Olopatadine, a non-sedating H1 antihistamine, decreases the nocturnal scratching without affecting sleep quality in atopic dermatitis.

We have demonstrated for the first time that a second-generation antihistamine ameliorates nocturnal scratching behavior in atopic dermatitis patients using a modified wristwatch-type acoustic scratching counting system that we have recently developed. We also analyzed the sleep quality by simultaneous recording of electroencephalogram, and found that sleep quality was unaffected.

Arrhythmogenic right ventricular cardiomyopathy in a 20-year-old woman with systemic sclerosis.

A 20-year-old Japanese woman with systemic sclerosis was evaluated for the progressive aggravation of chest pain, palpitations and dyspnea. Cardiac magnetic resonance imaging revealed diffuse wall thinning, segmental dyskinesis and late gadolinium enhancement of the right ventricular (RV) myocardium. Cardiac catheterization demonstrated no pulmonary hypertension. 24-hour electrocardiography monitoring showed non-sustained ventricular tachycardia (VT). Pulseless VT was induced via programmed ventricular stimulation. An endomyocardial biopsy of the right side of the interventricular septum was performed, the histological specimen of which demonstrated massive myocardial atrophy and fibro-fatty replacement with predominant fibrotic changes. The patient was ultimately diagnosed with arrhythmogenic RV cardiomyopathy.

Novel acoustic evaluation system for scratching behavior in itching dermatitis: rapid and accurate analysis for nocturnal scratching of atopic dermatitis patients.

Quantitative analysis of itching in patients with itching dermatitis including atopic dermatitis (AD) is indispensable for the evaluation of disease activity and response to therapy. However, the objective evaluation system for itching is limited. We have developed a new objective and quantitative scratching behavior detection system using a wristwatch-type sound detector. The scratch sound detected on the wrist is recorded on a personal computer through a filtering, squaring and smoothing process by specific hardware. Subsequently, the data is automatically processed and judged for the scratching movement using specific software based on the periodicity and energy of the signal. Twenty-four measurements for healthy volunteers and those with AD by this system were evaluated by comparison with a simultaneously recorded video analysis system. The ratio of scratching time in sleeping time evaluated by these two systems was almost identical. The healthy subjects scratched their skin approximately 2 min during 6 h of sleeping time, while the mean scratching time of AD subjects was 24 min in their sleeping time. In contrast to the time-consuming video analysis system, this system takes only several minutes for evaluation of an overnight record. This scratch sound detection system is expected to serve as a new objective evaluation tool for itching dermatitis, namely, AD, and development of anti-itch therapies for dermatitis.

CD8+ T cell granzyme B activates keratinocyte endogenous IL-18.

IL-18 is a pro-inflammatory cytokine of the IL-1 family involved in Th1/Th2 polarization. IL-18 is produced and stored as an inactive precursor (proIL-18) in several cells including keratinocytes, and thus appropriate processing is required to release its active form. In a previous study using recombinant protein, we demonstrated that granzyme B (GrB) cleaves proIL-18 into its active forms in a similar fashion as caspase-1 and human mast cell chymase. GrB released from cytotoxic T lymphocyte (CTL) and NK cells has roles in apoptosis and cytotoxic activity. In certain inflammatory skin diseases with epidermal cell death, the epidermal keratinocytes are targets of CTL and NK cells. However, IL-18 activation during the direct interaction of CTL/NK with keratinocytes has not been described so far. We investigated the interaction between CTL and keratinocytes, and IL-18 processing by CTL-derived GrB using cultured CD8+ T cells and keratinocyte cell line HaCaT. GrB(+)/caspase-1(-) CD8+ T cells cultivated from healthy human PBMC were co-cultured with interferon(IFN)-γ-treated HaCaT cells. The expression of GrB and caspase-1 in HaCaT cells was analyzed by flow cytometry and PCR. The IL-18 concentration in the culture supernatant was measured by specific ELISA. The interaction between HaCaT cells and CTL co-culture increased the number of cytoplasmic GrB-positive HaCaT cells with limited endogenous GrB mRNA expression. The concentration of mature IL-18 levels increased in the co-culture supernatant. GrB from CTLs acts double roles to keratinocytes: a IL-18 converting enzyme and pro-apoptotic factor in the skin inflammatory diseases.

Granzyme B is a novel interleukin-18 converting enzyme.

BACKGROUND: Granzyme B (GrB) is recognized to induce apoptosis; however, little is known about its possible role in other biological events. IL-18, a potent inflammatory cytokine, is produced as an inactive precursor (proIL-18). Several cells, including monocytes/macrophage lineage and non-hematopoietic cells such as keratinocytes, produce proIL-18. ProIL-18 requires appropriate processing to become active. Caspase-1 is the authentic IL-18 processing enzyme and is essential for IL-18 release from monocyte/macrophage lineage cells. However, caspase-1 is absent in non-hematopoietic cells, suggesting that there is another candidate to cleave proIL-18 except for caspase-1. OBJECTIVE: GrB can invade and be active in cytoplasm of non-hematopoietic cells via perforin, therefore we investigated whether GrB converts proIL-18 into the biologically active form. METHODS: Recombinant proIL-18 (rproIL-18) was produced and purified for protease reaction with GrB; this incubate was evaluated by immunoblotting. Biological activity of the proteolytic fragment cleaved by GrB was determined by IFN-gamma assay using KG-1 cells. IFN-gamma induction was also analyzed between extracts from GrB(+)/caspase-1(-) human CD8+ T cells and proIL-18 from normal human keratinocytes (NHK). RESULTS: The proteolytic fragment that GrB cleaved proIL-18 had the same sequence and biological activity compared with mature IL-18 cleaved by caspase-1. Culture extracts from CD8+ T cells was able to cleave proIL-18 into authentic mature IL-18. IFN-gamma induction was also detected in NHK treated with CD8+ T cells. CONCLUSION: GrB is a potent IL-18 converting enzyme and suggest that GrB secreted by CTLs and/or NK cells may initiate IL-18 release from target cells, leading to the development of inflammation.

Human mast cell chymase cleaves pro-IL-18 and generates a novel and biologically active IL-18 fragment.

Increased release of IL-18 in the skin causes atopic dermatitis (AD)-like skin lesions, suggesting a role of IL-18 in the pathogenesis of AD. Caspase-1 is a well-known activator of IL-18, but caspase-1 knockout mice still have biologically active IL-18. Normal human keratinocyte constitutively produces pro-IL-18, but it is unable to activate it, suggesting the existence of an alternative pathway for IL-18 in the skin. Dermal accumulation of mast cells is commonly observed in AD patients and in experimental mouse models of AD. Connective tissue mast cells contain high amounts of chymase and tryptase in their cytoplasmic granules. In the present study, we demonstrated that activation of IL-18 is a novel function of human mast cell chymase. Human mast cell chymase rapidly cleaves recombinant pro-IL-18 at 56-phenylalanine and produces a biologically active IL-18 fragment that is smaller than any other reported IL-18-derived species. The human mast cell chymase and the novel IL-18-derived active peptide may be novel therapeutic targets in AD- and IL-18-associated diseases.

Keratin profiles may differ between intraepidermal and intradermal invasive eccrine porocarcinoma.

We report two cases of eccrine porocarcinoma (EPC), one of intrepidermal EPC (IEEPC) and one of intradermal invasive EPC (IDEPC) in an immunohistochemical study of cytokeratins (CK) using nine different anti-keratin antibodies against CK1, 7, 8, 10, 14, 16, 17, 18 and 19. IEEPC expressed terminal differentiated CK1 and CK10. In contrast, IDEPC expressed simple-epithelial keratins such as CK7, 8, 18 and 19. Keratin expression of IEEPC preserves the immunophenotypes of normal epidermis. IDEPC, however, expresses poorly differentiated keratin. These results suggest that the keratin profiles of EPC are correlated with the invasive degree and reflect the clinical prognosis of EPC.