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Sweat includes active components and metabolites, which are needed to maintain skin homeostasis. Component changes in sweat derived from atopic dermatitis (AD) have been reported. To investigate the influence of sweat components on the pathogenesis of AD, we performed a multifaceted assessment, including nuclear magnetic resonance spectroscopy-based metabolomic analysis, and linked these features to clinical features of AD. Distinctive properties of AD sweat are the quite-variation in protein, anti-microbial peptides and glucose concentrations. pH, sodium, and other salt levels in sweat of AD were comparable to that of healthy subjects. Sweat from AD patients with acute inflammation had a more prominent increase in glucose concentration than sweat from healthy individuals or those with AD with chronic inflammation. Topical glucose application delayed recovery of transepidermal water loss in barrier-disrupted mice. Furthermore, the glucose transporter GLUT2 was highly expressed in the lumen of sweat glands from AD patients. AD patients with chronic inflammation had significantly increased GLUT2 mRNA expression and near normal sweat glucose levels. Despite the small sample size in our study, we speculate that the increased glucose levels might be affected by AD severity and phenotype. We hope that this report will bring novel insight into the impact of sweat components on the clinical manifestation of AD.

Neurological disorders can cause hypohidrosis and/or anhidrosis by disturbing either the central or the peripheral nervous systems.1-3 Although a syringotropic variant of cutaneous sarcoidosis causes dysfunction of sweating, systemic sarcoidosis rarely causes hypohidrosis or anhidrosis.4,5 Here we present a novel case of an acquired anhidrosis in a patient with systemic sarcoidosis. Furthermore, we developed a novel methodology to quantify nerve fibers around eccrine glands using confocal microscopy and found that nerve fibers around eccrine glands in anhidrotic areas are significantly decreased compared to hidrotic areas. This article is protected by copyright. All rights reserved.

BACKGROUND Bilirubin is an essential antioxidant. Its oxidative metabolites, biopyrrins, are sensitive urinary markers of oxidative stress. Multiple studies suggest that oxidative stress affects the pathogenesis of skin diseases such as atopic dermatitis (AD). AIM To examine oxidative stress-induced bilirubin oxidation and its association with AD pathogenesis in adults. METHODS In total, 11 patients with AD and 7 healthy controls (HCs) were enrolled. Bilirubin oxidation profiles in the combined urine of the patients and that of the HCs were examined using high-performance liquid chromatography (HPLC) and fast atom bombardment mass spectrometry. The concentrations of urinary biopyrrins and serum biomarkers for AD disease severity, such as IgE and thymus and activation-regulated chemokine (TARC)/CCL17, were measured by ELISA to determine correlations between urinary biopyrrins and serum biomarkers. Local bilirubin oxidation in AD skin lesions was assessed by immunohistochemical analyses using two antibodies against bilirubin. RESULTS Levels of dipyrrole-monopyrrole-aldehyde, a novel urinary biopyrrin, were higher in patients with AD than in HCs, and increased with disease severity based on the SCORing Atopic Dermatitis (SCORAD) objective scoring system. Additionally, urinary biopyrrin levels correlated significantly with serum IgE and TARC/CCL17 levels. Furthermore, immunohistochemical analyses revealed that biopyrrins were strongly expressed in both infiltrating and resident cells in AD lesions. However, bilirubin was expressed at low levels in the lesions, suggesting that bilirubin oxidation is augmented in AD lesions. CONCLUSIONS Bilirubin oxidation derived from oxidative stress in the skin lesions can be associated with disease severity of AD.

The AMPK-related kinase NUAK2 has been implicated in melanoma growth and survival outcomes, but its therapeutic utility has yet to be confirmed. In this study, we show how its genetic amplification in PTEN-deficient melanomas may rationalize the use of CDK2 inhibitors as a therapeutic strategy. Analysis of array-CGH data revealed that PTEN deficiency is coupled tightly with genomic amplification encompassing the NUAK2 locus, a finding strengthened by immunohistochemical evidence that phospho-Akt overexpression was correlated with NUAK2 expression in clinical specimens of acral melanoma. Functional studies in melanoma cells showed that inactivation of the PI3K pathway upregulated p21 expression and reduced the number of cells in S phase. NUAK2 silencing and inactivation of the PI3K pathway efficiently controlled CDK2 expression, whereas CDK2 inactivation specifically abrogated the growth of NUAK2-amplified and PTEN-deficient melanoma cells. Immunohistochemical analyses confirmed an association of CDK2 expression with NUAK2 amplification and p-Akt expression in melanomas. Finally, pharmacologic inhibition of CDK2 was sufficient to suppress the growth of NUAK2-amplified and PTEN-deficient melanoma cells in vitro and in vivo. Overall, our results show how CDK2 blockade may offer a promising therapy for genetically defined melanomas, where NUAK2 is amplified and PTEN is deleted. Cancer Res; 75(13); 2708–15. ©2015 AACR.

Prurigo is a common, but treatment-resistant, skin disease characterized by persistent papules/nodules and severe itching. Prurigo occurs in association with various underlying diseases, such as diabetes, chronic renal failure, and internal malignancies. Atopic dermatitis is occasionally complicated by prurigo lesions. However, the pathology of prurigo is completely undefined. We demonstrate that repeated intradermal administration of Ag to IgE-transgenic mice causes persistent and pruritic papulonodular skin lesions mimicking prurigo. Skin lesions were histopathologically characterized by irregular acanthosis and dermal cellular infiltrates comprising eosinophils, mononuclear cells, and basophils, with epidermal nerve fiber sprouting. In vivo depletion of basophils alleviated skin reactions, indicating that the inflammation is basophil dependent. Unexpectedly, STAT6 signaling was unnecessary for skin lesion development if IgE was present. Moreover, the absence of STAT6 signaling exacerbated the inflammation, apparently as the result of impaired generation of an M2-type anti-inflammatory macrophage response. These results provide novel insights into the pathologic mechanisms underlying prurigo. Although basophils are indispensable for prurigo-like inflammation, Th2 immunity mediated by STAT6 appears to play a protective role, and therapies targeting Th2-type cytokines may risk aggravating the inflammation.

It is suggested that polymyositis, an autoimmune inflammatory myopathy, is mediated by autoaggressive CD8 T cells. Skeletal muscle C protein is a self-antigen that induces C protein-induced myositis, a murine model of polymyositis. To establish a new murine model of myositis inducible with a single CD8 T-cell epitope peptide that derives from the C protein, three internet-based prediction systems were employed to identify 24 candidate peptides of the immunogenic fragment of the C protein and bind theoretically to major histocompatibility complex class I molecules of C57BL/6 (B6) mice. RMA-S cell assay revealed that a HILIYSDV peptide, amino acid position 399–406 of the C protein, had the highest affinity to the H2-Kb molecules. Transfer of mature bone marrow-derived dendritic cells pulsed with HILIYSDV induced myositis in naive B6 mice. This myositis was suppressed by anti-CD8-depleting antibodies but not by anti-CD4-depleting antibodies. Because this myositis model is mediated by CD8 T cells independently of CD4 T cells, it should be a useful tool to investigate pathology of polymyositis and develop therapies targeting CD8 T cells.

An early and accurate diagnosis is critical for the optimal management of subungual melanoma; the absence of Hutchinson's nail sign makes an accurate diagnosis extremely difficult. Previous publications show that most subungual melanomas have Hutchinson's nail sign. In this report, we present a rare case of a subungual melanoma without Hutchinson's nail sign and discuss the importance of cautious evaluations of Hutchinson's nail sign by dermoscopy.

Atopic dermatitis (AD) is caused by a complex interrelationship of a variety of genetic and environmental factors, leading to the maintenance of the chronic inflammatory skin condition.

Using large-scale receipt data, we analyzed the differences in the prescription of drugs and their costs between dermatology and pediatrics in the treatment of atopic dermatitis (AD) in children. Between August 2010 and July 2011, 50 706 patients were diagnosed as having AD, and the data of 21 075 (15 257 dermatology, 5818 pediatric) patients aged 0-14 years were included in this study. The use of classes I (strongest), II (very strong), and III (strong) topical corticosteroids and tacrolimus was significantly higher in dermatology than in pediatrics (class I, 2.88% vs 0.76%; class II, 27.68% vs 8.32%; class III, 52.53% vs 39.88%; tacrolimus, 5.05% vs 2.82%; all P < 0.05). Although total drug costs were higher in dermatology than in pediatrics, mean drug costs per person were significantly higher in pediatrics. Moisturizers and protective agents had the highest cost (~ ¥690 million). The introduction rate of generic drugs was low at 8.3% among classes I-V. The introduction rate of moisturizers and protective agents, for which costs were the highest, was approximately 9%. The prescription of generic classes II-V topical corticosteroids and moisturizers and protective agents was also significantly higher in dermatology than in pediatrics (P < 0.05). Among patients younger than 2 years, 4405 received drugs for AD; classes I and II topical corticosteroids and tacrolimus (against the guidelines) were administrated in 35 (0.8%), 474 (10.8%) and 29 patients (0.7%), respectively. The introduction of generic drugs is still low, and the use of generic moisturizers and protective agents should be addressed further.

Among allergic skin diseases, atopic dermatitis is the most difficult to cure. In the majority of patients, atopic dermatitis can be easily controlled by treatment based on three therapeutic approaches: avoidance of precipitating factors, skin care, and medication. In some adult patients, however, severe atopic dermatitis is refractory to treatment, and no fundamental effective treatment modality has yet been established for such cases. Chronic contact dermatitis without an identified causative hapten is also considered an allergic skin disease that is difficult to cure. Topical nucleic acid-based medications are currently being applied clinically, and an ointment containing nuclear factor-κB decoy oligodeoxynucleotides (hereafter referred to as Decoy) has reached clinical trials. In addition, synthetic double-stranded DNA with high affinity for signal transducers and activators of transcription 6 (STAT6) introduced in vivo as a decoy cis element to bind the transcriptional factor and block the activated gene that contributes to the onset and progression of atopic dermatitis functions as an effective therapeutic agent. We also introduce another STAT1 decoy treatment, cytosine-phosphate-guanine-ODN or STAT6 small interfering RNA therapy, for allergic skin diseases.

Current studies have revealed that stem cells are more radiosensitive than mature cells. As somatic stem cells are mostly kept in a quiescent state, this conflicts with Bergonie and Tribondeau's law that actively mitotic cells are the most radiosensitive. In this study, we focused on hair graying to understand the stress-resistance of melanocyte stem cells (McSCs). We used Dct-H2B-GFP transgenic mice which enables the stable visualization of McSCs and an anti-Kit monoclonal antibody which selectively eradicates amplifying McSCs. The results demonstrate that quiescent McSCs are rather radiosensitive, but the coexistence of non-quiescent McSCs provides the stem cell pool with radioresistance. The irradiated quiescent McSCs prematurely differentiate in the niche upon their activation without sufficiently renewing themselves for cyclic hair pigmentation. These data indicate that tissue radiosensitivity is largely dependent on the state of somatic stem cells under their local microenvironment.

A 42-year-old Japanese woman presented with systemic skin sclerosis and erythema as well as back erosions in July 2012. She had developed intractable oral aphtha 8 years before. Depigmentation, which appeared on the neck and axilla, was resistant to narrow-band ultraviolet B therapy (nbUVB) during a previous clinic visit in 2005. Psoriasis-like lesions appeared around the patient's waist and developed on her entire body in January 2011 (figure 1A). The patient was diagnosed with psoriasis vulgaris [...]

Cutaneous angiosarcoma is a life-threatening tumor that is resistant to conventional therapies. The therapeutic effects of Sendai virus particles (hemagglutinating virus of Japan envelope: HVJ-E) carrying IL-2 gene (HVJ-E/IL-2) were examined in a mouse model of angiosarcoma. Intra-tumoral injection of HVJ-E/IL-2 effectively inhibited the growth of angiosarcoma cells (ISOS-1) inoculated in mice and improved tumor-free rates. HVJ-E/IL-2 stimulated local accumulation of CD8 (+) T cells and NK cells and reduced regulatory T cells in regional lymph nodes. Notably, the prevalence of myeloid-derived suppressor cells was lower in HVJ-E/IL-2-treated mice than in HVJ-E-treated mice. HVJ-E/IL-2 treatment promoted IFN-γ production from CD8 (+) T cells in response to tumor cells, more significantly than HVJ-E treatment. Greatly improved tumor-free rates were obtained when sunitinib, a tyrosine kinase inhibitor, was administered in combination with HVJ-E/IL-2. Immunogene therapy with HVJ-E/IL-2 with or without sunitinib could be a promising therapeutic option for cutaneous angiosarcoma.

Summary Indomethacin is a cyclo-oxygenase inhibitor, and shows therapeutic potential for various eosinophilic skin diseases, particularly eosinophilic pustular folliculitis. One of the unique characteristics of indomethacin is that, unlike other non-steroidal anti-inflammatory drugs, it is a potent agonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a receptor for prostaglandin D2 (PGD2). This study investigated the pharmacological actions of indomethacin on eosinophil migration to clarify the actual mechanisms underlying the therapeutic effects of indomethacin on eosinophilic pustular folliculitis. Eosinophils exhibited chemokinetic and chemotactic responses to both PGD2 and indomethacin through CRTH2 receptors. Pre-treatment of eosinophils with indomethacin greatly inhibited eosinophil migration to PGD2 and, to a much lesser extent, to eotaxin (CCL11); these effects could be mediated by homologous and heterologous desensitization of eosinophil CRTH2 and CCR3, respectively, by agonistic effects of indomethacin on CRTH2. Indomethacin also cancelled a priming effect of Δ12-PGJ2, a plasma metabolite of PGD2, on eosinophil chemotaxis to eotaxin. Indomethacin down-modulated cell surface expression of both CRTH2 and CCR3. Hair follicle epithelium and epidermal keratinocytes around eosinophilic pustules together with the eccrine apparatus of palmoplantar lesions of eosinophilic pustular folliculitis were immunohistochemically positive for lipocalin-type PGD synthase. Indomethacin may exert therapeutic effects against eosinophilic skin diseases in which PGD2-CRTH2 signals play major roles by reducing eosinophil responses to PGD2.

Background Aquaporin-5 (AQP5) is a member of the water channel protein family. Although AQP5 was shown to be present in sweat glands, the presence or absence of regulated intracellular translocation of AQP5 in sweat glands remained to be determined. Objective We investigated whether AQP5 in sweat glands translocated during sweating, and also sought to determine the intracellular signal that triggers this translocation. Methods Immunofluorescent analyses of AQP5 in mouse and human sweat glands were performed. Madin-Darby Canine kidney (MDCK) cell lines stably expressing human AQP5 were generated, and the regulated translocation of AQP5 in the polarized cells was assessed by immunofluorescent analysis and biotinylation assays. Results AQP5 showed rapid translocation to the apical membranes during sweating. In human eccrine sweat glands, immunoreactive AQP5 was detected in the apical membranes and the intercellular canaliculi of secretory coils, and in the basolateral membranes of the clear cells. Treatment of human AQP5-expressing MDCK cells with calcium ionophore A23187 resulted in a twofold increase of AQP5 in the apical membranes within 5 min. Conclusion The regulated AQP5 translocation may contribute to sweat secretion by increasing the water permeability of apical plasma membranes of sweat glands.

Symptoms of acquired idiopathic generalized anhidrosis (AIGA) include heat retention and/or heat stroke due to the effects of the disorder on the perspiration ability of the whole body under thermal environmental changes or exercise. Additionally, cholinergic urticaria can also occur in these patients. AIGA has a major impact on everyday life. However, the effects of AIGA severity on the quality of life (QOL) of the patients have not been sufficiently defined. The objective of this study was to evaluate the correlation between AIGA severity and QOL. Study subjects comprised 44 patients diagnosed with AIGA at three registered institutions. AIGA severity assessment was conducted and the Dermatology Life Quality Index (DLQI) questionnaire was administered. Correlations between AIGA severity and DLQI, as well as severity by DLQI subscale, were assessed. We found a positive correlation between total score of AIGA severity criteria and DLQI total scores (R = 0.720, P = 0.001). The impairment increased with the increase in AIGA severity (P < 0.01). In relation to the DLQI subscales, leisure (social and sporting activities) impairment was significantly higher for patients with severe AIGA than those with mild AIGA (P < 0.01). Comparing QOL for AIGA patients with that of patients with other dermatological disorders, it is possible that QOL impairment for AIGA patients is as severe as that for patients with atopic dermatitis. AIGA severity and DLQI are correlated and AIGA patients experience disruption of everyday life more broadly than conventionally perceived.

This chapter introduces the history of perspiration research and the latest perspiration research findings. Many investigators worldwide, particularly those in Japan, have carried forward globally leading studies on perspiration. This chapter will introduce the history of studies on the physiology of perspiration and perspiration research by classifying it in three stages, namely the early, maturation, and development stages, with a focus on Japanese researchers who have played active roles in each stage. In particular, I will introduce two historical physiologists in detail, Dr. Yasu Kuno, a former professor of Nagoya University, who dramatically revealed the physiology of perspiration in the early and maturation stages, and Dr. Kenzo Sato, a former professor of the University of Iowa.

This chapter introduces the history of perspiration research and the latest perspiration research findings. Many investigators worldwide, particularly those in Japan, have carried forward globally leading studies on perspiration. This chapter will introduce the history of studies on the physiology of perspiration and perspiration research by classifying it in three stages, namely the early, maturation, and development stages, with a focus on Japanese researchers who have played active roles in each stage. In particular, I will introduce two historical physiologists in detail, Dr. Yasu Kuno, a former professor of Nagoya University, who dramatically revealed the physiology of perspiration in the early and maturation stages, and Dr. Kenzo Sato, a former professor of the University of Iowa.

Objective It has been reported that polymyositis (PM) is driven by CD8+ cytotoxic T lymphocytes. The C protein–induced myositis (CIM) model we have established is similar to PM in pathology except that it undergoes spontaneous remission. We undertook the present study to delineate the roles of innate and acquired immunity in myositis. Methods C57BL/6 mice were immunized with recombinant C protein fragments together with Freund's complete adjuvant (CFA) and Toll-like receptor (TLR) ligands at hind leg footpads and tail bases. CIM mediated by adoptive transfer of T cells to naive mice was treated with cytokine antagonists. Results Second immunization with C protein fragments revealed no induction of tolerance. Injection of CFA and TLR ligands at the hind leg footpads reinduced myositis in the same legs. Interestingly, initial myositis was observed only in the CFA-treated forelegs. Transfer of C protein fragment–specific T cells from mice with CIM induced myositis in CFA- and TLR ligand–treated legs of recipient mice. CFA treatment resulted in the recruitment of macrophages producing inflammatory cytokines. Induction of myositis was inhibited by blocking interleukin-1 receptor or tumor necrosis factor α. Conclusion Myositis development requires activation of autoaggressive T cells and conditioning of muscle tissue. CIM regression is due to attenuation of local CFA-induced immune activation. These results are in accordance with a “seed and soil” model of disease development and might offer clues to decipher clinical aspects of PM.

Background Lichen planus (LP) is a common skin disorder of unknown aetiology that affects the skin, mucous membranes and nails. Although metal allergies have been implicated in the development of oral LP (OLP), the contribution of these allergies to nail LP (NLP) has yet to be studied in detail. Objective To elucidate the link between metal allergy and NLP. Methods We retrospectively analysed 115 LP patients with respect to the contribution of metals to either NLP or OLP. We also attempted to detect the specific metals involved in these nail lesions. Results Of the 79 patients that received a metal patch test (PT), 24 (30%) were positive for at least one of the metal compounds tested. Notably, the prevalence of positive reactions to metals in the NLP patients was significantly higher as compared with the OLP patients (59% vs. 27%, P

Itch accompanies various skin diseases. As a number of mediators other than histamine can be involved in the itch sensation, H1 receptor antagonists are not necessarily effective in treating itch. External application of antipruritic drugs is occasionally used as an alternative therapy for pruritic skin conditions, such as pruritus on primary non-diseased, non-inflamed skin. Even so, the actual effects of these drugs on the itch sensation have yet to be studied in detail. To verify the antipruritic effects of crotamiton, capsaicin, and a corticosteroid on the itch sensation, we examined the inhibitory effects of these drugs on various pruritogen-induced scratching behaviors in mice. Topical application of 10% crotamiton moderately inhibited histamine-, serotonin-, and PAR-2 agonist-induced scratching behaviors. Topical capsaicin (0.025%) also exerted a moderate suppressive effect on histamine-, substance P-, and PAR-2 agonist-induced itch responses. Notably, topical corticosteroid (0.05% clobetasol propionate) remarkably inhibited the scratching behaviors induced by all of the pruritogenic agents tested. Therapeutic effects of capsaicin on substance P-induced pruritus did not seem to be mediated by desensitization of the TRPV1 (+) C fibers and/or by altered responsiveness of the mast cells. In addition, the antipruritic effects of crotamiton and corticosteroid appear to be, at least partly, associated with a TRPV1-independent pathway. This study examined the itch responses to pruritogens and demonstrated the mode of action of the externally applied antipruritic drugs.

Summary Congenital insensitivity to pain with anhidrosis is a rare autosomal recessive hereditary disorder that is characterized by having both sensory neuropathy and anhidrosis. A 6-year-old Japanese boy presented with recurrent fever, lack of sweating, occult bone fractures and impaired pain sensation without mental retardation. Genetic analyses revealed compound heterozygous mutations in the NTRK1 gene that encodes TrkA, which is a receptor for nerve growth factor. While there were no apparent changes in the patient’s dermal eccrine glands, the quantitative sudomotor axon reflex test with acetylcholine chloride revealed a complete loss of both the axon reflex-mediated and the directly activated sweat responses. On the other hand, the histamine prick test induced a normal weal response surrounded by a flare phenomenon. Notably, the patient felt both an itch sensation after histamine and a burning sensation after topical capsaicin application. Consistent with these findings, PGP9.5+ nerve fibre innervation of the papillary dermis was observed, although the fibres were completely absent around the eccrine glands. These findings suggest that there was a partial preservation of the nerve endings that express the H1 receptor and/or TRPV1 in the upper dermis, even though there were mutations of the NTRK1 gene in this case.

Psoriasis is a chronic skin disease mediated by Th17 and/or Th1 cells. Tim-3 is a cell surface molecule preferentially expressed on Th17 and Th1 cells. The interaction of Tim-3 with Tim-3 ligand inhibits cytokine production. To assess whether T cells in psoriasis have functional abnormalities, expression of cell surface Tim-3 on blood T cells producing interleukin-17 (Th17/Tc17 cells) or interferon-γ (Th1/Tc1 cells) was examined by flow cytometry. Psoriasis patients had higher numbers of Th17 and Tc17 cells, as well as Th1 and Tc1 cells, than healthy donors. However, Th17, Th1 and Tc1 cells in psoriasis did not efficiently express Tim-3 upon activation, compared with those from atopic dermatitis and healthy donors. Tim-3- cells showed more potent cytokine production than Tim-3+ cells. Impaired Tim-3 expression allows Th17, Th1 and Tc1 cells to escape from Tim-3-mediated negative regulatory systems and may contribute to the pathogenesis of psoriasis.

Atopic dermatitis (AD) is a common, chronically relapsing skin disease. It is very difficult to treat severe type AD by steroid ointment. We therefore hypothesized that synthetic double-stranded DNA with a high affinity for Signal Transducers and Activators of Transcription 6 (STAT6) could be introduced in vivo as a decoy cis elements to bind the transcriptional factor and to block the gene activation of contributing the onset and progression of AD, thus providing effective therapy for AD. Treatment by the transfection of STAT6 decoy oligodeoxynucleotides (ODN), but not scrambled decoy ODN in the AD model mice, had a significantly inhibitory effect on not only STAT6 binding to nuclei but also on the third phase response. A histological analysis revealed that both edema and the infiltration of eosinophils and degranulated mast cells significantly decreased in STAT6 decoy ODN transfected mice. We herein report the first successful in vivo transfer of STAT6 decoy ODN to reduce the third phase reaction in AD model mice, thereby providing a new therapeutic strategy for atopic dermatitis. We also introduce another NF-kB Decoy Oligodeoxynucleotides therapy or STAT6siRNA therapy for allergic diseases.