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PDF file, 528KB, Flow cytometric analysis of IL-17+ cells in peripheral blood lymphocytes. PBMCs isolated from healthy controls, dermatophytosis patients without ATLL, ATLL without dermatophytosis patients.

PDF file, 2046KB, IL-17+ cells and CD25+ cells in skin lesions.

PDF file, 98KB.

Purpose: Superficial dermatophytosis is quite commonly seen in patients with adult T-cell leukemia/lymphoma (ATLL), as approximately 50% of the patients develop cutaneous mycotic infections. Because superficially infected fungi in the stratum corneum of the epidermis cannot directly contact with T cells infiltrating in the upper dermis, some perturbation of epidermal innate immunity has been postulated. Interleukin (IL)-17–producing helper T cells (Th17) can induce the keratinocyte production of antimicrobial peptides such as human β defensin (HBD)-2 and LL-37, which play an essential role in cutaneous innate immunity.Experimental Design: We investigated the frequency of circulating Th17 cells, serum levels of cytokines, and epidermal expression of HBD-1, 2, 3, and LL-37 in ATLL patients with or without superficial dermatophytosis.Results: The frequency of peripheral Th17 cells and the serum level of IL-17 was significantly decreased in ATLL patients, whereas the serum IL-10 and TGF-β1 levels were increased as compared with healthy controls. Furthermore, ATLL patients with dermatophytosis had higher IL-10 and TGF-β1 levels and lower IL-17 levels than did those without dermatophytosis. Immunohistochemical study revealed that the epidermal expression of both HBD-2 and LL-37 were significantly lower in ATLL patients with dermatophytosis than in non-ATLL patients with dermatophytosis.Conclusions: Taken together, these results suggest that the keratinocyte production of antimicrobial peptides promoted by Th17 cells is reduced in ATLL patients, leading to the perturbed innate immunity and the frequent occurrence of superficial dermatophytosis. Clin Cancer Res; 18(14); 3772–9. ©2012 AACR.

Comparing the incidence rate of in-hospital falls between patients hospitalized in window beds and nonwindow beds.Retrospective cohort study.A general hospital in Mie, Japan.A total of 2767 patients (mean age, 68.4 years) hospitalized in four-bedded rooms between January 2014 and December 2016.We identified patients' bed status (window/nonwindow) and the incidence of in-hospital falls using data on medical records and incidence reports, respectively.During an observation period of 25,450 person-days, 57 patients had in-hospital falls (incidence rate, 2.24/1000 person-days). Incidence rate for in-hospital falls was significantly lower in the window-bed group (n = 1273) than in the nonwindow-bed group (n = 1494) [incidence rate ratio (IRR) 0.49, 95% confidence interval (CI), 0.29, 0.84]. In the multivariable analysis adjusted for age, gender, BMI, smoking and drinking habit, surgical operation during hospitalization, and independence in daily living, the window-bed group exhibited significantly lower incidence rate for in-hospital falls than the nonwindow-bed group (IRR 0.54, 95% CI 0.32, 0.93). Sensitivity analysis excluding patients aged60 years suggested a consistent result: incidence rate for in-hospital falls was significantly lower in the window-bed group (n = 1123) than in the nonwindow-bed group (n = 925) (IRR 0.55, 95% CI 0.31, 0.95).The incidence rate of in-hospital falls was significantly lower among patients hospitalized in window beds than nonwindow beds. Hospitalization in window beds might be a novel, simple preventive option for in-hospital falls. Further large-scale, prospective, multicenter research is required.

Use of antimicrobials for acne treatment is correlated with an increased occurrence of antimicrobial-resistant Cutibacterium acnes. To clarify the role of antimicrobial use on the resistance and to investigate the characteristics of resistant strains, we conducted a multicenter study in dermatological clinics frequently visited by new patients with acne vulgaris. We collected specimens in 264 acne patients and tested 164 C. acnes strains isolated from 164 patients visiting 13 dermatological clinics. Antimicrobial susceptibility testing showed that the rates of resistance for tetracyclines, macrolides and clindamycin were significantly higher in C. acnes strains isolated from patients using antimicrobials for acne treatment than patients not using them. In particular, clindamycin-resistant strains were frequently isolated from patients with older median age (≥24 years) and severe/moderate acne. After investigating the resistance mechanism of 15 high-level clindamycin-resistant strains, the transposable clindamycin resistance genes, erm(X) or erm(50), were detected in 14 strains. Using single-locus sequence typing for C. acnes, the strains with erm(X) or multidrug resistance plasmid pTZC1 coding erm(50) and tetracycline resistance gene tet(W) were classified into clade F, which were specifically isolated from Japanese patients with acne, except for one strain. Our data showed that patients' information, such as antimicrobial use, age and acne severity, are valuable in estimating whether a patient carries antimicrobial-resistant C. acnes. Additionally, our results suggest that the clade F strains have a high risk of acquiring multidrug resistance.

SummaryBackground It is unclear whether hair washing is effective against scalp eruption and pruritus caused by seborrheic dermatitis or psoriasis vulgaris. Aims To assess whether a proper hair-washing regimen, including the use of antibacterial shampoo, can ameliorate scalp eruption symptoms and alter the composition of the scalp microflora. Methods Eighteen patients with seborrheic dermatitis or psoriasis vulgaris scalp eruptions were instructed in proper techniques of daily hair washing, rinsing, and shampooing, which they underwent for 12 weeks. They used control shampoo in weeks 1–4 and 9–12, and an antibacterial shampoo during weeks 5–8. At the start of the test period and at weeks 4, 8, and 12, we assessed scalp symptoms (erythema, scaling/desquamation, dryness, itchiness, and scratching scars); microbial DNA levels from lesion and nonlesion areas; and levels of interleukin (IL)-1α, IL-1ra, and total protein in the scalp's horny layer. Results Compared to baseline values, scaling/desquamation and itchiness improved significantly at weeks 8 and 12. Other observed skin symptoms also improved over time. Malassezia colonization levels in lesion and nonlesion areas decreased gradually; the decrease was significant at week 8 in lesion areas and at weeks 4 and 8 in nonlesion areas. Bacterial colonization levels also decreased gradually, achieving significance in lesion areas at week 4. Gradual decreases in IL-1ra/IL-1α level showed statistical significance at weeks 4 and 12, while the protein quantity significantly decreased at week 12. Conclusion Proper hair washing improved scalp condition symptoms, and possibly the underlying etiology.

Poor adherence to medication is a major public health challenge. Here, we aimed to determine the adherence to oral and topical medications and to analyze underlying associated factors using the translated Japanese version of Morisky Medication Adherence Scale‐8 regarding urticaria treatment. Web‐based questionnaires were performed for 3096 registered dermatological patients, along with a subanalysis of 751 registered urticaria patients in this study. The adherence to oral medication was significantly associated with the frequency of hospital visits. Variables that affected the adherence to topical medication included age and experience of drug effectiveness. The rate of responses that “It felt like the symptoms had improved” varied significantly among the dermatological diseases treated with oral medications. Dermatologists should be aware that adherence to the treatment of urticaria is quite low. Regular visits and active education for patients with urticaria are mandatory in order to achieve a good therapeutic outcome by increasing the adherence.

Light is crucial for the synchronization of internal biological rhythms with environmental rhythms. Hospitalization causes a range of unfavorable medical conditions, including delirium, sleep disturbances, depressed mood, and increased fall, especially in elderly people. The hospital room environment contributes significantly to patients' circadian physiology and behavior; however, few studies have evaluated light intensity in hospital settings. In this study, bedside light intensity during the daytime (6:00-21:00) was measured at 1-min intervals using a light meter on 4869 bed-days at the Inabe General Hospital in Mie, Japan (latitude 35°N), for approximately 1 month in each season. Daytime light exposure in home settings was measured in nonhospitalized elderly individuals (n = 1113) for two consecutive days at 1-min intervals using a wrist light meter. Median daytime light intensities at window and nonwindow hospital beds were 327.9 lux [interquartile range (IQR), 261.5-378.4] and 118.4 lux (IQR, 100.6-142.9), respectively, and daytime light intensity measured in nonhospitalized elderly individuals was 337.3 lux (IQR, 165.5-722.7). Compared with data in nonhospitalized elderly individuals, nonwindow beds were exposed to significantly lower daytime light intensity (p 0.001), whereas window beds were exposed to similar daytime light intensity to that of home settings (p = 1.00). These results were consistent regardless of seasons (spring, summer, fall, and winter) or room directions (north vs. south facing). The lowest median daytime light intensity was observed at nonwindow beds in north-facing rooms during the winter (84.8 lux; IQR, 76.0-95.8). Further studies evaluating the incidence of in-hospital outcomes between patients hospitalized in window and nonwindow beds are needed.

Dear Editor, Recent studies have shown that adherence to treatment is an important factor for good therapeutic outcome in various chronic disorders such as hypertension and diabetes.1,2 In dermatology, patient nonadherence to therapy is also very problematic and has been associated with poor therapeutic outcomes in common skin diseases.3–5 Although there is no ‘gold standard’ to measure medication adherence, an eight-item self-reported scale called the Morisky Medication Adherence Scale-8 (MMAS-8) has been developed by Morisky et al.1 MMAS-8 originally targeted oral medication for hypertensive patients, but it is now applied to measure medication adherence in a wide range of disorders such as diabetes and osteoporosis.2,6 However, there are no reports of studies investigating dermatological adherence using this scale. Therefore, this study assessed medication adherence for oral and topical remedies using a translated version of MMAS-8 together with other socioeconomic background factors in 3096 Japanese dermatological patients. This study was conducted among patients registered in a monitoring system established by Macromill Inc. (Tokyo, Japan). The registered individuals (n = 4144) were prescreened in terms of skin diseases and their intention to participate in this study. In total 3096 eligible patients were enrolled, 1327 with atopic dermatitis, 751 with urticaria, 237 with psoriasis and 781 with tinea. Our web-based questionnaire included the following items: age, sex, marital status, annual income, employment status, educational status, smoking habit, alcohol consumption, frequency of hospital visits, main healthcare institution, oral or topical medication, experience of the effectiveness of oral medication, experience of the effectiveness of topical medication, experience of adverse events associated with oral medication, experience of adverse events associated with topical medication, overall satisfaction with treatment, MMAS-8 for oral medication and MMAS-8 for topical medication. The original MMAS-8 was translated into Japanese according to international guidelines.7 Forward translation of the original questionnaire was undertaken by translation from English into Japanese to produce a version that was semantically and conceptually as close as possible to the original questionnaire. Translation was carried out by two qualified independent linguistic translators; both are native speakers of Japanese and proficient in English. Back translation from Japanese into English was then carried out by another translator, who is a native speaker of English and proficient in Japanese. The back translation form was sent to the original author. Inconsistencies were resolved after repeated discussion among the original author, the English translator and the Japanese investigators and a final version was generated. According to the MMAS-8 score (range 0–8), adherence was defined as high (score 8), medium (score 6 to

Background Dopamine transduces signals via five subtypes of G protein-coupled receptors. Among these subtypes, the D1 and D5 receptors belong to the D1-like group. Although dopamine is known to mediate immune responses, its involvement in cutaneous immunity remains unclear. Objective The aim of this study is to determine the role of dopamine and its D1-like receptors in cutaneous immune responses. Methods By using the D1-like receptor antagonist SCH 23390, we examined the role of D1-like receptors in murine models of Th1-type contact hypersensitivity and Th2-type atopic dermatitis in vivo , and in mast cells and Th2 cell differentiation in vitro. Results Administration of SCH 23390 did not affect Th1-type contact hypersensitivity but suppressed the immediate-type reaction (ITR) and the late phase reaction (LPR) in the atopic dermatitis model. In addition, SCH 23390-treated mice showed higher IFN-γ and lower IL-4 mRNA levels in the ear skin of challenged mice than did non-treated mice as analyzed by real-time RT PCR. Consistently, the passive cutaneous anaphylaxis reaction was significantly reduced in SCH 23390-treated mice. Moreover, dopamine enhanced mast cell degranulation and Th2 cell differentiation, and both activities were abrogated by SCH 23390. Conclusion These findings suggest that the D1-like receptors mediate immediate and late phase skin reactions by promoting Th2 induction and mast cell degranulation.

Approximately 50% of patients with adult T-cell leukemia/lymphoma (ATLL) have skin involvement, and the smoldering, skin lesion-bearing cases are often treated with various skin-directed therapies, such as phototherapy and radiation therapy. Daily oral administration of etoposide plus prednisolone (EP) is also used for smoldering-type ATLL. However, it remains unclear whether these therapies improve patients' survival. We retrospectively analyzed the prognosis of patients with smoldering, skin lesion-bearing ATLL (n = 62), who were treated, as first therapy, with one skin-directed therapy (n = 29), oral EP alone (n = 14) or a combination of skin-directed therapy and oral EP (n = 19). Multivariate analysis revealed that the hazard ratios (HRs) for the overall survival (OS) and progression-free survival (PFS) with the combination therapy were significantly lower than those with the skin-directed therapy (HR 0.1, p = 0.001; HR 0.2, p = 0.002, respectively). These results suggest that the combination of skin-directed therapy and oral EP improves the clinical outcome of patients with smoldering, skin lesion-bearing ATLL.

Purpose: Superficial dermatophytosis is quite commonly seen in patients with adult T-cell leukemia/lymphoma (ATLL), as approximately 50% of the patients develop cutaneous mycotic infections. Because superficially infected fungi in the stratum corneum of the epidermis cannot directly contact with T cells infiltrating in the upper dermis, some perturbation of epidermal innate immunity has been postulated. Interleukin (IL)-17–producing helper T cells (Th17) can induce the keratinocyte production of antimicrobial peptides such as human β defensin (HBD)-2 and LL-37, which play an essential role in cutaneous innate immunity. Experimental Design: We investigated the frequency of circulating Th17 cells, serum levels of cytokines, and epidermal expression of HBD-1, 2, 3, and LL-37 in ATLL patients with or without superficial dermatophytosis. Results: The frequency of peripheral Th17 cells and the serum level of IL-17 was significantly decreased in ATLL patients, whereas the serum IL-10 and TGF-β1 levels were increased as compared with healthy controls. Furthermore, ATLL patients with dermatophytosis had higher IL-10 and TGF-β1 levels and lower IL-17 levels than did those without dermatophytosis. Immunohistochemical study revealed that the epidermal expression of both HBD-2 and LL-37 were significantly lower in ATLL patients with dermatophytosis than in non-ATLL patients with dermatophytosis. Conclusions: Taken together, these results suggest that the keratinocyte production of antimicrobial peptides promoted by Th17 cells is reduced in ATLL patients, leading to the perturbed innate immunity and the frequent occurrence of superficial dermatophytosis. Clin Cancer Res; 18(14); 3772–9. ©2012 AACR.

Atopic dermatitis (AD) can be classified into the major extrinsic type with high serum IgE levels and impaired barrier, and the minor intrinsic type with normal IgE levels and unimpaired barrier.To characterize the intrinsic type of Japanese AD patients in the T helper cell polarization in relation to the barrier condition.Enrolled in this study were 21 AD patients with IgE200kU/L (IgE-low group; 82.5±59.6kU/L) having unimpaired barrier, and 48 AD patients with IgE500kU/L (IgE-high group; 8.050±10.400kU/L). We investigated filaggrin gene (FLG) mutations evaluated in the eight loci common to Japanese patients, circulating Th1, Th2 and Th17 cells by intracellular cytokine staining and flow cytometry, and blood levels of CCL17/TARC, IL-18, and substance P by ELISA.The incidence of FLG mutations was significantly lower in the IgE-low group (10.5%) than the IgE-high group (44.4%) (normal individuals, 3.7%). The percentage of IFN-γ-producing Th1, but not Th2 or Th17, was significantly higher in the IgE-low than IgE-high group. Accordingly, Th2-attracting chemokine CCL17/TARC, was significantly lower in the IgE-low than the IgE-high group. There were no differences between them in serum IL-18 levels, or the plasma substance P levels or its correlation with pruritus.The IgE-low group differed from the IgE-high group in that it had much less FLG mutations, increased frequency of Th1 cells, and lower levels of CCL17. In the intrinsic type, non-protein antigens capable of penetrating the unimpaired barrier may induce a Th1 eczematous response.

There are increasing cases of wheat dependent exercise-induced anaphylaxis (WDEIA) with transcutaneous or transmucosal sensitization. Hydrolyzed wheat included in a certain brand of soap was identified as a cause of sensitization. The useful clues to detect this disorder consist of the patient's past usage of a soap containing hydrolyzed wheat, the appearance of cutaneous or mucosal symptoms after the intake of wheat or washing with this soap, and a high level of specific IgE for wheat gluten. Because hydrolyzed wheat is used as an additive in a wide variety of cosmetics, we should pay careful attention to the ingredients of cosmetics when observing WDEIA.

A quality review revealed pressure ulcers at the ala of nose in 16 cases (2.2%) over 3 years. We therefore retrospectively investigated the risk factors for alar pressure ulcers from nasal tubes. Male gender was the highest risk factor (odds ratio = 9.1411; 95% confidence interval = 1.680–170.58), and the second highest risk factor was duration of anesthesia (odds ratio = 1.0048/min of anesthesia; 95% confidence interval = 1.0034–1.0065). Male gender and duration of anesthesia appear to be risk factors for nasal tube pressure ulcers at the ala of nose in patients.

Topical retinoid and antibiotic combination therapy is an integral part of acne treatment and is considered the appropriate first-line therapy according to the Japanese guideline for moderate and severe acne. In this combination, clindamycin or doxycycline are mostly used as antibiotics, but there have been no reports on the effectiveness of nadifloxacin, a widely used antibiotic in Japan and European countries for acne, in combination with topical retinoid. To confirm the efficacy and safety of adapalene gel and nadifloxacin cream in the treatment of Japanese patients with acne vulgaris, a total of 50 patients were randomized to the two groups, the combination therapy and the adapalene monotherapy, and each therapy was tested for 8 weeks. The percentage reduction in the number of inflammatory acne lesions was evaluated and the safety was monitored through adverse events. The combination of adapalene gel and nadifloxacin cream produced a significantly higher reduction in the inflammatory lesions at 2 weeks (P = 0.047) and at 8 weeks (P = 0.011) after the starting than did adapalene gel monotherapy. The combination did not elevate the side effects of erythema and scale scores, but rather significantly depressed erythema at 1 week. This study showed the efficacy and safety of the combination therapy of nadifloxacin cream with adapalene gel for the inflammatory acne.

Cutaneous involvement is seen in ∼ 50% of adult T-cell leukemia/lymphoma (ATLL) patients. We investigated the association between skin eruption type and prognosis in 119 ATLL patients. ATLL eruptions were categorized into patch (6.7%), plaque (26.9%), multipapular (19.3%), nodulotumoral (38.7%), erythrodermic (4.2%), and purpuric (4.2%) types. When the T stage of the tumor-node-metastasis-blood (TNMB) classification of mycosis fungoides/Sézary syndrome was applied to ATLL staging, 16.0% were T1, 17.7% T2, 38.7% T3, and 4.2% T4, and the remaining 23.5% were of the multipapular and purpuric types. For the patch type, the mean survival time (median survival time could not be estimated) was 188.4 months. The median survival times (in months) for the remaining types were as follows: plaque, 114.9; multipapular, 17.3; nodulotumoral, 17.3; erythrodermic, 3.0; and purpuric, 4.4. Kaplan-Meier curves of overall survival showed that the erythrodermic type had the poorest prognosis, followed by the nodulotumoral and multipapular types. The patch and plaque types were associated with better survival rates. Multivariate analysis demonstrated that the hazard ratios of the erythrodermic and nodulotumoral types were significantly higher than that of the patch type, and that the eruption type is an independent prognostic factor for ATLL. The overall survival was worse as the T stage became more advanced: the multipapular type and T2 were comparable, and the purpuric type had a significantly poorer prognosis than T1.

Cholecystokinin (CCK) serves as a gastrointestinal hormone and also functions as a neuropeptide in the central nervous system (CNS). CCK may be a downregulator in the CNS, as represented by its anti-opioid properties. The existence of CCK in the peripheral nervous system has also been reported. We investigated the suppressive effects of various CCKs on peripheral pruritus in mice. The clipped backs of ICR mice were painted with CCK synthetic peptides and injected intradermally with substance P (SP). The frequency of SP-induced scratching was reduced significantly by topical application of sulfated CCK8 (CCK8S) and CCK7 (CCK7S), but not by nonsulfated CCK8, CCK7, or CCK6. Dermal injection of CCK8S also suppressed the scratching frequency, suggesting that dermal cells as well as epidermal keratinocytes (KCs) are the targets of CCKs. As determined using real-time PCR, mRNA for CCK2R, one of the two types of CCK receptors, was expressed highly in mouse fetal skin-derived mast cells (FSMCs) and moderately in ICR mouse KCs. CCK8S decreased in vitro compound 48/80-promoted degranulation of FSMCs with a transient elevation of the intracellular calcium concentration. These findings suggest that CCK may exert an antipruritic effect via mast cells and that topical CCK may be clinically useful for pruritic skin disorders.

Background Both neurotrophins and chemorepellents are involved in the elongation and sprouting of itch-associated C-fibers in the skin. Nerve growth factor (NGF) and semaphorin 3A (Sema3A) are representatives of these two types of axon-guidance factors, respectively. Objective We investigated the effects of calcium concentration and histamine on the expression of NGF and Sema3A in normal human epidermal keratinocytes (NHEK) and normal human fibroblasts (NHFb). Methods NHEK and NHFb were cultured under different calcium concentrations (0.15–0.9 mM) with or without histamine, and the expression of mRNA for NGF and SEMA3A was assessed by real-time PCR analysis. An immunohistochemical study was performed for Sema3A using normal skin and skin cancer specimens. Results In NHEK, SEMA3A expression was elevated by high calcium concentration and reduced by low calcium condition, while NGF expression was not dependent on calcium. Their expressions were unchanged by calcium in NHFb. Immunohistochemically, keratinocytes in the prickle layer of normal epidermis and squamous cell carcinoma cells were positive for Sema3A, sparing basal cells and suprabasal cells. The addition of histamine to NHEK at 10 μg/ml enhanced SEMA3A expression but depressed NGF expression. In NHFb, however, histamine decreased both NGF and SEMA3A levels. Conclusions Sema3A inhibits C-fiber elongation/sprouting in the upper layers of the epidermis, where calcium concentration is high, thereby determining the nerve endings. Histamine reduces Sema3A production by fibroblasts, allowing C-fibers to elongate in the dermis. In contrast, the histamine-augmented keratinocyte production of Sema3A might suppress C-fiber elongation and exaggerated pruritus.

第2世代抗ヒスタミン薬は，抗ヒスタミン作用以外にも様々な免疫学的調整作用を併せ持つ。アトピー性皮膚炎(atopic dermatitis : AD)患者におけるかゆみ増強サイクルにおいて重要な役割を担う，サブスタンスP(substance P : SP)の産生にも一部の抗ヒスタミン薬は影響することが報告されている。また近年，ADの病勢に応じてIL-17産生CD4陽性細胞(Th17細胞)が重要な役割を果たすことが判明している。今回我々は，当院におけるAD患者15名に対して塩酸オロパタジンの内服療法を行い，内服前後の血中SPとTh17細胞割合の変動を測定した。同時にかゆみの程度としてvisual analogue scale(VAS)，ADの重症度としてscoring atopic dermatitis(SCORAD)を評価し，SPとTh17細胞割合の変動との関連性を検討した。結果，塩酸オロパタジン内服前後で，VASとSCORADの改善とともにSPの有意な低下がみられた。Th17細胞は，有意差はないものの，検討した9名中7名で低下していた。塩酸オロパタジンによるSP産生・遊離抑制効果が，AD患者の臨床症状改善に寄与している可能性が示された。

月経時に外陰部皮膚に痒み・痛み等の自覚症状や皮膚症状が発生することは，多くの女性に認知されている。これらの皮膚症状は月経血そのものによる刺激や，ナプキン使用による高温高湿度局所環境による皮膚の水和・閉塞により誘導されると推定される。しかしながら，月経時のナプキン接触部における様々な刺激増大が，アトピー性皮膚炎(AD)患者にどのような影響を及ぼしているのかは判っていない。ADコントロールを行う上で外陰部皮膚症状への配慮も必要であると考え，アンケート調査を行った。月経時の外陰部皮膚症状に関して，健常者を含む全体の約3/4が痒みを自覚しており，約半数には皮膚症状を伴っていた。これらの症状の頻度は高重症度皮疹を伴うAD 患者ほど高くなっていた。次いで，経血付着や皮膚膨潤軽減を謳ったサンプルナプキン(ロリエ® F)を使用させ，外陰部皮膚症状への影響を調査した結果，自覚症状を軽減することが示された。

Skin barrier damage induces various harmful or even protective reactions in the skin, as represented by enhancement of keratinocyte cytokine production. To investigate whether acute removal of stratum corneum modulates the production of chemokines by epidermal cells, we treated ears of BALB/c and C57BL/6 mice by tape-stripping, or acetone-rubbing as a control of acute barrier disruption procedure. There was no difference between the tape-stripped and acetone-rubbed skin sites in the increased and recovered levels of transepidermal water loss. The mRNA expression levels of all the chemokines tested, including Th1 chemokines (CXCL10, CXCL9 and CXCL11), Th2 chemokines (CCL17 and CCL22) and eosinophil chemoattractant (CCL5), were higher in the epidermal cells from BALB/c than in those of C57BL/6 mice. In particular, CCL17, CCL22 and CCL5 were remarkably elevated in BALB/c mice and augmented by tape-stripping more markedly than acetone-rubbing, whereas Th1 chemokines were enhanced by acetone-rubbing more remarkably. Tape-stripping induced dermal infiltration of eosinophils in BALB/c but not C57BL/6 mice. In a contact hypersensitivity model, where BALB/c mice were sensitized on the abdomen and challenged on the ears with fluorescein isothiocyanate, mice exhibited higher ear swelling responses at the late-phase as well as delayed-type reactions, when challenged via the tape-stripped skin. The challenge via tape-stripped skin augmented the expression of IL-4 and CCR4 in the skin homogenated samples, indicating infiltration of Th2 cells. These findings suggest that acute barrier removal induces the expression of Th2 and eosinophil chemokines by epidermal cells and easily evokes the late phase reaction upon challenge with antigen.

Background Two types of atopic dermatitis (AD) have been proposed, with different pathophysiological mechanisms underlying this seemingly heterogeneous disorder. The extrinsic type shows high IgE levels presumably as a consequence of skin barrier damage and feasible allergen permeation, whereas the intrinsic type exhibits normal IgE levels and is not mediated by allergen-specific IgE. Objectives To investigate the relationship between pruritus perception threshold and skin barrier function of patients with AD in a comparison between the extrinsic and intrinsic types. Methods Enrolled in this study were 32 patients with extrinsic AD, 17 with intrinsic AD and 24 healthy individuals. The barrier function of the stratum corneum was assessed by skin surface hydration and transepidermal water loss (TEWL), and pruritus perception was evaluated by the electric current perception threshold (CPT) of sensory nerves upon neuroselective transcutaneous electric stimulation. Results Skin surface hydration was significantly lower and TEWL was significantly higher in extrinsic AD than intrinsic AD or normal controls. Although there was no statistically significant difference in CPT among extrinsic AD, intrinsic AD and normal controls, CPT was significantly correlated with skin surface hydration and inversely with TEWL in intrinsic AD and normal controls, but not extrinsic AD. Finally, CPT was correlated with the visual analogue scale of itch in the nonlesional skin of patients with extrinsic but not intrinsic AD. Conclusions Patients with extrinsic AD have an impaired barrier, which increases the pre-existing pruritus but rather decreases sensitivity to external stimuli. In contrast, patients with intrinsic AD retain a normal barrier function and sensory reactivity to external pruritic stimuli.

Bepotastine besilate is an antihistaminic drug of the second generation with superior clinical responses. In this study, we investigated whether bepotastine modulates the production of cytokines/chemokines and the expression of CD54 in human epidermal keratinocytes. The production of IL-1α, CXCL10, and CCL17 and the expression of CD54 were significantly suppressed by the addition of bepotastine. Bepotastine exerts its antiallergic action on keratinocytes by suppressing the production of certain proinflammatory cytokines, both Th1 and Th2 chemokines, and possibly by inhibiting the expression of CD54.

Growing evidence has demonstrated that chemokinesreleased from epidermal cells control inflammatory skin diseases.Keratinocytes elaborate both Th1- and Th2-associatedchemokines, although the former is more abundantly producedthan the latter. Downmodulation of keratinocyte production ofchemokines is one of the therapeutic approaches for cutaneousinflammatory disorders. Recent observations have shown thatkeratinocyte chemokine production can be modulated by well-used drugs, including antihistamines, antibiotics and antifungals.Utilization of the beneficial side effects of these drugs may byclinically valuable. Key words: antibiotic – antifungal – antihistamine – chemokine –epidermis Please cite this paper as: Epidermal chemokines and modulation by antihistamines, antibiotics and antifungals. Experimental Dermatology 2008; 17: 81–90. Introduction Skin is a well-orchestrated immune organ where epidermalcells produce various cytokines, chemokines and mediators,thereby inducing leucocytes infiltration in the dermis andeven epidermis and evoking contact dermatitis and otherskin lesions (1). Recent accumulating evidence has clarifiedthat chemokines play an important role in cutaneousimmunity (2). Allergic contact dermatitis and atopic der-matitis (AD) are the typical conditions to show the essen-tial roles of chemokines by which immunocompetent cellsinteract dynamically with each other (3,4). Keratinocytesare the major producers of epidermal chemokines, whichare controlled by various cytokines (5–7).Keratinocyte production of chemokines may be modu-lated by clinically used therapeutic reagents. Cytokines suchas interferon-c (IFN-c) and anticytokine antibodies such asantitumor necrosis factor-a (TNF-a) duly alter the chemo-kine production as seen in patients with mycosis fungoidestreated with IFN-c (8) and psoriasis with anti-TNF-a anti-body (9). Besides these biologics or biological responsemodifiers, recent findings have revealed that certain drugshave a capacity to modulate the chemokine production.These seemingly attractive drugs include antihistamines,antibiotics and antifungals. The fact that antihistamineshave this capacity is perhaps not particularly surprising, asit has been known for many years that antihistamines altercytokine production. However, it is of particular interestthat antibiotic and antifungal drugs have this potential. Wecan hypothesize that they possibly exert beneficial, notadverse, side effects in patients with not only skin allergybut also bacterial⁄fungal infections, although physiciansand patients have not noticed such pleasant effects of thedrugs. This article aims to review the roles of epidermalchemokines and highlight the drugs capable of modulatingkeratinocyte chemokine production.

Dermatophytes reside in the stratum corneum of the epidermis, and one scenario in superficial dermatophytosis is that fungi stimulate keratinocytes to secrete chemokines, thereby attracting inflammatory cells. We investigated the effect of the cytokine / chemokine production of keratinocytes solely stimulated by fungal elements. The fungal elements beta-D-glucan and trichophytin from Trichophyton rubrum and Trichophyton mentagrophytes augmented production of IL-8 and IL-1 alpha of cultured normal human epidermal keratinocytes. It was found that keratinocytes can recognize elements of dermatophytes as a pathogen. Next we examined the effect of liranaftate, a representative Japanese thiocarbamate antifungal agent, on the production of IL-8 and IL-1 alpha. Keratinocytes were incubated with this antifungal drug in the presence of beta -glucan or trichophytin. Augmented production of IL-8 was profoundly suppressed by the addition of liranaftate to the culture in a dose-dependent manner. Clinically, liranaftate an antifungal drug with IL-8-decreasing activity may reduce infiltration of neutrophils in the skin and their invasion into the epidermis.

CCR7 is regarded as an essential chemokine receptor for cutaneous dendritic cell (DC) migration into the regional lymph nodes. However, complete migratory inhibition cannot be obtained in CCR7-deficient mice, suggesting that there exist other chemokine receptors involved in this process. Initially, we found that CXCR4 was highly expressed on migrated cutaneous DCs and that its ligand, CXCL12, was detected in the LYVE-1(+) lymphatic vessels in the skin. FITC-induced cutaneous DC migration into the draining lymph nodes was impaired by the specific CXCR4 antagonist 4-F-Benzoyl-TN14003. Among FITC(+) cells, Langerin(+) Langerhans cells and Langerin(-) (dermal) dDC subsets were detected as CD11c(high+)CD11b(int+) cells and CD11c(high+)CD11b(high+) plus CD11c(low+)CD11b(int+) cells, respectively, both of which were suppressed by CXCR4 antagonist. Moreover, in vivo contact hypersensitivity response was impaired by CXCR4 antagonist administered during the sensitization phase. The in vitro proliferative response to dinitrobenzene sulfonic acid of sensitized lymph node cells was inhibited by CXCR4 antagonist treatment. These findings demonstrated that CXCL12-CXCR4 engagement on cutaneous DCs plays a crucial role in the initiation of skin immune response by enhancing cutaneous DC migration.

Adherence is defined as the extent to which a person's behavior corresponds with recommendations from health care providers. Adherence to treatment is an important factor for a good therapeutic outcome.This study aimed to examine the adherence of patients with tinea pedis and to clarify the factors related to it.We assessed medication adherence for oral and topical drugs using a translated version of the Morisky Medication Adherence Scale-8 (MMAS-8) together with other background factors in 445 Japanese patients with tinea pedis, using a questionnaire in a web-based monitoring system.Overall, high, medium and low adherence rates as assessed by MMAS-8 were 8.7%, 31.7% and 59.6% for oral medication, and 8.6%, 17.4% and 74.0% for topical medication, respectively. The adherence level was significantly higher for oral medication than for topical medication. Subgroup analyses showed that the adherence level for topical medication was significantly higher when topical and oral medications were used in combination than when topical medication was used alone. A low adherence level was shown in employed patients, those for whom their oral medication had not been effective and those with topical medication who had visited their hospital less often than once every six months.Patient adherence to therapy can be effectively improved by selecting highly effective medication while considering the prescription of topical and oral antifungal medications concomitantly, by carefully selecting a therapy plan for employed patients and by encouraging patients to visit their doctor regularly.

© 2015 Z. Background: Patients' high adherence to medication is indispensable for the management of skin diseases including atopic dermatitis. We previously showed poor medication adherence in Japanese dermatological patients. Objective: This study was conducted to determine the level of adherence to oral or topical medication in Japanese patients with atopic dermatitis, attempting to characterize the socioeconomic status of those patients with poor adherence. Methods: A web questionnaire survey on demographic data as well as adherence level was conducted on patients registered in the monitoring system. Adherence level was assessed with Morisky Medication Adherence Scale-8 (MMAS-8). Among a total of 3096 respondents with dermatological disorders, data of 1327 subjects with atopic dermatitis were extracted and analyzed. Results: More than 80% of subjects felt that both oral and topical medications were safe and efficacious, while less than 60% of them were satisfied with their treatment. Levels of adherence to oral and topical treatments were evaluated with MMAS-8, giving scores of 4.6 and 4.2, respectively. Demographic factors such as gender, marital status, state of employment, alcohol consumption, frequency of hospital visits, and experience of drug effectiveness had a significant impact on the degree of adherence to treatment. Conclusion: Medication adherence level in Japanese subjects with atopic dermatitis was relatively low compared with that of other chronic diseases. Our survey has characterized patients with poor adherence, who are good targets for interventions to maximize potentially limited healthcare resources.

© 2015 Japanese Dermatological Association. Previously we assessed the medication adherence for oral and topical remedies by a translated Japanese version of the Morisky Medication Adherence Scale-8 (MMAS-8) together with socioeconomic backgrounds in 3096 Japanese dermatological patients, and found the medication adherence, especially to topical drugs, was poor in these patients. In order to elucidate the disease-specific sociomedical factors, we further sub-analyzed the medication adherence in 237 psoriasis patients and compared it with that in other dermatological diseases such as atopic dermatitis, urticaria or tinea. This study was conducted among patients registered in monitoring system and 3096 eligible patients were enrolled. Our web-based questionnaire included the following items such as age, sex, annual income, main health-care institution, experience of effectiveness by oral or topical medication, overall satisfaction with treatment, and MMAS-8 for oral or topical medication. Mean adherence score by MMAS-8 was 5.2 for oral and 4.3 for topical medication. More patients with psoriasis used a university hospital and fewer used a private clinic compared with those with the other skin disease patients. Experience of drug effectiveness by oral medication and overall satisfaction with treatment was lower in psoriasis patients than in other patients. In oral medication, significantly better adherence was observed in those of higher age and with higher annual income. The adherence to medication, especially to topical drugs, was poor in 237 psoriasis patients. We speculated that some severe psoriasis patients were not sufficiently treated systemically and were resistant to topical therapy, leading to poor adherence.

Roxithromycin (RXM), an anti-bacterial macrolide, has various immunomodulatory activities. To investigate the ability of RXM to downregulate skin-infiltration of T-lymphocytes, we examined the effects of RXM on keratinocyte production of chemokines and T cell expression of chemokine receptors. Normal human and HaCaT keratinocytes were cultured with RXM and stimulants. RXM at 1 or 10 microM significantly suppressed the production/expression of Th2 chemokines MDC and TARC in these keratinocytes, but the production of IP-10 was not affected. The effect of RXM on T-cell expression of the corresponding chemokine receptors was also tested in Th2-rich peripheral blood lymphocytes. The IL-2-enhanced expression level of Th2 chemokine receptor CCR4 was decreased by RXM at 10 microM, whereas the expression of CXCR3 was unchanged. Thus, RXM downmodulates both the production and receptor expression of Th2 but not Th1 chemokines involved in cutaneous immunity, suggesting its beneficial therapeutic effects on Th2-mediated or allergic skin disorders.

症例1は57歳の男性。外傷を契機に臀部慢性膿皮症を発症し,罹病約2年で有棘細胞癌を併発した。両鼠径リンパ節転移があり,化学療法,放射線療法および手術療法を行ったが,8ヵ月後に遠隔転移がみつかった。症例2は68歳の男性。20年前より臀部慢性膿皮症で治療を受けていたが,有棘細胞癌を併発した。放射線療法,手術療法を行い術後3年まで再発および転移はみつかっていない。臀部慢性膿皮症は有棘細胞癌の発生母地として取り扱い,早期に根治的手術療法を行うべきである。

© 2015 The Authors. doi: 10.2340/00015555-2091 Journal Compilation © 2015 Acta Dermato-Venereologica. ISSN 0001-5555 Coelomycetes are asexual fungi which produce their conidiospores within fruiting structures known as conidiomata. They are ubiquitous in soil and freshwater environments, and recognized as plant pathogens (1, 2). Although human infections with coelomycetous fungi are exceedingly rare, some may cause an opportunistic soft tissue infection, particularly as phaeohyphomycosis, in immunocompromised hosts (1, 3). We recently experienced 2 independent Japanese cases of infection by Microsphaeropsis arundinis, a coelomycete fungus (2). This is the first report of M. arundinis infection in Asia.

Eleven cases of sporotrichosis treated in our clinic were statically evaluated and two cases suffered by farmers are presented. In urban areas, because of the great popularity of gardening, patients with sporotrichosis are increasing among gardeners. Because sporotrichosis is an occupational skin disease, enlightenment of farmers and gardeners regarding the importance of prevention of skin injury as a route to infection during farm work or gardening is necessary. In addition, dermatologists have to spread information regarding the fungal infections to the public.

Benign lymphangioendothelioma (BL) represents a very rare lymphatic vascular proliferation. Our aim is to be aware that owing to its characteristic features, pathologists can easily misinterpret it as cutaneous low-grade angiosarcoma when examining only small specimens. In the present case, multiple small and yellowish to reddish soft nodules were noticed in the edematous left arm of a 54-year-old Japanese female 4 years after the radical mastectomy with axillary lymph nodes dissection and following radiotherapy to the chest for the left breast carcinoma. The biopsy specimen showed an ill-defined lesion composed of a proliferation of irregular and sometimes anastomosing vascular structures in the dermis, lined by endothelial cells having mildly hyperchromatic and pleomorphic nuclei, but no mitotic figures. As the lesion grew within deeper dermis, these proliferating vessels dissected dermal collagenous bands, occasionally arranged in low-papillary projections and/or characteristic hobnail cytomorphology. We first interpreted it as low-grade angiosarcoma following chronic lymphedema due to the operation, i.e., the so-called Stewart-Treves syndrome. Although additional treatments were performed for 7 years, she had neither local invasion nor metastases of these tumors, respectively, and was alive and well. Retrospective immunohistochemical findings demonstrated that these mildly atypical endothelial cells were strongly positive for lymphatic vessel endothelial hyaluronan receptor (LYVE)-1 as well, and MIB-1 labeling index was less than 1%. Therefore, we finally made a diagnosis of BL of the skin. MIB-1 labeling index might be useful and adjunctive aids for reaching the correct diagnosis of cutaneous BL, especially in case of small or inadequate specimens. Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_197

We report two patients who suffered from acid burns while working in chemical factories. Case 1: a 44-year-old man who received burn induced by nitric acid on the face and extremities. Despite his protecting facial mask, he was exposed to nitric acid on his face through a gap between the mask and skin surface. Nitric acid was also sprinkled on his scalp which was not covered by a helmet or a protecting device. In addition, he suffered from acid burn on the right scapular region, the right upper arm, and the lower extremities through the work clothes. Case 2: a 26-year-old man who suffered from sulfuric acid burn on the forearms. Both patients were accidentally exposed to acids while they filled tanks with the acids through a hose. Following the manual of the factories, they washed the exposed skin with water for more than 15 minutes after the exposure. Although they recovered without any serious sequel, there remained partial deep tissue destruction of the skin. We reviewed these two cases from the aspect of industrial medicine, and proposed the following three points for improvement in the workplace to prevent accidental acid burns. 1) re-education or enlightenment activities for the well-experienced workers to avoid negligence to the danger of strong acid. 2) recommendation to take a complete shower to avoid overlooking of unaware acid injury. 3) improvement in the protecting facial mask. In addition, clinicians who examine acid-burn patients should not pass over the presence of deep ulcers lying behind the thick crust on the injured area.

Among the several forms of Langerhans cell histiocytosis (LCH), Letterer-Siwe disease is the most acute disseminated multisystemic variant. The course of Letterer-Siwe disease is usually rapid and fatal. We report here a cases of Letterer-Siwe disease which showed a good response to chemotherapy. We also describe the unusual ultrastructural findings in the histiocyte-like cells in this case.