Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank

Background: Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank. Methods: A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure. Results: After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death. Conclusion: We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.</p

Understanding perceptions on 'Buruli' in northwestern Uganda: A biosocial investigation.

BACKGROUND: An understudied disease, little research thus far has explored responses to Buruli ulcer and quests for therapy from biosocial perspective, despite reports that people seek biomedical treatment too late. METHODS AND FINDINGS: Taking an inductive approach and drawing on long-term ethnographic fieldwork in 2013-14, this article presents perspectives on this affliction of people living and working along the River Nile in northwest Uganda. Little is known biomedically about its presence, yet 'Buruli', as it is known locally, was and is a significant affliction in this region. Establishing a biosocial history of 'Buruli', largely obscured from biomedical perspectives, offers explanations for contemporary understandings, perceptions and practices. CONCLUSIONS/SIGNIFICANCE: We must move beyond over-simplifying and problematising 'late presentation for treatment' in public health, rather, develop biosocial approaches to understanding quests for therapy that take into account historical and contemporary contexts of health, healing and illness. Seeking to understand the context in which healthcare decisions are made, a biosocial approach enables greater depth and breadth of insight into the complexities of global and local public health priorities such as Buruli ulcer

Human pluripotent stem cell-derived neurons are functionally mature in vitro and integrate into the mouse striatum following transplantation

Human Pluripotent Stem Cells (hPSCs) are a powerful tool for modelling human development. In recent years, hPSCSs have become central in cell-based therapies for neurodegenerative diseases given their potential to replace affected neurons. However, directing hPSCs into specific neuronal types is complex and requires an accurate protocol that mimics endogenous neuronal development. Here we describe step-by-step a novel and fast feeder-free neuronal differentiation protocol to direct hPSCs onto mature forebrain neurons in 37 days in vitro (DIV). The protocol is grounded on a combination of specific morphogens, trophic and growth factors, ions, neurotransmitters and extracellular matrix elements. An induced hPSC line (Ctr-Q33) and an embryonic hPSC line (GEN-Q18) were used to reinforce the potential of the protocol. Neuronal activity was analysed by single-cell calcium imaging. At 8 DIV, we obtained a homogeneous population of hPSCs-derived neuroectodermal progenitors which self-arranged in bi-dimensional neural tube-like structures. At 16 DIV, we generated hPSC-derived neural progenitors (NPCs) with mostly subpallial identity along with a subpopulation of pallial NPCs. Terminal in vitro neuronal differentiation was confirmed by the expression of microtubule associated protein 2b (Map2b) by almost 100% of hPSC-derived neurons and the expression of specific-striatal neuronal markers including GABA, CTIP2 and DARPP-32. HPSC-derived neurons showed mature and functional phenotypes as they expressed synaptic markers, voltage-gated ion channels and neurotransmitter receptors. Neurons displayed diverse spontaneous activity patterns that were classified into three major groups, namely 'high', 'intermediate' and 'low' firing neurons. Finally, transplantation experiments in vivo showed that highly relevant, committed NPCs survived within mouse striatum for at least 3 months. NPCs embodied host environmental cues and differentiated into striatal medium size spiny neurons (MSNs), which successfully integrated into the endogenous circuitry without the appearance of any teratoma symptom. Altogether, present findings demonstrate the potential of this in vitro human neuronal differentiation protocol, which will bring new opportunities for the study of human neurodevelopment and neurodegeneration, and will open new avenues in cell-based therapies, cutting-edge pharmacological studies and toxicology

European badger (Meles meles) responses to low-intensity, selective culling: using mark recapture and relatedness data to assess social perturbation

Publication history: Accepted - 20 June 2022; Published online - 28 July 2022Culling the main wildlife host of bovine tuberculosis in Great Britain (GB) and Ireland, the European badger (Meles meles), has been employed in both territories to reduce infections in cattle. In GB, this has been controversial, with results suggesting that culling induces disturbance to badger social structure, facilitating wider disease dissemination. Previous analyses hypothesized that even very low-level, selective culling may cause similar deleterious effects by increasing ranging of individuals and greater mixing between social groups. To assess this hypothesis, a novel, prospective, landscape-scale ‘before-and-after’ Test and Vaccinate or Remove (TVR) study was implemented. Test-positive badgers were culled and test-negative badgers were Bacillus Calmette–Guérin (BCG) vaccinated and released. Mark–recapture metrics of badger ranging and genetic metrics of social group relatedness did not change significantly over the study period. However, selective culling was associated with a localized reduction in social group relatedness in culled groups. Ecological context is important; extrapolation across territories and other disease epidemiological systems (epi-systems) is likely to be challenging. However, we demonstrate that small-scale, selective removal of test-positive badgers was not associated with metrics of increased ranging but was associated with localized changes in social group relatedness. This adds to the evidence base on badger control options for policy makers.Department of Agriculture, Environment and Rural Affairs (DAERA) N

Paternal and maternal influences on differences in birth weight between Europeans and Indians born in the UK.

BACKGROUND: Ethnic groups differ significantly in adult physique and birth weight. We aimed to improve understanding of maternal versus paternal contributions to ethnic differences in birth weight, by comparing the offspring of same-ethnic versus mixed-ethnic unions amongst Europeans and South Asian Indians in the UK. METHODOLOGY AND PRINCIPAL FINDINGS: We used data from the UK Office for National Statistics Longitudinal Study (LS) and the Chelsea and Westminster Hospital (CWH), London. In the combined sample at all gestational ages, average birth weight of offspring with two European parents was significantly greater than that of offspring with two Indian parents [Δ = 344 (95% CI 329, 360) g]. Compared to offspring of European mothers, the offspring of Indian mothers had lower birth weight, whether the father was European [Δ = -152 (95% CI -92, -212) g] or Indian [Δ = -254 (95% -315, -192) g]. After adjustment for various confounding factors, average birth weight of offspring with European father and Indian mother was greater than that of offspring with two Indian parents [LS: Δ = 249 (95% CI 143, 354) g; CWH: Δ = 236 (95% CI 62, 411) g]. Average birth weight of offspring with Indian father and European mother was significantly less than that of offspring with two European parents [LS: Δ = -117 (95% CI -207, -26) g; CWH: Δ = -83 (-206, 40) g]. CONCLUSIONS/SIGNIFICANCE: Birth weight of offspring with mixed-ethnic parentage was intermediate between that of offspring with two European or two Indian parents, demonstrating a paternal as well as a maternal contribution to ethnic differences in fetal growth. This can be interpreted as demonstrating paternal modulation of maternal investment in offspring. We suggest long-term nutritional experience over generations may drive such ethnic differences through parental co-adaptation

The Macroecology of Sustainability

Global consumption rates of vital resources suggest that we have surpassed the capacity of the Earth to sustain current levels, much less future trajectories of growth in human population and economy

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease

Activin-A is a pleiotropic cytokine that participates in developmental, inflammatory, and tissue repair processes. Still, its effects on T helper (Th) cell–mediated immunity, critical for allergic and autoimmune diseases, are elusive. We provide evidence that endogenously produced activin-A suppresses antigen-specific Th2 responses and protects against airway hyperresponsiveness and allergic airway disease in mice. Importantly, we reveal that activin-A exerts suppressive function through induction of antigen-specific regulatory T cells that suppress Th2 responses in vitro and upon transfer in vivo. In fact, activin-A also suppresses Th1-driven responses, pointing to a broader immunoregulatory function. Blockade of interleukin 10 and transforming growth factor β1 reverses activin-A–induced suppression. Remarkably, transfer of activin-A–induced antigen-specific regulatory T cells confers protection against allergic airway disease. This beneficial effect is associated with dramatically decreased maturation of draining lymph node dendritic cells. Therapeutic administration of recombinant activin-A during pulmonary allergen challenge suppresses Th2 responses and protects from allergic disease. Finally, we demonstrate that immune cells infiltrating the lungs from individuals with active allergic asthma, and thus nonregulated inflammatory response, exhibit significantly decreased expression of activin-A's responsive elements. Our results uncover activin-A as a novel suppressive factor for Th immunity and a critical controller of allergic airway disease