Cardiac Hypertrophy and Fibrosis in the Metabolic Syndrome: A Role for Aldosterone and the Mineralocorticoid Receptor

Obesity and hypertension, major risk factors for the metabolic syndrome, render individuals susceptible to an increased risk of cardiovascular complications, such as adverse cardiac remodeling and heart failure. There has been much investigation into the role that an increase in the renin-angiotensin-aldosterone system (RAAS) plays in the pathogenesis of metabolic syndrome and in particular, how aldosterone mediates left ventricular hypertrophy and increased cardiac fibrosis via its interaction with the mineralocorticoid receptor (MR). Here, we review the pertinent findings that link obesity with elevated aldosterone and the development of cardiac hypertrophy and fibrosis associated with the metabolic syndrome. These studies illustrate a complex cross-talk between adipose tissue, the heart, and the adrenal cortex. Furthermore, we discuss findings from our laboratory that suggest that cardiac hypertrophy and fibrosis in the metabolic syndrome may involve cross-talk between aldosterone and adipokines (such as adiponectin)

Adiponectin in Cardiovascular Inflammation and Obesity

Inflammation is widely known to play a key role in the development and progression of cardiovascular diseases. It is becoming increasingly evident that obesity is linked to many proinflammatory and obesity-associated cardiovascular conditions (e.g., metabolic syndrome, acute coronary syndrome, and congestive heart failure). It has been observed that adipokines play an increasingly large role in systemic and local inflammation. Therefore, adipose tissue may have a more important role than previously thought in the pathogenesis of several disease types. This review explores the recently described role of adiponectin as an immunomodulatory factor and how it intersects with the inflammation associated with both cardiovascular and autoimmune pathologies

Ubiquitin D regulates IRE1 α/c-Jun N-terminal kinase (JNK) protein-dependent apoptosis in pancreatic beta cells

Pro-inflammatory cytokines contribute to pancreatic beta cell apoptosis in type 1 diabetes at least in part by inducing endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). It remains to be determined what causes the transition from "physiological" to "apoptotic" UPR, but accumulating evidence indicates that signaling by the ER transmembrane protein IRE1 alpha is critical for this transition. IRE1 alpha activation is regulated by both intra-ER and cytosolic cues. We evaluated the role for the presently discovered cytokine-induced and IRE1 alpha-interacting protein ubiquitin D (UBD) on the regulation of IRE1 alpha and its downstream targets. UBD was identified by use of a MAPPIT (mammalian protein-protein interaction trap)-based IRE1 alpha interactome screen followed by comparison against functional genomic analysis of human and rodent beta cells exposed to pro-inflammatory cytokines. Knockdown ofUBDin human and rodent beta cells and detailed signal transduction studies indicated that UBD modulates cytokine-induced UPR/IRE1 alpha activation and apoptosis. UBD expression is induced by the pro-inflammatory cytokines interleukin (IL)-1 beta and interferon (IFN)-gamma in rat and human pancreatic beta cells, and it is also up-regulated in beta cells of inflamed islets from non-obese diabetic mice. UBD interacts with IRE1 alpha in human and rodent beta cells, modulating IRE1 alpha-dependent activation of JNK and cytokine-induced apoptosis. Our data suggest that UBD provides a negative feedback on cytokine-induced activation of the IRE1 alpha/JNK pro-apoptotic pathway in cytokine-exposed beta cells

The psychological burden of skin diseases: a cross-sectional multicenter study among dermatological out-patients in 13 European countries.

The contribution of psychological disorders to the burden of skin disease has been poorly explored, and this is a large-scale study to ascertain the association between depression, anxiety, and suicidal ideation with various dermatological diagnoses. This international multicenter observational cross-sectional study was conducted in 13 European countries. In each dermatology clinic, 250 consecutive adult out-patients were recruited to complete a questionnaire, reporting socio-demographic information, negative life events, and suicidal ideation; depression and anxiety were assessed with the Hospital Anxiety and Depression Scale. A clinical examination was performed. A control group was recruited among hospital employees. There were 4,994 participants--3,635 patients and 1,359 controls. Clinical depression was present in 10.1% patients (controls 4.3%, odds ratio (OR) 2.40 (1.67-3.47)). Clinical anxiety was present in 17.2% (controls 11.1%, OR 2.18 (1.68-2.82)). Suicidal ideation was reported by 12.7% of all patients (controls 8.3%, OR 1.94 (1.33-2.82)). For individual diagnoses, only patients with psoriasis had significant association with suicidal ideation. The association with depression and anxiety was highest for patients with psoriasis, atopic dermatitis, hand eczema, and leg ulcers. These results identify a major additional burden of skin disease and have important clinical implications.Peer reviewedFinal Published versio

Attachment styles of dermatological patients in europe : A multicentre study in 13 countries

This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License https://creativecommons.org/licenses/by-nc/4.0/. © 2017 Acta Dermato-Venereologica.Attachment styles of dermatological outpatients and satisfaction with their dermatologists were investigated within the framework of a multicentre study conducted in 13 European countries, organized by the European Society for Dermatology and Psychiatry. Attachment style was assessed with the Adult Attachment Scale. Patient satisfaction with the dermatologist was assessed with an 11-degree scale. A total of 3,635 adult outpatients and 1,359 controls participated in the study. Dermatological outpatients were less able to depend on others, were less comfortable with closeness and intimacy, and experienced similar rates of anxiety in relationships as did the controls. Participants who had secure attachment styles reported stressful life events during the last 6 months significantly less often than those who had insecure attachment styles. Patients with secure attachment styles tended to be more satisfied with their dermatologist than did insecure patients. These results suggest that secure attachment of dermatological outpatients may be a protective factor in the management of stress.Peer reviewedFinal Published versio

Impact of Glutathione S-Transferase M1 and T1 Gene Polymorphisms on the Smoking-Related Coronary Artery Disease

Glutathione S-transferase (GST) plays a key role in the detoxification of xenobiotic atherogen generated by smoking. To analyze the effect of GSTM1/T1 gene polymorphisms on the development of smoking-related coronary artery disease (CAD), 775 Korean patients who underwent coronary angiography were enrolled. The subjects were classified by luminal diameter stenosis into group A (>50%), B (20-50%), or C (<20%). GSTM1 and GSTT1 gene polymorphisms were analyzed using multiplex polymerase chain reaction (PCR) for GSTM1/T1 genes and CYP1A1 gene for internal control. Of 775 subjects, 403 patients belonged to group A. They had higher risk factors for CAD than group B (N=260) and group C (N=112). The genotype frequencies of null GSTM1 and GSTT1 showed no significant differences among 3 groups. Considering the effect of GSTM1 gene polymorphisms on the smoking-related CAD, smokers with GSTM1 null genotype had more increased risk for CAD than non-smoker with GSTM1 positive genotype (odds ratios [OR], 2.07, confidence interval [CI], 1.06-4.07). Also the effect of GSTT1 gene polymorphism on smoking-related CAD showed the same tendency as GSTM1 gene (OR, 2.00, CI, 1.05-3.84). This effect of GSTM1/T1 null genotype on smoking-related CAD was augmented when both gene polymorphisms were considered simultaneously (OR, 2.76, CI, 1.17-6.52). We concluded that GSTM1/T1 null genotype contributed to the pathogenesis of smoking-related CAD to some degree

State hospitals, academic medicine and the decline of health care in South Africa: A cry of support from those who have left for those who stay.

Recently a group of concerned South African doctors published a comment on the occupational-specific dispensation negotiations that have failed to address their concerns. As a group of South African trained physicians working out of South Africa we would like to add our voice in support of these concerned doctors. In particular, the South African public and government needs to acknowledge that poor working conditions and inadequate compensation play a large role in the loss of medical skill from South Africa

Exploring the EQ-5D Dimension of Pain/Discomfort in Dermatology Outpatients from a Multicentre Study in 13 European Countries

Pain and discomfort are important symptoms in dermatology. The aim of this cross-sectional, multicentre study was to describe the prevalence of pain/discomfort and its associations in patients with several dermatological conditions across 13 European countries. The outcome was the prevalence of pain/discomfort according to a question of the EQ-5D questionnaire. Data collected from November 2011 to February 2013 were complete for 3,509 consecutive outpatients. Moderate or extreme pain/discomfort was reported by 55.5% of patients and 31.5% of controls with no skin conditions. The highest proportions were reported by patients with hidradenitis suppurativa (92.9%), leg ulcer (81.4%), prurigo (80%) and lichen planus (75.6%). Pain/discomfort was associated with older age, low educational level, clinical severity, flare on scalp or hands, itch, depression, anxiety, low quality of life, and thoughts of suicide. It is important to enquire specifically about pain/discomfort during clinical consultations and to address it when planning a patient's care.publishedVersio

Generation and transmission of interlineage recombinants in the SARS-CoV-2 pandemic.

We present evidence for multiple independent origins of recombinant SARS-CoV-2 viruses sampled from late 2020 and early 2021 in the United Kingdom. Their genomes carry single-nucleotide polymorphisms and deletions that are characteristic of the B.1.1.7 variant of concern but lack the full complement of lineage-defining mutations. Instead, the remainder of their genomes share contiguous genetic variation with non-B.1.1.7 viruses circulating in the same geographic area at the same time as the recombinants. In four instances, there was evidence for onward transmission of a recombinant-origin virus, including one transmission cluster of 45 sequenced cases over the course of 2 months. The inferred genomic locations of recombination breakpoints suggest that every community-transmitted recombinant virus inherited its spike region from a B.1.1.7 parental virus, consistent with a transmission advantage for B.1.1.7's set of mutations.The COG-UK Consortium is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) (MC_PC_19027), and Genome Research Limited, operating as the Wellcome Sanger Institute. O.G.P. was supported by the Oxford Martin School. J.T.M., R.M.C., N.J.L., and A.R. acknowledge the support of the Wellcome Trust (Collaborators Award 206298/Z/17/Z – ARTIC network). D.L.R. acknowledges the support of the MRC (MC_UU_12014/12) and the Wellcome Trust (220977/Z/20/Z). E.S. and A.R. are supported by the European Research Council (grant agreement no. 725422 – ReservoirDOCS). T.R.C. and N.J.L. acknowledge the support of the MRC, which provided the funding for the MRC CLIMB infrastructure used to analyze, store, and share the UK sequencing dataset (MR/L015080/1 and MR/T030062/1). The samples sequenced in Wales were sequenced partly using funding provided by the Welsh Government