A high incidence of skin cancers has been noted around the Semipalatinsk Nuclear Testing Site (SNTS) in Kazakhstan. Recently, basal cell carcinoma (BCC) susceptibility genes, human homolog of the Drosophila pathed gene (PTCH), and the xeroderma pigmentosa group A-complementing gene (XPA), have been cloned and localized on chromosome 9q22.3. To clarify the effect of low-dose irradiation on the occurrence of BCC, we used microdissection and polymerase chain reaction to identify loss of heterozygosity (LOH) at 9q22.3 using BCC samples obtained from this region. Ten Japanese samples were analyzed as controls. LOH with at least 1 marker was identified in 5 of 14 cases from around SNTS, whereas only 1 case with 1 marker was identified among the 10 Nagasaki cases. The total number of LOH alleles from SNTS (8 of 45) was significantly higher than the number from Nagasaki (1 of 26) (P = 0.03). The higher incidence of LOH on 9q22.3 in BCC from around SNTS suggests involvement of chronic low-dose irradiation by fallout from the test site as a factor in the cancers.

Adult↗

PubMed2004

Pro-inflammatory cytokine IL-1alpha potential for tissue repair in chemically and mechanically induced injury in cultured human keratinocytes.

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Cells, Cultured↗

PubMed2004

Therapeutic effects of streptococcal preparation OK-432 on atopic dermatitis-like lesions in NC/Nga mice: possible shift from a Th2- to Th1-predominance.

BACKGROUND: The inducement of Th1 cell-mediated immune response, possibly brought about through bacterial stimulation, may serve to control atopic disorders such as atopic dermatitis (AD). The streptococcal preparation, OK-432, has been shown a potent Th1 inducer through the action of IL-12. NC/Nga mice under ordinary conditions have been found to contract dermatitis similar to human AD. OBJECTIVE: Examination was made of the therapeutic effects of OK-432 local intra- and/or subcutaneous injections on AD-like lesions in NC/Nga mice. METHODS: Immunohistochemical staining with IL-4/IL-12p40 and CD80/86 and phosphorylated STAT4/p-STAT6 and RT-PCR for IL-4/IL-12p40 and STAT6/STAT4 mRNA was conducted for the evaluation of OK-432 treatment of spontaneous AD-like lesions in NC/Nga mice. RESULTS: At 5 weeks following injection of OK-432, for treating head and back lesions in NC/Nga mice, 10 of 12 OK-432 treated NC mice were found to have clinically improved quite considerably. On the head and back skin of OK-432-treated mice, IL-12p40/CD80 positive cellular infiltration was conspicuous, in contrast to non-treated mice. IL-4/CD86 positive cellular infiltrates in OK-432-treated mice had decreased significantly more than in non-treated mice and IL-4 mRNA expression was virtually absent in OK-432-treated mice. P-STAT4 positive cells could be seen abundantly present in OK-432-treated mice, and p-STAT6 positive cells were much fewer than in non-treated mice. CONCLUSIONS: OK-432-treatment appears to induce Th1 cellular response and to down-regulate that of the Th2 pathway in AD-like lesions of NC/Nga mice. The present results demonstrate bacterial components from such Streptococcus to likely constitute an effective new therapeutic approach in the treatment of AD.

Animals↗

PubMed2004

Topical glucocorticoid augments scratching behaviour in dinitrofluorobenzene-sensitized mice by the induction of substance P.

Topical glucocorticoid (GC) is commonly applied in atopic dermatitis treatment. However, the chronic use of GC may be associated with significant side effects. In this study, we investigated whether long-term epicutaneous application of GC modulates scratching behaviour in dinitrofluorobenzene (DNFB) contact-sensitized mice. After challenge with DNFB, scratching behaviour was increased in DNFB-sensitized mice treated with GC in contrast to control mice. In addition, reverse transcriptase-polymerase chain reaction analysis demonstrated that the expression of preprotachykinin-A (PPT-A) mRNA, a precursor of substance P (SP), and inducible nitric oxide synthase (iNOS) mRNA in mice, to which GC was applied, was only observed. In order to evaluate the factors responsible for the augmented scratching behaviour, we injected various cytokines (interleukin-1alpha (IL-1alpha), IL-2, IL-3 and tumour necrosis factor-alpha (TNF-alpha)) subcutaneously into the ear of DNFB contact-sensitized mice before DNFB challenge. Among the cytokines, only IL-3 and TNF-alpha significantly increased scratching behaviour in DNFB contact dermatitis mice. Furthermore, PPT-A mRNA was only expressed in mice pre-injected with IL-3 before challenge, but not in those pre-injected with other cytokines. Taken together, our results suggest that topical GC may augment the itching sensation in DNFB-sensitized mice through modulation of iNOS and SP induced by IL-3.

Administration, Topical↗

PubMed2004

Unusual erythemas with eosinophilia, caused by H2-blocker famotidine in a male patient with glioblastoma.

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Aged↗

PubMed2004

Dosage and adverse effects of topical tacrolimus and steroids in daily management of atopic dermatitis.

Since 1999, combination therapy with tacrolimus and topical steroids has been widely used for the treatment of adolescent/adult-type atopic dermatitis. In order to determine the clinical doses of topical tacrolimus and steroids for daily treatment of atopic dermatitis and to elucidate their beneficial and adverse effects, we analyzed the clinical data from 215 patients with atopic dermatitis who were more than 16 years old. Less than 70 g of tacrolimus and less than 15 g of steroids were applied to 90% of the patients on the face and neck, and less than 75.8 g of tacrolimus and less than 322 g of steroids were applied to 90% of the patients on the trunk and extremities during the six-month treatment period. Topical tacrolimus is much more frequently used on face and neck lesions (99.1%); in only 39.5% of cases was it used on the trunk and extremities. The majority of patients improved after six months of the combination topical therapy; however, atopic dermatitis was not controlled in 6% of the patients. The combination therapy did not seem to increase the risk of cutaneous infections; however, the incidence of herpes simplex infection on the face and neck was 2.8% at pre-treatment and slightly increased to 4.7% during the therapy. The incidence of all steroid-induced adverse effects was reduced both in frequency and intensity with a decrease in the dose of topical steroids through simultaneous tacrolimus application. Combination therapy with topical tacrolimus and steroids is useful for treating atopic dermatitis, but a small percentage of the patients still cannot be satisfactorily treated. For such patients, adjustments of the dose and rank of topical steroids and tacrolimus and other therapeutic adjuncts are necessary.

Administration, Cutaneous↗

PubMed2004

[New perspective of vitamin D3 ointment--pruritic skin diseases: focused on prurigo].

It is generally accepted that topical steroid ointment and anti-histamine drug are the first choice of the treatment on pruritic skin diseases such as contact dermatitis, urticaria, prurigo, or pruritus cutanea. Among these diseases, prurigo is one of the most refractory skin disease to the common therapies. In this review, we would like to summarize the effect of vitamin D(3) to refractory skin disease on the basis of our clinical study.

Administration, Topical↗

PubMed2003

Disruption of tumor necrosis factor receptor p55 impairs collagen turnover in experimentally induced sclerodermic skin fibroblasts.

OBJECTIVE: To determine the role of tumor necrosis factor receptor p55 (TNFRp55)-mediated signaling in the pathogenesis of scleroderma. METHODS: A murine model of scleroderma that closely resembles systemic sclerosis in humans was used. Wild-type and TNFRp55-deficient (TNFRp55(-/-)) mice received a subcutaneous injection of bleomycin each day. The extent of skin fibrosis was determined by measurements of the dermal thickness, as well as histologic examinations. Expression levels of fibrogenic cytokines, procollagen alpha1, and matrix metalloproteinase 1 (MMP-1), MMP-2, and MMP-9 messenger RNA (mRNA) were analyzed, both in vivo and in vitro, by reverse transcriptase-polymerase chain reaction assay or Western blotting. RESULTS: TNFRp55(-/-) mice began to develop severe sclerotic changes of the dermis on day 3 of the subcutaneous injections of bleomycin, while wild-type mice did not. The expression levels of fibrogenic cytokines, procollagen alpha1, and MMP-2 and MMP-9 mRNA were unaffected in the skin of both wild-type and TNFRp55(-/-) mice, with or without bleomycin treatment. Induction of MMP-1 expression was significantly inhibited in the skin from bleomycin-treated TNFRp55(-/-) mice, and this phenomenon was also observed in vitro. CONCLUSION: These results indicated that signaling mediated by TNFRp55 plays an essential role in MMP-1 expression and a key role in the collagen degradation process in this murine model. This study might provide a basis for understanding the pathogenesis of scleroderma and formulating therapeutic intervention.

Animals↗

PubMed2003

Suplatast tosilate inhibits eosinophil production and recruitment into the skin in murine contact sensitivity.

Antiallergic drugs and antihistamines have been widely used for controlling mucosal allergic diseases in which eosinophilia is prominent. Although H1-receptor antagonists are effective for treating histamine-induced wheal and itch in urticaria, the effects of antihistamines and antiallergic agents on other eosinophilic skin diseases remain to be determined. We investigated the effects of oral administration of antiallergic drugs and antihistamines, such as suplatast tosilate, emedastine difumarate, and azelastine hydrochloride, on a novel murine model of eosinophilia in contact sensitivity to picryl chloride. Among the drugs tested, only suplatast tosilate remarkably inhibited blood and tissue eosinophilia and the ear swelling responses. The inhibitory effects on eosinophilia seemed to be mediated by the suppression of IL-5 production in spleen cells during eosinophil development, while the effects on the ear swelling response seemed to be mediated by suppression of IL-4 production in immune lymph node cells in the efferent phase. Suplatast tosilate may effectively treat eosinophilic skin diseases in which Th2-cell-derived cytokines are predominant.

Administration, Oral↗

PubMed2003

Palpebral edema as a cutaneous manifestation of hyperthyroidism.

Three cases of palpebral edema associated with Graves' disease are described. These patients had unilateral edema and minimal erythema of the upper eyelid. Notable was that, histologically, dermal edema and dilation of lymphatic vessels were observed, but deposition of mucopolysaccharides was not. In 2 cases, edema of the eyelid was resistant to treatment with an antithyroid drug. Unilateral edema of the upper eyelid is an important cutaneous manifestation that indicates the presence of hyperthyroidism.

Edema↗

PubMed2003

Serum antioxidant levels in Yusho victims over 30 years after the accidental poisoning of polychlorinated biphenyls in Nagasaki, Japan.

Over 30 years have passed since the accidental polychlorinated biphenyls (PCB) poisoning in Japan and yet high concentrations of PCB are still detected in the serum of the victims. PCB produces superoxide and thus victims of PCB poisoning are in a persistent state of oxidative stress. To examine the antioxidative state, we measured the serum concentrations of Cu, Zn-superoxide dismutase (SOD) and Mn-SOD in 38 victims and 20 age-matched control subjects. The mean serum concentration of Cu, Zn-SOD was significantly lower and that of Mn-SOD higher than those of the control. Such an antioxidative state is indicative of an imbalance of Redox regulation mechanism. Persistence of imbalance could result in serious ailments in the future.

Aged↗

PubMed2003

The induction of heme oxygenase-1 by exogenous nitric oxide in ex vivo normal human skin.

Gaseous carbon monoxide (CO) has received attention as a neurotransmitter and as a material involved in persistent dilatation of vessels. CO is released by heme oxygenase (HO) during the process from heme to bilirubin or biliverdin. Many reports have revealed that exogenous nitric oxide (NO) can induce HO-1 in vitro, which is the induced isoform of HO. In the present study, we attempted an ex vivo system as an explant culture. A quantitative analysis was performed in combination with a reverse transcription-competitive polymerase chain reaction method, which proved to be very accurate, as well as a qualitative analysis with an immunohistochemistry. With this system we confirmed the induction of HO-1 mRNA and protein by exogenous NO in normal human skin. Our results concluded that this ex vivo system was very useful, because skin samples could be handled easily under conditions close to the in vivo situation.

Adult↗

PubMed2003

[Examination of "areas cutanea" in Yusho patients].

In the field of Dermatology, one of the representatives of oxidative stresses is ultraviolet irradiation. Repetitive ultraviolet exposure results in cutaneous photoaging. Otherwise, polychlorinated biphenyls (PCB) give rise to superoxide, which means Yusho patients have been affected by oxidative stress for more than thirty years. In order to examine the influence of oxidative stress by PCB to the skin, we measured the "areas cutanea" in the inner aspect of upper arm in Yusho patients and in age-matched controls. "Areas cutanea" were significantly smaller in Yusho patients than in controls. Although PCB can give an oxidative stress, the influence seemed to be little to the skin. There might be another mechanisms involved in this result except the oxidative stress by PCB. Further examination should be conducted in the future.

Adult↗

PubMed2002

Fas-mediated apoptosis of melanoma cells and infiltrating lymphocytes in human malignant melanomas.

In a rodent system, melanoma cells expressing Fas ligand (FasL) could kill Fas-positive lymphocytes, suggesting that FasL expression was an essential factor for melanoma cell survival in vivo. These findings led us to investigate apoptosis, and to histochemically analyze involvement of Fas and FasL in the induction of apoptosis, in human malignant melanoma tissues. The percentages of terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end-labeling (TUNEL)-positive melanoma cells and of proliferating cell nuclear antigen (PCNA)-positive melanoma cells in melanoma tissues (n = 22) were greater than those in melanocytes in uninvolved skin (n = 6) and nevus cells in nevi tissues (n = 9). The infiltrating lymphocytes around melanomas were also TUNEL positive. Immunohistochemistry revealed expression of Fas and FasL in melanoma cells and lymphocytes, whereas no Fas or FasL expression was detected in normal skin melanocytes and nevus cells. There was significant correlation between Fas-positive indices and TUNEL indices in melanoma tissues. Moreover, TUNEL-, Fas-, and FasL-positive indices of melanoma cells from patients with Stage 3 melanomas were significantly lower than those with Stage 2 melanomas. The PCNA index of Stage 1 melanoma was significantly lower than that of the other stages, although the difference of PCNA index was insignificant among Stages 2 to 4. Among Stages 1 to 4, there was no difference in the PCNA, TUNEL-, and Fas-positive indices of lymphocytes, although the FasL-positive index of lymphocytes from Stage 3 melanomas was significantly lower than in that from Stage 2. These data reveal that melanoma cells and infiltrating lymphocytes have the potential to induce their own apoptosis regulated by Fas and FasL in an autocrine and/or paracrine fashion and that the decline of Fas-mediated apoptosis of melanoma cells, rather than the apoptosis of infiltrating lymphocytes, may affect the prognosis of melanoma patients, possibly through the accumulation of more aberrant cells acquiring metastatic activity.

Adult↗