Nagoya Central Hospital

Nagoya-shi, Japan

Nagoya Central Hospital

Nagoya-shi, Japan
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Tsuboi K.,Nagoya Central Hospital | Yamamoto H.,Nagoya Central Hospital
BMC Pharmacology and Toxicology | Year: 2017

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the α-galactosidase A gene mutations. Enzyme-replacement-therapy (ERT) products for FD currently used include agalsidase alfa and agalsidase beta. There are many reports on efficacy and safety of ERT. However, most of the previous studies are done as a retrospective medical records analysis. Methods: The Japan Fabry Research - 002 (JFR-002) was a prospective observational clinical study of 36 ERT-naïve FD patients (14 men and 22 women) at baseline (BL) and after initiation of ERT with agalsidase alfa 0.2 mg/kg every two weeks, a median period 62.5 months. The parameters measured included globotriaosylceramide (Gb3), globotriaosylsphingosine (Lyso-Gb3), left ventricular mass index (LVMI), brain natriuretic peptide (BNP), high-sensitivity troponin I (hs-Trop I), estimated glomerular filtration rate (eGFR), and anti-agalsidase alfa IgG antibody formation. Results: All parameters remained steady during ERT treatment period. BNP levels in 14 patients whose BL levels were within the normal range (<19.5 pg/mL) remained within the same range, while 22 patients whose BL levels were abnormally high (≥19.5 pg/mL) gradually showed decreased levels after start of ERT. Gb3 and Lyso-Gb3 levels remarkably decreased after the initiation of ERT and remained low. Conclusion: The JFR-002 suggests that agalsidase alfa is effective in maintaining organ function in FD patients, and that the incidence of infusion reactions related to the treatment with agalsidase alfa is low, indicating the good tolerability to this ERT. Trial registration: The JFR-002 was retrospectively registered at Japan Medical Association Center for Clinical Trials (Registration number: JMA-IIA00291) on May 19th, 2017. © 2017 The Author(s).

Onishi T.,Nagoya University | Kurimoto S.,Nagoya University | Suzuki M.,Nagoya Central Hospital | Imaeda T.,Kinjo Gakuin University | Hirata H.,Nagoya University
International Archives of Occupational and Environmental Health | Year: 2014

Purpose: The Hand20 is an outcome assessment tool developed in Japan to measure upper extremity disability. The purpose of this study was to investigate occupational musculoskeletal disorders in the upper extremity of hospital personnel and to obtain normative data for the Hand20 in a nonclinical population. Methods: A cross-sectional questionnaire study was carried out among 2,600 researchers and staff members of the Faculty of Medicine and its affiliated hospital. Results: There were 1,120 responders who went to their daily work without consulting a doctor about any upper extremity disorders, and 232 of these responders complained of upper extremity pain. The mean Hand20 score was 2.67 [standard deviation (SD) 7.06]. Women tended to have significantly higher total Hand20 scores than men (mean ± SD: men = 2.03 ± 5.15, women = 2.94 ± 7.71, p < 0.01). The Hand20 score tended to increase in participants over 40 years of age (p < 0.001). Significant differences were not found by work intensity (p = 0.712). Binominal logistic analysis revealed that the risk of a high Hand20 score (over the 75 % inter-quartile range, over 13.1) was greater with increasing age [odd ratios (ORs) 1.051, 1.071, respectively] and female sex (ORs 1.786, 1.966, respectively), and that the risk of upper extremity pain was greater with increasing age (OR 1.051), heavy physical work (OR 2.042), and physical work (OR 1.916). Conclusions: Females in all age groups and both sexes in middle age or older need to be informed about their higher risk of upper extremity disorders and should be educated about how to avoid work-related musculoskeletal disorders and their progression. © 2013 Springer-Verlag Berlin Heidelberg.

Suzuki A.,Nagoya University | Sanda N.,Nagoya University | Miyawaki Y.,Nagoya University | Fujimori Y.,Nagoya University | And 5 more authors.
Journal of Biological Chemistry | Year: 2010

Pregnant women show a low level of protein S (PS) in plasma, which is known to be a risk for deep venous thrombosis. 17β-Estradiol (E2), an estrogen that increases in concentration in the late stages of pregnancy, regulates the expression of various genes via the estrogen receptor (ER). Here, we investigated the molecular mechanisms behind the reduction in PS levels caused by E2 in HepG2-ERα cells, which stably express ERα, and also the genomic ER signaling pathway, which modulates the ligand-dependent repression of the PSα gene (PROS1). We observed that E2 repressed the production of mRNA and antigen of PS. A luciferase reporter assay revealed that E2 down-regulated PROS1 promoter activity and that this E2-dependent repression disappeared upon the deletion or mutation of two adjacent GC-rich motifs in the promoter. An electrophoretic mobility shift assay andDNApulldown assay revealed that the GC-rich motifs were associated with Sp1, Sp3, and ERα. In a chromatin immunoprecipitation assay, we found ERα-Sp protein-promoter interaction involved in the E2-dependent repression of PROS1 transcription. Furthermore, we demonstrated that E2 treatment recruited RIP140 and the NCoR-SMRT-HDAC3 complex to the PROS1 promoter, which hypoacetylated chromatin. Taken together, this suggested that E2 might repress PROS1 transcription depending upon ERα-Sp1 recruiting transcriptional repressors in HepG2-ERα cells and, consequently, that high levels of E2 leading to reduced levels of plasma PS would be a risk for deep venous thrombosis in pregnant women. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Yamada S.,Nagoya University | Fujii T.,Nagoya University | Shimoyama Y.,Nagoya University | Kanda M.,Nagoya University | And 7 more authors.
Annals of Surgical Oncology | Year: 2014

Purpose: Morphological subtypes of intraductal papillary mucinous neoplasm (IPMN) have been established. Invasive IPMNs include colloid carcinoma and tubular carcinoma. Few studies have explored the association between the morphological and invasive subtypes in a large population. Clinical relevance of the morphological subtypes remains unclear. Methods: One hundred sixty-nine consecutive patients who underwent curative resection of IPMN were enrolled. The intraductal components were classified into four distinct epithelial subtypes: gastric, intestinal, pancreatobiliary, and oncocytic. The invasive components were classified as colloid or tubular. Results: The numbers of patients with gastric, intestinal, pancreatobiliary, and oncocytic subtypes were 123, 42, 3, and 1, respectively. Fifty-six patients had invasive cancer (tubular type, 42; colloid type, 14). The proportions of gastric type IPMN within each histological grade were 88 % among adenomas, 43 % among noninvasive carcinomas, 41 % among minimally invasive carcinomas, and 74 % among invasive carcinomas. Gastric subtype was more commonly associated with branch duct type and intestinal subtype with main duct type, and these tendencies were statistically significant (P = 0.0131). Furthermore, there was a strong correlation between gastric and tubular types and between intestinal and colloid types (P < 0.0001). The 5-year survival rate among the 56 invasive cancers was 52.7 % for gastric type and 89.7 % for intestinal type, which was statistically significant (P = 0.030). Conclusions: Gastric type IPMN is mostly derived from branch duct IPMN and often demonstrates benign behavior, as seen with adenomas. However, once gastric type IPMN develops into invasive carcinoma, the survival rate is significantly lower than other types. © 2014 Society of Surgical Oncology.

Kunishima S.,National Hospital Organization Nagoya Medical Center | Kashiwagi H.,Osaka University | Otsu M.,Tokyo Medical University | Takayama N.,Tokyo Medical University | And 8 more authors.
Blood | Year: 2011

Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. αIIbβ3 has not been implicated in these conditions. We identified a novel, conserved heterozygous ITGA2B R995W mutation in 4 unrelated families. The surface expression of platelet αIIbβ3 was decreased to 50% to 70% of control. There was spontaneous PAC-1 and fibrinogen binding to resting platelets without CD62p expression. The activation state of αIIbβ3 in 293T cells was higher for αIIb-W995 than for β3-H723 but was weaker than for β3-N562. FAK was spontaneously phosphorylated in αIIb-W995/β3-transfected 293T cells. These results indicate that αIIb-W995/β3 has a constitutive, activated conformation but does not induce platelet activation. αIIb-W995/β3-transfected CHO cells developed membrane ruffling and abnormal cytoplasmic protrusions. The increased size and decreased number of proplatelet tips in αIIb-W995/ β3-transduced mouse fetal liver-derived megakaryocytes indicate defective proplatelet formation. We propose that activating mutations in ITGA2B and ITGB3 represent the etiology of a subset of congenital macrothrombocytopenias. © 2011 by The American Society of Hematology.

Kunishima S.,National Hospital Organization Nagoya Medical Center | Saito H.,Nagoya Central Hospital
Current Opinion in Hematology | Year: 2010

Purpose of review: MYH9 disorders are autosomal dominant macrothrombocytopenias with leukocyte inclusion bodies caused by mutations in MYH9, the gene for the nonmuscle myosin heavy chain IIA. May-Hegglin anomaly and Sebastian, Fechtner, and Epstein syndromes belong to MYH9 disorders. The present review summarizes the recent advances in genetic diagnosis and our understanding of the pathogenetic mechanisms of MYH9 mutations and the development of nonhematological complications. Recent findings: A genotype-phenotype cohort study showed that patients with an MYH9 mutation in the motor head domain of myosin IIA have severe macrothrombocytopenia and are at a high risk for the development of glomerulonephritis and deafness. Among these, Arg702 mutations are associated with the most severe phenotype. In-vitro studies on cultured megakaryocytes elucidated that myosin IIA inhibits proplatelet formation. The loss of myosin IIA function owing to MYH9 mutations promotes proplatelet formation and may trigger precocious and premature platelet release, resulting in macrothrombocytopenia. Giant platelets only residually express mutant myosin IIA that has a loss of function and cannot participate in the reorganization of cytoskeletal contractile structures. Renal histopathological and immunochemical studies have suggested that glomerulonephritis in MYH9 disorders is caused by podocyte malfunction owing to defects in the myosin IIA structure and MYH9 expression. Summary: MYH9 disorders are not merely benign hematological abnormalities, but serious syndromic disorders affecting the kidney, inner ear, and lens. A genetic diagnosis is mandatory for an accurate prognosis of nonhematological complications and management or possibly prophylactic treatment. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Tsuboi K.,Nagoya Central Hospital | Yamamoto H.,Nagoya Central Hospital
Genetics in medicine : official journal of the American College of Medical Genetics | Year: 2014

BACKGROUND: Between 2009 and 2012, there was a worldwide shortage of agalsidase-β for the treatment of Fabry disease. Therefore, alternative treatments were needed, including switching to a different enzyme-replacement therapy.PURPOSE: This is an ongoing observational study assessing the effects of switching from agalsidase-β (1.0 mg/kg every other week) to agalsidase-α (0.2 mg/kg every other week) in 11 patients with Fabry disease.METHODS: Clinical data were collected for 5 years-2 years before switching and 3 years after switching.RESULTS: Measures of renal function such as estimated glomerular filtration rate remained stable during the 3 years after switching to agalsidase-α. Improvements in cardiac mass were recorded in both male and female patients 12 months after switching to agalsidase-α, and the benefit was maintained during 36 months of follow-up. There was no significant difference in the severity of pain experienced by patients before and after switching enzyme-replacement therapy, and no difference in quality-of-life parameters. Agalsidase-α was generally well tolerated, and no patients experienced allergy or developed antibodies to agalsidase-α.CONCLUSION: This observational study supports the safety of switching from agalsidase-β to agalsidase-α at the approved doses, with no loss of efficacy. It also suggests that if an infusion-related allergic reaction occurs in a patient receiving agalsidase-β, switching to agalsidase-α may be a viable option.

Saito H.,Nagoya Central Hospital
Thrombosis and Haemostasis | Year: 2010

The way by which contact of blood with foreign surface accelerates clotting has been elucidated from the discovery of four rare disorders of blood coagulation; Hageman trait, plasma thromboplastin antecedent (PTA) deficiency, Fletcher trait, and Fitzgerald trait. Interestingly, it was unexpectedly found that Fletcher factor is plasma prekallikrein and Fitzgerald factor is high-molecular-weight kininogen; components of the kinin-generating system, thus disclosing intimate relationships among clotting, fibrinolysis and kinin generation which may be viewed as body's defense reactions against injury. This review mainly reflects our research on Fletcher trait and Fitzgerald trait during the 1970s in Cleveland. © Schattauer 2010.

Yamada S.,Nagoya University | Fujii T.,Nagoya University | Sugimoto H.,Nagoya University | Nomoto S.,Nagoya University | And 3 more authors.
Pancreas | Year: 2013

OBJECTIVES: The objective of this study was to evaluate the relevance of defining borderline resectable (BR) pancreatic cancer as a distinct entity in the treatment scheme of pancreatic cancer as proposed by the National Comprehensive Cancer Network. METHODS: Among 375 patients with pancreatic cancer, 137 patients were deemed to have resectable disease (R) by preoperative imaging studies, whereas 96 were found to have an unresectable disease during surgery. The remaining 142 patients fulfilled the definition of BR and were further classified into 3 subgroups based on the National Comprehensive Cancer Network guidelines: portal vein invasion (PV[+]), common hepatic artery invasion (CHA[+]), and superior mesenteric artery invasion (SMA[+]). PV(+) was subdivided into types B, C, and D according to the degree of portal vein invasion. RESULTS: Patients in the R group had significantly better survival than those in the PV(+) group (P = 0.0038), who in turn survived significantly longer than those classified as SMA(+) (P = 0.041). Type B patients survived significantly longer than did types C and D patients (P = 0.013 and P = 0.030, respectively). In PV(+) patients, compliance with postoperative chemotherapy at 3 and 6 months was 56.9% and 44.6%, respectively, substantially inferior to patients with resectable disease (72.6% and 54.7%, respectively). CONCLUSIONS: The optimal treatment strategy may differ among various subgroups within the BR category. Copyright © 2013 by Lippincott Williams &Wilkins.

Tsuboi K.,Nagoya Central Hospital | Yamamoto H.,Nagoya Central Hospital
Genetics in Medicine | Year: 2012

Purpose:Fabry disease is a rare, X-linked, inherited lysosomal storage disorder that can be treated with the enzymes agalsidase alfa (Replagal) and agalsidase beta (Fabrazyme). Currently, there is a global shortage of agalsidase beta, and this has increased global demand for agalsidase alfa. We assess the feasibility of switching patients on agalsidase beta treatment to agalsidase alfa instead.Methods:This analysis is part of an ongoing observational study involving 11 patients with Fabry disease in whom the treatment was switched from agalsidase beta (1 mg/kg every other week) to agalsidase alfa (0.2 mg/kg every other week). Data were collected for a minimum of 36 months: 24 months before and 12 months after the switch. Serial data were evaluated with respect to renal function, cardiac mass, pain, quality of life, and tolerability/safety.Results: Indexes of renal function (estimated glomerular filtration rate) and cardiac mass (left-ventricular mass index), pain (Brief Pain Inventory), and quality of life (EuroQoL-Dimensions) clearly showed that, in patients switched to agalsidase alfa, Fabry disease stabilized during the 12 months of follow-up.Conclusion:Despite the limitations of this preliminary observational study, it was found that all the patients maintained disease stability when treated with agalsidase alfa, as evidenced by estimated glomerular filtration rate, left-ventricular mass index, pain scores, and quality-of-life indexes, throughout 12 months of follow-up. © American College of Medical Genetics and Genomics.

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