To elucidate the contributions of GATA-1 to definitive hematopoiesis in vivo, we have examined adult mice that were rendered genetically defective in GATA-1 synthesis (Takahashi et al, J Biol Chem272:12611, 1997). Because the GATA-1 gene is located on the X chromosome, which is randomly inactivated in every cell, heterozygous females can bear either an active wild-type or mutant (referred to asGATA-1.05) GATA-1 allele, consequently leading to variable anemic severity. These heterozygous mutant mice usually developed normally, but they began to die after 5 months. These affected animals displayed marked splenomegaly, anemia, and thrombocytopenia. Proerythroblasts and megakaryocytes massively accumulated in the spleens of the heterozygotes, and we showed that the neomycin resistance gene (which is the positive selection marker in ES cells) was expressed profusely in the abnormally abundant cells generated in the GATA-1.05 mutant females. We also observed hematopoiesis outside of the bone marrow in the affected mutant mice. These data suggest that a small number of GATA-1.05 mutant hematopoietic progenitor cells begin to proliferate vigorously during early adulthood, but because the cells are unable to terminally differentiate, this leads to progenitor proliferation in the spleen and consequently death. Thus, GATA-1 plays important in vivo roles for directing definitive hematopoietic progenitors to differentiate along both the erythroid and megakaryocytic pathways. The GATA-1 heterozygous mutant mouse shows a phenotype that is analogous to human myelodysplastic syndrome and thus may serve as a useful model for this disorder.
Objective The present study was undertaken to clarify the clinical course and prognosis of adult patients with primary IgA nephropathy (IgAN), especially with mild pro-teinuria or mild histological alternations. Patients and Methods A population of 735 IgAN patients whomwe were able to observe for morethan two years was examined. Results A total of 115 patients (15.6%) was on dialysis during the observation period. The overall 5-year renal survival rate was 92.0%. On the other hand, 166 patients (22.6%) were in clinical remission. A group with mild pro-teinuria included 197 patients (26.8 %). Forty-seven patients of this group showedminor glomerular abnormalities, whereas 12 patients with mild proteinuria showed severe mesangial involvement. Three patients with mild pro-teinuria were on dialysis during the observation period, whose proteinuria was increased during the clinical course. A group with minor glomerular abnormalities included 82 patients (1 1.2 %). Forty-seven patients of this group showed mild proteinuria, of whom12 patients showed moderate proteinuria. However, three patients with minor glomeru-lar abnormalities who were not on dialysis showed loss of renal function. Conclusion These results indicated the heterogeneity of the course and prognosis in IgAN. Even if a patient's initial clinical or histological findings are comparatively mild, strict follow-up management is needed. (Internal Medicine 40: 697-702, 2001)
To elucidate the contributions of GATA-1 to definitive hematopoiesis in vivo, we have examined adult mice that were rendered genetically defective in GATA-1 synthesis (Takahashi et al, J Biol Chem272:12611, 1997). Because the GATA-1 gene is located on the X chromosome, which is randomly inactivated in every cell, heterozygous females can bear either an active wild-type or mutant (referred to asGATA-1.05) GATA-1 allele, consequently leading to variable anemic severity. These heterozygous mutant mice usually developed normally, but they began to die after 5 months. These affected animals displayed marked splenomegaly, anemia, and thrombocytopenia. Proerythroblasts and megakaryocytes massively accumulated in the spleens of the heterozygotes, and we showed that the neomycin resistance gene (which is the positive selection marker in ES cells) was expressed profusely in the abnormally abundant cells generated in the GATA-1.05 mutant females. We also observed hematopoiesis outside of the bone marrow in the affected mutant mice. These data suggest that a small number of GATA-1.05 mutant hematopoietic progenitor cells begin to proliferate vigorously during early adulthood, but because the cells are unable to terminally differentiate, this leads to progenitor proliferation in the spleen and consequently death. Thus, GATA-1 plays important in vivo roles for directing definitive hematopoietic progenitors to differentiate along both the erythroid and megakaryocytic pathways. The GATA-1 heterozygous mutant mouse shows a phenotype that is analogous to human myelodysplastic syndrome and thus may serve as a useful model for this disorder.
Objective Some angiotensin receptor blockers (ARBs), including irbesartan, increase the peroxisome proliferator-activated receptor (PPAR)-g activity in vitro. The aim of this study was to evaluate the interactions between obesity and the effects of irbesartan on inflammatory cytokines in chronic glomerulonephritis patients without diabetes. Methods The anti-inflammatory effects of irbesartan were evaluated in 29 hypertensive chronic glomerulonephritis patients without diabetes in a prospective, single-arm study. Results Following treatment with irbesartan for 26 weeks, blood pressure and proteinuria significantly decreased, as previously reported (blood pressure decreased from 142±1/87±1 to 131±1/81±1 mmHg and the urine protein/creatinine ratio decreased from 1,030±143 to 779±121 mg/g Cr). BMI did not significantly change after the study. Among the inflammatory parameters, the concentrations of adiponectin and highsensitivity C-reactive protein (hsCRP) significantly improved after treatment; however, the changes in the concentrations of interleukin-6 (IL-6), tumor necrosis factor (TNF)-a and leptin did not reach statistical significance. Moreover, the changes in these five parameters following treatment were moderately correlated with the BMI values obtained at the initiation of the study, and the improvements were particularly prominent in those with a BMI greater than 25. Improvements in proteinuria were significantly correlated with increases in the adiponectin concentration, but not with BMI. There was also a moderate correlation between the changes in the adiponectin and insulin concentrations. Conclusion Irbesartan improves metabolic parameters in nondiabetic hypertensive chronic glomerulonephritis patients, especially those with a high BMI. Improving the adiponectin concentration may be important for reducing proteinuria.
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