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Biomedical subjects

Masashi Tanaka

Publications and source records attributed to Masashi Tanaka.

At least 73 records · Page 4Linked to original sources
PubMed2003

Association of the mitochondrial DNA 15497G/A polymorphism with obesity in a middle-aged and elderly Japanese population.

Although polymorphism of the mitochondrial DNA 15497guanine/adenine (Mt15497G-->A) leads to the Gly251Ser amino acid replacement on human cytochrome b, it is unknown whether functional alteration of the mitochondrion is induced by the Gly251Ser replacement. To see if an association exists between the Mt15497G-->A polymorphism and obesity, we examined differences in body size, body composition, and regional body fat distribution between the two genotypes in middle-aged and elderly Japanese individuals (825 women and 906 men). The Mt15497 genotype was determined with an automated colorimetric allele-specific DNA probe assay system using the polymerase chain reaction (PCR) method. The Mt15497G-->A polymorphism was detected in 3.5% ( n=60) of all subjects: 2.8% ( n=23) among women and 4.1% ( n=37) among men. After adjusting for age and smoking, we found that body weight, body mass index, waist and hip circumferences, fat mass, fat-free mass, intra-abdominal fat and triglycerides were significantly greater in women with the A allele compared with the G allele ( p=0.001-0.025). For men, waist to hip ratio was significantly greater ( p=0.032), and waist circumference, intra-abdominal fat and triglycerides had a trend to be significantly greater ( p=0.062-0.087) in subjects with the A allele compared with the G allele. These data suggest that the Mt15497 polymorphism may be associated with obesity-related variables and lipid metabolism.

Absorptiometry, Photon↗
PubMed2003

Prediction of genetic risk for hypertension.

Although genetic epidemiological 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. Large-scale association studies that examine many gene polymorphisms simultaneously are required to predict genetic risk for hypertension. The population of the present study comprised 1940 unrelated Japanese individuals, including 1067 subjects with hypertension (574 men, 493 women) and 873 controls (533 men, 340 women). The genotypes for 33 single nucleotide polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that 2 polymorphisms (825C-->T in the G protein beta3 subunit gene and 190G-->A in the CC chemokine receptor 2 gene) were significantly associated with hypertension in men and that one polymorphism (-238G-->A in the tumor necrosis factor alpha gene) was significantly associated with hypertension in women. These results suggest that 2 and 1 genes may be susceptibility loci for hypertension in Japanese men and women, respectively, and that genotyping of these polymorphisms may prove informative for prediction of the genetic risk for hypertension.

Aged↗
PubMed2003

Association of a polymorphism of the phospholipase D2 gene with the prevalence of colorectal cancer.

Phospholipase D plays an important role in transmembrane signaling in a variety of cell types and its activity is increased in certain cancers, suggesting that it also contributes to tumorigenesis. A C-->T transition at nucleotide 1814 of the human phospholipase D(2) gene, which results in a Thr-->Ile substitution at amino acid 577, was noted in the GenBank database. The relationship of this polymorphism to the prevalence of cancer of the esophagus, stomach, colon-rectum, lung, and breast in Japanese was investigated in a case-control study. The genotype of the phospholipase D(2) gene was determined by the polymerase chain reaction with confronting two-pair primers. Multivariate logistic regression analysis with adjustment for age, gender, and smoking status revealed that the frequency of the T allele of the 1814C-->T polymorphism was significantly higher in individuals with colorectal cancer than in controls. A significant association of the polymorphism with the prevalence of colorectal cancer was found in analyses assuming either dominant (TT+CT vs. CC) or additive (CT vs. CC) effects of the T allele, but the T allele was not associated with the prevalence of esophageal, gastric, lung, or breast cancer. The activities of phospholipase D in cell lysates or membrane fractions did not differ between cells transfected with cDNAs encoding the Thr-577 or Ile-577 variants of phospholipase D(2). These results suggest that the phospholipase D(2) gene is a susceptibility locus for colorectal cancer in Japanese individuals, although a functional effect of the 1814C-->T (Thr577Ile) polymorphism was not detected.

Colorectal Neoplasms↗
PubMed2003

Platelet dysfunction in acute type A aortic dissection evaluated by the laser light-scattering method.

OBJECTIVES: Platelet dysfunction contributes to bleeding tendency in acute type A aortic dissection. Particle counting by new laser light-scattering methods more accurately quantifies changes in the number of different-sized platelet aggregates than do conventional optical density methods. We studied platelet aggregation kinetics and patterns of aggregation deficiency in acute-phase aortic dissection with laser light scattering. METHODS: Blood from 20 acute type A aortic dissection patients undergoing surgery was sampled during acute (9.1 +/- 6.8 hours from onset) and chronic (postoperative day 20, control) phases of aortic dissection. Platelet count and aggregability were assessed by optical density and laser light-scattering methods after aggregation was induced (addition of 2.0 microg/mL collagen to samples). RESULTS: Optical density showed significant reduction in acute-phase platelet aggregation (acute vs chronic: 65 +/- 27% vs 77 +/- 17%, P <.03). Laser light scattering showed significant reduction in medium (25-50 microm) and large (50-70 microm) but not small aggregate (9-25 microm) generation (acute vs chronic: small, 1.2 +/- 0.6 x 10(7) vs 1.5 +/- 1.0 x 10(7), NS; medium, 0.6 +/- 0.3 x 10(7) vs 1.1 +/- 0.5 x 10(7), P <.001; large, 1.4 +/- 1.2 x 10(7) vs 2.6 +/- 1.7 x 10(7), P <.001). Acute- versus chronic-phase platelet counts were significantly decreased (1.7 +/- 0.1 x 10(5)/microL vs 3.6 +/- 0.3 x 10(5)/microL, P <.001). CONCLUSIONS: Platelet aggregation is suppressed in acute-phase aortic dissection. This suppression does not occur in the initial phase of small aggregate formation; rather, it occurs during the conglomeration of small aggregates into larger aggregates.

Acute Disease↗
PubMed2003

Significance of capsular attachment and invasion of cancer tissues in prostate cancer.

BACKGROUND: There is a discrepancy in tumor node metastasis (TNM) staging of capsular attachment and invasion; the condition was classified as pT3 in 1987, then as pT2 in 1992. Because capsular finding associated with radical prostatectomy is an important prognostic factor, the present study was conducted to characterize clinicopathological states of cancer tissues attached to and invading the capsule. METHODS: Specimens removed by radical prostatectomy exhibiting pT2 or pT3 from 90 patients who did not receive any treatment before surgery were classified as Loc (24%, cancer tissues localized and apart from capsule), Inv (59%, attached to and invading but not penetrating capsule) and Pen (17%, penetrating capsule). Their clinicopathological profiles were examined. RESULTS: Gleason score, volume of cancer tissues, seminal vesicle invasion, positive surgical margin and regional lymph node metastasis of Inv were distributed between those of Loc and Pen. Postoperative management was decided as routine check-up or endocrine therapy according to pathological findings. Median follow-up was 59 months. Prostate-specific antigen (PSA) relapse occurred in 13 patients, one of whom died of prostate cancer. The remaining of these patients lived. Rate of PSA relapse was not different between Loc and Inv, mainly due to endocrine therapy to Inv with high risk factors. CONCLUSION: Pathological profile of Inv lies between those of Loc and Pen. Therefore, pT2a (1997) would be subclassified as Loc and Inv. Patients with Inv may be required to receive the respective management according to clinicopathological profile, which would be different to that of Loc.

Aged↗
PubMed2003

[Stage A prostate cancer: comparison of subclassification between Japanese rule and TNM, and outcome].

Between 1980 and June, 2002, transurethral resection of prostate was performed against 3294 cases of benign prostatic hyperplasia, and 144 cases of stage A cancer were detected (4.4%). Among these cases, 136 cases which had complete records of examination were studied. Annual number of stage A and A1:A2 ratio were not influenced by introducing PSA determination from 1991, although the number of T1c has been increasing gradually. Since subclassification of stage A is different between Japanese rules (A1; 3 chips of cancer with well-differentiated adenocarcinoma, A2; others) and TNM (T1a; 5% of less number of chips with cancer, T1b; others), two criteria were compared. Coincidence was found with 93.7%, and disagreement was due to ratio of number of chips with cancer to whole number resected, or different grade. The former difference was caused by a larger or smaller prostate. Most cases of A1 and A2 were subjected to watchful waiting or subsequent therapy. PSA was elevated in 10 cases (7%), two of which died from progression of cancer. Other cases were disease-free. Individual pathological findings are important for subclassification of stage A.

Adenocarcinoma↗
PubMed2002

Prediction of the risk of myocardial infarction from polymorphisms in candidate genes.

BACKGROUND: Although epidemiologic studies have suggested that several genetic variants increase the risk of myocardial infarction, large-scale association studies that examine many polymorphisms simultaneously are required to allow reliable prediction of the genetic risk of myocardial infarction. METHODS: We used a fluorescence- or colorimetry-based allele-specific DNA-primer-probe assay system to determine the genotypes of 112 polymorphisms of 71 candidate genes in 2819 unrelated Japanese patients with myocardial infarction (2003 men and 816 women) and 2242 unrelated Japanese controls (1306 men and 936 women). RESULTS: In an initial screening of the 112 polymorphisms for an association with myocardial infarction in 909 subjects, 19 polymorphisms were selected in men and 18 in women by means of logistic-regression analysis, after adjustment for age, body-mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia. In a large-scale study involving the selected polymorphisms and the remaining 4152 subjects, similar logistic-regression analysis revealed that the risk of myocardial infarction was significantly associated with the C1019T polymorphism in the connexin 37 gene (P<0.001) in men and the 4G-668/5G polymorphism in the plasminogen-activator inhibitor type 1 gene (P<0.001) and the 5A-1171/6A polymorphism in the stromelysin-1 gene (P<0.001) in women. CONCLUSIONS: Determination of the genotypes of the connexin 37, plasminogen-activator inhibitor type 1, and stromelysin-1 genes may prove reliable in predicting the genetic risk of myocardial infarction and might thus contribute to the primary prevention of this condition.

Case-Control Studies↗
PubMed2002

Golden mean to longevity: rareness of mitochondrial cytochrome b variants in centenarians but not in patients with Parkinson's disease.

To test the hypothesis that centenarians are free from deleterious mitochondrial variations, we analyzed amino acid variations in the cytochrome b molecule of 64 Japanese centenarians. Although the frequencies of some variations, such as N260D and G251S, differed significantly between centenarians and patients with Parkinson's disease, the most striking feature of centenarian cytochrome b was the rareness of amino acid variations in contrast to the variety of amino acid replacements in patients with Parkinson's disease. These results suggest that centenarians are genetically hitting the "golden mean" (less variation from the consensus cytochrome b sequence or less mismatch with other subunits). A multiplex detection system for various deleterious variations in combination with genetic tests for longevity-associated genotypes will be necessary to predict longevity or age-related diseases.

Adult↗
PubMed2002

Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction.

Inflammatory conditions are associated with tumor development. IL-1beta is a multifunctional and proinflammatory cytokine that affects nearly all types of cells. To investigate the role of IL-1beta in tumor growth in vivo, we transduced the retroviral vector coding human IL-1beta gene into mouse Lewis lung carcinoma (LLC) cells and subsequently inoculated the transformant (LLC/IL-1beta) to syngeneic C57BL/6 mice. Tumors derived from LLC/IL-1beta grew faster (240%, day 18, vs null-vector control LLC/neo; p < 0.01) and showed more abundant vasculature (250%, vs LLC/neo; p < 0.05), whereas LLC/IL-1beta cells, LLC/neo cells, and wild-type LLC cells did not show any significant difference in the growth rate in vitro. As compared with LLC/neo cells, LLC/IL-1beta cells secreted 2-fold the amount of vascular endothelial growth factor and >10-fold the amount of macrophage-inflammatory protein-2 (CXCL2), one of whose main functions is angiogenesis. Although LLC/IL-1beta itself did not secrete hepatocyte growth factor (HGF), the tumor derived from LLC/IL-1beta cells also contained a >4-fold higher concentration of HGF, another angiogenic factor. In situ hybridization of HGF mRNA in LLC/IL-1beta tumor sections demonstrated that stromal fibroblasts and infiltrating cells overexpressed HGF mRNA. Moreover, when cultured in the presence of HGF in vitro, LLC/IL-1beta cells secreted even larger amounts of vascular endothelial growth factor and macrophage-inflammatory protein-2. The antiangiogenic agent TNP-470 and anti-CXCR2 Ab inhibited the tumor growth of LLC/IL-1beta cells in vivo. These results indicated that secreting IL-1beta into the tumor milieu induces several angiogenic factors from tumor and stromal cells and thus promotes tumor growth through hyperneovascularization.

Angiogenesis Inducing Agents↗
PubMed2002

Mitochondrial ATPase subunit 6 and cytochrome B gene polymorphisms in young obese adults.

We hypothesized that the mutational strand asymmetry is more strongly exerted upon the mitochondrial cytochrome b (Cytb) gene, which is distant from the origin of the light-strand replication (Ori(L)), than upon the ATPase subunit 6 (ATP6) gene, which is close to the Ori(L). To test this hypothesis, we determined the sequences of these two genes in 96 Japanese young obese adults. The frequency of G-->A transitions was significantly higher than that of C-->T transitions in the Cytb gene, whereas the frequencies of G-->A and C-->T transitions were not significantly different in the ATP6 gene. The marked mutational strand asymmetry in the Cytb gene can be explained by the deamination of C to uracil in the long single-stranded state of the heavy strand during replication. The ratio of the nonsynonymous substitutions at the second codon positions to those at the first codon positions was significantly lower in the Cytb gene than in the ATP6 gene. The physicochemical differences between the standard and the replaced amino acid residues were significantly smaller in the Cytb gene than in ATP6 one. The present study indicates that amino acid sequences are less variable for Cytb than for ATP6 in spite of the strong mutational strand asymmetry for the Cytb gene.

Adenosine Triphosphatases↗
PubMed2002

Gene transfer of thromboxane A(2) synthase and prostaglandin I(2) synthase antithetically altered tumor angiogenesis and tumor growth.

Cyclooxygenase, involved in tumor growth and angiogenesis, converts arachidonic acid to prostaglandin (PG)H(2), which is immediately converted to bioactive prostanoids including PGE(2), PGD(2), thromboxane (TX)A(2) and PGI(2). To test the hypothesis that changes in the prostanoid profile alter cancer growth, we transduced the retroviral vectors carrying TXA(2) synthase cDNA or PGI(2) synthase cDNA to colon-26 adenocarcinoma cells and subsequently inoculated each transformant to syngeneic BALB/c mice. Tumors derived from TXA(2) synthase transformants grew faster (280%, day 8, versus null-vector control; P < 0.05) and showed more abundant vasculature (204%, versus null-vector control; P < 0.01), whereas tumors from PGI(2) synthase transformants presented opposite effects. These effects by the transgenes were reversed by administration of specific inhibitors. These results suggest that the profile of downstream metabolites of cyclooxygenase in cancer cells can be a determinant for tumor development.

Adenocarcinoma↗
PubMed2002

Cardiac surgery in patients aged 80 years and older.

OBJECTIVE: We studied disease and surgical outcomes in an 80-plus age group to determine the feasibility of cardiac surgery at this age. METHODS: Between January 1991 and August 2000, we statistically analyzed 19 variables in 62 consecutive cases of cardiac surgery in the 80-plus age group to predict in-hospital and long-term mortality. Cases were classified by disease type (ischemic heart disease (IHD), n = 39; valvular heart disease (VHD) n = 19; and mechanical complications associated with acute myocardial infarction, n = 4; and by surgical status (emergency, n = 6; urgent, n = 10; and elective, n = 46). We compared these with 370 patients 70 to 79 years undergoing similar procedures during the same interval. RESULTS: No significant difference was seen between groups in total in-hospital mortality--9.7% vs. 3.8%--or in-hospital mortality for IHD--2.6% vs. 4.2%--or VHD--10.5% vs. 2.8%. We found cardiopulmonary bypass time > 150 min. and dialysis to be independent risk factors for hospital death. Actuarial survival at 7.5 years overall was 39% in the 80-plus age group vs. 53% in the 70-79 age group for VHD and 38% in the 80-plus age group vs. 62% in the 70-79 age group. No significant difference was seen in survival between groups for IHD. Stroke proved to be an independent prognostic factor. CONCLUSIONS: Cardiac surgery is conducted feasibly in selected octogenarians, providing acceptable mortality and results similar to those achieved in those 70 to 79 years old.

Aged↗
PubMed2002

Infected left atrial myxoma with mitral valve endocarditis.

We report a rare case of infected left atrial myxoma associated with mitral valve endocarditis. The tumor and a small amount of vegetative growth on the anterior mitral leaflet were surgically excised. Subsequent antibiotic therapy may have prevented the infection from recurring. Histological findings showed myxoma cells embedded in mucinous stroma at the tumor base and an organized thrombus with bacterial colonization at the tumor tip.

Aged↗
PubMed2002

Mitochondrial genotypes and cytochrome b variants associated with longevity or Parkinson's disease.

We are currently sequencing the entire mitochondrial genome from 600 persons, including centenarians, patients with Parkinson's disease or diabetes, and young adults with or without obesity to search for single nucleotide polymorphisms (SNPs) associated with longevity or diseases. To test the hypothesis that centenarians are free from deleterious mitochondrial variations, we analyzed amino acid variations in cytochrome b of 64 Japanese centenarians. Although the frequencies of some variations, such as N260D and G251S, differed significantly between centenarians and patients with Parkinson's disease, the most striking feature of centenarian cytochrome b was the much greater scarceness of amino acid variations in contrast with the variety of amino acid replacements in patients with Parkinson's disease. Particular deviations from the standard amino acid sequence may be associated with increased production by mitochondria of reactive oxygen species. The absence of certain variations in centenarians and their presence in patients with Parkinson's disease indicate that these variations do not benefit long-term survival but do predispose to adult-onset diseases and that centenarians are genetically hitting the "golden mean."

Adult↗
PubMed2002

Association of a polymorphism of the transforming growth factor-beta1 gene with blood pressure in Japanese individuals.

Transforming growth factor-beta1 (TGF-beta1) is an important regulator of blood pressure (BP) and vascular remodeling, and thus may contribute to the pathogenesis of hypertension. A T-->C transition at nucleotide 869 of the TGF-beta1 gene results in a Leu-->Pro substitution at amino acid 10 of the signal peptide. We have now examined the possible association of the 869T-->C polymorphism of the TGF-beta1 gene with BP and the prevalence of hypertension in 2241 community-dwelling Japanese individuals (1126 men and 1115 women). TGF-beta1 genotype was determined by an allele-specific polymerase chain reaction method. For women, both systolic and diastolic BP was significantly higher in individuals with the CC genotype than in those with the TT or TC genotype. No significant association between TGF-beta1 genotype and BP was detected in men. The frequency of the CC genotype was significantly higher in women with hypertension than in those with normal BP. These results suggest that the TGF-beta1 gene at chromosome 19q13.1 may be a candidate susceptibility locus for hypertension in Japanese women.

Adult↗
PubMed2002

Reduction in the extent of atherosclerosis in apolipoprotein E-deficient mice induced by electroporation-mediated transfer of the human plasma platelet-activating factor acetylhydrolase gene into skeletal muscle.

The effect of increasing the activity of plasma platelet-activating factor (PAF) acetylhydrolase (AH) (PAF-AH) on the progression of atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice was examined by gene delivery to skeletal muscle. The expression vector pcDNA3.1 containing either human PAF-AH cDNA (pcDNA/PAF-AH) or green fluorescent protein cDNA (pcDNA/GFP) was introduced into the skeletal muscle of both hind legs of 6-week-old apoE(-/-) mice by electroporation. The activity of PAH-AH in plasma was significantly increased 4-16 weeks after electroporation of apoE(-/-) mice with 120 microg of pcDNA/PAF-AH; the maximal (2.5-fold) increase was apparent after 8 weeks. The mean thickness of the aortic wall, determined by 160 measurements in each mouse, was significantly reduced in apoE(-/-) mice 8-16 weeks after exposure to pcDNA/PAF-AH compared with that in corresponding control animals that received pcDNA/GFP. These results suggest that the electrotransfer of the plasma PAF-AH gene to skeletal muscle reduces the extent of atherosclerosis in apoE(-/-) mice.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2002

Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria.

The restriction endonuclease SmaI has been used for the diagnosis of neurogenic muscle weakness, ataxia and retinitis pigmentosa disease or Leigh's disease, caused by the Mt8993T-->G mutation which results in a Leu156Arg replacement that blocks proton translocation activity of subunit a of F(0)F(1)-ATPase. Our ultimate goal is to apply SmaI to gene therapy for this disease, because the mutant mitochondrial DNA (mtDNA) coexists with the wild-type mtDNA (heteroplasmy), and because only the mutant mtDNA, but not the wild-type mtDNA, is selectively restricted by the enzyme. For this purpose, we transiently expressed the SmaI gene fused to a mitochondrial targeting sequence in cybrids carrying the mutant mtDNA. Here, we demonstrate that mitochondria targeted by the SmaI enzyme showed specific elimination of the mutant mtDNA. This elimination was followed with repopulation by the wild-type mtDNA, resulting in restoration of both the normal intracellular ATP level and normal mitochondrial membrane potential. Furthermore, in vivo electroporation of the plasmids expressing mitochondrion-targeted EcoRI induced a decrease in cytochrome c oxidase activity in hamster skeletal muscles while causing no degenerative changes in nuclei. Delivery of restriction enzymes into mitochondria is a novel strategy for gene therapy of a special form of mitochondrial diseases.

Apoptosis↗