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T Ogihara

Publications and source records attributed to T Ogihara.

At least 145 records · Page 8Linked to original sources
PubMed2000

Age-related association of MHC class I chain-related gene A (MICA) with type 1 (insulin-dependent) diabetes mellitus.

To assess the contribution of the HLA class I region to susceptibility to and heterogeneity of type 1 diabetes, we investigated the association of polymorphism of MHC class I chain-related gene A (MICA) with age-at-onset as well as susceptibility to type 1 diabetes. One hundred one Japanese patients and 110 healthy control subjects were studied. The frequency of A4 allele was significantly higher and that of A6 allele was significantly lower in patients than in control subjects. The frequency of A5.1 allele was highest in early-onset patients (23.0%), intermediate in intermediate-onset patients (9.2%) and lowest in late-onset patients (7.7%) (trend chi-squared test, p = 0.0098). A5. 1 allele was strongly associated with HLA-B7 and Cw7, suggesting that MICA*A5.1-B7-Cw7 haplotype contains a gene responsible for age-at-onset. A4 allele was associated with a susceptible haplotype, DR4-DQB1*0401, and A6 allele was associated with a protective haplotype, DR2-DQB1*0601, suggesting that the association of MICA with type 1 diabetes susceptibility may be due to linkage disequilibrium with class II haplotypes. These data suggest that MICA gene is associated with age-at-onset and that a gene (or genes) responsible for age-at-onset of type 1 diabetes is located in the HLA class I region, probably near the region of MICA-B-C.

Adolescent↗
PubMed2000

Human G-protein beta3 subunit variant is associated with serum potassium and total cholesterol levels but not with blood pressure.

The activity of a sodium-proton exchanger is enhanced in the patients with essential hypertension and regulated via G-protein, which is a signal transducer between receptors and intracellular effectors. A recent study has revealed that a novel variant (C825T) in exon 10 of the gene encoding the beta3 subunit of heterotrimetric G proteins (GNB3) is a genetic factor predisposing to hypertension in Caucasians. We examined the association between GNB3/ C825T and blood pressure, lipids, electrolytes, and other parameters in a Japanese population. Subjects (n = 352) were selected from the Ohasama Study, the population of which is regarded as from a rural community in Japan. To obtain precise clinical measurements, 24-h ambulatory blood pressure monitoring (ABPM), brain magnetic resonance imaging (MRI), and carotid ultrasonography (CUS) were conducted in this population. In addition, we recruited 762 subjects from outpatients at the Osaka University Medical School to carry out the association study between hypertension and GNB3. The GNB3 genotype distribution did not differ significantly between normotensives and hypertensives in either of the two studies. The T825 allele of GNB3 was not associated with the presence of hypertension, blood pressure level, the number of brain lacunae or carotid wall thickness. However, the serum potassium and total cholesterol levels were significantly higher in subjects with the T allele (P < .005). The T825 allele of GNB3 is associated with increased serum potassium and total cholesterol levels but not with blood pressure in a Japanese population.

Adult↗
PubMed2000

Gene polymorphism of the renin-angiotensin system associates with risk for lacunar infarction. The Ohasama study.

The polymorphism of the angiotensin-converting enzyme gene is considered to be associated with increased risk for stroke, but there is a diversity in the results obtained. The genetic involvement of the renin-angiotensin system in stroke also remains unclear. To predict the genetic risk of lacunar infarction, we conducted an association study in an Ohasama population, which is the cohort in a rural region of northern Japan. A total of 134 subjects without major neurological, cardiovascular, or metabolic disorders were recruited. Using brain magnetic resonance imaging, the number of lacunae in each of four brain regions were calculated, and periventricular hyperintensity was classified into five grades. We used the following four candidate gene polymorphisms: angiotensin converting enzyme (ACE)/Insertion(I)-Deletion(D), angiotensinogen (AGT)/M235T, angiotensin II type 1 receptor (AT1)/ A1166C, type 2 receptor (AT2)/C3123A, to examine the association between polymorphisms and the severity of lacunar infarction. AGT/M235T was significantly associated with the number of lacunae in the brain stem, the basal ganglia (P < .05), and whole brain (P < .005) regions. The AT1 polymorphism was also significantly associated with the number of lacunae in the basal ganglia and whole brain regions (P < .05), and with periventricular hyperintensity grade (P < .005) in the younger population. However, ACE and AT2 polymorphisms failed to show an association with either the number of lacunae or the PVH grade. We concluded that AGT and AT1 polymorphisms are independent genetic risk factors for lacunar infarction.

Aged↗
PubMed2000

Practitioner's Trial on the Efficacy of Antihypertensive Treatment in the Elderly Hypertension (The PATE-Hypertension Study) in Japan.

Patients aged 60 years and older with essential hypertension were treated with an angiotensin-converting enzyme inhibitor (ACE-I), delapril (Adecut) or a long-acting calcium (Ca)-antagonist, manidipine (Calslot) for 3 years. The incidences of cardiovascular events as well as drug-related side effects were compared between the two groups to investigate whether both classes of antihypertensive drugs are beneficial in elderly hypertensive patients. There were no significant differences in characteristics of patients between the two intervention groups, except for slightly lower blood pressure (P = .08) in the Ca-antagonist group at the initiation of the study. There were no significant differences in total death between the two groups. Cardiovascular events (both fatal and nonfatal) were noted in 34 of 699 patients (22.5/1000 patient-years) in the ACE-I group and 50 of 1049 patients (19.7/1000 patient-years) in the Ca-antagonist group, with no significant difference found between the two groups. The correlation between cardiovascular incidence and the blood pressure attained during treatment showed a J-shaped phenomenon and suggests that an excessive reduction less than 120 mm Hg in systolic blood pressure (SBP) is unnecessary and may be harmful in certain cases. Side effects were more frequent in the ACE-I group than in the Ca-antagonist group (P = .01). Cough was the major adverse event, occurring in 5.0% of patients in the ACE-I group. In conclusion, the study indicates that both ACE-I (delapril) and Ca-antagonist (manidipine) were equally beneficial for reducing cardiovascular morbidity and mortality in elderly hypertensive patients. However, tolerability of ACE-I was lower due to the adverse event of coughing.

Aged↗
PubMed2000

Efficacy of reduced dosage of rabeprazole in PPI/AC therapy for Helicobacter pylori infection: comparison of 20 and 40 mg rabeprazole with 60 mg lansoprazole.

Proton pump inhibitor (PPI)- based triple therapy has been a recent trend for treatment of Helicobacter pylori infection, with the PPI-amoxicillin-clarithromycin (PPI/AC) regimen being one of the most popular. We have reported the effectiveness of PPI/AC regimens in the Japanese population and have demonstrated that the effectiveness of 40 mg rabeprazole, a recently developed PPI, is similar to that of 40 mg of omeprazole and 60 mg of lansoprazole when used in combination with amoxicillin and clarithromycin. In this study, we focused on whether 20 mg of rabeprazole is effective in our patient population by comparing that dosage with 40 mg of rabeprazole and 60 mg of lansoprazole. In all, 308 H. pylori-infected patients [236 men and 72 women; age (mean +/- SEM) 49.3+/-0.6 years] with peptic ulcer disease (N = 270) or nonulcer dyspepsia (N = 38) were randomly assigned to one of three different PPI/AC regimens for seven days: LAC (N = 104), consisting of lansoprazole 30 mg twice a day, amoxicillin 500 mg three times a day, and clarithromycin 200 mg twice a day; RAC (N = 104), consisting of rabeprazole 20 mg twice a day, amoxicillin 500 mg three times a day, and clarithromycin 200 mg twice a day; and the R1/2AC regimen (N = 100), which included rabeprazole 10 mg twice a day, amoxicillin 500 mg three times a day, and clarithromycin 200 mg twice a day. Cure of the infection was determined by the [13C]urea breath test one month after completion of the treatment. Intention-to-treat based and per-protocol based cure rates for the LAC, RAC, and R1/2AC regimens were 82.7 (95% CI, 74-89) and 88.7% (81-94), 85.6 (77-92) and 89.8% (82-95), and 87.0 (79-93) and 89.7% (82-95), respectively. Although adverse effects were reported by 20.3% of the patients, these affected compliance in only five patients in the RAC and LAC regimens and none in the R1/2AC group. Overall complete compliance was achieved in 94.7% of interviewed patients. In conclusion, the effectiveness of the PPI/AC regimen with 20 mg of rabeprazole is comparable with and even safer than that of 40 mg of rabeprazole and 60 mg of lansoprazole in our patient population.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Low density lipoprotein receptor-related protein gene polymorphisms and risk for late-onset Alzheimer's disease in a Japanese population.

Low density lipoprotein (LDL) receptor-related protein (LRP) gene polymorphisms located in the 5' region and in exon 3, and the apolipoprotein E (APOE) genotype were determined in 100 Japanese patients affected by late-onset Alzheimer's disease (AD). We matched 246 controls for age and found no association between the polymorphism located in the 5' region of the LRP gene. The distribution of LRP exon 3 genotypes and alleles did not differ between AD and the control groups. However, the frequency of T allele in the Alzheimer's group having APOE-epsilon4 was lower than that in the control group having APOE-epsilon4, but it was only marginally significant (p = 0.022). Age of onset was significantly younger in the patients with CC genotype than those carrying the T allele (p = 0.03), and this trend was more evident among non-APOE-epsilon4 carriers (p = 0.008). These results support the possibility that ApoE and LRP may contribute to the development of AD.

Age of Onset↗
PubMed2000

Angiogenesis induced by hepatocyte growth factor in non-infarcted myocardium and infarcted myocardium: up-regulation of essential transcription factor for angiogenesis, ets.

The feasibility of a novel therapeutic strategy using angiogenic growth factors to expedite and/or augment collateral artery development has recently entered the realm of treatment of ischemic diseases. Hepatocyte growth factor (HGF) is a novel member of endothelium-specific growth factors whose mitogenic activity on endothelial cells is very potent. Although it has been demonstrated that HGF is a potential angiogenic growth factor in in vitro culture systems, there is no direct in vivo evidence for the angiogenic activity of HGF in physiological conditions. In this study, we hypothesized that transfection of HGF gene into infarcted myocardium could induce angiogenesis, potentially resulting in a beneficial response to hypoxia. Human HGF gene or control vector driven by the SRalpha promoter was transfected into rat myocardium by the HVJ-liposome method. Four days after in vivo transfection of human HGF gene, there was a marked increase in human immunoreactive HGF as compared with control vector (P < 0.01). In myocardium transfected with HGF vector, a significant increase in PCNA-positive endothelial cells was observed, while few PCNA-positive endothelial cells were detected in both control-vector-transfected and untreated myocardium. The number of vessels around the HGF injection sites was significantly increased as compared with control vector or vehicle (P < 0.01). Angiogenic activity induced by the transfection of HGF vector was also confirmed by the activation of a transcription factor, ets, which is essential for angiogenesis. Furthermore, we studied the pathophysiological role of HGF in a myocardial infarction model. The concentration of endogenous HGF was significantly decreased in infarcted myocardium. Therefore, we hypothesized that transfection of HGF gene into infarcted myocardium could induce a beneficial response to the decreased endogenous HGF. Indeed, transfection of human HGF into infarcted myocardium also resulted in a significant increase in the number of vessels (P < 0. 01), accompanied by marked induction of ets binding activity and a significant increase in blood flow. Overall, the present results provide direct in vivo evidence for the induction of angiogenesis by transfection of the human HGF gene in rat non-infarcted and infarcted myocardium. The constant production of local HGF resulting from the transgene may be considered as an innovative therapeutic angiogenesis strategy for ischemic diseases such as myocardial infarction. Gene Therapy (2000) 7, 417-427.

Animals↗
PubMed2000

Transcription factor decoy for NFkappaB inhibits TNF-alpha-induced cytokine and adhesion molecule expression in vivo.

The expression of several cytokines and adhesion molecules is regulated by the transcription factor NFkappaB, which is activated by tumor necrosis factor alpha (TNF-alpha). In this study, we employed a mouse model of nephritis induced by TNF-alpha to examine whether inhibition of NFkappaB activity using transcription factor decoy oligonucleotides (ODN) blocks cytokine and adhesion molecule expression and attenuates the renal inflammatory response. First, we developed a method for delivering FITC-ODN in vivo into mouse kidney glomeruli by employing HVJ-liposome. Then, in order to study the feasibility of decoy strategy in vivo, the reporter gene chloramphenicol acetyltransferase (CAT) driven by three tandemly repeated NFkappaB binding sequences was transfected into the kidney. Intrapenetorial injection of TNF-alpha stimulated CAT expression in vivo, and the increase in CAT expression was completely abolished by NFkappaB decoy ODN, but not scrambled ODN. Therefore, we examined the effect of NFkappaB decoy ODN transfection on TNF-alpha-induced endogenous interleukin (IL)-1alpha, IL-1beta, IL-6, ICAM-1 and VCAM-1 gene expression as assessed by RT-PCR and Northern blotting. Our present data showed that NFkappaB decoy, but not scrambled, ODN abolished TNF-alpha induced gene expression in vivo, as well as glomerular inflammation as assessed by CD45 staining. Taken together, our results suggest the potential utility of NFkappaB decoy strategy for molecular therapy to glomerular inflammatory diseases.

Animals↗
PubMed2000

In vivo transfer of human hepatocyte growth factor gene accelerates re-endothelialization and inhibits neointimal formation after balloon injury in rat model.

Although most therapeutic strategies to prevent restenosis are designed to inhibit vascular smooth muscle cell (VSMC) proliferation directly, VSMC proliferation might be indirectly inhibited by re-endothelialization, as endothelial cells secrete antiproliferative and antithrombotic substances. We hypothesized that application of an endothelium-specific growth factor to balloon-injured arteries could accelerate re-endothelialization, thereby attenuating intimal hyperplasia. In this study, we investigated in vivo gene transfer of human HGF that exclusively stimulated endothelial cells without replication of VSMC growth into injured vessels. Transfection of human HGF gene into rat balloon-injured carotid artery resulted in significant inhibition of neointimal formation up to at least 8 weeks after transfection, accompanied by detection of human immunoreactive HGF. Induction of re-endothelialization induced by overexpression of human HGF gene transfer into balloon-injured vessels is supported by several lines of evidence: (1) Administration of HGF vector. but not control vector, markedly inhibited neointimal formation, accompanied by a significant increase in vascular human and rat HGF concentrations. (2) Planimetric analysis demonstrated a significant increase in re-endothelialized area in arteries transfected with human HGF vector. (3) Induction of NO content in balloon-injured vessels transfected with human HGF vector was observed in accordance with the recovery of endothelial vasodilator properties in response to acetylcholine. As endogenous HGF expression in balloon-injured vessels was significantly decreased as compared with normal vessels, the present study demonstrated the successful inhibition of neointimal formation by transfection of human HGF gene as 'cytokine supplement therapy' in a rat balloon injury model.

Acetylcholine↗
PubMed2000

Effects of growth factors on aspirin-induced inhibition of wound repair in a rabbit gastric epithelial cell model.

BACKGROUND: Aspirin is known to cause adverse effects, including gastric mucosal injury, and to retard gastric wound healing. Growth factors including hepatocyte growth factor (HGF), epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) have been shown to play an important role in the repair of gastric mucosal injury. AIM: To employ the cultured gastric epithelial cell model to elucidate the effects of aspirin, as well as several growth factors (HGF, EGF and IGF-I), on gastric wound repair. METHODS: Isolated rabbit gastric epithelial cells (92% mucous cells) were cultured in F-12 medium and formed a complete monolayer cell sheet in 48 h. A wound with a cell-free area of constant size (2 mm2) was then created and the wound repair process was monitored by measuring wound size every 12 h. Proliferating cells were detected by BrdU staining. Effects of aspirin (8 mM), HGF (10 ng/mL), EGF (10 ng/mL) and IGF-I (30 ng/mL) were assessed. RESULTS: Aspirin significantly retarded wound healing, but simultaneous addition of growth factors significantly accelerated wound repair compared with aspirin alone. Growth factors reversed the aspirin-induced inhibition of cell proliferation. CONCLUSION: Growth factors, including HGF, EGF and IGF-I, reversed the aspirin-induced inhibition of wound repair through their cytoprotective effects on gastric epithelial cells.

Animals↗
PubMed2000

Deletion polymorphism of angiotensin-converting enzyme gene is associated with postprandial hyperglycaemia in individuals undergoing general check-up.

1. Deletion polymorphism, DD, of the angiotensin-converting enzyme (ACE) gene is reported to be related to cardiovascular disease, which is frequently based on insulin resistance. 2. To clarify the relationship between the ACE genotype DD and plasma glucose increases after an oral glucose load, we performed 75 g oral glucose tolerance test (OGTT) in 301 nondiabetic men (age range 30-60 years) undergoing general check-up. 3. Insertion/deletion (I/D) polymorphism of the ACE gene was explored using a polymerase chain reaction. The frequency of the II, ID and DD genotypes was 0.43, 0.43 and 0.14, respectively. 4. There were no differences in baseline clinical characteristics between subjects with each ACE genotype. 5. The mean (+/- SEM) plasma glucose level at 60 min of the OGTT was significantly higher in subjects with the DD genotype (170.8 +/- 6.9 mg/dL) than in subjects with either the II or ID genotype (mean value for two groups 156.6 +/- 2.7 mg/dL; P < 0.05). Moreover, the mean percentage change of plasma glucose after 60 min of the OGTT, a marker of plasma glucose increase, was significantly higher in individuals with the DD genotype than in individuals with either the II or ID genotypes. 6. In contrast, the mean fasting plasma glucose level, the plasma glucose level at 120 min, the glucose response area and the fasting insulin level were not different between individuals with the DD genotype and individuals with other genotypes. 7. In conclusion, subjects with the DD genotype showed transiently higher levels of plasma glucose after an oral glucose load than subjects with other genotypes. Further studies are required to determine whether the association between ACE genotype and postprandial hyperglycaemia influences the incidence of cardiovascular disease and diabetes mellitus.

Adult↗
PubMed2000

KL-6, a mucinous glycoprotein, as an indicator of chronic lung disease of the newborn.

KL-6 is a mucinous glycoprotein that is preferentially expressed by alveolar type 2 cells. Plasma KL-6 was higher in infants with chronic lung disease (n = 12) than in infants without chronic lung disease (n = 14) on day 0-1, 10, and 30 (P =.04). KL-6 correlated with the alveolar-arterial oxygen tension difference on day 10 and day 30. Plasma KL-6 may be useful as an early marker of chronic lung disease and an indicator of severity.

Antigens↗
PubMed2000

Japanese individuals do not harbor the T594M mutation but do have the P592S mutation in the C-terminus of the beta-subunit of the epithelial sodium channel: the Ohasama study.

OBJECTIVE: To assess the implications of polymorphisms of the amiloride-sensitive epithelial sodium channel in essential hypertension in the Japanese population by determining the incidence of the T594M mutation in the , subunit of the epithelial sodium channel, and by screening the C-terminus of the epithelial sodium channel. METHODS: Single-strand confirmational polymorphism (SSCP) analysis using two sets of primers which cover the last two-thirds of the last exon coding the B epithelial sodium channel and modification of a specific enzyme restriction site (NlaIII) for the T594M mutation were performed on 803 Japanese subjects. They were randomly selected from the study participants representative of a general population of Ohasama, Japan, who measured their home blood pressure. Polymerase chain reaction (PCR) products presenting a shift in SSCP gel, as well as controls, were directly sequenced by autoanalyser to identify the mutation. RESULTS: SSCP analysis identified altered migration in five subjects. Four SSCP variants found by sequencing were heterogeneous for the P592S (CCT to TCT) mutation conserving the PY motif, although it was not significantly associated with either home or casual blood pressure values. The resting polymorphism was at codon Thr 594, leading to no change in the amino acid sequence (ACG to ACA). None of the PCR products were modified by NlaIII, indicating the absence of the T594M mutation. CONCLUSIONS: The epithelial sodium channel variants at the C-terminus are not involved in the common form of essential hypertension in Japanese.

Adult↗
PubMed2000

Anti-apoptotic action of hepatocyte growth factor through mitogen-activated protein kinase on human aortic endothelial cells.

OBJECTIVE: To investigate the molecular mechanisms of the anti-apoptotic action of hepatocyte growth factor (HGF), a novel angiogenic growth factor that may have a pivotal role in the regulation of endothelial cells, on human aortic endothelial cells. METHODS: An index of cell number and death was determined using a water-soluble tetrazolium salt dye assay, DNA fragmentation enzyme-linked immunosorbent assay, and non-confocal fluorescence microscopy of nuclear staining with Hoechst 33258 and propidium iodide. Extracellular-signal-regulated protein kinase (ERK) and the p38 mitogen-activated protein kinase (p38MAPK) were analysed by Western blotting using a phospho-specific antibody. RESULTS: Treatment of quiescent endothelial cells with HGF resulted in significant dose-dependent increases in cell numbers and decreases in lactate dehydrogenase (LDH) release. Moreover, HGF significantly attenuated endothelial cell death induced by culture in serum-free conditions. We therefore focused on the signal transduction system, and in particular on ERK and p38MAPK. ERK was markedly phosphorylated by HGF. The contribution of ERK to cell growth was supported by the observation that addition of PD98059, a specific inhibitor of MAPK kinase, significantly attenuated the increase in endothelial cell numbers induced by HGF, in a dose-dependent manner. Similarly, PD98059 also attenuated the decrease in LDH release and DNA fragmentation by HGF under serum-free conditions. Interestingly, ERK was re-phosphorylated at 12 h after stimulation. Re-phosphorylation of ERK was the result of induction of endogenous HGF by exogenously added HGF, as addition of neutralizing anti-HGF antibody to the conditioned medium attenuated re-phosphorylation of ERK at 12 h. In contrast, although p38MAPK was also phosphorylated by HGF, SB203580, a specific inhibitor of p38MAPK, failed to change the endothelial cell growth induced by HGF. CONCLUSION: We have demonstrated that the anti-apoptotic action of HGF against endothelial cell death was mainly through phosphorylation of ERK on human endothelial cells.

Aorta↗
PubMed2000

Genetic analysis of essential hypertension in Japanese populations.

The reverse genetic approach, which examines genetic factors underlying the root of pathogenesis first, is a powerful tool to clarify the genetic cause of essential hypertension. Using the rat cross model, studies of the genetically hypertensive inbred rat model indicated several candidate loci on the rat chromosome responsible for blood pressure, but failed to identify the exact causal gene. Moreover, it was not certain that the rat data really reflect the human case. Thus, we shifted our focus to human genetics and carried out case control studies using the candidate gene approach. We mainly focused on gene components of the renin-angiotensin system as candidates, finding that angiotensinogen gene polymorphisms are genetic predisposing factors for hypertension. However, the results obtained from case-control studies using Japanese subjects were not consistent, suggesting that there was a problem in control sampling. In our recent study, we recruited more than 5,000 residents of an urban community as a general population and examined the association between genetic factors and their health status. Our results indicate that angiotensin-converting enzyme gene polymorphism is a male-specific genetic risk for essential hypertension. In light of our previous investigations, we present a discussion concerning the design of future studies of the genetics of hypertension.

Angiotensinogen↗
PubMed2000

Negative feedback regulation of activated macrophages via Fas-mediated apoptosis.

Apoptosis is a critical event for eliminating activated macrophages. Here we show that Fas-mediated apoptosis may participate in the mechanism of negative feedback regulation of activated macrophages. Cytokine-activated macrophages released high levels of nitric oxide (NO) that induced apoptosis in macrophages themselves. This NO-induced macrophage apoptosis was inhibited by a Fas-Fc chimeric molecule that binds to Fas ligand (FasL) and prevents its interaction with endogenous cell surface Fas. High levels of NO stimulated the release of the soluble form of FasL that was inhibited by a matrix metalloproteinase inhibitor KB-8301. High levels of NO also upregulated the expression of Fas mRNA in macrophages. In addition, macrophages isolated from Fas-lacking mice were resistant to NO-induced apoptosis. Finally, inhibition of apoptosis by a caspase inhibitor augmented peroxide production from activated macrophages. These findings suggest that high levels of NO released from activated macrophages may promote the Fas-mediated macrophage apoptosis that may be a negative feedback mechanism for elimination and the downregulation of activated macrophages in the vessel wall.

Animals↗