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SummaryBackground The aryl hydrocarbon receptor (AhR) recognizes diverse small molecules such as dioxins, tryptophan photoproducts and phytochemicals. It also plays crucial roles in epidermal homeostasis by upregulating epidermal barrier proteins. In preliminary screening, we found that Galactomyces fermentation filtrate (GFF), a cosmetic compound, was capable of activating AhR. Aim To examine whether GFF upregulates the expression of the filaggrin and loricrin genes, FLG and LOR, in an AhR-dependent manner. Methods The activation (cytoplasmic to nuclear translocation) of AhR was confirmed by immunofluorescence study and by upregulation of an AhR-specific marker, cytochrome P450-1A1 (CYP1A1). Gene expression levels were compared by quantitative reverse transcription PCR with or without GFF, interleukin (IL)-4 or IL-13 in normal human keratinocytes. AhR or control knockdown was carried out by transfection with AhR or control small interfering RNA. The protein expression of FLG and LOR was examined by immunohistochemistry using a three-dimensional epidermal equivalent treated with or without GFF or T helper (Th)2 cytokines. Results GFF induced the nuclear translocation of AhR with significant and dose-dependent upregulation of CYP1A1, FLG and LOR gene expression. The enhancing effects of GFF were abolished in AhR-knockdown keratinocytes. Th2 cytokines decreased expression of genes for FLG and LOR, and this expression was completely restored in the presence of GFF. The downregulated expression of the FLG gene with its restoration by GFF was also evident in the epidermal equivalent. GFF also upregulated the gene expression of genes encoding occludin, claudin-1 and 4, and kallikrein 5 and 7. Conclusions Use of GFF is feasible to prevent the Th2-mediated reduction of FLG in an AhR-dependent fashion.

Cases of Sparganum mansoni, caused by the plerocercoid larva of the tapeworm S. mansoni, occur through­out the world, particularly in Asian, Middle Eastern, and European countries. However, cases of infection with this parasite are rarely seen in Japan. Here, we present a case of a 61-year-old woman with a solitary subcutaneous nodule in left inner aspect of the thigh, from which a long, slender, whitish worm was surgically removed. The parasite was histopathologically identified as S. mansoni. Serological testing confirmed cure of the infection after surgical removal of the parasite. The authors advocate immunoserological examination in case of S. mansoni.

57歳, 男性。10歳時に交通事故のため右大腿部より切断し, 左大腿外側には広範な皮膚欠損があり, 瘢痕治癒していた。約1年前より同部位に潰瘍が出現し, しだいに腫瘤を形成したが, ガーゼ保護のみで放置していた。その後, 徐々に増大し, 疼痛や出血が出現してきたため近医を受診した。生検で有棘細胞癌と診断され, 当科紹介となった。左大腿外側に20×13cmの辺縁が堤防状に隆起した潰瘍局面を認めた。各種検査で, 明らかなリンパ節転移や多臓器への転移は認められずT4N0M0, Stage IIIと診断した。巨大な腫瘍に対し, 術前に動注化学療法 (CDDP+ADR) と放射線療法 (total 67Gy) を行った。腫瘍は著明に縮小し, 根治的手術を実施することができた。

Treatment with an epidermal growth factor receptor inhibitor (EGFRI) in patients having non-small-cell lung cancer can cause frequent and diverse skin toxicities, an acneiform rash being one of the commonest. Although the exact pathophysiology of this rash and its development mechanisms remain unknown, investigators have noted that egfri-induced skin toxicity might be partly associated with sebaceous gland function. Sebum is composed mainly of the lipids squalene (SQ), wax ester (WE), triglyceride, free fatty acid, and cholesterol, which are secreted mostly from the sebaceous glands and by keratinocytes. We therefore investigated the lipid composition of sebum before and after administration of egfri and whether sebum composition was associated with the development of acneiform rash. To investigate any associated changes in sebum gland activity, we focused especially on alterations in the amounts of SQ and WE , which are secreted solely from the sebaceous glands. In contrast to our expectations, we observed no substantial changes in the lipid composition of sebum before and after administration of egfri. Composition varies with the individual; however, the proportion of SQ and WE derived from the sebaceous glands was significantly lower in regions that did not develop acneiform rash than in regions that did. Our results suggest that development of an acneiform rash after administration of EGFRI could be related to sebaceous gland activity. Measurement of the lipid composition of sebum before therapy with EGFRI might predict which patients will be prone to acneiform rash.

Dendritic cells (DCs) are potent antigen-presenting cells and can induce tumour- or pathogen-specific T cell responses. For adoptive immunotherapy purposes, immature DCs can be generated from adherent monocytes using granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin (IL)-4, and further maturation is usually achieved by incubation with tumour necrosis factor (TNF)-alpha. However, TNF-alpha-stimulated DCs produce low levels of IL-12. In this study, we compared the effects of TNF-alpha, interferon (IFN)-gamma, IL-1beta or IFN-gamma + IL-1beta on the phenotypic and functional maturation of DCs. Our results show that IFN-gamma, but not IL-1beta, augmented the surface expression of CD80, CD83 and CD86 molecules without inducing IL-12 production from DCs. However, IL-1beta, but not IFN-gamma, induced IL-12 p40 production by DCs without enhancing phenotypic maturation. When combined, IFN-gamma + IL-1beta treatment profoundly up-regulated the expression of CD80, CD83, CD86 and major histocompatibility complex (MHC) class II antigens. Furthermore, IFN-gamma + IL-1beta-treated DCs produced larger amounts of IL-12 and induced stronger T cell proliferation and IFN-gamma secretion in primary allogeneic mixed lymphocyte reaction (MLR) than did TNF-alpha-treated DCs. Our results show that IFN-gamma + IL-1beta induced human monocyte-derived DCs to differentiate into Th1-prone mature DCs.

In the excited state of the peptide-bridged Ru(II)/Os(II) binuclear complex, [L 2 Ru(II)mbCO- l -Leu-NHbpyOs(II)(bpy) 2 ] and [L 2 Ru(II)mbCO- l -Pro-NHbpy-Os(II)(bpy) 2 ] [L=bpy (=2,2′-bipyridine) or BTFMB (=4,4′-bis-trifluoromethyl-2,2′-bipyridine), and mb=4-methyl-bpy], a nearly complete quenching of Ru II →π* (Ligand) MLCT emission was observed at room temperature. Lifetime measurements were performed to evaluate the quenching rate and the mechanism on a quantitative basis. In complexes with L=bpy, the intramolecular energy transfer process had a unitary efficiency. In complexes with L=BTFMB, the evidence for the occurrence of competitive energy and electron-transfer processes was provided from the time dependence of the emission spectra. The main pathway for energy-transfer in both systems could be explained by the Forster mechanism. It was suggested that the direction of MLCT excitation to either bridging or non-bridging bpy-ligand causes the large difference of dipole–dipole distance.

We describe a 70-year-old man with cutaneous granulocytic sarcoma who presented with numerous cutaneous nodules but without any leukaemic involvement of the peripheral blood. The tumour cells were positive for lysozyme, peroxidase, CD11a, CD11c, CD33 and HLA-DR, and weakly positive for CD4 and CD14, suggesting granulocytic differentiation. The bone marrow at admission showed dysplasia of the erythrocytic and granulocytic lineage and complex chromosomal abnormalities in association with an increase in monocytes. The patient was diagnosed as having granulocytic sarcoma of monocytic lineage with concomitant myelodysplastic syndrome. In this case, tumour cells also expressed the neural cell adhesion molecule (CD56), which has been suggested as a possible risk factor for developing granulocytic sarcoma in acute myelogenous leukaemia.

Background Complete excision is the most promising treatment for basal cell carcinoma (BCC) and a surgical margin of at least 4 mm is recommended. However, little is known about the appropriate surgical margin of pigmented BCC. Objective To investigate the reliability of narrower margin excision of well-defined, pigmented BCC. Methods We identified a total of 263 patients with 288 well-defined, primary pigmented BCC at the Department of Dermatology, Kyushu University (Fukuoka, Japan), between January 2006 and December 2013. All lesions were surgically excised with 1–6-mm margins and analysed. For 30 recent lesions out of the 288 lesions, border gaps between dermoscopy and histopathology were assessed. Results Of the 288 lesions, 218 (75.7%) were excised with a narrow margin (≤3 mm) and 60 lesions (24.3%) with a wide margin (≥4 mm). Only two lesions (0.7%), which were excised with 2-mm margins, were associated with tumour-positive margins. Narrow-margin excision showed a complete removal rate of 99% (2-mm margins, 95.3%; 3-mm margins, 100%). Dermoscopically determined borders almost exactly corresponded to the histopathological ones; 71.2% of border gaps between dermoscopy and histopathology were within 1 mm and there were no cases in which tumours spread beyond 1 mm of their dermoscopic borders. Conclusion Surgical excision with a 2–3-mm margin is reliable treatment for well-defined, primary pigmented BCC, with a complete removal rate of 99%.

Chronic itch affects millions of patients worldwide and has a significant impact on quality of life. The assessment of itch and its associated effects is a significant component of clinical practice in itch management. Despite itch being a common complaint, there are few studies describing the use of structured questionnaires for evaluation and measurement of itch and its sensory and affective dimensions. The International Society of the Study of Itch (IFSI) has recently provided invaluable data on the use of visual analogue scales as an assessment tool for itch. However, it is clear that additional tools are needed to better assess the different dimensions of chronic itch and better tailor management. With this goal in mind, a Special Interest Group was initiated by members of IFSI to determine which of the various psychometric properties of itch questionnaires offer the greatest utility in the evaluation of chronic itch. This first consensus paper addresses what domains and structure of itch questionnaires need to be implemented to better assess chronic itch and guide therapy.

Milk fat globule epidermal growth factor-VIII (MFG-E8) is a secreted protein that binds phosphatidylserine and promotes apoptotic cell ingestion by phagocytes, mediating the immune tolerance and maintenance of homeostasis. A recent study has shown that MFG-E8 expression in human melanoma is increased with tumour progression; however, the effect of its expression on patient survival has not yet been clarified.To analyse MFG-E8 expression in melanoma, and to determine whether it can serve as a marker for diagnosis, tumour progression and/or prognosis.MFG-E8 expression was examined by immunohistochemistry in 60 primary melanomas, 22 metastatic lesions and 30 benign naevi. The following clinicopathological variables were evaluated: age, gender, histological type, tumour site, Breslow thickness, Clark's level, the presence or absence of ulceration and tumour-infiltrating lymphocytes, and survival periods. Statistical analyses were performed to assess associations and melanoma-specific survival.MFG-E8 expression was significantly higher in primary and metastatic melanoma than in naevus. Furthermore, it increased according to tumour progression and metastasis. Patients with MFG-E8 expression in primary tumours had significantly shorter survival periods than those without MFG-E8 expression. Univariate and multivariate analyses revealed that MFG-E8 expression was a statistically significant and independent prognostic factor.MFG-E8 expression may serve as a tumour progression marker and can predict an unfavourable prognosis in patients with melanoma.

Interleukin (IL)-27 and WSX-1, the receptor α-specific subunit, have been shown to play important roles in initiating Th1 responses and in inducing immune modulation, and the immunosuppressive effect of IL-27 appears to be exerted via suppression of IL-10 and IL-17, which may participate in the pathogenesis of human systemic lupus erythematosus (SLE).To examine the significance of IL-27/WSX-1 signalling in spontaneous skin inflammation of MRL/lpr mice, a model for SLE.The severity and development of skin lesions, dermal inflammatory cells and epidermal-dermal depositions in the skin lesions of MRL/lpr mice with CD2-promoted WSX-1 overexpression (WSX-1 Tg mice) and those with globally disrupted WSX-1 (WSX-1 KO mice) were examined and compared with those of MRL/lpr mice.By 4 months of age, both WSX-1 KO mice and control MRL/lpr mice developed predominantly similar skin inflammation, while WSX-1 Tg mice hardly did so, demonstrating that intensifying IL-27/WSX-1 signalling on T cells prevents the spontaneous skin inflammation. WSX-1 KO mice showed Th2-type skin inflammation as evidenced by the Th2-prone dermal infiltrating cells and an absence of cutaneous Th1-type IgG deposition. Interestingly, there were significant IL-17+ dermal infiltrating cells in both WSX-1 KO and control MRL/lpr mice, which might potentially contribute to the formation of skin inflammation in these mice.These data indicate that IL-27/WSX-1 signalling may play a protective role in the development of SLE-like skin inflammation, and modulating IL-27/WSX-1 signalling might be an interesting therapeutic strategy in the treatment of SLE.

We report a rare case of angiomyolipoma located in the subcutis on the nose. A 54-year-old female first noticed a small, asymptomatic mass on her nose in 1994 and underwent tumor excision in April 1999. Histopathological examination revealed a typical form of angiomyolipoma, showing a proliferation of mature adipocytes, smooth muscle fascicles, and small- to medium-sized blood vessels.

Cathepsin K (CTSK), a cysteine protease with strong collagenolytic and elastolytic properties involved in extracellular matrix turnover, may be produced by neoplastic cells as well as stromal macrophages and fibroblasts. Its expression is suggested as associated with increased invasive and metastatic potential.The aim of this study is to examine stromal expression of cathepsin K in skin tumors.A series of 13 normal skin and 109 skin tumours, including 51 benign and 58 malignant epidermal tumours were tested for CTSK and Ki-67 expression by immunohistochemical analysis.Stromal CTSK expression and the tumoral Ki-67 labelling index were significantly higher in invasive squamous cell carcinoma (SCC) than in other epidermal tumours.Cathepsin K-positive stromal fibroblasts may play a crucial role in SCC progression by promoting extracellular matrix degradation, thereby facilitating SCC growth and invasion into surrounding tissue and vasculature. CTSK inhibitors may be a potential novel therapeutic option to decrease SCC progression.

Recently, we established an acne severity classification that is based on scientific evidence. Our classification allows three different methods for grading, which include general impression of consulted dermatologist, photograph-based estimation by independent experts, and grading by lesion counting. In our classification, we proposed standard photographs for the estimation of general severity to adjust the basis of judgments. In this study, we evaluated the validity of our classification. We made questionnaires of acne severity using acne patients' photographs, which were selected from the collection of representative photographs of our classification. Participants answered these questionnaires before and after our presentations about our classification of acne severity. We identified the conformity rate with our consensus decision. The results revealed that average conformity rates were raised from 67.0% to 88.9% among Japanese dermatologists and from 68.0% to 79.8% among Korean ones. These data show the adequacy of both our grading system itself and its presentation. We believe our classification will be one of the most effective and reasonable grading systems to classify acne severity.

For the epidemiological surveys and evaluations of therapy, it is essential to evaluate the severity of diseases. There are several reported methods of assessment for acne severity including lesion counting, comparison of the patient's to a photographic standard and comparison of the patient's to a text description. But all of these are based on opinions of specialists. In this study, we attempted to make an evidence-based grading criteria for acne severity, which was expected to yield consents from most dermatologists. The dermatologists consulted classified the global severity of acne patients without any standard and then counted the numbers of eruptions. Three independent expert dermatologists graded the photographs of these patients. We compared the verdicts of the consulted dermatologist and three experienced dermatologists, and analyzed the relationships between these classifications and numbers of eruptions. Our results showed that most of the dermatologists have similar latent recognitions of acne severity. We selected representative photographs as standards, which would contribute to making adjustments for judgments. Global classifications of dermatologists correlated with numbers of inflammatory eruptions (papules plus pustules), but did not with numbers of comedones. The appropriate divisions of inflammatory eruptions of half of the face to decide classifications were: 0-5, "mild"; 6-20, "moderate"; 21-50, "severe"; and more than 50, "very severe".

Activation of T lymphocytes induces transcription of several important genes which encode lymphokines and lymphokine receptors as well as "proliferation complementary" protooncogenes like c-myc or c-fos. Recently, the expression of lck gene, one of the src family gene, has also been shown to be modulated during T cell activation. We, therefore, assessed the question of whether other src family genes are expressed during the activation of T cells and of whether cyclosporine, a potent immunosuppressive drug, affects expression of these genes. We examined the expression of four different src family genes (lck, c-src, fyn, and c-fgr) in addition to the expression of IL-2, c-fos, c-myc, and actin genes in murine T cells which were activated with PMA plus ionomycin or PMA plus anti-CD3 mAb. We found that T cell activation was associated with the up-regulation of these src family genes and that the expression of these genes was specifically blocked in the presence of cyclosporine indicating that these activation-related genes were coordinately regulated.

We report on a 27-year-old man with acanthosis nigricans (AN) associated with severe obesity, insulin resistance and hypothyroidism. A very low-calory diet treatment decreased his weight and then ameliorated the insulin-resistant state. These effects were followed by remarkable improvement of the AN prior to the correction of the hypothyroidism. This confirms that AN may be mainly attributed to insulin resistance rather than hypothyroidism per se.

The insulin-like growth factor-1 (IGF-1) receptor (R)-induced phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/ERK signal transduction cascade, which have critical roles in prevention of apoptosis and regulation of cell cycle progression, plays an important role in tumorigenesis. The expression of IGF-1R, AKT and ERK1/2 has been described in some human malignancies, but not in extramammary Paget's disease (EMPD).To study the expression of IGF-1R, p-AKT and p-ERK1/2 in EMPD and to evaluate the relationships among them.Thirty-six tissue samples of 34 patients with primary EMPD were subjected to immunohistochemical staining for IGF-1R, p-AKT and p-ERK1/2.Of thirty-six EMPD tissue samples, 34, 34 and 28 were positive for IGF-IR, p-AKT and p-ERK1/2 expression, respectively; 27, 23 and 17 of the 36 specimens stained positive for IGF-IR, p-AKT and p-ERK1/2 in more than half of Paget's cells, respectively. There were significant correlations between the IGF-1R and p-AKT expression as well as between IGF-1R and p-ERK1/2 expression. Taken together, these results indicate that IGF-1R is overexpressed, and AKT and ERK1/2 are frequently phosphorylated in EMPD.Our study shows that the expression of IGF-1R and the induction of p-AKT and the p-ERK1/2 pathway may play an important role in the pathogenesis of EMPD. The IGF-IR system might be a potential therapeutic target in EMPD.

Stat3 (Signal transducer and activator of transcription-3) is an oncogene that plays a critical role in regulating fundamental processes associated with malignant transformation and cell survival. It participates in oncogenesis through upregulation of genes encoding apoptosis inhibitors (Bcl-xL) and cell cycle regulators (cyclin D1). The expression of Stat3, Bcl-xL and cyclin D1 protein has not been investigated in extramammary Paget disease (EMPD).To study the expression of phosphorylated Stat3 (p-Stat3), Bcl-xL and cyclin D1 protein in EMPD and to evaluate the relationships among them.Thirty-six tissue samples from 34 patients with primary EMPD were subjected to immunohistochemical staining for p-Stat3, cyclin D1 and Bcl-xL.Thirty-five of 36 specimens were clearly positive for p-Stat3 in EMPD, while 30 of 36 and 32 of 36 were positive for cyclin D1 and Bcl-xL expression, respectively. In all of four invasive EMPD specimens, strong and frequent expression of these three molecules was evident; moreover, two invasive EMPD specimens with lymph nodal metastasis showed very strong nuclear and membranous p-Stat3 staining. Two metastatic lymph node specimens showed very strong nuclear and local membrane p-Stat3 staining. There were significant correlations between p-Stat3 and cyclin D1 expression and between p-Stat3 and Bcl-xL expression.Our study shows that the expression of p-Stat3, cyclin D1 and Bcl-xL may play a pivotal role in the pathogenesis of EMPD.

Granuloma formation is a common response in the skin infection of sporotrichosis. The involvement of interferon-gamma (IFN-gamma) and inducible nitric oxide synthase (iNOS) in the granuloma formation of sporotrichosis is less known. The aim of this study was to describe by immunohistochemistry the exact tissue distribution of IFN-gamma-positive cells and iNOS-positive cells in the granuloma of skin lesions from patients with sporotrichosis. Formalin-fixed paraffin-embedded skin biopsy sections from five patients were stained by immunohistochemical methods. Mixture of CD4-positive T cells and CD8-positive T cells were present in and around the granulomatous lesions. IFN-gamma-positive cells, like mononuclear lymphoid cells, were detected in the periphery of the granulomas in all samples. The pattern of IFN-gamma staining appeared to be a combination of intracellular staining in mononuclear lymphoid cells and extracellular deposition in the surrounding tissue. The majority of the epitheloid cells and multinucleated giant cells within the granuloma were identified by immunostaining for CD68. In contrast, no expression of immunoreactive iNOS was observed in those cells in all samples. These findings indicate that granulomas of sporotrichosis are coupled with Th1 response.

We describe a unique case of various types of basal cell carcinoma (BCC) associated with basaloid follicular hamartoma (BFH) in a 56-year-old female patient. The lesion consisted of a dark brown and elastic soft nodule and papules within the area of a birthmark on the neck. The lesion was surgically excised. Histological examination of the nodular region revealed aggregations of neoplastic basaloid cells. We diagnosed the nodule as BCC with a racemiform or reticular pattern. In addition, a specimen taken from brownish black papules within the birthmark was found to be composed of anastomosing cords of basaloid cells accompanied by infundibular cystic structures. These features were consistent with an infundibulocystic BCC. In contrast, specimens from a hamartomatous plaque showed distinctive branching strands of basaloid cells that are suggestive of BFH. Therefore, our findings indicate that several types of BCC may develop within a BFH.

Seborrheic keratoses are very common epidermal neoplasms. We describe a patient with seborrheic keratoses presenting multifocal spontaneous regression. The patient had a concurrent nasal adenoid cystic carcinoma. The simultaneous regression of seborrheic keratoses ceased after total resection of the nasal carcinoma. Histological examination revealed marked infiltration of mononuclear cells, including CD4+, CD8+, CD68+ and cutaneous lymphocyte-associated antigen-positive cells, with profound accumulation of CD1a+ dendritic cells. Although apoptotic keratinocytes were not found in the lesional epidermis by histology, the majority of keratinocytes in the regressing seborrheic keratosis were positively stained by the TUNEL method. We postulate that the internal malignancy may induce spontaneous regression of seborrheic keratoses.