Failure to Downregulate the Epithelial Sodium Channel Causes Salt Sensitivity in Hsd11b2 Heterozygote Mice

In vivo, the enzyme 11β-hydroxysteroid dehydrogenase type 2 influences ligand access to the mineralocorticoid receptor. Ablation of the encoding gene, HSD11B2, causes the hypertensive syndrome of apparent mineralocorticoid excess. Studies in humans and experimental animals have linked reduced 11β-hydroxysteroid dehydrogenase type 2 activity and salt sensitivity of blood pressure. In the present study, renal mechanisms underpinning salt sensitivity were investigated in Hsd11b2(+/-) mice fed low-, standard-, and high-sodium diets. In wild-type mice, there was a strong correlation between dietary sodium content and fractional sodium excretion but not blood pressure. High sodium feeding abolished amiloride-sensitive sodium reabsorption, consistent with downregulation of the epithelial sodium channel. In Hsd11b2(+/-) mice, the natriuretic response to increased dietary sodium content was blunted, and epithelial sodium channel activity persisted. High-sodium diet also reduced renal blood flow and increased blood pressure in Hsd11b2(+/-) mice. Aldosterone was modulated by dietary sodium in both genotypes, and salt sensitivity in Hsd11b2(+/-) mice was associated with increased plasma corticosterone levels. Chronic administration of an epithelial sodium channel blocker or a glucocorticoid receptor antagonist prevented salt sensitivity in Hsd11b2(+/-) mice, whereas mineralocorticoid receptor blockade with spironolactone did not. This study shows that reduced 11β-hydroxysteroid dehydrogenase type 2 causes salt sensitivity of blood pressure because of impaired renal natriuretic capacity. This reflects deregulation of epithelial sodium channels and increased renal vascular resistance. The phenotype is not caused by illicit activation of mineralocorticoid receptors by glucocorticoids but by direct activation of glucocorticoid receptors

The comorbidities of dysmenorrhea: a clinical survey comparing symptom profile in women with and without endometriosis

Purpose: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. The frequency of 14 associated symptoms both within and outside the pelvis was determined. Patients and methods: Symptom questionnaires were completed by 168 women with dysmenorrhea, allocated to three groups based on their diagnostic status for endometriosis confirmed (Endo+), endometriosis excluded (Endo−), or endometriosis diagnosis unknown (No Lap). Those with endometriosis confirmed were further divided into current users (Endo+ Hx+) and non-users of hormonal treatments (Endo+ Hx–). Users of hormonal treatments were further divided into users (Endo+ Hx+ LIUCD+) and non-users (Endo+ Hx+ LIUCD–) of a levonorgestrel-releasing intra-uterine contraceptive device (LIUCD). The frequency and number of symptoms within groups and the effect of previous distressing sexual events were sought. Results: Women with and without endometriosis lesions had similar symptom profiles, with a mean of 8.5 symptoms per woman. Only 0.6% of women reported dysmenorrhea alone. The presence of stabbing pelvic pains was associated with more severe dysmenorrhea (P=0.006), more days per month of dysmenorrhea (P=0.003), more days per month of pelvic pain (P=0.016), and a diagnosis of migraine (P=0.054). The symptom profiles of the Endo+ Hx+ and Endo+ Hx– groups were similar. A history of distressing sexual events was associated with an increased number of pain symptoms (P=0.003). Conclusion: Additional symptoms are common in women with dysmenorrhea, and do not correlate with the presence or absence of endometriosis lesions. Our study supports the role of central sensitization in the pain of dysmenorrhea. The presence of stabbing pelvic pains was associated with increased severity of dysmenorrhea, days per month of dysmenorrhea, days per month of pelvic pain, and a diagnosis of migraine headache. A past history of distressing sexual events is associated with an increased number of pain symptoms

Action of earthworms on flint burial – a return to Darwin’s estate

For thirty years, from the early 1840s, Charles Darwin documented the disappearance of flints in the grounds of Down House in Kent, at a location originally known as the “Stony Field”. This site (Great Pucklands Meadow - GPM) was visited in 2007 and an experiment set up in this ungrazed grassland. Locally-sourced flints (either large - 12 cm, or small – 5 cm dia.) were deposited at two densities within sixteen 1 m2 plots in a randomised factorial design. The area selected was distant from public access routes and remained unmown throughout the duration here reported. Fixed point photographs were taken at the outset to enable later photogrammetric analysis. After 6 years, the site was re-examined. The flints had generally been incorporated into the soil. Photographs were re-taken, proportion of buried flints recorded and measurements made of burial depth from a quarter of each plot. Results showed that large flints were more deeply incorporated than smaller (p=0.025), but more of the latter were below the soil surface. A controlled laboratory experiment was also conducted using Aporrectodea longa (the dominant earthworm species in GPM) to assess effects of casting in the absence of other biota. Results suggested that this species has a major influence on flint burial through surface casting. Combined with a long term, but small scale collection of A. longa casts from an area close to GPM, all results were consistent with those provided by Darwin and showed that rate of flint burial was within the range 0.21-0.96 cm y-1

Prevalence of physical frailty, including risk factors, up to 1 year after hospitalisation for COVID-19 in the UK: a multicentre, longitudinal cohort study.

Background The scale of COVID-19 and its well documented long-term sequelae support a need to understand long-term outcomes including frailty. Methods This prospective cohort study recruited adults who had survived hospitalisation with clinically diagnosed COVID-19 across 35 sites in the UK (PHOSP-COVID). The burden of frailty was objectively measured using Fried's Frailty Phenotype (FFP). The primary outcome was the prevalence of each FFP group—robust (no FFP criteria), pre-frail (one or two FFP criteria) and frail (three or more FFP criteria)—at 5 months and 1 year after discharge from hospital. For inclusion in the primary analysis, participants required complete outcome data for three of the five FFP criteria. Longitudinal changes across frailty domains are reported at 5 months and 1 year post-hospitalisation, along with risk factors for frailty status. Patient-perceived recovery and health-related quality of life (HRQoL) were retrospectively rated for pre-COVID-19 and prospectively rated at the 5 month and 1 year visits. This study is registered with ISRCTN, number ISRCTN10980107. Findings Between March 5, 2020, and March 31, 2021, 2419 participants were enrolled with FFP data. Mean age was 57.9 (SD 12.6) years, 933 (38.6%) were female, and 429 (17.7%) had received invasive mechanical ventilation. 1785 had measures at both timepoints, of which 240 (13.4%), 1138 (63.8%) and 407 (22.8%) were frail, pre-frail and robust, respectively, at 5 months compared with 123 (6.9%), 1046 (58.6%) and 616 (34.5%) at 1 year. Factors associated with pre-frailty or frailty were invasive mechanical ventilation, older age, female sex, and greater social deprivation. Frail participants had a larger reduction in HRQoL compared with before their COVID-19 illness and were less likely to describe themselves as recovered. Interpretation Physical frailty and pre-frailty are common following hospitalisation with COVID-19. Improvement in frailty was seen between 5 and 12 months although two-thirds of the population remained pre-frail or frail. This suggests comprehensive assessment and interventions targeting pre-frailty and frailty beyond the initial illness are required. Funding UK Research and Innovation and National Institute for Health Research

Changes in the arctic ocean carbon cycle with diminishing ice cover

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in DeGrandpre, M., Evans, W., Timmermans, M., Krishfield, R., Williams, B., & Steele, M. Changes in the arctic ocean carbon cycle with diminishing ice cover. Geophysical Research Letters, 47(12), (2020): e2020GL088051, doi:10.1029/2020GL088051.Less than three decades ago only a small fraction of the Arctic Ocean (AO) was ice free and then only for short periods. The ice cover kept sea surface pCO2 at levels lower relative to other ocean basins that have been exposed year round to ever increasing atmospheric levels. In this study, we evaluate sea surface pCO2 measurements collected over a 6‐year period along a fixed cruise track in the Canada Basin. The measurements show that mean pCO2 levels are significantly higher during low ice years. The pCO2 increase is likely driven by ocean surface heating and uptake of atmospheric CO2 with large interannual variability in the contributions of these processes. These findings suggest that increased ice‐free periods will further increase sea surface pCO2, reducing the Canada Basin's current role as a net sink of atmospheric CO2.This research was made possible by grants from the NSF Arctic Observing Network program (ARC‐1107346, PLR‐1302884, PLR‐1504410, and OPP‐1723308). In addition, M. S. was supported by ONR (Grant 00014‐17‐1‐2545), NASA (Grant NNX16AK43G), and NSF (Grants PLR‐1503298 and OPP‐1751363)

A qualitative risk assessment of imports of animal feed as a potential pathway for Aujeszky's disease virus incursion

Aujeszky's disease (AD) is a highly contagious disease of pigs that primarily transmits by respiratory and oral routes. Evidence from recent outbreaks suggests that some swine viruses can survive in contaminated animal feed, thus posing a risk of entry via imports from other countries. To this end, a qualitative risk assessment was undertaken to determine the risk of introduction of AD virus (ADV) and infection of pigs via this route to determine if contaminated animal feed is a viable pathway for the spread of ADV. The feed categories investigated were soya bean/meal/oilcake, pet food, choline/lysine and spray dried porcine plasma. These were chosen based on their use in animal feed and the available data on viral contamination. The overall probability of an animal becoming infected from the importation of feed contaminated with ADV was estimated as Negligible or Very Low for all feed categories. The uncertainty associated with the estimates was assessed as Medium, due to the lack of data around the mechanisms that ADV could contaminate feedstuffs and for infection of susceptible animals from ADV infected feed

A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor