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As a major intracellular degradation system, autophagy contributes to the maintenance of skin keratinocyte homeostasis. However, the precise role of autophagy in skin differentiation has not been fully investigated. To clarify whether autophagy plays a role in skin differentiation and maturation, autophagy-related gene 7 (Atg7)-deficient mice were generated. Atg7-deficient mice cannot survive for more than 24 h after birth. Therefore, the skins of Atg7-deficient mice and wild-type mice (as a control) were grafted onto severe combined immunodeficient mice. The resulting morphological and pathological changes were monitored for 28 days. Histopathological examination revealed acanthosis, hyperkeratosis, and abnormal hair growth in the skin grafts from the Atg7-deficient mice. Immune-density analysis of the skin grafts revealed reduced immunostaining of keratinization-related proteins, including loricrin, filaggrin, and involucrin, in the skin grafts from the Atg7-deficient mice. Furthermore, quantitative RT-PCR and Western blot analyses revealed the reduced expression of these three keratinization-related proteins in the skin grafts from the Atg7-deficient mice. Morphometric analysis using electron microscopy further revealed a reduction in the number and diameter of the keratohyalin and trichohyalin granules in these skin grafts. The differences were maintained for at least 1 month after transplantation. These results show that autophagy has a significant role in epidermal keratinization and hair growth until a certain stage of maturation.

Generalized pustular psoriasis (GPP) is a rare form of psoriasis characterized by the presence of variable numbers of sterile pustules appearing in erythematous and scaly lesions, which are associated with moderate to severe constitutional symptoms. It can be life-threatening especially in the elderly; therefore, medical care must be performed in rapid succession of treatment especially in refractory cases. We have performed granulocyte and monocyte adsorption apheresis (GCAP) on three GPP cases associated with several systemic and laboratory findings. As a result, the edema, erythema and numbers of sterile pustules on the skin lesions were reduced dramatically in all three patients after the first sessions of GCAP therapy. The sizes of the psoriatic lesions were reduced in all three patients following a weekly GCAP treatment for 5 consecutive weeks. Psoriasis area and severity index on discharge had improved in all three patients. No serious adverse effects were observed for up to at least 8 months after treatment. We therefore considered GCAP as one effective alternative to currently existing therapies, especially for recalcitrant cases of GPP.

24歳，男性。頚部，腋窩，鼠径部を中心に弛緩性水疱，びらんが多発し，口腔内にも難治性アフタが出現した。皮膚生検の結果，棘融解細胞を伴う表皮内水疱を認め，蛍光抗体直接法では表皮細胞間にIgG，C3の沈着を認めた。血清中の抗デスモグレイン1，3抗体価も高値を示したため，粘膜皮膚型の尋常性天疱瘡と診断した。ステロイド内服，免疫抑制剤の投与にも関わらず，皮疹が増悪したため難治例と判断した。γ -グロブリン大量静注療法（IVIG）を施行したところ，臨床症状と自己抗体価などの検査所見はともに著明改善した。難治で治療に抵抗する症例および合併症や日和見感染などのおそれがあるために十分量のステロイド全身投与が困難な症例では，IVIGは優れたオプション治療である。

Recessive dystrophic epidermolysis bullosa (RDEB) is a disease characterized by recurrent blistering and chronic ulceration of the skin. In these patients, recurrent blisters frequently result in intractable skin ulcers due to impaired wound healing caused by mutations in the type VII collagen gene and malnutrition as well as by increased collagenase activity. To evaluate the efficacy of amnia for intractable ulcers in RDEB, we treated RDEB patients with amnia. The amniotic membrane was simply placed on the cleansed wound surface. The procedure was repeated once a week for up to 10 weeks. As a result, wound conditions improved remarkably after treatment with amnia for 2-10 weeks in all the patients, resulting in total re-epithelization of the ulcers. Amnia could be an effective therapy for intractable skin ulcers in RDEB patients, and should be considered as a re-emerging therapeutic option for the disease.

We report a 6-day-old Japanese girl showing generalized erythroderma accompanied by yellowish, exfoliative scaling that was accentuated on the face and scalp. Histological analysis showed psoriasiform dermatitis with acanthotic epidermis and premature shedding of the stratum corneum. Measurement of trypsin-like hydrolytic activity in SC showed six-fold greater activity compared with age-matched controls. DNA analysis revealed two mutations, 375delAT and 966insC, in exons 5 and 11, respectively, of the SPINK5 gene. Although at 4 weeks the child was still too young to display characteristic hair abnormalities or atopic diathesis, we diagnosed Netherton syndrome based on enzyme assay and DNA analysis.

Acne conglobata is an uncommon disorder characterized by the presence of nodulocystic lesions. Conservative therapy with oral and topical antibiotics is of limited efficacy in many cases, and surgical excision is often needed for removal of the cystic lesions. Treatment is particularly difficult in cases with lesions located in aesthetically sensitive areas, such as the face. We successfully treated a case of acne conglobata by CO(2) laser ablation to remove the top of the sinuses and their tracts. In addition, topical tretinoin therapy was also initiated simultaneously to prevent the appearance of new acne lesions. Based on the results, we propose that the use of CO(2) laser for opening the cysts, combined with topical tretinoin therapy to prevent the appearance of new lesions, is a powerful treatment option for acne conglobata.

Generalized pustular psoriasis (GPP) is a rare form of psoriasis characterized by the presence of variable numbers of sterile pustules appearing in erythematous and scaly lesions, which are associated with moderate to severe constitutional symptoms. It can be life-threatening especially in the elderly; therefore, medical care must be performed in rapid succession of treatment especially in refractory cases. We have performed granulocyte and monocyte adsorption apheresis (GCAP) on three GPP cases associated with several systemic and laboratory findings. As a result, the edema, erythema and numbers of sterile pustules on the skin lesions were reduced dramatically in all three patients after the first sessions of GCAP therapy. The sizes of the psoriatic lesions were reduced in all three patients following a weekly GCAP treatment for 5 consecutive weeks. Psoriasis area and severity index on discharge had improved in all three patients. No serious adverse effects were observed for up to at least 8 months after treatment. We therefore considered GCAP as one effective alternative to currently existing therapies, especially for recalcitrant cases of GPP.

Ablative fractional laser skin resurfacing (FLSR) has recently been used for the amelioration of acne scars, and previous studies have shown clinical effectiveness. Despite its extensive use, few studies have focused on the associated changes in biophysical properties of the epidermis. Herein, we evaluate transepidermal water loss, sebum levels, skin hydration, and skin elasticity, following FLSR treatments with an Er:YSGG laser device (Pearl FractionalTM, Cutera Inc., Brisbane, CA), employing non-invasive measurements.Five Japanese patients with facial acne scars underwent one FLSR session. Some acne scars appeared to become less obvious as a consequence of the treatment. All patients were aware of a feeling of skin tightness in treated areas.Objective measurements on the lower lateral angle of the eye and on the inner cheeks were evaluated at baseline and at 3 days, 1 week, and 4 weeks after FLSR. Transepidermal water loss showed a significant two-fold (100%) increase at day 3, but had returned to almost the baseline level at week 4 in both areas. Sebum secretion showed a 50% increase at day 3, but had returned to the baseline level after day 7. Skin hydration showed a significant decrease at day 3, but had returned to the baseline level by day 7, and showed significant improvement at the end of the study. Skin elasticity (R2) was still at baseline on day 3, but showed some improvement--an increase of at least 30%--at the end of the study.Based on our findings, we believe that FLSR should be performed no more than once a month to allow sufficient time for the damaged skin to recover its barrier function in most areas of the face.

The state of the skin changes drastically depending on the ambient temperature. Skin epidermal keratinocytes express thermosensitive transient receptor potential vanilloid (TRPV) cation channels, TRPV3 and TRPV4. These multimodal receptors are activated by various kinds of chemical and physical stimuli, including warm temperatures (30°C). It has been suggested that TRPV4 is involved in cell-cell junction maturation; however, the effect of temperature fluctuations on TRPV4-dependent barrier homeostasis is unclear. In the present study, we demonstrated that activation of TRPV4 was crucial for barrier formation and recovery, both of which were critical for the prevention of excess dehydration of human skin keratinocytes. TRPV4 activation by physiological skin temperature (33°C), GSK1016790A or 4α-PDD allowed influx of Ca(2+) from extracellular spaces which promoted cell-cell junction development. These changes resulted in augmentation of intercellular barrier integrity in vitro and ex vivo. TRPV4 disruption reduced the increase in trans-epidermal resistance and increased intercellular permeation after a Ca(2+) switch. Furthermore, barrier recovery after the disruption of the stratum corneum was accelerated by the activation of TRPV4 either by warm temperature or a chemical activator. Our results suggest that physiological skin temperatures play important roles in cell-cell junction and skin barrier homeostasis through TRPV4 activation.

Photodynamic therapy (PDT) with topical 5-aminolevulinic acid (ALA) is reported to be an effective and safe treatment for superficial non-melanoma skin cancers. We have developed an photodynamic therapy with topical delta-aminolevulinic acid (ALA-PDT) protocol using intense pulsed light (IPL) for treating Bowen's disease (BD). Three patients diagnosed with BD by skin biopsy were recruited in this study. They received IPL treatment after 3 h of occlusive dressing with application of ALA. This protocol was repeated every 2 weeks for a total of five sessions. The treated areas did not show any signs of BD for more than 1 year; therefore, it appeared that the affected areas showed improvement in all the patients. No patients withdrew from the study because of side-effects. ALA-PDT with IPL as a light source is well tolerated by patients and is beneficial for treating BD.

Venous leg ulcers are resistant to various treatments, including autologous skin grafting. We applied an allogeneic cultured dermal substitute in a patient with such a wound, and the wound improved, healthy granulation tissue formed, and the size of the wound was reduced.

A 37-year-old Japanese male presented to us with persistent asteatotic skin with mild erythema on the trunk and extremities. Skin biopsy from the left knee showed marked epidermal acanthosis and hyperkeratosis, and milder granular degeneration. Ultrastructural analysis revealed clumping of the keratin filaments within suprabasal keratinocytes of the epidermis. Following direct sequencing, we found a single nucleotide substitution in one allele at the residue position 466 of the 1A rod domain segment (CGC to TGC, arginine to cysteine; R156C) in keratin 10. Clinical manifestations and molecular analysis indicated that R156C mutation in keratin 10 gene (KRT10) causes a mild form of epidermolytic hyperkeratosis (EHK) in the presented case.

Recessive dystrophic epidermolysis bullosa (RDEB) is a disease characterized by recurrent blistering and chronic ulceration of the skin. In these patients, recurrent blisters frequently result in intractable skin ulcers due to impaired wound healing caused by mutations in the type VII collagen gene and malnutrition as well as by increased collagenase activity. To evaluate the efficacy of amnia for intractable ulcers in RDEB, we treated RDEB patients with amnia. The amniotic membrane was simply placed on the cleansed wound surface. The procedure was repeated once a week for up to 10 weeks. As a result, wound conditions improved remarkably after treatment with amnia for 2-10 weeks in all the patients, resulting in total re-epithelization of the ulcers. Amnia could be an effective therapy for intractable skin ulcers in RDEB patients, and should be considered as a re-emerging therapeutic option for the disease.

The patient, 56-year-old man who was working as a clerk and a farmer, presented with nodules that had appeared on the dorsa of both his hands 3 months earlier. At the first examination, there were multiple dark-red nodules scattered on the fingers, dorsa and wrists of both hands. The nodules were up to 3 cm in diameter and had crusts in the incenters. The patient was suspected to suffer from prurigo and was subsequently treated with topical steroid, but the nodules did not respond. Therefore, a skin biopsy and fungal culture were performed, and the patient was finally diagnosed as having bilateral multiple sporotrichosis. He was then successfully treated with local thermotherapy and oral potassium iodide. Bilaterally-distributed lymphangitic sporotrichosis is very rare and often difficult to diagnose. Careful attention is required to avoid misdiagnosis.