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The incidence of type 2 diabetes mellitus (DM) has been increasing rapidly, and the disease has become a serious sociomedical problem. Many skin problems, such as xerosis, pruritus, skin infections and delayed wound healing, that might be related to chronic impairment of skin barrier function decrease the quality of life in patients with DM. However, the status of the permeability and antimicrobial barrier of the skin in DM remains unknown. This study aimed to elucidate skin barrier impairment in patients with type 2 DM and its pathomechanisms using classic animal models of type 2 DM. Functional studies of the skin barrier and an analysis of stratum corneum (SC) lipids were compared between patients with type 2 DM and age- and sex-matched non-diabetes controls. Also, functional studies on the skin barrier, epidermal lipid analyses, and electron microscopy and biomolecular studies were performed using type 2 DM animal models, db/db and ob/ob mice. Patients with type 2 DM presented with epidermal barrier impairments, including SC hydration, which was influenced by blood glucose control (HbA1c level). In the lipid analysis of SC, ceramides, fatty acids and cholesterol were significantly decreased in patients with type 2 DM compared with controls. Type 2 DM murine models presented with severe hyperglycaemia, impairment of skin barrier homeostasis, decreases in epidermal proliferation and epidermal lipid synthesis, decreases in lamellar body (LB) and epidermal antimicrobial peptides (AMPs), an increase in receptors for advanced glycation end-product (AGE) in the epidermis and an increase in serum AGE. Impairment of the skin barrier was observed in type 2 DM, which results in part from a decrease in epidermal proliferation. Serum AGE and its epidermal receptors were increased in type 2 diabetic mice which display impaired skin barrier parameters such as epidermal lipid synthesis, LB production, epidermal AMP and SC lipids.

The presence of congenitally impaired skin barrier followed by atopic dermatitis (AD) is an initial step in the atopic march. The maintenance of acidic pH in the stratum corneum (SC) has been suggested as a therapeutic or preventive strategy for barrier impairment caused by skin inflammation. To determine whether an AD murine model, flaky tail mice, with inherited filaggrin deficiency could develop airway inflammation by repeated topical application followed by nasal inhalation of house dust mite (HDM) antigen (defined as a novel "atopic march animal model"), and whether maintenance of an acidic SC environment by continuous application of acidic cream could interrupt the following atopic march. During the course of HDM treatment, acidic cream (pH2.8) or neutral cream (pH7.4) was applied to flaky tail mice twice daily. Repeated applications and inhalations of HDM to flaky tail mice induced AD skin lesions followed by respiratory allergies. Maintenance of SC acidity inhibited the occurrence of respiratory allergic inflammation as well as AD-like skin lesions. Collectively, a novel atopic march model could be developed by repeated epicutaneous and nasal applications of HDM to flaky tail mice, and that the acidification of SC could prevent the atopic march from AD to respiratory allergy.

Long-standing or repeated skin barrier damage followed by atopic dermatitis (AD) is the initial step of the atopic march that eventually progresses to respiratory allergies. Maintenance of an acidic pH in the stratum corneum (SC) is an important factor for normal skin barrier function. We performed this study to determine whether an oxazolone (Ox)-induced AD murine model can develop airway inflammation by topical application and nasal inhalation of a house dust mite, Dermatofagoides pteronyssinus (Dp), which is a novel 'atopic march animal model', and whether an acidic SC environment, made by repeated application of acidic cream, can interrupt this atopic march. During repeated treatment with Ox and Dp to make an atopic march murine model, acidic cream (pH 2.8) and neutral cream (pH 7.4) adjusted by citric acid and sodium hydroxide mixed with vehicle were applied twice daily. Repeated treatment with Ox and Dp to hairless mice induced AD-like skin lesions followed by respiratory allergy, defining it as an atopic march model. Acidic cream inhibited the occurrence of respiratory allergic inflammation as well as AD-like skin lesions. These results indicate that a novel atopic march animal model can be developed by repeated topical and nasal treatments with house dust mite on Ox-induced AD mice and that the acidification of SC could be a novel intervention method to block the atopic march.

Uncontrolled chronic hyperglycaemia including type 2 diabetes mellitus (DM) induces many skin problems related to chronic impaired skin barrier state. However, little is known about the skin barrier state of chronic hyperglycaemia patients, the dysfunction of which may be a major cause of their skin problems. In this study, we investigated whether a long-standing hyperglycaemic condition including type 2 DM impairs skin barrier homoeostasis in proportion to the duration and its pathomechanism. We utilized the Otsuka Long-Evans Tokushima Fatty (OLETF) rats as an animal model of long-standing hyperglycaemia and Long-Evans Tokushima Otsuka rats as a control strain. We confirmed that a long-standing hyperglycaemia delayed skin barrier homoeostasis, which correlated with haemoglobin A1c levels. OLETF rats as a long-standing hyperglycaemia model exhibited decreased epidermal lipid synthesis and antimicrobial peptide expression with increasing age. Decreased epidermal lipid synthesis accounted for decreased lamellar body production. In addition, OLETF rats had significantly higher serum levels of advanced glycation end products (AGEs) and elevated levels of the receptor for AGE in the epidermis. A long-standing hyperglycaemic condition impairs skin barrier function including permeability and antimicrobial barriers by accelerating skin ageing process in proportion to the duration of hyperglycaemia, which could be a major pathophysiology underlying cutaneous complications of DM.

Recently, we reported on the anti-ageing effects of K6PC-5. This compound induced keratinocyte differentiation and fibroblast proliferation by increasing sphingosine-1 phosphate synthesis. We performed this study to confirm the anti-ageing effects of new synthetic products (the K6EAA series) derived from K6PC-5 through an amino group induction. Cellular responses such as differentiation, proliferation and calcium mobilization were investigated using cultured human keratinocytes and fibroblasts. Also, we measured the expressions of collagen mRNA and protein using real time RT-PCR and ELISA, respectively. The K6EAA-L12 product, selected by in vitro screening, was evaluated for anti-ageing effects on intrinsically and extrinsically (photo) aged models of hairless mice. In the intrinsically aged murine skin, K6EAA-L12 showed anti-ageing effects by activating collagen synthesis, eventually causing dermal thickening. Also, in the photo-aged skin, the dermal collagen density and dermal thickness were increased. In photo-aged murine skin, K6EAA-L12 increased stratum corneum integrity by increasing corneodesmosome density and improved the barrier recovery rate. However, there were no changes in the expressions of epidermal differentiation maker proteins. In conclusion, topical K6EAA-L12, a new synthetic K6PC-5 derivative, improves intrinsically and extrinsically (photo) aged skin by increasing the collagen density and improving the skin barrier function.

Stem cells are undifferentiated cells, which have the important properties of self-renewal and differentiation. Adipose-derived stem cells (ADSC) have relative advantages in accessibility and abundance compared to other kinds of stem cells. Regeneration therapy using ADSC has received attention in the treatment of various dermatologic diseases. In previous studies, ADSC were shown to have antioxidant, whitening and wound-healing effects in the skin through secretion of growth factors and by activating fibroblasts. In this study, we investigated whether ADSC could be used as an anti-ageing therapy, especially by dermal collagen synthesis and angiogenesis. Subcutaneous injection of ADSC significantly increased collagen synthesis in hairless mice, and dermal thickness, collagen density and fibroblast number also increased. In addition, procollagen type I protein and mRNA expression increased, which accounts for the increased dermal collagen density. Angiogenesis, which was visualized by CD31 and NG2 immunofluorescence stains, also increased in ADSC-treated skin. Our results suggest that ADSC therapy may be useful in ageing skin. Its effects are mainly mediated by stimulating collagen synthesis in dermal fibroblasts and increasing angiogenesis.

Please cite this paper as: Topical calcineurin inhibitors compromise stratum corneum integrity, epidermal permeability and antimicrobial barrier function. Experimental Dermatology 2010; 19: 501–510. Abstract Background: Topical calcineurin inhibitors (TCIs) such as pimecrolimus and tacrolimus have recently been used for dermatologic diseases including atopic dermatitis instead of topical glucocorticoids, because they display comparable efficacy, but less-frequent side effects. Although even short-term topical glucocorticoid compromise epidermal permeability barrier homeostasis, the effects of TCI on barrier function have not yet been reported. However, viral infections such as eczema herpeticum and molluscum contagiosum, which could indicate an impaired skin barrier, continue to occur with TCI use in atopic dermatitis. Objectives: We determined here whether TCIs disrupt epidermal permeability barrier and antimicrobial function, and whether these effects can be prevented. Methods and results: In normal humans, topical pimecrolimus and tacrolimus applied twice-daily for 5 days, delay barrier recovery without an increase in basal transepidermal water loss was observed. Co-application of physiologic lipid mixture (PLM) containing an equimolar ratio of ceramides, cholesterol and free fatty acids normalized barrier homeostasis in the face of topical TCIs. In hairless mice, 4 days of TCI treatment also disrupted barrier function significantly. TCIs-treated epidermis showed the decrease of epidermal lipid content, lamellar body number and secretion, and lipid synthesis-related enzymes such as 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, serine-palmitoyl transferase and fatty acid synthase, implying decreased lipid synthesis. TCIs also suppressed expression of IL-1α and antimicrobial peptides, CRAMP and mouse β-defensin 3. However, these TCI-induced abnormalities can be overridden by topical replacement with PLM. Conclusions: Our results demonstrate that TCIs induce negative effects on the skin barrier including permeability and antimicrobial functions, which are mediated by decreasing epidermal lipid synthesis, lamellar body secretion and antimicrobial peptides expression through suppression of cytokine such as IL-1α, therefore co-treatment with PLM would be helpful to overcome these negative effects.

Summary The JPEG format employs Huffman codes to compress the entropy data of an image. Huffman codewords are of variable length, which makes parallel entropy decoding a difficult problem. To determine the start position of a codeword in the bitstream, the previous codeword must be decoded first. We present JParEnt, a new approach to parallel entropy decoding for JPEG decompression on heterogeneous multicores. JParEnt conducts JPEG decompression in two steps: (1) an efficient sequential scan of the entropy data on the CPU to determine the start-positions (boundaries) of coefficient blocks in the bitstream, followed by (2) a parallel entropy decoding step on the graphics processing unit (GPU). The block boundary scan constitutes a reinterpretation of the Huffman-coded entropy data to determine codeword boundaries in the bitstream. We introduce a dynamic workload partitioning scheme to account for GPUs of low compute power relative to the CPU. This configuration has become common with the advent of SoCs with integrated graphics processors (IGPs). We leverage additional parallelism through pipelined execution across CPU and GPU. For systems providing a unified address space between CPU and GPU, we employ zero-copy to completely eliminate the data transfer overhead. Our experimental evaluation of JParEnt was conducted on six heterogeneous multicore systems: one server and two desktops with dedicated GPUs, one desktop with an IGP, and two embedded systems. For a selection of more than 1000 JPEG images, JParEnt outperforms the SIMD–implementation of the libjpeg-turbo library by up to a factor of 4.3×, and the previously fastest JPEG decompression method for heterogeneous multicores by up to a factor of 2.2×. JParEnt's entropy data scan consumes 45% of the entropy decoding time of libjpeg-turbo on average. Given this new ratio for the sequential part of JPEG decompression, JParEnt achieves up to 97% of the maximum attainable speedup (95% on average). On the IGP-based desktop platform, JParEnt achieves energy savings of up to 45% compared to libjpeg-turbo's SIMD-implementation.