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Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.

ObjectivesTo assess the frequency of discharge against medical advice (DAMA) in a large UK teaching hospital, explore factors which increase the risk of DAMA and identify how DAMA impacts patient risk of mortality and readmission.DesignRetrospective cohort study.SettingLarge acute teaching hospital in the UK.Patients36 683 patients discharged from the acute medical unit of a large UK teaching hospital between 1 January 2012 and 31 December 2016.MeasurementsPatients were censored on 1 January 2021. Mortality and 30-day unplanned readmission rates were assessed. Deprivation, age and sex were taken as covariates.Results3% of patients discharged against medical advice. These patients were younger (median age (years) (IQR)): planned discharge (PD) 59 (40–77); DAMA 39 (28–51), predominantly of male sex (PD 48%; DAMA 66%) and were of greater social deprivation (in three most deprived quintiles PD 69%; DAMA 84%). DAMA was associated with increased risk of death in patients under the age of 33.3 years (adjusted HR 2.6 (1.2–5.8)) and increased incidence of 30-day readmission (standardised incidence ratio 1.9 (1.5–2.2)).LimitationsReadmission to acute hospitals outside of the local health board may have been missed. We were unable to include information regarding comorbidity or severity of presentation.ConclusionsThese data highlight the vulnerability of younger patients who DAMA, even in a free-at-the-point-of-delivery healthcare setting.

[...]flaviviruses have no such subgenomic RNA. [...]a large number of flavivirus sequences have been examined, including strains of four dengue serotypes which co-circulate in the same vectors and hosts in endemic regions, which arrive at the same conclusion: there are no examples of inter-specific recombination despite these flaviviruses having evolved about 1500 years ago [5], and despite infection with two or more dengue viruses occurring in individuals living in areas of hyperendemic dengue transmission for at least the past 50 years. [...]the wild-type virus would have to infect the host cell simultaneously with vaccine virus for recombination to occur.

BackgroundHyponatraemia often occurs after subarachnoid haemorrhage (SAH). However, its clinical significance and optimal management are uncertain. We audited the screening, investigation and management of hyponatraemia after SAH.MethodsWe prospectively identified consecutive patients with spontaneous SAH admitted to neurosurgical units in the United Kingdom or Ireland. We reviewed medical records daily from admission to discharge, 21 days or death and extracted all measurements of serum sodium to identify hyponatraemia (<135 mmol/L). Main outcomes were death/dependency at discharge or 21 days and admission duration >10 days. Associations of hyponatraemia with outcome were assessed using logistic regression with adjustment for predictors of outcome after SAH and admission duration. We assessed hyponatraemia-free survival using multivariable Cox regression.Results175/407 (43%) patients admitted to 24 neurosurgical units developed hyponatraemia. 5976 serum sodium measurements were made. Serum osmolality, urine osmolality and urine sodium were measured in 30/166 (18%) hyponatraemic patients with complete data. The most frequently target daily fluid intake was >3 L and this did not differ during hyponatraemic or non-hyponatraemic episodes. 26% (n/N=42/164) patients with hyponatraemia received sodium supplementation. 133 (35%) patients were dead or dependent within the study period and 240 (68%) patients had hospital admission for over 10 days. In the multivariable analyses, hyponatraemia was associated with less dependency (adjusted OR (aOR)=0.35 (95% CI 0.17 to 0.69)) but longer admissions (aOR=3.2 (1.8 to 5.7)). World Federation of Neurosurgical Societies grade I–III, modified Fisher 2–4 and posterior circulation aneurysms were associated with greater hazards of hyponatraemia.ConclusionsIn this comprehensive multicentre prospective-adjusted analysis of patients with SAH, hyponatraemia was investigated inconsistently and, for most patients, was not associated with changes in management or clinical outcome. This work establishes a basis for the development of evidence-based SAH-specific guidance for targeted screening, investigation and management of high-risk patients to minimise the impact of hyponatraemia on admission duration and to improve consistency of patient care.

Sequence homology and molecular modeling studies have suggested that the N-terminal one-third of the flavivirus nonstructural protein NS3 functions as a trypsin-like serine protease. To examine the putative proteolytic activity of NS3, segments of the yellow fever virus genome were subcloned into plasmid transcription/translation vectors and cell-free translation products were characterized. The results suggest that a protease activity encoded within NS2B and the N-terminal one-third of yellow fever virus NS3 is capable of cisacting site-specific proteolysis at the NS2B-NS3 cleavage site and dilution-insensitive cleavage of the NS2A-NS2B site. Site-directed mutagenesis of the His-53, Asp-77, and Ser-138 residues of NS3 that compose the proposed catalytic triad implicates this domain as a serine protease. Infectious virus was not recovered from mammalian cells transfected with RNAs transcribed from full-length yellow fever virus cDNA templates containing mutations at Ser-138 (which abolish or dramatically reduce protease activity in vitro), suggesting that the protease is required for viral replication.

Glucocorticoids (GC) are prescribed for periods >3 months to 1-3% of the UK population; 10-50% of these patients develop hypothalamus- pituitary-adrenal (HPA) axis suppression, which may last over 6 months and is associated with morbidity and mortality. Recovery of higher nodes of the axis is necessary for recovery of adrenal function. We developed a mouse model of Dexamethasone (DEX)-induced HPA axis dysfunction in order to further explore recovery in the pituitary. Adult male C57BL6/J or those crossed with Pomc-eGFP mice were randomly assigned to receive DEX (~0.4 mg/kg bodyweight/day) or vehicle via drinking water for 4 weeks following which treatment was withdrawn. Tissues were harvested at 0, 1, and 4 weeks following withdrawal of treatment. Corticotrophs were isolated from Pomc-eGFP pituitaries using FACS, and RNA extracted for RNA-seq. DEX treatment suppressed corticosterone production, which remained partially suppressed at least 1 week following DEX withdrawal. In the adrenal, at time 0, Hsd3b2, Cyp11a1, and Mc2r mRNA levels were significantly reduced, with Mc2r and Cyp11a1 remaining reduced 1 week following DEX withdrawal. The corticotroph transcriptome was modified by DEX treatment with some differences between groups persisting 4 weeks following withdrawal. No genes supressed by DEX exhibited ongoing attenuation 1 and 4 weeks following withdrawal, whilst only 2 genes were upregulated and remained so following withdrawal. A pattern of rebound at 1 and 4 weeks was observed in 14 genes that increased following suppression, and 6 genes that were reduced by DEX and then increased. Chronic GC treatment may induce persistent changes in the pituitary that may influence future response to GC treatment or stress. Competing Interest Statement The authors have declared no competing interest.

Peatlands are globally-important carbon sinks at risk of degradation from climate change and direct human impacts, including drainage and burning. Peat accumulates when there is a positive mass balance between plant productivity inputs and litter/peat decomposition losses. However, the factors influencing the rate of peat accumulation over time are still poorly understood. We examine apparent peat accumulation rates (aPAR) during the last two millennia from 28 well-dated, intact European peatlands and find a range of between 0.005 and 0.448 cm yr-1 (mean = 0.118 cm yr-1). Our work provides important context for the commonplace assertion that European peatlands accumulate at ~0.1 cm per year. The highest aPAR values are found in the Scandinavian and Baltic regions, in contrast to Britain, Ireland, and Continental Europe. We find that summer temperature is a significant climatic control on aPAR across our European sites. Furthermore, a significant relationship is observed between aPAR and water-table depth (reconstructed from testate-amoeba subfossils), suggesting that higher aPAR levels are often associated with wetter conditions. We also note that the highest values of aPAR are found when the water table is within 5-10 cm of the peatland surface. aPAR is generally low when water table depths are < 0 cm (standing water) or > 25 cm, which may relate to a decrease in plant productivity and increased decomposition losses, respectively. Model fitting indicates that the optimal water table depth (WTD) for maximum aPAR is ~10 cm. Our study suggests that, in some European peatlands, higher summer temperatures may enhance growth rates, but only if a sufficiently high water table is maintained. In addition, our findings corroborate contemporary observational and experimental studies that have suggested an average water-table depth of ~10 cm is optimal to enable rapid peat growth and therefore carbon sequestration in the long term. This has important implications for peatland restoration and rewetting strategies, in global efforts to mitigate climate change.

Climate warming and human impacts are thought to be causing peatlands to dry, potentially converting them from sinks to sources of carbon. However, it is unclear whether the hydrological status of peatlands has moved beyond their natural envelope. Here we show that European peatlands have undergone substantial, widespread drying during the last ~300 years. We analyse testate amoeba-derived hydrological reconstructions from 31 peatlands across Britain, Ireland, Scandinavia and Continental Europe to examine changes in peatland surface wetness during the last 2,000 years. We find that 60% of our study sites were drier during the period 1800–2000 ce than they have been for the last 600 years, 40% of sites were drier than they have been for 1,000 years and 24% of sites were drier than they have been for 2,000 years. This marked recent transition in the hydrology of European peatlands is concurrent with compound pressures including climatic drying, warming and direct human impacts on peatlands, although these factors vary among regions and individual sites. Our results suggest that the wetness of many European peatlands may now be moving away from natural baselines. Our findings highlight the need for effective management and restoration of European peatlands.

ObjectiveThe colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.DesignTo investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.ResultsPropionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.ConclusionsThese data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.Trial registration numberNCT00750438.