Prevalence of Gastroesophageal Reflux in Cats During Anesthesia and Effect of Omeprazole on Gastric pH.

BackgroundGastroesophageal reflux (GER) is poorly characterized in anesthetized cats, but can cause aspiration pneumonia, esophagitis, and esophageal stricture formation.ObjectiveTo determine whether pre-anesthetic orally administered omeprazole increases gastric and esophageal pH and increases serum gastrin concentrations in anesthetized cats, and to determine the prevalence of GER using combined multichannel impedance and pH monitoring.AnimalsTwenty-seven healthy cats undergoing elective dental procedures.MethodsProspective, double-masked, placebo-controlled, randomized clinical trial. Cats were randomized to receive 2 PO doses of omeprazole (1.45-2.20 mg/kg) or an empty gelatin capsule placebo 18-24 hours and 4 hours before anesthetic induction. Blood for measurement of serum gastrin concentration was collected during anesthetic induction. An esophageal pH/impedance catheter was utilized to continuously measure esophageal pH and detect GER throughout anesthesia.ResultsMean gastric pH in the cats that received omeprazole was 7.2 ± 0.4 (range, 6.6-7.8) and was significantly higher than the pH in cats that received the placebo 2.8 ± 1.0 (range, 1.3-4.1; P < .001). Omeprazole administration was not associated with a significant increase in serum gastrin concentration (P = .616). Nine of 27 cats (33.3%) had ≥1 episode of GER during anesthesia.Conclusions and clinical relevancePre-anesthetic administration of 2 PO doses of omeprazole at a dosage of 1.45-2.20 mg/kg in cats was associated with a significant increase in gastric and esophageal pH within 24 hours, but was not associated with a significant increase in serum gastrin concentration. Prevalence of reflux events in cats during anesthesia was similar to that of dogs during anesthesia

Comment on "Protein assemblies ejected directly from native membranes yield complexes for mass spectrometry".

Chorev et al (Reports, 16 November 2018, p. 829) describe mass spectrometry on mitochondrial membrane proteins ionized directly from their native environment. However, the assignments made to measured masses are incorrect or inconclusive and lack experimental validation. The proteins are not in their "native" condition: They have been stripped of tightly bound lipids, and the complexes are fragmented or in physiologically irrelevant oligomeric states

Free-standing graphene membranes on glass nanopores for ionic current measurements

A method is established to reliably suspend graphene monolayers across glass nanopores as a simple, low cost platform to study ionic transport through graphene membranes. We systematically show that the graphene seals glass nanopore openings with areas ranging from 180 nm2 to 20 μm2, allowing detailed measurements of ionic current and transport through graphene. In combination with in situ Raman spectroscopy, we characterise the defects formed in ozone treated graphene, confirming an increase in ionic current flow with defect density. This highlights the potential of our method for studying single molecule sensing and filtration.The authors would like to thank S. Purushothaman and K. Göpfrich for careful reading of the manuscript and V. Thacker for useful discussions. This work was supported by the EPSRC Cambridge NanoDTC, EP/G037221/1, and EPSRC grant GRAPHTED, EP/K016636/1. R.S.W. acknowledges a Research Fellowship from St. John's College, Cambridge. N.A.W.B. acknowledges an EPSRC doctoral prize award.This is the accepted manuscript. Copyright 2015 American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The final version is available in Applied Physics Letters 106, 023119 (2015); doi: 10.1063/1.490623

Measuring the proton selectivity of graphene membranes

By systematically studying the proton selectivity of free-standing graphene membranes in aqueous solutions we demonstrate that protons are transported by passing through defects. We study the current-voltage characteristics of single-layer graphene grown by chemical vapour deposition (CVD) when a concentration gradient of HCl exists across it. Our measurements can unambiguously determine that H+ ions are responsible for the selective part of the ionic current. By comparing the observed reversal potentials with positive and negative controls we demonstrate that the as-grown graphene is only weakly selective for protons. We use atomic layer deposition to block most of the defects in our CVD graphene. Our results show that a reduction in defect size decreases the ionic current but increases proton selectivity.This is the author accepted manuscript. The final version is available from AIP via http://dx.doi.org/10.1063/1.493633

The DNA damage checkpoint pathway promotes extensive resection and nucleotide synthesis to facilitate homologous recombination repair and genome stability in fission yeast.

DNA double-strand breaks (DSBs) can cause chromosomal rearrangements and extensive loss of heterozygosity (LOH), hallmarks of cancer cells. Yet, how such events are normally suppressed is unclear. Here we identify roles for the DNA damage checkpoint pathway in facilitating homologous recombination (HR) repair and suppressing extensive LOH and chromosomal rearrangements in response to a DSB. Accordingly, deletion of Rad3(ATR), Rad26ATRIP, Crb2(53BP1) or Cdc25 overexpression leads to reduced HR and increased break-induced chromosome loss and rearrangements. We find the DNA damage checkpoint pathway facilitates HR, in part, by promoting break-induced Cdt2-dependent nucleotide synthesis. We also identify additional roles for Rad17, the 9-1-1 complex and Chk1 activation in facilitating break-induced extensive resection and chromosome loss, thereby suppressing extensive LOH. Loss of Rad17 or the 9-1-1 complex results in a striking increase in break-induced isochromosome formation and very low levels of chromosome loss, suggesting the 9-1-1 complex acts as a nuclease processivity factor to facilitate extensive resection. Further, our data suggest redundant roles for Rad3ATR and Exo1 in facilitating extensive resection. We propose that the DNA damage checkpoint pathway coordinates resection and nucleotide synthesis, thereby promoting efficient HR repair and genome stability

Validation of Exercise Capacity as a Surrogate Endpoint in Exercise-Based Rehabilitation for Heart Failure: A Meta-Analysis of Randomized Controlled Trials

This is the final version. Available on open access from Elsevier via the DOI in this recordObjectives: This study sought to validate exercise capacity (EC) as a surrogate for mortality, hospitalization, and health-related quality of life (HRQOL). Background: EC is often used as a primary outcome in exercise-based cardiac rehabilitation (CR) trials of heart failure (HF) via direct cardiorespiratory assessment of maximum oxygen uptake (VO2peak) or through submaximal tests, such as the 6-min walk test (6MWT). Methods: After a systematic review, 31 randomized trials of exercise-based CR compared with no exercise control (4,784 HF patients) were included. Outcomes were pooled using random effects meta-analyses, and inverse variance weighted linear regression equations were fitted to estimate the relationship between the CR on EC and all-cause mortality, hospitalization, and HRQOL. Spearman correlation coefficient (ρ), R2 at trial level, and surrogate threshold effect (STE) were calculated. STE represents the intercept of the prediction band of the regression line with null effect on the final outcome. Results: Exercise-based CR is associated with positive effects on EC measured through VO2peak (+3.10 ml/kg/min; 95% confidence interval [CI]: 2.01 to 4.20) or 6MWT (+41.15 m; 95% CI: 16.68 to 65.63) compared to control. The analyses showed a low level of association between improvements in EC (VO2peak or 6MWT) and mortality and hospitalization. Moderate levels of correlation between EC with HRQOL were seen (e.g., R2 <52%; |ρ| < 0.72). Estimated STE was an increase of 5 ml/kg/min for VO2peak and 80 m for 6MWT to predict a significant improvement in HRQOL. Conclusions: The study results indicate that EC is a poor surrogate endpoint for mortality and hospitalization but has moderate validity as a surrogate for HRQOL. Further research is needed to confirm these findings across other HF interventions.National Institute for Health Research (NIHR)University of Exete

The role of mutation rate variation and genetic diversity in the architecture of human disease

Background We have investigated the role that the mutation rate and the structure of genetic variation at a locus play in determining whether a gene is involved in disease. We predict that the mutation rate and its genetic diversity should be higher in genes associated with disease, unless all genes that could cause disease have already been identified. Results Consistent with our predictions we find that genes associated with Mendelian and complex disease are substantially longer than non-disease genes. However, we find that both Mendelian and complex disease genes are found in regions of the genome with relatively low mutation rates, as inferred from intron divergence between humans and chimpanzees, and they are predicted to have similar rates of non-synonymous mutation as other genes. Finally, we find that disease genes are in regions of significantly elevated genetic diversity, even when variation in the rate of mutation is controlled for. The effect is small nevertheless. Conclusions Our results suggest that gene length contributes to whether a gene is associated with disease. However, the mutation rate and the genetic architecture of the locus appear to play only a minor role in determining whether a gene is associated with disease

Late night salivary cortisol and cortisone should be the initial screening test for Cushing’s syndrome

Endogenous Cushing’s syndrome (CS) poses considerable diagnostic challenges. Although late night salivary cortisol (LNSC) is recommended as a first line screening investigation, it remains the least widely used test in many countries. The combined measurement of LNSC and late-night salivary cortisone (LNS cortisone) has shown to further improve diagnostic accuracy1. We present a retrospective study in a tertiary referral centre comparing LNSC, LNS cortisone, overnight dexamethasone suppression test, low dose dexamethasone suppression test and 24-hour urinary free cortisol results of patients investigated for CS. Patients were categorised into those who had CS (21 patients) and those who did not (33 patients).LNSC had a sensitivity of 95% and a specificity of 91%. LNS cortisone had a specificity of 100% and a sensitivity of 86%. With an optimal cut-off for LNS cortisone of >14.5 nmol/l the sensitivity was 95.2%, and the specificity was 100% with an area under the curve of 0.997, for diagnosing CS. Saliva collection is non-invasive and can be carried out at home.We therefore advocate simultaneous measurement of LNSC and LNS cortisone as the first-line screening test to evaluate patients with suspected CS

Restoration of spermatogenesis and male fertility using an androgen receptor transgene

Androgens signal through the androgen receptor (AR) to regulate male secondary sexual characteristics, reproductive tract development, prostate function, sperm production, bone and muscle mass as well as body hair growth among other functions. We developed a transgenic mouse model in which endogenous AR expression was replaced by a functionally modified AR transgene. A bacterial artificial chromosome (BAC) was constructed containing all AR exons and introns plus 40 kb each of 5' and 3' regulatory sequence. Insertion of an internal ribosome entry site and the EGFP gene 3' to AR allowed co-expression of AR and EGFP. Pronuclear injection of the BAC resulted in six founder mice that displayed EGFP production in appropriate AR expressing tissues. The six founder mice were mated into a Sertoli cell specific AR knockout (SCARKO) background in which spermatogenesis is blocked at the meiosis stage of germ cell development. The AR-EGFP transgene was expressed in a cyclical manner similar to that of endogenous AR in Sertoli cells and fertility was restored as offspring were produced in the absence of Sertoli cell AR. Thus, the AREGFP transgene under the control of AR regulatory elements is capable of rescuing AR function in a cell selective, AR-null background. These initial studies provide proof of principle that a strategy employing the AR-EGFP transgene can be used to understand AR functions. Transgenic mice expressing selective modifications of the AR-EGFP transgene may provide crucial information needed to elicit the molecular mechanisms by which AR acts in the testis and other androgen responsive tissues

Evolutionary fitness as a function of pubertal age in 22 subsistence-based traditional societies

<p>Abstract</p> <p>Context</p> <p>The age of puberty has fallen over the past 130 years in industrialized, western countries, and this fall is widely referred to as the secular trend for earlier puberty. The current study was undertaken to test two evolutionary theories: (a) the reproductive system maximizes the number of offspring in response to positive environmental cues in terms of energy balance, and (b) early puberty is a trade-off response for high mortality rate and reduced resource availability.</p> <p>Methods</p> <p>Using a sample of 22 natural-fertility societies of mostly tropical foragers, horticulturalists, and pastoralists from Africa, South America, Australia, and Southeastern Asia, this study compares indices of adolescence growth and menarche with those of fertility fitness in these non-industrial, traditional societies.</p> <p>Results</p> <p>The average age at menarche correlated with the first reproduction, but did not correlate with the total fertility rate TFR or reproductive fitness. The age at menarche correlated negatively with their average adult body mass, and the average adult body weight positively correlated with reproductive fitness. Survivorship did not correlate with the age at menarche or age indices of the adolescent growth spurt. The population density correlated positively with the age at first reproduction, but not with menarche age, TFR, or reproductive fitness.</p> <p>Conclusions</p> <p>Based on our analyses, we reject the working hypotheses that reproductive fitness is enhanced in societies with early puberty or that early menarche is an adaptive response to greater mortality risk. Whereas body mass is a measure of resources is tightly associated with fitness, the age of menarche is not.</p