Yoshinori Sasaki

A Comparison of the Efficacy, Relapse Rate and Side Effects among Three Modalities of Systemic Corticosteroid Therapy for Alopecia Areata

Background: Systemic corticosteroids are one of the most commonly used therapeutic modalities for patients with extensive alopecia areata (AA), although they entail several drawbacks. Objective: To determine the best modality for systemic corticosteroid use in terms of their efficacy, relapse rate, and side effects. Methods: Fifty-one patients with single or multiple AA (AA/multiplex) and 38 patients with alopecia totalis or AA universalis (AA totalis/universalis) were enrolled in this open study. They were randomly divided into three groups depending on the time of their initial visit. They were administered (1) oral dexamethasone (Dex) 0.5 mg/day for 6 months (Dex group), (2) intramuscular triamcinolone acetonide (imTA) 40 mg once a month for 6 months followed by 40 mg once every 1.5 months for 1 year (imTA group), and (3) pulse therapy (PT) using oral predonine 80 mg for 3 consecutive days once every 3 months (PT group). After the treatment, each treatment modality was evaluated by the response rate, relapse rate, and side effect profile. Results: The response rate of AA/multiplex was significantly better in the imTA group than in the Dex group. The overall relapse rate and that of AA totalis/universalis were significantly better in the PT group than in the Dex group. Dysmenorrhea was the most common and problematic side effect. Impairment of the adrenocortical reserve was seen in 7% of the PT group and 23% of the imTA group, which was recov ered without any further medical treatment. Conclusion: imTA or pulse therapy is effective for AA and has an acceptable level of side effects. The development of a new strategy to reduce the relapse rate is needed.

TGF-β1 dampens the susceptibility of dendritic cells to environmental stimulation, leading to the requirement for danger signals for activation

In contrast to its favourable effects on Langerhans cell (LC) differentiation, transforming growth factor (TGF)‐β1 has been reported to prevent dendritic cells from maturing in response to tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β, or lipopolysaccharide (LPS). We first characterized the effects of TGF‐β1 on dendritic cell function by testing the response of TGF‐β1‐treated monocyte‐derived dendritic cells (MoDCs) to maturation stimuli that LCs receive in the epidermis, namely, haptens, ATP and ultraviolet (UV). TGF‐β1 treatment, which augmented E‐cadherin and down‐regulated dendritic cell‐specific ICAM3‐grabbing non‐integrin on MoDCs, significantly suppressed their CD86 expression and hapten‐induced expression of IL‐1β and TNF‐α mRNA and protein. As TGF‐β1‐treated MoDCs lacked Langerin expression, we demonstrated the suppressive effects of TGF‐β1 on haematopoietic progenitor cell‐derived dendritic cells expressing both CD1a and Langerin. These suppressive effects of TGF‐β1 increased with the duration of treatment. Furthermore, TGF‐β1‐treated MoDCs became resistant to apoptosis/necrosis induced by high hapten, ATP or UV doses. This was mainly attributable to dampened activation of p38 mitogen‐activated protein kinase (MAPK) in TGF‐β1‐treated MoDCs. Notably, although ATP or hapten alone could only induce CD86 expression weakly and could not augment the allogeneic T‐cell stimulatory function of TGF‐β1‐treated MoDCs, ATP and hapten synergized to stimulate these phenotypic and functional changes. Similarly, 2,4‐dinitro, 1‐chlorobenzene (DNCB) augmented the maturation of TGF‐β1‐treated MoDCs upon co‐culture with a keratinocyte cell line, in which ATP released by the hapten‐stimulated keratinocytes synergized with the hapten to induce their maturation. These data may suggest that TGF‐β1 protects LCs from being overactivated by harmless environmental stimulation, while maintaining their ability to become activated in response to danger signals released by keratinocytes.

Oxidation of Cell Surface Thiol Groups by Contact Sensitizers Triggers the Maturation of Dendritic Cells

p38 mitogen-activated protein kinase (MAPK) has a crucial role in the maturation of dendritic cells (DCs) by sensitizers. Recently, it has been reported that the oxidation of cell surface thiols by an exogenous impermeant thiol oxidizer can phosphorylate p38 MAPK. In this study, we examined whether sensitizers oxidize cell surface thiols of monocyte-derived DCs (MoDCs). When cell surface thiols were quantified by flow cytometry using Alexa fluor maleimide, all the sensitizers that we examined decreased cell surface thiols on MoDCs. To examine the effects of decreased cell surface thiols by sensitizers on DC maturation, we analyzed the effects of an impermeant thiol oxidizer, o-phenanthroline copper complex (CuPhen). The treatment of MoDCs with CuPhen decreased cell surface thiols, phosphorylated p38 MAPK, and induced MoDC maturation, that is, the augmentation of CD83, CD86, HLA-DR, and IL-8 mRNA, as well as the downregulation of aquaporin-3 mRNA. The augmentation of CD86 was significantly suppressed when MoDCs were pretreated with N-acetyl-L-cystein or treated with SB203580. Finally, we showed that epicutaneous application of 2,4-dinitrochlorobenzene on mouse skin significantly decreased cell surface thiols of Langerhans cells in vivo. These data suggest that the oxidation of cell surface thiols has some role in triggering DC maturation by sensitizers.

Molecular Events in Human T Cells Treated with Diesel Exhaust Particles or Formaldehyde that Underlie Their Diminished Interferon-γ and Interleukin-10 Production

Background: A series of epidemiological and experimental studies have suggested that diesel exhaust particles (DEP) and formaldehyde (FA) may help trigger T helper type 2 (Th2)-mediated allergic responses. Methods: To identify the molecular events by which DEP and FA induce a Th2-skewed immune response, we stimulated T cells from healthy subjects with anti-CD3/anti-CD28 monoclonal antibodies and examined the effect of pretreatment with DEP or FA on mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-κB by Western blotting and colorimetric NF-κB assays. We also examined the mRNA expression profiles of the T cells by microarray and real-time PCR analyses. Results:FA selectively suppressed interferon (IFN)-γ and interleukin-10 mRNA expression and protein production in stimulated T cells, as we previously reported with DEP. In the present study, we found that both DEP and FA suppressed NF-κB signaling and activated MAPKs. Both also significantly suppressed the mRNA expression of T-bet, Txk and c-Maf. Microarrays revealed significant augmentation of the expression of 2 FoxO3a-dependent genes, namely glucocorticoid-induced leucine zipper and growth arrest and DNA damage-inducible gene 45α (Gadd45a), which are known to modulate T cell immune responses. Treatment with N-acetylcysteine reversed the augmented Gadd45a mRNA response and caused the suppressed IFN-γ mRNA response to recover. Conclusions:DEP and FA have similar transcriptional and nontranscriptional effects on T cell signaling that together promote a Th2-skewed immune response.

Anaphylaxis due to burdock

A 53‐year‐old Japanese man, with a history of developing urticaria (once after consuming mackerel and 10 times after consuming boiled burdock, carrot, curry, and rice), presented with redness over his entire body and dyspnea 1 h after eating boiled burdock. Physical examination revealed a low blood pressure of 64/29 mmHg and stridor, together with striking redness of the whole body; he was diagnosed to be in anaphylactic shock.

Alleviation of the Plantar Discomfort Caused by Pachyonychia congenita with Topical Applications of Aluminum Chloride and Salicylic Acid Ointments

Mariko Takayama a , Ryuhei Okuyama a , Yoshinori Sasaki a , Toshihiro Ohura b , Hachiro Tagami a , Setsuya Aiba a Departments of a Dermatology and b Pediatrics, Tohoku University Graduate School of Medicine, Sendai , Japan pear at various locations on the body around that time. One of them had been removed by a local physician at the age of 25 years and was diagnosed as an epidermal cyst. On physical examination, all of her fi ngernails and toenails were thickened with subungual hyperkeratosis despite frequent shaving, revealing a yellowish brown color. Her soles were elastic and hard due to hyperkeratosis but wet with hyperhidrosis. There were multiple subcutaneous tumors in the axillae, buttocks and internal side of thighs. However, there were no hair abnormalities or laryngeal leukokeratosis. From her history of natal teeth and multiple subcutaneous cysts, we diagnosed her as having pachyonychia congenita type II. Based on recent reports that there are mutations of keratin 6a and keratin 16 genes in pachyonychia congenita type I, and of keratin 6b and keratin 17 genes in pachyonychia congenita type II, especially many mutations in the 1A domain of the keratin 17 gene in type II, we carried out gene analysis. However, we could not detect any mutations in the 1A domain of the keratin 17 gene in either her, her daughter or her sister. Twice daily applications of 20% AlCl 3 ointment to her soles improved not only the hyperhidrosis but also the tenderness when walking. After the use of AlCl 3 ointment, we attempted to apply 10% salicylic acid ointment for the treatment of the hyperkeratosis. Her soles softened after these applications which further reduced the tenderness when walking. The treatment with 20% AlCl 3 ointment and salicylic acid was found to be much more effective for her 3-year-old daughter, probably due to the thinner epidermis of the child’s skin. Our clinical experience in the present case suggests that topical treatment with AlCl 3 together with salicylic acid is effective for controlling the discomfort caused by pachyonychia congenita.