Differences in hidradenitis suppurativa patterns of cutaneous involvement between sexes: Insights from a cross-sectional study.

Hidradenitis suppurativa is a chronic, inflammatory condition of the pilosebaceous unit in which patients manifest multiple, painful cutaneous nodules, abscesses and tunnels. These lesions are described to affect the intertriginous zones, however, the condition exhibits significant phenotypic variability. Such variability is influenced by the patients lifestyle, genetic predisposition and sex. In this cross-sectional study, we investigate sex differences in patterns of hidradenitis suppurativa skin involvement, specifically at site of first involvement and most bothersome cutaneous site of involvement.

Phenotyping obesity: A focus on metabolically healthy obesity and metabolically unhealthy normal weight.

Over the past 4 decades, research has shown that having a normal body weight does not automatically imply preserved metabolic health and a considerable number of lean individuals harbour metabolic abnormalities typically associated with obesity. Conversely, excess adiposity does not always equate with an abnormal metabolic profile. In fact, evidence exists for the presence of a metabolically unhealthy normal weight (MUHNW) and a metabolically healthy obese (MHO) phenotype. It has become increasingly recognised that different fat depots exert different effects on the metabolic profile of each individual by virtue of their location, structure and function, giving rise to these different body composition phenotypes. Furthermore, other factors have been implicated in the aetiopathogenesis of the body composition phenotypes, including genetics, ethnicity, age and lifestyle/behavioural factors. Even though to date both MHO and MUHNW have been widely investigated and documented in the literature, studies report different outcomes on long-term cardiometabolic morbidity and mortality. Future large-scale, observational and population-based studies are required for better profiling of these phenotypes as well as to further elucidate the pathophysiological role of the adipocyte in the onset of metabolic disorders to allow for better risk stratification and a personalised treatment paradigm.

Investigating Adiposity-Related Metabolic Health Phenotypes in Patients with Hidradenitis Suppurativa: A Cross-Sectional Study.

BACKGROUND: Obesity and hidradenitis suppurativa (HS) are related through meta-inflammation and are both associated with increased cardiometabolic risk. Notwithstanding, cardiometabolic pathology is not uniform in obesity and a subset of individuals with excess adiposity exhibit a healthy metabolic profile. Whilst the incidence of cardiometabolic endpoints and transitions across different adiposity-related body composition phenotypes within several populations and across different ethnicities have been investigated, data regarding metabolic health (MetH) and body composition phenotypes in individuals with HS are lacking. The objective of this study was to evaluate the relationship between different body composition phenotypes in individuals with HS. METHODS: This was a cross-sectional study of 632 individuals with and without HS from a population with a high prevalence of both obesity and HS. A total of four body composition phenotypes were generated based on BMI and metabolic status (defined using either the metabolic syndrome definition or the homeostasis model of insulin resistance (HOMA-IR)): metabolically healthy overweight/obese (MHOWOB), metabolically unhealthy overweight/obese (MUOWOB), metabolically healthy normal weight (MHNW), and metabolically unhealthy normal weight (MUNW). RESULTS: Generally, subjects with HS exhibited a worse metabolic profile with higher levels of indices of central adiposity measures (including Visceral Adiposity Index and waist circumference), systolic blood pressure and markers of insulin resistance, as well as a higher prevalence of the metabolic syndrome. Moreover, when sub-stratified into the different body composition phenotypes, individuals with HS typically also demonstrated adverse metabolic characteristics relative to controls matched for both adiposity and metabolic health, particularly in the normal weight category and despite being classified as metabolically healthy. Being metabolically unhealthy in addition to being overweight/obese increases an individual's risk of HS. CONCLUSIONS: Metabolic risk-assessment should be prioritized in the clinical management of individuals with HS even in those who are lean. Patients attending HS clinics provide a valuable opportunity for targeted cardiovascular risk reduction with respect to the management of both obesity and metabolic health.

Lack of guidelines and translational knowledge is hindering the implementation of psychiatric genetic counseling and testing within Europe - A multi-professional survey study.

Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field. We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders. Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant. We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe.

Obesity and hidradenitis suppurativa: targeting meta-inflammation for therapeutic gain.

Hidradenitis suppurativa (HS) is a chronic, inflammatory condition of the pilosebaceous unit. The typical patient with HS is characterized as someone with obesity, who smokes and who has nodules, abscesses and/or draining tunnels predominantly distributed in intertriginous skin. It has been established that lifestyle and genetic factors are the main pathophysiological drivers of HS. In this critical review, we explore the interrelatedness of meta-inflammation, obesity and HS and discuss if and how this relationship may be manipulated for a therapeutic end.

The relationship between adipokine levels and bone mass-A systematic review.

INTRODUCTION: Adipose tissue is the source of a broad array of signalling molecules (adipokines), which mediate interorgan communication and regulate metabolic homeostasis. Alterations in adipokine levels have been causally implicated in various metabolic disorders, including changes in bone mass. Osteoporosis is the commonest progressive metabolic bone disease, characterized by elevated risk of fragility fractures as a result of a reduced bone mass and microarchitectural deterioration. The effects of different adipokines on bone mass have been studied in an attempt to identify novel modulators of bone mass or diagnostic biomarkers of osteoporosis. METHODS: In this review, we sought to aggregate and assess evidence from independent studies that quantify specific adipokines and their effect on bone mineral density (BMD). RESULTS: A literature search identified 57 articles that explored associations between different adipokines and BMD. Adiponectin and leptin were the most frequently studied adipokines, with most studies demonstrating that adiponectin levels are associated with decreased BMD at the lumbar spine and femoral neck. Conversely, leptin levels are associated with increased BMD at these sites. However, extensive heterogeneity with regards to sample size, characteristics of study subjects, ethnicity, as well as direction and magnitude of effect at specific skeletal anatomical sites was identified. The broad degree of conflicting findings reported in this study can be attributed several factors. These include differences in study design and ascertainment criteria, the analytic challenges of quantifying specific adipokines and their isoforms, pre-analytical variables (in particular patient preparation) and confounding effects of co-existing disease. CONCLUSIONS: This review highlights the biological relevance of adipokines in bone metabolism and reinforces the need for longitudinal research to elucidate the causal relationship of adipokines on bone mass.

Management of patients with hidradenitis suppurativa having underlying genetic variation: a systematic review and a call for precision medicine.

Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the pilosebaceous unit characterized by inflammation and hyperkeratinization. A small but significant proportion of patients with HS have a strong genetic susceptibility to (or a syndromic form of) the disease. Current HS treatment guidelines prioritize patients who manifest classic HS and may therefore not be suitable for the minority of patients harbouring genetically driven forms of disease. In this manuscript, we review the extant literature with regards to therapeutic strategies used for patients with HS having disease-associated genetic variants and syndromic forms of the condition. The findings of this review suggest that patients with HS harbouring underlying genetic variants may not be adequately represented in current European and British HS treatment guidelines. Moreover, these patients may be less responsive to the recommended therapeutic options. We therefore make recommendations for future therapeutic guidelines to incorporate considerations for the management of this patient subset.

Serum Immunoglobulin G Is a Marker of Hidradenitis Suppurativa Disease Severity.

Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the skin that is brought about by autoinflammation and hyperkeratosis at the pilosebaceous unit. The clinical severity of HS can be measured using static (Hurley Severity Scoring (HSS)) and/or dynamic (International HS Severity Scoring System (IHS4)) severity scoring instruments. However, few clinically available serological parameters have been found to correlate with disease severity. In this study, we sought to investigate the role of serum immunoglobulin (Ig) G, M and A levels as biomarkers of disease severity and to compare them with other, more conventional inflammatory indices, such as the erythrocyte sedimentation rate, C-reactive protein, the neutrophil-lymphocyte ratio, the platelet-lymphocyte ratio and the systemic immune-inflammation index. In this cross-sectional study, patients were recruited from the only dermatology referral centre in Malta, Europe, and subjected to clinical examination and the assessment of inflammatory and immunologic parameters. Serum IgG, M and A levels were assessed using the Atellica® NEPH 630 System (SIEMENS-Healthineers AF, Erlangen, Germany) nephelometric analyser. Serum IgG, M and A levels correlate with both dynamic and static HS severity scoring systems. Serum IgG behaves as a marker of severe HS disease as categorised by HSS and the IHS4. Our findings suggest that the serum IgG level can be used in the clinical setting as a biomarker of disease severity and, therefore, as an adjunct to clinical severity scoring.

Interpreting the spectrum of gamma-secretase complex missense variation in the context of hidradenitis suppurativa-An in-silico study.

Hidradenitis suppurativa (HS) is a disease of the pilosebaceous unit characterized by recurrent nodules, abscesses and draining tunnels with a predilection to intertriginous skin. The pathophysiology of HS is complex. However, it is known that inflammation and hyperkeratinization at the hair follicle play crucial roles in disease manifestation. Genetic and environmental factors are considered the main drivers of these two pathophysiological processes. Despite a considerable proportion of patients having a positive family history of disease, only a minority of patients suffering from HS have been found to harbor monogenic variants which segregate to affected kindreds. Most of these variants are in the ɣ secretase complex (GSC) protein-coding genes. In this manuscript, we set out to characterize the burden of missense pathogenic variants in healthy reference population using large scale genomic dataset thereby providing a standard for comparing genomic variation in GSC protein-coding genes in the HS patient cohort.

Metabolic syndrome and hidradenitis suppurativa: epidemiological, molecular, and therapeutic aspects.

Hidradenitis suppurativa (HS) is a chronic, suppurative condition of the pilosebaceous unit. Patients suffering from HS demonstrate a molecular profile in keeping with a state of systemic inflammation and are often found to fit the criteria for a diagnosis of metabolic syndrome (MetS). In this paper, we review the literature with regards to established data on the prevalence of MetS in HS patients and revise the odds ratio of comorbid disease. Furthermore, we attempt to draw parallels between inflammatory pathways in HS and MetS and evaluate how convergences may explain the risk of comorbid disease, necessitating the need for multidisciplinary care.

Metformin as an adjuvant in breast cancer treatment.

Breast cancer is one of the most common malignancies in females. It is an etiologically complex disease driven by a multitude of cellular pathways. The proliferation and spread of breast cancer is intimately linked to cellular glucose metabolism, given that glucose is an essential cellular metabolic substrate and that insulin signalling has mitogenic effects. Growing interest has focused on anti-diabetic agents in the management of breast cancer. Epidemiologic studies show that metformin reduces cancer incidence and mortality among type 2 diabetic patients. Preclinical in vitro and in vivo research provides intriguing insight into the cellular mechanisms behind the oncostatic effects of metformin. This article aims to provide an overview of the mechanisms in which metformin may elicit its anti-cancerous effects and discuss its potential role as an adjuvant in the management of breast cancer.

Circulating visfatin levels in the second and third trimester of pregnancies with gestational diabetes: a systematic review.

INTRODUCTION: There are multiple published conflicting associations of the adipocytokine visfatin with gestational diabetes. In this study, we attempted to investigate this relationship via a systematic review of the published literature. EVIDENCE ACQUISITION: Literature retrieval using PubMed, Google Scholar, Scopus and Hydi databases followed by article selection and data extraction were conducted. Relevant studies published up to June 2018 were included. In total, 29 cohorts that were published in 27 articles were analyzed. Three studies carried out in early pregnancy were excluded. A total of 2365 individuals, with 1069 gestational diabetes (GDM) cases and 1296 controls from studies describing visfatin in the second or third trimester of gestation were included. EVIDENCE SYNTHESIS: The difference in visfatin levels between women with GDM and the controls in the second and third trimester was measured by weighted mean difference (WMD) and 95% confidence intervals (CI). Heterogeneity was inspected by using both subgroup and meta-regression analysis. Analysis was restricted to studies describing singleton pregnancies. The quality of included studies was assessed by the Newcastle-Ottawa Scale. CONCLUSIONS: No significant difference in circulating visfatin levels in GDM during the second trimester of pregnancy (WMD -0.30 ng/mL, 95% CI: -2.06, 1.45, SE=0.895, P=0.733) was detected. Meta-analysis of the studies in the third trimester revealed a significant negative effect, that was however driven by only one study. This finding limits the meaningful interpretation of the pooled analysis. Significant heterogeneity was identified between studies, and meta-regression analysis showed that homeostatic model assessment for insulin resistance contributes significantly to heterogeneity. In conclusion, our findings suggest that peripheral blood visfatin concentration cannot be robustly associated with gestational diabetes status in the second and third trimesters of pregnancy.

Two novel GJA1 variants in oculodentodigital dysplasia.

BACKGROUND: Oculodentodigital dysplasia (ODDD) is a rare disorder with pleiotropic effects involving multiple body systems, caused by mutations in the gap junction protein alpha 1 (GJA1) gene. GJA1 gene encodes a polytopic connexin membrane protein, Cx43, that is a component of connexon membrane channels. METHODS: We describe two unrelated female probands referred for a genetic review in view of a dysmorphic clinical phenotype. RESULTS: Two novel missense mutations in GJA1 that substitute conserved amino acids in the first and second transmembrane domains (NM_000165.5: c.77T>C p.Leu26Pro and NM_000165.5:c.287T>G p.Val96Gly) were detected through targeted sequencing of GJA1. These variants were detected in the heterozygous state in the two Maltese probands and segregated with the disease phenotype. CONCLUSION: This report further expands the mutational spectrum of ODDD.

Genetic determinants of low birth weight.

Birth weight depends on the elaborate interaction between maternal and fetal genotypes, placental function, maternal nutrition and lifestyle and their effect on epigenetic regulators of gene activity. The maternal environment in which the fetus develops is a critical factor in determining birth weight. This review provides an overview of the effect of several genetic variants leading to intrauterine growth restriction and low birth weight. Irrespective of the exact cause of genetic variations of fetal genes, intrauterine growth restriction is most likely due to alteration in the growth hormone and insulin like growth factor axis with distinct changes in the growth factors and their interaction with corresponding receptors. Interactions also occur between the fetal genotype and the intrauterine environment, influencing expression certain genes required for fetal growth. Genomic imprinting is an important mechanism whereby the restraint of fetal growth could be determined through the maternal line. Furthermore, maternal cigarette smoking results in genetic variations in two specific genes, which interact synergistically, resulting in low birth weight. Confined placental mosaicism can also lead to clinically compelling intrauterine growth restriction or even intrauterine fetal death.

The Microbial Hypothesis: Contributions of Adenovirus Infection and Metabolic Endotoxaemia to the Pathogenesis of Obesity.

The global obesity epidemic, dubbed "globesity" by the World Health Organisation, is a pressing public health issue. The aetiology of obesity is multifactorial incorporating both genetic and environmental factors. Recently, epidemiological studies have observed an association between microbes and obesity. Obesity-promoting microbiome and resultant gut barrier disintegration have been implicated as key factors facilitating metabolic endotoxaemia. This is an influx of bacterial endotoxins into the systemic circulation, believed to underpin obesity pathogenesis. Adipocyte dysfunction and subsequent adipokine secretion characterised by low grade inflammation, were conventionally attributed to persistent hyperlipidaemia. They were thought of as pivotal in perpetuating obesity. It is now debated whether infection and endotoxaemia are also implicated in initiating and perpetuating low grade inflammation. The fact that obesity has a prevalence of over 600 million and serves as a risk factor for chronic diseases including cardiovascular disease and type 2 diabetes mellitus is testament to the importance of exploring the role of microbes in obesity pathobiology. It is on this basis that Massachusetts General Hospital is sponsoring the Faecal Microbiota Transplant for Obesity and Metabolism clinical trial, to study the impact of microbiome composition on weight. The association of microbes with obesity, namely, adenovirus infection and metabolic endotoxaemia, is reviewed.

The role of testosterone in colorectal carcinoma: pathomechanisms and open questions.

Colorectal cancer (CRC) is the fourth commonest type of malignancy after breast, lung and prostate in the USA and accounts for approximately 49,190 deaths annually in USA alone. The 5-year survival rate of CRC has increased over the past decades, in part, due to greater awareness and the widespread implementation of national screening programmes. Recently, a number of studies reported that males have a higher risk of developing CRC due to the action of testosterone. Testosterone is an androgen that is responsible for the development of male secondary sex characteristics and for spermatogenesis. Studies on rats with mutated Apc tumour-suppressor gene subjected to either ovariectomy or orchidectomy exhibit different risks of CRC. Female rats subjected to ovariectomy are at higher risk of CRC, whereas orchidectomised male rats exhibit a lower risk of developing CRC. Sex hormones, in particular estrogen and testosterone, play a significant role in the development of CRC since the anti-neoplastic effect of estrogen lost during ovariectomy increases the risk of females developing CRC. Male mice exposed to testosterone after orchidectomy were also at greater risk than those who were orchidectomised but administered placebo only. Moreover, the recently established role of membrane androgen receptors in regression of CRC via non-genomic androgen-dependent action sets these receptors apart from intracellular androgen receptors (iARs) which themselves promote CRC development. In addition, testosterone-albumin conjugates are selective to membrane androgen receptors (mARs) and lead to apoptosis via caspase-3 activation. Akt kinases promote invasion of colon cancer cells when phosphorylated. These kinases are dephosphorylated upon activation of mARs, thereby reducing colon cancer cell motility and invasiveness. Testosterone similarly plays important roles in human CRC. Long cytosine-adenine-guanine (CAG) repeats in the gene for the androgen receptors have been associated with a poor 5-year survival compared to shorter CAG repeats. Very recently, the measurement of serum unbound testosterone has been suggested as a novel biomarker along with carcinoembryonic antigen in CRC. In conclusion, testosterone may promote the development of CRC via a number of pathways, which may place males at greater risk. Testosterone holds promise as a potential biomarker in CRC risk prediction; however, further studies are required to better define its role in colorectal neoplasia.

The Role of TLR2, TLR4, and TLR9 in the Pathogenesis of Atherosclerosis.

Toll-like receptors (TLRs) are key players in the pathogenesis of inflammatory conditions including coronary arterial disease (CAD). They are expressed by a variety of immune cells where they recognize pathogen-associated molecular patterns (PAMPs). TLRs recruit adaptor molecules, including myeloid differentiation primary response protein (MYD88) and TIRF-related adaptor protein (TRAM), to mediate activation of MAPKs and NF-kappa B pathways. They are associated with the development of CAD through various mechanisms. TLR4 is expressed in lipid-rich and atherosclerotic plaques. In TLR2-/- and TLR4-/- mice, atherosclerosis-associated inflammation was diminished. Moreover, TLR2 and TLR4 may induce expression of Wnt5a in advanced staged atheromatous plaque leading to activation of the inflammatory processes. TLR9 is activated by CpG motifs in nucleic acids and have been implicated in macrophage activation and the uptake of oxLDL from the circulation. Furthermore, TLR9 also stimulates interferon-α (INF-α) secretion and increases cytotoxic activity of CD4+ T-cells towards coronary artery tunica media smooth muscle cells. This review outlines the pathophysiological role of TLR2, TLR4, and TLR9 in atherosclerosis, focusing on evidence from animal models of the disease.