SHS/newest_biored · Datasets at Hugging Face

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15485686	A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia. OBJECTIVE: Congenital long QT syndrome (LQTS) with in utero onset of the rhythm disturbances is associated with a poor prognosis. In this study we investigated a newborn patient with fetal bradycardia, 2:1 atrioventricular block and ventricular tachycardia soon after birth. METHODS: Mutational analysis and DNA sequencing were conducted in a newborn. The 2:1 atrioventricular block improved to 1:1 conduction only after intravenous lidocaine infusion or a high dose of mexiletine, which also controlled the ventricular tachycardia. RESULTS: A novel, spontaneous LQTS-3 mutation was identified in the transmembrane segment 6 of domain IV of the Na(v)1.5 cardiac sodium channel, with a G-->A substitution at codon 1763, which changed a valine (GTG) to a methionine (ATG). The proband was heterozygous but the mutation was absent in the parents and the sister. Expression of this mutant channel in tsA201 mammalian cells by site-directed mutagenesis revealed a persistent tetrodotoxin-sensitive but lidocaine-resistant current that was associated with a positive shift of the steady-state inactivation curve, steeper activation curve and faster recovery from inactivation. We also found a similar electrophysiological profile for the neighboring V1764M mutant. But, the other neighboring I1762A mutant had no persistent current and was still associated with a positive shift of inactivation. CONCLUSIONS: These findings suggest that the Na(v)1.5/V1763M channel dysfunction and possible neighboring mutants contribute to a persistent inward current due to altered inactivation kinetics and clinically congenital LQTS with perinatal onset of arrhythmias that responded to lidocaine and mexiletine.	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16046395	Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. As a primary target for opioid drugs and peptides, the mu opioid receptor (OPRM1) plays a key role in pain perception and addiction. Genetic variants of OPRM1 have been implicated in predisposition to drug addiction, in particular the single nucleotide polymorphism A118G, leading to an N40D substitution, with an allele frequency of 10-32%, and uncertain functions. We have measured allele-specific mRNA expression of OPRM1 in human autopsy brain tissues, using A118G as a marker. In 8 heterozygous samples measured, the A118 mRNA allele was 1.5-2.5-fold more abundant than the G118 allele. Transfection into Chinese hamster ovary cells of a cDNA representing only the coding region of OPRM1, carrying adenosine, guanosine, cytidine, and thymidine in position 118, resulted in 1.5-fold lower mRNA levels only for OPRM1-G118, and more than 10-fold lower OPRM1 protein levels, measured by Western blotting and receptor binding assay. After transfection and inhibition of transcription with actinomycin D, analysis of mRNA turnover failed to reveal differences in mRNA stability between A118 and G118 alleles, indicating a defect in transcription or mRNA maturation. These results indicate that OPRM1-G118 is a functional variant with deleterious effects on both mRNA and protein yield. Clarifying the functional relevance of polymorphisms associated with susceptibility to a complex disorder such as drug addiction provides a foundation for clinical association studies.	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18457324	Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer. BACKGROUND: Exposure to anthracyclines as part of cancer therapy has been associated with the development of congestive heart failure (CHF). The potential role of genetic risk factors in anthracycline-related CHF remains to be defined. Thus, in this study, the authors examined whether common polymorphisms in candidate genes involved in the pharmacodynamics of anthracyclines (in particular, the nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 gene NQO1 and the carbonyl reductase 3 gene CBR3) had an impact on the risk of anthracycline-related CHF. METHODS: A nested case-control study was conducted within a cohort of 1979 patients enrolled in the Childhood Cancer Survivor Study who received treatment with anthracyclines and had available DNA. Thirty patients with CHF (cases) and 115 matched controls were genotyped for polymorphisms in NQO1 (NQO12) and CBR3 (the CBR3 valine [V] to methionine [M] substitution at position 244 [V244M]). Enzyme activity assays with recombinant CBR3 isoforms (CBR3 V244 and CBR3 M244) and the anthracycline substrate doxorubicin were used to investigate the functional impact of the CBR3 V244M polymorphism. RESULTS: Multivariate analyses adjusted for sex and primary disease recurrence were used to test for associations between the candidate genetic polymorphisms (NQO12 and CBR3 V244M) and the risk of CHF. Analyses indicated no association between the NQO1*2 polymorphism and the risk of anthracycline-related CHF (odds ratio [OR], 1.04; P=.97). There was a trend toward an association between the CBR3 V244M polymorphism and the risk of CHF (OR, 8.16; P=.056 for G/G vs A/A; OR, 5.44; P=.092 for G/A vs A/A). In line, recombinant CBR3 V244 (G allele) synthesized 2.6-fold more cardiotoxic doxorubicinol per unit of time than CBR3 M244 (A allele; CBR3 V244 [8.26+/-3.57 nmol/hour.mg] vs CBR3 M244 [3.22+/-0.67 nmol/hour.mg]; P=.01). CONCLUSIONS: The functional CBR3 V244M polymorphism may have an impact on the risk of anthracycline-related CHF among childhood cancer survivors by modulating the intracardiac formation of cardiotoxic anthracycline alcohol metabolites. Larger confirmatory case-control studies are warranted.	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1848636	Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers. The metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)	[ "Debrisoquine", "phenotype", "and", "the", "pharmacokinetics", "and", "beta", "-", "2", "receptor", "pharmacodynamics", "of", "metoprolol", "and", "its", "enantiomers", ".", "The", "metabolism", "of", "the", "cardioselective", "beta", "-", "blocker", "metoprolol", "is", "under", "genetic", "control", "of", "the", "debrisoquine", "/", "sparteine", "type", ".", "The", "two", "metabolic", "phenotypes", ",", "extensive", "(", "EM", ")", "and", "poor", "metabolizers", "(", "PM", ")", ",", "show", "different", "stereoselective", "metabolism", ",", "resulting", "in", "apparently", "higher", "beta", "-", "1", "adrenoceptor", "antagonistic", "potency", "of", "racemic", "metoprolol", "in", "EMs", ".", "We", "investigated", "if", "the", "latter", "also", "applies", "to", "the", "beta", "-", "2", "adrenoceptor", "antagonism", "by", "metoprolol", ".", "The", "drug", "effect", "studied", "was", "the", "antagonism", "by", "metoprolol", "of", "terbutaline", "-", "induced", "hypokalemia", ".", "By", "using", "pharmacokinetic", "pharmacodynamic", "modeling", "the", "pharmacodynamics", "of", "racemic", "metoprolol", "and", "the", "active", "S", "-", "isomer", ",", "were", "quantitated", "in", "EMs", "and", "PMs", "in", "terms", "of", "IC50", "values", ",", "representing", "metoprolol", "plasma", "concentrations", "resulting", "in", "half", "-", "maximum", "receptor", "occupancy", ".", "Six", "EMs", "received", "0", ".", "5", "mg", "of", "terbutaline", "s", ".", "c", ".", "on", "two", "different", "occasions", ":", "1", ")", "1", "hr", "after", "administration", "of", "a", "placebo", "and", "2", ")", "1", "hr", "after", "150", "mg", "of", "metoprolol", "p", ".", "o", ".", "Five", "PMs", "were", "studied", "according", "to", "the", "same", "protocol", ",", "except", "for", "a", "higher", "terbutaline", "dose", "(", "0", ".", "75", "mg", ")", "on", "day", "2", ".", "Blood", "samples", "for", "the", "analysis", "of", "plasma", "potassium", ",", "terbutaline", ",", "metoprolol", "(", "racemic", ",", "R", "-", "and", "S", "-", "isomer", ")", ",", "and", "alpha", "-", "hydroxymetoprolol", "concentrations", "were", "taken", "at", "regular", "time", "intervals", ",", "during", "8", "hr", "after", "metoprolol", ".", "In", "PMs", ",", "metoprolol", "increased", "the", "terbutaline", "area", "under", "the", "plasma", "concentration", "vs", ".", "time", "curve", "(", "+", "67", "%", ")", ".", "Higher", "metoprolol", "/", "alpha", "-", "hydroxymetoprolol", "ratios", "in", "PMs", "were", "predictive", "for", "higher", "R", "-", "/", "S", "-", "isomer", "ratios", "of", "unchanged", "drug", ".", "There", "was", "a", "difference", "in", "metoprolol", "potency", "with", "higher", "racemic", "metoprolol", "IC50", "values", "in", "PMs", "(", "72", "+", "/", "-", "7", "ng", ".", "ml", "-", "1", ")", "than", "EMs", "(", "42", "+", "/", "-", "8", "ng", ".", "ml", "-", "1", ",", "P", "less", "than", ".", "001", ")", ".", "(", "ABSTRACT", "TRUNCATED", "AT", "250", "WORDS", ")" ]	[ "3", "0", "0", "0", "0", "0", "1", "1", "1", "1", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "1", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "1", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "3", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
19394258	The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome. Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.	[ "The", "first", "founder", "DGUOK", "mutation", "associated", "with", "hepatocerebral", "mitochondrial", "DNA", "depletion", "syndrome", ".", "Deoxyguanosine", "kinase", "(", "dGK", ")", "deficiency", "is", "a", "frequent", "cause", "of", "mitochondrial", "DNA", "depletion", "associated", "with", "a", "hepatocerebral", "phenotype", ".", "In", "this", "study", ",", "we", "describe", "a", "new", "splice", "site", "mutation", "in", "the", "DGUOK", "gene", "and", "the", "clinical", ",", "radiologic", ",", "and", "genetic", "features", "of", "these", "DGUOK", "patients", ".", "This", "new", "DGUOK", "homozygous", "mutation", "(", "c", ".", "444", "-", "62C", ">", "A", ")", "was", "identified", "in", "three", "patients", "from", "two", "North", "-", "African", "consanguineous", "families", "with", "combined", "respiratory", "chain", "deficiencies", "and", "mitochondrial", "DNA", "depletion", "in", "the", "liver", ".", "Brain", "MRIs", "are", "normal", "in", "DGUOK", "patients", "in", "the", "literature", ".", "Interestingly", ",", "we", "found", "subtentorial", "abnormal", "myelination", "and", "moderate", "hyperintensity", "in", "the", "bilateral", "pallidi", "in", "our", "patients", ".", "This", "new", "mutation", "creates", "a", "cryptic", "splice", "site", "in", "intron", "3", "(", "in", "position", "-", "62", ")", "and", "is", "predicted", "to", "result", "in", "a", "larger", "protein", "with", "an", "in", "-", "frame", "insertion", "of", "20", "amino", "acids", ".", "In", "silico", "analysis", "of", "the", "putative", "impact", "of", "the", "insertion", "shows", "serious", "clashes", "in", "protein", "conformation", ":", "this", "insertion", "disrupts", "the", "alpha5", "helix", "of", "the", "dGK", "kinase", "domain", ",", "rendering", "the", "protein", "unable", "to", "bind", "purine", "deoxyribonucleosides", ".", "In", "addition", ",", "a", "common", "haplotype", "that", "segregated", "with", "the", "disease", "in", "both", "families", "was", "detected", "by", "haplotype", "reconstruction", "with", "10", "markers", "(", "microsatellites", "and", "SNPs", ")", ",", "which", "span", "4", ".", "6", "Mb", "of", "DNA", "covering", "the", "DGUOK", "locus", ".", "In", "conclusion", ",", "we", "report", "a", "new", "DGUOK", "splice", "site", "mutation", "that", "provide", "insight", "into", "a", "critical", "protein", "domain", "(", "dGK", "kinase", "domain", ")", "and", "the", "first", "founder", "mutation", "in", "a", "North", "-", "African", "population", "." ]	[ "0", "0", "0", "1", "0", "0", "0", "2", "2", "2", "2", "2", "0", "2", "2", "2", "2", "2", "2", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "4", "0", "0", "0", "1", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "4", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
19565319	Adenosine A(2A) receptor gene (ADORA2A) variants may increase autistic symptoms and anxiety in autism spectrum disorder. Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A(2A) receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product, the adenosine A(2A) receptor, is strongly expressed in the caudate nucleus, which also is involved in ASD. As autistic symptoms are increased in individuals with 22q11.2 deletion syndrome, and large 22q11.2 deletions and duplications have been observed in ASD individuals, in this study, 98 individuals with ASD and 234 control individuals were genotyped for eight single-nucleotide polymorphisms in ADORA2A. Nominal association with the disorder was observed for rs2236624-CC, and phenotypic variability in ASD symptoms was influenced by rs3761422, rs5751876 and rs35320474. In addition, association of ADORA2A variants with anxiety was replicated for individuals with ASD. Findings point toward a possible mediating role of ADORA2A variants on phenotypic expression in ASD that need to be replicated in a larger sample.	[ "Adenosine", "A", "(", "2A", ")", "receptor", "gene", "(", "ADORA2A", ")", "variants", "may", "increase", "autistic", "symptoms", "and", "anxiety", "in", "autism", "spectrum", "disorder", ".", "Autism", "spectrum", "disorders", "(", "ASDs", ")", "are", "heterogeneous", "disorders", "presenting", "with", "increased", "rates", "of", "anxiety", ".", "The", "adenosine", "A", "(", "2A", ")", "receptor", "gene", "(", "ADORA2A", ")", "is", "associated", "with", "panic", "disorder", "and", "is", "located", "on", "chromosome", "22q11", ".", "23", ".", "Its", "gene", "product", ",", "the", "adenosine", "A", "(", "2A", ")", "receptor", ",", "is", "strongly", "expressed", "in", "the", "caudate", "nucleus", ",", "which", "also", "is", "involved", "in", "ASD", ".", "As", "autistic", "symptoms", "are", "increased", "in", "individuals", "with", "22q11", ".", "2", "deletion", "syndrome", ",", "and", "large", "22q11", ".", "2", "deletions", "and", "duplications", "have", "been", "observed", "in", "ASD", "individuals", ",", "in", "this", "study", ",", "98", "individuals", "with", "ASD", "and", "234", "control", "individuals", "were", "genotyped", "for", "eight", "single", "-", "nucleotide", "polymorphisms", "in", "ADORA2A", ".", "Nominal", "association", "with", "the", "disorder", "was", "observed", "for", "rs2236624", "-", "CC", ",", "and", "phenotypic", "variability", "in", "ASD", "symptoms", "was", "influenced", "by", "rs3761422", ",", "rs5751876", "and", "rs35320474", ".", "In", "addition", ",", "association", "of", "ADORA2A", "variants", "with", "anxiety", "was", "replicated", "for", "individuals", "with", "ASD", ".", "Findings", "point", "toward", "a", "possible", "mediating", "role", "of", "ADORA2A", "variants", "on", "phenotypic", "expression", "in", "ASD", "that", "need", "to", "be", "replicated", "in", "a", "larger", "sample", "." ]	[ "1", "1", "1", "1", "1", "1", "0", "0", "1", "0", "0", "0", "0", "2", "2", "0", "2", "0", "2", "2", "2", "0", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "1", "1", "1", "1", "1", "1", "0", "0", "1", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "2", "2", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "5", "0", "5", "0", "5", "0", "0", "0", "0", "0", "0", "1", "0", "0", "2", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
21976953	Identification of a novel FBN1 gene mutation in a Chinese family with Marfan syndrome. PURPOSE: To identify the mutation in the fibrillin-1 gene (FBN1) in a Chinese family with Marfan syndrome (MFS). METHODS: Patients and family members were given complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of six individuals in the family and 170 healthy Chinese individuals. All of the 65 coding exons and their flanking intronic boundaries of FBN1 were amplified in the proband by polymerase chain reaction and followed by direct sequencing. The mutation identified in the proband was screened in the other family members and the 170 healthy Chinese individuals by direct sequencing. Protein conservation analysis was performed in six species using an online ClustalW tool. Protein structure was modeled based on the Protein data bank and mutated in DeepView v4.0.1 to predict the functional consequences of the mutation. RESULTS: A novel heterozygous c.3703T>C change in exon 29 of FBN1 was detected in the proband, which resulted in the substitution of serine by proline at codon 1235 (p.S1235P). This mutation was also present in two family members but absent in the other, unaffected family members and the 170 healthy Chinese individuals. The mutant residue located in the calcium binding epidermal growth factor-like#15 domain is highly conserved among mammalian species and could probably induce conformation change of the domain. CONCLUSIONS: We indentified a novel p.S1235P mutation in FBN1, which is the causative mutation for MFS in this family. Our result expands the mutation spectrum of FBN1 and contributes to the study of the molecular pathogenesis of Marfan syndrome.	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2491010	Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene. Eighty unrelated individuals with Duchenne muscular dystrophy (DMD)or Becker muscular dystrophy (BMD) were found to have deletions in the major deletion-rich region of the DMD locus. This region includes the last five exons detected by cDNA5b-7, all exons detected by cDNA8, and the first two exons detected by cDNA9. These 80 individuals account for approximately 75% of 109 deletions of the gene, detected among 181 patients analyzed with the entire dystrophin cDNA. Endpoints for many of these deletions were further characterized using two genomic probes, p20 (DXS269; Wapenaar et al.) and GMGX11 (DXS239; present paper). Clinical findings are presented for all 80 patients allowing a correlation of phenotypic severity with the genotype. Thirty-eight independent patients were old enough to be classified as DMD, BMD, or intermediate phenotype and had deletions of exons with sequenced intron/exon boundaries. Of these, eight BMD patients and one intermediate patient had gene deletions predicted to leave the reading frame intact, while 21 DMD patients, 7 intermediate patients, and 1 BMD patient had gene deletions predicted to disrupt the reading frame. Thus, with two exceptions, frameshift deletions of the gene resulted in more severe phenotype than did in-frame deletions. This is in agreement with recent findings by Baumbach et al. and Koenig et al. but is in contrast to findings, by Malhotra et al. at the 5 ' end of the gene.	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25006961	Absence of PKC-alpha attenuates lithium-induced nephrogenic diabetes insipidus. Lithium, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in 40% of patients. The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating lithium-induced polyuria. PKC-alpha null mice (PKCa KO) and strain-matched wild type (WT) controls were treated with lithium for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCa KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCa KO. Similar results were observed with UT-A1 expression. Animals were also treated with lithium for 6 weeks. Lithium-treated WT mice had 19-fold increased urine output whereas treated PKCa KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week lithium-treated WT animals whereas in treated PKCa KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in lithium-fed WT but not in lithium-fed PKCa KO mice. Our data show that ablation of PKCa preserves AQP2 and UT-A1 protein expression and localization in lithium-induced NDI, and prevents the development of the severe polyuria associated with lithium therapy.	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27464336	Decreased Whole-Body Fat Mass Produced by Chronic Alcohol Consumption is Associated with Activation of S6K1-Mediated Protein Synthesis and Increased Autophagy in Epididymal White Adipose Tissue. BACKGROUND: Chronic alcohol consumption leads to a loss of white adipose tissue (WAT) but the underlying mechanisms for this lipodystrophy are not fully elucidated. This study tested the hypothesis that the reduction in WAT mass in chronic alcohol-fed mice is associated with a decreased protein synthesis specifically related to impaired function of mammalian target of rapamycin (mTOR). METHODS: Adult male mice were provided an alcohol-containing liquid diet for 24 weeks or an isonitrogenous isocaloric control diet. In vivo protein synthesis was determined at this time and thereafter epididymal WAT (eWAT) was excised for analysis of signal transduction pathways central to controling protein synthesis and degradation. RESULTS: While chronic alcohol feeding decreased whole-body and eWAT mass, this was associated with a discordant increase in protein synthesis in eWAT. This increase was not associated with a change in mTOR, 4E-BP1, Akt, or PRAS40 phosphorylation. Instead, a selective increase in phosphorylation of S6K1 and its downstream substrates, S6 and eIF4B was detected in alcohol-fed mice. Alcohol also increased eEF2K phosphorylation and decreased eEF2 phosphorylation consistent with increased translation elongation. Alcohol increased Atg12-5, LC3B-I and -II, and ULK1 S555 phosphorylation, suggesting increased autophagy, while markers of apoptosis (cleaved caspase-3 and -9, and PARP) were unchanged. Lipolytic enzymes (ATGL and HSL phosphorylation) were increased and lipogenic regulators (PPARgamma and C/EBPalpha) were decreased in eWAT by alcohol. Although alcohol increased TNF-alpha, IL-6, and IL-1beta mRNA, no change in key components of the NLRP3 inflammasome (NLRP3, ACS, and cleaved caspase-1) was detected suggesting alcohol did not increase pyroptosis. Plasma insulin did not differ between groups. CONCLUSIONS: These results demonstrate that the alcohol-induced decrease in whole-body fat mass resulted in part from activation of autophagy in eWAT as protein synthesis was increased and mediated by the specific increase in the activity of S6K1.	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"fed", "mice", ".", "Alcohol", "also", "increased", "eEF2K", "phosphorylation", "and", "decreased", "eEF2", "phosphorylation", "consistent", "with", "increased", "translation", "elongation", ".", "Alcohol", "increased", "Atg12", "-", "5", ",", "LC3B", "-", "I", "and", "-", "II", ",", "and", "ULK1", "S555", "phosphorylation", ",", "suggesting", "increased", "autophagy", ",", "while", "markers", "of", "apoptosis", "(", "cleaved", "caspase", "-", "3", "and", "-", "9", ",", "and", "PARP", ")", "were", "unchanged", ".", "Lipolytic", "enzymes", "(", "ATGL", "and", "HSL", "phosphorylation", ")", "were", "increased", "and", "lipogenic", "regulators", "(", "PPARgamma", "and", "C", "/", "EBPalpha", ")", "were", "decreased", "in", "eWAT", "by", "alcohol", ".", "Although", "alcohol", "increased", "TNF", "-", "alpha", ",", "IL", "-", "6", ",", "and", "IL", "-", "1beta", "mRNA", ",", "no", "change", "in", "key", "components", "of", "the", "NLRP3", "inflammasome", "(", "NLRP3", ",", "ACS", ",", "and", "cleaved", "caspase", "-", "1", ")", "was", "detected", "suggesting", "alcohol", "did", "not", "increase", "pyroptosis", ".", "Plasma", "insulin", "did", "not", "differ", "between", "groups", ".", "CONCLUSIONS", ":", "These", "results", "demonstrate", "that", "the", "alcohol", "-", "induced", "decrease", "in", "whole", "-", "body", "fat", "mass", "resulted", "in", "part", "from", "activation", "of", "autophagy", "in", "eWAT", "as", "protein", "synthesis", "was", "increased", "and", "mediated", "by", "the", "specific", "increase", "in", "the", "activity", "of", "S6K1", "." ]	[ "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", 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8829135	Nefiracetam (DM-9384) reverses apomorphine-induced amnesia of a passive avoidance response: delayed emergence of the memory retention effects. Nefiracetam is a novel pyrrolidone derivative which attenuates scopolamine-induced learning and post-training consolidation deficits. Given that apomorphine inhibits passive avoidance retention when given during training or in a defined 10-12h post-training period, we evaluated the ability of nefiracetam to attenuate amnesia induced by dopaminergic agonism. A step-down passive avoidance paradigm was employed and nefiracetam (3 mg/kg) and apomorphine (0.5 mg/kg) were given alone or in combination during training and at the 10-12h post-training period of consolidation. Co-administration of nefiracetam and apomorphine during training or 10h thereafter produced no significant anti-amnesic effect. However, administration of nefiracetam during training completely reversed the amnesia induced by apomorphine at the 10h post-training time and the converse was also true. These effects were not mediated by a dopaminergic mechanism as nefiracetam, at millimolar concentrations, failed to displace either [3H]SCH 23390 or [3H]spiperone binding from D1 or D2 dopamine receptor subtypes, respectively. It is suggested that nefiracetam augments molecular processes in the early stages of events which ultimately lead to consolidation of memory.	[ "Nefiracetam", "(", "DM", "-", "9384", ")", "reverses", "apomorphine", "-", "induced", "amnesia", "of", "a", "passive", "avoidance", "response", ":", "delayed", "emergence", "of", "the", "memory", "retention", "effects", ".", "Nefiracetam", "is", "a", "novel", "pyrrolidone", "derivative", "which", "attenuates", "scopolamine", "-", "induced", "learning", "and", "post", "-", "training", "consolidation", "deficits", ".", "Given", "that", "apomorphine", "inhibits", "passive", "avoidance", "retention", "when", "given", "during", "training", "or", "in", "a", "defined", "10", "-", "12h", "post", "-", "training", "period", ",", "we", "evaluated", "the", "ability", "of", "nefiracetam", "to", "attenuate", "amnesia", "induced", "by", "dopaminergic", "agonism", ".", "A", "step", "-", "down", "passive", "avoidance", "paradigm", "was", "employed", "and", "nefiracetam", "(", "3", "mg", "/", "kg", ")", "and", "apomorphine", "(", "0", ".", "5", "mg", "/", "kg", ")", "were", "given", "alone", "or", "in", "combination", "during", "training", "and", "at", "the", "10", "-", "12h", "post", "-", "training", "period", "of", "consolidation", ".", "Co", "-", "administration", "of", "nefiracetam", "and", "apomorphine", "during", "training", "or", "10h", "thereafter", "produced", "no", "significant", "anti", "-", "amnesic", "effect", ".", "However", ",", "administration", "of", "nefiracetam", "during", "training", "completely", "reversed", "the", "amnesia", "induced", "by", "apomorphine", "at", "the", "10h", "post", "-", "training", "time", "and", "the", "converse", "was", "also", "true", ".", "These", "effects", "were", "not", "mediated", "by", "a", "dopaminergic", "mechanism", "as", "nefiracetam", ",", "at", "millimolar", "concentrations", ",", "failed", "to", "displace", "either", "[", "3H", "]", "SCH", "23390", "or", "[", "3H", "]", "spiperone", "binding", "from", "D1", "or", "D2", "dopamine", "receptor", "subtypes", ",", "respectively", ".", "It", "is", "suggested", "that", "nefiracetam", "augments", "molecular", "processes", "in", "the", "early", "stages", "of", "events", "which", "ultimately", "lead", "to", "consolidation", "of", "memory", "." ]	[ "3", "0", "3", "3", "3", "0", "0", "3", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "3", "0", "0", "0", "3", "0", "0", "2", "2", "2", "2", "2", "2", "2", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "2", "0", "0", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "2", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "3", "0", "0", "3", "0", "3", "0", "0", "1", "1", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
9672936	Pethidine-associated seizure in a healthy adolescent receiving pethidine for postoperative pain control. A healthy 17-year-old male received standard intermittent doses of pethidine via a patient-controlled analgesia (PCA) pump for management of postoperative pain control. Twenty-three h postoperatively he developed a brief self-limited seizure. Both plasma pethidine and norpethidine were elevated in the range associated with clinical manifestations of central nervous system excitation. No other risk factors for CNS toxicity were identified. This method allowed frequent self-dosing of pethidine at short time intervals and rapid accumulation of pethidine and norpethidine. The routine use of pethidine via PCA even for a brief postoperative analgesia should be reconsidered.	[ "Pethidine", "-", "associated", "seizure", "in", "a", "healthy", "adolescent", "receiving", "pethidine", "for", "postoperative", "pain", "control", ".", "A", "healthy", "17", "-", "year", "-", "old", "male", "received", "standard", "intermittent", "doses", "of", "pethidine", "via", "a", "patient", "-", "controlled", "analgesia", "(", "PCA", ")", "pump", "for", "management", "of", "postoperative", "pain", "control", ".", "Twenty", "-", "three", "h", "postoperatively", "he", "developed", "a", "brief", "self", "-", "limited", "seizure", ".", "Both", "plasma", "pethidine", "and", "norpethidine", "were", "elevated", "in", "the", "range", "associated", "with", "clinical", "manifestations", "of", "central", "nervous", "system", "excitation", ".", "No", "other", "risk", "factors", "for", "CNS", "toxicity", "were", "identified", ".", "This", "method", "allowed", "frequent", "self", "-", "dosing", "of", "pethidine", "at", "short", "time", "intervals", "and", "rapid", "accumulation", "of", "pethidine", "and", "norpethidine", ".", "The", "routine", "use", "of", "pethidine", "via", "PCA", "even", "for", "a", "brief", "postoperative", "analgesia", "should", "be", "reconsidered", "." ]	[ "3", "0", "0", "2", "0", "0", "0", "0", "0", "3", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0" ]
18503483	Recovery of tacrolimus-associated brachial neuritis after conversion to everolimus in a pediatric renal transplant recipient--case report and review of the literature. TAC has been shown to be a potent immunosuppressive agent for solid organ transplantation in pediatrics. Neurotoxicity is a potentially serious toxic effect. It is characterized by encephalopathy, headaches, seizures, or neurological deficits. Here, we describe an eight-and-a-half-yr-old male renal transplant recipient with right BN. MRI demonstrated hyperintense T2 signals in the cervical cord and right brachial plexus roots indicative of both myelitis and right brachial plexitis. Symptoms persisted for three months despite TAC dose reduction, administration of IVIG and four doses of methylprednisolone pulse therapy. Improvement and eventually full recovery only occurred after TAC was completely discontinued and successfully replaced by everolimus.	[ "Recovery", "of", "tacrolimus", "-", "associated", "brachial", "neuritis", "after", "conversion", "to", "everolimus", "in", "a", "pediatric", "renal", "transplant", "recipient", "-", "-", "case", "report", "and", "review", "of", "the", "literature", ".", "TAC", "has", "been", "shown", "to", "be", "a", "potent", "immunosuppressive", "agent", "for", "solid", "organ", "transplantation", "in", "pediatrics", ".", "Neurotoxicity", "is", "a", "potentially", "serious", "toxic", "effect", ".", "It", "is", "characterized", "by", "encephalopathy", ",", "headaches", ",", "seizures", ",", "or", "neurological", "deficits", ".", "Here", ",", "we", "describe", "an", "eight", "-", "and", "-", "a", "-", "half", "-", "yr", "-", "old", "male", "renal", "transplant", "recipient", "with", "right", "BN", ".", "MRI", "demonstrated", "hyperintense", "T2", "signals", "in", "the", "cervical", "cord", "and", "right", "brachial", "plexus", "roots", "indicative", "of", "both", "myelitis", "and", "right", "brachial", "plexitis", ".", "Symptoms", "persisted", "for", "three", "months", "despite", "TAC", "dose", "reduction", ",", "administration", "of", "IVIG", "and", "four", "doses", "of", "methylprednisolone", "pulse", "therapy", ".", "Improvement", "and", "eventually", "full", "recovery", "only", "occurred", "after", "TAC", "was", "completely", "discontinued", "and", "successfully", "replaced", "by", "everolimus", "." ]	[ "0", "0", "3", "0", "0", "2", "2", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "0", "2", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "3", "0" ]
26991973	MOL1 is required for cambium homeostasis in Arabidopsis. Plants maintain pools of pluripotent stem cells which allow them to constantly produce new tissues and organs. Stem cell homeostasis in shoot and root tips depends on negative regulation by ligand-receptor pairs of the CLE peptide and leucine-rich repeat receptor-like kinase (LRR-RLK) families. However, regulation of the cambium, the stem cell niche required for lateral growth of shoots and roots, is poorly characterized. Here we show that the LRR-RLK MOL1 is necessary for cambium homeostasis in Arabidopsis thaliana. By employing promoter reporter lines, we reveal that MOL1 is active in a domain that is distinct from the domain of the positively acting CLE41/PXY signaling module. In particular, we show that MOL1 acts in an opposing manner to the CLE41/PXY module and that changing the domain or level of MOL1 expression both result in disturbed cambium organization. Underlining discrete roles of MOL1 and PXY, both LRR-RLKs are not able to replace each other when their expression domains are interchanged. Furthermore, MOL1 but not PXY is able to rescue CLV1 deficiency in the shoot apical meristem. By identifying genes mis-expressed in mol1 mutants, we demonstrate that MOL1 represses genes associated with stress-related ethylene and jasmonic acid hormone signaling pathways which have known roles in coordinating lateral growth of the Arabidopsis stem. Our findings provide evidence that common regulatory mechanisms in different plant stem cell niches are adapted to specific niche anatomies and emphasize the importance of a complex spatial organization of intercellular signaling cascades for a strictly bidirectional tissue production.	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16112787	In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, desquamation, and necrosis in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels.	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21405999	Mutation screening of the GUCA1B gene in patients with autosomal dominant cone and cone rod dystrophy. Background: Heterozygous mutations in GUCA1A (MIM # 600364) have been identified to cause autosomal dominantly inherited cone dystrophy, cone rod dystrophy and macular dystrophy. However, the role of GUCA1B gene mutations in inherited retinal disease has been controversial. We therefore performed a mutation analysis of the GUCA1B gene in a clinically well characterized group of patients of European and North-American geographical origin with autosomal dominantly inherited cone dystrophy and cone rod dystrophy. Material and Methods: Twenty-four unrelated patients diagnosed with cone dystrophy or cone rod dystrophy according to standard diagnostic criteria and a family history consistent with an autosomal dominant mode of inheritance were included in the study. Mutation analysis of all coding exons of the GUCA1B gene was performed by polymerase chain reaction amplification of genomic DNA and subsequent DNA sequencing. Results: Three different sequence variants, c.-17T>C, c.171T>C, c.465G>T were identified. The sequence variant c.465G>T encodes a conservative amino acid substitution, p.Glu155Asp, located in EF-hand 4, the calcium binding site of GCAP2 protein. All sequence variants were previously reported in healthy subjects. Conclusion: The absence of clearly pathogenic mutations in the selected patient group suggests that the GUCA1B gene is a minor cause for retinal degenerations in Europeans or North-Americans.	[ "Mutation", "screening", "of", "the", "GUCA1B", "gene", "in", "patients", "with", "autosomal", "dominant", "cone", "and", "cone", "rod", "dystrophy", ".", "Background", ":", "Heterozygous", "mutations", "in", "GUCA1A", "(", "MIM", "#", "600364", ")", "have", "been", "identified", "to", "cause", "autosomal", "dominantly", "inherited", "cone", "dystrophy", ",", "cone", "rod", "dystrophy", "and", "macular", "dystrophy", ".", "However", ",", "the", "role", "of", "GUCA1B", "gene", "mutations", "in", "inherited", "retinal", "disease", "has", "been", "controversial", ".", "We", "therefore", "performed", "a", "mutation", "analysis", "of", "the", "GUCA1B", "gene", "in", "a", "clinically", "well", "characterized", "group", "of", "patients", "of", "European", "and", "North", "-", "American", "geographical", "origin", "with", "autosomal", "dominantly", "inherited", "cone", "dystrophy", "and", "cone", "rod", "dystrophy", ".", "Material", "and", "Methods", ":", "Twenty", "-", "four", "unrelated", "patients", "diagnosed", "with", "cone", "dystrophy", "or", "cone", "rod", "dystrophy", "according", "to", "standard", "diagnostic", "criteria", "and", "a", "family", "history", "consistent", "with", "an", "autosomal", "dominant", "mode", "of", "inheritance", "were", "included", "in", "the", "study", ".", "Mutation", "analysis", "of", "all", "coding", "exons", "of", "the", "GUCA1B", "gene", "was", "performed", "by", "polymerase", "chain", "reaction", "amplification", "of", "genomic", "DNA", "and", "subsequent", "DNA", "sequencing", ".", "Results", ":", "Three", "different", "sequence", "variants", ",", "c", ".", "-", "17T", ">", "C", ",", "c", ".", "171T", ">", "C", ",", "c", ".", "465G", ">", "T", "were", "identified", ".", "The", "sequence", "variant", "c", ".", "465G", ">", "T", "encodes", "a", "conservative", "amino", "acid", "substitution", ",", "p", ".", "Glu155Asp", ",", "located", "in", "EF", "-", "hand", "4", ",", "the", "calcium", "binding", "site", "of", "GCAP2", "protein", ".", "All", "sequence", "variants", "were", "previously", "reported", "in", "healthy", "subjects", ".", "Conclusion", ":", "The", "absence", "of", "clearly", "pathogenic", "mutations", "in", "the", "selected", "patient", "group", "suggests", "that", "the", "GUCA1B", "gene", "is", "a", "minor", "cause", "for", "retinal", "degenerations", "in", "Europeans", "or", "North", "-", "Americans", "." ]	[ "0", "0", "0", "0", "1", "0", "0", "4", "0", "0", "0", "2", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "2", "2", "0", "2", "2", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "2", "2", "0", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "0", "5", "5", "5", "5", "5", "0", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0" ]
15233872	Cardioprotective effect of tincture of Crataegus on isoproterenol-induced myocardial infarction in rats. Tincture of Crataegus (TCR), an alcoholic extract of the berries of hawthorn (Crataegus oxycantha), is used in herbal and homeopathic medicine. The present study was done to investigate the protective effect of TCR on experimentally induced myocardial infarction in rats. Pretreatment of TCR, at a dose of 0.5 mL/100 g bodyweight per day, orally for 30 days, prevented the increase in lipid peroxidation and activity of marker enzymes observed in isoproterenol-induced rats (85 mg kg(-1) s. c. for 2 days at an interval of 24 h). TCR prevented the isoproterenol-induced decrease in antioxidant enzymes in the heart and increased the rate of ADP-stimulated oxygen uptake and respiratory coupling ratio. TCR protected against pathological changes induced by isoproterenol in rat heart. The results show that pretreatment with TCR may be useful in preventing the damage induced by isoproterenol in rat heart.	[ "Cardioprotective", "effect", "of", "tincture", "of", "Crataegus", "on", "isoproterenol", "-", "induced", "myocardial", "infarction", "in", "rats", ".", "Tincture", "of", "Crataegus", "(", "TCR", ")", ",", "an", "alcoholic", "extract", "of", "the", "berries", "of", "hawthorn", "(", "Crataegus", "oxycantha", ")", ",", "is", "used", "in", "herbal", "and", "homeopathic", "medicine", ".", "The", "present", "study", "was", "done", "to", "investigate", "the", "protective", "effect", "of", "TCR", "on", "experimentally", "induced", "myocardial", "infarction", "in", "rats", ".", "Pretreatment", "of", "TCR", ",", "at", "a", "dose", "of", "0", ".", "5", "mL", "/", "100", "g", "bodyweight", "per", "day", ",", "orally", "for", "30", "days", ",", "prevented", "the", "increase", "in", "lipid", "peroxidation", "and", "activity", "of", "marker", "enzymes", "observed", "in", "isoproterenol", "-", "induced", "rats", "(", "85", "mg", "kg", "(", "-", "1", ")", "s", ".", "c", ".", "for", "2", "days", "at", "an", "interval", "of", "24", "h", ")", ".", "TCR", "prevented", "the", "isoproterenol", "-", "induced", "decrease", "in", "antioxidant", "enzymes", "in", "the", "heart", "and", "increased", "the", "rate", "of", "ADP", "-", "stimulated", "oxygen", "uptake", "and", "respiratory", "coupling", "ratio", ".", "TCR", "protected", "against", "pathological", "changes", "induced", "by", "isoproterenol", "in", "rat", "heart", ".", "The", "results", "show", "that", "pretreatment", "with", "TCR", "may", "be", "useful", "in", "preventing", "the", "damage", "induced", "by", "isoproterenol", "in", "rat", "heart", "." ]	[ "0", "0", "0", "3", "3", "3", "0", "3", "0", "0", "2", "2", "0", "4", "0", "3", "3", "3", "0", "3", "0", "0", "0", "3", "3", "3", "3", "3", "3", "3", "0", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "2", "2", "0", "4", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "3", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "3", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "4", "0", "0" ]
17059986	A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension. We report a case of Gitelman syndrome (GS) in a dizygotic twin who presented at 12 years of age with growth delay, metabolic alkalosis, hypomagnesemia and hypokalemia with inappropriate kaliuresis, and idiopathic intracranial hypertension with bilateral papilledema (pseudotumor cerebri). The patient, her twin sister, and her mother also presented with cerebral cavernous malformations. Based on the early onset and normocalciuria, Bartter syndrome was diagnosed first. However, mutation analysis showed that the proband is a compound heterozygote for 2 mutations in SLC12A3: a substitution of serine by leucine at amino acid position 555 (p.Ser555Leu) and a novel guanine to cytosine transition at the 5' splice site of intron 22 (c.2633+1G>C), providing the molecular diagnosis of GS. These mutations were not detected in 200 normal chromosomes and cosegregated within the family. Analysis of complementary DNA showed that the heterozygous nucleotide change c.2633+1G>C caused the appearance of 2 RNA molecules, 1 normal transcript and 1 skipping the entire exon 22 (r.2521_2634del). Supplementation with potassium and magnesium improved clinical symptoms and resulted in catch-up growth, but vision remained impaired. Three similar associations of Bartter syndrome/GS with pseudotumor cerebri were found in the literature, suggesting that electrolyte abnormalities and secondary aldosteronism may have a role in idiopathic intracranial hypertension. This study provides further evidence for the phenotypical heterogeneity of GS and its association with severe manifestations in children. It also shows the independent segregation of familial cavernomatosis and GS.	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18991055	Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population. According to recent genome-wide association studies, a number of single nucleotide polymorphisms (SNPs) are reported to be associated with type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association among the polymorphisms of SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1 and KCNQ1 and the risk of T2DM in the Korean population. This study was based on a multicenter case-control study, including 908 patients with T2DM and 502 non-diabetic controls. We genotyped rs13266634, rs1111875, rs10811661, rs4402960, rs8050136, rs734312, rs7754840 and rs2237892 and measured the body weight, body mass index and fasting plasma glucose in all patients and controls. The strongest association was found in a variant of CDKAL1 [rs7754840, odds ratio (OR) = 1.77, 95% CI = 1.50-2.10, p = 5.0 x 10(-11)]. The G allele of rs1111875 (OR = 1.43, 95% CI = 1.18-1.72, p = 1.8 x 10(-4)) in HHEX), the T allele of rs10811661 (OR = 1.47, 95% CI = 1.23-1.75, p = 2.1 x 10(-5)) in CDKN2A/B) and the C allele of rs2237892 (OR = 1.31, 95% CI = 1.10-1.56, p = 0.003) in KCNQ1 showed significant associations with T2DM. Rs13266634 (OR = 1.19, 95% CI = 1.00-1.42, p = 0.045) in SLC30A8 showed a nominal association with the risk of T2DM, whereas SNPs in IGF2BP2, FTO and WFS1 were not associated. In conclusion, we have shown that SNPs in HHEX, CDKN2A/B, CDKAL1, KCNQ1 and SLC30A8 confer a risk of T2DM in the Korean population.	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20705401	Serotonin 6 receptor gene is associated with methamphetamine-induced psychosis in a Japanese population. BACKGROUND: Altered serotonergic neural transmission is hypothesized to be a susceptibility factor for psychotic disorders such as schizophrenia. The serotonin 6 (5-HT6) receptor is therapeutically targeted by several second generation antipsychotics, such as clozapine and olanzapine, and d-amphetamine-induced hyperactivity in rats is corrected with the use of a selective 5-HT6 receptor antagonist. In addition, the disrupted prepulse inhibition induced by d-amphetamine or phencyclidine was restored by 5-HT6 receptor antagonist in an animal study using rats. These animal models were considered to reflect the positive symptoms of schizophrenia, and the above evidence suggests that altered 5-HT6 receptors are involved in the pathophysiology of psychotic disorders. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an analysis of the association of the 5-HT6 gene (HTR6) with METH-induced psychosis. METHOD: Using five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. RESULTS: rs6693503 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this association remained significant after Bonferroni correction. In the haplotype-wise analysis, we detected an association between two markers (rs6693503 and rs1805054) and three markers (rs6693503, rs1805054 and rs4912138) in HTR6 and METH-induced psychosis patients, respectively. CONCLUSION: HTR6 may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population.	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22369755	Reciprocal effects of NNK and SLURP-1 on oncogene expression in target epithelial cells. AIMS: To elucidate how the nicotinic acetylcholine receptors expressed on bronchial and oral epithelial cells targeted by the tobacco nitrosamine (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) (NNK) facilitate carcinogenic transformation. MAIN METHODS: Since NNK-dependent transformation can be abolished by the nicotinergic secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1 (SLURP-1), we compared effects of NNK and recombinant (r)SLURP-1 on the expression of genes related to tumorigenesis in human immortalized bronchial and oral epithelial cell lines BEP2D and Het-1A, respectively. KEY FINDINGS: NNK stimulated expression of oncogenic genes, including MYB and PIK3CA in BEP2D, ETS1, NRAS and SRC in Het-1A, and AKT1, KIT and RB1 in both cell types, which could be abolished in the presence of rSLURP-1. Other cancer-related genes whose upregulation by NNK was abolishable by rSLURP-1 were the growth factors EGF in BEP2D cells and HGF in Het-1A cells, and the transcription factors CDKN2A and STAT3 (Het-1A only). NNK also upregulated the anti-apoptotic BCL2 (Het-1A) and downregulated the pro-apoptotic TNF (Het-1A), BAX and CASP8 (BEP2D), all of which could be abolished, in part, by rSLURP-1. NNK decreased expression of the CTNNB1 gene encoding the intercellular adhesion molecule beta-catenin (BEP2D), as well as tumor suppressors CDKN3 and FOXD3 in BEP2D cells and SERPINB5 in Het-1A cells. These pro-oncogenic effects of NNK were abolished by rSLURP-1 that also upregulated RUNX3. SIGNIFICANCE: The obtained results identified target genes for both NNK and SLURP-1 and shed light on the molecular mechanism of their reciprocal effects on tumorigenic transformation of bronchial and oral epithelial cells.	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27959387	Long-term exposure of MCF-7 breast cancer cells to ethanol stimulates oncogenic features. Alcohol consumption is a risk factor for breast cancer. Little is known regarding the mechanism, although it is assumed that acetaldehyde or estrogen mediated pathways play a role. We previously showed that long-term exposure to 2.5 mM ethanol (blood alcohol ~0.012%) of MCF-12A, a human normal epithelial breast cell line, induced epithelial mesenchymal transition (EMT) and oncogenic transformation. In this study, we investigated in the human breast cancer cell line MCF-7, whether a similar exposure to ethanol at concentrations ranging up to peak blood levels in heavy drinkers would increase malignant progression. Short-term (1-week) incubation to ethanol at as low as 1-5 mM (corresponding to blood alcohol concentration of ~0.0048-0.024%) upregulated the stem cell related proteins Oct4 and Nanog, but they were reduced after exposure at 25 mM. Long-term (4-week) exposure to 25 mM ethanol upregulated the Oct4 and Nanog proteins, as well as the malignancy marker Ceacam6. DNA microarray analysis in cells exposed for 1 week showed upregulated expression of metallothionein genes, particularly MT1X. Long-term exposure upregulated expression of some malignancy related genes (STEAP4, SERPINA3, SAMD9, GDF15, KRT15, ITGB6, TP63, and PGR, as well as the CEACAM, interferon related, and HLA gene families). Some of these findings were validated by RT-PCR. A similar treatment also modulated numerous microRNAs (miRs) including one regulator of Oct4 as well as miRs involved in oncogenesis and/or malignancy, with only a few estrogen-induced miRs. Long-term 25 mM ethanol also induced a 5.6-fold upregulation of anchorage-independent growth, an indicator of malignant-like features. Exposure to acetaldehyde resulted in little or no effect comparable to that of ethanol. The previously shown alcohol induction of oncogenic transformation of normal breast cells is now complemented by the current results suggesting alcohol's potential involvement in malignant progression of breast cancer.	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21684788	Large contiguous gene deletions in Sjogren-Larsson syndrome. Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.	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26937641	Serum Amyloid A Induces Inflammation, Proliferation and Cell Death in Activated Hepatic Stellate Cells. Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IkappaB kinase, c-Jun N-terminal kinase (JNK), Erk and Akt and enhanced NF-kappaB-dependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-kappaB- and JNK-dependent manner. Blockade of NF-kappaB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-kappaB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs.	[ "Serum", "Amyloid", "A", "Induces", "Inflammation", ",", "Proliferation", "and", "Cell", "Death", "in", "Activated", "Hepatic", "Stellate", "Cells", ".", "Serum", "amyloid", "A", "(", "SAA", ")", "is", "an", "evolutionary", "highly", "conserved", "acute", "phase", "protein", "that", "is", "predominantly", "secreted", "by", "hepatocytes", ".", "However", ",", "its", "role", "in", "liver", "injury", "and", "fibrogenesis", "has", "not", "been", "elucidated", "so", "far", ".", "In", "this", "study", ",", "we", "determined", "the", "effects", "of", "SAA", "on", "hepatic", "stellate", "cells", "(", "HSCs", ")", ",", "the", "main", "fibrogenic", "cell", "type", "of", "the", "liver", ".", "Serum", "amyloid", "A", "potently", "activated", "IkappaB", "kinase", ",", "c", "-", "Jun", "N", "-", "terminal", "kinase", "(", "JNK", ")", ",", "Erk", "and", "Akt", "and", "enhanced", "NF", "-", "kappaB", "-", "dependent", "luciferase", "activity", "in", "primary", "human", "and", "rat", "HSCs", ".", "Serum", "amyloid", "A", "induced", "the", "transcription", "of", "MCP", "-", "1", ",", "RANTES", "and", "MMP9", "in", "an", "NF", "-", "kappaB", "-", "and", "JNK", "-", "dependent", "manner", ".", "Blockade", "of", "NF", "-", "kappaB", "revealed", "cytotoxic", "effects", "of", "SAA", "in", "primary", "HSCs", "with", "signs", "of", "apoptosis", "such", "as", "caspase", "3", "and", "PARP", "cleavage", "and", "Annexin", "V", "staining", ".", "Serum", "amyloid", "A", "induced", "HSC", "proliferation", ",", "which", "depended", "on", "JNK", ",", "Erk", "and", "Akt", "activity", ".", "In", "primary", "hepatocytes", ",", "SAA", "also", "activated", "MAP", "kinases", ",", "but", "did", "not", "induce", "relevant", "cell", "death", "after", "NF", "-", "kappaB", "inhibition", ".", "In", "two", "models", "of", "hepatic", "fibrogenesis", ",", "CCl4", "treatment", "and", "bile", "duct", "ligation", ",", "hepatic", "mRNA", "levels", "of", "SAA1", "and", "SAA3", "were", "strongly", "increased", ".", "In", "conclusion", ",", "SAA", "may", "modulate", "fibrogenic", "responses", "in", "the", "liver", "in", "a", "positive", "and", "negative", "fashion", "by", "inducing", "inflammation", ",", "proliferation", "and", "cell", "death", "in", "HSCs", "." ]	[ "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "0", "0", "1", "1", "0", "1", "1", "1", "1", "1", "1", "1", "0", "1", "0", "0", "1", "0", "1", "0", "0", "1", "1", "1", "0", "0", "0", "0", "0", "0", "4", "0", "4", "0", "0", "1", "1", "1", "0", "0", "0", "0", "1", "1", "1", "0", "1", "0", "1", "0", "0", "1", "1", "1", "0", "0", "1", "0", "0", "0", "0", "0", "0", "1", "1", "1", "0", "2", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "0", "1", "0", "0", "1", "1", "0", "0", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "1", "0", "1", "0", "1", "0", "0", "0", "0", "0", "0", "1", "0", "0", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "0", "0", "0", "0", "0", "0", "2", "2", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]
15464247	Influence of interleukin 12B (IL12B) polymorphisms on spontaneous and treatment-induced recovery from hepatitis C virus infection. BACKGROUND/AIMS: Interleukin-12 (IL-12) governs the Th1-type immune response, affecting the spontaneous and treatment-induced recovery from HCV-infection. We investigated whether the IL12B polymorphisms within the promoter region (4 bp insertion/deletion) and the 3'-UTR (1188-A/C), which have been reported to influence IL-12 synthesis, are associated with the outcome of HCV infection. METHODS: We analyzed 186 individuals with spontaneous HCV clearance, 501 chronically HCV infected patients, and 217 healthy controls. IL12B 3'-UTR and promoter genotyping was performed by Taqman-based assays with allele-specific oligonucleotide probes and PCR-based allele-specific DNA-amplification, respectively. RESULTS: The proportion of IL12B promoter and 3'-UTR genotypes did not differ significantly between the different cohorts. However, HCV genotype 1-infected patients with high baseline viremia carrying the IL12B 3'-UTR 1188-C-allele showed significantly higher sustained virologic response (SVR) rates (25.3% vs. 46% vs. 54.5% for A/A, A/C and C/C) due to reduced relapse rates (24.2% vs. 12% vs. zero % for A/A, A/C and C/C). CONCLUSIONS: IL12B 3'-UTR 1188-C-allele carriers appear to be capable of responding more efficiently to antiviral combination therapy as a consequence of a reduced relapse rate. No association of IL12B polymorphisms and self-limited HCV infection could be demonstrated.	[ "Influence", "of", "interleukin", "12B", "(", "IL12B", ")", "polymorphisms", "on", "spontaneous", "and", "treatment", "-", "induced", "recovery", "from", "hepatitis", "C", "virus", "infection", ".", "BACKGROUND", "/", "AIMS", ":", "Interleukin", "-", "12", "(", "IL", "-", "12", ")", "governs", "the", "Th1", "-", "type", "immune", "response", ",", "affecting", "the", "spontaneous", "and", "treatment", "-", "induced", "recovery", "from", "HCV", "-", "infection", ".", "We", "investigated", "whether", "the", "IL12B", "polymorphisms", "within", "the", "promoter", "region", "(", "4", "bp", "insertion", "/", "deletion", ")", "and", "the", "3", "'", "-", "UTR", "(", "1188", "-", "A", "/", "C", ")", ",", "which", "have", "been", "reported", "to", "influence", "IL", "-", "12", "synthesis", ",", "are", "associated", "with", "the", "outcome", "of", "HCV", "infection", ".", "METHODS", ":", "We", "analyzed", "186", "individuals", "with", "spontaneous", "HCV", "clearance", ",", "501", "chronically", "HCV", "infected", "patients", ",", "and", "217", "healthy", "controls", ".", "IL12B", "3", "'", "-", "UTR", "and", "promoter", "genotyping", "was", "performed", "by", "Taqman", "-", "based", "assays", "with", "allele", "-", "specific", "oligonucleotide", "probes", "and", "PCR", "-", "based", "allele", "-", "specific", "DNA", "-", "amplification", ",", "respectively", ".", "RESULTS", ":", "The", "proportion", "of", "IL12B", "promoter", "and", "3", "'", "-", "UTR", "genotypes", "did", "not", "differ", "significantly", "between", "the", "different", "cohorts", ".", "However", ",", "HCV", "genotype", "1", "-", "infected", "patients", "with", "high", "baseline", "viremia", "carrying", "the", "IL12B", "3", "'", "-", "UTR", "1188", "-", "C", "-", "allele", "showed", "significantly", "higher", "sustained", "virologic", "response", "(", "SVR", ")", "rates", "(", "25", ".", "3", "%", "vs", ".", "46", "%", "vs", ".", "54", ".", "5", "%", "for", "A", "/", "A", ",", "A", "/", "C", "and", "C", "/", "C", ")", "due", "to", "reduced", "relapse", "rates", "(", "24", ".", "2", "%", "vs", ".", "12", "%", "vs", ".", "zero", "%", "for", "A", "/", "A", ",", "A", "/", "C", "and", "C", "/", "C", ")", ".", "CONCLUSIONS", ":", "IL12B", "3", "'", "-", "UTR", "1188", "-", "C", "-", "allele", "carriers", "appear", "to", "be", "capable", "of", "responding", "more", "efficiently", "to", "antiviral", "combination", "therapy", "as", "a", "consequence", "of", "a", "reduced", "relapse", "rate", ".", "No", "association", "of", "IL12B", "polymorphisms", "and", "self", "-", "limited", "HCV", "infection", "could", "be", "demonstrated", "." ]	[ "0", "0", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "1", "1", "1", "0", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "2", "2", "4", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "4", "0", "0", "0", "2", "0", "0", "1", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0" ]
15824163	No Evidence for BRAF as a melanoma/nevus susceptibility gene. Somatic mutations of BRAF have been identified in both melanoma tumors and benign nevi. Germ line mutations in BRAF have not been identified as causal in families predisposed to melanoma. However, a recent study suggested that a BRAF haplotype was associated with risk of sporadic melanoma in men. Polymorphisms or other variants in the BRAF gene may therefore act as candidate low-penetrance genes for nevus/melanoma susceptibility. We hypothesized that promoter variants would be the most likely candidates for determinants of risk. Using denaturing high-pressure liquid chromatography and sequencing, we screened peripheral blood DNA from 184 familial melanoma cases for BRAF promoter variants. We identified a promoter insertion/deletion in linkage disequilibrium with the previously described BRAF polymorphism in intron 11 (rs1639679) reported to be associated with melanoma susceptibility in males. We therefore investigated the contribution of this BRAF polymorphism to melanoma susceptibility in 581 consecutively recruited incident cases, 258 incident cases in a study of late relapse, 673 female general practitioner controls, and the 184 familial cases. We found no statistically significant difference in either genotype or allele frequencies between cases and controls overall or between male and female cases for the BRAF polymorphism in the two incident case series. Our results therefore suggest that the BRAF polymorphism is not significantly associated with melanoma and the promoter insertion/deletion linked with the polymorphism is not a causal variant. In addition, we found that there was no association between the BRAF genotype and mean total number of banal or atypical nevi in either the cases or controls.	[ "No", "Evidence", "for", "BRAF", "as", "a", "melanoma", "/", "nevus", "susceptibility", "gene", ".", "Somatic", "mutations", "of", "BRAF", "have", "been", "identified", "in", "both", "melanoma", "tumors", "and", "benign", "nevi", ".", "Germ", "line", "mutations", "in", "BRAF", "have", "not", "been", "identified", "as", "causal", "in", "families", "predisposed", "to", "melanoma", ".", "However", ",", "a", "recent", "study", "suggested", "that", "a", "BRAF", "haplotype", "was", "associated", "with", "risk", "of", "sporadic", "melanoma", "in", "men", ".", "Polymorphisms", "or", "other", "variants", "in", "the", "BRAF", "gene", "may", "therefore", "act", "as", "candidate", "low", "-", "penetrance", "genes", "for", "nevus", "/", "melanoma", "susceptibility", ".", "We", "hypothesized", "that", "promoter", "variants", "would", "be", "the", "most", "likely", "candidates", "for", "determinants", "of", "risk", ".", "Using", "denaturing", "high", "-", "pressure", "liquid", "chromatography", "and", "sequencing", ",", "we", "screened", "peripheral", "blood", "DNA", "from", "184", "familial", "melanoma", "cases", "for", "BRAF", "promoter", "variants", ".", "We", "identified", "a", "promoter", "insertion", "/", "deletion", "in", "linkage", "disequilibrium", "with", "the", "previously", "described", "BRAF", "polymorphism", "in", "intron", "11", "(", "rs1639679", ")", "reported", "to", "be", "associated", "with", "melanoma", "susceptibility", "in", "males", ".", "We", "therefore", "investigated", "the", "contribution", "of", "this", "BRAF", "polymorphism", "to", "melanoma", "susceptibility", "in", "581", "consecutively", "recruited", "incident", "cases", ",", "258", "incident", "cases", "in", "a", "study", "of", "late", "relapse", ",", "673", "female", "general", "practitioner", "controls", ",", "and", "the", "184", "familial", "cases", ".", "We", "found", "no", "statistically", "significant", "difference", "in", "either", "genotype", "or", "allele", "frequencies", "between", "cases", "and", "controls", "overall", "or", "between", "male", "and", "female", "cases", "for", "the", "BRAF", "polymorphism", "in", "the", "two", "incident", "case", "series", ".", "Our", "results", "therefore", "suggest", "that", "the", "BRAF", "polymorphism", "is", "not", "significantly", "associated", "with", "melanoma", "and", "the", "promoter", "insertion", "/", "deletion", "linked", "with", "the", "polymorphism", "is", "not", "a", "causal", "variant", ".", "In", "addition", ",", "we", "found", "that", "there", "was", "no", "association", "between", "the", "BRAF", "genotype", "and", "mean", "total", "number", "of", "banal", "or", "atypical", "nevi", "in", "either", "the", "cases", "or", "controls", "." ]	[ "0", "0", "0", "1", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "2", "2", "0", "0", "2", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "2", "2", "0", "4", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0" ]
26900322	CFI-rs7356506 polymorphisms associated with Vogt-Koyanagi-Harada syndrome. PURPOSE: Complement factor I (CFI) plays an important role in complement activation pathways and is known to affect the development of uveitis. The present study was performed to investigate the existence of an association between CFI genetic polymorphisms and Vogt-Koyanagi-Harada (VKH) syndrome. METHODS: A total of 100 patients diagnosed with VKH syndrome and 300 healthy controls were recruited for the study. Two milliliters of peripheral blood were collected in a sterile anticoagulative tube. CFI-rs7356506 polymorphisms were genotyped using Sequenom MassARRAY technology. Allele and genotype frequencies were compared between patients and controls using a X(2) test. The analyses were stratified for recurrent status, complicated cataract status, and steroid-sensitive status. RESULTS: No significant association was found between CFI-rs7356506 polymorphisms and VKH syndrome. However, patients with recurrent VKH syndrome had lower frequencies of the G allele and GG homozygosity in CFI-rs7356506 when compared to the controls (p=0.016, odds ratio [OR]=0.429, 95% confidence interval [CI]=0.212-0.871; p=0.014, OR=0.364, 95% CI=0.158-0.837, respectively). Furthermore, there were significant decreases in the frequencies of the G allele and GG homozygosity in CFI-rs7356506 in patients with VKH syndrome with complicated cataract compared to the controls (p<0.001, OR=0.357, 95% CI=0.197-0.648; p<0.001, OR=0.273, 95% CI=0.135-0.551, respectively). Nevertheless, no significant association with patients with VKH syndrome in steroid-sensitive statuses was detected for CFI-rs7356506 polymorphisms. CONCLUSIONS: Our results indicate that CFI polymorphisms are not significantly associated with VKH syndrome; nevertheless, we identified a trend for the association of CFI-7356506 with VKH syndrome that depends on the recurrent status and the complicated cataract status but not on the steroid-sensitive status.	[ "CFI", "-", "rs7356506", "polymorphisms", "associated", "with", "Vogt", "-", "Koyanagi", "-", "Harada", "syndrome", ".", "PURPOSE", ":", "Complement", "factor", "I", "(", "CFI", ")", "plays", "an", "important", "role", "in", "complement", "activation", "pathways", "and", "is", "known", "to", "affect", "the", "development", "of", "uveitis", ".", "The", "present", "study", "was", "performed", "to", "investigate", "the", "existence", "of", "an", "association", "between", "CFI", "genetic", "polymorphisms", "and", "Vogt", "-", "Koyanagi", "-", "Harada", "(", "VKH", ")", "syndrome", ".", "METHODS", ":", "A", "total", "of", "100", "patients", "diagnosed", "with", "VKH", "syndrome", "and", "300", "healthy", "controls", "were", "recruited", "for", "the", "study", ".", "Two", "milliliters", "of", "peripheral", "blood", "were", "collected", "in", "a", "sterile", "anticoagulative", "tube", ".", "CFI", "-", "rs7356506", "polymorphisms", "were", "genotyped", "using", "Sequenom", "MassARRAY", "technology", ".", "Allele", "and", "genotype", "frequencies", "were", "compared", "between", "patients", "and", "controls", "using", "a", "X", "(", "2", ")", "test", ".", "The", "analyses", "were", "stratified", "for", "recurrent", "status", ",", "complicated", "cataract", "status", ",", "and", "steroid", "-", "sensitive", "status", ".", "RESULTS", ":", "No", "significant", "association", "was", "found", "between", "CFI", "-", "rs7356506", "polymorphisms", "and", "VKH", "syndrome", ".", "However", ",", "patients", "with", "recurrent", "VKH", "syndrome", "had", "lower", "frequencies", "of", "the", "G", "allele", "and", "GG", "homozygosity", "in", "CFI", "-", "rs7356506", "when", "compared", "to", "the", "controls", "(", "p=0", ".", "016", ",", "odds", "ratio", "[", "OR", "]", "=0", ".", "429", ",", "95", "%", "confidence", "interval", "[", "CI", "]", "=0", ".", "212", "-", "0", ".", "871", ";", "p=0", ".", "014", ",", "OR=0", ".", "364", ",", "95", "%", "CI=0", ".", "158", "-", "0", ".", "837", ",", "respectively", ")", ".", "Furthermore", ",", "there", "were", "significant", "decreases", "in", "the", "frequencies", "of", "the", "G", "allele", "and", "GG", "homozygosity", "in", "CFI", "-", "rs7356506", "in", "patients", "with", "VKH", "syndrome", "with", "complicated", "cataract", "compared", "to", "the", "controls", "(", "p", "<", "0", ".", "001", ",", "OR=0", ".", "357", ",", "95", "%", "CI=0", ".", "197", "-", "0", ".", "648", ";", "p", "<", "0", ".", "001", ",", "OR=0", ".", "273", ",", "95", "%", "CI=0", ".", "135", "-", "0", ".", "551", ",", "respectively", ")", ".", "Nevertheless", ",", "no", "significant", "association", "with", "patients", "with", "VKH", "syndrome", "in", "steroid", "-", "sensitive", "statuses", "was", "detected", "for", "CFI", "-", "rs7356506", "polymorphisms", ".", "CONCLUSIONS", ":", "Our", "results", "indicate", "that", "CFI", "polymorphisms", "are", "not", "significantly", "associated", "with", "VKH", "syndrome", ";", "nevertheless", ",", "we", "identified", "a", "trend", "for", "the", "association", "of", "CFI", "-", "7356506", "with", "VKH", "syndrome", "that", "depends", "on", "the", "recurrent", "status", "and", "the", "complicated", "cataract", "status", "but", "not", "on", "the", "steroid", "-", "sensitive", "status", "." ]	[ "1", "0", "5", "0", "0", "0", "2", "2", "2", "2", "2", "2", "0", "0", "0", "1", "1", "1", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "2", "2", "2", "2", "2", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", 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16840830	Two novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1. Multiple endocrine neoplasia type 1 (MEN1) is characterized by parathyroid, enteropancreatic endocrine and pituitary adenomas as well as germline mutation of the MEN1 gene. We describe 2 families with MEN1 with novel mutations in the MEN1 gene. One family was of Turkish origin, and the index patient had primary hyperparathyroidism (PHPT) plus a prolactinoma; three relatives had PHPT only. The index patient in the second family was a 46-yr-old woman of Chinese origin living in Taiwan. This patient presented with a complaint of epigastric pain and watery diarrhea over the past 3 months, and had undergone subtotal parathyroidectomy and enucleation of pancreatic islet cell tumor about 10 yr before. There was also a prolactinoma. Sequence analysis of the MEN1 gene from leukocyte genomic DNA revealed heterozygous mutations in both probands. The Turkish patient and her affected relatives all had a heterozygous A to G transition at codon 557 (AAG-->GAG) of exon 10 of MEN1 that results in a replacement of lysine by glutamic acid. The Chinese index patient and one of her siblings had a heterozygous mutation at codon 418 of exon 9 (GAC-->TAT) that results in a substitution of aspartic acid by tyrosine. In conclusion, we have identified 2 novel missense mutations in the MEN1 gene.	[ "Two", "novel", "mutations", "in", "the", "MEN1", "gene", "in", "subjects", "with", "multiple", "endocrine", "neoplasia", "-", "1", ".", "Multiple", "endocrine", "neoplasia", "type", "1", "(", "MEN1", ")", "is", "characterized", "by", "parathyroid", ",", "enteropancreatic", "endocrine", "and", "pituitary", "adenomas", "as", "well", "as", "germline", "mutation", "of", "the", "MEN1", "gene", ".", "We", "describe", "2", "families", "with", "MEN1", "with", "novel", "mutations", "in", "the", "MEN1", "gene", ".", "One", "family", "was", "of", "Turkish", "origin", ",", "and", "the", "index", "patient", "had", "primary", "hyperparathyroidism", "(", "PHPT", ")", "plus", "a", "prolactinoma", ";", "three", "relatives", "had", "PHPT", "only", ".", "The", "index", "patient", "in", "the", "second", "family", "was", "a", "46", "-", "yr", "-", "old", "woman", "of", "Chinese", "origin", "living", "in", "Taiwan", ".", "This", "patient", "presented", "with", "a", "complaint", "of", "epigastric", "pain", "and", "watery", "diarrhea", "over", "the", "past", "3", "months", ",", "and", "had", "undergone", "subtotal", "parathyroidectomy", "and", "enucleation", "of", "pancreatic", "islet", "cell", "tumor", "about", "10", "yr", "before", ".", "There", "was", "also", "a", "prolactinoma", ".", "Sequence", "analysis", "of", "the", "MEN1", "gene", "from", "leukocyte", "genomic", "DNA", "revealed", "heterozygous", "mutations", "in", "both", "probands", ".", "The", "Turkish", "patient", "and", "her", "affected", "relatives", "all", "had", "a", "heterozygous", "A", "to", "G", "transition", "at", "codon", "557", "(", "AAG", "-", "-", ">", "GAG", ")", "of", "exon", "10", "of", "MEN1", "that", "results", "in", "a", "replacement", "of", "lysine", "by", "glutamic", "acid", ".", "The", "Chinese", "index", "patient", "and", "one", "of", "her", "siblings", "had", "a", "heterozygous", "mutation", "at", "codon", "418", "of", "exon", "9", "(", "GAC", "-", "-", ">", "TAT", ")", "that", "results", "in", "a", "substitution", "of", "aspartic", "acid", "by", "tyrosine", ".", "In", "conclusion", ",", "we", "have", "identified", "2", "novel", "missense", "mutations", "in", "the", "MEN1", "gene", "." ]	[ "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "2", "2", "2", "2", "2", "0", "2", "2", "2", "2", "2", "0", "2", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "2", "2", "0", "2", "0", "0", "0", "2", "0", "0", "0", "0", "2", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "2", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "0", "0", "0", "0", "4", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0" ]
15668505	Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers. The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population.	[ "Common", "BRCA2", "variants", "and", "modification", "of", "breast", "and", "ovarian", "cancer", "risk", "in", "BRCA1", "mutation", "carriers", ".", "The", "HH", "genotype", "of", "the", "nonconservative", "amino", "acid", "substitution", "polymorphism", "N372H", "in", "the", "BRCA2", "gene", "was", "reported", "to", "be", "associated", "with", "a", "1", ".", "3", "-", "to", "1", ".", "5", "-", "fold", "increase", "in", "risk", "of", "both", "breast", "and", "ovarian", "cancer", ".", "As", "these", "studies", "concerned", "sporadic", "cancer", "cases", ",", "we", "investigated", "whether", "N372H", "and", "another", "common", "variant", "located", "in", "the", "5", "'", "-", "untranslated", "region", "(", "203G", ">", "A", ")", "of", "the", "BRCA2", "gene", "modify", "breast", "or", "ovarian", "cancer", "risk", "in", "BRCA1", "mutation", "carriers", ".", "The", "study", "includes", "778", "women", "carrying", "a", "BRCA1", "germ", "-", "line", "mutation", "belonging", "to", "403", "families", ".", "The", "two", "BRCA2", "variants", "were", "analyzed", "by", "the", "TaqMan", "allelic", "discrimination", "technique", ".", "Genotypes", "were", "analyzed", "by", "disease", "-", "free", "survival", "analysis", "using", "a", "Cox", "proportional", "hazards", "model", ".", "We", "found", "no", "evidence", "of", "a", "significant", "modification", "of", "breast", "cancer", "penetrance", "in", "BRCA1", "mutation", "carriers", "by", "either", "polymorphism", ".", "In", "respect", "of", "ovarian", "cancer", "risk", ",", "we", "also", "saw", "no", "effect", "with", "the", "N372H", "variant", "but", "we", "did", "observe", "a", "borderline", "association", "with", "the", "5", "'", "-", "untranslated", "region", "203A", "allele", "(", "hazard", "ratio", ",", "1", ".", "43", ";", "CI", ",", "1", ".", "01", "-", "2", ".", "00", ")", ".", "In", "contrast", "to", "the", "result", "of", "Healey", "et", "al", ".", "on", "newborn", "females", "and", "adult", "female", "controls", ",", "we", "found", "no", "departure", "from", "Hardy", "-", "Weinberg", "equilibrium", "in", "the", "distribution", "of", "N372H", "alleles", "for", "our", "female", "BRCA1", "carriers", ".", "We", "conclude", "that", "if", "these", "single", "-", "nucleotide", "polymorphisms", "do", "modify", "the", "risk", "of", "cancer", "in", "BRCA1", "mutation", "carriers", ",", "their", "effects", "are", "not", "significantly", "larger", "than", "that", "of", "N372H", "previously", "observed", "in", "the", "general", "population", "." ]	[ "0", "1", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "2", "2", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "5", "5", "0", "0", "0", "1", "0", "0", "2", "2", "2", "2", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "4", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "5", "0", "0", "0", "0", "0", "0", "0" ]
26847345	Transgelin increases metastatic potential of colorectal cancer cells in vivo and alters expression of genes involved in cell motility. BACKGROUND: Transgelin is an actin-binding protein that promotes motility in normal cells. Although the role of transgelin in cancer is controversial, a number of studies have shown that elevated levels correlate with aggressive tumor behavior, advanced stage, and poor prognosis. Here we sought to determine the role of transgelin more directly by determining whether experimental manipulation of transgelin levels in colorectal cancer (CRC) cells led to changes in metastatic potential in vivo. METHODS: Isogenic CRC cell lines that differ in transgelin expression were characterized using in vitro assays of growth and invasiveness and a mouse tail vein assay of experimental metastasis. Downstream effects of transgelin overexpression were investigated by gene expression profiling and quantitative PCR. RESULTS: Stable overexpression of transgelin in RKO cells, which have low endogenous levels, led to increased invasiveness, growth at low density, and growth in soft agar. Overexpression also led to an increase in the number and size of lung metastases in the mouse tail vein injection model. Similarly, attenuation of transgelin expression in HCT116 cells, which have high endogenous levels, decreased metastases in the same model. Investigation of mRNA expression patterns showed that transgelin overexpression altered the levels of approximately 250 other transcripts, with over-representation of genes that affect function of actin or other cytoskeletal proteins. Changes included increases in HOOK1, SDCCAG8, ENAH/Mena, and TNS1 and decreases in EMB, BCL11B, and PTPRD. CONCLUSIONS: Increases or decreases in transgelin levels have reciprocal effects on tumor cell behavior, with higher expression promoting metastasis. Chronic overexpression influences steady-state levels of mRNAs for metastasis-related genes.	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15818664	Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5'-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate. OBJECTIVE: Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis. METHODS: ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes. RESULTS: Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5'-untranslated region (5'-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen. CONCLUSION: A subset of sporadic chondrocalcinosis appears to be heritable via a -4-bp G-to-A ANKH 5'-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.	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"patients", "with", "severe", "sporadic", "chondrocalcinosis", "or", "pseudogout", "and", "in", "ethnically", "matched", "healthy", "controls", ".", "The", "effects", "of", "specific", "variants", "on", "expression", "of", "common", "markers", "were", "evaluated", "by", "in", "vitro", "transcription", "/", "translation", ".", "The", "function", "of", "these", "variants", "was", "studied", "in", "transfected", "human", "immortalized", "CH", "-", "8", "articular", "chondrocytes", ".", "RESULTS", ":", "Sporadic", "chondrocalcinosis", "was", "associated", "with", "a", "G", "-", "to", "-", "A", "transition", "in", "the", "ANKH", "5", "'", "-", "untranslated", "region", "(", "5", "'", "-", "UTR", ")", "at", "4", "bp", "upstream", "of", "the", "start", "codon", "(", "in", "homozygotes", "of", "the", "minor", "allele", ",", "genotype", "relative", "risk", "6", ".", "0", ",", "P", "=", "0", ".", "0006", ";", "overall", "genotype", "association", "P", "=", "0", ".", "02", ")", ".", "This", "-", 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".", "CONCLUSION", ":", "A", "subset", "of", "sporadic", "chondrocalcinosis", "appears", "to", "be", "heritable", "via", "a", "-", "4", "-", "bp", "G", "-", "to", "-", "A", "ANKH", "5", "'", "-", "UTR", "transition", "that", "up", "-", "regulates", "expression", "of", "ANKH", "and", "extracellular", "PPi", "in", "chondrocyte", "cells", ".", "Distinct", "ANKH", "mutations", "associated", "with", "heritable", "chondrocalcinosis", "may", "promote", "disease", "by", "divergent", "effects", "on", "extracellular", "PPi", "and", "chondrocyte", "hypertrophy", ",", "which", "is", "likely", "to", "mediate", "differences", "in", "the", "clinical", "phenotypes", "and", "severity", "of", "the", "disease", "." ]	[ "0", "0", "2", "2", "0", "0", "5", "5", "5", "5", "5", "5", "5", "5", "5", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "3", "3", "0", "0", "0", "0", "0", "0", "1", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", 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22729903	Contribution of STAT4 gene single-nucleotide polymorphism to systemic lupus erythematosus in the Polish population. The STAT4 has been found to be a susceptible gene in the development of systemic lupus erythematosus (SLE) in various populations. There are evident population differences in the context of clinical manifestations of SLE, therefore we investigated the prevalence of the STAT4 G > C (rs7582694) polymorphism in patients with SLE (n = 253) and controls (n = 521) in a sample of the Polish population. We found that patients with the STAT4 C/G and CC genotypes exhibited a 1.583-fold increased risk of SLE incidence (95 % CI = 1.168-2.145, p = 0.003), with OR for the C/C versus C/G and G/G genotypes was 1.967 (95 % CI = 1.152-3.358, p = 0.0119). The OR for the STAT4 C allele frequency showed a 1.539-fold increased risk of SLE (95 % CI = 1.209-1.959, p = 0.0004). We also observed an increased frequency of STAT4 C/C and C/G genotypes in SLE patients with renal symptoms OR = 2.259 (1.365-3.738, p = 0.0014), (p (corr) = 0.0238) and in SLE patients with neurologic manifestations OR = 2.867 (1.467-5.604, p = 0.0016), (p (corr) = 0.0272). Moreover, we found a contribution of STAT4 C/C and C/G genotypes to the presence of the anti-snRNP Ab OR = 3.237 (1.667-6.288, p = 0.0003), (p (corr) = 0.0051) and the presence of the anti-Scl-70 Ab OR = 2.665 (1.380-5.147, p = 0.0028), (p (corr) = 0.0476). Our studies confirmed an association of the STAT4 C (rs7582694) variant with the development of SLE and occurrence of some clinical manifestations of the disease.	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"incidence", "(", "95", "%", "CI", "=", "1", ".", "168", "-", "2", ".", "145", ",", "p", "=", "0", ".", "003", ")", ",", "with", "OR", "for", "the", "C", "/", "C", "versus", "C", "/", "G", "and", "G", "/", "G", "genotypes", "was", "1", ".", "967", "(", "95", "%", "CI", "=", "1", ".", "152", "-", "3", ".", "358", ",", "p", "=", "0", ".", "0119", ")", ".", "The", "OR", "for", "the", "STAT4", "C", "allele", "frequency", "showed", "a", "1", ".", "539", "-", "fold", "increased", "risk", "of", "SLE", "(", "95", "%", "CI", "=", "1", ".", "209", "-", "1", ".", "959", ",", "p", "=", "0", ".", "0004", ")", ".", "We", "also", "observed", "an", "increased", "frequency", "of", "STAT4", "C", "/", "C", "and", "C", "/", "G", "genotypes", "in", "SLE", "patients", "with", "renal", "symptoms", "OR", "=", "2", ".", "259", "(", "1", ".", "365", "-", "3", ".", "738", ",", "p", "=", "0", ".", "0014", ")", ",", "(", "p", "(", "corr", ")", "=", "0", ".", "0238", ")", "and", "in", "SLE", "patients", "with", "neurologic", "manifestations", "OR", "=", "2", ".", "867", "(", "1", ".", "467", "-", "5", ".", "604", ",", "p", "=", "0", ".", "0016", ")", ",", "(", "p", "(", "corr", ")", "=", "0", ".", "0272", ")", ".", "Moreover", ",", "we", "found", "a", "contribution", "of", "STAT4", "C", "/", "C", "and", "C", "/", "G", "genotypes", "to", "the", "presence", "of", "the", "anti", "-", "snRNP", "Ab", "OR", "=", "3", ".", "237", "(", "1", ".", "667", "-", "6", ".", "288", ",", "p", "=", "0", ".", "0003", ")", ",", "(", "p", "(", "corr", ")", "=", "0", ".", "0051", ")", "and", "the", "presence", "of", "the", "anti", "-", "Scl", "-", "70", "Ab", "OR", "=", "2", ".", "665", "(", "1", ".", "380", "-", "5", ".", "147", ",", "p", "=", "0", ".", "0028", ")", ",", "(", "p", "(", "corr", ")", "=", "0", ".", "0476", ")", ".", "Our", "studies", "confirmed", "an", "association", "of", "the", "STAT4", "C", "(", "rs7582694", ")", "variant", "with", "the", "development", "of", "SLE", "and", "occurrence", "of", 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25277705	Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection. BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study. METHODS: A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-b (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection. RESULTS AND DISCUSSION: RSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-b). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1b, IL-4, IL-5, IL-6, IL-12(p40), IFN-g, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1b, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-g. Silencing of retinoic acid-inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment. CONCLUSIONS: RSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection.	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15130900	Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide. OBJECTIVE: To assess and characterise the risk of bladder cancer, and its relation to cyclophosphamide, in patients with Wegener's granulomatosis. METHODS: In the population based, nationwide Swedish Inpatient Register a cohort of 1065 patients with Wegener's granulomatosis, 1969-95, was identified. Through linkage with the Swedish Cancer Register, all subjects in this cohort diagnosed with bladder cancer were identified. Nested within the cohort, a matched case-control study was performed to estimate the association between cyclophosphamide and bladder cancer using odds ratios (ORs) as relative risk. In the cohort the cumulative risk of bladder cancer after Wegener's granulomatosis, and the relative prevalence of a history of bladder cancer at the time of diagnosis of Wegener's granulomatosis, were also estimated. RESULTS: The median cumulative doses of cyclophosphamide among cases (n = 11) and controls (n = 25) were 113 g and 25 g, respectively. The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide (OR = 2.0, 95% confidence interval (CI) 0.8 to 4.9). Treatment duration longer than 1 year was associated with an eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). The absolute risk for bladder cancer in the cohort reached 10% 16 years after diagnosis of Wegener's granulomatosis, and a history of bladder cancer was (non-significantly) twice as common as expected at the time of diagnosis of Wegener's granulomatosis. CONCLUSION: The results indicate a dose-response relationship between cyclophosphamide and the risk of bladder cancer, high cumulative risks in the entire cohort, and also the possibility of risk factors operating even before Wegener's granulomatosis.	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18257781	Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease. BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians. MATERIALS AND METHODS: We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing. RESULTS: We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls. CONCLUSIONS: We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation.	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20534762	Two novel mutations of the TSH-beta subunit gene underlying congenital central hypothyroidism undetectable in neonatal TSH screening. CONTEXT: Patients with TSH-beta subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening. OBJECTIVE: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-beta subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia. RESULTS: Patient 1 had a homozygous G to A nucleotide change at the 5' donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-beta subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution. CONCLUSIONS: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology.	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15485686

A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia. OBJECTIVE: Congenital long QT syndrome (LQTS) with in utero onset of the rhythm disturbances is associated with a poor prognosis. In this study we investigated a newborn patient with fetal bradycardia, 2:1 atrioventricular block and ventricular tachycardia soon after birth. METHODS: Mutational analysis and DNA sequencing were conducted in a newborn. The 2:1 atrioventricular block improved to 1:1 conduction only after intravenous lidocaine infusion or a high dose of mexiletine, which also controlled the ventricular tachycardia. RESULTS: A novel, spontaneous LQTS-3 mutation was identified in the transmembrane segment 6 of domain IV of the Na(v)1.5 cardiac sodium channel, with a G-->A substitution at codon 1763, which changed a valine (GTG) to a methionine (ATG). The proband was heterozygous but the mutation was absent in the parents and the sister. Expression of this mutant channel in tsA201 mammalian cells by site-directed mutagenesis revealed a persistent tetrodotoxin-sensitive but lidocaine-resistant current that was associated with a positive shift of the steady-state inactivation curve, steeper activation curve and faster recovery from inactivation. We also found a similar electrophysiological profile for the neighboring V1764M mutant. But, the other neighboring I1762A mutant had no persistent current and was still associated with a positive shift of inactivation. CONCLUSIONS: These findings suggest that the Na(v)1.5/V1763M channel dysfunction and possible neighboring mutants contribute to a persistent inward current due to altered inactivation kinetics and clinically congenital LQTS with perinatal onset of arrhythmias that responded to lidocaine and mexiletine.

[ "A", "novel", "SCN5A", "mutation", "manifests", "as", "a", "malignant", "form", "of", "long", "QT", "syndrome", "with", "perinatal", "onset", "of", "tachycardia", "/", "bradycardia", ".", "OBJECTIVE", ":", "Congenital", "long", "QT", "syndrome", "(", "LQTS", ")", "with", "in", "utero", "onset", "of", "the", "rhythm", "disturbances", "is", "associated", "with", "a", "poor", "prognosis", ".", "In", "this", "study", "we", "investigated", "a", "newborn", "patient", "with", "fetal", "bradycardia", ",", "2:1", "atrioventricular", "block", "and", "ventricular", "tachycardia", "soon", "after", "birth", ".", "METHODS", ":", "Mutational", "analysis", "and", "DNA", "sequencing", "were", "conducted", "in", "a", "newborn", ".", "The", "2:1", "atrioventricular", "block", "improved", "to", "1:1", "conduction", "only", "after", "intravenous", "lidocaine", "infusion", "or", "a", "high", "dose", "of", "mexiletine", ",", "which", "also", "controlled", "the", "ventricular", "tachycardia", ".", "RESULTS", ":", "A", "novel", ",", "spontaneous", "LQTS", "-", "3", "mutation", "was", "identified", "in", "the", "transmembrane", "segment", "6", "of", "domain", "IV", "of", "the", "Na", "(", "v", ")", "1", ".", "5", "cardiac", "sodium", "channel", ",", "with", "a", "G", "-", "-", ">", "A", "substitution", "at", "codon", "1763", ",", "which", "changed", "a", "valine", "(", "GTG", ")", "to", "a", "methionine", "(", "ATG", ")", ".", "The", "proband", "was", "heterozygous", "but", "the", "mutation", "was", "absent", "in", "the", "parents", "and", "the", "sister", ".", "Expression", "of", "this", "mutant", "channel", "in", "tsA201", "mammalian", "cells", "by", "site", "-", "directed", "mutagenesis", "revealed", "a", "persistent", "tetrodotoxin", "-", "sensitive", "but", "lidocaine", "-", "resistant", "current", "that", "was", "associated", "with", "a", "positive", "shift", "of", "the", "steady", "-", "state", "inactivation", "curve", ",", "steeper", "activation", "curve", "and", "faster", "recovery", "from", "inactivation", ".", "We", "also", "found", "a", "similar", "electrophysiological", "profile", "for", "the", "neighboring", "V1764M", "mutant", ".", "But", ",", "the", "other", "neighboring", "I1762A", "mutant", "had", "no", "persistent", "current", "and", "was", "still", "associated", "with", "a", "positive", "shift", "of", "inactivation", ".", "CONCLUSIONS", ":", "These", "findings", "suggest", "that", "the", "Na", "(", "v", ")", "1", ".", "5", "/", "V1763M", "channel", "dysfunction", "and", "possible", "neighboring", "mutants", "contribute", "to", "a", "persistent", "inward", "current", "due", "to", "altered", "inactivation", "kinetics", "and", "clinically", "congenital", "LQTS", "with", "perinatal", "onset", "of", "arrhythmias", "that", "responded", "to", "lidocaine", "and", "mexiletine", "." ]

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16046395

Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. As a primary target for opioid drugs and peptides, the mu opioid receptor (OPRM1) plays a key role in pain perception and addiction. Genetic variants of OPRM1 have been implicated in predisposition to drug addiction, in particular the single nucleotide polymorphism A118G, leading to an N40D substitution, with an allele frequency of 10-32%, and uncertain functions. We have measured allele-specific mRNA expression of OPRM1 in human autopsy brain tissues, using A118G as a marker. In 8 heterozygous samples measured, the A118 mRNA allele was 1.5-2.5-fold more abundant than the G118 allele. Transfection into Chinese hamster ovary cells of a cDNA representing only the coding region of OPRM1, carrying adenosine, guanosine, cytidine, and thymidine in position 118, resulted in 1.5-fold lower mRNA levels only for OPRM1-G118, and more than 10-fold lower OPRM1 protein levels, measured by Western blotting and receptor binding assay. After transfection and inhibition of transcription with actinomycin D, analysis of mRNA turnover failed to reveal differences in mRNA stability between A118 and G118 alleles, indicating a defect in transcription or mRNA maturation. These results indicate that OPRM1-G118 is a functional variant with deleterious effects on both mRNA and protein yield. Clarifying the functional relevance of polymorphisms associated with susceptibility to a complex disorder such as drug addiction provides a foundation for clinical association studies.

[ "Allelic", "expression", "imbalance", "of", "human", "mu", "opioid", "receptor", "(", "OPRM1", ")", "caused", "by", "variant", "A118G", ".", "As", "a", "primary", "target", "for", "opioid", "drugs", "and", "peptides", ",", "the", "mu", "opioid", "receptor", "(", "OPRM1", ")", "plays", "a", "key", "role", "in", "pain", "perception", "and", "addiction", ".", "Genetic", "variants", "of", "OPRM1", "have", "been", "implicated", "in", "predisposition", "to", "drug", "addiction", ",", "in", "particular", "the", "single", "nucleotide", "polymorphism", "A118G", ",", "leading", "to", "an", "N40D", "substitution", ",", "with", "an", "allele", "frequency", "of", "10", "-", "32", "%", ",", "and", "uncertain", "functions", ".", "We", "have", "measured", "allele", "-", "specific", "mRNA", "expression", "of", "OPRM1", "in", "human", "autopsy", "brain", "tissues", ",", "using", "A118G", "as", "a", "marker", ".", "In", "8", "heterozygous", "samples", "measured", ",", "the", "A118", "mRNA", "allele", "was", "1", ".", "5", "-", "2", ".", "5", "-", "fold", "more", "abundant", "than", "the", "G118", "allele", ".", "Transfection", "into", "Chinese", "hamster", "ovary", "cells", "of", "a", "cDNA", "representing", "only", "the", "coding", "region", "of", "OPRM1", ",", "carrying", "adenosine", ",", "guanosine", ",", "cytidine", ",", "and", "thymidine", "in", "position", "118", ",", "resulted", "in", "1", ".", "5", "-", "fold", "lower", "mRNA", "levels", "only", "for", "OPRM1", "-", "G118", ",", "and", "more", "than", "10", "-", "fold", "lower", "OPRM1", "protein", "levels", ",", "measured", "by", "Western", "blotting", "and", "receptor", "binding", "assay", ".", "After", "transfection", "and", "inhibition", "of", "transcription", "with", "actinomycin", "D", ",", "analysis", "of", "mRNA", "turnover", "failed", "to", "reveal", "differences", "in", "mRNA", "stability", "between", "A118", "and", "G118", "alleles", ",", "indicating", "a", "defect", "in", "transcription", "or", "mRNA", "maturation", ".", "These", "results", "indicate", "that", "OPRM1", "-", "G118", "is", "a", "functional", "variant", "with", "deleterious", "effects", "on", "both", "mRNA", "and", "protein", "yield", ".", "Clarifying", "the", "functional", "relevance", "of", "polymorphisms", "associated", "with", "susceptibility", "to", "a", "complex", "disorder", "such", "as", "drug", "addiction", "provides", "a", "foundation", "for", "clinical", "association", "studies", "." ]

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18457324

Genetic polymorphisms in the carbonyl reductase 3 gene CBR3 and the NAD(P)H:quinone oxidoreductase 1 gene NQO1 in patients who developed anthracycline-related congestive heart failure after childhood cancer. BACKGROUND: Exposure to anthracyclines as part of cancer therapy has been associated with the development of congestive heart failure (CHF). The potential role of genetic risk factors in anthracycline-related CHF remains to be defined. Thus, in this study, the authors examined whether common polymorphisms in candidate genes involved in the pharmacodynamics of anthracyclines (in particular, the nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 gene NQO1 and the carbonyl reductase 3 gene CBR3) had an impact on the risk of anthracycline-related CHF. METHODS: A nested case-control study was conducted within a cohort of 1979 patients enrolled in the Childhood Cancer Survivor Study who received treatment with anthracyclines and had available DNA. Thirty patients with CHF (cases) and 115 matched controls were genotyped for polymorphisms in NQO1 (NQO1*2) and CBR3 (the CBR3 valine [V] to methionine [M] substitution at position 244 [V244M]). Enzyme activity assays with recombinant CBR3 isoforms (CBR3 V244 and CBR3 M244) and the anthracycline substrate doxorubicin were used to investigate the functional impact of the CBR3 V244M polymorphism. RESULTS: Multivariate analyses adjusted for sex and primary disease recurrence were used to test for associations between the candidate genetic polymorphisms (NQO1*2 and CBR3 V244M) and the risk of CHF. Analyses indicated no association between the NQO1*2 polymorphism and the risk of anthracycline-related CHF (odds ratio [OR], 1.04; P=.97). There was a trend toward an association between the CBR3 V244M polymorphism and the risk of CHF (OR, 8.16; P=.056 for G/G vs A/A; OR, 5.44; P=.092 for G/A vs A/A). In line, recombinant CBR3 V244 (G allele) synthesized 2.6-fold more cardiotoxic doxorubicinol per unit of time than CBR3 M244 (A allele; CBR3 V244 [8.26+/-3.57 nmol/hour.mg] vs CBR3 M244 [3.22+/-0.67 nmol/hour.mg]; P=.01). CONCLUSIONS: The functional CBR3 V244M polymorphism may have an impact on the risk of anthracycline-related CHF among childhood cancer survivors by modulating the intracardiac formation of cardiotoxic anthracycline alcohol metabolites. Larger confirmatory case-control studies are warranted.

[ "Genetic", "polymorphisms", "in", "the", "carbonyl", "reductase", "3", "gene", "CBR3", "and", "the", "NAD", "(", "P", ")", "H", ":", "quinone", "oxidoreductase", "1", "gene", "NQO1", "in", "patients", "who", "developed", "anthracycline", "-", "related", "congestive", "heart", "failure", "after", "childhood", "cancer", ".", "BACKGROUND", ":", "Exposure", "to", "anthracyclines", "as", "part", "of", "cancer", "therapy", "has", "been", "associated", "with", "the", "development", "of", "congestive", "heart", "failure", "(", "CHF", ")", ".", "The", "potential", "role", "of", "genetic", "risk", "factors", "in", "anthracycline", "-", "related", "CHF", "remains", "to", "be", "defined", ".", "Thus", ",", "in", "this", "study", ",", "the", "authors", "examined", "whether", "common", "polymorphisms", "in", "candidate", "genes", "involved", "in", "the", "pharmacodynamics", "of", "anthracyclines", "(", "in", "particular", ",", "the", "nicotinamide", "adenine", "dinucleotide", "phosphate", ":", "quinone", "oxidoreductase", "1", "gene", "NQO1", "and", "the", "carbonyl", "reductase", "3", "gene", "CBR3", ")", "had", "an", "impact", "on", "the", "risk", "of", "anthracycline", "-", "related", "CHF", ".", "METHODS", ":", "A", "nested", "case", "-", "control", "study", "was", "conducted", "within", "a", "cohort", "of", "1979", "patients", "enrolled", "in", "the", "Childhood", "Cancer", "Survivor", "Study", "who", "received", "treatment", "with", "anthracyclines", "and", "had", "available", "DNA", ".", "Thirty", "patients", "with", "CHF", "(", "cases", ")", "and", "115", "matched", "controls", "were", "genotyped", "for", "polymorphisms", "in", "NQO1", "(", "NQO1", "*", "2", ")", "and", "CBR3", "(", "the", "CBR3", "valine", "[", "V", "]", "to", "methionine", "[", "M", "]", "substitution", "at", "position", "244", "[", "V244M", "]", ")", ".", "Enzyme", "activity", "assays", "with", "recombinant", "CBR3", "isoforms", "(", "CBR3", "V244", "and", "CBR3", "M244", ")", "and", "the", "anthracycline", "substrate", "doxorubicin", "were", "used", "to", "investigate", "the", "functional", "impact", "of", "the", "CBR3", "V244M", "polymorphism", ".", "RESULTS", ":", "Multivariate", "analyses", "adjusted", "for", "sex", "and", "primary", "disease", "recurrence", "were", "used", "to", "test", "for", "associations", "between", "the", "candidate", "genetic", "polymorphisms", "(", "NQO1", "*", "2", "and", "CBR3", "V244M", ")", "and", "the", "risk", "of", "CHF", ".", "Analyses", "indicated", "no", "association", "between", "the", "NQO1", "*", "2", "polymorphism", "and", "the", "risk", "of", "anthracycline", "-", "related", "CHF", "(", "odds", "ratio", "[", "OR", "]", ",", "1", ".", "04", ";", "P=", ".", "97", ")", ".", "There", "was", "a", "trend", "toward", "an", "association", "between", "the", "CBR3", "V244M", "polymorphism", "and", "the", "risk", "of", "CHF", "(", "OR", ",", "8", ".", "16", ";", "P=", ".", "056", "for", "G", "/", "G", "vs", "A", "/", "A", ";", "OR", ",", "5", ".", "44", ";", "P=", ".", "092", "for", "G", "/", "A", "vs", "A", "/", "A", ")", ".", "In", "line", ",", "recombinant", "CBR3", "V244", "(", "G", "allele", ")", "synthesized", "2", ".", "6", "-", "fold", "more", "cardiotoxic", "doxorubicinol", "per", "unit", "of", "time", "than", "CBR3", "M244", "(", "A", "allele", ";", "CBR3", "V244", "[", "8", ".", "26", "+", "/", "-", "3", ".", "57", "nmol", "/", "hour", ".", "mg", "]", "vs", "CBR3", "M244", "[", "3", ".", "22", "+", "/", "-", "0", ".", "67", "nmol", "/", "hour", ".", "mg", "]", ";", "P=", ".", "01", ")", ".", "CONCLUSIONS", ":", "The", "functional", "CBR3", "V244M", "polymorphism", "may", "have", "an", "impact", "on", "the", "risk", "of", "anthracycline", "-", "related", "CHF", "among", "childhood", "cancer", "survivors", "by", "modulating", "the", "intracardiac", "formation", "of", "cardiotoxic", "anthracycline", "alcohol", "metabolites", ".", "Larger", "confirmatory", "case", "-", "control", "studies", "are", "warranted", "." ]

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1848636

Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers. The metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

[ "Debrisoquine", "phenotype", "and", "the", "pharmacokinetics", "and", "beta", "-", "2", "receptor", "pharmacodynamics", "of", "metoprolol", "and", "its", "enantiomers", ".", "The", "metabolism", "of", "the", "cardioselective", "beta", "-", "blocker", "metoprolol", "is", "under", "genetic", "control", "of", "the", "debrisoquine", "/", "sparteine", "type", ".", "The", "two", "metabolic", "phenotypes", ",", "extensive", "(", "EM", ")", "and", "poor", "metabolizers", "(", "PM", ")", ",", "show", "different", "stereoselective", "metabolism", ",", "resulting", "in", "apparently", "higher", "beta", "-", "1", "adrenoceptor", "antagonistic", "potency", "of", "racemic", "metoprolol", "in", "EMs", ".", "We", "investigated", "if", "the", "latter", "also", "applies", "to", "the", "beta", "-", "2", "adrenoceptor", "antagonism", "by", "metoprolol", ".", "The", "drug", "effect", "studied", "was", "the", "antagonism", "by", "metoprolol", "of", "terbutaline", "-", "induced", "hypokalemia", ".", "By", "using", "pharmacokinetic", "pharmacodynamic", "modeling", "the", "pharmacodynamics", "of", "racemic", "metoprolol", "and", "the", "active", "S", "-", "isomer", ",", "were", "quantitated", "in", "EMs", "and", "PMs", "in", "terms", "of", "IC50", "values", ",", "representing", "metoprolol", "plasma", "concentrations", "resulting", "in", "half", "-", "maximum", "receptor", "occupancy", ".", "Six", "EMs", "received", "0", ".", "5", "mg", "of", "terbutaline", "s", ".", "c", ".", "on", "two", "different", "occasions", ":", "1", ")", "1", "hr", "after", "administration", "of", "a", "placebo", "and", "2", ")", "1", "hr", "after", "150", "mg", "of", "metoprolol", "p", ".", "o", ".", "Five", "PMs", "were", "studied", "according", "to", "the", "same", "protocol", ",", "except", "for", "a", "higher", "terbutaline", "dose", "(", "0", ".", "75", "mg", ")", "on", "day", "2", ".", "Blood", "samples", "for", "the", "analysis", "of", "plasma", "potassium", ",", "terbutaline", ",", "metoprolol", "(", "racemic", ",", "R", "-", "and", "S", "-", "isomer", ")", ",", "and", "alpha", "-", "hydroxymetoprolol", "concentrations", "were", "taken", "at", "regular", "time", "intervals", ",", "during", "8", "hr", "after", "metoprolol", ".", "In", "PMs", ",", "metoprolol", "increased", "the", "terbutaline", "area", "under", "the", "plasma", "concentration", "vs", ".", "time", "curve", "(", "+", "67", "%", ")", ".", "Higher", "metoprolol", "/", "alpha", "-", "hydroxymetoprolol", "ratios", "in", "PMs", "were", "predictive", "for", "higher", "R", "-", "/", "S", "-", "isomer", "ratios", "of", "unchanged", "drug", ".", "There", "was", "a", "difference", "in", "metoprolol", "potency", "with", "higher", "racemic", "metoprolol", "IC50", "values", "in", "PMs", "(", "72", "+", "/", "-", "7", "ng", ".", "ml", "-", "1", ")", "than", "EMs", "(", "42", "+", "/", "-", "8", "ng", ".", "ml", "-", "1", ",", "P", "less", "than", ".", "001", ")", ".", "(", "ABSTRACT", "TRUNCATED", "AT", "250", "WORDS", ")" ]

[ "3", "0", "0", "0", "0", "0", "1", "1", "1", "1", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "1", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "1", "1", "1", "1", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "3", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]

19394258

The first founder DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome. Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.

[ "The", "first", "founder", "DGUOK", "mutation", "associated", "with", "hepatocerebral", "mitochondrial", "DNA", "depletion", "syndrome", ".", "Deoxyguanosine", "kinase", "(", "dGK", ")", "deficiency", "is", "a", "frequent", "cause", "of", "mitochondrial", "DNA", "depletion", "associated", "with", "a", "hepatocerebral", "phenotype", ".", "In", "this", "study", ",", "we", "describe", "a", "new", "splice", "site", "mutation", "in", "the", "DGUOK", "gene", "and", "the", "clinical", ",", "radiologic", ",", "and", "genetic", "features", "of", "these", "DGUOK", "patients", ".", "This", "new", "DGUOK", "homozygous", "mutation", "(", "c", ".", "444", "-", "62C", ">", "A", ")", "was", "identified", "in", "three", "patients", "from", "two", "North", "-", "African", "consanguineous", "families", "with", "combined", "respiratory", "chain", "deficiencies", "and", "mitochondrial", "DNA", "depletion", "in", "the", "liver", ".", "Brain", "MRIs", "are", "normal", "in", "DGUOK", "patients", "in", "the", "literature", ".", "Interestingly", ",", "we", "found", "subtentorial", "abnormal", "myelination", "and", "moderate", "hyperintensity", "in", "the", "bilateral", "pallidi", "in", "our", "patients", ".", "This", "new", "mutation", "creates", "a", "cryptic", "splice", "site", "in", "intron", "3", "(", "in", "position", "-", "62", ")", "and", "is", "predicted", "to", "result", "in", "a", "larger", "protein", "with", "an", "in", "-", "frame", "insertion", "of", "20", "amino", "acids", ".", "In", "silico", "analysis", "of", "the", "putative", "impact", "of", "the", "insertion", "shows", "serious", "clashes", "in", "protein", "conformation", ":", "this", "insertion", "disrupts", "the", "alpha5", "helix", "of", "the", "dGK", "kinase", "domain", ",", "rendering", "the", "protein", "unable", "to", "bind", "purine", "deoxyribonucleosides", ".", "In", "addition", ",", "a", "common", "haplotype", "that", "segregated", "with", "the", "disease", "in", "both", "families", "was", "detected", "by", "haplotype", "reconstruction", "with", "10", "markers", "(", "microsatellites", "and", "SNPs", ")", ",", "which", "span", "4", ".", "6", "Mb", "of", "DNA", "covering", "the", "DGUOK", "locus", ".", "In", "conclusion", ",", "we", "report", "a", "new", "DGUOK", "splice", "site", "mutation", "that", "provide", "insight", "into", "a", "critical", "protein", "domain", "(", "dGK", "kinase", "domain", ")", "and", "the", "first", "founder", "mutation", "in", "a", "North", "-", "African", "population", "." ]

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19565319

Adenosine A(2A) receptor gene (ADORA2A) variants may increase autistic symptoms and anxiety in autism spectrum disorder. Autism spectrum disorders (ASDs) are heterogeneous disorders presenting with increased rates of anxiety. The adenosine A(2A) receptor gene (ADORA2A) is associated with panic disorder and is located on chromosome 22q11.23. Its gene product, the adenosine A(2A) receptor, is strongly expressed in the caudate nucleus, which also is involved in ASD. As autistic symptoms are increased in individuals with 22q11.2 deletion syndrome, and large 22q11.2 deletions and duplications have been observed in ASD individuals, in this study, 98 individuals with ASD and 234 control individuals were genotyped for eight single-nucleotide polymorphisms in ADORA2A. Nominal association with the disorder was observed for rs2236624-CC, and phenotypic variability in ASD symptoms was influenced by rs3761422, rs5751876 and rs35320474. In addition, association of ADORA2A variants with anxiety was replicated for individuals with ASD. Findings point toward a possible mediating role of ADORA2A variants on phenotypic expression in ASD that need to be replicated in a larger sample.

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21976953

Identification of a novel FBN1 gene mutation in a Chinese family with Marfan syndrome. PURPOSE: To identify the mutation in the fibrillin-1 gene (FBN1) in a Chinese family with Marfan syndrome (MFS). METHODS: Patients and family members were given complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of six individuals in the family and 170 healthy Chinese individuals. All of the 65 coding exons and their flanking intronic boundaries of FBN1 were amplified in the proband by polymerase chain reaction and followed by direct sequencing. The mutation identified in the proband was screened in the other family members and the 170 healthy Chinese individuals by direct sequencing. Protein conservation analysis was performed in six species using an online ClustalW tool. Protein structure was modeled based on the Protein data bank and mutated in DeepView v4.0.1 to predict the functional consequences of the mutation. RESULTS: A novel heterozygous c.3703T>C change in exon 29 of FBN1 was detected in the proband, which resulted in the substitution of serine by proline at codon 1235 (p.S1235P). This mutation was also present in two family members but absent in the other, unaffected family members and the 170 healthy Chinese individuals. The mutant residue located in the calcium binding epidermal growth factor-like#15 domain is highly conserved among mammalian species and could probably induce conformation change of the domain. CONCLUSIONS: We indentified a novel p.S1235P mutation in FBN1, which is the causative mutation for MFS in this family. Our result expands the mutation spectrum of FBN1 and contributes to the study of the molecular pathogenesis of Marfan syndrome.

[ "Identification", "of", "a", "novel", "FBN1", "gene", "mutation", "in", "a", "Chinese", "family", "with", "Marfan", "syndrome", ".", "PURPOSE", ":", "To", "identify", "the", "mutation", "in", "the", "fibrillin", "-", "1", "gene", "(", "FBN1", ")", "in", "a", "Chinese", "family", "with", "Marfan", "syndrome", "(", "MFS", ")", ".", "METHODS", ":", "Patients", "and", "family", "members", "were", "given", "complete", "physical", ",", "ophthalmic", ",", "and", "cardiovascular", "examinations", ".", "Genomic", "DNA", "was", "extracted", "from", "leukocytes", "of", "venous", "blood", "of", "six", "individuals", "in", "the", "family", "and", "170", "healthy", "Chinese", "individuals", ".", "All", "of", "the", "65", "coding", "exons", "and", "their", "flanking", "intronic", "boundaries", "of", "FBN1", "were", "amplified", "in", "the", "proband", "by", "polymerase", "chain", "reaction", "and", "followed", "by", "direct", "sequencing", ".", "The", "mutation", "identified", "in", "the", "proband", "was", "screened", "in", "the", "other", "family", "members", "and", "the", "170", "healthy", "Chinese", "individuals", "by", "direct", "sequencing", ".", "Protein", "conservation", "analysis", "was", "performed", "in", "six", "species", "using", "an", "online", "ClustalW", "tool", ".", "Protein", "structure", "was", "modeled", "based", "on", "the", "Protein", "data", "bank", "and", "mutated", "in", "DeepView", "v4", ".", "0", ".", "1", "to", "predict", "the", "functional", "consequences", "of", "the", "mutation", ".", "RESULTS", ":", "A", "novel", "heterozygous", "c", ".", "3703T", ">", "C", "change", "in", "exon", "29", "of", "FBN1", "was", "detected", "in", "the", "proband", ",", "which", "resulted", "in", "the", "substitution", "of", "serine", "by", "proline", "at", "codon", "1235", "(", "p", ".", "S1235P", ")", ".", "This", "mutation", "was", "also", "present", "in", "two", "family", "members", "but", "absent", "in", "the", "other", ",", "unaffected", "family", "members", "and", "the", "170", "healthy", "Chinese", "individuals", ".", "The", "mutant", "residue", "located", "in", "the", "calcium", "binding", "epidermal", "growth", "factor", "-", "like", "#", "15", "domain", "is", "highly", "conserved", "among", "mammalian", "species", "and", "could", "probably", "induce", "conformation", "change", "of", "the", "domain", ".", "CONCLUSIONS", ":", "We", "indentified", "a", "novel", "p", ".", "S1235P", "mutation", "in", "FBN1", ",", "which", "is", "the", "causative", "mutation", "for", "MFS", "in", "this", "family", ".", "Our", "result", "expands", "the", "mutation", "spectrum", "of", "FBN1", "and", "contributes", "to", "the", "study", "of", "the", "molecular", "pathogenesis", "of", "Marfan", "syndrome", "." ]

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2491010

Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene. Eighty unrelated individuals with Duchenne muscular dystrophy (DMD)or Becker muscular dystrophy (BMD) were found to have deletions in the major deletion-rich region of the DMD locus. This region includes the last five exons detected by cDNA5b-7, all exons detected by cDNA8, and the first two exons detected by cDNA9. These 80 individuals account for approximately 75% of 109 deletions of the gene, detected among 181 patients analyzed with the entire dystrophin cDNA. Endpoints for many of these deletions were further characterized using two genomic probes, p20 (DXS269; Wapenaar et al.) and GMGX11 (DXS239; present paper). Clinical findings are presented for all 80 patients allowing a correlation of phenotypic severity with the genotype. Thirty-eight independent patients were old enough to be classified as DMD, BMD, or intermediate phenotype and had deletions of exons with sequenced intron/exon boundaries. Of these, eight BMD patients and one intermediate patient had gene deletions predicted to leave the reading frame intact, while 21 DMD patients, 7 intermediate patients, and 1 BMD patient had gene deletions predicted to disrupt the reading frame. Thus, with two exceptions, frameshift deletions of the gene resulted in more severe phenotype than did in-frame deletions. This is in agreement with recent findings by Baumbach et al. and Koenig et al. but is in contrast to findings, by Malhotra et al. at the 5 ' end of the gene.

[ "Molecular", "and", "phenotypic", "analysis", "of", "patients", "with", "deletions", "within", "the", "deletion", "-", "rich", "region", "of", "the", "Duchenne", "muscular", "dystrophy", "(", "DMD", ")", "gene", ".", "Eighty", "unrelated", "individuals", "with", "Duchenne", "muscular", "dystrophy", "(", "DMD", ")", "or", "Becker", "muscular", "dystrophy", "(", "BMD", ")", "were", "found", "to", "have", "deletions", "in", "the", "major", "deletion", "-", "rich", "region", "of", "the", "DMD", "locus", ".", "This", "region", "includes", "the", "last", "five", "exons", "detected", "by", "cDNA5b", "-", "7", ",", "all", "exons", "detected", "by", "cDNA8", ",", "and", "the", "first", "two", "exons", "detected", "by", "cDNA9", ".", "These", "80", "individuals", "account", "for", "approximately", "75", "%", "of", "109", "deletions", "of", "the", "gene", ",", "detected", "among", "181", "patients", "analyzed", "with", "the", "entire", "dystrophin", "cDNA", ".", "Endpoints", "for", "many", "of", "these", "deletions", "were", "further", "characterized", "using", "two", "genomic", "probes", ",", "p20", "(", "DXS269", ";", "Wapenaar", "et", "al", ".", ")", "and", "GMGX11", "(", "DXS239", ";", "present", "paper", ")", ".", "Clinical", "findings", "are", "presented", "for", "all", "80", "patients", "allowing", "a", "correlation", "of", "phenotypic", "severity", "with", "the", "genotype", ".", "Thirty", "-", "eight", "independent", "patients", "were", "old", "enough", "to", "be", "classified", "as", "DMD", ",", "BMD", ",", "or", "intermediate", "phenotype", "and", "had", "deletions", "of", "exons", "with", "sequenced", "intron", "/", "exon", "boundaries", ".", "Of", "these", ",", "eight", "BMD", "patients", "and", "one", "intermediate", "patient", "had", "gene", "deletions", "predicted", "to", "leave", "the", "reading", "frame", "intact", ",", "while", "21", "DMD", "patients", ",", "7", "intermediate", "patients", ",", "and", "1", "BMD", "patient", "had", "gene", "deletions", "predicted", "to", "disrupt", "the", "reading", "frame", ".", "Thus", ",", "with", "two", "exceptions", ",", "frameshift", "deletions", "of", "the", "gene", "resulted", "in", "more", "severe", "phenotype", "than", "did", "in", "-", "frame", "deletions", ".", "This", "is", "in", "agreement", "with", "recent", "findings", "by", "Baumbach", "et", "al", ".", "and", "Koenig", "et", "al", ".", "but", "is", "in", "contrast", "to", "findings", ",", "by", "Malhotra", "et", "al", ".", "at", "the", "5", "'", "end", "of", "the", "gene", "." ]

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25006961

Absence of PKC-alpha attenuates lithium-induced nephrogenic diabetes insipidus. Lithium, an effective antipsychotic, induces nephrogenic diabetes insipidus (NDI) in 40% of patients. The decreased capacity to concentrate urine is likely due to lithium acutely disrupting the cAMP pathway and chronically reducing urea transporter (UT-A1) and water channel (AQP2) expression in the inner medulla. Targeting an alternative signaling pathway, such as PKC-mediated signaling, may be an effective method of treating lithium-induced polyuria. PKC-alpha null mice (PKCa KO) and strain-matched wild type (WT) controls were treated with lithium for 0, 3 or 5 days. WT mice had increased urine output and lowered urine osmolality after 3 and 5 days of treatment whereas PKCa KO mice had no change in urine output or concentration. Western blot analysis revealed that AQP2 expression in medullary tissues was lowered after 3 and 5 days in WT mice; however, AQP2 was unchanged in PKCa KO. Similar results were observed with UT-A1 expression. Animals were also treated with lithium for 6 weeks. Lithium-treated WT mice had 19-fold increased urine output whereas treated PKCa KO animals had a 4-fold increase in output. AQP2 and UT-A1 expression was lowered in 6 week lithium-treated WT animals whereas in treated PKCa KO mice, AQP2 was only reduced by 2-fold and UT-A1 expression was unaffected. Urinary sodium, potassium and calcium were elevated in lithium-fed WT but not in lithium-fed PKCa KO mice. Our data show that ablation of PKCa preserves AQP2 and UT-A1 protein expression and localization in lithium-induced NDI, and prevents the development of the severe polyuria associated with lithium therapy.

[ "Absence", "of", "PKC", "-", "alpha", "attenuates", "lithium", "-", "induced", "nephrogenic", "diabetes", "insipidus", ".", "Lithium", ",", "an", "effective", "antipsychotic", ",", "induces", "nephrogenic", "diabetes", "insipidus", "(", "NDI", ")", "in", "40", "%", "of", "patients", ".", "The", "decreased", "capacity", "to", "concentrate", "urine", "is", "likely", "due", "to", "lithium", "acutely", "disrupting", "the", "cAMP", "pathway", "and", "chronically", "reducing", "urea", "transporter", "(", "UT", "-", "A1", ")", "and", "water", "channel", "(", "AQP2", ")", "expression", "in", "the", "inner", "medulla", ".", "Targeting", "an", "alternative", "signaling", "pathway", ",", "such", "as", "PKC", "-", "mediated", "signaling", ",", "may", "be", "an", "effective", "method", "of", "treating", "lithium", "-", "induced", "polyuria", ".", "PKC", "-", "alpha", "null", "mice", "(", "PKCa", "KO", ")", "and", "strain", "-", "matched", "wild", "type", "(", "WT", ")", "controls", "were", "treated", "with", "lithium", "for", "0", ",", "3", "or", "5", "days", ".", "WT", "mice", "had", "increased", "urine", "output", "and", "lowered", "urine", "osmolality", "after", "3", "and", "5", "days", "of", "treatment", "whereas", "PKCa", "KO", "mice", "had", "no", "change", "in", "urine", "output", "or", "concentration", ".", "Western", "blot", "analysis", "revealed", "that", "AQP2", "expression", "in", "medullary", "tissues", "was", "lowered", "after", "3", "and", "5", "days", "in", "WT", "mice", ";", "however", ",", "AQP2", "was", "unchanged", "in", "PKCa", "KO", ".", "Similar", "results", "were", "observed", "with", "UT", "-", "A1", "expression", ".", "Animals", "were", "also", "treated", "with", "lithium", "for", "6", "weeks", ".", "Lithium", "-", "treated", "WT", "mice", "had", "19", "-", "fold", "increased", "urine", "output", "whereas", "treated", "PKCa", "KO", "animals", "had", "a", "4", "-", "fold", "increase", "in", "output", ".", "AQP2", "and", "UT", "-", "A1", "expression", "was", "lowered", "in", "6", "week", "lithium", "-", "treated", "WT", "animals", "whereas", "in", "treated", "PKCa", "KO", "mice", ",", "AQP2", "was", "only", "reduced", "by", "2", "-", "fold", "and", "UT", "-", "A1", "expression", "was", "unaffected", ".", "Urinary", "sodium", ",", "potassium", "and", "calcium", "were", "elevated", "in", "lithium", "-", "fed", "WT", "but", "not", "in", "lithium", "-", "fed", "PKCa", "KO", "mice", ".", "Our", "data", "show", "that", "ablation", "of", "PKCa", "preserves", "AQP2", "and", "UT", "-", "A1", "protein", "expression", "and", "localization", "in", "lithium", "-", "induced", "NDI", ",", "and", "prevents", "the", "development", "of", "the", "severe", "polyuria", "associated", "with", "lithium", "therapy", "." ]

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27464336

Decreased Whole-Body Fat Mass Produced by Chronic Alcohol Consumption is Associated with Activation of S6K1-Mediated Protein Synthesis and Increased Autophagy in Epididymal White Adipose Tissue. BACKGROUND: Chronic alcohol consumption leads to a loss of white adipose tissue (WAT) but the underlying mechanisms for this lipodystrophy are not fully elucidated. This study tested the hypothesis that the reduction in WAT mass in chronic alcohol-fed mice is associated with a decreased protein synthesis specifically related to impaired function of mammalian target of rapamycin (mTOR). METHODS: Adult male mice were provided an alcohol-containing liquid diet for 24 weeks or an isonitrogenous isocaloric control diet. In vivo protein synthesis was determined at this time and thereafter epididymal WAT (eWAT) was excised for analysis of signal transduction pathways central to controling protein synthesis and degradation. RESULTS: While chronic alcohol feeding decreased whole-body and eWAT mass, this was associated with a discordant increase in protein synthesis in eWAT. This increase was not associated with a change in mTOR, 4E-BP1, Akt, or PRAS40 phosphorylation. Instead, a selective increase in phosphorylation of S6K1 and its downstream substrates, S6 and eIF4B was detected in alcohol-fed mice. Alcohol also increased eEF2K phosphorylation and decreased eEF2 phosphorylation consistent with increased translation elongation. Alcohol increased Atg12-5, LC3B-I and -II, and ULK1 S555 phosphorylation, suggesting increased autophagy, while markers of apoptosis (cleaved caspase-3 and -9, and PARP) were unchanged. Lipolytic enzymes (ATGL and HSL phosphorylation) were increased and lipogenic regulators (PPARgamma and C/EBPalpha) were decreased in eWAT by alcohol. Although alcohol increased TNF-alpha, IL-6, and IL-1beta mRNA, no change in key components of the NLRP3 inflammasome (NLRP3, ACS, and cleaved caspase-1) was detected suggesting alcohol did not increase pyroptosis. Plasma insulin did not differ between groups. CONCLUSIONS: These results demonstrate that the alcohol-induced decrease in whole-body fat mass resulted in part from activation of autophagy in eWAT as protein synthesis was increased and mediated by the specific increase in the activity of S6K1.

[ "Decreased", "Whole", "-", "Body", "Fat", "Mass", "Produced", "by", "Chronic", "Alcohol", "Consumption", "is", "Associated", "with", "Activation", "of", "S6K1", "-", "Mediated", "Protein", "Synthesis", "and", "Increased", "Autophagy", "in", "Epididymal", "White", "Adipose", "Tissue", ".", "BACKGROUND", ":", "Chronic", "alcohol", "consumption", "leads", "to", "a", "loss", "of", "white", "adipose", "tissue", "(", "WAT", ")", "but", "the", "underlying", "mechanisms", "for", "this", "lipodystrophy", "are", "not", "fully", "elucidated", ".", "This", "study", "tested", "the", "hypothesis", "that", "the", "reduction", "in", "WAT", "mass", "in", "chronic", "alcohol", "-", "fed", "mice", "is", "associated", "with", "a", "decreased", "protein", "synthesis", "specifically", "related", "to", "impaired", "function", "of", "mammalian", "target", "of", "rapamycin", "(", "mTOR", ")", ".", "METHODS", ":", "Adult", "male", "mice", "were", "provided", "an", "alcohol", "-", "containing", "liquid", "diet", "for", "24", "weeks", "or", "an", "isonitrogenous", "isocaloric", "control", "diet", ".", "In", "vivo", "protein", "synthesis", "was", "determined", "at", "this", "time", "and", "thereafter", "epididymal", "WAT", "(", "eWAT", ")", "was", "excised", "for", "analysis", "of", "signal", "transduction", "pathways", "central", "to", "controling", "protein", "synthesis", "and", "degradation", ".", "RESULTS", ":", "While", "chronic", "alcohol", "feeding", "decreased", "whole", "-", "body", "and", "eWAT", "mass", ",", "this", "was", "associated", "with", "a", "discordant", "increase", "in", "protein", "synthesis", "in", "eWAT", ".", "This", "increase", "was", "not", "associated", "with", "a", "change", "in", "mTOR", ",", "4E", "-", "BP1", ",", "Akt", ",", "or", "PRAS40", "phosphorylation", ".", "Instead", ",", "a", "selective", "increase", "in", "phosphorylation", "of", "S6K1", "and", "its", "downstream", "substrates", ",", "S6", "and", "eIF4B", "was", "detected", "in", "alcohol", "-", "fed", "mice", ".", "Alcohol", "also", "increased", "eEF2K", "phosphorylation", "and", "decreased", "eEF2", "phosphorylation", "consistent", "with", "increased", "translation", "elongation", ".", "Alcohol", "increased", "Atg12", "-", "5", ",", "LC3B", "-", "I", "and", "-", "II", ",", "and", "ULK1", "S555", "phosphorylation", ",", "suggesting", "increased", "autophagy", ",", "while", "markers", "of", "apoptosis", "(", "cleaved", "caspase", "-", "3", "and", "-", "9", ",", "and", "PARP", ")", "were", "unchanged", ".", "Lipolytic", "enzymes", "(", "ATGL", "and", "HSL", "phosphorylation", ")", "were", "increased", "and", "lipogenic", "regulators", "(", "PPARgamma", "and", "C", "/", "EBPalpha", ")", "were", "decreased", "in", "eWAT", "by", "alcohol", ".", "Although", "alcohol", "increased", "TNF", "-", "alpha", ",", "IL", "-", "6", ",", "and", "IL", "-", "1beta", "mRNA", ",", "no", "change", "in", "key", "components", "of", "the", "NLRP3", "inflammasome", "(", "NLRP3", ",", "ACS", ",", "and", "cleaved", "caspase", "-", "1", ")", "was", "detected", "suggesting", "alcohol", "did", "not", "increase", "pyroptosis", ".", "Plasma", "insulin", "did", "not", "differ", "between", "groups", ".", "CONCLUSIONS", ":", "These", "results", "demonstrate", "that", "the", "alcohol", "-", "induced", "decrease", "in", "whole", "-", "body", "fat", "mass", "resulted", "in", "part", "from", "activation", "of", "autophagy", "in", "eWAT", "as", "protein", "synthesis", "was", "increased", "and", "mediated", "by", "the", "specific", "increase", "in", "the", "activity", "of", "S6K1", "." ]

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8829135

Nefiracetam (DM-9384) reverses apomorphine-induced amnesia of a passive avoidance response: delayed emergence of the memory retention effects. Nefiracetam is a novel pyrrolidone derivative which attenuates scopolamine-induced learning and post-training consolidation deficits. Given that apomorphine inhibits passive avoidance retention when given during training or in a defined 10-12h post-training period, we evaluated the ability of nefiracetam to attenuate amnesia induced by dopaminergic agonism. A step-down passive avoidance paradigm was employed and nefiracetam (3 mg/kg) and apomorphine (0.5 mg/kg) were given alone or in combination during training and at the 10-12h post-training period of consolidation. Co-administration of nefiracetam and apomorphine during training or 10h thereafter produced no significant anti-amnesic effect. However, administration of nefiracetam during training completely reversed the amnesia induced by apomorphine at the 10h post-training time and the converse was also true. These effects were not mediated by a dopaminergic mechanism as nefiracetam, at millimolar concentrations, failed to displace either [3H]SCH 23390 or [3H]spiperone binding from D1 or D2 dopamine receptor subtypes, respectively. It is suggested that nefiracetam augments molecular processes in the early stages of events which ultimately lead to consolidation of memory.

[ "Nefiracetam", "(", "DM", "-", "9384", ")", "reverses", "apomorphine", "-", "induced", "amnesia", "of", "a", "passive", "avoidance", "response", ":", "delayed", "emergence", "of", "the", "memory", "retention", "effects", ".", "Nefiracetam", "is", "a", "novel", "pyrrolidone", "derivative", "which", "attenuates", "scopolamine", "-", "induced", "learning", "and", "post", "-", "training", "consolidation", "deficits", ".", "Given", "that", "apomorphine", "inhibits", "passive", "avoidance", "retention", "when", "given", "during", "training", "or", "in", "a", "defined", "10", "-", "12h", "post", "-", "training", "period", ",", "we", "evaluated", "the", "ability", "of", "nefiracetam", "to", "attenuate", "amnesia", "induced", "by", "dopaminergic", "agonism", ".", "A", "step", "-", "down", "passive", "avoidance", "paradigm", "was", "employed", "and", "nefiracetam", "(", "3", "mg", "/", "kg", ")", "and", "apomorphine", "(", "0", ".", "5", "mg", "/", "kg", ")", "were", "given", "alone", "or", "in", "combination", "during", "training", "and", "at", "the", "10", "-", "12h", "post", "-", "training", "period", "of", "consolidation", ".", "Co", "-", "administration", "of", "nefiracetam", "and", "apomorphine", "during", "training", "or", "10h", "thereafter", "produced", "no", "significant", "anti", "-", "amnesic", "effect", ".", "However", ",", "administration", "of", "nefiracetam", "during", "training", "completely", "reversed", "the", "amnesia", "induced", "by", "apomorphine", "at", "the", "10h", "post", "-", "training", "time", "and", "the", "converse", "was", "also", "true", ".", "These", "effects", "were", "not", "mediated", "by", "a", "dopaminergic", "mechanism", "as", "nefiracetam", ",", "at", "millimolar", "concentrations", ",", "failed", "to", "displace", "either", "[", "3H", "]", "SCH", "23390", "or", "[", "3H", "]", "spiperone", "binding", "from", "D1", "or", "D2", "dopamine", "receptor", "subtypes", ",", "respectively", ".", "It", "is", "suggested", "that", "nefiracetam", "augments", "molecular", "processes", "in", "the", "early", "stages", "of", "events", "which", "ultimately", "lead", "to", "consolidation", "of", "memory", "." ]

[ "3", "0", "3", "3", "3", "0", "0", "3", "0", "0", "2", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "3", "0", "0", "0", "3", "0", "0", "2", "2", "2", "2", "2", "2", "2", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "2", "0", "0", "3", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "2", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "2", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "3", "3", "0", "0", "3", "0", "3", "0", "0", "1", "1", "1", "1", "1", "0", "0", "0", "0", "0", "0", "0", "0", "3", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0", "0" ]

9672936

Pethidine-associated seizure in a healthy adolescent receiving pethidine for postoperative pain control. A healthy 17-year-old male received standard intermittent doses of pethidine via a patient-controlled analgesia (PCA) pump for management of postoperative pain control. Twenty-three h postoperatively he developed a brief self-limited seizure. Both plasma pethidine and norpethidine were elevated in the range associated with clinical manifestations of central nervous system excitation. No other risk factors for CNS toxicity were identified. This method allowed frequent self-dosing of pethidine at short time intervals and rapid accumulation of pethidine and norpethidine. The routine use of pethidine via PCA even for a brief postoperative analgesia should be reconsidered.

[ "Pethidine", "-", "associated", "seizure", "in", "a", "healthy", "adolescent", "receiving", "pethidine", "for", "postoperative", "pain", "control", ".", "A", "healthy", "17", "-", "year", "-", "old", "male", "received", "standard", "intermittent", "doses", "of", "pethidine", "via", "a", "patient", "-", "controlled", "analgesia", "(", "PCA", ")", "pump", "for", "management", "of", "postoperative", "pain", "control", ".", "Twenty", "-", "three", "h", "postoperatively", "he", "developed", "a", "brief", "self", "-", "limited", "seizure", ".", "Both", "plasma", "pethidine", "and", "norpethidine", "were", "elevated", "in", "the", "range", "associated", "with", "clinical", "manifestations", "of", "central", "nervous", "system", "excitation", ".", "No", "other", "risk", "factors", "for", "CNS", "toxicity", "were", "identified", ".", "This", "method", "allowed", "frequent", "self", "-", "dosing", "of", "pethidine", "at", "short", "time", "intervals", "and", "rapid", "accumulation", "of", "pethidine", "and", "norpethidine", ".", "The", "routine", "use", "of", "pethidine", "via", "PCA", "even", "for", "a", "brief", "postoperative", "analgesia", "should", "be", "reconsidered", "." ]

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18503483

Recovery of tacrolimus-associated brachial neuritis after conversion to everolimus in a pediatric renal transplant recipient--case report and review of the literature. TAC has been shown to be a potent immunosuppressive agent for solid organ transplantation in pediatrics. Neurotoxicity is a potentially serious toxic effect. It is characterized by encephalopathy, headaches, seizures, or neurological deficits. Here, we describe an eight-and-a-half-yr-old male renal transplant recipient with right BN. MRI demonstrated hyperintense T2 signals in the cervical cord and right brachial plexus roots indicative of both myelitis and right brachial plexitis. Symptoms persisted for three months despite TAC dose reduction, administration of IVIG and four doses of methylprednisolone pulse therapy. Improvement and eventually full recovery only occurred after TAC was completely discontinued and successfully replaced by everolimus.

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26991973

MOL1 is required for cambium homeostasis in Arabidopsis. Plants maintain pools of pluripotent stem cells which allow them to constantly produce new tissues and organs. Stem cell homeostasis in shoot and root tips depends on negative regulation by ligand-receptor pairs of the CLE peptide and leucine-rich repeat receptor-like kinase (LRR-RLK) families. However, regulation of the cambium, the stem cell niche required for lateral growth of shoots and roots, is poorly characterized. Here we show that the LRR-RLK MOL1 is necessary for cambium homeostasis in Arabidopsis thaliana. By employing promoter reporter lines, we reveal that MOL1 is active in a domain that is distinct from the domain of the positively acting CLE41/PXY signaling module. In particular, we show that MOL1 acts in an opposing manner to the CLE41/PXY module and that changing the domain or level of MOL1 expression both result in disturbed cambium organization. Underlining discrete roles of MOL1 and PXY, both LRR-RLKs are not able to replace each other when their expression domains are interchanged. Furthermore, MOL1 but not PXY is able to rescue CLV1 deficiency in the shoot apical meristem. By identifying genes mis-expressed in mol1 mutants, we demonstrate that MOL1 represses genes associated with stress-related ethylene and jasmonic acid hormone signaling pathways which have known roles in coordinating lateral growth of the Arabidopsis stem. Our findings provide evidence that common regulatory mechanisms in different plant stem cell niches are adapted to specific niche anatomies and emphasize the importance of a complex spatial organization of intercellular signaling cascades for a strictly bidirectional tissue production.

[ "MOL1", "is", "required", "for", "cambium", "homeostasis", "in", "Arabidopsis", ".", "Plants", "maintain", "pools", "of", "pluripotent", "stem", "cells", "which", "allow", "them", "to", "constantly", "produce", "new", "tissues", "and", "organs", ".", "Stem", "cell", "homeostasis", "in", "shoot", "and", "root", "tips", "depends", "on", "negative", "regulation", "by", "ligand", "-", "receptor", "pairs", "of", "the", "CLE", "peptide", "and", "leucine", "-", "rich", "repeat", "receptor", "-", "like", "kinase", "(", "LRR", "-", "RLK", ")", "families", ".", "However", ",", "regulation", "of", "the", "cambium", ",", "the", "stem", "cell", "niche", "required", "for", "lateral", "growth", "of", "shoots", "and", "roots", ",", "is", "poorly", "characterized", ".", "Here", "we", "show", "that", "the", "LRR", "-", "RLK", "MOL1", "is", "necessary", "for", "cambium", "homeostasis", "in", "Arabidopsis", "thaliana", ".", "By", "employing", "promoter", "reporter", "lines", ",", "we", "reveal", "that", "MOL1", "is", "active", "in", "a", "domain", "that", "is", "distinct", "from", "the", "domain", "of", "the", "positively", "acting", "CLE41", "/", "PXY", "signaling", "module", ".", "In", "particular", ",", "we", "show", "that", "MOL1", "acts", "in", "an", "opposing", "manner", "to", "the", "CLE41", "/", "PXY", "module", "and", "that", "changing", "the", "domain", "or", "level", "of", "MOL1", "expression", "both", "result", "in", "disturbed", "cambium", "organization", ".", "Underlining", "discrete", "roles", "of", "MOL1", "and", "PXY", ",", "both", "LRR", "-", "RLKs", "are", "not", "able", "to", "replace", "each", "other", "when", "their", "expression", "domains", "are", "interchanged", ".", "Furthermore", ",", "MOL1", "but", "not", "PXY", "is", "able", "to", "rescue", "CLV1", "deficiency", "in", "the", "shoot", "apical", "meristem", ".", "By", "identifying", "genes", "mis", "-", "expressed", "in", "mol1", "mutants", ",", "we", "demonstrate", "that", "MOL1", "represses", "genes", "associated", "with", "stress", "-", "related", "ethylene", "and", "jasmonic", "acid", "hormone", "signaling", "pathways", "which", "have", "known", "roles", "in", "coordinating", "lateral", "growth", "of", "the", "Arabidopsis", "stem", ".", "Our", "findings", "provide", "evidence", "that", "common", "regulatory", "mechanisms", "in", "different", "plant", "stem", "cell", "niches", "are", "adapted", "to", "specific", "niche", "anatomies", "and", "emphasize", "the", "importance", "of", "a", "complex", "spatial", "organization", "of", "intercellular", "signaling", "cascades", "for", "a", "strictly", "bidirectional", "tissue", "production", "." ]

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16112787

In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine. The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, desquamation, and necrosis in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels.

[ "In", "vivo", "evidences", "suggesting", "the", "role", "of", "oxidative", "stress", "in", "pathogenesis", "of", "vancomycin", "-", "induced", "nephrotoxicity", ":", "protection", "by", "erdosteine", ".", "The", "aims", "of", "this", "study", "were", "to", "examine", "vancomycin", "(", "VCM", ")", "-", "induced", "oxidative", "stress", "that", "promotes", "production", "of", "reactive", "oxygen", "species", "(", "ROS", ")", "and", "to", "investigate", "the", "role", "of", "erdosteine", ",", "an", "expectorant", "agent", ",", "which", "has", "also", "antioxidant", "properties", ",", "on", "kidney", "tissue", "against", "the", "possible", "VCM", "-", "induced", "renal", "impairment", "in", "rats", ".", "Rats", "were", "divided", "into", "three", "groups", ":", "sham", ",", "VCM", "and", "VCM", "plus", "erdosteine", ".", "VCM", "was", "administrated", "intraperitoneally", "(", "i", ".", "p", ".", ")", "with", "200mgkg", "(", "-", "1", ")", "twice", "daily", "for", "7", "days", ".", "Erdosteine", "was", "administered", "orally", ".", "VCM", "administration", "to", "control", "rats", "significantly", "increased", "renal", "malondialdehyde", "(", "MDA", ")", "and", "urinary", "N", "-", "acetyl", "-", "beta", "-", "d", "-", "glucosaminidase", "(", "NAG", ",", "a", "marker", "of", "renal", "tubular", "injury", ")", "excretion", "but", "decreased", "superoxide", "dismutase", "(", "SOD", ")", "and", "catalase", "(", "CAT", ")", "activities", ".", "Erdosteine", "administration", "with", "VCM", "injections", "caused", "significantly", "decreased", "renal", "MDA", "and", "urinary", "NAG", "excretion", ",", "and", "increased", "SOD", "activity", ",", "but", "not", "CAT", "activity", "in", "renal", "tissue", "when", "compared", "with", "VCM", "alone", ".", "Erdosteine", "showed", "histopathological", "protection", "against", "VCM", "-", "induced", "nephrotoxicity", ".", "There", "were", "a", "significant", "dilatation", "of", "tubular", "lumens", ",", "extensive", "epithelial", "cell", "vacuolization", ",", "atrophy", ",", "desquamation", ",", "and", "necrosis", "in", "VCM", "-", "treated", "rats", "more", "than", "those", "of", "the", "control", "and", "the", "erdosteine", "groups", ".", "Erdosteine", "caused", "a", "marked", "reduction", "in", "the", "extent", "of", "tubular", "damage", ".", "It", "is", "concluded", "that", "oxidative", "tubular", "damage", "plays", "an", "important", "role", "in", "the", "VCM", "-", "induced", "nephrotoxicity", "and", "the", "modulation", "of", "oxidative", "stress", "with", "erdosteine", "reduces", "the", "VCM", "-", "induced", "kidney", "damage", "both", "at", "the", "biochemical", "and", "histological", "levels", "." ]

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21405999

Mutation screening of the GUCA1B gene in patients with autosomal dominant cone and cone rod dystrophy. Background: Heterozygous mutations in GUCA1A (MIM # 600364) have been identified to cause autosomal dominantly inherited cone dystrophy, cone rod dystrophy and macular dystrophy. However, the role of GUCA1B gene mutations in inherited retinal disease has been controversial. We therefore performed a mutation analysis of the GUCA1B gene in a clinically well characterized group of patients of European and North-American geographical origin with autosomal dominantly inherited cone dystrophy and cone rod dystrophy. Material and Methods: Twenty-four unrelated patients diagnosed with cone dystrophy or cone rod dystrophy according to standard diagnostic criteria and a family history consistent with an autosomal dominant mode of inheritance were included in the study. Mutation analysis of all coding exons of the GUCA1B gene was performed by polymerase chain reaction amplification of genomic DNA and subsequent DNA sequencing. Results: Three different sequence variants, c.-17T>C, c.171T>C, c.465G>T were identified. The sequence variant c.465G>T encodes a conservative amino acid substitution, p.Glu155Asp, located in EF-hand 4, the calcium binding site of GCAP2 protein. All sequence variants were previously reported in healthy subjects. Conclusion: The absence of clearly pathogenic mutations in the selected patient group suggests that the GUCA1B gene is a minor cause for retinal degenerations in Europeans or North-Americans.

[ "Mutation", "screening", "of", "the", "GUCA1B", "gene", "in", "patients", "with", "autosomal", "dominant", "cone", "and", "cone", "rod", "dystrophy", ".", "Background", ":", "Heterozygous", "mutations", "in", "GUCA1A", "(", "MIM", "#", "600364", ")", "have", "been", "identified", "to", "cause", "autosomal", "dominantly", "inherited", "cone", "dystrophy", ",", "cone", "rod", "dystrophy", "and", "macular", "dystrophy", ".", "However", ",", "the", "role", "of", "GUCA1B", "gene", "mutations", "in", "inherited", "retinal", "disease", "has", "been", "controversial", ".", "We", "therefore", "performed", "a", "mutation", "analysis", "of", "the", "GUCA1B", "gene", "in", "a", "clinically", "well", "characterized", "group", "of", "patients", "of", "European", "and", "North", "-", "American", "geographical", "origin", "with", "autosomal", "dominantly", "inherited", "cone", "dystrophy", "and", "cone", "rod", "dystrophy", ".", "Material", "and", "Methods", ":", "Twenty", "-", "four", "unrelated", "patients", "diagnosed", "with", "cone", "dystrophy", "or", "cone", "rod", "dystrophy", "according", "to", "standard", "diagnostic", "criteria", "and", "a", "family", "history", "consistent", "with", "an", "autosomal", "dominant", "mode", "of", "inheritance", "were", "included", "in", "the", "study", ".", "Mutation", "analysis", "of", "all", "coding", "exons", "of", "the", "GUCA1B", "gene", "was", "performed", "by", "polymerase", "chain", "reaction", "amplification", "of", "genomic", "DNA", "and", "subsequent", "DNA", "sequencing", ".", "Results", ":", "Three", "different", "sequence", "variants", ",", "c", ".", "-", "17T", ">", "C", ",", "c", ".", "171T", ">", "C", ",", "c", ".", "465G", ">", "T", "were", "identified", ".", "The", "sequence", "variant", "c", ".", "465G", ">", "T", "encodes", "a", "conservative", "amino", "acid", "substitution", ",", "p", ".", "Glu155Asp", ",", "located", "in", "EF", "-", "hand", "4", ",", "the", "calcium", "binding", "site", "of", "GCAP2", "protein", ".", "All", "sequence", "variants", "were", "previously", "reported", "in", "healthy", "subjects", ".", "Conclusion", ":", "The", "absence", "of", "clearly", "pathogenic", "mutations", "in", "the", "selected", "patient", "group", "suggests", "that", "the", "GUCA1B", "gene", "is", "a", "minor", "cause", "for", "retinal", "degenerations", "in", "Europeans", "or", "North", "-", "Americans", "." ]

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15233872

Cardioprotective effect of tincture of Crataegus on isoproterenol-induced myocardial infarction in rats. Tincture of Crataegus (TCR), an alcoholic extract of the berries of hawthorn (Crataegus oxycantha), is used in herbal and homeopathic medicine. The present study was done to investigate the protective effect of TCR on experimentally induced myocardial infarction in rats. Pretreatment of TCR, at a dose of 0.5 mL/100 g bodyweight per day, orally for 30 days, prevented the increase in lipid peroxidation and activity of marker enzymes observed in isoproterenol-induced rats (85 mg kg(-1) s. c. for 2 days at an interval of 24 h). TCR prevented the isoproterenol-induced decrease in antioxidant enzymes in the heart and increased the rate of ADP-stimulated oxygen uptake and respiratory coupling ratio. TCR protected against pathological changes induced by isoproterenol in rat heart. The results show that pretreatment with TCR may be useful in preventing the damage induced by isoproterenol in rat heart.

[ "Cardioprotective", "effect", "of", "tincture", "of", "Crataegus", "on", "isoproterenol", "-", "induced", "myocardial", "infarction", "in", "rats", ".", "Tincture", "of", "Crataegus", "(", "TCR", ")", ",", "an", "alcoholic", "extract", "of", "the", "berries", "of", "hawthorn", "(", "Crataegus", "oxycantha", ")", ",", "is", "used", "in", "herbal", "and", "homeopathic", "medicine", ".", "The", "present", "study", "was", "done", "to", "investigate", "the", "protective", "effect", "of", "TCR", "on", "experimentally", "induced", "myocardial", "infarction", "in", "rats", ".", "Pretreatment", "of", "TCR", ",", "at", "a", "dose", "of", "0", ".", "5", "mL", "/", "100", "g", "bodyweight", "per", "day", ",", "orally", "for", "30", "days", ",", "prevented", "the", "increase", "in", "lipid", "peroxidation", "and", "activity", "of", "marker", "enzymes", "observed", "in", "isoproterenol", "-", "induced", "rats", "(", "85", "mg", "kg", "(", "-", "1", ")", "s", ".", "c", ".", "for", "2", "days", "at", "an", "interval", "of", "24", "h", ")", ".", "TCR", "prevented", "the", "isoproterenol", "-", "induced", "decrease", "in", "antioxidant", "enzymes", "in", "the", "heart", "and", "increased", "the", "rate", "of", "ADP", "-", "stimulated", "oxygen", "uptake", "and", "respiratory", "coupling", "ratio", ".", "TCR", "protected", "against", "pathological", "changes", "induced", "by", "isoproterenol", "in", "rat", "heart", ".", "The", "results", "show", "that", "pretreatment", "with", "TCR", "may", "be", "useful", "in", "preventing", "the", "damage", "induced", "by", "isoproterenol", "in", "rat", "heart", "." ]

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17059986

A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension. We report a case of Gitelman syndrome (GS) in a dizygotic twin who presented at 12 years of age with growth delay, metabolic alkalosis, hypomagnesemia and hypokalemia with inappropriate kaliuresis, and idiopathic intracranial hypertension with bilateral papilledema (pseudotumor cerebri). The patient, her twin sister, and her mother also presented with cerebral cavernous malformations. Based on the early onset and normocalciuria, Bartter syndrome was diagnosed first. However, mutation analysis showed that the proband is a compound heterozygote for 2 mutations in SLC12A3: a substitution of serine by leucine at amino acid position 555 (p.Ser555Leu) and a novel guanine to cytosine transition at the 5' splice site of intron 22 (c.2633+1G>C), providing the molecular diagnosis of GS. These mutations were not detected in 200 normal chromosomes and cosegregated within the family. Analysis of complementary DNA showed that the heterozygous nucleotide change c.2633+1G>C caused the appearance of 2 RNA molecules, 1 normal transcript and 1 skipping the entire exon 22 (r.2521_2634del). Supplementation with potassium and magnesium improved clinical symptoms and resulted in catch-up growth, but vision remained impaired. Three similar associations of Bartter syndrome/GS with pseudotumor cerebri were found in the literature, suggesting that electrolyte abnormalities and secondary aldosteronism may have a role in idiopathic intracranial hypertension. This study provides further evidence for the phenotypical heterogeneity of GS and its association with severe manifestations in children. It also shows the independent segregation of familial cavernomatosis and GS.

[ "A", "novel", "splicing", "mutation", "in", "SLC12A3", "associated", "with", "Gitelman", "syndrome", "and", "idiopathic", "intracranial", "hypertension", ".", "We", "report", "a", "case", "of", "Gitelman", "syndrome", "(", "GS", ")", "in", "a", "dizygotic", "twin", "who", "presented", "at", "12", "years", "of", "age", "with", "growth", "delay", ",", "metabolic", "alkalosis", ",", "hypomagnesemia", "and", "hypokalemia", "with", "inappropriate", "kaliuresis", ",", "and", "idiopathic", "intracranial", "hypertension", "with", "bilateral", "papilledema", "(", "pseudotumor", "cerebri", ")", ".", "The", "patient", ",", "her", "twin", "sister", ",", "and", "her", "mother", "also", "presented", "with", "cerebral", "cavernous", "malformations", ".", "Based", "on", "the", "early", "onset", "and", "normocalciuria", ",", "Bartter", "syndrome", "was", "diagnosed", "first", ".", "However", ",", "mutation", "analysis", "showed", "that", "the", "proband", "is", "a", "compound", "heterozygote", "for", "2", "mutations", "in", "SLC12A3", ":", "a", "substitution", "of", "serine", "by", "leucine", "at", "amino", "acid", "position", "555", "(", "p", ".", "Ser555Leu", ")", "and", "a", "novel", "guanine", "to", "cytosine", "transition", "at", "the", "5", "'", "splice", "site", "of", "intron", "22", "(", "c", ".", "2633", "+", "1G", ">", "C", ")", ",", "providing", "the", "molecular", "diagnosis", "of", "GS", ".", "These", "mutations", "were", "not", "detected", "in", "200", "normal", "chromosomes", "and", "cosegregated", "within", "the", "family", ".", "Analysis", "of", "complementary", "DNA", "showed", "that", "the", "heterozygous", "nucleotide", "change", "c", ".", "2633", "+", "1G", ">", "C", "caused", "the", "appearance", "of", "2", "RNA", "molecules", ",", "1", "normal", "transcript", "and", "1", "skipping", "the", "entire", "exon", "22", "(", "r", ".", "2521_2634del", ")", ".", "Supplementation", "with", "potassium", "and", "magnesium", "improved", "clinical", "symptoms", "and", "resulted", "in", "catch", "-", "up", "growth", ",", "but", "vision", "remained", "impaired", ".", "Three", "similar", "associations", "of", "Bartter", "syndrome", "/", "GS", "with", "pseudotumor", "cerebri", "were", "found", "in", "the", "literature", ",", "suggesting", "that", "electrolyte", "abnormalities", "and", "secondary", "aldosteronism", "may", "have", "a", "role", "in", "idiopathic", "intracranial", "hypertension", ".", "This", "study", "provides", "further", "evidence", "for", "the", "phenotypical", "heterogeneity", "of", "GS", "and", "its", "association", "with", "severe", "manifestations", "in", "children", ".", "It", "also", "shows", "the", "independent", "segregation", "of", "familial", "cavernomatosis", "and", "GS", "." ]

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18991055

Association between polymorphisms in SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1, KCNQ1 and type 2 diabetes in the Korean population. According to recent genome-wide association studies, a number of single nucleotide polymorphisms (SNPs) are reported to be associated with type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate the association among the polymorphisms of SLC30A8, HHEX, CDKN2A/B, IGF2BP2, FTO, WFS1, CDKAL1 and KCNQ1 and the risk of T2DM in the Korean population. This study was based on a multicenter case-control study, including 908 patients with T2DM and 502 non-diabetic controls. We genotyped rs13266634, rs1111875, rs10811661, rs4402960, rs8050136, rs734312, rs7754840 and rs2237892 and measured the body weight, body mass index and fasting plasma glucose in all patients and controls. The strongest association was found in a variant of CDKAL1 [rs7754840, odds ratio (OR) = 1.77, 95% CI = 1.50-2.10, p = 5.0 x 10(-11)]. The G allele of rs1111875 (OR = 1.43, 95% CI = 1.18-1.72, p = 1.8 x 10(-4)) in HHEX), the T allele of rs10811661 (OR = 1.47, 95% CI = 1.23-1.75, p = 2.1 x 10(-5)) in CDKN2A/B) and the C allele of rs2237892 (OR = 1.31, 95% CI = 1.10-1.56, p = 0.003) in KCNQ1 showed significant associations with T2DM. Rs13266634 (OR = 1.19, 95% CI = 1.00-1.42, p = 0.045) in SLC30A8 showed a nominal association with the risk of T2DM, whereas SNPs in IGF2BP2, FTO and WFS1 were not associated. In conclusion, we have shown that SNPs in HHEX, CDKN2A/B, CDKAL1, KCNQ1 and SLC30A8 confer a risk of T2DM in the Korean population.

[ "Association", "between", "polymorphisms", "in", "SLC30A8", ",", "HHEX", ",", "CDKN2A", "/", "B", ",", "IGF2BP2", ",", "FTO", ",", "WFS1", ",", "CDKAL1", ",", "KCNQ1", "and", "type", "2", "diabetes", "in", "the", "Korean", "population", ".", "According", "to", "recent", "genome", "-", "wide", "association", "studies", ",", "a", "number", "of", "single", "nucleotide", "polymorphisms", "(", "SNPs", ")", "are", "reported", "to", "be", "associated", "with", "type", "2", "diabetes", "mellitus", "(", "T2DM", ")", ".", "The", "aim", "of", "the", "present", "study", "was", "to", "investigate", "the", "association", "among", "the", "polymorphisms", "of", "SLC30A8", ",", "HHEX", ",", "CDKN2A", "/", "B", ",", "IGF2BP2", ",", "FTO", ",", "WFS1", ",", "CDKAL1", "and", "KCNQ1", "and", "the", "risk", "of", "T2DM", "in", "the", "Korean", "population", ".", "This", "study", "was", "based", "on", "a", "multicenter", "case", "-", "control", "study", ",", "including", "908", "patients", "with", "T2DM", "and", "502", "non", "-", "diabetic", "controls", ".", "We", "genotyped", "rs13266634", ",", "rs1111875", ",", "rs10811661", ",", "rs4402960", ",", "rs8050136", ",", "rs734312", ",", "rs7754840", "and", "rs2237892", "and", "measured", "the", "body", "weight", ",", "body", "mass", "index", "and", "fasting", "plasma", "glucose", "in", "all", "patients", "and", "controls", ".", "The", "strongest", "association", "was", "found", "in", "a", "variant", "of", "CDKAL1", "[", "rs7754840", ",", "odds", "ratio", "(", "OR", ")", "=", "1", ".", "77", ",", "95", "%", "CI", "=", "1", ".", "50", "-", "2", ".", "10", ",", "p", "=", "5", ".", "0", "x", "10", "(", "-", "11", ")", "]", ".", "The", "G", "allele", "of", "rs1111875", "(", "OR", "=", "1", ".", "43", ",", "95", "%", "CI", "=", "1", ".", "18", "-", "1", ".", "72", ",", "p", "=", "1", ".", "8", "x", "10", "(", "-", "4", ")", ")", "in", "HHEX", ")", ",", "the", "T", "allele", "of", "rs10811661", "(", "OR", "=", "1", ".", "47", ",", "95", "%", "CI", "=", "1", ".", "23", "-", "1", ".", "75", ",", "p", "=", "2", ".", "1", "x", "10", "(", "-", "5", ")", ")", "in", "CDKN2A", "/", "B", ")", "and", "the", "C", "allele", "of", "rs2237892", "(", "OR", "=", "1", ".", "31", ",", "95", "%", "CI", "=", "1", ".", "10", "-", "1", ".", "56", ",", "p", "=", "0", ".", "003", ")", "in", "KCNQ1", "showed", "significant", "associations", "with", "T2DM", ".", "Rs13266634", "(", "OR", "=", "1", ".", "19", ",", "95", "%", "CI", "=", "1", ".", "00", "-", "1", ".", "42", ",", "p", "=", "0", ".", "045", ")", "in", "SLC30A8", "showed", "a", "nominal", "association", "with", "the", "risk", "of", "T2DM", ",", "whereas", "SNPs", "in", "IGF2BP2", ",", "FTO", "and", "WFS1", "were", "not", "associated", ".", "In", "conclusion", ",", "we", "have", "shown", "that", "SNPs", "in", "HHEX", ",", "CDKN2A", "/", "B", ",", "CDKAL1", ",", "KCNQ1", "and", "SLC30A8", "confer", "a", "risk", "of", "T2DM", "in", "the", "Korean", "population", "." ]

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20705401

Serotonin 6 receptor gene is associated with methamphetamine-induced psychosis in a Japanese population. BACKGROUND: Altered serotonergic neural transmission is hypothesized to be a susceptibility factor for psychotic disorders such as schizophrenia. The serotonin 6 (5-HT6) receptor is therapeutically targeted by several second generation antipsychotics, such as clozapine and olanzapine, and d-amphetamine-induced hyperactivity in rats is corrected with the use of a selective 5-HT6 receptor antagonist. In addition, the disrupted prepulse inhibition induced by d-amphetamine or phencyclidine was restored by 5-HT6 receptor antagonist in an animal study using rats. These animal models were considered to reflect the positive symptoms of schizophrenia, and the above evidence suggests that altered 5-HT6 receptors are involved in the pathophysiology of psychotic disorders. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an analysis of the association of the 5-HT6 gene (HTR6) with METH-induced psychosis. METHOD: Using five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. RESULTS: rs6693503 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this association remained significant after Bonferroni correction. In the haplotype-wise analysis, we detected an association between two markers (rs6693503 and rs1805054) and three markers (rs6693503, rs1805054 and rs4912138) in HTR6 and METH-induced psychosis patients, respectively. CONCLUSION: HTR6 may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population.

[ "Serotonin", "6", "receptor", "gene", "is", "associated", "with", "methamphetamine", "-", "induced", "psychosis", "in", "a", "Japanese", "population", ".", "BACKGROUND", ":", "Altered", "serotonergic", "neural", "transmission", "is", "hypothesized", "to", "be", "a", "susceptibility", "factor", "for", "psychotic", "disorders", "such", "as", "schizophrenia", ".", "The", "serotonin", "6", "(", "5", "-", "HT6", ")", "receptor", "is", "therapeutically", "targeted", "by", "several", "second", "generation", "antipsychotics", ",", "such", "as", "clozapine", "and", "olanzapine", ",", "and", "d", "-", "amphetamine", "-", "induced", "hyperactivity", "in", "rats", "is", "corrected", "with", "the", "use", "of", "a", "selective", "5", "-", "HT6", "receptor", "antagonist", ".", "In", "addition", ",", "the", "disrupted", "prepulse", "inhibition", "induced", "by", "d", "-", "amphetamine", "or", "phencyclidine", "was", "restored", "by", "5", "-", "HT6", "receptor", "antagonist", "in", "an", "animal", "study", "using", "rats", ".", "These", "animal", "models", "were", "considered", "to", "reflect", "the", "positive", "symptoms", "of", "schizophrenia", ",", "and", "the", "above", "evidence", "suggests", "that", "altered", "5", "-", "HT6", "receptors", "are", "involved", "in", "the", "pathophysiology", "of", "psychotic", "disorders", ".", "The", "symptoms", "of", "methamphetamine", "(", "METH", ")", "-", "induced", "psychosis", "are", "similar", "to", "those", "of", "paranoid", "type", "schizophrenia", ".", "Therefore", ",", "we", "conducted", "an", "analysis", "of", "the", "association", "of", "the", "5", "-", "HT6", "gene", "(", "HTR6", ")", "with", "METH", "-", "induced", "psychosis", ".", "METHOD", ":", "Using", "five", "tagging", "SNPs", "(", "rs6693503", ",", "rs1805054", ",", "rs4912138", ",", "rs3790757", "and", "rs9659997", ")", ",", "we", "conducted", "a", "genetic", "association", "analysis", "of", "case", "-", "control", "samples", "(", "197", "METH", "-", "induced", "psychosis", "patients", "and", "337", "controls", ")", "in", "the", "Japanese", "population", ".", "The", "age", "and", "sex", "of", "the", "control", "subjects", "did", "not", "differ", "from", "those", "of", "the", "methamphetamine", "dependence", "patients", ".", "RESULTS", ":", "rs6693503", "was", "associated", "with", "METH", "-", "induced", "psychosis", "patients", "in", "the", "allele", "/", "genotype", "-", "wise", "analysis", ".", "Moreover", ",", "this", "association", "remained", "significant", "after", "Bonferroni", "correction", ".", "In", "the", "haplotype", "-", "wise", "analysis", ",", "we", "detected", "an", "association", "between", "two", "markers", "(", "rs6693503", "and", "rs1805054", ")", "and", "three", "markers", "(", "rs6693503", ",", "rs1805054", "and", "rs4912138", ")", "in", "HTR6", "and", "METH", "-", "induced", "psychosis", "patients", ",", "respectively", ".", "CONCLUSION", ":", "HTR6", "may", "play", "an", "important", "role", "in", "the", "pathophysiology", "of", "METH", "-", "induced", "psychosis", "in", "the", "Japanese", "population", "." ]

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22369755

Reciprocal effects of NNK and SLURP-1 on oncogene expression in target epithelial cells. AIMS: To elucidate how the nicotinic acetylcholine receptors expressed on bronchial and oral epithelial cells targeted by the tobacco nitrosamine (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) (NNK) facilitate carcinogenic transformation. MAIN METHODS: Since NNK-dependent transformation can be abolished by the nicotinergic secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1 (SLURP-1), we compared effects of NNK and recombinant (r)SLURP-1 on the expression of genes related to tumorigenesis in human immortalized bronchial and oral epithelial cell lines BEP2D and Het-1A, respectively. KEY FINDINGS: NNK stimulated expression of oncogenic genes, including MYB and PIK3CA in BEP2D, ETS1, NRAS and SRC in Het-1A, and AKT1, KIT and RB1 in both cell types, which could be abolished in the presence of rSLURP-1. Other cancer-related genes whose upregulation by NNK was abolishable by rSLURP-1 were the growth factors EGF in BEP2D cells and HGF in Het-1A cells, and the transcription factors CDKN2A and STAT3 (Het-1A only). NNK also upregulated the anti-apoptotic BCL2 (Het-1A) and downregulated the pro-apoptotic TNF (Het-1A), BAX and CASP8 (BEP2D), all of which could be abolished, in part, by rSLURP-1. NNK decreased expression of the CTNNB1 gene encoding the intercellular adhesion molecule beta-catenin (BEP2D), as well as tumor suppressors CDKN3 and FOXD3 in BEP2D cells and SERPINB5 in Het-1A cells. These pro-oncogenic effects of NNK were abolished by rSLURP-1 that also upregulated RUNX3. SIGNIFICANCE: The obtained results identified target genes for both NNK and SLURP-1 and shed light on the molecular mechanism of their reciprocal effects on tumorigenic transformation of bronchial and oral epithelial cells.

[ "Reciprocal", "effects", "of", "NNK", "and", "SLURP", "-", "1", "on", "oncogene", "expression", "in", "target", "epithelial", "cells", ".", "AIMS", ":", "To", "elucidate", "how", "the", "nicotinic", "acetylcholine", "receptors", "expressed", "on", "bronchial", "and", "oral", "epithelial", "cells", "targeted", "by", "the", "tobacco", "nitrosamine", "(", "4", "-", "(", "methylnitrosamino", ")", "-", "1", "-", "(", "3", "-", "pyridyl", ")", "-", "1", "-", "butanone", ")", "(", "NNK", ")", "facilitate", "carcinogenic", "transformation", ".", "MAIN", "METHODS", ":", "Since", "NNK", "-", "dependent", "transformation", "can", "be", "abolished", "by", "the", "nicotinergic", "secreted", "mammalian", "Ly", "-", "6", "/", "urokinase", "plasminogen", "activator", "receptor", "related", "protein", "-", "1", "(", "SLURP", "-", "1", ")", ",", "we", "compared", "effects", "of", "NNK", "and", "recombinant", "(", "r", ")", "SLURP", "-", "1", "on", "the", "expression", "of", "genes", "related", "to", "tumorigenesis", "in", "human", "immortalized", "bronchial", "and", "oral", "epithelial", "cell", "lines", "BEP2D", "and", "Het", "-", "1A", ",", "respectively", ".", "KEY", "FINDINGS", ":", "NNK", "stimulated", "expression", "of", "oncogenic", "genes", ",", "including", "MYB", "and", "PIK3CA", "in", "BEP2D", ",", "ETS1", ",", "NRAS", "and", "SRC", "in", "Het", "-", "1A", ",", "and", "AKT1", ",", "KIT", "and", "RB1", "in", "both", "cell", "types", ",", "which", "could", "be", "abolished", "in", "the", "presence", "of", "rSLURP", "-", "1", ".", "Other", "cancer", "-", "related", "genes", "whose", "upregulation", "by", "NNK", "was", "abolishable", "by", "rSLURP", "-", "1", "were", "the", "growth", "factors", "EGF", "in", "BEP2D", "cells", "and", "HGF", "in", "Het", "-", "1A", "cells", ",", "and", "the", "transcription", "factors", "CDKN2A", "and", "STAT3", "(", "Het", "-", "1A", "only", ")", ".", "NNK", "also", "upregulated", "the", "anti", "-", "apoptotic", "BCL2", "(", "Het", "-", "1A", ")", "and", "downregulated", "the", "pro", "-", "apoptotic", "TNF", "(", "Het", "-", "1A", ")", ",", "BAX", "and", "CASP8", "(", "BEP2D", ")", ",", "all", "of", "which", "could", "be", "abolished", ",", "in", "part", ",", "by", "rSLURP", "-", "1", ".", "NNK", "decreased", "expression", "of", "the", "CTNNB1", "gene", "encoding", "the", "intercellular", "adhesion", "molecule", "beta", "-", "catenin", "(", "BEP2D", ")", ",", "as", "well", "as", "tumor", "suppressors", "CDKN3", "and", "FOXD3", "in", "BEP2D", "cells", "and", "SERPINB5", "in", "Het", "-", "1A", "cells", ".", "These", "pro", "-", "oncogenic", "effects", "of", "NNK", "were", "abolished", "by", "rSLURP", "-", "1", "that", "also", "upregulated", "RUNX3", ".", "SIGNIFICANCE", ":", "The", "obtained", "results", "identified", "target", "genes", "for", "both", "NNK", "and", "SLURP", "-", "1", "and", "shed", "light", "on", "the", "molecular", "mechanism", "of", "their", "reciprocal", "effects", "on", "tumorigenic", "transformation", "of", "bronchial", "and", "oral", "epithelial", "cells", "." ]

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27959387

Long-term exposure of MCF-7 breast cancer cells to ethanol stimulates oncogenic features. Alcohol consumption is a risk factor for breast cancer. Little is known regarding the mechanism, although it is assumed that acetaldehyde or estrogen mediated pathways play a role. We previously showed that long-term exposure to 2.5 mM ethanol (blood alcohol ~0.012%) of MCF-12A, a human normal epithelial breast cell line, induced epithelial mesenchymal transition (EMT) and oncogenic transformation. In this study, we investigated in the human breast cancer cell line MCF-7, whether a similar exposure to ethanol at concentrations ranging up to peak blood levels in heavy drinkers would increase malignant progression. Short-term (1-week) incubation to ethanol at as low as 1-5 mM (corresponding to blood alcohol concentration of ~0.0048-0.024%) upregulated the stem cell related proteins Oct4 and Nanog, but they were reduced after exposure at 25 mM. Long-term (4-week) exposure to 25 mM ethanol upregulated the Oct4 and Nanog proteins, as well as the malignancy marker Ceacam6. DNA microarray analysis in cells exposed for 1 week showed upregulated expression of metallothionein genes, particularly MT1X. Long-term exposure upregulated expression of some malignancy related genes (STEAP4, SERPINA3, SAMD9, GDF15, KRT15, ITGB6, TP63, and PGR, as well as the CEACAM, interferon related, and HLA gene families). Some of these findings were validated by RT-PCR. A similar treatment also modulated numerous microRNAs (miRs) including one regulator of Oct4 as well as miRs involved in oncogenesis and/or malignancy, with only a few estrogen-induced miRs. Long-term 25 mM ethanol also induced a 5.6-fold upregulation of anchorage-independent growth, an indicator of malignant-like features. Exposure to acetaldehyde resulted in little or no effect comparable to that of ethanol. The previously shown alcohol induction of oncogenic transformation of normal breast cells is now complemented by the current results suggesting alcohol's potential involvement in malignant progression of breast cancer.

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21684788

Large contiguous gene deletions in Sjogren-Larsson syndrome. Sjogren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis.

[ "Large", "contiguous", "gene", "deletions", "in", "Sjogren", "-", "Larsson", "syndrome", ".", "Sjogren", "-", "Larsson", "syndrome", "(", "SLS", ")", "is", "an", "autosomal", "recessive", "disorder", "characterized", "by", "ichthyosis", ",", "mental", "retardation", ",", "spasticity", "and", "mutations", "in", "the", "ALDH3A2", "gene", "for", "fatty", "aldehyde", "dehydrogenase", ",", "an", "enzyme", "that", "catalyzes", "the", "oxidation", "of", "fatty", "aldehyde", "to", "fatty", "acid", ".", "More", "than", "70", "mutations", "have", "been", "identified", "in", "SLS", "patients", ",", "including", "small", "deletions", "or", "insertions", ",", "missense", "mutations", ",", "splicing", "defects", "and", "complex", "nucleotide", "changes", ".", "We", "now", "describe", "2", "SLS", "patients", "whose", "disease", "is", "caused", "by", "large", "contiguous", "gene", "deletions", "of", "the", "ALDH3A2", "locus", "on", "17p11", ".", "2", ".", "The", "deletions", "were", "defined", "using", "long", "distance", "inverse", "PCR", "and", "microarray", "-", "based", "comparative", "genomic", "hybridization", ".", "A", "24", "-", "year", "-", "old", "SLS", "female", "was", "homozygous", "for", "a", "352", "-", "kb", "deletion", "involving", "ALDH3A2", "and", "4", "contiguous", "genes", "including", "ALDH3A1", ",", "which", "codes", "for", "the", "major", "soluble", "protein", "in", "cornea", ".", "Although", "lacking", "corneal", "disease", ",", "she", "showed", "severe", "symptoms", "of", "SLS", "with", "uncommon", "deterioration", "in", "oral", "motor", "function", "and", "loss", "of", "ambulation", ".", "The", "other", "19", "-", "month", "-", "old", "female", "patient", "was", "a", "compound", "heterozygote", "for", "a", "1", ".", "44", "-", "Mb", "contiguous", "gene", "deletion", "and", "a", "missense", "mutation", "(", "c", ".", "407C", ">", "T", ",", "P136L", ")", "in", "ALDH3A2", ".", "These", "studies", "suggest", "that", "large", "gene", "deletions", "may", "account", "for", "up", "to", "5", "%", "of", "the", "mutant", "alleles", "in", "SLS", ".", "Geneticists", "should", "consider", "the", "possibility", "of", "compound", "heterozygosity", "for", "large", "deletions", "in", "patients", "with", "SLS", "and", "other", "inborn", "errors", "of", "metabolism", ",", "which", "has", "implications", "for", "carrier", "testing", "and", "prenatal", "diagnosis", "." ]

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26937641

Serum Amyloid A Induces Inflammation, Proliferation and Cell Death in Activated Hepatic Stellate Cells. Serum amyloid A (SAA) is an evolutionary highly conserved acute phase protein that is predominantly secreted by hepatocytes. However, its role in liver injury and fibrogenesis has not been elucidated so far. In this study, we determined the effects of SAA on hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Serum amyloid A potently activated IkappaB kinase, c-Jun N-terminal kinase (JNK), Erk and Akt and enhanced NF-kappaB-dependent luciferase activity in primary human and rat HSCs. Serum amyloid A induced the transcription of MCP-1, RANTES and MMP9 in an NF-kappaB- and JNK-dependent manner. Blockade of NF-kappaB revealed cytotoxic effects of SAA in primary HSCs with signs of apoptosis such as caspase 3 and PARP cleavage and Annexin V staining. Serum amyloid A induced HSC proliferation, which depended on JNK, Erk and Akt activity. In primary hepatocytes, SAA also activated MAP kinases, but did not induce relevant cell death after NF-kappaB inhibition. In two models of hepatic fibrogenesis, CCl4 treatment and bile duct ligation, hepatic mRNA levels of SAA1 and SAA3 were strongly increased. In conclusion, SAA may modulate fibrogenic responses in the liver in a positive and negative fashion by inducing inflammation, proliferation and cell death in HSCs.

[ "Serum", "Amyloid", "A", "Induces", "Inflammation", ",", "Proliferation", "and", "Cell", "Death", "in", "Activated", "Hepatic", "Stellate", "Cells", ".", "Serum", "amyloid", "A", "(", "SAA", ")", "is", "an", "evolutionary", "highly", "conserved", "acute", "phase", "protein", "that", "is", "predominantly", "secreted", "by", "hepatocytes", ".", "However", ",", "its", "role", "in", "liver", "injury", "and", "fibrogenesis", "has", "not", "been", "elucidated", "so", "far", ".", "In", "this", "study", ",", "we", "determined", "the", "effects", "of", "SAA", "on", "hepatic", "stellate", "cells", "(", "HSCs", ")", ",", "the", "main", "fibrogenic", "cell", "type", "of", "the", "liver", ".", "Serum", "amyloid", "A", "potently", "activated", "IkappaB", "kinase", ",", "c", "-", "Jun", "N", "-", "terminal", "kinase", "(", "JNK", ")", ",", "Erk", "and", "Akt", "and", "enhanced", "NF", "-", "kappaB", "-", "dependent", "luciferase", "activity", "in", "primary", "human", "and", "rat", "HSCs", ".", "Serum", "amyloid", "A", "induced", "the", "transcription", "of", "MCP", "-", "1", ",", "RANTES", "and", "MMP9", "in", "an", "NF", "-", "kappaB", "-", "and", "JNK", "-", "dependent", "manner", ".", "Blockade", "of", "NF", "-", "kappaB", "revealed", "cytotoxic", "effects", "of", "SAA", "in", "primary", "HSCs", "with", "signs", "of", "apoptosis", "such", "as", "caspase", "3", "and", "PARP", "cleavage", "and", "Annexin", "V", "staining", ".", "Serum", "amyloid", "A", "induced", "HSC", "proliferation", ",", "which", "depended", "on", "JNK", ",", "Erk", "and", "Akt", "activity", ".", "In", "primary", "hepatocytes", ",", "SAA", "also", "activated", "MAP", "kinases", ",", "but", "did", "not", "induce", "relevant", "cell", "death", "after", "NF", "-", "kappaB", "inhibition", ".", "In", "two", "models", "of", "hepatic", "fibrogenesis", ",", "CCl4", "treatment", "and", "bile", "duct", "ligation", ",", "hepatic", "mRNA", "levels", "of", "SAA1", "and", "SAA3", "were", "strongly", "increased", ".", "In", "conclusion", ",", "SAA", "may", "modulate", "fibrogenic", "responses", "in", "the", "liver", "in", "a", "positive", "and", "negative", "fashion", "by", "inducing", "inflammation", ",", "proliferation", "and", "cell", "death", "in", "HSCs", "." ]

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15464247

Influence of interleukin 12B (IL12B) polymorphisms on spontaneous and treatment-induced recovery from hepatitis C virus infection. BACKGROUND/AIMS: Interleukin-12 (IL-12) governs the Th1-type immune response, affecting the spontaneous and treatment-induced recovery from HCV-infection. We investigated whether the IL12B polymorphisms within the promoter region (4 bp insertion/deletion) and the 3'-UTR (1188-A/C), which have been reported to influence IL-12 synthesis, are associated with the outcome of HCV infection. METHODS: We analyzed 186 individuals with spontaneous HCV clearance, 501 chronically HCV infected patients, and 217 healthy controls. IL12B 3'-UTR and promoter genotyping was performed by Taqman-based assays with allele-specific oligonucleotide probes and PCR-based allele-specific DNA-amplification, respectively. RESULTS: The proportion of IL12B promoter and 3'-UTR genotypes did not differ significantly between the different cohorts. However, HCV genotype 1-infected patients with high baseline viremia carrying the IL12B 3'-UTR 1188-C-allele showed significantly higher sustained virologic response (SVR) rates (25.3% vs. 46% vs. 54.5% for A/A, A/C and C/C) due to reduced relapse rates (24.2% vs. 12% vs. zero % for A/A, A/C and C/C). CONCLUSIONS: IL12B 3'-UTR 1188-C-allele carriers appear to be capable of responding more efficiently to antiviral combination therapy as a consequence of a reduced relapse rate. No association of IL12B polymorphisms and self-limited HCV infection could be demonstrated.

[ "Influence", "of", "interleukin", "12B", "(", "IL12B", ")", "polymorphisms", "on", "spontaneous", "and", "treatment", "-", "induced", "recovery", "from", "hepatitis", "C", "virus", "infection", ".", "BACKGROUND", "/", "AIMS", ":", "Interleukin", "-", "12", "(", "IL", "-", "12", ")", "governs", "the", "Th1", "-", "type", "immune", "response", ",", "affecting", "the", "spontaneous", "and", "treatment", "-", "induced", "recovery", "from", "HCV", "-", "infection", ".", "We", "investigated", "whether", "the", "IL12B", "polymorphisms", "within", "the", "promoter", "region", "(", "4", "bp", "insertion", "/", "deletion", ")", "and", "the", "3", "'", "-", "UTR", "(", "1188", "-", "A", "/", "C", ")", ",", "which", "have", "been", "reported", "to", "influence", "IL", "-", "12", "synthesis", ",", "are", "associated", "with", "the", "outcome", "of", "HCV", "infection", ".", "METHODS", ":", "We", "analyzed", "186", "individuals", "with", "spontaneous", "HCV", "clearance", ",", "501", "chronically", "HCV", "infected", "patients", ",", "and", "217", "healthy", "controls", ".", "IL12B", "3", "'", "-", "UTR", "and", "promoter", "genotyping", "was", "performed", "by", "Taqman", "-", "based", "assays", "with", "allele", "-", "specific", "oligonucleotide", "probes", "and", "PCR", "-", "based", "allele", "-", "specific", "DNA", "-", "amplification", ",", "respectively", ".", "RESULTS", ":", "The", "proportion", "of", "IL12B", "promoter", "and", "3", "'", "-", "UTR", "genotypes", "did", "not", "differ", "significantly", "between", "the", "different", "cohorts", ".", "However", ",", "HCV", "genotype", "1", "-", "infected", "patients", "with", "high", "baseline", "viremia", "carrying", "the", "IL12B", "3", "'", "-", "UTR", "1188", "-", "C", "-", "allele", "showed", "significantly", "higher", "sustained", "virologic", "response", "(", "SVR", ")", "rates", "(", "25", ".", "3", "%", "vs", ".", "46", "%", "vs", ".", "54", ".", "5", "%", "for", "A", "/", "A", ",", "A", "/", "C", "and", "C", "/", "C", ")", "due", "to", "reduced", "relapse", "rates", "(", "24", ".", "2", "%", "vs", ".", "12", "%", "vs", ".", "zero", "%", "for", "A", "/", "A", ",", "A", "/", "C", "and", "C", "/", "C", ")", ".", "CONCLUSIONS", ":", "IL12B", "3", "'", "-", "UTR", "1188", "-", "C", "-", "allele", "carriers", "appear", "to", "be", "capable", "of", "responding", "more", "efficiently", "to", "antiviral", "combination", "therapy", "as", "a", "consequence", "of", "a", "reduced", "relapse", "rate", ".", "No", "association", "of", "IL12B", "polymorphisms", "and", "self", "-", "limited", "HCV", "infection", "could", "be", "demonstrated", "." ]

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15824163

No Evidence for BRAF as a melanoma/nevus susceptibility gene. Somatic mutations of BRAF have been identified in both melanoma tumors and benign nevi. Germ line mutations in BRAF have not been identified as causal in families predisposed to melanoma. However, a recent study suggested that a BRAF haplotype was associated with risk of sporadic melanoma in men. Polymorphisms or other variants in the BRAF gene may therefore act as candidate low-penetrance genes for nevus/melanoma susceptibility. We hypothesized that promoter variants would be the most likely candidates for determinants of risk. Using denaturing high-pressure liquid chromatography and sequencing, we screened peripheral blood DNA from 184 familial melanoma cases for BRAF promoter variants. We identified a promoter insertion/deletion in linkage disequilibrium with the previously described BRAF polymorphism in intron 11 (rs1639679) reported to be associated with melanoma susceptibility in males. We therefore investigated the contribution of this BRAF polymorphism to melanoma susceptibility in 581 consecutively recruited incident cases, 258 incident cases in a study of late relapse, 673 female general practitioner controls, and the 184 familial cases. We found no statistically significant difference in either genotype or allele frequencies between cases and controls overall or between male and female cases for the BRAF polymorphism in the two incident case series. Our results therefore suggest that the BRAF polymorphism is not significantly associated with melanoma and the promoter insertion/deletion linked with the polymorphism is not a causal variant. In addition, we found that there was no association between the BRAF genotype and mean total number of banal or atypical nevi in either the cases or controls.

[ "No", "Evidence", "for", "BRAF", "as", "a", "melanoma", "/", "nevus", "susceptibility", "gene", ".", "Somatic", "mutations", "of", "BRAF", "have", "been", "identified", "in", "both", "melanoma", "tumors", "and", "benign", "nevi", ".", "Germ", "line", "mutations", "in", "BRAF", "have", "not", "been", "identified", "as", "causal", "in", "families", "predisposed", "to", "melanoma", ".", "However", ",", "a", "recent", "study", "suggested", "that", "a", "BRAF", "haplotype", "was", "associated", "with", "risk", "of", "sporadic", "melanoma", "in", "men", ".", "Polymorphisms", "or", "other", "variants", "in", "the", "BRAF", "gene", "may", "therefore", "act", "as", "candidate", "low", "-", "penetrance", "genes", "for", "nevus", "/", "melanoma", "susceptibility", ".", "We", "hypothesized", "that", "promoter", "variants", "would", "be", "the", "most", "likely", "candidates", "for", "determinants", "of", "risk", ".", "Using", "denaturing", "high", "-", "pressure", "liquid", "chromatography", "and", "sequencing", ",", "we", "screened", "peripheral", "blood", "DNA", "from", "184", "familial", "melanoma", "cases", "for", "BRAF", "promoter", "variants", ".", "We", "identified", "a", "promoter", "insertion", "/", "deletion", "in", "linkage", "disequilibrium", "with", "the", "previously", "described", "BRAF", "polymorphism", "in", "intron", "11", "(", "rs1639679", ")", "reported", "to", "be", "associated", "with", "melanoma", "susceptibility", "in", "males", ".", "We", "therefore", "investigated", "the", "contribution", "of", "this", "BRAF", "polymorphism", "to", "melanoma", "susceptibility", "in", "581", "consecutively", "recruited", "incident", "cases", ",", "258", "incident", "cases", "in", "a", "study", "of", "late", "relapse", ",", "673", "female", "general", "practitioner", "controls", ",", "and", "the", "184", "familial", "cases", ".", "We", "found", "no", "statistically", "significant", "difference", "in", "either", "genotype", "or", "allele", "frequencies", "between", "cases", "and", "controls", "overall", "or", "between", "male", "and", "female", "cases", "for", "the", "BRAF", "polymorphism", "in", "the", "two", "incident", "case", "series", ".", "Our", "results", "therefore", "suggest", "that", "the", "BRAF", "polymorphism", "is", "not", "significantly", "associated", "with", "melanoma", "and", "the", "promoter", "insertion", "/", "deletion", "linked", "with", "the", "polymorphism", "is", "not", "a", "causal", "variant", ".", "In", "addition", ",", "we", "found", "that", "there", "was", "no", "association", "between", "the", "BRAF", "genotype", "and", "mean", "total", "number", "of", "banal", "or", "atypical", "nevi", "in", "either", "the", "cases", "or", "controls", "." ]

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26900322

CFI-rs7356506 polymorphisms associated with Vogt-Koyanagi-Harada syndrome. PURPOSE: Complement factor I (CFI) plays an important role in complement activation pathways and is known to affect the development of uveitis. The present study was performed to investigate the existence of an association between CFI genetic polymorphisms and Vogt-Koyanagi-Harada (VKH) syndrome. METHODS: A total of 100 patients diagnosed with VKH syndrome and 300 healthy controls were recruited for the study. Two milliliters of peripheral blood were collected in a sterile anticoagulative tube. CFI-rs7356506 polymorphisms were genotyped using Sequenom MassARRAY technology. Allele and genotype frequencies were compared between patients and controls using a X(2) test. The analyses were stratified for recurrent status, complicated cataract status, and steroid-sensitive status. RESULTS: No significant association was found between CFI-rs7356506 polymorphisms and VKH syndrome. However, patients with recurrent VKH syndrome had lower frequencies of the G allele and GG homozygosity in CFI-rs7356506 when compared to the controls (p=0.016, odds ratio [OR]=0.429, 95% confidence interval [CI]=0.212-0.871; p=0.014, OR=0.364, 95% CI=0.158-0.837, respectively). Furthermore, there were significant decreases in the frequencies of the G allele and GG homozygosity in CFI-rs7356506 in patients with VKH syndrome with complicated cataract compared to the controls (p<0.001, OR=0.357, 95% CI=0.197-0.648; p<0.001, OR=0.273, 95% CI=0.135-0.551, respectively). Nevertheless, no significant association with patients with VKH syndrome in steroid-sensitive statuses was detected for CFI-rs7356506 polymorphisms. CONCLUSIONS: Our results indicate that CFI polymorphisms are not significantly associated with VKH syndrome; nevertheless, we identified a trend for the association of CFI-7356506 with VKH syndrome that depends on the recurrent status and the complicated cataract status but not on the steroid-sensitive status.

[ "CFI", "-", "rs7356506", "polymorphisms", "associated", "with", "Vogt", "-", "Koyanagi", "-", "Harada", "syndrome", ".", "PURPOSE", ":", "Complement", "factor", "I", "(", "CFI", ")", "plays", "an", "important", "role", "in", "complement", "activation", "pathways", "and", "is", "known", "to", "affect", "the", "development", "of", "uveitis", ".", "The", "present", "study", "was", "performed", "to", "investigate", "the", "existence", "of", "an", "association", "between", "CFI", "genetic", "polymorphisms", "and", "Vogt", "-", "Koyanagi", "-", "Harada", "(", "VKH", ")", "syndrome", ".", "METHODS", ":", "A", "total", "of", "100", "patients", "diagnosed", "with", "VKH", "syndrome", "and", "300", "healthy", "controls", "were", "recruited", "for", "the", "study", ".", "Two", "milliliters", "of", "peripheral", "blood", "were", "collected", "in", "a", "sterile", "anticoagulative", "tube", ".", "CFI", "-", "rs7356506", "polymorphisms", "were", "genotyped", "using", "Sequenom", "MassARRAY", "technology", ".", "Allele", "and", "genotype", "frequencies", "were", "compared", "between", "patients", "and", "controls", "using", "a", "X", "(", "2", ")", "test", ".", "The", "analyses", "were", "stratified", "for", "recurrent", "status", ",", "complicated", "cataract", "status", ",", "and", "steroid", "-", "sensitive", "status", ".", "RESULTS", ":", "No", "significant", "association", "was", "found", "between", "CFI", "-", "rs7356506", "polymorphisms", "and", "VKH", "syndrome", ".", "However", ",", "patients", "with", "recurrent", "VKH", "syndrome", "had", "lower", "frequencies", "of", "the", "G", "allele", "and", "GG", "homozygosity", "in", "CFI", "-", "rs7356506", "when", "compared", "to", "the", "controls", "(", "p=0", ".", "016", ",", "odds", "ratio", "[", "OR", "]", "=0", ".", "429", ",", "95", "%", "confidence", "interval", "[", "CI", "]", "=0", ".", "212", "-", "0", ".", "871", ";", "p=0", ".", "014", ",", "OR=0", ".", "364", ",", "95", "%", "CI=0", ".", "158", "-", "0", ".", "837", ",", "respectively", ")", ".", "Furthermore", ",", "there", "were", "significant", "decreases", "in", "the", "frequencies", "of", "the", "G", "allele", "and", "GG", "homozygosity", "in", "CFI", "-", "rs7356506", "in", "patients", "with", "VKH", "syndrome", "with", "complicated", "cataract", "compared", "to", "the", "controls", "(", "p", "<", "0", ".", "001", ",", "OR=0", ".", "357", ",", "95", "%", "CI=0", ".", "197", "-", "0", ".", "648", ";", "p", "<", "0", ".", "001", ",", "OR=0", ".", "273", ",", "95", "%", "CI=0", ".", "135", "-", "0", ".", "551", ",", "respectively", ")", ".", "Nevertheless", ",", "no", "significant", "association", "with", "patients", "with", "VKH", "syndrome", "in", "steroid", "-", "sensitive", "statuses", "was", "detected", "for", "CFI", "-", "rs7356506", "polymorphisms", ".", "CONCLUSIONS", ":", "Our", "results", "indicate", "that", "CFI", "polymorphisms", "are", "not", "significantly", "associated", "with", "VKH", "syndrome", ";", "nevertheless", ",", "we", "identified", "a", "trend", "for", "the", "association", "of", "CFI", "-", "7356506", "with", "VKH", "syndrome", "that", "depends", "on", "the", "recurrent", "status", "and", "the", "complicated", "cataract", "status", "but", "not", "on", "the", "steroid", "-", "sensitive", "status", "." ]

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16840830

Two novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia-1. Multiple endocrine neoplasia type 1 (MEN1) is characterized by parathyroid, enteropancreatic endocrine and pituitary adenomas as well as germline mutation of the MEN1 gene. We describe 2 families with MEN1 with novel mutations in the MEN1 gene. One family was of Turkish origin, and the index patient had primary hyperparathyroidism (PHPT) plus a prolactinoma; three relatives had PHPT only. The index patient in the second family was a 46-yr-old woman of Chinese origin living in Taiwan. This patient presented with a complaint of epigastric pain and watery diarrhea over the past 3 months, and had undergone subtotal parathyroidectomy and enucleation of pancreatic islet cell tumor about 10 yr before. There was also a prolactinoma. Sequence analysis of the MEN1 gene from leukocyte genomic DNA revealed heterozygous mutations in both probands. The Turkish patient and her affected relatives all had a heterozygous A to G transition at codon 557 (AAG-->GAG) of exon 10 of MEN1 that results in a replacement of lysine by glutamic acid. The Chinese index patient and one of her siblings had a heterozygous mutation at codon 418 of exon 9 (GAC-->TAT) that results in a substitution of aspartic acid by tyrosine. In conclusion, we have identified 2 novel missense mutations in the MEN1 gene.

[ "Two", "novel", "mutations", "in", "the", "MEN1", "gene", "in", "subjects", "with", "multiple", "endocrine", "neoplasia", "-", "1", ".", "Multiple", "endocrine", "neoplasia", "type", "1", "(", "MEN1", ")", "is", "characterized", "by", "parathyroid", ",", "enteropancreatic", "endocrine", "and", "pituitary", "adenomas", "as", "well", "as", "germline", "mutation", "of", "the", "MEN1", "gene", ".", "We", "describe", "2", "families", "with", "MEN1", "with", "novel", "mutations", "in", "the", "MEN1", "gene", ".", "One", "family", "was", "of", "Turkish", "origin", ",", "and", "the", "index", "patient", "had", "primary", "hyperparathyroidism", "(", "PHPT", ")", "plus", "a", "prolactinoma", ";", "three", "relatives", "had", "PHPT", "only", ".", "The", "index", "patient", "in", "the", "second", "family", "was", "a", "46", "-", "yr", "-", "old", "woman", "of", "Chinese", "origin", "living", "in", "Taiwan", ".", "This", "patient", "presented", "with", "a", "complaint", "of", "epigastric", "pain", "and", "watery", "diarrhea", "over", "the", "past", "3", "months", ",", "and", "had", "undergone", "subtotal", "parathyroidectomy", "and", "enucleation", "of", "pancreatic", "islet", "cell", "tumor", "about", "10", "yr", "before", ".", "There", "was", "also", "a", "prolactinoma", ".", "Sequence", "analysis", "of", "the", "MEN1", "gene", "from", "leukocyte", "genomic", "DNA", "revealed", "heterozygous", "mutations", "in", "both", "probands", ".", "The", "Turkish", "patient", "and", "her", "affected", "relatives", "all", "had", "a", "heterozygous", "A", "to", "G", "transition", "at", "codon", "557", "(", "AAG", "-", "-", ">", "GAG", ")", "of", "exon", "10", "of", "MEN1", "that", "results", "in", "a", "replacement", "of", "lysine", "by", "glutamic", "acid", ".", "The", "Chinese", "index", "patient", "and", "one", "of", "her", "siblings", "had", "a", "heterozygous", "mutation", "at", "codon", "418", "of", "exon", "9", "(", "GAC", "-", "-", ">", "TAT", ")", "that", "results", "in", "a", "substitution", "of", "aspartic", "acid", "by", "tyrosine", ".", "In", "conclusion", ",", "we", "have", "identified", "2", "novel", "missense", "mutations", "in", "the", "MEN1", "gene", "." ]

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15668505

Common BRCA2 variants and modification of breast and ovarian cancer risk in BRCA1 mutation carriers. The HH genotype of the nonconservative amino acid substitution polymorphism N372H in the BRCA2 gene was reported to be associated with a 1.3- to 1.5-fold increase in risk of both breast and ovarian cancer. As these studies concerned sporadic cancer cases, we investigated whether N372H and another common variant located in the 5'-untranslated region (203G > A) of the BRCA2 gene modify breast or ovarian cancer risk in BRCA1 mutation carriers. The study includes 778 women carrying a BRCA1 germ-line mutation belonging to 403 families. The two BRCA2 variants were analyzed by the TaqMan allelic discrimination technique. Genotypes were analyzed by disease-free survival analysis using a Cox proportional hazards model. We found no evidence of a significant modification of breast cancer penetrance in BRCA1 mutation carriers by either polymorphism. In respect of ovarian cancer risk, we also saw no effect with the N372H variant but we did observe a borderline association with the 5'-untranslated region 203A allele (hazard ratio, 1.43; CI, 1.01-2.00). In contrast to the result of Healey et al. on newborn females and adult female controls, we found no departure from Hardy-Weinberg equilibrium in the distribution of N372H alleles for our female BRCA1 carriers. We conclude that if these single-nucleotide polymorphisms do modify the risk of cancer in BRCA1 mutation carriers, their effects are not significantly larger than that of N372H previously observed in the general population.

[ "Common", "BRCA2", "variants", "and", "modification", "of", "breast", "and", "ovarian", "cancer", "risk", "in", "BRCA1", "mutation", "carriers", ".", "The", "HH", "genotype", "of", "the", "nonconservative", "amino", "acid", "substitution", "polymorphism", "N372H", "in", "the", "BRCA2", "gene", "was", "reported", "to", "be", "associated", "with", "a", "1", ".", "3", "-", "to", "1", ".", "5", "-", "fold", "increase", "in", "risk", "of", "both", "breast", "and", "ovarian", "cancer", ".", "As", "these", "studies", "concerned", "sporadic", "cancer", "cases", ",", "we", "investigated", "whether", "N372H", "and", "another", "common", "variant", "located", "in", "the", "5", "'", "-", "untranslated", "region", "(", "203G", ">", "A", ")", "of", "the", "BRCA2", "gene", "modify", "breast", "or", "ovarian", "cancer", "risk", "in", "BRCA1", "mutation", "carriers", ".", "The", "study", "includes", "778", "women", "carrying", "a", "BRCA1", "germ", "-", "line", "mutation", "belonging", "to", "403", "families", ".", "The", "two", "BRCA2", "variants", "were", "analyzed", "by", "the", "TaqMan", "allelic", "discrimination", "technique", ".", "Genotypes", "were", "analyzed", "by", "disease", "-", "free", "survival", "analysis", "using", "a", "Cox", "proportional", "hazards", "model", ".", "We", "found", "no", "evidence", "of", "a", "significant", "modification", "of", "breast", "cancer", "penetrance", "in", "BRCA1", "mutation", "carriers", "by", "either", "polymorphism", ".", "In", "respect", "of", "ovarian", "cancer", "risk", ",", "we", "also", "saw", "no", "effect", "with", "the", "N372H", "variant", "but", "we", "did", "observe", "a", "borderline", "association", "with", "the", "5", "'", "-", "untranslated", "region", "203A", "allele", "(", "hazard", "ratio", ",", "1", ".", "43", ";", "CI", ",", "1", ".", "01", "-", "2", ".", "00", ")", ".", "In", "contrast", "to", "the", "result", "of", "Healey", "et", "al", ".", "on", "newborn", "females", "and", "adult", "female", "controls", ",", "we", "found", "no", "departure", "from", "Hardy", "-", "Weinberg", "equilibrium", "in", "the", "distribution", "of", "N372H", "alleles", "for", "our", "female", "BRCA1", "carriers", ".", "We", "conclude", "that", "if", "these", "single", "-", "nucleotide", "polymorphisms", "do", "modify", "the", "risk", "of", "cancer", "in", "BRCA1", "mutation", "carriers", ",", "their", "effects", "are", "not", "significantly", "larger", "than", "that", "of", "N372H", "previously", "observed", "in", "the", "general", "population", "." ]

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26847345

Transgelin increases metastatic potential of colorectal cancer cells in vivo and alters expression of genes involved in cell motility. BACKGROUND: Transgelin is an actin-binding protein that promotes motility in normal cells. Although the role of transgelin in cancer is controversial, a number of studies have shown that elevated levels correlate with aggressive tumor behavior, advanced stage, and poor prognosis. Here we sought to determine the role of transgelin more directly by determining whether experimental manipulation of transgelin levels in colorectal cancer (CRC) cells led to changes in metastatic potential in vivo. METHODS: Isogenic CRC cell lines that differ in transgelin expression were characterized using in vitro assays of growth and invasiveness and a mouse tail vein assay of experimental metastasis. Downstream effects of transgelin overexpression were investigated by gene expression profiling and quantitative PCR. RESULTS: Stable overexpression of transgelin in RKO cells, which have low endogenous levels, led to increased invasiveness, growth at low density, and growth in soft agar. Overexpression also led to an increase in the number and size of lung metastases in the mouse tail vein injection model. Similarly, attenuation of transgelin expression in HCT116 cells, which have high endogenous levels, decreased metastases in the same model. Investigation of mRNA expression patterns showed that transgelin overexpression altered the levels of approximately 250 other transcripts, with over-representation of genes that affect function of actin or other cytoskeletal proteins. Changes included increases in HOOK1, SDCCAG8, ENAH/Mena, and TNS1 and decreases in EMB, BCL11B, and PTPRD. CONCLUSIONS: Increases or decreases in transgelin levels have reciprocal effects on tumor cell behavior, with higher expression promoting metastasis. Chronic overexpression influences steady-state levels of mRNAs for metastasis-related genes.

[ "Transgelin", "increases", "metastatic", "potential", "of", "colorectal", "cancer", "cells", "in", "vivo", "and", "alters", "expression", "of", "genes", "involved", "in", "cell", "motility", ".", "BACKGROUND", ":", "Transgelin", "is", "an", "actin", "-", "binding", "protein", "that", "promotes", "motility", "in", "normal", "cells", ".", "Although", "the", "role", "of", "transgelin", "in", "cancer", "is", "controversial", ",", "a", "number", "of", "studies", "have", "shown", "that", "elevated", "levels", "correlate", "with", "aggressive", "tumor", "behavior", ",", "advanced", "stage", ",", "and", "poor", "prognosis", ".", "Here", "we", "sought", "to", "determine", "the", "role", "of", "transgelin", "more", "directly", "by", "determining", "whether", "experimental", "manipulation", "of", "transgelin", "levels", "in", "colorectal", "cancer", "(", "CRC", ")", "cells", "led", "to", "changes", "in", "metastatic", "potential", "in", "vivo", ".", "METHODS", ":", "Isogenic", "CRC", "cell", "lines", "that", "differ", "in", "transgelin", "expression", "were", "characterized", "using", "in", "vitro", "assays", "of", "growth", "and", "invasiveness", "and", "a", "mouse", "tail", "vein", "assay", "of", "experimental", "metastasis", ".", "Downstream", "effects", "of", "transgelin", "overexpression", "were", "investigated", "by", "gene", "expression", "profiling", "and", "quantitative", "PCR", ".", "RESULTS", ":", "Stable", "overexpression", "of", "transgelin", "in", "RKO", "cells", ",", "which", "have", "low", "endogenous", "levels", ",", "led", "to", "increased", "invasiveness", ",", "growth", "at", "low", "density", ",", "and", "growth", "in", "soft", "agar", ".", "Overexpression", "also", "led", "to", "an", "increase", "in", "the", "number", "and", "size", "of", "lung", "metastases", "in", "the", "mouse", "tail", "vein", "injection", "model", ".", "Similarly", ",", "attenuation", "of", "transgelin", "expression", "in", "HCT116", "cells", ",", "which", "have", "high", "endogenous", "levels", ",", "decreased", "metastases", "in", "the", "same", "model", ".", "Investigation", "of", "mRNA", "expression", "patterns", "showed", "that", "transgelin", "overexpression", "altered", "the", "levels", "of", "approximately", "250", "other", "transcripts", ",", "with", "over", "-", "representation", "of", "genes", "that", "affect", "function", "of", "actin", "or", "other", "cytoskeletal", "proteins", ".", "Changes", "included", "increases", "in", "HOOK1", ",", "SDCCAG8", ",", "ENAH", "/", "Mena", ",", "and", "TNS1", "and", "decreases", "in", "EMB", ",", "BCL11B", ",", "and", "PTPRD", ".", "CONCLUSIONS", ":", "Increases", "or", "decreases", "in", "transgelin", "levels", "have", "reciprocal", "effects", "on", "tumor", "cell", "behavior", ",", "with", "higher", "expression", "promoting", "metastasis", ".", "Chronic", "overexpression", "influences", "steady", "-", "state", "levels", "of", "mRNAs", "for", "metastasis", "-", "related", "genes", "." ]

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15818664

Association of sporadic chondrocalcinosis with a -4-basepair G-to-A transition in the 5'-untranslated region of ANKH that promotes enhanced expression of ANKH protein and excess generation of extracellular inorganic pyrophosphate. OBJECTIVE: Certain mutations in ANKH, which encodes a multiple-pass transmembrane protein that regulates inorganic pyrophosphate (PPi) transport, are linked to autosomal-dominant familial chondrocalcinosis. This study investigated the potential for ANKH sequence variants to promote sporadic chondrocalcinosis. METHODS: ANKH variants identified by genomic sequencing were screened for association with chondrocalcinosis in 128 patients with severe sporadic chondrocalcinosis or pseudogout and in ethnically matched healthy controls. The effects of specific variants on expression of common markers were evaluated by in vitro transcription/translation. The function of these variants was studied in transfected human immortalized CH-8 articular chondrocytes. RESULTS: Sporadic chondrocalcinosis was associated with a G-to-A transition in the ANKH 5'-untranslated region (5'-UTR) at 4 bp upstream of the start codon (in homozygotes of the minor allele, genotype relative risk 6.0, P = 0.0006; overall genotype association P = 0.02). This -4-bp transition, as well as 2 mutations previously linked with familial and sporadic chondrocalcinosis (+14 bp C-to-T and C-terminal GAG deletion, respectively), but not the French familial chondrocalcinosis kindred 143-bp T-to-C mutation, increased reticulocyte ANKH transcription/ANKH translation in vitro. Transfection of complementary DNA for both the wild-type ANKH and the -4-bp ANKH protein variant promoted increased extracellular PPi in CH-8 cells, but unexpectedly, these ANKH mutants had divergent effects on the expression of extracellular PPi and the chondrocyte hypertrophy marker, type X collagen. CONCLUSION: A subset of sporadic chondrocalcinosis appears to be heritable via a -4-bp G-to-A ANKH 5'-UTR transition that up-regulates expression of ANKH and extracellular PPi in chondrocyte cells. Distinct ANKH mutations associated with heritable chondrocalcinosis may promote disease by divergent effects on extracellular PPi and chondrocyte hypertrophy, which is likely to mediate differences in the clinical phenotypes and severity of the disease.

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22729903

Contribution of STAT4 gene single-nucleotide polymorphism to systemic lupus erythematosus in the Polish population. The STAT4 has been found to be a susceptible gene in the development of systemic lupus erythematosus (SLE) in various populations. There are evident population differences in the context of clinical manifestations of SLE, therefore we investigated the prevalence of the STAT4 G > C (rs7582694) polymorphism in patients with SLE (n = 253) and controls (n = 521) in a sample of the Polish population. We found that patients with the STAT4 C/G and CC genotypes exhibited a 1.583-fold increased risk of SLE incidence (95 % CI = 1.168-2.145, p = 0.003), with OR for the C/C versus C/G and G/G genotypes was 1.967 (95 % CI = 1.152-3.358, p = 0.0119). The OR for the STAT4 C allele frequency showed a 1.539-fold increased risk of SLE (95 % CI = 1.209-1.959, p = 0.0004). We also observed an increased frequency of STAT4 C/C and C/G genotypes in SLE patients with renal symptoms OR = 2.259 (1.365-3.738, p = 0.0014), (p (corr) = 0.0238) and in SLE patients with neurologic manifestations OR = 2.867 (1.467-5.604, p = 0.0016), (p (corr) = 0.0272). Moreover, we found a contribution of STAT4 C/C and C/G genotypes to the presence of the anti-snRNP Ab OR = 3.237 (1.667-6.288, p = 0.0003), (p (corr) = 0.0051) and the presence of the anti-Scl-70 Ab OR = 2.665 (1.380-5.147, p = 0.0028), (p (corr) = 0.0476). Our studies confirmed an association of the STAT4 C (rs7582694) variant with the development of SLE and occurrence of some clinical manifestations of the disease.

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25277705

Leukemia inhibitory factor protects the lung during respiratory syncytial viral infection. BACKGROUND: Respiratory syncytial virus (RSV) infects the lung epithelium where it stimulates the production of numerous host cytokines that are associated with disease burden and acute lung injury. Characterizing the host cytokine response to RSV infection, the regulation of host cytokines and the impact of neutralizing an RSV-inducible cytokine during infection were undertaken in this study. METHODS: A549, primary human small airway epithelial (SAE) cells and wild-type, TIR-domain-containing adapter-inducing interferon-b (Trif) and mitochondrial antiviral-signaling protein (Mavs) knockout (KO) mice were infected with RSV and cytokine responses were investigated by ELISA, multiplex analysis and qPCR. Neutralizing anti-leukemia inhibitory factor (LIF) IgG or control IgG was administered to a group of wild-type animals prior to RSV infection. RESULTS AND DISCUSSION: RSV-infected A549 and SAE cells release a network of cytokines, including newly identified RSV-inducible cytokines LIF, migration inhibitory factor (MIF), stem cell factor (SCF), CCL27, CXCL12 and stem cell growth factor beta (SCGF-b). These RSV-inducible cytokines were also observed in the airways of mice during an infection. To identify the regulation of RSV inducible cytokines, Mavs and Trif deficient animals were infected with RSV. In vivo induction of airway IL-1b, IL-4, IL-5, IL-6, IL-12(p40), IFN-g, CCL2, CCL5, CCL3, CXCL1, IP-10/CXCL10, IL-22, MIG/CXCL9 and MIF were dependent on Mavs expression in mice. Loss of Trif expression in mice altered the RSV induction of IL-1b, IL-5, CXCL12, MIF, LIF, CXCL12 and IFN-g. Silencing of retinoic acid-inducible gene-1 (RIG-I) expression in A549 cells had a greater impact on RSV-inducible cytokines than melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2), and Trif expression. To evaluate the role of LIF in the airways during RSV infection, animals were treated with neutralizing anti-LIF IgG, which enhanced RSV pathology observed with increased airspace protein content, apoptosis and airway hyperresponsiveness compared to control IgG treatment. CONCLUSIONS: RSV infection in the epithelium induces a network of immune factors to counter infection, primarily in a RIG-I dependent manner. Expression of LIF protects the lung from lung injury and enhanced pathology during RSV infection.

[ "Leukemia", "inhibitory", "factor", "protects", "the", "lung", "during", "respiratory", "syncytial", "viral", "infection", ".", "BACKGROUND", ":", "Respiratory", "syncytial", "virus", "(", "RSV", ")", "infects", "the", "lung", "epithelium", "where", "it", "stimulates", "the", "production", "of", "numerous", "host", "cytokines", "that", "are", "associated", "with", "disease", "burden", "and", "acute", "lung", "injury", ".", "Characterizing", "the", "host", "cytokine", "response", "to", "RSV", "infection", ",", "the", "regulation", "of", "host", "cytokines", "and", "the", "impact", "of", "neutralizing", "an", "RSV", "-", "inducible", "cytokine", "during", "infection", "were", "undertaken", "in", "this", "study", ".", "METHODS", ":", "A549", ",", "primary", "human", "small", "airway", "epithelial", "(", "SAE", ")", "cells", "and", "wild", "-", "type", ",", "TIR", "-", "domain", "-", "containing", "adapter", "-", "inducing", "interferon", "-", "b", "(", "Trif", ")", "and", "mitochondrial", "antiviral", "-", "signaling", "protein", "(", "Mavs", ")", "knockout", "(", "KO", ")", "mice", "were", "infected", "with", "RSV", "and", "cytokine", "responses", "were", "investigated", "by", "ELISA", ",", "multiplex", "analysis", "and", "qPCR", ".", "Neutralizing", "anti", "-", "leukemia", "inhibitory", "factor", "(", "LIF", ")", "IgG", "or", "control", "IgG", "was", "administered", "to", "a", "group", "of", "wild", "-", "type", "animals", "prior", "to", "RSV", "infection", ".", "RESULTS", "AND", "DISCUSSION", ":", "RSV", "-", "infected", "A549", "and", "SAE", "cells", "release", "a", "network", "of", "cytokines", ",", "including", "newly", "identified", "RSV", "-", "inducible", "cytokines", "LIF", ",", "migration", "inhibitory", "factor", "(", "MIF", ")", ",", "stem", "cell", "factor", "(", "SCF", ")", ",", "CCL27", ",", "CXCL12", "and", "stem", "cell", "growth", "factor", "beta", "(", "SCGF", "-", "b", ")", ".", "These", "RSV", "-", "inducible", "cytokines", "were", "also", "observed", "in", "the", "airways", "of", "mice", "during", "an", "infection", ".", "To", "identify", "the", "regulation", "of", "RSV", "inducible", "cytokines", ",", "Mavs", "and", "Trif", "deficient", "animals", "were", "infected", "with", "RSV", ".", "In", "vivo", "induction", "of", "airway", "IL", "-", "1b", ",", "IL", "-", "4", ",", "IL", "-", "5", ",", "IL", "-", "6", ",", "IL", "-", "12", "(", "p40", ")", ",", "IFN", "-", "g", ",", "CCL2", ",", "CCL5", ",", "CCL3", ",", "CXCL1", ",", "IP", "-", "10", "/", "CXCL10", ",", "IL", "-", "22", ",", "MIG", "/", "CXCL9", "and", "MIF", "were", "dependent", "on", "Mavs", "expression", "in", "mice", ".", "Loss", "of", "Trif", "expression", "in", "mice", "altered", "the", "RSV", "induction", "of", "IL", "-", "1b", ",", "IL", "-", "5", ",", "CXCL12", ",", "MIF", ",", "LIF", ",", "CXCL12", "and", "IFN", "-", "g", ".", "Silencing", "of", "retinoic", "acid", "-", "inducible", "gene", "-", "1", "(", "RIG", "-", "I", ")", "expression", "in", "A549", "cells", "had", "a", "greater", "impact", "on", "RSV", "-", "inducible", "cytokines", "than", "melanoma", "differentiation", "-", "associated", "protein", "5", "(", "MDA5", ")", "and", "laboratory", "of", "genetics", "and", "physiology", "2", "(", "LGP2", ")", ",", "and", "Trif", "expression", ".", "To", "evaluate", "the", "role", "of", "LIF", "in", "the", "airways", "during", "RSV", "infection", ",", "animals", "were", "treated", "with", "neutralizing", "anti", "-", "LIF", "IgG", ",", "which", "enhanced", "RSV", "pathology", "observed", "with", "increased", "airspace", "protein", "content", ",", "apoptosis", "and", "airway", "hyperresponsiveness", "compared", "to", "control", "IgG", "treatment", ".", "CONCLUSIONS", ":", "RSV", "infection", "in", "the", "epithelium", "induces", "a", "network", "of", "immune", "factors", "to", "counter", "infection", ",", "primarily", "in", "a", "RIG", "-", "I", "dependent", "manner", ".", "Expression", "of", "LIF", "protects", "the", "lung", "from", "lung", "injury", "and", "enhanced", "pathology", "during", "RSV", "infection", "." ]

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15130900

Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide. OBJECTIVE: To assess and characterise the risk of bladder cancer, and its relation to cyclophosphamide, in patients with Wegener's granulomatosis. METHODS: In the population based, nationwide Swedish Inpatient Register a cohort of 1065 patients with Wegener's granulomatosis, 1969-95, was identified. Through linkage with the Swedish Cancer Register, all subjects in this cohort diagnosed with bladder cancer were identified. Nested within the cohort, a matched case-control study was performed to estimate the association between cyclophosphamide and bladder cancer using odds ratios (ORs) as relative risk. In the cohort the cumulative risk of bladder cancer after Wegener's granulomatosis, and the relative prevalence of a history of bladder cancer at the time of diagnosis of Wegener's granulomatosis, were also estimated. RESULTS: The median cumulative doses of cyclophosphamide among cases (n = 11) and controls (n = 25) were 113 g and 25 g, respectively. The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide (OR = 2.0, 95% confidence interval (CI) 0.8 to 4.9). Treatment duration longer than 1 year was associated with an eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). The absolute risk for bladder cancer in the cohort reached 10% 16 years after diagnosis of Wegener's granulomatosis, and a history of bladder cancer was (non-significantly) twice as common as expected at the time of diagnosis of Wegener's granulomatosis. CONCLUSION: The results indicate a dose-response relationship between cyclophosphamide and the risk of bladder cancer, high cumulative risks in the entire cohort, and also the possibility of risk factors operating even before Wegener's granulomatosis.

[ "Urinary", "bladder", "cancer", "in", "Wegener", "'s", "granulomatosis", ":", "risks", "and", "relation", "to", "cyclophosphamide", ".", "OBJECTIVE", ":", "To", "assess", "and", "characterise", "the", "risk", "of", "bladder", "cancer", ",", "and", "its", "relation", "to", "cyclophosphamide", ",", "in", "patients", "with", "Wegener", "'s", "granulomatosis", ".", "METHODS", ":", "In", "the", "population", "based", ",", "nationwide", "Swedish", "Inpatient", "Register", "a", "cohort", "of", "1065", "patients", "with", "Wegener", "'s", "granulomatosis", ",", "1969", "-", "95", ",", "was", "identified", ".", "Through", "linkage", "with", "the", "Swedish", "Cancer", "Register", ",", "all", "subjects", "in", "this", "cohort", "diagnosed", "with", "bladder", "cancer", "were", "identified", ".", "Nested", "within", "the", "cohort", ",", "a", "matched", "case", "-", "control", "study", "was", "performed", "to", "estimate", "the", "association", "between", "cyclophosphamide", "and", "bladder", "cancer", "using", "odds", "ratios", "(", "ORs", ")", "as", "relative", "risk", ".", "In", "the", "cohort", "the", "cumulative", "risk", "of", "bladder", "cancer", "after", "Wegener", "'s", "granulomatosis", ",", "and", "the", "relative", "prevalence", "of", "a", "history", "of", "bladder", "cancer", "at", "the", "time", "of", "diagnosis", "of", "Wegener", "'s", "granulomatosis", ",", "were", "also", "estimated", ".", "RESULTS", ":", "The", "median", "cumulative", "doses", "of", "cyclophosphamide", "among", "cases", "(", "n", "=", "11", ")", "and", "controls", "(", "n", "=", "25", ")", "were", "113", "g", "and", "25", "g", ",", "respectively", ".", "The", "risk", "of", "bladder", "cancer", "doubled", "for", "every", "10", "g", "increment", "in", "cyclophosphamide", "(", "OR", "=", "2", ".", "0", ",", "95", "%", "confidence", "interval", "(", "CI", ")", "0", ".", "8", "to", "4", ".", "9", ")", ".", "Treatment", "duration", "longer", "than", "1", "year", "was", "associated", "with", "an", "eightfold", "increased", "risk", "(", "OR", "=", "7", ".", "7", ",", "95", "%", "CI", "0", ".", "9", "to", "69", ")", ".", "The", "absolute", "risk", "for", "bladder", "cancer", "in", "the", "cohort", "reached", "10", "%", "16", "years", "after", "diagnosis", "of", "Wegener", "'s", "granulomatosis", ",", "and", "a", "history", "of", "bladder", "cancer", "was", "(", "non", "-", "significantly", ")", "twice", "as", "common", "as", "expected", "at", "the", "time", "of", "diagnosis", "of", "Wegener", "'s", "granulomatosis", ".", "CONCLUSION", ":", "The", "results", "indicate", "a", "dose", "-", "response", "relationship", "between", "cyclophosphamide", "and", "the", "risk", "of", "bladder", "cancer", ",", "high", "cumulative", "risks", "in", "the", "entire", "cohort", ",", "and", "also", "the", "possibility", "of", "risk", "factors", "operating", "even", "before", "Wegener", "'s", "granulomatosis", "." ]

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18257781

Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease. BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians. MATERIALS AND METHODS: We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing. RESULTS: We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls. CONCLUSIONS: We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation.

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20534762

Two novel mutations of the TSH-beta subunit gene underlying congenital central hypothyroidism undetectable in neonatal TSH screening. CONTEXT: Patients with TSH-beta subunit defects and congenital hypothyroidism are missed by TSH-based neonatal screening. OBJECTIVE: Our objective was to report the molecular consequences of a novel splice-junction mutation and a novel missense mutation in the TSH-beta subunit gene found in two patients with congenital central hypothyroidism and conventional treatment-resistant anemia. RESULTS: Patient 1 had a homozygous G to A nucleotide change at the 5' donor splice site of exon/intron 2. This resulted in a silent change at codon 34 of the mature protein. In vitro splicing assays showed that the mutant minigene dramatically affected pre-mRNA processing, causing exon 2 to be completely skipped. The putative product from a new out-of-frame translational start point in exon 3 is expected to yield a nonsense 25-amino-acid peptide. In patient 2, sequence analysis revealed a compound heterozygosis for the already reported 313delT (C105Vfs114X) mutation and for a second novel mutation in exon 3, substituting G for A at cDNA nucleotide position 323, resulting in a C88Y change. This cysteine residue is conserved among all dimeric pituitary and placental glycoprotein hormone-beta subunits. Data from in silico analysis confirmed that the C88Y mutation would affect subunit conformation. Indeed, two different bioinformatics approaches, PolyPhen and SIFT analysis, predicted C88Y to be a damaging substitution. CONCLUSIONS: In isolated TSH deficiency, the exact molecular diagnosis is mandatory for diagnosis of isolated pituitary deficiency, delineation of prognosis, and genetic counseling. Moreover, diagnosis of central hypothyroidism should be considered in the face of severe infant anemia of uncertain etiology.

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newest_biored

Dataset Card for "newest_biored"