Ad Libitum Fluid Ingestion Rates in a Euhydrated State and Following Two Methods of Dehydration

For standardisation purposes, studies adopting fixed, and often very large, fluid ingestion volumes were primarily used by expert bodies to develop their post-exercise fluid replacement guidelines. In addition, these studies mainly used exercise-induced dehydration methods. The aim of the present study was to assess whether voluntary post-exercise rehydration was influenced by the method of weight loss. Six recreationally active (4 male, 2 female) participants either remained euhydrated (EU) or reduced their body mass by 2% by 24h fluid restriction (FR), or a combination of intermittent exercise in the heat (34°C, 60% rh) followed by 13h fluid restriction (FREX). 15 min post-performance of a short maximal exercise capacity test, they remained in the laboratory for 60 min and voluntarily ingested a carbohydrate electrolyte drink (6% carbohydrate and 19 mM Na+) ad libitum. Drink volumes were monitored without participants knowledge at 10-, 30- and 60-min after the start of drinking and water intake from food and fluids was monitored for a further 240 min. Blood and urine samples were collected. Data were analysed using repeated measures ANOVA and are presented as mean (SD). Drink volumes ingested were unexpectedly high in all three conditions (Table 1), particularly on the EU trial where prior body mass losses were small(0.31 (0.11) kg). The nature of the exercise led to transient, but markedly elevated self-reported thirst and mouth dryness, serum sodium concentration and reduced plasma volume which may have driven these high drinking rates on the EU trial. Drink rates were greatest in the initial 10 min of fluid access, ranging between 40-50% of total fluid intake in the initial 60 min, but did not differ between trials. Total urine volume and net fluid balance were significantly greater in the EU trial compared with the FR and FREX trials, but did not differ between the FR and FREX trials. In conclusion, voluntary post-exercise fluid ingestion rates can be high and are similar despite varied methods of dehydration

Historical flash floods in England:new regional chronologies and database

There is increasing interest in past occurrences of flooding from intense rainfall, commonly referred to as “flash flooding,” and the associated socioeconomic consequences. Historical information can help us to place recent events in context and to understand the effect of low frequency climate variability on changing flash flood frequencies. Previous studies have focussed on fluvial flooding to reconstruct the temporal and spatial patterns of past events. Here, we provide an online flood chronology for the north and south‐west of England for flash floods, including both surface water and fluvial flooding, with coverage from ~1700 to ~2013 (http://ceg-fepsys.ncl.ac.uk/fc). The primary source of documentary material is local newspaper reports, which often give detailed descriptions of impacts. This provides a new resource to inform communities and first responders of flood risks, especially those from rapid rise in water level whose severity may be greater than those of accompanying peak flow. Examples are provided of historical flash floods that exemplify how the chronologies can help to place recent floods in the context of the preinstrumental record for: (a) more robust estimates of event return period, (b) identification of catchment or settlement susceptibility to flash flood events, and (c) characterisation of events in ungauged catchments

Dietary analysis of an uncharacteristic population of the Mountain Pygmy-possum (Burramys parvus) in the Kosciuszko National Park, New South Wales, Australia

Background The Mountain Pygmy-possum (Burramys parvus) is a critically endangered marsupial, endemic to alpine regions of southern Australia. We investigated the diet of a recently discovered population of the possum in northern Kosciuszko National Park, NSW, Australia. This new population occurs at elevations well below the once-presumed lower elevation limit of 1,600 m. Goals and Methods Faecal material was analysed to determine if dietary composition differed between individuals in the newly discovered northern population and those in the higher elevation southern population, and to examine how diet was influenced by rainfall in the southern population and seasonal changes in resource availability in the northern population. Results and Discussion The diet of B. parvus in the northern population comprised of arthropods, fruits and seeds. Results indicate the diet of both populations shares most of the same invertebrate orders and plant species. However, in the absence of preferred food types available to the southern population, individuals of the northern population opportunistically consumed different species that were similar to those preferred by individuals in higher altitude populations. Differing rainfall amounts had a significant effect on diet, with years of below average rainfall having a greater percentage composition and diversity of invertebrates. Seasonal variation was also recorded, with the northern population increasing the diversity of invertebrates in their diet during the Autumn months when Bogong Moths (Agrotis infusa) were absent from those sites, raising questions about the possum’s dependence on the species Conclusions Measurable effects of rainfall amount and seasonal variation on the dietary composition suggest that predicted climatic variability will have a significant impact on its diet, potentially impacting its future survival. Findings suggest that it is likely that B. parvus is not restricted by dietary requirements to its current pattern of distribution. This new understanding needs to be considered when formulating future conservation strategies for this critically endangered species

Involvement of propranolol in suicides: A cross-sectional study using Coroner-Reported Data

Background: Propranolol is a beta-blocker medication indicated mostly for heart rhythm conditions and for physical symptoms of anxiety. Prescriptions for propranolol in the UK have increased since 2008. Recently, there have been concerns about the involvement of propranolol in intentional poisonings, but such deaths are not routinely reported. Therefore, use of coroner-reported and toxicology data enables unique investigation into the scale of involvement of propranolol in suicide. Aims: To describe the extent to which propranolol is involved in suicides, including patterns over time and characteristics of people whose suicide involved propranolol compared with other suicides. Method: Data were derived from the National Programme on Substance Use Mortality (NPSUM). All suicides and deaths of undetermined intent between 2010 and 2021 in England, Wales and Northern Ireland were extracted, and a subset was identified where propranolol was involved in death. Results: There were 4473 suicides of which 297 (6.6%) involved propranolol, with the proportion involving propranolol nearly quadrupling during the study period (3.4% v. 12.3%). Compared with all other suicides, a greater proportion of propranolol suicides were in women (56.6% v. 37.1%) and in people with diagnoses of depression (39.1% v. 27.1%) and anxiety (22.2% v. 8.6%). When suicide involved propranolol, an antidepressant was detected at post-mortem in 81.8% of deaths, most commonly a selective serotonin reuptake inhibitor (SSRIs) (51.5%), and most often citalopram (24.6%). Conclusions: A small number, but increasing proportion, of suicides reported to the NPSUM involve propranolol. Vigilance to the combined toxicity profile of medicines used alongside propranolol may be pertinent

The Burramys Project: a conservationist's reach should exceed history's grasp, or what is the fossil record for?

The fossil record provides important information about changes in species diversity, distribution, habitat and abundance through time. As we understand more about these changes, it becomes possible to envisage a wider range of options for translocations in a world where sustainability of habitats is under increasing threat. The Critically Endangered alpine/subalpine mountain pygmy-possum, Burramys parvus (Marsupialia, Burramyidae), is threatened by global heating. Using conventional strategies, there would be no viable pathway for stopping this iconic marsupial from becoming extinct. The fossil record, however, has inspired an innovative strategy for saving this species. This lineage has been represented over 25 Myr by a series of species always inhabiting lowland, wet forest palaeocommunities. These fossil deposits have been found in what is now the Tirari Desert, South Australia (24 Ma), savannah woodlands of the Riversleigh World Heritage Area, Queensland (approx. 24-15 Ma) and savannah grasslands of Hamilton, Victoria (approx. 4 Ma). This palaeoecological record has led to the proposal overviewed here to construct a lowland breeding facility with the goal of monitoring the outcome of introducing this possum back into the pre-Quaternary core habitat for the lineage. If this project succeeds, similar approaches could be considered for other climate-change-threatened Australian species such as the southern corroboree frog (Pseudophryne corroboree) and the western swamp tortoise (Pseudemydura umbrina)

The Coxiella burnetii Dot/Icm System Delivers a Unique Repertoire of Type IV Effectors into Host Cells and Is Required for Intracellular Replication

Coxiella burnetii, the causative agent of human Q fever, is an intracellular pathogen that replicates in an acidified vacuole derived from the host lysosomal network. This pathogen encodes a Dot/Icm type IV secretion system that delivers bacterial proteins called effectors to the host cytosol. To identify new effector proteins, the functionally analogous Legionella pneumophila Dot/Icm system was used in a genetic screen to identify fragments of C. burnetii genomic DNA that when fused to an adenylate cyclase reporter were capable of directing Dot/Icm-dependent translocation of the fusion protein into mammalian host cells. This screen identified Dot/Icm effectors that were proteins unique to C. burnetii, having no overall sequence homology with L. pneumophila Dot/Icm effectors. A comparison of C. burnetii genome sequences from different isolates revealed diversity in the size and distribution of the genes encoding many of these effectors. Studies examining the localization and function of effectors in eukaryotic cells provided evidence that several of these proteins have an affinity for specific host organelles and can disrupt cellular functions. The identification of a transposon insertion mutation that disrupts the dot/icm locus was used to validate that this apparatus was essential for translocation of effectors. Importantly, this C. burnetii Dot/Icm-deficient mutant was found to be defective for intracellular replication. Thus, these data indicate that C. burnetii encodes a unique subset of bacterial effector proteins translocated into host cells by the Dot/Icm apparatus, and that the cumulative activities exerted by these effectors enables C. burnetii to successfully establish a niche inside mammalian cells that supports intracellular replication

Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy

Background Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy. Methods We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation. Results 8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort. Conclusions We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults

ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression.

Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3FAX -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Upregulation of GALNT7 in prostate cancer modifies O-glycosylation and promotes tumour growth.

Prostate cancer is the most common cancer in men and it is estimated that over 350,000 men worldwide die of prostate cancer every year. There remains an unmet clinical need to improve how clinically significant prostate cancer is diagnosed and develop new treatments for advanced disease. Aberrant glycosylation is a hallmark of cancer implicated in tumour growth, metastasis, and immune evasion. One of the key drivers of aberrant glycosylation is the dysregulated expression of glycosylation enzymes within the cancer cell. Here, we demonstrate using multiple independent clinical cohorts that the glycosyltransferase enzyme GALNT7 is upregulated in prostate cancer tissue. We show GALNT7 can identify men with prostate cancer, using urine and blood samples, with improved diagnostic accuracy than serum PSA alone. We also show that GALNT7 levels remain high in progression to castrate-resistant disease, and using in vitro and in vivo models, reveal that GALNT7 promotes prostate tumour growth. Mechanistically, GALNT7 can modify O-glycosylation in prostate cancer cells and correlates with cell cycle and immune signalling pathways. Our study provides a new biomarker to aid the diagnosis of clinically significant disease and cements GALNT7-mediated O-glycosylation as an important driver of prostate cancer progression

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year