Perivascular adipose tissue: An immune cell metropolis.

NEW FINDINGS: What is the topic of this review? The review discusses how eosinophils can contribute to the function of perivascular adipose tissue and explores the mechanisms involved. What advances does it highlight? Understanding the communication between the cell populations that constitute perivascular adipose tissue function is important for exploring therapeutic options in the treatment of obesity-related cardiovascular complications. This article highlights that eosinophils are able to contribute directly to healthy perivascular adipose tissue function. These immune cells contribute to adrenergic signalling and nitric oxide- and adiponectin-dependent mechanisms in perivascular adipose tissue. ABSTRACT: Perivascular adipose tissue is a heterogeneous tissue that surrounds most blood vessels in the body. This review focuses on the contribution of eosinophils located within the adipose tissue to vascular contractility. A high-fat diet reduces the number of these immune cells within perivascular adipose tissue, and this loss is linked to an increase in vascular contractility and hypertension. We explored the mechanisms by which eosinophils contribute to this function using genetically modified mice, ex vivo assessment of contractility and pharmacological tools. We found that eosinophils contribute to adrenergic signalling and nitric oxide- and adiponectin-dependent mechanisms in perivascular adipose tissue. It is now important to explore whether manipulation of these pathways in obesity can alleviate cardiovascular complications, in order to determine whether eosinophils are a valid target for obesity-related disease.

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility.

BACKGROUND: Several new genes and clinical subtypes have been identified since the publication in 2014 of the report of the last International Consensus Meeting on Epidermolysis Bullosa (EB). OBJECTIVES: We sought to reclassify disorders with skin fragility, with a focus on EB, based on new clinical and molecular data. METHODS: This was a consensus expert review. RESULTS: In this latest consensus report, we introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Other disorders with skin fragility, where blisters are a minor part of the clinical picture or are not seen because skin cleavage is very superficial, are classified as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the common manifestation of skin fragility, these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. CONCLUSIONS: The proposed classification scheme should be of value both to clinicians and researchers, emphasizing both clinical and genetic features of EB. What is already known about this topic? Epidermolysis bullosa (EB) is a group of genetic disorders with skin blistering. The last updated recommendations on diagnosis and classification were published in 2014. What does this study add? We introduce the concept of genetic disorders with skin fragility, of which classical EB represents the prototype. Clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors and natural history of EB are reviewed. Other disorders with skin fragility, e.g. peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility are classified as separate categories; these 'EB-related' disorders should be considered under the EB umbrella in terms of medical and socioeconomic provision of care. Linked Comment: Pope. Br J Dermatol 2020; 183:603.

The measurement of adult blood pressure and management of hypertension before elective surgery: Joint Guidelines from the Association of Anaesthetists of Great Britain and Ireland and the British Hypertension Society.

This guideline aims to ensure that patients admitted to hospital for elective surgery are known to have blood pressures below 160 mmHg systolic and 100 mmHg diastolic in primary care. The objective for primary care is to fulfil this criterion before referral to secondary care for elective surgery. The objective for secondary care is to avoid spurious hypertensive measurements. Secondary care should not attempt to diagnose hypertension in patients who are normotensive in primary care. Patients who present to pre-operative assessment clinics without documented primary care blood pressures should proceed to elective surgery if clinic blood pressures are below 180 mmHg systolic and 110 mmHg diastolic.

Successful renal transplant in a patient with non-Herlitz junctional epidermolysis bullosa.

Non-Herlitz junctional epidermolysis bullosa (NH-JEB) is a very rare inherited disorder, with an array of complications. We present the case of a 33-year-old patient of Chinese origin, diagnosed with NH-JEB in childhood, who developed severe IgA nephropathy. His renal impairment was initially treated by haemodialysis. He underwent successful renal transplantation, resulting in normalization of his renal function. To our knowledge, this is the first report of renal transplantation in a patient with epidermolysis bullosa, which should support use of this intervention in other similar cases.

Long-term safety of unopposed estrogen used by women surviving myocardial infarction: 14-year follow-up of the ESPRIT randomised controlled trial.

OBJECTIVE: To compare health outcomes during 14-year observational follow-up in women initially randomised to unopposed estrogen or placebo. DESIGN: At recruitment to the Estrogen for the Prevention of Re-Infarction Trial (ESPRIT) women were assigned to estradiol valerate: 2 mg or placebo treatment for 2 years. SETTING: Women were recruited from 35 hospitals in the northwest of England and Wales in July 1996-February 2000. SAMPLE: Women aged 50-69 surviving their first myocardial infarction. METHODS: All women were followed by data linkage to UK mortality and cancer records; mean follow-up 14.1 and 12.6 years, respectively. In an intention-to-treat analysis, hazard ratios (HRs) were computed, overall and stratified by age at recruitment. OUTCOME MEASURES: Death (all-cause, cardiac disease, stroke or cancer) and cancer incidence (any, breast or endometrium). RESULTS: There were 418 deaths in 1017 women randomised. The all-cause mortality HR of 1.07 (95% CI 0.88-1.29) indicated no significant difference between treatment groups. Women aged 50-59 years at recruitment had lower HRs than women aged 60-69 years for all outcomes except ischaemic heart disease. Among 149 incident cancers there were seven cases of breast cancer in the intervention arm and 15 in the placebo; HR 0.47 (95% CI 0.19-1.15). There were no deaths from endometrial cancer but three incident cases, one in the active arm and two in placebo. CONCLUSIONS: These results suggest that unopposed estrogen may be used safely by women with an intact uterus surviving a first myocardial infarction.

Stimulated release of a hyperpolarizing factor (ADHF) from mesenteric artery perivascular adipose tissue: involvement of myocyte BKCa channels and adiponectin.

BACKGROUND AND PURPOSE: Perivascular adipose tissue (PVAT) releases adipocyte-derived hyperpolarizing factors (ADHFs) that may partly act by opening myocyte K(+) channels. The present study in rat and mouse mesenteric arteries aimed to identify the myocyte K(+) channel activated by PVAT and to determine whether adiponectin contributed to the hyperpolarizing effects of PVAT. EXPERIMENTAL APPROACH: Myocyte membrane potential was recorded from de-endothelialized, non-contracted rat and mouse mesenteric arteries in the presence and absence of PVAT. KEY RESULTS: The ß3 -adrenoceptor agonist, CL-316,243 (10 µM), generated PVAT-dependent, iberiotoxin-sensitive myocyte hyperpolarizations resulting from BKCa channel opening and which were partially blocked by L-NMMA (100 µM). Adiponectin (5 µg·mL(-1) ) also produced iberiotoxin-sensitive hyperpolarizations in PVAT-denuded arterioles. Activation of myocyte AMP-activated protein kinase (AMPK) using 5 µM A-769662 also induced BKCa -mediated hyperpolarizations. Dorsomorphin abolished hyperpolarizations to CL-316,243, adiponectin and A-769662. In vessels from Adipo(-/-) mice, hyperpolarizations to CL-316,243 were absent whereas those to A-769662 and adiponectin were normal. In rat vessels, adipocyte-dependent hyperpolarizations were blocked by glibenclamide and clotrimazole but those to NS1619 (33 µM) were unaltered. CONCLUSIONS AND IMPLICATIONS: Under basal, non-contracted conditions, ß3 -adrenoceptor stimulation of PVAT releases an ADHF, which is probably adiponectin. This activates AMPK to open myocyte BKCa channels indirectly and additionally liberates NO, which also contributes to the observed PVAT-dependent myocyte hyperpolarizations. Clotrimazole and glibenclamide each reversed hyperpolarizations to adiponectin and A-769662, suggesting the involvement of myocyte TRPM4 channels in the ADHF-induced myocyte electrical changes mediated via the opening of BKCa channels.

Diabetes, Obesity and Atrial Fibrillation: Epidemiology, Mechanisms and Interventions.

Body mass index (BMI) is a powerful predictor of death, type 2 diabetes (T2DM) and cardiovascular (CV) morbidity and mortality. Over the last few decades, we have witnessed a global rise in adult obesity of epidemic proportions. Similarly, there has been a parallel increase in the incidence of atrial fibrillation (AF), itself a significant cause of cardiovascular morbidity and mortality. This may be partly attributable to advances in the treatment of coronary heart disease (CHD) and heart failure (HF) improving life expectancy, however, epidemiological studies have demonstrated an independent association between obesity, diabetes and AF, suggesting possible common pathophysiological mechanisms and risk factors. Indeed, cardiac remodeling, haemodynamic alterations, autonomic dysfunction, and diastolic dysfunction have been reported in obese and diabetic cohorts. Moreover, diabetic cardiomyopathy is characterized by an adverse structural and functional cardiac phenotype, which may predispose to the development of AF. In this review, we discuss the pathophysiological and mechanistic relationships between obesity, diabetes and AF, and some of the challenges posed in the management of this high-risk group of individuals.

Obesity, diabetes and atrial fibrillation; epidemiology, mechanisms and interventions.

The last few decades have witnessed a global rise in adult obesity of epidemic proportions. The potential impact of this is emphasized when one considers that body mass index (BMI) is a powerful predictor of death, type 2 diabetes (T2DM) and cardiovascular (CV) morbidity and mortality [1, 2]. Similarly we have witnessed a parallel rise in the incidence of atrial fibrillation (AF), the commonest sustained cardiac arrhythmia, which is also a significant cause of cardiovascular morbidity and mortality. Part of this increase is attributable to advances in the treatment of coronary heart disease (CHD) and heart failure (HF) improving life expectancy and consequently the prevalence of AF. However, epidemiological studies have demonstrated an independent association between obesity and AF, possibly reflecting common pathophysiology and risk factors for both conditions. Indeed, weight gain and obesity are associated with structural and functional changes of the cardiovascular system including left atrial and ventricular remodeling, haemodynamic alterations, autonomic dysfunction, and diastolic dysfunction. Moreover, diabetic cardiomyopathy is characterized by an adverse structural and functional cardiac phenotype which may predispose to the development of AF [3]. In this review, we discuss the pathophysiological and mechanistic relationships between obesity, diabetes and AF, and the challenges posed in the management of this high-risk group of individuals.

Relationship of endothelial function and atherosclerosis to treatment response in late-life depression.

OBJECTIVE: Treatment response in late-life depression has been linked to cerebrovascular disease notably via the vascular depression hypothesis. This study investigated the relationship between endothelial function and atherosclerosis and treatment response to antidepressant monotherapy. METHODS: Twenty five patients with late-life depression were compared with 21 non-depressed control subjects in a case control study. Nine of the depressed subjects were responders to antidepressant monotherapy and 16 were not. Vascular measures included assessment of carotid intima media thickness (IMT) representing atherosclerosis and biopsied small artery dilatation to acetylcholine to assess endothelial function in a subset of subjects. RESULTS: There were no group differences in vascular risks or sociodemographic variables. There was a significant group difference (responders versus non-responders versus controls) on both IMT and endothelial function (p < 0.01 and p < 0.05, respectively) with a significant difference between controls and non-responders (p < 0.001) on IMT and between controls and responders (p < 0.05) and control versus non-responders (p < 0.05) on endothelial function but no significant difference between responders and non-responders. On both IMT and endothelial function, there was a gradient across groups, with control subjects having best vascular structure or function, non-responders worse and responders in-between. CONCLUSIONS: The results are consistent with a hypothesis that poorer antidepressant response in later life depressive disorder may be linked to an underlying vascular dysfunction and pathology. The study is small, and the results require replication but if confirmed, trials with vasoprotective medication aimed at improving vascular function in order to alter the prognosis of late-life depression would be a rational development.

The role of ß-blockers in the management of hypertension: an Asian perspective.

Following publication of the National Institute of Clinical Excellence (NICE) Guidelines in 2006, the use of ß-blockers as first-line therapy in hypertension has been somewhat controversial. However, a recent reappraisal of the European Society of Hypertension guidelines highlights that these agents exhibit similar BP lowering efficacy to other classes of agents, prompting a re-examination of the utility of these agents in various patient populations. The authors felt that it is important to address this controversy and provide an Asian perspective on the place of ß-blockers in current clinical practice and the benefits of ß-blockade in selected patient populations. In addition to their use as a potential first-line therapy in uncomplicated hypertension, ß-blockers have a particular role in patients with hypertension and comorbidities such as heart failure or coronary artery disease, including those who had a myocardial infarction. One advantage which ß-blockers offer is the additional protective effects in patients with prior cardiovascular events. Some of the disadvantages attributed to ß-blockers appear more related to the older drugs in this class and further appraisal of the efficacy and safety profile of newer ß-blockers will lend support to the current guideline recommendations in Asian countries and encourage increased appropriate use of ß-blockade in current clinical practice within Asia.

Two cases of pustular toxic epidermal necrolysis.

Toxic epidermal necrolysis (TEN) is a life-threatening, immune-mediated reaction, characterized by severe cutaneous and mucosal blisters and erosions. It often presents with flu-like symptoms, followed by a maculopapular, urticarial, purpuric or erythema multiforme-like eruption, which then evolves into blisters and sheet-like erosions. Presentation with pustules, however, is not well described in the English literature, and may lead to delayed diagnosis. We present two unusual cases of TEN that initially presented with pustular lesions.

A rare case of recessive dystrophic epidermolysis bullosa and verruciform xanthoma.

A 33-year-old man with recessive dystrophic epidermolysis bullosa presented with a 3-month history of an enlarging mass within scarring on the posterior aspect of the right shoulder. The clinical appearance of the mass with an almost cobbled, verrucous surface, and its rapid evolution suggested the development of a squamous cell carcinoma (SCC) in a chronically scarred site. Histopathological examination of a biopsy taken from the lesion subsequently revealed it to be a verruciform xanthoma. This case shows that benign phenomena can mimic SCC and underlines the need for a biopsy to be taken promptly.

An international multicenter randomized study of computer-assisted oral anticoagulant dosage vs. medical staff dosage.

BACKGROUND: Increased demand for oral anticoagulants is overwhelming facilities worldwide, resulting in increasing use of computer assistance. A multicenter clinical endpoint study has been performed to compare the safety and effectiveness of computer-assisted dosage with dosage by experienced medical staff at the same centers. METHODS: A randomized study of dosage of two commercial computer-assisted dosage programs (PARMA 5 and DAWN AC) vs. manual dosage at 32 centers with an established interest in oral anticoagulation in 13 countries. The aim was to recruit a minimum of 16,000 patient-years randomized to medical staff or computer-assisted dosage. In total, 13,219 patients participated, 6503 patients being randomized to medical staff and 6716 to computer-assisted dosage. The safety and effectiveness of computer-assisted dosage were compared with those of medical staff dosage. RESULTS: In total, 13,052 patients were recruited (18,617 patient-years). International Normalized Ratio (INR) tests numbered 193 890 with manual dosage and 193,424 with computer-assisted dosage. The number of clinical events with computer-assisted dosage was lower (P = 0.1), but in the 3209 patients with deep vein thrombosis/pulmonary embolism, they were reduced by 37 (24%, P = 0.001). Time in target INR range was significantly improved by computer assistance as compared with medical staff dosage at the majority of centers (P < 0.001). CONCLUSIONS: The safety and effectiveness of computer-assisted dosage has been demonstrated using two different marketed programs in comparison with experienced medical staff dosage at the centers with established interest in anticoagulation. Significant prevention of clinical events in patients with deep vein thrombosis/pulmonary embolism and the achievement of target INR in all clinical groups has been observed. The reliability and safety of other marketed computer-assisted dosage programs need to be established.

Hepatocyte growth factor and c-Met expression in pericytes: implications for atherosclerotic plaque development.

Intraplaque neovascularization contributes to the progression of atherosclerosis. Our aim is to understand the mobilization of cells and factors involved in this process. We investigated the localization of hepatocyte growth factor (HGF) and its receptor, c-Met, in human atherosclerotic plaques, together with the effects of HGF on pericyte migration in vitro. Atherosclerotic femoral arterial segments were collected and analysed from 13 subjects who were undergoing lower limb amputation. Pericytes were identified in human lesions using a 3G5 antibody. Immunohistochemical analysis localized HGF mainly around microvessels, in association with some, but not all, CD31-positive endothelial cells. c-Met expression was mainly associated with smooth muscle cells and pericytes, around some, but not all, microvessels within the atherosclerotic lesions; no detection was apparent in normal internal mammary arteries. Using RT-PCR, we demonstrated expression of HGF and c-Met in a rat pericyte cell-line, TR-PCT1, and in primary pericytes. HGF treatment of TR-PCT1 cells induced their migration, but not their proliferation, in a dose-dependent manner (10-100 ng/ml, p<0.01), an effect mediated by activation of the serine/threonine kinase Akt, shown by western blot analysis. Treating the cells with the PI3K inhibitors Wortmannin (0.1 microM) or LY294002 (10 microM) abolished these effects. This work demonstrates the expression of c-Met and HGF in human atherosclerotic arteries, in association with SM-actin-positive cells and CD-31-positive cells, respectively. HGF induces pericyte migration via PI3-kinase and Akt activation in vitro. HGF and c-Met may be involved in neovascularization during plaque development, and may recruit pericytes to neovessels. Since pericytes are thought to mechanically stabilize new blood vessels, these factors may function to protect against haemorrhage.

Allogeneic bone marrow transplantation in a 7-year-old girl with congenital erythropoietic porphyria: a treatment dilemma.

Congenital erythropoietic porphyria (CEP, Günther's disease) has a very variable phenotype. In the more severely affected, bone marrow transplantation (BMT) is potentially curative, but is not without risks. We describe a 7-year-old girl with CEP characterized by severe photosensitivity but only mild anaemia, in whom the difficult decision to proceed with allogeneic BMT was made after discussion in a multidisciplinary team. She has shown successful engraftment, accompanied by biochemical and clinical resolution of her metabolic disease. She remains well 3 years later, the oldest patient with CEP receiving BMT to survive beyond 12 months. However, she has experienced significant morbidity including florid cutaneous graft-versus-host disease with postinflammatory hypopigmentation. Her case is important in highlighting the delay in diagnosis not uncommon in this condition and the complex decision-making process involved in proceeding with BMT.