Multi-ethnic fine-mapping of 14 central adiposity loci.

The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowing the signals remains necessary. Twelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Trans-ethnic analyses at five loci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within ± 250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality.

The transventricular-transseptal access to the aortic root: a new route for extrapleural trans-catheter aortic stent-valve implantation.

Objective: The aim of this study was to investigate the feasibility of transventricular-transseptal approach (TVSA) for extrapleural transcatheter aortic valved stent implantation via a subxyphoidian access. Methods: In five porcine experiments (52.3 +/- 10.9 kg) the right ventricle was exposed via subxyphoidian access. Under the guidance of intracardiac echocardiography (ICE) and fluoroscopy, the transseptal access from right ventricle to left ventricle was created progressively by puncture and dilation with dilators (8F-26F). Valved stents built in-house from commercial tanned pericardium and self-expandable Nitinol stents were loaded into a cartridge. A delivery sheath was then introduced from the right ventricle into the left ventricle and then into the ascending aorta. The cartridge was connected and the valved stent was deployed in the aortic position. Then, the ventricular septal access was sealed with an Amplatzer septal occluder device and the right ventricular access was closed by tying prepared purse-string suture directly. Thirty minutes after the whole procedure, the animals were sacrificed for macroscopic evaluation of the position of valved stent and septal closure device. Result: Procedural success of TVSA was 100% at the first attempt. Mean procedure time was 49 +/- 4 min. Progressive dilatation of the transseptal access resulted in a measurable ventricular septal defect (VSD) after dilator sizes 18F and more. All valved stents were delivered at the target site over the native aortic valve with good acute valve function and no paravalvular leaks. During the procedure, premature beats (5/5) and supraventriclar tachycardias (5/5) were observed, but no atrial-ventricular block (0/5) occurred. Heart rate before (after) was 90 +/- 3 beats min(-1) (100 +/- 2 beats min(-1): p < 0.05), whereas blood pressure was 60 + 1 mm Hg (55 + 2 mm Hg (p < 0.05)). Total blood loss was 280 + 10 ml. The Amplatzer septal occluder devices were fully deployed and the ventricular septal accesses were sealed successfully, without detectable residual shunt. Conclusion: Trans-catheter implantation of aortic valved stent via extrapleural transventricular-transseptal access is technically feasible and has the potential for a simplified procedure under local anaesthesia. (C) 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B. V. All rights reserved.

The UniProtKB/Swiss-Prot Tox-Prot program: A central hub of integrated venom protein data.

Animal toxins are of interest to a wide range of scientists, due to their numerous applications in pharmacology, neurology, hematology, medicine, and drug research. This, and to a lesser extent the development of new performing tools in transcriptomics and proteomics, has led to an increase in toxin discovery. In this context, providing publicly available data on animal toxins has become essential. The UniProtKB/Swiss-Prot Tox-Prot program (http://www.uniprot.org/program/Toxins) plays a crucial role by providing such an access to venom protein sequences and functions from all venomous species. This program has up to now curated more than 5000 venom proteins to the high-quality standards of UniProtKB/Swiss-Prot (release 2012_02). Proteins targeted by these toxins are also available in the knowledgebase. This paper describes in details the type of information provided by UniProtKB/Swiss-Prot for toxins, as well as the structured format of the knowledgebase.

Contrasted influences of moon phases on the reproduction and movement patterns of four amphibian species inhabiting different habitats in central Italy

Many studies have provided evidence that prey adjust their behaviour to adaptively balance the fitness effects of reproduction and predation risk. Nocturnal terrestrial animals should deal with a range of environmental conditions during the reproductive season at the breeding sites, including a variable amount of natural ambient light. High degrees of illumination are expected to minimize those behaviours that might increase the animal detection by predators. Therefore, under habitat variable brightness conditions and in different ecosystems, the above mentioned behaviours are expected to depend on the variation in predation risk. Although moon effects on amphibian biology have been recognized, the direction of this influence is rather controversial with evidences of both increased and depressed activity under full moon. We tested in four nocturnal amphibian species (Hyla intermedia, Rana dalmatina, Rana italica, Salamandrina perspicillata) the effects of different (i) light conditions and (ii) habitats (open land vs. dense forest) on the reproductive phenology. Our results showed that the effects of the lunar cycle on the study species are associated with the change in luminosity, and there is no evidence of an endogenous rhythm controlled by biological clocks. The habitat type conditioned the amphibian reproductive strategy in relation to moon phases. Open habitat breeders (e. g., ponds with no canopy cover) strongly avoided conditions with high brightness, whereas forest habitat breeders were apparently unaffected by the different moon phases. Indeed, for all the studied species no effects of the moon phase itself on the considered metrics were found. Rather, the considered amphibian species seem to be conditioned mainly by moonlight irrespective of the moon phase. The two anurans spawning in open habitat apparently adjust their oviposition timing by balancing the fitness effects of the risk to be detected by predators and the reproduction.

Estimating attributable mortality due to nosocomial infections acquired in intensive care units.

BACKGROUND: The strength of the association between intensive care unit (ICU)-acquired nosocomial infections (NIs) and mortality might differ according to the methodological approach taken. OBJECTIVE: To assess the association between ICU-acquired NIs and mortality using the concept of population-attributable fraction (PAF) for patient deaths caused by ICU-acquired NIs in a large cohort of critically ill patients. SETTING: Eleven ICUs of a French university hospital. DESIGN: We analyzed surveillance data on ICU-acquired NIs collected prospectively during the period from 1995 through 2003. The primary outcome was mortality from ICU-acquired NI stratified by site of infection. A matched-pair, case-control study was performed. Each patient who died before ICU discharge was defined as a case patient, and each patient who survived to ICU discharge was defined as a control patient. The PAF was calculated after adjustment for confounders by use of conditional logistic regression analysis. RESULTS: Among 8,068 ICU patients, a total of 1,725 deceased patients were successfully matched with 1,725 control patients. The adjusted PAF due to ICU-acquired NI for patients who died before ICU discharge was 14.6% (95% confidence interval [CI], 14.4%-14.8%). Stratified by the type of infection, the PAF was 6.1% (95% CI, 5.7%-6.5%) for pulmonary infection, 3.2% (95% CI, 2.8%-3.5%) for central venous catheter infection, 1.7% (95% CI, 0.9%-2.5%) for bloodstream infection, and 0.0% (95% CI, -0.4% to 0.4%) for urinary tract infection. CONCLUSIONS: ICU-acquired NI had an important effect on mortality. However, the statistical association between ICU-acquired NI and mortality tended to be less pronounced in findings based on the PAF than in study findings based on estimates of relative risk. Therefore, the choice of methods does matter when the burden of NI needs to be assessed.

The central role of mosquito cytochrome P450 CYP6Zs in insecticide detoxification revealed by functional expression and structural modelling.

The resistance of mosquitoes to chemical insecticides is threatening vector control programmes worldwide. Cytochrome P450 monooxygenases (CYPs) are known to play a major role in insecticide resistance, allowing resistant insects to metabolize insecticides at a higher rate. Among them, members of the mosquito CYP6Z subfamily, like Aedes aegypti CYP6Z8 and its Anopheles gambiae orthologue CYP6Z2, have been frequently associated with pyrethroid resistance. However, their role in the pyrethroid degradation pathway remains unclear. In the present study, we created a genetically modified yeast strain overexpressing Ae. aegypti cytochrome P450 reductase and CYP6Z8, thereby producing the first mosquito P450-CPR (NADPH-cytochrome P450-reductase) complex in a yeast recombinant system. The results of the present study show that: (i) CYP6Z8 metabolizes PBAlc (3-phenoxybenzoic alcohol) and PBAld (3-phenoxybenzaldehyde), common pyrethroid metabolites produced by carboxylesterases, producing PBA (3-phenoxybenzoic acid); (ii) CYP6Z8 transcription is induced by PBAlc, PBAld and PBA; (iii) An. gambiae CYP6Z2 metabolizes PBAlc and PBAld in the same way; (iv) PBA is the major metabolite produced in vivo and is excreted without further modification; and (v) in silico modelling of substrate-enzyme interactions supports a similar role of other mosquito CYP6Zs in pyrethroid degradation. By playing a pivotal role in the degradation of pyrethroid insecticides, mosquito CYP6Zs thus represent good targets for mosquito-resistance management strategies.

Influence of environmental conditions on the distribution of Central Asian green toads with three ploidy levels.

We studied the distribution of Palearctic green toads (Bufo viridis subgroup), an anuran species group with three ploidy levels, inhabiting the Central Asian Amudarya River drainage. Various approaches (one-way, multivariate, components variance analyses and maximum entropy modelling) were used to estimate the effect of altitude, precipitation, temperature and land vegetation covers on the distribution of toads. It is usually assumed that polyploid species occur in regions with harsher climatic conditions (higher latitudes, elevations, etc.), but for the green toads complex, we revealed a more intricate situation. The diploid species (Bufo shaartusiensis and Bufo turanensis) inhabit the arid lowlands (from 44 to 789 m a.s.l.), while tetraploid Bufo pewzowi were recorded in mountainous regions (340-3492 m a.s.l.) with usually lower temperatures and higher precipitation rates than in the region inhabited by diploid species. The triploid species Bufo baturae was found in the Pamirs (Tajikistan) at the highest altitudes (2503-3859 m a.s.l.) under the harshest climatic conditions.