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DOI： 10.1684/ejd.2021.4138

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Tildrakizumab is a high-affinity, humanized immunoglobulin G1κ, anti-interleukin-23p19 monoclonal antibody recently approved in Japan for treatment of plaque psoriasis. We report results from Japanese patients treated with tildrakizumab in the multinational, randomized, double-blind, placebo-controlled reSURFACE 1 study (clinicaltrials.gov NCT01722331). Adults with moderate to severe plaque psoriasis were randomized (2:2:1) to receive subcutaneous tildrakizumab 100 or 200 mg or placebo every 12 weeks. Placebo recipients were rerandomized to tildrakizumab 100 or 200 mg at week 12. The global study coprimary endpoints were the proportions of patients achieving 75% improvement from baseline Psoriasis Area and Severity Index (PASI 75) and Physician Global Assessment (PGA) response (0/1 with ≥2 grade reduction from baseline) at week 12. Analyses included 158 Japanese patients randomized to tildrakizumab 100 (n = 64) or 200 mg (n = 62) or placebo (n = 32). Japanese patients had higher mean baseline body surface area involvement and PASI versus all reSURFACE 1 patients. At week 12, significantly more Japanese patients receiving tildrakizumab 100 and 200 mg versus placebo achieved PASI 75 (54.7% and 54.8% vs 6.3%, respectively, both nominal p < 0.001) and PGA 0/1 response (54.7% and 56.5% vs 9.4%, respectively, both nominal P < 0.001). Response rates increased over time with maximal efficacy after 22-28 weeks; >80% of patients achieving PASI 75 or PASI 90 at week 28 and continuing tildrakizumab treatment at the same dose maintained response at week 64. From baseline to week 28, absolute PASI decreased from >12 in all patients to ≤2 in >40% and ≤3 in >50% of patients receiving tildrakizumab. Tildrakizumab was generally well tolerated with an adverse event profile similar to that of placebo. Tildrakizumab treatment was associated with durable efficacy in Japanese patients with moderate to severe plaque psoriasis despite greater baseline disease severity versus the global reSURFACE 1 population.

DOI： 10.1111/1346-8138.15789

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BACKGROUND: Plaque psoriasis significantly affects patients' health-related quality of life. To aid treatment decisions, not only objective assessment by physicians but also subjective assessment by patients is important. OBJECTIVE: To assess the significance of Dermatology Life Quality Index (DLQI) evaluation at the time of biologics introduction in clinical practice in Japanese patients with plaque psoriasis. METHODS: This was a single-arm, open-label, multicenter study. At baseline, Psoriasis Area and Severity Index (PASI) and DLQI scores were measured and stratified based on DLQI scores ≥6/≤5 and PASI scores ≤10/>10. Other patient-reported outcomes assessed included EQ-5D-5L, itch numerical rating scale (NRS), skin pain NRS, Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-8 (PHQ-8), Sleep Problem Index-II (SPI-II), and Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9). RESULTS: Of the 73 enrolled patients, 23 had PASI scores ≤10. Those with PASI/DLQI scores >10/≥6 had a significantly higher median PASI score than those with PASI/DLQI scores >10/≤5 (p = 0.0125). Regardless of PASI scores (>10/≤10), median itch NRS and GAD-7 scores were significantly higher in patients with DLQI scores ≥6 than in those with DLQI scores ≤5 (itch NRS, p = 0.0361 and p = 0.0086, respectively; GAD-7, p = 0.0167 and p = 0.0273, respectively). Patients with PASI/DLQI scores ≤10/≥6 had significantly higher skin pain NRS (p = 0.0292) and PHQ-8 (p = 0.0255) scores and significantly lower median SPI-II scores (p = 0.0137) and TSQM-9 Effectiveness domain scores (p = 0.0178) than those with PASI/DLQI scores ≤10/≤5. CONCLUSION: DLQI may be useful for assessing patients' concerns that cannot be identified by PASI alone while initiating biologics or switching from other biologics in clinical practice.

DOI： 10.1016/j.jdermsci.2021.01.002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NLM (Medline)  

Aluminum chloride (AlCl3) is the main active ingredient in commonly used antiperspirant. Antiperspirant use may cause a rare keratinization disease, granular parakeratosis (GP), then AlCl3 may be associated with the etiology of GP. The objective of this study is to elucidate the skin effect of topical aluminum application using a mouse model. We sprayed 20% aluminum chloride every day on the depilated mice skin and analyzed the skin clinically, histopathologically, and immunohistologically. We have succeeded in the histological replication of GP on mouse skin. The basophilic granules in the stratum corneum contained filaggrin, and processing of profilaggrin to filaggrin was disrupted in aluminum-treated mouse skin (Al-mouse). In Al-mouse, cytochrome c and cleaved-caspase 3 were upregulated mainly in the granular layer, and caspase 3 p20 subunit was upregulated. TUNEL-positive cells increased significantly in the Al-mouse from the granular to the horny layer. Caspase 3 inhibitor inhibited granular parakeratotic change of Al-mouse. Our results indicated that aluminum-induced apoptosis leads to keratinization arrest and acceleration of nuclear degradation before completion of profilaggrin processing. This could lead to retention of the basophilic granules composed of underprocessed profilaggrin in the horny layer of Al-mouse skin, the hallmark of GP.

DOI： 10.1097/DAD.0000000000001513

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Publishing Ltd  

DOI： 10.1111/1346-8138.15017

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DOI： 10.1111/1346-8138.14650

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Verlag  

Epidermal stem cells adhere more efficiently to the extracellular matrix (ECM) than the less adhesive differentiating cells due to their high expression of cell adhesion molecules including β1-integrin. Podoplanin is majorly expressed in the markedly proliferative and differentiating basal cells of the wounded and psoriatic epidermis. This study was designed to reveal podoplanin’s function in human epidermal keratinocytes (HEK) focusing on its interaction with β1-integrin. We analyzed the adhesion and differentiation of HEK in both podoplanin-overexpressing and -knock-down cells, considering their β1-integrin levels. The basal layer of IL-22-treated hyperproliferative reconstituted epidermis cells (simulating basal hyperproliferative psoriatic epidermal basal cells) expressed higher podoplanin levels than the untreated control cells. The adhesiveness of HaCaT cells, which do not express podoplanin, was reduced after the overexpression of podoplanin. HEK with podoplanin overexpression suppressed the cell adhesion to type I collagen (while downregulating β1-integrin functions) and podoplanin silencing augmented it (by increasing active ECM-bound β1-integrin). The increased cell adhesion to type I collagen induced by podoplanin silencing could be reversed by addition of P5D2, a neutralizing antibody against β1-integrin. In the psoriatic epidermis, podoplanin expression was especially upregulated on the rete ridges of the basal cell layer. This expression pattern was inversely correlated with the total/ECM-bound active β1-integrin-expression, which was stronger at the basal cell layer covering the dermal papillae. Our results indicate that podoplanin inhibits the cell ECM attachment by suppressing β1-integrin and initiating HEK differentiation. Podoplanin is presumably involved in the pathogenesis of psoriasis.

DOI： 10.1007/s00403-018-1878-9

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

Eosinophilic granulomatosis with polyangiitis (EGPA
ie, Churg–Strauss syndrome) is one of the antineutrophil cytoplasmic antibody–associated vasculitis syndromes. Although extravascular granulomatoses are a well-known histopathological feature, the diverse histopathologic spectrum of cutaneous lesions has not been described in detail. Thus, this study sought to investigate the possible correlation between the clinical features and histopathology of cutaneous lesions in EGPA cases, focusing on systemic thrombogenic conditions, such as visceral infarction and deep vein thrombosis. Fourteen cases of EGPA diagnosed at the Department of Dermatology in Asahikawa Medical University from 1977 to 2017 were clinically and histopathologically reviewed. In 6 (43%) cases, skin lesions were the initial manifestation of EGPA. Among the cutaneous lesions, purpura and erythema were the most common. Persistent proteinuria and mac-rohematuria were observed in only 2 myeloperoxidase–antineutrophil cytoplasmic antibody–positive cases. Systemic thrombotic symptoms, such as cerebral infarction and deep vein thrombosis, were detected in 5 (36%) cases, and, in 3 of those cases, thromboses in dermal or subcutaneous vessels were observed histopathologically. Elevation of plasma D-dimer level (.2.5 mg/mL) was significantly correlated with concomitant systemic thrombotic symptoms (P = 0.0152, Fischer exact test). The histopathological finding of thrombotic features and increased plasma D-dimer were predictive factors of EGPA accompanied with systemic thromboses, such as deep vein thromboses and cerebral infarction.

DOI： 10.1097/DAD.0000000000001202

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Azathioprine (AZA)-metabolizing enzyme gene polymorphism is strongly related to thiopurine-induced leukocytopenia, which has not been well recognized in dermatological practice. We tried to see whether NUDT15 gene polymorphism can be the most susceptible genetic factor for AZA toxicity and the gene screening is beneficial to avoid the adverse events of AZA for the treatment of skin diseases. A retrospective study was carried out on 15 adult Japanese patients who were treated with AZA. Gene polymorphism of thiopurine-metabolizing enzymes NUDT15 R139C, ITPA 94C&gt
A, TPMT*2, TPMT*3B and TPMT*3C was analyzed. The single nucleotide polymorphisms were prospectively investigated in eight patients who were considered to have received AZA treatments. Two NUDT15 R139C homozygous patients developed agranulocytosis, severe thrombocytopenia and massive hair loss. The gene screening prior to AZA treatment identified one heterozygote of NUDT15 R139C and ITPA 94C&gt
A, and three heterozygotes of ITPA 94C&gt
A or TMPT*3C. Although this study was a retrospective single-center case–control observational study that enrolled a small number of patients, NUDT15 R139C homozygosity is a genetic risk of thiopurine-induced potentially fetal hematological abnormalities. To avoid serious adverse events, gene screening of thiopurine-metabolizing enzymes, at least NUDT15 R139C, should be considered prior to administration in genetically predisposed populations, such as Japanese. We highlight that massive hair loss in the early period of the initiation of AZA would be a sign of impending severe myelotoxicity.

DOI： 10.1111/1346-8138.14588

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ireland Ltd  

Background: Psoriasis, a common inflammatory skin disorder characterized by scaly erythema and plaques, is induced by dysregulation of dendritic cell- and T cell-mediated immune reaction. Receptor-interacting protein kinase 1 (RIPK1) regulates inflammatory signaling in response to stimuli such as TNF-α TRAIL, and TLRs, resulting in apoptosis, necroptosis and NF-κB activation. However, the physiological relevance in human epidermis remains elusive. Objective: In this study, we examined whether RIPK1 is involved in the pathogenesis of psoriasis vulgaris. Methods: Skin samples of eight patients with psoriasis vulgaris were investigated by western blotting and immunohistochemistry. The functions of RIPK1 in keratinocytes were examined by RT-PCR and ELISA in vitro. TRAIL-neutralization-experiment was employed in an imiquimod-induced murine psoriasis model. Results: In lesional psoriatic epidermis, RIPK1-expression was decreased compared with that in normal epidermis. Cytokines involved in the pathomechanism of psoriasis, such as IL-1β IL-17A, IL-22 and TRAIL, reduced RIPK1-expression in normal human epidermal keratinocytes (HEK) in vitro. In addition, RIPK1-knockdown enhanced TRAIL-mediated expression of psoriasis-relating cytokines, such as IL-1β IL-6, IL-8, TNF-α in HEK. Numerous TRAIL-positive cells were detected in the dermis of lesional psoriatic skin, and TRAIL receptors were expressed in psoriatic epidermis and HEK in conventional cultures. Moreover, TRAIL-neutralization in an imiquimod-induced murine psoriasis model remarkably improved skin phenotypes, such as ear thickness, and TNF-α expression in lesional skin. Conclusions: These results lead us to conclude that RIPK1-downregulation in keratinocytes increases their susceptibility to TRAIL stimulation, and plays a role in the pathogenesis of psoriasis vulgaris.

DOI： 10.1016/j.jdermsci.2018.04.007

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Biologics show great efficacy in treating psoriasis, a chronic inflammatory skin disease. The high cost and side-effects of biologics, dose-reduction, elongation of administration interval and suspension are possible options. However, there has been no reliable biomarker we can use when we consider these moderations in therapy. This study was conducted to test the possibility of using serum thymus and activation-regulated chemokine (TARC) level as an indicator for step down of biologic therapy. Serum TARC level was measured in 70 psoriatic patients at Asahikawa Medical University, and a correlation of TARC and severity of skin lesions was analyzed. Referring to serum TARC level, psoriatic patients can be divided into two groups. One is a population in which serum TARC level is positively correlated with severity of skin lesions, and the other is a population with low psoriatic severity and high TARC level. Serum TARC level was higher in the group that achieved PASI-clear with biologics than in the group which did not achieve PASI-clear. Among biologics, the group treated with secukinumab, an anti-interleukin (IL)-17A agent, showed significantly higher TARC level compared with the group treated with anti-tumor necrosis factor agents. In certain populations achieving PASI-clear, serum TARC level may be a potent marker reflecting better response to IL-17A inhibitors, and in this case step down of treatment for psoriasis is possible.

DOI： 10.1111/1346-8138.14308

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DOI： 10.1111/1346-8138.14313

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DOI： 10.1684/ejd.2017.3174

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33歳,男性の左上背部に生じた限局性丘疹型異型ジベルばら色粃糠疹を経験した。初診時,左肩甲骨部にherald patchと考えられる辺縁に襟飾り状の鱗屑を付着する長径2cmの淡紅色類円形局面があり,その周囲に5mm大までの紅色丘疹が多発していた。ジベルばら色粃糠疹は頻度の高い代表的な炎症性皮膚疾患で,通常その典型的な臨床像から診断は比較的容易であることが多い。一方,非典型的な臨床像をとる異型ジベルばら色粃糠疹も全体の20%程度でみられるとされ,自験例でみられた限局性丘疹型を含め,各種亜型の臨床像について十分に理解する必要がある。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Psoriatic arthritis (PsA), a chronic inflammatory arthropathy associated with psoriasis, is an intractable immune disorder and refractory to pharmacological intervention. We assessed efficacy of selective depletion of myeloid lineage leukocytes in patients with PsA in a multicenter setting. A total of 20 patients with moderate to severe PsA refractory to conventional and biological disease-modifying antirheumatic drugs were included. Eligible patients had 3 points or more in the classification criteria for PsA. Each patient received five sessions, once a week, of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn((R)). The primary efficacy outcome was 20% or more decrease in the American College of Rheumatology score 20 (ACR20). Partial responders could receive an additional five GMA sessions. Of 20 patients, two did not complete the study, nine responded to five GMA sessions and nine received 10 sessions. At the first evaluation 2 weeks after the last GMA session, 13 of the 20 (65.0%) patients achieved ACR20. ACR20 was maintained in seven of 10 (70%) and five of 10 (50%) patients at the follow-up evaluation points 8 and 20 weeks after the last GMA session, respectively. GMA was well tolerated without any safety concern. This study demonstrates that GMA with the Adacolumn was effective with good safety profile in patients with PsA refractory to pharmacologicals. The results indicate a major role for myeloid leukocytes in the immunopathogenesis of PsA. A large controlled study is warranted to fully evaluate the efficacy of Adacolumn GMA in patients with PsA.

DOI： 10.1111/1346-8138.13975

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Psoriasis is a multifactorial inflammatory disorder, in which the inflammation affects not only the skin but also the other internal organs, and can induce cardiovascular and cerebrovascular involvements. However, few predictive factors of cardiovascular diseases have been clarified in patients with psoriasis. This study was performed to verify whether diagonal earlobe creases (ELC) can reflect the hidden comorbidities in Japanese psoriatic patients. Prevalence and subtypes of ELC were analyzed in patients with psoriatic and with non-psoriatic skin diseases, and the correlation with coronary artery calcification (CAC) or fatty liver (FL) detected by computed tomography. Prevalence of CAC was approximately twice higher than data of a Japanese resident-based study previously reported. Generally, prevalence of ELC in a psoriatic group and mean age of psoriatic groups accompanied by ELC were higher and younger than those of a non-psoriatic skin disease group, respectively. Statistically significant differences were detected in the mean age of total or male subjects accompanied by bilateral ELC with complete and incomplete length. Bilateralism of ELC was closely correlated with prevalence of CAC and CAC on multiple branches in psoriatic patients (P = 6.6e-6 and odds ratio [OR] = 14.1, P = 0.00884 and OR = 10.7, respectively), but not with that of FL. On the contrary, body mass index of more than 25 was closely correlated with prevalence of FL, but not that of CAC. Comorbidities of psoriatic patients are frequently unnoticed. ELC, an apparatus-related feature, can be a useful predictive factor for hidden coronary artery involvements in psoriatic patients.

DOI： 10.1111/1346-8138.13895

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71歳女性。慢性腎不全のため血液透析中であった。今回、左下腿に多発する難治性の皮疹を主訴に当科へ紹介となった。受診時、左下腿には2～3cm大の発赤・腫脹を伴う皮下膿瘍が多発してみられた。病理組織像、一般細菌培養の結果、Serratia marcescensによる多発皮下膿瘍と診断された。膿瘍部の切開・排膿を行い、ミノサイクリン塩酸塩の内服を開始したが改善せず、メロペネムの点滴静注を17日間行ったところ、炎症所見および皮膚病変は改善した。以後、時折、膿瘍の再燃がみられるも、ミノサイクリン塩酸塩の投与を予防的に行った。また、色素沈着があり、ロキシスロマイシンに変更し、内服を継続することで、膿瘍の再燃は認められなくなった。

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アトピー性皮膚炎(AD)の主要な根本原因は皮膚バリア機能異常であると考えられるようになってきた。本稿では、表皮で発現するフィラグリン以外の皮膚バリア関連分子について概説した。さらに、それらの遺伝的異常による疾患(ネザートン症候群、炎症型ピーリングスキン病、SAM症候群、魚鱗癬未熟児症候群)とアトピー症状発症の関連性について解説した。皮膚バリア機能に関連する分子は多数あり、その異常によって著しくバリア機能が侵される疾患も知られている。代表例のひとつが辺縁体の形成を司る酵素であるトランスグルタミナーゼ1の変異によって生じる葉状魚鱗癬である。皮膚バリア機能が低下していてもADを発症する場合としない場合があるのはどのような理由によるのかは今後の大きな課題であり、これを明らかにすることでADの発症メカニズムをより正しく理解することができると思われる。

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Anhidrosis/hypohidrosis are conditions presenting various level of sweating dysfunction. Among them, acquired idiopathic generalized anhidrosis (AIGA) presents inadequate decrease or loss of sweating without apparent neurological and dermatological symptoms except cholinergic urticaria. Recently, serum level of carcinoembryonic antigen (CEA), one of the most well-known tumor markers, has been proposed as a clinical marker reflecting activity of AIGA. This study was performed to verify the specificity and independence of serum CEA level from the other serum tumor markers especially related to adenocarcinoma. The expression of various tumor markers in the serum collected from three healthy control subjects, four AIGA cases, and a cholinergic urticaria (CU) case with elevation of serum CEA level and history of hyperthermia was analyzed using a membrane-based antibody array. In all AIGA and CU cases, the intensity of CEA was significantly increased (7.60-15.9 times compared with that of control), relatively well-reflecting the serum CEA level, and the mean intensity of CEA was 11.8 times higher than the control subjects (P = 0.0011). On the other hand, the ratio of carbohydrate antigen (CA) 125 and CA19-9 was 1.93 and 0.23 times compared with the mean intensity of the control subjects, respectively, and there was no statistical significance. Immunohistochemistry on 10 AIGA cases showed increased expression of CEA but not CA19-9 and CA125 in the eccrine sweat glands. In conclusion, the elevation of serum CEA level was independent from the other tumor markers in hypohidrotic condition represented by AIGA.

DOI： 10.1111/1346-8138.13828

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DOI： 10.1684/ejd.2017.2996

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42歳,男性.初診の1ヵ月前から体幹部に紅色皮疹が出現し四肢に拡大した.10年前から浸潤性胸腺腫があり化学療法を施行されていた.病理組織像で表皮上層の個細胞角化とリンパ球の表皮内浸潤がみられ,浸潤する細胞の多くはCD8陽性T細胞であった.胸腺腫の既往と移植片対宿主病(graft versus host disease:GVHD)様の皮膚症状,肝障害からthymoma-associated multiorgan autoimmunity(TAMA)と診断した.合併症の重症筋無力症の治療にγグロブリン大量療法(intravenous immunoglobulin:IVIG)を施行したところ皮膚症状の改善をみたが,その後消化器症状が出現した.ステロイドパルス療法およびステロイドの増量で改善したが,胸腺腫に対する化学療法を開始したところ侵襲性肺アスペルギルス症を発症し永眠された.TAMAは制御性T細胞が減少しGVHD様の症状がみられるが,確立した治療法がなく,免疫抑制治療による感染症で死亡する例が多い.自験例ではIVIGで皮疹の改善がみられ,ある一定の効果が得られたことから,考慮されるべき治療法と考えた.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J01559&link_issn=&doc_id=20170609060007&doc_link_id=10.11477%2Fmf.1412205136&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1412205136&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

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Kallikrein-related peptidasesは,複数の遺伝子から構成される分泌型のセリンプロテアーゼファミリーである.表皮では顆粒層から角層において発現している.これらは,コルネオデスモソームの分解により角層の剥離において重要な役割を果たす.さらにprotease-activated receptor 2を介した炎症反応の誘導,抗菌ペプチドのプロセッシングなど多彩な機能を持つ.表皮におけるkallikrein-related peptidasesの生理的な役割について述べるとともに,Netherton症候群,アトピー性皮膚炎,乾癬など炎症性皮膚疾患で認められるkallikrein-related peptidasesの過剰な活性化とその意義について最近の知見を解説する.(著者抄録)

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Language：Japanese   Publishing type：Research paper (scientific journal)  

眉毛は表情表出に大きな役割を担っており、外傷や悪性腫瘍切除などにより生じた眉毛欠損は患者にとって精神的な負担が大きい。一方、悪性腫瘍の治療では根治性、再発防止のために十分なマージンをとっての切除が必要となるため、広範な眉毛部欠損を避け得ない症例が存在する。今回、我々は眉毛部の有棘細胞癌の切除術によって眉毛が欠損した2症例に対して、耳後部生え際から採皮した頭毛を含んだ全層植皮術により眉毛再建を施行した。再建された眉毛は自然な眉毛に近い毛流や毛の軟らかさをもち、整容的に満足できる結果が得られた。耳後部生え際の頭毛は眉毛と太さ、毛の柔らかさなどの性状が近く、手術痕は髪の中へ隠すことができるため優れた再建方法と考えた。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

DOI： 10.1111/exd.13204

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Atopic dermatitis (AD) is a common inflammatory skin disorder. Chronic AD lesions present hyperkeratosis, indicating a disturbed desquamation process. KLK7 is a serine protease involved in the proteolysis of extracellular corneodesmosome components, including desmocollin 1 and corneodesmosin, which leads to desquamation. KLK7 is secreted by lamellar granules and upregulated in AD lesional skin. However, despite increased KLK7 protein levels, immunostaining and electron microscopy indicated numerous corneodesmosomes remaining in the uppermost layer of the stratum corneum from AD lesions. We aimed to clarify the discrepancy between KLK7 overexpression and retention of corneodesmosomes on AD corneocytes. Western blot analysis indicated abnormal corneodesmosin degradation patterns in stratum corneum from AD lesions. The KLK activity of tape-stripped corneocytes from AD lesions was not significantly elevated in in situ zymography, which was our new attempt to detect the protease activity more precisely than conventional assays. This ineffective KLK activation was associated with impaired KLK7 secretion from lamellar granules and increased expression of LEKTI in AD. Such imbalances in protease-protease inhibitor interactions could lead to abnormal proteolysis of corneodesmosomes and compact hyperkeratosis. Upregulated expression of LEKTI might be a compensatory mechanism to prevent further barrier dysfunction in AD.

DOI： 10.1016/j.jid.2016.10.015

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57歳女。右膝の皮膚腫瘍を主訴とした。数ヵ月前より右膝に鈍痛と軽度のそう痒を伴う腫瘤を自覚し、再診時には中央に黒色斑を伴いドーム状に隆起する赤褐色腫瘤(11mm大)を認めた。ダーモスコピー所見ではspoke wheel areaやblue-gray ovoid globules様の構造が観察され、皮膚生検では基底細胞癌(BCC)を否定できなかったため、全摘出術を行った。病理組織学的所見では上皮成分の下床の真皮では紡錘型細胞と線維成分が放射状に増生しており、皮膚線維腫(DF)の所見であった。また、病巣直上で表皮と連続して網状に増生する基底細胞様細胞の細胞質内にCK-20陽性のMerkel細胞が散在しており、病理組織所見と免疫染色所見よりDF上に生じたbasaloid epidermal proliferationと診断した。切除後1年現在、再発はない。

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Language：Japanese   Publishing type：Research paper (scientific journal)  

デスモソームやコルネオデスモソームの構成成分や、その分解過程を調節する分子の遺伝的異常が角化異常症の原因となる。症状は多彩で、加圧部に顕著な掌蹠角化症、皮膚バリア機能の低下によるIgE高値をともなう魚鱗癬症候群、心筋症を伴う角化異常症、予後不良の表皮水疱症、毛髪異常などの様々な組み合わせがみられる。また軽度な異常はアトピー性皮膚炎のリスクファクターの一つであり、一般的な皮膚疾患の発症要因にデスモソーム異常がからんでいることが明らかとなってきた。(著者抄録)

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Language：Japanese   Publishing type：Research paper (scientific journal)  

外来で管理可能な熱傷は、受傷面積が限局性であるものに限られる。このような熱傷の好発部位は四肢遠位部であり、深達度を正確に判断し、機能的障害を残さないことに配慮することが重要である。外用剤、創傷被覆材を適切に使用し、適度な湿潤環境下で治療を行う。瘢痕形成の軽減、上皮化の促進を目的として、II度熱傷においても早期からトラフェルミンの使用が推奨される。限局性の深達性病変では局所麻酔下に植皮術の施行が可能である。(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

BackgroundHypohidrosis/anhidrosis are congenital or acquired sweating impairments. Among them, acquired idiopathic generalized anhidrosis/hypohidrosis (AIGA) is the most common, and characterized by favourable response to systemic corticosteroid, however, no clinical markers for disease severity or activity have been developed.
ObjectiveOur aim was to verify the usefulness of serum carcinoembryonic antigen (CEA) level monitoring as a clinical marker for disease activity of AIGA.
MethodsTen cases of AIGA diagnosed at Asahikawa Medical University, from 1980 to 2014 were included in the study. CEA and/or CEACAM1 expression level was analysed using immunohistochemistry and enzyme-linked immunosorbent assay.
ResultCEA expression was restricted to the apical membrane of glandular cells in eccrine sweat glands in most of the three types of cases we examined [healthy control, patients with atopic dermatitis (AD) or urticaria]. However, CEA expression was detected diffusely and much more intensively in eight of the 10 AIGA cases included in this study. CEACAM1-expression was much more restricted on the apical membrane of glandular cells of both the AIGA cases and the other control subjects. While serum CEA levels increased in all five AIGA cases examined (5.8-43.2 ng/mL), it remained within normal limits in all control subjects: nine healthy individuals; 10 cases of AD; 10 cases of idiopathic urticaria; four cases of normohidrotic cholinergic urticaria (Mann-Whitney's U-test, P &lt; 0.05). The increased serum CEA levels in AIGA decreased in conjunction with improved sweating during methyl prednisolone pulse therapy or repeated bathing.
ConclusionSerum CEA level may serve as a clinical marker for AIGA activity.

DOI： 10.1111/jdv.13390

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Language：Japanese   Publishing type：Research paper (scientific journal)  

63歳男。顔面・体幹の紅色局面を主訴に受診した。治療は当初、尋常性乾癬の診断でステロイドと活性型ビタミンD3の外用を行ったが、皮疹は急激に増悪し、島嶼状の正常皮膚を残して紅皮症化した。両膝には毛孔性角化性丘疹を認め、手掌・足全体に角質増殖と亀裂を認めた。特徴的な臨床所見と生検の結果から毛孔性紅色粃糠疹と診断した。治療は初めNB-UVBによる光線療法を行ったが、無効であった。次にエトレチナートの内服を約1ヵ月間行い、掌蹠の角化性病変・亀裂の改善には有効であったが、紅皮症は持続したため、シクロスポリン150mg分1(食前2.5mg/kg)の投与を開始した。結果、約1週間で皮疹は改善傾向を示し、以後、100～120mg/日の投与を1年3ヵ月間継続したところ、皮疹はほぼ消退した。

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：金原出版(株)  

症例は54歳男性で、背部に径10mm大までの発赤のある皮下硬結を5ヶ所に認めた。明らかな波動は触れず、熱感と強い疼痛を伴っていた。中央の痂皮を除去すると小潰瘍を呈するも、排膿はみられなかった。せつ腫症と診断し、セフトリアキソンナトリウム点滴とミノサイクリン塩酸塩(MINO)内服を開始したが、翌日には発赤・疼痛が増強し、切開すると皮下から少量の排膿を認め、発熱38℃、WBC 14010/μl、CRP 20.02mg/dlと強い炎症反応を示した。創部から細菌培養でメチシリン耐性黄色ブドウ球菌(MRSA)が検出され、抗菌薬をバンコマイシン塩酸塩点滴に変更し、比較的速やかに症状は改善し11日目からMINO内服に変更、40日目にはCRPが陰性化した。易感染性を招く基礎疾患がないせつ腫症であったことからパントン-バレンタイン・ロイコシジン陽性(PVL)毒素の関与を疑い検査したところ、PVL-RPLA陽性で、PVL産生MRSAと判明した。また、6月の右下腿、9月の背部創から検出されたMRSAと薬剤感受性結果が一致しており、PCRで確認したところ同一株と考えられた。

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Language：Japanese   Publishing type：Research paper (scientific journal)  

64歳女。Helicobacter pylori除菌のためランサップ800を7日間内服したが、内服開始11日後に四肢・体幹に強いそう痒を伴う紅斑が出現したため当科紹介となった。初診時、四肢・体幹に爪甲大までの滲出性紅斑が散在し、四肢伸側や大腿部では浮腫性紅斑が融合し、紅色局面を形成していた。DLSTではすべて陰性であったが、薬剤パッチテストの結果から、アモキシシリン水和物による薬疹と診断された。プレドニゾロンおよびエピナスチン塩酸塩、ベポタスチンベシル酸塩の内服を開始し、皮疹は約3週間で略治した。

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Language：Japanese   Publisher：公益社団法人 日本皮膚科学会  

<p>デスモソームやコルネオデスモソームの構成成分や，その分解過程を調節する分子の遺伝的異常が角化異常症の原因となる．症状は多彩で，加圧部に顕著な掌蹠角化症，皮膚バリア機能の低下によるIgE高値をともなう魚鱗癬症候群，心筋症を伴う角化異常症，予後不良の表皮水疱症，毛髪異常などの様々な組み合わせがみられる．また軽度な異常はアトピー性皮膚炎のリスクファクターの一つであり，一般的な皮膚疾患の発症要因にデスモソーム異常がからんでいることが明らかとなってきた．</p>

DOI： 10.14924/dermatol.126.2259

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.1111/exd.12794

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Herpes zoster (HZ), a common vesiculo-erythematous skin disease associated with reactivation of varicella zoster virus in the cranial nerve, dorsal root, and autonomic ganglia, is accompanied by several related symptoms represented by postherpetic neuralgia. Among them, involvement of vesicorectal dysfunction is relatively rare. The vesicorectal symptom can usually be recovered in transient course, but is quite important in terms of impaired quality of life. Male individuals affected with HZ and skin lesions on sacral dermatome have been reported as independent risk factors of zoster-related voiding dysfunction. In this study, urinary symptoms were focused upon and six patients with zoster-related voiding dysfunction at a single faculty of dermatology in Japan from 2009 to 2014 were retrospectively analyzed. All patients showed HZ lesions on the sacral area and the urinary symptom recovered in approximately 2months (14days to 7months). The term of treatment for zoster-associated urinary dysfunction was positively correlated with that for zoster-related pain without significance (r=0.661, P=0.153). Average treatment term for pain relief of sacral HZ accompanied by voiding dysfunction (91.3 +/- 76.44days) was significantly longer than that of sacral HZ without urinary symptom (18.9 +/- 20.42days) (P=0.032). These results suggested that zoster-related voiding dysfunction would mainly be involved in sacral HZ and closely associated with severity of zoster-related pain. Dermatologists should be aware that severe zoster-related pain accompanied by sacral HZ, which is related to prolonged treatment of pain relief, can be a predictive factor of voiding dysfunction.

DOI： 10.1111/1346-8138.12957

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

S100-negative, CD1a-positive histiocytosis is a rare histiocytic disorder characterized by proliferation of histiocytic cells possessing a phenotype of epidermal Langerhans cells except for the lack of S100 expression and Birbeck granules. We report the case of a Japanese man suffering from S100-negative, CD1a-positive histiocytosis. The patient showed numerous smooth erythematous 5-10-mm papules/nodules on most of his body. The key histopathological feature was the presence of dermal infiltrates of non-epidermotropic S100-negative CD1a-positive mononuclear cells. No systemic involvement was detected. Initially bath-psoralen plus ultraviolet A therapy was effective, but the lesions became recalcitrant to this treatment. Methylprednisolone pulse therapy followed by low-dose methotrexate (up to 30mg/week) in combination with prednisolone (15mg/day) effectively controlled the skin lesions.

DOI： 10.1111/1346-8138.12944

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Hypohidrosis and anhidrosis are congenital or acquired conditions which are characterized by inadequate sweating. Acquired idiopathic generalized hypohidrosis/anhidrosis (AIGA) includes idiopathic pure sudomotor failure (IPSF), which has the following distinct features: sudden onset in youth, increased serum immunoglobulin E and responds favorably to systemic corticosteroid. No clinical markers reflecting the disease severity or activity have been established. Here, we report a case of AIGA in a Japanese patient successfully treated with repeated methylprednisolone pulse therapy. In this case, serum carcinoembryonic antigen (CEA) levels increased up to 19.8ng/mL along with aberrant CEA immunoreactivity of eccrine sweat glands. Interestingly, the serum CEA level normalized as sweating improved with repeated methylprednisolone pulse therapy. Therefore, serum CEA level may serve as a useful clinical marker of hypohidrosis or anhidrosis.

DOI： 10.1111/1346-8138.12926

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IMPACT JOURNALS LLC  

Podoplanin (PDPN) is a unique transmembrane receptor that promotes tumor cell motility. Indeed, PDPN may serve as a chemotherapeutic target for primary and metastatic cancer cells, particularly oral squamous cell carcinoma (OSCC) cells that cause most oral cancers. Here, we studied how a monoclonal antibody (NZ-1) and lectin (MASL) that target PDPN affect human OSCC cell motility and viability. Both reagents inhibited the migration of PDPN expressing OSCC cells at nanomolar concentrations before inhibiting cell viability at micromolar concentrations. In addition, both reagents induced mitochondrial membrane permeability transition to kill OSCC cells that express PDPN by caspase independent nonapoptotic necrosis. Furthermore, MASL displayed a surprisingly robust ability to target PDPN on OSCC cells within minutes of exposure, and significantly inhibited human OSCC dissemination in zebrafish embryos. Moreover, we report that human OSCC cells formed tumors that expressed PDPN in mice, and induced PDPN expression in infiltrating host murine cancer associated fibroblasts. Taken together, these data suggest that antibodies and lectins may be utilized to combat OSCC and other cancers that express PDPN.

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Language：Japanese   Publisher：The Japanese Skin Cancer Society  

DOI： 10.5227/skincancer.30.140

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Other Link： http://search.jamas.or.jp/link/ui/2016167835

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Psoriasis is a chronic inflammatory skin disease, which may be associated with metabolic syndrome accompanied by cardio- and cerebrovascular diseases. We investigated the relation between serum C-reactive protein (CRP) and cardio- and cerebrovascular diseases in Japanese psoriasis vulgaris patients. Ninety-seven psoriasis vulgaris patients and 79 healthy controls were assessed for serum CRP levels by immunoturbidimetry. The data were analyzed in terms of Psoriasis Area and Severity Index (PASI) scores, and comorbidity of cardio- and cerebrovascular disease and metabolic syndrome. Serum CRP levels in psoriasis vulgaris patients were significantly higher than those of healthy controls. There was no significant difference between male and female CRP levels in either psoriasis or healthy controls. No correlation was detected between PASI scores and serum CRP levels, either. Psoriasis with cardio- and cerebrovascular disease showed significantly higher CRP levels compared with those without the diseases. Furthermore, psoriasis with metabolic syndrome showed significantly higher serum CRP levels than those without the metabolic syndrome. In conclusion, serum CRP level is increased in psoriasis, and may be a useful marker for the prediction of the future risk of cardio- and cerebrovascular disease.

DOI： 10.1111/1346-8138.12632

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Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease, which is characterized by recurrent and paroxysmal fever, peritonitis, arthritis, myalgia, and skin rashes. Although various skin lesions such as erysipelas-like erythema, urticaria, nonspecific purpura, and subcutaneous nodules have been described, cutaneous vasculitis is rare. We report a Japanese case of sporadic FMF accompanied by cutaneous arteritis at the time of febrile attacks of FMF. Gene analysis revealed M694I mutation in a single allele of the MEFV gene, and oral colchicine successfully controlled both periodic fever and subcutaneous nodules of arteritis. Cutaneous necrotizing vasculitis repeatedly emerging with febrile attacks should be included among the skin manifestations of FMF.

DOI： 10.1111/1346-8138.12588

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Although mental health is hampered in various skin disorders, few studies regarding anxiety in psoriasis patients are available, and specifically, no evaluation exists between mental health and psoriasis severity or the patients' quality of life. To examine the relation between mental health, psoriasis severity and patient's quality of life, 119 psoriasis vulgaris patients were assessed for anxiety using the General Health Questionnaire (GHQ)-30. Psoriasis area and severity index (PASI) and Dermatological Life Quality Index (DLQI) scores were also measured. The average total GHQ-30 score was significantly decreased from 4.41 to 2.11 (52.2% decrease) in biologics-treated patients. That of patients treated with other systemic agents decreased from 4.36 to 3.32 (23.9% decrease) and that of those treated with topical agents from 4.21 to 3.48 (17.3% decrease). In the biologics-treated group five of the six categories of GHQ-30, i.e. general illness, somatic symptoms, sleep disturbance, social dysfunction, and anxiety and dysphoria, were significantly decreased after the treatment. In contrast, in the other systemic treatment and topical treatment groups, three of the six categories, general illness, somatic symptoms, and sleep disturbance were significantly decreased. There was a significant correlation between GHQ-30 and DLQI, but not with PASI. The psoriasis patients show impaired mental health and among various treatment modalities biologics are superior to other systemic or topical treatments for improving the defective mental state.

DOI： 10.1111/1346-8138.12544

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm characterized by clonal proliferation of Langerhans cells in multi-organ systems including skin, bone, pituitary gland, liver and spleen. Skin-limited involvement of LCH usually indicates an indolent clinical course; however, in rare cases, LCH is accompanied by other myeloproliferative disorders, which may determine the prognosis. An 82-year old Japanese man presented with numerous asymptomatic facial papules clinically simulating rhinophyma. Although findings of histopathology and general examination including bone marrow biopsy led to the diagnosis of cutaneous LCH, he died from chronic myelomonocytic leukemia, which emerged 10months after the initial diagnosis of LCH. The previously reported cases of LCH concomitant with other hematological disorders are also summarized and described compared with the present case.

DOI： 10.1111/1346-8138.12417

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Peeling skin syndrome (PSS) type B is a rare recessive genodermatosis characterized by lifelong widespread, reddish peeling of the skin with pruritus. The disease is caused by small-scale mutations in the Corneodesmosin gene (CDSN) leading to premature termination codons. We report for the first time a Japanese case resulting from complete deletion of CDSN. Corneodesmosin was undetectable in the epidermis, and CDSN was unamplifiable by PCR. QMPSF analysis demonstrated deletion of CDSN exons inherited from each parent. Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49-72kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33. This observation widens the spectrum of molecular defects underlying PSS type B and shows that loss of these five genes from the PSORS1 region does not result in an additional cutaneous phenotype.

DOI： 10.1111/exd.12292

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Background: Although physical properties of neonatal-infantile stratum corneum (SC) change drastically after birth, precise developmental alterations of specific sites have not been fully elucidated.
Objective: To determine the longitudinal alterations of neonatal-infantile SC functions and components of upper thighs and diaper-covered buttocks during the first year of life. The data were compared with those of adults.
Methods: Nineteen full-term neonates and their mothers were subjected to the measurements. Skin hydration, water sorption/retention capacity, TEWL were measured. Superficial SC analyses for NMF, ester binding sebum, and free fatty acids were performed by ATR-FTIR spectrometer. Total amount of ceramides (CERs) and CER subclasses were analyzed by NPLC-ESI-MS.
Results: SC hydration of neonatal thighs was lower than that of their mothers, which rapidly increased during the 1st month. Skin hydration of neonatal buttocks was similar to that of their mothers. This also rapidly increased during the 1st month. The neonatal TEWL was less than those of their mothers indicating more efficient barrier function at both sites, which significantly increased during the 1st year development. This was mostly correlated decreased in the omega-hydroxy fatty acid-esterified CERs. Superficial ester-binding sebum content of neonates was similar to that of their mothers, which significantly decreased during the measurement; the decrease was more marked on buttocks. Neither NMF nor FFA of the superficial SC showed significant alteration during the 1-year development.
Conclusion: Our results indicate that physical functions and components of neonatal-infantile SC show considerable alterations between diaper-covered buttocks and upper thighs during the 1st year development. (C) 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.jdermsci.2013.08.015

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DOI： 10.1016/j.jdermsci.2013.05.004

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Background: The analysis of prognostic factors in Japanese cases of cutaneous T-cell lymphoma (CTCL) is scarce. Clusterin is a ubiquitous 80. kDa heterodimeric glycoprotein expressed on tumor cells of systemic and primary cutaneous anaplastic large cell lymphoma. The expression of clusterin in mycosis fungoides (MF) and Sézary syndrome (SS) has only been sporadically reported in a small number of cases. Objective: To determine the long-term prognosis of Japanese patients with MF and SS, to identify clinical and pathological factors predictive of survival, and to evaluate the prognostic significance of the International Society for Cutaneous Lymphomas (ISCL) revised staging system (2007). Methods: We performed a retrospective cohort study of 105 Japanese patients with MF and SS managed at the Department of Dermatology Asahikawa Medical University from 1976 to 2011. Formalin-fixed, paraffin-embedded sections of MF and SS were immunostained for clusterin, CD30, and Ki-67. Results: No statistically significant difference in survival was found between stages IA-IIA and IIIA patients. The significant prognostic factors in the univariate analysis were higher age, TNMB classification, clinical staging, performance status, increased serum LDH level, dermal Ki-67-positive cells, and clusterin expression. In the multivariate analysis, T classification, extracutaneous disease, increased serum LDH level, clusterin expression, and performance status were the significant independent prognostic factors. Conclusion: Japanese stage IIIA MF/SS patients contain a subpopulation with a favorable prognosis. The most significant prognostic factor for survival of MF and SS was the presence of extracutaneous disease. Clusterin expression was shown to be a novel unfavorable prognostic factor. © 2013 Japanese Society for Investigative Dermatology.

DOI： 10.1016/j.jdermsci.2013.04.020

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Personality and emotional factors are supposed to influence the course of skin diseases, such as psoriasis and atopic dermatitis. Few reports exist, however, showing distinct personality traits among patients with psoriasis, atopic dermatitis patients and healthy controls. The aim of the present study was to examine personality differences among psoriasis patients, atopic dermatitis patients and healthy controls in Japan. A total number of 51 psoriasis patients, 97 atopic dermatitis patients and 48 healthy individuals were enrolled in the study. Questionnaires of YatabeGuilford Personality Inventory were administered individually. These groups were evaluated by 12 dimensions of temperaments. According to the dimension scores, personality was defined as five groups. Atopic dermatitis patients showed significantly higher scores regarding temperaments of depression, feelings of inferiority, nervousness and lack of objectivity than psoriasis patients. Regarding a temperament of cyclic tendency and lack of cooperativeness, female atopic dermatitis patients showed significantly higher scores than female psoriasis patients. Regarding general activity, female atopic dermatitis patients showed significantly lower scores than those of female psoriasis patients. No significant difference in scores of temperaments of lack of agreeableness, rhathymia, thinking extraversion, ascendance and social extraversion were detected among psoriasis patients, atopic dermatitis patients and healthy controls. The personalities of male psoriasis patients were significantly different from those of atopic dermatitis patients and healthy controls. Female psoriasis patients showed a significantly different personality profile from that of atopic dermatitis patients, but not from healthy controls. Japanese psoriasis and atopic dermatitis patients show distinct personality profiles suggesting that specific a psychosomatic approach may be required during the treatment.

DOI： 10.1111/1346-8138.12087

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The transmembrane glycoprotein podoplanin (PDPN) plays an important role in cell motility. However, mechanisms regulating PDPN expression have not been fully elucidated. Here, we investigated the effect of intercellular contact on signal transduction pathways and PDPN expression in human squamous cell carcinoma (SCC) cell lines. PDPN expression was higher in confluent SCC cells than sparse cultures. This PDPN induction leads to increased SCC cell migration and invasion, which was reversed by shRNA PDPN knockdown. This cell density dependent PDPN induction required activation of epidermal growth factor receptor (EGFR) and its effector, signal transducer and activator of transcription 3 (STAT3). These observations also extend to human clinical specimens, in which PDPN expression localized to confluent basal cell layers at the invading front of in situ SCC lesions. Taken together, these results illuminate an EGFR-STAT3-PDPN pathway as a potential pharmacological opportunity to target invasive SCC cells. © 2012 Elsevier Inc.

DOI： 10.1016/j.cellsig.2012.12.004

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Psoriasis is associated with obesity accompanied by insulin resistance. A recent study disclosed increased plasma resistin and decreased plasma omentin levels in obesity. Few studies of plasma levels of resistin and omentin are available in psoriasis. We analyzed plasma levels of resistin and omentin in psoriasis and compared them with those of healthy controls. Evaluation of plasma levels of resistin and omentin was performed by enzyme-linked immunosorbent assay (ELISA) for 62 psoriasis patients and 58 healthy controls. The severity of psoriasis was evaluated by psoriasis area and severity index (PASI) score. Plasma levels of resistin were significantly increased in psoriasis as compared with those of healthy controls. In contrast, plasma levels of omentin were significantly decreased in psoriasis patients. Plasma levels of resistin and omentin were positively and negatively correlated with PASI scores, respectively. After the treatment of psoriasis, resistin levels were decreased and omentin levels were increased, respectively, compared with those of pretreated. Plasma levels of resistin and omentin might be useful for evaluating the disease activity of psoriasis.

DOI： 10.1007/s00403-012-1310-9

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DOI： 10.1111/j.1346-8138.2011.01487.x

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DOI： 10.1111/j.1346-8138.2011.01482.x

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DOI： 10.1111/j.1346-8138.2011.01359.x

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DOI： 10.1111/j.1346-8138.2011.01345.x

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DOI： 10.1111/j.1346-8138.2011.01331.x

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Defects in epidermal barrier function and/or vesicular transport underlie severe skin diseases including ichthyosis and atopic dermatitis. Tight junctions (TJs) form a single layered network in simple epithelia. TJs are important for both barrier functions and vesicular transport. Epidermis is stratified epithelia and lamellar granules (LGs) are secreted from the stratum granulosum (SG) in a sequential manner. Previously, continuous TJs and paracellular permeability barriers were found in the second layer (SG2) of SG in mice, but their fate and correlation with LG secretion have been poorly understood. We studied epidermal TJ-related structures in humans and in mice and found occludin/ZO-1 immunoreactive multilayered networks spanning the first layer of SG (SG1) and SG2. Paracellular penetration tracer passed through some TJs in SG2, but not in SG1. LG secretion into the paracellular tracer positive spaces started below the level of TJs of SG1. Our study suggests that LG-secretion starts before the establishment of TJ barrier in the mammalian epidermis.

DOI： 10.1371/journal.pone.0031641

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Background: Podoplanin (PDPN)/T1 alpha/aggrus/PA2.26 antigen, a transmembranous glycoprotein, is a well-known lymphatic endothelial marker. Recent evidence indicates that PDPN is also expressed in keratinocytes especially of sebaceous glands.
Objective: To verify expression-pattern and the regulatory mechanism of PDPN in human epidermal keratinocytes.
Methods: PDPN-expression pattern was analyzed in normal and psoriatic epidermis by immunostaining. The regulatory mechanism of PDPN-expression of keratinocytes by cytokines was analyzed using specific inhibitors, siRNA, and adenoviral shRNA of signaling pathways.
Results: In normal skin. PDPN was expressed on the basal cell layer of sebaceous glands and on the outer root sheath of hair follicles. While no expression was detected in the normal interfollicular epidermis, PDPN was detected in the basal cell layer of wound and hyperproliferative psoriatic epidermis, where the granular layer is lacking. TGF-beta 1 and IFN-gamma independently upregulated PDPN-expression of keratinocytes via TGF-beta receptor-Smad pathway and JAK-STAT pathway, respectively. IL-6 and IL-22 also stimulated PDPN-expression of keratinocytes accompanied by STAT-3 phosphorylation. siRNA of STAT-1, inhibitors of STAT-3 signaling, AG490, STAT-3 inhibitor VI, and si/shRNA of STAT-3 inhibited the PDPN-expression of keratinocytes induced by IFN-gamma, IL-6 and IL-22 but not by TGF-beta 1.
Conclusion: These results indicate that TGF-beta 1, IFN-gamma, IL-6, and IL-22 induce PDPN-expression of keratinocytes, which might be significantly involved in the wound healing process as well as in the pathomechanism of hyperproliferative psoriatic epidermis. (C) 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.jdermsci.2011.11.011

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Background. Distinguishing keratoacanthoma (KA) from well-differentiated squamous cell carcinoma (SCC) is sometimes difficult. Recent evidence indicates that the nuclear factor kappa B p50 subunit (p50) and cortactin might be useful to distinguish between these two conditions.
Aim. To verify whether p50 and cortactin are useful differentiation markers to distinguish between subungual KA and well-differentiated SCC.
Methods. Immunohistochemistry using p50, cortactin and Ki-67 was performed on 20 patients with KA and 20 patients with facial well-differentiated SC. Ki-67 staining was also evaluated and scored.
Results. Both p50 and cortactin had higher levels of expression in KA than in SCC. Both were localized to the basal-cell layer of KA, whereas they were scattered without polarity throughout the SCC lesions. Although the Ki-67 index was not significantly different between KA and SCC, the staining pattern also showed loss of polarity in SCC.
Conclusion. p50 and cortactin might be useful makers to distinguish between KA and well-differentiated SCC.

DOI： 10.1111/j.1365-2230.2011.04118.x

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DOI： 10.1111/j.1346-8138.2010.01159.x

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Adult orbital xanthogranulomatous disease (AOXGD) is a rare granulomatous disorder, which has four subtypes: adult-onset xanthogranuloma (AOX), adult-onset asthma with periocular xanthogranuloma, necrobiotic xanthogranuloma and Erdheim-Chester disease. We report a 42-year-old woman who presented with yellowish nonulcerative nodules on her eyelids. On histopathological examination of a nodule, mild degeneration of collagen fibres was seen, with surrounding infiltration of numerous foam cells and Touton giant cells in the deep dermis. Lymphoid follicles were seen in the reticular dermis. There was no apparent necrobiosis of collagen fibres. There were no clinical symptoms of asthma and no laboratory signs of paraproteinaemia during a follow-up of more than 5 years. We diagnosed this case as AOX, but further long-term follow-up would be required for the differentiation from the other AOXGDs. Dermatologists should be aware of these rare granulomatous disease conditions with ocular/orbital location, because they may cause ophthalmological complications.

DOI： 10.1111/j.1365-2230.2011.04041.x

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P&gt;Pemphigus vulgaris (PV) is an autoimmune bullous disease characterized by autoantibodies against desmogleins. We report a case of recalcitrant PV, which progressed from the mucosal to the mucocutaneous type, with a corresponding increase in anti-desmoglein (Dsg)1 and decrease in anti-Dsg3 antibody titres. Thus, the clinical features seemed to correlate with the ratio of anti-Dsg1 and 3. The patient also had anti-Dsg4 antibodies, which might be related to the nonscarring diffuse hair loss and marked facial involvement she also had. The patient did not respond to treatment with systemic steroid, ciclosporin, azathioprine, cyclophosphamide or double filtration plasmapheresis, and eventually died from fulminant thrombotic thrombocytopenic purpura of unknown cause.

DOI： 10.1111/j.1365-2230.2010.03920.x

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Primary cutaneous gamma delta-T-cell lymphoma (CGD-TCL) is a rare entity of cutaneous T-cell lymphomas (CTCL) and is characterized by tumoral growth of mature gamma delta-T-cell expressing cytotoxic molecules. The prognosis of CGD-TCL is generally worse than other CTCL. However, relatively indolent patch/plaque lesions have been described suggesting the heterogeneous nature of this entity. Here, we present a case of CGD-TCL with various skin manifestations, such as erythematous plaques/tumors and subcutaneous panniculitis-like lesions. During the follow up, testicular involvement was detected, which was surgically removed. Histopathology showed mixed features from epidermotropism, dermal infiltration and subcutaneous panniculitis-like lesions depending on the clinical manifestations. The tumor cells were positive for CD3 and revealed cytotoxic markers, TIA-1 and perforin, but not for CD4, CD8, CD20, CD56, TCR beta F1 or EBER. Topical glucocorticoid ointment, narrowband ultraviolet B (NB-UVB) irradiation and low-dose methotrexate (MTX) were effective to control these skin lesions. No visceral involvement was detected thereafter. While CGD-TCL is usually associated with poor prognosis, it seems to be composed of various clinical manifestations, and NB-UVB and low-dose MTX could be a choice for indolent patch/plaque and possibly nodular lesions, especially for the aged.

DOI： 10.1111/j.1346-8138.2010.00998.x

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DOI： 10.1111/j.1346-8138.2010.00965.x

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To maintain stratum corneum integrity while simultaneously desquamating at a steady rate, degradation of corneodesmosomes must proceed in a controlled manner. It is unknown why corneodesmosomes are present only at the cell periphery in the upper stratum corneum. To explore this, we studied distributions of three major corneodesmosomal components, corneodesmosin, desmoglein 1 and desmocollin 1 in normal adult human epidermis. Immunofluorescent microscopy studies of skin surface corneocytes detected all three components only at the cell edges. Immunoelectron microscopy revealed selective loss of these components at the central areas starting from the deep cornified layers. We hypothesized that tight junctions (TJs) formed in the superficial granular layer may prevent protease access by functioning as a barrier between the peripheral and the central intercellular spaces in the stratum corneum. Ultrastructural examination demonstrated TJs up to the junctions between the seventh and the eighth deepest cornified layers. Immunoelectron microscopy also detected clusters of occludin and claudin-1 immunolabels at the cell periphery, and kallikrein 7 immunolabels outside of TJs in the lower cornified layers. With colloidal lanthanum nitrate perfusion assay of stripped stratum corneum, the tracer was excluded from TJ domains. Taken together, we propose that TJs inhibit access of proteases to the peripheral corneodesmosomes forming the structural basis for the basket-weave-like appearance of the stratum corneum.

DOI： 10.1111/j.1600-0625.2010.01170.x

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P&gt;Background.
Subungual keratoacanthoma (SUKA) is a rare cutaneous tumour with several features distinct from ordinary KA. SUKA may not show spontaneous regression and sometimes grows progressively, resulting in phalangeal bone destruction. This makes its distinction from digital squamous cell carcinoma (SCC) difficult.
Aim.
To investigate differences in molecular expression between SUKA and digital SCC.
Methods.
In addition to immunohistochemical analysis of Ki-67, one of the markers differentiating KA from SCC, we investigated the copy numbers of various oncogenes by multiplex ligation-dependent probe amplification (MLPA) using two cases of SUKA and three cases of periungual SCC.
Results.
Ki-67 was moderately or strongly positive in SCC but negative in SUKA. The MLPA analysis showed that the nuclear factor (NF)kappa B1 and cortactin (CTTN; formerly known as EMS1) genes are amplified in SUKA but not in digital SCC. This increase in NF kappa B1 was confirmed by immunohistochemical analysis.
Conclusion.
NF kappa B1 could be a novel marker to differentiate between SUKA and SCC. Although this study was performed on limited numbers of patients with SUKA, MLPA analysis could be applied to differentiate other benign tumours from their malignant counterparts.

DOI： 10.1111/j.1365-2230.2010.03841.x

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A 64-year-old Japanese woman had a lightly brown-blackish pigmented macule (1.2 cm in diameter) on the left sole of her foot. She received surgical excision following a diagnosis of acral lentiginous melanoma (ALM), which was confirmed histopathologically. One month after the operation, a second melanoma lesion was noticed adjacent to the grafted site. Histopathologically, the two lesions had no continuity, but HMB-45 and cyclin D1 double-positive cells were detected not only on aggregates of atypical melanocytes but also on single cells near the cutting edge of the first lesion. The unique occurrence of a sequential lesion of a primary melanoma might be caused by stimulated subclinical field cells during the wound healing process following the initial operation. This case warrants further investigation to establish the appropriate surgical margin of ALM lesions. © 2010 S. Karger AG, Basel.

DOI： 10.1159/000323467

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DOI： 10.1016/j.jdermsci.2010.06.004

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Tumor necrosis factor-alpha (TNF-alpha) antagonists are effective for inflammatory diseases, such as Crohn&apos;s disease, rheumatoid arthritis (RA) and psoriasis. Although TNF-alpha antagonists are also useful for sarcoidosis, paradoxical occurrence of sarcoidosis or sarcoidal reaction may be observed. We report a Crohn&apos;s disease patient, who developed sarcoidosis during infliximab therapy. A 35-year-old man had been receiving infliximab for 7 months for Crohn&apos;s disease. He developed cough and fever, accompanied by an infiltrated erythematous plaque on his right knee. The chest radiography, skin biopsy and laboratory findings were all consistent with sarcoidosis.

DOI： 10.1111/j.1346-8138.2010.00861.x

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DOI： 10.1016/j.jdermsci.2009.11.002

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A 37-year-old Japanese man presented with confluent erythemas and progressive erosive lesions on the almost entire body including the oral mucosa and genitalia. This was accompanied with prominent facial pustules. Although a lymphocyte stimulation test was positive only for acetaminophen, he took other agents including carbamazepine for his depression. He was diagnosed as having toxic epidermal necrolysis with prominent facial pustules and treated by methylprednisolone pulse therapy, which resulted in a good response. During the course, human herpesvirus 7 (HHV-7) DNA was detected in his peripheral blood. The HHV-7 reactivation might be related to facial pustulosis, which is occasionally observed in drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms. Copyright (C) 2010 S. Karger AG, Basel

DOI： 10.1159/000319756

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DOI： 10.1111/j.1346-8138.2009.00687.x

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DOI： 10.1111/j.1346-8138.2009.00680.x

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DOI： 10.1016/j.jdermsci.2009.04.004

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Focal adhesion kinase (FAK) is a ubiquitously expressed non-receptor tyrosine kinase involved in cancer progression and metastasis that is found overexpressed in a large number of tumors such as breast, colon, prostate, melanoma, head and neck, lung and ovary. Thus, FAK could be an attractive tumor associated antigen (TAA) for developing immunotherapy against a broad type of malignancies. In this study, we determined whether predicted T cell epitopes from FAK would be able to induce anti-tumor immune cellular responses.
To validate FAK as a TAA recognized by CD4 helper T lymphocytes (HTL), we have combined the use of predictive peptide/MHC class II binding algorithms with in vitro vaccination of CD4 T lymphocytes from healthy individuals and melanoma patients.
Two synthetic peptides, FAK(143-157) and FAK(1,000-1,014), induced HTL responses that directly recognized FAK-expressing tumor cells and autologous dendritic cells pulsed with FAK-expressing tumor cell lysates in an HLA class II-restricted manner. Moreover, since the FAK peptides were recognized by melanoma patient&apos;s CD4 T cells, this is indicative that T cell precursors reactive with FAK already exist in peripheral blood of these patients.
Our results provide evidence that FAK functions as a TAA and describe peptide epitopes that may be used for designing T cell-based immunotherapy for FAK-expressing cancers, which could be used in combination with newly developed FAK inhibitors.

DOI： 10.1007/s00262-008-0608-0

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DOI： 10.1159/000182262

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Apart from for cutaneous deep fungal or mycobacterial infections, thermotherapy has been used for various malignant tumors. We report a case of primary cutaneous anaplastic large cell lymphoma, which responded quite well to topical thermotherapy using chemical pocket hand warmers. The treatment resulted in an immediate tumor regression without recurrence. This method is simple and might be a useful tool against solitary cutaneous lymphoma, especially of elderly patients with poor performance status or with various systemic complications.

DOI： 10.1111/j.1346-8138.2008.00560.x

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DOI： 10.1016/j.jdermsci.2008.03.006

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DOI： 10.1016/j.jdermsci.2007.10.009

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The authors have designed high-throughput screens to identify compounds that promote or inhibit terminal differentiation of primary human epidermal keratinocytes. Eleven known inhibitors of signaling pathways and approximately 4000 compounds of diverse structure were screened using an In-Cell Western system based on immunofluorescent staining of the terminal differentiation marker, involucrin. Staurosporine, a nonspecific protein kinase C inhibitor, and H89, a protein kinase A inhibitor, promoted expression of involucrin. Conversely, U0126, a MEK inhibitor, and SAHA or SBHA, 2 histone deacetylase inhibitors, reduced the expression of involucrin during calcium-induced stratification. In addition, the authors found 1 novel compound that induced keratinocyte differentiation and 2 novel compounds that were inhibitory to calcium-induced differentiation. The differentiation-inducing compound also inhibited growth of a human squamous cell carcinoma line by stimulating both differentiation and apoptosis. Because the compound affected the tumor cells at a lower concentration than primary keratinocytes, it may have potential as an antitumor therapy.

DOI： 10.1177/1087057106292556

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We present evidence that LIM kinases can control cell adhesion and compaction in human epidermis. LIMK2 is expressed in the epidermal basal layer and signals downstream of the GTPase Rac1 to promote extracellular matrix adhesion and inhibit terminal differentiation. Conversely, LIMK1 is expressed in the upper granular layers and phosphorylates and inhibits cofilin. Expression of LIMK1 is lost in psoriatic lesions and other skin disorders characterized by lack of cell compaction in the differentiating cell layers. In psoriatic lesions down-regulation of LIMK1 correlates with up-regulation of Myc. Expression of constitutively active cofilin or Myc in reconstituted human epidermis blocks cell compaction. Overexpression of LIMK1 leads to down-regulation of Myc, whereas inhibition of Rho kinase, an upstream activator of LIMK1, stimulates Myc expression. Inhibition of Myc by LIMK1 is via inhibition of Stat3 phosphorylation, because constitutively active cofilin or inhibition of Rho kinase results in Stat3 phosphorylation and increased Myc levels, whereas dominant negative Stat3 abolishes the effect. In conclusion, we have uncovered a novel antagonistic relationship between the LIMK1/phosphocofilin and Myc/Stat3 pathways in the differentiating layers of human epidermis and propose that down-regulation of LIMK1 contributes to one of the pathological features of psoriatic epidermal lesions.

DOI： 10.1091/mbc.E05-12-1173

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29歳女.2ヵ月前,パスタを摂取した後にバドミントンをしたところ四肢に膨疹が出現,全身に拡大し,意識消失した.近医に入院し,補液と安静のみで翌日退院した.今回,市販のパンを摂取した後に軽いジョギングをしたところ再び四肢に膨疹が出現した.安静により膨疹は消失したが,翌日近医を受診し,病歴から小麦による食物依存性運動誘発性アナフィラキシー(FDEIA)を疑われ紹介入院した.膨疹誘発試験としてアスピリン500mg内服1時間後にパンを摂取させ,さらに1時間後に運動負荷を加えた.結果,顔面と体幹に膨疹が誘発され,小麦によるFDEIAと診断した.食物摂取後2時間は運動しないよう指導するとともにベシル酸ベポタスチン(タリオン)20mg/日の定期内服を行い,膨疹は出現しなくなった.膨疹誘発試験では運動負荷を定量化できるトレッドミルを用いることで誘発に必要な運動量を算出し,患者の許容運動量を推定した

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38歳女.ほぼ全身の浮腫性紅斑,発熱,全身倦怠感が出現した.2ヵ月前に躁鬱病のために近医精神科でカルバマゼピンを処方されており,薬剤性肝障害,または伝染性単核症を疑われた.内服薬を中止し,ステロイド内服を開始したが改善しなかった.経過中,ヒトヘルペスウイルス(HHV)-6 DNA陽性化,HHV6/7 IgG抗体価が上昇した.カルバマゼピンに対するパッチテストは陽性であり,臨床経過,およびHHV-6抗体価の上昇から,カルバマゼピンによるHHV-6,およびHHV-7再活性化を伴うdrug-induced hypersensitivity syndromeと診断した.ステロイドは内服開始4ヵ月で中止し,中止後に軽度の蕁麻疹が時々生じるものの,外来での経過観察となっている.HHV-6抗体価の他に,HHV-7抗体価の病態への関与が推測された

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症例1:70歳男.尋常性乾癬と診断され,ステロイド外用薬にて治療されていた.皮疹が増悪し,エトレチナートを内服するも皮疹は改善せず当科入院した.入院後エトレチナートを増量,体幹,四肢にマキサカルシトール軟膏,頭部はフラボン酸モメタゾン液で治療を開始した.しかし,意識障害が出現し,BUN,Cr,血清Caの上昇を認めた.症例2:38歳男.尋常性乾癬との診断で種々の治療を受けていた.薬剤を,エトレチナート,マキサカルシトール軟膏,吉草酸ジフルコルトロンに変更したところ意識障害が出現し,BUN,Cr,血清Caの上昇,尿量減少がみられるようになった.いずれもマキサカルシトール軟膏による高Ca血症および急性腎不全と診断し,マキサカルシトールの使用を中止し,補液療法および利尿剤による治療を開始した.その結果,検査所見は正常化し,意識も正常に回復した

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Intracellular cyclic AMP (cAMP) increased by extracellular stimuli induces various biological effects, such as cell proliferation, differentiation, and migration. Previous reports regarding the effect of cAMP on keratinocyte proliferation are contradictory and indicate that the effect apparently depends on cellular density. Recent studies have revealed that cAMP signaling regulates cell proliferation by modulating mitogen-activated protein kinase (MAPK) activity. The precise mechanism by which cAMP affects keratinocyte proliferation and/or the crosstalk between the cAMP and MAPK signaling pathways, however, remain to be determined. Using normal human keratinocytes (NHK), we investigated the effect of cAMP on keratinocyte proliferation and its molecular mechanism in terms of cellular density. In confluent NHK, cyclic AMP decreased extracellular regulated kinase (ERK) phosphorylation and cell proliferation in a Ras-independent and Rap1-dependent manner. The decreased cell proliferation by cAMP was blocked by the MEK-1 inhibitor, PD98059. In contrast, in subconfluent NHK, cAMP increased ERK phosphorylation and cell proliferation. Western blot analysis revealed that NHK expressed B-Raf and Rap-1. Although both 95 kDa and 62 kDa B-Raf isoforms were expressed in subconfluent NHK, only 62 kDa B-Raf was detected in confluent NHK. Transfection of 95 kDa B-Raf into confluent NHK resulted in a cAMP-dependent increase in ERK phosphorylation and cell proliferation. These findings indicate that differential expression of B-Raf isoforms is critical for cAMP-dependent regulation of NHK proliferation that depends on phosphorylation of ERK.

DOI： 10.1007/s00403-004-0478-z

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Language：English   Publisher：JAPANESE DERMATOLGICAL ASSOC  

The keratinization process in psoriasis is a unique phenomenon. We have proposed an organized system for keratinization in psoriasis based on the recognition of early and late differentiation markers combined with premature cell death. The early differentiation markers, such as involucrin, small proline-rich proteins (SPRR), cystatin A and transglutaminase 1, are more conspicuously expressed in psoriasis, while the late differentiation markers, such as profilaggrin and loricrin, are abolished. Keratinization markers that are not observed in the normal epidermis are also detected; these include SKALP/elafin as well as K6 and K16. With a markedly diminished turnover time, the psoriatic epidermis idly synthesizes differentiation markers that are mostly under the control of the protein kinase GAPI transcriptional control system. Because of the premature cell death, however, the late differentiation markers are not expressed. During the improvement of the lesion and the therefore longer turnover time, the late differentiation markers rapidly catch up to reveal their expression. This explains the rapid appearance of keratohyalin granules (profilaggrin) in the healing lesion of psoriasis. Thus the keratinization process in psoriasis can be explained by the accelerated keratinization combined with premature cell death. The keratinization process in psoriasis is unique, because both accelerated kerb atinization and premature cell death co-exist, resulting in the disappearance of late differentiation markers such as profilaggrin and loricrin. It is interesting to note that the premature cell death is also tinder the control of protein kinase C signaling.

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER-VERLAG  

The active form of vitamin D-3, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), regulates proliferation and differentiation of keratinocytes. Cystatin A, a cysteine proteinase inhibitor, is a cornified cell envelope constituent and a differentiation marker of keratinocytes. In the present study, we examined the effect of 1,25(OH)(2)D-3 on the expression of cystatin A of cultured normal human keratinocytes (NHK). 1,25(OH)(2)D-3 suppressed NHK proliferation in a dose-dependent manner with the maximal effect at 1X10(-7) M. It also stimulated cystatin A promoter activity and its expression with similar dose effects. The increased cystatin A was detected by 24 h and the effect was accompanied by the suppression of ERK activity. Cystatin A promoter activity was not affected by cotransfection of vitamin D-3 receptor or retinoid X receptor. Further analyses disclosed that the 12-o-tetradecanoylphorbol-13-acetate (TPA)-responsive element (TRE), T2 (-272 to -278), in cystatin A promoter is critical for the regulation by 1,25(OH)(2)D-3. Transfection of the dominant-negative form of ERK adenovirus (Ad-dnERK) increased cystatin A promoter activity and its expression, which was markedly augmented by 1,25(OH)(2)D-3 treatment. Transfection of the dominant-active form of Raf-1 (Ad-daRaf-1) or MEK 1 (Ad-daMEK 1) inhibited 1,25(OH)(2)D-3-dependent cystatin A promoter activity and its expression. Consistent with these results, the MEK1 inhibitor, PD98059, further augmented 1,25(OH)(2)D-3-induced cystatin A promoter activity and its expression. The present study demonstrated that the 1,25(OH)(2)D-3-responsive element in the cystatin A gene is identical to the TRE, T2 (-272 to -278), and that the suppression of Raf1/MEK1/ERK1,2 signaling pathway increases cystatin A expression of NHK.

DOI： 10.1007/s00403-003-0396-5

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING LTD  

Axotomy-induced neuronal death occurs in neonatal motoneurons, but not in adult rat. Here we demonstrated that during the course of postnatal development, nerve injury induced down-regulation of the glial cell line-derived neurotrophic factor (GDNF) receptor GFRalpha1 in axotomized hypoglossal motoneurons of rat are gradually converted to the adult up-regulation pattern of response. The compensatory expression of GFRalpha1 specifically in the injured motoneurons of neonates by adenovirus succeeded in rescuing the injured neurons without an application of growth factors. To the contrary, the nuclear antisense RNA for GFRalpha1 expression accelerates the axotomy-induced neuronal death in pups. These findings suggest that the receptor expression response after nerve injury is critical for the determination of injured motoneuron fate.

DOI： 10.1046/j.1471-4159.2002.01043.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The mRNA expression of the microtubule disassembly molecules (SCG10, stathmin, SCLIP and RB3) in response to nerve injury was examined using a rat hypoglossal nerve injury model. After nerve injury prominent increase in mRNA expression of SCG 10, stathmin and RB3 was observed, while only slight increase in SCLIP mRNA was observed in injured motor neurons. The increase in SCG10 and RB3 mRNA expression was quicker than that of stathmin and SCLIP. All the elevated signals decreased gradually to control levels by 4 weeks after nerve injury. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0169-328X(02)00187-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC PHOTOBIOLOGY  

Bcl-2 is a member of the large Bcl-2 family and protects cells from apoptosis. Ultraviolet B (UVB) irradiation induces apoptosis of keratinocytes that is known as "sun-burn cells." Previously we reported that UVB irradiation induces apoptosis accompanied by sequential activation of caspase 8, 3 and 1 in keratinocytes, and that the process is inhibited by various caspase inhibitors. Using bcl-2-expressing adenovirus vector we investigated the effect of Bcl-2 on UVB-induced apoptosis. Adenovirus vector efficiently introduced bcl-2 gene in cultured normal mouse keratinocytes (NMK cells); almost all NMK cells (1 X 10(6)) were transfected at 1 x 10(8) plaque-forming unit (PFU)/mL. Bcl-2-transfected NMK cells were significantly resistant to UVB-induced apoptosis with the suppressive effect dependent on the Bcl-2 expression level. Following UVB irradiation caspase 8, 3 and 9 activities were stimulated in NMK cells, whereas in bcl-2-transfected cells only caspase 8, but not caspase 3 or 9, activity was stimulated. In order to investigate the effect of Bcl-2 in vivo topical application of Ad-bcl-2 on tape-stripped mouse skin was performed. Following the application Bcl-2 was efficiently overexpressed in almost all viable keratinocytes. The expression was transient with the maximal expression of Bcl-2 on the first day following the application of 1 X 10(9) PFU in 200 muL. The introduced Bcl-2 remained at least for 6 days. UVB irradiation (1250 J/m(2)) induced apoptosis within 12 h and the maximal effect was observed at 24 h in control mouse skin. Both bcl-2-transfected and topical caspase 3 inhibitor-treated mice skin were resistant to UVB-induced apoptosis. The suppressive effect of Bcl-2 was more potent than that of caspase 3 inhibitor application. Topical application of empty adenovirus vector alone had no effect on Bcl-2 expression or UVB-induced apoptosis. These results indicate that adenovirus vector is an efficient gene delivery system into keratinocytes and that Bcl-2 is a potent inhibitor of UVB-induced apoptosis both in vitro and in vivo.

DOI： 10.1562/0031-8655(2001)074<0579:IVAIVT>2.0.CO;2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Cystatin A, a cysteine proteinase inhibitor, is a cornified cell envelope constituent expressed in the upper epidermis. We previously reported that a potent protein kinase C activator, 12-O-tetradecanoylphorbol-13-acetate, increases human cystatin A expression by the activation of AP-1 proteins. Here, we delineate the signaling cascade responsible for this regulation. Co-transfection of the cystatin A promoter into normal human keratinocytes together with a dominant active form of ras increased the promoter activity by 3-fold. In contrast, a dominant negative form of ras suppressed basal cystatin A promoter activity. Further analyses disclosed that transfection of dominant negative forms of raf-1, MEK1, ERK1, ERK2, or wild-type MEKK1 all increased cystatin A promoter activity in normal human keratinocytes, whereas wild-type raf-1, ERK1, ERK2, or dominant negative forms of MEKK1, MKK7, or JNK1 suppressed the promoter activity. The increased or decreased promoter activity reflected the expression of cystatin A on mRNA and protein levels. These effects were not observed when a cystatin A promoter with a T2 (-272 to -278) deletion was used. In contrast, transfection of dominant negative forms of MKK3, MKK4, or p38 did not affect cystatin A promoter activity. Immunohistochemical analyses revealed that phosphorylated active extracellular signal-regulated kinases and c-Jun N-terminal kinase were expressed in the nuclei of basal cells and cells in the suprabasal-granular cell layer, respectively. These results indicate that the expression of cystatin A is regulated via mitogen-activated protein kinase pathways positively by Ras/MEKK1/MKK7/JNK and negatively by Ras/Raf/MEK1/ERK.

DOI： 10.1074/jbc.M102021200

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

Ciliary neurotrophic factor (CNTF) can prevent injury-induced motor neuron death. However, it is also evident that expression of CNTF in Schwann cells is suppressed during nerve regeneration. In this report, we have addressed the mechanism underlying the down-regulation of CNTF expression in injured nerves using a mouse Schwann cell line IMS32 and mouse sciatic nerve. In IMS32 cells, activation of the Ras extracellular-signal-regulated kinase (ERK) pathway by adenoviral vector-mediated expression of dominant active MEK1 did not alter a basal level of CNTF expression, whereas inhibition of the Ras-ERK pathway by using adenoviral vectors resulted in a marked increase in CNTF expression. This inverse relation between before and after axotomy was also observed in mouse sciatic nerve. In the axotomized sciatic nerve, the phosphorylated ERK was markedly increased; in contrast, the expression of CNTF was markedly decreased. These findings suggest that an inactive state of ERK is crucial for the CNTF expression in Schwann cells, and that activation of ERK following nerve injury critically influences the expression of CNTF. This might well explain why CNTF is highly expressed in quiescent Schwann cells in the peripheral nervous system, and also why CNTF is not abundant in axotomized nerves or cultured Schwann cells in which the proliferation signal is obviously active.

DOI： 10.1046/j.1471-4159.2001.00286.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC NEUROSCIENCE  

Motoneurons require neurotrophic factors for their survival and axonal projection during development, as well as nerve regeneration. By using the axotomy-induced neuronal death paradigm and adenovirus-mediated gene transfer, we attempted to gain insight into the functional significances of major growth factor receptor downstream cascades, Ras-extracellular signal-regulated kinase (Ras-ERK) pathway and phosphatidylinositol-3 kinase-Akt (PI3K-Akt) pathway. After neonatal hypoglossal nerve transection, the constitutively active Akt-overexpressing neurons could survive as well as those overexpressing Bcl-2, whereas the constitutively active ERK kinase (MEK)-overexpressing ones failed to survive. A dominant negative Akt experiment demonstrated that inhibition of Akt pathway hastened axotomy-induced neuronal death in the neonate. In addition, the dominant active Akt-overexpressing adult hypoglossal neurons showed accelerated axonal regeneration after axotomy. These results suggest that Akt plays dual roles in motoneuronal survival and nerve regeneration in vivo and that PI3K-Akt pathway is probably more vital in neuronal survival after injury than Ras-ERK pathway.

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：科学評論社  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本臨床皮膚科医会  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本医事新報  

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DOI： 10.1111/1346-8138.15231

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DOI： 10.1111/1346-8138.15082

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DOI： 10.1111/1346-8138.15105

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DOI： 10.1111/1346-8138.14638

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：ラジオ日経マルホ皮膚科セミナー放送集  

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DOI： 10.1111/1346-8138.14333

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DOI： 10.1111/1346-8138.14284

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DOI： 10.1111/1346-8138.14108

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：Blackwell Publishing Ltd  

Desmosomes provide the main intercellular adhesive properties between epidermal keratinocytes. Their distribution becomes uneven in severe dermatitis, multiple allergies and metabolic wasting syndrome due to desmoglein 1 deficiency and the loss of intercellular adhesion or acantholysis. When keratinocytes differentiate from granular cells into cornified cells, desmosomes are transformed into corneodesmosomes and can provide stronger intercellular adhesion. Degradation of corneodesmosomes is a tightly regulated process involving a number of proteases and their inhibitors. Peripheral corneodesmosomes are protected from proteolytic degradation by the tight junction-related structures around them, and this construction provides the basis for the normal basket weave-like structure of the stratum corneum. In Netherton syndrome, which is caused by an absence of the protease inhibitor lymphoepithelial Kazal-type-related inhibitor, premature degradation of corneodesmosomes occurs due to the overactivation of proteases involved in corneodesmosome degradation. Inflammatory peeling skin disease is caused by the absence of corneodesmosin, a unique component of corneodesmosomes. In this disease, corneodesmosomes are structurally abnormal, and their adhesiveness is compromised, which leads to intercellular splitting between the stratum corneum and stratum granulosum. The better we understand desmosome and corneodesmosome ultrastructure in normal and diseased skin, the clearer the physiological and pathological mechanisms of epidermal integrity become.

DOI： 10.1111/1346-8138.14202

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DOI： 10.1111/1346-8138.14185

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Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本皮膚免疫アレルギー学会雑誌  

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：WILEY  

DOI： 10.1111/1346-8138.13992

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DOI： 10.1111/1346-8138.13924

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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DOI： 10.1111/1346-8138.13919

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DOI： 10.1111/1346-8138.13674

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DOI： 10.1111/1346-8138.13944

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Other Link： http://search.jamas.or.jp/link/ui/2017373569

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Other Link： http://search.jamas.or.jp/link/ui/2017390673

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Other Link： http://search.jamas.or.jp/link/ui/2017264643

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DOI： 10.1111/1346-8138.13754

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DOI： 10.1111/1346-8138.13732

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DOI： 10.1111/1346-8138.13738

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：EDIZIONI MINERVA MEDICA  

Desmosomes are critical intercellular junctions between keratinocytes in the living cell layers of the epidermis. When the cells are differentiated and become cornified cells, desmosomes are transformed into corneodesmosomes. Distribution patterns of corneodesmosomes change with cell development. Namely, in the lower stratum corneum, corneodesmosomes are seen all around the cell membrane, but in the upper layers, they are only found at the edges of the flattened cells. Recently, it has been proposed that tight junction-derived structures are involved in this unique distribution of corneodesmosomes by protecting corneodesmosome degradation from proteases. Various types of skin diseases can be caused by abnormalities in the genes encoding components of desmosomes and corneodesmosomes or regulators of the proteolytic processing of these structures. Their clinical symptoms vary greatly: palmoplantar keratoderma on the pressure points, syndromic ichthyosis associated with atopic manifestations, diffuse keratoderma with cardiomyopathy, lethal epidermolysis bullosa, hair abnormalities, or a combination of these symptoms. Polymorphisms in some of the genes are risk factors for atopic dermatitis. Genetic diseases of desmosomes and corneodesmosomes are rare, but by studying them we will be enlightened about pathological mechanisms of more common multifactorial skin diseases such as atopic dermatitis.

DOI： 10.23736/S0392-0488.16.05528-0

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DOI： 10.1111/1346-8138.13504

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DOI： 10.1111/1346-8138.13554

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DOI： 10.1111/1346-8138.13470

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DOI： 10.1111/1346-8138.13689

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DOI： 10.1111/1346-8138.13531

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DOI： 10.1111/1346-8138.13456

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：皮膚病診療  

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© 2016 Japanese Dermatological Association Generalized pustular psoriasis (GPP) is a severe inflammatory skin disease characterized by the presence of sterile pustules covering almost the entire body and systemic symptoms such as fever. Secukinumab, a fully human-recombinant anti-interleukin-17A monoclonal antibody was indicated for psoriasis vulgaris and psoriatic arthritis in Japan but is not yet investigated for GPP. In this phase III, open-label multicenter single arm study, the efficacy and safety of secukinumab as monotherapy or with co-medication was evaluated in 12 Japanese patients with GPP. All the patients received secukinumab 150 mg s.c. at baseline, week 1, 2, 3 and 4, and then every 4 weeks. Two non-responders were up-titrated to 300 mg. Change in GPP severity from baseline was evaluated by clinical global impression (CGI) categorized as “worsened”, “no change”, “minimally improved”, “much improved” or “very much improved”. Treatment success was achieved by 83.3% (n = 10) of patients at week 16 (primary end-point) with CGI evaluated as “very much improved” (n = 9) and “much improved” (n = 1). Moreover, the area of erythema with pustules improved as early as week 1 and resolved by week 16 in most of the patients. The improvements were sustained throughout 52 weeks. Over the 52-week treatment period, secukinumab was well tolerated with no unexpected safety signals. Nasopharyngitis, urticaria, diabetes mellitus and arthralgia were the frequent adverse events reported. The data from this study shows that secukinumab can become one of the potent treatment options for GPP.

DOI： 10.1111/1346-8138.13306

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DOI： 10.1016/j.jdermsci.2016.01.012

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DOI： 10.1111/1346-8138.13223

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DOI： 10.1111/1346-8138.13076

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DOI： 10.1111/1346-8138.12828

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/1346-8138.12832

Web of Science

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/1346-8138.12751

Web of Science

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Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2015069177

Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2015069181

Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

Web of Science

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Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2014325077

Language：Japanese   Publisher：(株)医学書院  

80歳,男性.38℃台の発熱,多関節痛および圧痛を伴う体幹の浸潤性紅斑を主訴に当科を初診した.血液検査所見で好中球を主体とした白血球11,230/μlおよびCRP 17.29mg/dlと上昇があり,病理組織学的に真皮上層から深層にかけて血管周囲に好中球の浸潤をみたことからSweet症候群と診断した.明らかな悪性腫瘍や血液疾患の合併はみなかったものの,骨髄検査で20細胞中5個のトリソミー8を認めた.内服プレドニゾロン(PSL)を増量すると症状は改善するものの10mg/日以下にすると再燃を繰り返し治療に難渋した.自験例は骨髄異形成症候群(myelodysplastic syndrome:MDS)の診断には至らなかったが,MDSの誘因となりうるトリソミー8を認めた.Sweet症候群では好中球の異常活性化が起こるとされているが,トリソミー8が好中球のアポトーシスを抑制することにより本症の病態に関与している可能性がある.(著者抄録)

DOI： 10.11477/mf.1412103886

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/1346-8138.12223

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Language：Japanese   Publisher：金原出版(株)  

74歳男性。下垂体腺腫術後、ヒドロコルチゾン20mg/日内服中であった。しかし、約1ヵ月前から左上肢にびらん、潰瘍が生じていた。患者はこれまで老人性皮膚萎縮を基盤として皮慮潰瘍に対しラップ療法が以前から施行されており、自宅にて同処置を継続していたが、今回、潰瘍が急速に増悪した。全身検索では他臓器病変は認められなかったが、病理組織学的を行なったところ、真皮〜皮下組織に好酸性類円形構造物が多数認められ、真菌培養にてCryptococcus neoformansが証明された。以上より、本症例は原発性皮膚クリプトコッカス症と診断された。治療としてイトラコナゾール100mg内服およびルリコナゾール外用を開始した結果、7週間後にはほぼ完全に上皮化した。

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

Web of Science

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

Web of Science

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1111/1346-8138.12060

Scopus

PubMed

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)   Publisher：日本皮膚科学会雑誌  

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1346-8138.2012.01545.x

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Language：Japanese  

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2013087960

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CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2013129424

Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/j.1346-8138.2012.01513.x

Web of Science

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：日本皮膚科学会-西部支部  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：金原出版(株)  

症例1:81歳男。進行性核上性麻痺で在宅治療中であったが、ほぼ寝たきり状態となり、右大転子部および仙骨部に褥瘡を生じた。デブリードマンおよび外用療法で大部分の壊死組織を除去した後、V.A.C.システムを用いた持続陰圧吸引療法(VAC療法)を開始した。肉芽形成が得られた後に右大転子の褥瘡周囲から採皮してスタンプ植皮を行い、継続してVAC療法を行ったところ、4日後には50%程度の植皮片の生着を認めた。更に外用療法を継続し、植皮後3ヵ月時点で植皮部の皮膚潰瘍は上皮化が進み著明縮小した。症例2:45歳女。両下肢の著明リンパ浮腫の加療中、右下腿打撲後に比較的広汎な皮膚壊死を伴う皮下血腫の形成を生じた。血腫除去後の潰瘍形成に対し、左大腿からの採皮によるスタンプ植皮を行い、VAC療法を併用開始したところ、植皮片は80%程度が生着し、以後は外用療法にて軽快した。

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Language：Japanese   Publisher：日本皮膚病理組織学会  

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Language：Japanese   Publisher：(公社)日本皮膚科学会