Spectrum of glutamate dehydrogenase mutations in Japanese patients with congenital hyperinsulinism and hyperammonemia syndrome.

INTRODUCTION: Congenital hyperinsulinism and hyperammonemia (CHH) is caused by gain of function of glutamate dehydrogenase (GDH). The genetic abnormalities are known to be located in three specific regions on the GDH protein. We describe here three different missense mutations identified in five new Japanese patients with CHH. And to study the genotype-phenotype correlations in patients with GLUD1 mutations, we analyzed previously reported Japanese cases. METHODS: An Epstein-Barr virus-transformed lymphoblastoid cell line was established from the 5 patients and control subjects, and was used for enzymatic and molecular analyses. RESULTS: All patients developed seizures with loss of consciousness associated with hypoglycemia and had persistent hyperammonemia. All patients had similar basal GDH activity of lymphoblasts and insensitivity to GTP inhibition. Genetic studies identified heterozygous I444M mutation in Patient 11, S217C mutation in Patient 1, and H262Y mutation in Patients 2, 3, and 4. Patients 3 and 4 were child and father, respectively. COS cell expression study confirmed that I444M and H262Y mutations were disease-causing genes. CONCLUSIONS: We identified three mutations (I444M, H262Y, and S217C), and the former is a newly described mutation. A summary of 17 reported Japanese patients (10 boys and 7 girls) with GDH mutations showed 8 patients had mutation at the site of the GTP-binding region, 2 at the site of the antenna-like structure, and 7 at the site of the hinge region. Analysis of the reported cases showed no clear association between clinical phenotype and mutation sites. However, G446D mutation seems to be associated with serious abnormalities.

Specific substance of Maruyama (SSM) suppresses immune responses in atopic dermatitis-like skin lesions in DS-Nh mice by modulating dendritic cell functions.

BACKGROUND: Specific substance of Maruyama (SSM) is a carcinostatic immunotherapeutic agent extracted from Mycobacterium tuberculosis. The efficacy of SSM induced interleukin(IL)-12 and IFN-γ production, and inhibition of IL-4, resulting in a shift from Th2 to Th1 in vivo. OBJECTIVE: The DS-Nh mice are a model of human atopic dermatitis (AD), which spontaneously develop dermatitis under conventional conditions. In this study, to determine whether SSM can prevent the development of skin lesions in a murine model of AD. METHODS: DS-Nh mice were injected with SSM 5 days per week for 11 weeks. Pharmacological, histological and serological studies were performed to investigate the therapeutic effect of SSM for DS-Nh mice. Analysis of cytokines responses to SSM using quantitative RT-PCR and flow cytometry were also performed to evaluate their therapeutic mechanisms in these AD model mice. RESULTS: Clinically, erythema, erosions, excoriation, and edema were observed in DS-Nh mice at 16 weeks of age, which advanced with age. Histologically, the relative number of mast cells increased in DS-Nh mice. SSM treatment alleviated the clinical and histological findings in accord with reduced serum IgE level, and increased IgG2a level. TSLP expression was not induced, but IL-1ß, IL-12, IL-17A, and IFN-γ were induced in SSM-treated DS-Nh mice. Overall, SSM treatments increased the number of activated DCs in lesions. SSM induced CD80, CD86, and MHC class II expression on bone marrow-derived DCs. CONCLUSIONS: SSM enhanced IL-12 production, but suppressed TSLP expression, resulting in a shift from Th2 to Th1 responses. This shift suppressed AD-like skin lesions in a similar fashion as the BCG vaccine. Therefore, SSM may be a useful adjuvant for suppressing skin lesions in AD models.

Combination of carbon dioxide laser therapy and artificial dermis application in plantar warts: human papillomavirus DNA analysis after treatment.

BACKGROUND: Various laser therapies have been used to treat viral warts, and numerous successful results have been reported, but plantar warts are notoriously difficult to treat and eradicate. MATERIALS & METHODS: This study included 35 lesions in 31 patients (17 female, 14 male) with plantar warts. We used a carbon dioxide (CO2) laser for incisions, and the defect was covered with artificial dermis. Follow-up periods ranged from 3 to 12 months. Overall, we examined the presence or absence of human papillomaviruses (HPVs) DNA in the lesional skin of all cases and at the excisional site after treatment in 20 cases. RESULTS: Thirty-one of 35 lesions (88.6%) achieved complete clearance after one treatment session. We observed local recurrence in four lesions (11.4%). The application of salicylic acid was effective in treating minor recurrent cases. After complete remission, HPV DNA was not detected in the upper epidermis of the postoperative site. No significant scars or severe pain were seen in any patients. CONCLUSION: A combination of CO2 laser therapy and artificial dermis application effectively treated the majority of plantar warts after one treatment, with complete and rapid clearance and no persistent pain. The authors have indicated no significant interest with commercial supporters.

[Incidence and onset time of fentanyl-induced cough depends on the dose of IV fentanyl].

BACKGROUND: IV fentanyl en bolus can provoke cough reflex. We evaluated the effects of the IV fentanyl dose on the incidence and onset time of fentanyl-induced cough. METHODS: Tree hundred and eighteen ASA physical status I - II patients scheduled for oral surgery under general anesthesia were randomly assigned to receive 1 microg x kg(-1), 3 microg x kg(-1) or 5 microg x kg(-1) of IV fentanyl (n = 106 for each group). We recorded, in each patient, presence/absence and onset time, if present, of cough reflex for 60 seconds after fentanyl injection. RESULTS: The incidences of fentanyl-induced cough were 6.6%, 22.5%, and 44.3% in the 1 microg x kg(-1), 3 microg x kg(-1), and 5 microg x kg(-1) groups, respectively. The onset times of fentanyl-induced cough were 29.0 +/- 11.8 seconds, 22.5 +/- 7.9 seconds, and 19.5 +/- 7.0 seconds in the 1 microg x kg(-1), 3 microg x kg(-1), and 5 microg x kg(-1) groups, respectively. CONCLUSIONS: The results indicated that the incidence of fentanyl-induced cough increased, and the onset time decreased, with the increasing dose of fentanyl.

Papulonecrotic tuberculid with spontaneous remission.

We describe a 62-year-old Japanese woman who had skin lesions involving her extremities, chest and back that showed spontaneous remission. The skin lesions consisted of slightly atrophic scars and crusted, reddish or necrotic papules. A tuberculin test showed induration and bulla, which was regarded as strongly positivity. Histopathologically, a tuberculoid granuloma with necrosis was present in the upper dermis and the deep dermis, including the adipose tissues. Bacterial cultures were not positive from sputum, urine or stool, and the chest X-P was also normal. After skin biopsy, all the lesions disappeared within 1 month. No relapse was noted in the entire body.

Cimetidine treatment for viral warts enhances IL-2 and IFN-gamma expression but not IL-18 expression in lesional skin.

Cimetidine has been shown to improve various types of human neoplasms and more recently it has been shown to be effective in treating recalcitrant or multiple viral warts in some reports. However, it is not well understood why cimetidine is effective on those kinds of viral warts. We investigated 55 patients with multiple viral warts treated only with oral cimetidine for up to 4 months to examine the efficacy of treatment. The patients were divided into two groups: group A received oral cimetidine (<20 mg/kg/day) and group B received the drug (30 to 40 mg/kg/day). In addition, using real time PCR, we measured mRNA levels of the cytokines interleukin-2 (IL-2), IL-18, and interferon (IFN)-gamma taken from selected punch biopsy specimens before and during treatment. As a result, 34.5% (19/55) of the patients had a dramatic clinical improvement or complete remission (CR) of their viral warts and 23.6% (13/55) of the patients had partial responses (PR) within 4 months of cimetidine therapy. IL-2 and IFN-gamma mRNA levels were significantly increased and IL-18 mRNA levels were decreased in tissues of effectively treated viral warts. Our results show that the higher dose of oral cimetidine was more effective in treating multiple viral warts, that cimetidine activates Th1 cells to produce IL-2 and IFN-c and that their expression correlates with wart remission. These results suggest that cimetidine is an effective treatment for viral warts. In addition, based on the decrease in IL-18 mRNA elicited by the drug, IL-18 might be expressed by keratinocytes infected with HPV.