Cyclosporin-A suppresses p53-dependent repair DNA synthesis and apoptosis following ultraviolet-B irradiation.

BACKGROUND: The combination of cyclosporin-A (CS-A) and ultraviolet-B (UV-B) irradiation is not recommended in the treatment of psoriasis, because risks of UV-B-induced skin cancer are increased. The recommendation, however, has not well been confirmed by basic researches. PURPOSE: In this study, we investigated the effects of CS-A on UV-B-induced repair DNA synthesis, apoptosis and p53 expression. METHODS: Following the short-term administration of CS-A (5 and 50 mg/kg/day) or vehicle (V) alone, female BALB/c mice, 8-10 weeks old, were treated with UV-B irradiation (100 and 500 mJ(2) cm) or tape stripping (TS). After the treatment, the effects of CS-A on the increased rate of epidermal DNA synthesis were examined by using 5'-bromodeoxyuridine (BrdU) pulse-labelling techniques. In separate experiments, the effects of CS-A on the number of sunburn cells, nick-end labelling+ cells and p53+ cells were examined 24 h after UV-B irradiation. RESULTS: Cyclosporin-A significantly suppressed the UV-B-induced increase in BrdU uptake, which occurs to repair DNA damage, while there were no significant effects on the stripping (S)-induced increase or the rate of normal epidermal proliferation, which is not associated with any DNA injuries. The number of sunburn cells, nick-end labelling+ cells and p53+ cells was significantly reduced by pretreatment with CS-A. CONCLUSION: Cyclosporin-A interferes with the self- protective mechanisms involved in both repair and apoptotic removal of UV-B-induced DNA damage. The loss of p53 expression is responsible for the effects of CS-A.

Essential contribution of germline-encoded lysine residues in Jgamma1.2 segment to the recognition of nonpeptide antigens by human gammadelta T cells.

Human gammadelta T cells display unique repertoires of Ag specificities largely imposed by selective usages of distinct Vgamma and Vdelta genes. Among them, Vgamma2/Vdelta2(+) T cells predominate in the circulation of healthy adults and respond to various microbial small molecular mass nonpeptide Ags. The present results indicate that the primary Vgamma2/Vdelta2(+) T cells stimulated with the distinct groups of nonpeptide Ags, including monoethyl pyrophosphate, isobutyl amine, and aminobisphosphonate, invariably exhibit Jgamma1.2 in the Vgamma2(+) TCR-gamma chains. Gene transfer studies revealed that most of the randomly cloned Vgamma2/Jgamma1.2(+) TCR-gamma genes bearing diverse Vgamma/Jgamma junctional sequences could confer the responsiveness to all these nonpeptide Ags, while none of the Vgamma2/Jgamma1.1(+) or Vgamma2/Jgamma1.3(+) TCR-gamma genes could do so. Furthermore, mutation of the lysine residues encoded by the Jgamma1.2 gene, which are unique in human Jgamma1.2 and absent in other human or mouse Jgamma segments, completely abrogated the responsiveness to all the nonpeptide Ags without affecting the response to anti-CD3 mAb. These results strongly suggested that the positively charged lysine residues in the TCR-gamma chain CDR3 region encoded by the germline Jgamma1.2 gene play a key role in the recognition of diverse small molecular mass nonpeptide Ags.

Near-infrared irradiation stimulates cutaneous wound repair: laboratory experiments on possible mechanisms.

BACKGROUND/AIMS: Several physical agents such as low-energy lasers have been used in the treatment of chronic skin ulcers. This study was performed to investigate potential effects of a newly-developed, specific near-infrared light source on wound repair. METHODS: Cultured human keratinocytes, endothelial cells and fibroblasts were exposed to the light, and the production of transforming growth factor (TGF)-beta1 and matrix metalloproteinase (MMP)-2 was examined by enzyme immunoassay, zymography and reverse transcription polymerase chain reaction. Incisional wounds were created in ICR and db/db diabetic mice and the effect of irradiation on wound closure was followed photographically. RESULTS: The TGF-beta1 and MMP-2 content of the medium of cultured cells was significantly elevated after irradiation. The amount of MMP-2 mRNA extracted from irradiated fibroblasts was also upregulated. Negative results in thermal controls suggested that the action of the light was athermic in nature. In animal models, the rate of wound closure was significantly accelerated by repeated exposures. CONCLUSION: Near-infrared irradiation potentially enhances the wound healing process, presumably by its biostimulatory effects.

Pemphigus foliaceus with prominent neutrophilic pustules.

We describe four patients with generalized scaly and pustular skin lesions showing extensive neutrophilic infiltration in the subcorneal region of the epidermis. Immunofluorescence, immunoblot and enzyme-linked immunosorbent assay analyses detected IgG antibodies reacting exclusively with desmoglein 1, the pemphigus foliaceus antigen. This study indicates that pemphigus foliaceus may show prominent neutrophilic pustular skin lesions.

Solar urticaria: report of two cases with augmentation spectrum.

Two adult Japanese patients with severe solar urticaria are reported. In both patients, an action spectrum existed in the visible light range, and an augmentation spectrum was demonstrated in the visible light range longer than the action spectrum. The augmentation phenomenon has rarely been documented, and in the previous reports, it was induced by preirradiation with the augmentation spectrum. In our cases, however, only postirradiation with the augmentation spectrum enhanced urticarial reactions.

Unilateral Schamberg disease in a 14-year-old Japanese boy.

We report a 14-year-old Japanese boy who has had asymptomatic, multiple, reddish-brown macules and petechiae distributed segmentally only in the right lower extremity for the last 6 months. Histological examination showed a perivascular lymphohistiocytic infiltrate in the papillary dermis, extravasation of red blood cells, and hemosiderin deposition. Treatment with tranilast and topical corticosteroid was dramatically effective. Although the histological findings were compatible with those of Schamberg disease, this case was unusual because the patient was very young and only one extremity was affected.

PUVA therapy: current concerns in Japan.

Photochemotherapy using methoxsalen in combination with long-wave ultraviolet light (PUVA) is an essential modality in the treatment of various skin diseases. Major therapeutic regimens include oral, topical and water-delivery methods. An adequate regimen should be chosen regarding cases of disease, extent of involvement and the age of patients. In Japan, however, treatment techniques and protocols have not yet been standardized. PUVA therapy may be a first choice in the early stages of mycosis fungoides and a second choice or an adjunctive measure in other diseases, such as psoriasis, vitiligo and atopic dermatitis, which have been disabling or resistant to conventional treatments. Japanese guidelines for PUVA therapy of psoriasis are being prepared to be produced. Risks and benefits must be weighed and the patient orientation is necessary to complete the treatment and also to minimize side-effects. Although possible risks for skin cancers in Japanese patients have been reported to be much lower, a careful monitoring of the patient's skin changes is recommended. While action mechanisms are not completely understood, recent investigations suggest that both antiproliferative and immunomodulatory effects are involved. This review article deals with the recent progress in clinical and basic research on PUVA therapy, focusing on our current concerns.

Combination therapy with low-dose etretinate and eicosapentaenoic acid for psoriasis vulgaris.

A randomized open study was undertaken to compare the therapeutic effects between low-dose etretinate alone and low-dose etretinate combined with eicosapentaenoic acid in 40 patients with chronic, stable psoriasis vulgaris. Better and more rapid improvement was obtained with the combination therapy for 12 weeks than with low-dose etretinate monotherapy. Eicosapentaenoic acid was safe, and adverse reactions due to low-dose etretinate were mild or tolerable. The combination regimen, therefore, has a satisfactory effect on psoriasis without marked adverse reactions.

Ultraviolet light is an environmental factor aggravating facial lesions of adult atopic dermatitis.

An increasing number of adult patients with atopic dermatitis (AD) in Japan are distressed by persistent eczematous lesions of the face (so-called atopic red face). Phototests were carried out in 28 patients with the atopic red face to test a possibility that ultraviolet (UV) light could be an aggravating factor. Contact and photocontact dermatitis had been ruled out by repeated patch and photopatch tests. All of the patients had a normal response to a screening dose of UVA (10 J/sq cm) and a normal minimal erythema dose (MED) of UVB. Ten of these patients, however, showed an abnormal papular response to a single or 3-times consecutive UVB radiation above the MED (90 mJ/sq cm).

Density and fine structure of peripheral nerves in various skin lesions of atopic dermatitis.

The density and fine structure of the peripheral nerve system in various skin lesions of 64 patients with atopic dermatitis (AD) was quantitatively analyzed by immunohistochemical staining with antibodies directed against protein gene product (PGP) and substance P (SP). The density of PGP-positive peripheral nerves was 2.5 x 10(3) microns2/delta s (delta s = 0.24 mm2 selected area) in early acute lesions, 3.8 x 10(3) microns2/delta s in subacute lesions, 4.9 x 10(3) microns2/delta s in lichenified lesions and 7.1 x 10(3) microns2/delta s in prurigo lesions of AD. The density of nerve fibers in subacute, lichenified and prurigo lesions was significantly higher than in uninvolved skin of AD patients (2.0 x 10(3) microns2/delta s). Electron microscopically, bulging of axons with many mitochondria and a loss of their surrounding sheath of Schwann cells suggests that the free nerve endings in skin lesions of AD are in an active state of excitation. Many pinocytotic vesicles in the periphery of basal keratinocytes facing nerve endings which contained many neurovesicles suggests reciprocal effects between keratinocytes and nerve endings. The number of SP-positive nerve fibers in AD lesions was far less than one-tenth of the number of PGP-positive nerve fibers.

Effects of near-infrared radiation on the epidermal proliferation and cutaneous immune function in mice.

While ultraviolet radiation alters various cutaneous cell functions, little is known about the photobiological effects of infrared radiation (IR) on the skin except its local thermal effect. This study demonstrated that single exposure of mouse skin to near IR (0.7-1.3 microns) reversibly suppressed the proliferating activity of the epidermis, the density of Langerhans cells, and the ability of skin to induce contact hypersensitivity reaction. During the exposure, the ear surface temperature was elevated from a mean of 27 to 31.2 degrees C. The results suggest that near IR can modulate the epidermal proliferation and part of the skin immune system, with a mild thermal effect.

Alterations in ICAM-1 and ELAM-1 expression in psoriatic lesions following various treatments.

The expression of endothelial leukocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1) in psoriatic lesions was immunohistochemically examined before and after various single and combination therapies. The increased staining intensity of both adhesion molecules on the proliferated papillary venules in pretreated lesion was markedly reduced after cyclosporin-A monotherapy and etretinate therapy combined with oral eicosapentaenoic acid (EPA), psoralen plus ultraviolet-A radiation (PUVA) or ultraviolet-B radiation (UVB). Less pronounced alterations were observed with etretinate, EPA, PUVA, UVB, and topical corticosteroid alone. The epidermal expression of ICAM-1, on the other hand, faded out completely following any of the treatment measures. The findings suggest that cyclosporin-A monotherapy and the etretinate combination therapies have greater inhibitory effects on the endothelial expression of the adhesion molecules than the other monotherapies. Loss of the epidermal expression of ICAM-1 may be nonspecific to the treatment.

Increased met-enkephalin plasma levels in hemodialysis patients with or without pruritus.

Met-enkephalin plasma levels were measured in 21 hemodialysis patients with or without pruritus. The mean value was significantly increased in the total of the patients compared with that in ten healthy subjects. There was, however no correlation between met-enkephalin levels and the degree of pruritus. The findings suggest that the opioid system may be activated in this condition, although the relevance of this endogenous opioid peptide to pruritus remains to be determined.

Lectin staining of the endothelial cell membrane is more sensitive to ultraviolet radiation than the epidermal cell staining in guinea-pig skin.

Ultraviolet radiation (UVR)-induced alterations in lectin stainings of both endothelial and epidermal cells were histochemically analysed in guinea-pig skin using Bandeiraea simplicifolia agglutinin-I and Ricinus communis agglutinin-I. The endothelial cell staining with both lectins was more sensitive to a single exposure to middle-wave UVR (UVB) and topical psoralen plus long-wave UVR (UVA) (PUVA) than the epidermal cell staining. More remarkable changes were seen following PUVA radiation than UVB radiation. No significant alterations were induced by UVA radiation alone or psoralen alone. The results suggest that the endothelial cell is a susceptible target for UVB and PUVA radiation.