Brief inhalation of nitric oxide increases resuscitation success and improves 7-day-survival after cardiac arrest in rats: a randomized controlled animal study

Introduction: Inhaled nitric oxide (iNO) improves outcomes when given post systemic ischemia/reperfusion injury. iNO given during cardiopulmonary resuscitation (CPR) may therefore improve return of spontaneous circulation (ROSC) rates and functional outcome after cardiac arrest (CA). Methods: Thirty male Sprague-Dawley rats were subjected to 10 minutes of CA and at least 3 minutes of CPR. Animals were randomized to receive either 0 (n = 10, Control), 20 (n = 10, 20 ppm), or 40 (n = 10, 40 ppm) ppm iNO during CPR until 30 minutes after ROSC. A neurological deficit score was assessed daily for seven days following the experiment. On day 7, brains, hearts, and blood were sampled for histological and biochemical evaluation. Results: During CPR, 20 ppm iNO significantly increased diastolic arterial pressure (Control: 57 ± 5.04 mmHg; 20 ppm: 71.57 ± 57.3 mmHg, p < 0.046) and decreased time to ROSC (Control: 842 ± 21 s; 20 ppm: 792 ± 5 s, (p = 0.02)). Thirty minutes following ROSC, 20 ppm iNO resulted in an increase in mean arterial pressure (Control: 83 ± 4 mmHg; 20 ppm: 98 ± 4 mmHg, p = 0.035), a less pronounced rise in lactate and inflammatory cytokine levels, and attenuated cardiac damage. Inhalation of NO at 20 ppm improved neurological outcomes in rats 2 to 7 days after CA and CPR. This translated into increases in 7 day survival (Control: 4; 20 ppm: 10; 40 ppm 6, (p ≤ 0.05 20 ppm vs Control and 40 ppm). Conclusions: Our study revealed that breathing NO during CPR markedly improved resuscitation success, 7-day neurological outcomes and survival in a rat model of VF-induced cardiac arrest and CPR. These results support the beneficial effects of NO inhalation after cardiac arrest and CPR

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Spent fuel sabotage aerosol test program :FY 2005-06 testing and aerosol data summary.

This multinational, multi-phase spent fuel sabotage test program is quantifying the aerosol particles produced when the products of a high energy density device (HEDD) interact with and explosively particulate test rodlets that contain pellets of either surrogate materials or actual spent fuel. This program has been underway for several years. This program provides source-term data that are relevant to some sabotage scenarios in relation to spent fuel transport and storage casks, and associated risk assessments. This document focuses on an updated description of the test program and test components for all work and plans made, or revised, primarily during FY 2005 and about the first two-thirds of FY 2006. It also serves as a program status report as of the end of May 2006. We provide details on the significant findings on aerosol results and observations from the recently completed Phase 2 surrogate material tests using cerium oxide ceramic pellets in test rodlets plus non-radioactive fission product dopants. Results include: respirable fractions produced; amounts, nuclide content, and produced particle size distributions and morphology; status on determination of the spent fuel ratio, SFR (the ratio of respirable particles from real spent fuel/respirables from surrogate spent fuel, measured under closely matched test conditions, in a contained test chamber); and, measurements of enhanced volatile fission product species sorption onto respirable particles. We discuss progress and results for the first three, recently performed Phase 3 tests using depleted uranium oxide, DUO{sub 2}, test rodlets. We will also review the status of preparations and the final Phase 4 tests in this program, using short rodlets containing actual spent fuel from U.S. PWR reactors, with both high- and lower-burnup fuel. These data plus testing results and design are tailored to support and guide, follow-on computer modeling of aerosol dispersal hazards and radiological consequence assessments. This spent fuel sabotage--aerosol test program, performed primarily at Sandia National Laboratories, with support provided by both the U.S. Department of Energy and the Nuclear Regulatory Commission, had significant inputs from, and is strongly supported and coordinated by both the U.S. and international program participants in Germany, France, and the U.K., as part of the international Working Group for Sabotage Concerns of Transport and Storage Casks, WGSTSC

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Sodium ion interactions with aqueous glucose: Insights from quantum mechanics, molecular dynamics, and experiment

In the last several decades, significant efforts have been conducted to understand the fundamental reactivity of glucose derived from plant biomass in various chemical environments for conversion to renewable fuels and chemicals. For reactions of glucose in water, it is known that inorganic salts naturally present in biomass alter the product distribution in various deconstruction processes. However, the molecular-level interactions of alkali metal ions and glucose are unknown. These interactions are of physiological interest as well, for example, as they relate to cation-glucose cotransport. Here, we employ quantum mechanics (QM) to understand the interaction of a prevalent alkali metal, sodium, with glucose from a structural and thermodynamic perspective. The effect on B-glucose is subtle: a sodium ion perturbs bond lengths and atomic partial charges less than rotating a hydroxymethyl group. In contrast, the presence of a sodium ion significantly perturbs the partial charges of α-glucose anomeric and ring oxygens. Molecular dynamics (MD) simulations provide dynamic sampling in explicit water, and both the QM and the MD results show that sodium ions associate at many positions with respect to glucose with reasonably equivalent propensity. This promiscuous binding nature of Na + suggests that computational studies of glucose reactions in the presence of inorganic salts need to ensure thorough sampling of the cation positions, in addition to sampling glucose rotamers. The effect of NaCl on the relative populations of the anomers is experimentally quantified with light polarimetry. These results support the computational findings that Na + interacts similarly with a- and B-glucose