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.

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.

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.

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.

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.

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.

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.

Upregulated TRPC1 channel in vascular injury in vivo and its role in human neointimal hyperplasia.

Occlusive vascular disease is a widespread abnormality leading to lethal or debilitating outcomes such as myocardial infarction and stroke. It is part of atherosclerosis and is evoked by clinical procedures including angioplasty and grafting of saphenous vein in bypass surgery. A causative factor is the switch in smooth muscle cells to an invasive and proliferative mode, leading to neointimal hyperplasia. Here we reveal the importance to this process of TRPC1, a homolog of Drosophila transient receptor potential. Using 2 different in vivo models of vascular injury in rodents we show hyperplasic smooth muscle cells have upregulated TRPC1 associated with enhanced calcium entry and cell cycle activity. Neointimal smooth muscle cells after balloon angioplasty of pig coronary artery also express TRPC1. Furthermore, human vein samples obtained during coronary artery bypass graft surgery commonly exhibit an intimal structure containing smooth muscle cells that expressed more TRPC1 than the medial layer cells. Veins were organ cultured to allow growth of neointimal smooth muscle cells over a 2-week period. To explore the functional relevance of TRPC1, we used a specific E3-targeted antibody to TRPC1 and chemical blocker 2-aminoethoxydiphenyl borate. Both agents significantly reduced neointimal growth in human vein, as well as calcium entry and proliferation of smooth muscle cells in culture. The data suggest upregulated TRPC1 is a general feature of smooth muscle cells in occlusive vascular disease and that TRPC1 inhibitors have potential as protective agents against human vascular failure.

Optimizing hypertension management in clinical practice.

A clear relationship exists between elevated blood pressure (BP) and various manifestations of cardiovascular disease. Despite the availability of numerous treatment guidelines, hypertension remains inadequately controlled, with only a small proportion of patients achieving target BP levels. Many factors, both patient and physician related, contribute to this poor level of hypertension control. Major determinants include the implementation of inappropriate treatment regimens that do not enable patients to achieve goal and poor patient compliance. For example, it is widely acknowledged that most patients require two or more antihypertensive drugs to achieve BP goal; however, physicians may be reluctant to employ such treatment strategies. The aim of this review is to explore factors that contribute to poor hypertension control rates and how to overcome these, including the rationale for selecting combination therapy, with particular reference to angiotensin II receptor blocker combinations.

Polymorphism at the glutathione S-transferase locus GSTM3: interactions with cytochrome P450 and glutathione S-transferase genotypes as risk factors for multiple cutaneous basal cell carcinoma.

The influence of polymorphism in the glutathione S-transferase, GSTM3 gene on susceptibility to cutaneous basal cell carcinoma (BCC) has been investigated. We have reported previously two GSTM3 alleles, GSTM3*A and GSTM3*B, distinguished by a recognition motif for the YY1 transcription factor in GSTM3*B. In this study, immunohistochemistry was used to identify GSTM3 expression in the epidermis of skin samples from 11 controls and 9 patients with BCC. A PCR method was used to identify GSTM3*A and GSTM3*B and thereby the GSTM3 AA, GSTM3 AB, and GSTM3 BB genotypes in 300 controls and 286 Caucasians with 1-35 primary BCCs. Genotypes at GSTM1, GSTT1, and the cytochrome P450 CYP1A1 and CYP2D6 loci were also determined. Frequencies of GSTM3, GSTM1, GSTT1, CYP2D6, and CYP1A1 genotypes in the cases and controls were not different. Dividing the BCC cases into groups of 92 patients with 1 lesion and 194 patients with 2-35 lesions showed that the frequencies of GSTM3 BB (2.6%) and GSTM1 A/B (1.3%) in the group with 2-35 tumors were almost significantly lower than in the group with 1 lesion (7.6%, exact P = 0.0601, chi 2(1) = 3.390; 6.5%, exact P = 0.055, chi 2(1) = 4.946, respectively). Within the cases with 2-35 tumors, a Poisson regression model was used to identify genotypes, characteristics such as skin type, and interactions between genotypes and characteristics associated with increasing numbers of tumors. This showed, after correction for male gender and age, that GSTM3 AA was not associated with risk of increased numbers of tumors, although in combination with skin type 1, GSTM1 null, and CYP1A1 m1m1, the genotype did confer increased risk (P < 0.001, rate ratio, 2.058; P < 0.001, rate ratio, 1.606; P < 0.001, rate ratio, 1.470 respectively). The data suggest that, like other allelic GST, GSTM3 influences cancer risk. As GSTM3 AA was associated with increased tumor numbers, it appears that YY1 acts as an activator of the recognition motif in GSTM3*B.

Adenovirus-mediated gene transfer of a secreted transforming growth factor-beta type II receptor inhibits luminal loss and constrictive remodeling after coronary angioplasty and enhances adventitial collagen deposition.

BACKGROUND: Extracellular matrix (ECM) remodeling is central to the development of restenosis after coronary angioplasty (PTCA). As a regulator of ECM deposition by vascular cells, substantial evidence implicates transforming growth factor-beta1 (TGF-beta1) in the pathogenesis of restenosis. We investigated the effects of intracoronary expression of a transgenic antagonist of TGF-beta1 on luminal loss after PTCA. METHODS AND RESULTS: Porcine coronary arteries were randomized to receive a recombinant adenovirus expressing a secreted form of TGF-beta type II receptor (Ad5-RIIs), an adenovirus expressing beta-galactosidase (Ad5-lacZ), or vehicle only by intramural injection at the site of PTCA. Computerized morphometry 28 days after angioplasty revealed a greater minimum luminal area in Ad5-RIIs-injected arteries (1.71+/-0.12 mm(2)) than in the Ad5-lacZ (1.33+/-0.13 mm(2)) or vehicle-only (1.08+/-0.17 mm(2); P=0.010 by ANOVA) groups. This was accompanied by greater areas within the internal (P=0.013) and external (P=0.031) elastic laminae in Ad5-RIIs-treated vessels. Adventitial collagen content at the site of injury was increased in the Ad5-RIIs group, in contrast to decreases in the Ad5-lacZ and vehicle-only groups (P=0.004). CONCLUSIONS: Adenovirus-mediated antagonism of TGF-beta1 at the site of PTCA reduces luminal loss after PTCA by inhibiting constrictive remodeling. Antagonism of TGF-beta1 stimulates the formation of a dense collagenous adventitia, which prevents constrictive remodeling by acting as an external scaffold. These findings demonstrate the potential of gene therapy-mediated antagonism of TGF-beta1 as prophylactic therapy for restenosis.

Influence of arterial diameter on vasomotor responses in the porcine coronary vasculature.

OBJECTIVE: The aim was to determine whether regional differences in arterial responses to vasoconstrictor and vasorelaxant agonists exist within the minipig coronary vasculature. METHODS: Hearts were obtained from miniature pigs (20-40 kg) immediately after death. First and third order arterial branches of the left anterior descending artery were dissected from within the subepicardium and mounted as ring preparations in a small vessel myograph for measurement of isometric tension under standardised conditions. Contractile responses to acetylcholine, noradrenaline, and U46619, and the relaxation responses to noradrenaline, bradykinin, and substance P were measured. Arterial tone was increased with KCl or acetylcholine prior to addition of vasodilator agonists. RESULTS: First order branches were more sensitive to the constrictor influence of acetylcholine than third order branches [pD2 values 6.42(SEM 0.07), n = 13, and 6.26(0.07), n = 13, for first and third order respectively, p < 0.05]. U46619 did not induce contractile responses in arteries less than 210 microns in diameter. Noradrenaline only induced small contractile responses in the presence of propranolol following removal of the endothelium. In arteries preconstricted with 40 mM KCl, noradrenaline induced relaxation which was inhibited by propranolol and was uninfluenced by arterial calibre. In the presence of propranolol, noradrenaline-mediated relaxations of acetylcholine-preconstricted arteries were endothelium dependent and alpha 2 adrenoceptor mediated, and greater in first order than in third order branches [58(5)%, n = 9, and 26(8)%, n = 9, for first and third order branches respectively, p < 0.05]. Relaxations mediated by bradykinin and substance P were not influenced significantly by arterial calibre but were greater in arteries preconstricted with acetylcholine than with KCl. CONCLUSIONS: In isolated minipig coronary arteries the vasoconstrictor responses to acetylcholine and U46619, and the endothelium dependent, noradrenaline mediated relaxations, differ according to the branching order studied. These data provide further evidence for a regional heterogeneity of vascular responses in the porcine coronary vasculature.

The effect of afterload and angiotensin II on proto-oncogene mRNA levels in the isolated working rat heart.

OBJECTIVES: The proto-oncogenes c-fos, c-myc and H-ras have been shown to rise in a characteristic pattern in the left ventricle undergoing hypertrophy in the coarctation model of experimental hypertension and there is some evidence to suggest that they might play a role in the initiation of hypertrophic growth. However, in vivo studies do not discriminate between the direct effects of pressure and pressure-independent trophic stimuli such as angiotensin II. To examine these influences separately we studied isolated working hearts exposed to different afterloads in the presence or absence of angiotensin II. METHODS: Hearts from normotensive female Wistar rats were perfused with a modified Krebs-Henseleit solution, with and without angiotensin II (100 nmol/1) and exposed to low (60 mmHg) or high (140 mmHg) afterload (n > 17/group). Proto-oncogene mRNA induction in the left ventricle was assessed by Northern blot analysis. RESULTS: Aortic pressures were 101 +/- 14/63 +/- 6 mmHg (mean +/- s.d.) with low and 175 +/- 13/93 +/- 20 mmHg with high afterload; hearts in both groups maintained a stable cardiac output over 240 min, except for high afterload hearts not perfused with angiotensin II, which showed a 59% drop by the end of the experiment (P < 0.001). There was a 50% (32%, 72%) (geometric mean and 95% confidence interval) increase of c-myc and 54% (27%, 86%) increase in c-fos, but a 32% (25%, 40%) suppression of H-ras with high (140 mmHg) as compared with low (60 mmHg) afterloads (P < 0.0001 for each). There was no significant difference in c-myc and c-fos induction with different levels of high afterload (110, 120, 140 mmHg), but for H-ras suppression progressively increased with increasing afterload (P = 0.003). At high afterload, levels of c-fos rose at 30 min and peaked at 60 min, c-myc continued to rise up to 240 min, and H-ras was suppressed at all four time points. The addition of angiotensin II (100 nmol/l) to the perfusate resulted in 18% (6%, 28%; P = 0.006) lower c-myc levels, 12% (-6%, 28%; P = 0.18) lower c-fos levels and an 11% (-0.1%, 24%; P = 0.056) increase of H-ras. CONCLUSION: The isolated perfused working rat heart is capable of performing stably for a period of at least 240 min at high afterload pressures comparable to those encountered in hypertension. A proto-oncogene induction similar to that seen in the hypertrophying heart can be induced by increased pressure alone, without the mediating effects of circulating angiotensin II. Hearts perfused with angiotensin II showed a more stable performance at high levels of afterload which was associated with a minor attenuation of pressure-induced changes in proto-oncogene expression.

Rapid prenatal diagnosis and exclusion of epidermolysis bullosa using novel antibody probes.

Prenatal diagnosis of recessive dystrophic epidermolysis bullosa was successfully achieved at 19 weeks' gestation by indirect immunofluorescence examination of a fetal skin biopsy sample using the monoclonal antibody LH 7:2. The abortus displayed marked blistering and the diagnosis was confirmed by transmission electron microscopy (TEM). In 3 further pregnancies at risk for lethal junctional epidermolysis bullosa the diagnosis was excluded using the polyclonal antibody AA3. In all these studies the results were available within 4 h of receiving the samples. These new techniques offer a quick and simple alternative to TEM for midtrimester prenatal diagnosis of 2 severe recessive forms of epidermolysis bullosa.

Type VII collagen is a normal component of epidermal basement membrane, which shows altered expression in recessive dystrophic epidermolysis bullosa.

The murine monoclonal antibody LH 7:2, which reacts with the basement membrane of stratified squamous epithelia including epidermis, has been characterized biochemically and shown to bind to part of the type VII collagen molecule. Immunoblotting reveals that the antibody binding site lies in the non-helical carboxy terminal region of the type VII collagen dimer and immunoelectron microscopy shows that the epitope is within the lamina densa of the basement membrane. Loss of LH 7:2 binding in the hereditary blistering disease recessive dystrophic epidermolysis bullosa suggests that inadequate synthesis or excessive breakdown of type VII collagen may form the biologic basis for the disease.

Susceptibility to melanoma: influence of skin type and polymorphism in the melanocyte stimulating hormone receptor gene.

Allelic variation at the melanocyte stimulating hormone receptor (MC1R) gene has been linked with sun-sensitive skin types, suggesting it is a susceptibility candidate for melanoma. We determined the frequency of the val92met, asp294his, and asp84glu MC1R alleles in 190 Caucasian controls and 306 melanoma cases and studied their association with skin type and hair color. The percentage of controls with at least one val92met, asp294his, or asp84glu allele was 17.3%, 6.8%, and 3.5%, respectively. Individually, frequencies of the val92met, asp294his, or asp84glu alleles in the controls with skin types 3 and 4 were similar to those with skin types 1 and 2. Trend analysis, however, did identify an association (exact p = 0.048, two-sided test) between skin type and MC1R variants in the group comprising all controls with any one or more of these alleles. There was no association between MC1R alleles and hair color. Allele frequencies were not different in melanoma cases and controls. There were no associations between skin types and the proportion of cases with the asp294his or asp84glu alleles, though the association between skin type and the val92met allele approached significance (exact p = 0.09, two-sided test). Unexpectedly, in the group comprising all cases with one or more variant alleles, the proportion of subjects with variant alleles increased with skin types associated with tanning rather than burning, although trend analysis showed that this association did not quite reach statistical significance (exact p = 0.08, two-sided test). Asp84glu (but not val92met or asp294his) variant alleles were more common in subjects with blonde hair, although the relationship between the asp84glu allele and hair color did not achieve statistical significance (chi(2)3 = 6.16, exact p = 0.10). We interpret the data presented as indicating that polymorphism at MC1R does not appear a major determinant of skin type, at least in terms of these allelic variants. Furthermore, considered alone, these alleles are not susceptibility candidates for malignant melanoma.