Determinants of Plasma Renin Activity: Role of a Human Renin Gene Variant as a Genetic Factor

The plasma renin activity (PRA) is affected by a number of environmental factors. However, significant heritability has been shown for the activity. A hypothesis that a candidate regulatory single-nucleotide polymorphism, C-5312T, of human renin gene should have a significant effect on PRA was elucidated and updating of independent determinants of PRA was attempted.Cross sectional study.Outpatient study.We enrolled consecutive 810 subjects who had consulted our hospitals for lifestyle-related diseases.Genotypes were assayed with genomic DNA for C-5312T. Among the genetic variants, the difference of PRA was evaluated. Monovariate linear regression analysis was performed to test the correlation between PRA and clinical variables. Finally, stepwise multiple regression analysis was performed to evaluate the independent determinants.On comparing 2 genotype groups, CC/CT and T allele homozygote, the geometric means of PRA were 0.778 and 0.941 ng/ml/h, respectively (F = 5.992, P = 0.015). Monovariate linear regression analysis revealed that a number of variables have a significant correlation with the activity, including urinary salt excretion. A stepwise multivariate regression analysis revealed that renin C-5312T variant (TT) is one of the independent determinants of PRA.Thus, for the first time, a human renin gene variant was associated with a significant increase in PRA as a genetic factor and the independent determinants for the activity were updated including genetic factor.     

Dynamics of genomic 5‐hydroxymethylcytosine during mouse oocyte growth

Recent studies of the demethylation process in murine zygotes have shown that 5‐methylcytosine (5mC) is first converted into 5‐hydroxymethylcytosine (5hmC) or further‐oxidized cytosines in the paternal genome by the maternal ten–eleven translocation 3 (TET3) enzyme. This process is crucial for normal embryogenesis, and our aim was to elucidate the effect of Tet3 on the maternal genome during female germ‐line development. Immunofluorescence analysis showed that 5hmC was clearly present in fully grown oocytes but not in nongrowing and early growth‐stage oocytes. The 5hmC in the maternal genome was clearly detectable in DNA methyltransferase 3‐like enzyme (Dnmt3L)‐null oocytes and their fertilized zygotes, although Dnmt3L is essential for DNA methylation in oocytes. An analysis using an enzyme digestion‐based method showed that 5hmC was present in LTR retrotransposons from the late growth period of oocytes. Quantitative RT‐PCR analysis showed that Tet3 expression was enhanced during oocyte growth and exhibited an approximately 40‐fold increase between nongrowing and fully grown oocytes. Our results show that 5hmC is generated since the oocyte growth stage, accompanied by up‐regulation of Tet3; 5hmC is located mainly in LTR retrotransposons, indicating that 5hmC generated in growth‐stage oocytes is responsible for genomewide demethylation after fertilization.     

Importance of bilateral sympathetic innervation on cerebral blood flow autoregulation in the thalamus

Effects of bilateral sympathetic innervation on the regulation of cerebral blood flow to the thalamus were examined in spontaneously hypertensive rats (SHR). The superior cervical ganglion was removed on one side or bilaterally, and blood flow in the thalamus was repeatedly measured with a hydrogen clearance technique during a stepwise increase in arterial pressure. Regional blood flow in the thalamus was unchanged following acute ganglionectomy: 55 +/- 6 ml/100 g/min in the intact rats and 56 +/- 4 in the denervated rats. Sympathectomy on one side neither had effects on the pressure-flow relationship nor on the blood pressure levels of upper limits of autoregulation in the ipsilateral thalamus. In contrast, bilateral sympathetic denervation impaired the autoregulatory function in the thalamus and the upper limits were significantly lower than those in intact rats: 206 +/- 8 vs 226 +/- 10 mm Hg, respectively (P less than 0.02). It is concluded that overlapping innervation of sympathetic nerves has an important role in regulation of blood flow to the thalamus during an acute rise in arterial pressure in SHR.     

Clinical,hematologic, and pathologic features of leukemic T-cell lymphoma

Cells obtained from malignant lymph nodes and the peripheral blood of 106 patients with non-Hodgkin's lymphomas were examined for T- and B-cell characteristics. Surprisingly, 79 cases were of the T-cell type on the basis of spontaneous rosette formation with sheep erythrocytes (E-rosettes). Of the remaining cases, 15 were B-cell in nature (monoclonal S-Ig positive), seven were non T-, non B-cell and four cases were undetermined. Forty-nine (62.0%) of the T-cell malignancies were of a leukemic variety, characterized by pleomorphism in the peripheral blood cell size, and histological appearance. Most of the leukemic T-cells showed obvious lymphocytic differentiation, with condensed nuclear chromatin and scant cytoplasm, although in many of the cases, the lymphomatous infiltrate was dominated by large or pleomorphic lymphoid cells. All tumors were of a diffuse variety, and on histologic examination included a mixed type (21 cases), PDLL forms (15 cases), a large lymphoid cell type (eight cases), and WDLL forms (five cases). Although the mixed type with a pleomorphic lymphoid infiltrate was distinctive, there has been considerable variation from case to case. Clinically this unusual T-cell, leukemic variety of non-Hodgkin's lymphomas primarily involved middle-aged and elderly subjects, and was characterized by wide spread organ invasion (preferentially to the liver, spleen and skin), resistence to chemotherapy, and a poor prognosis. A mediastinal mass was not observed in all cases. The patients had a median survival of only ten months.     

Heme oxygenase-1-generated biliverdin ameliorates experimental murine colitis

BACKGROUND: Heme oxygenase-1 (HO-1) seems to have an important protective role in acute and chronic inflammation. The products of heme catalysis, biliverdin/bilirubin, carbon monoxide (CO), and iron (that induces apoferritin) mediate the beneficial effects of HO-1. Blockade of HO-1 activity results in exacerbation of experimental colitis. We tested whether HO-1 has protective effects in the development of colitis and determined that specific enzymatic products of HO-1 are responsible for these effects. METHODS: Colitis was induced by oral administration of dextran sodium sulfate (5%) to C57BL/6 mice for 7 days. HO-1 was up-regulated by cobalt-protoporphyrin (5 mg/kg, intraperitoneally). Biliverdin, exogenous CO, or the iron chelator desferrioxamine was administered to other groups. RESULTS: Cobalt-protoporphyrin treatment resulted in significant up-regulation of HO-1 protein in mucosal and submucosal cells. Induction of HO-1 was associated with significantly less loss of body weight in mice with induced colitis (-12% versus -22% in the control animals, P < 0.001). Development of diarrhea and gastrointestinal hemorrhage was substantially delayed in animals in which HO-1 was induced, and mucosal injury was significantly attenuated. Administration of CO or desferrioxamine alone had no significant effects, whereas enhanced protection with lesser evidence of bowel inflammation was observed with systemic biliverdin administration (50 micromol/kg, 3 times per day, intraperitoneally). CONCLUSIONS: We conclude that heightened HO-1 expression or administration of biliverdin ameliorates dextran sodium sulfate-induced experimental colitis. Novel therapeutic strategies based on HO-1 and/or biliverdin administration may have use in inflammatory bowel disease.     

Retroviruses and autoimmunity

The investigation of human retroviruses has shown dramatic progress since the discovery of human immunodeficiency virus (HIV). These studies have also contributed to the exploration of the role of retroviruses, including endogenous retroviruses, in the induction of autoimmune diseases such as systemic lupus erythematosus (SLE). This review describes the potential role of retroviruses in autoimmunity, based on recent findings including our own results.