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Search Results: 1 - 10 of 464234 matches for " Russell A. Wilke "
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A Common CNR1 (Cannabinoid Receptor 1) Haplotype Attenuates the Decrease in HDL Cholesterol That Typically Accompanies Weight Gain
Qiping Feng,Lan Jiang,Richard L. Berg,Melissa Antonik,Erin MacKinney,Jennifer Gunnell-Santoro,Catherine A. McCarty,Russell A. Wilke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015779
Abstract: We have previously shown that genetic variability in CNR1 is associated with low HDL dyslipidemia in a multigenerational obesity study cohort of Northern European descent (209 families, median = 10 individuals per pedigree). In order to assess the impact of CNR1 variability on the development of dyslipidemia in the community, we genotyped this locus in all subjects with class III obesity (body mass index >40 kg/m2) participating in a population-based biobank of similar ancestry. Twenty-two haplotype tagging SNPs, capturing the entire CNR1 gene locus plus 15 kb upstream and 5 kb downstream, were genotyped and tested for association with clinical lipid data. This biobank contains data from 645 morbidly obese study subjects. In these subjects, a common CNR1 haplotype (H3, frequency 21.1%) is associated with fasting TG and HDL cholesterol levels (p = 0.031 for logTG; p = 0.038 for HDL-C; p = 0.00376 for log[TG/HDL-C]). The strength of this relationship increases when the data are adjusted for age, gender, body mass index, diet and physical activity. Mean TG levels were 160±70, 155±70, and 120±60 mg/dL for subjects with 0, 1, and 2 copies of the H3 haplotype. Mean HDL-C levels were 45±10, 47±10, and 48±9 mg/dL, respectively. The H3 CNR1 haplotype appears to exert a protective effect against development of obesity-related dyslipidemia.
CNR1 Genotype Influences HDL-Cholesterol Response to Change in Dietary Fat Intake
Heidi J. Silver, Kevin D. Niswender, Charles D. Keil, Lan Jiang, Qiping Feng, Sally Chiu, Ronald M. Krauss, Russell A. Wilke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036166
Abstract: Background Success in further reducing the burden of cardiovascular disease (CVD) is threatened by the increasing prevalence of obesity-related atherogenic dyslipidemia. HDL-cholesterol (HDL-C) level is inversely correlated with CVD risk; each 1 mg/dl decrease in HDL-C is associated with a 6% reduction in risk. We previously showed that a common CNR1 haplotype, H3 (frequency 20%), is protective against the reduction in HDL-C that typically accompanies weight gain. In the present study, we extend that observation by reporting the effect of CNR1 haplotype on HDL-C response to modification of dietary fat intake in weight maintenance and weight loss. Methods Six haplotype tagging SNPs that cover the CNR1 gene locus were genotyped in 590 adults of varying body mass index (cohort 1 is 411 males with BMI 18.5–30.0 kg/m2; cohort 2 is 71 females with BMI18.5–30.0 kg/m2; and cohort 3 is 108 females with BMI 30–39.9 kg/m2). Dietary intakes were modified so that fat intake in the “high fat” condition was 15–20% greater than in the “low fat” condition, and lipid profiles were compared between carriers versus noncarriers for each of the five commonly observed CNR1 haplotypes (H1–H5). Results In normal to overweight subjects on eucaloric diets, the H3 haplotype was significantly associated with short-term high fat diet induced changes in HDL-C level in females (carriers 5.9 mg/dl>noncarriers, p = 0.007). The H3 haplotype was also significantly associated with HDL-C level after 16 weeks on high fat calorie restricted diet in obese females (carriers 6.8 mg/dl>noncarriers, p = 0.009). Conclusion Variability within the CNR1 gene locus contributes to gender-related differences in the HDL-cholesterol response to change in dietary fat intake. Functional characterization of this relationship in vitro may offer insights that potentially yield therapeutic guidance targeting dietary macronutrient composition, a direction much needed in the current epidemic of obesity.
Knowledge-Driven Multi-Locus Analysis Reveals Gene-Gene Interactions Influencing HDL Cholesterol Level in Two Independent EMR-Linked Biobanks
Stephen D. Turner,Richard L. Berg,James G. Linneman,Peggy L. Peissig,Dana C. Crawford,Joshua C. Denny,Dan M. Roden,Catherine A. McCarty,Marylyn D. Ritchie,Russell A. Wilke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019586
Abstract: Genome-wide association studies (GWAS) are routinely being used to examine the genetic contribution to complex human traits, such as high-density lipoprotein cholesterol (HDL-C). Although HDL-C levels are highly heritable (h2~0.7), the genetic determinants identified through GWAS contribute to a small fraction of the variance in this trait. Reasons for this discrepancy may include rare variants, structural variants, gene-environment (GxE) interactions, and gene-gene (GxG) interactions. Clinical practice-based biobanks now allow investigators to address these challenges by conducting GWAS in the context of comprehensive electronic medical records (EMRs). Here we apply an EMR-based phenotyping approach, within the context of routine care, to replicate several known associations between HDL-C and previously characterized genetic variants: CETP (rs3764261, p = 1.22e-25), LIPC (rs11855284, p = 3.92e-14), LPL (rs12678919, p = 1.99e-7), and the APOA1/C3/A4/A5 locus (rs964184, p = 1.06e-5), all adjusted for age, gender, body mass index (BMI), and smoking status. By using a novel approach which censors data based on relevant co-morbidities and lipid modifying medications to construct a more rigorous HDL-C phenotype, we identified an association between HDL-C and TRIB1, a gene which previously resisted identification in studies with larger sample sizes. Through the application of additional analytical strategies incorporating biological knowledge, we further identified 11 significant GxG interaction models in our discovery cohort, 8 of which show evidence of replication in a second biobank cohort. The strongest predictive model included a pairwise interaction between LPL (which modulates the incorporation of triglyceride into HDL) and ABCA1 (which modulates the incorporation of free cholesterol into HDL). These results demonstrate that gene-gene interactions modulate complex human traits, including HDL cholesterol.
Genome-Wide Association of Lipid-Lowering Response to Statins in Combined Study Populations
Mathew J. Barber,Lara M. Mangravite,Craig L. Hyde,Daniel I. Chasman,Joshua D. Smith,Catherine A. McCarty,Xiaohui Li,Russell A. Wilke,Mark J. Rieder,Paul T. Williams,Paul M. Ridker,Aurobindo Chatterjee,Jerome I. Rotter,Deborah A. Nickerson,Matthew Stephens,Ronald M. Krauss
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0009763
Abstract: Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs) contributing to this variation, we performed a combined analysis of genome-wide association (GWA) results from three trials of statin efficacy.
Methodische aspekte und ergebnisse der vergleiche einiger milchrind-und zweinutzungsherkünfte sowie deren kreuzungen
G Sch?nmuth, G Seeland, A Wilke
Genetics Selection Evolution , 1975, DOI: 10.1186/1297-9686-7-2-234b
Stochastic field theory for a Dirac particle propagating in gauge field disorder
T. Guhr,T. Wilke,H. A. Weidenmueller
Physics , 1999, DOI: 10.1103/PhysRevLett.85.2252
Abstract: Recent theoretical and numerical developments show analogies between quantum chromodynamics (QCD) and disordered systems in condensed matter physics. We study the spectral fluctuations of a Dirac particle propagating in a finite four dimensional box in the presence of gauge fields. We construct a model which combines Efetov's approach to disordered systems with the principles of chiral symmetry and QCD. To this end, the gauge fields are replaced with a stochastic white noise potential, the gauge field disorder. Effective supersymmetric non-linear sigma-models are obtained. Spontaneous breaking of supersymmetry is found. We rigorously derive the equivalent of the Thouless energy in QCD. Connections to other low-energy effective theories, in particular the Nambu-Jona-Lasinio model and chiral perturbation theory, are found.
Bi-log-concave distribution functions
Lutz Duembgen,Petro Kolesnyk,Ralf A. Wilke
Statistics , 2015,
Abstract: A distribution function F is called bi-log-concave, if both log(F) and log(1 - F) are concave. Many commonly considered distributions meet this new shape-constraint. For instance, any c.d.f. F with log-concave density f = F' is bi-log-concave. But bi-log-concavity alone allows for multi-modal densities. Various characterizations are provided. It is shown that combining any nonparametric confidence band for F with the new shape-constraint leads to substantial improvements, particularly in the tails. To pinpoint this, we show that these confidence bands imply non-trivial confidence bounds for arbitrary moments and the moment generating function of F.
Bench-to-bedside review: Vasopressin in the management of septic shock
James A Russell
Critical Care , 2011, DOI: 10.1186/cc8224
Abstract: Vasopressin stimulates a family of receptors: AVPR1a (also known as V1 receptor, mainly vascular), AVPR1b (V3 receptor, mainly central), AVPR2 (V2 receptor, mainly renal), oxytocin receptors and purinergic receptors. AVPR1a, a G-protein coupled receptor, is responsible for vasoconstriction associated with vasopressin and is expressed on vascular smooth muscle, hepatocytes and platelets (Figure 1). G proteins stimulate a phosphatidyl-inositol-calcium signaling pathway, causing smooth muscle contraction [1-3]. Stimulation of the AVPR1a receptor also induces production of the potent vasodilator nitric oxide in coronary vessels [4] and pulmonary vessels [5-7]. Genetic variants of AVPR1a have been associated with essential hypertension [2], autism [8], and generosity [9]. The effects of sepsis on AVPR1a are complex and include downregulation of the receptor [10,11], yet there can be increased sensitivity to vasopressin in sepsis (compared with normal controls who are hemodynamically stable) [12].AVPR1b (or V3 receptor) is expressed in the anterior pituitary gland and hippocampus. Stimulation of AVPR1b by vasopressin releases adrenocorticotropic hormone (ACTH) because vasopressin flows from the posterior pituitary through pituitary portal capillaries to bind to the AVPR1b on corticotrophic cells of the anterior pituitary. Vasopressin thus interacts with the corticosteroid axis in response to stresses such as hypotension [13,14]. Vasopressin and corticotrophin-releasing hormone stimulate different signaling systems and have synergistic effects on release of ACTH. AVPR1b knockout mice have an impaired stress response because of blunted ACTH response [15]. In contrast, overexpression of AVPR1b has been associated with pituitary adenomas and ectopic ACTH syndrome [16].AVPR2 (V2 receptor) is expressed in the renal collecting duct. Vasopressin is a trophic factor of the ascending limb of Henle and thereby creates the gradient that mediates vasopressin's antidiuretic effect. AVP
Gene expression in human sepsis: what have we learned?
James A Russell
Critical Care , 2011, DOI: 10.1186/cc9384
Abstract: In the previous issue of Critical Care, Tang and colleagues [1] offer a very novel systematic review of 12 studies of gene expression in blood of humans who have sepsis. The studies conclude that there was no discernable transition from a pro- to an anti-inflammatory expression pheno-type in whole blood in human sepsis. The authors posit that sepsis as a pro-inflammatory phenotype that shifts to an anti-inflammatory phenotype may be flawed. This provocative conclusion disagrees with the evidence (animal and clinical); furthermore, ongoing translational and clinical studies hinge on the premise that there is indeed a transition (at about days 3 to 5 of clinical sepsis) from a brisk pro-inflammatory to an anti-inflammatory phenotype.The innate immune system is the 'hard-wired' rapid response system of each individual [2]. The first step in recognition of microorganisms is that pattern recognition receptors (such as the Toll-like receptor family) bind to highly conserved molecules called pathogen-associated molecular proteins. Accordingly, Tang and colleagues [1] found that upregulation of pathogen recognition receptors and signal transduction pathways was a consistent theme in expression studies.The review by Tang and colleagues [1] has strengths, including defined screening criteria, broad literature review, strict inclusion criteria, and transparent methods for assessing strengths and weaknesses of studies to say nothing of the research strengths of the authors. Further-more, the summary is presented in clear tables accessible to expert and non-expert readers alike.There are other issues to consider in the review. First, one source of variation in gene expression studies in sepsis is variability in time from onset of sepsis to time of blood draw. The authors found no obvious pattern to suggest differences in gene expression over time. However, the only studies that can be sure of onset of sepsis are the human endotoxemia studies (because time of endotoxin administra
Epidemiology of vasomotor rhinitis
Russell A Settipane
World Allergy Organization Journal , 2009, DOI: 10.1097/wox.0b013e3181ac91ae
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