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Articles by H Takahashi
Total Records ( 13 ) for H Takahashi
  H Horigome , M Nagashima , N Sumitomo , M Yoshinaga , H Ushinohama , M Iwamoto , J Shiono , K Ichihashi , S Hasegawa , T Yoshikawa , T Matsunaga , H Goto , K Waki , M Arima , H Takasugi , Y Tanaka , N Tauchi , M Ikoma , N Inamura , H Takahashi , W Shimizu and M. Horie

Background— Data on the clinical presentation and genotype-phenotype correlation of patients with congenital long-QT syndrome (LQTS) diagnosed at perinatal through infantile period are limited. A nationwide survey was conducted to characterize how LQTS detected during those periods is different from that in childhood or adolescence.

Methods and Results— Using questionnaires, 58 cases were registered from 33 institutions. Diagnosis (or suspicion) of LQTS was made during fetal life (n=18), the neonatal period (n=31, 18 of them at 0 to 2 days of life), and beyond the neonatal period (n=9). Clinical presentation of LQTS included sinus bradycardia (n=37), ventricular tachycardia/torsades de pointes (n=27), atrioventricular block (n=23), family history of LQTS (n=21), sudden cardiac death/aborted cardiac arrest (n=14), convulsion (n=5), syncope (n=5), and others. Genetic testing was available in 41 (71%) cases, and the genotype was confirmed in 29 (71%) cases, consisting of LQT1 (n=11), LQT2 (n=11), LQT3 (n=6), and LQT8 (n=1). Ventricular tachycardia/torsades de pointes and atrioventricular block were almost exclusively observed in patients with LQT2, LQT3, and LQT8, as well as in those with no known mutation. In LQT1 patients, clues to diagnosis were mostly sinus bradycardia or family history of LQTS. Sudden cardiac death/aborted cardiac arrest (n=14) was noted in 4 cases with no known mutations as well as in 4 genotyped cases, although the remaining 6 did not undergo genotyping. Their subsequent clinical course after aborted cardiac arrest was favorable with administration of β-blockers and mexiletine and with pacemaker implantation/implantable cardioverter-defibrillator.

Conclusions— Patients with LQTS who showed life-threatening arrhythmias at perinatal periods were mostly those with LQT2, LQT3, or no known mutations. Independent of the genotype, aggressive intervention resulted in effective suppression of arrhythmias, with only 7 deaths recorded.

  H Ishii , T Toriyama , T Aoyama , H Takahashi , T Amano , M Hayashi , M Tanaka , Y Kawamura , Y Yasuda , Y Yuzawa , S Maruyama , S Matsuo , T Matsubara and T. Murohara

Background— Percutaneous coronary intervention (PCI) using drug-eluting stents significantly reduces the risk of restenosis in the general population. However, in patients on hemodialysis, adverse cardiac events are frequently seen even if treated with drug-eluting stents. Recent studies suggest that C-reactive protein (CRP) reflects vascular wall inflammation and can predict adverse cardiac events. We evaluated possible prognostic values of CRP on outcomes in patients on hemodialysis undergoing PCI with drug-eluting stents.

Methods and Results— A total of 167 patients undergoing PCI with sirolimus-eluting stents for stable angina (322 lesions) were enrolled. They were divided into tertiles according to serum CRP levels. We analyzed the incidence of major adverse cardiovascular events including cardiovascular death, nonfatal myocardial infarction, and target lesion revascularization after PCI as well as quantitative coronary angiographic data. The mean follow-up was 31 months (SD, 14). Major adverse cardiac events occurred in 11 patients (19.6%) of the lowest tertile, in 22 patients (39.3%) of the middle tertile, and in 28 patients (50.9%) of the highest tertile during follow-up period (P=0.0009). There was a progressive increase in neointimal growth after sirolimus-eluting stent implantation during follow-up because preprocedural CRP levels were higher, despite similar angiographic data just after PCI. Angiographic restenosis at 6 to 8 months after PCI was seen in 10.6% in the lowest tertile, 17.9% in the middle tertile, and 32.0% in the highest tertile (P=0.0007).

Conclusions— Increased preprocedural serum CRP levels would predict higher major adverse cardiac events and restenosis rates after sirolimus-eluting stents implantation in patients on hemodialysis.

  S Yamada , H Ishii , H Takahashi , T Aoyama , Y Morita , H Kasuga , K Kimura , Y Ito , R Takahashi , T Toriyama , Y Yasuda , M Hayashi , H Kamiya , Y Yuzawa , S Maruyama , S Matsuo , T Matsubara and T. Murohara

Background and objectives: Cardiac failure is directly affected by left ventricular (LV) dysfunction, and particularly LV systolic dysfunction is strongly associated with survival in ESRD patients. The aim of this study was to determine the prognostic value of reduced LV ejection fraction (LVEF) measured at the time of initiation of hemodialysis (HD) in incident HD patients.

Design, setting, participants, & measurements: 1254 consecutive ESRD patients who electively started HD therapy were screened by echocardiography within 1 month after its inception. They were divided into five groups according to LVEF levels with a decrease of 0.1 each and were followed up for up to 7 years. Survival was examined with the Kaplan-Meier method and compared using the log-rank test.

Results: Among the 1254 patients, LVEF levels ≥0.6, 0.5 to 0.6, 0.4 to 0.5, 0.3 to 0.4, and <0.3 were seen in 842 (67.1%), 247 (19.7%), 107 (8.5%), 41 (3.3%), and 17 (1.4%) patients, respectively. On Kaplan-Meier analysis, 7-year event-free rates from cardiovascular death were 84.2, 83.7, 73.6, 59.4, and 30.9% in order of groups with decreasing LVEF of 0.1 each, respectively. Seven-year event-free rates from all-cause death were 69.2, 61.7, 57.1, 45.9, and 23.1% in the respective groups. Even after adjustment for other risk factors, decreasing LVEF was a strong independent predictor for cardiovascular death.

Conclusions: Reduced LVEF on starting HD therapy could stratify risk of cardiovascular and all-cause mortality in ESRD patients. Screening by echocardiography at start of HD therapy might be recommended to predict prognosis in patients with ESRD.

  T Takeuchi , K Nishiyama , K. i Sugiura , M Takahashi , A Yamada , S Kobayashi , H Takahashi , H Natsugari and K. i. Kasai

Galβ1-4GlcNAc is thought to be a common disaccharide unit preferentially recognized by vertebrate galectins. Eight-amino-acid residues conserved in proteins belonging to the galectin family have been suggested to be responsible for recognition. Meanwhile, we isolated and analyzed endogenous N-glycans of Caenorhabditis elegans that were captured by a C. elegans galectin LEC-6 and demonstrated that the unit of recognition for LEC-6 is a Gal-Fuc disaccharide, though the linkage between these residues was not confirmed. In the present study, we chemically synthesized Galβ1-4Fuc and Galβ1-3Fuc labeled with 2-aminopyridine (PA) and demonstrated that LEC-6 interacts with PA-Galβ1-4Fuc more strongly than PA-Galβ1-3Fuc by frontal affinity chromatography (FAC). Galβ1-4Fuc also inhibited hemagglutination caused by LEC-6 more strongly than Galβ1-3Fuc. FAC analysis using LEC-6 point mutants revealed that some of the conserved amino acid residues which have proven to be important for the recognition of Galβ1-4GlcNAc are not necessary for the binding to Galβ1-4Fuc. Another major C. elegans galectin, LEC-1, also showed preferential binding to Galβ1-4Fuc. These results suggest that Galβ1-4Fuc is the endogenous unit structure recognized by C. elegans galectins, which implies that C. elegans glycans and galectins may have co-evolved through an alteration in the structures of C. elegans glycans and a subsequent conversion in the sugar-binding mechanism of galectins. Furthermore, since glycans containing the Galβ1-4Fuc disaccharide unit have been found in organisms belonging to Protostomia, this unit might be a common glyco-epitope recognized by galectins in these organisms.

  K Shida , H Korekane , Y Misonou , S Noura , M Ohue , H Takahashi , H Ohigashi , O Ishikawa and Y. Miyamoto

We have precisely analyzed the structures of glycosphingolipids of human cancer cells and normal epithelial cells using several methods, including enzymatic release of carbohydrate moieties, fluorescent labeling, and identification using 2D mapping, enzymatic digestion, and mass spectrometry. These analyses enabled the identification of novel tumor-associated carbohydrate antigens that can be used to elucidate the involvement of carbohydrates in cancer malignancy and could act as candidate tumor markers. In our previous study, we identified a novel glycosphingolipid that accumulates in colon cancer cells, NeuAc2-6(Fuc1-2)Galβ1-4GlcNAcβ1-3Galβ1-4Glc (2-6 sialylated type 2H, ST2H). Here, structural analyses of cancer cells and normal epithelial cells from 60 colorectal and five pancreatic cancer patients, including four and two Lewis-negative individuals, respectively, reveal the presence of an additional novel glycosphingolipid, NeuAc2-6(Fuc1-2)Galβ1-3GlcNAcβ1-3Galβ1-4Glc (2-6 sialylated type 1H, ST1H). ST2H was found in colorectal and pancreatic cancer cells from about half of the cases. Unlike ST2H, ST1H was found in cancer cells from three out of six Lewis-negative patients (i.e., two cases of colorectal and one case of pancreatic cancer). However, the moiety was not found in normal epithelial cells or cancer cells from 59 Lewis-positive patients. These findings suggest that the accumulation of this carbohydrate antigen occurs predominantly in cancer cells of Lewis-negative patients. When the ST1H epitope is also carried on mucins as well as glycosphingolipids, this epitope is a promising tumor marker candidate, especially for Lewis-negative individuals.

  K Sawada , H Takahashi , K Abe , T Ichii , K Watanabe and Y. Takao

Sawada, K., Takahashi, H., Abe, K., Ichii, T., Watanabe, K., and Takao, Y. 2009. Target-strength, length, and tilt-angle measurements of Pacific saury (Cololabis saira) and Japanese anchovy (Engraulis japonicus) using an acoustic-optical system. – ICES Journal of Marine Science, 66: 1212–1218.

Pacific saury and Japanese anchovy generally congregate in dense groups or schools. An acoustic-optical system (the Japanese Quantitative Echosounder and Stereo-video Camera System or J-QUEST) has been developed to measure accurately the target strength (TS) of fish in a dense school. J-QUEST comprises a quantitative, 70 kHz, split-beam echosounder and a stereo-video camera. It was deployed from a research vessel to collect concomitant measures of TS and stereo images of in situ Pacific saury and Japanese anchovy. The stereo-video camera provides estimates of the fish lengths (L) and tilt-angles corrected for J-QUEST motion. In this way, empirical models of TS vs. log(L) were derived for Pacific saury and Japanese anchovy and compared with theory.

  H Ajima , H Ogata , K. i Fujita , K Miwa , Y Sunakawa , K Mizuno , H Ishida , K Yamashita , H Nakayama , K Kawara , H Takahashi and Y. Sasaki

Recently, significant progress in treatment of metastatic colorectal cancer has been achieved. Either FOLFIRI (fluorouracil, leucovorin and irinotecan) or modified FOLFOX6 (fluorouracil, leucovorin and oxaliplatin, oxaliplatin dose 85 mg/m2) is selected as first-line therapy in clinical practice in Japan. However, economic burden of colorectal cancer is considerable.


Analysis was made for all patients who were treated with FOLFIRI or modified FOLFOX6 for metastatic colorectal cancer. Regimen of FOLFIRI was compared with modified FOLFOX6 under consideration from clinical and economic standpoints. Progression free survival, response, toxicity and cancer care cost in patients with metastatic colorectal cancer was analyzed. Direct costs based on the fee schedule of the Japanese national health insurance were calculated.


Median progression free survival was 7.7 months for FOLFIRI versus 8.4 months for modified FOLFOX6 (P = 0.48). Overall cost for first four cycles was ¥756 284 for FOLFIRI and ¥1 081 162 for modified FOLFOX6 (P < 0.0001). All grade alopecia was significantly more frequent with FOLFIRI than with modified FOLFOX6 (P = 0.04). All grade neuropathy was more observed with modified FOLFOX6 than FOLFIRI (P = 0.0002).


FOLFIRI is inexpensive in the initial stage of treatment which a number of patients can receive chemotherapy than modified FOLFOX6 as first-line therapy for metastatic colorectal cancer in Japanese national insurance system.

  J Chen , B Walker , A Sorimachi , H Takahashi and S. Tokonami

The alpha-track detector was well designed for long-term radon measurements in the 1992 Winnipeg case–control study. However, its diffusion characteristic for thoron in comparison to radon was yet unknown. An investigation on radon and thoron response of these detectors was undertaken. The results showed that the relative sensitivity between thoron and radon is 2 %, i.e. the detector sensitivity to radon is about 50 times higher than the sensitivity to thoron. It can be concluded that there was no significant influence of thoron on the radon measurements with these detectors.

  H Takahashi , A Yokota , T Takenawa and M. Iwakura

Because amino acid residues intrinsically possess many factors participating in protein structures and functions, to determine main (or unique) factors at a specific site in a protein sequence should be of great help for understanding how a protein obtains its structure and function. In this study, we proposed a means of sequence perturbation analysis to address the above concerns involving comprehensive AA indices. We constructed all 19 possible single mutant proteins as to the three sites in the C-terminal of Escherichia coli dihydrofolate reductase (DHFR), and measured the activity and thermal stability of each of all the single mutant proteins. The significantly perturbed properties with each systematic single mutation at each mutational site were examined in terms of the linear correlation with each AA index. As a result, at each of Arg158 and Arg159 of DHFR, the AA index for the isoelectric points of amino acids showed strong correlation with the transition temperature of thermal denatuation, suggesting that the electrostatic interaction is the main factor influencing the C-terminal role of the DHFR. The feasibility and general versatility of our sequence perturbation analysis were also examined by application to other sites of DHFR.

  K Shimamura , H Takahashi , H Kitazawa , Y Miyamoto , A Nagumo , C Tang , D Dean , T Nagase , N Sato and S. Tokita

ELOVL6, a member of the elongation of very long-chain fatty acids (ELOVL) family, has recently been identified as the rate-limiting enzyme for the elongation of palmitoyl-CoA. ELOVL6 deficient mice are protected from high-fat diet induced insulin resistance, suggesting that ELOVL6 might be a promising target for the treatment of metabolic disorders. Despite the increasing interest in Elovl6 as a therapeutic target, the lack of chemical tools for this enzyme has limited further elucidation of the biochemical and pharmacological properties of ELOVL6. We have identified Compound-A, a potent inhibitor for ELOVL6, by screening our company library and subsequently optimizing hit compounds. Compound-A potently inhibited human and mouse ELOVL6 and displayed >100-fold greater selectivity for ELOVL6 over other ELOVL family members. Consistent with its potent and selective inhibitory activity toward ELOVL6, [3H]Compound-A bound to ELOVL6 with high affinity while showing no specific binding to other ELOVL enzymes. The observation that [3H]Compound-A bound to ELOVL6 in a palmitoyl-CoA-dependent manner in the absence of malonyl-CoA and NADPH suggests that Compound-A might recognize an enzyme–substrate complex, e.g. an acyl–enzyme intermediate. Collectively, these observations demonstrate that Compound-A and its tritiated form are useful tools for biochemical and pharmacological characterization of ELOVL6.

  K Kobayashi , A Tanaka , H Takahashi , J Igarashi , Y Ishitsuka , N Yokota and T. Shimizu

A phosphodiesterase (PDE) from Escherichia coli (Ec DOS) is a novel haem-based oxygen sensor enzyme. Binding of O2 to the reduced haem in the sensor domain enhances PDE activity exerted by the catalytic domain. Kinetic analysis of oxygen-dependent catalytic enhancement showed a sigmoidal curve with a Hill coefficient value of 2.8. To establish the molecular mechanism underlying allosteric regulation, we analysed binding of the O2 ligand following reduction of haem in the isolated dimeric sensor domain using pulse radiolysis. Spectral changes accompanying O2 binding were composed of two phases as a result of reduction of two haem complexes when high-dose electron beams were applied. In contrast, upon reduction of the dimer with a low-dose beam, the kinetics of O2 ligation displayed single-phase behaviour as a result of the reduction of one haem complex within dimer. Based on these results, we propose that the faster phase corresponds to binding of the first O2 molecule to one subunit of the dimer, followed by binding of the second O2 molecule to the other subunit. Notably, for the haem axial ligand mutant proteins, M95A and M95L, O2 binding displayed single-phase kinetics and was independent of electron beam dose.

  Y Kayama , T Minamino , H Toko , M Sakamoto , I Shimizu , H Takahashi , S Okada , K Tateno , J Moriya , M Yokoyama , A Nojima , M Yoshimura , K Egashira , H Aburatani and I. Komuro

To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, Alox15 encoding the protein 12/15 lipoxygenase (LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that Alox15 transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in Alox15 transgenic mice with advancing age and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein 1 (MCP-1) was up-regulated in Alox15 transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenoic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells but not in cardiomyocytes. Inhibition of MCP-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in Alox15 transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac MCP-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition.

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