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Biomedical subjects

S Harada

Publications and source records attributed to S Harada.

At least 325 records · Page 18Linked to original sources
PubMed1994

Involvement of genetic polymorphism of alcohol and aldehyde dehydrogenases in individual variation of alcohol metabolism.

The involvement of genetic polymorphism at the alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) loci in determining blood acetaldehyde levels and the rate of ethanol elimination after ethanol intake was investigated. Sixty-eight healthy subjects ingested 0.4 g of ethanol per kg of body weight over 10 min. Blood acetaldehyde levels scarcely increased in the subjects homozygous for ALDH2*1, regardless of their ADH2 genotypes (ADH2*1/*1, ADH2*1/*2 and ADH2*2/*2). The acetaldehyde levels in the subjects with the ALDH2*1/*2 heterozygote increased to 23.4 microM on average, and no significant differences were observed between the three ADH2 genotype groups. Subjects homozygous for ALDH2*2 showed very high levels of blood acetaldehyde, and the average value was 79.3 microM. The values of Widmark's beta 60 (mg/ml/hr) and ethanol elimination rate (mg/kg/hr) showed significant differences among the three ALDH2 genotypes, and in decreasing order the values were ALDH2*1/*1, ALDH2*1/*2, ALDH2*2/*2. However, no significant differences were seen among the ADH2 genotypes.

Acetaldehyde↗
PubMed1994

[A study on drug resistance of newly admitted pulmonary tuberculosis patients with special reference to the resistance to SM, INH, EB and RFP].

Previously untreated 347 tuberculosis patients newly admitted to our hospital from 1980 to 1991 with positive bacilli and the full record of the drug sensitivity tests were analysed in this study. Among them, 49 cases showed primary resistance to either of major 4 anti-tuberculosis drugs (SM, INH, EB, RFP). The results obtained were as follows: 1. The number of patients with positive bacilli increased with age. The rate of primary drug resistance in patients of age group below 49 were significantly higher than that of age group over 50. 2. The rate of resistance was 8.6% to SM, 4.0% to INH, 1.4% to RFP and 0.6% to EB. These results are consistent with the results of studies of the Tuberculosis Research Committee, Ryoken. EB was frequently substituted to resistant drugs. 3. There was no significant difference between a group with primary resistance and a sensitive group in the various risk and intractable factors, laboratory data as a indicator of risk factors, and in the results of tuberculin skin test. There was also no significant difference in the rate of culture negative conversion of tubercle bacilli and the improvement in radiological findings. 4. We could rarely find the source of infection in 49 cases with primary resistance. In only 5 cases, family contacts were suspected and in another 1 case, the contact in a work place was suspected.

Adult↗
PubMed1994

Effect of long-term therapy with nipradilol on esophageal varices in patients with compensated cirrhosis. Results of a multicenter open study.

The effect of long-term administration of nipradilol (NIP, Hypadil Kowa, CAS 81486-22-8), a beta-blocker with a vasodilatory action, on esophageal varices was studied in 66 patients with compensated liver cirrhosis. Administration of NIP (6-12 mg/d) for 3-12 months produced progressive improvement of endoscopic findings over time (30% for C, 25% for F, and 40% for the R-C sign after 12 months). At the last examination (mean: 9 +/- 4 months), the improvement rates were 16.7%, 16.7% and 22.7%, respectively. No significant relationship was found between endoscopic improvement and the Child-Pugh score or the dose of NIP. Gastrointestinal bleeding occurred in five patients: one had bleeding esophageal varices, three had bleeding gastric varices, and one had a bleeding gastric ulcer. The systolic blood pressure was decreased significantly (4.6-12.3%) at 2 weeks as well as 1 and 2 months, and the heart rate showed a significant decrease throughout the study (10-18.4%). With the exception of the patients who had gastrointestinal bleeding, no symptoms of decompensation appeared, and there was no deterioration of laboratory parameters including ammonia. Adverse effects occurred in about 10% of the patients, most of which were related to bradycardia and/or hypotension, and they improved when the drug was withdrawn or the dose reduced. These results suggest that long-term administration of NIP is useful in the treatment of esophageal varices.

Adult↗
PubMed1994

[An investigation on risk factors relating to the treatment difficulty in originally treated pulmonary tuberculosis cases].

In order to investigate whether so-called risk factors relating to treatment difficulty are true risk or not, treatment results of 520 in-patients originally treated for pulmonary tuberculosis during 12 years' period from 1980 to 1991 in our hospital were analyzed. The proportion of cases with so-called risk factors among total 520 cases was as follows: Aged patients (70 years of age and over) 31.5%. Cases discharging abundant bacilli in sputum (Gaffky scale VII or above or culture, +3 positive) 29.4%. Adverse reactions to drugs 18.1%. Far advanced cavitary lesions (GAKKAI Classification I or II3) 15.6%. Relative risk of various risk factors in cases of group A (died of tuberculosis), group B (showed delay in the negative conversion of bacilli; namely, cases converted to negative only 4th month of treatment or later) and group C (cases of groups A and B) were calculated comparing with cases of the control group (pretreatment negative bacilli cases or cases converted to negative within 3 months). In cases of group A died of tuberculosis, the results were as follows; pretreatment abundant bacilli discharge 3.1, far advanced cavitary lesions 4.6, emaciation and/or malnutrition 5.1. Other risk factors identified were the following; unhealthy life style 4.0, severe gastrointestinal tract disease 3.9, impaired pulmonary function 3.3, complicated infections 3.2, cerebrovascular injuries including psychosis and nervous system diseases 2.3, diabetes mellitus 2.0, and the adverse reactions to drugs 1.9. In cases of group B showing delay in the negative conversion of bacilli, significant risk factors were pretreatment abundant bacilli discharge, far advanced cavitary lesions, emaciation and/or malnutrition and diabetes mellitus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Reproductive toxicity studies of the new cognition-enhancing agent nefiracetam in rats and rabbits.

The reproductive toxicity of nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384, CAS 77191-36-7) was investigated in rats and rabbits. Nefiracetam was administered orally for 9 weeks or more until successful copulation to male rats at doses of up to 480 mg/kg/d. Female rats were treated with nefiracetam at the same doses for more than 2 weeks prior to and in the early stages of pregnancy. No adverse effects on fertility were noted at any dose level. Nefiracetam elicited no evidence of teratogenicity when administered during the fetal organogenesis period to pregnant rats at doses of up to 1000 mg/kg/d, or to pregnant rabbits at doses of up to 270 mg/kg/d. Rat fetuses in the 1000 mg/kg group exhibited decreased body weights, delayed ossification and an increased incidence of skeletal variations such as cervical ribs and shortening of the 13th ribs. Decreased body weight gain and decreased food intake were also noted in rat dams of the 1000 mg/kg group. Nefiracetam showed no adverse effects on postnatal development, behavior or reproductive performance of rat offspring, except for decreased body weight gain in the 1000 mg/kg group. Rabbit fetuses in the 270 mg/kg group exhibited increased skeletal variations, mainly presence of the 13th ribs. Decreased body weight gain and decreased food intake were also noted in rabbit dams of the 270 mg/kg group. In a perinatal and postnatal toxicity study in rats using doses of up to 500 mg/kg, decreased food intakes were noted in dams of the 500 mg/kg group.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1994

[Lack of association between alcoholism and alleles in the delta-aminolevulinic acid dehydratase (ALAD) gene].

delta-Aminolevulinic acid dehydratase (ALAD) is the second enzyme in the heme biosynthetic pathway and catalyzes two molecules of delta-aminolevulinate (ALA), which is a potent agonist for GABA autoreceptors. ALAD has two common alleles and thus consists of three distinct isozymes, designated 1-1, 1-2, and 2-2. It has been shown recently that ALAD1 allele is associated with alcoholic liver injury. This association was ascribed to possible differences among isozymes in sensitivity to oxidized glutathione (GSSG), and this sensitivity is increased in erythrocytes of alcoholic patients. In the present study we measured erythrocyte ALAD activity from subjects with different ALAD genotype and found ALAD-1 is most sensitive to GSSG. We then investigated allele frequencies of ALAD in alcoholics (n = 126) and healthy controls (n = 115). For the control group, the frequencies were 0.94 (ALAD1) and 0.06 (ALAD2) and for the overall alcoholic group, 0.91 (ALAD1) and 0.09 (ALAD2). There were no significant differences in allele frequencies at the ALAD locus between the two groups. Subtyping the alcoholics according to the presence or absence of delirium tremens, hallucinosis, withdrawal seizure or liver cirrhosis failed to show statistically significant differences in the allele frequencies. We conclude that our data do not support the evidence of an allelic association between the ALAD1 and alcoholism.

Adult↗
PubMed1994

[A case of hypogamma-globulinemia with thymoma (Good's syndrome) follow-up for 8 years].

A 58-year-old woman, who had a past history of left upper lobectomy with thoracoplasty for pulmonary tuberculosis and resection of thyroid cancer, was diagnosed as having a mediastinal tumor by chest X-ray examination. It was found to be a malignant thymoma (spindle cell type) after resection. The level of serum gammaglobulin, which had been low before resection, progressively decreased. Afterward, she frequently suffered from airway infections which resulted in severe bronchiecatsis. She died due to respiratory failure 8 years later. In the early stage, though the percentage of pan T cells in peripheral blood lymphocyte subsets was normal, CD4 T cells decreased and CD8 T cells increased. A decrease in helper T cells and an increase in cytotoxic T cells were especially marked. In the late stage, all T cells subsets decreased. In particular, naive T (CD45RA* CD3+ T) cells decreased markedly. However, the percentage of B cells remained normal and that of NK cells was elevated. From the findings of lymphocyte subsets and lymphocyte reactivity to PHA stimulation, it is suggested that T cell dysfunction caused hypogrammaglobulinemia in this case.

Agammaglobulinemia↗
PubMed1994

Cytotoxic T cell response and expression of the target antigen in HTLV-I infection.

The cytotoxic T cell response of peripheral blood mononuclear cells (PBMC) to in vitro stimulation with human T cell leukemia virus type I (HTLV-I) was compared among HTLV-I-infected individuals with various clinical conditions. Induction of HTLV-I-specific cytotoxic T lymphocytes (CTL) was observed in 57% of asymptomatic HTLV-I carriers, 86% of patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) or other HTLV-I-related inflammatory diseases, and 18% of adult T cell leukemia (ATL) patients. HTLV-I p40tax, one of the major CTL target antigens, has an epitope strongly associated with HLA-A2. HTLV-I p40tax-specific CTL were frequently induced from HLA-A2-positive donors with HTLV-I-related inflammatory diseases regardless of neurological symptoms, but not from all the HLA-A2-positive HTLV-I-infected individuals tested. Leukemic cells of an ATL patient with HLA-A2, whose PBMC did not show an HTLV-I-specific CTL response, could be lyzed by p40tax-specific CTL derived from an HAM/TSP patient. This indicates that i) the presence of a certain HLA presenting CTL epitopes is not the sole determinant of the individual CTL response to HTLV-I, ii) HTLV-I-specific CTL act as potential effectors of anti-tumor surveillance in vivo. The role of HTLV-I-specific CTL, however, may be limited by another in vivo mechanism suppressing the expression of HTLV-I antigens. This suppression, presumably mediated by a plasma factor and commonly observed in HTLV-I-infected individuals, could be one reason for the persistence of HTLV-I-infection.

Base Sequence↗
PubMed1994

Investigation of the genetic markers associated with alcoholic liver diseases.

Polymorphic alleles of three genes (GSTMl, CYP1A1 and ApoB) were analysed in the context of the relationship between alcohol and liver diseases. DNAs were prepared from whole blood samples of 84 male controls, 71 male patients with alcoholic liver diseases. PCR and related techniques were used for detection of these polymorphic loci. The frequency of GSTMl gene deletion was significantly higher in the patients with alcoholic liver diseases than in controls (P < 0.05), whereas the frequencies of the genotypes (A, AB, B) in the individuals with GSTMl gene were not statistically different between both groups. In addition, the frequency of GYP1A1*A was found to be significantly higher in alcoholic liver diseases than in controls (P < 0.01). Gene frequencies of ApoB were not different between the two groups. These data suggest that GSTM1 gene deletion and CYP1A1*A gene increase the risk for alcoholic liver diseases.

Alleles↗
PubMed1993

Expression of the target antigen for cytotoxic T lymphocytes on adult T-cell-leukemia cells.

Adult T-cell-leukemia (ATL) cells were examined for susceptibility to human T-cell-leukemia virus type I (HTLV-I) tax-specific cytotoxic T lymphocytes (CTL) derived from a patient with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). These CTL efficiently killed HLA-matched leukemia cells of an ATL patient after overnight incubation. However, ATL cells immediately after isolation from the peripheral blood were only marginally susceptible to the CTL. This is not due to inappropriate expression of major-histocompatibility-complex (MHC)-class-I antigen on the leukemia cells. Addition of synthetic peptide, corresponding to the CTL epitope, to the assay enabled the CTL to kill the fresh ATL cells. Scarcity of HTLV-I antigens in the fresh ATL cells and induction of these antigens by in vitro incubation were demonstrated both on the cell surface and in the cytoplasm. Lectin stimulation augmented synthesis of HTLV-I antigens, but was not essential for the induction. The presence in the culture of human plasma containing a high titer of antibodies to HTLV-I did not affect the induction of HTLV-I expression in the ATL cells. Furthermore, significantly lower levels of HTLV-I tax mRNA were present in the fresh ATL cells than in the cultured ATL cells, whereas the levels of HTLV-I proviral tax gene did not differ among these cells. This suppression of HTLV-I transcription in fresh ATL cells accounts for resistance to the CTL, and could be a reason for the persistence of HTLV-I infection in vivo.

Aged↗
PubMed1993

Crystallization and preliminary X-ray studies of a protease from Pseudomonas aeruginosa.

A protease produced by Pseudomonas aeruginosa has been crystallized by the vapor-diffusion method using polyethylene glycol 4000 as a precipitant. The crystals belong to the hexagonal space group P6(1) (P6(5) with unit cell dimensions; a = b = 106.9 A, c = 96.9 A. There are two molecules per asymmetric unit. The crystals diffract X-rays to at least 3.0 A and are suitable for X-ray crystallographic studies.

Crystallization↗
PubMed1993

Relationship between alcohol consumption and the activity of GTP-binding regulatory proteins in human erythrocyte membranes.

Activity of stimulatory GTP-binding regulatory protein (Gs) in human erythrocyte membranes was assessed by activation of adenylate cyclase in S49 murine lymphoma variant cells to elucidate a relationship to alcohol consumption. In apparently healthy subjects, alcohol consumption < 50 g ethanol per week did not alter the Gs activity, but it was significantly higher (14.3%, P < 0.05) in moderate drinkers (50-150 g/week) than non-drinkers. Then, the Gs activity declined with a further increase in alcohol consumption (150-550 g/week). Those subjects with drinking levels of > 50 g/week also showed significant increases in other alcohol-related markers, Na+, K(+)-ATPase and gamma-glutamyltransferase. The Gs activity was significantly low in alcoholics (a 34.9% reduction). No such reduction was noted in patients with other diseases. The results indicate that the Gs activity in erythrocyte membranes is an alcohol-related marker in humans. The variation of Gs activity is distinctive from those of other alcohol-related markers.

Adenylyl Cyclases↗
PubMed1993

Protein phosphatase type 2B (calcineurin)-mediated, FK506-sensitive regulation of intracellular ions in yeast is an important determinant for adaptation to high salt stress conditions.

To assess the physiological function of Ca(2+)-dependent protein phosphatase (PP2B) in the yeast Saccharomyces cerevisiae, the phenotypes of PP2B-deficient mutants were investigated. Although PP2B was dispensable for growth under normal conditions, the mutations did, however, cause growth inhibition under certain stress circumstances. The growth of the mutants was inhibited by NaCl and LiCl, but not by KCl, CaCl2, MgCl2 or nonspecific osmotic stresses. Upon shift to high NaCl medium, intracellular Na+ levels of both wild type yeast and the mutants initially increased at a comparable rate. However, internal Na+ in wild type cells started to decline more rapidly than the mutant cells during cultivation in high NaCl medium, indicating that PP2B is important in maintaining a gradient across the membrane. The protection against salt stress was achieved, at least in part, by the stimulation of Na+ export. The maintenance of a high level of internal K+ in high NaCl medium was also PP2B-dependent. In the presence of the immunosuppressant FK506, the growth behaviour and intracellular Na+ and K+ of wild type cells in high NaCl medium became very similar to those of the PP2B-deficient mutant in a manner dependent on the presence of the FK506 binding protein.

Adaptation, Physiological↗
PubMed1993

Modulation of host cell nuclear proteins that bind to HIV-1 trans-activation-responsive element RNA by phorbol ester.

The trans-activation-responsive (TAR) element located within the 5' untranslated region of HIV-1 mRNA is the cis-responsive element for Tat, the viral trans-activator protein. Several TAR RNA binding proteins (TRBPs) have been identified in the nuclear extract from HeLa cells as cellular factors required for a full Tat-mediated trans-activation. In this study, we have tried to identify TRBPs in human T cell line (MOLT-4) persistently infected with HIV-1. Nuclear extract from the infected MOLT-4 cells was analyzed by gel-retardation and uv cross-linking assays with radiolabeled TAR RNA probe. Two major complexes of TAR RNA with some cellular proteins were detected in the gel-retardation assay. As the components of these complexes, at least five TRBPs (p30, p37, p46, p50, and p56) showing specific binding to the TAR RNA were detected in the uv cross-linking assay. We also observed that the detectable levels of p37 and p50 in the infected MOLT-4 cells were greatly reduced after phorbol ester (TPA) treatment under the condition of which HIV-1 gene expression was increased by about fivefold. These results suggest that the modulation of TRBPs by some mitogenic stimuli such as TPA might have a role in the trans-activation of HIV-1 gene expression in vivo.

Binding Sites↗
PubMed1993

Analysis of 3' terminals of human immunodeficiency virus type 1 transcripts in persistently infected cells.

To examine the 3' terminal processing of human immunodeficiency virus type 1 (HIV-1) transcripts and the effects of phorbol ester (TPA) on this processing, cellular RNAs from persistently infected T cells (MOLT-4) or promonocytes (U937), with or without TPA treatment, were analyzed. To map the 3' terminals of viral transcripts, the RNA samples were examined by RNase-protection assay with an HIV-1 long terminal repeat (LTR) antisense riboprobe. Without TPA treatment, the viral transcripts initiated at the cap site in 5' LTR and polyadenylated at poly(A) site in 3' LTR were dominantly detected in both types of cells. This analysis demonstrated that some occlusion mechanism inactivating the poly(A) site in 5' LTR might exist in these infected cells. After TPA treatment, we found a dramatic shift in the protected patterns of viral transcripts in MOLT-4 cells, while the shift in U937 cells was less dramatic. These results suggested that the primary factor(s) involved in the observed effect of TPA might be cellular. We also demonstrated that the shift in the protected patterns of viral transcripts was associated with increased steady-state levels of viral transcripts. These results indicated that the factors involved in the TPA-induced shift might have some relation to the trans-activation of HIV-1 by similar substances.

Base Sequence↗
PubMed1993

New strategy for detection of ALDH2 mutant.

Genetic polymorphism of the ALDH2 gene was analysed according to a new technique designated as amplification created restriction site (ACRS). A restriction site for the enzyme (Mbo II) was artificially created in the amplification product using an oligonucleotide primer possessing one mismatched base. Analysis using ACRS technique concerning 41 healthy controls and 63 alcoholics with liver diseases confirmed that the ALDH2 mutant was significantly lower in alcoholics than in healthy controls.

Aldehyde Dehydrogenase↗