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H Kadowaki

Publications and source records attributed to H Kadowaki.

At least 37 records · Page 2Linked to original sources
PubMed1997

The primary structure of the Cl(-)-translocating ATPase, b subunit of Acetabularia acetabulum, which belongs to the F-type ATPase family.

The genes possibly encoding the b subunit (50 kDa) of the Cl(-)-translocating ATPase of Acetabularia acetabulum were cloned from total RNA and from poly(A)+ RNA and sequenced. The deduced amino acid sequence of the open reading frame consisted of 478 amino acids and showed high similarity to the beta subunit of chloroplast F1-ATPase. Gene fragments encoding the putative beta subunit of chloroplast F1- (273 bp) and mitochondrial F1-ATPases (332 bp) were also cloned from A. acetabulum and sequenced, respectively. The deduced amino acid sequence of the chloroplast F1-ATPase showed 92.5% identity to be primary structure of the b subunit of the Cl(-)-translocating ATPase, while the nucleotide sequences were 79.9% identical. The deduced amino acid sequence of the latter was 77.3% identical to that of the b subunit of the Cl(-)-translocating ATPase and the nucleotide sequences were 67.5% identical. By Northern analysis, these three beta-like genes were demonstrated to be transcribed with different sizes of RNA species. A putative chloroplast F1-beta fragment also hybridized with chloroplast DNA isolated from the organism.

Acetabularia↗
PubMed1997

Effects of oxygen tension and shear stress on human endothelial cell prostacyclin production.

Under in vivo conditions of ischemia and reperfusion, vascular endothelium (EC) experience concurrent changes in oxygen tension, shear stress, and the local concentration of metabolites. These studies explored the combined effects of shear stress and oxygen tension on EC prostacyclin production. EC grown on microcarrier beads were exposed to 120 min of normoxia and basal shear stress by stirring at 20 rpm. After normoxia, EC were exposed to hypoxia (2% 0(2), 20 rpm), ischemia (2%, 0(2), 5 rpm) or sham ischemia (20% 0(2), 5 rpm). Following hypoxia, EC were reoxygenated (20% 0(2), 20 rpm). After ischemia and sham ischemia, EC were reperfused (20% 0(2), 20 rpm). Minimal accumulation of metabolites occurred during normoxia, hypoxia, and reperfusion. All metabolites were allowed to accumulate in the flasks during ischemia and sham ischemia. Prostacyclin levels were measured by ELISA, and prostaglandin H2 synthase levels in cells were analyzed by immunoblotting. An acute decrease in shear stress decreased prostacyclin production. An acute decrease only in oxygen tension did not alter prostacyclin production significantly. The combined acute decrease in both shear stress and oxygen tension significantly stimulated prostacyclin production for 30 min. By 120 min of ischemia and hypoxia, prostacyclin release was significantly less than sham ischemia. Prostacyclin production after 30 min of reoxygenation was significantly less than that of cells subjected to reperfusion. By 120 min of reperfusion and reoxygenation, there was no significant difference in EC prostacyclin synthesis. These findings suggest that temporal and quantitative aspects of EC prostaglandin synthesis are dependent on both oxygen tension and shear stress.

Cell Hypoxia↗
PubMed1997

A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism.

We report a homozygous missense mutation at position 1092 (substitution of glutamine for arginine) in the tyrosine kinase domain of the insulin receptor in a patient with leprechaunism associated with severe insulin resistance and intrauterine growth retardation. Site-directed mutagenesis as well as analyses of the patient's lymphocytes revealed that this mutation causes a marked decrease in tyrosine kinase activity of the insulin receptor without any defect in insulin binding, which causes severe defects in insulin-stimulated glucose transport, glycogen synthesis and DNA synthesis. Thus, this is the first homozygous mutation resulting in a selective-kinase defect of the insulin receptor. Interestingly, the parents who are cousins and are heterozygous for the mutation have type A insulin resistance syndrome. This correlation between genotype and phenotype in a single pedigree suggests that the severity of the mutation will determine the phenotype. Based upon this assumption, we have been successful in prenatal diagnosis of the fifth child. Furthermore, we have demonstrated the effectiveness of clinical administration of insulin-like growth factor-I (IGF-I) in this patient and in vitro analysis of the patient's skin fibroblasts, suggesting that IGF-I can compensate for insulin action via the IGF-I receptor in a patient almost lacking functional insulin receptors.

Adult↗
PubMed1997

Diabetes mellitus associated with the 3243 mitochondrial tRNA(Leu)(UUR) mutation: insulin secretion and sensitivity.

To investigate the pathophysiology of diabetes mellitus associated with the 3243 mitochondrial tRNA(Leu)(UUR) mutation (DM-Mt3243), insulin secretion and sensitivity were studied using the 75-g oral glucose tolerance test (oGTT), 1-mg intravenous glucagon test, and euglycemic glucose clamp test. Twelve DM-Mt3243 patients were investigated (seven men and five women). Their ages ranged from 36 to 74 years, and the onset of diabetes occurred at 44.5 +/- 9.5 years (mean +/- SD). In the glucose tolerance test, nine patients (75.0%) showed lower C-peptide reactivity (CPR) than normal at 30 minutes, suggesting blunted insulin secretion. Three patients showed an impaired glucose tolerance (IGT) pattern, although they had absolute hyperglycemia at the onset of diabetes. In the glucagon test, 10 patients (76.3%) had CPR within the normal range at 6 minutes, indicating an adequate response. In the glucose clamp test, the M value was 8.70 +/- 2.35 mg/kg/min and was within normal limits in all patients. The glucose metabolized (M value) was negatively correlated with 24-hour urinary C-peptide excretion (r = .696, P < .05). Thus, plasma CPR to glucose loading was blunted in many DM-Mt3243 patients, but CPR to glucagon was relatively well preserved. This difference in the intrinsic insulin response to the two stimuli may be characteristic of DM-Mt3243. Although M values were normal in all subjects, the correlation with 24-hour urinary C-peptide excretion suggests a relationship between insulin sensitivity and insulin secretion. These two mechanisms may cooperate to maintain homeostasis in this disease. Since three patients did not progress with aging, this mutation may not always cause gradual beta-cell destruction.

Adult↗
PubMed1997

Effect of hypoxia on steady-state arachidonic acid metabolism in bovine aortic endothelial cells.

At the onset of acute hypoxia, eicosanoid synthesis by bovine aortic endothelial cells (BAEC) markedly decreases, reflecting a decreased release of arachidonic acid from endogenous stores. To determine the cause of decreased arachidonic acid release, we pulse-labeled BAEC with [14C]arachidonic acid for 5 min under normoxic conditions and chased cells for 1 h under normoxic or hypoxic conditions. The 14C incorporation and specific activity (disintegrations per minute per nanomole) of three major arachidonyl molecular species (16:0-20:4, 18:1-20:4, and 18:0-20:4) of each phospholipid class were determined in cells chased under either of the two conditions. There was no relevant difference between normoxic and hypoxic cells in the metabolism of any of the arachidonyl molecular species of diacyl lipids. However, there was a marked decrease (approximately 40%) in the turnover of arachidonyl alkenylacyl phosphatidylethanolamine in the hypoxic cells. From these results, it appears that the source of arachidonic acid supporting constitutive eicosanoid synthesis in BAEC is alkenylacyl phosphatidylethanolamine and that the limiting enzyme activity determining the rate of eicosanoid synthesis is a plasmalogen-specific phospholipase A2.

Animals↗
PubMed1997

Roles of insulin receptor substrate-1 and Shc on insulin-like growth factor I receptor signaling in early passages of cultured human fibroblasts.

Insulin-like growth factor-I (IGF-I) improves glucose metabolism and growth in patients with leprechaunism. We investigated signal transduction through IGF-I receptor in comparison with epidermal growth factor (EGF) receptor in early passages of cultured skin fibroblasts from a normal subject and a patient with leprechaunism whose insulin receptor tyrosine kinase was almost nonexistent. Insulin receptor substrate-1 (IRS-1) became tyrosine-phosphorylated and bound growth factor receptor-bound protein 2 (GRB2) quickly by IGF-I. The association of Shc with GRB2 by IGF-I was detected by immunoblot with anti-Shc antibody but was hardly visible with antiphosphotyrosine antibody, which was in marked contrast to efficient tyrosine phosphorylation of Shc by EGF. However, the potency of IGF-I for DNA synthesis was far stronger than EGF, which was not parallel with the potency of these growth factors to activate Shc or MAP kinase. Rather, phosphatidylinositol (PI) 3-kinase activity, which was activated by IGF-I about 5- to 10-fold more strongly than EGF, appeared to correlate with mitogenesis. Signal transduction pathways following IGF-I receptor or EGF receptor activation were indistinguishable between the normal subject and the patient. Our results strongly suggest that in human skin fibroblasts, which represent a more physiological cell culture: 1) IRS-1, rather than Shc, is the major tyrosine-phosphorylated protein binding GRB2 in initial phase of IGF-I signaling; 2) mitogenic potency of receptor tyrosine kinases such as IGF-I receptor and EGF receptor may not be determined solely by the amount of Shc-GRB2 complex or the activity of MAP kinase; and 3) in contrast to previous reports, IGF-I and EGF receptor signalings are not defective in leprechaunism.

Adaptor Proteins, Signal Transducing↗
PubMed1997

[Blood amino acid levels in sarin poisoning patients].

Since plasma is generally employed for amino acid analysis, we compared amino acid levels in plasma with those in serum for healthy individuals and examined the influence of separation and storage conditions on the stability of the samples. Then, we determined the amino acid levels of frozen serum samples obtained from sarin poisoned patients. A. Comparison of Amino Acid Levels in Plasma and Those in Serum Blood was collected from 5 healthy individuals. Then, heparinated plasma and serum were separated by centrifugation immediately after blood collection. Serum was also separated by centrifugation after standing whole blood at room temperature for 1 hour. Frozen plasma and serum were store at -40 degrees C for 5 months. All were subjected to analysis in an amino acid analyzer. It was found that the cystine (Cys) and 3-methyl-histidine (3-M-His) levels in serum and plasma were affected when stored in a frozen state, that the aspartate (Asp) level was changed according to the method of collecting serum, and that the taurine (Tau) and ornithine (Orn) levels were affected by standing blood. B. Analysis of Blood Taken from Sarin Poisoned Patients Twelve sarin poisoned patients were selected as subjects, and serum cholinesterase (Ch-E) and serum albumin (Alb) levels were determined. Amino acid analysis was conducted using an amino acid analyzer. Serum samples which had been obtained from the 6 patients and frozen and stored at -40 degrees C from 5 months were used for amino acid analysis. As a result, the serum Ch-E level decreased and the Alb level tended to rise. Since the Ch-E/Alb ratio was reduced in the sarin poisoned patients, it is considered useful for discrimination from liver cirrhosis in which both Ch-E and Alb levels decreased. Amino acid levels in the serum obtained from the sarin poisoned patients were compared with those of healthy individuals, both of which had been stored under the same conditions. There were significant differences in Asp, glutamate (Glu), phenylalanine (Phe), 3-M-His, glutamine (Gln), and Cys levels. The Glu, Phe, and Gln levels were not affected by storage of serum in a frozen state, while the Glu and Phe levels were elevated and the Gln level was reduced. Although Cys exhibited lower values in frozen serum samples, the Cys level was elevated with a rise in the serum Ch-E levels. Therefore, we deduced that Cys metabolism disorders also occur in sarin poisoning. As stated above, the Glu and Phe levels were elevated and the Gln and Cys levels were reduced, suggesting the presence of abnormal amino acid metabolism, in patients with sarin-poisoning.

Adolescent↗
PubMed1997

[The long-term cystic bleb appearance and safety after trabeculectomy with mitomycin C].

The clinical appearance of cystic blebs and the incidence of bleb infection were retrospectively evaluated in 215 trabeculectomies with mitomycin C. The incidence of cystic bleb formation in trabeculectomy was 79% (169/215). The cumulative incidence of the cystic bleb survival when using the Kaplan-Meier method was 73% in the 50th month after surgery. The incidence of large cystic bleb survival was better than that of small and localized cystic blebs. There was statistically significant difference. The incidence of cystic bleb survival without Seidel phenomenon and bleb infection was 96% in the first year after surgery and 91% in the third year. Bleb infections occurred in two of 169 eyes (1.2%). Bleb infection was successfully treated and there were no cases of endophthalmitis. The large cystic blebs had a higher incidence of bleb infection than the small ones. In one of 25 eyes treated with antibiotic eye drops after surgery, the Seidel test was positive and bleb infection occurred. The Seidel test was positive in 5 of 96 eyes in which antibiotic eye drops were not used and bleb infection occurred in one of these 5 eyes.

Female↗
PubMed1996

Diabetes with the 3243 mitochondrial tRNALeu(UUR) mutation. Characteristic neuroimaging findings.

OBJECTIVE: To investigate the basis of central nervous system dysfunction in diabetes associated with the 3243 mitochondrial tRNA mutation, we studied neuroimaging findings in patients with this disease. RESEARCH DESIGN AND METHODS: We screened 205 diabetic patients. Those patients who had the 3243 mutation in leukocytes or muscle were enrolled. All the subjects underwent computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and N-isopropyl-p-[123I]iodoamphetamine ([123I]IMP) single-photon emission computed tomography (SPECT) of the brain. RESULTS: None of the nine subjects with the 3243 mutation had the typical clinical picture of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, and none had neurological focal signs. CT or MRI revealed diffuse brain atrophy in three patients (33%) and cerebellar atrophy in one (11%). Abnormal high intensity areas were observed on MRI in five patients (56%). The overall prevalence of brain abnormalities was 56% (5 of 9) on CT and 78% (7 of 9) on MRI scans. MRA revealed no stenotic lesions. SPECT showed reduced accumulation of [123I]IMP in the right or left parieto-occipital region in eight patients (89%). CONCLUSIONS: Reduced accumulation of [123I]IMP in the parieto-occipital cortex was found in a high proportion of our subjects on SPECT. This imaging finding might be characteristic of diabetes associated with the 3243 mitochondrial tRNA mutation and may be a sign of latent central nervous system dysfunction.

Adult↗
PubMed1996

Recurrent anaplastic ganglioglioma: pathological characterization of tumor cells. Case report.

A total resection of a left frontal lobe tumor in a 26-year-old man revealed differentiated ganglioglioma with small foci of atypical glial cells exhibiting mild atypia. Six and one-half years later, a large, well-demarcated tumor recurred; at that time, histological analysis revealed both typical ganglioglioma and highly cellular anaplastic areas, the latter predominating. Although the patient subsequently underwent total and subtotal resections, radiation therapy, and chemotherapy, tumors continued to recur at progressively shorter intervals and he died at the age of 35 years. Biopsies of tissue obtained at the last three resections and the autopsy revealed only anaplastic tumor cells. Routine histological examinations indicated that these tumors were uniformly composed of undifferentiated cells. However, pathological studies using immunohistochemical analysis, electron microscopy, and immunoblot analysis demonstrated that a small number of recurrent anaplastic cells had astrocytic features. Results of Ki-67/MIB-1 labeling and silver nucleolar organizer region counts for those cells were high for glial tumors. A retrospective study of the initial tumor showed slightly high MIB-1 labeling for atypical glial cells. This case is characterized by pathological findings of recurrent tumors that correspond to an unusual form of malignant glioma exhibiting slight astrocytic differentiation. The present case suggests that a longer follow-up period ( > 5 years) is necessary in cases of ganglioglioma with mild atypia and that careful examinations, including proliferating potential analysis of initial tumor cells, could be important for the diagnosis and treatment of ganglioglioma.

Adult↗
PubMed1996

[Renal metastasis originating from liver cancer].

The patient was a 52-year-old man. He was suspected of having right renal carcinoma with hepatic metastasis and was referred to our hospital. The result of percutaneous needle biopsy on the right renal tumor showed a renal cell carcinoma. For the treatment, he underwent transcatheter arterial embolization (TAE) and intramuscular injection of interferon alpha. However, he was getting weaker and weaker and two months later he died due to hepatic failure. The result of autopsy showed that the renal carcinoma was a metastatic tumor from the primary hepatic cancer. This case was thought to be the second case of metastatic renal tumor from hepatic cancer reported in the Japanese literature.

Carcinoma, Hepatocellular↗
PubMed1995

A mutation in the beta 3-adrenergic receptor gene is associated with obesity and hyperinsulinemia in Japanese subjects.

The Trp 64 Arg mutation in the beta 3-adrenergic receptor (beta 3AR) gene was investigated in 350 Japanese subjects. This mutation was not associated with non-insulin-dependent diabetes mellitus (NIDDM). In 191 subjects without NIDDM, body mass index (BMI) was significantly higher in subjects homozygous for this mutation than in those homozygous for the normal allele (24.7 +/- 1.4 vs 22.1 +/- 0.2 kg/m2, p = 0.009). Moreover, the frequency of the mutant allele in obese subjects (BMI > 26.4) was significantly higher than that in non-obese subjects (BMI < 22) (0.37 vs 0.15, p = 0.009). The presence of this mutation was also accompanied by significantly higher fasting (p = 0.000) and 2 hrs (p = 0.018) serum insulin levels during an oral glucose tolerance test. The beta 3AR may be one of the loci contributing to obesity and hyperinsulinemia/insulin resistance in Japanese subjects.

Adult↗
PubMed1995

No evidence for mutations in a putative subunit of the beta-cell ATP-sensitive potassium channel (K-ATP channel) in Japanese NIDDM patients.

The ATP-sensitive K channel (K-ATP channel) in pancreatic beta cells is believed to play a crucial role in glucose-stimulated insulin release. We investigated whether defects in the recently cloned gene for a putative subunit of this channel (KATP-2) could be a cause of diabetes in Japanese patients. The coding region of this beta-cell type channel gene was investigated in 192 diabetics with a family history of the disorder by single-stranded conformational polymorphism (SSCP) analysis. Two silent polymorphisms were found and confirmed by sequencing, but no missense or nonsense mutations were detected. The allele frequency of the polymorphisms was compared with 96 control subjects without a family history of the disease, and no clear difference was found. These results indicate that genetic defects of the KATP-2 channel may not be a major cause of diabetes in Japan.

Adult↗
PubMed1995

A subtype of diabetes mellitus associated with a mutation in the mitochondrial gene.

Recently, in patients with diabetes and deafness, researchers have identified an A to G transition at position 3243 in transfer ribonucleic acid(Leu)(UUR) [3243 base-pair (bp) mutation], originally found in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. To determine the prevalence of diabetic patients with this mutation in Japan, we screened selected cohorts of diabetic patients based upon type of diabetes, family history of diabetes, and age of onset; also screened were 550 unselected cohorts of diabetic patients, without prior information. We identified 5 patients with the 3243-bp mutation, suggesting that approximately 0.9% of diabetic patients have it. However, there were none with this mutation in 250 controls with normal glucose tolerance. We also studied the clinical characteristics and insulin secretory characteristics of diabetic patients with 3243-bp mutation. We propose that diabetes mellitus with 3243-bp mutation is a novel subtype of diabetes mellitus, maternally inherited diabetes, and deafness (MIDD).

Adult↗
PubMed1995

Two mutant alleles of the insulin receptor gene in a family with a genetic form of insulin resistance: a 10 base pair deletion in exon 1 and a mutation substituting serine for asparagine-462.

Mutations in the insulin receptor gene cause several genetic syndromes associated with extreme insulin resistance. We have studied three insulin resistant siblings with acanthosis nigricans, dental abnormalities, and acral hypertrophy. The female patient also had primary amenorrhea due to hyperandrogenism. All three patients were compound heterozygotes with two mutant alleles of the insulin receptor gene. One allele had a 10-bp deletion in the region of exon 1 encoding the hydrophobic signal peptide; this leads to a frameshift and premature chain termination at codon 61. The deletion occurs at the site of a direct repeat of a hexanucleotide sequence interrupted by a tetranucleotide sequence; the deletion may have resulted from recombination between the upstream and downstream hexanucleotide repeats. In the other mutant allele, there is a missense mutation substituting serine for Asn462-a mutation identified previously in one allele of the insulin receptor gene in a patient with type-A insulin resistance. The Ser462 mutation impaired the ability of acidic pH to dissociate insulin from the receptor. Thus, Thus, like the previously described Glu460 mutation, the Ser462 mutation may retard dissociation of insulin from the receptor in the acidic compartment of the endosome and may, as a result, accelerate the rate of receptor degradation.

Alleles↗
PubMed1995

Insulin edema in diabetes mellitus associated with the 3243 mitochondrial tRNA(Leu(UUR)) mutation; case reports.

We encountered a patient with diabetes mellitus due to the 3243 mitochondrial tRNA mutation(DM-Mt3243), who developed insulin edema and hepatic dysfunction after starting insulin. Such a rare phenomenon was unlikely to be a fortuitous coincidence in mitochondrial diabetes, as none in 197 non-mutant NIDDM patients had same episode. Moreover, similar leg edema was noticed in another DM-Mt3243 patient, and other two DM-Mt3243 patients had leg edema which responded to coenzyme Q10. These observations suggest further a role of mitochondrial function on leg edema. The mechanism of his insulin edema may involve vasomotor changes induced by the rapidly glycemic control, because our case of insulin edema had a prominent increase of strong succinate dehydrogenase reactive vessels. Alternatively, myocardial dysfunction might have produced leg edema and hepatic dysfunction, because he had subclinical myocardial dysfunction, judged by imaging with beta-methyl-p-(123I)-iodophenyl-pentadecanoic acid. The third explanation is that a rapid improvement of glycemic control might have induced hepatic reoxygenation and the production of reactive oxygen species in the liver that contributed to cell damage. Thus, although we cannot draw definite conclusion, our experiences here suggest that mitochondrial dysfunction is important in the etiology of insulin edema.

Aged↗
PubMed1995

A case of diabetic amyotrophy associated with 3243 mitochondrial tRNA(leu; UUR) mutation and successful therapy with coenzyme Q10.

We report the case of 71-year-old male who was once diagnosed as having diabetic amyotrophy, because of pronounced wasting in proximal muscles, massive weight loss, and development of paresthesia in his legs. Afterwards, ragged red fibers and mitochondrial tRNA mutation at position 3243 were documented in muscle biopsy. He had diabetes mellitus associated with 3243 mitochondrial DNA mutation, suggesting that clinically, diabetic amyotrophy may be overlapped with mitochondria-related disease entities in some parts. Coenzyme Q10 administration was effective in relieving the symptoms in his legs, fatigue, and residual urine in his bladder. These were confirmed with the improvement in neurological parameters. In conclusion, this case gives important help in understanding myopathy in diabetes. It would be important to check on the 3243 mitochondrial tRNA mutation in patients with diabetic amyotrophy and/or diabetic neuropathic symptoms.

Animals↗