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Purpose. This study was undertaken to assess the effects of ropivacaine on the membrane action potential and the voltage-dependent L-type calcium channel current (I Ca) in guinea-pig single ventricular myocytes. Methods. Single ventricular myocytes were prepared by enzymatic dispersion. Whole-cell current and voltage-clamp techniques were used to monitor membrane potentials and I Ca. Results. Ropivacaine (10−5 and 10−4 M) reduced the overshoot and shortened the duration of the action potential. Hyperpolarization of the resting membrane potential was observed in the presence of ropivacaine (10−4 M). Ropivacaine (10−5–10−3 M) reduced I Ca dose-dependently and reversibly, and the 50% inhibitory concentration (IC50) of ropivacaine was estimated as 4.3 × 10−4 M. Furthermore, the inhibition of I Ca was not a use-dependent block. Conclusion. Ropivacaine has an inhibitory effect on I Ca in the guinea-pig single ventricular myocyte. It is concluded that the mild negative inotropic effect induced by ropivacaine can be attributed in part to shortening of the duration of the action potential, which is caused by inhibition of I Ca.

A 68-year-old Japanese woman was referred to our hospital with a 1-year history of multiple erosions on the oral mucosa and a few pruritic, bean-sized, reddish-blue plaques on the body. Based on physical examination, pathological findings, and immunofluorescence findings, a diagnosis of lichen planus (LP) was made. Computed tomography scan revealed a thymoma. After thymectomy, cutaneous LP lesions subsided spontaneously. Oral lesions responded well to oral etretinate therapy. We speculate that direct tissue injury by CD8(+) T cells, activated by abnormal regulation of lymphocytes within the thymus, may cause LP.

CCN1 is a pleiotropic molecule involved in angiogenesis and postnatal vasculogenesis, both of which are impaired in systemic sclerosis (SSc). To elucidate the potential role of CCN1 in the development of SSc, we investigated CCN1 expression in the lesional skin of SSc patients and SSc animal models and the clinical correlation of serum CCN1 levels. CCN1 expression was markedly decreased in dermal small blood vessels of SSc patients compared with those of healthy controls, while comparable between normal and SSc dermal fibroblasts. Transcription factor Fli1, whose deficiency due to epigenetic suppression is implicated in the pathogenesis of SSc, occupied the CCN1 promoter and gene silencing of Fli1 resulted in the reduction of CCN1 expression in human dermal microvascular endothelial cells. Consistently, CCN1 expression was suppressed uniformly and remarkably in dermal blood vessels of Fli1(+/-) mice and partially in those of endothelial cell-specific Fli1 knockout mice. Furthermore, serum CCN1 levels were significantly decreased in SSc patients with previous and current history of digital ulcers as compared to those without. Collectively, these results suggest that endothelial CCN1 downregulation at least partially due to Fli1 deficiency may contribute to the development of digital ulcers in SSc patients. This study further supports the idea that epigenetic downregulation of Fli1 is a potential predisposing factor in the pathogenesis of SSc.

Adipokines have been shown to be potentially involved in various pathological processes of systemic sclerosis (SSc), including inflammation, vasculopathy and fibrosis, through their pleiotropic effects. Omentin is a member of the adipokines, and has a protective effect against vascular inflammation and pathological remodeling leading to atherosclerosis as well as a vasodilatory effect. To assess the potential role of omentin in the development of SSc, we determined serum omentin levels by enzyme-linked immunosorbent assay in 66 SSc and 21 control subjects and evaluated their clinical correlation. Serum omentin levels were significantly decreased in diffuse cutaneous SSc patients compared with limited cutaneous SSc patients, while comparable between total SSc patients and healthy controls. In diffuse cutaneous (dc)SSc, patients with a disease duration of 5 years or less had serum omentin levels significantly lower than those with a disease duration of more than 5 years. In total SSc, serum omentin levels were significantly higher in patients with elevated right ventricular systolic pressure than in the others, while serum omentin levels did not correlate with fibrotic and systemic inflammatory parameters. These results suggest that a loss of omentin-dependent protection against vascular inflammation and remodeling may be related to pathological vascular events of early dcSSc. The elevation of serum omentin levels may serve as a marker of vascular involvement leading to pulmonary arterial hypertension in SSc, which is possibly due to the compensatory induction of omentin against the increased pulmonary vascular tone.

Objectives Chemerin is a member of adipocytokines with a chemoattractant effect on plasmacytoid dendritic cells and macrophages and pro-angiogenic properties. We investigated the potential role of chemerin in the development of SSc. Methods Chemerin expression was evaluated by immunostaining and/or real-time quantitative RT-PCR in human and murine skin. The mechanisms regulating chemerin expression in dermal fibroblasts and endothelial cells were examined using the gene silencing technique and chromatin immunoprecipitation. Serum chemerin levels were determined by ELISA in 64 SSc patients and 19 healthy subjects. Results In SSc lesional skin, chemerin was up-regulated in small blood vessels, while it was down-regulated in fibroblasts surrounded with thickened collagen bundles. The decreased expression of chemerin was significantly reversed by TGF-β1 antisense oligonucleotide in cultured SSc dermal fibroblasts and chemerin expression was markedly decreased in dermal fibroblasts of bleomycin-treated mice. Gene silencing of transcription factor Fli1, which binds to the chemerin promoter, induced chemerin expression in human dermal microvascular endothelial cells and Fli1(+/-) mice exhibited elevated chemerin expression in dermal blood vessels. Serum chemerin levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. In SSc patients with normal renal function, patients with digital ulcers had higher serum chemerin levels than those without. Conclusion Chemerin is down-regulated in SSc dermal fibroblasts by autocrine TGF-β, while it is up-regulated in SSc dermal blood vessels through endothelial Fli1 deficiency. Increased chemerin expression in dermal blood vessels may be associated with the development of digital ulcers in SSc.

Purpose: Atopic dermatitis is characterized by decreased expression of filaggrin and loricrin. Patients with atopic dermatitis often suffer from skin infections, which are also frequently seen in patients with cutaneous T-cell lymphoma (CTCL). In this study, we aimed to investigate the skin barrier in CTCL. Experimental Design: We assessed skin moisture and transepidermal water loss (TEWL) in patients with CTCL. We next examined mRNA expression levels of filaggrin, loricrin, and antimicrobial peptides (AMP) in skin samples of CTCL, using skin from healthy volunteers and patients with atopic dermatitis or psoriasis as controls. Immunostainings for filaggrin, loricrin, and S100 proteins were also performed. Results: Lower levels of skin moisture accompanied by higher levels of TEWL were seen in lesional skin of CTCL than in normal skin. CTCL lesional skin contained lower levels of filaggrin and loricrin mRNA than normal skin, which was also true with atopic dermatitis and psoriatic skin. mRNA expression levels of filaggrin in CTCL skin negatively correlated with disease severity markers. Expression levels of AMPs in lesional skin of CTCL and atopic dermatitis were significantly lower than in psoriatic skin. Immunohistochemistry confirmed decreased expression of filaggrin and loricrin in CTCL, atopic dermatitis, and psoriatic skin and enhanced expression of S100 proteins in psoriatic skin. Conclusions: Our results show that there is barrier dysfunction in CTCL skin, similar to what is seen with atopic dermatitis skin. In addition, low AMP expression in CTCL skin was documented when compared with psoriatic skin, which may explain frequent infections that can occur in patients with CTCL. Clin Cancer Res; 20(16); 4339–48. ©2014 AACR.

Early cutaneous T cell lymphoma clinically and histologically resembles benign inflammatory skin diseases, which sometimes makes it difficult to reach a correct diagnosis. It is recently reported that thymocyte selection-associated high mobility group box factor (TOX) serves as a molecular marker for histological diagnosis of early-stage mycosis fungoides (MF). To examine whether TOX could be a marker of tumour cells in different types of cutaneous lymphoma, we investigated immunohistochemical staining for TOX with the lesional skin of patch, plaque, and tumour MF, Sézary syndrome (SS), lymphomatoid papulosis (LyP), primary cutaneous anaplastic large cell lymphoma (PCALCL), adult T cell leukemia/lymphoma (ATLL), peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), atopic dermatitis (AD), and normal skin. TOX and CCR4 messenger RNA (mRNA) levels in lesional skin of MF/SS were also examined. Immunohistological staining showed that a high specific nuclear staining of TOX was observed at a high frequency in MF, SS, and PTCL, NOS. Tumour cells in LyP, PCALCL, and ATLL showed a slightly dim nuclear staining of TOX. TOX(+) cells in MF and LyP expressed surface molecules characteristics of tumour cells in these diseases. Lesional skin of SS expressed higher levels of TOX mRNA, compared to normal skin or MF lesional skin. Moreover, TOX expression significantly correlated with CCR4 expression. TOX may be a specific marker for tumour cells in some types of cutaneous lymphoma.

Progranulin is a growth factor that is active in wound repair and is an antagonist of tumor necrosis factor (TNF) receptors, regulating fibroblast activation, angiogenesis, and inflammation. Because long-standing activation of gene programs related to wound healing is a hallmark of systemic sclerosis (SSc), we sought to investigate the role of progranulin in SSc.Progranulin expression levels in human and murine skin samples were determined by immunohistochemical analysis and quantitative reverse transcription-polymerase chain reaction. The role of progranulin in fibroblast activation was examined using a gene-silencing technique. Progranulin levels in serum obtained from 60 patients with SSc and 16 healthy control subjects were determined by enzyme-linked immunosorbent assay.Progranulin expression was increased in SSc dermal fibroblasts compared with normal dermal fibroblasts, both in vivo and in vitro. Transcription factor Fli-1, a deficiency of which is involved in the activation of SSc dermal fibroblasts, served as a potent repressor of the progranulin gene, and Fli-1(+/-) mice and bleomycin-treated wild-type mice exhibited up-regulated expression of progranulin in dermal fibroblasts. SSc dermal fibroblasts were resistant to the antifibrotic effect of TNF, but this resistance was reversed by gene silencing of progranulin. Serum progranulin levels were elevated in patients with early diffuse cutaneous SSc (dcSSc), especially in those with inflammatory skin symptoms, and were positively correlated with the C-reactive protein level.Progranulin overproduction due to Fli-1 deficiency may contribute to the constitutive activation of SSc dermal fibroblasts by antagonizing the antifibrotic effect of TNF. Progranulin may also be involved in the inflammatory process associated with progressive skin sclerosis in early dcSSc.

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by immune abnormalities, vasculopathy and fibrosis of the skin and certain internal organs. Recent evidence suggests the potential contribution of a dysregulated innate immune system to its pathogenesis [1]. Mannose-binding lectin (MBL), a member of the collectin family produced mainly by liver hepatocytes and, to a smaller extent, by gastrointestinal and reproductive tracts, binds to various pathogens as a pattern-recognition [...]

Background: Various types of histone deacetylase inhibitor (HDACi) are currently under development or being used for non-Hodgkin's lymphomas including cutaneous T-cell lymphoma (CTCL). However, there is little molecular-based evidence to support the proposed efficacy of HDACi against advanced CTCL or information on the possible pivotal target genes of HDACi. We have shown that a tumor suppressive microRNA (miRNA), miR-150 inhibits metastasis via combining "seed sequence" of messenger RNA of a chemokine receptor CCR6 in advanced CTCL (Blood 2014). Because HDACi yielded excellent outcome for treating advanced CTCL, HDACi might have a potential to reduce metastasis capability of CTCL via targeting miR-150 and CCR6. Indeed we previously showed that a tumor suppressive miRNA, miR-16 was epigenetically downregulated and HDACi restored its expression leading to induce cellular senescence or apoptosis in various T-cell lymphomas (Oncogene 2015). This led us to consider that HDACis might upregulate variety of tumor suppressive miRNAs and there might be deep association of restoration for some critical gene(s) or/and miRNA(s) expression with HDACis in CTCL oncogenesis. In this study, we focused on to investigate relationship between miRNAs and HDACis, especially focused on to detect CCR6 associated miRNA(s). Methods: My-La, HH, and HUT78 (CTCL cell lines) were used for functional analysis because their xenografts in NOD/Shi-scid IL-2γnul mice (CTCL mice) shortened survival, owing to multiple metastases. To investigate changes of miRNA expression by HDACis, we conducted miRNA microarray analysis. To examine the expression of miR-150 in primary CTCL, we conducted a qRT-PCR analysis of samples from early (patch and/or plaque phase, n = 26) and advanced cases (tumor phase, n = 14). The control samples were obtained from patients with atopic dermatitis (AD, n = 18). Results: We demonstrated that pan-HDACis (vorinostat and panobinostat) inhibited migration of CTCL cells with downregulating CCR6. When we examined miRNA array against CTCL cells treated with and without respective HDACi, 161 miRNAs were commonly upregulated by pan-HDACis in My-La, HH and HUT78. Among these 161 miRNAs, 35 miRNAs that possesses seed sequence of CCR6 showed upregulation by HDACis treatment (e.g., miR-150, miR-96, miR-183, miR-185, miR-194, miR-320a, miR-371a, miR-3135b). To examine the miRNAs that has a functional role in CTCL metastasis, we conducted northern blot analysis of these candidate miRNAs in the CTCL cell lines and primary tissue samples. We found that the miR-150 was strongly expressed in normal CD4+ cells with downregulation of advanced CTCL samples, but the others showed very low or no expressions. In addition, the transduction of candidate miRNAs against the CTCL cells revealed that miR-150 downregulated CCR6 and inhibited their migration most efficiently. These data strongly suggest that the most likely target miRNA of the pan-HDACis in metastasis inhibition was the miR-150 in the metastatic CTCL. To examine whether there was a change in miR-150 expression during disease progression of primary CTCL, we conducted a qRT-PCR analysis of samples from early and advanced cases. The qRT-PCR demonstrated that the expression of miR-150 was significantly lower in the advanced specimens than it was in samples from patients with AD. The miR-150 levels did not significantly differ between the early and the AD specimens, but a significant difference was detected between the early and advanced specimens. These results suggest that miR-150 expression declines with disease progression in CTCL. Finally, we conducted in vivo experiment to examine whether miR-150 indeed inhibit tumor metastasis. We demonstrated that administration of miR-150 against CTCL model mice led to prolong their survivals. Conclusion: miR-150 and CCR6 are essential targets of pan-HDACi in advanced CTCL. Our results provide rational reasons for using pan-HDACi against metastatic CTCL. Furthermore, these results suggest that miR-150 could be not only powerful biomarker for molecular diagnosis, and predictive of metastasis, but also novel therapeutic molecule in advanced CTCL. Disclosures Kitadate: Daiichi Sankyo: Research Funding; Kyowa Kirin: Research Funding; Otsuka: Research Funding; Toyama Chemical: Research Funding; Chugai: Research Funding; AsahiKasei: Research Funding; Eisai: Research Funding; Fujimoto: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Abe:AsahiKasei: Research Funding; Chugai: Research Funding; Otsuka: Research Funding; Kyowa Kirin: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Eisai: Research Funding; Toyama Chemical: Research Funding; Fujimoto: Research Funding. Ikeda:AsahiKasei: Research Funding; Chugai: Research Funding; Otsuka: Research Funding; Kyowa Kirin: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Eisai: Research Funding; Toyama Chemical: Research Funding; Fujimoto: Research Funding. Takahashi:BMS: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Tagawa:Daiichi Sankyo: Research Funding; Kyowa Kirin: Research Funding; Otsuka: Research Funding; Chugai: Research Funding; AsahiKasei: Research Funding; Eisai: Research Funding; Toyama Chemical: Research Funding; Fujimoto: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

症例は89歳,女性.右股関節痛および右大腿部に広範な皮下気腫を認め,ガス壊疽を疑われ当院内科紹介入院.入院時は両側胸水と小腸イレウスを認め,右鼠径部から大腿内側に腫脹,圧痛,握雪感を伴っていた.大腿部切開ドレナージで膿性浸出液を認め外科紹介となる.右大腿内側から下腿にかけての疾痛,しびれあり,閉鎖孔ヘルニア嵌頓穿孔による大腿部膿瘍と診断し,全身状態改善後開腹手術施行.回盲部より約100cm口側の回腸壁が右閉鎖孔に嵌頓し穿孔していたため,同部を切除側々吻合した.ヘルニア門は示指頭大で,大腿部膿瘍との交通を確認後縫合閉鎖した.術後86病日に軽快退院した.大腿部膿瘍の診断には,閉鎖孔ヘルニア嵌頓穿孔を疑う必要がある.また本症の外科的治療方針決定に際し,高齢,全身状態不良例が多いことから大腿部膿瘍ドレナージ先行による二期的手術が術後合併症も少なく安全と考えられた.

Angioimmunoblastic T cell lymphoma (AILD) is a type of peripheral T cell lymphoma associated with fever and generalized lymphadenopathy. Cutaneous manifestations are seen in approximately 40% of the patients. We report herein a Japanese male patient with AILD associated with generalized purpura. The histology of the purpura included leukocytoclastic vasculitis with IgA deposits, which is rare in this disease. Using in situ hybridization and PCR methods, we showed that the involved lymph node was positive for Epstein-Barr virus and that the purpura was negative.

We reported a case of dermatomyositis (DM) with liver disturbance in a 50-year-old Japanese female. She presented with fever, muscle weakness, and typical DM rashes. On clinical and serological examinations, the liver impairment was initially diagnosed as probable autoimmune hepatitis, which was denied by a histological study despite positive anti-liver-kidney microsome-1 antibody. Finally, she was diagnosed as having DM with "liver disease associated with rheumatoid diseases", and treatment with oral prednisone (40 mg/day) achieved normalization of liver and muscle enzyme levels as well as improvement of symptoms associated with DM. Liver involvement in patients with polymyositis (PM)/DM has not been well described and is considered to be uncommon. Full clarification of the etiology of liver impairment with a histological examination in collagen diseases including PM/DM is useful to determine the proper dose of corticosteroids for the treatment of collagen diseases and their liver complications.

Background: Pustulosis palmaris et plantaris (PPP) is a chronic inflammatory disease consisting of polymorphonuclear leukocyte infiltration, and is often exacerbated by focal infections such as tonsillitis. In some cases, metal allergy has been reported. Objective: The purpose of this study was to evaluate (1) the significance of metal allergy in the formation of pustules, and (2) the participation of leukotriene (LT) B 4 in the formation of pustules of PPP. Methods: Patch tests with metals were performed on 7 patients with PPP, and both pustular and plasma levels of LTB 4 were measured in these 7 patients before and 48 hours after metal patch tests. Results: Palmoplantar pustules were exacerbated after the metal patch tests in all 7 patients. The mean levels of LTB 4 in plasma and pustules of the volar surface at 48 hours after the metal patch tests were significantly higher than those before the metal patch tests. Conclusion: Metals can be important in the pathogenesis of PPP by contributing to the induction of high LTB 4 concentration in the pustules. (J Am Acad Dermatol 2000;42:1021–5.)

A unique subset of gammadelta T cells, termed dendritic epidermal T cells, reside in murine epidermis. It was previously reported that freshly isolated dendritic epidermal T cells and dendritic epidermal T cell lines expressed mRNA for interferon-gamma. Recent studies indicated that interleukin-18, a novel cytokine which strongly induces interferon-gamma production by T cells, was produced by murine keratinocytes and Langerhans cells. Interleukin-12, which is regarded as a key cytokine for Th1 type helper clone responses, has also been reported to be produced by these cells in murine skin. In this study, we demonstrated by enzyme-linked immunosorbent assay that interleukin-18 and interleukin-12 synergistically upregulated interferon-gamma production by dendritic epidermal T cells in short-term cultures. This was the case in both C57/BL6 mice and BALB/C mice, although the quantity of interferon-gamma produced was different in the two mouse strains. Interleukin-18 or interleukin-12 alone did not induce interferon-gamma production by dendritic epidermal T cells. Interferon-gamma mRNA was only weakly detected by the semiquantitative reverse transcriptase-polymerase chain reaction method in freshly isolated dendritic epidermal T cells, and the mRNA expression was much increased 12 h after stimulation with interleukin-18 and interleukin-12. We also confirmed biologic activity of interferon-gamma produced by dendritic epidermal T cells by showing upregulation of major histocompatibility complex class II expression on Pam 212, murine keratinocyte cell line. Thus, this study suggests that interleukin-18 and interleukin-12 produced by keratinocytes and Langerhans cells regulate interferon-gamma production by dendritic epidermal T cells and thus may play important parts in the regulation of immune responses in skin-associated lymphoid tissues.

We describe a patient with Sezary syndrome (SS) who was successfully treated with topical steroid and narrowband UVB. Sezary cells in peripheral blood correlated with severity of skin lesions. In addition, serum levels of CCL17 and CCL27 decreased as disease activity improved. These chemokines may be important for the pathogenesis of SS.

We have investigated the antitumor effect of murine colon carcinoma cells developed to produce cytokines. Retrovirally transduced cells were inoculated into syngeneic mice, and their survivals were examined. Inoculation of interleukin-4 (IL-4)- or granulocyte macrophage-colony stimulating factor (GM-CSF)-producing cells alone did not affect the survival of the mice. In the tumors derived from an admixture of IL-4 and GM-CSF producers, however, regression developed spontaneously, and prolonged survival of the challenged mice was consequently observed. Histological examination revealed predominant infiltration of neutrophils around the tumor of a mixed population of IL-4 and GM-CSF producers.

胸部食道癌の至適切除範囲を, 食道の切除範囲, リンパ節の郭清範囲および隣接臓器の合併切除の3要因に分け検討した. 胸部食道全摘例は部分切除例に比べ残遺食道再発率が低く, 術前あるいは術中診断が困難な微小壁内転移や脈管内侵襲の遺残を防ぐために全摘することが望ましい. n (+) 例において, 3領域郭清では有意にリンパ節再発率の減少がみられ, 予後向上が得られた. リンパ節転移およびリンパ節再発の状況から, 深達度mm以上のIu・Im例およびmp以上のEi例では3領域郭清を原則とすべきである. また, 癌の浸潤が粘膜筋板に達しない症例では, 内視鏡的粘膜切除術やriskに応じたリンパ節郭清の縮小化, あるいは非開胸食道抜去術を適応することができるものと思われた. 隣接臓器浸潤例に対する重要臓器合併切除は, 手術成績・遠隔成績とも極めて不良であり, 現時点における根治手術の対象は, 術前補助療法の奏効例に限定すべきであると考えられた.

Bleomycin-induced fibrosis and the tight skin (TSK/+) mouse are well-established experimental murine models of human systemic sclerosis (SSc). Growing evidence has demonstrated the pivotal role of Toll-like receptors (TLRs) in several autoimmune inflammatory diseases, including SSc. This study was undertaken to determine the role of TLR-4 in the fibrotic processes in these murine models.We generated a murine model of bleomycin-induced SSc using TLR-4(-/-) mice and TLR-4(-/-) ;TSK/+ mice. The mechanisms by which TLR-4 contributes to pathologic tissue fibrosis were investigated in these 2 models by histologic examination, hydroxyproline assay, enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and flow cytometry.Dermal and lung fibrosis was attenuated in bleomycin-treated TLR-4(-/-) mice compared with their wild-type counterparts. Inflammatory cell infiltration, expression of various inflammatory cytokines, and pathologic angiogenesis induced by bleomycin treatment were suppressed with TLR-4 deletion. Furthermore, the increased expression of interleukin-6 (IL-6) in fibroblasts, endothelial cells, and immune cells in response to bleomycin in vivo and to lipopolysaccharide in vitro was notably abrogated in the absence of TLR-4. Moreover, TLR-4 deletion was associated with alleviated B cell activation and skew toward a Th2/Th17 response against bleomycin treatment. Importantly, in TSK/+ mice, another SSc murine model, TLR-4 abrogation attenuated hypodermal fibrosis.These results indicate the pivotal contribution of TLR-4 to the pathologic tissue fibrosis of SSc murine models. Our results indicate the critical role of TLR-4 signaling in the development of tissue fibrosis, suggesting that biomolecular TLR-4 targeting might be a potential therapeutic approach to SSc.

Atopic dermatitis (AD) is a chronic or relapsing inflam-matory skin disease. Scratching in AD patients results in proinflammatory cytokine and chemokine production. Thus, serum levels of monocyte chemotactic protein-1 (MCP-1), regulated on activation, normal T-cell expressed and secreted (RANTES ), macrophage inflammatory pro-tein (MIP)-1β, eotaxin, thymus and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) were increased in AD patients, compared with normal controls (1–4). With regards to Th1 chemokines such as interferon (IFN)-γ-inducible protein 10 (IP-10), IFN-γ-inducible T-cell α-chemoattractant (I-TAC), and monokine induced by IFN-γ (MIG), their expression in le-sional AD skin was confirmed by immunohistochemistry ±(5). They may negatively contribute to the development of AD because macrophages from AD patients produced lower levels of IP-10 compared to cells from healthy con -trols in response to α-toxin (6) and the expression of MIG and IP-10 was lower in Langerhans cells from patients with AD than from patients with psoriasis, whereas the opposite was observed for TARC and MDC (7).Visual analogue scale (VAS) is a valuable method to assess pruritus intensity in patients with pruritic der-matoses (8). In this study , we focus on temporal variation of pruritus in each patient and compare serum samples taken at different time points when there were only slight, if any, changes in disease activity. The aim of this study was to highlight the most sensitive chemokine associated with changes in pruritus in AD patients. MATERIALS AND METHODS

Visfatin, a novel adipocytokine, is related with chronic inflammatory diseases, especially those characterized by T helper (Th)1-type immune responses. In this study, we examined serum visfatin levels in patients with atopic dermatitis (AD) or cutaneous T-cell lymphoma (CTCL), both of which are Th2-dominant diseases. Serum visfatin levels in patients with AD or advanced stage CTCL were significantly elevated compared to healthy controls. In CTCL patients, serum visfatin levels significantly decreased after treatment. Serum visfatin levels correlated with eosinophil counts in AD patients, whereas they correlated with the visual analogue scale itch scores and serum C-C motif ligand (CCL) 11 and CCL26 levels in CTCL patients. Visfatin expression by adipose tissue in lesional skin of AD and advanced stage CTCL was enhanced compared to that of healthy controls. These results suggest that visfatin may also be important in the development of Th2-dominant diseases as well as in Th1-type diseases.

A multisite, open-label, non-randomized, single-arm phase II study was conducted to evaluate the efficacy and safety profiles of interferon-γ in Japanese patients diagnosed with stage IA-IIIA mycosis fungoides (MF). Interferon-γ was administrated i.v. to 15 patients at a dose of 2 million Japan reference units once daily over 5 days a week for the first 4 weeks, followed by subsequent intermittent injection. The primary efficacy end-point was the overall skin response during the study as assessed according to the evaluation criteria for chemotherapeutics for malignant skin carcinomas. Of the 15 patients, 11 (73.3%) achieved the objective response. Of the other four patients, three remained on treatment during study with stable disease and one showed disease progression. The median duration of stable disease was not reached but was 170 days or more (range, 29 to ≥253 days). As assessed according to the modified severity weighted assessment tool, nine patients (60.0%) achieved the objective response. The most common drug-related adverse event (AE) was influenza-like illness occurring in all patients enrolled, which did not lead to discontinuation of the study. Two serious AE were reported in two patients: aggravation of MF and aggravation of cataract, neither of which was considered directly related to the study drug. The patient with aggravation of MF died 50 days after the initiation of the study treatment. Another patient was withdrawn from the study due to drug-related cough, which disappeared after discontinuation of the drug. Overall, interferon-γ was effective and well-tolerated in Japanese patients with MF.

Our latest studies demonstrated the potential role of adipocytokines, including adiponectin, visfatin, retinol binding protein-4, and apelin, in the pathogenesis of systemic sclerosis (SSc). Given that resistin is another member of adipocytokines with pro-inflammatory and pro-angiogenic properties, we measured serum resistin levels by enzyme-linked immunosorbent assay in 52 SSc and 19 control subjects and evaluated their clinical correlation. Since serum resistin levels greatly and inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction [r = −0.78, p < 0.05 (n = 9)], we evaluated the clinical correlation of serum resistin levels in SSc patients with normal renal function (n = 43). Although serum resistin levels were comparable between diffuse cutaneous SSc (n = 22), limited cutaneous SSc (n = 21), and control subjects (n = 19) [median (25–75 percentiles); 18.7 ng/ml (13.3–48.0), 23.3 ng/ml (12.9–54.1), and 22.9 ng/ml (9.4–36.7), respectively], the prevalence of elevated right ventricular systolic pressure (RVSP) was significantly higher in SSc patients with elevated serum resistin levels than in those with normal levels [67 % (4/6) vs. 16 % (6/37), p < 0.05], and serum resistin levels were significantly increased in SSc patients with elevated RVSP (n = 10) as compared to those with normal RVSP (n = 33) [52.1 ng/ml (20.8–117.5) vs. 18.5 ng/ml (12.2–46.2), p < 0.05]. Thus, serum resistin levels may serve as a useful marker for pulmonary vascular involvement in SSc, suggesting a possible contribution of resistin to the pathogenesis of pulmonary arterial hypertension associated with SSc.