Biomedical subjects
Publications and source records attributed to S Hirose.
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The human renin gene was isolated from a Charon 4A human genomic library and characterized. The gene spans about 11.7 kilobases and consists of 10 exons and 9 introns that map at points that could be variable surface loops of the enzyme. The complete coding regions, the 5'- and 3'-flanking regions, and the exon-intron boundaries were sequenced. The active site aspartyl residues Asp-38 and Asp-226 are encoded by the third and eighth exons, respectively. The extra three amino acids (Asp-165, Ser-166, Glu-167) that are not present in mouse renin are encoded by the separate sixth exon, an exon as small as 9 nucleotides. The positions of the introns are in remarkable agreement with those in the human pepsin gene, supporting the view that the genes coding for aspartyl proteinases have arisen as the result of duplication of a common ancestral gene. As in most eukaryotic genes, the putative T-A-T-A and C-A-A-T sequences, which may play a role in the initiation of gene transcription, are found in the vicinity of -29 and -51 nucleotides of the cap site. Further upstream, at nucleotides -456 to -451, is located the hexanucleotide T-G-T-T-C-T, which has recently been suggested as a binding site for the glucocorticoid receptor. In the 3'-flanking region, there is the conserved hexanucleotide sequence A-A-T-A-A-A, thought to be necessary for polyadenylylation. Blot-hybridization analyses of the isolated gene clone and the total cellular DNA after digestion with restriction enzymes revealed that human renin is encoded by a single gene.
An efficient method for oligonucleotide-directed mutagenesis was developed to construct a set of site-specific mutations by using a mixture of oligodeoxyribonucleotides. With this method, as high as 40% of the tested clones turned out to be desired mutants. Seven single-point mutants were isolated in the "TATA" box region of the fibroin gene. In vitro transcription experiments showed that single-base transversions at the TATA box (A----T at position -29, T----A or G at -28, A----T at -27, and A----T at -26) resulted in decreased promoter activities, whereas A----G transitions at positions -24 and -23 had no effect. The initiation site of transcription was normal in three down-promoter mutants at positions -28 and -26, but the A----T transversions at positions -29 and -27 induced an additional transcription start from position +4. Using 10 single-point mutants obtained as above or by nitrous acid-induced mutagenesis, we have prepared a pair of heteroduplex DNAs consisting of a mutant strand and the wild-type one. The molecules heterozygous at positions -30, -21, and -20 showed reduced transcription activities when the noncoding strand bears the mutation, whereas that at position -26 gave a low activity when the coding strand carries the mutation. Both types of heteroduplex at positions -29, -28, -27, and -17 exhibited decreased activities. These results suggest a transcription machinery contact to a major groove of the DNA helix at the TATA box and region of position -20.
A branched chain amino acid (BCAA) solution was infused for 2 weeks following major hepatic resection in patients with malignant tumors of the liver. The infusion caused a significant reduction in plasma concentrations of phenylalanine, tyrosine, methionine, and ammonia as compared with the control patients. The BCAA infusion also prevented a marked fall in the molar ratio of valine, leucine, and isoleucine to phenylalanine and tyrosine. No untoward effects of the treatment were found. Although further studies are necessary to determine an ideal dose of BCAAs from the viewpoint of nitrogen balance, the BCAA solution seems to be a useful nutritional element after major hepatic resection if given with hypertonic glucose.
Truncated templates of a cloned actin gene (actin 5) of Dictyostelium discoideum were transcribed in a HeLa cell extract from a position indistinguishable from the in vivo initiation site. The efficiency of this accurate transcription, however, was very low compared with that of the adenovirus 2 major late gene in the same system. Transcription of the actin 6 and 8 genes, of which the 5'-flanking regions differ in their base sequences from the corresponding region of the actin 5 gene, was not good in either fidelity or efficiency. When the partially purified RNA polymerase II of D. discoideum was used instead of the HeLa cell extract, no accurate transcription of the actin 5 gene occurred. However, simultaneous addition of RNA polymerase II and HeLa cell extract into the cell-free system caused a shift of the in vitro initiation point of transcription of the actin 5 gene to a position about 20 nucleotides downstream from the presumed in vivo initiation site. The reason for the shift remains unknown, but it is supposed that some factor(s) other than RNA polymerase II are involved in the accurate initiation of transcription and the maintenance of transcription efficiency of the actin genes.
Interferon induces oligo-2',5'-adenylate synthetase in cells. In various diseases, interferon was detectable in the circulation or was produced spontaneously from peripheral blood mononuclear leukocytes. The oligo-2',5'-adenylate synthetase activity in peripheral blood mononuclear leukocytes was examined in various diseases, including systemic lupus erythematosus, sarcoidosis, Vogt-Koyanagi-Harada disease, and Behcet's disease. The activity of this enzyme was significantly increased in systemic lupus erythematosus (P less than 0.01), sarcoidosis (P less than 0.01), and Vogt-Koyanagi-Harada disease (P less than 0.01) compared with that in controls, but the increase of activity was not significant in Behcet's disease (P greater than 0.05).
Activation of the alternative pathway of human complement (C) by soluble C activators resulted in a decrease of C9 antigen, measured by single radial immunodiffusion, concomitant with a decrease of C9 hemolytic activity. In the presence of ethylene glycol bis-(beta-aminoethylether)-tetraacetic acid (EGTA) and Mg2+, this decrease of C9 antigen in the presence of soluble activators such as dinitrophenylated bovine serum albumin depends mainly on the activation of the alternative C pathway. Therefore, an assay system to express the total activity of the alternative C pathway in human serum - the C9 depletion test (C9DT) -, was devised. C9DT showed significantly lower values for patients with systemic lupus erythematosus and rheumatoid arthritis than for control patients.
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A 22-year-old Japanese woman with systemic sarcoidosis had retinal neovascularizations at seven loci with repeated vitreous hemorrhage in her right eye. Oral administration of prednisone was not effective. However, argon laser photocoagulation to the neovascularizations obliterated the neovascular fronds except at the optic nerve head; three months from the treatment, the neovascularization at the optic nerve head regressed spontaneously. No serious complications have occurred, and the vitreous hemorrhage has not recurred for the past two years. From these results, argon laser photocoagulation was thought to be effective for the treatment of retinal neovascularization in sarcoidosis.
To assess the natural history of non-alcoholic liver cirrhosis, one hundred and eighty medically treated Japanese cases, including 110 accompanied by esophageal varices were investigated retrospectively. Among those patients with varices fifty-one (46.4%) bled from the upper gastrointestinal (GI) tract and thirty-two (29.1%) from esophageal varices, while GI bleeding was found in only six out of 70 patients without varices. The GI bleeding rate was the highest in patients with varices and concomitant hepatoma (76.5%). The mortality rate of the GI bleeders was 68.6% in patients with varices and 33.3% in patients without varices. The mortality on the first variceal bleeding episode was 65.6%, and another 25.0% had rebleeding from varices, resulting in a one-year survival of 9.4%. The ten-year cumulative percentage of variceal bleeding was 61.2% in patients with varices, and that of occurrence of hepatoma was 50.7% in total of 180 patients. This study revealed that the non-alcoholic cirrhotic patients have a highly rate of complication by hepatoma and that the development of hepatoma doubles the risk of varix rupture.
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To determine the inheritance patterns of both IgM class and IgG class hypergammaglobulinaemias, the locations of genes and the relations of these genes to other autoimmune traits in NZB X NZW (B/W) F1 hybrid, we measured serum levels of both IgM and IgG in NZB, NZW, B/W F1 hybrid, B/W F1 X NZW back-cross and B/W F1 X NZB back-cross mice. The highest serum IgM levels were observed in NZB mice, however the serum IgG levels were normal. In contrast, a large amount of IgG was produced in B/W F1 hybrids, in which the serum IgM levels were lower than those observed in NZB mice. The NZW mice had fairly normal values for both measures. Progeny studies suggested that a single dominant locus (Imh-1) of NZB strain, which is loosely linked to brown-black coat colour locus b and Mup-1 locus on chromosome 4, determines the IgM class hypergammaglobulinaemia. The estimated gene order was Mup-1:b:Imh-1. This IgM class hypergammaglobulinaemia in NZB mice was suppressed to a considerable extent in B/W F1 hybrid mice by either a gene dosage effect or more likely, a regulatory gene locus of NZW strain, being also loosely linked to Mup-1 locus on chromosome 4. As for the IgG class hypergammaglobulinaemia, a complementary effect of two or three genes, either one or two dominant genes derived from NZB and a single dominant gene from NZW strains, determines this trait in B/W F1 hybrid mice. There appeared to be no relationships between the genes responsible for the IgM class and IgG class hypergammaglobulinaemias. When looking at the correlations between the hypergammaglobulinaemias and the traits, anti-double stranded DNA (dsDNA) antibodies and renal disease in both back-cross mice, we found a significant quantitative correlation only between the IgG class hypergammaglobulinaemia and the IgG class anti-dsDNA antibodies in B/W F1 X NZB back-cross mice.
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beta 2-microglobulin (BMG) and conventional renal function parameters (creatinine clearance (C-cr) etc.) were measured in 36 adult patients before and after open heart surgery (Group-2). Same study was performed in 14 adult patients abdominal surgery (Group-1). Urinary BMG concentration (U-BMG) increased remarkably in both groups immediately after surgery. U-BMG returned to the preoperative level on the 4th postoperative day (4-POD) in Group-1, and 7-POD in Group-2. The degree of increase in Group-2 was remarkable comparing with that in Group-1. The tubular dysfunction after surgery was believed to result in a marked rise in U-BMG, therefore, the later recovery and higher increase of U-BMG in Group-2 indicated that the tubular dysfunction after open heart surgery was severer comparing with that after abdominal surgery. On 7-POD, in Group-2, U-BMG was still abnormal in 13 cases, which suggested the prolonged tubular dysfunction after open heart surgery. A retrospective study to determine the risk factors of prolonged tubular dysfunction was performed in 34 patients in Group-2. Significant risk factors were preoperative blood urea nitrogen and urine osmolarity. Several factors were not significant including perfusion time, aortic alamp time, preoperative C-cr, U-BMG, serum creatinine concentration and free water clearance.
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