteinemia. Report of two cases and review of therapy.","Illingworth",7425890,"Abetalipoproteinemia. Report of two cases and review of therapy.    Abstract:   The clinical presentation and course of abetalipoproteinemia in two male patients, a child and an adult, are described. Apoprotein B was absent in both cases and each patient had gt; 50% acanthocytes present on peripheral blood smear. Family studies revealed normal lipid profiles in the parents of both patients, which is consistent with the usual autosomal recessive inheritance of this disorder. In addition to a low-fat diet, both patients have been maintained on high doses of vitamins A and E. In the adult patient, detailed evaluations over a five-year period have failed to show any progression of neurological disease while maintained on high-dose vitamins. The role of supplemental vitamins A and E in the therapy of abetalipoprotenemia is discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1398,I1398)","v":6774607},{"$f":"(LEN($J1398) - LEN(SUBSTITUTE(LOWER($J1398),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1398) - LEN(SUBSTITUTE(LOWER($J1398),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1398) - LEN(SUBSTITUTE(LOWER($J1398),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1398:D1398)","v":0},1980,"The interaction of vitamin A and zinc: implications for human nutrition.","Solomons",6774607,"The interaction of vitamin A and zinc: implications for human nutrition.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1399,I1399)","v":7400487},{"$f":"(LEN($J1399) - LEN(SUBSTITUTE(LOWER($J1399),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1399) - LEN(SUBSTITUTE(LOWER($J1399),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1399) - LEN(SUBSTITUTE(LOWER($J1399),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1399:D1399)","v":0},1980,"Effect of oral contraceptive agents on vitamin and mineral requirements.","Thorp",7400487,"Effect of oral contraceptive agents on vitamin and mineral requirements.    Abstract:   Oral contraceptive agents alter the metabolism of some nutrients, which could affect nutritional requirements. The effects of oral contraceptives on pyridoxine, folacin, thiamin, riboflavin, vitamin A, ascorbic acid, zinc, and copper as determined by studies done in the last five years are reviewed. Evidence for actual nutritional deficiencies due to the use of oral contraceptives is still insufficient, and more research is needed. Supplements are advised only for those women in whom other factors, such as disease, impair nutritional adequacy. Metabolic changes caused by oral contraceptives (OCs) in terms of the vitamins pyridoxine, folacin, thiamin, riboflavin, ascorbic acid, and A and the minerals zinc and copper are discussed. Pyroxidine in the form of coenzyme pyridoxal phosphate is involved in conversion of tryptophan to niacin, and tryptophan load tests have shown that certain metabolites of B6 have increased secretion when OCs are used. Folic acid deficiency has been found in some OC users. As with pyroxidine and folacin, OC users may require supplementation of thiamin as well. When riboflavin deficiency is preexistent, OCs exacerbate the condition (this effect may be race-dependent). Vitamin A, in contrast to the B vitamins, increases in the plasma of women taking OCs, perhaps due to greater mobilization of the vitamin by the liver. OC users generally show significantly lower leukocyte and platelet levels of ascorbic acid, and supplementation may be necessary. Zinc levels generally decrease, whereas copper levels in serum significantly increase in association with OC use. At present, supplements of vitamins and minerals are recommended only for high-risk groups."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1400,I1400)","v":6252490},{"$f":"(LEN($J1400) - LEN(SUBSTITUTE(LOWER($J1400),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1400) - LEN(SUBSTITUTE(LOWER($J1400),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1400) - LEN(SUBSTITUTE(LOWER($J1400),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1400:D1400)","v":0},1980,"[Neurological disorders in hyper- and hypovitaminosis].","Neundörfer",6252490,"[Neurological disorders in hyper- and hypovitaminosis].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1401,I1401)","v":6993411},{"$f":"(LEN($J1401) - LEN(SUBSTITUTE(LOWER($J1401),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1401) - LEN(SUBSTITUTE(LOWER($J1401),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1401) - LEN(SUBSTITUTE(LOWER($J1401),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1401:D1401)","v":0},1980,"Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs.","Wake",6993411,"Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1402,I1402)","v":6182689},{"$f":"(LEN($J1402) - LEN(SUBSTITUTE(LOWER($J1402),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1402) - LEN(SUBSTITUTE(LOWER($J1402),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1402) - LEN(SUBSTITUTE(LOWER($J1402),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1402:D1402)","v":0},1980,"Systemic mode of action of vitamin A.","Ganguly",6182689,"Systemic mode of action of vitamin A.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1403,I1403)","v":394040},{"$f":"(LEN($J1403) - LEN(SUBSTITUTE(LOWER($J1403),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1403) - LEN(SUBSTITUTE(LOWER($J1403),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1403) - LEN(SUBSTITUTE(LOWER($J1403),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1403:D1403)","v":0},1979,"Plasma vitamin A homeostasis: the relative dose response as a measure of liver vitamin A reserves.","Ganguly",394040,"Plasma vitamin A homeostasis: the relative dose response as a measure of liver vitamin A reserves.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1404,I1404)","v":492633},{"$f":"(LEN($J1404) - LEN(SUBSTITUTE(LOWER($J1404),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1404) - LEN(SUBSTITUTE(LOWER($J1404),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1404) - LEN(SUBSTITUTE(LOWER($J1404),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1404:D1404)","v":0},1979,"Paraneoplastic hypercalcemia in ovarian tumors.","Holtz",492633,"Paraneoplastic hypercalcemia in ovarian tumors.    Abstract:   Two cases of paraneoplastic hypercalcemia secondary to ovarian tumors are presented. Both cases were secondary to ectopic parathormone (PTH) production. Other mediators postulated to cause this syndrome are prostaglandins, vitamin D-like sterols, non-vitamin D sterols, vitamin A, cortisol, and quot;osteoclast-activating factor. The key treatment modalities for acute hypercalcemia are hydration and diuresis with furosemide; phosphates, steroids, antiprostaglandins, and hemodialysis may also be of value. Calcitonin is theoretically the most attractive treatment modality, but the rapid development of resistance limits its use to acute management. Mithramycin is most effective for long-term palliation of hypercalcemia if tumor-directed therapy is unsuccessful. Review of the literature confirms the previously made observation that mesonephromas are disproportionaately represented in association with this syndrome."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1405,I1405)","v":387373},{"$f":"(LEN($J1405) - LEN(SUBSTITUTE(LOWER($J1405),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1405) - LEN(SUBSTITUTE(LOWER($J1405),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1405) - LEN(SUBSTITUTE(LOWER($J1405),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1405:D1405)","v":0},1979,"Drugs and vitamin deficiency.","Ovesen",387373,"Drugs and vitamin deficiency.    Abstract:   During the past 10 to 20 years it has become increasingly clear that a certain number of drugs may lead to increased vitamin requirements. However, it is unusual for symptomatic avitaminosis to develop, and then only when circumstances are present which in themselves increase the risk of vitamin deficiency. Therapeutic doses of drugs will interfere with the vitamin status only to a restricted degree, provided they are administered for brief periods and to patients receiving a normal supply of vitamins. Most cases of vitamin deficiency have in fact been described in connection with drugs usually taken for a longer period of time by patients who were already in negative vitamin balance as a result of disease or marginal supply of the necessary vitamins. This review describes some of the more important articles covering this topic."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1406,I1406)","v":463921},{"$f":"(LEN($J1406) - LEN(SUBSTITUTE(LOWER($J1406),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1406) - LEN(SUBSTITUTE(LOWER($J1406),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1406) - LEN(SUBSTITUTE(LOWER($J1406),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1406:D1406)","v":0},1979,"Hypertrophic hepatic osteoarthropathy. Clinical, roentgenologic, biochemical, hormonal and cardiorespiratory studies, and review of the literature.","Epstein",463921,"Hypertrophic hepatic osteoarthropathy. Clinical, roentgenologic, biochemical, hormonal and cardiorespiratory studies, and review of the literature.    Abstract:   Twenty patients with biopsy proved liver disease, and roentgenologic features of hypertrophic osteoarthropathy have been studied, and the literature has been reviewed. The syndrome is a rare association of many chronic liver diseases, including primary biliary cirrhosis, bile duct carcinoma, benign bile duct stricture, chronic active hepatitis, posthepatitic cirrhosis and alcoholic cirrhosis. Patients may be asymptomatic, although bone pain, arthralgia or arthritis may be presenting symptoms. Ninety per cent of the patients are clinical jaundiced at the time of diagnosis, and 95 per cent have digital clubbing. The distal tibia and fibula are the first bones to become involved, although wrist, foot bones, femurs, hand bones and humeri may be affected in order of frequency. There is no correlation between the presence of esophageal varices or surgical portacaval shunts and the extent of the syndrome, neither is there a correlation with the degree of liver function impairment. Serum calcium and phosphate levels are normal, as is urinary hydroxyproline and estrogen excretion. There was no evidence to implicate elevated levels of growth hormone or overdosage of vitamin A. Although the majority of patients tested had mild arterial hypoxemia, increased cardiac output and evidence of right to left shunting, these were also present in disease-matched control subjects without osteoarthropathy. For screening purposes, patients with chronic liver disease and clubbing should have roentgenologic studies of the lower tibias and fibulas, to select those patients suitable for a more extensive skeletal survey."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1407,I1407)","v":386178},{"$f":"(LEN($J1407) - LEN(SUBSTITUTE(LOWER($J1407),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1407) - LEN(SUBSTITUTE(LOWER($J1407),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1407) - LEN(SUBSTITUTE(LOWER($J1407),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1407:D1407)","v":0},1979,"Vitamin A, tumor initiation and tumor promotion.","Epstein",386178,"Vitamin A, tumor initiation and tumor promotion.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1408,I1408)","v":115164},{"$f":"(LEN($J1408) - LEN(SUBSTITUTE(LOWER($J1408),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1408) - LEN(SUBSTITUTE(LOWER($J1408),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1408) - LEN(SUBSTITUTE(LOWER($J1408),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1408:D1408)","v":0},1979,"[Complexes of vitamin A with proteins and their role in the bodies of animals].","Chernukhina",115164,"[Complexes of vitamin A with proteins and their role in the bodies of animals].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1409,I1409)","v":367444},{"$f":"(LEN($J1409) - LEN(SUBSTITUTE(LOWER($J1409),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1409) - LEN(SUBSTITUTE(LOWER($J1409),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1409) - LEN(SUBSTITUTE(LOWER($J1409),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1409:D1409)","v":0},1979,"Cocarcinogenesis.","Sivak",367444,"Cocarcinogenesis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1410,I1410)","v":369274},{"$f":"(LEN($J1410) - LEN(SUBSTITUTE(LOWER($J1410),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1410) - LEN(SUBSTITUTE(LOWER($J1410),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1410) - LEN(SUBSTITUTE(LOWER($J1410),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1410:D1410)","v":0},1978,"[Structure and function of the fat-storing cell (FSC) in the liver--a review (authors transl)].","Ito",369274,"[Structure and function of the fat-storing cell (FSC) in the liver--a review (authors transl)].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1411,I1411)","v":382231},{"$f":"(LEN($J1411) - LEN(SUBSTITUTE(LOWER($J1411),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1411) - LEN(SUBSTITUTE(LOWER($J1411),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1411) - LEN(SUBSTITUTE(LOWER($J1411),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1411:D1411)","v":0},1978,"Genes, pollutants and human diseases.","Trosko",382231,"Genes, pollutants and human diseases.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1412,I1412)","v":73439},{"$f":"(LEN($J1412) - LEN(SUBSTITUTE(LOWER($J1412),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1412) - LEN(SUBSTITUTE(LOWER($J1412),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1412) - LEN(SUBSTITUTE(LOWER($J1412),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1412:D1412)","v":0},1978,"Nutrition and experimental carcinogenesis.","Visek",73439,"Nutrition and experimental carcinogenesis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1413,I1413)","v":343429},{"$f":"(LEN($J1413) - LEN(SUBSTITUTE(LOWER($J1413),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1413) - LEN(SUBSTITUTE(LOWER($J1413),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1413) - LEN(SUBSTITUTE(LOWER($J1413),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1413:D1413)","v":0},1977,"[Etiology, pathogenesis, and therapy of lichen ruber planus].","Bazyka",343429,"[Etiology, pathogenesis, and therapy of lichen ruber planus].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1414,I1414)","v":333318},{"$f":"(LEN($J1414) - LEN(SUBSTITUTE(LOWER($J1414),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1414) - LEN(SUBSTITUTE(LOWER($J1414),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1414) - LEN(SUBSTITUTE(LOWER($J1414),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1414:D1414)","v":0},1977,"The effect of oral contraceptive agents on plasma vitamin A in the human and the rat.","Bazyka",333318,"The effect of oral contraceptive agents on plasma vitamin A in the human and the rat.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1415,I1415)","v":329348},{"$f":"(LEN($J1415) - LEN(SUBSTITUTE(LOWER($J1415),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1415) - LEN(SUBSTITUTE(LOWER($J1415),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1415) - LEN(SUBSTITUTE(LOWER($J1415),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1415:D1415)","v":0},1977,"Application of the radiological sciences to advance clinical and fundamental knowledge of the animal kingdom. New Horizons for Radiologists Lecture.","James",329348,"Application of the radiological sciences to advance clinical and fundamental knowledge of the animal kingdom. New Horizons for Radiologists Lecture.    Abstract:   Many radiological techniques are useful in fundamental research. Selected clinical problems in animals as well as certain basic research projects are utilized to emphasize the potential of radiological imaging. The author describes the use of several radiological methods in studies of how birds breathe."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1416,I1416)","v":331153},{"$f":"(LEN($J1416) - LEN(SUBSTITUTE(LOWER($J1416),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1416) - LEN(SUBSTITUTE(LOWER($J1416),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1416) - LEN(SUBSTITUTE(LOWER($J1416),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1416:D1416)","v":0},1977,"Liver vitamin A mobilization during zinc deficiency and restricted food intake.","James",331153,"Liver vitamin A mobilization during zinc deficiency and restricted food intake.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1417,I1417)","v":192435},{"$f":"(LEN($J1417) - LEN(SUBSTITUTE(LOWER($J1417),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1417) - LEN(SUBSTITUTE(LOWER($J1417),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1417) - LEN(SUBSTITUTE(LOWER($J1417),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1417:D1417)","v":0},1977,"Diet and cancer.","Lowenfels",192435,"Diet and cancer.    Abstract:   Differences in food intake patterns are positively correlated with differences in the incidence of various cancers in world populations. It is postulated here that dietary factors play a vital role in the genesis of several major neoplasms, specifically gastric and colon carcinomas. In addition to the food consumed, such variables as total caloric intake, nutrtional excess or deficit, exposure to carcinogens and consumption of alcohol also increase the risk of cancer. Through recognition of these factors and subsequent long-term manipulation of diet, it should be possible to reduce cancer morbidity and mortality."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1418,I1418)","v":786000},{"$f":"(LEN($J1418) - LEN(SUBSTITUTE(LOWER($J1418),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1418) - LEN(SUBSTITUTE(LOWER($J1418),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1418) - LEN(SUBSTITUTE(LOWER($J1418),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1418:D1418)","v":0},1976,"Diet, nutrition, and cancer.","Alcantara",786000,"Diet, nutrition, and cancer.    Abstract:   As the second leading cause of death in the United States, cancer is a major public health problem today. Cancer incidence varies worldwide and tends to change with migration. These epidemiological observations have led to the concept that environmental factors may be important in carcinogenesis. Diet and nutrition are receiving increased attention and the National Cancer Institute, as mandated by the Nation Cancer Act Amendments of 1974, is playing a major leadership role in expanding research efforts in the areas of environmental carcinogenesis, and nutrition in relation to cancer. The subject of diet, nutrition, and cancer is complex. Different types of cancer are not necessarily affected by dietary components in the same manner. Although the development of certain neoplasms may be repressed by specific dietary deficiencies, other types, particularly those of the liver and upper gastrointestinal tract, are actually augmented or potentiated by such deficienceis. In extrapolating results from animal experiments to humans, caution must be exercised because of possible differences in species response to the same dietary stimulus and because spontaneous tumors may react differently from experimentally-induced tumors. Diet and nutrition are viewed more appropriately as modifiers, rather than initiators, of tumorigenesis. Caloric intake, type and amount of fat, protein, amino acids, vitamins, minerals, fiber, and other dietary constituents have been studied in regard to their influence on the development of neoplasms. Dietary components may have opposing effects on tumorigenesis, i.e., protective and predisposing, and the consequence to the host will depend on the balance between these opposing forces. Studies conducted to date indicate that the modifying effect of diet and nutrition may be exerted through specific effects on 1) intestinal bacteria and substrates for bacterial metabolism, 2) microsomal mixed-function oxidase system, 3) endocrine system, 4) immunological system, 5) availability of metabolites for cell proliferations, and 6) rate of carcinogen transfer and duration of exposure to the carcinogen. More research is needed to elucidate the interaction between diet and each of these factors and to test the validity of the mechanisms proposed to explain such interactions. These studies will lead not only to a better understanding of carcinogenesis itself but also to a new understanding of the influence of diet on human physiology and metabolism."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1419,I1419)","v":780184},{"$f":"(LEN($J1419) - LEN(SUBSTITUTE(LOWER($J1419),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1419) - LEN(SUBSTITUTE(LOWER($J1419),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1419) - LEN(SUBSTITUTE(LOWER($J1419),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1419:D1419)","v":0},1976,"Alcoholism: its effect on hypothalamic pituitary gonadal function.","Van Thiel",780184,"Alcoholism: its effect on hypothalamic pituitary gonadal function.    Abstract:   Both as the result of liver disease and of alcoholism per se, chronic alcoholics develop infertility, sterility, gonadal atrophy, hypoandrogenization, and feminization. The hypothalamic-pituitary abnormalities associated with alcoholism include hyperprolactenemia-increased estrogen-stimulated neurophysin levels, suppressed secretion of plasma gonadotropins, and loss of gonadotropin reserve. Several of the possible mechanisms potentially responsible for the development of these endocrine abnormalities have been discussed. The rational for suspecting that alcohol might interfere with either vitamin A metabolism of alter the redox state of the testes, thus affecting germ cell proliferation and steroidogenesis, has been presented. A possible mechanism for the sexual changes observed in chronic alcoholic men has been proposed. Much work remains to be done in this area before a complete understanding of the pathogenesis of these phenomena is obtained. The omission of any consideration of the effects of alcohol on sexual function in women is an admission of gross ignorance greatly in need of rectification. The necessity for couching a description of even the natural history of the syndrome in alcoholic men in conditional terms is a reflection of the limited state of the art. Nevertheless, it behooves the gastroenterologist, who is frequently called upon to be the primary physician for alcoholic men, to keep abreast of the nongastrointestinal medical consequences of alcohol addiction so that they can be recognized early and incorporated into long range medical planning designed to care for the chronic alcoholic patient."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1420,I1420)","v":775753},{"$f":"(LEN($J1420) - LEN(SUBSTITUTE(LOWER($J1420),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1420) - LEN(SUBSTITUTE(LOWER($J1420),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1420) - LEN(SUBSTITUTE(LOWER($J1420),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1420:D1420)","v":0},1976,"Nutrition and bone disease in the dog and cat.","Bennett",775753,"Nutrition and bone disease in the dog and cat.    Abstract:   The most commonly encountered nutritional bone disease is nutritional secondary hyperparathyroidism. This is primarily of importance in the dog but is occasionally seen in kittens, particularly of the Siamese breed, and is often associated with the feeding of owner compiled, meat-rich diets. Classic rickets is now a rare clinical entity. Hypertrophic osteodystrophy is regularly seen in the larger breeds of dog and the aetiology remains obscure. Hypervitaminosis A associated with liver-rich diets is often encountered in the cat. Hypovitaminosis A has been described but its true clinical significance is unknown."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1421,I1421)","v":772484},{"$f":"(LEN($J1421) - LEN(SUBSTITUTE(LOWER($J1421),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1421) - LEN(SUBSTITUTE(LOWER($J1421),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1421) - LEN(SUBSTITUTE(LOWER($J1421),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1421:D1421)","v":0},1976,"The transport of vitamin A in hypervitaminosis A.","Bennett",772484,"The transport of vitamin A in hypervitaminosis A.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1422,I1422)","v":768831},{"$f":"(LEN($J1422) - LEN(SUBSTITUTE(LOWER($J1422),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1422) - LEN(SUBSTITUTE(LOWER($J1422),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1422) - LEN(SUBSTITUTE(LOWER($J1422),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1422:D1422)","v":0},1976,"Zinc deficiency in pregnant, fetal and young rats.","Bennett",768831,"Zinc deficiency in pregnant, fetal and young rats.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1423,I1423)","v":822591},{"$f":"(LEN($J1423) - LEN(SUBSTITUTE(LOWER($J1423),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1423) - LEN(SUBSTITUTE(LOWER($J1423),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1423) - LEN(SUBSTITUTE(LOWER($J1423),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1423:D1423)","v":0},1976,"Vitamin A deficiency and xerophthalmia. Report of a Joint WHO/USAID Meeting.","Bennett",822591,"Vitamin A deficiency and xerophthalmia. Report of a Joint WHO/USAID Meeting.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1424,I1424)","v":782598},{"$f":"(LEN($J1424) - LEN(SUBSTITUTE(LOWER($J1424),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1424) - LEN(SUBSTITUTE(LOWER($J1424),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1424) - LEN(SUBSTITUTE(LOWER($J1424),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1424:D1424)","v":0},1976,"Abetalipoproteinemia and the eye.","Carr",782598,"Abetalipoproteinemia and the eye.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1425,I1425)","v":768933},{"$f":"(LEN($J1425) - LEN(SUBSTITUTE(LOWER($J1425),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1425) - LEN(SUBSTITUTE(LOWER($J1425),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1425) - LEN(SUBSTITUTE(LOWER($J1425),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1425:D1425)","v":0},1976,"[Side effects of oral contraceptives].","Kuczyńska-Sicińska",768933,"[Side effects of oral contraceptives].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1426,I1426)","v":766084},{"$f":"(LEN($J1426) - LEN(SUBSTITUTE(LOWER($J1426),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1426) - LEN(SUBSTITUTE(LOWER($J1426),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1426) - LEN(SUBSTITUTE(LOWER($J1426),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1426:D1426)","v":0},1976,"[Biochemistry of C-P compounds in higher animal system, particularly, on the ciliatine-containing phosphonolipid (authors transl)].","Tamari",766084,"[Biochemistry of C-P compounds in higher animal system, particularly, on the ciliatine-containing phosphonolipid (authors transl)].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1427,I1427)","v":776510},{"$f":"(LEN($J1427) - LEN(SUBSTITUTE(LOWER($J1427),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1427) - LEN(SUBSTITUTE(LOWER($J1427),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1427) - LEN(SUBSTITUTE(LOWER($J1427),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1427:D1427)","v":0},1975,"[Liver cirrhosis : nosographic and therapeutic studies].","Grossi",776510,"[Liver cirrhosis : nosographic and therapeutic studies].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1428,I1428)","v":53098},{"$f":"(LEN($J1428) - LEN(SUBSTITUTE(LOWER($J1428),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1428) - LEN(SUBSTITUTE(LOWER($J1428),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1428) - LEN(SUBSTITUTE(LOWER($J1428),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1428:D1428)","v":0},1975,"Dietary effects on chemical carcinogenesis in animal models for colon and liver tumors.","Rogers",53098,"Dietary effects on chemical carcinogenesis in animal models for colon and liver tumors.    Abstract:   Studies of dietary effects on chemical carcinogenesis in rats have demonstrated that colon tumor induction is enhanced by increased dietary fat intake or dietary deficiency of vitamin A in some but not all cases. The enhancing effect of a high-fat diet is augmented by lipotrope deficiency. Induction of hepatic tumors by several different carcinogens also is enhanced in rats fed a high-fat diet marginally deficient in lipotropes. The dietary effects may be exerted through alteration of metabolism of carcinogens, which has been demonstrated in lipotrope-deficient rats, through immunological mechanisms, which influence induction of colon tumors, or through effects on gastrointestinal bacteria and bile acid metabolism. Demonstration of dietary effects on carcinogenesis may require utilization of combined dietary stresses that alter metabolic loads but do not seriously impair growth."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1429,I1429)","v":53097},{"$f":"(LEN($J1429) - LEN(SUBSTITUTE(LOWER($J1429),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1429) - LEN(SUBSTITUTE(LOWER($J1429),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1429) - LEN(SUBSTITUTE(LOWER($J1429),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1429:D1429)","v":0},1975,"Nutrition and experimental carcinogenesis: a review.","Clayson",53097,"Nutrition and experimental carcinogenesis: a review.    Abstract:   Restriction of the total diet or the number of calories fed to rats and mice inhibits the formation of tumors in several tissues. Unless animals are fed equivalent levels of food, or attain equivalent body weights, it is difficult to assess the significance of the effect of other nutritional modifications on carcinogenesis. The effects of altering the levels of protein or fat are much less than those seen with dietary restriction. Feeding a protein-free diet is tolerated for a limited period and can alter the metabolism of carcinogens. It may thus affect the tumor incidence induced by one-shot carcinogens. Vitamins have specific effects on the activity of certain carcinogens, the fullest information being available for vitamin A, which has been shown to inhibit or enhance carcinogenesis, and vitamin C, which by reducing sodium nitrite, prevents nitrosation of secondary and tertiary amines occurring in acidic conditions of the stomach. Inorganic substances, such as iodine (thyroid) and copper (liver), may affect the tumor incidence in specific tissues. The metabolic activation of carcinogens is modified by enzyme induction and the administration of antioxidants. The relevance of these results to the induction of cancer in humans is briefly discussed."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1430,I1430)","v":1102220},{"$f":"(LEN($J1430) - LEN(SUBSTITUTE(LOWER($J1430),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1430) - LEN(SUBSTITUTE(LOWER($J1430),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1430) - LEN(SUBSTITUTE(LOWER($J1430),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1430:D1430)","v":0},1975,"Vitamins and minerals in pregnancy.","Pitkin",1102220,"Vitamins and minerals in pregnancy.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1431,I1431)","v":808573},{"$f":"(LEN($J1431) - LEN(SUBSTITUTE(LOWER($J1431),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1431) - LEN(SUBSTITUTE(LOWER($J1431),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1431) - LEN(SUBSTITUTE(LOWER($J1431),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1431:D1431)","v":0},1975,"Lysosomes and the skin.","Lazarus",808573,"Lysosomes and the skin.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1432,I1432)","v":1095012},{"$f":"(LEN($J1432) - LEN(SUBSTITUTE(LOWER($J1432),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1432) - LEN(SUBSTITUTE(LOWER($J1432),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1432) - LEN(SUBSTITUTE(LOWER($J1432),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1432:D1432)","v":0},1975,"Vitamin A a absorption - nutritional aspects.","Berger",1095012,"Vitamin A a absorption - nutritional aspects.    Abstract:   A brief review of the present knowledge of vitamin A (both performed and precursor forms) absorption is outlined with special emphasis on the dietary factors involved in this process. Some details are discussed related to the techniques used for measurement of vitamin A absorption from different sources and under different experimental conditions. Suggestions are also made to standardize appropriate procedure in this respect; this might enable comparisons and wide use of respective results obtained in various laboratories. Nutritional significance, including advantages or disadvantages of the liver test in these studies, is specifically highlighted with special reference to the determination of vitamin A bio-potency in various products. Some selected results and experience in this field are briefly presented."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1433,I1433)","v":820577},{"$f":"(LEN($J1433) - LEN(SUBSTITUTE(LOWER($J1433),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1433) - LEN(SUBSTITUTE(LOWER($J1433),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1433) - LEN(SUBSTITUTE(LOWER($J1433),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1433:D1433)","v":0},1975,"Lysosomes and the skin.","Lazarus",820577,"Lysosomes and the skin.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1434,I1434)","v":4142091},{"$f":"(LEN($J1434) - LEN(SUBSTITUTE(LOWER($J1434),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1434) - LEN(SUBSTITUTE(LOWER($J1434),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1434) - LEN(SUBSTITUTE(LOWER($J1434),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1434:D1434)","v":0},1974,"Role of nutrition in the drug-metabolizing enzyme system.","Campbell",4142091,"Role of nutrition in the drug-metabolizing enzyme system.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1435,I1435)","v":4208157},{"$f":"(LEN($J1435) - LEN(SUBSTITUTE(LOWER($J1435),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1435) - LEN(SUBSTITUTE(LOWER($J1435),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1435) - LEN(SUBSTITUTE(LOWER($J1435),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1435:D1435)","v":0},1974,"Metabolic effects of oral contraceptives in monkeys fed on adequate and low protein diets.","Campbell",4208157,"Metabolic effects of oral contraceptives in monkeys fed on adequate and low protein diets.    Abstract:   Rhesus monkeys were given either high estrogen, low progesterone or low estrogen-high progesterone oral contraceptive agents (OCAs) and maintained on either a 16% protein diet or a 4% protein diet. Both OCAs created a small but significant fall in hemoglobin and serum protein. On both diets, OCAs led to a gradual elevation of serum alkaline phosphatase and serum glutamic oxalic transaminase (SGOT) activities. There were no histologic liver lesions. On the low protein diet, glucose tolerance was impaired between cycles 10 and 11, and on the high protein diet between cycles 16 and 20. Vitamins B-12, A, and thiamine tended to be lower in OCA animals. The conclusion of these experiments is that the hazard of using OCAs is not exaggerated by protein deficiency."]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1436,I1436)","v":4609779},{"$f":"(LEN($J1436) - LEN(SUBSTITUTE(LOWER($J1436),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1436) - LEN(SUBSTITUTE(LOWER($J1436),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1436) - LEN(SUBSTITUTE(LOWER($J1436),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1436:D1436)","v":0},1974,"[Rhino mouse (authors transl)].","Kawaji",4609779,"[Rhino mouse (authors transl)].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1437,I1437)","v":4608760},{"$f":"(LEN($J1437) - LEN(SUBSTITUTE(LOWER($J1437),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1437) - LEN(SUBSTITUTE(LOWER($J1437),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1437) - LEN(SUBSTITUTE(LOWER($J1437),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1437:D1437)","v":0},1974,"Neurological manifestations of nutritional disorders.","Pallis",4608760,"Neurological manifestations of nutritional disorders.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1438,I1438)","v":4617401},{"$f":"(LEN($J1438) - LEN(SUBSTITUTE(LOWER($J1438),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1438) - LEN(SUBSTITUTE(LOWER($J1438),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1438) - LEN(SUBSTITUTE(LOWER($J1438),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1438:D1438)","v":0},1974,"Metabolism of vitamin A and the determination of vitamin A status.","Rietz",4617401,"Metabolism of vitamin A and the determination of vitamin A status.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1439,I1439)","v":4616468},{"$f":"(LEN($J1439) - LEN(SUBSTITUTE(LOWER($J1439),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1439) - LEN(SUBSTITUTE(LOWER($J1439),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1439) - LEN(SUBSTITUTE(LOWER($J1439),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1439:D1439)","v":0},1974,"The determination of vitamin A and some aspects of its distribution, mobilization and transport in health and disease.","Underwood",4616468,"The determination of vitamin A and some aspects of its distribution, mobilization and transport in health and disease.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1440,I1440)","v":4616467},{"$f":"(LEN($J1440) - LEN(SUBSTITUTE(LOWER($J1440),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1440) - LEN(SUBSTITUTE(LOWER($J1440),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1440) - LEN(SUBSTITUTE(LOWER($J1440),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1440:D1440)","v":0},1974,"The manifestations and management of severe protein-calorie malnutrition (kwashiorkor).","Pereira",4616467,"The manifestations and management of severe protein-calorie malnutrition (kwashiorkor).    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1441,I1441)","v":4202969},{"$f":"(LEN($J1441) - LEN(SUBSTITUTE(LOWER($J1441),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1441) - LEN(SUBSTITUTE(LOWER($J1441),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1441) - LEN(SUBSTITUTE(LOWER($J1441),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1441:D1441)","v":0},1973,"Infantile malnutrition and malabsorption.","Pereira",4202969,"Infantile malnutrition and malabsorption.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1442,I1442)","v":4586199},{"$f":"(LEN($J1442) - LEN(SUBSTITUTE(LOWER($J1442),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1442) - LEN(SUBSTITUTE(LOWER($J1442),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1442) - LEN(SUBSTITUTE(LOWER($J1442),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1442:D1442)","v":0},1973,"Phytate and rickets.","Pereira",4586199,"Phytate and rickets.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1443,I1443)","v":4588455},{"$f":"(LEN($J1443) - LEN(SUBSTITUTE(LOWER($J1443),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1443) - LEN(SUBSTITUTE(LOWER($J1443),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1443) - LEN(SUBSTITUTE(LOWER($J1443),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1443:D1443)","v":0},1973,"[Morphology associated with endocrine function].","Watari",4588455,"[Morphology associated with endocrine function].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1444,I1444)","v":4201469},{"$f":"(LEN($J1444) - LEN(SUBSTITUTE(LOWER($J1444),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1444) - LEN(SUBSTITUTE(LOWER($J1444),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1444) - LEN(SUBSTITUTE(LOWER($J1444),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1444:D1444)","v":0},1973,"Nutrition and disease.","Gopalan",4201469,"Nutrition and disease.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1445,I1445)","v":4201467},{"$f":"(LEN($J1445) - LEN(SUBSTITUTE(LOWER($J1445),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1445) - LEN(SUBSTITUTE(LOWER($J1445),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1445) - LEN(SUBSTITUTE(LOWER($J1445),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1445:D1445)","v":0},1973,"Undernutrition.","McLaren",4201467,"Undernutrition.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1446,I1446)","v":4572179},{"$f":"(LEN($J1446) - LEN(SUBSTITUTE(LOWER($J1446),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1446) - LEN(SUBSTITUTE(LOWER($J1446),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1446) - LEN(SUBSTITUTE(LOWER($J1446),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1446:D1446)","v":0},1972,"Vitamin E and the biological antioxidant theory.","Green",4572179,"Vitamin E and the biological antioxidant theory.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1447,I1447)","v":4264252},{"$f":"(LEN($J1447) - LEN(SUBSTITUTE(LOWER($J1447),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1447) - LEN(SUBSTITUTE(LOWER($J1447),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1447) - LEN(SUBSTITUTE(LOWER($J1447),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1447:D1447)","v":0},1972,"Advances in the treatment of diseases of the skin.","Pegum",4264252,"Advances in the treatment of diseases of the skin.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1448,I1448)","v":4552382},{"$f":"(LEN($J1448) - LEN(SUBSTITUTE(LOWER($J1448),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1448) - LEN(SUBSTITUTE(LOWER($J1448),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1448) - LEN(SUBSTITUTE(LOWER($J1448),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1448:D1448)","v":0},1972,"Analogies between the defects characteristic of osteogenesis imperfecta and aberrations in vitamin A metabolism. A collective review.","Bovill",4552382,"Analogies between the defects characteristic of osteogenesis imperfecta and aberrations in vitamin A metabolism. A collective review.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1449,I1449)","v":4614802},{"$f":"(LEN($J1449) - LEN(SUBSTITUTE(LOWER($J1449),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1449) - LEN(SUBSTITUTE(LOWER($J1449),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1449) - LEN(SUBSTITUTE(LOWER($J1449),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1449:D1449)","v":0},1972,"Chemistry and metabolism of beta-apocarotenals and their epoxides.","Singh",4614802,"Chemistry and metabolism of beta-apocarotenals and their epoxides.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1450,I1450)","v":4949303},{"$f":"(LEN($J1450) - LEN(SUBSTITUTE(LOWER($J1450),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1450) - LEN(SUBSTITUTE(LOWER($J1450),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1450) - LEN(SUBSTITUTE(LOWER($J1450),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1450:D1450)","v":0},1971,"Environmental and nutritional diseases of captive reptiles.","Wallach",4949303,"Environmental and nutritional diseases of captive reptiles.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1451,I1451)","v":4941080},{"$f":"(LEN($J1451) - LEN(SUBSTITUTE(LOWER($J1451),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1451) - LEN(SUBSTITUTE(LOWER($J1451),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1451) - LEN(SUBSTITUTE(LOWER($J1451),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1451:D1451)","v":0},1971,"Hypervitaminosis A: a review.","Clark",4941080,"Hypervitaminosis A: a review.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1452,I1452)","v":5000559},{"$f":"(LEN($J1452) - LEN(SUBSTITUTE(LOWER($J1452),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1452) - LEN(SUBSTITUTE(LOWER($J1452),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1452) - LEN(SUBSTITUTE(LOWER($J1452),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1452:D1452)","v":0},1971,"Whats new-1970.","Kierland",5000559,"Whats new-1970.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1453,I1453)","v":4330879},{"$f":"(LEN($J1453) - LEN(SUBSTITUTE(LOWER($J1453),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1453) - LEN(SUBSTITUTE(LOWER($J1453),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1453) - LEN(SUBSTITUTE(LOWER($J1453),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1453:D1453)","v":0},1971,"Effect of calcitonin on bone resorption induced by excess vitamins A and D.","Kierland",4330879,"Effect of calcitonin on bone resorption induced by excess vitamins A and D.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1454,I1454)","v":4932663},{"$f":"(LEN($J1454) - LEN(SUBSTITUTE(LOWER($J1454),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1454) - LEN(SUBSTITUTE(LOWER($J1454),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1454) - LEN(SUBSTITUTE(LOWER($J1454),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1454:D1454)","v":0},1971,"[Gastrointestinal symptoms and pathophysiology of Basedows disease].","Nagata",4932663,"[Gastrointestinal symptoms and pathophysiology of Basedows disease].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1455,I1455)","v":4930698},{"$f":"(LEN($J1455) - LEN(SUBSTITUTE(LOWER($J1455),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1455) - LEN(SUBSTITUTE(LOWER($J1455),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1455) - LEN(SUBSTITUTE(LOWER($J1455),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1455:D1455)","v":0},1971,"Vitamin A and the synthesis of a lipid containing mannose in rat liver.","Nagata",4930698,"Vitamin A and the synthesis of a lipid containing mannose in rat liver.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1456,I1456)","v":4941899},{"$f":"(LEN($J1456) - LEN(SUBSTITUTE(LOWER($J1456),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1456) - LEN(SUBSTITUTE(LOWER($J1456),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1456) - LEN(SUBSTITUTE(LOWER($J1456),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1456:D1456)","v":0},1971,"[Vitamin A and protein metabolism (review of the literature)].","Natanson",4941899,"[Vitamin A and protein metabolism (review of the literature)].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1457,I1457)","v":4920145},{"$f":"(LEN($J1457) - LEN(SUBSTITUTE(LOWER($J1457),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1457) - LEN(SUBSTITUTE(LOWER($J1457),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1457) - LEN(SUBSTITUTE(LOWER($J1457),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1457:D1457)","v":0},1970,"Vitamin A physiology.","Roels",4920145,"Vitamin A physiology.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1458,I1458)","v":4916138},{"$f":"(LEN($J1458) - LEN(SUBSTITUTE(LOWER($J1458),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1458) - LEN(SUBSTITUTE(LOWER($J1458),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1458) - LEN(SUBSTITUTE(LOWER($J1458),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1458:D1458)","v":0},1970,"Vitamin A and glucocorticoid biosynthesis.","Roels",4916138,"Vitamin A and glucocorticoid biosynthesis.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1459,I1459)","v":4324116},{"$f":"(LEN($J1459) - LEN(SUBSTITUTE(LOWER($J1459),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1459) - LEN(SUBSTITUTE(LOWER($J1459),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1459) - LEN(SUBSTITUTE(LOWER($J1459),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1459:D1459)","v":0},1970,"[Physiological properties of ubiquinone].","Morimoto",4324116,"[Physiological properties of ubiquinone].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1460,I1460)","v":4926626},{"$f":"(LEN($J1460) - LEN(SUBSTITUTE(LOWER($J1460),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1460) - LEN(SUBSTITUTE(LOWER($J1460),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1460) - LEN(SUBSTITUTE(LOWER($J1460),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1460:D1460)","v":0},1970,"[Toxic liver injury].","Bode",4926626,"[Toxic liver injury].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1461,I1461)","v":4947202},{"$f":"(LEN($J1461) - LEN(SUBSTITUTE(LOWER($J1461),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1461) - LEN(SUBSTITUTE(LOWER($J1461),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1461) - LEN(SUBSTITUTE(LOWER($J1461),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1461:D1461)","v":0},1970,"Interrelations between vitamin E and polyunsaturated fatty acids.","Dam",4947202,"Interrelations between vitamin E and polyunsaturated fatty acids.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1462,I1462)","v":4922143},{"$f":"(LEN($J1462) - LEN(SUBSTITUTE(LOWER($J1462),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1462) - LEN(SUBSTITUTE(LOWER($J1462),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1462) - LEN(SUBSTITUTE(LOWER($J1462),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1462:D1462)","v":0},1970,"Hypervitaminosis A of the cat.","Seawright",4922143,"Hypervitaminosis A of the cat.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1463,I1463)","v":4906655},{"$f":"(LEN($J1463) - LEN(SUBSTITUTE(LOWER($J1463),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1463) - LEN(SUBSTITUTE(LOWER($J1463),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1463) - LEN(SUBSTITUTE(LOWER($J1463),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1463:D1463)","v":0},1970,"A report on the first fifty years of the Nutrition Research Laboratories, Hyderabad.","Gopalan",4906655,"A report on the first fifty years of the Nutrition Research Laboratories, Hyderabad.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1464,I1464)","v":4316909},{"$f":"(LEN($J1464) - LEN(SUBSTITUTE(LOWER($J1464),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1464) - LEN(SUBSTITUTE(LOWER($J1464),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1464) - LEN(SUBSTITUTE(LOWER($J1464),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1464:D1464)","v":0},1970,"Degradation processes in bone and cartilage.","Reynolds",4316909,"Degradation processes in bone and cartilage.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1465,I1465)","v":4251266},{"$f":"(LEN($J1465) - LEN(SUBSTITUTE(LOWER($J1465),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1465) - LEN(SUBSTITUTE(LOWER($J1465),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1465) - LEN(SUBSTITUTE(LOWER($J1465),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1465:D1465)","v":0},1970,"[Biological effect of vitamin A].","Dusheĭko",4251266,"[Biological effect of vitamin A].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1466,I1466)","v":4901690},{"$f":"(LEN($J1466) - LEN(SUBSTITUTE(LOWER($J1466),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1466) - LEN(SUBSTITUTE(LOWER($J1466),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1466) - LEN(SUBSTITUTE(LOWER($J1466),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1466:D1466)","v":0},1969,"Protein synthesis in intestinal mucosa of rats deficienct in vitamin A.","Dusheĭko",4901690,"Protein synthesis in intestinal mucosa of rats deficienct in vitamin A.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1467,I1467)","v":4984933},{"$f":"(LEN($J1467) - LEN(SUBSTITUTE(LOWER($J1467),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1467) - LEN(SUBSTITUTE(LOWER($J1467),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1467) - LEN(SUBSTITUTE(LOWER($J1467),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1467:D1467)","v":0},1969,"[Gamma globulins and hyperlipemia. Hyperlipemia caused by autoantibodies].","Beaumont",4984933,"[Gamma globulins and hyperlipemia. Hyperlipemia caused by autoantibodies].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1468,I1468)","v":4898010},{"$f":"(LEN($J1468) - LEN(SUBSTITUTE(LOWER($J1468),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1468) - LEN(SUBSTITUTE(LOWER($J1468),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1468) - LEN(SUBSTITUTE(LOWER($J1468),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1468:D1468)","v":0},1969,"Absorption of vitamin A.","Ganguly",4898010,"Absorption of vitamin A.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1469,I1469)","v":4895301},{"$f":"(LEN($J1469) - LEN(SUBSTITUTE(LOWER($J1469),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1469) - LEN(SUBSTITUTE(LOWER($J1469),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1469) - LEN(SUBSTITUTE(LOWER($J1469),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1469:D1469)","v":0},1969,"[Diagnostic methods in diseases of the small intestine].","Kasper",4895301,"[Diagnostic methods in diseases of the small intestine].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1470,I1470)","v":4893712},{"$f":"(LEN($J1470) - LEN(SUBSTITUTE(LOWER($J1470),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1470) - LEN(SUBSTITUTE(LOWER($J1470),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1470) - LEN(SUBSTITUTE(LOWER($J1470),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1470:D1470)","v":0},1969,"Vitamin A deficiency and mitochondrial lipids in rat liver.","Kasper",4893712,"Vitamin A deficiency and mitochondrial lipids in rat liver.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1471,I1471)","v":4318822},{"$f":"(LEN($J1471) - LEN(SUBSTITUTE(LOWER($J1471),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1471) - LEN(SUBSTITUTE(LOWER($J1471),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1471) - LEN(SUBSTITUTE(LOWER($J1471),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1471:D1471)","v":0},1968,"[Kidney and vitamin E].","Arvy",4318822,"[Kidney and vitamin E].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1472,I1472)","v":5652970},{"$f":"(LEN($J1472) - LEN(SUBSTITUTE(LOWER($J1472),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1472) - LEN(SUBSTITUTE(LOWER($J1472),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1472) - LEN(SUBSTITUTE(LOWER($J1472),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1472:D1472)","v":0},1968,"Kyrles disease. I. Clinical findings in five cases and review of literature.","Carter",5652970,"Kyrles disease. I. Clinical findings in five cases and review of literature.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1473,I1473)","v":4890102},{"$f":"(LEN($J1473) - LEN(SUBSTITUTE(LOWER($J1473),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1473) - LEN(SUBSTITUTE(LOWER($J1473),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1473) - LEN(SUBSTITUTE(LOWER($J1473),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1473:D1473)","v":0},1968,"Some aspects of vitamin A metabolism.","Olson",4890102,"Some aspects of vitamin A metabolism.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1474,I1474)","v":4882496},{"$f":"(LEN($J1474) - LEN(SUBSTITUTE(LOWER($J1474),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1474) - LEN(SUBSTITUTE(LOWER($J1474),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1474) - LEN(SUBSTITUTE(LOWER($J1474),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1474:D1474)","v":0},1968,"[Some new aspects of calcium metabolism: applications to the physiology and pathology of ruminants].","Larvor",4882496,"[Some new aspects of calcium metabolism: applications to the physiology and pathology of ruminants].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1475,I1475)","v":4331872},{"$f":"(LEN($J1475) - LEN(SUBSTITUTE(LOWER($J1475),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1475) - LEN(SUBSTITUTE(LOWER($J1475),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1475) - LEN(SUBSTITUTE(LOWER($J1475),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1475:D1475)","v":0},1967,"Differentiation of connective tissues.","Thorp",4331872,"Differentiation of connective tissues.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1476,I1476)","v":5329001},{"$f":"(LEN($J1476) - LEN(SUBSTITUTE(LOWER($J1476),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1476) - LEN(SUBSTITUTE(LOWER($J1476),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1476) - LEN(SUBSTITUTE(LOWER($J1476),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1476:D1476)","v":0},1966,"Vitamin A and lysosomes.","Thorp",5329001,"Vitamin A and lysosomes.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1477,I1477)","v":5328517},{"$f":"(LEN($J1477) - LEN(SUBSTITUTE(LOWER($J1477),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1477) - LEN(SUBSTITUTE(LOWER($J1477),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1477) - LEN(SUBSTITUTE(LOWER($J1477),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1477:D1477)","v":0},1966,"The effect of dietary nitrite on liver storage of vitamin A in the rat.","Thorp",5328517,"The effect of dietary nitrite on liver storage of vitamin A in the rat.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1478,I1478)","v":5333888},{"$f":"(LEN($J1478) - LEN(SUBSTITUTE(LOWER($J1478),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1478) - LEN(SUBSTITUTE(LOWER($J1478),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1478) - LEN(SUBSTITUTE(LOWER($J1478),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1478:D1478)","v":0},1966,"[Current concepts of physiology and new orientations in the pathology of connective tissue. 3. Experimental diseases of the connective tissue].","Lenzi",5333888,"[Current concepts of physiology and new orientations in the pathology of connective tissue. 3. Experimental diseases of the connective tissue].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1479,I1479)","v":14292504},{"$f":"(LEN($J1479) - LEN(SUBSTITUTE(LOWER($J1479),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1479) - LEN(SUBSTITUTE(LOWER($J1479),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1479) - LEN(SUBSTITUTE(LOWER($J1479),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1479:D1479)","v":0},1965,"FACTORS INFLUENCING THE PROTEIN METABOLISM OF THE BRAIN.","RICHTER",14292504,"FACTORS INFLUENCING THE PROTEIN METABOLISM OF THE BRAIN.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1480,I1480)","v":14191110},{"$f":"(LEN($J1480) - LEN(SUBSTITUTE(LOWER($J1480),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1480) - LEN(SUBSTITUTE(LOWER($J1480),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1480) - LEN(SUBSTITUTE(LOWER($J1480),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1480:D1480)","v":0},1964,"SELECTED TOPICS IN OPHTHALMIC BIOCHEMISTRY.","KINOSHITA",14191110,"SELECTED TOPICS IN OPHTHALMIC BIOCHEMISTRY.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1481,I1481)","v":14238547},{"$f":"(LEN($J1481) - LEN(SUBSTITUTE(LOWER($J1481),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1481) - LEN(SUBSTITUTE(LOWER($J1481),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1481) - LEN(SUBSTITUTE(LOWER($J1481),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1481:D1481)","v":0},1964,"[THE VITAMIN CONTROL OF CALCIUM METABOLISM].","RAOUL",14238547,"[THE VITAMIN CONTROL OF CALCIUM METABOLISM].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1482,I1482)","v":14169664},{"$f":"(LEN($J1482) - LEN(SUBSTITUTE(LOWER($J1482),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1482) - LEN(SUBSTITUTE(LOWER($J1482),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1482) - LEN(SUBSTITUTE(LOWER($J1482),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1482:D1482)","v":0},1964,"[THE ESSENTIAL HYPERGLYCERIDEMIA OF ATHEROSCLEROSIS PATIENTS].","SWYNGHEDAUW",14169664,"[THE ESSENTIAL HYPERGLYCERIDEMIA OF ATHEROSCLEROSIS PATIENTS].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1483,I1483)","v":14110964},{"$f":"(LEN($J1483) - LEN(SUBSTITUTE(LOWER($J1483),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1483) - LEN(SUBSTITUTE(LOWER($J1483),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1483) - LEN(SUBSTITUTE(LOWER($J1483),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1483:D1483)","v":0},1964,"[CLINICAL ASPECTS OF FATTY LIVER].","YOSHITOSHI",14110964,"[CLINICAL ASPECTS OF FATTY LIVER].    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1484,I1484)","v":14084341},{"$f":"(LEN($J1484) - LEN(SUBSTITUTE(LOWER($J1484),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1484) - LEN(SUBSTITUTE(LOWER($J1484),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1484) - LEN(SUBSTITUTE(LOWER($J1484),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1484:D1484)","v":0},1963,"INHIBITION OF KERATINIZING STRUCTURES BY SYSTEMIC DRUGS.","FLESCH",14084341,"INHIBITION OF KERATINIZING STRUCTURES BY SYSTEMIC DRUGS.    Abstract:  "]
[{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & I1485,I1485)","v":14095290},{"$f":"(LEN($J1485) - LEN(SUBSTITUTE(LOWER($J1485),LOWER(B$3),\"\")))/LEN(B$3)","v":0},{"$f":"(LEN($J1485) - LEN(SUBSTITUTE(LOWER($J1485),LOWER(C$3),\"\")))/LEN(C$3)","v":0},{"$f":"(LEN($J1485) - LEN(SUBSTITUTE(LOWER($J1485),LOWER(D$3),\"\")))/LEN(D$3)","v":0},{"$f":"SUM(B1485:D1485)","v":0},1963,"[CELIAC DISEASE AND PANCREATIC FIBROSIS].","KONZERT",14095290,"[CELIAC DISEASE AND PANCREATIC FIBROSIS].    Abstract:  "]

{"sheet":"Abstract","index":1,"n_rows":5,"n_cols":4,"rows_kept":5,"cut":false,"hidden":false,"merged":[[0,0,0,1]]}
["Abstract with highlights"]
["Article:",{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & C2,C2)","v":16054987},16054987,"Pub Yr: 2005"]
[]
["Title:","Alcohol, vitamin A, and cancer.",null,"Fauthor: Wang"]
["Title and Abstract:","Alcohol, vitamin A, and cancer.    Abstract:   Chronic and excessive alcohol intake is associated with an increased risk of a variety of cancers (e.g., oral cavity, larynx, esophagus, liver, lung, colorectal, and breast). Retinoids (vitamin A and its derivatives) are known to exert profound effects on cellular growth, cellular differentiation, and apoptosis, thereby controlling carcinogenesis. Lower hepatic vitamin A levels have been well documented in alcoholics. Substantial research has been done, investigating the mechanisms by which excessive alcohol interferes with retinoid metabolism. More specifically, (1) alcohol acts as a competitive inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases; (2) alcohol-induced cytochrome P450 enzymes (CYP), particularly CYP2E1, enhance catabolism of vitamin A and retinoic acid; and (3) alcohol alters retinoid homeostasis by increasing vitamin A mobilization from liver to extrahepatic tissues. As a consequence, long-term and excessive alcohol intake results in impaired status of retinoic acid, the most active derivative of vitamin A and a ligand for both retinoic acid receptors and retinoid X receptors. Moreover, this alcohol-impaired retinoic acid homeostasis interferes with (1) retinoic acid signaling (e.g., down-regulates retinoid target gene expression) and (2) retinoic acid quot;cross-talkquot; with the mitogen-activated protein kinase [(MAPK), including Jun N-terminal kinase, extracellular signal-regulated kinase, and p38 kinase] signaling pathway. In addition, restoration of retinoic acid homeostasis by retinoic acid supplementation restored the normal status of both retinoid and MAPK signaling, thereby maintaining normal cell proliferation and apoptosis in alcohol-fed animals. These observations would have implications for the prevention of alcohol-promoted liver (and peripheral tissue) carcinogenesis. However, a better understanding of the alcohol-retinoid interaction and the molecular mechanisms involved is needed before retinoids can be pursued in the prevention of alcohol-related carcinogenesis in human beings, particularly regarding the detrimental effects of polar metabolites of vitamin A."]

{"sheet":"Notes","index":2,"n_rows":3,"n_cols":8,"rows_kept":3,"cut":false,"hidden":false,"merged":[]}
[null,"My Notes"]
["Chemical","PMID ","DOI","Note ","Title","LinkDOI","LinkID","Link"]
[null,{"$f":"HYPERLINK(\"http://www.ncbi.nlm.nih.gov/pubmed/\" & G3,G3)","v":15203181},null,"GABA and cp; picrotoxin and 3-mercaptopropionic acid","Cleft palate by picrotoxin or 3-MP and palatal shelf elevation in GABA-deficient mice.",null,15203181]