Acculturation is associated with left ventricular mass in a multiethnic sample: the Multi-Ethnic Study of Atherosclerosis.

BackgroundAcculturation involves stress-related processes and health behavioral changes, which may have an effect on left ventricular (LV) mass, a risk factor for cardiovascular disease (CVD). We examined the relationship between acculturation and LV mass in a multiethnic cohort of White, African-American, Hispanic and Chinese subjects.MethodsCardiac magnetic resonance assessment was available for 5004 men and women, free of clinical CVD at baseline. Left ventricular mass index was evaluated as LV mass indexed by body surface area. Acculturation was characterized based on language spoken at home, place of birth and length of stay in the United States (U.S.), and a summary acculturation score ranging from 0 = least acculturated to 5 = most acculturated. Mean LV mass index adjusted for traditional CVD risk factors was compared across acculturation levels.ResultsUnadjusted mean LV mass index was 78.0 ± 16.3 g/m(2). In adjusted analyses, speaking exclusively English at home compared to non-English language was associated with higher LV mass index (81.3 ± 0.4 g/m(2) vs 79.9 ± 0.5 g/m(2), p = 0.02). Among foreign-born participants, having lived in the U.S. for ≥ 20 years compared to < 10 years was associated with greater LV mass index (81.6 ± 0.7 g/m(2) vs 79.5 ± 1.1 g/m(2), p = 0.02). Compared to those with the lowest acculturation score, those with the highest score had greater LV mass index (78.9 ± 1.1 g/m(2) vs 81.1 ± 0.4 g/m(2), p = 0.002). There was heterogeneity in which measure of acculturation was associated with LV mass index across ethnic groups.ConclusionsGreater acculturation is associated with increased LV mass index in this multiethnic cohort. Acculturation may involve stress-related processes as well as behavioral changes with a negative effect on cardiovascular health

Fenofibrate reduces osteonecrosis without affecting antileukemic efficacy in dexamethasone-treated mice

Recent clinical trials in children with acute lymphoblastic leukemia (ALL) indicate that severe hypertriglyceridemia (> 1000 mg/dL) during therapy is associated with increased frequency of symptomatic osteonecrosis. Interventions to lower triglycerides have been considered, but there have been no pre-clinical studies investigating impact of lowering triglycerides on osteonecrosis risk, nor whether such interventions interfere with the antileukemic efficacy of ALL treatment. We utilized our clinically relevant mouse model of dexamethasone-induced osteonecrosis to determine if fenofibrate decreased osteonecrosis. To test whether fenofibrate affected the antileukemic efficacy of dexamethasone, we utilized a BCR-ABL+ model of ALL. Serum triglycerides were reduced with fenofibrate throughout treatment, with the most pronounced 4.5-fold decrease at week 3 (p<1x10-6). Both frequency (33% versus 74%, p=0.006) and severity (median necrosis score of 0 versus 75; p=6x10-5) of osteonecrosis were reduced with fenofibrate. Fenofibrate had no impact on BCR-ABL+ ALL survival (p=0.65) nor on the antileukemic properties of dexamethasone (p=0.49). These data suggest that lowering triglycerides with fenofibrate reduces dexamethasone-induced osteonecrosis while maintaining antileukemic efficacy, and thus may be considered for clinical trials

Concentraciones de inmunoglobulina G sérica en alpacas neonatas muertas por enterotoxemia

The objective of the present study was to determine the levels of serum immunoglobulin G (IgG) in neonatal alpacas (5-23 days of age) killed by enterotoxemia and in animals of similar ages, but clinically healthy. In a first phase, a standard curve of physiological degradation of serum IgG was established from blood sera of six apparently healthy neonates from day 2 to 21 days of age (n=9). In a second phase, serum IgG concentrations were determined in 17 dead neonatal alpacas with lesions compatible with enterotoxemia and in 26 animals of similar ages, apparently healthy. The concentrations of IgG, determined by the Radial Immunodiffusion test, showed that all the animals at 48 hours of birth had adequate concentrations of IgG, while only three of the animals killed by enterotoxemia had IgG levels below the obtained standard curve, although only one of them with levels below 900 mg/dl at 14 days, which could be considered as a partial passive transfer failure. The serum IgG concentrations of the 26 clinically normal animals (2893 mg/dl) and those obtained from animals killed by enterotoxemia (2361 mg/dl) were statistically similar. The risk analysis using the Odds Ratio test (OR: 5.35, CI = 0.50-57.22) indicated that there is no association between adequate levels of IgG and mortality from enterotoxemia in neonatal alpacas.El presente estudio tuvo como objetivo determinar los niveles de Inmunoglobulina G (IgG) sérica en alpacas neonatas (5-23 días de edad) muertas por enterotoxemia y en animales de edades similares, pero clínicamente sanos. En una primera fase se estableció una curva estándar de degradación fisiológica de la IgG sérica a partir de sueros sanguíneos de seis neonatos aparentemente sanos a partir del día 2 y hasta los 21 días de edad (n=9). En una segunda fase se determinaron las concentraciones de IgG sérica en 17 alpacas neonatas muertas con lesiones compatibles con enterotoxemia y en 26 animales, de edades similares, aparentemente sanos. Las concentraciones de IgG, determinadas por la prueba de Inmunodifusión Radial, evidenciaron que todas las crías a las 48 horas del nacimiento presentaron concentraciones adecuadas de IgG, mientras que solo tres de los animales muertos por enterotoxemia tenían niveles de IgG por debajo de la curva estándar de degradación, aunque solo una de ellas con niveles inferiores a 900 mg/dl a los 14 días, lo que podría ser considerado como falla parcial de transferencia pasiva. Las concentraciones de IgG sérica de los 26 animales clínicamente normales (2893 mg/dl) y aquellas obtenidas de animales muertos por enterotoxemia (2361 mg/dl) fueron estadísticamente similares. El análisis de riesgo mediante la prueba de Odds Ratio (OR: 5.35; IC= 0.50-57.22) indicó que no existe asociación entre niveles adecuados de IgG y la mortalidad por enterotoxemia en alpacas neonatas

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Open Data, Open Source and Open Standards in chemistry: The Blue Obelisk five years on

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background The Blue Obelisk movement was established in 2005 as a response to the lack of Open Data, Open Standards and Open Source (ODOSOS) in chemistry. It aims to make it easier to carry out chemistry research by promoting interoperability between chemistry software, encouraging cooperation between Open Source developers, and developing community resources and Open Standards. Results This contribution looks back on the work carried out by the Blue Obelisk in the past 5 years and surveys progress and remaining challenges in the areas of Open Data, Open Standards, and Open Source in chemistry. Conclusions We show that the Blue Obelisk has been very successful in bringing together researchers and developers with common interests in ODOSOS, leading to development of many useful resources freely available to the chemistry community.Peer Reviewe

Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders

Background: De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder. Methods: To minimise ascertainment bias, we recruited nine additional individuals with CDK13 pathogenic variants from clinical and research exome laboratory sequencing cohorts. Each individual underwent dysmorphology exam and comprehensive medical history review. Results: We demonstrate greater than expected phenotypic heterogeneity, including 33% (3/9) of individuals without structural heart disease on echocardiogram. There was a high penetrance for a unique constellation of facial dysmorphism and global developmental delay, as well as less frequently seen renal and sacral anomalies. Two individuals had novel CDK13 variants (p.Asn842Asp, p.Lys734Glu), while the remaining seven unrelated individuals had a recurrent, previously published p.Asn842Ser variant. Summary of all variants published to date demonstrates apparent restriction of pathogenic variants to the protein kinase domain with clustering in the ATP and magnesium binding sites. Conclusions: Here we provide detailed phenotypic and molecular characterisation of individuals with pathogenic variants in CDK13 and propose management guidelines based upon the estimated prevalence of anomalies identified. Keywords: CDK13, CHDFIDD, De novo variant, Neurodevelopmental disorders, Agenesis of the corpus callosum, Hypertelorism, Developmental delay, Cyclin-dependent kinase, Undiagnosed Diseases Networ

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Improved imputation quality of low-frequency and rare variants in European samples using the 'Genome of the Netherlands'

Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with 'true' genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05-0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r 2, increased from 0.61 to 0.71. W