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Biomedical subjects

S Manabe

Publications and source records attributed to S Manabe.

At least 127 records · Page 7Linked to original sources
PubMed1988

Carcinogenic glutamic acid pyrolysis product in the dialysate of uremic patients treated by continuous ambulatory peritoneal dialysis.

By using a high-performance liquid chromatography (HPLC) method, we determined the contents of 2-amino-6-methyldipyrido[1,2-a:3', 2'-d] imidazole (Glu-P-1) and 2-aminodipyrido[1,2-a:3', 2'-d]imidazole (Glu-P-2) in the dialysate of patients with uremia. The total dialysate (approximately 6 liters) per day of the patients who had received continuous ambulatory peritoneal dialysis (CAPD) was examined. The amounts of Glu-P-1 and Glu-P-2 in the total dialysate per day were 552.2 +/- 266.9 pmole and 386.3 +/- 146.0 pmole (mean +/- SD, n = 10), respectively. The recoveries of Glu-P-1 and Glu-P-2 in the dialysate on our assay method were 68.2% and 54.3%, respectively. Based on the recoveries, the average amounts of Glu-P-1 and Glu-P-2 in the dialysate of uremic patients were assumed to be 809.7 pmole and 711.4 pmole, respectively.

Adult↗
PubMed1987

Accumulation of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole and 2-aminodipyrido[1,2-a:3',2'-d]imidazole, carcinogenic glutamic acid pyrolysis products, in plasma of patients with uremia.

In order to investigate the exposure of humans to 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole [(Glu-P-1) Chemical Abstracts Service:67730-11-4] and 2-aminodipyrido[1,2-a:3',2'-d]imidazole [(Glu-P-2) Chemical Abstracts Service:67730-10-3], carcinogenic heterocyclic amines, we developed a high-performance liquid chromatography method to detect Glu-P-1 and Glu-P-2 in biological samples, and compared the plasma levels of the carcinogens in normal subjects with those in uremic patients in which higher incidence of malignancy has been reported. Glu-P-1 and Glu-P-2 levels in plasma of uremic patients before induction of hemodialysis treatment were 12.62 +/- 3.65 (SD) pmol/ml (n = 5) and 14.81 +/- 5.17 pmol/ml (n = 5), respectively, whereas Glu-P-1 and/or Glu-P-2 could be detected in only two of seven normal subjects and the levels were lower than 3.1 pmol/ml. Approximately 10% of these carcinogens in plasma of uremic patients could be removed by the first hemodialysis treatment, and reasonable amounts of these carcinogens could be detected in the dialysate of uremic patients. However, significant amounts of Glu-P-1 and Glu-P-2 were still detected in plasma of all uremic patients even after 1 month-hemodialysis treatments. These results suggest that one of the excretory pathways of these carcinogens is via kidney.

Adult↗
PubMed1987

Detection of Trp-P-1 and Trp-P-2, carcinogenic tryptophan pyrolysis products, in dialysis fluid of patients with uremia.

In order to estimate the exposure levels of mutagenic and carcinogenic heterocyclic amines in humans, we developed a high-performance liquid chromatography method to detect 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) in dialysis fluid of patients with uremia. Using this methods, dialysis fluid of 12 patients who had received hemodialysis treatment or continuous ambulatory peritoneal dialysis was examined. Trp-P-1 was detected in dialysate of all uremic patients (727 +/- 282 pmoles, n = 12). In patients who had been treated with continuous ambulatory peritoneal dialysis, the average amount of Trp-P-1 found in whole dialysate (6 l) per day was 710 +/- 203 pmoles (mean +/- S.D., n = 8). Moreover, Trp-P-2 could be detected in 5 out of 12 patients (206 +/- 85 pmoles, n = 5). These results indicate that patients with uremia are actually exposed to carcinogenic tryptophan pyrolysis products. The average exposure level of Trp-P-1 in uremic patients apparently exceeded 710 pmoles (150 ng) per day.

Carbolines↗
PubMed1987

Inhibitory effects of tryptophan pyrolysis products on human platelet aggregation through inhibition of prostaglandin endoperoxide synthetase.

To determine the effects of the carcinogenic heterocyclic amines on the stimulus-reaction system in cells, the effects of several such amines, including 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), on human platelet aggregation and of Trp-P-1 and Trp-P-2 on human polymorphonuclear leucocyte aggregation were investigated. Of the carcinogens studied, only Trp-P-1 and Trp-P-2 had potent inhibitory effects on human platelet aggregation induced by sodium arachidonate. The concentrations of Trp-P-1 and Trp-P-2 causing 50% inhibition of human platelet aggregation induced by sodium arachidonate were 15 and 25 microM, respectively. The heterocyclic amines examined had no significant effects on human polymorphonuclear leucocyte aggregation. Moreover, radiochemical studies of arachidonate metabolism showed that Trp-P-1 and Trp-P-2 inhibited, in a dose-dependent manner, the formation of cyclooxygenase products in platelets induced by sodium arachidonate. These results indicate that Trp-P-1 and Trp-P-2 have potent inhibitory effects on prostaglandin endoperoxide synthetase in the stimulus-reaction system of human platelets.

Adult↗
PubMed1987

Studies in the development of Japanese encephalitis vaccine: expression of virus envelope glycoprotein V3 (E) gene in yeast.

A safe, effective and economical vaccine is required for the prevention of Japanese encephalitis (JE), a disease with high mortality and grave sequelae, which is prevalent in Japan and other countries in east, south-east and southern Asia. As the initial step to produce a second-generation vaccine, recombinant DNA technology was utilized to express the JE virus envelope glycoprotein V3 (E) gene in yeast cells.This report describes the construction of a yeast expression vector in which a cDNA clone covering the V3 gene was connected to the acid-phosphatase promoter of a yeast vector plasmid. Successful expression of the V3 gene was detected by ELISA and Western blotting using monoclonal antibodies against JE V3. Immunization of mice with the V3 antigen expressed in yeast produced limited but definite levels of anti-JE antibodies which could neutralize JE virus. The results are an encouraging step in the development of a practical second-generation JE vaccine.

DNA, Recombinant↗
PubMed1987

Regulation of hepatic sulfotransferase catalyzing the activation of N-hydroxyarylamide and N-hydroxyarylamine by growth hormone.

The regulatory mechanism of hepatic sulfation of N-hydroxyarylamine and N-hydroxyarylamide by endocrine factors has been studied in rats. The cytosolic sulfations of N-hydroxy-2-acetylaminofluorene (N-hydroxy-AAF) and 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-hydroxy-Glu-P-1), which were determined by the reductive formations of 2-acetylaminofluorene and Glu-P-1, were seven to nine times and three times higher, respectively, in male than female rats. Hypophysectomy of male rats decreased their activities to 23% and 41% of the levels of the untreated animals, respectively. Intermittent treatment of hypophysectomized male and female rats with human growth hormone (hGH) significantly increased their sulfating activities of both compounds. Infusion of hGH also enhanced the sulfating activity of N-hydroxy-AAF but not of N-hydroxy-Glu-P-1. The sulfating activity of N-hydroxy-AAF was also decreased by castration at neonate and was increased by the administration of testosterone propionate to gonadectomized male and female rats. Testosterone propionate and estradiol benzoate had no effect on hypophysectomized rats, but estradiol benzoate repressed the sulfating activities of N-hydroxy-AAF and N-hydroxy-Glu-P-1 in hGH-treated hypophysectomized male rats. These results indicate that sex steroids elicit their effects on the sulfations of N-hydroxyl-aryl compounds through modulating the action of growth hormone at hypothalamus-pituitary and hepatic levels in rat livers.

2-Acetylaminofluorene↗
PubMed1986

Presence of 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx) in dialysate from patients with uremia.

MeIQx (2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline), a carcinogenic heterocyclic amine, was found to be present in dialysis fluid of 8 patients with uremia, but not in fresh dialysis fluid before dialysis treatment. Concentrations of MeIQx in dialysates ranged from 14 to 32 pM. The mean absolute contents of MeIQx in dialysates (6 to 40 liters) was 334 p mole. These results indicate that the carcinogenic heterocyclic amine is present in the plasma of all patients with uremia.

Adult↗
PubMed1986

Miconazole inhibition of platelet aggregation by inhibiting cyclooxygenase.

Platelet dysfunction was found in rabbits to which a dose of miconazole nitrate (1.6 mg/kg body wt) therapeutic for human subjects had been given intravenously. The present experiments were conducted to elucidate the mechanism of inhibitory effects of miconazole on platelet function. After administration of a single dose of miconazole, rabbit platelet aggregation induced by collagen and sodium arachidonate was inhibited significantly for approximately 24 hr. On the other hand, hypertriglycemia, one of the major side effects of this drug, was not seen during 2 days of observations, nor were any other outstanding manifestations observed. In in vitro experiments, miconazole nitrate (10 microM) also significantly inhibited rabbit and human platelet aggregation (P less than 0.01). Biochemical analyses revealed that the stimulant-induced formation of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2), metabolites via cyclooxygenase, was inhibited by miconazole nitrate in both human and rabbit platelets in vitro. PGE2 production was decreased dose-dependently with the increase of miconazole concentration (10 to 100 microM), and the decrease was in parallel with a decrease of TXB2 production. In addition, malondialdehyde (MDA) production of human and rabbit platelets induced by exogenous arachidonate and collagen was also inhibited significantly by miconazole. Chromatographic studies showed that the amount of 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE), a metabolite via lipoxygenase, was increased markedly in accordance with the miconazole-induced decrease of TXB2 and 12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) formation in both human and rabbit platelets. These results indicate that miconazole nitrate inhibits platelet cyclooxygenase, without affecting the stimulant-induced release of arachidonic acid from platelet phospholipids. Use of this drug in the treatment of systemic fungal infection appears to be increasing. Careful attention should be paid to the inhibitory effects of miconazole on platelet function, especially in the case of intravenous treatment.

Adenosine Diphosphate↗
PubMed1986

Epidural migration of extruded cervical disc and its surgical treatment.

Twenty-two patients with epidural migration of cervical disc fragments were reviewed. Disc sequestrations can migrate to the anterior, posterior, and lateral aspects of the spinal canal and are divided into four types according to their localizations. Those migrating to the anterior or posterior surface of the spinal canal, causing myelopathy, were removed through either an anterior or posterior route. Removal of lateral sequestration by uncoforaminotomy provided full recovery for all patients with radiculopathy and drop-attacks. The number of disc sequestrations was not always one: three fragments were present in three patients and two fragments in five patients. Various routes combined with other approaches were indicated to eliminate completely the freely migrating disc sequestra.

Cervical Vertebrae↗
PubMed1986

[Toxicity assessments of chemical substances using primary culture of rat hepatocytes].

A primary hepatocyte culture was used as a model system to assess the toxicity of various chemical substances. Chemical substances tested in this experiment included 14 kinds of organic solvents, arsenic acid and N-nitrosodiumethylamine, most of which are known as hepatotoxic materials. Enzyme (GPT and LDH) leakage and albumin secreted from the hepatocytes to culture medium were measured to evaluate the cell damage after exposure to the chemical substances at various concentrations for 3 d. Cell counts and protein contents before and after exposure to the chemical substances were also measured during the course of these experiments. The extent of LDH leakage from hepatocytes was parallel to that of GPT leakage after exposure to the chemicals. Albumin secreted from the hepatocytes in the culture medium evidently decreased at concentrations of the chemicals which increased the enzyme leakage. Viable cell counts were significantly decreased by chemicals that increased the enzyme leakage, although the cell protein contents were not significantly affected. The minimum concentration of the chemicals at which enzyme leakage from hepatocytes was significantly increased was defined as the lowest toxic concentration (TCL0). Judging from TCL0 values, the degree of toxicity in these chemicals seems to be almost identical to the degree of in vivo hepatotoxicity reported previously. We, furthermore, observed that there is a positive correlation (r = 0.780, p less than 0.01) between PT50 calculated by the LD50 value reported previously and -Log magnitude of TCL0.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1986

[Protein C dynamics in peripheral arterial occlusive diseases and myocardial infarction: association of homozygous protein C deficiency with heterozygous dysplasminogenemia found among patients with deep vein thrombosis].

Protein C(PC) is the zymogen of a serine protease which regulates blood coagulation by inactivating activated blood coagulation factors V and VIII. We investigated the plasma level of PC in patients with deep vein thrombosis (DVT, n = 50), Buerger's disease (n = 34), arteriosclerosis obliterans (n = 37) and myocardial infarction (n = 17). PC in plasma was determined by rocket immunoelectrophoresis using a monospecific anti-PC antiserum raised in rabbits. Our study indicated that only in DVT the level of PC was decreased in comparison with the normal control (p less than 0.05). This decrease may be accounted for by increased utilization of PC for the regulation of continuously activated blood coagulation mechanism possibly ongoing in patients with DVT. On the other hand, among the patients with the DVT, we found a homozygous PC deficiency combined with a heterozygous dysplasminogenemia in a 22-year old male who had been suffering from recurrent venous thrombosis since the age of 14. Although the homozygous form of PC deficiency has been reported to be closely associated with fatal thrombotic disorders including purpura furminans during the neonatal period, the patient reported here had surprisingly survived the neonatal period and the childhood without any clinical manifestation relevant to thrombosis.

Adult↗
PubMed1986

[Congenital abnormalities related to coagulation and the fibrinolytic system in patients with vein thrombosis of the lower extremities].

Plasma concentrations of antithrombin III (AT III), plasminogen (Plg), and protein C (PC) were assayed in 28 patients with venous thrombosis of lower extremities without distinct underlying disorders. Three abnormalities were found in 5 cases (17.8%) in relation to coagulation and fibrinolytic system (3 with congenital AT III deficiency, one each with dysplasminogenemia and congenital PC deficiency). In the patients with either one of these abnormalities, characteristic features of thrombosis are summarized as follows; 1. early onset of clinical symptoms. 2. high frequency of superficial vein thrombosis. 3. high recurrence rate. 4. high frequency of pulmonary embolism.

Adolescent↗
PubMed1985

Hereditary tyrosinemia. Formation of succinylacetone-amino acid adducts.

Succinylacetone (SA) (4,6-dioxoheptanoic acid) is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumaryl acetoacetate hydrolase activity. Patients with this disease are associated with a number of abnormalities, including aminoaciduria, proteinuria, liver failure, commonly hepatoma, and decreased GSH concentration in the liver. In the course of our studies of tyrosinemia, we found that the urine of patients with this disorder contains material(s) that absorbs light at 315 nm. We investigated the nature of the 315 nm material in detail. SA was found to react with amino acids and protein nonenzymatically, to form stable adducts at physiological temperature and pH. All SA adducts with amino acids and/or proteins exhibited an absorption peak at 315 nm. Although all amino acids reacted with SA, the most reactive amino acid was lysine (Lys), followed, in order, by glycine, methionine, phenylalanine, serine, alanine, and glutamine. SA-adducts were unstable at pH below 6, while they were made considerably more stable after reduction with NaBH4, suggesting that SA forms an adduct via Schiff base formation. High-performance liquid chromatography (HPLC) analysis of urines from patients with tyrosinemia revealed the existence of SA-glycine, SA-methionine, SA-tyrosine, and SA-phenylalanine. After digestion of urines with proteinase K, three more HPLC peaks appeared, which all corresponded to SA-Lys adducts. TLC analysis of SA-Lys showed that SA-Lys could form as many as seven different adducts. No SA-adduct peaks were observed in HPLC in urines from normal subjects, patients with other forms of aminoaciduria, or patients with the nephrotic syndrome. In addition to amino acids and proteins, SA reacted with reduced glutathione (GSH) and formed a stable adduct. These findings suggest that SA adduct formation with amino acids, GSH, and proteins is a significant process occurring in tyrosinemia, and may account for certain of the pathologic findings in this hereditary disorder.

Amino Acid Metabolism, Inborn Errors↗
PubMed1985

Homozygous protein C deficiency combined with heterozygous dysplasminogenemia found in a 21-year-old thrombophilic male.

A congenital, probably homozygous deficiency of protein C combined with a heterozygous molecular abnormality of plasminogen was found in a 21-year-old male who had been suffering from recurrent venous thrombosis since the age of 14. Although the homozygous deficiency of protein C has been reported to be closely associated with fatal purpura fulminans or severe and massive thrombotic diseases during the neonatal period, the patient had survived the neonatal period without any clinical manifestations relevant to thrombosis. The patient apparently inherited the genetic abnormality of protein C deficiency from both of his parents and that of abnormal plasminogen from his father.

Adult↗