Gut dysbiosis has been linked to cardiovascular diseases including hypertension. We tested the hypothesis that hypertension could be induced in a normotensive strain of rats or attenuated in a ...hypertensive strain of rats by exchanging the gut microbiota between the two strains. Cecal contents from spontaneously hypertensive stroke prone rats (SHRSP) were pooled. Similarly, cecal contents from normotensive WKY rats were pooled. Four-week-old recipient WKY and SHR rats, previously treated with antibiotics to reduce the native microbiota, were gavaged with WKY or SHRSP microbiota, resulting in four groups; WKY with WKY microbiota (WKY g-WKY), WKY with SHRSP microbiota (WKY g-SHRSP), SHR with SHRSP microbiota (SHR g-SHRSP), and SHR with WKY microbiota (SHR g-WKY). Systolic blood pressure (SBP) was measured weekly using tail-cuff plethysmography. At 11.5 wk of age systolic blood pressure increased 26 mmHg in WKY g-SHRSP compared with that in WKY g-WKY (182 ± 8 vs. 156 ± 8 mmHg,
= 0.02). Although the SBP in SHR g-WKY tended to decrease compared with SHR g-SHRSP, the differences were not statistically significant. Fecal pellets were collected at 11.5 wk of age for identification of the microbiota by sequencing the 16S ribosomal RNA gene. We observed a significant increase in the Firmicutes:Bacteroidetes ratio in the hypertensive WKY g-SHRSP, as compared with the normotensive WKY g-WKY (
= 0.042). Relative abundance of multiple taxa correlated with SBP. We conclude that gut dysbiosis can directly affect SBP. Manipulation of the gut microbiota may represent an innovative treatment for hypertension.
Summary Background Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are ...modified by diabetes is unknown. Methods We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes. Findings We analysed data for 1 024 977 participants (128 505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75 306 deaths occurred during a mean follow-up of 8·5 years (SD 5·0). In the 23 studies with data for cardiovascular mortality, 21 237 deaths occurred from cardiovascular disease during a mean follow-up of 9·2 years (SD 4·9). In the general and high-risk cohorts, mortality risks were 1·2–1·9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1·73 m2 vs 95 mL/min per 1·73 m2 , HR 1·35; 95% CI 1·18–1·55; vs 1·33; 1·19–1·48 and at ACR 30 mg/g vs 5 mg/g, 1·50; 1·35–1·65 vs 1·52; 1·38–1·67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts. Interpretation Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes. Funding US National Kidney Foundation.
ABSTRACT
We contrast the latest observations of the cosmic metal density in neutral gas ($\rho _{ {met,neu}}$) with three cosmological galaxy evolution simulations: L-Galaxies 2020, TNG100, and ...EAGLE. We find that the fraction of total metals that are in neutral gas is <40 per cent at 3 ≲ $z$ ≲ 5 in these simulations, whereas observations of damped Lyman-α (DLA) systems suggest ≳ 85 per cent. In all three simulations, hot, low-density gas is also a major contributor to the cosmic metal budget, even at high redshift. By considering the evolution in cosmic SFR density ($\rho _{ {\rm {\small {sfr}}}$), neutral gas density ($\rho _{ {HI}}$), and mean gas-phase metallicity ($\langle {} {M/H}\rangle _{ {neu}}$), we determine two possible ways in which the absolute $\rho _{ {met,neu}}$ observed in DLAs at high redshift can be matched by simulations: (i) the $\rho _{ {\rm {\small {sfr}}}$ at $z$ ≳ 3 is greater than inferred from current FUV observations, or (ii) current high-redshift DLA metallicity samples have a higher mean host mass than the overall galaxy population. If the first is correct, TNG100 would match the ensemble data best, however there would be an outstanding tension between the currently observed $\rho _{ {\rm {\small {sfr}}}$ and $\rho _{ {met,neu}}$. If the second is correct, L-Galaxies 2020 would match the ensemble data best, but would require an increase in neutral gas mass inside subhaloes above $z$ ∼ 2.5. If neither is correct, EAGLE would match the ensemble data best, although at the expense of overestimating $\langle {} {M/H}\rangle _{ {neu}}$. Modulo details related to numerical resolution and H i mass modelling in simulations, these incompatibilities highlight current tensions between key observed cosmic properties at high redshift.
Disruption of the gut microbiota, termed gut dysbiosis, has been described in animal models of hypertension and hypertensive patients. We have shown that gut dysbiosis plays a causal role in the ...development of hypertension in a rat model of obstructive sleep apnea (OSA). Functional analysis of the dysbiotic microbiota in OSA demonstrates a loss of short chain fatty acid-producing bacteria. However, measurements of short chain fatty acid concentrations and testing of their role in blood pressure regulation are lacking. We hypothesized that reduced short chain fatty acids in the gut are responsible for OSA-induced hypertension. OSA significantly increased systolic blood pressure at 7 and 14 days ( P<0.05), an effect that was abolished by the probiotic Clostridium butyricum or the prebiotic Hylon VII. The 16S rRNA analysis identified several short chain fatty acid-producing bacteria that were significantly increased by Cbutyricum and Hylon treatment. Acetate concentration in the cecum was decreased by 48% after OSA ( P<0.05), an effect that was prevented by Cbutyricum and Hylon. Cbutyricum and Hylon reduced OSA-induced dysbiosis, epithelial goblet cell loss, mucus barrier thinning, and activation of brain microglia ( P<0.05 for each). To examine the role of acetate in OSA-induced hypertension, we chronically infused acetate into the cecum during 2 weeks of sham or OSA. Restoring cecal acetate concentration prevented OSA-induced gut inflammation and hypertension ( P<0.05). These studies identify acetate as a key player in OSA-induced hypertension. We demonstrate that various methods to increase cecal acetate concentrations are protective from the adverse effects of OSA on the microbiota, gut, brain, and blood pressure.
ABSTRACT
We perform a comparison, object by object and statistically, between the Munich semi-analytical model, L-GALAXIES, and the IllustrisTNG hydrodynamical simulations. By running L-GALAXIES on ...the IllustrisTNG dark matter-only merger trees, we identify the same galaxies in the two models. This allows us to compare the stellar mass, star formation rate, and gas content of galaxies, as well as the baryonic content of subhaloes and haloes in the two models. We find that both the stellar mass functions and the stellar masses of individual galaxies agree to better than ${\sim} 0.2\,$dex. On the other hand, specific star formation rates and gas contents can differ more substantially. At z = 0, the transition between low-mass star-forming galaxies and high-mass quenched galaxies occurs at a stellar mass scale ${\sim} 0.5\,$dex lower in IllustrisTNG than that in L-GALAXIES. IllustrisTNG also produces substantially more quenched galaxies at higher redshifts. Both models predict a halo baryon fraction close to the cosmic value for clusters, but IllustrisTNG predicts lower baryon fractions in group environments. These differences are primarily due to differences in modelling feedback from stars and supermassive black holes. The gas content and star formation rates of galaxies in and around clusters and groups differ substantially, with IllustrisTNG satellites less star forming and less gas rich. We show that environmental processes such as ram-pressure stripping are stronger and operate to larger distances and for a broader host mass range in IllustrisTNG. We suggest that the treatment of galaxy evolution in the semi-analytic model needs to be improved by prescriptions that capture local environmental effects more accurately.
Abstract Purpose The aim of this study was to develop an evidence-based communication skills training workshop to improve the communication skills of critical care fellows. Materials and methods ...Pulmonary and critical care fellows (N = 38) participated in a 3-day communication skills workshop between 2008 and 2010 involving brief didactic talks, faculty demonstration of skills, and faculty-supervised small group skills practice sessions with simulated families. Skills included the following: giving bad news, achieving consensus on goals of therapy, and discussing the limitations of life-sustaining treatment. Participants rated their skill levels in a pre-post survey in 11 core communication tasks using a 5-point Likert scale. Results Of 38 fellows, 36 (95%) completed all 3 days of the workshop. We compared pre and post scores using the Wilcoxon signed rank test. Overall, self-rated skills increased for all 11 tasks. In analyses by participant, 95% reported improvement in at least 1 skill; with improvement in a median of 10 of 11 skills. Ninety-two percent rated the course as either very good/excellent, and 80% recommended that it be mandatory for future fellows. Conclusions This 3-day communication skills training program increased critical care fellows' self-reported family meeting communication skills.
ABSTRACT
We present a variation of the recently updated Munich semi-analytical galaxy formation model, L-Galaxies, with a new gas stripping method. Extending earlier work, we directly measure the ...local environmental properties of galaxies to formulate a more accurate treatment of ram-pressure stripping for all galaxies. We fully recalibrate the modified L-Galaxies model using a Markov Chain Monte Carlo (MCMC) method with the stellar mass function and quenched fraction of galaxies as a function of stellar mass at 0 ≤ z ≤ 2 as constraints. Due to this recalibration, global galaxy population relations, including the stellar mass function, quenched fractions versus galaxy mass, and H i mass function are all largely unchanged and remain consistent with observations. By comparing to data on galaxy properties in different environments from the SDSS and HSC surveys, we demonstrate that our modified model improves the agreement with the quenched fractions and star formation rates of galaxies as a function of environment, stellar mass, and redshift. Overall, in the vicinity of haloes with total mass 1012 to $10^{15}\, \rm M_{\odot }$ at z = 0, our new model produces higher quenched fractions and stronger environmental dependencies, better recovering observed trends with halocentric distance up to several virial radii. By analysing the actual amount of gas stripped from galaxies in our model, we show that those in the vicinity of massive haloes lose a large fraction of their hot halo gas before they become satellites. We demonstrate that this affects galaxy quenching both within and beyond the halo boundary. This is likely to influence the correlations between galaxies up to tens of megaparsecs.
Summary Background The Thai phase 3 HIV vaccine trial RV 144 showed modest efficacy of a vaccine against HIV acquisition. Baseline variables of age, sex, marital status, and risk did not modify ...vaccine efficacy. We did a post-hoc analysis of the trial's data to investigate behavioural risk and efficacy every 6 months after vaccination. Methods RV 144 was a randomised, multicentre, double-blind, placebo-controlled efficacy trial testing the combination of the HIV vaccines ALVAC-HIV (vCP1521) and AIDSVAX B/E to prevent HIV infection or reduce setpoint viral load. Male and female volunteers aged 18–30 years were recruited from the community. In this post-hoc analysis of the modified intention-to-treat population (16 395 participants), HIV risk behaviour was assessed with a self-administered questionnaire at the time of initial vaccination in the trial and every 6 months thereafter for 3 years. We classified participants' behaviour as low, medium, or high risk. Both the acquisition endpoint and the early viral-load endpoint were examined for interactions with risk status over time and temporal effects after vaccination. Multiple proportional hazards regression models with treatment and time-varying risk covariates were analysed. Findings Risk of acquisition of HIV was low in each risk group, but 9187 (58·2%) participants reported higher-risk behaviour at least once during the study. Participants classified as high or increasing risk at least once during follow-up were compared with those who maintained low-risk or medium-risk behaviour as a time-varying covariate, and the interaction of risk status and acquisition efficacy was significant (p=0·01), with greater benefit in low-risk individuals. Vaccine efficacy seemed to peak early—cumulative vaccine efficacy was estimated to be 60·5% (95% CI 22–80) through the 12 months after initial vaccination—and declined quickly. Vaccination did not seem to affect viral load in either early or late infections. Interpretation Future HIV vaccine trials should recognise potential interactions between challenge intensity and risk heterogeneity in both population and treatment effects. The regimen tested in the RV 144 phase 3 trial might benefit from extended immunisation schedules. Funding US Army Medical Research and Materiel Command and Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health.
The ON pathway of the visual system, which detects increases in light intensity, is established at the first retinal synapse between photoreceptors and ON-bipolar cells. Photoreceptors hyperpolarize ...in response to light and reduce the rate of glutamate release, which in turn causes the depolarization of ON-bipolar cells. This ON-bipolar cell response is mediated by the metabotropic glutamate receptor, mGluR6, which controls the activity of a depolarizing current. Despite intensive research over the past two decades, the molecular identity of the channel that generates this depolarizing current has remained elusive. Here, we present evidence indicating that TRPM1 is necessary for the depolarizing light response of ON-bipolar cells, and further that TRPM1 is a component of the channel that generates this light response. Gene expression profiling revealed that TRPM1 is highly enriched in ON-bipolar cells. In situ hybridization experiments confirmed that TRPM1 mRNA is found in cells of the retinal inner nuclear layer, and immunofluorescent confocal microscopy showed that TRPM1 is localized in the dendrites of ON-bipolar cells in both mouse and macaque retina. The electroretinogram (ERG) of TRPM1-deficient (TRPM1⁻/⁻) mice had a normal a-wave, but no b-wave, indicating a loss of bipolar cell response. Finally, whole-cell patch-clamp recording from ON-bipolar cells in mouse retinal slices demonstrated that genetic deletion of TRPM1 abolished chemically simulated light responses from rod bipolar cells and dramatically altered the responses of cone ON-bipolar cells. Identification of TRPM1 as a mGluR6-coupled cation channel reveals a key step in vision, expands the role of the TRP channel family in sensory perception, and presents insights into the evolution of vertebrate vision.
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