High glucose up-regulates ENaC and SGK1 expression in HCD-cells

Background/Aim: Diabetic nephropathy is associated with progressive renal damage, leading to impaired function and end-stage renal failure. Secondary hypertension stems from a deranged ability of cells within the kidney to resolve and appropriately regulate sodium resorption in response to hyperglycaemia. However, the mechanisms by which glucose alters sodium re-uptake have not been fully characterised. Methods: Here we present RT-PCR, western blot and immunocytochemistry data confirming mRNA and protein expression of the serum and glucocorticoid inducible kinase (SGK1) and the a conducting subunit of the epithelial sodium channel (ENaC) in a model in vitro system of the human cortical collecting duct (HCD). We examined changes in expression of these elements in response to glucose challenge, designed to mimic hyperglycaemia associated with type 2 diabetes mellitus. Changes in Na+ concentration were assessed using single-cell microfluorimetry. Results: Incubation with glucose, the Ca2+-ionophore ionomycin and the cytokine TGF-beta 1 were all found to evoke significant and time-dependent increases in both SGK1 and alpha ENaC protein expression. These molecular changes were correlated to an increase in Na+-uptake at the single-cell level. Conclusion: Together these data offer a potential explanation for glucose-evoked Na+-resorption and a potential contributory role of SGK1 and ENaCs in development of secondary hypertension, commonly linked to diabetic nephropathy

Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours

Although compulsive sexual behaviour (CSB) has been conceptualized as a "behavioural" addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions

Critical Thinking in Nursing Education: Literature Review

The need for critical thinking in nursing has been accentuated in response to the rapidly changing health care environment. Nurses must think critically to provide effective care whilst coping with the expansion in role associated with the complexities of current health care systems. This literature review will present a history of inquiry into critical thinking and research to support the conclusion that critical thinking is necessary not only in the clinical practice setting, but also as an integral component of nursing education programs to promote the development of nurses’ critical thinking abilities. The aims of this paper are: (a) to review the literature on critical thinking; (b) to examine the dimensions of critical thinking; (c) to investigate the various critical thinking strategies for their appropriateness to enhance critical thinking in nurses, and; (d) to examine issues relating to evaluation of critical thinking skills in nursing.</ul

Blunted endogenous opioid release following an oral amphetamine challenge in pathological gamblers

Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [(11)C]carfentanil PET with an oral amphetamine challenge. Fourteen PG and 15 healthy volunteers (HV) underwent two [(11)C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [(11)C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [(11)C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may have an important role in the pathophysiology of addictions

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Five-Factor Model personality profiles of drug users

<p>Abstract</p> <p>Background</p> <p>Personality traits are considered risk factors for drug use, and, in turn, the psychoactive substances impact individuals' traits. Furthermore, there is increasing interest in developing treatment approaches that match an individual's personality profile. To advance our knowledge of the role of individual differences in drug use, the present study compares the personality profile of tobacco, marijuana, cocaine, and heroin users and non-users using the wide spectrum Five-Factor Model (FFM) of personality in a diverse community sample.</p> <p>Method</p> <p>Participants (<it>N </it>= 1,102; mean age = 57) were part of the Epidemiologic Catchment Area (ECA) program in Baltimore, MD, USA. The sample was drawn from a community with a wide range of socio-economic conditions. Personality traits were assessed with the Revised NEO Personality Inventory (NEO-PI-R), and psychoactive substance use was assessed with systematic interview.</p> <p>Results</p> <p>Compared to never smokers, current cigarette smokers score lower on Conscientiousness and higher on Neuroticism. Similar, but more extreme, is the profile of cocaine/heroin users, which score very high on Neuroticism, especially Vulnerability, and very low on Conscientiousness, particularly Competence, Achievement-Striving, and Deliberation. By contrast, marijuana users score high on Openness to Experience, average on Neuroticism, but low on Agreeableness and Conscientiousness.</p> <p>Conclusion</p> <p>In addition to confirming high levels of negative affect and impulsive traits, this study highlights the links between drug use and low Conscientiousness. These links provide insight into the etiology of drug use and have implications for public health interventions.</p

Action to protect the independence and integrity of global health research

Storeng KT, Abimbola S, Balabanova D, et al. Action to protect the independence and integrity of global health research. BMJ GLOBAL HEALTH. 2019;4(3): e001746

Eosinophils in glioblastoma biology

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)