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Background: Atopic dermatitis (AD) is characterized by immune dysregulations and an impaired skin barrier, including abnormalities in lipid organization. In the stratum corneum (SC), β-glucocerebrosidase (GBA) mediates transformation of glucosylceramide (GlcCER) into ceramide (CER) and cholesterol into glucosylcholesterol (GlcChol). Alteration in GBA activity might contribute to skin barrier defects in AD., Objectives: To investigate GBA activity in the SC of children with AD before and after topical corticosteroid therapy and to compare it with healthy controls; to determine SC levels of GlcCER- and CER-containing hydroxysphingosine base (GlcCER[H] and CER[H], respectively) and GlcChol; and to relate them to disease severity, skin barrier function and the local cytokine milieu., Methods: Lipid markers and cytokines of innate, T helper 1 and T helper 2 immunity were determined in SC collected from healthy children and from clinically unaffected skin of children with AD, before and after 6 weeks of therapy with topical corticosteroids. AD severity was assessed by Scoring Atopic Dermatitis and skin barrier function by transepidermal water loss (TEWL)., Results: Baseline GBA activity and GlcChol levels were increased in children with AD but declined after therapy. CER[H] levels and the CER[H] to GlcCER[H] ratio were increased in AD. GBA activity and GlcChol correlated with TEWL and levels of multiple cytokines, especially interleukin-1α and interleukin-18. GlcChol was strongly associated with disease severity., Conclusions: We show increased GBA activity and levels of GlcChol in AD. Our data suggest an important role of inflammation in disturbed lipid processing. GBA activity or GlcChol might be useful biomarkers in the monitoring of therapeutic responses in AD. What is already known about this topic? Patients with atopic dermatitis (AD) have a reduced skin barrier, mainly caused by altered lipid organization. The mechanisms underlying these lipid anomalies are not fully understood but likely reflect both genetic abnormalities in AD skin and the local cutaneous inflammatory environment. What does this study add? We show increased activity of the ceramide-generating enzyme β-glucocerebrosidase in AD. Activity of this enzyme was correlated with the local cytokine milieu and declined after local corticosteroid therapy. We show that glucosylcholesterol levels in the stratum corneum are increased in AD. The function of glucosylcholesterol and the physiological consequences of increased levels are not clear yet; however, its levels were strongly correlated with skin barrier function: high transepidermal water loss strongly correlated with high levels of glucosylcholesterol. What is the translational message? Correction of cutaneous inflammation largely restores alterations in lipid metabolism in the stratum corneum of infants with AD., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Atopic dermatitis (AD) is the most common inflammatory skin disease. It is highly heterogeneous in clinical presentation, treatment response, disease trajectory and associated atopic comorbidities. Immune biomarkers are dysregulated in skin and peripheral blood., Aims: We used noninvasive skin and peripheral biomarkers to observe the effects of real-world topical corticosteroid (TCS) treatment in infants with AD, by measuring skin and blood biomarkers before and after therapy., Methods: Seventy-four treatment-naïve infants with AD underwent 6 weeks of TCS treatment. Stratum corneum (SC) and plasma blood biomarkers as well as SC natural moisturizing factor (NMF) were measured before and after TCS therapy. Immune markers included innate, T helper (Th)1 and Th2 immunity, angiogenesis, and vascular factors. AD severity was assessed by the Scoring Atopic Dermatitis index, and skin barrier function by transepidermal water loss (TEWL). Twenty healthy infants were recruited as controls., Results: TCS therapy predictably led to improvement in disease severity. Levels of immune markers in the skin and in the peripheral blood showed significant change from baseline, though most did not reach healthy control levels. The most prominent change from baseline in the SC was in markers of innate immune activation, interleukin (IL)-18, IL-8 and IL-1α, and the Th2 chemokines C-C motif chemokine (CCL)17 and CCL22. In blood, the largest changes were in Th2-skewed biomarkers: CCL17, IL-13, CCL22, IL-5, and CCL26. TEWL decreased after therapy; no significant changes from baseline were found for NMF., Conclusions: The profound impact of topical therapy on systemic biomarkers suggests that the skin compartment generates a major component of dysregulated systemic cytokines in infant AD. There may be long-term beneficial effects of correcting systemic immune dysregulation through topical therapy., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Loose anagen hair is a rare form of impaired hair anchorage in which anagen hairs that lack inner and outer root sheaths can be gently and painlessly plucked from the scalp. This condition usually occurs in children and is often self-limiting. A genetic basis for the disorder has been suggested but not proven. A better understanding the aetiology of loose anagen hair may improve prevention and treatment strategies., Objectives: To identify a possible genetic basis of loose anagen hair using next-generation DNA sequencing and functional analysis of variants identified., Methods: In this case study, whole-exome sequencing analysis of a pedigree with one affected individual with features of loose anagen hair was performed., Results: The patient was found to be compound heterozygous for two single-nucleotide substitutions in TKFC resulting in the following missense mutations: c.574G> C (p.Gly192Arg) and c.682C> T (p.Arg228Trp). Structural analysis of human TKFC showed that both mutations are located near the active site cavity. Kinetic assays of recombinant proteins bearing either of these amino acid substitutions showed almost no dihydroxyacetone kinase or D-glyceraldehyde kinase activity, and FMN cyclase activity reduced to just 10% of wildtype catalytic activity., Conclusions: TKFC missense mutations may predispose to the development of loose anagen hairs. Identification of this new biochemical pathobiology expands the metabolic and genetic basis of hypotrichosis., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: MicroRNAs (miRNAs), important regulators of gene expression, have been implicated in a variety of disorders. The expression pattern of miRNAs in paediatric atopic dermatitis (AD) has not been well studied., Objectives: We sought to investigate miRNA expression profiles in different blood compartments of infants with AD., Methods: Small RNA and analysis with the HTG EdgeSeq system were performed to identify differentially expressed miRNAs in peripheral blood mononuclear cells (PBMCs) and plasma of infants with AD vs. age-matched healthy controls, with reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) used for validation and measurement of miRNA targets. Logistic regression models with area under the receiving operating characteristic estimation was used to evaluate the diagnostic potential of chosen miRNAs for AD., Results: RNA sequencing was performed to access miRNA expression profiles in paediatric AD. We identified 10 differentially expressed miRNAs in PBMCs and eight dysregulated miRNAs in plasma of infants with AD compared with controls. Upregulated miRNAs in PBMCs included miRNAs known to be involved in inflammation: miR-223-3p, miR-126-5p and miR-143-3p. Differential expression of only one miRNA, miR-451a, was observed in both PBMCs and plasma of children with AD. Dysregulation of three miRNAs (miR-451a, miR-143-3p and miR-223-3p) was validated in larger numbers of samples and miR-451a was identified as a predictive biomarker for the early diagnosis of the disease. Experimentally verified targets of miR-451a, interleukin 6 receptor (IL6R) and proteasome subunit beta type-8 (PSMB8), were increased in patients with AD, negatively correlated with miR-451a levels and upregulated following inhibition of miR-451a in PBMCs., Conclusions: In infants with AD, a distinct peripheral blood miRNA signature is seen, highlighting the systemic effects of the disease. miR-451a is uniquely expressed in different blood compartments of patients with AD and may serve as a promising novel biomarker for the early diagnosis of AD., (© 2020 British Association of Dermatologists.)

Background: Biomarkers of atopic dermatitis (AD) are largely lacking, especially in infant AD. Those that have been examined to date have focused mostly on serum cytokines, with few on noninvasive biomarkers in the skin., Objectives: We aimed to explore biomarkers obtainable from noninvasive sampling of infant skin. We compared these with plasma biomarkers and structural and functional measures of the skin barrier., Methods: We recruited 100 infants at first presentation with AD, who were treatment naive to topical or systemic anti-inflammatory therapies, and 20 healthy children. We sampled clinically unaffected skin by tape stripping the stratum corneum (SC). Multiple cytokines and chemokines and natural moisturizing factor were measured in the SC and plasma. We recorded disease severity and skin barrier function., Results: Nineteen SC and 12 plasma biomarkers showed significant differences between healthy and AD skin. Some biomarkers were common to both the SC and plasma, and others were compartment specific. Identified biomarkers of AD severity included T helper 2-skewed markers [interleukin (IL)-13, CCL17, CCL22, IL-5]; markers of innate activation (IL-18, IL-1α, IL1β, CXCL8) and angiogenesis (Flt-1, vascular endothelial growth factor); and others (soluble intercellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, IL-16, IL-17A)., Conclusions: We identified clinically relevant biomarkers of AD, including novel markers, easily sampled and typed in infants. These markers may provide objective assessment of disease severity and suggest new therapeutic targets, or response measurement targets for AD. Future studies will be required to determine whether these biomarkers, seen in very early AD, can predict disease outcomes or comorbidities., (© 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Carriage rates of Staphylococcus aureus on affected skin in atopic dermatitis (AD) are approximately 70%. Increasing disease severity during flares and overall disease severity correlate with increased burden of S. aureus. Treatment in AD therefore often targets S. aureus with topical and systemic antimicrobials., Objectives: To determine whether antimicrobial sensitivities and genetic determinants of resistance differed in S. aureus isolates from the skin of children with AD and healthy child nasal carriers., Methods: In this case-control study, we compared S. aureus isolates from children with AD (n = 50) attending a hospital dermatology department against nasal carriage isolates from children without skin disease (n = 49) attending a hospital emergency department for noninfective conditions. Using whole genome sequencing we generated a phylogenetic framework for the isolates based on variation in the core genome, then compared antimicrobial resistance phenotypes and genotypes between disease groups., Results: Staphylococcus aureus from cases and controls had on average similar numbers of phenotypic resistances per isolate. Case isolates differed in their resistance patterns, with fusidic acid resistance (Fus R ) being significantly more frequent in AD (P = 0·009). The genetic basis of Fus R also differentiated the populations, with chromosomal mutations in fusA predominating in AD (P = 0·049). Analysis revealed that Fus R evolved multiple times and via multiple mechanism in the population. Carriage of plasmid-derived qac genes, which have been associated with reduced susceptibility to antiseptics, was eight times more frequent in AD (P = 0·016)., Conclusions: The results suggest that strong selective pressure drives the emergence and maintenance of specific resistances in AD., (© 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Filaggrin is central to the pathogenesis of atopic dermatitis (AD). The cheeks are a common initiation site of infantile AD. Regional and temporal expression of levels of filaggrin degradation products [natural moisturizing factors (NMFs)], activities of filaggrin-processing enzymes [bleomycin hydrolase (BH) and calpain-1 (C-1)] and plasmin, and corneocyte envelope (CE) maturity in early life are largely unknown., Objectives: We conducted a cross-sectional, observational study investigating regional and age-dependent variations in NMF levels, activity of proteases and CE maturity in stratum corneum (SC) from infants to determine whether these factors could explain the observed predilection sites for AD in early life., Methods: We measured NMF using a tape-stripping method at seven sites in the SC of 129 children (aged < 12 months to 72 months) and in three sites in 56 neonates and infants (< 48 h to 3 months). In 37 of these neonates and infants, corneocyte size, maturity, BH, C-1 and plasmin activities were determined., Results: NMF levels are low at birth and increase with age. Cheek SC, compared with elbow flexure and nasal tip, has the lowest NMF in the first year of life and is the slowest to reach stable levels. Cheek corneocytes remain immature. Plasmin, BH and C-1 activities are all elevated by 1 month of age in exposed cheek skin, but not in elbow skin., Conclusions: Regional and temporal differences in NMF levels, CE maturity and protease activities may explain the predilection for AD to affect the cheeks initially and are supportive of this site as key for allergen priming in early childhood. These observations will help design early intervention and treatment strategies for AD., (© 2018 The Authors British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The association between psoriasis and alcohol consumption is complex. Epidemiological evidence suggests that patients with moderate to severe psoriasis have an increased incidence of alcohol-related diseases and mortality. This appears to be unique to psoriasis compared with other autoimmune diseases. Excessive alcohol consumption may contribute to systemic inflammation and the comorbidities associated with psoriasis, including cardiovascular disease and depression. Screening for hazardous alcohol consumption and appropriate interventions may be useful in patients with moderate to severe psoriasis., (© 2013 British Association of Dermatologists.)

Human papilloma virus is a common and often distressing cutaneous disease. It can be therapeutically challenging, especially in immunocompromised patients. We report a case of recalcitrant cutaneous warts that resolved with intravenous cidofovir treatment. The patient was immunocompromised secondary to monoclonal antibody therapy for psoriasis., (© The Author(s). CED © 2011 British Association of Dermatologists.)

Background: Moderate to severe psoriasis is associated with increased alcohol intake and excessive mortality from alcohol-related causes. Alcohol biomarkers provide an objective measure of alcohol consumption. Carbohydrate-deficient transferrin (CDT) is the single most sensitive and specific alcohol biomarker., Objectives: To assess alcohol consumption in a cohort of patients with moderate to severe psoriasis using standard alcohol screening questionnaires and biomarkers. We investigated whether there was an association between alcohol intake, anxiety, depression and disease severity., Methods: Consecutive patients with chronic plaque psoriasis were recruited and completed a range of anonymized assessments. Psoriasis severity, anxiety and depression, and the impact of psoriasis on quality of life were assessed. Alcohol screening questionnaires were administered. Blood specimens were taken and γ-glutamyltransferase (γGT) and CDT were measured., Results: A total of 135 patients completed the study. Using validated questionnaires, between 22% and 32% had difficulties with alcohol. Seven per cent had CDT > 1·6% indicating a heavy alcohol intake. The Alcohol Use Disorders Identification Test (AUDIT) questionnaire was superior to other validated questionnaires in detecting alcohol misuse. There were no significant associations between measures of excessive alcohol consumption and disease severity. Excessive alcohol intake as measured by the CAGE questionnaire was associated with increased depression (P = 0·001) but other measures of alcohol excess did not correlate with psychological distress. Men had significantly more difficulties with alcohol than women (P < 0·001)., Conclusion: Alcohol misuse is common in patients with moderate to severe psoriasis. Screening with the AUDIT questionnaire and CDT may allow the identification of patients who are misusing alcohol and allow appropriate intervention., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Calciphylaxis is a rare, life-threatening cause of skin necrosis. The condition is primarily reported in patients with end-stage renal disease, and is associated with significant morbidity and mortality. Treatment has mainly been empirical. We report a case of calciphylaxis in a patient with normal renal function and hypoparathyroidism, who responded to treatment with sodium thiosulfate. To our knowledge, this is the first reported case of the use of sodium thiosulfate to treat calciphylaxis in a patient with normal renal function.

Fifty sequences from the mouse genome database containing simple sequence repeats or microsatellites have been analysed for size variation using the polymerase chain reaction and gel electrophoresis. 88% of the sequences, most of which contain the dinucleotide repeat, CA/GT, showed size variations between different inbred strains of mice and the wild mouse, Mus spretus. 62% of sequences had 3 or more alleles. GA/CT and AT/TA-containing sequences were also variable. About half of these size variants were detectable by agarose gel electrophoresis. This simple approach is extremely useful in linkage and genome mapping studies and will facilitate construction of high resolution maps of both the mouse and human genomes.