Stephen V. Faraone

Bio: Stephen V. Faraone is an academic researcher from State University of New York Upstate Medical University. The author has contributed to research in topics: Attention deficit hyperactivity disorder & Bipolar disorder. The author has an hindex of 188, co-authored 1427 publications receiving 140298 citations. Previous affiliations of Stephen V. Faraone include University of Bergen & National Institute for Health Research.

A double-blind comparison of galantamine hydrogen bromide and placebo in adults with attention-deficit/hyperactivity disorder: a pilot study.

Abstract: Background Galantamine hydrogen bromide (HBr) is a competitive and reversible inhibitor of acetylcholinesterase. Because of its cholinergic nicotinic mechanism of action, galantamine HBr was hypothesized to have therapeutic activity in the treatment of attention-deficit/hyperactivity disorder (ADHD). Method We conducted a 12-week, double-blind, placebo-controlled, randomized clinical trial using daily doses of up to 24 mg/d of galantamine HBr in the treatment of adults who met full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD with childhood-onset and persistent adult symptoms. All analyses were intention to treat with the last observation carried forward for subjects who did not complete the full study schedule. Results The mean daily doses at week 12 were 19.8 +/- 6.4 mg for galantamine HBr and 21.8 +/- 4.6 mg for placebo (P = 0.3). There was no statistically or clinically significant greater reduction in ADHD symptoms in subjects treated with galantamine HBr relative to those receiving placebo (P = 0.5). Using last observation carried forward, 4 (22%) of 18 of patients receiving galantamine HBr were considered responders (much or very much improved on the Clinical Global Impression Improvement Scale and at least a 30% reduction on the ADHD Investigator Symptom Report Scale compared with 11% [2/18] on placebo; P = 0.4). Conclusion These results do not support the clinical utility of galantamine HBr in the treatment of ADHD at the doses used in this pilot study.

No confirmation of Geschwind's hypothesis of associations between reading disability, immune disorders, and motor preference in ADHD

Abstract: Geschwind and colleagues have proposed an association among reading disability, immune disorder, and motor preference. Although reading disability commonly overlaps with attention deficit hyperactivity disorder (ADHD), ADHD has not been previously examined in studies evaluating Geschwind's hypothesis. In this paper we evaluate whether ADHD is associated with either asthma or left motor preference and whether asthma and left motor preference are associated with each other. Subjects were 6- to 17-year-old boys with DSM-III-R ADHD (n= 140) and normal controls (n= 120). Information on reading disability, asthma, and motor preference was obtained in a standardized manner blind to the proband's clinical status. Neither ADHD nor reading disability was associated with either asthma or left motor preference nor was asthma and left motor preference associated with one another. Our results are not consistent with Geschwind's hypothesis linking reading disability, immune disorder, and left motor preference.

Effects of Extended-Release Guanfacine on ADHD Symptoms and Sedation-Related Adverse Events in Children with ADHD

Abstract: Objective: Guanfacine extended release (GXR) is a selective α2A-adrenoceptor agonist that is shown to be an effective nonstimulant treatment for the symptoms of attention-deficit/hyperactivity disorder. This report documents the time course and predictors of symptom efficacy and sedation-related adverse events (AEs) that emerge during GXR treatment throughout 3 randomized, placebo-controlled, double-blind trials of the drug. Method: Analysis of data from 3 GXR clinical trials. Results: Few variables related to the study participants or their treatment regimen affects the emergence or magnitude of sedation-related AEs. The best predictor of sedation is treatment duration, with the likelihood of sedation-related AEs decreasing with increasing time on medication. Sedation-related AEs are not predicted by the actual dose a participant receives, the magnitude of any dose changes, or the relationship between dose received and the magnitude of dose changes. Rates of discontinuation because of sedation-related si...

Novel Loci Associated With Attention-Deficit/Hyperactivity Disorder Are Revealed by Leveraging Polygenic Overlap With Educational Attainment.

Abstract: Background Attention-Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition that affects about 5% of children and adolescents worldwide. Despite its high heritability little is known about underlying genetic factors. Among other things ADHD is tightly associated with educational failure. However, potential genetic overlap between ADHD and educational attainment has not been examined in detail so far. Exploiting epidemiological similarity between ADHD and educational attainment we aimed to improve discovery of ADHD-associated genetic factors and investigated genetic overlap between these phenotypes. Methods We used ADHD data from the PGC (2064 trios, 896 cases, 2455 controls) and educational attainment data from the SSGAC (N=328917). To investigate polygenic overlap between ADHD and educational attainment we constructed fold-enrichment plots and conditional QQ plots in both directions: conditioning ADHD on educational attainment and vice versa. To explore the nature of the polygenic overlap and test a hypothesis that investigated traits correlate genetically we calculated correlations between z-scores of ADHD and educational attainment variants for nested strata of variants, representing subsets of SNPs with increasing significance of p-values in one of the traits. Additionally we supported this hypothesis by estimating genetic correlation between ADHD and educational attainment using LD score regression. We applied condFDR/conjFDR method to identify specific loci associated with ADHD and loci associated with both ADHD and educational attainment simultaneously. Consistency of effect directions for top association signals detected in our condFDR/conjFDR analyses was tested in the independent GWAS of ADHD symptoms from EAGLE consortium (N=17666). Results Using condFDR/conjFDR method we identified five novel loci associated with ADHD, three of these being shared between ADHD and educational attainment. Leading variants for four of five identified regions are located in introns of protein coding genes: KDM4A, MEF2C, PINK1, RUNX1T1, while the remaining one is an intergenic SNP on chromosome 2 at 2p24. Four of five loci have opposite directions of effect in ADHD and educational attainment and consistent directions of effect in the independent GWAS of ADHD symptoms from the EAGLE consortium. A hypothesis of polygenic overlap between ADHD and educational attainment was supported by significant genetic correlation (rg=-0.403, p=7.90E-8), consistent pleiotropic enrichment in conditional QQ plots, >10-fold mutual enrichment of SNPs associated with both traits and growing negative correlation of association z-scores for the nested SNP strata with increasing significance in both phenotypes. Discussion We found five novel loci associated with ADHD and provided evidence for a shared genetic basis between ADHD and educational attainment, implicating three genetic loci in this overlap. Four of five identified loci showed consistent effects in the independent data set of ADHD symptoms, and inverse correlation with educational attainment. The latter is in line with prior epidemiological and genetic studies. We belive that altogether these findings provide new insights into the relationship between ADHD and educational attainment, suggesting shared molecular genetic mechanisms. Further research is required to clarify the biological effects of the identified genetic variants and how these may influence educational attainment and ADHD pathogenesis.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Using Multivariate Statistics

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Human biochemical genetics

Abstract: So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.