Circadian protection against bacterial skin infection by epidermal CXCL14-mediated innate immunity.

The epidermis is the outermost layer of the skin and the body's primary barrier to external pathogens; however, the early epidermal immune response remains to be mechanistically understood. We show that the chemokine CXCL14, produced by epidermal keratinocytes, exhibits robust circadian fluctuations and initiates innate immunity. Clearance of the skin pathogen Staphylococcus aureus in nocturnal mice was associated with CXCL14 expression, which was high during subjective daytime and low at night. In contrast, in marmosets, a diurnal primate, circadian CXCL14 expression was reversed. Rhythmically expressed CXCL14 binds to S. aureus DNA and induces inflammatory cytokine production by activating Toll-like receptor (TLR)9-dependent innate pathways in dendritic cells and macrophages underneath the epidermis. CXCL14 also promoted phagocytosis by macrophages in a TLR9-independent manner. These data indicate that circadian production of the epidermal chemokine CXCL14 rhythmically suppresses skin bacterial proliferation in mammals by activating the innate immune system.

Quantitative evaluation of atrophic acne scars using 3D image analysis with reflected LED light.

BACKGROUND: Methods for objective evaluation of acne scars have not been established yet. In this study, the capability of three-dimensional image analysis of acne scarring was examined. METHODS: Two dermatologists evaluated the severity and counted the number of atrophic acne scars in a defined evaluation area of each cheek (3.5 cm × 3.5 cm) of 22 subjects (age, 21-38 years). Images of the evaluation area were obtained with an Antera 3D® (Miravex Limited, Ireland) camera three times, and three parameters (affected area, volume, and max depth) were measured. Three different filters (small, medium, and large), which limit measurement targets based on the diameters of concavities, were used for measurement. The relationships between each parameter and the evaluation results of scars by dermatologists were analyzed using Spearman's correlation coefficients. RESULTS: The correlations between the evaluation results of scars by dermatologists and each parameter measured were the highest when the large filter was used. The correlation coefficients between the severity of scars by dermatologists and each of affected area, volume, and max depth were 0.736, 0.728, and 0.722, respectively, and those between scar counts and each of affected area and volume were 0.783 and 0.770, respectively. The correlations, scatter plots, and regression lines among three measurements of parameters suggested high repeatability. CONCLUSIONS: Three-dimensional image analysis has the capability to evaluate changes in the shape of scars before and after treatment quantitatively.

Regulatory T Cells in Melanoma Revisited by a Computational Clustering of FOXP3+ T Cell Subpopulations.

CD4(+) T cells that express the transcription factor FOXP3 (FOXP3(+) T cells) are commonly regarded as immunosuppressive regulatory T cells (Tregs). FOXP3(+) T cells are reported to be increased in tumor-bearing patients or animals and are considered to suppress antitumor immunity, but the evidence is often contradictory. In addition, accumulating evidence indicates that FOXP3 is induced by antigenic stimulation and that some non-Treg FOXP3(+) T cells, especially memory-phenotype FOXP3(low) cells, produce proinflammatory cytokines. Accordingly, the subclassification of FOXP3(+) T cells is fundamental for revealing the significance of FOXP3(+) T cells in tumor immunity, but the arbitrariness and complexity of manual gating have complicated the issue. In this article, we report a computational method to automatically identify and classify FOXP3(+) T cells into subsets using clustering algorithms. By analyzing flow cytometric data of melanoma patients, the proposed method showed that the FOXP3(+) subpopulation that had relatively high FOXP3, CD45RO, and CD25 expressions was increased in melanoma patients, whereas manual gating did not produce significant results on the FOXP3(+) subpopulations. Interestingly, the computationally identified FOXP3(+) subpopulation included not only classical FOXP3(high) Tregs, but also memory-phenotype FOXP3(low) cells by manual gating. Furthermore, the proposed method successfully analyzed an independent data set, showing that the same FOXP3(+) subpopulation was increased in melanoma patients, validating the method. Collectively, the proposed method successfully captured an important feature of melanoma without relying on the existing criteria of FOXP3(+) T cells, revealing a hidden association between the T cell profile and melanoma, and providing new insights into FOXP3(+) T cells and Tregs.

CD8⁺ tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma.

Tumor-infiltrating lymphocytes (TILs) have been reported as a prognostic factor in various cancers and are a promising target for immunotherapy. To investigate whether TILs have any impact on the prognosis of angiosarcoma patients, 55 non-treated patients (40 patients at stage 1 with cutaneous localized tumors, 4 patients at stage 2 with lymph node metastases and 11 patients at stage 3 with distant metastases) with angiosarcoma were evaluated retrospectively by immunohistochemistry stained CD4, CD8, FOXP3 and Ki67. The Kaplan-Meier method was used to estimate overall survival with patients at stage 1. Survival differences were analyzed by the log-rank test. Patients with higher numbers of CD8(+) TILs in their primary tumors survived significantly longer compared with patients with lower values. Moreover, the number of CD8 in TILs was positively correlated with a distant metastasis-free period. The total number of primary TILs (CD4 plus CD8) and CD8(+) primary TILs of stage 3 patients with distant metastases was positively correlated with their overall survival. To evaluate whether CD8(+) effector T cells are activated or differentiated, flow cytometric analysis of peripheral blood mononuclear cells (PBMC) was performed. The percentages of CD8(+) T cells producing IFN-γ in PBMC were significantly higher in patients with angiosarcoma (n = 10) compared not only with that of healthy controls (n = 20) but also patients with advanced melanoma (n = 11). These results suggest that anti-tumor immunity is clinically relevant in angiosarcoma.

Three school-age cases of xeroderma pigmentosum variant type.

BACKGROUND: Xeroderma pigmentosum (XP) is a photosensitive genodermatosis with increased susceptibility to skin cancers. Patients are typically diagnosed with XP when they consult a dermatologist for skin cancers. CASE/METHODS: The genetic analysis and 2-8 years of follow-up for three school-age patients with XP-V is described. The patients were referred to us because of increased pigmented freckles; they had not experienced abnormal sunburn or developed skin cancer at their first visit. All patients harbored a genetic mutation in the POLH gene. XPV9KO was diagnosed at age 13 with a homozygous del1661A that creates a stop codon in the non-catalytic domain of POLH. The patient practiced sun protection, effectively preventing the development of skin cancer by age 21. XPV19KO was diagnosed at age 11 with a compound heterozygous mutation of G490T and C1066T, causing POLH truncation in the catalytic domain. This patient developed basal cell carcinoma at ages 12 and 13. XPV18KO was referred to us at age 11 and diagnosed with compound heterozygous variants of c.1246_1311del66 (exon 9 skipping), a novel mutation, and c.661_764 del104 (exon 6 skipping). CONCLUSION: Freckle-like pigmentation on sun-exposed skin is sometimes the only sign of XP-V, and early diagnosis is extremely important for children.

Bilateral disseminated herpes zoster in an immunocompetent host.

Herein we report a rare case of disseminated herpes zoster(HZ) infection involving two widely separated bilateral dermatomes in an immunocompetent host. HZ involving two widely separated areas simultaneously is referred to as HZ duplex bilateralis. It is very rare, with an incidence of less than 0.1 percent of all HZ cases, and usually develops in immunocompromised patients.

Another pitfall of sentinel lymph node biopsy: scar after lymph node biopsy 30 years ago revealed a sentinel lymph node.

In recent years, sentinel lymph node (SLN) biopsy has been used as a diagnostic and prognostic indicator for a number of tumors, including malignant melanoma. Sentinel lymph node biopsy using combined dye-radiotracer technique improved the detection rate and made the method easier. However, many pitfalls on the SLN procedure have been reported. Herein, we present a new pitfall. A formation of scar and lymph node tissue was detected as a SLN 30 years after lymph node biopsy.

An adult case of severe hand-foot-mouth disease accompanying persistent fever and systemic arthritis.

This paper reports a case of adult HFMD with vesicles scattered on the whole body and severe oral lesions. In addition, a long-lasting elevated level of C-reactive protein (CRP) was a feature of this case. Our case is unusual for HFMD with long-lasting joint pain and high fever.

Refractory pyoderma gangrenosum associated with ulcerative colitis successfully treated with infliximab.

Pyoderma gangrenosum (PG) is a rare, immune-mediated ulcerating skin disease. In up to 50 percent of the cases, PG is associated with underlying systemic disorders, most commonly inflammatory bowel diseases, connective tissue diseases, or hematological disorders. Herein, we present a case of refractory PG associated with ulcerative colitis (UC), successfully treated with infliximab.

Letter: an adult case of hand-foot-mouth disease showing severe mucous involvement.

Hand-foot-mouth disease is a common childhood viral infection. Generally, small vesicles and erosions occur on the hands, feet and oral mucosa. We report an unusual case of this disease that occurred in an immunocompent adult and resulted in severe erosion on the lips and mucous membranes.

Bullous dermatosis associated with IgG antibodies specific for desmocollins.

We describe a 53-year-old man with a two-year history of bullous disease. He had also had stage IV gastric cancer for 3 years. He presented with cutaneous erythemas and blisters, showing an annular arrangement. Histopathological examination revealed intraepidermal pustules of eosinophils and neutrophils without apparent acantholysis. Indirect immunofluorescence (IIF) analysis showed IgG anti-keratinocyte cell surface antibodies. The result of IIF on rat bladder was positive. IgG enzyme-linked immunosorbent assays failed to detect antibodies to either anti-desmoglein-1 (Dsg1), Dsg3, or BP180. Immunoblot analysis with normal human epidermal extract revealed IgG reactivity with 120, 110, and 100 kDa species. Immunofluorescence analysis using COS-7 cells that expressed desmocollin (Dsc) 1, 2, and 3 demonstrated that IgG autoantibodies in the patient's serum reacted with all Dsc1-3. A heterogeneous autoantibody profile including IgG reactivity against Dsc1-3 implicated association with cancer-related pemphigoid, although the findings did not fulfill the diagnostic criteria of paraneoplastic pemphigus. A review of the literature revealed that rare autoantibodies to Dsc, most of which were IgA class, were detected in 7 reported bullous diseases. In 5 out of 7 cases, they were combined with autoantibodies to bullous pemphigoid or pemphigus vulgaris. This is the first case that has IgG autoantibodies to all Dsc1~3.

Characterization of acne patients carrying clindamycin-resistant Cutibacterium acnes: A Japanese multicenter study.

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

Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition.

"Wound, pressure ulcer and burn guidelines - 6: Guidelines for the management of burns, second edition" is revised from the first edition which was published in the Japanese Journal of Dermatology in 2016. The guidelines were drafted by the Wound, Pressure Ulcer and Burn Guidelines Drafting Committee delegated by the Japanese Dermatological Association, and intend to facilitate physicians' clinical decisions in preventing, diagnosing and treating burn injury. All sections are updated by collecting documents published since the publication of the first edition. Especially, the recommendation levels of dressing materials newly covered by the Japanese national health insurance are mentioned. In addition, the clinical questions (CQ) regarding the initial treatment of electrical (CQ15) and chemical burns (CQ16), and also the use of escharotomy (CQ22), are newly created.

Wound, pressure ulcer and burn guidelines - 1: Guidelines for wounds in general, second edition.

The Japanese Dermatological Association prepared the clinical guidelines for the "Wound, pressure ulcer and burn guidelines", second edition, focusing on treatments. Among them, "Guidelines for wounds in general" is intended to provide the knowledge necessary to heal wounds, without focusing on particular disorders. It informs the basic principles of wound treatment, before explanations are provided in individual chapters of the guidelines. We updated all sections by collecting references published since the publication of the first edition. In particular, we included new wound dressings and topical medications. Additionally, we added "Question 6: How should wound-related pain be considered, and what should be done to control it?" as a new section addressing wound pain, which was not included in the first edition.

Wound, pressure ulcer and burn guidelines - 4: Guidelines for the management of connective tissue disease/vasculitis-associated skin ulcers.

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS.

Camouflage for vitiligo.

Cosmetic camouflage is indispensable for patients with vitiligo and can result in an improvement of their quality of life. Recent cosmetic advances enabled camouflage to obtain a suitable color match and keep it waterproof. However, camouflage needs some techniques. Therefore, patient education through a camouflage lesson is required to enjoy camouflage. Here the authors introduced a few tips for suitable camouflage, which were devised through camouflage lessons.

Predictive factors of response to pulse methylprednisolone therapy in patients with alopecia areata: A follow-up study of 105 Japanese patients.

Pulse corticosteroid therapy is effective for alopecia areata (AA) in the early stage. The risk and efficacy of this therapy for patients with several backgrounds, however, remains controversial. To explore the predictive factors of the response and risk factors of this therapy, data from 105 AA patients treated with methylprednisolone (500 mg) i.v. for 3 days consecutively in our facility were retrospectively analyzed. Among good responders, longer time from the onset to therapy was correlated with longer time required for hair regrowth (P = 0.037, n = 27). Multivariate models demonstrated that "severity", "relapse" and longer "duration from the latest onset" were significantly and independently associated with poorer outcome (P < 0.01). "History of atopic dermatitis (AD)" was also associated with poorer outcome, but this correlation could be explained by the effect that duration from the latest onset of AA was longer among participants with AD. We propose that earlier initiation of pulse corticosteroid therapy is preferable for better outcome of AA, particularly among patients with AD. Clinicians should be mindful of the occurrence of mild adverse effects in the elderly patients.