Biomedical subjects

Norifumi Metoki

Publications and source records attributed to Norifumi Metoki.

14 recordsLinked to original sources

PubMed2007

Association of gene polymorphisms with myocardial infarction in individuals with or without conventional coronary risk factors.

The purpose of the present study was to assess the genetic risk for myocardial infarction (MI) in individuals with or without conventional coronary risk factors and thereby to contribute to the personalized prevention of MI in such individuals. The study population comprised 3483 unrelated Japanese individuals (1913 men, 1570 women). The 1192 subjects with MI (926 men, 266 women) and 2291 controls (987 men, 1304 women) either had or did not have conventional coronary risk factors, including hypertension, hypercholesterolemia, and diabetes mellitus. The genotypes for 164 polymorphisms of 137 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis and a stepwise forward selection procedure revealed that nine different polymorphisms were significantly (P<0.005) associated with MI among individuals with or without hypertension, hypercholesterolemia, or diabetes mellitus: 1018Cright curved arrow T of GP1BA, -108/3Gright curved arrow 4G of IPF1, 677Cright curved arrow T of MTHFR, and Gright curved arrow A of UTS2 in hypertensive individuals; 2445Gright curved arrow A of FABP2, -108/3Gright curved arrow 4G of IPF1, 677Cright curved arrow T of MTHFR, -11,377Cright curved arrow G of ACDC, Aright curved arrow G of AKAP10, 11,496Gright curved arrow A of F7, and 46Cright curved arrow T of F12 in individuals without hypercholesterolemia; 2445Gright curved arrow A of FABP2 in diabetic individuals; and -108/3Gright curved arrow 4G of IPF1 in nondiabetic individuals. Polymorphisms associated with MI may thus differ among individuals with different conventional coronary risk factors. Stratification of subjects on the basis of such risk factors may thus be important in order to achieve personalized prevention of MI with the use of genetic information.

Case-Control Studies↗

PubMed2006

Genetic risk for ischemic and hemorrhagic stroke.

OBJECTIVE: We performed an association study to identify gene polymorphisms for assessing the genetic risk of ischemic or hemorrhagic stroke. METHODS AND RESULTS: The study population comprised 3151 unrelated Japanese individuals: 1141 stroke patients (636 with atherothrombotic cerebral infarction, 282 with intracerebral hemorrhage, and 223 with subarachnoid hemorrhage) and 2010 controls. The genotypes for 202 polymorphisms of 152 genes were determined by suspension array technology. Multivariable logistic regression analysis with adjustment for conventional risk factors revealed that the -572G-->C polymorphism of the interleukin-6 (IL-6) gene (IL6) was significantly (P<0.001) associated with both atherothrombotic cerebral infarction and intracerebral hemorrhage and that the -55C-->T polymorphism of the uncoupling protein 3 gene (UCP3), the -863C-->A polymorphism of the tumor necrosis factor (TNF) gene (TNF), and the G-->A (Gly243Asp) polymorphism of the polycystic kidney disease 1-like gene (PKD1-like) were significantly associated with subarachnoid hemorrhage. CONCLUSIONS: IL6 genotype may be useful in assessing the genetic risk for atherothrombotic cerebral infarction and intracerebral hemorrhage, and genotypes for UCP3, TNF, and PKD1-like may be similarly beneficial in assessment of the risk for subarachnoid hemorrhage. Validation of our findings will require additional studies with independent subject panels.

Aged↗

PubMed2006

Interleukin-1beta enhances the angiotensin-induced expression of plasminogen activator inhibitor-1 through angiotensin receptor upregulation in human astrocytes.

Plasminogen activator inhibitor-1 (PAI-1) regulates not only fibrinolysis but extracellular matrix remodeling, and angiotensin II is known to play an important role in controlling the expression of PAI-1 in astrocytes. We have studied the effect of interleukin-1beta (IL-1beta), one of major cytokines also active in the nervous system, on the angiotensin II-induced expression of PAI-1 in human astrocytes. Cultures of normal human astrocytes were stimulated with IL-1beta and angiotensin II, and the expression of mRNAs for angiotensin II type 1 receptor (AT1) and PAI-1 was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) or real-time quantitative PCR. PAI-1 protein in astrocyte-conditioned medium was measured by enzyme-linked immunosorbent assay (ELISA). IL-1beta enhanced the expression of AT1 in astrocytes in time- and concentration-dependent manners. After 24-h stimulation, 10 ng/ml IL-1beta and 10 nM angiotensin II increased the levels of PAI-1 protein in astrocyte-conditioned medium by 1.9-fold and 1.8-fold of the basal value, respectively. There was no synergistic effect when the cells were stimulated simultaneously with IL-1beta and angiotensin II. When the cells were stimulated, with angiotensin II, 16 h after the stimulation with IL-1beta, the production of PAI-1 was enhanced by 1.4-fold as compared to the cells stimulated only with IL-1beta. CV-11794, an AT1 antagonist, inhibited the enhanced PAI-1 production in response to angiotensin II. We conclude that IL-1beta increases angiotensin II-induced PAI-1 secretion by astrocytes through the induction of AT1, and the enhanced secretion of PAI-1 may modulate functions of plasminogen activators in the nervous system.

Angiotensin II↗

PubMed2006

Assessment of the genetic component of hypertension.

BACKGROUND: Although genetic epidemiologic studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. We have now performed a large-scale association study to identify gene polymorphisms for reliable assessment of the genetic component of hypertension. METHODS: The study population comprised 4853 unrelated Japanese individuals, including 2818 subjects with hypertension (1677 men, 1141 women) and 2035 controls (1011 men, 1024 women). The genotypes for 150 polymorphisms of 128 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. RESULTS: Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking revealed that four polymorphisms (1648G-->A in ITGA2, -30G-->A in GCK, A-->G in SAH, and 1117C-->A in PTGIS) were significantly (P < .01) associated with hypertension. A stepwise forward selection procedure demonstrated that ITGA2, GCK, and PTGIS genotypes significantly affected the prevalence of hypertension. Combined genotype analysis of these polymorphisms yielded a lowest odds ratio of 0.47 for the genotypes of AA or AG for ITGA2, GA or AA for GCK, and CC for PTGIS, which were present in 1.1% and 2.0% of hypertensive and control individuals, respectively. CONCLUSIONS: These results suggest that the genotypes for ITGA2, GCK, and PTGIS may prove reliable for the assessment of the genetic component of hypertension. Determination of the combined genotypes for these genes may contribute to personalized prevention of this condition.

Aged↗

PubMed2006

Assessment of genetic factors for type 2 diabetes mellitus.

The purpose of the present study was to identify gene polymorphisms for reliable assessment of genetic factors for type 2 diabetes mellitus. The study population comprised 4853 unrelated Japanese individuals (2688 men, 2165 women), including 1489 subjects with type 2 diabetes mellitus (969 men, 520 women) and 3364 controls (1719 men, 1645 women). The genotypes for 148 polymorphisms of 124 candidate genes were determined with a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Sixteen polymorphisms were related (p<0.05) to the prevalence of type 2 diabetes mellitus as determined by the chi-square test. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of smoking revealed that, among these polymorphisms, the -603A --> G polymorphism of the gene for coagulation factor III (F3) was significantly (p<0.001) associated with the prevalence of type 2 diabetes mellitus, with the -603G allele representing a risk factor for this condition. A stepwise forward selection procedure demonstrated that F3 genotype (GG versus AA + AG) significantly (p<0.001) and independently affected the prevalence of type 2 diabetes mellitus. Genotype for F3 may prove reliable for assessment of genetic factors for type 2 diabetes mellitus. Determination of the genotype for this gene may contribute to personalized prevention of this condition.

Aged↗

PubMed2006

Assessment of genetic risk for myocardial infarction.

Although lifestyle and environmental factors influence the prevalence of myocardial infarction, genetic epidemiological studies have suggested that several genetic variants increase the risk for this condition. We have performed a large-scale association study to identify gene polymorphisms for reliable assessment of the genetic risk of myocardial infarction. The study population comprised 3,483 unrelated Japanese individuals (1,913 men; 1,570 women), including 1,192 subjects with myocardial infarction and 2,291 controls. The genotypes for 164 polymorphisms of 137 candidate genes were determined with an oligonucleotide ligation assay based on analysis of fluorescent microspheres with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hypercholesterolemia revealed that the 677C-->T (Ala222Val) polymorphism of MTHFR, the 1595C-->G (Ser447Stop) polymorphism of LPL, and the -108/3G-->4G polymorphism of IPF1 were significantly associated with the prevalence of myocardial infarction. A stepwise forward selection procedure demonstrated that IPF1, MTHFR, and LPL genotypes significantly affected the prevalence of myocardial infarction. Combined genotype analysis of these polymorphisms yielded a maximum odds ratio of 2.54 for the combined genotype of TT for MTHFR, CC for LPL, and 3G3G for IPF1. The genotypes for MTHFR, LPL, and IPF1 may prove reliable for assessment of genetic risk for myocardial infarction. Determination of the combined genotype for these genes may contribute to primary, personalized prevention of this condition.

Aged↗

PubMed2006

Genetic risk for atherothrombotic cerebral infarction in individuals stratified by sex or conventional risk factors for atherosclerosis.

The aim of the present study was to assess the genetic risk for atherothrombotic cerebral infarction (ACI) in men and women separately as well as in individuals with or without conventional risk factors for atherosclerosis and thereby to contribute to the personalized prevention of ACI. The study population comprised 2705 unrelated Japanese individuals (1244 men, 1461 women), including 636 subjects (372 men, 264 women) with ACI. Subjects with ACI and controls either had or did not have conventional risk factors for atherosclerosis, including hypertension, hypercholesterolemia, and diabetes mellitus. The genotypes for 202 polymorphisms of 152 candidate genes were determined by a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis and a stepwise forward selection procedure revealed that 11 different polymorphisms were significantly (P < 0.005) associated with ACI in women or men or in individuals with or without hyper-tension, hypercholesterolemia, or diabetes mellitus: the 584C-->T polymorphism of LIPG, 5665G-->T of EDN1, and G-->A of CCL11 in women; 677C-->T of MTHFR, 1323C-->T of ITGB2, 3932T-->C of APOE, and -231A-->G of EDNRA in men; -572 G -->C of IL6 in hypertensive individuals; -403G-->A of CCL5 and G-->A of COMT in individuals with hypercholesterolemia; and 3932T--> C of APOE and A-->G of TNFSF4 in diabetic individuals. Polymorphisms associated with ACI may thus differ between women and men as well as among individuals with different risk factors. Stratification of subjects on the basis of sex or conventional risk factors for atherosclerosis may therefore be important in order to achieve the personalized prevention of ACI with the use of genetic information.

Aged↗

PubMed2005

Platelet-activating factor enhances the expression of nerve growth factor in normal human astrocytes under hypoxia.

Nerve growth factor (NGF) is required for the survival of neurons. We have addressed the effect of platelet-activating factor (PAF), one of the mediators of ischemic injury of the brain, on NGF expression in astrocytes. Normal human astrocytes in culture were stimulated with PAF, and levels of NGF mRNA and protein were analyzed by reverse transcription-polymerase chain reaction (RT-PCR), real-time quantitative PCR and enzyme-linked immunosorbent assay (ELISA). PAF increased the expressions of NGF mRNA and protein in astrocytes in time- and concentration-dependent manners. After 48-h stimulation, 10 nmol/L PAF increased the levels of NGF protein in astrocyte-conditioned medium by 1.4-fold. The PAF-induced stimulation of NGF expression was further enhanced (2.1-fold of the control) in the cells under hypoxic culture condition. BN52021 (Ginkgolide B), an antagonist for PAF binding sites, suppressed the effect of PAF. We conclude that PAF enhances NGF gene expression in human astrocytes, and the PAF-induced increase in the expression of NGF under hypoxia may benefit the protection of the nervous tissue by promoting neuronal survival.

Astrocytes↗

PubMed2005

Nocturnal blood pressure decrease is associated with increased regional cerebral blood flow in patients with a history of ischemic stroke.

BACKGROUND: It remains controversial whether there is a J-shaped relationship between blood pressure and recurrent stroke among patients with a recent history of ischemic stroke. OBJECTIVE: To investigate the relationship between regional cerebral blood flow (rCBF) and the dipping of nocturnal blood pressure in patients receiving antihypertensive treatment after ischemic stroke. METHODS AND RESULTS: Forty-seven patients with a previous history of ischemic stroke and 37 patients with a history of non-ischemic stroke underwent 24-h ambulatory blood pressure monitoring and rCBF measurement with single photon emission computed tomography. Of the 47 patients with ischemic stroke, 30 were diagnosed as having suffered atheromatous or embolic stroke, and 37 had an ischemic lesion in the territory of the carotid artery. Systolic and diastolic blood pressures during daytime and night-time were controlled at less than 140/90 mmHg by a low-salt diet or long-acting antihypertensive agents, or both. In patients with ischemic stroke, there were significant negative correlations between the percentage change in nocturnal blood pressure and rCBFs in the thalamus (r = -0.33, P = 0.02), putamen (r = -0.34, P = 0.02) and cerebral cortex (r = -0.31, P = 0.03). Multivariate analysis revealed that only the percentage change in nocturnal blood pressure was related to rCBF. There was a significant positive correlation between rCBFs in the thalamus and the cerebral cortex (r = 0.74, P < 0.05). In patients with non-ischemic stroke, there was no significant correlation between the percentage change in nocturnal blood pressure and rCBFs. CONCLUSIONS: These findings indicate that the decrease in nocturnal blood pressure is associated with the increase in rCBF in patients with a history of ischemic stroke in the territory of the carotid artery.

Adult↗

PubMed2003

Coagulation-fibrinolysis abnormalities in patients receiving antiparkinsonian agents.

Neuroleptic malignant syndrome (NMS) is induced by alteration of medication in Parkinson's disease (PD); and blood coagulation disorder is regarded as one of the mechanisms implicated in NMS. We have studied markers of blood coagulation and fibrinolysis in 270 patients with PD and 159 healthy controls matched in age and gender. The average values of prothrombin time (international normalized ratio) and plasma levels of prothrombin fragment(1+2), D-dimer, plasmin-alpha 2 antiplasmin complex, thrombomodulin and E-selectin were higher in patients receiving antiparkinsonian agents as compared to the patients without any medication or healthy controls. The effect of antiparkinsonian drugs was analyzed by dividing the patients into three groups according to the medication: the patients under the combination therapy with levodopa and a dopamine agonist, the patients administered levodopa, and those that received a dopamine agonist. Of the three groups, the patients under the combination therapy had the highest values of these markers, and those treated with only levodopa had the lowest values. PD patients receiving antiparkinsonian drugs are often associated with blood coagulation abnormalities, and plasma hemostatic markers should be routinely assessed in the management of such patients. Further study is needed to determine whether these abnormalities predispose to the development of NMS.

Aged↗

PubMed2003

Amelioration of osteoporosis and hypovitaminosis D by sunlight exposure in stroke patients.

BACKGROUND: The authors' previous investigations have disclosed low serum 25-hydroxyvitamin D (25-OHD) concentrations in 45 patients during long-term hospitalization following stroke (mean 5.9 ng/mL). This 25-OHD deficiency resulted from sunlight deprivation. OBJECTIVE: To evaluate the efficacy of sunlight exposure in increasing serum 25-OHD, in reducing the severity of osteoporosis in bone mineral density (BMD), and in decreasing the risk of hip fractures in chronically hospitalized, disabled stroke patients. METHODS: In a 12-month randomized and prospective study of stroke patients, 129 received regular sunlight exposure for 12 months, and the remaining 129 (sunlight-deprived) did not. RESULTS: At baseline, patients of both groups showed vitamin D deficiency. BMD increased by 3.1% in the sunlight-exposed group and decreased by 3.3% in the sunlight-deprived group (p = 0.0001). 25-OHD level increased by fourfold in the sunlight-exposed group. Six patients sustained hip fractures on the hemiplegic side in the sunlight-deprived group, and one hip fracture occurred among the sunlight-exposed group (p = 0421; odds ratio = 6.1). CONCLUSION: Sunlight exposure can increase the BMD of vitamin D-deficient bone by increasing 25-OHD concentration.

Aged↗

PubMed2003

Muscular atrophy in the hemiplegic thigh in patients after stroke.

OBJECTIVES: This study evaluated muscular atrophy in the hemiplegic limbs by assessing the muscle volume of the thighs in stroke patients. DESIGN: Muscle volume of the bilateral thighs was determined by computed tomographic scanning in 50 hemiplegic patients after stroke. RESULTS: The average muscle volume in the hemiplegic side was significantly lower than that in the nonhemiplegic side. When the patients were divided into the two groups aged <65 yr old and >/=65 yr, age-dependent reduction in the muscle volume was significant only in the nonhemiplegic side. In addition, the ratio of the muscle volume in hemiplegic side to that in non-hemiplegic side was lower in the younger group than in the older group, with close to significance (P = 0.07). Muscle volume in both hemiplegic and nonhemiplegic sides correlated positively with Barthel index and negatively with patient age. CONCLUSION: Muscle volume decreases in the hemiplegic side in stroke patients.

Age Factors↗

PubMed2002

Hyperhomocysteinemia in Japanese patients with convalescent stage ischemic stroke: effect of combined therapy with folic acid and mecobalamine.

Hyperhomocysteinemia is considered to be a risk factor for vascular diseases including ischemic stroke. It has been shown that plasma homocysteine level can be lowered by folic acid supplementation. Vitamin B(12) may be also beneficial when included in the supplement regimen with folic acid. We have examined in Japanese patients with ischemic stroke the homocysteine-lowering potential of a combination therapy with folic acid and vitamin B(12). Patients with ischemic stroke were randomized into three groups and each group received vitamin B(12) (1500 microg/day, n = 63), folic acid (5 mg/day, n = 64), or both vitamin B(12) and folic acid (n = 64) for 8 weeks. Plasma levels of homocysteine and these vitamins were followed. Significant reduction in plasma homocysteine was observed in all three groups, and the combination therapy yielded the most remarkable result, i.e., plasma total homocysteine was reduced by 38.5% and this was significantly larger than the reduction in other two groups (22.4% and 10.9% in the groups received folic acid and vitamin B(12), respectively). Vitamin B(12) synergizes with folic acid in reducing plasma homocysteine in Japanese patients with ischemic stroke and the combined therapy may be particularly effective in the secondary prevention.

Aged↗

PubMed2002

Effect of losartan on nocturnal blood pressure in patients with stroke: comparison with angiotensin converting enzyme inhibitor.

BACKGROUND: Treatment of nocturnal hypertension has been reported to be beneficial for primary and secondary prevention of stroke. We compared the effects of angiotensin II antagonist (losartan) and angiotensin converting enzyme inhibitor (quinapril) on nocturnal blood pressure (BP) and sympathetic nervous activity in patients with hypertension and stroke. METHODS: According to a prospective, randomized, cross-over design, 30 hypertensive patients with a previous history of stroke (25 hemorrhage, 5 infarction) were assigned randomly to receive losartan (50 mg) or quinapril (10 mg) once daily for 4 weeks. The patients were switched to the alternative regimen for an additional 4-week period. In the last week of each treatment, 24-h ambulatory BP monitoring was performed every 30 min, and 24-h urine was collected for the measurement of catecholamine. RESULTS: Neither systolic nor diastolic BP during daytime differed between losartan and quinapril treatments, but those during nighttime were lower with losartan treatment than with quinapril treatment. The nocturnal decreases in systolic and diastolic BP were both greater with losartan treatment than with quinapril treatment (systolic BP: 6.1% +/- 5.9% v 2.5% +/- 6.9%, diastolic BP: 6.4% +/- 6.5% v 3.3% +/- 7.8%, both P <.05). The nocturnal decrease in urinary norepinephrine excretion was greater with losartan treatment than with quinapril treatment (52.8% +/- 9.7% v 42.8% +/- 17.2%, P <.05). CONCLUSIONS: Losartan enhances the nocturnal decrease in ambulatory BP compared with that of quinapril in patients with a previous history of stroke presumably by way of the suppression of nocturnal sympathetic nervous activity.

Adult↗