Faculty Profiles - TSUKAHARA Hirokazu

MISC - TSUKAHARA Hirokazu

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先天代謝異常症における一酸化窒素代謝系の病態学的意義の探索: 新規の予防・治療法の開発に向けて

塚原宏一, 徳力周子, 田村知史, 川谷正男, 畑郁江, 大嶋勇成, 西島浩二

福井大学重点研究成果集 (in press) 2010

極低出生体重児のビタミンD蓄積および骨ミネラル代謝の評価

巨田尚子, 塚原宏一, 徳力周子, 小倉一将, 川谷正男, 畑郁江, 眞弓光文

第27回代謝性骨疾患研究会発表論文集 (in press) 2010

小児における二重エネルギーX線吸収測定法を用いた骨塩定量の論文報告の総括

塚原宏一

平成21年度腎不全病態研究助成成果報告書 2010

小児科診療に強くなる！- 知ってほしい診断のポイントとコツ. 最終回: 追加・補足事項 - 薬物療法から精神疾患まで

塚原宏一, 塚原康代

内科 105 ( 2 ) 318 - 323 2010

書評: 小児・新生児診療ゴールデンハンドブック（旭川医科大学小児科学講座藤枝憲二, 梶野浩樹編著）. 小児医療の安全ルートを指し示すガイドブック

塚原宏一

内科 105 ( 3 ) 530 2010

早産低出生体重児の生体環境偏移の長期評価とその対策: 「成人病胎児期発症説」の検証

塚原宏一

平成21年度科学研究費補助金実績報告書（基盤研究C） 2010

小児科領域における一酸化窒素および酸化ストレスに関連する生体マーカーの現況

塚原宏一, 眞弓光文, 長坂博範

発達腎研究会誌 2010

ホタル（火垂る）物語とMitochondriaそしてNO、REDOX

塚原宏一

発達腎研究会誌 2010

先天性代謝疾患と一酸化窒素、酸化ストレス.

長坂博範, 塚原宏一

発達腎研究会誌 2010

内科疾患の診断基準・病型分類・重症度: 溶血性尿毒症症候群

塚原宏一

内科（in press） 2010

内科疾患の診断基準・病型分類・重症度: Alport症候群

塚原宏一

内科（in press） 2010

未熟児くる病 (周産期診療指針2010) -- (新生児編新生児疾患の治療指針)

塚原宏一, 吉本順子, 横内恵子

周産期医学 40 757 - 762 2010

Ureaplasma urealyticum感染が病因と考えられ、呼吸管理に難渋したWilson-Mikity症候群の1例

徳力周子, 五十嵐愛子, 菊地尚子, 田村知史, 畑郁江, 塚原宏一, 眞弓光文, 高橋仁, 西島浩二, 小辻文和, 長谷川妙子, 小出亜希子, 柳原格, 佐々木裕子, 見理剛

日本小児科学会雑誌 113 ( 12 ) 1867 - 1867 2009.12

HYPERCITRULLINEMIA, HYPERCHOLESTEROLEMIA AND AUGMENTED OXIDATIVE STRESS IN THE PATIENTS WITH CITRIN DEFICIENCY DURING THE SILENT PERIOD

Y. Okano, H. Nagasaka, Y. Shigematsu, H. Tsukahara, T. Momoi, T. Yorifuji, T. Ohura, T. Miida, K. Hirano, K. Kobayashi, T. Saheki, M. Takayanagi

MOLECULAR GENETICS AND METABOLISM 98 ( 1-2 ) 10 - 10 2009.9

ALTERED METABOLISMS OF MEDIATORS CONTROLLING VASCULAR FUNCTION AND EVIDENCE OF OXIDATIVE STRESS IN ASYMPTOMATIC CHILDREN WITH CONGENITAL PORTOSYSTEMIC VENOUS SHUNT

H. Nagasaka, Y. Okano, H. Tsukahara

MOLECULAR GENETICS AND METABOLISM 98 ( 1-2 ) 110 - 110 2009.9

Lipoprotein profiles in children with two common cholesteryl ester transfer protein gene mutations, D442G and I14A, during the first year of life

Hironori Nagasaka, Tohru Yorifuji, Toru Momoi, Junko Yorifuji, Kenichi Hirano, Akemi Ota, Tomozumi Takatani, Hirokazu Tsukahara, Masaki Takayanagi, Kunihiko Kobayashi, Hitoshi Chiba, Yukiyasu Sato, Takashi Miida

CLINICA CHIMICA ACTA 406 ( 1-2 ) 52 - 56 2009.8

Language：English Publisher：ELSEVIER SCIENCE BV

Background: Hyperalphalipoproteinemia is associated with cholesteryl ester transfer protein (CETP) deficiency in adults but has unclear associations in children.
Methods: We measured lipoproteins in 19 heterozygotes (D442G, n = 17; I14A, n = 2), one D442G/I14A compound heterozygote, 13 non-affected siblings, and 30 healthy controls at birth, 3-4 months, and 12 months.
Results: CETP mass was 32-70% lower in heterozygotes than in controls throughout the year. Low-density lipoprotein-cholesterol (LDL-C) was lower in heterozygotes than in controls by 30, 20, and 15% at birth, 34 months, and 12 months, respectively. High-density lipoprotein-cholesterol (HDL-C) was similar among the groups at birth, but was 10% higher in heterozygotes compared with controls at 3-4 and 12 months. ApoE-rich HDL-C was similar between the two groups at birth, but was 50% higher in heterozygotes than in controls at 3-4 and 12 months. These lipoprotein profile characteristics were prominent in the compound heterozygote but were not found in non-affected siblings. In heterozygotes. CETP mass correlated positively with LDL-C but negatively with HDL-C at 3-4 and 12 months.
Conclusion: CETP is a determinant for LDL-C and HDL-C in CETP-deficient individuals in the first year of life. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.cca.2009.05.007

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Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period

Hironori Nagasaka, Yoshiyuki Okano, Hirokazu Tsukahara, Yosuke Shigematsu, Toru Momoi, Junko Yorifuji, Takashi Miida, Toshihiro Ohura, Keiko Kobayashi, Takeyori Saheki, Kenichi Hirano, Masaki Takayanagi, Tohru Yorifuji

MOLECULAR GENETICS AND METABOLISM 97 ( 1 ) 21 - 26 2009.5

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) shows diverse metabolic abnormalities such as urea cycle dysfunction together with citrullinemia, galactosemia, and suppressed gluconeogenesis. Such abnormalities apparently resolve during the first year of life. However, metabolic profiles of the silent period remain unknown. We analyzed oxidative stress markers and profiles of amino acids, carbohydrates, and lipids in 20 asymptomatic children with aspartate/glutamate carrier isoform 2-citrin-deficiency aged 1-10 years, for whom tests showed normal liver function. Despite normal plasma ammonia levels, the affected children showed higher blood levels of ornithine (p < 0.001) and citrulline (p < 0.01)-amino acids involved in the urea cycle-than healthy children. Blood levels of nitrite/nitrate, metabolites of nitric oxide (NO), and asymmetric dimethylarginine inhibiting NO production from arginine were not different between these two groups. Blood glucose, galactose, pyruvate, and lactate levels after 4-5 h fasting were not different between these groups, but the affected group showed a significantly higher lactate to pyruvate ratio. Low-density and high-density lipoprotein cholesterol levels in the affected group were 1.5 times higher than those in the controls. Plasma oxidized low-density lipoprotein apparently increased in the affected children; their levels of urinary oxidative stress markers such as 8-hydroxy-2'-deoxyguanosine and acrolein-lysine were significantly higher than those in the controls. Results of this study showed, even during the silent period, sustained hypercitrullinemia, hypercholesterolemia, and augmented oxidative stress in children with citrin deficiency. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ymgme.2009.01.009

Evaluation of endogenous nitric oxide synthesis in congenital urea cycle enzyme defects

Hironori Nagasaka, Hirokazu Tsukahara, Tohru Yorifuji, Takashi Miida, Kei Murayama, Tomoko Tsuruoka, Tomozumi Takatani, Masaki Kanazawa, Kunihiko Kobayashi, Yoshiyuki Okano, Masaki Takayanagi

METABOLISM-CLINICAL AND EXPERIMENTAL 58 ( 3 ) 278 - 282 2009.3

Language：English Publisher：W B SAUNDERS CO-ELSEVIER INC

Nitric oxide (NO) is synthesized from arginine and O-2 by nitric oxide synthase (NOS). Citrulline, which is formed as a by-product of the NOS reaction, can be recycled to arginine by the 2 enzymes acting in the urea cycle: argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). Although the complete Urea cycle is expressed only in the liver, ASS and ASL are expressed in other organs including the kidney and vascular endothelium. To examine possible alterations of the NO pathway in urea cycle defects, we measured plasma concentrations of arginine and citrulline and serum concentrations of nitrite/nitrate (NOx(-), stable NO metabolites) and asymmetric dimethylarginine (ADMA, an endogenous NOS inhibitor) in patients with congenital urea cycle disorders of 3 types: ornithine transcarbamylase (OTC) deficiency, ASS deficiency, and ASL deficiency. All were receiving oral arginine replacement at the time of this study. The same parameters were also measured in healthy subjects, who participated as controls. The OTC-deficient patients had significantly high NOx(-) and nonsignificantly high ADMA concentrations. Their NOx(-) was significantly positively correlated with arginine. The ASS-deficient patients had significantly low NOx(-) and significantly high ADMA concentrations. The ASL-deficient patients had normal NOx(-) and nonsignificantly high ADMA concentrations. In ASS-deficient and ASL-deficient patients, the NOx(-) was significantly inversely correlated with citrulline, These results suggest that NO synthesis is enhanced in OTC-deficient patients while receiving arginine but that NO synthesis remains low in ASS-deficient patients despite receiving arginine. They also suggest that endogenous NO synthesis is negatively affected by citrulline and ADMA in ASS-deficient and ASL-deficient patients. Although the molecular mechanisms remain poorly understood, we infer that the NO pathway might play a role in the pathophysiology related to congenital urea cycle disorders. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.metabol.2008.09.025

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Effects of bezafibrate on dyslipidemia with cholestasis in children with familial intrahepatic cholestasis-1 deficiency manifesting progressive familial intrahepatic cholestasis

Hironori Nagasaka, Tohru Yorifuji, Kenichi Hirano, Akemi Otac, Yumiko Toyama-Nakagawa, Tomozumi Takatani, Hirokazu Tsukahara, Kunihiko Kobayashi, Masaki Takayanagi, Yukihiro Inomata, Shinji Uemoto, Takashi Miida

METABOLISM-CLINICAL AND EXPERIMENTAL 58 ( 1 ) 48 - 54 2009.1

Language：English Publisher：W B SAUNDERS CO-ELSEVIER INC

No appropriate pharmaceutical therapy has been established for dyslipidemia with cholestasis in progressive familial intrahepatic cholestasis(PFIC)-1. We evaluated the efficacy of bezafibrate in PFIC-1. We monitored the clinical presentation and lipoprotein metabolism of 3 patients, aged 3, 4, and 8 years. with FIC1 deficiency, manifesting PFIC-1, over 12 months of bezafibrate therapy. Pruritus was substantially alleviated in the 3 patients after initiation of bezafibrate. Cholestasis was alleviated in 2 of them. Serum high-density lipoprotein cholesterol and low-density lipoprotein cholesterol increased 1.6- to 2.0-fold and 1.1 - to 1.2-fold, respectively; but the values remained low and normal, respectively. Serum lipoprotein X, which was at normal levels before treatment, was elevated to levels above the upper limit of the reference range. High serum triglyceride levels decreased by 15% to 30%, to normal levels, after treatment initiation. The activities of lipoprotein lipase and hepatic triglyceride lipase were increased, but those of high-density lipoprotein regulators remained unchanged. Liver expression Of multidrug resistance protein-3, which regulates lipoprotein X synthesis, was enhanced by bezafibrate therapy. Bezafibrate treatment favorably affected pruritus, dyslipidemia, and cholestasis in PFIC-1. (C) 2009 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.metabol.2008.08.005

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Children's toxicology from bench to bed - Liver Injury (3): Oxidative stress and anti-oxidant systems in liver of patients with Wilson disease

Hironori Nagasaka, Masaki Takayanagi, Hirokazu Tsukahara

Journal of Toxicological Sciences 34 ( 2 ) SP229 - SP236 2009

Language：English

The role of oxidative stress in the pathogenesis of liver disease in Wilson disease (WD), a genetic disorder characterized by excess hepatic deposition of copper, which generates free radicals, remains unclear. This study investigates oxidative stress on the liver and hepatic anti-oxidant responses in WD using liver specimens from affected patients showing mild liver damage (group I, n = 3), moderate or greater liver damage (group II, n = 5) and fulminant hepatic failure (group III, n = 5), and from asymptomatic carriers (n = 2). Decreased ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) and increased thiobarbituric acid reactive substance (TBARS), a lipid peroxidation product, were found in every affected patient, especially in groups II and III patients. Activities and protein expressions of Mn-dependent superoxide dismutase (Mn-SOD), CuZn-SOD, and catalase were decreased in all patients, especially in group III patients. Glutathione peroxidase activity was decreased only in group III patients. Asymptomatic carriers without any clinical manifestations showed normal TBARS level and GSH/GSSG ratio with increases in both GSH and GSSG levels. Their CuZn-SOD, Mn-SOD and catalase activities were increased. These results suggest that excessive copper-derived oxidants contribute to development and progression of liver disease in WD.

DOI： 10.2131/jts.34.SP229

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