UV Irradiation and Cutaneous Vitamin A: An Experimental Study in Rabbit and Human Skin

The effect of UV irradiation on the concentration of cutaneous retinoids (retinol and 3-dehydroretinol) in rabbit skin in vivo and in human skin in vitro was investigated. Irradiation with 4 different narrow-wavelength bands produced dose-dependent reductions of retinol in epidermis and dermis. The maximal effect was obtained at 334 nm, a wavelength which coincides with the absorption maximum for retinol in organic solutions. 3-Dehydroretinol was not reduced to the same extent as was retinol. In human skin the photodecomposition of retinol was most extensive in epidermis and progressively less so in dermis, presumably reflecting the extent to which 334 nm radiation penetrates the tissue. The regeneration of cutaneous retinol took over a week in the rabbit. The nutritional and biologic implications of the UV-induced reduction of cutaneous retinol remain to be established

Induction of p53 Expression in Skin by Radiotherapy and UV Radiation: a Randomized Study

Background: p53 protein plays an important role in the response to DNA damage, and radiotherapy can cause radiation dermatitis. p53 and p21 levels increase in vitro when DNA is damaged by UVA, UVB, or γ-radiation. To determine whether this response occurs in human skin and predicts the level of radiation dermatitis, we investigated levels of p53 and p21 in skin exposed to different types of radiation as part of a randomized study of women with breast cancer to evaluate topical steroid or emollient cream treatments for radiation dermatitis of their irradiated breast. Methods: After surgery but before receiving tangential 5-mV photo-beam radiotherapy (2 Gy and 54 Gy) to the affected breast parenchyma, multiple areas on the backs of 50 women were irradiated with UVA and other areas were irradiated with UVB. Skin biopsy samples were taken from areas of normal unirradiated skin and all irradiated areas, and p53 and p21 were detected immunohistochemically. All statistical tests are two-sided. Results: In skin irradiated with UVA or UVB, medians of 4.4% (range = 0%-40.5%) or 45.5% (range = 5.3%-74.6%) p53-positive keratinocytes, respectively, were observed. Radiotherapy produced medians of 31.0% (range = 0%-79.3%) p53-immunoreactive cells after 2 Gy of radiation and 83.2% (range = 37.6%-95.2%) after 54 Gy of radiation. Despite large interindividual differences in p53 response, comparable increases in epidermal p53 response were independent of the type of radiation. A correlation between p53 and p21 was also evident (rs = .78). In breast skin, there was no association between the p53 response and the degree of erythema (a measure of radiation dermatitis) and no statistically significant difference between treatment arms and p21/p53 responses. Conclusions: Individual responses to radiation-induced DNA damage varied widely and may be independent of the type of radiation. The epidermal p53 response does not predict the degree of radiation dermatiti

Filaggrin Genotype Determines Functional and Molecular Alterations in Skin of Patients with Atopic Dermatitis and Ichthyosis Vulgaris

BACKGROUND: Several common genetic and environmental disease mechanisms are important for the pathophysiology behind atopic dermatitis (AD). Filaggrin (FLG) loss-of-function is of great significance for barrier impairment in AD and ichthyosis vulgaris (IV), which is commonly associated with AD. The molecular background is, however, complex and various clusters of genes are altered, including inflammatory and epidermal-differentiation genes. OBJECTIVE: The objective was to study whether the functional and molecular alterations in AD and IV skin depend directly on FLG loss-of-function, and whether FLG genotype determines the type of downstream molecular pathway affected. METHODS AND FINDINGS: Patients with AD/IV (n = 43) and controls (n = 15) were recruited from two Swedish outpatient clinics and a Swedish AD family material with known FLG genotype. They were clinically examined and their medical history recorded using a standardized questionnaire. Blood samples and punch biopsies were taken and trans-epidermal water loss (TEWL) and skin pH was assessed with standard techniques. In addition to FLG genotyping, the STS gene was analyzed to exclude X-linked recessive ichthyosis (XLI). Microarrays and quantitative real-time PCR were used to compare differences in gene expression depending on FLG genotype. Several different signalling pathways were altered depending on FLG genotype in patients suffering from AD or AD/IV. Disease severity, TEWL and pH follow FLG deficiency in the skin; and the number of altered genes and pathways are correlated to FLG mRNA expression. CONCLUSIONS: We emphasize further the role of FLG in skin-barrier integrity and the complex compensatory activation of signalling pathways. This involves inflammation, epidermal differentiation, lipid metabolism, cell signalling and adhesion in response to FLG-dependent skin-barrier dysfunction

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The effect of two endogenous retinoids on the mRNA expression profile in human primary keratinocytes, focusing on genes causing autosomal recessive congenital ichthyosis

Retinoids (natural forms and synthetic derivatives of vitamin A) are used as therapeutic agents for numerous skin diseases such as keratinization disorders (e.g. ichthyoses) and psoriasis. Two endogenous ligands for retinoic acid receptors exist, retinoic acid (atRA) and 3,4-didehydroretinoic acid (ddRA). In primary human epidermal keratinocytes many transcriptional targets for atRA are known, whereas the targets for ddRA are unknown. In an attempt to determine the targets, we compared the effect of atRA and ddRA on transcriptional profiles in undifferentiated and differentiating human primary keratinocytes. First, as expected, many genes were induced or suppressed in response to keratinocyte differentiation. Furthermore, the two retinoids affected substantially more genes in differentiated keratinocytes (&gt; 350) than in proliferating keratinocytes (a parts per thousand 20). In differentiating keratinocytes markers of cornification were suppressed suggesting a de-differentiating effect by the two retinoids. When comparing the expression profile of atRA to that of ddRA, no differently regulated genes were found. The array analysis also found that a minor number of miRNAs and a large number of non-coding transcripts were changed during differentiation and in response to the two retinoids. Furthermore, the expression of all, except one, genes known to cause autosomal recessive congenital ichthyosis (ARCI) were found to be induced by differentiation. These results comprehensively document that atRA and ddRA exert similar transcriptional changes in keratinocytes and also add new insights into the molecular mechanism influenced by retinoids in the epidermis. Furthermore, it suggests which ARCI patients could benefit from therapy with retinoids

Patch testing with own cosmetics-a prospective study of testing and reporting of adverse effects to the Swedish Medical Products Agency.

Background: The Swedish Medical Products Agency (MPA) provides a voluntary reporting system for adverse reactions to cosmetics. However, the reporting is sparse, and the products involved are sometimes difficult to identify. Objectives: To investigate how often patients referred for patch testing were tested with the cosmetic products that they had been using themselves, and to improve the reporting to the MPA by the use of photographic documentation of product labels. Patients and methods: Consecutive patients at five dermatology departments who were patch tested with their own cosmetics were included. Reports including protocols of positive patch test results for the patients' own cosmetics and photographs/photocopies of product labels were sent to the MPA. Results: Three hundred and sixteen of 948 patients (33%) were tested with their own cosmetics, and 15% of these tested positive with one or more products. The number of reports was more than three times higher than in corresponding periods in earlier years. For 79% of the products, photographs/photocopies of the containers were submitted, and for 30%, batch numbers were submitted. Conclusions: For a substantial number of patients, their own cosmetics were suspected of causing adverse reactions and were therefore tested. During the study, the number of reports to the MPA tripled, and the relevant products were easier to identify