These results indicate that Smad4 is essential for basal and TGF-beta-induced COL1A1 expression, and contributes to the early, but not sustained TGF-beta-induced PAI-1 expression in mesangial cells. However, TGF-beta-induced FN expression is independent of Smad4. In conclusion, Smad4 has a discriminate effect in mediating specific ECM molecules stimulated by TGF-beta in mesangial cells.

Background. Iron overload syndromes include a wide spectrum of genetic and acquired conditions. Recent studies suggest suppressed hepcidin synthesis in the liver to be the molecular basis of hemochromatosis. However, a liver with acquired iron overload synthesizes an adequate amount of hepcidin. Thus, hepcidin could function as a biochemical marker for differential diagnosis of iron overload syndromes.Methods. We measured serum iron parameters and hepcidin-25 levels followed by sequencing HFE, HJV, HAMP, TFR2, and SLC40A1 genes in 13 Japanese patients with iron overload syndromes. In addition, we performed direct measurement of serum hepcidin-25 levels using liquid chromatography-tandem mass spectrometry in 3 Japanese patients with aceruloplasminemia and 4 Italians with HFE-hemochromatosis. Results.One patient with HJV-hemochromatosis, 2 with TFR2-hemochromatosis, and 3 with ferroportin disease were found among the 13 Japanese patients. The remaining 7 Japanese patients showed no evidence for genetic basis of iron overload syndrome. As far as the serum hepcidin-25 was concerned, seven patients with hemochromatosis and 3 with aceruloplasminemia showed markedly decreased serum hepcidin-25 levels. In contrast, 3 patients with ferroportin disease and 7 with secondary iron overload syndromes showed serum hepcidin levels parallel to their hyperferritinemia. Patients with iron overload syndromes were divided into 2 phenotypes presenting as low and high hepcidinemia. These were then associated with their genotypes. Conclusion.Determining serum hepcidin-25 levels may aid differential diagnosis of iron overload syndromes prior to genetic analysis. (231 words)

ObjectivesGLP-1 improves hyperglycemia, and it has been reported to have favorable effects on atherosclerosis. However, it has not been fully elucidated whether GLP-1 is able to improve endothelial function in patients with type 2 diabetes. Therefore, we investigated the efficacy of the GLP-1 analogue, liraglutide on endothelial function and glycemic metabolism compared with insulin glargine therapy.Materials and MethodsIn this multicenter, prospective randomized parallel-group comparison study, 31 diabetic outpatients (aged 60.3 ± 10.3 years with HbA1c levels of 8.6 ± 0.8%) with current metformin and/or sulfonylurea treatment were enrolled and randomly assigned to receive liraglutide or glargine therapy once daily for 14 weeks. Flow mediated dilation (FMD), a comprehensive panel of hemodynamic parameters (Task Force Monitor), and serum metabolic markers were assessed before and after the treatment period.ResultsA greater reduction (worsening) in %FMD was observed in the glargine group, although this change was not statistically different from the liraglutide group (liraglutide; 5.7 to 5.4%, glargine 6.7 to 5.7%). The augmentation index, C-peptide index, derivatives of reactive oxygen metabolites and BMI were significantly improved in the liraglutide group. Central systolic blood pressure and NT-proBNP also tended to be improved in the liraglutide-treated group, while improvements in HbA1c levels were similar between groups. Cardiac index, blood pressure and most other metabolic parameters were not different.ConclusionsRegardless of glycemic improvement, early liraglutide therapy did not affect endothelial function but may provide favorable effects on beta-cell function and cardioprotection in type 2 diabetics without advanced atherosclerosis.Trial RegistrationUMIN Clinical Trials Registry System as trial ID UMIN000005331.

We found that a homogenous CD4-/CD8- T cell bearing an invariant TCR encoded by V alpha 14J alpha 281 with a one-base N-region is highly dominant in the periphery (2-3% in spleen). Surprisingly, the high expression of this invariant V alpha 14 TCR is a general phenomenon in all laboratory strains irrespective of MHC haplotype and in some wild mouse subspecies. The majority of V alpha 14+ TCR is associated with J alpha other than J alpha 281 during the neonatal stage, after which the frequency of invariant V alpha 14J alpha 281 TCR expression increases with time reaching a maximum at around 5-8 weeks after birth. The dominant expression of V alpha 14J alpha 281 TCR is found in both euthymic and athymic mice. These results indicate that homogenous V alpha 14J alpha 281 T cells are positively selected in the periphery without thymic influence and that their VJ junction is important for positive selection. We also demonstrate that V alpha 14+ TCR gene rearrangements take place at extrathymic sites, such as bone marrow, liver, and intestine, since frequent nonproductive V alpha 14 TCR products and V alpha 14-J alpha 281 gene mediated signal sequences in circular DNA are detected as a result of TCR rearrangements in extrathymic tissues rather than in the thymus. This indicates the extrathymic development of V alpha 14J alpha 281 T cells. Furthermore, the biological roles of homogenous T cells bearing V alpha 14J alpha 281 TCR and the human counterpart of this invariant TCR are also discussed.

To investigate relationship of dietary factors, especially source of calcium intake, to bone mineral density (BMD) among Japanese middle-aged women, a total of 995 healthy women age of 40 to 49 (mean +/- SD, 45 +/- 3), who lives in Yokohama-city, were recruited through convenience sampling by the municipal information paper and health announcement at each 18 public health center in 18 wards for the three-day course on prevention of osteoporosis from October 1996 to March 1998. The BMD of the 2nd metacarpal bone was measured using Computed X-ray Densitometry (CXD) method, by a trained radiologist. Dietary intake of calcium was assessed by self-reporting food frequency questionnaire on calcium dietary sources such as milk, dairy products, small fish, vegetables, and soybeans and carefully checked by trained dietician. An independent gradient of non-adjusted and adjusted BMD for age and weekly calcium intake, through soybeans intake frequency (p = 0.03) was noted. This study suggest soybeans, through possible beneficial effects of vitamin-K, soyprotein, and isoflavonoid, may affect BMD of middle aged women.