ORCID Profile
0000-0001-7115-9105
Current Organisation
Kumamoto University
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Publisher: MDPI AG
Date: 06-01-2015
DOI: 10.3390/IJMS16011192
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2012
DOI: 10.1002/HEP.25803
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.AHJ.2016.05.018
Abstract: End-stage renal disease is a major clinical and public health problem, and cardiovascular disease accounts for half of the mortality in hemodialysis patients. An existing mortality risk score (AROii score) or N-terminal pro-brain natriuretic peptide (NT-proBNP) level have modest predictive power, but there is room for improvement. There are emerging cardiac biomarkers (soluble isoforms of ST2 [sST2], galectin-3 [Gal-3]), and uremic toxicity (indoxyl sulfate). We sought to determine whether these biomarkers predict cardiovascular outcomes in hemodialysis patients and have incremental prognostic value over the clinical score and NT-proBNP level. A total of 423 hemodialysis patients were prospectively followed up for primary (all-cause death) and secondary end points (a composite of all-cause death or cerebrocardiovascular events). During a mean follow-up of 2.1 ± 0.4 years, there were 48 all-cause deaths and 78 composite outcomes. Soluble isoforms of ST2, Gal-3, and NT-proBNP were associated with all-cause deaths but indoxyl sulfate was not in both log-rank test and receiver operating characteristic analysis. Both sST2 and Gal-3 had independent and incremental prognostic value for both outcomes over the AROii score and NT-proBNP. Although adding sST2 did not reclassify over the model-based AROii score and NT-proBNP for all-cause death, further addition of Gal-3 did. Subgroup analyses of patients with left ventricular ejection fraction measurement (n = 301) corroborated these results, where the 2 biomarkers remained independent and incremental for both all-cause death and composite outcome after adjusting for the risk score and the ejection fraction. Both sST2 and Gal-3 had independent and incremental prognostic values over NT-proBNP and an established risk score in patients with hemodialysis. Assessment of sST2 and Gal-3 further enhances risk stratification.
Publisher: Japan Epidemiological Association
Date: 2006
DOI: 10.2188/JEA.16.214
Publisher: Portland Press Ltd.
Date: 07-12-2012
DOI: 10.1042/BJ20121286
Abstract: Coagulation FVII (Factor VII) is a vitamin K-dependent glycoprotein synthesized in hepatocytes. It was reported previously that FVII gene (F7) expression was up-regulated by ribavirin treatment in hepatitis C virus-infected haemophilia patients however, its precise mechanism is still unknown. In the present study, we investigated the molecular mechanism of ribavirin-induced up-regulation of F7 expression in HepG2 (human hepatoma cell line). We found that intracellular GTP depletion by ribavirin as well as other IMPDH (inosine-5′-monophosphate dehydrogenase) inhibitors, such as mycophenolic acid and 6-mercaptopurine, up-regulated F7 expression. FVII mRNA transcription was mainly enhanced by accelerated transcription elongation, which was mediated by the P-TEFb (positive-transcription elongation factor b) complex, rather than by promoter activation. Ribavirin unregulated ELL (eleven-nineteen lysine-rich leukaemia) 3 mRNA expression before F7 up-regulation. We observed that ribavirin enhanced ELL3 recruitment to F7, whereas knockdown of ELL3 diminished ribavirin-induced FVII mRNA up-regulation. Ribavirin also enhanced recruitment of CDK9 (cyclin-dependent kinase 9) and AFF4 to F7. These data suggest that ribavirin-induced intracellular GTP depletion recruits a super elongation complex containing P-TEFb, AFF4 and ELL3, to F7, and modulates FVII mRNA transcription elongation. Collectively, we have elucidated a basal mechanism for ribavirin-induced FVII mRNA up-regulation by acceleration of transcription elongation, which may be crucial in understanding its pleiotropic functions in vivo.
Publisher: Elsevier BV
Date: 07-2001
Abstract: There is a significant relationship between inheritance of high transforming growth factor (TGF)-beta1 and angiotensinogen-producing genotypes and the development of progressive hepatic fibrosis in patients with chronic hepatitis C. In cardiac and renal fibrosis, TGF-beta1 production may be enhanced by angiotensin II, the principal effector molecule of the renin-angiotensin system. The aim of the present study was to determine the effects of the angiotensin-converting enzyme inhibitor, captopril, on the progression of hepatic fibrosis in the rat bile duct ligation model. Rats were treated with captopril (100 mg. kg(-1). day(-1)) commencing 1 or 2 weeks after bile duct ligation. Animals with bile duct ligation only and sham-operated animals served as controls. Four weeks after bile duct ligation, indices of fibrosis were assessed. Captopril treatment significantly reduced hepatic hydroxyproline levels, mean fibrosis score, steady state messenger RNA levels of TGF-beta1 and procollagen alpha1(I), and matrix metalloproteinase 2 and 9 activity. Captopril significantly attenuates the progression of hepatic fibrosis in the rat bile duct ligation model, and its effectiveness should be studied in human chronic liver diseases associated with progressive fibrosis.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2018
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.JOCN.2015.10.043
Abstract: Although a wide range of strategies have been established to improve intravenous tissue plasminogen activator (IV-tPA) treatment rates, international benchmarking has not been regularly used as a systems improvement tool. We compared acute stroke codes (ASC) between two hospitals in Australia and Japan to study the activation process and potentially improve the implementation of thrombolysis. Consecutive patients who were admitted to each hospital via ASC were prospectively collected. We compared IV-tPA rates, factors contributing to exclusion from IV-tPA, and pre- and in-hospital process of care. IV-tPA treatment rates were significantly higher in the Australian hospital than in the Japanese (41% versus 25% of acute ischaemic stroke patients, p=0.0016). In both hospitals, reasons for exclusion from IV-tPA treatment were intracerebral haemorrhage, mild symptoms, and stroke mimic. Patients with baseline National Institutes of Health Stroke Scale score⩽5 were more likely to be excluded from IV-tPA in the Japanese hospital. Of patients treated with IV-tPA, the door-to-needle time (median, 63 versus 54minutes, p=0.0355) and imaging-to-needle time (34 versus 27minutes, p=0.0220) were longer in the Australian hospital. Through international benchmarking using cohorts captured under ASC, significant differences were noted in rates of IV-tPA treatment and workflow speed. This variation highlights opportunity to improve and areas to focus targeted practice improvement strategies.
Publisher: American Physical Society (APS)
Date: 06-07-2006
Publisher: Elsevier BV
Date: 08-2011
DOI: 10.1038/LABINVEST.2011.71
Abstract: Transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP) is characterized by systemic accumulation of amyloid fibrils caused by a point mutation in the TTR gene. Despite the urgent need for alternative therapeutic strategies, the pathogenesis of FAP still remains elusive. In our study reported here, we focused on albumin, the most abundant protein in plasma, and described the role of albumin in the TTR amyloid-formation process. Patients with FAP evidenced significantly decreased serum albumin levels as the disease progressed. Biacore analysis showed that albumin had a binding affinity for TTR and exhibited higher affinity for TTR amyloid than native TTR. Albumin functioning as an antioxidant effectively suppressed TTR amyloid formation. In patients with FAP, albumin was significantly oxidized as the disease progressed. Moreover, loss of functional albumin accelerated TTR deposition in analbuminemic rats possessing a human variant TTR gene. Taken together, these results indicate that albumin may have an inhibitory role in the TTR amyloid-formation process.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.AHJ.2015.02.003
Abstract: Although cardiovascular events in hemodialysis (HD) patients are the most frequent on the day after a long (2 days) interdialytic interval (IDT), it has been uncertain whether accumulation or elimination of large extracellular fluid volume, electrolyte, and/or uremic substances is the culprit for this. We sought to test our hypothesis that the long IDT alters echocardiographic parameters at rest and during exercise in stable maintenance HD patients compared with other IDTs. We performed a cross-sectional comparison using 1-way repeated analysis of variance or Friedman test of echocardiograms at 3 different IDTs, just after HD, after short IDT (1 day), and after long IDT, among 80 stable Japanese outpatients (age 61 ± 9 years, 60 males) on thrice weekly maintenance. End-systolic elastance (Ees), arterial elastance (Ea), and pressure-volume area (PVA) were estimated using a noninvasive single-beat technique. Ventricular-arterial coupling was assessed by Ea/Ees ratio. Measurements were repeated after 2-minute handgrip stress to evaluate cardiac reserve. Resting left ventricular end-diastolic volume index and stroke volume index were significantly larger after a 1-day IDT compared with just after HD and even more after a 2-day IDT. Although Ees, Ea, and Ea/Ees ratio at rest remained similar between short and long intervals, stroke work (SW) and PVA were higher after the long interval. During handgrip stress, a significant increase in Ea without corresponding rise in Ees was observed only after long IDT, resulting in decreased stroke volume index, SW, and SW/PVA efficiency. In a selective Japanese outpatient population on maintenance HD, there were no differences in resting cardiovascular function measured by echocardiography at 3 different IDTs. However, exercise-induced afterload mismatch assessed by the changes in Ea, SV, SW, and SW/PVA efficiency was most pronounced in in iduals after the long IDT compared with other IDTs. Our findings report potential pathophysiologic echocardiographic parameters that attempt to explain why cardiovascular events are highest on the day after the long IDT compared to other IDTs in dialysis patients.
Publisher: Wiley
Date: 21-12-2015
DOI: 10.1111/HAE.12849
Abstract: Haemophilia B is an X‐linked bleeding disorder caused by a coagulation factor IX gene ( F9 ) abnormality. Numerous F9 defects have been identified to date however, only a few with an entire F9 deletion have been reported in detail. To elucidate the cause of severe haemophilia B, we investigated the precise X chromosome abnormalities in four Japanese patients who did not show all lifications in F9 ‐specific PCR . We analysed the patient's genomic DNA using Multiplex ligation‐dependent probe lification ( MLPA ). To assess the extent of any deletions, we further performed mapping PCR s, inverse PCR s or long‐range PCR s and direct sequencing analyses of the X chromosome. We detected entire F9 deletions in four haemophilia B patients and identified the precise deleted regions of the X chromosome including F9 . Patient 1 had a 149‐kb deletion with breakpoints 90‐kb upstream and 30‐kb downstream from F9 . Patients 2 and 3 showed 273‐kb and 1.19‐Mb deletions respectively. Patient 4 had two deleted regions: a 1663‐bp deletion 1.34‐Mb upstream from F9 and a 7.2‐Mb deletion including F9 . These distinct breakpoints found in four different patients suggest that the mechanism of X chromosome deletion may be different between in iduals. Non‐allelic homologous recombination ( NAHR ), microhomology‐mediated break‐induced replication ( MMBIR ) or fork stalling and template switching (Fo ST eS) may occur in respective X chromosomes of the four haemophilia B patients analysed. We identified erse X chromosomal rearrangements in four haemophilia B patients, which might be caused by distinct mechanisms of genomic rearrangement.
Publisher: Oxford University Press (OUP)
Date: 10-2014
DOI: 10.1111/CEI.12415
Abstract: Treatment of primary biliary cirrhosis (PBC) has lagged behind that of other autoimmune diseases. In this study we have addressed the potential utility of immunotherapy using regulatory T cells (Treg) to treat murine autoimmune cholangitis. In particular, we have taken advantage of our ability to produce portal inflammation and bile duct cell loss by transfer of CD8+T cells from the dominant negative form of transforming growth factor beta receptor type II (dnTGF-βRII) mice to recombination-activating gene (Rag)1–/– recipients. We then used this robust established adoptive transfer system and co-transferred CD8+T cells from dnTGF-βRII mice with either C57BL/6 or dnTGF-βRII forkhead box protein 3 (FoxP3+) T cells. Recipient mice were monitored for histology, including portal inflammation and intralobular biliary cell damage, and also included a study of the phenotypical changes in recipient lymphoid populations and local and systemic cytokine production. Importantly, we report herein that adoptive transfer of Treg from C57BL/6 but not dnTGF-βRII mice significantly reduced the pathology of autoimmune cholangitis, including decreased portal inflammation and bile duct damage as well as down-regulation of the secondary inflammatory response. Further, to define the mechanism of action that explains the differential ability of C57BL/6 Tregversus dnTGF-βRII Treg on the ability to down-regulate autoimmune cholangitis, we noted significant differential expression of glycoprotein A repetitions predominant (GARP), CD73, CD101 and CD103 and a functionally significant increase in interleukin (IL)-10 in Treg from C57BL/6 compared to dnTGF-βRII mice. Our data reflect the therapeutic potential of wild-type CD4+FoxP3+Treg in reducing the excessive T cell responses of autoimmune cholangitis, which has significance for the potential immunotherapy of PBC.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.THROMRES.2014.07.040
Abstract: Prothrombin Yukuhashi (p.Arg596Leu) mutation can result in thrombophilia associated with antithrombin (AT) resistance. Mutant thrombin, an active form of prothrombin Yukuhashi, demonstrated moderately lower clotting activity than the wild-type but substantially impaired the formation of the complex with AT. However, the effects of the mutation on the thrombomodulin (TM)-protein C (PC) anticoagulant system have not been previously elucidated. We prepared recombinant wild-type and mutant prothrombins, converted to thrombins using Oxyuranus scutellatus venom, and performed fibrinogen-clotting assays with or without recombinant soluble TM (rTM). We also evaluated activated PC (APC) generation activity of recombinant thrombins by measuring APC activity after incubation with human PC in the presence or absence of rTM. rTM treatment reduced the relative fibrinogen-clotting activity of the wild-type down to 8.4% in a concentration-dependent manner, whereas the activity of the mutant was only decreased to 44%. In the absence of rTM, APC generation activity (∆A/min at 405nm) was fairly low (0.0089 for the wild-type and 0.0039 for the mutant). In the presence of rTM, however, APC generation activity was enhanced to 0.0907 (10.2-fold) for the wild-type and to 0.0492 (12.6-fold) for the mutant, and the relative activity of the mutant with rTM was 54% of that of the wild-type. These data suggested that the prothrombin Yukuhashi mutation may cause TM resistance in terms of inhibition of fibrinogen clotting this may contribute to susceptibility to thrombosis, although the enhancing effect of APC generation can be maintained.
Publisher: American Physical Society (APS)
Date: 23-03-2004
Publisher: Oxford University Press (OUP)
Date: 11-03-2013
DOI: 10.1111/CEI.12046
Abstract: The phagocytic clearance of apoptotic cells is critical for tissue homeostasis a number of non-professional phagocytic cells, including epithelial cells, can both take up and process apoptotic bodies, including the release of anti-inflammatory mediators. These observations are particularly important in the case of human intrahepatic biliary cells (HiBEC), because such cells are themselves a target of destruction in primary biliary cirrhosis, the human autoimmune disease. To address the apoptotic ability of HiBECs, we have focused on their ability to phagocytize apoptotic blebs from autologous HiBECs. In this study we report that HiBEC cells demonstrate phagocytic function from autologous HiBEC peers accompanied by up-regulation of the chemokines CCL2 [monocyte chemotactic protein-1 (MCP-1)] and CXCL8 [interleukin (IL)-8]. In particular, HiBEC cells express the phagocytosis-related receptor phosphatidylserine receptors (PSR), implying that HiBECs function through the ‘eat-me’ signal phosphatidylserine expressed by apoptotic cells. Indeed, although HiBEC cells acquire antigen-presenting cell (APC) function, they do not change the expression of classic APC function surface markers after engulfment of blebs, both with and without the presence of Toll-like receptor (TLR) stimulation. These results are important not only for understanding of the normal physiological function of HiBECs, but also explain the inflammatory potential and reduced clearance of HiBEC cells following the inflammatory cascade in primary biliary cirrhosis.
Publisher: Elsevier BV
Date: 05-2017
Publisher: Oxford University Press (OUP)
Date: 12-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2013
DOI: 10.1002/HEP.25829
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.THROMRES.2013.11.021
Abstract: We recently reported a variant prothrombin (p.Arg596Leu: prothrombin Yukuhashi) that confers antithrombin resistance to patients with hereditary thrombosis. To detect antithrombin resistance in plasma, we devised a laboratory test analyzing the kinetics of thrombin inactivation using antithrombin. After incubation with prothrombin activator components (phospholipids, CaCl2, and snake venom), s les were treated with excess antithrombin in the presence or absence of heparin for various time periods. Subsequently, H-D-Phe-Pip-Arg-p-nitoranilide was added and changes in absorbance/min (ΔA/min) were measured at 405 nm. After 1 min inactivation using antithrombin and heparin, the relative residual thrombin activity of recombinant mutant prothrombin (34.3% ± 2.2%) was higher than that of the wild-type (6.3% ± 1.2 %). After 30 min without heparin, the relative residual thrombin activity of recombinant mutant prothrombin (95.8% ± 0.4%) was higher than that of the wild-type (10.1% ± 1.7%), indicating that this assay could detect antithrombin resistance of the variant 596Leu prothrombin. Moreover, warfarinized plasmas from 2 heterozygous patients with prothrombin Yukuhashi mutation clearly showed higher values of the relative residual thrombin activity than those from 5 thrombosis patients lacking the mutation in the presence or absence of heparin. We have devised a laboratory test to detect antithrombin resistance in plasma by analyzing the kinetics of thrombin inactivation using antithrombin. This assay may be useful for detecting antithrombin resistance in plasma, even in warfarinized patients.
Publisher: Springer Science and Business Media LLC
Date: 03-06-2014
DOI: 10.1007/S12185-014-1596-9
Abstract: Hereditary antithrombin (AT) deficiency is an autosomal dominant thrombophilic disorder caused by SERPINC1 abnormality. In the present study, we analyzed SERPINC1 in a Japanese patient with AT deficiency and autoimmune disease-like symptoms. Direct sequencing and multiplex ligation-dependent probe lification revealed that the patient was hemizygous for the entire SERPINC1 deletion. Single nucleotide polymorphism genotyping, gene dose measurement, and long-range polymerase chain reaction (PCR) followed by mapping PCR and direct sequencing of the long-range PCR products revealed that the patient had an approximately 111-kb gene deletion from exon 2 of ZBTB37 to intron 5 of RC3H1, including the entire SERPINC1 in chromosome 1. We also found a 7-bp insertion of an unknown origin in the breakpoint, which may be a combination of three parts with a few base-pair microhomologies, resulting from a replication-based process known as 'fork stalling and template switching'. Because RC3H1, which encodes the protein roquin is involved in the repression of self-immune responses, the autoimmune disease-like symptoms of the patient may have resulted from this gene defect. In conclusion, we identified an entire SERPINC1 deletion together with a large deletion of RC3H1 in an AT-deficient patient with autoimmune disease-like symptoms.
Publisher: Oxford University Press (OUP)
Date: 09-04-2013
DOI: 10.1093/JB/MVT024
Abstract: Syndecan-4, a cell-surface heparan sulfate proteoglycan, can participate in inflammation and wound healing as a host defense molecule. Tumour necrosis factor (TNF)-α, one of the most potent proinflammatory cytokines, is known to upregulate syndecan-4 expression, but the precise mechanisms are unclear. To elucidate these mechanisms in detail, we examined syndecan-4 upregulation by TNF-α in the endothelium-like EAhy926 cell. Of the two putative nuclear factor kappa-B (NF-κB) binding sites in the syndecan-4 gene (SDC4) promoter, deletion or mutation of one or both sites significantly diminished the effects of TNF-α. Electrophoretic mobility shift assays showed that p65 and c-Rel, but not p50, bound to these NF-κB binding sites, whereas pull-down assays showed binding of all three NF-κB components. Chromatin immunoprecipitation assays clearly showed that p65 and phosphorylated p65, but not p50 or c-Rel, bound to the SDC4 promoter. An NF-κB inhibitor, p65 knockdown and a transcriptional elongation inhibitor completely blocked the effect of TNF-α on SDC4 promoter activity and significantly, but not completely, blocked that on SDC4 mRNA expression. These data suggest that NF-κB p65 could be a key mediator of syndecan-4 upregulation by TNF-α through two binding sites in the SDC4 promoter, but other NF-κB-p65 independent pathways might also be involved through transcriptional elongation.
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.ECHO.2016.12.014
Abstract: Left ventricular ejection fraction (LVEF) is a predictor of adverse outcomes in hemodialysis patients. LVEF is, however, an integral parameter determined by contractility, loading condition, and coupling. We sought to determine whether these components would better predict adverse outcomes and have incremental prognostic value over a validated clinical score and EF. Two hundred thirty-four hemodialysis patients were prospectively followed up for primary composite endpoint: all-cause death, nonfatal myocardial infarction, and hospitalization due to worsening heart failure (HF). Load-independent contractility (end-systolic elastance [Ees] and preload recruitable stroke work [PRSW]) and arterial afterload (arterial elastance [Ea]) were noninvasively estimated. Ventricular-arterial coupling was assessed using the Ea/Ees ratio. LV global longitudinal strain (GLS) and mitral E-wave over annular velocity E' ratio (E/E') were also measured. During a median follow-up of 776 days, 30 patients developed the primary endpoint. Ees, PRSW, GLS, S', Ea/Ees, E/E', and EF were independently associated with the outcome after adjusting for the clinical score and prior HF hospitalization, whereas end-diastolic volume index or arterial afterload parameters were not. The nested Cox models indicated that Ea/Ees had independent and incremental predictive value over the model based on the score and either EF or E/E'. Furthermore, Ea/Ees continued to have predictive value after adjusting for GLS. The classification and regression analysis stratified event rates ranging from 4.2% to 68.8%. LV contractility and Ea/Ees were independently associated with adverse outcome in hemodialysis patients. Ea/Ees had an incremental prognostic value over the clinical score and EF.
No related grants have been discovered for Yukio Ando.