Distribution by Scientific Domains
Distribution within Medical Sciences

Kinds of Variants

  • allelic variants
  • alternative splice variants
  • anatomic variants
  • anatomical variants
  • antigenic variants
  • apc variants
  • cell variants
  • clinical variants
  • coding variants
  • common gene variants
  • common genetic variants
  • common variants
  • copy number variants
  • deletion variants
  • different variants
  • distinct variants
  • dna sequence variants
  • dna variants
  • drug-resistant variants
  • enzyme variants
  • functional variants
  • gene variants
  • genetic variants
  • germline variants
  • gfp variants
  • hb variants
  • hbv variants
  • hemoglobin variants
  • histological variants
  • improved variants
  • intronic variants
  • mc1r variants
  • missense variants
  • molecular variants
  • morphological variants
  • multiple genetic variants
  • multiple variants
  • new variants
  • nod2 variants
  • nod2/card15 variants
  • normal variants
  • novel variants
  • nucleotide variants
  • number variants
  • orientational variants
  • other variants
  • phenotypic variants
  • polymorphic variants
  • promoter variants
  • protein variants
  • rare variants
  • resistant variants
  • risk variants
  • sequence variants
  • several variants
  • somaclonal variants
  • splice variants
  • splicing variants
  • structural variants
  • susceptibility variants
  • transcript variants
  • unclassified variants
  • viral variants
  • virus variants

  • Selected Abstracts


    María E Danoviz
    SUMMARY 1The polymorphism C825T of the gene encoding the G-protein b3-subunit (GNB3) was found to be associated with an increased prevalence of hypertension in a number of studies. The aim of the present study was to investigate the association between this polymorphism and blood pressure phenotypes in an urban, large and ethnically mixed population of Brazil. 2Individuals (n = 1 568) were randomly selected from the general population of the Vitória City metropolitan area. The GNB3 C825T polymorphism was genotyped in each individual. Baseline cardiovascular risk factors were collected for all participants. Cardiovascular risk variables and genotypes were compared using anova and the Chi-squared test for univariate comparisons and logistic regression for multiple comparisons. 3A statistically significant interaction between the 825T allele and obesity was observed for systolic blood pressure (SBP; P = 0.02). In fact, the C825T genotype was predictive of SBP only in individuals with increased body mass index (P = 0.02). In addition, in a multiple logistic regression model conducted in the obese population and adjusted for age, sex, ethnicity, diabetes, triglycerides and total cholesterol, the presence of the T allele was significantly associated with a 1.5-fold (95% confidence interval 1.04,2.26) increased risk of hypertension. Lack of statistical power does not explain the absence of other positive gene,environment interactions. 4The present results suggest that an important gene ¥ environment interaction may take place between bodyweight regulation and the GNB3 gene. This finding provides further evidence for a role of the 825T allele in hypertension susceptibility and may be used for better disease stratification. [source]

    Genetic variations associated with psoriasis and psoriatic arthritis found by genome-wide association

    Kristina Callis Duffin
    ABSTRACT Psoriasis and psoriatic arthritis are immune disorders with a complex polygenic basis. HLA-Cw6, which lies in the major histocompatibility region on chromosome 6, is considered the major genetic determinant of psoriasis. Recent genome-wide association studies have identified new variants outside of the MHC with relevance to the immunology of psoriasis. Variants in or near genes that encode subunits of cytokines (IL12B, IL23A) or cytokine receptors (IL23R) are interesting given that the gene product of IL12B, p40, is the target of a recently approved monoclonal antibody therapy for psoriasis (ustekinumab). Association with psoriasis and psoriatic arthritis has been found in TNFAIP3 and TNFIP1, ubiquitin ligases in the NF-,B pathway, and IL13, a Th2 cytokine. Copy number variation of human beta-defensin and late cornified envelope genes also associate with psoriasis. Many of these genetic variations also associate with immune disorders considered psoriatic co-morbidities, including Crohn's disease and diabetes. [source]

    Posterior Quadrantic Epilepsy Surgery: Technical Variants, Surgical Anatomy, and Case Series

    EPILEPSIA, Issue 8 2007
    Roy Thomas Daniel
    Summary:,Objective: Patients with intractable epilepsy due to extensive lesions involving the posterior quadrant (temporal, parietal, and occipital lobes) form a small subset of epilepsy surgery. This study was done with a view to analyze our experience with this group of patients and to define the changes in the surgical technique over the last 15 years. We also describe the microsurgical technique of the different surgical variants used, along with their functional neuroanatomy. Methods: In this series there were 13 patients with a median age of 17 years. All patients had extensive presurgical evaluation that provided concordant evidence localizing the lesion and seizure focus to the posterior quadrant. The objective of the surgery was to eliminate the effect of the epileptogenic tissue and preserve motor and sensory functions. Results: During the course of this study period of 15 years, the surgical procedure performed evolved toward incorporating more techniques of disconnection and minimizing resection. Three technical variants were thus utilized in this series, namely, (i) anatomical posterior quadrantectomy (APQ), (ii) functional posterior quadrantectomy (FPQ), and (iii) periinsular posterior quadrantectomy (PIPQ). After a median follow-up period of 6 years, 12/13 patients had Engel's Class I seizure outcome. Conclusion: The results of surgery for posterior quadrantic epilepsy have yielded excellent seizure outcomes in 92% of the patients in the series with no mortality or major morbidity. The incorporation of disconnective techniques in multilobar surgery has maintained the excellent results obtained earlier with resective surgery. [source]

    Semantic Differences in Sifaka (Propithecus verreauxi) Alarm Calls: A Reflection of Genetic or Cultural Variants?

    ETHOLOGY, Issue 9 2006
    Claudia Fichtel
    In this study, we compared the usage of alarm calls and anti-predator strategies between a captive and a wild lemur population. The wild lemur population was studied earlier in Western Madagascar (Fichtel & Kappeler 2002). The captive population was studied in outdoor enclosures of the Duke University Primate Center. Alarm calls and anti-predator behavior were elicited by conducting experiments with both vocal and visual dummies. We scored the subjects' immediate behavioral responses, including alarm calls, from video recordings made during the experiments. In principle, both populations have a mixed alarm call system with functionally referential alarm calls for aerial predators and general alarm calls for terrestrial and aerial predators and for situations associated with high arousal, such as group encounters. Although wild and captive sifakas exhibit the same alarm call system and use the same alarm call types, we discovered striking differences in the usage and perception of some of the alarm calls. We argue that these differences indicate either an evolutionary drift in the meaning of these calls or reflect cultural variation. The latter possibility is consistent with our understanding of the ontogeny of call usage and comprehension. [source]

    Water Deprivation Headache: "New" Variants of Phenomenology

    HEADACHE, Issue 10 2004
    Vinod Kumar Gupta MD
    No abstract is available for this article. [source]

    Variants of two major T cell epitopes within the hepatitis B surface antigen are not recognized by specific T helper cells of vaccinated individuals

    HEPATOLOGY, Issue 2 2002
    Tanja Bauer
    Several naturally occurring variants of immunogenic T cell epitopes were identified within the hepatitis B surface antigen (HBsAg). The effect of these variants on the cellular immune response was studied in individuals vaccinated against HBV. Class-II restricted T-cell responses of 30 vaccinees were analyzed after stimulation of peripheral blood mononuclear cells (PBMCs) with 4 synthetic peptides representing the 4 T-cell epitopes of HBsAg known as of yet. The 2 epitopes P1 (aa 16-33) and P4 (aa 213-226) could be identified as the dominant ones in our vaccinees by proliferation assays and enzyme-linked immunospot assays. Responses to these epitopes were compared with responses to their naturally occurring variants found in HBV isolates of chronic virus carriers. Three of 11 variants of epitope P4 led to a complete loss of T-cell reactivity in 4 of 10 donors, all of whom reacted well to the corresponding wild-type sequence. The remaining 6 donors recognized these variants as well as the vaccine epitope. Similarly, 3 P1-variants of the 12 found induced only a significantly reduced reactivity in 4 of 10 donors, whereas they led to a normal response in the other 6 individuals. Stimulation of T cells also induced the secretion of antibody to HBsAg (anti-HBs) by specific B cells; however, those peptides that failed to activate T cells were also unable to cause any significant anti-HBs production. In conclusion, our results suggest an immune escape of certain mutant strains of HBV in vaccinated individuals could exist at the T-cell level. [source]

    Detection of pathogenic gene copy number variations in patients with mental retardation by genomewide oligonucleotide array comparative genomic hybridization,,

    HUMAN MUTATION, Issue 11 2007
    Yao-Shan Fan
    Abstract Genomic imbalance is a major cause of developmental disorders. Microarray-based comparative genomic hybridization (aCGH) has revealed frequent imbalances associated with clinical syndromes, but also a large number of copy number variations (CNVs), which have complicated the interpretation of results. We studied 100 consecutive patients with unexplained mental retardation and a normal karyotype using several platforms of CGH arrays. A genomewide array with 44,290 oligonucleotide probes (OaCGH44K) detected imbalances in 15% of cases studied with sizes ranged from 459,kb to 19,Mb while revealing a small number of CNVs (0.72/individual). Another platform with ,240,000 oligonucleotide probes (OaCGH244K) revealed a large number of CNVs (20/individual) in selected cases and their normal parents. We used a comprehensive approach for interpreting the results of aCGH, including consideration of the size, inheritance and gene content of CNVs, and consultation with an online Database of Genomic Variants (DGV) and Online Mendelian Inheritance in Men (OMIM) for information on the genes involved. Our study suggests that genomewide oligonucleotide arrays such as the OaCGH44K platform can be used as a powerful diagnostic tool for detection of genomic imbalances associated with unexplained mental retardation or syndromic autism spectrum disorders. It is interesting to note that a small number of common variants were revealed by OaCGH244K in some study subjects but not in their parents and that some inherited CNVs had altered breakpoints. Further investigations on these alterations may provide useful information for understanding the mechanism of CNVs. Hum Mutat 28(11),1124,1132, 2007. © 2007 Wiley-Liss, Inc. [source]

    Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR),,

    HUMAN MUTATION, Issue 7 2007
    Philip A. Chan
    Abstract The human genome contains frequent single-basepair variants that may or may not cause genetic disease. To characterize benign vs. pathogenic missense variants, numerous computational algorithms have been developed based on comparative sequence and/or protein structure analysis. We compared computational methods that use evolutionary conservation alone, amino acid (AA) change alone, and a combination of conservation and AA change in predicting the consequences of 254 missense variants in the CDKN2A (n = 92), MLH1 (n = 28), MSH2 (n = 14), MECP2 (n = 30), and tyrosinase (TYR) (n = 90) genes. Variants were validated as either neutral or deleterious by curated locus-specific mutation databases and published functional data. All methods that use evolutionary sequence analysis have comparable overall prediction accuracy (72.9,82.0%). Mutations at codons where the AA is absolutely conserved over a sufficient evolutionary distance (about one-third of variants) had a 91.6 to 96.8% likelihood of being deleterious. Three algorithms (SIFT, PolyPhen, and A-GVGD) that differentiate one variant from another at a given codon did not significantly improve predictive value over conservation score alone using the BLOSUM62 matrix. However, when all four methods were in agreement (62.7% of variants), predictive value improved to 88.1%. These results confirm a high predictive value for methods that use evolutionary sequence conservation, with or without considering protein structural change, to predict the clinical consequences of missense variants. The methods can be generalized across genes that cause different types of genetic disease. The results support the clinical use of computational methods as one tool to help interpret missense variants in genes associated with human genetic disease. Hum Mutat 28(7), 683,693, 2007. Published 2007 Wiley-Liss, Inc. [source]

    Contribution of TNFSF15 gene variants to Crohn's disease susceptibility confirmed in UK population

    Mark Tremelling MRCP
    Abstract Background: Identification of Crohn's disease (CD)-associated genetic variants is key to understanding pathogenic pathways underlying disease susceptibility. Recent reports of an association between TNFSF15 variants and CD have been modestly replicated in European populations, suggesting heterogeneity at this locus with stronger CD association in Japanese than European populations. Methods: We investigated the association between variants in TNFSF15 and CD in 756 CD patients and 636 controls. Disease subphenotype associations were also investigated. Results:TNFSF15 single nucleotide polymorphism (SNP) variants were associated with CD in our panel with peak odds ratio (OR) 1.2 (95% confidence interval [CI] 1.01,1.41) P = 0.033. The presence of a risk haplotype was replicated for the first time in a European population (frequency 67% in cases and 61% in controls) OR = 1.44 (95% CI 1.23,1.68) P = 0.00012. This result mirrors the UK panel in the index study (Yamazaki et al [2005] Hum Mol Genet 14:3499,3506) but is less significant than that reported in Japanese populations. There was no evidence of association with any individual CD subphenotype. Conclusions: Variants in TNFSF15 contribute to overall CD susceptibility in European populations, although to a lesser extent than that seen in the Japanese. Further studies to define the precise disease-causing variants as well as targeted functional studies are now required in human CD as TNFSF15 is a potential target for biological therapies. (Inflamm Bowel Dis 2008) [source]

    Association of DLG5 variants with inflammatory bowel disease in the New Zealand caucasian population and meta-analysis of the DLG5 R30Q variant,

    Brian L. Browning PhD
    Abstract Background: Variants in the DLG5 gene have been associated with inflammatory bowel disease (IBD) in samples from some, but not all populations. In particular, 2 nonsynonymous single-nucleotide polymorphisms (SNPs), R30Q (rs1248696) and P1371Q (rs2289310), have been associated with an increased risk of IBD, and a common haplotype (called haplotype "A") has been associated with reduced risk. Methods: We genotyped R30Q, P1371Q, and a haplotype A tagging SNP (rs2289311) in a New Zealand Caucasian cohort of 389 Crohn's disease (CD) patients, 406 ulcerative colitis (UC) patients, and 416 population controls. Each SNP was tested for association with disease susceptibility and clinical phenotypes. We also performed a meta-analysis of R30Q data from published association studies. Results: The haplotype A tagging SNP was associated with reduced risk of IBD at the 0.05 significance level (P = 0.036) with an allelic odds ratio of 0.83 (95% confidence interval [CI]: 0.69,0.99). Association with haplotype A was strongest (odds ratio ,0.57) in UC patients with familial IBD or extraintestinal manifestations. The R30Q and P1371Q polymorphisms were not significantly associated with UC, CD, or IBD. Analysis of male and female data did not find any gender-specific associations. Meta-analysis gave no evidence of association of R30Q with IBD. Conclusions: Meta-analysis demonstrates that the minor allele of R30Q is not a risk factor for IBD across populations. This study provides some evidence that DLG5 haplotype A is associated with reduced risk of IBD in the New Zealand Caucasian population, but this association will need to be replicated in an independent sample. (Inflamm Bowel Dis 2007) [source]

    Characterization of Phosphatase and Tensin Homolog expression in the mosquito Aedes aegypti: Six splice variants with developmental and tissue specificity

    Michael A. Riehle
    Abstract Phosphatase and tensin homologue (PTEN), an inhibitor of insulin signalling, was characterized in Aedes aegypti. Surprisingly, six splice variants were identified: three with alternative terminal exons (AaegPTEN2 : 3 : 6) and three formed by intron retention (AaegPTEN1 : 4 : 5). All variants encoded active phosphatase domains. Variants with alternative terminal exons also encoded C2 and COOH-domains, and AaegPTEN6 encoded a PDZ binding motif. These three variants also had unique expression patterns. AaegPTEN2 was expressed primarily in the ovary. AaegPTEN3 was predominant in heads and midguts, and throughout development, except early embryogenesis. AaegPTEN6 was expressed in fat body, ovaries, and throughout development. Intron retention variants were weakly expressed in most samples. These expression patterns suggest that AaegPTEN variants play unique roles in regulating insulin's pleiotropic effects. [source]

    How Nature Modulates a Fiber's Mechanical Properties: Mechanically Distinct Fibers Drawn from Natural Mesogenic Block Copolymer Variants

    ADVANCED MATERIALS, Issue 4 2009
    Matthew J. Harrington
    Mussel byssal threads are functionally graded biological fibers adapted for tethering the soft tissue of the organism (,1 MPa) to hard surfaces !(25 GPa) in the rocky seashore. A stiffness gradient mitigates contact deformation and is defined by an incrementally regulated distribution of two protein block copolymer variants with stiff and pliable domains, respectively. [source]

    Anorexia nervosa treatment: A systematic review of randomized controlled trials,

    Cynthia M. Bulik PhD
    Abstract Objective: The RTI International-University of North Carolina at Chapel Hill Evidence-based Practice Center (RTI-UNC EPC) systematically reviewed evidence on efficacy of treatment for anorexia nervosa (AN), harms associated with treatments, factors associated with treatment efficacy, and differential outcome by sociodemographic characteristics. Method: We searched six major databases for studies on the treatment of AN from 1980 to September 2005, in all languages against a priori inclusion/exclusion criteria focusing on eating, psychiatric or psychological, or biomarker outcomes. Results: Thirty-two treatment studies involved only medications, only behavioral interventions, and medication plus behavioral interventions for adults or adolescents. The literature on medication treatments and behavioral treatments for adults with AN is sparse and inconclusive. Cognitive behavioral therapy may reduce relapse risk for adults with AN after weight restoration, although its efficacy in the underweight state remains unknown. Variants of family therapy are efficacious in adolescents, but not in adults. Conclusion: Evidence for AN treatment is weak; evidence for treatment-related harms and factors associated with efficacy of treatment are weak; and evidence for differential outcome by sociodemographic factors is nonexistent. Attention to sample size and statistical power, standardization of outcome measures, retention of patients in clinical trials, and developmental differences in treatment appropriateness and outcome is required. © 2007 by Wiley Periodicals, Inc. Int J Eat Disord 2007 [source]

    Evaluation of IL10, IL19 and IL20 gene polymorphisms and chronic hepatitis B infection outcome

    Ann L. Truelove
    Summary Hepatitis B virus (HBV) infection remains a serious global health problem despite the availability of a highly effective vaccine. Approximately 5% of HBV-infected adults develop chronic hepatitis B, which may result in liver cirrhosis or hepatocellular carcinoma. Variants of interleukin-10 (IL10) have been previously associated with chronic hepatitis B infection and progression to hepatocellular carcinoma. Single nucleotide polymorphisms (SNP; n = 42) from the IL10, IL19 and IL20 gene regions were examined for an association with HBV infection outcome, either chronic or recovered, in a nested case,control study of African Americans and European Americans. Among African Americans, three nominally statistically significant SNP associations in IL10, two in IL20, and one haplotype association were observed with different HBV infection outcomes (P = 0.005,0.04). A SNP (rs1518108) in IL20 deviated significantly from Hardy,Weinberg equilibrium in African Americans, with a large excess of heterozygotes in chronic HBV-infected cases (P = 0.0006), which suggests a strong genetic effect. Among European Americans, a nominally statistically significant SNP association in IL20 and an IL20 haplotype were associated with HBV recovery (P = 0.01,0.04). These results suggest that IL10 and IL20 gene variants influence HBV infection outcome and encourage the pursuit of further studies of these cytokines in HBV pathogenesis. [source]

    Construction of Recombinant Escherichia coli Catalysts which Simultaneously Express an (S)-Oxynitrilase and Different Nitrilase Variants for the Synthesis of (S)-Mandelic Acid and (S)-Mandelic Amide from Benzaldehyde and Cyanide

    Olga Sosedov
    Abstract Recombinant Escherichia coli strains were constructed which simultaneously expressed the genes encoding the (S)-oxynitrilase from cassava (Manihot esculenta) together with the wild-type or a mutant variant of the arylacetonitrilase from Pseudomonas fluorescens EBC191 in a single organism under the control of a rhamnose-inducible promoter. The whole cell catalysts obtained converted benzaldehyde and potassium cyanide in aqueous media at pH,5.2 mainly to (S)-mandelic acid and/or (S)-mandelic amide and synthesized only low amounts of the corresponding (R)-enantiomers. The conversion of benzaldehyde and potassium cyanide (KCN) by a whole-cell catalyst simultaneously expressing the (S)-oxynitrilase and the wild-type nitrilase resulted in a ratio of (S)-mandelic acid to (S)-mandelic amide of about 4:3. This could be explained by the strong nitrile hydratase activity of the wild-type nitrilase with (S)-mandelonitrile as substrate. The relative proportion of (S)-mandelic amide formed in this system was significantly increased by coexpressing the (S)-oxynitrilase with a carboxy-terminally truncated variant of the nitrilase. This whole-cell catalyst converted benzaldehyde and KCN to mandelic amide and mandelic acid in a ratio of about 9:1. The ee of the (S)-mandelic amide formed was calculated to be >95%. [source]

    Two C-Terminal Variants of NBC4, a New Member of the Sodium Bicarbonate Cotransporter Family: Cloning, Characterization, and Localization

    IUBMB LIFE, Issue 1 2000
    Alexander Pushkin
    Abstract We report the cloning, characterization, and chromosomal assignment of a new member of the sodium bicarbonate cotransporter (NBC) family, NBC4. The NBC4 gene was mapped to chromosome 2p13 and is a new candidate gene for Alstrom syndrome. Two variants of the transporter have been isolated from human testis and heart, which differ in their C termini. NBC4a encodes a 1137-residue polypeptide and is widely expressed in various tissues, including liver, testis, and spleen. NBC4b is identical to NBC4a except that it has a 16-nucleotide insert, creating a C-terminal frame shift. NBC4b encodes a 1074-residue polypeptide and is highly expressed in heart. Amino acids 1-1046 are common to both NBC4 variants. NBC4a has two protein-interacting domains that are lacking in NBC4b: a proline-rich sequence, PPPSVIKIP (amino acids 1102-1110), and a consensus PDZ-interacting domain, SYSL (1134-1137). NBC4b lacks the stretch of charged residues present in the C terminus of NBC4a and other members of the NBC family.Unlike other members of the NBC family, both NBC4a and NBC4b have a unique glycine-rich region (amino acids 440- 469). In comparison with other members of the bicarbonate transport superfamily, NBC4a and NBC4b are most similar structurally to the electrogenic sodium bicarbonate cotransporters (NBC1). [source]

    Anatomy of the cystic artery arising from the gastroduodenal artery and its choledochal branch,a case report

    JOURNAL OF ANATOMY, Issue 3 2000
    A. K. SARKAR
    Variations in the branching pattern of the common hepatic artery often occur and may be encountered during cholecystectomy. Variants of the cystic artery, its branches and relations with the biliary structures and blood vessels emphasise the importance of arterial dissection in biliary surgery. In this study, a rare variant of the cystic artery and its choledochal branch is described. The cystic artery arose from the gastroduodenal artery, passed anterior to structures in the free margin of lesser omentum and travelled a long distance before supplying the gall bladder. A long choledochal branch was noted accompanying the common bile duct. Surgical implications of this variation of the cystic and choledochal arteries are discussed. [source]

    Association of Molecular Variants, Haplotypes, and Linkage Disequilibrium Within the Human Vitamin D-Binding Protein (DBP) Gene With Postmenopausal Bone Mineral Density,

    Yoichi Ezura
    Abstract Possible contribution of vitamin D-binding protein (DBP) gene for determination of BMD was tested by characterizing 13 SNPs in 384 adult Japanese women. When the effect of a specific single SNP was tested, five SNPs (,39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, and IVS11+1097G>C) correlated with BMD significantly at various levels. The chromosomal dosage of one haplotype (T-C-C-G-T-C in ,39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, D432E, and IVS11+1097G>C) displayed significant correlation with adjusted radial BMD (r = 0.15, p = 0.008; n = 331). Multiple regression analyses revealed a most significant correlation with the combination of IVS1+827C>T and D432E (r2 = 0.029, p = 0.005). These results indicate a complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis. Introduction: Osteoporosis results from the interplay of multiple environmental and genetic determinants. The gene encoding vitamin D-binding protein (DBP), a key factor for regulating calcium homeostasis through the vitamin D endocrine system, is a probable candidate for conferring susceptibility to osteoporosis. Methods: To test a possible contribution of the DBP gene for determination of bone mineral density (BMD) of adult women, we have characterized 13 single nucleotide polymorphisms (SNPs) within the DBP gene in DNA from 384 adult Japanese women and attempted to correlate specific SNPs with BMD. Results and Conclusions: Sixteen major haplotypes accounted for 80% of the variations, indicating allelic complexity in this genomic region. Pairwise linkage disequilibrium (LD), measured by the D, and r2 statistics, demonstrated a general pattern of decline with increasing distance, but individual LD values within small genomic segments were diverse. Regression analysis for adjusted BMD revealed significant correlation with respect to five of them (,39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, and IVS11+1097G>C) at various levels. An intronic SNP (IVS11+1097G>C) with the highest significance of association (p = 0.006) showed significant LD with four SNPs located around the first exon (r2 values >0.18, D, > 0.5). A non-synonymous coding SNP, D432E, showed a comparable level of correlation, but it was in a moderate LD only with IVS11+1097G>C. The chromosomal dosage of one haplotype (T-C-C-G-T-C in ,39C>T, IVS1+827C>T, IVS1+1916C>T, IVS1-1154A>G, D432E and IVS11+1097G>C) estimated in each subject displayed significant correlation with adjusted radial BMD (r = 0.15, p = 0.008; n = 331). Furthermore, multiple regression analyses revealed that the most significant correlation was achieved for the combination of IVS1+827C>T and D432E (r2 = 0.029, p = 0.005). These results indicate a complex combined effect of several SNPs within the DBP gene that might underlie susceptibility to low radial BMD and osteoporosis. [source]

    Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity

    AGING CELL, Issue 4 2009
    Ludmila Pawlikowska
    Summary The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan , 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (lifespan , 79y, mean = 75.7 ± 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68,0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15,1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan. [source]

    Region-Specific Expression and Hormonal Regulation of the First Exon Variants of Rat Prolactin Receptor mRNA in Rat Brain and Anterior Pituitary Gland

    H. Nogami
    Recent studies have revealed the occurrence of five first exon variants of the rat prolactin receptor mRNA, suggesting that multiple promoters direct prolactin receptor transcription in response to different regulatory factors. In the present study, regional expression of these first exon variants, as well as two prolactin receptor subtypes generated by alternative splicing, was examined in the brains and anterior pituitary glands of female rats. Expression of the long-form was detected in the choroid plexus, hypothalamus, hippocampus, cerebral cortex and anterior pituitary gland, whereas the short form was detected only in the choroid plexus. E1-3 mRNA, a first exon variant, was detected in the choroid plexus, hypothalamus, and anterior pituitary gland, whereas E1-4 was detected only in the choroid plexus. Other variants were not detectable by the polymerase chain reaction protocol employed in this study. Ovariectomy increased the short form in the choroid plexus and the E1-3 expression in the choroid plexus and pituitary gland, but changes in the long-form and E1-4 expression were minimal. Replacement of oestrogens and prolactin suggest that oestrogens down-regulate E1-3 expression in the choroid plexus and pituitary gland, and that the negative effect of oestrogen is mediated by prolactin in the pituitary gland. The present results revealed the region-specific promoter usage in prolactin receptor mRNA transcription, as well as the involvement of oestrogens in the regulation of E1-3 mRNA expression in the brain and pituitary gland. [source]

    Single Chain Variants of the Glycoprotein Hormones and Their Receptors as Tools to Study Receptor Activation and for Analogue Design

    D. Ben-Menahem
    Abstract One of the crucial steps in the biosynthesis of multisubunit proteins is their assembly. The glycoprotein hormone, thyroid-stimulating hormone, and the gonadotropins, luteinizing hormone, follicle-stimulating hormone and chorionic gonadotropin, are noncovalent heterodimers. Their assembly is critical for bioactivity because the heterodimers, but not the monomeric subunits, efficiently bind to and activate the cognate heptahelical receptor. Occasionally, mutated subunits cannot combine into a functional hormone, or the bioactivity of the assembled, yet modified, heterodimer is suboptimal. [source]

    Oestrogen Receptors, Receptor Variants and Oestrogen Actions in the Hypothalamic-Pituitary Axis

    M. A. Shupnik
    Abstract Information on oestrogen action has grown exponentially in the past decade, and recent studies have begun to define the mechanism of ligand-dependent activation and cell-specific effects. Oestrogen-mediated gene transcription in a specific tissue depends on several factors, the most important of which is the presence of at least one of the two nuclear oestrogen receptor (ER) isoforms, ER, and ER,. The presence and levels of specific ER isoform variants, along with receptor coactivator, corepressor and integrator proteins, directly modulate overall nuclear ER activity. The structure of the ligand, including both physiological oestrogens and synthetic oestrogen receptor modulators, influences ER interactions with these other proteins and thus determines the biological response. Furthermore, peptide and neurotransmitter-stimulated intracellular signalling pathways activate specific enzyme cascades and may modify the receptors and their interacting proteins, resulting in either independent or ligand-enhanced ER-mediated responses. Finally, several rapid effects of oestrogen probably occur at the membrane through nongenomic pathways that may or may not require the same ER proteins that are found in the nucleus. This review concentrates on the pituitary-hypothalamic axis and the genomic effects of oestrogen, and discusses the current knowledge of each of these factors in determining oestrogen actions in the neuroendocrine system. [source]

    Variation in the secreted frizzled-related protein-3 gene and risk of Osteolysis and heterotopic ossification after total hip arthroplasty

    Andrew Gordon
    Abstract Secreted frizzled-related protein-3 (sFRP3) antagonizes ligands that promote new bone formation in adult tissues. We examined whether variation in the FRZB gene that encodes sFRP3 is associated with development of osteolysis or heterotopic ossification (HO) after total hip arthroplasty (THA). Genomic DNA was extracted from 609 subjects (osteolysis group n,=,268) at a mean of 11 years following cemented THA for idiopathic osteoarthritis and genotyped for the FRZB Arg200Trp and Arg324Gly polymorphisms. The Brooker classification was used to assess HO following primary THA in 563 of the subjects. The carriage rate of the FRZB 200Trp allele was 14.2% in subjects with osteolysis versus 21.0% in controls (p,=,0.041). The carriage rate of this allele was 21.7% in subjects with HO (n,=,299) versus 12.0% in those without HO (p,=,0.063). The odds ratio for osteolysis with carriage of FRZB 200Trp was 0.62 (95% CI 0.38 to 0.99; p,=,0.049) and for HO was 1.64 (1.05 to 2.54; p,=,0.028), after adjustment for the effects of other risk factors associated with the development of osteolysis or HO. Variants in the FRZB 324 locus alone were not associated with osteolysis or HO. However, the most frequent haplotype (FRZB 200Arg:324Arg) was associated with osteolysis (OR 1.50, 95% CI 1.09 to 2.07; p,=,0.014). Our data suggest that the FRZB Arg200Trp locus may be a marker for pro-osteoblastic activity after THA. Carriage of the FRZB 200Trp allele is associated with a "positive" bone balance phenotype (osteolysis ,: HO+). © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:1665,1670, 2007 [source]

    Should we be ,pushing meds'?

    The implications of pharmacogenomics
    Medication continues to be the most widely prescribed treatment in the NHS for mental health problems. It has been known for many years that individuals differ in the way they respond to a given pharmaceutical therapy, and one reason for this lies in the genetic variation between individuals. This paper recognizes the impact that pharmacogenomics and pharmacogenetics are having in the field of mental health. Variants in genes that code for the drug metabolizing enzymes in the liver have been found to influence the way in which these enzymes handle psychotropic medication. Individuals can be classified as poor, moderate or extensive metabolizers when standard regimes are used, and this can lead to huge differences in therapeutic effect and toxicity. There are now genotyping tests available which provide information on the individual's ability to metabolize psychotropic medication. One author provides an account of the effects of medication on her son's physical and psychological well-being. Genotyping provided evidence for his poor metabolism of psychotropic medication, and his life is now changing as he is being very gradually weaned off this medication. This emerging field of work has implications for the way in which practitioners consider medication adherence. [source]

    Possible Emergence of Drug-Resistant Variants of Babesia gibsoni in Clinical Cases Treated with Atovaquone and Azithromycin

    M. Sakuma
    Background: There is no well-established treatment strategy for Babesia gibsoni infection. A new therapeutic protocol using atovaquone (ATV) and azithromycin (AZM) has been proposed, but there is concern about the possible induction of relapse and the emergence of ATV-resistant variants after treatment. Objective: To evaluate the clinical use of combination therapy with ATV and AZM as a first-line treatment of clinical B. gibsoni infection in dogs, and to investigate the emergence of ATV-resistant variants. Animals: Eight B. gibsoni naturally infected dogs showing signs of acute onset of disease. Methods: Retrospective case study. Eight clinical cases received combination therapy with ATV and AZM at Kagoshima University Veterinary Teaching Hospital during 2007,2008, and their clinical courses and clinicopathological parameters were evaluated. In addition, alterations in the cytochrome b (CYTb) gene of B. gibsoni were analyzed by polymerase chain reaction and DNA sequencing techniques. Results: All of the dogs responded well to the treatment, with rapid improvement in their clinical condition and hematological parameters. However, 5 of the 8 dogs relapsed after treatment. Analysis of the CYTb gene strongly suggested the emergence of ATV-resistant variants after treatment. Conclusions and Clinical Importance: The combination of ATV and AZM can be used as a first-line treatment for dogs with babesiosis, but relapses occur. Attention should be paid to the possible in vivo selection of drug-resistant variants. [source]


    METROECONOMICA, Issue 3 2008
    Till Van TreeckArticle first published online: 28 APR 200
    ABSTRACT A Post-Keynesian growth model is developed, in which financial variables are explicitly taken into account. Variants of an investment function are estimated econometrically, applying the ARDL (auto-regressive distributed lag)-based approach proposed by Pesaran et al. (Journal of Applied Econometrics, 16 (3), pp. 289,326). The econometric results are discussed with respect to a remarkable phenomenon that can be observed for some important OECD countries since the early 1980s: accumulation has generally been declining while profit shares and rates have shown a tendency to rise. We concentrate on one potential explanation of this phenomenon, which is particularly relevant for the USA and relies on a high propensity to consume out of capital income. [source]

    Association of DRD3 and GRIN2B with impulse control and related behaviors in Parkinson's disease,

    MOVEMENT DISORDERS, Issue 12 2009
    Jee-Young Lee MD
    Abstract We aimed to assess whether allelic variants of dopamine receptor, glutamate receptor, and serotonin transporter genes are associated with the appearance of impulse control and related behaviors (ICRB) in Parkinson's disease (PD) with dopamine replacement therapy (DRT). We surveyed ICRB in consecutive Korean patients with PD who were treated with stable DRT using modified Minnesota Impulsive Disorders Interview over a period of 4 months. In the 404 patients who completed the interview and the 559 Korean healthy normal controls, genotyping was performed for variants of the DRD3 p.S9G, DRD2Taq1A, GRIN2B c.366C>G, c.2664C>T and c.-200T>G, and the promoter region of the serotonin transporter gene (5-HTTLPR). Behavioral abnormalities suggestive of ICRB including compulsive buying, gambling, sexual behavior and eating, and punding, were present in 14.4% of the patients. Variants of DRD2 and 5-HTTLPR were not associated with the risk of developing ICRB. However, the AA genotype of DRD3 p.S9G and the CC genotype of GRIN2B c.366C>G were more frequent in patients with ICRB than in nonaffected patients (odds ratio [OR] = 2.21, P = 0.0094; and 2.14, P = 0.0087, after adjusting for age and sex). After controlling for clinical variables in the multivariate analysis, carriage of either AA genotype of DRD3 or CC genotype of GRIN2B was identified as an independent risk factor for ICRB (adjusted OR: 2.57, P = 0.0087). Variants of DRD3 p.S9G and GRIN2B c.366C>G may be associated with the appearance of ICRB in PD. © 2009 Movement Disorder Society [source]

    Identification of five novel variants in the thiazide-sensitive NaCl co-transporter gene in Chinese patients with Gitelman syndrome

    NEPHROLOGY, Issue 1 2009
    SUMMARY Aim: Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy characterized by hypokalaemic metabolic alkalosis, significant hypomagnesemia, low urinary calcium, secondary aldosteronism and normal blood pressure. GS is caused by inactivating variants in the SLC12A3 gene, which encodes the thiazide-sensitive NaCl co-transporter. So far, more than 100 variants have been described in the SLC12A3 gene in Gitelman syndrome. Methods: Biochemical parameters in blood and urine were measured and documented. Genomic DNA was extracted from peripheral blood of all patients. Variants were screened for the SLC12A3 and CLCNKB gene by sequencing directly. Reverse-transcription polymerase chain reaction and complementary DNA sequence analysis were performed to confirm deletion or splicing variants. Results: We identified 13 variants in the SLC12A3 gene in 13 Chinese patients, including 10 missense substitutions, two splicing variants, and one deletion/insertion variant. Five novel variants were identified for the first time in patients with Gitelman syndrome. We did not find any variants in the CLCNKB gene. A homozygous Thr60Met carrier suffered from hypothyroidism and received thyroxine replacement therapy. Conclusion: We have identified 13 variants, including five novel variants in the SLC12A3 gene in 13 patients with Gitelman syndrome. T60M is the most frequent variant in our patients. There was no significant correlation between genotype and phenotype in our patients. [source]

    Automatic Mode Switching Variants: Dual Demand Pacing, Retriggerable Atrial Refractory Periods, Automatic Mode Adaptation, and Pseudomode Switching.

    Enlightenment or Obfuscation?
    No abstract is available for this article. [source]

    Alterations in Mitochondrial and Apoptosis-regulating Gene Expression in Photodynamic Therapy-resistant Variants of HT29 Colon Carcinoma Cells,

    Xiao Yun Shen
    ABSTRACT Photodynamic therapy (PDT) is a novel cancer therapy inducing irreversible photodamage to tumor tissue via photosensitizer-mediated oxidative cytotoxicity. The cellular and molecular responses associated with PDT are only partially understood. We have reported previously the generation of several photosensitizer-specific PDT-resistant cell variants of HT29 human colon adenocarcinoma cells by selecting cells from sequential PDT treatment using different photosensitizers. In this report, we describe the use of messenger RNA (mRNA) differential display to identify genes that were differentially expressed in the parental HT29 cells compared with their resistant variants. In comparison with parental HT29 cells, mRNA expression was increased in the PDT-resistant cell variants for BNIP3, estrogen receptor-binding fragmentassociated gene 9, Myh-1c, cytoplasmic dynein light chain 1, small membrane protein I and differential dependent protein. In contrast, expression in the PDT-resistant variants was downregulated for NNX3, human HepG2 3,region Mbol complementary DNA, glutamate dehydrogenase, hepatomaderived growth factor and the mitochondrial genes coding for 16S ribosomal RNA (rRNA) and nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 4. The reduction for mitochondrial 16S rRNA in the PDT-resistant variants was confirmed by Northern blotting, and the elevated expression of the proapoptotic BNIP3 in the PDT-resistant variants was confirmed by Northern and Western blotting analysis. We also examined the expression of some additional apoptosis-regulating genes using Western blotting. We show an increased expression of Bcl-2 and heat shock protein 27 and a downregulation of Bax in the PDT-resistant variants. In addition, the mutant p53 levels in the parental HT29 cells were reduced substantially in the PDT-resistant variants. We suggest that the altered expression in several mitochondria1 and apoptosisregulating genes contributes to PDT resistance. [source]