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Biomedical subjects

T Hanafusa

Publications and source records attributed to T Hanafusa.

At least 37 records · Page 2Linked to original sources
PubMed2001

Analysis of a non-functional HNF-1alpha (TCF1) mutation in Japanese subjects with familial type 1 diabetes.

Mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha; gene symbol TCF1) cause maturity-onset diabetes of the young type 3 (MODY3), a form of diabetes mellitus characterized by autosomal dominant inheritance, early onset, and pancreatic beta-cell dysfunction. Recent genetic studies, however, also found mutations in patients diagnosed with idiopathic (non-autoimmune based) type 1 diabetes. We identified a novel frameshift mutation (142delG) in the TCF1 gene in a family with a strong family history of type 1 diabetes and examined the functional properties of the mutant HNF 1alpha. The expression of the mutant protein was not detected in COS-7 cells by Western blot analysis after transfection of the mutant cDNA. This is the first case of an unstable mutant HNF-1alpha protein. Reporter gene analysis indicated that the mutant HNF-1alpha had no transactivation activity in HeLa and MIN6 cells. Haploinsufficiency for HNF-1alpha may lead to severe forms of diabetes like type 1 diabetes.

Adolescent↗
PubMed2001

Pneumoperitoneum following the spontaneous rupture of a gas-containing pyogenic liver abscess: report of a case.

We report herein the case of a ruptured liver abscess that resulted in pneumoperitoneum. A patient with diabetes mellitus presented with symptoms of acute abdomen. The plain abdominal radiograph and computed tomography findings revealed abdominal free air and a gas-containing liver abscess, whereby a diagnosis of a ruptured liver abscess was made. An emergency operation was performed, and the abscess was drained followed by peritoneal lavage and the administration of appropriate antibiotics. To the best of our knowledge, very few cases of spontaneous pneumoperitoneum occurring secondary to the rupture of a gas-containing liver abscess have been encountered in Japan.

Anti-Bacterial Agents↗
PubMed2001

Beraprost sodium regulates cell cycle in vascular smooth muscle cells through cAMP signaling by preventing down-regulation of p27(Kip1).

OBJECTIVE: Beraprost sodium (BPS), a prostacyclin (PGI(2)) analogue, has been reported to exhibit beneficial effects on atherosclerosis in both human and animal models. To clarify the underlying mechanism, we investigated the effects of BPS on neointimal formation after balloon injury in the canine coronary artery. Furthermore, we determined its anti-atherosclerotic effects in cultured smooth muscle cells (SMCs). METHODS: Adult beagle dogs (10-12 kg) were fed on a high-cholesterol diet (10 g/day) and underwent balloon-denudation of the coronary artery. The dogs were divided into two groups: a BPS-treated group (20 microg/kg per day) and a control group. Twenty-eight days after injury, the dogs were killed and the coronary arteries were examined morphometrically. Three days after injury, the proliferative activity in the medial layer of the coronary artery was evaluated by 5-bromo-2'-deoxyuridine (BrdU) incorporation, and p27(Kip1), a cyclin-dependent kinase (cdk) inhibitor, expression was examined by immunohistochemistry. We also examined the effects of BPS on SMC proliferation based on BrdU incorporation and cell cycle analysis. In addition, p27(Kip1) regulation was evaluated in primary-cultured SMCs. RESULTS: BPS administration decreased the intima/media ratio (I/M) by 88% in the control group. Three days after injury, BPS attenuated the proliferation rate of the cells in the media of the coronary artery by 35%, and maintained p27(Kip1) expression, which declined in the control cells. In the cultured proliferating SMC, BPS prevented the down-regulation of p27(Kip1). The 8-bromo-cyclic adenosine monophosphate (8-br-cAMP), a cAMP analogue, had similar actions as BPS in the regulation of p27(Kip1). The proliferation of cultured SMC was inhibited in a dose-dependent manner, and cell cycle arrest in the G1 phase was induced by BPS. CONCLUSIONS: Our data suggest that BPS inhibits neointimal formation after balloon denudation in the coronary artery through its inhibitory effect on SMC proliferation by preventing p27(Kip1) down-regulation.

Angioplasty, Balloon, Coronary↗
PubMed2001

Mutation screening of the hepatocyte nuclear factor (HNF)-6 gene in Japanese subjects with diabetes mellitus.

Heterozygous mutations in the genes encoding transcription factors (HNF-1alpha, HNF-1beta and HNF-4alpha) in the hepatocyte nuclear factor (HNF) network are associated with maturity-onset diabetes of the young (MODY). We screened HNF-6 gene for mutations in 34 Japanese subjects with MODY/early-onset diabetes mellitus and 56 subjects with late-onset diabetes mellitus. One single nucleotide polymorphism (SNP) at codon 287 (GGG to GGT) was found in the gene and the frequency was similar among MODY/early-onset diabetes, late-onset diabetes and control subjects. Genetic variations in the HNF-6 gene are not likely to contribute to the susceptibility to diabetes mellitus in Japanese.

Adolescent↗
PubMed2001

Vascular cell adhesion molecule-1 as a biochemical marker of left ventricular mass in the patients with hypertension.

Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1), vascular adhesion molecule-1 (sVCAM-1), and E-selectin were measured in 80 outpatients with uncomplicated essential hypertension. Although the levels of E-selectin and sICAM-1 were similar between the patients with and without left ventricular (LV) hypertrophy, sVCAM-1 level was significantly elevated in the patients with LV hypertrophy (759.7+/-154.6 ng/mL nu 984.4+/-240.6 ng/mL, P < .0001). The LV mass normalized to body surface area or height were significantly correlated with sVCAM-1 (r=0.615, P < .0001 and r=0.571, P < .0001, respectively). These results indicate that a soluble adhesion molecule is correlated with LV mass in uncomplicated essential hypertensive patients.

Aged↗
PubMed2001

Analytic validation of the enzyme multiplied immunoassay technique for the determination of mycophenolic acid in plasma from renal transplant recipients compared with a high-performance liquid chromatographic assay.

The analysis of mycophenolic acid (MPA) has proved a valuable adjunct to the clinical care of organ transplant recipients. The analytic validation of the enzyme multiplied immunoassay technique (EMIT) for the determination of MPA in plasma is described. The EMIT MPA standard curve was 0 to 15.0 microg/mL, and curve storage was maintained for 4 weeks. The MPA EMIT assay proved reliable and reproducible, as shown by the intra-assay and interassay coefficients of variation (1.58-3.68% and 1.23-7.57%, respectively). Excellent linear correlation ( r = 0.999) was observed for dilution linearity. The sensitivity of the assay was 0.01 microg/mL. Recoveries of 99.4% to 104.2% were obtained by spiking aliquots of three controls of known MPA concentrations with MPA. No interference was observed for endogenous substances and coadministered immunosuppressant drugs, and no cross-reactivity from the major metabolite MPA glucuronide was found. The high-performance liquid chromatography (HPLC) assay used protein precipitation and C18 ion-pair chromatography with ultraviolet detection at 304 nm. Plasma concentrations of MPA were measured using EMIT and HPLC. A linear relationship was observed between EMIT and HPLC (EMIT = 1.091 x HPLC - 0.089; r 2 = 0.990, n = 129). These results indicate that EMIT is a simple, rapid, and sensitive assay method for the measurement of MPA in plasma.

Chromatography, High Pressure Liquid↗
PubMed2001

The Pro12 -->Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes.

The allele frequencies for a Pro12-->Ala substitution in peroxisome proliferator-activated receptor-gamma differ among ethnic groups, and its relationship with diabetes and associated diseases is controversial. The prevalence of this polymorphism and its effects on clinical characteristics have now been evaluated with a large number of Japanese individuals with type 2 diabetes (n = 2,201) and normal control subjects (n = 1,212) recruited by 10 institutions located in seven different cities in Japan. The allele frequency for the Ala12 variant was significantly lower in the type 2 diabetic group than in the control group (2.39 vs. 4.13%, P = 0.000054). However, compared with subjects without the Ala12 variant, the diabetic subjects with this variant exhibited a significantly higher serum concentration of total cholesterol (P = 0.001), manifested a reduced capacity for insulin secretion as evaluated by homeostasis model assessment (P = 0.007), and tended to possess a higher level of HbA1c. These data suggest that the Ala12 variant is associated with a reduced risk for the development of diabetes in the general population, but that it may be also a risk factor for insulin deficiency and disease severity in individuals with type 2 diabetes.

Adult↗
PubMed2001

Pancreatic biopsy as a procedure for detecting in situ autoimmune phenomena in type 1 diabetes: close correlation between serological markers and histological evidence of cellular autoimmunity.

To better understand the pathogenesis of type 1 diabetes, we have developed pancreatic biopsy under laparoscope for recent-onset type 1 diabetic patients. The patients included 29 acute-onset type 1 diabetic patients, 5 latent-onset type 1 diabetic patients, and 1 type 2 diabetic patient. Their median age was 28 years, and the duration of diabetes at the time of biopsy was approximately 3 months. In 31 of 35 patients, we could obtain the pancreas tissue by punching. No serious complications, such as heavy bleeding, peritonitis, or pancreatitis, have been experienced. Pneumoderma was observed in two patients, and abdominal dull pain had continued for 2 days in two patients. However, special treatment was not necessary for these complications. T-cell-predominant infiltration to islets (insulitis) and hyperexpression of major histocompatibility complex class I antigens on islet cells were the two major findings and were observed in 17 of 29 recent-onset type 1 diabetic patients. These findings could be regarded as evidence of immune attack against beta-cells, and their presence was closely correlated with the presence of either anti-GAD or anti-IA-2 antibodies (P = 0.02). In conclusion, pancreatic biopsy under laparoscope is a safe procedure without serious complications, according to our findings, for detecting in situ autoimmune phenomenon in recent-onset type 1 diabetic patients.

Adolescent↗
PubMed2001

[A case of adult Wilms' tumor].

Wilms' tumor is very rarely found in adults and there are no established treatment guidelines for such tumors in adults. A 56-year-old woman was referred to our hospital for further examination of macroscopic hematuria. Computed tomography scan revealed a large right renal mass with enlarged lymph nodes. Angiography showed a hypovascular tumor. She underwent right nephrectomy and resection of lymph node metastasis with a diagnosis of malignant renal tumor. Histopathological examination revealed nephroblastoma with lymph node metastasis. The disease was classified as stage III according to the National Wilms' Tumor Study classification. The patient received adjuvant chemotherapy consisting of ifosfamide, cisplatin, and etoposide. This protocol was selected because of the published poor results with the standard Wilms' tumor chemotherapeutic agents when used in adults. She remained without tumor recurrence as of six months after surgery. Development of better therapeutic approaches to adult Wilms' tumor is awaited.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-1, and TNF receptor-2 molecules.

Several death-signaling or death-inducing molecules have been implicated in beta cell destruction, including Fas, perforin, and TNFR-1. In this study, we examined the role of each death-signaling molecule in the IL-10-accelerated diabetes of nonobese diabetic (NOD) mice. Groups of IL-10-NOD mice, each deficient in either Fas, perforin, or TNFR-1 molecules, readily developed insulitis, and subsequently succumbed to diabetes with an accelerated kinetics and incidence similar to that observed in their wild-type or heterozygous IL-10-NOD littermates. Similarly, a TNFR-2 deficiency did not block accelerated diabetes in IL-10-NOD mice and spontaneous diabetes in NOD mice. These results demonstrate that pancreatic IL-10 promotes diabetes independent of Fas, perforin, TNFR-1, and TNFR-2 molecules. Subsequently, when cyclophosphamide, a diabetes-inducing agent, was injected into insulitis-free NOD. lpr/lpr mice, none of these mice developed insulitis or diabetes. Our data suggest that cyclophosphamide- but not IL-10-induced diabetes is Fas dependent. Overall, these findings provide evidence that pancreatic expression of IL-10 promotes diabetes independent of the major death pathways and provide impetus for identification of novel death pathways precipitating autoimmune destruction of insulin-producing beta cells.

Adoptive Transfer↗
PubMed2000

A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group.

BACKGROUND AND METHODS: Type 1 diabetes mellitus is now classified as autoimmune (type 1A) or idiopathic (type 1B), but little is known about the latter. We classified 56 consecutive Japanese adults with type 1 diabetes according to the presence or absence of glutamic acid decarboxylase antibodies (their presence is a marker of autoimmunity) and compared their clinical, serologic, and pathological characteristics. RESULTS: We divided the patients into three groups: 36 patients with positive tests for serum glutamic acid decarboxylase autoantibodies, 9 with negative tests for serum glutamic acid decarboxylase antibodies and glycosylated hemoglobin values higher than 11.5 percent, and 11 with negative tests for serum glutamic acid decarboxylase antibodies and glycosylated hemoglobin values lower than 8.5 percent. In comparison with the first two groups, the third group had a shorter mean duration of symptoms of hyperglycemia (4.0 days), a higher mean plasma glucose concentration (773 mg per deciliter [43 mmol per liter]) in spite of lower glycosylated hemoglobin values, diminished urinary excretion of C peptide, a more severe metabolic disorder (with ketoacidosis), higher serum pancreatic enzyme concentrations, and an absence of islet-cell, IA-2, and insulin antibodies. Immunohistologic studies of pancreatic-biopsy specimens from three patients with negative tests for glutamic acid decarboxylase autoantibodies and low glycosylated hemoglobin values revealed T-lymphocyte-predominant infiltrates in the exocrine pancreas but no insulitis and no evidence of acute or chronic pancreatitis. CONCLUSIONS: Some patients with idiopathic type 1 diabetes have a nonautoimmune, fulminant disorder characterized by the absence of insulitis and of diabetes-related antibodies, a remarkably abrupt onset, and high serum pancreatic enzyme concentrations.

Adolescent↗
PubMed2000

Cloning of cDNA and the gene encoding human hepatocyte nuclear factor (HNF)-3 beta and mutation screening in Japanese subjects with maturity-onset diabetes of the young.

AIMS/HYPOTHESIS: Molecular defects of the genes for transcription factors, hepatocyte nuclear factor (HNF)-4 alpha, HNF-1 alpha, HNF-1 beta and insulin promoter factor-1 cause maturity-onset diabetes of the young (MODY1, 3, 5, and 4, respectively). This suggests the HNF-related transcription cascade is important in insulin secretion which is induced by glucose. These genes and the gene encoding glycolytic enzyme glucokinase (MODY2) are, however, responsible for only 15-20% of cases of MODY in the Japanese. Searching for a novel form of MODY in this population, we cloned a new candidate gene encoding human HNF-3 beta, a winged helix transcription factor, which also belongs to the same HNF-transcription cascade. METHODS: The cDNA clone for human HNF-3 beta was isolated from a liver cDNA library. The gene was also cloned from a genomic library and its organization and chromosomal localization were determined. We screened 68 Japanese subjects with MODY/early-onset diabetes for mutations in this gene. RESULTS: Human HNF-3 beta is composed of 457 amino acids. The human gene, which was mapped to the segment 30 cR from SHGC-37039 on chromosome 20p by radiation hybrid mapping, spans approximately 4.5 kb and consists of three exons. Direct sequencing of the exons and flanking regions identified one missense mutation A328 V and seven polymorphisms, although the functional significance of the mutation in the pathogenesis of diabetes is not known. CONCLUSION/INTERPRETATION: The characterization of the structure of the HNF-3 beta gene and its mapping in the framework of markers will be helpful in genetic studies of the various forms of diabetes mellitus.

Amino Acid Sequence↗
PubMed2000

R127W-HNF-4alpha is a loss of function mutation but not a rare polymorphism and causes Type II diabetes in a Japanese family with MODY1.

AIMS/HYPOTHESIS: Mutations in the hepatocyte nuclear factor (HNF)-4alpha gene cause the type 1 form of maturity-onset diabetes of the young (MODY1). The R127W mutation is a missense mutation located in the T-box region of HNF-4alpha that was first identified in a Japanese family with MODY. We have examined the functional properties of this mutation in order to clarify the molecular basis of MODY1. METHODS: The intracellular localisation, DNA binding ability, transactivation activity and functional synergism with the coactivator CREB-binding protein (CBP) of R127W-HNF-4alpha were investigated. RESULTS: The nuclear import and functional synergy with CBP of R127W-HNF-4alpha were normal. The DNA binding ability of the mutant was decreased as was its transcriptional activation of the HNF-1alpha and L-type pyruvate kinase (PKL) genes. CONCLUSION/INTERPRETATION: The R127W mutation seems to be a loss-of-function mutation.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed2000

Identification of missense mutations in the hepatocyte nuclear factor-3beta gene in Japanese subjects with late-onset Type II diabetes mellitus.

AIMS/HYPOTHESIS: Hepatocyte nuclear factor (HNF)-3beta, a transcription factor expressed in pancreatic beta cells, is an upstream regulator of HNF-1alpha/MODY3, HNF-4alpha/MODY1 and IPF1/MODY5 genes. Our previous screening of MODY subjects showed that mutations in the HNF-3beta gene are not a common cause of this form of diabetes in the Japanese. We tested the hypothesis that mutations in the HNF-3beta gene cause late-onset Type II (non-insulin-dependent) diabetes mellitus in this population. METHODS: Genotyping of the polymorphic TCC repeat in the HNF-3beta gene was done in 112 Japanese subjects with Type II diabetes (age at diagnosis > 35 and family history of Type II diabetes among their second-degree relatives) and 96 Japanese control subjects. Furthermore, we screened 57 Type II diabetic patients for mutations of the HNF-3beta gene. Transactivation activity of variant HNF-3beta was investigated by transfection assay. RESULTS: The distribution of alleles of the TCC repeat was similar between diabetic and control groups. Mutation screening identified two missense mutations, A86T and G114E. Neither mutation was observed in 225 control subjects. The transactivation activity of G114E-HNF-3beta was similar to that of wild typeHNF-3beta. In contrast, the activity of A86T-HNF-3beta was statistically significantly reduced to 83-86 % of that of wild type. CONCLUSIONS/INTERPRETATION: The A86T mutation in the HNF-3beta gene might be involved in the development of late-onset Type II diabetes in a small group of Japanese people.

Adult↗