Molecular and comparative analysis of Salmonella enterica Senftenberg from humans and animals using PFGE, MLST and NARMS

<p>Abstract</p> <p>Background</p> <p><it>Salmonella </it>species are recognized worldwide as a significant cause of human and animal disease. In this study the molecular profiles and characteristics of <it>Salmonella enterica </it>Senftenberg isolated from human cases of illness and those recovered from healthy or diagnostic cases in animals were assessed. Included in the study was a comparison with our own sequenced strain of <it>S. </it>Senfteberg recovered from production turkeys in North Dakota. Isolates examined in this study were subjected to antimicrobial susceptibility profiling using the National Antimicrobial Resistance Monitoring System (NARMS) panel which tested susceptibility to 15 different antimicrobial agents. The molecular profiles of all isolates were determined using Pulsed Field Gel Electrophoresis (PFGE) and the sequence types of the strains were obtained using Multi-Locus Sequence Type (MLST) analysis based on amplification and sequence interrogation of seven housekeeping genes (<it>aroC</it>, <it>dnaN</it>, <it>hemD</it>, <it>hisD</it>, <it>purE</it>, <it>sucA</it>, and <it>thrA</it>). PFGE data was input into BioNumerics analysis software to generate a dendrogram of relatedness among the strains.</p> <p>Results</p> <p>The study found 93 profiles among 98 <it>S</it>. Senftenberg isolates tested and there were primarily two sequence types associated with humans and animals (ST185 and ST14) with overlap observed in all host types suggesting that the distribution of <it>S. </it>Senftenberg sequence types is not host dependent. Antimicrobial resistance was observed among the animal strains, however no resistance was detected in human isolates suggesting that animal husbandry has a significant influence on the selection and promotion of antimicrobial resistance.</p> <p>Conclusion</p> <p>The data demonstrates the circulation of at least two strain types in both animal and human health suggesting that <it>S. </it>Senftenberg is relatively homogeneous in its distribution. The data generated in this study could be used towards defining a pathotype for this serovar.</p

A primordial origin for the atmospheric methane of Saturn's moon Titan

The origin of Titan's atmospheric methane is a key issue for understanding the origin of the Saturnian satellite system. It has been proposed that serpentinization reactions in Titan's interior could lead to the formation of the observed methane. Meanwhile, alternative scenarios suggest that methane was incorporated in Titan's planetesimals before its formation. Here, we point out that serpentinization reactions in Titan's interior are not able to reproduce the deuterium over hydrogen (D/H) ratio observed at present in methane in its atmosphere, and would require a maximum D/H ratio in Titan's water ice 30% lower than the value likely acquired by the satellite during its formation, based on Cassini observations at Enceladus. Alternatively, production of methane in Titan's interior via radiolytic reactions with water can be envisaged but the associated production rates remain uncertain. On the other hand, a mechanism that easily explains the presence of large amounts of methane trapped in Titan in a way consistent with its measured atmospheric D/H ratio is its direct capture in the satellite's planetesimals at the time of their formation in the solar nebula. In this case, the mass of methane trapped in Titan's interior can be up to 1,300 times the current mass of atmospheric methane.Comment: Accepted for publication in Icaru

Nighttime Blood Pressure Dipping in Postmenopausal Women With Coronary Heart Disease

Blunted nighttime blood pressure (BP) dipping is prognostic of cardiovascular morbidity and mortality. This relationship may be stronger among women than men. The present study hypothesized that coronary artery disease (CAD) and advancing age would be associated with reduced BP dipping in postmenopausal women. The effects of daytime physical activity and nighttime sleep quality on BP dipping were also examined

The Active for Life Year 5 (AFLY5) school based cluster randomised controlled trial: study protocol for a randomized controlled trial

Background: Low levels of physical activity, high levels of sedentary behaviour and low levels of fruit and vegetable consumption are common in children and are associated with adverse health outcomes. The aim of this paper is to describe the protocol for a cluster randomised controlled trial (RCT) designed to evaluate a school-based intervention that aims to increase levels of physical activity, decrease sedentary behaviour and increase consumption of fruit and vegetables in school children. Methods/design: The Active for Life Year 5 (AFLY5) study is a school-based, cluster RCT that targets school children in Year 5 (age 9-10 years). All state junior/primary schools in the area covered by Bristol City and North Somerset Council are invited to participate; special schools are excluded. Eligible schools are randomised to one of two arms: intervention arm (receive the intervention 2011-2012) and control arm (receive the intervention after the final follow-up assessment, 2013-2014). The primary outcomes of the trial are levels of accelerometer assessed physical activity and sedentary behaviour and questionnaire assessed fruit and vegetable consumption. A number of secondary outcomes will also be measured, including body mass index, waist circumference and overweight/obesity. Outcomes will be assessed at baseline (prior to intervention when the children are in Year 4), at the end of intervention ‘immediate follow-up’ and ‘12 months long-term’ follow-up. We will use random effects linear and logistic regression models to compare outcomes by randomised arm. The economic evaluation from a societal perspective will take the form of a cost consequence analysis. Data from focus groups and interviews with pupils, parents and teachers will be used to increase understanding of how the intervention has any effect and is integrated into normal school activity. Discussion: The results of the trial will provide information about the public health effectiveness of a school-based intervention aimed at improving levels of physical activity, sedentary behaviour and diet in children.Debbie A Lawlor, Russell Jago, Sian M Noble, Catherine R Chittleborough, Rona Campbell, Julie Mytton, Laura D Howe, Tim J Peters and Ruth R Kippin

CXCR3 Antagonism of SDF-1(5-67) Restores Trabecular Function and Prevents Retinal Neurodegeneration in a Rat Model of Ocular Hypertension

Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-α, and TGF-β2, factors known to be involved in glaucoma. CXCL12 protects in vitro trabecular cells from apoptotic death via CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration

lincRNAs act in the circuitry controlling pluripotency and differentiation

Although thousands of large intergenic non-coding RNAs (lincRNAs) have been identified in mammals, few have been functionally characterized, leading to debate about their biological role. To address this, we performed loss-of-function studies on most lincRNAs expressed in mouse embryonic stem (ES) cells and characterized the effects on gene expression. Here we show that knockdown of lincRNAs has major consequences on gene expression patterns, comparable to knockdown of well-known ES cell regulators. Notably, lincRNAs primarily affect gene expression in trans. Knockdown of dozens of lincRNAs causes either exit from the pluripotent state or upregulation of lineage commitment programs. We integrate lincRNAs into the molecular circuitry of ES cells and show that lincRNA genes are regulated by key transcription factors and that lincRNA transcripts bind to multiple chromatin regulatory proteins to affect shared gene expression programs. Together, the results demonstrate that lincRNAs have key roles in the circuitry controlling ES cell state.Broad InstituteHarvard UniversityNational Human Genome Research Institute (U.S.)Merkin Family Foundation for Stem Cell Researc

Home and Online Management and Evaluation of Blood Pressure (HOME BP) using a digital intervention in poorly controlled hypertension: randomised controlled trial

Objective: The HOME BP (Home and Online Management and Evaluation of Blood Pressure) trial aimed to test a digital intervention for hypertension management in primary care by combining self-monitoring of blood pressure with guided self-management. Design: Unmasked randomised controlled trial with automated ascertainment of primary endpoint. Setting: 76 general practices in the United Kingdom. Participants: 622 people with treated but poorly controlled hypertension (&gt;140/90 mm Hg) and access to the internet. Interventions: Participants were randomised by using a minimisation algorithm to self-monitoring of blood pressure with a digital intervention (305 participants) or usual care (routine hypertension care, with appointments and drug changes made at the discretion of the general practitioner; 317 participants). The digital intervention provided feedback of blood pressure results to patients and professionals with optional lifestyle advice and motivational support. Target blood pressure for hypertension, diabetes, and people aged 80 or older followed UK national guidelines. Main outcome measures: The primary outcome was the difference in systolic blood pressure (mean of second and third readings) after one year, adjusted for baseline blood pressure, blood pressure target, age, and practice, with multiple imputation for missing values. Results: After one year, data were available from 552 participants (88.6%) with imputation for the remaining 70 participants (11.4%). Mean blood pressure dropped from 151.7/86.4 to 138.4/80.2 mm Hg in the intervention group and from 151.6/85.3 to 141.8/79.8 mm Hg in the usual care group, giving a mean difference in systolic blood pressure of −3.4 mm Hg (95% confidence interval −6.1 to −0.8 mm Hg) and a mean difference in diastolic blood pressure of −0.5 mm Hg (−1.9 to 0.9 mm Hg). Results were comparable in the complete case analysis and adverse effects were similar between groups. Within trial costs showed an incremental cost effectiveness ratio of £11 ($15, €12; 95% confidence interval £6 to £29) per mm Hg reduction. Conclusions: The HOME BP digital intervention for the management of hypertension by using self-monitored blood pressure led to better control of systolic blood pressure after one year than usual care, with low incremental costs. Implementation in primary care will require integration into clinical workflows and consideration of people who are digitally excluded. Trial registration: ISRCTN13790648

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development