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Biomedical subjects

K Nonaka

Publications and source records attributed to K Nonaka.

At least 109 records · Page 6Linked to original sources
PubMed1997

Association between Ala54Thr substitution of the fatty acid-binding protein 2 gene with insulin resistance and intra-abdominal fat thickness in Japanese men.

Alanine to threonine substitution at codon 54 of the fatty acid-binding protein 2 (FABP2) gene was recently shown to be associated with insulin resistance in Pima Indians. It has been hypothesized that the mutation may result in enhanced intestinal up-take of fatty acids, and thereby an impairment of insulin action. We analysed the association of the Ala54Thr substitution with insulin sensitivity and abdominal fat thickness in 395 Japanese men aged 50.5 +/- 8.8 years (mean +/- SD) with a body mass index of 24.4 +/- 3.0 kg/m2. The frequency of the Thr54 allele was 0.34. Although the polymorphism was not significantly associated with diabetes or impaired glucose tolerance, subjects homozygous for the Thr54 allele had higher basal insulin levels. Analysis by homeostasis model assessment showed an association between the amino acid substitution and greater insulin resistance, and slightly higher beta-cell function. Oral glucose tolerance tests performed in 392 subjects without fasting hyperglycaemia showed higher 2-h insulin concentrations in individuals homozygous for the Thr54 allele when compared with heterozygotes or homozygotes for the Ala54 allele. No significant association was obtained between the polymorphism of the FABP2 gene and body mass index. However, ultrasound measurements of abdominal fat thickness revealed a greater accumulation of intra-abdominal fat in subjects homozygous for the Thr54 allele, whereas subcutaneous fat thickness was not associated with the polymorphism. These observations suggest that the Ala54Thr substitution in the FABP2 gene is associated with insulin resistance in Japanese men, and that visceral fat accumulation might be involved in the impaired insulin action associated with the substitution.

Abdomen↗
PubMed1997

Permeability of a neuroprotective compound NS-7 into brain: comparison between normal and middle cerebral artery-occluded rats.

The pharmacokinetics of 4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride (NS-7), a novel neuroprotective compound, in brains of normal and ischemic rats were investigated. In normal rats, the concentrations of NS-7 in the cerebral cortex and striatum were more than 10-folds higher than those in plasma during 5 min and 12 h after intravenous injection. The time course changes in plasma concentration of NS-7 were fitted to the two-compartment open model, in which elimination half-life (t(1/2)beta) was 6.0 h and distribution volume (V1) was 4.4. The estimated striatal interstitial concentration of NS-7 measured by microdialysis was unexpectedly low and almost constant after intravenous injection. Subsequently, the level of NS-7 in brain was compared between sham-operated and middle cerebral artery (MCA)-occluded rats. In MCA-occluded rats, the concentrations of NS-7 in the ischemic cerebral cortex and striatum were 64-71% of those in sham-operated group at 1 h after injection, although the initial concentrations (at 2-5 min) were much lower (about 20%) in MCA-occluded rats. The t(max) was observed at 1 h after injection, which was later than that (5 min) determined in sham-operated rats. Moreover, its elimination half-life was longer in MCA-occluded rats than in sham-operated animals. From these results it is suggested that peripherally administered NS-7 readily penetrates into brain, in which it exists for the most part in parenchymal fraction. In addition, substantial amount of NS-7 may distribute to the ischemic brain regions when it was injected after MCA occlusion.

Animals↗
PubMed1997

Beta 3-adrenergic receptor gene polymorphism is not a major genetic determinant of obesity and diabetes in Japanese general population.

To assess the contribution of a replacement of Trp at codon 64 of beta 3-adrenergic receptor by Arg to fat distribution and metabolic disturbances in Japanese general population, we examined the missense mutation in 1122 persons consisting of 817 men aged 50.0 +/- 8.9 years and 305 women aged 50.8 +/- 8.5 years in Kyushu, Japan. The incidence of Arg64 allele was 0.21; no age-dependent decrease of the allele frequency was observed, suggesting that the mutation was not associated with early mortality. The genotype was not significantly correlated with body mass index or the thickness of visceral fat estimated by ultrasonography. Glucose tolerance and glucose-induced insulin secretion were not significantly different among subjects with Trp/Trp, Trp/Arg and Arg/Arg at codon 64. Although in obese persons the ratio of heterozygotes for the mutation tended to be higher in subjects with impaired glucose tolerance than in subjects with normal glucose tolerance, the tendency was not observed in non-obese persons. Furthermore none of 39 non-obese individuals homozygous for the mutation was diabetic, whereas two out of six obese homozygous persons were diabetic. These observations suggest that the missense mutation may not be a main determinant of obesity in populations taking low fat/low energy Japanese-style diet and it may not be deleterious at least in non-obese individuals.

Adipose Tissue↗
PubMed1997

Combined measurements of GAD65 and ICA512 antibodies in acute onset and slowly progressive IDDM.

Autoantibodies to 65 kD glutamic acid decarboxylase (GADAA) and ICA512 (ICA512AA) were measured by radioimmunoassays using as antigens in vitro transcribed and translated [35S]-methionine-labeled human GAD65 and ICA512 (IA-2). The prevalence of GADAA and ICA512AA in sera from 87 patients with IDDM was 39 and 23%, respectively. The frequency and titer of ICA512AA declined sharply within 5 years after the onset of IDDM. Among patients tested within 4 years after diagnosis, the prevalence of ICA512AA was significantly higher in acute onset IDDM than in slowly progressive IDDM (37 versus 6%, P < 0.025) irrespective of age, while there was no difference in GADAA frequency between acute onset and slowly progressive subtypes (51 versus 63%). A total of two patients out of 121 patients with NIDDM were positive for GADAA, and two other NIDDM patients, who were suffering from sarcoidosis, were positive for ICA512AA. Neither of the antibodies were positive in sera from four atypical NIDDM patients, aged < 20 years, who showed ketosis at onset and required insulin followed by excellent metabolic control with diet restriction alone. These observations suggest that ICA512AA are associated with rapid progression of beta cell damage in IDDM. ICA512 radioassay, in combination with GAD assay may provide a useful diagnostic marker for IDDM especially in youth.

Adolescent↗
PubMed1997

Rising trizygotic triplet rates in Japan, 1975-1994.

Zygosity of triplet births in Japan was estimated by Allen's equation with the assumption that the rate of dizygotic (DZ) triplets reflects that of twins. Whereas the DZ triplet rate increased during the period from 1975 to 1994, reflecting the increase in the DZ twinning rate in the period, monozygotic (MZ) triplet rates remained constant from 1975 (28 per million births) to 1994 (23). The trizygotic (TZ) triplet rate gradually increased from 1975 (18) up to 1985 (29), and rapidly increased thereafter to 1994 (202). The higher TZ triplet rate since 1986 is most likely attributed to the higher proportion of mothers treated with ovulation-inducing hormones and partially to in-vitro fertilization in Japan. As for maternal age, MZ triplet rates remained nearly constant for all the maternal age groups except the youngest and the oldest ones. On the other hand, TZ triplet rates increased up to the age group of 30-34 years and decreased thereafter in almost every year. The TZ rate in the age group of 30-34 years slowly increased from 1975 to 1988 (63 per million births) and rapidly increased thereafter (314 in 1994). The TZ rate was statistically significantly higher in the period 1986-1994 than in the period 1975-1985 in each of the nine districts in Japan. Geographical variations in the TZ rates in the latest period have drastically changed from those during the period from 1955-1959 and in 1974.

Adult↗
PubMed1997

The twinning rates by zygosity in Japan, 1975-1994.

The monozygotic (MZ) twinning rate in Japan had remained nearly constant from 1975 (3.74 per 1,000 births) to 1994 (4.23), whereas the dizygotic (DZ) twinning rate had remained nearly constant from 1975 (1.86) to 1986 (2.27), and had gradually increased up to 1994 (3.89). The higher DZ twinning rate since 1987 has been attributed to the higher proportion of mothers treated with ovulation-inducing hormones and partially attributed to in-vitro fertilisation in Japan. As for maternal age, MZ twinning rates have remained nearly constant for maternal age groups except the youngest and the oldest age groups. On the other hand, DZ twinning rates increased up to the 35-39 years of age group and decrease thereafter. In 1994, the twinning rate was higher in DZ twins than in MZ twins for maternal age groups of 30-34 years and of 35-39 years. As for geographical variations in twinning rates, DZ rates statistically significantly increased with the year during the period from 1986 to 1994 in 31 out of 47 prefectures. In 1994, twinning rates in 21 out of 47 prefectures were higher in the DZ than the MZ rate, and the DZ rate is equal to the MZ rate in two prefectures. Geographical variations in twinning rates by zygosity in 1994 drastically changed from those during the period from 1955-1959 and in 1974.

Adult↗
PubMed1997

Mutation of RET proto-oncogene in Japanese patients with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.

To determine whether patients with medullary thyroid carcinoma (MTC) develop other endocrine neoplasms or their relatives develop MTC, we investigated the mutations in the RET proto-oncogene in patients with multiple endocrine neoplasia type 2B (MEN 2B, N = 1) and sporadic MTC (N = 6). DNA from MTC tissue and the peripheral blood was screened by polymerase chain reaction single-strand conformational polymorphism (PCR-SSCP) analysis of exons 10 and 11. PCR products of exons 13 and 16 were also analyzed by AluI and FokI restriction enzyme digestion methods, respectively, and then sequenced. We did not find structural abnormalities in exon 10 or 11, or at codon 768 in exon 13, but a mutation at codon 918, ATG to ACG, was found in the peripheral blood and the MTC tissue from a patient with MEN 2B. The same mutation was also found in tumor tissue from 2 of 6 patients with sporadic MTC, but not in their peripheral blood.

Adult↗
PubMed1997

Effects of fetus weight, dam strain, dam weight, and litter size on the craniofacial morphogenesis of CL/Fr mouse fetuses affected with cleft lip and palate.

OBJECTIVE: This study examined the factors related to the morphogenesis of the craniofacial complex of the CL/Fr mouse fetus affected with CLP based on the findings of a lateral cephalogram. DESIGN: Embryo transfer experiments were performed to determine the effect of the fetus weight, dam strain, dam weight, and litter size on the Intra-uterine craniofacial morphogenesis of CL/Fr mouse fetuses. On the 18th gestational day, each pregnant dam that had received CL/Fr mouse embryos was laparotomized to remove the transferred fetuses that had developed in the uteri of the cleft lip and palate (CLP)-susceptible CL/Fr strain dam and the CLP-resistant C57BL strain dam. A cephalometric observation of the craniofacial morphology of each fetus was subsequently performed. RESULTS: Based on a multiple regression analysis, the standardized partial regression coefficients of the affected fetus weight, the dam weight, and the litter size on the maxillary size of the affected CL/Fr fetus were 0.71 (p < .01), 0.03, and -0.07. According to a least-squares analysis of variance, the dam strain effect in addition to the effect of the affected fetus weight on the maxillary size and the cranial size of the affected fetuses was significant (p < .01 for cranial size, p < .05 for maxillary size) and close to a significant level (p = .09) for the mandibular size of the affected fetuses. The adjusted maxillary size and cranial size after statistically eliminating the effects of the affected fetus weight, dam weight, and litter size on each original craniofacial size of the affected fetuses that had developed in the CL/Fr dam strain were also significantly smaller than those of the affected fetuses that had developed in the C57BL dam strain. CONCLUSIONS: The present results indicate that the craniofacial growth of the CL/Fr mouse fetus affected with CLP increased in proportion to the fetus weight. The dam strain effect, in addition to the effect of the affected fetus weight, could thus not be ignored when the etiology of the spontaneous CLP was examined, while the uterine environment, provided by the CL/Fr strain dam, retarded the intra-uterine craniofacial growth of the affected fetuses. It was therefore concluded that the dam strain effect, as well as the effect of the affected fetus weight, both play an important role on the craniofacial morphogenesis of the CL/Fr strain of the affected fetuses that developed in both strain dams.

Analysis of Variance↗
PubMed1997

Clinical characteristics of Japanese men with glucokinase gene beta-cell promoter variant.

OBJECTIVE: To study the association between a variant at the position of -30 of beta-cell-specific promoter of the glucokinase gene and glucose tolerance in the Japanese general population and to assess the clinical characteristics of subjects with the variant. RESEARCH DESIGN AND METHODS: The genotype of 657 Japanese men aged 51.0 +/- 8.8 years (mean +/- SD) was analyzed by an allele-specific assay using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The variant allele frequency was 0.188 in subjects with normal glucose tolerance, 0.211 in subjects with impaired glucose tolerance, and 0.176 in diabetic subjects. In subjects with fasting plasma glucose levels <140 mg/dl, homozygous subjects for the promoter variant had significantly higher plasma glucose levels 60 min after oral glucose administration when compared with subjects without the variant allele. A cross-sectional analysis showed age-related elevation of basal glucose levels only in subjects without the promoter variant. Individuals heterozygous for the variant had significantly lower levels of HDL cholesterol than normal subjects. HDL cholesterol values were lower in homozygous people than in normal and heterozygous subjects, although the differences were not statistically significant. CONCLUSIONS: The beta-cell promoter variant in homozygous state was associated with impaired glucose tolerance, but not with diabetes, and low HDL cholesterol levels in Japanese men. It is unlikely that the glucose intolerance associated with the promoter variant is progressive with age.

Adult↗
PubMed1996

Mouse islet cell lysis mediated by interleukin-1-induced Fas.

This study was conducted to investigate the possible involvement of Fas in beta-cell death in insulitis of Type 1 (insulin-dependent) diabetes mellitus. Although primary cultured Balb/c mouse islet cells did not express Fas mRNA, 4-12 hours of treatment with 10(2)-10(3) U/l of mouse interleukin-1 alpha (IL-1 alpha) induced the expression of Fas mRNA. Surface Fas expression was detected by immunofluorescence flow cytometry using a non-cytolytic anti-Fas monoclonal antibody after 6 or 12 h of incubation with 10(3) U/l of IL-1 alpha. Primary islet cells were resistant to an agonistic anti-Fas monoclonal antibody. However, 12 h pretreatment with IL-1 alpha sensitized islet cells to its cytolytic effect. Significant cell death was observed 24 h after the addition of anti-Fas, and progressively increased until 72 h, when specific 51Cr release was 72 +/- 6%. Agarose gel electrophoresis of DNA extracted from cells exposed to IL-1 alpha and agonistic anti-Fas showed internucleosomal DNA fragmentation, a hallmark of apoptotic cell death. Since the Fas antibody showed no cross-reactive activity of tumour necrosis factor (TNF), the cytotoxic effect was not mediated by TNF receptors. A protein synthesis inhibitor cycloheximide augmented Fas-mediated islet cell death. The Fas-mediated killing of islet cells was not L-arginine-dependent, or blocked by N(G)-monomethyl-L-arginine. beta-TC1 cells also expressed Fas mRNA when exposed to IL-1 alpha or IL-1 alpha plus interferon-gamma. These observations suggest that Fas-mediated apoptosis may be a mechanism of islet cell death in autoimmune insulitis.

Animals↗
PubMed1996

Endogenous tumor necrosis factor-alpha production by a pancreatic beta-cell line: inhibitory effects of hydrocortisone and nicotinamide.

The purpose of this study was to examine regulation of interleukin-1(IL-1)-induced tumor necrosis factor-alpha (TNF-alpha) production by a mouse beta-cell line (beta TC1). Three-hour incubation of beta TC1 cells with 5 U/ml of IL-1 beta results in the expression of TNF-alpha mRNA and intracellular accumulation of TNF-alpha. It has been shown that glucocorticoids and immunosuppressive agents such as cyclosporin and FK-506 inhibit TNF-alpha generation by T-lymphocytes and monocytes. Hydrocortisone of 1 and 10 mumol/l suppressed TNF-alpha mRNA levels and the TNF-alpha content of beta TC1 cells exposed to IL-1 beta, whereas neither cyclosporin nor FK-506 altered the TNF-alpha content. Nicotinamide of 5-10 mmol/l also reduced TNF-alpha mRNA and TNF-alpha protein levels in beta TC1 cells. Addition of exogenous TNF-alpha did not inhibit IL-1-induced transcription of TNF-alpha gene. These observations support the potential therapeutic role of glucocorticoids and nicotinamide in protecting beta-cells against cytokine-mediated damage, although glucocorticoid agonists have hyperglycemic metabolic effects.

Animals↗
PubMed1996

Localization and clinical significance of thyrotropin receptor mRNA expression in orbital fat and eye muscle tissues from patients with thyroid-associated ophthalmopathy.

We have studied the cellular localization of thyrotropin receptor (TSH-R) mRNA in orbital fat and extraocular muscle tissues from patients with thyroid-associated ophthalmopathy (TAO) using Northern blot, reverse transcriptase polymerase chain reaction (RT-PCR), and in situ hybridization, and we correlated the findings with clinical estimates of ophthalmopathy. Although we failed to detect TSH-R mRNA in orbital tissues by Northern blot, TSH-R cDNA was amplified in orbital fat tissue from 13 of 25 patients with TAO and from 2 of 4 control subjects, in eye muscle tissue from 2 out of 7 patients with TAO, and in cultured orbital fibroblasts and subcutaneous fibroblasts from TAO patients. In situ hybridization showed that TSH-R mRNA was detected in cultured orbital fibroblasts as well as skin fibroblasts obtained from the patient. Furthermore, the expression of TSH-R mRNA in orbital fat tissue from patients with TAO significantly correlated with the orbital fat volume and the severity of ophthalmopathy, especially the extent of eye muscle dysfunction. These results suggest that the expression of TSH-R in the orbit, especially fibroblasts, may play a role in the pathogenesis and clinical manifestations of the ophthalmopathy in patients with TAO, although a secondary effect, involving fibroblasts in TAO is also possible.

Adipose Tissue↗
PubMed1996

Acid lipase inhibitor in chicken plasma identified as apolipoprotein A-I.

We have reported a inhibitor of acid lipases in liver lysosomes and erythrocytes from chickens [M. Fujii et al., Int. J. Biochem., 22, 895-898 (1990)]. In this paper, the properties of the inhibitor were described in comparison with those of apo A-I of chicken. The purified inhibitor migrated with the same mobility on SDS-PAGE as apo A-I, and had a molecular weight of 27,000. The peptide map from the lipase inhibitor was similar to that of apo A-I. Antibodies to the acid lipase inhibitor also reacted with apo A-I. Apo A-I inhibited the acid lipase activities of liver lysosomes and erythrocytes from chickens as strongly as the lipase inhibitor. The N-terminal amino acid sequence of lipase inhibitor was identical to that of apo A-I as far as residue 20. The amino acid sequence of peptides obtained from the inhibitor by cleavage with CNBr corresponded to internal sequence of apo A-I, and so the CNBr-peptides were derived by cleavage after the methionine residues in apo A-I. The findings showed that the inhibitor of the acid lipases in liver lysosomes and erythrocytes from chickens was identical to apo A-I.

Amino Acid Sequence↗
PubMed1996

[Two cases of mitral stenosis associated with ball thrombus in the left atrium].

Two patients (55-year-old female and 77-year-old female) were operated on for mitral stenosis associated with left atrial ball thrombus. The first case had the episode of cerebral infarction and second case had syncopal attack. Both of them presented with systemic arterial embolism. After confirmation of the diagnosis by echocardiography, removal of ball thrombi, OMC and MVR were carried out urgently. Considering high risk of "hole in one sudden death" and multiple-episodes of systemic embolization, ball thrombus should be removed as urgent following confirmation of diagnosis.

Coronary Thrombosis↗
PubMed1996

[A case report of surgical management of blunt ruptured right atrium with blunt ruptured liver].

This is a case report of a 23 year old female involved in a car accident that caused blunt trauma to the patient. First of all, she was found to have cardiac tamponade when the abdomen was explored to suture and to put the gaze compression on for hemostasis of the ruptured liver. Then, she was brought to our institution by the ambulance. Upon the exploration of the heart under standby of extracorporal circulation (ECC), small multiple lacerations were found at the junction of the right atrium and superior vena cava. These were sutured directly to close without ECC. On the 2nd postoperative day, she was bought to the OR again to removal of the gaze tamponade from the ruptured liver and to complete hemostasis. The patient was discarded 35 days after admission.

Accidents, Traffic↗