Faculty Profiles - TSUKAHARA Hirokazu

MISC - TSUKAHARA Hirokazu

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原因不明の小児急性肝炎に関する実態調査(一次調査)報告書

近藤宏樹, 多屋馨子, 天羽清子, 乾あやの, 笠原群生, 鈴木光幸, 田中孝明, 津川毅, 別所一彦, 保科隆之, 宮入烈, 虫明聡太郎, 吉川哲史, 齋藤昭彦, 塚原宏一, 森岡一朗, 須磨崎亮, 細矢光亮, 日本小児科学会予防接種・感染症対策委員会原因不明の小児の急性肝炎対策ワーキンググループ

日本小児科学会雑誌 127 ( 7 ) 1033 - 1038 2023.7

Language：Japanese Publisher：(公社)日本小児科学会

2022年より欧米から「原因不明の小児急性肝炎」について多くの報告があがるようになり、アデノウイルスや新型コロナウイルス感染症(COVID-19)流行との関連が疑われている。これまで本邦では小児の急性肝炎のサーベイランスが行われていないことから、今回、日本小児科学会会員が所属する全国の病院小児科責任者を対象に、2017年1月～2022年6月までの期間における同疾患の実態について質問紙調査を行い、947名より回答を得た。その結果、COVID-19流行前の報告数は2017年260名、2018年257名、2019年243名で、COVID-19流行中の報告数は2020年164名、2021年192名、2022年1～6月で113名と、COVID-19流行中の方が少ない傾向がみられた。COVID-19流行前は0歳および1～4歳群の症例数が他の年齢群と比較して多い傾向がみられたが、流行中はこれらの年齢群で減少が著明であった。地域別では、COVID-19流行前・流行後ともに、京都府・愛知県・福島県からの報告が多かった。

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原因不明の小児急性肝炎に関する実態調査(一次調査)報告書

日本小児科学会雑誌 127 ( 7 ) 1033 - 1038 2023.7

小児における院内迅速対応システムに対する意識調査

芳賀大樹, 冨田健太朗, 藤原直樹, 石戸美妃子, 岡本吉生, 糟谷周吾, 上村克徳, 堤義之, 平本龍吾, 松井彦郎, 松永綾子, 朱田博聖, 池山由紀, 西原正人, 福井美保, 塚原宏一, 山岸敬幸

日本小児科学会雑誌 127 ( 11 ) 2023

FBT(Family Based Treatment)実施中の低血糖についての検討

藤井智香子, 藤井智香子, 藤井智香子, 岡田あゆみ, 岡田あゆみ, 岡田あゆみ, 田中知絵, 田中知絵, 重安良恵, 重安良恵, 椙原彰子, 椙原彰子, 堀内真希子, 堀内真希子, 塚原宏一, 塚原宏一, 塚原宏一

子どもの心とからだ 32 ( 2 ) 2023

Two cases of post-transfusion iron overload in which MRI was useful for differentiating liver injury after hematopoietic stem cell transplantation

鷲尾佳奈, 藤原かおり, 石田悠志, 金光喜一郎, 建部泰尚, 越智元春, 為房宏輔, 塩飽孝宏, 塚原宏一

日本小児血液・がん学会雑誌(Web) 60 ( 4 ) 2023

頸部痛を契機に腸管嚢胞様気腫症が判明したSLEの1例

八代将登, 茂原研司, 宇田和宏, 斎藤有希惠, 津下充, 塚原宏一

日本小児リウマチ学会総会・学術集会プログラム・抄録集 31回 163 - 163 2022.10

長期入院後復学した脳腫瘍患者への発達支援 2症例の報告

田中知絵, 岡田あゆみ, 藤井智香子, 重安良恵, 椙原彰子, 堀内真希子, 塚原宏一

子どもの心とからだ 31 ( 2 ) 279 - 279 2022.8

心身症児のP-Fスタディ(Picture Frustration Study)第2報:U反応の特徴

椙原彰子, 岡田あゆみ, 堀内真希子, 重安良恵, 藤井智香子, 赤木朋子, 田中知絵, 塚原宏一

子どもの心とからだ 31 ( 2 ) 278 - 278 2022.8

養育機能低下家庭における心身症児診療保護者支援の検討

重安良恵, 岡田あゆみ, 椙原彰子, 堀内真希子, 田中知絵, 藤井智香子, 塚原宏一

子どもの心とからだ 31 ( 2 ) 271 - 271 2022.8

親子並行面接が奏功した抜毛症の女児例

椙原彰子, 重安良恵, 堀内真希子, 田中知絵, 藤井智香子, 岡田あゆみ, 塚原宏一

小児心身症研究 ( 28 ) 16 - 23 2022.6

Language：Japanese Publisher：日本小児心身医学会-中国四国地方会

抜毛症は、繰り返し体毛を抜くことと、これを減らそう・やめようとする試みが特徴の、身体に焦点化した反復行動である。学童期から思春期に多く、抜毛によって満足や快感、安心感を得ることがあるとされる。本報告では、抜毛症女子の親子並行面接過程を振り返り、治療の意義を考察する。患児は、学校で過剰適応な行動が指摘されており、面接でも自分の希望を言うことは少なかった。治療が進むにつれて自ら遊びを選ぶなどの自己表現が増えた。また、箱庭療法や遊戯療法で繰り返し「家」を表現し、環境への信頼を獲得した。母は、心療内科治療歴があり、育児困難感や夫婦関係の問題を抱えていた。母面接では、抜毛の背景を説明し、母の苦労を傾聴しながら、母の対応や患児の変化を肯定的にフィードバックした。患児は学校でも自己主張が可能となり、抜毛は減少した。母も患児の成長を語るようになった。親子並行面接の構造と家族支援の視点が母子を支えたと考えた。(著者抄録)

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新生児領域における酸化ストレス制御の意義

塚原宏一, 宮原宏幸, 鷲尾洋介, 津下充, 馬場健児

日本小児高血圧研究会誌(Web) 18 ( 1 ) 2022

Medical safety management at university hospital

塚原宏一

日本小児腎臓病学会雑誌(Web) 35 ( 2 ) 2022

Achondroplasia

長谷川高誠, 二川奈都子, 宮原宏幸, 塚原宏一

岡山医学会雑誌 134 ( 3 ) 2022

【周産期医学必修知識(第9版)】血中リン異常

塚原宏一, 宮原宏幸, 馬場健児

周産期医学 51 ( 増刊 ) 883 - 885 2021.12

【小児疾患診療のための病態生理2 改訂第6版】腎・泌尿器疾患腎・尿路結石

宮原宏幸, 塚原宏一

小児内科 53 ( 増刊 ) 598 - 600 2021.12

コロナ禍における鼻腔検体採取方法に関する検討

八代将登, 茂原研司, 宇田和宏, 斎藤有希惠, 津下充, 塚原宏一

日本小児感染症学会総会・学術集会プログラム・抄録集 53回 166 - 166 2021.10

新型コロナウイルス感染症(COVID-19)流行の現況と展望

塚原宏一

現代産婦人科 69 ( Suppl. ) S35 - S35 2021.9

経口負荷経験で診断に至った食用クラゲアレルギーの1小児例

津下充, 茂原研司, 宇田和宏, 斎藤有希惠, 八代将登, 池田政憲, 塚原宏一

日本小児アレルギー学会誌 35 ( 4 ) 385 - 385 2021.9

医学部学生に対する予防接種記録の判定方法に関する検討

八代将登, 茂原研司, 宇田和宏, 塚原宏一

日本環境感染学会総会プログラム・抄録集 36回 253 - 253 2021.9

岡山大学病院での急性単純性膀胱炎に対する尿検査実施状況および経口抗菌薬の処方動向に関する実態調査

森下陽介, 東恩納司, 稲葉裕明, 草野展周, 塚原宏一

日本環境感染学会総会プログラム・抄録集 36回 298 - 298 2021.9

岡山大学病院における抗菌薬適正使用支援チーム(AST)の取り組みと評価

東恩納司, 森下陽介, 稲葉裕明, 草野展周, 塚原宏一

日本環境感染学会総会プログラム・抄録集 36回 245 - 245 2021.9

医学部学生に対する予防接種記録判定方法の現状と問題点

茂原研司, 八代将登, 宇田和宏, 塚原宏一

日本環境感染学会総会プログラム・抄録集 36回 253 - 253 2021.9

起立性調節障害患者の下肢血行動態についての検討

藤井智香子, 岡田あゆみ, 重安良恵, 赤木朋子, 田中知絵, 椙原彰子, 堀内真希子, 塚原宏一

子どもの心とからだ 30 ( 2 ) 229 - 229 2021.8

心身症の子どものP-Fスタディ(Picture Frustration Study)の特徴

椙原彰子, 岡田あゆみ, 藤井智香子, 重安良恵, 田中知絵, 赤木朋子, 堀内真希子, 塚原宏一

子どもの心とからだ 30 ( 2 ) 228 - 228 2021.8

食物アレルゲン経口負荷試験で診断に至った食用クラゲアレルギーの1小児例

津下充, 茂原研司, 斎藤有希恵, 八代将登, 池田政憲, 塚原宏一

アレルギー 70 ( 6-7 ) 788 - 788 2021.8

チームアプローチによって疼痛が改善した消化管GVHDの1例

藤本耕慈, 藤井智香子, 岡田あゆみ, 重安良恵, 椙原彰子, 堀内真希子, 塚原宏一

子どもの心とからだ 30 ( 2 ) 236 - 236 2021.8

起立性調節障害患者のQOLについての検討(第3報) 治療後の変化

重安良恵, 岡田あゆみ, 藤井智香子, 田中知絵, 赤木朋子, 椙原彰子, 堀内真希子, 塚原宏一

子どもの心とからだ 30 ( 2 ) 247 - 247 2021.8

妊娠高血圧症の母親から生まれた児における3歳の肥満有病率および関連リスク因子

光井崇, 谷和祐, 三島桜子, 鷲尾洋介, 吉本順子, 塚原宏一, 増山寿

日本周産期・新生児医学会雑誌 57 ( Suppl. ) P158 - P158 2021.6

妊娠高血圧症候群の母体より出生したSGA児のcatch-upに影響する因子

三島桜子, 光井崇, 三苫智裕, 横畑理美, 大平安希子, 谷和祐, 牧尉太, 衛藤英理子, 早田桂, 鷲尾洋介, 吉本順子, 塚原宏一, 増山寿

日本周産期・新生児医学会雑誌 57 ( Suppl. ) P218 - P218 2021.6

ステロイド使用中のネフローゼ症候群における骨微細構造の検討

宮原宏幸, 宮井貴之, 二川奈都子, 宮原大輔, 長谷川高誠, 塚原宏一

日本腎臓学会誌 63 ( 4 ) 500 - 500 2021.6

日本小児腎臓病学会のBCP(事業継続計画) 日本小児腎臓病学会のBCP 医療安全・倫理・災害対応・COI委員会から

塚原宏一

日本小児腎臓病学会雑誌 34 ( 1Suppl. ) 52 - 52 2021.5

ステロイド使用中のネフローゼ症候群における骨微細構造の評価

宮原宏幸, 宮井貴之, 二川奈都子, 長谷川高誠, 宮原大輔, 塚原宏一

日本小児腎臓病学会雑誌 34 ( 1Suppl. ) 137 - 137 2021.5

大学病院における医療安全管理

塚原宏一

日本小児腎臓病学会雑誌 34 ( 1Suppl. ) 48 - 48 2021.5

重症神経疾患の病原体同定のための検体採取の実態解明

八代将登, 多屋馨子, 茂原研司, 津下充, 塚原宏一

感染症学雑誌 95 ( 臨増 ) 275 - 275 2021.4

岡山県における新型コロナウイルス感染症流行の疫学的特徴

東恩納司, 千堂年昭, 草野展周, 塚原宏一

岡山医学会雑誌 133 ( 1 ) 43 - 48 2021.4

Language：Japanese Publisher：岡山医学会

岡山県の新型コロナウイルス(SARS-CoV-2)感染者の発生状況を詳細に調査した。調査対象者は、岡山県において2020年3月22日から8月24日までの間にPCR法またはLAMP法にてSARS-CoV-2感染者と公表された患者で、第1波で25人、第2波で116人の合計141人であった。第1波では50代の感染者が29%で最も多く、50代以降で全体の54%を占めていた。第2波では20代の感染者が40%で最も多く、30代が14%、40代が17%であり、20代から40代が全体の71%を占めていた。居住地は、第1波、第2波ともに岡山市に居住する感染者が最も多く、それぞれ、全体の65%、73%を占めていた。第2波では、第1波と比較して非同居間での感染割合が高かった。疫学リンク不明例を除いた検討(第1波6人、第2波62人)では、20歳未満より20歳以上への感染、20歳未満同士の感染の事例はなかった。第1波ではクラスターはなかったが、第2波では三つのクラスターが認められた。クラスターはすべて岡山市で発生しており、各クラスターにおける感染者数は5人、8人、6人で、総計19人であった。疫学リンク不明例を除いた検討であるが、第1波(総計6人)、第2波(総計62人)におけるPCR陽性確認間隔について、それぞれの平均±標準偏差/中央値(最小値-最大値)は、第1波で0.8±0.8日/1(0〜2)日、第2波で2.0±1.4日/2(0〜9)であった。

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新生児医療における酸化ストレス制御の意義

塚原宏一

日本産科婦人科学会雑誌 73 ( 臨増 ) S - 43 2021.3

急性散在性脳脊髄炎との鑑別に苦慮した中枢神経原発悪性リンパ腫の1例

宮原大輔, 嶋田明, 道上理絵, 兵頭勇紀, 花岡義行, 秋山倫之, 塚原宏一, 小林勝弘

日本小児科学会雑誌 125 ( 2 ) 271 - 271 2021.2

小児科で経験する過敏性腸症候群の特徴

藤井智香子, 岡田あゆみ, 重安良恵, 塚原宏一

心身医学 61 ( 1 ) 57 - 63 2021.1

Language：Japanese Publisher：(一社)日本心身医学会

過敏性腸症候群(irritable bowel syndrome:IBS)は児童・思春期の代表的な機能性消化管疾患であるが、その実態については不明な点も多い。IBSは心理的ストレスの影響を受けやすく、患者の心理社会的背景を理解することは適切な治療介入につながると考えられる。児童・思春期のIBS患者の特徴を明らかにすることを目的に、岡山大学病院小児科を受診したIBS患者のうち発症が18歳以下であった69例の性別や併存疾患などの特徴について検討を行った。男性35例、女性34例で、59例は不登校状態にあり、外出困難をきたしている症例もあった。併存疾患として起立性調節障害やアレルギー性疾患を有する症例が多く、24例が自閉スペクトラム症(autism spectrum disorder:ASD)の診断を受けていた。ASDの感覚過敏やこだわりが強いという特性が、症状の遷延や訴えの増加につながる可能性があり、発達特性に留意して診療を行うことが必要であると考えられた。また男性に外出困難を伴う症例を多く認め、このような症例では特に、環境調整や心理療法を含めた対応が有効だった。(著者抄録)

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Abnormality of phosphate metabolism

塚原宏一, 宮原宏幸, 馬場健児

周産期医学 51 2021

【新型コロナウイルス感染症】総論および岡山大学病院における新型コロナウイルス感染症への対応

塚原宏一

岡山医学会雑誌 132 ( 3 ) 152 - 162 2020.12

心因性腹痛が疑われた小児好酸球性消化管疾患の1例

國近公介, 吉川知伸, 宮原大輔, 藤井洋輔, 藤井智香子, 八代将登, 岡田あゆみ, 塚原宏一

子どもの心とからだ 29 ( 3 ) 281 - 285 2020.11

Language：Japanese Publisher：(一社)日本小児心身医学会

好酸球性消化管疾患は慢性の嘔吐や腹痛の原因となり、内視鏡検査所見で非特異的な所見を呈する症例や肉眼的な異常を呈さない症例では診断が難しい場合がある。今回、慢性の嘔吐・腹痛があり、心因性の腹痛と考えられていたが、アレルギー素因があることから好酸球性消化管疾患が疑われ、上部消化管内視鏡検査で粘膜生検をすることで、好酸球性消化管疾患と診断することができた症例を経験した。プロトンポンプ阻害薬およびロイコトリエン受容体拮抗薬による治療を開始し、症状の改善を認めた。慢性の消化器症状を有する患者でアレルギー素因がある場合には、好酸球性消化管疾患を鑑別に加える必要があると考えられた。(著者抄録)

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嘔吐恐怖症に認知行動療法(Cognitive behavioral therapy:CBT)を施行した14歳女子例

住友裕美, 藤井智香子, 岡田あゆみ, 重安良恵, 椙原彰子, 堀内真希子, 塚原宏一

子どもの心とからだ 29 ( 3 ) 298 - 304 2020.11

Language：Japanese Publisher：(一社)日本小児心身医学会

認知行動療法(Cognitive behavioral therapy:CBT)は、不安や恐怖に対する有効性が実証されており、近年小児領域でも実施が増えている。しかし、小児の場合は言語理解や認知能力が発達途上のため、適応には配慮が必要である。嘔吐恐怖症(phagophobia)は、「嘔吐」に対する単一の恐怖症である。従来、成人の嘔吐恐怖症に対する治療法としてCBTが有効であるという報告は多かったが、小児での報告は少ない。今回、嘔吐恐怖症に対しCBTを施行した症例について、その有効性を含めて検討し報告した。症例は14歳女子、受診の1年前から嘔気や呼吸苦を自覚し、以降外出が困難となっていた。認知再構成法などのCBTを実施し、約1年後に外出や外食が可能となった。患児に治療意欲があり、CBTモデルに沿って振り返る力があったことから、早期の改善を得た。本症の小児例においてもCBTは有効と考えた。(著者抄録)

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インフルエンザA(H1N1)pdm09による急性呼吸窮迫症候群に対して体外式膜型人工肺とペラミビル・バロキサビルマルボキシル併用療法で改善した一例

津下充, 茂原研司, 斎藤有希惠, 八代将登, 塚原宏一

日本小児感染症学会総会・学術集会プログラム・抄録集 52回 206 - 206 2020.11

小児造血幹細胞移植患者において、タクロリムス経口製剤の生体利用率に影響を及ぼす因子に関する検討

金光喜一郎, 頼藤貴志, 石田悠志, 藤原かおり, 鷲尾佳奈, 嶋田明, 塚原宏一

日本小児血液・がん学会雑誌 57 ( 4 ) 327 - 327 2020.10

【抗菌薬の「なぜ?」に答える】造血幹細胞移植時の予防抗微生物薬の選択

津下充, 塚原宏一

小児内科 52 ( 10 ) 1494 - 1498 2020.10

Language：Japanese Publisher：(株)東京医学社

＜Key Points＞(1)造血幹細胞移植では移植後の遷延する免疫不全によって感染症のリスクが増加するため、リスクに応じた抗微生物薬の予防投薬が必要である。(2)抗菌薬の予防投与の有用性は確立しておらず、耐性菌増加も懸念されており、患者の背景因子を考慮した予防投与が推奨される。(3)抗真菌薬の予防投与の第一選択薬はフルコナゾールであるがアスペルギルス症に無効であり、ミカファンギンやポリコナゾールの有用性が報告される。(4)単純ヘルペスウイルス・水痘帯状疱疹ウイルスの発症予防にアシクロビルが有効である。(著者抄録)

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重症食物アレルギーにおける腸管上皮バリアに関連した血清バイオマーカーの検討

津下充, 茂原研司, 斎藤有希惠, 八代将登, 池田政憲, 塚原宏一

アレルギー 69 ( 臨時増刊号 ) 290 - 290 2020.10

重症食物アレルギーにおける腸管上皮バリアに関連した血清バイオマーカーの検討

津下充, 茂原研司, 斎藤有希惠, 八代将登, 池田政憲, 塚原宏一

日本小児アレルギー学会誌 34 ( 4 ) 484 - 484 2020.9

起立性調節障害患者のP-Fスタディに関する研究

椙原彰子, 岡田あゆみ, 田中知絵, 赤木朋子, 藤井智香子, 重安良恵, 堀内真希子, 塚原宏一

子どもの心とからだ 29 ( 2 ) 225 - 225 2020.8

回避・制限性食物摂取症(制限摂食)の男児例

藤井智香子, 岡田あゆみ, 重安良恵, 椙原彰子, 堀内真希子, 田中知絵, 赤木朋子, 塚原宏一

日本小児科学会雑誌 124 ( 8 ) 1301 - 1301 2020.8

起立性調節障害患者のQOLについての検討(第2報)

重安良恵, 岡田あゆみ, 田中知絵, 赤木朋子, 藤井智香子, 椙原彰子, 堀内真希子, 塚原宏一

子どもの心とからだ 29 ( 2 ) 217 - 217 2020.8

視神経低形成に下垂体低形成を合併した3例

二川奈都子, 長谷川高誠, 塚原宏一

日本内分泌学会雑誌 96 ( 1 ) 286 - 286 2020.8

岡山大学病院Family support teamの発足とその活動報告

塚原紘平, 塚原宏一, 中尾篤典, 虐待連絡委員会,Family support team

日本小児科学会雑誌 124 ( 8 ) 1300 - 1300 2020.8

MT Seminar 酸化ストレスと酸化ストレスマーカーの知識

塚原宏一, 馬場健児, 鷲尾洋介, 大野直幹

Medical Technology 48 ( 7 ) 786 - 796 2020.7

Language：Japanese Publisher：医歯薬出版(株)

＜要点＞・酸化ストレスは、内部・外部刺激により生体内で活性酸素群(活性窒素も含む)が抗酸化システムで捕捉しきれないほど過剰に生じる状況である。・酸化ストレス亢進は血管内皮障害と深く関連する。とりわけ、血管内皮での一酸化窒素(nitric oxide;NO)生成は生体のレドックス環境を保持するうえで必須である。酸化ストレス亢進はarginineを基質とするNO合成を抑制し、内因性NO合成酵素阻害因子であるasymmetric dimethylarginineの生成を刺激する。・小児の急速進行性疾患、慢性遷延性疾患ではしばしば酸化ストレスが増幅され、生体の構造や機能が酸化劣化を受けて、組織障害が不可逆的に進展する。これらの疾患の治療、管理において酸化ストレスを制御することが重要である。そのためには酸化ストレスの病態生理、それへの防御機制を把握し、特異的マーカーを用いて患者の酸化ストレス環境を非〜低侵襲的に評価することが必要である。・小児医療の現場で実施される種々の治療は酸化ストレス制御を目指すものでもあるが、今後は"レドックス"に関連してより特異性の高い細胞機能修飾薬が開発され、それらが重症疾患への集学治療のなかに組み込まれていくことが期待される。(著者抄録)

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身体症状を窓口としてつながった思春期女子の1例

椙原彰子, 藤井智香子, 堀内真希子, 田中知絵, 赤木朋子, 重安良恵, 岡田あゆみ, 塚原宏一

小児心身症研究 ( 27 ) 14 - 21 2020.6

Language：Japanese Publisher：日本小児心身医学会-中国四国地方会

行動化のある思春期女子に小児科医、臨床心理士で行った母子並行面接の過程を報告する。症例は、朝起きられず登校しないことを母が心配して、中学3年時に来院した。初期は体調改善を目標に小児科医単独で治療を行った。高校入学後より気分の変動が激しくなり、医師より、薬物療法、臨床心理士による支持的カウンセリング、認知行動療法が提案された。試みに臨床心理士との面接を数回実施し、本人は支持的カウンセリングを選択したが、本人の特徴を考慮して認知行動療法を取り入れた統合的カウンセリングを行った。徐々に現実的な行動や相談が出来るようになり、自己理解が深まって通学を維持できた。初期に治療者と共有しやすく心理的負担が少ない身体症状を介した診療によって治療継続できたことが有効であった。また、行動化に限界設定を行い、認知行動療法を取り入れた治療が有効であった。(著者抄録)

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起立性調節障害治療における学校連携に関するアンケート調査

田中知絵, 岡田あゆみ, 赤木朋子, 藤井智香子, 重安良恵, 椙原彰子, 堀内真希子, 塚原宏一

小児心身症研究 ( 27 ) 30 - 30 2020.6

リストカット、大量服薬を認めた思春期女子の1例

椙原彰子, 藤井智香子, 堀内真希子, 田中知絵, 赤木朋子, 重安良恵, 岡田あゆみ, 塚原宏一

小児心身症研究 ( 27 ) 33 - 33 2020.6

起立性調節障害診療における学校連携に関するアンケート調査

田中知絵, 岡田あゆみ, 赤木朋子, 藤井智香子, 重安良恵, 椙原彰子, 堀内真希子, 塚原宏一

小児心身症研究 ( 27 ) 2 - 7 2020.6

Language：Japanese Publisher：日本小児心身医学会-中国四国地方会

起立性調節障害(Orthostatic Dysregulation:OD)は不登校を伴いやすく、その診療に際しては学校との疾病理解の共有と連携が必要である。今回我々は、学校連携において問題となりやすい連絡方法と周囲への説明に注目して調査を行った。対象:2018年8月1日〜2019年3月31日に当院子どものこころ診療部(現・小児心身医療科)を受診しODと診断され、初診時に年間90日以上の長期不登校状態であった患者とその保護者で、各15例から回答を得た。方法:無記名式アンケート調査で、選択式の設問と自由記述を行った。結果:欠席時に学校からの連絡を希望したのは、患者8人(53%)、保護者13人(87%)だった。連絡頻度は患者は様々だったが、保護者は週1回の希望が最も多かった。先生から友達への病気の説明を希望した患者は5人(33%)だった。考察:学校-家庭間の連絡は、事前に方法や頻度などを相談しておくことが必要となる。また友達への病気の説明は、患者に内容を確認し希望する場合にのみ行うことが望ましいと考えた。(著者抄録)

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入院中の子どもの心理・発達支援に関する研究

椙原彰子, 岡田あゆみ, 堀内真希子, 赤木朋子, 藤井智香子, 重安良恵, 塚原宏一

子どもの心とからだ 29 ( 1 ) 27 - 32 2020.5

Language：Japanese Publisher：(一社)日本小児心身医学会

慢性疾患のために長期入院している子どもに、心理社会的発達を支援することは、いうまでもなく重要である。現在、医師のみならずさまざまな職種が連携して子どもや保護者に心理社会的発達支援を行っており、そのニーズは高まっている。しかし、日本の小児医療においては専門職の配置も少なく、支援体制づくりの遅れが指摘されている。今回、岡山県内の小児入院病床を有する施設を対象に、入院中の子どもの心理社会的発達支援の実態調査を行い、課題と方策を検討した。その結果、看護師、臨床心理士、病棟保育士などの多職種が個別的また日常生活の中で子どもの心理社会的発達支援を行っていることが分かった。課題として、共通認識をもちにくい、専門知識の不足が指摘され、なかでも「病児を抱えた家族の心理」が得たい知識として挙げられた。今後、カンファレンスや家族支援ツールによる情報共有、講習会の開催による知識の向上などを図ることが必要と考えられた。(著者抄録)

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【[必携]専攻医と指導医のための新生児診療到達目標】疾患別到達目標代謝内分泌疾患未熟児骨減少症

塚原宏一, 岡村朋香, 大野直幹

周産期医学 50 ( 4 ) 676 - 680 2020.4

X染色体性の遺伝形式が示唆されるが原因遺伝子が不明なDent病の兄弟例

宮井貴之, 宮原宏幸, 片山寿夫, 高岩正典, 田中弘之, 塚原宏一

日本小児腎臓病学会雑誌 33 ( 1 ) 95 - 95 2020.4

酸化ストレス制御と小児疾患治療

塚原宏一

日本小児腎臓病学会雑誌 33 ( 1 ) 85 - 85 2020.4

比較的早期から経過観察できた若年性ネフロン癆の1例

宮井貴之, 宮原宏幸, 森貞直哉, 飯島一誠, 塚原宏一

日本小児腎臓病学会雑誌 33 ( 1 ) 85 - 86 2020.4

当科で尿中L-FABPを測定した症例の後方視的検討

宮井貴之, 吉川知伸, 塚原宏一

日本小児腎臓病学会雑誌 33 ( 1 ) 69 - 69 2020.4

経過観察中に尿蛋白が大きく増減した4歳女児の一例

宮井貴之, 清水順也, 神農陽子, 岡田あゆみ, 塚原宏一

日本小児腎臓病学会雑誌 33 ( 1 ) 76 - 76 2020.4

小児リウマチ性疾患における酸化ストレスマーカーの有用性について

八代将登, 茂原研司, 斎藤有希惠, 藤井洋輔, 津下充, 池田政憲, 塚原宏一

岡山医学会雑誌 132 ( 1 ) 47 - 47 2020.4

入院前の肝炎ウイルス検査結果について陰性者も含め説明する体制構築

難波志穂子, 宮村純子, 足立史帆, 山科由美子, 石田絵里, 畑中信子, 岩崎哲也, 塚原宏一, 草野展周, 安中哲也, 池田房雄, 高木章乃夫, 岡田裕之

肝臓 61 ( Suppl.1 ) A243 - A243 2020.4

岡山大学病院外来歯科領域における経口第三世代セフェム系抗菌薬の使用量の削減について

東恩納司, 岡崎昌利, 稲葉裕明, 飯尾耕二, 筧彩佳, 宮村純子, 草野展周, 塚原宏一, 千堂年昭

日本環境感染学会総会プログラム・抄録集 35回 P5 - 7 2020.2

VREのアウトブレイク事例とその解析

筧彩佳, 宮村純子, 飯尾耕治, 東恩納司, 岡崎昌利, 稲葉裕明, 草野展周, 塚原宏一

日本環境感染学会総会プログラム・抄録集 35回 P71 - 5 2020.2

起立性調節障害患者の背景因子についての検討

藤井智香子, 岡田あゆみ, 鶴丸靖子, 赤木朋子, 重安良恵, 山下美保, 椙原彰子, 堀内真希子, 塚原宏一

子どもの心とからだ 28 ( 4 ) 426 - 432 2020.2

Language：Japanese Publisher：(一社)日本小児心身医学会

起立性調節障害(orthostatic dysregulation:以下OD)の発症や経過には生活習慣、心理社会的要因が関与するといわれているが、具体的な報告は少ない。本研究では、OD患者の背景因子を検討し、その特徴を明らかにすることを目的として、岡山大学病院小児科においてODと診断した76例を対象に、背景因子を後方視的に検討した。結果、発達障害の併存を25例(32.9%)、うち自閉スペクトラム症を17例(22.4%)に認めた。また不登校を含め登校に何らかの困難を抱えた症例が67例(88.2%)で、34例(44.7%)が学校で友人関係や適応上の問題を認めており、17例(22.4%)の病前性格が過剰適応型だった。以上より、ODの発症や経過に心理社会的要因の影響を認めると推測され、約3割に発達障害を併存していることも踏まえて、心理社会的要因や発達特性に配慮した全人的治療が重要であると考えた。(著者抄録)

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小児がん患者に対する歯科介入の効果について

吉田衣里, 森川優子, 平野慶子, 松三友紀, 仲野道代, 嶋田明, 塚原宏一

小児歯科学雑誌 58 ( 地方会抄録号 ) 67 - 67 2020.2

低カルシウム血症による痙攣で発症し、胸腺低形成が診断契機となった22q11.2欠失症候群の新生児例

二川奈都子, 長谷川高誠, 塚原宏一

日本内分泌学会雑誌 95 ( 3 ) 1171 - 1171 2020.1

マルチターゲット療法で加療中,胃腸炎を機に急性腎障害に至った全身性エリテマトーデスの一例

宮原宏幸, 石井雅人, 茂原研司, 津下充, 八代将登, 塚原宏一

日本小児腎臓病学会雑誌(Web) 33 ( 1 ) 2020

起立性調節障害治療における学校連携に関するアンケート調査

田中知絵, 岡田あゆみ, 赤木朋子, 藤井智香子, 重安良恵, 椙原彰子, 堀内真希子, 塚原宏一

子どもの心とからだ 28 ( 3 ) 337 - 337 2019.11

リストカット、大量服薬を認めた思春期女子の1例

椙原彰子, 藤井智香子, 堀内真希子, 田中知絵, 赤木朋子, 重安良恵, 岡田あゆみ, 塚原宏一

子どもの心とからだ 28 ( 3 ) 340 - 340 2019.11

難治性真菌感染症、慢性心不全、慢性腎不全を有する児に発症した関節型若年性特発性関節炎に対する治療アプローチ

八代将登, 茂原研司, 藤井洋輔, 斎藤有希惠, 津下充, 塚原宏一

日本小児リウマチ学会総会・学術集会プログラム・抄録集 29回 114 - 114 2019.10

造血幹細胞移植施行患児における口腔内細菌叢の推移

森川優子, 吉田衣里, 平野慶子, 松三友紀, 嶋田明, 塚原宏一, 仲野道代

日本小児血液・がん学会雑誌 56 ( 4 ) 328 - 328 2019.10

小児重症喘息に対するオマリズマブの有効性と効果予測因子の探索

津下充, 茂原研司, 齋藤有希惠, 八代将登, 池田政憲, 塚原宏一

日本小児アレルギー学会誌 33 ( 4 ) 538 - 538 2019.10

ヒト脳血管内皮細胞を用いた高サイトカイン血症モデルにおけるhigh mobility group box 1抗体の血管透過性抑制効果

津下充, 難波貴弘, 西堀正洋, 斎藤有希恵, 八代将登, 塚原宏一, 森島恒雄

日本小児感染症学会総会・学術集会プログラム・抄録集 51回 200 - 200 2019.10

小児がん患者に対する口腔ケアの早期介入

吉田衣里, 森川優子, 松三友紀, 平野慶子, 嶋田明, 塚原宏一, 仲野道代

日本小児血液・がん学会雑誌 56 ( 4 ) 304 - 304 2019.10

骨形成不全症の遺伝子解析と臨床像の検討

樋口洋介, 長谷川高誠, 二川奈都子, 山下美保, 田中弘之, 塚原宏一

日本内分泌学会雑誌 95 ( 2 ) 707 - 707 2019.10

肺血管内皮細胞を用いたインフルエンザ重症肺炎モデルの構築とhigh mobility group box 1抗体による肺血管透過性亢進の抑制効果

難波貴弘, 津下充, 西堀正洋, 斎藤有希恵, 八代将登, 塚原宏一, 森島恒雄

日本小児感染症学会総会・学術集会プログラム・抄録集 51回 133 - 133 2019.10

エトスクシミドにより誘発された膠原病類似疾患の検討

茂原研司, 八代将登, 斎藤有希惠, 津下充, 塚原宏一

日本小児リウマチ学会総会・学術集会プログラム・抄録集 29回 88 - 88 2019.10

起立性調節障害患者の酸化ストレス環境についての検討

藤井智香子, 津下充, 岡田あゆみ, 田中知絵, 赤木朋子, 重安良恵, 椙原彰子, 堀内真希子, 塚原宏一

子どもの心とからだ 28 ( 2 ) 260 - 260 2019.8

心身症診療おけるP-Fスタディ(Picture Frustration Study)に関する研究自閉スペクトラム症併存例の検討

椙原彰子, 岡田あゆみ, 藤井智香子, 重安良恵, 赤木朋子, 田中知絵, 堀内真希子, 塚原宏一

子どもの心とからだ 28 ( 2 ) 271 - 271 2019.8

神経発達症児に対する入院中の心理・発達支援に関する調査

重安良恵, 岡田あゆみ, 椙原彰子, 堀内真希子, 田中知絵, 赤木朋子, 藤井智香子, 塚原宏一

子どもの心とからだ 28 ( 2 ) 259 - 259 2019.8

精神発達遅滞を伴った小児にウルトラロングカテーテルを用いて腹膜透析を導入した1例

宮井貴之, 宮原宏幸, 笠原由美子, 野田卓男, 塚原宏一, 田中弘之

日本小児腎不全学会雑誌 39 250 - 252 2019.7

Language：Japanese Publisher：日本小児腎不全学会

精神発達遅滞を伴った小児には、身体にテープを貼られたりカテーテルを留置されたりすることを拒絶する者がおり、腹膜透析(peritoneal dialysis:PD)の導入に難渋することがある。成人領域では認知症を伴った高齢者に肩甲骨部出口でPDを導入する報告がある。精神発達遅滞を伴う末期腎不全の小児に対し、工夫してPDを導入した症例を報告する。ジュベール症候群の男児が15歳で末期腎不全に至りPDを行って献腎移植を待機する方針を選択した。出口部保清を保つため肩甲骨部出口を採用し、ウルトラロングカテーテルを留置し、良好な注排液が得られた。この2点の工夫が精神発達遅滞を伴った小児におけるPD導入時の問題を軽減し、これまで導入をあきらめていた例でもPDが腎代替療法の選択肢になりうることが示唆された。(著者抄録)

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ACTH療法中に尿路結石を生じた乳幼児例における尿沈渣所見の経時的変化

宮原宏幸, 水野むつみ, 兵頭勇紀, 西本静香, 花岡義行, 松田奈央子, 金聖泰, 柴田敬, 遠藤文香, 秋山麻里, 岡牧郎, 秋山倫之, 小林勝弘, 塚原宏一

日本小児科学会雑誌 123 ( 7 ) 1199 - 1199 2019.7

骨形成不全症の遺伝子解析と臨床像の検討

樋口洋介, 長谷川高誠, 二川奈都子, 山下美保, 塚原宏一

日本内分泌学会雑誌 95 ( 1 ) 391 - 391 2019.4

乳酸カルシウムの内服でくる病の改善を認めたビタミンD依存性くる病2A型の男児例

長谷川高誠, 二川奈都子, 樋口洋介, 塚原宏一

日本内分泌学会雑誌 95 ( 1 ) 454 - 454 2019.4

病原体検索のための急性期検体採取に対する当院の取り組み

八代将登, 茂原研司, 斎藤有希惠, 藤井洋輔, 津下充, 塚原宏一

日本小児感染症学会総会・学術集会プログラム・抄録集 50回 162 - 162 2018.11

病原体検索のための急性期検体採取に対する当院の取り組み

八代将登, 茂原研司, 斎藤有希惠, 藤井洋輔, 津下充, 塚原宏一

日本小児感染症学会総会・学術集会プログラム・抄録集 50回 162 - 162 2018.11

食物アレルギーと診断されることに伴う経済負担についての研究

吉川知伸, 三橋利晴, 籔内俊彦, 斎藤有希惠, 藤井洋輔, 津下充, 八代将登, 池田政憲, 塚原宏一

日本小児アレルギー学会誌 32 ( 3 ) 607 - 607 2018.8

Failing Fontan患者におけるfenestration stentの有用性と中期予後について

栗田佳彦, 平井健太, 重光祐輔, 福嶋遥祐, 近藤麻衣子, 馬場健児, 大月審一, 塚原宏一, 笠原慎吾

日本小児循環器学会雑誌 34 ( Suppl.1 ) s1 - 229 2018.7

難聴と糸球体腎炎を伴うCharcot-Marie-Tooth病の男児例

花岡義行, 宮井貴之, 秋山麻里, 林裕美子, 岡牧郎, 塚原宏一, 小林勝弘

日本小児科学会雑誌 122 ( 2 ) 264 - 264 2018.2

閉鎖困難が予想された心室中隔欠損に対するCT評価の有用性について

栗田佳彦, 大月審一, 平井健太, 重光祐輔, 栄徳隆裕, 近藤麻衣子, 馬場健児, 塚原宏一, 佐野俊二, 笠原慎吾

日本小児循環器学会雑誌 33 ( Suppl.1 ) s1 - 344 2017.7

OFD1ヘミ接合性ミスセンス変異を認めたネフロン癆関連シリオパチーの1男児例

清水順也, 森貞直哉, 飯島一誠, 神農陽子, 城謙輔, 竹村司, 久保俊英, 塚原宏一

日本小児腎臓病学会雑誌 30 ( 1Suppl. ) 214 - 214 2017.5

Long-term conservative management for superior mesenteric artery syndrome : A case report

70 ( 4 ) 479 - 484 2017.4

新生児・乳児ビタミンK欠乏性出血症に対するビタミンK製剤投与の改訂ガイドライン(修正版) (特集助産師が押さえておきたいガイドライン : エビデンスに基づいたケアを実践するために)

鷲尾洋介, 岡村朋香, 塚原宏一

ペリネイタルケア 35 ( 11 ) 1088 - 1091 2016.11

【消化管アレルギー】消化管アレルギーと酸化ストレス

野坂宜之, 籔内俊彦, 塚原宏一

小児内科 48 ( 9 ) 1347 - 1351 2016.9

右室流出路再建術にContegraを使用した18症例の検討

平井健太, 馬場健児, 近藤麻衣子, 栗田佳彦, 栄徳隆裕, 福嶋遥佑, 重光祐輔, 大月審一, 笠原真悟, 佐野俊二, 塚原宏一

日本小児循環器学会雑誌 32 ( Suppl.1 ) s1 - 216 2016.7

二心室治療可能であった左心系低形成症例について

栗田佳彦, 大月審一, 平井健太, 重光祐輔, 福嶋遥佑, 栄徳隆裕, 近藤麻衣子, 馬場健児, 塚原宏一, 佐野俊二, 岩崎達雄

日本小児循環器学会雑誌 32 ( Suppl.1 ) s1 - 184 2016.7

維持腹膜透析導入となった、くも膜嚢胞を有する乳児型ネフロン癆の男児例

清水順也, 茂原研司, 高橋亨平, 吉本順子, 中原康雄, 後藤隆文, 神農陽子, 城謙輔, 竹村司, 久保俊英, 塚原宏一

日本小児腎不全学会雑誌 36 171 - 174 2016.7

Language：Japanese Publisher：日本小児腎不全学会

症例は2歳男児。出生時より巨大くも膜嚢胞・水頭症による発達障害を認め、脳室腹腔内シャント、胃瘻栄養などで管理されていた。1歳になった頃より徐々に腎機能低下を認めるようになり保存期治療を受けていたが、全身浮腫、低ナトリウム血症、高血圧、腎機能低下の進行を認め、2歳6ヵ月時に当院転院となった。血圧168/120mmHg、全身浮腫あり、24時間クレアチニンクリアランス(creatinine clearance:Ccr)4.06mL/min/1.73m2、腎エコーでは両側腎臓とも高輝度で、数mm大の嚢胞が数個あり。腎生検を施行し、臨床経過とあわせて乳児型ネフロン癆による末期腎不全と診断し、腹膜透析を導入した。浮腫や高血圧は改善し、降圧薬もすべて中止できた。脳室腹腔内シャント留置児への腹膜透析導入であることなどの留意点を含めて考察し報告する。(著者抄録)

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当科における過去10年のリアルタイムPCR法を用いたヘルペスウイルス感染症診断と病態解析

八代将登, 山田陸子, 吉川知伸, 野坂宜之, 藤井洋輔, 山下信子, 塚原宏一, 森島恒雄

日本小児科学会雑誌 120 ( 6 ) 1034 - 1034 2016.6

中国四国地区における急性弛緩性麻痺を認める症例の網羅的調査

八代将登, 藤井洋輔, 山下信子, 塚原宏一, 多屋馨子, 森島恒雄

臨床とウイルス 44 ( 2 ) S61 - S61 2016.5

経時的なADAMTS13活性値測定によりThrombotic Thrombocytopenic Purpura(TTP)再発前に治療介入することができたSLEの1例

吉川知伸, 野坂宜之, 齋藤有希惠, 藤井洋輔, 塚原宏一, 松本雅則

日本小児リウマチ学会総会・学術集会プログラム・抄録集 25回 135 - 135 2015.10

レドックス制御蛋白チオレドキシン(TRX)のインフルエンザ肺炎における治療的効果

八代将登, 野坂宜之, 藤井洋輔, 斎藤有希惠, 山下信子, 山田雅夫, 塚原宏一, 森島恒雄

臨床とウイルス 43 ( 2 ) S80 - S80 2015.5

急性脳症患者におけるCOX-2のDNAメチル化の関与

藤井洋輔, 齋藤有希惠, 野坂宜之, 八代将登, 山下信子, 塚原宏一, 森島恒雄

日本小児科学会雑誌 118 ( 2 ) 269 - 269 2014.2

Oxidative stress biomarkers

TSUKAHARA Hirokazu

24 ( 2 ) 181 - 189 2012.7

タクロリムスにより寛解導入を行った潰瘍性大腸炎の小児例

藤井洋輔, 小寺亜矢, 長岡義晴, 八代将登, 山下信子, 塚原宏一, 森島恒雄, 平岡佐規子, 加藤順

小児科臨床 65 ( 6 ) 1183 - 1188 2012.6

Language：Japanese Publisher：(株)日本小児医事出版社

症例は14歳女児。発熱、腹痛、下痢で発症し、入院後の大腸内視鏡検査で潰瘍性大腸炎(ulcerative colitis:以下UC)と診断された。全大腸炎型UCであり、臨床的重症度分類では中等症であった。プレドニゾロン、5-アミノサリチル酸製剤により寛解導入を試みたが、治療中に重症化したため、経口タクロリムス療法を併用した。治療開始5日目ころから血便、腹痛が改善し、寛解に導入できた。タクロリムス使用中重大な副作用は認められなかった。また、経過中に酸化ストレスの指標である血清総ハイドロペルオキシド濃度を計測した。その値は病勢に一致して変動しており、UCの病態生理に酸化ストレス亢進が関与することが示唆された。タクロリムスは近年内科領域で難治性のUCに対し使用され、効果をあげている。今後、小児のUCに対する有効な治療選択の1つとして期待される。(著者抄録)

CiNii Article

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Other Link： http://search.jamas.or.jp/link/ui/2012267026

Multiple biomarkers for oxidative stress in patients with brain disorders

Hirokazu Tsukahara, Yosuke Fujii, Yuko Hayashi, Tsuneo Morishima

Journal of the Neurological Sciences 313 ( 1-2 ) 196 2012.2

インフルエンザ感染におけるThioredoxin binding protein 2(TBP-2)の役割

八代将登, 山田睦子, 藤井洋輔, 斉藤有希恵, 長岡義晴, 津下充, 山下信子, 塚原宏一, 松川昭博, 森島恒雄

日本小児科学会雑誌 116 ( 2 ) 240 - 240 2012.2

早産極低出生体重児にビタミンD蓄積・骨ミネラル代謝に対する混合栄養の有用性についての検討

菊池尚子, 塚原宏一, 徳力周子, 川谷正男, 畑郁江, 眞弓光文, 大嶋勇成

小児科臨床 65 ( 5 ) 1051 - 1056 2012

Language：Japanese Publisher：(株)日本小児医事出版社

当院では母乳と低出生体重児用粉乳の長所を生かすべく、早産極低出生体重児には母乳と粉乳の混合栄養を実施している。この栄養法が児のビタミンD蓄積と骨ミネラル代謝に有効に働いているかどうか検討した。対象は在胎週数27.0±2.2週、体重820±290gで出生した19名の児である。経腸栄養は週齢1までは母乳単独とし、その後は母乳と低出生体重児用粉乳(明治ソフトカードLW)の混合栄養(粉乳の比率は全体の50%かそれ以上)とした。出生予定日前後で血清Ca、Mg、P、Cr、ALP、オステオカルシン、25-水酸化ビタミンD、intact PTH、尿Ca、P、Cr、ピリジノリン、デオキシピリジノリンなどを計測した。対象児では血清Ca、Mg、Pは正常域にあり、血清25-水酸化ビタミンDは38.8±14.4ng/mL(16.6〜70.3ng/mL)と全例15ng/mL以上であった。オステオカルシン、ピリジノリン、デオキシピリジノリンは全例高値であった。一部の児でintact PTHの高値やリン欠乏症候群を示唆する尿所見が認められた。本研究により、母乳と低出生体重児用粉乳の混合栄養が早産極低出生体重児のビタミンD蓄積に有効に働いていることが示された。一方、本栄養法はリン欠乏症候群の寛解、ミネラル蓄積の促進については決して十分でないことも示された。未熟児代謝性骨疾患には更なる対策が必要であると考えられた。(著者抄録)

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インフルエンザ脳症など重症インフルエンザの発症機序の解明とそれに基づく治療法,予防法の確立に関する研究生体マーカーを用いた脳炎・脳症患者の病態評価

塚原宏一, 藤井洋輔, 山田睦子, 斎藤有希恵, 長岡義晴, 津下充, 森島恒雄, 市山高志, 松原康策, 毎原敏郎, 羽田敦子, 梶俊策, 後藤振一郎

インフルエンザ脳症など重症インフルエンザの発症機序の解明とそれに基づく治療法、予防法の確立に関する研究平成23年度総合・分担研究報告書 2012

Perinatal circulatory changes and appropriate fluid therapy in preterm born infants

4 15 - 23 2012

【疑問解決小児の診かた】疾患別の診療腎・泌尿器・生殖器疾患急性腎盂腎炎の患者にはどのような形態・機能検査が必要ですか

塚原宏一, 八代将登, 山下信子

小児内科 43 ( 増刊 ) 756 - 759 2011.12

Evaluation of oxidative stress status in children with pervasive developmental disorder and attention deficit hyperactivity disorder using urinary-specific biomarkers

M.Kawatani, H.Tsukahara, M.Mayumi

Redox Report 16 ( 1 ) 45 - 46 2011

Favorable effect of 4-phenylacetate on liver functions attributable to enhanced bile salt export pump expression in ornithine transcarbamylase-deficient children

Hironori Nagasaka, Tohru Yorifuji, Kunihiko Kobayashi, Hajime Takikawa, Haruki Komatsu, Ayano Inui, Tomoo Fujisawa, Takashi Miida, Hirokazu Tsukahara, Tomozumi Takatani, Hisamitsu Hayashi

MOLECULAR GENETICS AND METABOLISM 100 ( 2 ) 123 - 128 2010.6

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

4-Phenylbutyrate (4-PB) acting against hyperammonemia has been administered to patients with urea cycle defects. Results of our recent experiments using animals and cultured cells strongly suggest that this agent enhances the function of bile salt export pump/ATP binding cassette B11 (BSEP/ABCB11) promoting bile acid excretion from hepatocytes to bile canaliculi, although it has not been confirmed in humans. Considering that 4-PB is converted easily into 4-phenylacetate (4-PA) in the liver, such an effect of 4-PB might occur through 4-PA. We performed retrospective analyzes of the effects of 4-PA on the liver functions of three ornithine transcarbamylase (OTC)-deficient female children receiving 4-PA. Two of the three received intravenous administration of 4-PA only at episodic periods of hyperammonemia; the remaining one received it orally at intercurrent periods. Soon after 4-PA administration, the serum total bile acid level was decreased to one-half or one-third of pre-treatment levels, but it returned to the basal levels within one month after 4-PA discontinuation. Other serum parameters for cholestasis such as gamma-glutamyl transferase also decreased markedly. Concomitantly, alanine aminotransferase and aspartate amino transferase levels decreased significantly. Western blot analyzes of the liver samples revealed that the 4-PA administration enhanced BSEP/ABCB11 protein expressions in the membranous fraction of liver cells, although the liver BSEP/ABCB11 messenger RNA level remained unchanged. These results suggest that 4-PA enhanced liver BSEP/ABCB11 function and thereby improved liver functions in OTC-deficient children. For treatment of liver disorders requiring enhancement of BSEP function, 4-PA might be a candidate. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ymgme.2010.02.008

Web of Science

PubMed

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On Being a Resident and a Mom

Koji Nishijima, Jin Takahashi, Makoto Yamamoto, Makoto Orisaka, Chiyo Suzuki, Hirokazu Tsukahara, Ken-ichi Shukunami, Tetsuji Kurokawa, Yoshio Yoshida, Fumikazu Kotsuji

ANNALS OF EMERGENCY MEDICINE 55 ( 5 ) 483 - + 2010.5

Detection of cytomegalovirus in preserved umbilical cord from a boy with autistic disorder

Masao Kawatani, Akio Nakai, Takashi Okuno, Ritsuyo Kobata, Masako Moriuchi, Hiroyuki Moriuchi, Hirokazu Tsukahara, Mitsufumi Mayumi

PEDIATRICS INTERNATIONAL 52 ( 2 ) 304 - 307 2010.4

Coupling of the citrulline recycling to endothelial NO production

Hirokazu Tsukahara, Hironori Nagasaka, Shuko Tokuriki, Mitsufumi Mayumi

MOLECULAR GENETICS AND METABOLISM 99 ( 4 ) 438 - 438 2010.4

Asymmetric dimethylarginine, an endogenous NO synthase inhibitor, in human breast milk

Hirokazu Tsukahara, Hironori Nagasaka

EARLY HUMAN DEVELOPMENT 86 ( 2 ) 69 - 70 2010.2

Altered metabolisms of mediators controlling vascular function and enhanced oxidative stress in asymptomatic children with congenital portosystemic venous shunt

Hironori Nagasaka, Yoshiyuki Okano, Madoka Aizawa, Takashi Miida, Tohru Yorifuji, Go Tajima, Nobuo Sakura, Tomozumi Takatani, Yoshitami Sanayama, Kenji Sugamoto, Mitsufumi Mayumi, Kunihiko Kobayashi, Kenichi Hirano, Masaki Takayanagi, Hirokazu Tsukaharah

METABOLISM-CLINICAL AND EXPERIMENTAL 59 ( 1 ) 107 - 113 2010.1

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

Children with congenital portosystemic venous shunt (PSVS) are at risk for developing pulmonary hypertension, irrespective of the severity of portal hypertension or liver damage. Altered metabolisms of nitric oxide (NO) and endothelin-1 (ET-1), which are linked with oxidative stress and control vascular tone, might contribute to the vascular disturbance. This study examined 14 children (aged 1-5 years) with congenital PSVS lacking major liver damage and portal hypertension. Serum levels of nitrite/nitrate (NOx) as stable metabolites of NO, and of asymmetric dimethylarginine (ADMA) as an endogenous NO synthase inhibitor were determined, along with the plasma level of ET-1. Oxidative stress, which might affect the production of such mediators, was also examined using specific urinary and blood markers. The NOx levels were significantly lower in affected children than in the age-matched control group, although ET-1 levels were significantly higher than the control levels. In the affected children, the ADMA levels and ADMA/NOx ratios were higher, respectively, by 30% and 130% and showed significant positive correlations with the shunt ratios. Oxidative stress markers, including plasma thiobarbiturate reactive substances and urinary acrolein-lysine and 8-hydroxy-2'-deoxyguanosine, were significantly higher in affected children than in the control group, consistent with them being subjected to enhanced oxidative stress. These results suggest the presence of altered metabolisms of vascular mediators and enhanced oxidative stress in asymptomatic preschool children with congenital PSVS. (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.metabol.2009.07.013

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内科疾患の診断基準・病型分類・重症度: 先天性ネフローゼ症候群

塚原宏一

内科（in press） 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

内科疾患の診断基準・病型分類・重症度: 先天性ネフローゼ症候群

塚原宏一

内科（in press） 2010

胎児・新生児の成長と骨

塚原宏一

骨粗鬆症治療 9 ( 2 ) 141 - 148 2010

母乳中の生理活性因子の生物学的・治療学的意義

塚原宏一

平成20年度総合健康推進財団研究助成成果報告書 (in press) 2010

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

胎児・新生児の成長と骨

塚原宏一

骨粗鬆症治療 2010

母乳中の生理活性因子の生物学的・治療学的意義

塚原宏一

平成20年度総合健康推進財団研究助成成果報告書 (in press) 2010

インフルエンザ脳症の発症におけるレドックスの役割と治療への応用

塚原宏一

平成21年度厚生労働科学研究費補助金（新型インフルエンザ等新興・再興感染症研究事業）分担研究報告書: インフルエンザ脳症など重症インフルエンザの発症機序の解明とそれに基づく治療法・予防法の確立に関する研究（主任研究者森島恒雄 2010

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

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

窒素（Ｎ）と酸素（Ｏ）の化学・生物学

塚原宏一

日本臨床高気圧酸素・潜水医学会雑誌 2009

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. ありふれた症状・症候 - プライマリーケア

塚原宏一

内科 103 ( 1 ) 160 - 163 2009

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. 連載にあたって

塚原宏一

内科 103 ( 1 ) 159 2009

小児腎疾患の診断・治療戦略. III. 腎疾患に用いられる治療法 – 12. 尿路感染症予防を目的とする抗菌薬投与

塚原宏一

小児内科 41 ( 2 ) 294 - 296 2009

知っておきたい泌尿器科の知識（その1）- 2. 周産期における腎機能の発達

塚原宏一, 巨田尚子, 徳力周子, 森夕起子

小児外科 41 ( 2 ) 98 - 103 2009

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. 小児の事故 - 誤飲・誤嚥・頭部外傷の迅速・適確な対処とは

田村知史, 塚原宏一

内科 103 ( 2 ) 362 - 366 2009

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, 巨田尚子, 徳力周子

福井大学重点研究成果集2009:明日への挑戦 64 - 65 2009

小児科領域における一酸化炭素ヘモグロビン・メトヘモグロビンの臨床生化学的意義

塚原宏一

平成20年度腎不全病態研究助成成果報告書 2009

VURに対する抗生剤予防内服: pros and cons - 小児腎臓病専門医の立場から

塚原宏一

第17回日本逆流性腎症フォーラム記録集 2009

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

DOI： 10.2131/jts.34.SP229

小児腎疾患の診断・治療戦略. III. 腎疾患に用いられる治療法 – 12. 尿路感染症予防を目的とする抗菌薬投与

塚原宏一

小児内科 41 ( 2 ) 294 - 296 2009

知っておきたい泌尿器科の知識（その1）- 2. 周産期における腎機能の発達

塚原宏一, 巨田尚子, 徳力周子, 森夕起子

小児外科 41 ( 2 ) 98 - 103 2009

小児科領域における一酸化炭素ヘモグロビン・メトヘモグロビンの臨床生化学的意義

塚原宏一

平成20年度腎不全病態研究助成成果報告書 2009

アルギニン代謝関連分子（NO，ADMA）による生体機能修飾についての統合的研究

塚原宏一

平成20年度科学研究費補助金実績報告書（基盤研究C） 2009

早産児の慢性肺疾患における酸化ストレスの病態学的意義についての検討: CO-HbとMet-Hbを指標として

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

小児科臨床 62 ( 5 ) 925 - 930 2009

超早産児のナトリウム補充に関する検討: 晩期循環不全発症予防における電解質管理の重要性

徳力周子, 巨田尚子, 古畑律代, 田村知史, 川谷正男, 畑郁江, 塚原宏一, 眞弓光文

発達腎研究会誌 17 ( 1 ) 7 - 12 2009

小児疾患診療のための病態生理2 - II. 新生児疾患. 21. 新生児代謝性骨疾患

塚原宏一, 巨田尚子, 徳力周子

小児内科 184 - 189 2009

厚生労働科学研究費補助金（新興・再興感染症研究事業）「インフルエンザ脳症の発症因子の解明とそれに基づく発症前診断方法の確立に関する研究」班（主任研究者森島恒雄）. インフルエンザ脳症ガイドライン（改訂版）

森島恒雄, 岡部信彦, 中村祐輔, 河岡義裕, 山口清次, 水口雅, 市山高志, 長谷川秀樹, 奥村彰久, 伊藤嘉規, 河島尚志, 新矢恭子, 塚原宏一, 中野貴司, 塩見正司, 鍵本聖一, 布井博幸, 和田智顕, 植田育也, 山内秀雄, 栗原まな, 宮崎千明, 山田至康, 坂下裕子, 岩田力, 大平雅之, 阪井裕一, 中村通子, 宮澤会美香, 吉川秀人

小児科臨床 62 ( 11 ) 2483 - 2528 2009

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. 小児の事故 - 誤飲・誤嚥・頭部外傷の迅速・適確な対処とは

田村知史, 塚原宏一

内科 103 ( 2 ) 362 - 366 2009

アルギニン代謝関連分子（NO，ADMA）による生体機能修飾についての統合的研究

塚原宏一

平成20年度科学研究費補助金実績報告書（基盤研究C） 2009

早産児の慢性肺疾患における酸化ストレスの病態学的意義についての検討: CO-HbとMet-Hbを指標として

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

小児科臨床 62 ( 5 ) 925 - 930 2009

アルギニン代謝関連分子（NO，ADMA）による生体機能修飾についての統合的研究

塚原宏一

平成19～20年度科学研究費補助金（基盤研究C）研究成果報告書 2009

超早産児のナトリウム補充に関する検討: 晩期循環不全発症予防における電解質管理の重要性

徳力周子, 巨田尚子, 古畑律代, 田村知史, 川谷正男, 畑郁江, 塚原宏一, 眞弓光文

発達腎研究会誌 17 ( 1 ) 7 - 12 2009

小児疾患診療のための病態生理2 - II. 新生児疾患. 21. 新生児代謝性骨疾患

塚原宏一, 巨田尚子, 徳力周子

小児内科 184 - 189 2009

小児科臨床 62 ( 11 ) 2483 - 2528 2009

周産期におけるMycoplasma hominis, Ureaplasma urealyticum感染の早期スクリーニング法と超早産児の気管支肺異形成発症予防策の確立

徳力周子, 塚原宏一, 西島浩二

トランスレーションリサーチ推進センター 2008年度活動報告書 7 - 8 2009

広汎性発達障害における酸化ストレスの関与に関する研究

川谷正男, 塚原宏一

トランスレーションリサーチ推進センター 2008年度活動報告書 2009

窒素（Ｎ）と酸素（Ｏ）の化学・生物学

塚原宏一

日本臨床高気圧酸素・潜水医学会雑誌 2009

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. ありふれた症状・症候 - プライマリーケア

塚原宏一

内科 103 ( 1 ) 160 - 163 2009

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. 連載にあたって

塚原宏一

内科 103 ( 1 ) 159 2009

Fluctuation of lipoprotein metabolism linked with bile acid-activated liver nuclear receptors in Alagille syndrome

Hironori Nagasaka, Takashi Miida, Ken-ichi Hirano, Akemi Ota, Kei Murayama, Tohru Yorifuji, Kunihiko Kobayashi, Tornommi Takatani, Hirokazu Tsukahara, Shu-Ping Hui, Masaki Takayanagi, Hitoshi Chiba

ATHEROSCLEROSIS 198 ( 2 ) 434 - 440 2008.6

Language：English Publisher：ELSEVIER IRELAND LTD

Alagille syndrome (AGS) is a rare hereditary disorder exhibiting fluctuating cholestasis and dyslipidemia. Farnesoid X receptor (FXR) and liver X receptor (LXR) are hepatic nuclear receptors that regulate bile acid and lipoprotein metabolism. To investigate whether cholestasis is related to dyslipidemia and hepatic nuclear receptor expression in AGS patients, we determined the blood levels of total bile acid (TBA) and lipoprotein parameters, and examined hepatic nuclear receptor expression in three AGS children and their three incomplete AGS parents repeatedly over several years. In the AGS children, TBA level showed significant positive correlations with low-density lipoprotein-cholesterol, apolipoprotein E (apoE)-rich high-density lipoprotein-cholesterol (HDL-C), apoA-I, apoE, and cholesteryl ester transfer protein (CETP) concentrations, but negative correlation with apoE-poor HDL-C concentration. Western blot analysis of liver biopsy specimens revealed that FXR and LXR expression increased in parallel with TBA level. CETP- and ATP-binding cassette transporter A1 expression also increased with TBA level, while scavenger receptor class B type-I expression showed the opposite response. However, apoA-I expression was similar to the control level at any TBA level. In the incomplete AGS parents, TBA and lipoprotein parameters showed little fluctuation. In summary, cholestasis is closely related to dyslipidemia and hepatic nuclear receptor expression in AGS patients. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.atheroscierosis.2008.02.020

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Reduced apolipoprotein E-rich high-density lipoprotein level at birth is restored to the normal range in patients with familial Hypercholesterolemia in the first year of life

Hironori Nagasaka, Takashi Miida, Kenichi Hirano, Akemi Ota, Tohru Yorifuji, Tomozumi Takatani, Hirokazu Tsukahara, Masaki Takayanagi, Shu-Ping Hui, Kunihiko Kobayashi, Hitoshi Chiba

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 93 ( 3 ) 779 - 783 2008.3

Language：English Publisher：ENDOCRINE SOC

Background: High-density lipoprotein (HDL) consists of apolipoprotein E (apoE)-rich and apoE-poor HDL particles. ApoE-rich HDL level is high at birth but decreases after birth with reciprocal elevation in low-density lipoprotein (LDL)-cholesterol.
Objectives: The objective of the study was to clarify whether apoE-rich HDL decreases after birth in children with familial hypercholesterolemia (FH), a disorder caused by impaired LDL clearance.
Methods: We measured apoE-rich HDL-cholesterol and LDL-cholesterol during the first year of life in 10 FH children (one homozygote and nine heterozygotes), 12 non-FH siblings, and 75 healthy controls.
Results: At birth, apoE-rich HDL-cholesterol was undetectable in a homozygous FH child and lower in heterozygous FH children than non-FH siblings and controls ( 4 +/- 2 vs. 12 +/- 4 and 11 +/- 4 mg/dl, P < 0.001). At 3-4 months, apoE-rich HDL-cholesterol increased in homozygous and heterozygous FH children and decreased in non-FH siblings and controls. At 12 months, apoE-rich HDL-cholesterol levels were similar among these four groups (6-7 mg/dl). In contrast, LDL-cholesterol concentration was always twice as high in heterozygous FH children as non-FH siblings and controls ( at birth, 50 +/- 15 vs. 25 +/- 7 and 25 +/- 5 mg/dl, P < 0.001; at 3 - 4 months of age, 159 +/- 29 vs. 71 similar to 16 and 73 +/- 15 mg/dl, P < 0.001; at 12 months of age, 156 +/- 29 vs. 75 +/- 18 and 76 +/- 17 mg/dl, P < 0.001).
Conclusion: ApoE- rich HDL level is low at birth in FH children and increases to the normal level in the first year of life, opposite to the change in normal children.

DOI： 10.1210/jc.2007-1621

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Determination of asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, in umbilical blood

Hirokazu Tsukahara, Naoko Ohta, Shuko Tokuriki, Koji Nishijima, Fumikazu Kotsuji, Hisako Kawakami, Norihito Ohta, Kyouichi Sekine, Hironori Nagasaka, Mitsimi Mayumi

METABOLISM-CLINICAL AND EXPERIMENTAL 57 ( 2 ) 215 - 220 2008.2

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

Endothelial cells produce nitric oxide (NO), a potent vasodilator. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. Little is known about the potential physiological roles of ADMA in a perinatal setting. This study measures concentrations of ADMA in umbilical blood using enzyme-linked immunosorbent assay and those of NO as nitrite/nitrate (NOx(-)) using the Griess assay. Their relationship to the degree of prematurity and maternal clinical condition is examined. Results show that ADMA concentrations in umbilical blood from control newborns were about twice as high as those of lactating women, healthy children, and healthy adults. Umbilical blood NOx(-) concentrations from control newborns were about half of those of lactating women, healthy children, and healthy adults. Consequently, the levels of ADMA relative to NOx(-) were about 4-fold higher in umbilical blood from control newborns than in blood from lactating women, healthy children, and healthy adults. Furthermore, the umbilical blood ADMA concentrations and the ratios of ADMA to NOx(-) in newborns were higher according to their birth prematurity and lower birth weight. The umbilical ADMA concentrations were independent of the delivery mode and maternal preeclampsia. We infer that the high ADMA levels play physiological roles in maintaining vascular tone and blood redistribution to vital organs during birth, thereby favoring the circulatory transition from fetal to neonatal life. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.metabol.2007.09.003

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High levels of growth factors in human breast milk

Ritsuyo Kobata, Hirokazu Tsukahara, Yusei Ohshima, Naoko Ohta, Shuko Tokuriki, Satoshi Tamura, Mitsufumi Mayumi

EARLY HUMAN DEVELOPMENT 84 ( 1 ) 67 - 69 2008.1

Language：English Publisher：ELSEVIER IRELAND LTD

We found very high concentrations of vascular endothelial growth factor, hepatic growth factor, and epidermal growth factor in early breast milk samples obtained from healthy mothers of term infants. This is the first report of simultaneous measurements of three major gastrointestinal trophic substances in human milk. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.earlhumdev.2007.07.005

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小児医療における腎機能評価

塚原宏一

臨床化学 37 ( 1 ) 35 - 44 2008

超早産児での晩期循環不全発症予防におけるナトリウム補充の重要性

徳力周子, 塚原宏一, 古畑律代, 巨田尚子, 田村知史, 鈴木孝二, 畑郁江, 眞弓光文

小児科臨床 61 ( 8 ) 1679 - 1684 2008

BOOK REVIEW: 新生児医療 - 治療方針選択に役立つ論文245（京都大学医学部附属病院NICU 河井昌彦編著）. 新生児医療を担う若手医師の実力向上を後押しする1冊

塚原宏一

日本医事新報 4404 35 2008

小児疾患診療のための病態生理1 - IV. 腎・泌尿器疾患. 11. 尿路感染症

塚原宏一

小児内科 40 867 - 873 2008

早期新生児のDIC診断基準: 多施設共同研究による京都大学案の検討

河井昌彦, 丹羽房子, 松倉崇, 水本洋, 金岡裕夫, 松原康策, 塚原宏一, 前田真治, 黒須英雄, 吉岡孝和, 武藤庫参, 中畑龍俊

日本周産期新生児医学会雑誌 44 ( 4 ) 1180 - 1185 2008

Clinical significance of the balance between the L-arginine/NOS/NO pathway and the PRMT/ADMA/DDAH pathway

H.Tsukahara, N.Oota, S.Tokuriki, S.Tamura, M.Toyooka, K.Nishijima, M.Orisaka, F.Kotsuji, N.Ohta, H.Kawakami, K.Sekine, H.Nagasaka, M.Mayumi

Journal of Developmental Nephrology 16 ( 1 ) 21 - 28 2008

小児疾患診療のための病態生理1 - IV. 腎・泌尿器疾患. 11. 尿路感染症

塚原宏一

小児内科 40 867 - 873 2008

早期新生児のDIC診断基準: 多施設共同研究による京都大学案の検討

河井昌彦, 丹羽房子, 松倉崇, 水本洋, 金岡裕夫, 松原康策, 塚原宏一, 前田真治, 黒須英雄, 吉岡孝和, 武藤庫参, 中畑龍俊

日本周産期新生児医学会雑誌 44 ( 4 ) 1180 - 1185 2008

超低出生体重児の消化管成熟に向けた治療戦略：肺サーファクタントを用いた動物実験

西島浩二, 宿南憲一, 高橋仁, 塚原宏一, 小辻文和

日本周産期・新生児医学会雑誌 44 ( 4 ) 978 - 981 2008

薬に関する素朴な疑問. 各論 - 泌尿・生殖器疾患: 尿路感染症の予防には何を用いますか、ST合剤の方がセファクロルより有効ですか

塚原宏一

小児内科 40 ( 2 ) 430 - 431 2008

薬に関する素朴な疑問. 各論 - 泌尿・生殖器疾患: 尿路感染症に対して抗菌薬はどのくらいの期間使用すればよいですか

塚原宏一

小児内科 40 ( 2 ) 428 - 429 2008

先天性腎尿路異常症児における骨代謝・骨発育の臨床検査医学的評価

塚原宏一

平成19年度腎不全病態研究助成成果報告書 2008

新生児の循環の適応生理: 新生児の心臓血管ホルモンの適応生理

塚原宏一

Neonatal Care 21 ( 5 ) 437 - 444 2008

新生児骨代謝の評価: 特に子宮収縮抑制剤の作用について

徳力周子, 塚原宏一, 古畑律代, 巨田尚子, 田村知史, 畑郁江, 西島浩二, 宿南憲一, 小辻文和, 眞弓光文

小児科臨床 61 ( 5 ) 1003 - 1009 2008

座談会: AKIの早期診断・早期治療へ向けて

野入英世, 伊西洋二, 塚原宏一, 菅谷健

内科 102 ( 1 ) 115 - 124 2008

動脈管早期閉鎖により新生児遷延性肺高血圧症をきたした1例

巨田尚子, 田村知史, 徳力周子, 小倉一将, 畑郁江, 塚原宏一, 鈴木千代, 西島浩二, 折坂誠, 小辻文和, 眞弓光文

小児科臨床 61 ( 8 ) 1685 - 1689 2008

超早産児での晩期循環不全発症予防におけるナトリウム補充の重要性

徳力周子, 塚原宏一, 古畑律代, 巨田尚子, 田村知史, 鈴木孝二, 畑郁江, 眞弓光文

小児科臨床 61 ( 8 ) 1679 - 1684 2008

要注意 - この感染症にこの合併症. 水痘感染後の脳梗塞

奥野貴士, 川谷正男, 中井昭夫, 畑郁江, 塚原宏一, 谷澤昭彦, 眞弓光文

小児内科 40 ( 3 ) 532 - 534 2008

胎児・胎盤機能を維持する分子機構の解明と周産期疾患の治療介入についての統合的研究

眞弓光文, 塚原宏一

平成17～19年度科学研究費補助金（基盤研究B）研究成果報告書 2008

胎児期・乳幼児期・学童期・思春期においてアルギニン代謝が循環制御に果たす役割についての分子医学的研究: 統合創薬の開拓に向けて

塚原宏一, 巨田尚子

福井大学重点研究成果集 72 - 73 2008

先天性腎尿路異常症児における骨代謝・骨発育の臨床検査医学的評価

塚原宏一

平成19年度腎不全病態研究助成成果報告書 2008

新生児の循環の適応生理: 新生児の心臓血管ホルモンの適応生理

塚原宏一

Neonatal Care 21 ( 5 ) 437 - 444 2008

新生児骨代謝の評価: 特に子宮収縮抑制剤の作用について

徳力周子, 塚原宏一, 古畑律代, 巨田尚子, 田村知史, 畑郁江, 西島浩二, 宿南憲一, 小辻文和, 眞弓光文

小児科臨床 61 ( 5 ) 1003 - 1009 2008

Clinical significance of the balance between the L-arginine/NOS/NO pathway and the PRMT/ADMA/DDAH pathway

H.Tsukahara, N.Oota, S.Tokuriki, S.Tamura, M.Toyooka, K.Nishijima, M.Orisaka, F.Kotsuji, N.Ohta, H.Kawakami, K.Sekine, H.Nagasaka, M.Mayumi

Journal of Developmental Nephrology（発達腎研究会誌） 16 ( 1 ) 21 - 28 2008

座談会: AKIの早期診断・早期治療へ向けて

野入英世, 伊西洋二, 塚原宏一, 菅谷健

内科 102 ( 1 ) 115 - 124 2008

塚原宏一

日本医事新報 4404 35 2008

薬に関する素朴な疑問. 各論 - 泌尿・生殖器疾患: 尿路感染症の予防には何を用いますか、ST合剤の方がセファクロルより有効ですか

塚原宏一

小児内科 40 ( 2 ) 430 - 431 2008

薬に関する素朴な疑問. 各論 - 泌尿・生殖器疾患: 尿路感染症に対して抗菌薬はどのくらいの期間使用すればよいですか

塚原宏一

小児内科 40 ( 2 ) 428 - 429 2008

前置癒着胎盤及び広範な前壁付着を伴う前置胎盤に対する新たな帝王切開法：子宮底部横切開法の安全性と有用性

西島浩二, 宿南憲一, 折坂誠, 田嶋公久, 塚原宏一, 河合泰一, 吉田好雄, 小辻文和

日本産婦人科・新生児血液学会誌 17 ( 2 ) 39 - 42 2008

Assessment of renal function in pediatric medicine

Hirokazu Tsukahara

Japanese Journal of Clinical Chemistry 37 ( 1 ) 35 - 44 2008

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19年度第2分冊 2008

Leukotriene D-4 enhances the function of endothelin-1-primed fibroblasts

Shuko Tokuriki, Yusei Ohshima, Akiko Yamada, Naoko Ohta, Hirokazu Tsukahara, Mitsufumi Mayumi

CLINICAL IMMUNOLOGY 125 ( 1 ) 88 - 94 2007.10

Language：English Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

Airway inflammation is accompanied by structural changes, termed remodeling, that lead to lung dysfunction over the tong term. Although both endothelin-1 (ET-1) and cysteinyl leukotrienes (CysLTs) appear to be involved in airway remodeling in several lung diseases, how these molecules interact remains largely unknown. In this study, we examined the effects of leukotriene (LT) D-4 on the function of ET-1-primed fibroblasts. ET-1 at 10(-7) M up-regulated the expression of the CysLT receptors at both the mRNA and protein levels in human lung fibroblasts. LTD4 enhanced matrix metalloproteinase-2 and pro-collagen production, and a-smooth muscle actin expression of ET-1-primed fibroblasts, but had little or no effect on unprimed fibroblasts. The CysLT1 receptor antagonist montelukast completely abrogated the effects of LTD4. Our data suggested that LTD4 may act as a precipitating factor during ET-1-mediated airway remodeling and that CysLT1 receptor antagonists may have a rote in preventing aberrant extracellutar matrix degradation. (c) 2007 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.clim.2007.05.018

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PTを重視した早期新生児期のDIC診断基準多施設での検討に基づくPT基準値の変更

河井昌彦, 松倉崇, 水本洋, 丹羽房子, 金岡裕夫, 塚原宏一, 武藤庫参, 中畑龍俊

日本未熟児新生児学会雑誌 19 ( 3 ) 631 - 631 2007.10

Depletion of high-density lipoprotein and appearance of triglyceride-rich low-density lipoprotein in a Japanese patient with FIC1 deficiency manifesting benign recurrent intrahepatic cholestasis

Hironori Nagasaka, Hitoshi Chiba, Shu-Ping Hui, Hajime Takikawa, Takashi Miida, Masaki Takayanagi, Tohru Yorifuji, Makoto Hasegawa, Akemi Ota, Ken-ichi Hirano, Hideaki Kikuchi, Hirokazu Tsukahara, Kunihiko Kobayashi

JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION 45 ( 1 ) 96 - 105 2007.7

Language：English Publisher：LIPPINCOTT WILLIAMS & WILKINS

Objective: Lipoprotein metabolism in FIC I deficiency due to ATP8B1 mutations has never been studied sufficiently. This study was performed to investigate the detailed lipoprotein metabolism in benign recurrent intrahepatic cholestasis (BRIC) caused by FIC1 deficiency.
Patients and Methods: Lipoprotein profile and major lipoprotein regulators such as lecithin: cholesterol acyltransferase (LCAT), hepatic triglyceride lipase (HTGL), lipoprotein lipase, and cholesteryl ester transfer protein in a Japanese patient with BRIC were serially examined during a bout of cholestasis. Liver expression of farnesoid X receptor (FXR), which suppresses high-density lipoprotein (HDL) generation., was also examined.
Results: Hypercholesterolemia and lipoprotein X accumulation were never observed throughout this study. When the cholestasis was severe, triglyceride-rich low-density lipoprotem (LDL) accounted for most of the plasma lipoproteins whereas HDL was hardly detectable. Concurrently, activities of all regulators were decreased, together with decreases of the serum parameter for liver protein synthesis. In particular, suppressions of LCAT and HTGL activities were severe and greatly contributed to the appearance of triglyceride-rich LDL. As the cholestasis improved, this LDL gradually transformed into normal LDL with the recoveries of LCAT and HTGL activities. The activities of all regulators for the last I to 2 months were normal but HDL remained depleted. His liver showed low FXR expression compared with control livers.
Conclusions: The present study showed an appearance of triglyceride-rich LDL due to suppressions of LCAT and HTGL activities and a depletion of HDL that is not able to be explained by lipoprotein regulators or FXR in our patient.

DOI： 10.1097/MPG.0b013e3180331df9

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小児の腎機能検査

塚原宏一

臨床化学 36 113 - 113 2007.6

プロトロンビン時間を重視した早期新生児期のDIC診断基準多施設共同での検討結果(第1報)

河井昌彦, 水本洋, 丹羽房子, 金岡裕夫, 松原康策, 塚原宏一, 武藤庫参, 中畑龍俊

日本産婦人科・新生児血液学会誌 17 ( 1 ) S - 35 2007.6

新生児医療の処置に関する合併症の検討

水本洋, 丹羽房子, 河井昌彦, 中畑龍俊, 奥村光祥, 加藤文英, 金岡裕夫, 黒須英雄, 塚原宏一, 橋本和廣, 前田真治, 山川勝, 吉岡孝和

日本小児科学会雑誌 111 ( 2 ) 426 - 426 2007.2

Lowest effective dose of dexamethasone in the respiratory care of very preterm infants

Hirokazu Tsukahara, Mitsufumi Mayumi

EARLY HUMAN DEVELOPMENT 83 ( 1 ) 3 - 3 2007.1

糖尿病血管系合併症における分子機構の解明と治療戦略への応用（研究課題番号 17591074）

塚原宏一

平成17～18年度科学研究費補助金（基盤研究C）研究成果報告書 2007

平成18年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総括研究報告書: 小児難治性腎尿路疾患の早期発見、診断管理・治療に関する研究（主任研究者五十嵐隆）

五十嵐隆, 伊藤雄平, 松山健, 塚原宏一, 中井秀郎, 飯島一誠, 塚口裕康, 関根孝司, 吉川徳茂, 本田雅敬, 山内邦昭, 二宮誠, 宮田純一, 北村明子, 中西浩一, 佐古まゆみ, 服部新三郎, 和田尚弘

平成18年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総括・分担研究報告書 1 - 23 2007

平成18年度厚生労働科学研究費補助金（子ども家庭総合研究事業）分担研究報告書: 小児難治性腎尿路疾患の早期発見、診断管理・治療に関する研究（主任研究者五十嵐隆）. 尿路感染症の診断、治療、管理システムの構築に関する研究

塚原宏一

平成18年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総括・分担研究報告書 58 - 62 2007

平成16年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総合研究報告書: 小児難治性腎尿路疾患の早期発見、診断管理・治療に関する研究（主任研究者五十嵐隆）

五十嵐隆, 松山健, 伊藤雄平, 平岡政弘, 塚原宏一, 中井秀郎, 飯島一誠, 塚口裕康, 関根孝司, 吉川徳茂, 本田雅敬

平成16年度～18年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総合研究報告書 1-8 2007

平成17年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総合研究報告書: 小児難治性腎尿路疾患の早期発見、診断管理・治療に関する研究（主任研究者五十嵐隆）

五十嵐隆, 松山健, 伊藤雄平, 塚原宏一, 中井秀郎, 飯島一誠, 塚口裕康, 関根孝司, 吉川徳茂, 本田雅敬, 服部新三郎, 幡谷浩志, 和田尚弘

平成16年度～18年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総合研究報告書 9 - 24 2007

平成18年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総合研究報告書: 小児難治性腎尿路疾患の早期発見、診断管理・治療に関する研究（主任研究者五十嵐隆）

五十嵐隆, 伊藤雄平, 松山健, 塚原宏一, 中井秀郎, 飯島一誠, 塚口裕康, 関根孝司, 吉川徳茂, 本田雅敬, 服部新三郎, 幡谷浩志, 和田尚弘

平成16年度～18年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総合研究報告書 25 - 48 2007

新生児期の栄養管理と長期予後: 早産児の栄養管理と骨発達

塚原宏一

第7回新生児栄養フォーラム発表論文集 58 - 65 2007

慢性腎臓病 - CKDキャンペーンをめぐる話題 - 国内外のCKDに対するエビデンス: 小児CKD

塚原宏一

内科 100 ( 1 ) 79 - 83 2007

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

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

Hepatocyte growth factor concentration in umbilical cord blood

R.Kobata, H.Tsukahara, M. Kawatani, K.Nishijima, K-I.Shukunami, F.Kotsuji, M.Ueno, M.Mayumi

Medical Postgraduate 44 ( 4 ) 415 - 417 2006

重症心身障害者における血清中セレンおよびチオレドキシンの計測

佐藤周子, 梶原真清恵, 紫英人, 竹内元治, 塚原宏一, 出口洋二, 眞弓光文

小児科臨床 59 ( 6 ) 1147 - 1151 2006

小児における異常ナトリウム血症の管理

塚原宏一

小児科臨床 59 ( 7 ) 1543 - 1553 2006

平成17年度小児科医会例会ミニシンポジウム（小児の画像診断）可逆性脳梁膨大部病変を伴う脳症・脳炎: 新しい疾患単位として

塚原宏一

平成18年度福井県小児科医会会報 35 24 - 29 2006

胎児期から青年期にかけてのAdvanced glycation end-products生成の評価ヒトにおける"carbonyl stress"の評価

塚原宏一, 古畑律代, 田村知史, 羽田敦子, 眞弓光文, 西島浩二, 宿南憲一, 上野正樹, 川上寿子, 内山真由美, 関根恭一, 三浦雅一

発達腎研究会誌 14 ( 1 ) 42 - 48 2006

Hepatocyte growth factor concentration in umbilical cord blood

R.Kobata, H.Tsukahara, M. Kawatani, K.Nishijima, K-I.Shukunami, F.Kotsuji, M.Ueno, M.Mayumi

Medical Postgraduate 44 ( 4 ) 415 - 417 2006

一酸化窒素（NO）と腎臓: 個人的考察

塚原宏一

小児腎臓病学会雑誌 19 ( 2 ) 96 - 103 2006

新生児骨代謝の評価: 特に子宮収縮抑制剤の作用について

徳力周子, 塚原宏一, 古畑律代, 田村知史, 眞弓光文

第23回小児代謝性骨疾患研究会発表論文集 13 - 17 2006

初診時に左心房内への進展を呈していた胸膜肺芽腫の１例

田村知史, 金谷由宇子, 塚原宏一, 谷澤昭彦, 眞弓光文, 今村好章

日児誌 110 ( 12 ) 1671 - 1675 2006

糖尿病血管系合併症における分子機構の解明と治療戦略への応用

塚原宏一

平成17年度科学研究費補助金実績報告書（基盤研究C） 2006

平成17年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総括研究報告書: 小児難治性腎尿路疾患の早期発見、診断管理・治療に関する研究（主任研究者五十嵐隆）

五十嵐隆, 松山健, 伊藤雄平, 塚原宏一, 中井秀郎, 飯島一誠, 塚口裕康, 関根孝司, 吉川徳茂, 本田雅敬, 服部新三郎, 幡谷浩志, 和田尚弘

平成17年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総括・分担研究報告書 1 - 16 2006

平成17年度厚生労働科学研究費補助金（子ども家庭総合研究事業）分担研究報告書: 小児難治性腎尿路疾患の早期発見、診断管理・治療に関する研究（主任研究者五十嵐隆）. 尿路感染症の診断、治療、管理システムの構築に関する研究

塚原宏一

平成17年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総括・分担研究報告書 2006

糖尿病血管系合併症における分子機構の解明と治療戦略への応用

塚原宏一

平成17年度科学研究費補助金実績報告書（基盤研究C） 2006

超早産（在胎28週未満）で出生した児の水電解質代謝の評価とその制御: 輸液療法のガイドライン作成に向けて

塚原宏一, 古畑律代

福井大学重点研究成果報告書 128 - 129 2006

五十嵐隆, 松山健, 伊藤雄平, 塚原宏一, 中井秀郎, 飯島一誠, 塚口裕康, 関根孝司, 吉川徳茂, 本田雅敬, 服部新三郎, 幡谷浩志, 和田尚弘

平成17年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総括・分担研究報告書 1 - 16 2006

塚原宏一

平成17年度厚生労働科学研究費補助金（子ども家庭総合研究事業）総括・分担研究報告書 2006

新生児: 体液・電解質異常

塚原宏一

小児科診療（増刊号: 小児の治療指針） 69 861 - 867 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

新生児: 体液・電解質異常

塚原宏一

小児科診療（増刊号: 小児の治療指針） 69 861 - 867 2006

乳幼児の尿路感染症の診断のポイント

塚原宏一

小児科 46 ( 13 ) 2133 - 2142 2005.12

Transient focal lesions in the splenium of the corpus callosum with restricted diffusion: An enigma

M Maeda, H Tsukahara

CURRENT MEDICAL IMAGING REVIEWS 1 ( 3 ) 313 - 318 2005.11

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

Small transient lesions in the central part of the splenium of the corpus callosum (SCC) have been reported in MR examinations, particularly in patients with encephalitis or encephalopathy, and in patients with or without epilepsy who are receiving antiepileptic drugs. The MR findings are characteristic: an ovoid T2-high signal lesion in the SCC, no enhancement after contrast agent, restricted diffusion shown by diffusion MR imaging, and complete disappearance on follow-up MR examinations. Most noteworthy is that these lesions have restricted diffusion but are reversible, which is distinct from infarction lesions seen in energy failure. The exact mechanism of these transient lesions remains uncertain and enigmatic. We review previously reported patients to show these unique MR findings and describe possible pathogenesis of particular SCC lesions.

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Quantitation of glutathione S transferase-pi in the urine of preterm neonates

H Tsukahara, M Toyo-Oka, Y Kanaya, K Ogura, M Kawatani, A Hata, M Hiraoka, M Mayumi

PEDIATRICS INTERNATIONAL 47 ( 5 ) 528 - 531 2005.10

Language：English Publisher：WILEY-BLACKWELL PUBLISHING, INC

Background: Glutathione S transferases (GSTs) are widely distributed enzymes found in highly varying amounts in tissues of the human body. The enzyme GST-pi in urine has been used as a marker of renal distal tubular cell damage. The present study was intended to evaluate urinary excretion of GST-pi and its relationship to other renal markers and to the status of oxidative stress in preterm neonates.
Methods: Levels of urinary GST-pi, N-acetyl-beta-glucosaminidase (a marker of proximal tubular damage), albumin (a marker of glomerular damage) and 8-hydroxy-2'-deoxyguanosine (a marker of oxidative stress) and serum creatinine were measured in preterm neonates at 1 and 4 weeks of age.
Results: The results showed that urinary excretion of GST-pi is increased in preterm neonates compared with reported values for healthy adults. No significant relationship was detected between urinary GST-pi and other markers for renal function. Urinary GST-pi showed significantly positive correlation with urinary 8-hydroxy-2'-deoxyguanosine at 1 and 4 weeks. Sick neonates treated with supplemental oxygen and mechanical ventilation showed significantly higher levels of GST-pi as well as 8-hydroxy-2'-deoxyguanosine than clinically stable neonates did at 4 weeks.
Conclusions: These results indicate the potential effect of systemic oxidative stress on urinary excretion of GST-pi. Further studies are necessary to explore the effect of oxidative conditions on expression of GST-pi in distal tubules in the human kidney.

DOI： 10.1111/j.1442-200x.2005.02123.x

PDTC and NO suppress CC chemokine production in TNF-alpha-stimulated human pulmonary microvascular endothelial cells

Y Mori, H Tsukahara, MZ Jiang, M Mayumi

RESPIRATORY MEDICINE 99 ( 8 ) 1068 - 1069 2005.8

Quantification of L-type fatty acid binding protein in the urine of preterm neonates

H Tsukahara, T Sugaya, K Hayakawa, Y Mori, M Hiraoka, A Hata, M Mayumi

EARLY HUMAN DEVELOPMENT 81 ( 7 ) 643 - 646 2005.7

Language：English Publisher：ELSEVIER IRELAND LTD

We measured urinary excretion of L-type fatty acid binding protein (LFABP) in preterm neonates on days 1, 5-10, and 25-30 of life. Urinary L-FABP levels (expressed as the ratio to creatinine) in preterm neonates were considerably higher than those of healthy adults. They did not change significantly during the study period. Urinary L-FABP levels showed significant positive correlation with those of urinary N-acetyl-beta-D-glucosaminidase activity on day 1, and with those of 8-hydroxy-2'-deoxyguanosine on days 25-30. These results suggest that L-FABP is expressed in the neonatal kidney. Our results may also point to potential effects of proximal tubular damage and oxidative stress on urinary excretion of L-FABP. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.earlhumdev.2005.03.012

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Effects of antioxidants and NO on TNF-alpha-induced adhesion molecule expression in human pulmonary microvascular endothelial cells

MZ Jiang, H Tsukahara, K Hayakawa, Y Todoroki, S Tamura, Y Ohshima, M Hiraoka, M Mayumi

RESPIRATORY MEDICINE 99 ( 5 ) 580 - 591 2005.5

Language：English Publisher：W B SAUNDERS CO LTD

Pro-inflammatory cytokines initiate the vascular inflammatory response via upregulation of adhesion molecules on the endothelium. Recent observations suggest that reactive oxygen intermediates may play a pivotal role in TNF-alpha signaling and upregulate gene expression. We therefore evaluated the effects of pyrrolidine dithiocarbamate (PDTC; 0.1 mM) and spermine NONOate (Sper-NO; 1 mM) on adhesion molecule expression and nuclear factor kappa B (NF-kappa B) activation induced by TNF-alpha (10ng/mL) in cultured human pulmonary microvascular endothelial cells (PMVEC). Treatment of cells with TNF-alpha. for 4h significantly induced the surface expression of E-selectin and ICAM-1. Treatment with TNF-alpha. for 8h significantly induced the surface expression of E-selectin, ICAM-1 and VCAM-1. The upregulation of these adhesion molecules was suppressed significantly by pretreatment with PDTC or Sper-NO for 1 h. 8-Bromo-cyctic GMP (1 mM) had no such effect, suggesting that the NO donor's effect was non-cGMP-dependent. The mRNA expression of E-selectin, ICAM-1 and VCAM-1, and activation of NF-kappa B induced by TNF-alpha for 2h were decreased significantly by the above two pretreatments. N-acetytcysteine (10 mM) and S-nitroso-N-acetylpenicillamine (1 mM) had little inhibitory effects on the cell surface and mRNA expression of these adhesion molecules stimulated by TNF-alpha. Treatment with TNF-alpha for 4 h enhanced HL-60 leukocyte adhesion to human PMVEC, the effect of which was inhibited significantly by pretreatment with PDTC or Sper-NO. These findings indicate that both cell surface and mRNA expression of adhesion molecules in human PMVEC induced by TNF-alpha are inhibited significantly by pretreatment with PDTC or Sper-NO, possibly in part through blocking the activation of NF-kappa B. Although our in vitro results cannot be directly extrapolated to the in vivo situation, they suggest a potential therapeutic approach for intervention in cytokine-mediated inflammatory processes in the human lung. (c) 2004 Elsevier Ltd. All rights reserved.

DOI： 10.1016/rmed.2004.10.007

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Parameters for measurement of oxidative stress in diabetes mellitus: Applicability of enzyme-linked immunosorbent assay for clinical evaluation

E Noiri, H Tsukahara

JOURNAL OF INVESTIGATIVE MEDICINE 53 ( 4 ) 167 - 175 2005.5

Language：English Publishing type：Book review, literature introduction, etc. Publisher：LIPPINCOTT WILLIAMS & WILKINS

Investigations of the mechanisms involved in the onset and progression of diabetes have recently confronted the role of reactive oxygen species (ROS) and oxidative stress. Prolonged exposure to hyperglycemic conditions induces nonenzymatic glycation of protein via the so-called Maillard reaction, resulting in Schiff-base products and Amadori products that engender ROS production. These processes initiate and exacerbate micro- and macrovascular complications in diabetes. Increased oxidative stress is induced by excessive ROS production and inadequate antioxidant defenses. Recently, oxidative stress status markers have been associated directly with the severity and prognosis of diabetes. To examine oxidative stress, reliable and high-throughput methods are needed to examine large numbers of clinical samples. The emerging availability of enzyme-linked immunosorbent assay (ELISA) for oxidative stress status markers allows its application to assessment of various pathophysiologic conditions, including diabetes. This review outlines the recent achievements of ELISA application for clinical studies elucidating oxidative stress. It introduces the potential applicability of ELISA for investigating oxidative stress in diabetes.

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Salivary-type hyperamylasemia in theophylline poisoning

K Suzuki, Y Ohshima, Hata, I, H Tsukahara, N Omata, M Yasutomi, A Yamada, M Mayumi

PEDIATRICS INTERNATIONAL 47 ( 2 ) 209 - 210 2005.4

Concentrations of thioredoxin, a redox-regulating protein, in umbilical cord blood and breast milk

Y Todoroki, H Tsukahara, Y Ohshima, K Shukunami, K Nishijima, F Kotsuji, A Hata, K Kasuga, K Sekine, H Nakamura, J Yodoi, M Mayumi

FREE RADICAL RESEARCH 39 ( 3 ) 291 - 297 2005.3

Language：English Publisher：TAYLOR & FRANCIS LTD

Growing evidence indicates that oxidative stress occurs during the fetal-to-neonatal transition. Such stress plays an important role in the pathogenesis of many neonatal diseases. Thioredoxin (TRX), a redox-regulating protein with antioxidant activity, is induced in various cells against oxidative stress and is secreted extracellularly. This study was undertaken to examine the clinical and biological importance of TRX in the perinatal setting. We measured concentrations of TRX in umbilical cord blood and breast milk using a sandwich ELISA. Our study demonstrated that concentrations of TRX in umbilical cord blood were six to seven times higher than those in blood of healthy adults. This study also showed that umbilical concentrations of TRX were correlated significantly with the extent of prematurity of the newborn, and that they were elevated significantly in newborns of mothers with preeclampsia compared to those of mothers without preeclampsia. In contrast, concentrations of coenzyme Q(10) and vitamin E in umbilical blood were lower than adult blood levels. Breast milk concentrations of TRX during the early postpartum period were seven to eight times higher than those in blood of lactating women. Those of the coenzyme Q(10) were lower than adult blood levels, while those of vitamin E were comparable to adult blood levels. Our findings suggest that the systemic release of TRX is enhanced at birth, and that early breast milk is a rich source of this protein. Consequent high levels of TRX in newborns may provide a unique protective mechanism that allows the maintenance of redox balance during the fetal-to-neonatal transition.

DOI： 10.1080/10715760500053578

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Marked renal damage in a child with hydronephrosis infected by Trichosporon asahii

Y Mori, M Hiraoka, M Katsu, H Tsukahara, Y Mikami, M Mayumi

PEDIATRIC NEPHROLOGY 20 ( 2 ) 234 - 236 2005.2

Language：English Publisher：SPRINGER

We describe a case of urinary infection caused by Trichosporon asahii, which drastically aggravated renal function in a left hydronephrotic kidney. Previous implantation of a nephrostomy tube and a ureteral J-stent and administration of broad-spectrum antibiotics seemed to have predisposed the non-granulocytopenic child to the urinary fungal infection.

DOI： 10.1007/s00467-004-1731-6

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Conservative versus extirpative management in cases of placenta accreta

K Nishijima, K Shukunami, H Tsukahara, F Kotsuji

OBSTETRICS AND GYNECOLOGY 105 ( 1 ) 220 - 220 2005.1

早産児の代謝性骨疾患

塚原宏一

周産期医学 35 1671 - 1679 2005

会報編集委員会: 報告と編集後記

橋本剛太郎, 加藤英治, 清水紘昭, 塚原宏一, 寺尾正

平成17年度福井県小児科医会会報 34(10) 2005

栄養補助物質の使用: ビタミンの補充

塚原宏一, 塚原康代

周産期医学 35(増刊号) 474 - 483 2005

周産期のレドックス制御: 特に母乳の抗酸化作用の分析についての研究

塚原宏一

2003年度財団法人森永奉仕会研究奨励金成果報告書 2005

ペプチド分解乳で牛乳アレルギーの予防ができるのか？母乳はアトピー性皮膚炎に良くないのか？

塚原宏一, 大嶋勇成

小児内科 37(5) ( 5 ) 677 - 680 2005

免疫・炎症性疾患におけるレドックス・マーカーの現況

塚原宏一

臨床病理 53(8) 759 - 767 2005

生直後に著明な赤芽球増加,低血糖を呈した胎児水腫の極低出生体重児例

小倉一将, 塚原宏一, 巨田尚子, 佐藤周子, 古畑律代, 田村知史, 谷澤昭彦, 眞弓光文

小児科臨床 58 ( 8 ) 1691 - 1695 2005

Quantitative unspun-urine microscopy as a quick, reliable examination for bacteriuria

M Hiraoka, Y Hida, Y Mori, H Tsukahara, Y Ohshima, H Yoshida, M Mayumi

SCANDINAVIAN JOURNAL OF CLINICAL & LABORATORY INVESTIGATION 65 ( 2 ) 125 - 132 2005

Language：English Publisher：TAYLOR & FRANCIS AS

The diagnosis and treatment of urinary infection are often delayed, causing renal damage, largely because of the unavailability of quick, accurate, diagnostic examinations. Three hundred and twenty-five urine samples from 130 patients were examined for significant bacteriuria using the standard culture method. The urine samples were also examined using the Gram-stain method and quantitative unspun-urine microscopy. When particles could not be distinguished definitely as bacilli by quantitative microscopy, the unspun urine was examined on a slide glass using oil-immersion microscopy at x 1000 magnification. Significant bacteriuria in 37 urine samples was detected by bacterial culture. Using quantitative microscopy, rods were found in 30, cocci in a chain in 3, and indefinite particles in 44 samples. In the 44 indefinite samples, oil-immersion microscopy was able to distinguish rods in one, cocci in a chain in one, cocci in a cluster in two, and negative in 40, which were confirmed by culture as rods, streptococci, staphylococci, and negative, respectively. The quantitative microscopy method was similarly reliable (94.6% sensitivity, 99.3% specificity) for diagnosis of significant bacteriuria when compared with the Gram-stain method (89.2% sensitivity, 98.6% specificity). Quantitative unspun-urine microscopy, confirmed by oil-immersion, is a quick, reliable method for diagnosis of significant bacteriuria, and is considered to be useful for early diagnosis of urinary infection.

DOI： 10.1080/00365510510013514

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環境ホルモンの影響に関する検討

眞弓光文, 大嶋勇成, 塚原宏一

独立行政法人環境再生保全機構公害健康被害補償予防協会委託業務報告書：気管支ぜん息等の発症・増悪リスクとしての環境要因の寄与の程度に関する研究報告書2004年度工藤翔二研究班報告書 61 - 71 2005

病的新生児、特に超低出生体重児の『後遺症なき生存』を目指して: 当院未熟児診療部における『レドックス（抗酸化ストレス）療法』の推進とその評価

塚原宏一, 大嶋勇成

福井大学重点研究成果報告書 80 - 81 2005

各種疾患におけるレドックス制御とその異常

塚原宏一, 眞弓光文

アレルギー・免疫 12 ( 5 ) 733 - 737 2005

腎尿路異常の早期発見のための3歳児検尿の施行法および費用対便益の検討

平岡政弘, 塚原宏一

平成16年度科学研究費補助金基盤研究C(2)実績報告書 2005

小児の食と栄養Q&A<アレルギー>ペプチド分解乳で牛乳アレルギーの予防ができるのか?母乳はアトピー性皮膚炎に良くないのか?

塚原宏一, 大嶋勇成

小児内科 37 ( 5 ) 2005

Clinically mild encephalitis/encephalopathy with a reversible splenial lesion

H Tada, J Takanashi, AJ Barkovich, H Oba, M Maeda, H Tsukahara, M Suzuki, T Yamamoto, T Shimono, T Ichiyama, T Taoka, O Sohma, H Yoshikawa, Y Kohno

NEUROLOGY 63 ( 10 ) 1854 - 1858 2004.11

Language：English Publisher：LIPPINCOTT WILLIAMS & WILKINS

Objective: To clarify whether patients with clinical diagnoses of encephalitis/encephalopathy with a reversible lesion in the splenium of the corpus callosum (SCC) share common clinical features. Methods: Possible encephalitis/encephalopathy patients with a reversible isolated SCC lesion on MRI were collected retrospectively. Their clinical, laboratory, and radiologic data were reviewed. Results: Fifteen encephalitis/encephalopathy patients with a reversible isolated SCC lesion were identified among 22 patients referred for this study. All 15 patients had relatively mild clinical courses. Twelve of the 15 patients had disorders of consciousness. Eight patients had seizures, and three of them received antiepileptic drugs. All 15 patients clinically recovered completely within 1 month ( 8 patients within a week) after the onset of neurologic symptoms. The SCC lesion was ovoid in six patients; it extended irregularly from the center to the lateral portion of SCC in the other eight patients. Homogeneously reduced diffusion was seen in all seven patients who underwent diffusion-weighted imaging. There was no enhancement in the five patients so examined. The SCC lesion had completely disappeared in all patients at follow-up MRI exams between 3 days and 2 months after the initial MRI ( within 1 week in eight patients). Conclusion: The clinical features among the affected patients were nearly identical, consisting of relatively mild CNS manifestations and complete recovery within 1 month.

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Neonatal bone abnormalities attributable to maternal administration of magnesium sulphate

H Tsukahara, R Kobata, S Tamura, M Mayumi

PEDIATRIC RADIOLOGY 34 ( 8 ) 673 - 674 2004.8

Effects of antioxidant and nitric oxide on chemokine production in TNF-alpha-stimulated human dermal microvascular endothelial cells

H Tsukahara, MZ Jiang, Y Ohshima, Y Todoroki, S Sato, S Tamura, M Hiraoka, M Maeda, M Mayumi

NITRIC OXIDE-BIOLOGY AND CHEMISTRY 11 ( 1 ) 118 - 118 2004.8

Impaired homeostasis of oxygen/nitrogen radicals in childhood atopic dermatitis

H Tsukahara, S Ito, Y Ohshima, N Omata, M Yasutomi, M Hiraoka, M Nambu, Y Deguchi, M Mayumi

NITRIC OXIDE-BIOLOGY AND CHEMISTRY 11 ( 1 ) 118 - 118 2004.8

Concentrations of pentosidine, an advanced glycation end-product, in umbilical cord blood

H Tsukahara, N Ohta, S Sato, M Hiraoka, K Shukunami, M Uchiyama, H Kawakami, K Sekine, M Mayumi

FREE RADICAL RESEARCH 38 ( 7 ) 691 - 695 2004.7

Language：English Publisher：TAYLOR & FRANCIS LTD

Advanced glycation end-products (AGEs) are formed over several weeks to months by non-enzymatic glycation and oxidation ("glycoxidation") reactions between carbohydrate-derived carbonyl groups and protein amino groups, known as the Maillard reaction. Pentosidine is one of the best-characterized AGEs and is accepted as a satisfactory marker for glycoxidation in vivo . The present study was intended to measure pentosidine concentrations in umbilical cord blood from newborns with various gestational ages using our recently established high-performance liquid chromatography method [Tsukahara, H. et al. (2003) Pediatr. Res. 54 , 419-424]. Our study demonstrates, for the first time, that pentosidine is detected in most of the umbilical blood samples. This study also shows that the umbilical blood concentrations of pentosidine are considerably lower than normal adult values, but that they increase with gestation progression and fetal growth. Umbilical pentosidine concentrations were significantly elevated in newborns of mothers with preeclampsia compared to those of mothers without preeclampsia. We conclude that accumulation of AGEs and oxidative stress occurs in fetal tissues and organs in utero at the early stage of human life and that their accumulation is augmented in the maternal preeclampsic condition.

DOI： 10.1080/1071576042000220256

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Oxidative stress in neonates: Evaluation using specific biomarkers

H Tsukahara, MZ Jiang, N Ohta, S Sato, S Tamura, M Hiraoka, M Maeda, M Mayumi

LIFE SCIENCES 75 ( 8 ) 933 - 938 2004.7

Language：English Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Increased oxidative stress has been implicated in pathogenesis of serious diseases in neonates. We measured urinary levels of 8-hydroxy-2'-deoxyguanosine (a marker of oxidative DNA damage), acroleinlysine adduct (a marker of lipid peroxidation and oxidative protein damage), and nitrite/nitrate (a marker of endogenous nitric oxide formation) in one-month-old neonates to examine the status of oxidative stress and its relationship to the degree of prematurity and clinical condition in neonates. Study subjects comprised three groups: healthy term neonates, clinically stable preterm neonates requiring no supplemental oxygen, and clinically sick preterm neonates requiring supplemental oxygen and ventilator support. Urinary levels of 8-hydroxy-2'-deoxyguanosine and acrolein-lysine adduct were significantly higher in sick preterm neonates than those of stable preterm and healthy term neonates. In the sick preterm group, neonates developing active retinopathy showed significantly higher levels of acrolein-lysine adduct than the other neonates without retinopathy. There were no significant differences in both urinary markers of oxidative stress between stable preterm and healthy term neonates. The urinary nitrite/nitrate levels were not significantly different among the three groups, suggesting no difference in endogenous nitric oxide fort-nation. Collectively, these results provide evidence of augmentation of oxidative damage to DNA, lipids and proteins, especially in clinically sick preterm neonates. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2004.01.025

Effects of antioxidants and nitric oxide on TNF-alpha-induced adhesion molecule expression and NF-kappa B activation in human dermal microvascular endothelial cells

MZ Jiang, H Tsukahara, Y Ohshima, Y Todoroki, M Hiraoka, M Maeda, M Mayumi

LIFE SCIENCES 75 ( 10 ) 1159 - 1170 2004.7

Language：English Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Cell adhesion molecules expressed on endothelial cells in inflamed skin appear to be controlled by the actions of cytokines and reactive oxygen species. However, molecular mechanisms of the expression of adhesion molecules during skin inflammation are currently not well understood. To evaluate the role of antioxidants and nitric oxide in modulating inflammatory processes in the skin, we examined the effects of pyrrolidine dithiocarbamate (PDTC, 0.1 mM) and spermine NONOate (Sper-NO, 1 mM) on adhesion molecule expression and nuclear factor kappa B (NF-KB) activation induced by TNF-alpha (10 ng/ml) in cultured human dermal microvascular endothelial cells (HDMEC). Treatment of cells with TNF-alpha for 4 h significantly induced the surface expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1). Treatment with TNF-alpha for 8 h significantly induced the surface expression of E-selectin, ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1). The up-regulation of these adhesion molecules was suppressed significantly by pretreatment with PDTC or Sper-NO for 1 h. The mRNA expression of E-selectin, ICAM-1 and VCAM-1, and activation of NF-kappaB induced by TNF-alpha for 2 h were significantly decreased by the above two pretreatments. N-acetylcysteine (10 mM) and S-nitroso-N-acetylpenicillamine (1 mM) had no significant inhibitory effects on the cell surface and mRNA expression of these adhesion molecules stimulated by TNF-. These findings indicate that both cell surface and mRNA expression of adhesion molecules in HDMEC induced by TNF-alpha are inhibited significantly by pretreatment with PDTC or Sper-NO, possibly in part through blocking the activation of NF-KB. These results suggest a potential therapeutic approach using antioxidant agents or nitric oxide pathway modulators in the treatment of inflammatory skin diseases. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2004.01.031

Nitric oxide metabolites and adrenomedullin in human breast milk

N Ohta, H Tsukahara, Y Ohshima, M Nishii, Y Ogawa, K Sekine, K Kasuga, M Mayumi

EARLY HUMAN DEVELOPMENT 78 ( 1 ) 61 - 65 2004.6

Language：English Publisher：ELSEVIER IRELAND LTD

We found high concentrations of nitrite/nitrate (166-1460 mumol/l) in 43 milk samples obtained from 32 women during postpartum days 1-8, which indicates enhanced mammary nitric oxide (NO) secretion. We detected adrenomedullin (AM) (2.7-20.7 pmol/l) only in 9 of the 43 samples using highly specific immunoradiometric assay. It is uncertain whether the entire adrenomedullin is actively secreted in human milk. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.earlhumdev.2004.04.002

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Many confounding factors influencing urinary beta(2)-microglobulin excretion in premature newborns

H Tsukahara, M Hiraoka, M Mayumi

JOURNAL OF PEDIATRICS 144 ( 6 ) 835 - 836 2004.6

Effects of antioxidant and nitric oxide on chemokine production in TNF-alpha-stimulated human dermal microvascular endothelial cells

MZ Jiang, H Tsukahara, Y Ohshima, S Sato, Y Todoroki, M Hiraoka, M Mayumi

FREE RADICAL RESEARCH 38 ( 5 ) 473 - 480 2004.5

Language：English Publisher：TAYLOR & FRANCIS LTD

Chemokines have been implicated convincingly in the driving of leukocyte emigration in different inflammatory reactions. Multiple signaling mechanisms are reported to be involved in intracellular activation of chemokine expression in vascular endothelial cells by various stimuli. Nevertheless, redox-regulated mechanisms of chemokine expression in human dermal microvascular endothelial cells (HDMEC) remain unclear. This study examined the effects of pyrrolidine dithiocarbamate (PDTC, 0.1 mM) and spermine NONOate (Sper-NO, 1 mM) on the secretion and gene expression of chemokines, interleukin (IL)-8, monocyte chemotactic protein (MCP)-1, regulated upon activation normal T cell expressed and secreted (RANTES), and eotaxin. This study also addresses PDTC and Sper-NO effects on activation of nuclear factor kappa B (NF-kappaB) induced by TNF-alpha (10 ng/ml). Treatment with TNF-alpha for 8 h significantly increased secretion of IL-8, MCP-1, and RANTES, but not of eotaxin, in cultured HDMEC. Up-regulation of these chemokines was suppressed significantly by pretreatment with PDTC or Sper-NO for 1 h, but not by 1 mM 8-bromo-cyclic GMP. The mRNA accumulation of IL-8, MCP-1, RANTES, and eotaxin, and activation of NF-kappaB were induced by TNF-alpha for 2 h; all were suppressed significantly by the above two pretreatments. These findings indicate that both secretion and mRNA accumulation of IL-8, MCP-1, and RANTES in HDMEC induced by TNF-alpha are inhibited significantly by pretreatment with PDTC or Sper-NO, possibly via blocking redox-regulated NF-kappaB activation. These results suggest that restoration of the redox balance using antioxidant agents or nitric oxide pathway modulators may offer new opportunities for therapeutic interventions in inflammatory skin diseases.

DOI： 10.1080/1071576042000209826

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Brain stem hypertensive encephalopathy evaluated by line scan diffusion-weighted imaging

M Nagata, M Maeda, H Tsukahara, SE Maier, K Takeda

AMERICAN JOURNAL OF NEURORADIOLOGY 25 ( 5 ) 803 - 806 2004.5

Language：English Publisher：AMER SOC NEURORADIOLOGY

Hypertensive encephalopathy rarely presents with predominant involvement of the brain stem and relative sparing of the supratentorial regions. We describe the MR imaging features in a patient with reversible brain stem hypertensive encephalopathy. Extensive hyperintensity was predominantly seen in brain stem regions on fluid-attenuated inversion-recovery and T2-weighted images. These lesions showed an increased apparent diffusion coefficient with the use of line scan diffusion-weighted imaging. The clinical findings and MR imaging abnormalities resolved with control of hypertension.

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Endothelial dysfunction in Kawasaki disease: focus on nitric oxide

S Sato, H Tsukahara, N Ohta, Y Todoroki, K Nishida, M Mayumi

PEDIATRICS INTERNATIONAL 46 ( 1 ) 114 - 114 2004.2

N2O anesthesia may exacerbate hyperhomocysteinemia and endothelial dysfunction in patients with renal impairment

H Tsukahara, Y Todoroki, M Hiraoka, M Mayumi

KIDNEY INTERNATIONAL 65 ( 1 ) 338 - 338 2004.1

Diffuse leptomeningeal hyperintensity on fluid-attenuated inversion recovery MR images in neurocutaneous melanosis

M Hayashi, M Maeda, T Maji, T Matsubara, H Tsukahara, K Takeda

AMERICAN JOURNAL OF NEURORADIOLOGY 25 ( 1 ) 138 - 141 2004.1

Language：English Publisher：AMER SOC NEURORADIOLOGY

Neurocutaneous melanosis (NCM) is a rare neuroectodermal dysplasia characterized by large or multiple cutaneous congenital pigmented nevi and benign or malignant melanocytic tumors of the leptomeninges. Although the MR manifestations of this disease have been reported in a small series of cases, the usefulness of fluid-attenuated inversion recovery (FLAIR) MR findings has not been documented. We present a case of NCM that showed diffuse leptomeningeal hyperintensity on FLAIR images. This FLAIR finding may be a clue to the detection of leptomeningeal abnormalities in NCM.

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MR signal changes in a child with cat scratch disease encephalopathy and status epilepticus

K Ogura, Y Hara, H Tsukahara, M Maeda, M Tsukahara, M Mayumi

EUROPEAN NEUROLOGY 51 ( 2 ) 109 - 110 2004

Changes of plasma coenzyme Q(10) levels in early infancy

S Sato, H Tsukahara, Y Ohshima, N Ohta, M Uchiyama, K Sekine, T Uetake, M Mayumi

REDOX REPORT 9 ( 5 ) 289 - 290 2004

Language：English Publisher：MANEY PUBLISHING

Rapid perfusion of oxygen in infants at birth may increase oxidative stress which has been incriminated in serious diseases including neonatal respiratory distress syndrome, chronic lung disease, and retinopathy of prematurity. Elucidating the antioxidant defense systems of neonates in clinical practice is important. Coenzyme Q(10) is a widely distributed, redox-active quinoid compound originally discovered as an essential part of the mitochondrial respiratory chain in mammals. Although coenzyme Q(10) is a powerful lipid antioxidant in vivo, few data pertain to plasma CoQ(10) levels in infants. This is the first paper to report plasma coenzyme Q(10) levels in preterm infants.

DOI： 10.1179/135100004225006768

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薬剤の胎児腎への影響：リトドリン、マグネシウム

塚原宏一

日本小児腎不全学会雑誌 24 30 - 34 2004

新生児単純ヘルペスウイルス感染症を呈した超低出生体重児の１例

早川和代, 畑郁江, 古畑律代, 山田直江, 川谷正男, 金谷由宇子, 塚原宏一, 谷澤昭彦, 眞弓光文

日児誌 108 ( 5 ) 782 - 785 2004

早産児の骨代謝マーカーとDXAを用いた骨量計測

塚原宏一

第4回新生児栄養フォーラム発表論文集 85-101 2004

アレルギーと酸化ストレス

塚原宏一, 眞弓光文

日児誌 108 ( 5 ) 744 - 752 2004

Acute bilateral medial medullary infarction: A unique 'heart appearance' sign by diffusion-weighted imaging

M Maeda, T Shimono, H Tsukahara, SE Maier, K Takeda

EUROPEAN NEUROLOGY 51 ( 4 ) 236 - 237 2004

Methylenetetrahydrofolate reductase polymorphism in patients with bronchial asthma

Mizu Jiang, Hirokazu Tsukahara, Yusei Ohshima, Chaochun Zou, Naoko Ohta, Shuko Sato, Yukiko Todoroki, Masahiro Hiraoka, Mitsuhiko Nambu, Toshio Tanaka, Etsuro Yamaguchi, Naomi Kondo, Mitsufumi Mayumi

International Medical Journal 11 ( 2 ) 119 - 123 2004

Objective: Bronchial asthma is a chronic inflammatory condition of the respiratory tract. The C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is reported to confer susceptibility to cardiovascular diseases and inflammatory conditions. We hypothesized that TT genotype of MTHFR may influence the development of bronchial asthma and thus examined the C677T polymorphism in our Japanese asthmatic patients. Design: Clinical Investigation. Methods: Genotypes for MTHFR were determined in 461 asthmatic patients (male/female ratio: 248/213) by the polymerase chain reaction and restriction fragment length polymorphism method and the results were compared with those obtained from 1430 healthy subjects (male/female ratio: 939/491). Results: For the male population, the frequency of the TT genotype in asthmatic patients was significantly higher than in healthy subjects (16.9% vs. 11.0%, odds ratio = 1.65, 95% confidence interval: 1.12-2.44, P = 0.011). For the female population, the frequency of the TT genotype in atopic asthmatic patients was insignificantly higher than in non-atopic asthmatic patients (17.3% vs. 11.8%). Conclusion: Our findings suggest that the TT genotype of MTHFR is a probable genetic risk factor for the development of bronchial asthma in Japanese males.

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Mobilizationの責任

塚原宏一

平成16年度福井県小児科医会会報33号 177 2004

小児疾患シリーズ（小児救急の手引き8）：ショック

塚原宏一, 眞弓光文

臨床医薬 20 ( 7 ) 795 - 805 2004

エンドセリン/エンドセリン受容体系の骨格系における生物学的役割

塚原宏一

第20回小児代謝性骨疾患研究会発表論文集 89 - 93 2004

An extremely low birthweight infant with metaphyseal osteopenia in long bones possibly due to maternal administration of magnesium sulphate

H.Tsukahara, N.Yamada, H.Kometani, Y.Kanaya, N.Ohta, S.Sato, A.Tanizawa, M.Mayumi

Repots for 21st Pediatric Metabolic Bone Disease Conference 45 - 48 2004

壊死性腸炎を呈するミルクアレルギーの新生児症例についての検討

塚原宏一

小児科臨床 57(2) ( 2 ) 273 - 276 2004

レドックス制御が急性肺傷害におよぼす治療的効果（研究課題番号 14370244）

眞弓光文, 塚原宏一

平成14～15年度科学研究費補助金 (基盤研究B2) 研究成果報告書 2004

乳児期早期の児における血漿中coenzyme Q10値の計測

佐藤周子, 塚原宏一, 大嶋勇成, 巨田尚子, 轟夕起子, 田村知史, 関根恭一, 西井学, 小川泰代, 内山真由美, 針田恭子, 黒瀬ルミ子, 植竹達雄, 眞弓光文

小児科臨床 57(9) ( 9 ) 1913 - 1917 2004

Language：Japanese Publisher：(株)日本小児医事出版社

正期産児5名,早産児15名について血漿中Coenzyme Q10(CoQ10)値の生後変化を調査した.生直後に呼吸障害を呈さなかった群(呼吸障害なし群,11名),呼吸障害を呈し酸素補充と人工換気療法を必要とした群(呼吸障害あり群,9名)とも,生直後においては血漿中CoQ10値が健常成人レベルを下回る児がほとんどであった.CoQ10値はその後上昇し,呼吸障害なし群では新生児期の後半に,呼吸障害あり群では新生児期を過ぎたころに健常成人レベルに達していた.母乳・人工粉乳中にも新生児血漿中とほぼ同レベルのCoQ10が含有されていた.これらの結果から,CoQ10がレドックス制御系(酸化ストレスに対する防御機構として種々の生体内還元装置が作動するシステム)の生後成熟に寄与している可能性が示唆された

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Oxidative stress in the pathogenesis of diabetic complications

TSUKAHARA H.

Recent Research Developments in Life Sciences 2 111 - 120 2004

Role of oxidative stress in allergic inflammation

TSUKAHARA H.

Recent Research Developments in Life Sciences 2 183 - 193 2004

High levels of urinary pentosidine, an advanced glycation end product, in children with acute exacerbation of atopic dermatitis: Relationship with oxidative stress

H Tsukahara, R Shibata, N Ohta, S Sato, M Hiraoka, S Ito, E Noiri, M Mayumi

METABOLISM-CLINICAL AND EXPERIMENTAL 52 ( 12 ) 1601 - 1605 2003.12

Language：English Publisher：W B SAUNDERS CO

Pentosidine is an advanced glycation end product formed by sequential glycation and oxidation. The formation of pentosidine is increased in diseases associated with oxidative stress, such as inflammatory conditions. The aim of the present study was to determine the urinary concentration of pentosidine in atopic dermatitis (AD) and its relationship to the inflammatory status of AD. Urine samples of 32 children with AD and 30 age-matched healthy control subjects were assayed for pentosidine, pyrraline (another advanced glycation end product formed by nonoxidative glycation), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) (an established marker of oxidative stress). Of these 3 markers, urinary concentrations of pentosidine were significantly higher in patients with acute exacerbation of AD than in healthy controls and patients with stable AD. Urinary concentrations of 8-OHdG were significantly higher in AD patients with and without acute exacerbation than in healthy controls. Urinary pentosidine levels correlated significantly with those of 8-OHdG when all data of healthy controls and AD patients were plotted. In patients with acute exacerbation of AD, both urinary pentosidine and 8-OHdG significantly decreased after 7 to 9 days of treatment. Our findings in patients with acute exacerbation of AD suggest that pentosidine levels are partly determined by the prevailing oxidative stress in these patients. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/S0026-0495(03)00310-X

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Formation of advanced glycosylation end products and oxidative stress in young patients with type 1 diabetes.

H Tsukahara, Hata, I, Y Todoroki, M Hiraoka, M Mayumi, M Uchiyama, H Kawakami, K Sekine, K Yoshihara, M Beppu

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 14 400A - 400A 2003.11

Formation of advanced glycosylation end products and oxidative stress in young patients with type 1 diabetes

H Tsukahara, K Sekine, M Uchiyama, H Kawakami, Hata, I, Y Todoroki, M Hiraoka, M Kaji, T Yorifuji, T Momoi, K Yoshihara, M Beppu, M Mayumi

PEDIATRIC RESEARCH 54 ( 3 ) 419 - 424 2003.9

Language：English Publisher：INT PEDIATRIC RESEARCH FOUNDATION, INC

Increased production of advanced glycosylation end products (AGEs) and augmented oxidative stress may contribute to vascular complications in diabetes. Little is known about the formation and accumulation of AGEs in young patients with type I diabetes. The aim of the present study was to investigate whether AGE production and oxidative stress are augmented in young patients with type I diabetes at early clinical stages of the disease. Urine samples of 38 patients with type I diabetes [mean age (+/-SD), 12.8 +/- 4.5 y; diabetes duration, 5.7 +/- 4.3 y; HbA(1c), 8.0 +/- 1.6%; urinary albumin excretion, 12.6 +/- 14.4 mg/g creatinine (Cr)] and those of 60 age-matched healthy control subjects were assayed for AGEs, pentosidine and pyrraline, and markers of oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and acrolein-lysine. Of these four markers, urinary concentrations of pentosidine, 8-OHdG, and acrolein-lysine were significantly higher in the patients with diabetes than in the healthy control subjects. For the patient group, pentosidine correlated significantly with 8-OHdG and acrolein-lysine, and pyrraline correlated significantly with acrolein-lysine. Urinary pentosidine, 8-OHdG, and acrolein-lysine but not pyrraline correlated significantly with urinary albumin excretion. Patients with microalbuminuria ( greater than or equal to15 mg/g Cr) showed significantly higher levels of all four markers than did normoalbuminuric patients and control subjects. The present study indicates that accumulation of AGEs, whose formation is closely linked to oxidative stress, and resultant endothelial dysfunction may start early in the course of type I diabetes. This means that the risk of vascular complications may be present at an early age and that the best possible glycemic control should be emphasized from the diagnosis of diabetes.

DOI： 10.1203/01.PDR.0000076662.72100.74

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Transient splenial lesion of the corpus callosum associated with antiepileptic drugs: evaluation by diffusion-weighted MR imaging

M Maeda, T Shiroyama, H Tsukahara, T Shimono, S Aoki, K Takeda

EUROPEAN RADIOLOGY 13 ( 8 ) 1902 - 1906 2003.8

Language：English Publisher：SPRINGER-VERLAG

Transient focal lesions in the splenium of the corpus callosum have been reported in epileptic patients receiving antiepileptic drugs. The characteristic imaging features included an oval high signal lesion on T2-weighted images in the central part of the splenium, no enhancement on post-contrast MR images, and complete reversibility without specific treatment. We report identical MR imaging findings in a depressive patient who had received antiepileptic drugs. In addition, diffusion-weighted MR imaging findings are described in our case, which is the first report on this unique lesion associated with antiepileptic drugs. Although this lesion has been assumed to be vasogenic edema in the previous reports, diffusion-weighted MR imaging showed markedly restricted diffusion of the lesion in the present case, suggesting that cytotoxic edema was the main pathophysiological abnormality.

DOI： 10.1007/s00330-002-1679-5

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A randomized study of two long-course prednisolone regimens for nephrotic syndrome in children

M Hiraoka, H Tsukahara, K Matsubara, M Tsurusawa, N Takeda, S Haruki, S Hayashi, K Ohta, T Momoi, Y Ohshima, N Suganuma, M Mayumi

AMERICAN JOURNAL OF KIDNEY DISEASES 41 ( 6 ) 1155 - 1162 2003.6

Language：English Publisher：W B SAUNDERS CO

Background Long-course prednisolone regimens have been shown to be more effective than short-course regimens In sustaining remission of nephrotic syndrome in children. However, the most beneficial approach among the long-course regimens remains unknown. Methods: Seventy-three children with new-onset nephrotic syndrome were allocated at random to the two long-course regimens and followed up for 2 years. Group A was administered prednisolone at a daily dose of 60 mg/m(2) for 6 weeks, followed by an alternate-day dose of 40 mg/m(2) for 6 weeks (the long daily regimen). Group B was administered the same daily dose for 4 weeks, followed by an alternate-day dose of 60 mg/m(2) for 4 weeks, and doses were tapered by 10 mg/m(2) every 4 weeks (the long alternate-day regimen). Results Group B had a lower incidence of corticosteroid toxicities than group A during the initial treatment. Kaplan-Meier analysis of the sustained remission rate of the two treatment groups showed a marginally significant difference (P = 0.069) and showed a significant difference when patients were stratified for age of disease onset (P = 0.048). In a subgroup of younger children (<4 years at onset), group B had a greater rate of sustained remission (P < 0.01) and fewer children with frequent relapses (P < 0.05) than group A, whereas in older children (&GE;4 years at onset), both groups had similar good sustained remission rates. Conclusion. These findings collectively indicate that the long alternate-day regimen may be more beneficial, with less corticosteroid toxicities, than the long daily regimen, and children with younger age at disease onset may be susceptible to relapse and especially benefit from the long alternate-day regimen for sustaining remission of the disease.

DOI： 10.1016/S0272-6386(03)00346-9

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Nitric oxide modulates bone mineralization in growing rats

H Tsukahara, Y Todoroki, S Sato, N Ohta, M Hiraoka, M Mayumi

BONE 32 ( 5 ) S202 - S202 2003.5

Oxidative stress and altered antioxidant defenses in children with acute exacerbation of atopic dermatitis

H Tsukahara, R Shibata, Y Ohshima, Y Todoroki, S Sato, N Ohta, M Hiraoka, A Yoshida, S Nishima, M Mayumi

LIFE SCIENCES 72 ( 22 ) 2509 - 2516 2003.4

Language：English Publisher：PERGAMON-ELSEVIER SCIENCE LTD

The underlying mechanisms of skin inflammation in atopic dermatitis (AD) are not completely understood. The purpose of the present study was to examine the involvement of oxidative stress and antioxidant defenses in children with acute exacerbation of AD. We studied 13 children who were hospitalized for acute exacerbation of AD with purulent skin infection by Staphylococcal aureus (age, 1.5 to 10.0 years), and 28 age-matched healthy subjects (controls). Urine samples obtained from the patients on admission, on 2nd and 7th-9th hospital days, as well as from the controls were analyzed for 8-hydroxy-2'-deoxyguanosine (8-OHdG) (a marker of oxidative DNA damage), acrolein-lysine adducts (a marker of lipid peroxidation), bilirubin oxidative metabolites (BOM) (a marker of antioxidant activity of bilirubin under oxidative stress) and nitrite/nitrate (NOx-) (a marker of endogenous nitric oxide production). Of these, urinary concentrations of 8-OHdG, acrolein-lysine adducts and BOM, but not NOx-, were significantly higher in AD children on admission than those in control subjects. Response to treatment was associated with significant falls in the concentrations of 8-OHdG and acrolein-lysine adducts. Urinary concentrations of acrolein-lysine adducts, but not 8-OHdG, were still significantly higher in AD patients on the 7th-9th hospital day relative to the control. Urinary BOM remained almost constant and significantly high in AD children during hospitalization. Our findings indicate that oxidative stress and altered antioxidant defenses are involved in the pathophysiology of acute exacerbation of AD, and that suppression of oxidative stress might be a potentially useful strategy for the treatment of AD. (C) 2003 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0024-3205(03)00145-0

Early treatment of urinary infection prevents renal damage on cortical scintigraphy

M Hiraoka, G Hashimoto, S Tsuchida, H Tsukahara, Y Ohshima, M Mayumi

PEDIATRIC NEPHROLOGY 18 ( 2 ) 115 - 118 2003.2

Language：English Publisher：SPRINGER-VERLAG

Diagnosis of urinary infection in young children is often delayed, which may result in renal damage. However, it remains to be clarified how soon the treatment should be started to prevent renal changes. The present study prospectively enrolled young children with diagnosis of their first febrile urinary infection who underwent technetium-99m dimercaptosuccinate renal cortical scintigraphy within 120 h of initiation of treatment. Patients with abnormal renoscintigraphy received antibiotics for 2 weeks and scintigraphy was repeated 1 year later. Twenty-two children were enrolled from July 1995 through March 2000. Acute-phase renoscintigraphy identified focal defects in 0 of the 14 children who were treated within 24 h of the disease, 1 of the 3 treated in 24-18 h, and 2 of the 5 treated in 48-72 h. Repeat renoscintigraphy showed disappearance of the focal defects in all 3 children. The present study has shown that early treatment within 24 h of onset of the fever due to urinary infection should deter renal changes. Fever for more than 24 h prior to diagnosis indicates a high risk for renal changes and needs an immediate effective treatment to avoid renal damage.

DOI： 10.1007/s00467-002-1023-y

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小児アトピー性皮膚炎の発症に関する因子および発症予測・予防に関する実験的・文献的解析

眞弓光文, 大嶋勇成, 塚原宏一

平成14年度厚生労働科学研究費補助金: 免疫アレルギー疾患予防・治療等研究事業研究報告書（免疫アレルギー疾患予防・治療研究事業事務局） 10 - 12 2003

1型糖尿病若年患者におけるカルボニル/酸化ストレスの評価

塚原宏一, 畑郁江, 巨田尚子, 佐藤周子, 轟夕起子, 平岡政弘, 眞弓光文, 内山真由美, 川上寿子, 関根恭一, 三浦雅一

日本小児腎臓病学会雑誌 16 ( 2 ) 143 - 150 2003

Language：Japanese Publisher：The Japanese Society for Pediatric Nephrology

糖尿病合併症の成因としてカルボニル／酸化ストレスの関与がおもに成人領域で注目されている。われわれは，１型糖尿病若年患者が受けるカルボニル／酸化ストレスについて検討した。１型糖尿病患者38名（男／女：17/21，年齢12.8±4.5歳，罹病期間：5.7±4.3年［平均±SD］），正常対照60名（男／女：28/32，年齢：11.4±4.5歳）の早朝尿中のpentosidine， pyrraline（カルボニルストレスマーカー)，8-OHdG，acrolein-lysine（酸化ストレスマーカー）濃度を計測した。１型糖尿病患者では尿pentosidine，8-OHdG，acrolein-lysineは正常対照よりも有意に高かった。pentosidine はpyrraline，8-OHdG，acrolein-lysineと，pyrralineはacrolein-lysineと有意に正相関した。pentosidine，8-OHdG，acrolein-lysineは尿中アルブミンと有意に正相関した。微小アルブミン尿陽性患者（≥15mg/g Cr; 11名）では，すべてのマーカーが微小アルブミン尿陰性患者および正常対照よりも有意に高かった。今回の研究により，１型糖尿病若年患者では酸化ストレスとそれに連動したカルボニルストレスが亢進していることが示された。

DOI： 10.3165/jjpn.16.143

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周生期における血管作動因子・利尿因子の果たす生理学的役割

塚原宏一

小児科臨床 56(2) ( 2 ) 163 - 167 2003

高マグネシウム血症, 低カルシウム血症, 心機能障害, 壊死性腸炎の発症に硫酸マグネシウムの母体投与の関連が考えられた早産児例

鈴木孝二, 塚原宏一, 椎間優子, 早川和代, 古畑律代, 佐藤周子, 西田公一, 谷澤昭彦, 平岡政弘, 宿南憲一, 小辻文和, 眞弓光文

小児科臨床 56 ( 2 ) 210 - 214 2003

Gas-phase disproportionation of nitric oxide at elevated pressures

H Tsukahara, T Ishida, Y Todoroki, M Hiraoka, M Mayumi

FREE RADICAL RESEARCH 37 ( 2 ) 171 - 177 2003

Language：English Publisher：TAYLOR & FRANCIS LTD

T.P. Melia's chemical kinetics study of the disproportionation of nitric oxide (NO), 3NO --> NO2 + N2O , (Melia, T.P. (1965) J. Inorg. Nucl. Chem. , 27 , 95-98), which is the most quoted quantitative investigation presently available, revealed a rather strong dependence of the effective rate constant, Kk', of Melia's third-order rate law,- d[NO]/dt = Kk'[NO](3) , on the initial pressure of NO. In order to estimate extent of accumulation of NO2 and N2O as a function of time by integration of the rate law, we have evaluated the dependence of the effective rate constant as a function of pressure and thus as a function of time on the basis of the non-ideality of NO gas. Although our approach is crude in that the non-idealities of NO2 and N2O and other NOx products and a probable deviation of the gas mixture from the Dalton's law have not been considered, it provides a means for approximately estimating the rate of accumulation of NO2 and N2O based on Melia's data. According to these calculations, the extent of the disproportionation is generally negligible at low initial pressures, e.g. 5 atm or less, while at 200 atm, the mole fractions of NO2 and N2O can become as high as 12-13% only after 10 days. These values are alarmingly high for handling pressured NO- in N-2-mixture in either research or clinical settings. This information must be borne in mind when compressed NO in commercial cylinders is employed in high precision experiments. Disproportionation of NO under pressure also deserves attention in inhalation of low doses of NO in the treatment of diseases characterized by pulmonary hypertension and hypoxemia.

DOI： 10.1080/1071576021000036489

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拡散強調画像にて明瞭な病変を認めたSalmonella脳症の1例

小淵信子, 塚原宏一, 西田公一, 大嶋勇成, 平岡政弘, 眞弓光文, 石森佳幸, 河村泰孝

福井MR研究会誌 6 15 - 16 2003

Reversible diffusion-weighted MR findings of Salmonella enteritidis-associated encephalopathy

N Kobuchi, H Tsukahara, Y Kawamura, Y Ishimori, Y Ohshima, M Hiraoka, Y Hiraizumi, M Ueno, M Mayumi

EUROPEAN NEUROLOGY 49 ( 3 ) 182 - 184 2003

MRIで脳梁膨大部正中に可逆性孤発病変を認めた急性脳炎の一例

麻生浩子, 前田正幸, 大達清美, 塚原宏一, 竹田寛

臨床放射線 48(3) ( 3 ) 425 - 428 2003

母体への硫酸マグネシウム長期投与による骨減少症が疑われた超低出生体重児例

山田直江, 塚原宏一, 古畑律代, 鈴木孝二, 早川和代, 佐藤周子, 平岡政弘, 眞弓光文

日児誌 107 925 - 927 2003

急性脳症を呈した猫ひっかき病の1小児例

小倉一将, 原慶和, 塚原宏一, 塚原正人, 眞弓光文

小児感染免疫 15 211 - 216 2003

高マグネシウム血症, 低カルシウム血症, 心機能障害, 壊死性腸炎の発症に硫酸マグネシウムの母体投与の関連が考えられた早産児例

鈴木孝二, 塚原宏一

Bibliography in Gastroenterology 17(3) ( 2 ) 38 - 214 2003

Intrauterine exposure to ritodrine and magnesium sulphate and infantile renal dysfunction

H.Tsukahara, N.Ohta, R.Kobata, Y.Todoroki, S.Sato, M.Hiraoka, M.Mayumi, K.Shukunami, F.Kotsuji

J Jpn Soc Pediatr Renal Fail 23 95 - 97 2003

The transition from fetus to neonate: Physiological significance of vasoactive and natriuretic mediators

Tsukahara, H

J Dev Nephrol 11(1) 26 - 31 2003

レドックス制御が急性肺傷害におよぼす治療的効果

眞弓光文, 塚原宏一

平成14年度科学研究費補助金基盤研究(B)(2) 研究実績報告書 2003

腎不全に対してレドックス制御がもたらす治療的効果

塚原宏一

平成13年度〜14年度科学研究費補助金基盤研究(C)(2) 研究実績報告書 2003

小児アトピー性皮膚炎における酸化ストレスおよびレドックス制御機構の関与に関する研究

眞弓光文, 塚原宏一, 大嶋勇成

平成14年度厚生労働科学研究費補助金: 免疫アレルギー疾患予防・治療等研究事業研究報告書（免疫アレルギー疾患予防・治療研究事業事務局） 13 - 15 2003

第1章輸液療法の基礎--新生児の輸液の特殊性を知る (新生児輸液マニュアル--早わかりポイント132)

塚原宏一

ネオネイタルケア 16 10 - 20 2003

Vasoactive and natriuretic mediators in umbilical cord blood: a report of our observation and review of the literature

H Tsukahara, K Sekine, M Miura, Y Todoroki, Y Ohshima, M Hiraoka, K Hosokawa, F Kotsuji, M Mayumi

EARLY HUMAN DEVELOPMENT 69 ( 1-2 ) 57 - 64 2002.10

Language：English Publisher：ELSEVIER SCI IRELAND LTD

Background: The relative potency and interrelationship among vasoactive and natriuretic mediators are thought to be important in the transition from fetal to neonatal life. However, little is known about their potential roles in the perinatal setting. Aim: The aim of this study was to evaluate further the potential roles of vasoactive and natriuretic mediators in the perinatal setting. Study design: We measured umbilical venous levels of arginine vasopressin, endothelin-1, adrenomedullin, natriuretic peptides and NO2-/NO3- in 24 vaginally delivered newborns and examined their possible functions. Results: Cord levels of vasopressin, endothelin-1 and adrenomedullin were considerably higher compared with normal adult values; the concentrations were more than 10-fold higher for vasopressin, and more than threefold higher for endothelin-1 and adrenomedullin. The levels of natriuretic peptides and NO2-/NO3- were almost comparable to those of normal adults. Among the mediators, there was a significant correlation between endothelin-1 and adrenomedullin. Conclusions: It appears from other studies that the postnatal fall in vasopressin and endothelin-1 levels is associated with increased levels of natriuretic peptides and NO2-/NO3-. Based on these observations, we consider that these mediators may play active roles in the initiation, maintenance or both of the transition from fetal to neonatal life. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

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Oxidant and antioxidant activities in childhood meningitis

H Tsukahara, T Haruta, Y Todoroki, M Hiraoka, E Noiri, M Maeda, M Mayumi

LIFE SCIENCES 71 ( 23 ) 2797 - 2806 2002.10

Language：English Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Animal studies have provided substantial evidence for a key role of reactive oxygen species, nitric oxide and its related compounds in the complex pathophysiology of bacterial meningitis. However, there is little information on changes in the redox status in human meningitis. In the present study, we evaluated the redox status and oxidative stress in the central nervous system of children with meningitis. Oxidant and antioxidant activities were assessed from cerebrospinal fluid levels of acrolein-lysine adducts (a marker of lipid peroxidation), nitrite (a marker of nitric oxide production) and bilirubin derivatives (a marker of antioxidant activity of bilirubin). All these markers were several times higher in children during the early phase of bacterial meningitis compared with those of children without meningitis and patients with aseptic meningitis. In the bacterial meningitis group, the levels of bilirubin derivatives correlated significantly with those of acrolein-lysine adducts and nitrite. Acrolein-lysine adducts and nitrite decreased significantly as the patients started to respond to treatment but bilirubin derivatives remained elevated. In conclusion, our data indicate the enhancement of both oxidant and antioxidant activities in the central nervous system of children with early bacterial meningitis, but not in those with aseptic meningitis. Clinical and laboratory improvement may be associated with a decrease in oxidant activities in the central nervous system. (C) 2002 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0024-3205(02)02137-9

Transient MR signal changes in the splenium of the corpus callosum in rotavirus encephalopathy: Value of diffusion-weighted imaging

R Kobata, H Tsukahara, A Nakai, A Tanizawa, Y Ishimori, Y Kawamura, H Ushijima, M Mayumi

JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY 26 ( 5 ) 825 - 828 2002.9

Language：English Publisher：LIPPINCOTT WILLIAMS & WILKINS

The authors report serial brain MR findings from a 2-year-old girl with rotavirus encephalopathy. The lesion in the splenium of the corpus callosum showed restricted proton diffusion, suggesting local cytotoxic edema. Diffusion-weighted images demonstrated the lesion more conspicuously than other techniques, such as fluid-attenuated inversion-recovery and T1- and T2-weighted images. The findings were reversible on follow-up MRI obtained 4 days later. Diffusion-weighted MRI is a potentially useful method for detecting early changes of rotavirus encephalopathy, although the mechanism of the restricted diffusion is not clearly identified.

DOI： 10.1097/00004728-200209000-00028

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Erythromycin in ELBW infants [6]

Yuhko Shiima, Hirokazu Tsukahara, Ritsuyo Kobata, Kazuyo Hayakawa, Masahiro Hiraoka, Mitsufumi Mayumi

Journal of Pediatrics 141 ( 2 ) 297 - 298 2002.8

Augmentation of NO-mediated vasodilation in metabolic acidosis

K Hattori, S Tsuchida, H Tsukahara, M Mayumi, T Tanaka, L Zhang, T Taniguchi, Muramatsu, I

LIFE SCIENCES 71 ( 12 ) 1439 - 1447 2002.8

Language：English Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Reduction of perivascular pH in acidemia produces hyporesponsiveness of vascular bed to vasoconstrictors. In the present study, we examined the effects of modest acidification on dilatory responses of isolated rat thoracic aorta. Acetylcholine produced endothelium-dependent relaxation in phenylephrine-precontracted aorta, which was markedly enhanced by acidification of Krebs-Henseleit solution from pH 7.4 to 7.0. A similar augmentation was observed in the relaxing responses to NO donors (SNP, SIN-1, SNAP), 8-Br-cGMP and NS-1619 (a putative K-Ca channel opener and/or Ca channel inhibitor) in endothelium-denuded, phenylephrine-contracted aorta. However, papaverine-induced relaxation was not affected by the change in pH. At pH 7.4, the relaxing responses to acetylcholine and SNP were partially inhibited by charybdotoxin (K-Ca channel inhibitor) but not glibenclamide (K-ATP channel inhibitor), while at pH 7.0 the relaxation induced by either drug was not affected by K+ channel inhibitors. Relaxation induced by 8-Br-cGMP or NS-1619 was not inhibited by charybdotoxin or glibenclamide. Acidification to pH 7.0 increased the cGMP production in response to acetylcholine in endothelium-intact aorta and to SNP in endothelium-denuded aorta. These results show that modest acidification augments NO-mediated relaxation in rat aorta, probably due to an enhancement of cGMP-dependent but K+ channel-unrelated relaxation mechanisms. (C) 2002 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0024-3205(02)01914-8

Bone mineral status in ambulatory patients on long-term antiepileptic drug therapy. (vol 44, pg 247, 2002)

H Tsukahara, K Kimura, Y Todoroki, Y Ohshima, M Hiraoka, Y Shigematsu, Y Tsukahara, M Miura, M Mayumi

PEDIATRICS INTERNATIONAL 44 ( 4 ) 466 - 466 2002.8

Infantile renal dysfunction associated with intrauterine exposure to ritodrine and magnesium sulfate

N Ohta, H Tsukahara, N Yamashita, R Kobata, M Hiraoka, K Shukunami, K Hosokawa, F Kotsuji, M Mayumi

NEPHRON 91 ( 2 ) 352 - 353 2002.6

原発性巣状糸球体硬化症患児におけるメチレンテトラヒドロフォレート還元酵素遺伝子多型の解析 (主題腎・尿路疾患)

Zou Chaochun, 塚原宏一, 平岡政弘

小児科臨床 55 ( 6 ) 945 - 948 2002.6

慢性肺疾患の薬物療法--生後早期ステロイド療法 (特集新生児の慢性肺疾患)

塚原宏一

周産期医学 32 ( 6 ) 777 - 784 2002.6

髄膜炎の発症と一酸化窒素(NO)

塚原宏一

小児感染免疫 14 ( 1 ) 31 - 39 2002.4

急性脳症を発症したSalmonella enteritidis腸炎の1例

山下信子, 塚原宏一, 川満徹, 西田公一, 大嶋勇成, 平岡政弘, 眞弓光文, 平泉泰

小児感染免疫 14 ( 1 ) 57 - 57 2002.4

Two cases of anaphylactic reaction to gelatin induced by a chloral hydrate suppository

A Yamada, Y Ohshima, H Tsukahara, M Hiraoka, Kimura, I, T Kawamitsu, K Kimura, M Mayumi

PEDIATRICS INTERNATIONAL 44 ( 1 ) 87 - 89 2002.2

気管支喘息治療中に舞踏アテトーゼ様症状を呈した１例

小倉一将, 大嶋勇成, 畑郁江, 小俣合歓子, 安冨素子, 塚原宏一, 谷澤昭彦, 平岡政弘, 眞弓光文

日本小児アレルギー学会誌 16 ( 2 ) 175 - 159 2002

Language：Japanese Publisher：(一社)日本小児アレルギー学会

4歳女児.主訴は右上下肢の不随意運動.アレルギー性鼻炎と気管支喘息を有しており,オキサトミド投与を7日間受けた後,喘息発作出現のためテオフィリン内服に変更され,投与開始3日目に右上下肢の舞踏アテトーゼ様不随意運動が出現した.不随意運動は投薬中止後2週間で消失し,以後の経過観察で再発を認めていない.paroxysmal dystonic choreoathetosis類似の病態がオキサトミドとテオフィリンの投与が契機となって生じた可能性が考えられた

DOI： 10.3388/jspaci.16.175

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Gas-phase oxidation and disproportionation of nitric oxide

H Tsukahara, T Ishida, M Mayumi

NITRIC OXIDE, PT D 359 168 - 179 2002

An Infantile Case of Partial Trisomy 4q Resulting from 46, XY. ish der (13) ins (13 ; 4) (q12.1 ; q25q35) (wcp4+, wcpl3+, LSI13+)

TODOROKI Yukiko, TSUKAHARA Hirokazu, SHIGEMATSU Yosuke, OBATA Koichiro, KOBATA Ritsuyo, ONO Nemuko, FUJISAWA Kazuo, HIRAOKA Masahiro, HORI Chikahide, MAYUMI Mitsufumi

105 ( 7 ) 785 - 788 2001.7

【腎・尿路疾患】肉眼的血尿を契機に発見された水腎症の1例

大坂陽子, 塚原宏一, 山田直江, 巨田尚子, 山下信子, 平岡政弘, 眞弓光文

小児科臨床 54 ( 7 ) 1478 - 1480 2001.7

Language：Japanese Publisher：(株)日本小児医事出版社

8歳男児.肉眼的血尿及び異常腹部腫瘤の精査目的で入院した.腹部超音波検査で両側腎盂の拡張(右腎は軽度,左腎は重度)が認められた.フロセミド負荷99mTc-DTPA腎臓シンチグラフィでは尿停滞が存在したが(左腎でより重度),それはフロセミドにより部分的に解除された.MRウログラフィでも左腎盂での重度の尿停滞が認められた.逆行性膀胱造影では異常は認められなかった.異常腹部腫瘤は左側尿管腎盂移行部狭窄による水腎症と診断した

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外陰部異常を呈し巣状糸球体硬化症から腎不全に至ったFrasier症候群の1男児例

山下信子, 平岡政弘, 西田公一, 大阪陽子, 塚原宏一, 眞弓光文

日本小児科学会雑誌 105 ( 2 ) 205 - 205 2001.2

全身性炎症性疾患における一酸化窒素(NO)の病態生理学的意義

塚原宏一

日本小児アレルギー学会誌 = The Japanese journal of pediatric allergy and clinical immunology 14 ( 3 ) 352 - 352 2000.10

Streptococcus pneumoniae-induced acute renal failure in a neonate

N Tomida, H Tsukahara, T Hiragi, N Ono, Y Osaka, M Hiraoka, M Mayumi

NEPHRON 86 ( 2 ) 190 - 191 2000.10

肺炎球菌による敗血症に伴い壊死性腸炎および急性腎不全をきたした早産児例

冨田直子, 塚原宏一, 平城徹, 小野合歓子, 木村宏輝, 平岡政弘, 眞弓光文

日本小児腎不全学会雑誌 : 小児腎不全研究会記事 20 163 - 165 2000.8

Role of nitric oxide in human pulmonary microvascular endothelial cell adhesion

H Tsukahara, E Noiri, MZ Jiang, M Hiraoka, M Mayumi

LIFE SCIENCES 67 ( 1 ) 1 - 11 2000.5

Language：English Publisher：PERGAMON-ELSEVIER SCIENCE LTD

We examined the effect of nitric oxide (NO) on cell adhesion using cultured human pulmonary microvascular endothelial cells (PMVEC). Attachment of these cells to fibronectin was significantly inhibited by NO donors, spermine NONOate and S-nitroso-N-acetyl-penicillamine or L-arginine, but not 8-bromoguanosine-3',5'-cyclic-monophosphate. Similar results were obtained with the electrical cell-substrate impedance sensor (ECIS) technique. Addition of NO donors or L-arginine, but not 8-bromoguanosine-3',5' -cyclic-monophosphate or N-2,2'-O-dibutyrylguanosine-3',5'-cyclic-monophosphate, to confluent PMVEC monolayers resulted in a transient decrease in cell adhesion, which was quantitated by the ECIS, Exposure to 1 U/ml alpha-thrombin reduced the monolayer electrical resistance by similar to 50%. The observed response was significantly suppressed by pretreatment of cells with intracellular calcium chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- acid or NO synthase inhibitor, NG-nitro-L-arginine methyl ester, but not guanylate cyclase inhibitor, 6-anilino-5,8-quinoline-quinone. Selective knockout of endothelial NO synthase with antisense oligodeoxynucleotides also significantly reduced thrombin-induced decrease in monolayer resistance. Our findings indicate that thrombin stimulates calcium-dependent release of NO from PMVEC, which mediates the retraction of endothelial cells via a cGMP-independent pathway. Our results suggest that NO modulates cell-matrix and/or cell-cell adhesion in PMVEC and that this molecule might modify microvascular permeability in the human lune. (C) 2000 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0024-3205(00)00598-1

塚原宏一, 冨田直子, 平城徹, 古畑律代, 川満徹, 木村宏輝, 平岡政弘, 眞弓光文

小児科臨床 53 262 - 266 2000.2

Language：Japanese Publisher：日本小児医事出版

新生児とくに早期産児の免疫系の機能は未熟で病原微生物に対しての防御能に劣る。一方、新生児医療の高度先進化は新生児感染症の頻度を低下させるには至らず、むしろその様相を複雑化させ、com-promised host を増加させている。これらの児の感染症羅患の危険性はとくに高い。以上の理由から、新生児集中治療室（NICU）での感染防御対策は極めて重要な臨床上のテーマであるといえる。本稿では、NICUでの感染防御対策についての基本的な考え方と当院 NICU における具体的な感染防御対策およびその成果についてまとめた。

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Increased oxidative stress in rats with chronic nitric oxide depletion: measurement of urinary 8-hydroxy-2 '-deoxyguanosine excretion

H Tsukahara, M Hiraoka, R Kobata, Hata, I, Y Ohshima, MZ Jiang, E Noiri, M Mayumi

REDOX REPORT 5 ( 1 ) 23 - 28 2000

Language：English Publisher：W S MANEY & SONS LTD

Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been reported to serve as a sensitive biomarker of oxidative stress. We examined the effect of chronic blockade of nitric oxide (NO) on urinary excretion of 8-OHdG in rats. Two types of NO synthase inhibitor were used: N-G-nitro-L-arginine methyl ester (L-NAME) as a non-selective inhibitor and aminoguanidine (AG) as a selective inhibitor of the inducible isoform. Oral administration of L-NAME (20, 50 and 80 mg/dl of drinking water), but not AG (400 mg/dl), for 4 weeks induced systemic hypertension and a significant reduction in urinary excretion of NO2-/NO3-. Rats treated with L-NAME also showed a significant increase in urinary 8-OHdG excretion compared with the control animals. The effects of L-NAME (50 mg/dl) on blood pressure and urinary excretion of NO2-/NO3- and 8-OHdG were restored by a large dose of L-arginine (2.0 g/dl). Chronic AG administration did not significantly alter urinary 8-OHdG excretion. On combining all the data, there was a significant negative correlation between urinary NO2-/NO3- and 8-OHdG. These observations suggest the importance of constitutive NO synthase activity in the maintenance of oxidant buffering capacity in rats. Oral administration of L-NAME may serve as a model of hypertension due to chronic NO deficiency with increased oxidative stress.

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一酸化窒素によるヒト肺微小血管内皮細胞接着の制御

塚原宏一

67 ( 1 ) 1 - 11 2000

一酸化窒素合成阻害ラットにおける酸化ストレスの増強 : 尿中8(OH)dG排泄による評価

塚原宏一

5 ( 1 ) 23 - 28 2000

Gas-phase oxidation of nitric oxide : Chemical kinetics and rate constant

H.Tsukahara

Nitric oxide : Biology and Chemistry 3 1999

Gas-phase oxidation of nitric oxide: Chemical kinetics and rate constant

H Tsukahara, T Ishida, M Mayumi

NITRIC OXIDE-BIOLOGY AND CHEMISTRY 3 ( 3 ) 191 - 198 1999

Language：English Publishing type：Book review, literature introduction, etc. Publisher：ACADEMIC PRESS INC

Inhaled nitric oxide (NO) is gaining popularity as a selective pulmonary vasodilator. Because of the potential toxicity of NO and its oxidizing product nitrogen dioxide (NO2), any system for the delivery of inhaled NO must aim at predictable and reproducible levels of NO and at as low concentrations of NO2 as possible. This review describes the chemical kinetics and rate constant values k for the reaction 2NO + O-2 = 2NO(2). This reaction has been well established as a third-order homogeneous reaction. Published data support two equally plausible two-step mechanisms for the reaction between NO and O-2 over a wide range of temperature and pressure. The Arrhenius equation k (L-2 . mol(-2) . s(-1)) = 1.2 x 10(3) e(530/T) (=1.2 x 10(3) x 10(230/T)) gives the best fit to the experimental values of the rate constant thus far reported in a temperature range of 273 to 600 K. Using the reaction mechanism and the rate constant k, one can make reliable predictions about NO2 formation in any set of NO inhalation therapy conditions. It is also pointed out that NO2 the intermediate of one of the two mechanisms, deserves serious attention in NO inhalation therapy. (C) 1999 Academic Press.

DOI： 10.1006/niox.1999.0232

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Endothelin subtype A receptor antagonist induces osteopenia in growing rats

H Tsukahara, C Hori, M Hiraoka, K Yamamoto, Y Ishii, M Mayumi

METABOLISM-CLINICAL AND EXPERIMENTAL 47 ( 11 ) 1403 - 1407 1998.11

Language：English Publisher：W B SAUNDERS CO

Previous studies suggested that endothelin (ET) peptides are involved in bone metabolism. We examined the effects of long-term blockade of the ETA, receptor, a receptor subtype primarily involved in the anabolic actions of ET, on bone mineral status in growing rats. Eight-week-old rats injected intraperitoneally with FR139317 50 mg/kg body weight, a specific ETA receptor antagonist, for 2 or 41 weeks were compared with control rats injected with vehicle only. Treatment with FR139317 caused a significant decrease in bone mass in the lumbar spine as determined by dual-energy x-ray absorptiometry (DXA). FR139317-induced osteopenia was associated with a significant decrease in the serum osteocalcin concentration but no change in the urinary excretion of pyridinium cross-links of collagen. Our findings indicate that long-term blockade of the ETA receptor reduces bone formation and induces osteopenia in growing rats. Our results suggest that Ei produced by vascular endothelial cells plays an important role in bone growth and metabolism in vivo. Copyright (C) 1998 by W.B. Saunders Company.

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Role of endothelin in erythropoietin-induced hypertension in rats

H Tsukahara, C Hori, S Tsuchida, M Hiraoka, K Fujisawa, M Mayumi

NEPHRON 79 ( 4 ) 499 - 500 1998.8

Experimentally-induced acute hyperinsulinemia stimulates endogenous nitric oxide production in humans: Detection using urinary NO2-/NO3- excretion.

H Tsukahara, K Kikuchi, Hata, I, C Hori, M Hiraoka, M Mayumi

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 8 A1570 - A1570 1997.9

Nitric oxide modulation of erythropoiesis in rats

H Tsukahara, C Nori, M Hiraoka, M Mayumi, T Okada, F Gejyo

BLOOD 90 ( 1 ) 473 - 474 1997.7

Use of ultrasonography in the detection of ureteric reflux in children suspected of having urinary infection

M Hiraoka, G Hashimoto, C Hori, H Tsukahara, Y Konishi, M Sudo

JOURNAL OF CLINICAL ULTRASOUND 25 ( 4 ) 195 - 199 1997.5

Language：English Publisher：JOHN WILEY & SONS INC

The present study investigated whether ultrasonography was effective in detecting ureteric reflux in children suspected of having urinary infection. Seventeen children with febrile episodes and pyuria were enrolled. The ultrasound examination revealed ballooning of the renal pelvis during bladder contraction in 4 children, dilatation of the distal ureters in 6, and small kidney in 2. Cystography was performed on the 6 children with these ultrasound abnormalities and 1 child with two episodes of suspected urinary infection. Four children showed reflux. All of the 4 children had been found to have renal pelvic ballooning on ultrasound. None of the 10 children who did not undergo cystography had recurrence of urinary infection or significant bacteriuria during a median follow-up period of 12 months. Thus, scanning during bladder contraction was effective in detecting significant ureteric reflux. (C) 1997 John Wiley & Sons, Inc.

DOI： 10.1002/(SICI)1097-0096(199705)25:4<195::AID-JCU7>3.0.CO;2-9

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Experimentally induced acute hyperinsulinemia stimulates endogenous nitric oxide production in humans: Detection using urinary NO2-/NO3- excretion

H Tsukahara, K Kikuchi, K Tsumura, K Kimura, Hata, I, M Hiraoka, M Sudo

METABOLISM-CLINICAL AND EXPERIMENTAL 46 ( 4 ) 406 - 409 1997.4

Language：English Publisher：W B SAUNDERS CO

Insulin-mediated glucose metabolism in skeletal muscle is associated with a proportional increase in muscle perfusion. The vasodilatory effect of insulin is thought to be mediated in part by endothelium-derived nitric oxide (NO), The present study was performed to determine whether acute hyperinsulinemia has any stimulatory effect on endogenous NO production in humans, Bolus intravenous injection of insulin (0.1 IU/kg body weight) caused a significant increase in urinary excretion of NO2-/NO3- together with a significant decrease in blood pressure, whereas saline infusion alone had no effect on these parameters. The increased NO response to insulin was almost comparable to that obtained with infusion of 30 g L-arginine. The acute effect of hyperinsulinemia on endogenous NO formation supports the concept that NO may mediate the vasodilatory action of insulin in humans. Copyright (C) 1997 by W.B. Saunders Company.

DOI： 10.1016/S0026-0495(97)90056-1

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Urinary nitrite versus nitrate excretion in children

H Tsukahara, Hata, I, M Sudo

JOURNAL OF PEDIATRICS 130 ( 1 ) 161 - 161 1997.1

未熟児慢性肺疾患に対する生後早期デキサメサゾン療法--最近の臨床試験から

塚原宏一

小児科診療 59 ( 12 ) 2077 - 2083 1996.12

Renal functional measurements in young rats with chronic inhibition of nitric oxide synthase

TSUKAHARA H

Acta Paediatrica Japonica 38 ( 6 ) 614 - 618 1996.12

Effect of nitric oxide synthase inhibitors on bone metabolism in growing rats

H Tsukahara, M Miura, S Tsuchida, Hata, I, K Hata, K Yamamoto, Y Ishii, Muramatsu, I, M Sudo

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM 270 ( 5 ) E840 - E845 1996.5

Language：English Publisher：AMER PHYSIOLOGICAL SOC

We examined the effects of chronic nitric oxide (NO) blockade on bone mineral status in growing rats. Oral administration of N-G-nitro-L-arginine methyl ester (L-NAME) for 4 wk caused hypertension and a significant reduction in urinary NO2- and NO3- excretion. Four-week oral aminoguanidine (AG, 400 mg/dl of drinking water) did not alter blood pressure but caused a significant decrease in urinary NO2- and NO3-. Rats treated with L-NAME at doses of 20 and 50 mg/dl had normal bone mineral mass in the lumbar spine, but the highest dose (80 mg/dl) caused a slight decrease in bone mass. Chronic AG induced a significant spine osteopenia. This effect of AG was abolished by the simultaneous administration of L-arginine (2.0 g/dl). AG-induced osteopenia was associated with a significant increase in urine excretion of collagen cross-links with normal serum osteocalcin. These findings indicate that chronic AG administration can cause an imbalance between bone resorption and formation, resulting in a decrease in bone mass in growing rats, and suggest that NO produced by inducible NO synthase plays an important role in basal osteoclast bone degradation activity in vivo.

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Urinary excretion of pyridinium cross-links of collagen in infancy

H Tsukahara, M Miura, C Hori, M Hiraoka, K Nosaka, K Hata, Y Konishi, M Sudo

METABOLISM-CLINICAL AND EXPERIMENTAL 45 ( 4 ) 510 - 514 1996.4

Language：English Publisher：W B SAUNDERS CO

This cross-sectional study evaluated urinary excretion of pyridinium cross-links of collagen, specific markers of ongoing hone resorption, in infants aged 1 week to 7 months and examined the relationship between urinary cross links and individual renal function. Spot urines from a total of 100 infants were analyzed. The collagen cross-links, pyridinoline (Pyd) and deoxypyridinoline (D-Pyd), were assayed by fluorescence detection after high-performance liquid chromatography (HPLC). beta(2)-Microglobulin (beta(2)M), an index of renal tubular function, was determined by radioimmunoassay. In healthy term infants, urinary collagen cross-links were several times higher than the reported data for older children, with peak values seen at 1 month of age. Excretion of Pyd and D-Pyd was also markedly elevated in 1-month-old preterm infants, despite poor somatic growth. Such high excretion of collagen cross-links probably reflects the state of accelerated bone turnover in infancy. The postnatal change in the doss-links was different from that in urinary beta(2)M, and the values obtained did not correlate with beta(2)M in either term or preterm infants. These results indicate that cross-link excretion is not influenced directly by individual renal function. (C) 1996 by W.B. Saunders Company

DOI： 10.1016/S0026-0495(96)90228-0

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Ultrasonographic findings of acute tubulointerstitial nephritis

M Hiraoka, C Hori, S Tsuchida, H Tsukahara, M Sudo

AMERICAN JOURNAL OF NEPHROLOGY 16 ( 2 ) 154 - 158 1996.3

Language：English Publisher：KARGER

Three children were diagnosed as having acute renal failure due to acute tubulointerstitial nephritis (TIN) associated with Yersinia pseudotuberculosis infection. The kidneys were observed ultrasonically during the disease course. The subjects presented with remittent fever, vomiting or diarrhea, and nonoliguric acute renal failure with sterile pyuria and tubular reabsorptive dysfunction. Ultrasound examination delineated marked enlargement of the kidneys with diffuse hyperechogenicity in the cortex, suggesting the diagnosis of TIN. The renal swelling was marked in the descending order of width, depth and length, respectively, and reached more than 200% in volume in 1 of the children who was examined at the culminating stage of acute renal failure. The enlarged kidneys reduced in size in parallel as the elevated serum creatinine levels decreased. However, the enlarged kidneys did not seem to return to their original sizes: the kidney size in 1 of the children remained well above the upper allowance limit of the body-height-related normals and in the other 2 they were only a little smaller than the upper limits. These ultrasound findings should help with the diagnosis and follow-up of the disease.

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Spontaneous Resolution of Lumbar Bone Mineral Depletion in Prematurely Born Children

TSUKAHARA Hirokazu, HORI Chikahide, FUJII Yasushi, TSUCHIDA Shinya, YAMAMOTO Kazutaka, ISII Yasushi, SUDO Masakatsu

5 ( 2 ) 171 - 177 1995.12

Dual Energy X-ray Absorptiometry in Growing Rats: Comparison with Biochemical Markers

TSUKAHARA Hirokazu, MIURA Masakazu, HATA Keishi, HORI Chikahide, TSUCHIDA Shinya, YAMAMOTO Kazutaka, ISHII Yasushi, SUDO Masakatsu

5 ( 2 ) 129 - 134 1995.12

FAVORABLE PROGNOSIS IN STEROID-RESPONSIVE NEPHROTIC CHILDREN IDENTIFIED BY CHANCE PROTEINURIA

M HIRAOKA, N TAKEDA, K KIMURA, K TAKAGI, S HAYASHI, E KATO, K OHTA, C HORI, S TSUCHIDA, H TSUKAHARA, M SUDO

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 5 ( 3 ) 352 - 352 1994.9

MOLECULAR AND FUNCTIONAL-CHARACTERIZATION OF THE NON-ISOPEPTIDE-SELECTIVE ET(B) RECEPTOR IN ENDOTHELIAL-CELLS

H TSUKAHARA, H ENDE, HI MAGAZINE, WF BAHOU, MS GOLIGORSKY

JOURNAL OF BIOLOGICAL CHEMISTRY 269 ( 34 ) 21778 - 21785 1994.8

Language：English Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

There is accumulating evidence that endothelial cells express a non-isopeptide-selective endothelin (ET) receptor, ET(B), which may be responsible for ET-1-induced transient vasorelaxation. The purpose of the present study was to seek direct evidence for ET(B) receptor expression in human umbilical vein endothelial cells (HUVEC) and to characterize its functional role in HUVEC and in Chinese hamster ovary cells stably transfected with ET(B) receptor cDNA (CHO-ET(B)). Reverse polymerase chain reaction using HUVEC total RNA and ET(B) receptor-specific oligonucleotide primers firmly demonstrated the presence of an endogenous transcript of the appropriate molecular size. Next, a biotinylated ligand specifically recognizing the ET(B) receptor, IRL-1620, was synthesized, and immunocytochemical mapping of binding sites was performed in CHO-ET(B) cells. Specific binding of biotinylated IRL-1620 was evident in CHO-ET(B) cells, confirming appropriate cell surface receptor expression. continuous nitric oxide (NO) monitoring with NO-selective electrode revealed a dose-dependent ET-1 stimulation of NO production by HUVEC. Stable transfection of CHO-ET(B) cells with endothelial nitric oxide synthase (NOS), but not mock-transfection, imparted responsiveness to ET-1 similar to that for HUVEC and was characterized by the immediate release of NO. Protein tyrosine kinase-dependent and calcium-calmodulin-dependent pathways were involved in ET-1-induced activation fo the constitutive NOS in CHO-ET(B)/NOS cells, but coupling of the receptor to the enzyme in HUVEC appeared to be predominantly protein tyrosine kinase-dependent. Although sufficient calcium/calmodulin system was not an obligatory prerequisite for the ET-1-induced activation of NOS in HUVEC. In conclusion, using two cell systems, we demonstrated that the ET(B) receptor is functionally coupled to NOS and coordinates the generation of NO via a tyrosine kinase-dependent and a calcium/calmodulin-dependent pathway.

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TETRODOTOXIN-BLOCKABLE DEPOLARIZATION-ACTIVATED NA+ CURRENTS IN A CULTURED ENDOTHELIAL-CELL LINE DERIVED FROM RAT INTERLOBAR ARTERY AND HUMAN UMBILICAL VEIN

DV GORDIENKO, H TSUKAHARA

PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 428 ( 1 ) 91 - 93 1994.8

Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：SPRINGER VERLAG

Voltage-dependent Na+ current (I-Na) was identified in cultured endothelial cells derived from rat interlobar artery (RIAE cells) and human umbilical vein (HUVE cells). Tetrodotoxin (TTX) reduced I-Na in a dose-dependent manner with the apparent dissociation constant (K-d) of 1.4 mu M. Low sensitivity of I-Na to TTX as well as its kinetics and voltage-dependent properties indicates that voltage-gated Na channels expressed in vascular endothelial cells belong to the so-called TTX-resistant type [2].

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DECREASE IN AMBIENT [CL-] STIMULATES NITRIC-OXIDE RELEASE FROM CULTURED RAT MESANGIAL CELLS

H TSUKAHARA, Y KRIVENKO, LC MOORE, MS GOLIGORSKY

AMERICAN JOURNAL OF PHYSIOLOGY 267 ( 1 ) F190 - F195 1994.7

Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：AMER PHYSIOLOGICAL SOC

It has been hypothesized that fluctuations of the ionic composition in the interstitium of juxtaglomerular apparatus (JGA) modulate the function of extraglomerular mesangial cells (MC), thereby participating in tubuloglomerular feedback (TGF) signal transmission. We examined the effects of isosmotic reductions in ambient sodium concentration ([Na+]) and [Cl-] on cytosolic calcium concentration ([Ca2+](i)) in cultured rat MC. Rapid reduction of [Na+] or [Cl-] in the bath induced a concentration-dependent rise in [Ca2+](i). MC are much more sensitive to decreases in ambient [Cl-] than to [Na+]; a decrease in [Cl-] as small as 14 mM was sufficient to elicit a detectable [Ca2+](i) response. These observations suggest that MC can be readily stimulated by modest perturbations of extracellular [Cl-]. Next, we examined whether activation of MC by lowered ambient [Cl-] influences cellular nitric oxide (NO) production. Using an amperometric NO sensor, we found that a 13 mM decrease in ambient [Cl-] caused a rapid, Ca2+/calmodulin-dependent rise in NO release from MC. This response was not inhibitable by dexamethasone, indicating the involvement of the constitutive rather than the inducible type of NO synthase in MC. In addition, the NO release was blunted by indomethacin pretreatment, suggesting that a metabolite(s) of cyclooxygenase regulates the activation of NO synthase in MC. Our findings that small perturbations in external [Cl-] stimulate MC to release NO, a highly diffusible and rapidly acting vasodilator, provide a possible mechanism to explain the transmission of the signal for the TGF response within the JGA.

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SCAPHOID MEGALOURETHRA WITH MULTIPLE UROGENITAL ANOMALIES

A HATA, H TSUKAHARA, Y SHIGEMATSU, S NISHIBUCHI, K OKADA, M SUDO

PEDIATRIC NEPHROLOGY 8 ( 2 ) 218 - 220 1994.4

Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：SPRINGER VERLAG

A male infant with scaphoid megalourethra, which is a rare congenital anomaly, is presented. At birth he exhibited a grossly swollen, malformed penis and cryptorchidism. The corpus spongiosum was not palpable. The infant had congenital renal failure. Retrograde urethrography revealed a crescent-shaped dilatation of the anterior urethra, and the diagnosis of scaphoid megalourethra was made. Subsequent uroradiological examinations showed that there were also severe urogenital anomalies, i. e. renal hypoplasia-dysplasia, hydronephrosis, hydroureter and vesicoureteral reflux. This disorder is frequently associated with other urogenital anomalies. Therefore, once the diagnosis is reached, a careful investigation for other associated abnormalities should be undertaken.

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Ultrasound findings of ureteral reflux in early infancy

Masahiro Hiraoka, Chikahide Hori, Shinya Tsuchida, Hirokazu Tsukahara, Masakatsu Sudo

Pediatric Nephrology 8 ( 2 ) 264 - 265 1994.4

DIRECT DEMONSTRATION OF INSULIN-LIKE GROWTH FACTOR-I-INDUCED NITRIC-OXIDE PRODUCTION BY ENDOTHELIAL-CELLS

H TSUKAHARA, DV GORDIENKO, B TONSHOFF, MC GELATO, MS GOLIGORSKY

KIDNEY INTERNATIONAL 45 ( 2 ) 598 - 604 1994.2

Language：English Publishing type：Article, review, commentary, editorial, etc. (scientific journal) Publisher：BLACKWELL SCIENCE INC

Several lines of evidence indicate that insulin-like growth factor-I (IGF-I) is a potent mediator of vasodilation. To elucidate the mechanism and site of action of IGF-I, we performed continuous monitoring of nitric oxide (NO) release from endothelial cells using a highly-sensitive amperometric NO-sensor. Two types of cultured cells were used: human umbilical vein endothelial cells and immortalized rat renal interlobar artery endothelial cells. In separate experiments, [Ca2+]i changes in response to IGF-I were measured spectrofluorometrically in fura-2-loaded cells. Stimulation with IGF-I resulted in a rapid, dose-dependent increase in [NO] as detected by the NO-probe positioned 1 mm above the monolayers, followed by a sustained elevation lasting for at least five minutes. The effect of IGF-I was significantly suppressed by pretreatment with anti-IGF-I antibody, suggesting that it was specific for IGF-I. N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthesis, significantly blunted responses to IGF-I, but dexamethasone preincubation did not reduce the IGF-I-induced release of NO. These results indicate that the observed IGF-I-induced release of NO is a result of activation of the constitutive, rather than the inducible type of NO synthase in endothelial cells. Genistein, a tyrosine kinase inhibitor, resulted in a profound suppression of the IGF-I-induced release of NO. IGF-I did not affect [Ca2+]i in either type of cells. Therefore, IGF-I-induced NO production by both types of endothelial cells is mediated via a tyrosine kinase-dependent mechanism. IGF-I may be an important regulator of vascular tone in vivo through NO release from the vascular endothelium, and may contribute to the regulation of renal blood flow under physiological and pathophysiological conditions.

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CONTINUOUS MONITORING OF NITRIC-OXIDE RELEASE FROM HUMAN UMBILICAL VEIN ENDOTHELIAL-CELLS

H TSUKAHARA, DV GORDIENKO, MS GOLIGORSKY

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 193 ( 2 ) 722 - 729 1993.6

CALCIUM-CHANNEL CURRENT IN CULTURED RAT MESANGIAL CELLS

M NISHIO, H TSUKAHARA, M HIRAOKA, M SUDO, S KIGOSHI, MURAMATSU, I

MOLECULAR PHARMACOLOGY 43 ( 1 ) 96 - 99 1993.1

Language：English Publisher：WILLIAMS & WILKINS

The presence of voltage-dependent calcium channels has been suggested in mesangial cells by using calcium-sensitive fluorescent probes. However, direct electrophysiological evidence for voltage-dependent calcium channels has not yet been presented. In this study voltage-dependent calcium channels were studied in cultured rat mesangial cells. Whole-cell patch-clamp experiments were done with 50 mM Ba2+ as a charge carrier. Step depolarizing pulses from a holding potential of -50 mV produced an inward barium current at potentials more positive than -10 mV, and a peak current (10-45 pA) was obtained at a membrane potential of approximately +30 mV. The inward current was augmented by 1 00 nm Bay K 8644, attenuated by 1 muM nifedipine, and abolished by 50 muM Cd2+. These results indicate that the inward current is a barium current flowing through L-type calcium channels. This may be the first study that demonstrates the presence of L-type calcium channels in mesangial cells.

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Dual Energy X-Ray Absorptiometry in Growth Hormone Deficiency

Akio Nakai, Yosuke Shigematsu, Hirokazu Tsukahara, Masakatsu Sudo

clinical pediatric endocrinology 2 ( 1 ) 111 - 113 1993

Language：English

Bone mineral density (BMD) of the lumbar spine was measured by dual energy X-ray absorptiometry (DXA) in nine Japanese children with growth hormone (GH) deficiency. Before hGH therapy, BMDs of the GH-deficient patients were lower than those of controls. When their bone ages were substituted for their chronological ages, however, almost all BMDs of the patients were distributed within the normal range. After 12 months of hGH therapy, the BMDs increased in 8 of 9 GH-deficient patients
they were still lower as compared to controls. the relation between BMDs and bone ages suggested delayed skeletal maturation in GH-deficient patients. dual energy X-ray absorptiometry (DXA), growth hormone deficiency, bone mineral density (BMD), lumbar vertebrae, Japanese children. © 1993, The Japanese Society for Pediatric Endocrinology. All rights reserved.

DOI： 10.1297/cpe.2.Supple2_111

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Autosomal dominant polycystic kidney disease in a child diagnosed by ultrasonography

Masahiro Hiraoka, Keiko Kimura, Shiny A Tsuchida, Hirokazu Tsukahara, Masakazu Saito, Masakatsu Sudo

Japanese Journal of Nephrology 35 ( 4 ) 383 - 386 1993

Language：English

A 10-year-old boy with a chief complaint of nocturnal enuresis was identified as having three cysts in each kidney on ultrasonographic examination. These findings together with a positive family history for renal failure prompted us to examine his father ultrasonographically on the same day, resulting in the identification of multiple large cysts in both kidneys. These observations supported a diagnosis of autosomal dominant polycystic kidney disease. Enhanced X-ray CT demonstrated more sensitively the presence of renal cysts in the boy. He had a normal urinary concentrating ability and no other abnormalities except for mild hypertension, which was successfully treated only by salt restriction. Ultrasonography thus appears to be a valuable tool for diagnosing polycystic kidney diseases. © 1993, Japanese Society of Nephrology. All rights reserved.

DOI： 10.14842/jpnjnephrol1959.35.383

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URINARY ERYTHROCYTE VOLUME ANALYSIS - A SIMPLE METHOD FOR LOCALIZING THE SITE OF HEMATURIA IN PEDIATRIC-PATIENTS

H TSUKAHARA, M YOSHIMOTO, K MORIKAWA, T OKADA, M KURODA, M SUDO

JOURNAL OF PEDIATRICS 115 ( 3 ) 433 - 436 1989.9

INSULIN RESISTANCE IN A BOY WITH CONGENITAL GENERALIZED LIPODYSTROPHY

H TSUKAHARA, K KIKUCHI, H KUZUYA, E ITO, Y ODA, A KOSAKI, T KAKEHI, H NISHIMURA, K YAMADA, Y YOSHIMASA, H IMURA, H MIKAWA

PEDIATRIC RESEARCH 24 ( 6 ) 668 - 672 1988.12

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