Toshiyuki Miyata

National Cerebral and Cardiovascular Center, Ōsaka, Ōsaka, Japan

Are you Toshiyuki Miyata?

Claim your profile

Publications (334)1492.67 Total impact

  • Thrombosis and Haemostasis 04/2015; 114(1). DOI:10.1160/TH14-08-0656 · 5.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report a case of atypical hemolytic uremic syndrome (aHUS) in a 4-year-old boy. Although the patient had the typical triad of aHUS (microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury), urgent dialysis was not indicated because he had neither oliguria nor severe electrolyte abnormality. He was given eculizumab as first-line therapy, which led to significant clinical improvement, thus avoiding any risk of complications associated with plasma exchange and central venous catheterization. Retrograde functional analysis of the patient's plasma using sheep erythrocytes indicated an increase in hemolysis, suggesting impairment of host cell protection by complement factor H. The use of eculizumab as first-line therapy in place of plasma exchange might be reasonable for pediatric patients with aHUS. © 2015 Japan Pediatric Society.
    Pediatrics International 04/2015; 57(2):313-7. DOI:10.1111/ped.12469 · 0.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report the first case of familial C3 glomerulonephritis (C3GN) associated with mutations in the gene for complement factor B (CFB). A 12-year-old girl was diagnosed with biopsy-proven C3GN. Her mother had a history of treatment for membranoproliferative glomerulonephritis, and her brother had hypocomplementemia without urinary abnormalities. DNA analysis revealed heterozygosity for CFB p.S367R in the patient, mother and brother. Evaluation of the structure-function relationship supports that this mutation has gain-of-function effects in CFB. The present case suggests that CFB has an important role in the etiology of C3GN and provides a new insight into anticomplement therapy approaches. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
    Nephrology Dialysis Transplantation 03/2015; DOI:10.1093/ndt/gfv054 · 3.49 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In Japan, low-dose rivaroxaban [15 mg QD/10 mg QD for creatinine clearance of 30-49 mL/min] was approved for clinical use in NVAF patients partly because of its unique pharmacokinetics in Japanese subjects. The aim of the study was to determine the anticoagulation intensity of rivaroxaban and its determinant factors in Japanese stroke patients. Consecutive stroke patients with NVAF admitted between July 2012 and December 2013 were studied. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and estimated plasma concentration of rivaroxaban (Criv) based on an anti-factor Xa chromogenic assay were measured just before and 4 and 9 h after administration at the steady state level of rivaroxaban. Determinant factors for Criv were explored using a linear mixed-model approach. Of 110 patients (37 women, 75±9 years old), 59 took 15 mg QD of rivaroxaban and 51 took 10 mg QD. Criv at 4 h was 186 ng/mL for patients taking 15 mg QD and 147 ng/mL for those taking 10 mg QD. Both PT and aPTT were positively correlated with Criv. Criv was 72% lower at 4 h in 15 patients receiving crushed tablets than in the other patients, and tablet crushing was significantly associated with lower Criv (adjusted estimate -0.43, 95% CI -0.60 to -0.26) after multivariate-adjustment. The anticoagulation effects of rivaroxaban in the acute stroke setting for Japanese NVAF patients were relatively low as compared with those in the ROCKET-AF and J-ROCKET AF trials. Tablet crushing, common in dysphagic patients, decreased Criv.
    PLoS ONE 11/2014; 9(11):e113641. DOI:10.1371/journal.pone.0113641 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In pregnant women, activated partial thromboplastin time (APTT) does not precisely reflect the anticoagulant effect of a therapeutic dose of heparin. However, the measurement of anti-Xa activity can be used to monitor the anticoagulant effect of heparin, since the plasma concentrations of coagulation factors increase in pregnant women. We evaluated the in vitro effects of increased concentrations of fibrinogen and other coagulation factors (FVII, FVIII, and FIX) on the results of assays of APTT and anti-Xa activity in plasma samples with various therapeutic concentrations of unfractionated heparin (UFH). In the presence of UFH, APTT was shortened by increased concentrations of fibrinogen, FVII, or FVIII, and this effect was much stronger when the FVIII concentration was increased. In the plasma samples containing 0.5 or 0.7 U/mL of UFH, the APTT was shortened by approximately half or one-third, respectively, when 6 U FVIII/mL was added to the sample. The anti-Xa activity was not influenced by increased concentrations of the coagulation factors. In the present study, we also evaluated the sensitivities to UHF of four APTT reagents, and found a 1.65-fold difference in the sensitivity to UFH among APTT reagents. Our results demonstrate that increased FVIII concentration shortens APTT under therapeutic doses of UFH, and that APTT thus underestimates the anticoagulant effect of UFH in pregnant women, mainly due to the increased FVIII concentration.
    International Journal of Hematology 11/2014; 101(2). DOI:10.1007/s12185-014-1702-z · 1.68 Impact Factor
  • Journal of the American Society of Nephrology 11/2014; 25:343A. · 9.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Severe hypertension (HTN) and acute kidney injury frequently associated with atypical hemolytic uremic syndrome (aHUS) were refractory to various therapies in the pre-eculizumab era. Here we report the case of a 4-month-old boy who developed aHUS presenting with undetectable C3 protein, no predisposing mutations in complement factors, and no antibodies against factor H. Methods Repeated plasma infusions and nine sessions of plasmapheresis were ineffective. The patient initially required continuous hemodiafiltration and thereafter peritoneal dialysis. Despite vigorous antihypertensive treatment and improved fluid overload with dialysis, HTN persisted. His low C3 level ( Results Eculizumab therapy resulted in the control of severe HTN and cessation of peritoneal dialysis. Conclusions This infant with HTN and acute kidney injury associated with aHUS was treated successfully with eculizumab.
    Pediatric Nephrology 10/2014; 30(4). DOI:10.1007/s00467-014-2975-4 · 2.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Atypical hemolytic uremic syndrome (aHUS) is caused by abnormalities of the complement system and has a significantly poor prognosis. The clinical phenotypes of 12 patients in nine families with aHUS with familial or recurrent onset and ADAMTS13 activity of ≥20 % treated at the Mie University Hospital were examined. In seven of the patients, the first episode of aHUS occurred during childhood and ten patients experienced a relapse. All patients had renal dysfunction and three had been treated with hemodialysis. Seven patients experienced probable triggering events including common cold, influenza, bacterial infection and/or vaccination for influenza. All patients had entered remission, and renal function was improved in 11 patients. DNA sequencing of six candidate genes, identified a C3 p.I1157T missense mutation in all eight patients in six families examined and this mutation was causative for aHUS. A causative mutation THBD p.D486Y was also identified in an aHUS patient. Four missense mutations, CFH p.V837I, p.Y1058H, p.V1060L and THBD p.R403K may predispose to aHUS manifestation; the remaining seven missense mutations were likely neutral. In conclusion, the clinical phenotypes of aHUS are various, and there are often trigger factors. The C3 p.I1157T mutation was identified as the causative mutation for aHUS in all patients examined, and may be geographically concentrated in or around the Mie prefecture in central Japan.
    International Journal of Hematology 08/2014; DOI:10.1007/s12185-014-1655-2 · 1.68 Impact Factor
  • Haematologica 06/2014; 99(10). DOI:10.3324/haematol.2014.109512 · 5.87 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Hereditary thrombophilias may associate with uteroplacental thrombosis leading to adverse pregnancy outcomes. The present study was conducted to reveal the frequency of the low-frequency thrombophilic protein S K196E mutation, as well as the frequency of very rare nonsynonymous mutations in protein S, protein C, and antithrombin genes, in patients with adverse pregnancy outcomes. Patients and methods We enrolled 330 Japanese patients with adverse pregnancy outcomes and divided them into 233 patients with two or more miscarriages and 114 patients with fetal growth restriction (FGR) and/or intrauterine fetal death (IUFD); 17 patients belonged to both groups. We sequenced the entire coding regions of three anticoagulant genes in all 330 patients. Results We found that protein S K196E mutation was identified in 4 out of 233 patients with recurrent miscarriage and in 2 out of 114 patients with FGR and/or IUFD. The frequencies of this mutation in these patient groups were not different from that in a Japanese general population. Very rare nonsynonymous mutations were identified in 3.3% (11 out of 330) of patients with adverse pregnancy outcomes. Conclusions Although the low-frequency protein S K196E mutation can increase the risk for venous thromboembolism, it did not increase the risk for adverse pregnancy outcomes even in Japanese.
    Thrombosis Research 05/2014; 133(5). DOI:10.1016/j.thromres.2014.02.012 · 2.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Direct sequencing is a popular method to discover mutations in candidate genes responsible for hereditary diseases. A certain type of mutation, however, can be missed by the method. Here, we report a comprehensive genomic quantitative polymerase chain reaction (qPCR) to complement the weakness of direct sequencing. Upshaw-Schulman syndrome (USS) is a recessively inherited disease associated with severe deficiency of plasma ADAMTS13 activity. We previously analyzed ADAMTS13 in 47 USS patients using direct sequencing, and 44 of them had either homozygous or compound heterozygous mutations. Then, we sought to reveal more extensive defects of ADAMTS13 in the remaining three patients. We quantified copy numbers of each ADAMTS13 exon in the patients by using genomic qPCR. Each primer pair was designed to contain at least one of the two primers used in direct sequencing, to avoid missing any exonic deletions. The qPCR demonstrated heterozygous loss of exons 7 and 8 in one patient and exon 27 in the other, and further analysis revealed c.746_987+373del1782 and c.3751_3892+587del729, respectively. Genomic qPCR provides an effective method for identifying extensive defects of the target genes.
    05/2014; 2(3). DOI:10.1002/mgg3.64
  • [Rinshō ketsueki] The Japanese journal of clinical hematology 01/2014; 55(1):93-104.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Atypical hemolytic uremic syndrome (aHUS) can be distinguished from typical or Shiga-like toxin-induced HUS. The clinical outcome is unfavorable; up to 50% of affected patients progress to end-stage renal failure and 25% die during the acute phase. Multiple conditions have been associated with aHUS, including infections, drugs, autoimmune conditions, transplantation, pregnancy, and metabolic conditions. aHUS in the nontransplant postsurgical period, however, is rare. An 8-month-old boy underwent surgical repair of tetralogy of Fallot. Neurological disturbances, acute renal failure, thrombocytopenia, and microangiopathic hemolytic anemia developed 25 days later, and aHUS was diagnosed. Further evaluation revealed that his complement factor H (CFH) level was normal and that anti-FH antibodies were not detected in his plasma. Sequencing of his CFH, complement factor I, membrane cofactor protein, complement factor B, and thrombomodulin genes was normal. His ADAMTS-13 (a disintegrin-like and metalloprotease with thrombospondin-1 repeats 13) activity was also normal. However, he had a potentially causative mutation (R425C) in complement component C3. Restriction fragment length polymorphism analysis revealed that his father and aunt also had this mutation; however, they had no symptoms of aHUS. We herein report a case of aHUS that developed after cardiovascular surgery and was caused by a complement C3 mutation.
    01/2014; 2014:784943. DOI:10.1155/2014/784943
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Integrin-linked kinase (ILK) is an important signaling regulator that assembles into the heteroternary complex with adaptor proteins PINCH and parvin (termed the IPP complex). We recently reported that ILK is important for integrin activation in a Chinese hamster ovary (CHO) cell system. We previously established parental CHO cells expressing a constitutively active chimeric integrin (αIIbα6Bβ3) and mutant CHO cells expressing inactive αIIbα6Bβ3 due to ILK deficiency. In this study, we further investigated the underlying mechanisms for ILK-dependent integrin activation. ILK-deficient mutant cells had trace levels of PINCH and α-parvin, and transfection of ILK cDNA into the mutant cells increased not only ILK but also PINCH and α-parvin, resulting in the restoration of αIIbα6Bβ3 activation. In the parental cells expressing active αIIbα6Bβ3, ILK, PINCH, and α-parvin were co-immunoprecipitated, indicating the formation of the IPP complex. Moreover, short interfering RNA (siRNA) experiments targeting PINCH-1 or both α- and β-parvin mRNA in the parent cells impaired the αIIbα6Bβ3 activation as well as the expression of the other components of the IPP complex. In addition, ILK mutants possessing defects in either PINCH or parvin binding failed to restore αIIbα6Bβ3 activation in the mutant cells. Kindlin-2 siRNA in the parental cells impaired αIIbα6Bβ3 activation without disturbing the expression of ILK. For CHO cells stably expressing wild-type αIIbβ3 that is an inactive form, overexpression of a talin head domain (THD) induced αIIbβ3 activation and the THD-induced αIIbβ3 activation was impaired by ILK siRNA through a significant reduction in the expression of the IPP complex. In contrast, overexpression of all IPP components in the αIIbβ3-expressing CHO cells further augmented THD-induced αIIbβ3 activation, whereas they did not induce αIIbβ3 activation without THD. These data suggest that the IPP complex rather than ILK plays an important role and supports integrin activation probably through stabilization of the active conformation.
    PLoS ONE 12/2013; 8(12):e85498. DOI:10.1371/journal.pone.0085498 · 3.53 Impact Factor
  • Source
    Tong Yin, Toshiyuki Miyata
    [Show abstract] [Hide abstract]
    ABSTRACT: Venous thromboembolism (VTE) is a life-threatening medical disorder worldwide. A great deal of evidence suggests that prevalence of VTE varies significantly among ethnic populations, with consistently lower incidence found in Asians. While the distribution of genetic risk factors may vary among races, genetic risk factors can play a major role among individuals with different genetic backgrounds. Two clinically evaluated low-frequency genetic mutations that predispose to VTE-the factor V Leiden mutation and prothrombin G20210A mutation-are found predominantly in Caucasians, and virtually never in Asians. The findings of a recent genetic study of VTE in northeast Asians, which greatly advanced our knowledge in this area, indicate that the most frequent genetic risk factors for VTE in northeast Asians can be attributed to a dysfunction of the protein C anticoagulant system. Several low-frequency genetic mutations, PROS1 p.Lys196Glu in Japanese and PROC p.Arg189Trp and p.Lys193del in Chinese, are significantly associated with increased risk for VTE, with odds ratio more than 2 through the reduced protein C anticoagulant activity. Construction of a multifactorial model based on the genetic risk factors in the protein C anticoagulant system could facilitate genetic counseling for VTE risk in these populations. The influence of prevalent genetic mutations on the risk of VTE should be further investigated in Asian countries.
    Journal of Thrombosis and Thrombolysis 11/2013; DOI:10.1007/s11239-013-1005-x · 2.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were randomly allocated to first-line treatment with a calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). Methods: We recruited 265 (93 for CCB, 71 for ACEI and 101 for ARB) patients who completed the genomic study. Home blood pressure was measured for 5 days off-treatment before randomization and for 5 days after 2-4 weeks of randomized drug treatment. Genotyping was performed by 500K DNA microarray chips. The blood pressure responses to the three drugs were analyzed separately as a quantitative trait. For replication of SNPs with p < 10(-4), we used the multicenter GEANE study, in which patients were randomized to valsartan or amlodipine. Results: SNPs in PICALM, TANC2, NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication. Conclusion: Our approach, the first based on high-fidelity phenotyping by home blood pressure measurement, might be a step in moving towards the personalized treatment of hypertension. Original submitted 29 April 2013; Revision submitted 14 August 2013.
    Pharmacogenomics 11/2013; 14(14):1709-21. DOI:10.2217/pgs.13.161 · 3.43 Impact Factor
  • Journal of the American Society of Nephrology 11/2013; 24:251A. · 9.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Herp was originally identified as an endoplasmic reticulum (ER) stress protein in vascular endothelial cells. ER stress is induced in atherosclerotic lesions, but it is not known whether Herp plays any role in the development of atherosclerosis. To address this question, we generated Herp- and apolipoprotein E (apoE)-deficient mice (Herp(-/-); apoE(-/-) mice) by crossbreeding Herp(-/-) mice and apoE(-/-) mice. Herp was expressed in the endothelial cells and medial smooth muscle cells of the aorta, as well as in a subset of macrophages in the atherosclerotic lesions in apoE(-/-) mice, while there was no expression of Herp in the Herp(-/-); apoE(-/-) mice. The doubly deficient mice developed significantly fewer atherosclerotic lesions than the apoE(-/-) mice at 36 and 72 weeks of age, whereas the plasma levels of cholesterol and triglycerides were not significantly different between the strains. The plasma levels of non-esterified fatty acids were significantly lower in the Herp(-/-); apoE(-/-) mice when they were eight and 16 weeks old. The gene expression levels of ER stress response proteins (GRP78 and CHOP) and inflammatory cytokines (IL-1β, IL-6, TNF-α and MCP-1) in the aorta were significantly lower in Herp(-/-); apoE(-/-) mice than in apoE(-/-) mice, suggesting that Herp mediated ER stress-induced inflammation. In fact, peritoneal macrophages isolated from Herp-deficient mice and RAW264.7 macrophages in which Herp was eliminated with a siRNA expressed lower levels of mRNA for inflammatory cytokines when they were treated with tunicamycin. Herp deficiency affected the major mediators of the unfolded protein response, including IRE1 and PERK, but not ATF6. These findings suggest that a deficiency of Herp suppressed the development of atherosclerosis by attenuating the ER stress-induced inflammatory reactions.
    PLoS ONE 10/2013; 8(10):e75249. DOI:10.1371/journal.pone.0075249 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A 34-year-old Japanese woman was admitted to our hospital complaining of developing bilateral pedal edema. Imaging studies led to a diagnosis of Budd-Chiari syndrome combined with internal jugular vein thrombus. We investigated the cause of thrombosis and found that the anticoagulant activity of protein C was decreased. Genetic analysis showed the presence of a c.125C>A (Arg42Ser) substitution in the protein C gene (PROC) of the proband, which generates an Arg42Ser mutation that replaces the scissile bond Arg42-Ala43 normally cleaved by a furin-like processing protease. Her father and younger brother also carried this mutation, although they had no evidence of thrombosis.
    Case Reports in Medicine 10/2013; 2013:270419. DOI:10.1155/2013/270419

Publication Stats

10k Citations
1,492.67 Total Impact Points

Institutions

  • 2000–2015
    • National Cerebral and Cardiovascular Center
      • Department of Cardiovascular Medicine
      Ōsaka, Ōsaka, Japan
    • New York Methodist Hospital
      New York, New York, United States
  • 1997–2008
    • Tokai University
      • School of Medicine
      Hiratuka, Kanagawa, Japan
  • 2007
    • Meiji University
      Edo, Tōkyō, Japan
    • Keio University
      • Department of Laboratory Medicine
      Edo, Tōkyō, Japan
  • 2006–2007
    • Tokyo Medical and Dental University
      Edo, Tōkyō, Japan
  • 1993–2006
    • Osaka University
      • Department of Immunoregulation
      Suika, Ōsaka, Japan
    • Nagoya Memorial Hospital
      Nagoya, Aichi, Japan
    • Gifu University
      • Department of Pediatrics
      Gihu, Gifu, Japan
  • 1985–2006
    • Kyushu University
      • Department of Biology
      Hukuoka, Fukuoka, Japan
  • 2004
    • Hirosaki University
      • Department of Pediatrics
      Khirosaki, Aomori, Japan
  • 2003
    • Osaka City General Hospital
      Ōsaka, Ōsaka, Japan
  • 1994–2002
    • Kyoto Institute of Technology
      • Department of Chemistry and Materials Technology
      Kioto, Kyōto, Japan
    • Nagoya University
      • Division of of Internal Medicine
      Nagoya, Aichi, Japan
    • Ealing, Hammersmith & West London College
      Londinium, England, United Kingdom
  • 1997–2000
    • Jichi Medical University
      • Division of Cardiology
      Totigi, Tochigi, Japan
  • 1998
    • St. Marianna University School of Medicine
      Kawasaki Si, Kanagawa, Japan
  • 1996–1998
    • Social Insurance Chukyo Hospital
      Nagoya, Aichi, Japan
    • Toranomon Hospital
      Edo, Tōkyō, Japan
  • 1991–1992
    • Kitasato University
      Edo, Tōkyō, Japan
    • Fujita Health University
      Nagoya, Aichi, Japan
  • 1987
    • The University of Tokushima
      Tokusima, Tokushima, Japan