Faculty Profiles - TSUKAHARA Hirokazu

MISC - TSUKAHARA Hirokazu

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エリスロポイエチン高値の生体応答学的意義について

塚原宏一, 小倉一将, 古畑律代, 田村知史, 眞弓光文, 西島浩二, 宿南憲一, 小辻文和, 上野正樹

発達腎研究会誌 15 ( 1 ) 25 - 33 2007

酸化ストレスとレドックス制御

塚原宏一

総合臨床 56 ( 10 ) 2915 - 2918 2007

腎・泌尿器疾患診療マニュアル - 小児から成人まで: Kの異常（小児）

塚原宏一

日本医師会雑誌 136 S102-S103 2007

腎尿路異常症患者における酸化ストレス環境の評価：当院の年齢別基準値に基づいて

塚原宏一, 平岡政弘, 森夕起子, 巨田尚子, 徳力周子, 川谷正男, 長坂博範, 川上寿子, 関根恭一, 眞弓光文

小児腎臓病学会雑誌 20 ( 2 ) 131 - 135 2007

周生期の循環制御: 特に母乳中の血管作動因子の分析についての研究

塚原宏一

平成16年財団法人森永奉仕会太田敬三記念賞: 研究実績報告書 2007

Procedures for prevention of perinatal group B streptococcal diseases: A multicenter questionnaire survey of hospitals in the Kyoto Neonatal Disease Study Group, Japan

Kousaku Matsubara, Masahiko Kawai, Tatsutoshi Nakahata, Fumihide Kato, Hirokazu Tsukahara, Masaru Yamakawa, Kazuhiro Hashimoto, Seiichi Shimada, Shinji Maeda, Mitsuyoshi Okumura, Hiroo Kanaoka

Journal of Infection and Chemotherapy 13 ( 1 ) 59 - 62 2007

Language：English Publishing type：Book review, literature introduction, etc. Publisher：Springer Japan

To explore clinical protocols for the prevention of early-onset group B Streptococcus (EOGBS) disease of the newborn in Japan, we conducted a multicenter questionnaire survey. Of 32 regional centers participating in the Kyoto Neonatal Study Group, 28 provided usable data concerning prevention practices undertaken between 2000 and 2004. Twenty-three (82%) of the 28 hospitals implemented bacteriological screening to identify maternal GBS carriage, and all 23 hospitals administered intrapartum antibiotics to all screening-positive pregnant women. There were no institutes that used risk-based strategies. In the 23 hospitals, bacteriological screening was conducted mostly by lower vaginal swab alone (n = 18). Eighteen hospitals performed screening once during pregnancy, either before 34 weeks' gestation (n = 6) or between 35 and 37 weeks' gestation (n = 12). Oral antepartum antibiotics, when carriage was identified, were administered at 12 (52%) hospitals. Twenty institutes used penicillins for intrapartum prophylaxis. However, the loading dose for chemoprophylaxis ranged from 0.5 to 2g, and the interval between repeat administrations ranged from 4 to 12h. Although the results indicated that more than 80% of the hospitals surveyed had introduced some screening-based prevention practices, the timing of the bacteriological screening during the pregnancy, the number of screenings, and the screening sites, as well as the antibiotics used, and their dosage, varied widely. Because of these highly variable methods, the efficacy of the implementation of preventive practices could not be determined. This study is the first to have described preventive practices for EOGBS disease in Japan in the era of Centers for Disease Control and Prevention guidelines. In light of the above results, a larger study under a unifying protocol would be warranted. © 2007 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

DOI： 10.1007/s10156-006-0487-2

Biomarkers for oxidative stress: Clinical application in pediatric medicine

Hirokazu Tsukahara

CURRENT MEDICINAL CHEMISTRY 14 ( 3 ) 339 - 351 2007

Language：English Publishing type：Book review, literature introduction, etc. Publisher：BENTHAM SCIENCE PUBL LTD

Loads of reactive oxygen species (ROS), including superoxide anion and nitric oxide, that overburden antioxidant systems induce oxidative stress in the body. Major cellular targets of ROS are membrane lipids, proteins, nucleic acids, and carbohydrates. Circumstantial evidence suggests that ROS play a crucial role in the initiation and progression of various diseases in children and adolescents. The involvement of ROS and oxidative stress in pediatric diseases is an important concern, but oxidative stress status in young subjects and appropriate methods for its measurement remain to be defined. Recently, specific biomarkers for oxidative damage and antioxidant defense have been introduced into the field of pediatric medicine. This review is intended to provide an overview of clinical applications of oxidative stress biomarkers in the field of pediatric medicine. First, this review presents the biochemistry and pathophysiology of ROS and antioxidant defense systems. Second, it presents a list of clinically applicable biomarkers, along with pediatric diseases in which enhanced oxidative stress might be involved. The discussion emphasizes that several reliable biomarkers are easily measurable using enzyme-linked immunosorbent assay. Third, this review presents age-related reference normal ranges of oxidative stress biomarkers, including urinary acrolein-lysine, 8-hydroxy-2'-deoxyguanosine, nitrite/nitrate, and pentosidine, and the changes of the parameters in several clinical conditions, including atopic dermatitis and diabetes mellitus. New and interesting data on oxidative stress and antioxidant defenses in neonatal biology are also presented. Fourth, this review discusses the ever-accumulating body of data linking oxidative stress to disturbances of the nitric oxide system and vascular endothelial activation/dysfunction. Finally, this review describes the reported clinical trials that have evaluated the efficacy of antioxidants for oxidative-stress related diseases. Suggestions are advanced for the direction of future trials using antioxidant therapies. Repeated measurement of appropriate parameters will enable us to discern the pathophysiological patterns of pediatric diseases and guide our therapies appropriately.

DOI： 10.2174/092986707779941177

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免疫アレルギー疾患予防・治療研究事業研究報告書アレルギー疾患の自己管理と個別化医療を目指した早期診断基準と早期治療法の確立及びその有効性と有害事象の評価に関する研究小児気管支喘息の早期診断・治療指針の作成と評価に関する研究

眞弓光文, 大嶋勇成, 塚原宏一

免疫アレルギー疾患予防・治療研究事業研究報告書平成18年度第3分冊 2007

Evaluation of a urinary multi-parameter biomarker set for oxidative stress in children, adolescents and young adults

Satoshi Tamura, Hirokazu Tsukahara, Masaki Ueno, Masayuki Maeda, Hisako Kawakami, Kyouichi Sekine, Mitsufumi Mayumi

FREE RADICAL RESEARCH 40 ( 11 ) 1198 - 1205 2006.11

Language：English Publisher：TAYLOR & FRANCIS LTD

The involvement of reactive oxygen species (ROS) and oxidative stress in pediatric diseases is an important concern, but oxidative stress status in healthy young subjects and appropriate methods for its measurement remain unclear. This study evaluated a comprehensive set of urinary biomarkers for oxidative stress in healthy children, adolescents and young adults. Results show that urinary excretion of acrolein-lysine, 8-hydroxy-2'-deoxyguanosine (8-OHdG), nitrite/nitrate and pentosidine were highest in the youngest subjects and decreased to constant levels by early adolescence. Urinary acrolein lysine, 8-OHdG, nitrite/nitrate and pentosidine showed significant inverse correlations with age, but pyrraline did not change significantly with age. No significant differences in biomarkers were apparent between males and females. Younger subjects grow rapidly and sustain immune activation, and are probably exposed to high concentrations of ROS and nitric oxide. Consequently, they are more vulnerable to oxidation of lipids, proteins, DNA and carbohydrates. Normal reported values in this study are a basis for future studies of disease mechanisms involving oxidative stress and for future trials using antioxidant therapies for oxidative stress-related diseases in the pediatric field.

DOI： 10.1080/10715760600895191

Reversible splenial lesion with restricted diffusion in a wide spectrum of diseases and conditions - Report of eight additional cases and literature review

M. Maeda, H. Tsukahara, H. Terada, S. Nakaji, H. Nakamura, H. Oba, O. Igarashi, K. Arasaki, T. Machida, K. Takeda, J. I. Takanashi

JOURNAL OF NEURORADIOLOGY 33 ( 4 ) 229 - 236 2006.10

Language：English Publishing type：Book review, literature introduction, etc. Publisher：MASSON EDITEUR

Objective: Reversible lesion in the central area of the splenium of the corpus callosum (SCC) is a unique phenomenon occurring particularly in patients with encephalitis or encephalopathy and in patients receiving antiepileptic drugs (AED). We report MR imaging findings, clinical courses, and outcomes in eight patients with various diseases and conditions.
Materials and methods: Eight patients with a reversible SCC lesion with transiently restricted diffusion were reviewed retrospectively. Diseases and conditions that were associated with a reversible lesion included epilepsy receiving AED (n=1), seizure from eclampsia receiving AED (n=1), mild infectious encephalitis (n=2), hypernatremia resulting in osmotic myelinolysis (n=1), and neoplasm (n=3) such as acute lymphocytic leukemia, spinal meningeal melanocytoma, and esophageal cancer. We evaluated MR imaging findings and clinical findings.
Results: Seven patients had isolated SCC lesions; one patient with osmotic myelinolysis showed additional parenchymal lesions. The reversible SCC lesion shape was oval (n=6) or extended (n=2). The mean apparent diffusion coefficient value of the splenial lesion was 0.40 +/- 0.16x10(-3)mm(2)/s, ranging from 0.22 to 0.64x10(-3)mm(2)/s. In a patient with osmotic myelinolysis, additional white matter lesions, shown as restricted diffusion, were revealed as not reversible on follow-up MR imaging. Neurological courses and outcomes were good in seven patients with isolated SCC lesions, but poor in one with osmotic myelinolysis.
Conclusion: Reversible SCC lesion with restricted diffusion is apparent in a wide spectrum of diseases and conditions. Neurological courses and outcomes are good, particularly in patients with isolated SCC lesions. Knowledge of MR imaging findings and the associated spectrum of diseases and conditions might prevent unnecessary invasive examinations and treatments.

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Relationship between oxidative stress and antioxidant systems in the liver of patients with Wilson disease: Hepatic manifestation in Wilson disease as a consequence of augmented oxidative stress

Hironori Nagasaka, Ikuo Inoue, Ayano Inui, Haruki Komatsu, Tsuyoshi Sogo, Kei Murayama, Tomoko Murakami, Tohru Yorifuji, Kotaro Asayama, Shigeo Katayama, Shinji Uemoto, Kunihiko Kobayashi, Masaki Takayanagi, Tomoo Fujisawa, Hirokazu Tsukahara

PEDIATRIC RESEARCH 60 ( 4 ) 472 - 477 2006.10

Language：English Publisher：INT PEDIATRIC RESEARCH FOUNDATION, INC

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 that generates free radicals, remains unclear. This study investigates oxidative stress on the liver and hepatic antioxidant responses in WD using liver specimens from affected patients showing mild liver damage (group 1, n = 3), moderate or greater liver damage (group 11, n = 5), and fulminant hepatic failure (group 111, 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 group 11 and III patients. Activities and protein expressions of Mn-dependent superoxide dismutase (Mn-SOD), CuZn-dependent superoxide dismutase (CuZn-SOD), and catalase were decreased in all patients, especially in group III patients. Glutathione peroxidase (GPx) 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, MnSOD, and catalase activities were increased. These results suggest that excessive copper-derived oxidants contribute to development and progression of liver disease in WD.

DOI： 10.1203/01.pdr.0000238341.12229.d3

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Micelles of pulmonary surfactant in human amniotic fluid at term

Koji Nishijima, Ken-Ichi Shukunami, Hirokazu Tsukahara, Makoto Orisaka, Jun'Ichiro Miura, Fumikazu Kotsuji

PEDIATRIC RESEARCH 60 ( 2 ) 196 - 199 2006.8

Language：English Publisher：INT PEDIATRIC RESEARCH FOUNDATION, INC

Studies using in vitro analysis have shown that the interaction between pulmonary surfactant and vernix caseosa could explain the appearance of amniotic fluid turbidity. That phenomenon is interpreted based on the "roll-up" hypothesis. We tested the roll-up hypothesis by examining the presence of micelles of pulmonary surfactant in human amniotic fluid at term. Amniotic fluid samples were collected from each of six healthy pregnant women at term and at 16 wk of gestation. These samples were stained negatively and analyzed using an electron microscope. Ultrastructures present in amniotic fluid were compared with the structure of micelles derived from suspended surfactant TA isolated from bovine lung. Surfactant TA formed spheroidal and rod-shaped micelles 10-70 nm in diameter above the critical micelle concentration. Identical micelle particles were described in human amniotic fluid at term. In addition, surfactant protein B was identified in the micelle fraction of amniotic fluid. However, no micelles were found in human amniotic fluid taken at 16 wk of gestation. Our results support the view that pulmonary surfactant could induce the detachment of vernix caseosa and increase the turbidity of the amniotic fluid.

DOI： 10.1203/01.pdr.0000228329.90502.3a

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Hypocalcemia in mitochondrial trifunctional protein deficiency

I. Hata, H. Tsukahara, Y. Shigematsu, M. Mayumi

JOURNAL OF INHERITED METABOLIC DISEASE 29 114 - 114 2006.8

Urinary creatinine excretion and protein/creatinine ratios vary by body size and gender in children

Y Mori, M Hiraoka, N Suganuma, H Tsukahara, H Yoshida, M Mayumi

PEDIATRIC NEPHROLOGY 21 ( 5 ) 683 - 687 2006.5

Language：English Publisher：SPRINGER

Urinary protein/creatinine ratio (Up/cr) is a simple measurement for evaluation of proteinuria. However, exact effects of body size and gender on urinary excretion of creatinine and Up/cr remain unknown. We aimed to clarify their effects. Early morning urine samples were collected from 124 children with urinary tract disorders. Urinary hourly excretion of creatinine, Ucr (in milligrams per hour), urinary hourly excretion of protein per body surface area, Up (milligrams per square meter per hour), and Up/cr (milligrams per milligram) were calculated. Effects of gender, age, body height, body weight and body surface area on Ucr and Up/cr were analyzed, respectively, in a multiple linear regression model. Body surface area and gender affected Ucr (r(2)=0.842, P < 0.0001). Ucr adjusted by body surface area increased as body surface area grew with moderate variation. Up/cr showed a close correlation with Up and was affected by body height and gender as well. The regression equation showed that Up/cr values corresponding to the normal upper limit of Up, i.e., 4 mg/m(2)/h, in boys and girls 170 cm tall were approximately one third of those in children 80 cm tall (0.121 vs 0.043 for boys, 0.132 vs 0.047 for girls). The present study indicates that estimation of Up/cr needs to include consideration of children's body height and gender.

DOI： 10.1007/s00467-005-0001-6

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Neonatal suppurative parotitis possibly associated with congenital cytomegalovirus infection and maternal methyldopa administration

Y Todoroki, H Tsukahara, M Kawatani, Y Ohshma, KI Shukunami, F Kotsuji, M Mayumi

PEDIATRICS INTERNATIONAL 48 ( 2 ) 185 - 186 2006.4

Widening spectrum of a reversible splenial lesion with transiently reduced diffusion

J Takanashi, AJ Barkovich, T Shiihara, H Tada, M Kawatani, H Tsukahara, M Kikuchi, M Maeda

AMERICAN JOURNAL OF NEURORADIOLOGY 27 ( 4 ) 836 - 838 2006.4

Language：English Publisher：AMER SOC NEURORADIOLOGY

Four patients with encephalitis/encephalopathy and parenchymal lesions accompanying reversible splenial lesions were retrospectively evaluated. In 3 patients, reversible lesions with transiently reduced diffusion were seen in the splenium and symmetrically in the peripheral frontoparietal white matter, clinical signs and symptoms were mild, and recovery was complete. These and previous observations suggest a less severe course and outcome for patients with reversible lesions isolated to the splenium or to the splenium and peripheral frontoparietal white matter.

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Urinary oxidative stress markers in young patients with type 1 diabetes

Hata, I, M Kaji, S Hirano, Y Shigematsu, H Tsukahara, M Mayumi

PEDIATRICS INTERNATIONAL 48 ( 1 ) 58 - 61 2006.2

Language：English Publisher：WILEY-BLACKWELL PUBLISHING, INC

Background: Involvement of oxidative stress in the pathogenesis of diabetic vascular complications has been proposed. However, there are few methods to determine the status of oxidative stress both directly and quantitatively in young patients with type 1 diabetes.
Methods: A total of 27 young patients with type 1 diabetes (mean age +/- SD, 12.6 +/- 4.2 years) with normal renal function and 38 healthy control subjects (13.0 +/- 4.6 years) were investigated. Early morning voiding urine samples were collected. The concentrations of acrolein-lysine adducts, 8-hydroxy-2'-deoxyguanosine (8-OHdG) were determined using competitive enzyme-linked immunosorbent assay, and nitric oxide metabolites were measured using the colorimetric, non-enzymatic assay.
Results: Urinary concentrations of 8-OHdG, but not acrolein-lysine adducts and nitric oxide metabolites, were significantly increased in the diabetic group. For diabetic patients, microalbuminuria was significantly correlated with higher concentrations of all three markers. Hemoglobin A(1c) values were significantly correlated with 8-OHdG values.
Conclusion: These findings indicate that increased oxidative stress and the risk of vascular complications may be present at early stages of type 1 diabetes.

DOI： 10.1111/j.1442-200X.2006.02156.x

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CoQ10の臨床的研究: 小児疾患とCoQ10

徳力周子, 塚原宏一, 大嶋勇成, 古畑律代, 塚原康代, 谷崎崇, 太田徳仁, 西井学, 関根恭一, 眞弓光文

機能姓食品と薬理栄養 3 ( 4 ) 241 - 248 2006

胎児超音波検査でPotter sequenceを疑われ、出生後urosepsisの管理に難渋した多発性嚢胞腎の1女児例

古畑律代, 金谷由宇子, 田村知史, 徳力周子, 塚原宏一, 谷澤昭彦, 平岡政弘, 眞弓光文, 西島浩二, 宿南憲一

Pharma Medica 24 ( 5 ) 126 - 129 2006

骨形成不全症IIA型の乳児例

早川和代, 藤永英志, 奥村光祥, 中西宏美, 三國貴康, 横尾憲孝, 濱畑啓悟, 吉田晃, 田中里江子, 塚原宏一, 百井亨

小児科臨床 59 ( 5 ) 995 - 999 2006

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