ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2007-March 2008

Introduction
This is the report of the University of Tokyo’s Faculty of Medicine and Graduate School of Medicine forthe year 2007. Here we document each department’s research and educational activities.
Among the many noteworthy events in the academic year that began in April of 2007 were the start ofour new School of Public Health, further accomplishments by our endowed departments, and expansion of
the recording and distribution of medical information via electronic media. With our historically unique roleas the leading force in medicine within Japan, we are naturally expected to also be in the forefront of
medicine worldwide. We take it as our mission to be an internationally recognized source of importantresearch results, and a center for training outstanding medical scientists and clinicians.
Our Faculty of Medicine and our Hospital were founded in 1858, and as we approach the 150th
anniversary of that event, we continue enthusiastically pursuing our educational and scientific missions.
Creating the future, let us strive to achieve the best in medical research and teaching.
Takao Shimizu
Dean, Faculty of medicine and Graduate School of Medicine
The University of Tokyo
March, 2008

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CONTENTS
Introduction
Teaching, Research, Secretarial and Administrative Staffs
Organization Chart
History
The University of Tokyo, Graduate School of Medicine
Molecular Cell Biology
1. Cell Biology and Anatomy ·················································································································

1

Department of Cell Biology and Anatomy ·························································································

2

Department of Cellular Neurobiology ································································································

4

2. Biochemistry and Molecular Biology ·································································································

6

Department of Molecular Biology ······································································································

7

Department of Cellular Signaling ·······································································································

10

Department of Physiological Chemistry and Metabolism ··································································

14

Functional Biology
1. Physiology ··········································································································································

17

Department of Integrative Physiology ································································································

18

Department of Cellular and Molecular Physiology ············································································

21

Department of Neurophysiology ········································································································

23

2. Pharmacology ·····································································································································

26

Department of Cellular and Molecular Pharmacology ·······································································

27

Department of Molecular Neurobiology ·····························································································

30

Pathology, Immunology and Microbiology
1. Pathology ············································································································································

33

Department of Pathology and Diagnostic Pathology ··········································································

34

Department of Molecular Pathology ···································································································

38

2. Microbiology ······································································································································

42

Department of Microbiology ··············································································································

43

Department of Infection Control and Prevention ················································································

45

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3. Immunology ········································································································································

49

Department of Immunology ················································································································

50

Radiology and Biomedical Engineering
1. Radiology ············································································································································

53

Department of Radiology ····················································································································

54

2. Biomedical Engineering ·····················································································································

59

Department of System Physiology ·····································································································

60

Department of Biosystem Construction & Control ············································································

64

Neuroscience
1. Basic Neuroscience ·····························································································································

67

Department of Neuropathology ··········································································································

68

Department of Neurochemistry ··········································································································

72

2. Speech and Cognitive Sciences ··········································································································

77

Department of Cognitive Neuroscience································································································

78

3. Clinical Neuroscience ·························································································································

80

Department of Neuropsychiatry ··········································································································

81

Department of Neurology ···················································································································

87

Department of Neurosurgery ··············································································································

92

Social Medicine
1. Occupational, Environmental and Preventive Medicine ····································································

96

Department of Molecular Preventive Medicine ··················································································

97

Department of Public Health (See Department of Health Policy [P.272] ) ·········································

100

2. Forensic Medicine, and Medical Informatics and Economics ····························································

103

Department of Forensic Medicine ······································································································

104

Department of Medical Informatics and Economics ··········································································

107

Internal Medicine
1. Medicine Ⅰ ·······································································································································

111

Department of Cardiovascular Medicine ····························································································

112

Department of Respiratory Medicine ·································································································

118

Department of Gastroenterology ········································································································

122

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2. Medicine Ⅱ ·······································································································································

128

Department of Nephrology and Endocrinology ··················································································

129

Department of Metabolic Disease ·······································································································

134

Department of Hematology and Oncology ·························································································

139

Department of Allergy and Rheumatology ·························································································

142

Department of Infectious Diseases ·····································································································

145

Department of Stress Science and Psychosomatic Medicine ······························································

149

3. Clinical Laboratory Medicine and Pathology ·····················································································

152

Department of Clinical Laboratory Medicine (See Clinical Laboratory Center [P.359] )Department of Transfusion Medicine ·································································································

153

Reproductive, Developmental and Aging Sciences
1. Obstetrics and Gynecology ·················································································································

156

Department of Reproductive Endocrinology ······················································································

157

Department of Gynecologic Oncology ·······························································································

159

Department of Perinatal Medicine ······································································································

165

2. Pediatric Sciences ·······························································································································

167

Department of Pediatrics, Department of Developmental Pediatrics ·················································

168

Department of Pediatric Surgery ········································································································

173

3. Aging Sciences ···································································································································

176

Department of Geriatric Medicine, Department of Aging Research ··················································

177

Surgical Sciences
1. Surgery ················································································································································

181

Department of Thoracic Surgery ·········································································································

182

Department of Cardiothoracic Surgery ·······························································································

185

Department of Gastrointestinal Surgery ······························································································

189

Department of Hepatobiliary Pancreatic Surgery and Department of Artificial
Organ and Transplantation Surgery ·····································································································

194

Department of Urology ·······················································································································

198

Department of Surgical Oncology ······································································································

201

Department of Vascular Surgrry ··········································································································

204

Department of Metabolic Care and Endocrine Surgery ······································································

207

2. Sensory and Motor System Medicine ·································································································

209

Department of Dermatology ···············································································································

210

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Department of Plastic and Reconstructive Surgery ·············································································

213

Department of Oral-Maxillofacial Surgery ·························································································

216

Department of Orthopaedic Surgery ···································································································

220

Department of Ophthalmology ···········································································································

226

Department of Otorhinolaryngology and Head & Neck Surgery ························································

230

Department of Rehabilitation Medicine ······························································································

235

3. Vital Care Medicine ····························································································································

237

Department of Anesthesiology ············································································································

238

Department of Emergency and Critical Care Medicine ······································································

241

Health Sciences and Nursing
1. Health Sciences ···································································································································

244

Department of Health Sociology (See Department of Health Sociology/Health Sociology
and Health Education [P.308] )Department of Mental Health (See Department of Mental Health [P.306] )Department of Biostatistics (See Department of Biostatistics [P.293] )Department of Social Gerontology (See Department of Social Gerontology [P.311] )Department of Biomedical Ethics & Department of Health Promotion Sciences (See Departmentof Biomedical Ethics & Department of Health Promotion Sciences [P.314] )2. Preventive and Administrative Nursing ······························································································

245

Department of Nursing Administration/ Advanced Clinical Nursing ·················································

246

Department of Family Nursing ···········································································································

249

Department of Community Health Nursing / Public Health Nursing ·················································

251

3. Clinical Nursing································································································································

255

Department of Adult Nursing / Palliative Care Nursing ·····································································

256

Department of Midwifery and Women’s Health ·················································································

261

Department of Psychiatric Nursing ·····································································································

264

Department of Gerontological Nursing / Wound Care Management ··················································

267

International Health
1. International Social Medicine ·············································································································

271

Department of Health Policy and Planning ·························································································

272

Department of International Community Health ················································································

275

2. International Biomedical Sciences ······································································································

278

Department of Human Genetics ··········································································································

279

v

Department of Developmental Medical Sciences ···············································································

282

Department of Human Ecology ··········································································································

286

Department of Biomedical Chemistry ································································································

290

School of Public Health
1. Epidemiology and Health Sciences ······································································································

292

Department of Biostatistics ·················································································································

293

Department of Social and Preventive Epidemiology ··········································································

297

Department of Health Economics and Epidemiology Research ···························································

300

Department of Health Communication ·······························································································

302

2. Behavioral Health Sciences ··················································································································

305

Department of Mental Health ·············································································································

306

Department of Health Sociology/ Health Sociology and Health Education ·······································

308

Department of Social Gerontology ·····································································································

311

Department of Biomedical Ethics & Department of Health Promotion Sciences ······························

314

3. Health Services Sciences ······················································································································

318

Department of Health Policy·················································································································

319

Department of Healthcare Informatics (See Department of Medical Informatics and Economics [P.107] )Department of Clinical Information Engineering ·················································································

323

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.104] )Endowment Department ·······························································································································

324

Department of Integrated Traditional Medicine ··················································································

325

Department of Metabolome ················································································································

328

Department of Clinical Epidemiology and Systems ···········································································

331

Department of Ubiquitous Preventive Medicine ·················································································

334

Hospital Logistics by Sagawa Express Co., Ltd. ················································································

338

Department of

Immunotherapeutics (Medinet) ················································································

340

Department of Integrated Molecular Science on Metabolic Diseases ················································

343

Department of Translational Research for Healthcare and Clinical Science ······································

345

Department of Joint Disease Research ································································································

347

Department of Health Management and Policy ··················································································

349

Department of Clinical Motor System Medicine ················································································

351

Department of Clinical Trial Data Management ·················································································

352

Department of Computational Diagnostic Radiology and Preventive Medicine ································

355

vi

University Hospital
Clinical Divisions ·····································································································································
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.112] )Respiratory Medicine (See Department of Respiratory Medicine [P.118] )Gastroenterology (See Department of Gastroenterology [P.122] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.129] )Metabolic Diseases (See Department of Metabolic Diseases [P.134] )Hematology and Oncology (See Department of Hematology and Oncology [P.139] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.142 )Infectious Diseases (See Department of [P.145]
Neurology (See Department of Infectious Diseases [P.145] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.177] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.149] )Stomach and Eophagus Surgery (See Department of Gastrointestinal Surgery [P.189] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.201] )Hepatobiliary Pancreatic Surgery(See Department of Hepatobiliary Pancreatic Surgery [P.194] )Vascular Surgery (See Department of Vascular Surgery [P.204] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.207] )Artificial Organ and Transplantation Surgery(See Department of Artificial Organ and Transplantation Surgery [P.194] )Cardiovascular Surgery (See Department of Cardiothoracic Surgery [P.185] )Thoracic Surgery (See Department of Thoracic Surgery [P.182] )Neurosurgery (See Department of Neurosurgery [P.92] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.238] )Urology and Andrology (See Department of Urology [P.198] )Gynecologic Surgery (See Department of Obstetrics and Gynecology [P.156] )Dermatology and Photolaser Medicine (See Department of Dermatology [P.210] )Ophthalmology and Vision Collection (See Department of Ophthalmology [P.226] )Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.220] )Otorhinolaryngology, and Auditory and Voices Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.230] )

357

vii

Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.235] )Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.213] )Oral-Maxillofacial Surgery Dentistry and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.216] )Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.168] )Pediatrics Surgery (See Department of Pediatrics Surgery [P.173] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of ynecologic Oncology/ Department of Perinatal Medicine [P.157] )Neuropsychiatry (See Department of Neuropsychiatry [P.81] )Radiology (See Department of Radiology [P.54] )Central Clinical Facilities ·························································································································

358

Department of Clinical Laboratory ·····································································································

359

Surgical Center ····································································································································

363

Department of Clinical Radiology ······································································································

367

Department of Emergency Services(See Department of Clinical Emergency and Critical Care Medicine [P.241] )Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine and Immunohematology [P.153] )Delivery Unit ·······································································································································

370

Central Rehabilitation Service ············································································································

371

Department of Intensive Care Unit
(See Department of Clinical Emergency and Critical Care Medicine [P.241] )Division of Diagnostic Pathology ·······································································································

373

Department of Corneal Transplantation ······························································································

375

Department of Planning, Information, and Management(See Department of Medical Informatics and Economics [P.107] )Department of Cell Therapy and Transplantation Medicine ·······························································

378

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.45] )Department of Endoscopy and Endoscopic Surgery ···········································································

381

Department of Hemodialysis & Apheresis ··························································································

384

Clinical Research Center ·····················································································································

387

University Hospital Medical Information Network (UMIN) Center ··················································

390

Organ Transplantation Service ············································································································

393

Department of Epidemiology and Preventive Medicine ·····································································

397

viii

Division of Tissue Engineering ···········································································································

402

Hospital Planning and Management ···································································································

407

Department of Child Physiology ·········································································································

410

Department of Palliative Medicine ·······································································································

414

Clinical Geonomics ·····························································································································

418

Cooperative Unit of Medicine and Engineering Research ··································································

420

Pharmaceutical Service·······························································································································

428

Department of Pharmacy ····················································································································

429

Center for Disease Biology and Integrative Medicine ··············································································

433

Division of Basic Medical Sciences (Ⅰ) ····························································································

434

Division of Basic Medical Sciences (Ⅱ) ····························································································

438

Division of Regenerative Medical Engineering ··················································································

440

Division of Clinical Biotechnology ····································································································

442

Division of Environmental Health Sciences ·······················································································

446

Section of Animal Research, Division of Research Resources and Support ·······································

450

Section of Radiation Biology ··············································································································

452

Section of Bioinformatics ···················································································································

455

Office of International Academic Affairs ··································································································

456

The International Research Center for Medical Education (IRCME) ························································

459

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008ix

Teaching, Research, Secretarial
andAdministrative Staffs
Chief Members of Administration
Dean, Graduate School of Medicine

Takao Shimizu(Dean, Faculty of Medicine)
Chairman, School of Health Sciences and Nursing

Katsuya Kanda

Director, Medical LibraryKazuhiko Ohe

Director General, University Hospital

Yuji Taketani

Director, Center for Disease Biology and Integrative Medicine

Tadatsugu Taniguchi

The director of the International Research Center for

Kazuhiko Yamamoto

Medical Education.

Graduate School of Medicine
Molecular Cell Biology
Department of Cell Biology and Anatomy

professor

Nobutaka Hirokawa

professor

Shigeo okabe

professor

Hiroto Okayama

professor

Takao Shimizu

professor

Hiroki Kurihara

professor

Yasushi Miyashita

professor

Kensaku Mori

professor

Masanobu Kano

professor

Masamitsu Iino

professor

Masayoshi Mishina

professor

Masashi Fukayama

professor

Kohei Miyazono

professor

Akio Nomoto

professor

Kazuhiko Koike

professor

Tadatsugu Taniguchi

Department of Radiology

professor

Kuni Otomo

Department of Biomedical Engineering

professor

Joji Andoprofessor

Takeshi Iwatsubo

Department of Biochemistry and Molecular Biology

Functional Biology
Department of Physiology

Department of Pharmacology

Pathology, Immunology and Microbiology
Department of Pathology
Department of Microbiology
Department of Immunology
Radiology and Biomedical Engineering

Neuroscience
Department of Basic Neuroscience
Department of Speech and Cognitive Sciences

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008x

Department of Clinical Neuroscience

professor

Shoji Tsuji

professor

Nobuhito Saito

Department of Occupational, Environmental and Preventive

professor

Koji Matsushima

Medicine

professor

Yasuki Kobayashi

Department of Forensic Medicine, and Medical Informatics

professor

Kenichi Yoshida

and Economics

professor

Kazuhiko Ohe

professor

Ryozo Nagai

professor

Takahide Nagase

professor

Masao Omata

professor

Toshiro Fujita

professor

Takashi Kadowaki

professor

Mineo Kurokawa

professor

Kazuhiko Yamamoto

professor

Kazuhiko Koike

professor

Akira Akabayashi

professor

Yutaka Yatomi

professor

Koki Takahashi

professor

Yuji Taketani

professor

Osamu Tsutsumi

professor

Takashi Igarashi

professor

Tadashi Iwanaka

professor

Yasuyoshi Ouchi

professor

Shinichi Takamoto

professor

Michio Kaminishi

professor

Norihiro Kokudo

professor

Tadaichi Kitamura

professor

Hirokazu Nagawa

professor

Kunihiko Tamaki

professor

Isao Koshima

professor

Tsuyoshi Takato

Professor

Kozo Nakamura

professor

Makoto Araie

professor

Tatsuya Yamasoba

professor

Nobuhiko Haga

Professor

Yoshitsugu Yamada

Social Medicine

Internal Medicine
Department of Medicine I

Department of Medicine II

Department of Clinical Laboratory Medicine and Pathology

Reproductive, Developmental and Aging Science
Department of Obstetrics and Gynecology
Department of Pediatric Science

Department of Aging Science
Surgical Sciences
Department of Surgery

Department of Sensory and Motor System Medicine

Department of Vital Care Medicine

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

xi

professor

Naoki Yahagi

professor

Norito Kawakami

professor

Yasuo Ohashi

professor

Ichiro Kai

professor

Akira Akabayashi

professor

Katsuya Kanda

professor

Sachiyo Murashima

professor

Keiko Kazuma

professor

Norito Kawakami

professor

Hiromi Sanada

Department of International Social Medicine

professor

Masamine Jinba

Department of International Biomedical Sciences

professor

Katsushi Tokunaga

professor

Masashi Mizuguchi

professor

Chiho Watanabe

professor

Kiyoshi Kita

Molecular Biomedicine for pathogenesis

professor

Toru Miyazaki

Division of Basic Medicine Sciences (2) Biophysics

professor

Haruo Kasai

Division of Biomedical Materials and Systems

professor

Takashi Ushida

Division of Clinical Biotechnology

professor

Kazunori Kataoka

Division of Environmental Biotechnology

professor

Chiharu Tohyama

professor

Akio Nomoto

Health Sciences and Nursing
Department of Health Sciences

Department of Preventive and Administrative Nursing
Department of Clinical Nursing

International HealthCenter for Disease Biology and Integrative Medicine
Division of Basic Medicine Sciences (Ⅰ)

Division of Research Resources and Support
Section of Animal Research
Section of Radiation Biology

Kiyoshi Miyakawa

Section of Bioinformatics
International Academic Affairs

professor

Kazuhiko Yamamoto

Associate professor

Kiyoshi Kubota

Associate professor

Tetsuro Okabe

Associate professor

Satoru Yamagami

Faculty of Medicine
Endowed Departments
Department of Pharmacoepidemiology
Department of Integrated Traditional Medicine(Tsumura)
Department of Corneal Tissue Regeneration (ArBlast Co.,Ltd.)
Department of Clinical Vascular Regeneration (Daiichi Pharmaceutical Co.)
Associate professor

Hiroyuki Koyama

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

xii

Department of Bone & Cartilage Regenerative Medicine
Department of Cartilage of Bone Regeneration(Fujisoft)

Associate professor

Kazuto Hoshi

Department of Clinical Renal Regeneration

Associate professor

Keiichi Hishikawa

professor

Hiroshi Suzuki

Professor

Ryo Taguchi

Associate professor

Yoshiya Oda

Hospital Logistics by Sagawa Express Co.,Ltd.

professor

Hirohito Kuse

Clinical Molecular Epidemiology (Tanabe Seiyaku Co., Ltd.)

Associate professor

Takanari Gotoda

Immunotherapeutics (Medinet)

Associate professor

Kazuhiro Kakimi

Healthcare Related Informatics (NTT DATA CORPORATION)

Associate professor

Shinya Oku

Division of Total Renal Care Medicine

Associate professor

Akira Ishikawa

Integrated Molecular Science on Metabolic Diseases

Associate professor

Toshimasa Yamauchi

Department of Advanced Clinical Science and Therapeutics

Associate professor

Masataka Sata

Sato Sports Plaza Co., Ltd Kaatsu Training

Associate professor

Toshiaki Nakajima

Department of Sleep Disorder Research (Alfresa)

Associate professor

Takashi Ebisawa

Translational Research Based on the Clinical Database

Associate professor

Dobun Hayashi

Department of Joint Disease Research

Associate professor

Noriko Yoshimura

Associate professor

Naoto Hayashi

Associate professor

Kansei Uno

Associate professor

Yushi Uetera

Clinical Drug Evalutaion

Associate professor

Fumihiko Kanai

Medical Safety Management (Tokio Marine & Nichido)

Professor

Yasushi Kodama

Associate professor

Shoichi Maeda

Molecular Cardiovascular Metabolism

Associate professor

Katsuyuki AndoThe Department of Healthcare Quality Assessment

Associate professor

Noboru Motomura

Coca-Cola Anti-Aging Medicine

professor

Satoshi Inoue

Integrated Imaging Informatics

Associate professor

Naoki Yoshioka

The Department of Nutriproteomics

Associate professor

Kazumi Yagasaki

Clinical Epidemiology and Systems

professor

Tsutomu Yamazaki

Associate professor

Daisuke Koide

Clinical Trial Data Manegement

Associate professor

Takuhiro Yamaguchi

Pharmacology and Pharmacokinetics

Associate professor

Akihiro Hisaka

Associate professor

Hoshio Uehara,

Associate professor

Tsukasa Sasaki

Associate professor

Yasushi Okubo

Director

Kazuhiko Yamamoto

Department of Developmental and Medical Technology (Sankyo)

Department of Metabolome

Health Care Management and Policy
Computational Diagnostic Radiology and Preventive Medicine
Hospital Environment
Clinical Motor System Medicine

Helth Service Center

International Research Center for Medical Education

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

xiii

professor

Kiyoshi Kitamura

Associate professor

Yuko Takeda

General Medicine

Head

Kazuhiko Yamamoto

Cardiovascular Medicine

Head

Ryozo Nagai

Respiratory Medicine

Head

Takahide Nagase

Gastroenterology

Head

Masao Omata

Nephrology and Endocrinology

HeadToshiro Fujita

Metabolic Diseases

Head

Takashi Kadowaki

Hematology and Oncology

Head

Mineo Kurokawa

Allergy and Rheumatology

Head

Kazuhiko Yamamoto

Infectious Diseases

Head

Kazuhiko Koike

Neurology

Head

Shoji Tsuji

Geriatric Medicine

Head

Yasuyosi Ouchi

Psychosomatic Medicine

Head

Akira Akabayashi

General Surgery

HeadMichio Kaminishi

Stomach and Esophagus Surgery

HeadMichio KaminishiColon and Rectal Surgery

Head

Hirokazu Nagawa

Hepatobiliary Pancreatic Surgery

Head

Norihiro Kokudo

Vascular Surgery

Head

Tetsuro Miyata

Breast and Endocrine Surgery

HeadMichio Kaminishi

Artificial organ and Transplantation Surgery

Head

Norihiro Kokudo

Cardiovascular Surgery

HeadShinichi Takamoto

Thoracic Surgery

Head

Jun Nakajima

Neurosurgery

Head

Nobuhito Saito

Anesthesiology and Pain Relief Center

Head

Yoshitsugu Yamada

Urology and Andrology

Head

Tadaichi Kitamura

Gynecologic Surgery

Head

Tetsu Yano

Dermatology and Photolaser Medicine

Head

Kunihiko Tamaki

Ophthalmology and Vision Collection

Head

Makoto Araie

Orthopaedic Surgery and Spinal Surgery

Head

Kouzo Nakamura

Otorhinolaryngology and Auditory and Voice Surgery

Head

Tatuya Yamasoba

Rehabilitation Medicine

Head

Nobuhiko Haga

Plastic, Reconstructive and Aesthetic Surgery

Head

Isao Koshima

Oral-Maxillofacial Surgery Dentistry and Orthodontics

Head

Tsuyoshi Takato

Pediatrics

Head

Takashi Igarashi

Pediatric Surgery

Head

Tadashi Iwanaka

Obstetrics and Gynecology

Head

Shiro Kozuma

University Hospital
Clinical Divisions

xiv

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

Neuropsychiatry

Head

Kiyoto Kasai

Radiology

Head

Kuni Ohtomo

Clinical Laboratory Center

Head

Yutaka Yatomi

Surgical Center

Head

Hiroshi YasuharaRadiological Center

Head

Kuni Ohtomo

Emergency Services

Head

Naoki Yahagi

Transfusion Medicine and Immunohematology

HeadKoki Takahashi

Department of Maternal, Fetal, and Neonatal Medicine

Head

Takashi Igarashi

Rehabilitation Service

Head

Nobuhiko Haga

Department of Medical Engineering

Head

Hisayoshi Tamai

Central Supply Service

Head

Yoshikazu Mimura

Intensive Care Unit

Head

Naoki Yahagi

Intensive Pathology

Head

Masashi Fukayama

Corneal Transplantation

Head

Shiro Amano

Department of Cell Therapy and Transplantation Medicine

Head

Shigeru Chiba

Department of Endoscopy and Endoscopic Surgery

Head

Takao Kawabe

Center for Hemodialysis and Apheresis

Head

Toshiro Fujita

Department of Medical Social Service and Welfare

Head

Yasuyoshi Ouchi

Clinical Research Center(tentative name)Head

Masao Omata

Infection Control and Prevention

Head

Kazuhiko Koike

Department of Planning, Information and Management

Head

Kazuhiko Ohe

University Hospital Medical Information Network Center

Head

Takahiro Kiuchi

Department of Organ Transplantation Service

Head

Norihiro Kokudo

Division of Tissue Engineering

Head

Tsuyoshi Takato

Department of Clinical and Genetic Informatics

Head

Ryozo Nagai

Department of Palliative Medicine

Head

Keiichi Nakagawa

Pharmaceutical Department

Head

Hiroshi Suzuki

Department of Child Psychiatry

Head

Takashi Igarashi

Central Clinical Facilites

Nakamura

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

xv

Organization Chart
Cell Biology
Cell Biology and Anatomy

Structural Biology
Structural Cell Biology

Molecular Cell Biology

Cellular Neurobiology
Molecular Biology
Biochemistry and Molecular Biology

Cellular Signaling
Physiological Chemistry andMetabolism
Integrative Physiology

Physiology
Functional Biology

Cellular and Molecular Physiology
Neurophysiology

Pharmacology

Cellular and Molecular Pharmacology
Molecular Neurobiology
Human Pathology and Diagnostic Pathology

Pathology

Molecular Pathology
Surgical Pathology

Pathology, Immunology
and Microbiology

Microbiology

Microbiology
Infection Control and Prevention

Immunology

Molecular Immunology
Clinical Immunology
Diagnoatic Radiology

Radiology

Radiotherapy
Nuclear Medicine

Radiology and Biomedical
Engineering

System Physiology
Biomedical Engineering

Bioimaging and Biomagnetics
Biosystem Construction and Control
Neuropathology

Basic Neuroscience

Neurochemistry
Neurobiology
Speech Science

Neuroscience

Speech and Cognitive Neurosciences

Cognitive Neuroscience
Speech Physiology

Graduate School of
Medicine

Neuropsychiatry
Clinical Neuroscience

Neurology
Neurosurgery
Molecular Preventive Medicine

Occupational, Environmental andPreventive Medicine

Public HealthRadiological HealthSocial Medicine

Forensic Medicine, and Medical
Informatics and Economics

Forensic Medicine
Medical Informatics and Economics

xvi

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

Cardiovascular Medicine
Vascular Biology
Medicine I

Respiratory Medicine
Gastroenterology
Nephrology
Endocrinology

Internal Medicine

Nutrition and Metabolism
Medicine II

Hematology and Oncology
Allergy and Rheumatology
Infectious Diseases
Stress Science and Psychosomatic
Medicine

Clinical Laboratory Medicine
and Pathology

Clinical Laboratory Medicine
Transfusion Medicine

Reproductive Endocrinology
Obstetrics and Gynecology

Gynecological Oncology
Perinatal Medicine
Molecular Reproductive Endocrinology
Pediatrics

Reproductive,
Developmental andAging Sciences

Pediatric Sciences

Developmental Pediatrics
Pediatric Surgery
Pediatric Oncology

Aging Sciences

Geriatrics
Aging ResearchThoracic Surgery
Cardiovascular Surgery
Gastrointestinal Surgery
Hepato Biliary Pancreatic Surgery

Surgery

Urology
Artificial Organ and Transplantation
Division
Surgical Oncology

Surgical Sciences

Vascular Surgery
Metabolic Care and Endocrine
Surgery
Dermatology
Plastic and Reconstructive Surgery
Oral and Maxillofacial Surgery
Sensory and Motor System
Medicine

Orthopaedic Surgery
Ophthalmology
Otorhinolaryngology and Head & Neck
Surgery
Rehabilitation Medicine

Vital Care Medicine

Anesthesiology
Emergency and Critical Care Medicine

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

xvii

Health Sociology
Mental Health
Epidemiology and Preventive Health
Sciences
Health Sciences

Social Gerontology
Health Promotion Sciences
Biostatistics
Biomedical Ethics

Health Sciences andNursing

Advanced Clinical Nursing
Nursing Administration
Preventive and Administrative
Nursing

Family Nursing
Community Health Nursing
Public Health Nursing
Adult Nursing
Palliative Care Nursing

Clinical Nursing

Midwifery and Woman’s Health
Psychiatric Nursing
Gerontological Nursing
Wound Care Management

International Social Medicine

Health Policy and Planning
International Community HealthInternational Health

Human Genetics
International Biomedical
Sciences

Developmental Medical Sciences
Human Ecology
Biomedical Chemistry
Biostatistics

Epidemiology and Health Sciences

Social and Preventive Epidemiology
Health Economics and Epidemiology Research
Health Communication
Mental Health

School of Public HealthBehavioral Health Sciences

Health Sociology and Health Education
Social Gerontology
Health Promotion Science
Biomedical Ethics
Health Policy

Health Services Sciences

Healthcare Informatics
Clinical Information Engineering
Forensic Medicine and Medical Law

Division of Basic Medical Sciences (Ⅰ)
Division of Basic Medical Sciences (Ⅱ)
Center for Disease Biology
and Integrative medicine

Division of Biomedical Materials and Systems
Division of Clinical Biotechnology
Division of Environmental Health Sciences
Division of Research Resources and Support

Section of Animal Research
Section of Radiation Biology
Section of Bioinformatics

xviiiThe Tokyo Journal of Medical Sciences. Vol. 117, October 2008

Office of International Academic Affairs
Institution

Medical Library
Medical Scientist Training Program
Pharmacoepidemiology
Integrated Traditional Medicine (Tsumura)
Corneal Tissue Regeneration (ArBlast Co., Ltd.)Clinical Vascular Regeneration (Daiichi Pharmaceutical Co.)
Bone & Cartilage Regenerative Medicine
Cartilarge &Bone Regeneration(Fujisoft)
Metabolome
Clinical Renal Regeneration
Hospital Logistics by Sagawa Express Co. Ltd.
Clinical Molecular Epidemiology (Tanabe Seiyaku Co. Ltd.)
Immunotherapeutics (Medinet)
Healthcare Related Informatics (NTT DATA CORPORATION)
Total Renal Care Medicine
Integrated Molecular Science on Metabolic Diseases
Sato Sports Plaza Co.Ltd. Kaatsu Training
Advanced Clinical Science and Therapeutics

Endowed Department

Translational Research Based on the Clinical Database
Joint Disease Research
Health Care Management and Policy
Computational Diagnostic Radiology and Preventive Medicine
Hospital Environment
Clinical Motor System Medicine
Clinical Drug Evalution
Medical Safety Management(Tokio Marine & Nichido)
Developmental and Medical Technology(DaiichiSankyo)
Healthcare Quality Assessment
Coca-Cola Anti-Aging Medicine
Integrated Imaging Informatics
Nutriproteomics
Clinical Epidemiology and Systems
Clinical Trial Data Management
Pharmacology and Pharmacokinetics
Ubiquitous Preventive Medicine
Science for Joint Reconstruction

General Affairs Office
Personnel Office
Research Liaison
Administrative office

Educational Affairs
Graduate Student Affairs
Buget Office
Purchasing Office

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

Faculty of Medicine
Graduate School of
Medicine

Finance Office
Administrative Division
Facilities OfficeAcquisition Office Medical Library
Cataloging Office Medical Library
Information Service Medical LibraryCenter for Disease Biology
and Integrative medicine

Administrative Office

Cell Biology and Anatomy
Biochemistry and Molecular Biology
Physiology
Pharmacology
Pathology
Microbiology
Immunology
Radiology
Biomedical Engineering
Basic Neuroscience
Speech and Cognitive Sciences
School of Medicine

Clinical Neuroscience
Occupational, Environmental and Preventive Medicine
Medical Principles and Medical Ethics
Forensic Medicine, and Medical Informatics and Economics
Medicine I
Medicine II
Clinical Laboratory Medicine and Pathology
Obstetrics and Gynecology
Pediatric Science
Aging Science
Surgery
Sensory and Motor System Medicine
Vital Care Medicine

Faculty of
Medicine

Family Nursing
Comunity Health Nursing
Fundamental Nursing
Adult Health and Nursing
School of Health Sciences
and Nursing

Mental Health and Nursing
Health Sociology
Health Administration
Epidemiology and Biostatistics
Human Ecology
Biochemistry and Nutrition
Maternal and Child Health

xix

xx

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

General Medicine
Cardiovascular Medicine
Respiratory Medicine
Gastroenterology
Nephrology and Endocrinology
Internal Medicine

Metabolic Diseases
Hematology and Oncology
Allergy and Rheumatology
Infectious Diseases

ClinicalDivisions

Neurology
Geriatric Medicine
Psychosomatic Medicine
General Surgery
Stomach and Esophageal Surgery

University
Hospital

Colon and Rectal Surgery
Hepato Biliary and Pancreatic Surgery
Vascular Surgery
Breast and Endocrine Surgery
Surgery

Artificial organ and Transplantation Surgery
Cardiovascular Surgery
Thoracic Surgery
Neurosurgery
Anesthesiology and Pain Relief Center
Urology and Andrology
Gynecologic Surgery
Dermatology and Photolaser Medicine
Ophthalmology and Vision Collection
Orthopaedic Surgery and Spinal Surgery

Sensory and Motor System
Medicine

Otorhinolaryngology, and Auditory and Voice Surgery
Rehabilitation Medicine
Plastic, Reconstructive, and Aesthetic Surgery
Oral-Maxillofacial Surgery, Dentistry andOrthodontics
Pediatrics

Pediatrics, Perinatal and
Women's Medicine

Pediatric Surgery

Neuropsychiatry

NeuropsychiatryRadiology

Obstetrics and Gynecology

Radiology
Pharmaceutical Department
Nursing Department
Administration Office
Clinical Laboratory Center
Surgical Center

Administrative Department
Management Department
Management Strategy Department
Medical Affairs Department

Radiological Center
Central Clinical Facilities

Emergency Services
Transfusion Medicine
Delivery Unit
Rehabilitation Service
Medial Engineering Supply Center

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

xxi

Intensive Care Unit
Pathology
Sectin of Corneal Transplantation
Department of Cell and Gene Therapy
Department of Endoscopy and Endoscopic Surgery
Department of Hemodialysis and Apheresis
Hospital Computer Center
Department of Medical Social Service and Welfare
Clinical Research Center
Infection Control and Prevention
University Hospital Medical Information
Network Center
Organ Transplantation Service
Department of Child Psychiatry
Tissue Bank
Hospital Office of University Corporate Relations
Public Relations Office
Department of Nutrition
Labor Safety and Health Management Office
Center for Epidemiology and Preventive Medicine
Division of Tissue Engineering
Department of Clinical and Genetic Informatics
Departments under the bylaws

Department of Clinical Genomics
Department of Palliative Medicine
Cooperative Unit of Medicine and Engineering Research

Organization of Supporting
Clinical Management

Organization of ClinicalManagement

Personnel Administrationand Human Resources

Hospitality Center

Performance Monitoring,
Risk Management, and Staff
Development

Performance Monitoring
Medical Safety management
CenterHospital Planning andManagement

General Education Center

Education andResearch support

Infection Control Center
Patient Help and Clinical
Ethics Center

Inpatient Services
Administration

Cancer Board

Outpatient Services
Administration

Vascular Board

Central HospitalServices
Administration
Translational Research Center
22nd Century Medical and Research Center

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

xxii

History1858

May.

82 practitioners trained in Dutch (European) medicine in Edo (Tokyo) laid out money andestablished at Kanda Mitamagaike Vaccination station called the Shutojyo (vaccination center).

Nov.

The Shutojyo burned by a fire which emerged from Kanda Aioicho, continued its operationat
othersites such as a residence of Ito Genboku.

1859

Sep.

The Shutojyo was moved to and reconstructed at Shitaya Izumibashi Dohri.

1860

Oct.

TheShutojyo became an official medical institution of the Shogunate Government.

1861

Oct.

The Shutojyo was renamed as Seiyo Igaku-syo (Institute of Western Medicine) and offeredcourses ofWestern medicine in the fields of education, autopsy, and vaccination.

1863

Feb.

The Seiyo Igaku-sho was renamed as Igaku-sho (Institute of Medicine).

1868

Jul.

The Igaku-sho, affiliated with the Military hospital which was moved from Yokohama to Todo
residence in Shitaya, was renamed as Daibyoin (the Great Hospital).

1869
1871

Feb.

The Daibyoin renamed as Igakko-ken-byoin (Medical School and Hospital).

Dec.

Igakko-ken-byoin was renamed as Daigaku-Higashiko (University East Building).

Jul.

Ministry of Education was established and Daigaku-Higashiko was renamed as Higashiko(EastBuilding).

1872

Aug.

SchoolSystemwasestablished,renaming

HigashikoasDaiichi-daigaku-ku-igakko(The1stUniversity District Medical School).
1874

May.

Daiichi-daigaku-ku-igakko was renamed as Tokyo-igakko (Tokyo Medical School).

1876

Nov.

Tokyo-Igakko was moved to Hongo.

1877

Apr.

Tokyo-Igakko, affiliated with Tokyo-Kaisei School, renamed as The University of Tokyo.Tokyo
Medical School was renamed as The University of Tokyo Faculty of Medicine.

1886

Mar.

The University of Tokyo was renamed as Imperial University, and University of Tokyo FacultyofMedicine renamed as Imperial University Medical college. Graduate School was established.

1897

Jun.

The Imperial University was renamed as Tokyo Imperial University.

1917

Aug.

Eiraku Hospital affiliated with Ministry of Education Medical Practice License Examination,
moved to Tokyo Imperial University and renamed as Koishikawa hospital affiliated to Tokyo
Imperial University Medical College.

1919

Apr.

Faculty system was established renaming Medical College as Faculty of Medicine.

1931

Feb.

The first building of the Faculty of Medicine was constructed.

1936

Jan.

Brain research office donated by Mr. Horikoshi Hisasaburo.

Nov.

The second building of the Faculty of Medicine (main building) was constructed.

1947

Oct.

Tokyo Imperial University renamed as The University of Tokyo.

1950

Apr.

Institute of Nursing renamed as University Nursing School.

1953

Apr.

School of Health Care and Nursing founded.

Jul.

Graduate School of the new system founded, Division of Biological Science Dr. Med.of
Medicine.

1956

Apr.

Midwives School established.

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

1958
1961
1965

Apr.

Division of Pharmaceutical Sciences became independent Faculty.

May.

Celebrated centennial of The University of Tokyo Faculty of Medicine.

Mar.

Medical Library was built in memorial of the centenary.

Apr.

Institute of Medical Electronics established.

Apr.

Research Institute of Logopedics and Poniatrics was established.

xxiii

School of Health Care and Nursing reorganized as the School of Health Sciences.
Graduate School of The University of Tokyo Reorganized and Division of Biological Science.
Dr.Med. Science course became Medical Science Division.
Health Science Course was established in Medical Science Division.
1966

Sep.

The third building of Faculty of Medicine was constructed.

1971

Apr.

Laboratory for Animal Experiments was established.

1973

Mar.

Animal Center for Biomedical Research was constructed.

1983

Jan.

Annex of the third building of the Faculty of Medicine was constructed.

1985

Sep.

Medical and International Academic Affairs established.

1987

Apr.

Graduate School specialized course was changed to major.

1992

Apr.

School of Health Sciences became The School of Health Science and Nursing.
School of International Health was established in Medical Science Division.

1995

Jul.

Radiation Research Institute was established.

Apr.

As the result of the shift to the chair system of the Graduate School of Medicine, four divisions
were abolished, Third Basic Medicine, Social Medicine, Third Clinical Medicine and Fourth
Clinical Medicine. Instead, four divisions were established, Pathology, Immunology andMicrobiology, Social Medicine, Reproductive, Developmental and Aging Science and Surgery.

1996

Apr.

As the result of the shift to the chair system of the Graduate School of Medicine, three divisions
were abolished, First Clinical Medicine, Health Science and International Health. Instead, threedivisions were established, Internal Medicine, Health Science and Nursing and International
Health.

1997

Apr.

As the result of the shift to the chair system of the Graduate School of Medicine, three divisions
were abolished, First Basic Medicine, Second Basic Medicine and Second Clinical Medicine.
Instead four divisions were established. Molecular Cell Biology, Functional Biology, Radiology
and Biomedical Engineering and Neuroscience.
As the result of above mentioned reorganization, three institutes were abolished, Institute ofBrain Research, Institute of Medical Electronics and Institute of Logopedics and Phoniatrics.

1999

Apr.

Master Course of Medical Science was established in Graduate School of Medicine.
This course accepts graduates of all faculties except those from Schools of Medicine, Dentistry,and Veterinary Medicine.

2000

Apr.

The International Research Center for Medical Education was established.
(The shared facility for education and research)

2001

Apr.

University Branch Hospital was united to University Hospital.

2003

Apr.

The Center for Disease Biology and Integrative Medicine was established.

The Tokyo Journal of Medical Sciences. Vol. 117, October 2008

xxiv

2007

Apr

The School of Public Health was establishrd. Thes school offers programs for Master public
Health.

The University of Tokyo,
Graduate School of Medicine

Molecular Cell Biology
1. Cell Biology and Anatomy

2

Department of Cell Biology andAnatomyProfessor
Nobutaka Hirokawa, M.D.

Associate Professor
Yoshimitsu Kanai, M. D., Takao Nakata, M. D.,

Yosuke Takei, M. D.,

Lecturer
Yasuko Noda, M. D.,

Associate
Yasushi Okada, M. D.,

Yosuke Tanaka, M. D.,

Ryo Nitta, M. D.,

Noriko Homma, Ph. D.,

Harukata Miki, Ph. D.,

Hiroaki Yajima, Ph. D.

Tadayuki Ogawa, Ph. D.

Homepage

http://cb.m.u-tokyo.ac.jp/

Teaching activities
Our teaching responsibility is following.
I.
1) Lecture on Cell Bilogy, Developmental Biology,
Histology and Neurocytology.
2) Lecture on Gross Anatomy and Neuroanatomy. to
medical students and students of other facultiesII.
1) Laboratory course of Gross Anatomy and
Neuroanatomy.
2) Laboratory course of Histology and Histology of
the Cenrtral Nervous System.
to medical students and students of other faculties.
In addition we offer a special training course (freequarter) of various kinds of molecular cell biology
techniques such as immunocytochemistry, electron
microscopy,
biochemistry,
molecular
biology,biophysics, and cellular and molecular neurobiology
technique to medical students.

Research activities
Our research field covers the molecular cell biologyof the cytoskeleton. We focus on the molecularmechanisms of cell morphogenesis and intracellulartransports.
Our laboratory studies molecular architecture,dynamics and function of the neuronal cytoskeleton
using various new molecular cell biologicalapproaches including new electron microscopy suchas the quick freeze deep etch electron microscopy,
cryoelectron microscopy at atomic resolution, andcryoultramicrotomy,
biochemistry,
immunocytochemistry, molecular biology, molecular
genetics such as gene targeting and transgenic mouseapproaches, molecular biophysics and structure
biology including X ray crystallography andcryoelectron microscopy.
In this way we can study structure, dynamics andfunctions of cytoskeleton from gene to cell, tissue andwhole body.
Nerve cells as units of complicated neuronal
networks in the brain develop very polarized

3

morphology composed of dendrites, cell body and along axon along the direction of impulse propagation.
The neuronal cytoskeleton plays three major
important roles.
1) It provides dynamic frameworks for neurite
extension and maintenance.
2) It provides structural bases for organelletransports in the cells. Namely it works as rails
and motor molecules to transport materials fromcell center to periphery and from periphery to cell
center.
3) It very importantly regulates release processes oftransmitters and also contributes to anchor
receptors at the postsynaptic sites.
Our laboratory studies molecular architecture,dynamics and function of the cytoskeleton focusing onthese three major roles.
To study these molecular mechanisms we use newmolecular cell biological approaches including
electron microscopy of molecular resolution,
biochemistry, biophysics, molecular biology andmolecular genetics and X-ray crystallography.

References
1. Nakata, T. and N. Hirokawa. Neuronal Polarity
and the Kinesin Superfamily Proteins. Science
STKE 6 Feb 2007:pe6
2. Hirokawa, N. and R. Takemura. Intracellulartransport and kinesinsuperfamily proteins:
structure, function and dynamics. In “Controlled
Nanoscale Motion, Lecture Notes in Physics,
Nobel Symposium 131,” edt by H. Linke and A.
Mansson, Springer-Verlag, 711: 85-121, 2007.
3. Oda, T., N. Hirokawa, and m. Kikkawa.
Three-dimensional structures of the flagellar
dynein–microtubule complex by cryoelectron
microscopy. Journal of Cell Biology 177 (2):243-252, 2007
4. Guillaud, L., R. Wong and N. Hirokawa.
Disruption of KIF17-Mint1 interation by
CamKII-dependent phosphorylation: a molecularmodel of kinesin-cargo release. Nature Cell
Biology 10: 19-29, 2008.
5. Hirokawa, N. and Y. Noda. Intracellular transportand Kinesin superfamily proteins, KIFs: structure,function, and dynamics. Physiological Review

in press 2008
6. Nitta, R., Y. Okada and N. Hirokawa. Structuralmodel for strain-dependent microtubule activationof Mg-ADP release from kinesin via
microtubule-sensor. Nature Structural andMolecular Biology in press 2008
7. Niwa, S. Y. Tanaka and N. Hirokawa. KIF1B
beta/KIF1A- mediated axonal transport ofpresynaptic regulator Rab3 in GTP-dependent
manner via DENN/MADD. Nature Cell Biology
in press 2008
8. Hirokawa, N. Y. Okada and Y. Tanaka Fluid
dynamic mechanism responsible for breaking theleft-right symmetry of the human body: The nodal
flow. Annual Review of Fluid Mechanics inpress 2008.

4

Department of Cellular
Neurobiology
Professor
Shigeo Okabe, M.D., Ph.D.

Lecturer
Satoru Kondo, Ph.D.

Research Associate
Kiyomasa Nishii, M.D., Ph.D.

Homepage http://synapse.m.u-tokyo.ac.jp/
Introduction and Organization

Research activities

The Department of Cellular Neurobiolgy was initiallyestablished as Neuroanatomy department of former
Brain Institute of Medical School of Imperial
University of Tokyo in 1936. Since the structural
reconstruction of School of Medicine in 1997 thisdepartment became one of the departments of Cell
Biology and Anatomy of Graduate School of Medicine.
This department is currently organized by Professor
Shigeo Okabe since September in 2007. The
department is constituted of other 11 members.

Brain functions, which are dependent on mutualcommunication of a tremendous number of neuronalcells, regulate the behavior of animals and humans.
The main structure specifically differentiated for
information exchange between neurons is called"synapse". Long-term maintenance of synaptic
properties underlies stability and reproducibility of
behavior in responses to external stimuli. In turn,
alterations of synaptic properties are thought to be thebasis of behavioral change in the course of animal
development and also after learning. Therefore,
synapses should be stabilized for a long term to realize
fidelity of various animal behaviors, but also shouldbe altered rapidly when animals adapt to a newenvironment. Molecular basis of this dichotomy,
which is unique to synapses, is the main interest of ourlaboratory.
The role of glia for synapse formation
Major structural components present in the vicinity ofsynapses are processes of glial cells. Electron
microscopic analysis confirmed the presence of directcontacts between synapses and astroglial processes.
By analyzing the relationship between astrocytic
contacts and subsequent stabilization and maturationof spines, we found that local astrocytic contacts
promote spine stabilization and structural maturation.

Teaching activities
For medical students, our department takes thefollowing lectures and courses.
1. Cell Biology, Histology and Neurocytology
2. Gross Anatomy and Neuroanatomy.
3. Free Quarter.
For graduate students, we offer the following lecturesand seminars.
1. Cellular Neurobiology.
2. Cell Biology and Histology.
3. Discussion seminars and progress reports ofexperiment.
4. Joint seminar with other departments

5

References
1. Nishida, H. and Okabe, S. Direct astrocytic
contacts regulate local maturation of dendritic
spines. Journal of Neuroscience 27, 331-340,
2007.
2. Gengyo-Ando, K., Kuroyanagi, H., Kobayashi, T.,
Murate, M., Fujimoto, K., Okabe, S. and Mitani, S.
The Sec1/Munc18 family protein, VSP-45, isrequiredfor
Rab-5-dependentendocytic
trafficking in C.elegance. EMBO Reports 8,
152-157, 2007.
3. Okabe, S. Molecular anatomy of the postsynaptic
density. Molecular and Cellular Neuroscience 34,
503-518, 2007.
4. Hori, H., Noguchi, H., Hashimoto, R., Okabe, S.,
Saitoh, O. and Kunugi, H. IQ decline and memory
impairment in Japanese patients with chronic
schizophrenia. Psychiatry Research, 158, 251-255,
2008.
5. Takahashi, A., Hirai, S., Ohtaka-Maruyama, C.,
Miwa, A., Hata, Y., Okabe, S. and Okado, H.
Co-localization of a novel transcriptional
repressor simiRP58 with RP58. Biochemical andBiophysical Research Communications, 368,
637-642, 2008.
6. Nakazawa, T., Kuriu, T., Tezuka, T., Umemori, H.,
Okabe, S. and Yamamoto, T. Regulation ofdendritic spine morphology by an NMDA
receptor-associated
Rho
GTPase-activating
protein, p250GAP. Journal of Neurochemistry,
105, 1384-1393, 2008.
7. Hori, H., Nagamine, M., Soshi, T., Okabe, S., Kim,
Y., and Kunugi, H. Schizotypal traits in healthy
women predict prefrontal activation patterns
during a verbal fluency task: A near-infrared
spectroscopy study. Neuropsychobiology, 57,
61-69, 2008.

Molecular Cell Biology
2. Biochemistry and Molecular Biology

7

Department of Molecular Biology
Professor
Hiroto Okayama, M.D., Ph.D.

Associate Professor
Shigeki Jinno, Ph.D.

Associate
Hanako Yamamoto,Homepage

Ph.D., Kenji Ito, Ph.D.,

Shiho Arakawa, Ph.D.

http://www.cellcycle.m.u-tokyo.ac.jp/

Introduction and Organization
This Department was established in 1893 initially as apart of Department of Physiology, but in 1897 became
independent. In 1927, it was renamed Department ofBiochemistry, in 1974 First Department ofBiochemistry and in 1997 Department of Molecular
Biology, according to the creation of new related
departments and the reorganization of Faculty of
Medicine. This Department has been headed by 7
professors, who made great contributions to thedevelopment of biochemistry, nutrition and molecularbiology in Japan.
Professor Muneo Kumagawa, who headed this first
Biochemistry or Medical Chemistry Department
established in this country, graduated in 1882 The
University of Tokyo Faculty of Medicine. In 1884 hewent to Department of Pathology, The University of
Berlin headed by Rudolf Virchow and under thesupervision of Ernst Salkowski. After returning toJapan, he was promoted to Lecture and Professor ofthis Department. In 1908, He discovered lack ofglycogenecity in lipids, which has been firmly
established besides some exceptions, and succeeded inpurification of vitamin B1, which was discovered by C.
Eijikman in 1906. He educated many including
Masahiro Sakaguchi, who developed a world-famouscolorimetric method for arginine and Takaoki Sasaki,
who first succeeded in generating liver cancer withchemicals.

Professor Samuro Kakiuchi graduated The Imperial
University of Tokyo Faculty of Medicine in 1906 andstudied under Professor Kumagawa. After studies in
US, he come back and succeeded late Kumagawa. He
published Journal of Biochemistry and founded theJapanese Society of Biochemistry. His students
included Professors Kodama and Shimazono.
Professor Keizo Kodama graduated the Imperial
University of Tokyo in 1918. Taking positions oflecturer and Associate Professor and making studies at
Cambridge University, he became Professor of
Biochemistry Kyushu Imperial University andsucceeded Professor Kodama in 1933. He studied
oxidation and reduction and nutrition.
Professor Norio Shimazono graduated The Imperial
University of Tokyo Faculty of Medicine in 1928,
followed by taking positions as associate, lecturer,
professor at Niigata Medical School. In 1952 hesucceeded Professor Kodama. He studied vitamin B1/
cocarboxylase, ketoacid metabolism and hexose
metabolism.
Professor Tamio Yamakawa graduated The Imperial
University of Tokyo Faculty of Medicine and began
studies at The Institute for Infectious Diseases, The
University of Tokyo. After becoming Associate
Professor and Professor, he succeeded Professor
Shimazono. He was a pioneer in glycolipid researchand discovered the involvement of sialic acid in the
ABO blood type antigens.
Professor Masami Muramatsu graduated The

8

University of Tokyo Faculty of Medicine in 1955. He
began studies in Department of Internal Medicine,went to Baylor Collage of Medicine to study under H.
Busch, and after coming back, took a position at
Cancer Institute and professorship at Tokushima
University School of Medicine. In 1982, he succeeded
Professor Yamakawa. He studied ribosomal RNA andcloned interferon and p450 genes.
Professor Hiroto Okayama graduated Kumamoto
University School of Medicine in 1973. After taking a
Ph.D. degree at Kyoto University School of Medicine,
he went to Stanford University to study under P. Berg.
Taking a position at NIH US, he became Professor of
Molecular Genetics, Osaka University Institute for
Infectious Diseases. In 1993 he succeeded Professor
Muramatsu. At Stanford and NIH, he studied genecloning and developed a full length cDNA cloning
method and a cDNA expression cloning vector system.
After return to Japan, he has been studying cell cycle
control and cancer.

Research Activities
Our current study focuses on the understanding of themolecular mechanism enabling the anchorageindependent S phase onset, which is the universal
property of cancer cells. All the members of ourlaboratory are participating in this study.
1. Molecular
Mechanismforanchorage
loss-induced Cdc6 degradation
In 2002, we reported that anchorage deprivation
led to termination of expression of Cdc6, a factor
essential for the assembly of Pre-RC, via
Rb-independent transcriptional repression andpapainfamilyprotease-led
degradation.
Subsequently, we identified the protease as
lysosomal cathepsins, released from lowcholesterol-content lysosomes upon anchorage
deprivation. Although cathepsins appear to be themajor Cdc6 degrading enzyme in NRK cells, they
are not major ones in other cells such as mouse or
rat embryonic fibroblasts. We recently found thatthree ubiquitin ligases are responsible foranchorage loss-induced Cdc6 degradation, one ofwhich is identified as Cdh1-APC. One is likely to
be FBW7 or a related. The third ubiquitin ligase isunknown but has an interesting property: degradesat least Cyclin A and E2F1, in addition to Cdc6

and seemingly requires p53 for its activity underanchorage deprivation. Its identity and themechanism by which it requires p53 for its
activity are unknown.
2. Identification of the signal pathways mediating
signals for cellular anchorage to extra-cellularmatrices
A key to understand the molecular basis formalignant transformation is elucidation of signal
pathways that mediate anchorage signals andcontrol expression and activity of cell cycle startfactors including Cdc6 and cyclin A. We haverecently identified that the TSC1/2-Rheb-mTOR
pathway mediates an anchorage signal andcontrols at least the activity of Cdh1-APC anubiquitin ligase that acts in G1 and degrades both
Cdc6 and cyclin A. Active mTOR is required forinactivation of Rb together with activated cyclin
D-dependent kinases. Inactivation of Rb activates
E2F resulting in induction of Emi1 as well as
Cdc6 and Cyclin A. Induced Emi1 inactivates
Cdh1-APC, thereby suppressing degradation of
Cdc6 and Cyclin A.
3. New function of Cdc6
Cdc6 is known as the assembler of pre-replicativecomplexes that is the initial step of chromosomal
replication. We found that this factor has anadditional function: the ability to activate
p21WAF1-inhibited Cdk2 in a ATP-dependent
manner, the function never anticipated for Cdc6
and never anticipated for the regulation of acyclin-dependent kinase.
This unbelievablefunction of Cdc6 is confirmed by the essentialityof the “Cy” motif and the ATPase domain for this
newly identified activity. Furthermore, we showthat Cdc6 determines utilization of the
p53-p21-dependent DNA damage checkpoint atleast in S phase cells. Whenever Cdc6 is notdestabilized, inactivation of Cdk2 by p21 isblocked in S phase. This discovery highlights theimportance of Cdc6 as a focal point of the control
of S phase onset and progression.

9

4. Inductionofanchorage-independent
proliferation of NRK cells by overexpression of
three cell cycle factors
One approach to understand the mechanism of
oncogenetic transformation is to find a way to
induce anchorage-independent proliferation ofcells by manipulating cell cycle factors. This
could be done with NRK cells and overexpressionof three factors: Cdc6, Cdk6 and cyclin D3, thelatter two of which can evade inhibition by
inhibitor proteins and activate E2F under growth
suppressive conditions like in anchorageloss-induced G1 arrest. This year we havesucceeded in inducing anchorage-independent
proliferation of mouse embryonic fibroblasts byoverexpression of Cdk6, cyclin D3 and aphosphor-mimetic mutant form of Cdc6. Attempts
to induce anchorage-independent proliferation ofhuman fibroblasts are underway.

Education
To medical students, we give lectures on DNA andrelated. DNA replication, transcription, nuclear export
of mRNA, translation, gene engineering and mobile
DNA are the topics covered by the lectures.
To graduate course students, the genetic engineeringcourse consisting of lectures and experiments isprovided.

References
1. Kan, Q., Jinno, S., Yamamoto, H., and Okayama,
H. Chemical DNA damage activates
p21WAF1/CIP1-dependent intra-S checkpoint. 2007,
FEBS Lett. 30, 5879-5884.

10Department of Cellular Signaling
Professor
Takao Shimizu, M,D., Ph.D.

Associate Professor
Motonao Nakamura, Ph.D.,

Satoshi Ishii, Ph.D.

Research Associate
Yoshihiro Kita, Ph.D.,

Homepage

Hideo Shindou, Ph.D.

http://biochem2.umin.jp/index.html

Introduction and Organization

Research activities

In addition to the above 5 faculty members, we have
15 graduate students (14 doctor course students
including 2 PhD-MD course students and 1 mastercourse student), and 7 undergraduate medical students(Free Quarter). Several clinical scientists and a
research fellow from pharmaceutical company are also
our members. Ms Toshie Takahashi (Assistant)belongs to the Dean of the Faculty and is in charge of
maintenance and education of various instruments forcommon use.

1. Lipid mediator and lipid metabolism.
Oxygenated products of arachidonic acid(prostaglandins,
leukotrienes,
andhydroxyeicosatetraenoic acids) as well as bioactive
phospholipids (platelet-activating factor and otherrelated phospholipids) activate cellular signaling
pathways in various cells. These lipid mediators,
working together with other bioactive substances suchas neurotransmitters and cytokines, are now
considered to play significant roles in neuronalplasticity and self-defense systems. To identify theroles of lipid mediators in the living systems,
principally three approaches are ongoing withdifferent strategies; (1) isolation of enzymes involved
in syntheses and degradation of lipid mediators,
cloning of cDNAs and genes, elucidation of enzyme
regulation at transcriptional and posttranscriptional
levels. (2) cloning of G-protein-coupled receptors forlipid mediators and clarification of intracellularsignaling mechanisms; and (3) target disruption oroverexpression of the gene of interest in mice, andidentification of the in vivo role of each molecule byexamining phenotypes of these mice. In the last
several years we have cloned several key enzymes ofphospholipid metabolism and receptors for lipid
mediators. Recently, we have successfully identified
several lysophospholipid acyltransferases involving in
Lands’ cycle. Thus, we are able to explain the

Teaching activities
For about 100 undergraduate students from theFaculty of Medicine, and about 5 students fromFaculty of Science (Department of Anthropology), we
deliver about 80 lectures, small-group seminars, andlaboratory course for a couple of weeks. Ourlaboratory is accepting Free Quarter students every
year, and the total number from 2003 to 2007 isaround 15. For graduate course students, we havethree-month lecture series (biochemistry and genetic
engineering), and an eight-week laboratory course forclinical scientists.

11

molecular mechanism and biological significance ofdiversity and asymmetry of membrane lipids.
Several lines of transgenic mice and knock-out mice
were established and their phenotypes were analyzed.
We found that these mediators are involved ininflammation, allergy, and neuronal functions.
2. Simultaneous quantitation of lipid mediators.
Lipid mediators are produced through a cascade
pathway. In the cascade known as “arachidonate
cascade”, several key enzymes such as cytosolic
phospholipase
A2,
cyclooxygenases,
andlipoxygenases function as common regulators incombination with various terminal synthases that
produce specific lipid mediator molecular species.
For a comprehensive analysis of lipid mediators, asimultaneous quantitation method with sensitivity andreliability is necessary. Thus, we have recently
developed a quantitation system for multiplex lipid
mediators by column-switching HPLC–tandem mass
spectrometry. When optimized, the system enables
the rapid analysis of 14 lipid mediators with athroughput of 96 samples/24 h, lower limits ofquantitation of 5 pg on column, and linear calibration
ranges up to 2000–5000 pg. Indeed, we successfully
detected dynamic changes in a series of lipid
mediators in some pathologic tissues of rodents.
3. Various instrumental analyses.
The Faculty of Medicine has various analyticaland preparative instruments for the common use,which include mass spectrometers (JEOL HX 110,
Hitachi M-80 and Finnigan MAT TSQ 7000
[ThermoQuest]) equipped with gas chromatographs or
HPLC, PerkinElmer peptide sequencers, FUJI BAS
2000 image analyzer, BD FACScan, and Beckman
capillary electrophoresis system (P/ACE 2000). Ms.
Takahashi is in charge of the maintenance of thesemachines and instruction for the beginners. As her
own projects, she is identifying peptide sequences ofvarious proteins by HPLC-MS, and identification ofsmall-molecular weight compounds by GC-MS andHPLC-MS.
4. Internet Web site
To see our research activities in more detail,please refer to our web site (http://biochem2.umin.jp/

index_j.html). In this homepage, you will also find
our experimental protocol useful for the molecular andcellular biology studies. Dr. Kita is responsible forthe homepage.
5. Collaboration with Department of Metabolome
In 2003, a new laboratory, Department ofMetabolome was established by the donation of
Shimadzu Co., Ltd, and Ono Pharmaceutical Co.
Professor Ryo Taguchi and Associate Professor
Yoshiya Oda are worldwide leading researchers onproteomics and metabolomics. In collaboration withthem, we are searching for novel lipid mediators thatbind to orphan G-protein-coupled receptors, lacking
identified cognate ligands. In this collaboration werecently
determined
12HHT(12(S)-Hydroxyheptadeca-5Z,8E,10E-trienoic acid) as
a novel ligand for BLT2 which has been recognized as
the low affinity second LTB4 receptor. We also
succeeded in molecular cloning of lung-typeacyl-coa:lysophosphatidylcholine acyltransferase 1(LPCAT1) involving in production of lung surfactant.

References
1. Kita Y, Ohto T, Uozumi N, Shimizu T. Biochemical properties and pathophysiological roles ofcytosolic phospholipase A2s. Biochim Biophys
Acta 2006; 1761: 1317-22.
2. Akiba S, Mukaida Y, Hane K, Oka M, Uozumi N,
Shimizu T, Sato T. Group IVA phospholipase
A(2)-mediated production of fibronectin byoxidized LDL in mesangial cells. Kidney Int. 2006;
70: 1013-18.
3. Shimizu T, Ohto T, Kita Y. Cytosolic
phospholipase A2: Biochemical properties andphysiological roles. IUBMB Life 2006; 58: 328-33.
4. Chiba Y, Shimada A, Satoh M, Saitoh Y,
Kawamura N, Hanai A, Keino H, et al. Sensory
system-predominant distribution of leukotriene a(4)hydrolase and its colocalization with calretinin in
the mouse nervous system. Neurosci. 2006; 141:917-27.
5. Nakanishi H, Shindou H, Hishikawa D, Harayama
T, Ogasawara R, Suwabe A, et al. Cloning andcharacterizationofmouse
lung-typeacyl-coa:lysophosphatidylcholine acyltransferase 1

12(LPCAT1): Expression in alveolar type II cells, andpossible involvement in surfactant production. J
Biol Chem. 2006; 281: 20140-7.
6. Yoshikawa K, Kita Y, Kishimoto K, Shimizu T.
Profiling of eicosanoid production in the rat
hippocampus during kainate-induced seizure:Dual-phase regulation and differential involvementof cox-1 and cox-2. J Biol Chem. 2006; 281:
14663-9.
7. Doi K, Okamoto K, Negishi K, Suzuki Y, Nakao A,
Fujita T, et al. Attenuation of folic acid-induced
renal inflammatory injury in platelet-activating
factor receptor-deficient mice. Am J Pathol. 2006;
168: 1413-24.
8. van der Sluijs KF, van Elden LJR, Nijhuis M,
Schuurman R, lorquin S, Shimizu T, et al.
Involvement of the platelet activating factor
receptor in host defense against Streptococcus
pneumoniae during postinfluenza pneumonia. Am J
Physiol. 2006; 290: L194-9.
9. Schaefer, M. B., Ott, J., Mohr, A., Bi, M. H., Grosz,A., Weissmann, N., Ishii, S., Grimminger, F.,
Seeger, W., and Mayer, K. Immunomodulation byn-3- vs. n-6-rich lipid emulsions in murine acutelung injury _ role of platelet-activating factor
receptor. Crit. Care Med. 2007; 35: 544-54.
10. Kuniyeda, K., Okuno, T., Terawaki, K., Miyano,M., Yokomizo, T., and Shimizu, T. Identificationof the intracellular region of the Leukotriene B4
receptor type-1 that specifically involves in
Gi-activation. J Biol Chem. 2007; 282: 3998-4006.
11. Yanagida, K., Ishii, S., Hamano, F., Noguchi, K.,
and Shimizu, T. LPA4/p2y9/GPR23 mediates
Rho-dependent morphological changes in a rat
neuronal cell line. J Biol Chem. 2007; 282:
5814-24.
12. Shindou, H., Hishikawa, D., Nakanishi, H.,
Harayama, T., Ishii, S., Taguchi, R., and Shimizu,
T. A single enzyme catalyzes both PAF production
and membrane biogenesis of inflammatory cells:cloning and characterization of acetyl-CoA:lysoPAF acetyltransferase. J Biol Chem. 2007; 282:6532-9.
13. Tsuda, M., Ishii, S., Masuda, T., Hasegawa, S.,
Nakamura, K., Nagata, K., Yamashita, T., Furue,
H., Tozaki-Saito, H., Yoshimura, M., Koizumi, S.,
Shimizu, T., and Inoue, K. Reduced pain behaviors

and ERK activation in primary sensory neurons byperipheral tissue injury in mice lacking
platelet-activating factor receptor. J. Neurochem.
2007; 102: 1658-68.
14. Witzenrath, M., Gutbier, B., Owen, J.S, Schmeck,B., Mitchell, T.J., Mayer, K., Thomas, M.J., Ishii,S., Rosseau, S., Suttorp, N., and Schutte H. Role ofplatelet-activating factor in pneumolysin-induced
acute lung injury. Crit. Care Med. 2007; 35:
1756-62.
15. Kitaura, H., Uozumi, N., Tohmi, M., Yamazaki, M.,
Sakimura, K., Kudoh, M., Shimizu, T., and Shibuki,
K. Roles of nitric oxide as a vasodilator inneurovascular coupling of mouse somatosensory
cortex. Neurosci. Res. 2007;59: 160-71.
16. Taguchi, R., Nishijima, M., and Shimizu, T. Basic
Analytical Systems for Lipidomics by Mass
Spectrometry in Japan. Methods Enzymol. 2007;
432: 183-209.
17. Li, Y., Yamada, H., Kita, Y., Kunimi, M., Horita.
S., Suzuki, M., Endo, Y., Shimizu, T., Seki, G., andFujita, T. Roles of ERK and group IVA cytosolic
PLA2 in biphasic regulation of renal proximaltransport by angiotensin II. J. Amer. Soc. Nephrol.
2007; 19: 252-9.
18. Kimura, M., Taniguchi, M., Mikami, Y., Masuda,T., Yoshida, T., Mishina, M., and Shimizu, T.
Identification and characterization of zebrafish
semaphorine 6D. Biochem. Biophys. Res. Commun.
2007; 363: 762-8.
19. Hikiji, H., Takato, T., Shimizu, T., and Ishii, S. The
roles of prostanoids, leukotrienes, and plateletactivating factor in bone metabolism and disease.
Prog. Lipid Res. 2008; 47: 107-26.
20. Hishikawa, D*., Shindou, H*. (*, equal
contribution), Kobayashi, S., Nakanishi, H.,
Taguchi, R., and Shimizu, T. Discovery of alysophospholipid acyltransferase family essential
for membrane asymmetry and diversity. Proc. Natl.
Acad. Sci. USA 2008; 105: 2830-35.
21. Harayama, T*., Shindou, H*. (*, equal
contribution), Ogasawara, R., Suwabe, A, andShimizu, T. Identification of a novel noninflammatory biosynthetic pathway of plateletactivating factor. J Biol Chem. 2008; 283: 11097106.

13

22. Tsujimura, Y., Obata, K., Mukai, K., Shindou, H.,
Yoshida, M., Nshikado, H., Kawano, Y., Minegishi,Y., Shimizu, T., and Karasuyama, H. Basophils
play a pivotal role in IgG-, but not IgE-mediatedsystemic anaphylaxis in contrast to mast cells.
Immunity 2008; 28: 581-9.
23. Okuno, T., Iizuka, Y., Okazaki, H., Yokomizo, T.,
Taguchi,R.,
andShimizu,T.
12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic acidis a natural ligand for leukotriene B4 receptor 2. J
Exp Med. 2008; 205: 759-66.
24. Jiang, W., Hall, S.R., Moos, M.P.W., Cao, R.Y.,
Ishii, S., Ogunyankin, K.O., Melo, L.G., and Funk,
C.D. Endothelial cysteinyl leukotriene 2 receptor(CysLT2R) expression mediates myocardialischemia-reperfusion injury. Am. J. Pathol. 2008;
172: 592-602.
25. Hase, M., Yokomizo, T., Shimizu, T., andNakamura, M. Characterization of an orphan G
protein-coupled
receptor,
GPR20,
that
constitutively activates Gi proteins. J Biol Chem.
2008; 283: 12747-55.

14Department of Physiological
Chemistry and Metabolism
Professor
Hiroki Kurihara, M.D.

Lecturer
Yukiko Kurihara, M.D.

Research Associate
Kouichi Nishiyama, M.D.

Associate
Yasunobu Uchijima, Ph.D.

URL

http://bio.m.u-tokyo.ac.jp/home-j.html

Introduction and Organization
The Department of Physiological Chemistry andNutrition, the predecessor of the present department,
was founded in 1952. Upon the restructuring of theuniversity system in 1997, the department was
renamed ‘Department of Physiological Chemistry andMetabolism’ as one unit of the Specialty of Molecular
Cell Biology. The present members include the above
stuffs, 1 postdoctoral fellows, 2 visiting scientist, 5
graduate students. In addition, MD-PhD course andMD-researcher course students will join us in 2008.

Teaching Activities
We give a series of lectures and laboratory courses
on biochemistry and molecular biology forundergraduate students from Faculty of Medicine andFaculty of Science. We also accept undergraduate
students taking “Free Quarter” and “Early-Exposureto-Medicine” courses every year. Several students arestaying in our lab beyond the term to join our research.
For graduate students, we hold progress-reportmeeting and journal club every week, and sometimes
invite established scientists for seminar to encourage

scientific discussion.

Research Activities
1. Developmental Biology and Medicine(1) Neural crest and craniofacial development
We have investigated the role of endothelin-1(ET-1) signaling in neural crest and craniofacial
development and identified the ET-1/ETA-receptor
to Dlx5/6 pathway in the dorsoventral axis
patterning of crest-driven branchial arch structures.
To further clarify the underlying mechanism, we
have established mice in which gene cassettes canbe efficiently knocked-in into the Ednra locus using
recombinase-mediated cassette exchange (RMCE)
based on the Cre-lox system. Using this system,
we have demonstrated that the dorsoventral axis
patterning of pharyngeal arches is regulated by the
ETA-receptor-selective, Gq/G11-dependent signaling,
while the formation of the distal pharyngeal regionis under the control of a Gq/G11-independent
signaling.
We also identified Calpain6 as adownstream molecule of the ET-1 pathway and its
biological function in cytoskeletal organization andcell motility. We further identified TAZ as a protein

15that binds to and coactivates Pax3, a key
transcription factor in neural crest development andits role in the organogenesis of the kidney and lungas revealed by gene knockout.
(2) Preimplantation development and epigenetics
To further understand the mechanisms of celldifferentiation, we are studying how the DNA
methylation status is controlled in preimplantation
development and how reprogramming occurs after
nuclear transfer. We identified the somatic type of
DNA methyltransferase 1 as an enzyme responsible
for maintenance methylation in preimplantation
development.
(3) Angiogenesis
We found that Id1 confers in vivo angiogenic
property to human vascular endothelial cells via
angiopoietin-1 upregulation, which may give a clue
to novel strategy for therapeutic angiogenesis. We
also found that the function of Id1 is controlled byprotein kinase A through nucleoplaasmic shuttling.
2. Mouse Genetics
Collaborative works as follows are going on byusing gene manipulation approach in mice.
(1) Physiological roles of vasoactive peptides(2) Pathophysiological roles of defensin(3) Developmental roles of non-coding RNA

References(1) Nishiyama, K., Takaji, K., Uchijima, Y., Kurihara,Y., Asano, T., Yoshimura, M., Ogawa, H. andKurihara, H. Protein kinase A-regulated
nucleocytoplasmic shuttling of Id1 during
angiogenesis. J. Biol. Chem. 2007; 282: 1720017209.
(2) Tonami, K., Kurihara, Y., Aburatani, H.,
Uchijima, Y., Asano, T. and Kurihara, H. Calpain
6 is involved in microtubule stabilization andcytoskeletal organization. Mol. Cell. Biol. 2007;
27: 2548-2561.
(3) Yamaguchi, Y., Nagase, T., Tomita, T., Nakamura,K., Fukuhara, S., Amano, T., Yamamoto, H., Ide,
Y., Suzuki, M., Teramoto, S., Asano, T.. Kangawa,
K., Nakagata, N., Ouchi, Y. and Kurihara, H.
ß-Defensin overexpression induces progressive
muscle degeneration in mice. Am. J. Physiol. Cell
Physiol. 2007; 292: C2141-C2149(4) Vieux-Rochas, M., Coen, L., Sato, T., Kurihara,Y., Gitton, Y., Barbieri, O., Le Blay, K., Merlo, G.,
Ekker, M., Kurihara, H., Janvier, P. and Levi, G.
Molecular dynamics of retinoic acid-induced
craniofacial malformations: implications for theorigin of gnathostome jaws. PLoS ONE 2007; 2:
e510.
(5) Yamamoto, H., Nagase, T., Shindo, T., Teramoto,S., Aoki-Nagase, T., Yamaguchi, Y., Hanaoka, Y.,
Kurihara, H. and Ouchi, Y. Adrenomedullin
insufficiency increases allergen induced airway
hyperresponsiveness in mice. J. Appl. Physiol.
2007; 102: 2361-2368.
(6) Aoki-Nagase, T., Nagase, T., Oh-Hashi, Y.,
Kurihara, Y., Yamaguchi, Y., Yamamoto, H.,
Nagata, T., Kurihara, H. and Ouchi, Y. (2007).
Calcitonin gene-related peptide mediates acidinduced lung injury in mice. Respirology 12,807-813.
(7) Harada, N., Okajima, K., Arai, M., Kurihara, H.
and Nakagata, N. Administration of capsaicin andisoflavone promotes hair growth by increasing
insulin-like growth factor-I production in miceand in humans with alopecia. Growth Horm. IGF
Res. 2007; 17: 408-415.
(8) Harada, N., Okajima, K., Kurihara, H. andNakagata, N. Stimulation of sensory neurons bycapsaicin increases tissue levels of IGF-I, thereby
reducing reperfusion-induced apoptosis in mice.
Neuropharmacology 2007; 52: 1303-1311.
(9) Hattori, K., Nakamura, K., Hisatomi, Y.,
Matsumoto, S., Suzuki, M., Harvey, R. P.,
Kurihara, H., Hattori, S., Yamamoto, T.,
Michalak, M. and Endo, F. Arrhythmia inducedby spatiotemporal overexpression of calreticulinin the heart. Mol. Genet. Metab. 2007; 91:
285-293.
(10) Ono, H., Sakoda, H., Fujishiro, M., Anai, M.,
Kushiyama, A., Fukushima, Y., Katagiri, H.,
Ogihara, T., Oka, Y., Kamata, H., Horike, N.,
Uchijima, Y., Kurihara, H. and Asano, T.
Carboxyl-terminal modulator protein (CTMP)
induces Akt phosphorylation and activation,
thereby enhancing anti-apoptotic, glycogensynthetic and glucose uptake pathways. Am. J.
Physiol. Cell Physiol. 2007; 293: C1576-C1585.
(11) Seyama, Y. and Uchijima, Y. Novel function of

16

lipids as a pheromone from the Harderian glandof golden hamster. Proc. Jpn. Acad. Ser. B-83,
77-96.
(12) Sato, T., Kawamura, Y., Asai, R., Amano, T.,
Uchijima, Y., Dettlaff-Swiercz, D.A., Offermanns,
S., Kurihara, Y. and Kurihara, H. Recombinasemediated cassette exchange revealed the selective
use of Gq/G11-dependent and -independent
endothelin-1/endothelin type-A receptor signaling
in pharyngeal arch development. Development
2008; 135: 755-765.
(13) Kurihara, Y., Kawamura, Y., Uchijima, Y., Amano,T., Kobayashi, H., Asano, T. and Kurihara, H.
Maintenance of genomic methylation patterns
during preimplantation development requires thesomatic form of DNA methyltransferase 1. Dev.
Biol. 2008; 313: 335-346.
(14) Makita, R., Uchijima, Y., Nishiyama, K., Amano,T., Chen, Q., Takeuchi, T., Mitani, A., Nagase, T.,
Yatomi, Y., Aburatani, H., Nakagawa, O., Small,
E. V., Cobo-Stark, P., Igarashi, P, Murakami, M.,
Tominaga, J., Sato, T., Asano, T., Kurihara, Y. andKurihara, H. Multiple renal cysts, urinary
concentration
defects,andpulmonaryemphysematous changes in mice lacking TAZ.
Am. J. Physiol. Renal Physiol. 2008: 294;
F542-F553.
(15) Fujio, J., Kushiyama, A., Sakoda, H., Fujishiro,
M., Ogihara, T., Fukushima, Y., Anai, M., Horike,N., Kamata, H., Uchijima, Y., Kurihara, H. andAsano, T. Regulation of gut-derived resistin-likemolecule beta expression by nutrients. Diabetes
Res. Clin. Pract. 2008; 79: 2-10.
(16) Ohno, T., Hattori, Y., Komine, R., Ae, T.,
Mizuguchi, S., Arai, K., Saeki, T., Suzuki, T.,
Hosono, K., Hayashi, I., Oh-hashi, Y., Kurihara,Y., Kurihara, H., Amagase, K., Okabe, S.,
Saigenji, K., Majima, M. Roles of calcitonin
gene-related peptide in maintenance of gastricmucosal integrity and in enhancement of ulcer
healing and angiogenesis. Gastroenterology
2008; 134; 215-225.
(17) Koketsu, Y., Sakoda, H., Fujishiro, M.,
Kushiyama, A., Fukushima, Y., Ono, H., Anai, M.,
Kikuchi, T., Fukuda, T., Kamata, H., Horike, N.,
Uchijima, Y., Kurihara, H. and Asano, T. Hepatic
overexpression of a dominant negative form ofRaptor enhances Akt phosphorylation andrestores insulin resistance in K/KAy mice. Am. J.
Physiol. Endocrinol. Metab. 2008; 294: E719E725.
(18) Harada, N., Okajima, K., Narimatsu, N., Kurihara,
H. and Nakagata, N. Effect of topical applicationof raspberry ketone on dermal production of
insulin-like growth factor-I in mice and on hair
growth and skin elasticity in humans. GrowthHorm. IGF Res. 2008; 18: 335-344.
(19) Harada, N., Okajima, K., Kurihara, H. andNakagata, N. Antithrombin prevents reperfusioninduced hepatic apoptosis by enhancing
insulinlike growth factor-I production in mice.
Crit. Care Med. 2008; 36: 971-974.
(20) Toda, M., Suzuki, T., Hosono, K., Kurihara, Y.,
Kurihara, H., Hayashi, I., Kitasato, H., Hoka, S.
and Majima M. Roles of calcitonin gene-related
peptide in facilitation of wound healing andangiogenesis. Biomed. Pharmacother. 2008; 62:352-359.

Functional Biology
1. Physiology

18

Department of Integrative
Physiology
Professor
Yasushi Miyashita, Ph.D.

Associate Professor
Seiki Konishi, M.D., Ph.D.

Research Associate
Tetsuya Fukushima, M.D., Ph.D.,

Toshiyuki Hirabayashi, Ph.D.,

Masaki Takeda, Ph.D.

Homepage

http://www.physiol.m.u-tokyo.ac.jp

Introduction
This laboratory was initially established in 1877 as
The First Department of Physiology, and reorganizedin 1997 as Laboratory of Integrative Physiology in the
Department of Physiology. Our laboratory cooperates
with other laboratories in the Department of
Physiology, that is, Laboratory of Molecular/Cellular
Physiology and Laboratory of Neurophysiology, inteaching activities for undergraduate courses and thenursing school. The fields in which our laboratory
specializes span the entire spectrum of animalfunctions of physiology, including general physiology,
sensory physiology, endocrinology, neurophysiology,
higher nervous functions and cognitive neurosciences.

Teaching activities
The staff members as well as experts from otheruniversities (Drs. A. Nambu, K. Honma and I.
Hasegawa) take part in giving lectures and laboratory
courses to the undergraduate students of the Medical
School. The lectures are aimed at providing a clear
understanding of the hierarchical functionalorganizations of living systems. The curriculum is
updated every year. For example, a newelectrocardiogram experiment in humans wasintroduced to the laboratory course, in which students
learned human physiology of electrocardiogram, its
practical procedure in clinical settings and its cellularphysiological origins. This practice gained popularity
and interest among students. We accept Free-Quarter
students every year. Usually these students' activities
are not limited to one Quarter, and 2 students (M3 andM4) continued to enjoy their researches from 2007
through 2008. Some of these students completed theirown projects, and gave oral presentations ininternational meetings and published original papers
in top-rank international journals. It is not rare thatstudents who enjoyed his/her Free-Quarter decided to
get into the Ph-D. course after the completion of the
2-year clinical training and started to study
neurophysiology in our laboratory. Furthermore、we
accepted a Ph-D.-M.D course student who enjoyed his
Free-Quarter and decided to get into the Ph-D.-M.D
course. Thus the Free-Quarter system has proved toprovide an excellent basis for bringing up M.D.
researchers for future Japanese basic medicine.
To facilitate communication among research groups
in our laboratory, a weekly conference is held for
discussing current research activities. We also have amonthly joint seminar with Department ofPharmacology, Department of Psychology in Facultyof Letters and Department of Biophysics in Faculty of19

Science. As part of a teaching activity for the graduate
students, we have another weekly English seminar, inwhich the graduate students learn how to givepresentations and hold discussions and debates inEnglish.

Research activities
Most of our research is focused on the higher brain
function of the mammalian central nervous system :(1) higher functions of vision and memory, (2)non-invasive measurements of human brain activitiesand (3) non-invasive functional measurements ofmonkey brain activities that links above (1) and (2).
The results of such research have been published infirst-rate journals, as listed in the reference. A briefsummary of each topic follows:(1) In the primate, visual information processing in
the cerebral cortex proceeds along the neuralpathway originating from the primary visual areain the occipital lobe to the anterior part of thetemporal association cortex. Our laboratory
discovered several classes of important
memory-neurons electrophysiologically in thetemporal lobe of the monkey. In theinferotemporal cortex, which we propose to be thestorehouse of visual long-term memory, we
discovered a group of neurons which encode
object-object association. We found that the
backward signal from the medial temporal lobe to
the inferotemporal cortex mediates formation of
the mnemonic neural circuits for the association.
Recently we also found that the top-down signal
from the prefrontal cortex to the inferotemporal
cortex plays a central role in retrieval of themnemonic associative neural code stored in theinferotemporal cortex. Since association is a basic
mechanism for constructing the humanmemory-based knowledge system, our finding
provides a key to understanding the basicorganization of the primate cerebral cortex.
(2) The recent explosion of new technologies fornoninvasive measurements of human brain
activities, especially of functional magnetic
resonance imaging (fMRI), allows us to observe
parallel activation of functional brain modules inhumans engaged in various mental tasks. We

contributed to development of a new method
called “event-related fMRI”, which enables toutilize the time resolution of fMRI. We applied
this “event-related fMRI” method to the analysis
of human cognition, and identified several
functional centers in the human prefrontal cortex
in cognitive tasks such as the Wisconsin Card
Sorting Task.
(3) Recently, we successfully applied fMRI method tomacaque monkeys performing highly intelligent
cognitive tasks. These fMRI studies were done inultra-high field MRI scanner at 4.7 Tesla,
successfully providing much higher spatial
resolution than in a conventional clinical MRI
scanner. This approach provides us a new
approach that bridges a gap between the humannon-invasive studies and the various invasive
studies in animals, including intra-corticalelectrical microstimulation and reversiblefunctional inactivation with GABA agonist drug
injections.

References
1. Matsui, T., Koyano, K.W., Koyama, M., Nakahara,K., Takeda, M., Ohashi, Y., Naya, Y. andMiyashita, Y. : MRI-based localization ofelectrophysiological recording sites within the
cerebral cortex at single voxel accuracy. Nature
methods 4, 161-168, 2007.
2. Chikazoe, J., Konishi, S., Asari, T., Jimura, K.
and Miyashita, Y.: Activation of right inferior
frontal gyrus during response inhibition acrossresponse modalities. J. Cogn. Neurosci. 19, 6980, 2007.
3. Nakahara, K., Adachi, Y., Osada, T. andMiyashita Y : Exploring the neural basis ofcognition: multi-modal links between humanfMRI and macaque neurophysiology. Trend Cogn.
Science 11, 84-92, 2007.
4. Botvinick M. and Watanabe T.: Fromnumerosity to ordinal rank: a gain-field model ofserial order representation in cortical working
memory. J. Neurosci. 27, 8636-8642, 2007.
5. Watanabe, T., Yagishita, S. and Kikyo H. :Memory of music: roles of right hippocampus andleft inferior frontal gyrus. NeuroImage 39,20

483-491, 2008.
6. Asari, T., Konishi, S., Jimura, K., Chikazoe, J.,
Nakamura, N. and Miyashita, Y. : Right
temporopolar activation associated with uniqueperception. NeuroImage, 41, 145-152, 2008.
7. Osada, T., Adachi, Y., Kimura, H.M. andMiyashita, Y. : Toward understanding of thecortical network underlying associative memory.
Phil. Trans. Royal Society B, 363, 2187-2199,
2008.
8. Konishi, S., Morimoto, H., Jimura, K., Asari, T.,
Chikazoe, J., Yamashita, K-I., Hirose, S. andMiyashita, Y. : Differential superior prefrontal
activity on initial versus subsequent shifts in naïve
subjects. NeuroImage 41, 575-580, 2008.
9. Morimoto, H.M., Hirose, S., Chikazoe, J., Jimura,K., Asari, T., Yamashita, K., Miyashita. Y. andKonishi, S. : On verbal/nonverbal modality
dependence of left and right inferior prefrontal
activation during performance flanker interferencetask. J. Cogn. Neurosci. in press, 2008.
10. Chikazoe, J., Jimura. K., Asari, T., Yamashita, K.,
Morimoto, H., Hirose, S., Miyashita, Y. andKonishi, S. : Functional dissociation in rightinferior frontal cortex during performance of
go/no-go task. Cereb. Cortex, in press, 2008.

21

Department of Cellular andMolecular Physiology
Professor
Kensaku Mori, Ph.D.

Lecturer
Masahiro Yamaguchi, M.D., Ph.D.

Research Associate
Hiroshi Nagao, Ph.D.,

Homepage

Hideki Kashiwadani, Ph.D.

http:// morilab.m.u-tokyo.ac.jp/

Introduction

Research

The Department of Cellular and Molecular
Physiology succeeded the former ‘Second Departmentof Physiology’, and belong to the Department of
Physiology. We participate in the teaching ofphysiology at undergraduate school and graduate
school.
The present members include the above stuffs, 1
visiting scientist, 11 graduate students and 2 secretary
stuffs.

Using multidisciplinary approaches including
electrophysiology, optical imaging, molecular andcellular biology, and molecular genetics, we at the
Department of Cellular and Molecular Physiology aim
at understanding neuronal mechanism for theperception of sensory inputs and for the emotional
states induced by the sensory inputs. Our recent focus
includes olfactory corticalmechanisms
forrecognizing food odors and for judging their edibility.
We have been investigating also the neuronalmechanisms for the incorporation of adult-borninterneurons into the pre-existing neuronal circuit in
the olfactory bulb, and the contact-mediatedinteractions between neurons and immune cells.
Currently we are focusing on the following three
topics.

Education
The department provides lectures and practice inphysiology for undergraduate students. We teachelectrophysiological methods and cell and molecularphysiology methods for free quarter students. The
department provides also lectures and instructions forlaboratory research for graduate and undergraduate
students in the fields of sensory physiology andmolecular and cellular neurobiology. Seminars,
progress reports, and journal club for graduate
students are routinely provided. Monthly joint
seminars (Functional Biology Seminars and RIKEN
BSI Group Seminars) are also provided for graduate
students.

(1) Analysis of the functional neuronal circuits in thecentral olfactory system.
Based on the knowledge of the ‘odorant
receptor maps’ in the olfactory bulb, we are
studying the manner of olfactory information
processing in the olfactory cortex and higher
olfactory association regions. We found that
individual neurons in the anterior piriform cortex
integrate signals from distinct categories of

22food-born odorants. These results suggest that theolfactory cortical neurons detect the odorantcategory profile of foods in order to distinguishdistinct food odors.
Individual neurons in the anterior olfactory
nucleus also showed odorant category profile
selectivity. Furthermore, for individual corticalneurons odorant category profile selectivity ofleft-nasal input was nearly equivalent with that of
the right-nasal input.
We found also that neuronal circuit in theolfactory bulb can actively prolong the odor
induced spike responses and thus keep the specificodor information for more than tens of seconds
after the cessation of odor stimulus. In addition,
we noted behavioral state-dependent change of thedendrodendritic synaptic inhibition in theolfactory bulb.
In addition, we found functional modularizationin the odor maps of the olfactory bulb.
(2) Cellular and molecular mechanisms for thecontact-mediated interactions between neurons
and immune cells in physiological andpathological conditions.
We are currently focusing on telecncephalonspecific cell adhesion molecule, telencephalin. We
are investigating the telencephalin-mediatedsignals between neurons and immune cells
especially microglia during recovery from theneuronal damage.
(3) Incorporation of adult-born interneurons in the
pre-existing neuronal circuit in the olfactory bulb.
The olfactory system is chosen as a model
system with which to study the recruitment of
newly-generated neurons in the adult neuronal
circuit. We are studying cellular and molecularmechanisms that segregate the fate of newneurons between successful incorporation andapoptotic elimination into/from the neuronal
circuit. Recently we noted the feeding-related
time window of fate decision of newly-generated
granule cells in the olfactory bulb, and current
focus of our study includes the reorganization of
the olfactory bulb circuit during and after theeating time.

Publications (2007)
1. Kobayakawa K, Kobayakawa R, Matsumoto H,
Oka Y, Imai T, Ikawa M, Okabe M, Ikeda T,
Itohara S, Kikusui T, Mori K, Sakano H. Innate
versus learned odor processing in the mouseolfactory bulb. Nature 450: 503-508 (2007)
2. Mori K. Olfaction-Vertebrates: Olfactory Bulb
Mapping. New Encyclopedia of Neuroscience(2007) Ed. By Squire, L.
3. Yoshida I, Mori K. Odorant category profile
selectivity of olfactory cortex neurons. J Neurosci.
27: 9105-9114 (2007)
4. Furutani Y, Matsuno H, Kawasaki M, Mori K,
Yoshihara Y. Interaction between telencephalin
and ERM family proteins mediates dendritic
filopodia formation. J Neurosci. 27: 8866-8876(2007)
5. Hasegawa S, Yamaguchi M, Nagao H, Mishina M,
Mori K. Enhanced cell-to-cell contacts between
activated microglia and pyramidal cell dendrites
following kainic acid-induced neurotoxicity in the
hippocampus. J Neuroimmunol. 186: 75-85(2007)
6. Mitsui M, Saito M, Mori K, Yoshihara Y. A
transcriptional
enhancerthatdirects
telencephalon-specific transgene expression inmouse brain. Cereb Cortex. 17: 522-530 (2007)

23

Department of Neurophysiology
Professor
Masanobu Kano, M.D., Ph.D.

Lecturer
Tetsuhiro Tsujimoto, M.D., Ph.D.

Associate
Kazuo Kitamura, Ph.D.

Homepage

http://plaza.umin.ac.jp/~neurophy/

Introduction and Organization
This laboratory was founded in 1953 as Departmentof Neurophysiology, Institute for Brain Research. In
1996, it was integrated into Graduate School of
Medicine. We teach neurophysiology for medical
undergraduates and for students in the Master andPh.D. courses. Our research aims at elucidating
cellular and molecular mechanisms underlying
regulation of synaptic transmission and postnatal
development of neuronal circuits.

Teaching activities
We
teachneurophysiology
formedicalundergraduates in lectures and practical courses.
Lectures are designed for students to learn basic
mechanisms underlying the generation of electricalsignals, synaptic transmission and their regulations in
the nervous system. Students also learn how functional
neural circuits in the brain are formed and matured
during postnatal development. In the practical courses,
students perform two types of classical experiments ofneurophysiology. First, students make intracellular
recording from frog skeletal muscle fibers andexamine the endplate potential for understanding basic
properties of synaptic transmission. Second, students
record electromyogram (EMG) from humangastrocnemius muscles and learn how the stretch
reflex works.

We accept Free-Quarter students. Students areencouraged to experience patch-clamp recordings
from neurons either in brain slices or in dissociatedculture, or to experience recordings of neuronal
activities from living animals.
For the training of Master and Ph.D. course students,
we have a weekly conference for discussing current
research activities. A laboratory member summarizes
his/her recent experimental data or presents papers
closely related to his/her research. Moreover, formutual communication between the laboratories withsimilar interests in neuroscience, we have a weekly
joint seminar with Department of Cellular
Neurobiology and Division of Structural Physiology.

Research activities
The brain consists of neuronal circuits in which
neurons are connected through numerous synapses. To
understand the brain function, it is necessary to
elucidate mechanisms of synaptic transmission andthose underlying changes in synapses related todevelopment, learning and memory (synaptic
plasticity). For this purpose, we use various
methodologicalapproaches
includingelectrophysiology, pharmacology, morphology, genetic
engineering of mouse and optical imaging offunctional molecules in living neurons. We
particularly focus on observing neuronal activities inreal time in intact neurons. We use whole-cell patch

24

clamp recording, calcium imaging, two-photon
imaging and their combinations in various
preparations (cultured neurons, brain slices and intact
animals) and investigate molecular mechanisms ofsynaptic transmission and plasticity.
The main subjects of our research are as follows(1) Refinement of synaptic organization during
cerebellar development:
In early postnatal days, all Purkinje cells in the
cerebellum are innervated by multiple climbing fibers.
These surplus climbing fibers are eliminated eventuallywith the progress of postnatal development, and mostPurkinje cells become innervated by single climbing
fibers by the end of the third postnatal week in mice.
We investigate the mechanisms how single climbing
fibers are selected and how the surplus climbing fibers
are eliminated.
(2) Retrograde synaptic modulation mediated byendogenous cannabinoids:
We reported in 2001 that endogenous cannabinoids
are released from postsynaptic neurons in an activitydependent manner, act retrogradely onto presynaptic
cannabinoid receptors and suppress transmitter release.
Since then, we have been investigating the mechanismsof this retrograde modulation. We are also interested in
elucidating the physiological significance of thisphenomenon including learning and memory.
(3) Synaptic integration in intact animals:
To understand the physiological function ofsynapses in vivo, we analyze synaptic transmission andintegration in single neurons in the intact brain by using
in vivo two-photon imaging and whole-cell recording.
We also develop new methods to implement theseexperiments.

References(1) Kitamura, K., Judkewitz, B., Kano, M., Denk, W. &Hausser, M.: Targeted patch-clamp recordings andsingle-cell electroporation of unlabeled neurons in vivo.
Nat. Methods 5, 61-67, 2008.
(2) Hashimotodani, Y., Ohno-Shosaku, T., Maejima, T.,
Fukami, K. & Kano, M.: Pharmacological evidence forthe involvement of diacylglycerol lipase in
depolarization-induced
endocanabinoid
release.
Neuropharmacology 54, 58-67, 2008.

(3) Hashimotodani, Y., Ohno-Shosaku, T., and Kano, M.:
Ca(2+)-assisted receptor-driven endocannabinoid
release: mechanisms that associate presynaptic andpostsynaptic activities. Curr Opin Neurobiol 17,
360-365, 2007.

(4) Hashimotodani, Y., Ohno-Shosaku, T., and Kano, M. :Endocannabinoids and synaptic function in the CNS.
Neuroscientist 13, 127-137, 2007.

(5) Hashimotodani, Y., Ohno-Shosaku, T., and Kano, M. :Presynaptic
monoacylglycerol
lipaseactivity
determines basal endocannabinoid tone andterminates retrograde endocannabinoid signaling in
the hippocampus. J Neurosci 27, 1211-1219, 2007.

(6) Hashimotodani, Y., Ohno-Shosaku, T., Watanabe, M.,
and Kano, M. : Roles of phospholipase Cβ andNMDA
receptorin
activity-dependentendocannabinoid release. J Physiol 584, 373-380,
2007.

(7) Kakizawa, S., Kishimoto, Y., Hashimoto, K.,
Miyazaki, T., Furutani, K., Shimizu, H., Fukaya, M.,
Nishi, M., Sakagami, H., Ikeda, A., et al. :Junctophilin-mediated channel crosstalk essential for
cerebellar synaptic plasticity. Embo J 26, 1924-1933,
2007.

(8) Kamikubo, Y., Tabata, T., Kakizawa, S., Kawakami,D., Watanabe, M., Ogura, A., Iino, M., and Kano, M. :Postsynaptic GABAB receptor signalling enhances
LTD in mouse cerebellar Purkinje cells. J Physiol 585,
549-563, 2007.

(9) Kina, S., Tezuka, T., Kusakawa, S., Kishimoto, Y.,
Kakizawa, S., Hashimoto, K., Ohsugi, M., Kiyama, Y.,
Horai, R., Sudo, K., et al. : Involvement of proteintyrosine phosphatase PTPMEG in motor learning andcerebellar long-term depression. Eur J Neurosci 26,
2269-2278, 2007.

(10)Nakao, H., Nakao, K., Kano, M., and Aiba, A. :Metabotropic glutamate receptor subtype-1 isessential for motor coordination in the adult
cerebellum. Neurosci Res 57, 538-543, 2007.

(11)Narushima, M., Uchigashima, M., Fukaya, M., Matsui,M., Manabe, T., Hashimoto, K., Watanabe, M., andKano, M. : Tonic enhancement of endocannabinoidmediated retrograde suppression of inhibition bycholinergic interneuron activity in the striatum. J
Neurosci 27, 496-506, 2007.

(12)Ohkawa, N., Hashimoto, K., Hino, T., Migishima, R.,
Yokoyama, M., Kano, M., and Inokuchi, K. : Motor

25

discoordination of transgenic mice overexpressing a
microtubule destabilizer, stathmin, specifically in
Purkinje cells. Neurosci Res 59, 93-100, 2007.

(13)Ohno-Shosaku, T., Hashimotodani, Y., Ano, M.,
Takeda, S., Tsubokawa, H., and Kano, M. :Endocannabinoid signalling triggered by NMDA
receptor-mediated calcium entry into rat hippocampal
neurons. J Physiol 584, 407-418, 2007.

(14)Tabata, T., Kawakami, D., Hashimoto, K., Kassai, H.,
Yoshida, T., Hashimotodani, Y., Fredholm, B. B.,
Sekino, Y., Aiba, A., and Kano, M. : G proteinindependent neuromodulatory action of adenosine on
metabotropic glutamate signalling in mouse cerebellar
Purkinje cells. J Physiol 581, 693-708, 2007.

(15)Takagishi, Y., Hashimoto, K., Kayahara, T., Watanabe,
M., Otsuka, H., Mizoguchi, A., Kano, M., and Murata,
Y. : Diminished climbing fiber innervation of Purkinjecells in the cerebellum of myosin Va mutant mice andrats. Dev Neurobiol 67, 909-923, 2007.

(16)Uchigashima, M., Narushima, M., Fukaya, M.,
Katona, I., Kano, M., and Watanabe, M. : Subcellulararrangementofmoleculesfor2-arachidonoyl-glycerol-mediatedretrogradesignaling and its physiological contribution tosynaptic modulation in the striatum. J Neurosci 27,
3663-3676, 2007.
(17) Wada, N., Kishimoto, Y., Watanabe, D., Kano, M.,
Hirano, T., Funabiki, K., and Nakanishi, S. :Conditioned eyeblink learning is formed and stored
without cerebellar granule cell transmission. Proc
Natl Acad Sci U S A 104, 16690-16695, 2007.

Functional Biology
2. Pharmacology

27

Department of Cellular
and Molecular Pharmacology
Professor
Masamitsu Iino, M.D., Ph.D.

Research Associate
Toshiko Yamazawa, Ph. D.,

Sho Kakizawa, Ph. D.

Yohei Okubo, Ph. D.

Homepage

http://calcium.cmp.m.u-tokyo.ac.jp/index_e.html

Introduction and Organization
Our department was founded in 1885 andcollaborates with the Department of Molecular
Neurobiology and Pharmacology in the education ofundergraduate medical students.

Teaching activities
Pharmacology lectures and laboratory courses forthe medical students are given by the staff members ofboth Departments of Pharmacology. We also invite
seven outside expert lecturers to cover rapidly
developing fields in pharmacology and related
medical sciences. The laboratory courses include bothtraditional and advanced pharmacological experiments.
A new intensive laboratory course for medical
students started in the year 2001, and we participatedin the program. We also give lectures for graduate
students including master course students and Ph.D.
candidates.

Research activities
Our department has a strong background in the fieldof Ca2+ signalling. Ca2+ signal is now known tofunction as a molecular switch in almost every
important cell function including muscle contraction,
exocytosis, cell proliferation, immune responses andregulation of synaptic functions. This is the reason
why this field is expanding rapidly and our research
activity is now diversifying. We are particularlyinterested in Ca2+ signalling in the central nervous
system.
1) Spatiotemporal regulation of Ca2+ signals
Ca2+ signals show very dynamic, temporal andspatial changes. This property allows the Ca2+
signal to be an extremely versatile cellular switch
regulating diverse cell functions. One of the mostnotable spatiotemporal patterns of Ca2+ signals is
the oscillatory change in intracellular Ca2+
concentration ([Ca2+]i), or Ca2+ oscillation. Many
cellular functions are regulated by the Ca2+
oscillation frequency. However, fundamental
questions remain. How and why does [Ca2+]i
oscillate? We have addressed these questions. First,
we studied inositol 1,4,5-trisphosphate (IP3)induced Ca2+ release mechanism, which is one of
the most important Ca2+ mobilizing mechanisms inmany types of cell. We showed that the activity of
the IP3 receptor (IP3R) is dependent on thecytoplasmic Ca2+ concentration. Therefore, Ca2+
release via the IP3R appears to be under the
feedback control of mobilized Ca2+. We identified
the Ca2+ sensor region of the IP3R and showed thatthe positive feedback regulation of IP3R via theCa2+ sensor of IP3R indeed plays an essential role28

in regulating the Ca2+ signal dynamics includingCa2+ oscillation.
In order to further study the mechanism
underlying Ca2+ oscillations, we visualized theCa2+ concentrations within the intracellularorganelles (the endoplasmic reticulum andmitochondria) during Ca2+ oscillations. We foundthat Ca2+ shuttles between these intracellularorganelles in phase with cytoplasmic Ca2+
oscillations. Our results also indicated that theCa2+ shuttling determines the Ca2+ oscillation
frequency. Thus, we have shown that mitochondria
play an important role in the generation of Ca2+
oscillation. These results provide a clue to themechanism of Ca2+ oscillation.
Why then does [Ca2+]i have to oscillate?
Transcription by the nuclear factor of activated T
cells (NFAT) is one of the important cellularfunctions that are regulated by the Ca2+ oscillation
frequency. NFAT is dephosphorylated by
Ca2+-dependent phosphatase, calcineurin, andtranslocates from the cytoplasm to the nucleus toinitiate transcription. We analyzed the kinetics ofthe dephosphorylation and translocation of NFAT,
and found that the dephosphorylated form of
NFAT functions as a working memory of transient
increases in [Ca2+]i. With increasing frequency ofoscillation,dephosphorylated
NFAT
Ca2+
accumulates in the cytoplasm to enhance its
nuclear translocation. This is the molecular basisof the mechanism that decodes the Ca2+ oscillation
frequency. We also showed that Ca2+ oscillation ismore cost-effective in regulating cell functions
than a continuous increase in Ca2+. These studies
provide us with an insight into the secrets of Ca2+
signalling.
2) Imaging of signalling molecules
Our study on Ca2+ signalling made us realize theimportance of visualization of signalling
molecules within living cells. Thus, our laboratory
has been involved in the generation of new
indicators of signalling molecules upstream anddownstream Ca2+ signals. We have succeeded in
imaging IP3 signalling in various cells including
intact neurons within cerebellar slice preparations.
We also developed an indicator to detect thephosphorylation of myosin regulatory light chain.
The indicator allowed us to image phosphorylation
state of myosin light chain in living cells. Recently,
we generated a nitric oxide (NO) indicator basedon the heme-binding domain of soluble guanylyl
cyclase. This indicator was successfully used in
cerebellar slice preparations to image NO signals
in response to parallel fiber (PF) stimulation. We
found that the NO signal intensity decreases
steeply with distance form the activated synapse
andgenerate
synapse-specificlong-term
potentiation (LTP) of PF-Purkinje cell synapses.
We also showed that the NO signal intensity
depends biphasically on the frequency of PF
stimulation. Importantly, the LTP depends
similarly on the frequency of PF stimulation. Thus,
our NO indicator provided us with valuable
information regarding the role of NO signals in thecentral nervous system.
Glutamate is the most important excitatory
synaptic transmitter in the brain. We havegenerated a glutamate indicator based on theglutamate-binding domain of the AMPA-typeglutamate receptor.
This will enable us tovisualize glutamate release from activatedsynapses of neurons in culture or in acute brainslices.
3) Exploration of new cellular functions that are
regulated by Ca2+ signals
Although many important cell functions havebeen found to be regulated by Ca2+ signals, not all
the Ca2+-dependent cell functions have been
identified. We are now searching for new cellfunctions that are regulated by Ca2+ signals.
Cells communicate with each other to form
organized structures by cell-cell adhesion andcell-cell repulsion, but it remains to be clarified
how cell-cell contact information is converted to
intracellular signals. We found that cells in contact
with neighbouring cells generate local transient
intracellular Ca2+ signals (Ca2+ lightning). Ca2+
lightning was exclusively observed near cell-cell
contact regions and was not observed in the central
regions of cells, nor was it found in solitary cells
that are not in contact with other cells. We also
show that Ca2+ lightning is capable of regulating

29

cell-cell repulsion in a Ca2+-dependent manner.
These results demonstrated that cell-cell contact
information may be transmitted by a new form of
Ca2+ signal, Ca2+ lightning, to regulate
intracellular events.
We also clarified a new synaptic maintenancemechanism in the parallel fiber→Purkinje cell
synapse in the cerebellum. We have found that
there is a retrograde signaling mechanism
downstreamofmetabotropic
glutamate
receptor-mediated IP3-Ca2+ signaling in Purkinjecells, which then generates BDNF (brain-derived
neurotrophic factor) that maintains the glutamaterelease function of the presynaptic terminal ofparallel fibers. This presents a new form ofactivity-dependent
synaptic
maintenancemechanism.
We have studied the role of IP3-Ca2+ signaling
in astrocytes (the most abundant glial cells) andfound that it regulates the expression of moleculeson the surface of astrocytes that regulate thegrowth of neurons. Our results indicate that
cadherin is involved in the regulation of neural
growth. There seems to be more molecules are
involved in this mechanism, and we searching forthe new molecular mechanisms.

Regulation of neurite growth by spontaneous Ca2+
oscillations in astrocytes.

J. Neurosci. 27, 8957-

8966, 2007.
5. Kina, S., Tezuka, T., Kusakawa, S., Kishimoto, Y.,
Kakizawa, S., Hashimoto, K., Ohsugi, M.,
Kiyama, Y., Horai, R., Sudo, K., Kakuta, S.,
Iwakura, Y., Iino, M., Kano, M., Manabe, T. andYamamoto, T.

Involvement of protein-tyrosine

phosphatase PTPMEG in motor learning andcerebellar

long-term

depression.

Eur.

J.

Neurosci. 26, 2269-2278, 2007.
6. Ikeda, A., Miyazaki, T., Kakizawa, S., Okuno, Y.,
Tsuchiya, S., Myomoto, A., Saito, S.Y., Yamamoto,T., Yamazaki, T., Iino, M., Tsujimoto, G.,
Watanabe, M. and Takeshima, H.

Abnormalfeatures in mutant cerebellar Purkinje cells
lacking junctophilins. Biochem. Biophys. Res.
Commun. 363, 835-839, 2007.
7.

Kamikubo, Y., Tabata, T., Kakizawa, S., Kawakami,D., Watanabe, M., Ogura, A., Iino, M. and Kano, M.
Postsynaptic GABAB receptor signalling enhances
LTD in mouse cerebellar Purkinje cells. J. Physiol.
26, 2269-2278, 2007.

8.

Uemura, T., Kakizawa, S., Yamasaki, M., Sakimura,K., Watanabe, M., Iino, M. and Mishina, M.

References

Regulation of long-term depression and climbing
fiber territory by glutamate receptor delta2 at

1.

Kakizawa, S., Kishimoto, Y., Hashimoto, K.,

parallel fiber synapses through its C-terminal

Miyazaki, T., Furutani, K., Shimizu, H., Fukaya, M.,domain in cerebellar Purkinje cells. J. Neurosci. 27,

Nishi, M., Sakagami, H., Ikeda, A., Kondo, H., Kano,

12096-12108, 2007.

M., Watanabe, M., Iino, M. and Takeshima, H.

9.

Yogo, T., Urano, Y., Mizushima, A., Sunahara, H.,

Junctophilin-mediated channel crosstalk essential forInoue, T., Hirose, K., Iino, M., Kikuchi, K. andcerebellar

Nagano, T.

synaptic

plasticity.

EMBO

J.

26,

1924-1923, 2007.

function through environment-sensitive switching of

2. Namiki, S., Sakamoto, H., Iinuma, S., Iino, M.
and Hirose, K. Optical glutamate sensor for
spatiotemporal analysis of synaptic transmission.
Eur. J. Neurosci. 25, 2249-2259, 2007.
3. Fujiwara, A., Kakizawa, S. and Iino, M. Inductionof

cerebellar

Selective photoinactivation of protein

long-term

depression

requiresactivation of calcineurin in Purkinje cells.
Neuropharmacology 52, 1663-1670, 2007.
4. Kanemaru, K., Okubo, Y., Hirose, K. and Iino, M.

singlet oxygen generation by photosensitizer. Proc.
Nat. Acad. Sci. U.S.A., 105, 28-32, 2008.

30

Department of
Molecular Neurobiology
Professor
Masayoshi Mishina, Ph.D.

Research Associate
Tomonori Takeuchi, Ph.D.,

Tomoyuki Yoshida, Ph.D.,

Takashi Uemura, Ph.D.,

Kazuto Nakao, Ph.D.

Homepage

http://www.pharmacol2.m.u-tokyo.ac.jp/

Teaching activities
Our Department, in collaboration with the
Department of Cellular and Molecular Pharmacology,
takes responsibility for lectures and laboratory courses
on pharmacology for the undergraduate students of theFaculty. There are some 41 lectures per year including
those given by seven invited lectures to cover
specialized and currently highlighted fields inpharmacology. We offer several laboratory courses,
and all the members of the Department participate in
the courses to provide close consultation for the
students.
For the graduate students, there are series ofseminars on molecular biology and neuroscience. We
also have research seminars to discuss and stimulate
the research activities of the graduate students in the
Department.

Research activities
Current research activities are focused on themolecular mechanism and regulation of learning andmemory. Brain function is based on highly complex
neural networks and their dynamics. The glutamate
receptor (GluR) plays a key role in brain dynamics.
We elucidated the diversity of the NMDA-type GluR
by molecular cloning and functional expression.
Ablation of the NMDA receptor GluRε1 by genetargeting resulted in the increase of thresholds for bothhippocampal LTP induction and contextual learning.
Furthermore, cerebellar Purkinje cell (PC)-specific
GluRδ2 mutant mice showed impairment of cerebellar
LTD and motor learning. These results suggest that
GluR is a key molecule of learning and memory.
Further analyses of GluRδ2 and GluRε1 mutant mice
revealed that the temporal relationship of conditioned
and unconditioned stimuli determines the neuralsubstrates of eyeblink conditioning, a simple form ofassociate learning, implying a systemic regulation oflearning and memory. Interestingly, the NMDA
receptor GluRε2 was essential for formation of thewhisker-related neuronal barrelette structure in thebrainstem trigeminal nucleus. The number of parallel
fiber (PF)-PC synapses was decreased in GluRδ2mutant mice and multiple climbing fiber innervation
was sustained. Thus, memory formation in the adultbrain and synapse refinement during development
may share common molecular mechanisms.
To investigate the molecular mechanism andregulation of learning and memory, we employed two
approaches, conditional gene targeting on the pure
C57BL/6 genetic background and neuron-specificgene manipulations in transparent zebrafish embryos.
Brain functions are the products of dynamic
interactions between multiple genes and environments.
Accordingly, there are large differences among mousestrains at the behavioral and neurobiological levels.

31

Therefore, it is crucial to manipulate genes on thesame and homogenous genetic background and then to
analyze and compare the phenotypes of various
genetically modified mice. We have established an
inducible and neuron-specific gene targeting systemon the pure C57BL/6 genetic background by
employing
Cre-progesterone
receptor
fusionrecombinase for temporal regulation of gene targetingand Flp/frt recombination system for elimination ofmarker genes. Inducible ablation of GluRδ2 in theadult cerebellum resulted in appearance of spines freefrom axon terminals and mismatching between active
zone and PSD at PF-PC synapses. We thus identified
GluRδ2 as a key molecule that regulates pre- andpostsynaptic matching and synaptic connection in theadult brain, providing evidence for the notion that
there is a common molecular mechanism underlying
synaptic plasticity and synapse formation. Among
GluRδ2-interacting molecules, we were interested in
Delphilin because of its selective expression in
cerebellar PCs. Ablation of Delphilin facilitated LTD
induction at PF-PC synapses and enhanced OKR
gain-increase adaptation without affecting any
detectable histological abnormalities. This finding
suggests that LTD induction at PF-PC synapses is a
crucial rate-limiting step for OKR gain-increase
adaptation, a simple form of motor learning. Studies
on conditional mutant mice also revealed the
involvement of striatal neurons in fear memory
formation and the novel role of hippocampal NMDA
receptors in network oscillation.
Transparent zebrafish embryos enable us tovisualize synapse formation in vivo. Using anolfactory sensory neuron-specific gene manipulation
system with effector-reporter double-cassette vectors,
we demonstrated that PKA-CREB signaling regulated
synaptic vesicle accumulation in the axon terminals
andcalcineurin-NFAT
signaling
controlled
morphological remodeling of the axon terminals
during synapse formation. Mental retardation (MR),defined as a failure to develop cognitive abilities, isthe most frequent cause of serious handicap inchildren and young adults. Nonsyndromic MR ischaracterized by reduced cognitive function without
any other clinical features, thus providing the mostdirect approach to specifically study the neurobiology
of cognition and pathogenesis of MR. The expressionof Il1rapl 1b, the zebrafish orthologue of mammalian
IL1RAPL1 responsible for a nonsyndromic form of
X-linkedMR,stimulated
synaptic
vesicleaccumulation in the axon terminal of olfactory sensory
neurons. On the other hand, the expression of Il1rapl
1b-P455H prevented the morphological remodeling ofaxon terminal from complex shape to simple ones.
These results suggest that Il1rapl 1b regulates synaptic
vesicle accumulation and morphological remodelingthrough the carboxyl-terminal domain and TIR
domain, respectively. We thus provide evidence thatmental retardation protein Il1rapl 1b plays animportant role in the axon terminal differentiation
during neuronal network formation.

References(1) Kakegawa, W., Miyzaki, T., Hirai, H., Motohashi,J., Mishina, M., Watanabe, M. and Yuzaki, M.
Ca2+ permeability of the channel pore is notessential for the δ2 glutamate receptor channel toregulate
synaptic
plasticity
and
motor
coordination. J. Physiol. 2007; 579, 729-735.
(2) Xu, L., Okuda-Ashitaka, E., Matsumura, S.,
Mabuchi, T., Okamoto, S., Sakimura, K., Mishina,
M. and Ito, S. Signal pathways coupled toactivation of neuronal nitric oxide synthase in the
spinal cord by nociceptin/orphanin FQ.
Neuropharmacology 2007; 52, 1318-1325.
(3) Aiba, A., Inokuchi, K., Ishida, Y., Itohara, S.,
Kobayashi, K., Masu, M., Mishina, M.,
Miyakawa, T., Mori, H., Nakao, K., Obata, Y.,
Sakimura, K., Shiroishi, T., Wada, K. and Yagi, Y.
Mouse liaison for integrative brain research.
Neurosci. Res. 2007; 58, 103-104.
(4) Mishina, M. and Sakimura, K. Conditional genetargeting on the pure C57BL/6 genetic
background. Neurosci. Res. 2007; 58, 105-112.
(5) Hasegawa, S., Yamaguchi, M., Nagao, H.,
Mishina, M. and Mori, K. Enhanced cell-to-cell
contacts between activated microglia andpyramidal cell dendrites following kainicacid-induced neurotoxicity in the hippocampus. J.
Neuroimmunol. 2007; 186, 75-85.
(6) Takemoto-Kimura, S., Ishihara-Ageta, N.,
Nonaka, M., Adachi-Morishima, A., Mano, T.,
Okamura, M., Fujii, H., Fuse, T., Hoshino, M.,

32

Suzuki, S., Kojima, M., Mishina, M., Okuno, H.
and Bito, H. Regulation of dendritogenesis via alipid raft-associated Ca2+/calmodulin-dependent
protein kinase CLICK-III/CaMKIγ. Neuron 2007;
54, 755-770.
(7) Xu, L., Mabuchi, T., Katano, T., Matsumura, S.,
Okuda-Ashitaka, E., Sakimura, K., Mishina, M.
and Ito, S. Nitric oxide (NO) serves as a
retrograde messenger to activate neuronal NO
synthase in the spinal cord via NMDA receptors.
Nitric Oxide 2007; 17, 18-24.
(8) Tian, L., Stefanidakis, M., Ning, L., Lint, P. V.,
Nyman-Huttunen, H., Libert, C., Itohara, S.,
Mishina, M., Rauvala, H. and Gahmberg, C. G.
Activation of NMDA receptors promotes
dendritic
spine
development
through
MMP-mediated ICAM-5 cleavage. J. Cell Biol.
2007; 178, 687-700.
(9) Uemura, T., Kakizawa, S., Yamasaki, M.,
Sakimura, K., Watanabe, M., Iino, M. andMishina, M. Regulation of long-term depression
and climbing fiber territory by glutamate receptor
δ2 at parallel fiber synapses through its
C-terminal domain in cerebellar Purkinje cells. J.
Neurosci. 2007; 27, 12096-12108.
(10) Kimura, M., Taniguchi, M., Mikami, Y., Masuda,T., Yoshida, T., Mishina, M. and Shimizu, T.
Identification and characterization of zebrafish
semaphoring 6D. Biochem. Biophys. Res.
Commun. 2007; 363, 762-768.

Pathology, Immunology andMicrobiology
1. Pathology

34

Department of Pathology and
Diagnostic Pathology
Professor
Masashi Fukayama, M.D.,Ph.D.
Associate Professor
Noriyoshi Fukushima, M.D., Ph.D.

Lecturer
Satoshi Ota, M.D., Ph.D.
Hiroshi Uozaki, M.D., Ph.D. (Division of Diagnostic Pathology)

Lecturer (Hospital)
Yutaka Takazawa, M.D., Ph.D.,

Toru Motoi, M.D., Ph.D.

Kenji Kashima, M.D., Ph.D., (visiting researcher, UK)

Associate
Takashi Sakatani, M.D., Ph.D.,
Junji Shibahara, M.D., Ph.D.,
Tetsuo Ushiku, M.D., Ph.D.,
Shunpei Ishikawa, M.D., Ph.D.,
Rumi Hino, M.D., Ph.D.,
Teppei Morikawa, M.D., Ph.D.,
Akiteru Goto, M.D., Ph.D. (visiting researcher, USA)
Takeo Nakaya, M.D., Ph.D. (Human Resource Development for Cancer)

Technical Support Specialist
Yasuyuki Morishita,

Homepage

M.T., Shinichi Harada,

Kei Sakuma

http://pathol.umin.ac.jp/

Introduction and Organization
This department was re-organized in 2003, uniting
Department of Human Pathology and Department of
Diagnostic Pathology. It is responsible for the practiceof diagnostic pathology, education, and research inconjunction with Division of Diagnostic Pathology of
the University Hospital. Our aim is the construction of“pathology as clinical medicine” as well as“next-generation pathology for translational research”.
In 2007, Lecturer Dr. Kashima and Associate Dr.
Goto have started their research as a visiting scientist
in UK and USA, respectively. New members of
Associate were Drs. Ishikawa, Hino, and Morikawa.

Dr. Nakaya was taken in as Program Associate of
Human Resource Development for Cancer, which has
started in October.
Three postgraduate students finished the course
and received Ph.D. In the new fiscal year, 2008, there
are 11 postgraduates (including one foreign student).
The research is mainly based on morphology,
targeting human diseases. On the other hand, we takecharge of General pathology course for the 1st gradestudents in collaboration with Department of
Molecular Pathology, and Systematic pathology,
Clinical clerkship, and Bedside-learning (BSL) for the
2nd – 4th grade students.

35

Clinical activities (diagnostic
pathology and autopsy)

for them (Bunkodo, 2008).

Research activities

Together with Division of Diagnostic Pathology, we
are responsible for the pathologic diagnosis andautopsy in the University Hospital (see thecorresponding section of Division of Diagnostic
Pathology).
Clinico-pathological conferences (CPCs) for thetwo autopsy cases are held every month in the hospital.
They serve to the education of clinical residents inaddition to the weekly autopsy conferences. Surgicalpathology conferences are regularly held with eachclinical division, and discusses the cases of various
tumors, including thorax, upper gastrointestinal tract,neurosurgery, liver, pancreato-biliary tract, urology,
gynecology, breast, and orthopedics, as well as biopsy
cases of liver, kidney and skin.

Teaching activitiesst

We take on General Pathology course for the 1 gradeof undergraduate students, especially in its
morphological field. The course program and lecturenotes are open to public and available in UT OpenCourse Ware（http://ocw.u-tokyo.ac.jp/）.
Each class of Systematic Pathology course andthe exercise is held in parallel with that of Systematic
Medical course. Such integrated classes are expected
to promote the practical understanding of systemic
pathology for students. Handouts are available inevery half course of the pathological exercises.
Furthermore, all slides used in the course are now
transformed to virtual slides, and are accessible on our
website.
Clinical clerkship for the 3rd grade, and BSL for
the 4th grade are carried out. In BSL, following
courses are included; autopsy pathologic practices
including presentation of each case for paired students,
surgical pathologic practice using various tumor
sections, and a tour of the pathology laboratory.
The past examinations for the second gradestudents and for graduation are also referred on theweb.
We will start the lecture series of tumor
pathology for the Cancer Profession Training Programin postgraduate school, and have written the textbook

The firsrt major theme is “chronic inflammation andneoplasms”, for which various investigations aredeveloped, including Epstein-Barr virus associatedneoplasms (gastric carcinoma), lung carcinoma andscar formation, and carcinogenesis in pulmonary
fibrosis.
The second main theme is the search of target
molecules for cancer therapy by global analysis ofexpression profiles of various cancers, incollaboration with Research Center for Advanced
Science and Technology, the University of Tokyo.
We hosted the 4th Epstein-Barr Virus Conference
on June 29, 2007.

References
1. Abe T, Fukushima N, Brune K, Boehm C, Sato N,
Matsubayashi H, Canto M, Petersen GM, Hruban
RH, Goggins M. Genome-wide allelotypes offamilial pancreatic adenocarcinomas and familialand sporadic intraductal papillary mucinous
neoplasms. Clin Cancer Res 2007 Oct
15;13(20):6019-25.
2. Fujii K, Ishikawa S, Uchikawa H, Komura D,
Shapero MH, Shen F, Hung J, Arai H, Tanaka Y,
Sasaki K, Kohno Y, Yamada M, Jones KW,
AburataniH,
Miyashita
High-density
oligonucleotide array with sub-kilobase resolution
reveals breakpoint information of submicroscopicdeletions in nevoid basal cell carcinoma syndrome.
Hum Genet. 2007 Dec;122(5):459-66.
3. Fukushima N, Fukayama M. Mucinous cystic
neoplasms of the pancreas: pathology andmolecular genetics. J Hepatobiliary Pancreat Surg.
2007;14(3):238-42.
4. Fumimura Y, Ikemura M, Saito Y, Sengoku R,
Kanemaru K, Sawabe M, Arai T, Ito G, Iwatsubo T,
Fukayama M, Mizusawa H, Murayama S.
Analysis of the adrenal gland is useful forevaluating pathology of the peripheral autonomic
nervous system in lewy body disease. J
Neuropathol Exp Neurol. 2007 May;66(5):354-62.
5. Hashimoto T, Kitayama J, Hidemura A, Ishigami

36

H, Kaizaki S, Fukushima N, Miyata T, Nagawa H.
Ume (Japanese Apricot)-Induced Small Bowel
Obstruction with Chronic Radiation Enteritis.
Case Rep Gastroenterol 1:184-189, 2007.
6. Hibi Y, Fukushima N, Tsuchida A, Sofuni A, Itoi T,
Moriyasu F, Mukai K, Aoki T. Pancreatic juice
cytology and subclassification of intraductal
papillary mucinous neoplasms of the pancreas.
Pancreas. 2007 Mar;34(2):197-204.
7. Inamura K, Shimoji T, Ninomiya H, Hiramatsu M,
Okui M, Satoh Y, Okumura S, Nakagawa K, Noda
T, Fukayama M, Ishikawa Y. A metastatic
signature in entire lung adenocarcinomas
irrespective of morphological heterogeneity. Hum
Pathol. 2007 May;38(5):702-9.
8. Ishida K, Mitoma H, Wada Y, Oka T, Shibahara J,
Saito Y, Murayama S, Mizusawa H. Selective lossof Purkinje cells in a patient with anti-glutamic
acid decarboxylase antibody-associated cerebellar
ataxia. J Neurol Neurosurg Psychiatry. 2007 Feb;
78(2):190-2.
9. Itoi T, Sofuni A, Fukushima N, Itokawa F,
Tsuchiya T, Kurihara T, Moriyasu F, Tsuchida A,
Kasuya K. Ribonucleotide reductase subunit M2
mRNA expression in pretreatment biopsies
obtained from unresectable pancreatic carcinomas.
J Gastroenterol. 2007 May;42(5):389-94.
10. Kaji Y, Oshika T, Takazawa Y, Fukayama M,
Takata T, Fujii N. Localization of D-beta-aspartic
acid-containing proteins in human eyes. Invest
Ophthalmol Vis Sci. 2007 Sep;48(9):3923-7.
11. Kaji Y, Nagai R, Amano S, Takazawa Y,
Fukayama M, Oshika T. Advanced glycation end
product deposits in climatic droplet keratopathy.
Br J of Ophthal. 2007 Jan;91(1):85-8.
12. Kako S, Kanda Y, Sato T, Goyama S, Noda N,
Shoda E, Oshima K, Inoue M, Izutsu K, Watanabe
T, Motokura T, Chiba S, Fukayama M, Kurokawa
M. Early relapse of JAK2 V617F-positive chronic
neutrophilic leukemia with central nervous system
infiltration after unrelated bone marrowtransplantation. Am J Hematol. 2007 May;82(5):386-90.
13. Kunita A, Kashima TG, Morishita Y, Fukayama
M, Kato Y, Tsuruo T, Fujita N. The platelet
aggregation-inducing factor aggrus/podoplaninpromotes pulmonary metastasis. Am J Pathol.

2007 Apr;170(4):1337-47.
14. Maeda D, Fujii A, Yamaguchi K, Tominaga T,
Fukayama M, Mori M. Sarcomatoid carcinoma
with a predominant basaloid squamous carcinoma
component: the first report of an unusual biphasic
tumor of the ureter. Jpn J Clin Oncol. 2007
Nov;37(11):878-83.
15. Matsumoto L, Yamamoto T, Higashihara M,
Sugimoto I, Kowa H, Shibahara J, Nakamura K,
Shimizu J, Ugawa Y, Goto J, Dalmau J, Tsuji S.
Severe hypokinesis caused by paraneoplastic
anti-Ma2 encephalitis associated with bilateral
intratubular germ-cell neoplasm of the testes. Mov
Disord. 2007 Apr 15;22(5):728-31.
16. Minaguchi T, Nakagawa S, Takazawa Y, Nei T,
Horie K, Fujiwara T, Osuga Y, Yasugi T, Kugu K,
Yano T, Yoshikawa H, Taketani Y. Combined
phospho-Akt and PTEN expressions associatedwithpost-treatment
hysterectomy
afterconservative progestin therapy in complex
atypical hyperplasia and stage Ia, G1
denocarcinoma of the endometrium. Cancer Lett.
2007 Apr 8;248(1):112-22.
17. Morikawa T, Goto A, Tomita K, Tsurumaki Y, Ota
S, Kitamura T, Fukayama M. Recurrent prostatic
stromal sarcoma with massive high-grade
prostatic intraepithelial neoplasia. J Clin Pathol.
2007 Mar;60(3):330-2.
18. Morikawa T, Sugiyama A, Kume H, Ota S,
Kashima T, Tomita K, Kitamura T, Kodama T,
Fukayama M, Aburatani H. Identification ofToll-like receptor 3 as a potential therapeutictarget in clear cell renal cell carcinoma. Clin
Cancer Res. 2007 Oct 1;13(19):5703-9.
19. Moriyama A, Kii I, Sunabori T, Kurihara S,
Takayama I, Shimazaki M, Tanabe H, Oginuma M,
Fukayama M, Matsuzaki Y, Saga Y, Kudo A. GFP
transgenic mice reveal active canonical Wnt
signal in neonatal brain and in adult liver andspleen. Genesis. 2007 Feb;45(2):90-100.
20. Murata K, Ota S, Niki T, Goto A, Li CP, Ruriko
UM, Ishikawa S, Aburatani H, Kuriyama T,
Fukayama M. p63 - Key molecule in the earlyphase of epithelial abnormality in idiopathic
pulmonary fibrosis. Exp Mol Pathol. 2007
Dec;83(3):367-76.
21. Nakajima J, Goto A, Takamoto S, Murakawa T,

37

Fukami T, Kusakabe M. Invasive lymphangiomaof the lung manifesting as a large pulmonary mass
with hemoptysis: report of a case. Surg Today.
2007;37(5):418-22.
22. Nakajima J, Morota T, Matsumoto J, Takazawa Y,
Murakawa T, Fukami T, Yamamoto T, Takamoto S.
Pulmonary intimal sarcoma treated by a left
pneumonectomy with pulmonary arterioplasty
under cardiopulmonary bypass: report of a case.
Surgery Today. 2007;37(6):496-9.
23. Nakamura Y, Niki T, Goto A, Morikawa T,
Miyazawa K, Nakajima J, Fukayama M. c-Met
activation in lung adenocarcinoma tissues: an
immunohistochemical analysis. Cancer Sci. 2007
Jul;98(7):1006-13.
24. Nakamura Y, Matsubara D, Goto A, Ota S,
Sachiko O, Ishikawa S, Aburatani H, Miyazawa K,
Fukayama M, Niki T. Constitutive activation ofc-Met is correlated with c-Met overexpression anddependent on cell-matrix adhesion in lungadenocarcinoma cell lines. Cancer Sci. 2008 Jan;
99(1):14-22.
25. Nakao K, Watanabe K, Fujishiro Y, Ebihara Y,
Asakage T, Goto A, Kawahara N. Olfactory
neuroblastoma: long-term clinical outcome at asingle institute between 1979 and 2003. Acta
Otolaryngol Suppl. 2007 Dec;(559):113-7.
26. Nohara H, Furuya K, Kawahara N, Iijima A, Yako
K, Shibahara J, Kirino T. Lymphoplasmacyte-richmeningioma with atypical invasive nature. Neurol
Med Chir (Tokyo). 2007 Jan;47(1):32-5.
27. Sano A, Kage H, Sugimoto K, Kitagawa H, Aki N,
Goto A, Fukayama M, Nakajima J, Takamoto S,
Nagase T, Yatomi Y, Ohishi N, Takai D. A secondgeneration profiling system for quantitative
methylation analysis of multiple gene promoters:
application to lung cancer. Oncogene. 2007 Oct
4;26(45):6518-25
28. Sato N, Fukushima N, Hruban RH, Goggins M.
CpG island methylation profile of pancreatic
intraepithelial neoplasia. Modern Pathol. 2008
Mar;21(3):238-44.
29. Shi C, Fukushima N, Abe T, Bian Y, Hua L,
Wendelburg BJ, Yeo CJ, Hruban RH, Goggins MG,
Eshleman JR Sensitive and quantitative detectionof KRAS2 gene mutations in pancreatic duct juice
differentiates patients with pancreatic cancer fromchronic pancreatitis, potential for early detection.
Cancer Biol Ther. 2007 Dec 2;7(3).
30. Soda M, Choi YL, Enomoto M, Takada S,
Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H,
Kurashina K, Hatanaka H, Bando M, Ohno S,
Ishikawa Y, Aburatani H, Niki T, Sohara Y,
Sugiyama Y, Mano H. Identification of thetransforming EML4-ALK fusion gene in nonsmall-cell lung cancer. Nature. 2007 Aug2;448(7153):561-6.
31. Suzuki S, Kitazawa T, Ota Y, Okugawa S,
Tsukada K, Nukui Y, Hatakeyama S, Yamaguchi
D, Matsuse S, Ishii T, Matsubara T, Yamauchi C,
Ota S, Yahagi N, Fukayama M, Koike K. Dengue
hemorrhagic shock and disseminated candidiasis.
Intern Med. 2007;46(13):1043-6.
32. Ushiku T, Chong JM, Uozaki H, Hino R, Chang
MS, Sudo M, Rani BR, Sakuma K, Nagai H,
Fukayama M. p73 gene promoter methylation in
Epstein-Barr virus-associated gastric carcinoma.
Int J Cancer. 2007 Jan 1;120(1):60-6.
33. Yamauchi C, Hasebe T, Iwasaki M, Imoto S,
Wada N, Fukayama M, Ochiai A. Accurate
assessment of lymph vessel tumor emboli ininvasive ductal carcinoma of the breast according
to tumor areas, and their prognostic significance.
Hum Pathol. 2007 Feb;38(2):247-59.
34. Wang T, Niki T, Goto A, Ota S, Morikawa T,
Nakamura Y, Ohara E, Ishikawa S, Aburatani H,
Nakajima J, Fukayama M. Hypoxia increases the
motility of lung adenocarcinoma cell line A549
via activation of the epidermal growth factor
receptor pathway. Cancer Sci. 2007 Apr;98(4):506-11.

38

Department of MolecularPathology
Professor
Kohei Miyazono, M.D., D.M.S.

Associate Professor
Keiji Miyazawa, Ph.D.

Research Associates
Masao Saitoh, D.D.S.

Homepage

Tetsuro Watabe, Ph.D.

http://beta-lab.umin.ac.jp/

Introduction and Organization
Our department has a more than 100-year history
from its establishment as the Department of Pathology.
Prof. Miyazono started to work as the professor of the
Department of Molecular Pathology in August 2000.
Now, the Department consists of a professor, anassociate professor, two research associates, a project
research associate of the Center for Nano-Bio
Integration of University of Tokyo, 4 technicians, andseveral research fellows, including 19 graduate
students, 2 master course students, 3 post-doctoral
fellows, and a guest research fellow from Sweden.

Teaching activities
Our department takes responsibility for lectures on“General Pathology” for the undergraduate students of
the Faculty of Medicine in collaboration with the staffof the Department of Human Pathology. Teaching
responsibilities include lectures on General Pathology
related to the mechanisms of diseases. Since webelieve it very important for medical students to study
Basic Oncology, we teach a basic tumor biology
course in our lectures of General Pathology. In
addition, we offer several laboratory courses forstudents from molecular pathological points of view.
We also supervise research activities of thegraduate students of the Department. Our laboratory is
located at the 11th floor at the Research Building ofGraduate School of Medicine. The laboratory is very
convenient for doing research, since most of theexperiments can be done at this floor. We have
“Progress Meeting” twice a month and “Monday
Seminar” once a month.
We have been doing collaboration with the
Ludwig Institute for Cancer Research, Uppsala,Sweden for more than 10 years. We have annual
TGF-β meeting in Sweden every spring, and somegraduate students participate in the meeting and orally
present their results.
Graduate students also present data at various
meetings, including Annual Meetings of the JapaneseCancer Association, and Annual Meeting of the
Molecular Biology Society of Japan. At the corridor of
our laboratory, posters of our graduate students
reported at these meetings are presented.

Research activities
Our major research interest is to elucidate how
members of the TGF (transforming growth factor)-βfamily transduce signals, and how they regulate
growth, differentiation, and apoptosis of various cells.
We are also interested in the regulation ofangiogenesis and lymphangiogenesis using embryonic39stem (ES) cell-derived vascular progenitor cells andother endothelial cells.
A helix-loop-helix protein, DIP1 (D-type
cyclin-interacting protein 1), was identified as abinding
partnerofcyclinD,butits
patho/physiological function still remains unknown.
We examined the effect of DIP1 on TGF-β signaling.
DIP1 antagonized TGF-β-induced cell proliferationand cell migration but did not affect TGF-β-induced
epithelial-mesenchymal transition (EMT). Thisbilateral character is a unique phenomenon among
regulators of TGF-β signaling. To examine themechanism of this selective effect of DIP1 on TGF-βsignaling, we explored DIP1-binding proteins by mass
spectrometry and identified Olig1. Olig1 up-regulated
TGF-β signaling in concert with R-Smads, and DIP1
inhibited this synergistic effect of R-Smads and Olig1
on TGF-β signaling by interrupting their binding. We
also confirmed that siRNA against Olig1 downregulated only a subset of TGF-β-induced genes. Ourdata suggest that Olig1 up-regulates some
TGF-β-induced genes specifically, DIP1 inhibits
TGF-β signaling by interrupting the binding of Olig1
and R-Smads, and as a consequence DIP1 shows thebilateral character against TGF-β-induced cell
responses.
TGF-β signaling facilitates tumor growth andmetastasis in advanced cancer. We identified
differentially expressed in chondrocytes 1 (DEC1,
also known as SHARP2 and Stra13) as a downstream
target of TGF-β signaling which promotes the survivalof breast cancer cells. In the mouse mammary
carcinoma cell lines JygMC(A) and 4T1, the TGF-β
type I receptor kinase inhibitors A-44-03 andSB431542 induced apoptosis of cells under serum-free
conditions. Oligonucleotide microarray analyses
revealed that TGF-β induced DEC1 in these cells, andthe increase of DEC1 was suppressed by the TGF-β
type I receptor kinase inhibitors as well as byexpression of dominant-negative TGF-β type II
receptor. Overexpression of DEC1 prevented theapoptosis of JygMC(A) cells induced by A-44-03, andknockdown of endogenous DEC1 abrogated TGF-βpromoted cell survival. Moreover, a dominantnegative mutant of DEC1 prevented lung and liver
metastasis of JygMC(A) cells in vivo. Our
observations thus provide new insights into themolecular mechanisms governing TGF-β-mediatedcell survival and metastasis of cancer.
EMT plays important roles in various
physiological and pathological processes, and isregulated by signaling pathways mediated bycytokines including TGF-β. Embryonic endothelial
cells also undergo differentiation into mesenchymal
cells during heart valve formation and aortic
maturation. However, the molecular mechanisms that
regulatesuchendothelial-mesenchymal/muraltransition (EndMT) remain to be elucidated. We
showed that TGF-β plays important roles during muraldifferentiation of mouse embryonic stem cell-derived
endothelial cells (MESECs). TGF-β induced thedifferentiation of MESECs into mural cells withdecrease in expression of an endothelial marker,
claudin-5, and increase in that of mural markers,
smooth muscle α-actin (SMA), SM22α and calponin,
while a TGF-β type I receptor kinase inhibitor
inhibited it. Among transcription factors involved in
EMT, Snail was induced by TGF-β in MESECs.
Tetracycline-regulated expression of Snail induced thedifferentiation of MESECs into mural cells, whileknockdown of Snail expression abrogated TGF-βinduced mural differentiation of MESECs. These
results indicate that Snail mediates the actions ofendogenous TGF-β signals that induce EndMT.
Cyclooxygenase-2 (COX-2) inhibitor has beenreported to suppress tumor progression. However, it isunclear whether this inhibitor can also prevent
lymphatic metastasis. We determined the effects of
COX-2 inhibitor on lymphatic metastasis and toclarify the mechanisms of such effects. Etodolac, a
COX-2 inhibitor, was administered per os to micebearing orthotopic xenografts or with carcinomatous
peritonitis induced with a highly metastatic humangastric carcinoma cell line, OCUM-2MLN. We
evaluated lymphangiogenesis, lymph node metastasis,and distribution of lymphangiogenic growth factors.
We also used a mouse macrophage-like cell line andhuman dermal lymphatic microvascular endothelial
cells in vitro to examine whether etodolac regulates
the function of macrophages or lymphatic endothelial
cells, each of which may be involved inlymphangiogenesis. Tumor lymphangiogenesis, asmeasured by area density of lymphatic vessels, wassignificantly decreased in etodolac-treated mice40compared with control mice. Consistent with thisdecrease in lymphangiogenesis, the total weight ofmetastatic lymph nodes was less in etodolac-treatedthan in control mice. Immunohistochemical analysis
revealed that the major source of vascular endothelial
growth factor (VEGF)-C and VEGF-D was
F4/80-positive macrophages in our models. The
mRNA levels of VEGF-C in the mouse macrophagelike cells were dose-dependently suppressed byetodolac. The growth of human dermal lymphatic
microvascular endothelial cells was also suppressedby etodolac. Our findings suggested that COX-2
inhibitor may be useful for prophylaxis of lymph nodemetastasis by reducing macrophage-mediated tumor
lymphangiogenesis.

References
1. Shimanuki, T., Hara, T., Furuya, T., Imamura, T.,
and Miyazono, K. (2007) Modulation of thefunctional binding sites for TGF-β on the type II
receptor leads to suppression of TGF-β signaling.
Oncogene 26 (23), 3311-3320.
2. Ehata, S., Hanyu, A., Katsuno, Y., Fukunaga, E.,
Goto, K., Ishikawa, Y., Nomura, K., Ogata, E.,
Fujime, M., Miyazono, K., Shimizu, K., andImamura, T. (2007) Ki26894, a noveltransforming growth factor-β type I receptor
kinase inhibitor, inhibits in vitro cell motility andinvasion and in vivo bone metastasis of a humanbreast cancer cell line. Cancer Sci. 98 (1),127-133.
3. Ogawa, K., Saito, A., Matsui, H., Suzuki, H.,
Ohtsuka, S., Shimosato, D., Morishita, Y., Watabe,T., Niwa, H., and Miyazono, K. (2007) Activin/
Nodal signaling is involved in propagation ofmouse embryonic stem cells. J. Cell Sci. 120 (1),55-65.
4. Kano, M.R., Bae, Y., Iwata, C., Morishita, Y.,
Yashiro, M., Oka, M., Fujii, T., Komuro, A.,
Kiyono, K., Kaminishi, M., Hirakawa, K., Ouchi,
Y., Nishiyama, N., Kataoka, K., and Miyazono, K.
(2007) Improvement of cancer-targeting therapy
using nanocarriers for intractable solid tumors by
inhibition of TGF-β signalling. Proc. Natl. Acad.
Sci. USA 104 (9), 3460-3465.
5. Mishima, K., Watabe, T., Imaizumi, N., Masui, S.,

Hirashima, M., Morisada, T., Oike, Y., Araie, M.,
Niwa, H., Kubo, H., Suda, T., and Miyazono, K.
(2007) Prox1 induces lymphatic endothelial
differentiation via integrin α9 and other signalingcascades. Mol. Biol. Cell 18 (4), 1421-1429.
6. Kobayashi, N., Goto, K., Horiguchi, K., Nagata,
M., Kawata, M., Miyazawa, K., and Miyazono, K.
(2007) c-Ski activates MyoD in the nucleus ofmyoblastic cells through suppression of histone
deacetylases. Genes Cells 12(3), 375-385.
7. Shirakihara, T., Saitoh, M., and Miyazono K.
(2007) Differential regulation of epithelial andmesenchymal markers by δEF1 proteins inepithelial mesenchymal transition induced by
TGF-β. Mol. Biol. Cell 18 (9), 3533-3544.
8. Goto, K., Kamiya, Y., Imamura, T., Miyazono, K.,
and Miyazawa, K. (2007) Selective inhibitory
effects of Smad6 on bone morphogenetic protein
type I receptors. J. Biol. Chem. 282 (28), 2060320611.
9. Nagano, Y., Mavrakis, K.J., Lee, K.L., Fujii, T.,
Koinuma, D., Sase, H., Yuki, K., Isogaya, K.,
Saitoh, M., Imamura, T., Episkopou, V., Miyazono,
K., and Miyazawa, K. (2007) Arkadia induces
degradation of SnoN and c-Ski to enhance TGF-βsignaling. J. Biol. Chem. 282 (28), 20492-20501.
10. Ehata, S., Hanyu, A., Hayashi, M., Aburatani, H.,
Kato, Y., Fujime, M., Saitoh, M., Miyazawa, K.,
Imamura, T., and Miyazono, K. (2007)
Transforming growth factor-β promotes survivalof mammary carcinoma cells through induction ofanti-apoptotic transcription factor DEC1. Cancer
Res. 67 (20), 9694-9703.
11. Iwata, C., Kano, M.R., Komuro, A., Oka, M.,
Kiyono, K., Johansson, E., Morishita, Y., Yashiro,
M., Hirakawa, K., Kaminishi, M., and Miyazono,
K. (2007) Inhibition of cyclooxygenase-2
suppresses lymph node metastasis via reduction oflymphangiogenesis. Cancer Res. 67 (21), 1018110189.
12. Nakajima, M., Kizawa, H., Saitoh, M., Kou, I.,
Miyazono, K., and Ikegawa, S. (2007)
Mechanisms for asporin function and regulation inarticular cartilage. J. Biol. Chem. 282 (44), 3218532192.
13. Nakagome, K., Dohi, M., Okunishi, K., Tanaka,
R., Kouro, T., Kano, M.R., Miyazono, K.,41

Miyazaki, J., Takatsu, K., and Yamamoto, K.
(2007) IL-5-induced hypereosinophilia suppresses
the antigen-induced immune response via a
TGF-β-dependent mechanism. J. Immunol. 179(1), 284-294.
14. Tokuda, E., Fujita, N., Oh-hara, T., Sato, S.,
Kurata, A., Katayama, R., Itoh, T., Takenawa, T.,
Miyazono, K., and Tsuruo, T. (2007) Casein
kinase 2-interacting protein-1, a novel Akt
pleckstrin homology domain-interacting protein,
down-regulates
PI3K/Aktsignalingandsuppresses tumor growth in vivo. Cancer Res. 67(20), 9666-9676.

Pathology, Immunology andMicrobiology
2. Microbiology

43

Department of Microbiology
Professor
Akio Nomoto, Ph.D.

Research Associate
Seii Ohka, Ph.D.,

Tsubasa Munakata, Ph.D.,

Nobuhiko Kamoshita, M.D., Ph.D.

Homepage http://microbiology.m.u-tokyo.ac.jp/
Introduction and Organization
Microbial disease has been recognized as the major
threat to human health throughout the history. Despite
the development of preventive and therapeuticinterventions against some pathogenic microbes,
infectious disease is still one of the most significant
medical problems. On the other hand, microbialorganisms have served as a useful model as well for
elucidating the molecular mechanisms of a variety of
biological events, providing useful insights into life
science. Recently, efforts have also been initiated by anumber of research groups to utilize animal viruses asa tool for human gene therapy. In order to familiarize
students with these issues, importance of
microbiology in medical education is increasing more
rapidly than ever. To fulfill this requirement, ourdepartment, as the only basic microbiology unit in the
Faculty, currently assumes a responsibility forteaching bacteriology, mycology, and virology to
medical undergraduates.

Education
Undergraduate Course, Faculty of Medicine
In a series of lectures (totally 64 hr) and laboratory
courses (36 hr), the following subjects are covered.
1) Molecular biology of bacteria, phages, and animalviruses2) Mechanisms of microbial diseases
3) Laboratory diagnosis of pathogenic microbes
4) Infection control and biosafety
5) Applicationofmicrobialorganisms
forbiotechnology

6) Socioeconomic impact of microbial diseases
In addition to the staff of our department, experts
from the National Institute of Infectious Diseases (Dr.
Watanabe and Dr. Yoshikura), Faculty of Agriculture(Dr. Onodera), Institute of Medical Science (Dr.
Sasakawa, Dr. Kawaoka, Dr. Iwamoto, Dr. Saito, andDr. Matano), and professor emeritus (Dr. Kawana)contribute to the teaching activities.

Research
1. IRES (internal ribosome entry site)-dependenttranslation
Kamoshita, N., Munakata, T., and Nomoto, A.
2. PVR (poliovirus receptor)-dependent and-independent poliovirus entry
Ohka, S., Nihei, C., Mikame, M., and Nomoto, A.
3. Effect of viral infection on cell metabolism
Kamoshita, N., Matsuda, N., Nihei, C., Ohka, S.,
and Nomoto, A.
4. Blood brain barrier permeation of poliovirus
Mikame, M., Nihei, C., Ohka, S., and Nomoto, A.
5. Oral infection mechanism of poliovirus
Ohka, S., Kajiro, K., and Nomoto, A.
6. Development and application of poliovirus
vectorChiba, H., Igarashi, H., Shimizu, M., Ohka, S.,
and Nomoto, A.
7. Biochemical analysis of HCV (hepatitis C
virus) genome as an RNA replicon
Okamoto, Y., Munakata, T., Kamoshita, N., andNomoto, A.
8. Molecular basis for HCV pathogenesis

44

Munakata, T., Hayase, N., and Nomoto, A.
9. Development of novel inhibitors of HCV
replication
Munakata, T., Inada, M., and Nomoto, A.

Publications
1. Ohka S, Igarashi H, Nagata N, Sakai M, Koike
S, Nochi T, Kiyono H, and Nomoto A.
Establishment of a poliovirus oral infection
system in human poliovirus receptor-expressing
transgenic mice that are deficient in alpha/betainterferon receptor. J Virol. 81: 7902-7912, 2007.
2. Munakata T, Liang Y, Kim S, McGivern DR,
Huibregtse J, Nomoto A, and Lemon SM.
Hepatitis C virus induces E6AP-dependentdegradation of the retinoblastoma protein. PLoS
Pathog 3: 1335-1347, 2007.
3. Nomoto A. Molecular aspect of poliovirus
pathogenesis. Proc. Jpn. Acad., Ser. B 83: 266-275,
2007.
4. Nishimura T, Saito M, Takano T, Nomoto A,
KoharaM,
andTsukiyama-Kohara
K.
Comparative
aspects
on
the
role
of
polypyrimidine tract-binding protein in internal
initiation of hepatitis C virus and poliovirus RNAs.
Comparat Immunol Microbiol Infect Dis., inpress.

45

Department of Infection Control
and Prevention
Professor
Kazuhiko Koike, M.D., Ph.D.

Lecturer
Kyoji Moriya, M.D., Ph.D.
Yoshizumi Shintani, M.D., Ph.D.

Research Associate
Shuji Hatakeyama, M.D.,

Takatoshi Kitazawa, M.D., Ph.D.

Homepage http://www.cc.h.u-tokyo.ac.jp/mulins/kansen/index.html(inside the hospital only)
Introduction and Organization
3)
The Department of Infection Control and Prevention
started at first as the Division of Hospital Infection
Control Services on January 23, 1991. This divisiondeveloped into the Division of Infection Control andPrevention on September l, 1993 and the present
department on June 4, 1994. Currently, our faculty
consists of one professor, two lecturers, 6 guest
lecturers, two research associates, one research
student, 11 laboratory technicians, and two officeassistants. For isolation and identification of
microorganisms from clinical specimens, we
amalgamated the microbiology unit from the
Department of Clinical Laboratory in 2001.

Clinical activities
Our daily activities are as follows:
1) Surveillance and control of hospital-acquired
infection, such as infection or colonization ofmethicillin-resistant Staphylococcus aureus andother drug-resistant microbes.
2) Investigation of trends in weekly bases andmonthly reports to all departments; Screening ofcolonization; monitoring of appropriate use of

4)
5)
6)

antibiotics such as mupirocin and vancomycin.
Microbiological investigation of wards andenvironment (at request or need).
Detection, investigation, intervention and controlof the hospital infection outbreak.
Offering of information and advice on
HIV-infected patients’ management.
Direct inquiries and advises on management ofpatients with various infections through ward
rounds every week.

Teaching activities
We have been charged for education of undergraduate
students on the course of medicine (lectures andpractical exercises on the infection control for the 3rd
and 4th grade students and lectures on infectious
diseases for the 4th grade students), the course ofhealth science (lectures on microbiology), and theschool of nursing (lectures and practical exercises on
microbiology). These lectures and exercises contain
subjects not only on the hospital infection but also on
clinical microbiology. We are also engaged in the
education of graduate students as well as hospital
staff.
For postgraduate education, we have been committed

46

to the guidance for new postgraduates and residents
on the hospital and occupational infection control. We
have been also offering our information and techniqueon occasions of request.

Research activities
We have been mainly studying on following subjects:
1) Development of preemptive strategies for thecontrol of healthcare-associated infection2) Development of new methods in infection control
and treatment of viral hepatitis
3) Molecularpathogenesisofhepatocellular
carcinoma in HCV infection4) Pathogenesis of progression of HIV infection5) Molecular pathogenesis of the mitochondrial
disturbances in viral infections
6) Molecular pathogenesis of hepatitis B viral
infection7) Host defences to microorganisms
8) Molecular analysis of innate immunity inmicroorganism infection
9) New detection method and pathogenesis ofopportunistic cytomegaloviral infection10) Mechanismofmulti-drugresistantmicroorganisms

References
1)

2)

3)

4)

Koike K, Tsukada K, Yotsuyanagi H, Moriya K,
Kikuchi Y, Oka S, Kimura S. Prevalence of
Coinfection with Human Immunodeficiency
Virus and Hepatitis C Virus in Japan. Hepatol Res
2007;37:2-5.
Bi X, Gatanaga H, Koike K, Kimura S, Oka S.
Reversal periods and patterns from drug resistant
to wild-type HIV-1 after cessation of anti-HIV
therapy. AIDS Res Hum Retro 2007;23:43-50.
Miyamoto H, Moriishi K, Moriya K, Murata S,
Tanaka K, Suzuki T, Miyamura T, Koike K,
Matsuura Y. Hepatitis C Virus Core Protein
InducesInsulinResistancethrougha
PA28γ-Dependent Pathway. J Virol 2007;81:
1727-1735.
Moriishi K, Mochizuki R, Moriya K, Miyamoto
H, Mori Y, Abe T, Murata S, Tanaka K, Suzuki T,
Miyamura T, Koike K, Matsuura Y. Critical roleof PA28 γ in hepatitis C virus-associatedsteatogenesis and hepatocarcinogenesis. Proc Natl
Acad Sci USA 2007;104:1661-1666.
5) Ishizaka N, Saito K, Furuta K, Matsuzaki G,
Koike K, Noiri E, Nagai R. Angiotensin
II-induced regulation of the expression andlocalization of iron metabolism-related genes in
the rat kidney. Hypertens Res 2007;30:195-202.
6) Suzuki Y, Yotsuyanagi H, Okuse C, Nagase Y,
Takahashi H, Moriya K, Suzuki M, Koike K, Iino
S, Itoh F. Fatal liver failure caused by reactivationof lamivudine-resistant hepatitis B virus: A casereport. World J Gastroenterol 2007;13:964-969.
7) Hatakeyama S, Sugaya N, Ito M, Yamazaki M,
Ichikawa M, Kimura K, Kiso M, Shimizu H,
Kawakami C, Koike K, Mitamura K, Kawaoka Y.
Emergence of Influenza B Viruses With Reduced
Sensitivity to Neuraminidase Inhibitors. JAMA
2007;297:1435-1442.
8) Saito R, Kumita W, Sato K, Chida T, Okamura N,
Moriya K, Koike K. Detection of plasmidmediated quinolone resistance associated with
qnrA in an Escherichia coli clinical isolate
producing CTX-M-9 beta-lactamase in Japan. Int
J Antimicrob Agents 2007;29:600-602.
9) Ishizaka N, Ishizaka Y, Toda EI, Nagai R, Koike
K, Hashimoto H, Yamakado M. Relationshipbetween smoking, white blood cell count andmetabolic syndrome in Japanese women.
Diabetes Res Clin Pract 2007;78:72-76.
10) Kitazawa T, Nakayama K, Okugawa S, Koike K,
Shibasaki Y, Ota Y. Biphasic regulation oflevofloxacin
onlipopolysaccharide-induced
IL-1beta production. Life Sci 2007;80:15721577.
11) Okugawa S, Ota Y, Tatsuno K, Tsukada K,
Kishino S, Koike K. A case of invasive central
nervous system aspergillosis treated withmicafungin with monitoring of micafunginconcentrations in the cerebrospinal fluid. Scand J
Infect Dis 2007;39:344-346.
12) Yotsuyanagi H, Koike K. Mechanisms underlying
drug resistance in antiviral treatment for
infections with hepatitis B and C viruses. J
Gastroenterol 2007;42:329-335.
13) Saito R, Sato K, Kumita W, Inami N, Nishiyama
H, Okamura N, Moriya K, Koike K. Detection ofplasmid-mediated quinolone resistance associated47

with qnrA in Escherichia coli clinical isolate
producing CTX-M-9 beta-lactamase in Japan. Int
J Antimicrob Agents 2007;29:600-602.
14) Tsukada K, Kitazawa T, Fukushima A, Okugawa
S, Yanagimoto S, Tatsuno K, Koike K, Nagase H,
Hirai K, Ota Y. Macrophage tolerance induced bystimulation with Toll-like receptor 7/8 ligands.
Immunol Lett 2007;111:51-56.
15) Misawa Y, Yoshida A, Saito R, Yoshida H,
Okuzumi K, Ito N, Okada M, Moriya K, Koike K.
Applicationofloop-mediatedisothermal
amplification technique to rapid and direct
detection of methicillin-resistant Staphylococcus
aureus (MRSA) in blood cultures. J InfectChemother 2007;13:134-140.
16) Suzuki S, Kitazawa T, Ota Y, Okugawa S,
Tsukada K, Nukui Y, Hatakeyama S, Yamaguchi
D, Matsuse S, Ishii T, Matsubara T, Yamauchi C,
Ota S, Yahagi N, Fukayama M, Koike K. Dengue
Hemorrhagic
Shock
and
DisseminatedCandidiasis. Intern Med 2007;46:1043-1046.
17) Koike K. Hepatitis C virus contributes tohepatocarcinogenesis by modulating metabolicand intracellular signaling pathways. J
Gastroenterol Hepatol 2007;22:S108-111.
18) Koike K. Pathogenesis of HCV-associated HCC:
dual-pass carcinogenesis through the activation ofoxidative stress and intracellular signaling.
Hepatol Res 2007;37:S38-S43.
19) Aono J, Yotsuyanagi H, Miyoshi H, Tsutsumi T,
Fujie H, Shintani Y, Moriya K, Okuse C, Suzuki
M, Yasuda K, Iino S, Koike K. Amino acidsubstitutions in S region of hepatitis B virus in
the sera from patients with acute hepatitis.
Hepatol Res 2007;37:731-739.
20) Ichibangase T, Moriya K, Koike K, Imai K. A
novel proteomics method revealed disease-related
proteins in the liver of hepatitis C mouse model. J
Proteome Res 2007;6:2841-2849. (6.9)21) Ota Y, Tatsuno K, Okugawa S, Yanagimoto S,
Kitazawa T, Fukushima A, Tsukada K, Koike K.
Relationship between the initial dose of
micafungin ansd its efficacy in patients withcandidemia. J Infect Chemother 2007;13:208212.
22) Kitazawa T, Fukushima A, Okugawa S,
Yanagimoto S, Tsukada K, Tatsuno K, Koike K,

Kimura S, Kishimoto T, Shibasaki Y, Ota Y.
Chlamydophilal antigens induce foam cell
formation via c-Jun NH2-terminal kinase.
Microbes Infect 2007;9:1410-1414.
23) Ishizaka N, Ishizaka Y, Toda E, Koike K, Seki G,
Nagai R, Yamakado M. Association between
obesity and chronic kidney disease in Japanese:differences in gender and hypertensive status?
Hypertens Res 2007;30:1059-1064.
24) Ishizaka N, Ishizaka Y, Toda E, Koike K, Seki G,
Nagai R, Yamakado M. Association between
chronic kidney disease and carotid intima-media
thickening in individuals with hypertension andimpaired glucose metabolism. Hypertens Res
2007;30:1035-1041.
25) Okuse C, Yotsuyanagi H, Koike K. Hepatitis C asa Systemic Disease: Virus and Host Immunologic
Responses Underlie Hepatic and Extrahepatic
Manifestations. J Gastroenterol 2007;42:857865.
26) Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Moriya K, Koike K, Makuuchi M.
Impactofnewmethicillin-resistant
Staphylococcus aureus carriage postoperatively
after living donor liver transplantation. Transplant
Proc 2007;39:3271-3275.
27) Saito R, Okugawa S, Kumita W, Sato K,
Okamura N, Moriya K, Koike K. Clinicalepidemiology of ciprofloxacin-resistant Proteus
mirabilis isolated from urine samples in
hospitalized patients. Clin Microbiol Infect 2007;
13:1204-1206.
28) Tanaka N, Moriya K, Kiyosawa K, Koike K,
Aoyama T. Hepatitis C virus core protein induces
spontaneous and persistent activation ofperoxisome proliferator-activated receptor alphain transgenic mice: Implications for HCVassociated hepatocarcinogenesis. Int J Cancer
2008;122:124-31.
29) Koike K, Kikuchi Y, Kato M, Takamatsu J,
Shintani Y, Tsutsumi T, Fujie H, Miyoshi H,
Moriya K, Yotsuyanagi H. Prevalence of
Hepatitis B Virus Infection in Patients with
Human Immunodeficiency Virus in Japan. Hep
Res 2008;38:310-314.
30) Tanaka N, Moriya K, Kiyosawa K, Koike K,
Gonzalez FJ, Aoyama T. PPAR-a is essential for

48

severe hepatic steatosis and hepatocellular
carcinoma induced by HCV core protein. J Clin
Invest 2008;118:683-694.
31) Ishizaka N, Ishizaka Y, Toda EI, Koike K,
Yamakado M, Nagai R. Are Serum
Carcinoembryonic Antigen Levels AssociatedWith Carotid Atherosclerosis in Japanese Men?
Arterioscler Thromb Vasc Biol 2008;28:160-165.
32) Nagase Y, Yotsuyanagi H, Okuse C, Yasuda K,
Kato T, Koike K, Suzuki M, Nishioka K, Iino S,
Itoh F. Effect of treatment with interferonalpha-2b and ribavirin in patients infected withgenotype 2 hepatitis C virus. Hepatol Res 2008;
38:252-258.
33) Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Moriya K, Koike K, Makuuchi M.
Methicillin-resistant
Staphylococcus
aureusinfection after living-donor liver transplantationin adults. Transpl Infect Dis 2008;10:110-116.
34) Koike K, Tsutsumi T, Miyoshi H, Shinzawa S,
Shintani Y, Fujie H, Yotsuyanagi H, Moriya K.
Molecular Basis for the Synergy between Alcoholand Hepatitis C Virus in Hepatocarcinogenesis. J
Gastroenterol Hepatol 2008;23:S87-91.
35) Newell P, Villanueva A, Friedman SL, Koike K,
LlovetJM.
Experimental
modelsofhepatocellular carcinoma. J Hepatol 2008;48:
858-879.
36) Ishizaka N, Ishizaka Y, Toda E, Shimomura H,
Koike K, Seki G, Nagai R, Yamakado M.
Association between cigarette smoking andchronic kidney disease in Japanese men.
Hypertens Res 2008;31:485-92.
37) Ishizaka Y, Ishizaka N, Tani M, Toda A, Toda EI,
Koike K, Yamakado M. Relationship between
Albuminuria,
Low eGFR, and Carotid
Atherosclerosis in Japanese Women. Kidney
Blood Press Res 2008;31:164-170.
38) Ishizaka N, Ishizaka Y, Seki G, Nagai R,
Yamakado M, Koike K. Association between
hepatitis B/C viral infection, chronic kidneydisease and insulin resistance in individuals
undergoing general health screening. Hepatol Res
2008 in press.
39) Matsuzaki G, Ishizaka N, Furuta K, Hongo M,
Saito K, Sakurai R, Koike K, Nagai R.
Comparison of vasculoprotective effects ofbenidipine and losartan in a rat model ofmetabolic syndrome. Eur J Pharmacol 2008;587:
237-42.
40) Koike K. Steatosis, Liver Injury andHepatocarcinogenesis in Hepatitis C Viral
Infection. J Gastroenterol 2008 in press.

Pathology, Immunology andMicrobiology
3. Immunology

50

Department of Immunology
Professor
Tadatsugu Taniguchi, Ph.D.

Associate Professor
Tomohiko Tamura, M.D., Ph.D.

Assistant Professor
Hideyuki Yanai, Ph.D.;

Homepage

Makoto Nakasato, Ph.D.;

Hideo Negishi, Ph.D.

http://www.immunol.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Immunology was formerly
called the Department of Serology, which has ahistory going back to 1918. The department waschanged to its present name, when Dr. Tomio Tada,
now Professor Emeritus of The University of Tokyo,
took his position in 1977 as the professor and chair ofthe department. Dr. Tada has made great contributions
that made this department world-renowned, throughhis innovative research as well as his great
contributions to the international community of
immunologists. After his retirement in 1994, webasically followed the tradition of the department
established by Dr. Tada and tried to improve it further,in terms of providing high-standard education to
students and cutting-edge research in immunology
worldwide. Research projects currently being
conducted began with the original identification of
two cytokine genes and their characterization between
the late 1970s and the early 1980s, namely, the genes
encoding human fibroblast interferon (now known as
IFN-β) and interleukin-2 (IL-2). These initial studies
have led us to further characterization of thesecytokine systems in the context of the regulation of
immunity and oncogenesis. One of our major
contributions is the discovery and characterization of a
new family of transcription factors, termed interferon
regulatory factors (IRFs). Our current researchinterests are aimed at clarifying the function andregulation of the IRF family of transcription factors in

oncogenesis and immunity. As a part of our scientificand educational activities, we organize many seminars
by inviting distinguished scientists from all over theworld.

Teaching activities
Our teaching responsibility is to provide lectures on
immunobiology, immunochemistry and molecularimmunology to the undergraduate students of thefaculty. It is also our responsibility to provide
laboratory courses on basic immunology to students.
In addition to lectures and laboratory courses provided
by our own staff members, special lectures are also
given by guest experts. We also offer a special training
course (called ‘free quarter’) of basic and advanced
biological and immunological techniques to medical
students. The education of graduate students is basedon weekly conferences during which the students
present the progress of their own research projects anddiscuss on their future directions. Lectures on leading
research activities are given by active researchers
from overseas whenever they visit our department.
The students may gain a profound interest in the field
through these lectures.

Research activities
Our research field includes cellular and molecularimmunology in general. We have been extensively

51

analyzing mechanisms that function in the regulationof gene expression and signal transduction in hostdefense systems. In particular, we focus on themolecular mechanisms underlying host defense
against viral and bacterial infections. Among thesemechanisms, the interferon (IFN) system is the mostpowerful and important for the control of such
infections. During the course of the study, we haveidentified the interferon regulatory factor (IRF) family,
which play critical roles in immunity. Most notably,
studies of IRFs have revealed their remarkablefunctional diversity in regulating the immune systems,
in particular, as the key regulators of innate immune
responses. For example, the transcription factor IRF-7
isessential
for
both
the
virus-activated
MyD88-independent pathway as well as the
TLR-activated MyD88-dependent pathway of type I
IFN gene induction. Furthermore, IRF-5 was also
found to be essential for the MyD88-dependent geneinduction program, which is commonly activated by
TLRs. IRF-5 interacts with and is activated by MyD88
and TRAF6, and TLR activation results in the nuclear
translocation of IRF-5 to activate cytokine genetranscription.
It has been known that cytosolic exposure of DNA
can evoke strong immune responses, which occurs via
a TLR-independent mechanism. Recently, we haveidentified a molecule that acts as a cytosolic DNA
sensor. This molecule, named DAI (DNA-dependent
activator of IRFs), recognizes DNA exposed to thecytosol, and then associates with TBK1 kinase andIRF3 transcription factor to induce transcription oftype I Interferon (IFN) genes. We further identified
several important domains of DAI, and revealed that
DAI forms a multimer upon DNA recognition toactivate the down-stream signaling pathways.
We also found that IRF-5, which we previously
showed to be important for the TLR-mediatedcytokine gene induction, also regulates cellularsusceptibility to apoptosis triggered by various stimuli
such as virus, DNA damage, and a death receptor Fas.
We further revealed that IRF-5 has a tumor
suppressive activity. Thus, IRF-5 is important for boththe two main aspects of host defense, namely, immune
response to invading pathogens and suppression oftumor development, providing a new link in theirtranscriptional network. Another recent, criticalfinding is that IRF-1 transactivates the IL-12 receptor
β gene, thereby supporting Th1 differentiation.

References(1) Yanai, H., Chen, H., Inuzuka, T., Kondo, S., Mak,
T.W., Takaoka, A., Honda, K. and Taniguchi, T.;
Role of IFN regulatory factor 5 transcription
factor in antiviral immunity and tumor
suppression. (2007) Proc. Natl. Acad. Sci. USA
104, 3402-3407.
(2) Ouyang, X., Negishi, H., Takeda, R., Fujita, Y.,
Taniguchi, T. and Honda, K.; Cooperation
between MyD88 and TRIF pathways in TLR
synergy via IRF5 activation. (2007) Biochem.
Biophys. Res. Commun. 354, 1045-1051.
(3) Onoguchi, K., Yoneyama, M., Takemura, A.,
Akira, S., Taniguchi, T., Namiki, H., and Fujita
T.; Viral Infections Activate Types I and III
Interferon Genes through a Common Mechanism.
(2007) J. Biol. Chem. 282, 7576-7581.
(4) Takaoka, A., Wang, Z., Choi, M.K., Yanai, H.,
Negishi, H., Ban, T., Yan, L., Miyagishi, M.,
Kodama, T., Honda, K., Ohba, Y. and Taniguchi,T.; DAI (DLM-1/ZBP1) is a cytosolic DNA
sensor and an activator of innate immune
response. (2007) Nature 448, 501-506.
(5) Kano, S., Sato, K., Morishita, Y., Vollstedt, S.,
Kim, S., Bishop, K., Honda, K., Kubo, M., andTaniguchi, T.; The contribution of transcription
factor IRF1 to the interferon-γ-interleukin 12
signaling axis and TH-17 differentiation of CD4+
T cells. (2008) Nat. Immunol. 9, 34-41.
(6) Couzinet, A., Tamura, K., Chen, H., Nishimura,K., Wang, Z., Morishita, Y., Takeda, K., Yagita,
H., Yanai, H., Taniguchi, T., and Tamura, T.; A
cell type-specific requirement for IRF5 in
Fas-induced apoptosis. (2008) Proc. Natl. Acad.
Sci. USA. 105, 2556-2561.
(7) Takaoka, A., Tamura T., and Taniguchi, T.; IRF
family transcription factors and regulation of
oncogenesis. (2008) Cancer Sci. 99, 467-478.
(8) Mizutani, T., Tsuji, K., Ebihara, Y., Taki, S., Ohba,
Y., Taniguchi, T., and Honda, K.; Homeostatic
erythropoiesis by the transcription factor IRF2
through attenuation of type I interferon signaling.
(2008) Exp. Hematol. 36, 255-264..

52(9) Tamura, T., Yanai, H., Savitsky, D., and Taniguchi,T.; The IRF Family Transcription Factors in
Immunity and Oncogenesis. (2008) Annu. Rev.
Immunol. 26, 535-584.
(10)Takaoka, A., and Taniguchi, T.; Cytosolic DNA
recognition for triggering innate immune
responses. (2008). Adv. Drug Deliv. Rev. 60,
847-57.
(11)Wang, Z., Choi, M.K., Ban, T., Yanai, H., Negishi,
H., Lu, Y., Tamura, T., Takaoka, A., Nishikura, K.,
and Taniguchi, T.; Regulation of immune
responses by DAI (DLM-1/ZBP1) and otherDNA-sensing molecules. (2008) Proc. Natl. Acad.
Sci. USA 105, 5477-5482.

Radiology and Biomedical
Engineering
1. Radiology

54

Department of Radiology
Professor
Kuni Ohtomo, M.D.,Ph.D.

Associate Professor
Toshimitsu Momose, M.D.,Ph.D.,

Shigeki Aoki, M.D.,Ph.D.,

Keiichi Nakagawa, M.D.,Ph.D.

Lecturer
Atsurou Terahara M.D.,Ph.D,

Osamu Abe, M.D.,Ph.D.,

Masaaki Akahane, M.D.,

Yoshitaka Masutani, Ph.D.,

Tomohiko Masumoto, M.D.,Ph.D

Research Associate
Syuhei Komatsu, M.D.,

Shinichi Inoh, M.D.,

Harushi Mori, M.D.,

Nobuyuki Kato, M.D.

Kenshirou Shiraishi, M.D.,

Hideomi Yamashita, M.D.

Jiro Sato, M.D.,

Akiko Inano, M.D.

Homepage

http://www.m.u-tokyo.ac.jp/mcm/

Introduction and Organization
Department of Radiology was established in 1932.
Radiology covers three major fields that are,Diagnostic Radiology (imaging and intervention),
Radiation Oncology (radiotherapy) and Nuclear
Medicine. The clinical, educational and research
activities of our department are being carried out incooperation with Department of Radiology in The
Research Institute of Medical Science, which has
three (1 associate professor, 1 lecturer, and 1 assistantprofessor) positions. In addition, Department ofRadiology mainly takes care of radiation protection
and radiation safety in the hospital.

Clinical activities
Clinical services on Diagnostic Radiology, Nuclear
Medicine, and Radiation Oncology are provided in thecentralized Clinical Radiology Service Department incooperation with radiology technologists and nurses.
In the section of Diagnostic Radiology, all CT and
MRI examinations are monitored and reported bydiagnostic radiologists. Diagnostic radiologists,
gastroenterologists and cardiologists mainly perform
interventional procedures.
In the section of Nuclear Medicine, there are two
SPECT rooms and three PET rooms. These nuclear
imaging procedures are chiefly performed andreported by radiologists and cardiologists.
Each year, over 700 new patients receive radiation
therapy in the Radiation Oncology section. Highly
accurate 3D radiation therapy is the most outstanding
feature. Stereotactic radiation therapy for small lungor liver tumors was kicked off recently.
In the 9th floor of the new inpatient building, there
are 12 beds in the Radiology ward, which are usuallyused for oncology patients receiving radiation therapy
and chemotherapy. Some of them are sometimes used
for patients receiving invasive diagnostic procedures

55

such as interventional radiology (IVR), angiography
and myelography. There are two special beds forradionuclide (RN) therapy in the same floor. In
addition, four beds are allotted to terminal care ward
located in the 14th floor.

Teaching activities
Lectures are given to the fourth-, fifth- andsixth-year students to provide fundamental knowledgeof diagnostic radiology, radiation oncology andnuclear medicine. Professor, associate professors andlecturers as well as specialists assigned as part timelecturers take part in the education. A series of lectures
about fundamentals of radiology and related sciences
are given to the fourth-year students. As bed-sidelearning (BSL) curriculum, sixteen small groups ofthe fifth-year students are taking part in mini-lecturesand practice to learn basics of diagnostic radiology for
one week. For the sixth-year students, another weekof small group training and mini-lectures are preparedto learn advanced medical techniques of Radiation
Oncology and Nuclear Medicine. They will learn
detailed principles of image constructions in various
kinds of imaging modalities and technology inradiation therapy against cancer. Postgraduate students
are also welcome to each of subspecialties ofradiology according to their interests.

Research activities
Research activities in our department include
clinicalresearch,
animalexperiments
anddevelopment of instruments as well as computer-based
new technology. Diagnostic Radiology group in thedepartment promotes research activities aiming at
efficacy improvement of diagnostic imaging andexpansion of its application. Multi-row detector
helical computed tomography (MDCT) enables us totake tomographic images in three-dimensional (3D)fashion. Using the data acquired by MDCT various
kinds of diseases in almost all parts of the body, from
cerebral diseases to musculoskeletal diseases, can bedisplayed in 3D images. New 3D software developedin our departments is now widely used in the field of
the gastrointestinal tract, lung, and central nervous
system. In addition, we have opened a new laboratory

section named Image Computing and Analysis
Laboratory with invitation of a new staff from theFaculty of Engineering, the University of Tokyo. Thissection will contribute to development of novelsoftware to abstract clinically useful information fromthe 3D imaging data more sophisticatedly. In the fieldof magnetic resonance (MR) imaging, MR digital
subtraction angiography, perfusion imaging, anddiffusion tensor imaging are the foci of research.
These techniques are aggressively applied to theinvestigation of vascular and neoplastic diseases ofthe brain. Application of an open-type MR imaging
unit to interventional radiology is another field ofclinical research. In our section, MR imaging is
specifically used to the treatment of vascularmalformation. Basic animal experiments are also inprogress in the field of functional MR imaging anddiffusion and perfusion MR techniques.
Radiation oncology group promotes research
projects in two major fields, one is physicalengineering aspect of radiotherapy and the other isreduction of injuries due to radiation exposure. With
the purpose of achieving precise external irradiation, a
new linear accelerator with C-arm and multileaf
collimator systems was developed and installed,which is utilized mainly for non-coplanar radiation
therapy in many patients especially with brain tumor
or head and neck tumor. Dynamic conical conformal
radiotherapy (Dyconic therapy) for metastatic brain
tumors using the accelerator is under evaluation. In
addition to gamma knife radiosurgery, this new
accelerator based stereotactic radiotherapy for brain
diseases has been undergone, and stereotactic
radiotherapy for body tumors, such as lung and liver
tumors, has been investigated. A new technology to
track mobile tumors, represented by lung tumors isunder investigation in collaboration with accelerator
makers. Novel approach to terminal care of patientswith various cancers has been investigated andimplemented as the palliative care team in cooperation
with expert nurses. The relationship between terminal
condition and cytokines, and newly developed scoring
system of quality of life are being evaluated. The
gustatory injury due to radiotherapy has been
investigated through animal experiments incombination with the laboratory of biological function,
Graduate School of Agricultural and Life Sciences,

56

University of Tokyo, and through taste tests in clinicalsetting. Radiation injuries in many tissues in thecritically accident in Tokai-mura were also
investigated.
Nuclear Medicine group promote clinical researchon images of function by the application ofradioisotope-labeled tracer technology. In particular,emission tomography (PET and SPECT) is applied forthe evaluation of cerebral blood flow and metabolism
inpatients
withdementia,
epilepsy,andcerebrovascular diseases. Cerebral blood flow, glucose
metabolism and neural synaptic functions aremeasured for the understanding of normal andpathophysiological states of CNS disorders, using avariety of positron-emitter radiotracer, such as [O-15]
H2O, CO2, O2, CO, [F-18] FDG, [C-11] methionine,[F-18]Dopa, [C-11]NMSP, NMPB and [C-11]
raclopride. The study of dementia using SPECT andthe standard brain atlas has made it possible tocategorize the type of dementia. Evaluation of
dopaminergic function by PET is very important in the
differential diagnosis of parkinsonism. Cardiac PET
and SPECT are also active fields. Myocardial viability,
vascular reserve and sympathetic nerve denervation in
the ischemic heart disease are evaluated with [F-18]
FDG, [N-13] NH3, Tl-201 and [I-123] MIBG. Higher
brain functions such as reading, speech and thinking
have been studied with PET by comparing blood flow
and receptor binding potential (BP) under various
tasks and at rest. For the precise localization ofactivated brain function, computer processing andreconstruction of composite images of function andanatomy is an essential subject for investigation. At
present, whole body FDG-PET is one of the mosteffective tool for exploring metastatic lesions ofcancer patients. Combination display of SPECT/PET
with XCT/MRI would be a routine job andanatomo-functional images would play an importantrole in the clinical management of the patients.

References
1) Aoki S, Masutani Y, Abe O.
Magnetic resonance diffusion tractography in thebrain--its application and limitation.
Brain Nerve 59: 467-76, 2007
2) Byrnes V, Shi H, Kiryu S, Rofsky NM, Afdhal NH.

The clinical outcome of small (<20 mm) arteriallyenhancing nodules on MRI in the cirrhotic liver.
Am J Gastroenterol 102: 1654-9, 2007
3) Hashimoto M, Kokudo N, Imamura H, Akahane
M, Makuuch M.
Demonstration of the common hepatic arterycoursing
inthelesseromentumbythree-dimensional computed tomography.
Surgery 141: 121-3, 20074) Hori M, Ishigame K, Aoki S, Kumagai H, Araki
T:
Diffusion tensor imaging and 3D tractography ofthe cervical spinal cord using the ECG-gatedline-scan technique. A feasibility study.
The Neuroradiology Journal 20: 574-9, 2007
5) Inoue Y, Izawa K, Yoshikawa K, Yamada H, Tojo
A, Ohtomo K.
In vivo fluorescence imaging of thereticuloendothelial system using quantum dots incombination
withbioluminescenttumourmonitoring.
Eur J Nucl Med Mol Imaging 34: 2048-56, 2007
6) Inoue Y, Izawa K, Tojo A, Nomura Y, Sekine R,
Oyaizu N, Ohtomo K.
Monitoringof
diseaseprogression
bybioluminescence imaging and magnetic resonanceimaging in an animal model of hematologic
malignancy.
Exp Hematol 35: 407-15, 2007
7) Inoue Y, Yoshikawa K, Nomura Y, Izawa K,
Shimada M, Tojo A, Ohtomo K.
Gadobenate dimeglumine as a contrast agent for
MRI of the mouse liver.
NMR Biomed 20: 726-32, 20078) Iwase S, Murakami T, Saitou Y, Nakagawa K.
Preliminary stastical assessment of intervention
by a palliative care team working in a Japanesegeneral inpatient unit.
Am J Hosp Palliat Care 24: 1-7, 2007
9) Kabasawa H, Masutani Y, Aoki S, Abe O,
Masumoto T, Hayashi N, Ohtomo K.
3T PROPELLER diffusion tensor fiber
tractography: a feasibility study for cranial nerve
fiber tracking.
Radiat Med 25: 462-6, 200710) Kako S, Izutsu K, Ota Y, Minatani Y, Sugaya M,
Momose T, Momose K, Ohtomo K, Kanda Y,

57

Chiba S, Motokura T, Kurokawa M.
FDG-PET in T-cell and NK-cell neoplasms.
Ann Oncol 18: 1685-90, 200711) Kamada K, Todo T, Masutani Y, Aoki S, Ino K,
Morita A, Saito N.
Visualization of the frontotemporal language
fibers by tractography combined with functional
magnetic
resonance
imagingandmagnetoencephalography.
J Neurosurg 106: 90-8, 200712) Kiryu S, Sundaram T, Kubo S, Ohtomo K,
Asakura T, Gee J, Hatabu H, Takahashi M.
MRI assessment of lung parenchymal motion innormal mice and transgenic mice with sickle celldisease.
J Magn Reson Imaging 27: 49-56, 200713) Koyama M, Yagishita A, Nakata Y, Hayashi M,
Bandoh M, Mizutani T.
Imaging of corticobasal degeneration syndrome.
Neuroradiology 49: 905-12, 2007
14) Kunimatsu A, Itoh D, Nakata Y, Kunimatsu N,
Aoki S, Masutani Y, Abe O, Yoshida M, Minami
M, Ohtomo K.
Utilization of diffusion tensor tractography incombination with spatial normalization to assess
involvement of the corticospinal tract in
capsular/pericapsular stroke: feasibility andclinical implications.
J Magn Reson Imaging 26: 1399-404, 200715) Kuwabara K, Nishishita T, Morishita M, Oyaizu
N, Yamashita S, Kanematsu T, Obara T, Mimura Y,
Inoue Y, Kaminishi M, Kaga K, Amino N,
Kitaoka M, Ito K, Miyauchi A, Noguchi S,
Uchimaru K, Akagawa E, Watanabe N, Takahashi
TA, Sato K, Inazawa T, Nakaoka T, Yamashita N.
Results of a phase I clinical study using dendritic
cell vaccinations for thyroid cancer.
Thyroid 17: 53-8, 200716) Maeda E, Akahane M, Watadani T, Yoshioka N,
Goto A, Sugawara Y, Makuuchi M, Ohtomo K.
Isolated hepatic hemangiomatosis in adults: reportof two cases and review of the literature.
Eur J Radiol extra 61: 9-14, 200717) Maruyama K, Kamada K, Shin M, Itoh D,
Masutani Y, Ino K, Tago M, Saito N,
Optic radiation tractography integrated into
simulated treatment planning for Gamma Knife

surgery.
J Neurosurg 107: 721-6, 200718) Maruyama K, Shin M, Tago M, Kishimoto J,
Morita A, Kawahara N.
Radiosurgery to reduce the risk of firsthemorrhage
from
brain
arteriovenous
malformations.
Neurosurgery 60: 453-9, 200719) Mori H, Yagishita A, Takeda T, Mizutani T.
Symmetric temporal abnormalities on MR
imaging in amyotrophic lateral sclerosis withdementia.
AJNR Am J Neuroradiol 28: 1511-6, 200720) Mori H, Aoki S, Ohtomo K.
The "morning glory sign" may lead to false
impression according to slice angle.
Magn Reson Med Sci 6: 183-5, 200721) Nakagawa K, Yoda K, Masutani Y, Sasaki K,
Ohtomo K.
A rod matrix compensator for small-field intensity
modulated radiation therapy: a preliminary
phantom study.
IEEE Trans Biomed Eng 54: 943-6, 200722) Nakagawa K, Yoda K, Shiraki T, Sasaki K,
Miyazawa M, Ishidoya T, Ohtomo K, Hamada M.
Radiophotoluminescence dosimetry using a small
spherical glass: a preliminary phantom study.
Radiat Prot Dosimetry 123: 254-6, 200723) Nakamura N, Igaki H, Yamashita H, Shiraishi K,
Tago M, Sasano N, Shiina S, Omata M, Makuuchi
M, Ohtomo K, Nakagawa K.
A retrospective study of radiotherapy for spinal
bone metastases from hepatocellular carcinoma(HCC).
Jpn J Clin Oncol 37: 38-43, 200724) Nojo T, Takao H, Makita K, Miyata R, Kohyama J.
Diffusion-weighted magnetic resonance images
and blood perfusion of hemiconvulsionhemiplegia-epilepsy syndrome.
J Pediatr Neurol 5: 243-5, 200725) Ohmoto-Sekine Y, Suzuki J, Shimamoto R,
Yamazaki T, Tsuji T, Nagai R, Ohtomo K.
Gender-specific clinical characteristics of deep Q
waves in hypertrophic cardiomyopathy.
Gend Med 4: 274-83, 200726) Sakurai Y, Onuma Y, Nakazawa G, Ugawa Y,
Momose T, Tsuji S, Mannen T.

58

Parietal dysgraphia: characterization of abnormal
writing stroke sequences, character formation andcharacter recall.
Behav Neurol 18: 99-114, 200727) Sato N, Yagishita A, Oba H, Miki Y, Nakata Y,
Yamashita F, Nemoto K, Sugai K, Sasaki M.
Hemimegalencephaly: a study of abnormalities
occurring outside the involved hemisphere.
AJNR Am J Neuroradiol 28: 678-82, 200728) Shimamoto R, Suzuki J, Yamazaki T, Tsuji T,
Ohmoto Y, Morita T, Yamashita H, Honye J,
Nagai R, Akahane M, Ohtomo K.
A new method formeasuring coronary arterydiameters with CT spatial profile curves.
Radiography 13: 44-50, 200729) Takahashi M, Kubo S, Kiryu S, Gee J, Hatabu H.
MR microscopy of the lung in small rodents.
Eur J Radiol 64: 367-74, 200730) Takao H, Nojo T, Ohtomo K.
Evaluation of an automated system for temporalsubtraction of thin-section thoracic CT.
Br J Radiol 80: 85-9, 200731) Takao H, Doi I, Watanabe T.
Superselective
transcatheter
arterial
chemoembolisationofanunresectable
hepatocellular carcinoma using three-dimensionalrotational angiography.
Br J Radiol 80: 85-7, 200732) Takao H, Makita K, Doi I, Watanabe T.
Mycotic pulmonary artery aneurysm diagnosed 18
years after bacterial endocarditis.
Clin Imaging 31: 131-3, 2007
33) Takao H, Nojo T.
Treatment of unruptured intracranial aneurysms:
decision and cost-effectiveness analysis.
Radiology 244: 755-66, 2007
34) Terao Y, Ugawa Y, Yamamoto T, Sakurai Y,
Masumoto T, Abe O, Masutani Y, Aoki S, Tsuji S.
Primary face motor area as the motor
representation of articulation.
J Neurol 254: 442-7, 200735) Tsujino T, Kogure H, Sasahira N, Isayama H,
Tada M, Kawabe T, Omata M, Akahane M, Sano
K, Makuuchi M.
A huge intra-abdominal mass in a young man.
Gut 56: 1372, 2007
36) Yamasaki S, Yamasue H, Abe O, Yamada H,

Iwanami A, Hirayasu Y, Nakamura M, Furukawa
S, Rogers MA, Tanno Y, Aoki S, Kato N, Kasai K.
Reduced planum temporale volume anddelusional
behaviourinpatientswithschizophrenia.
Eur Arch Psychiatry Clin Neurosci 257: 318-24,
200737) Yamashita H, Nakagawa K, Shiraishi K, Tago M,
Igaki H, Nakamura N, Sasano N, Siina S, Omata
M, Ohtomo K.
Radiotherapy for lymph node metastases inpatients
withhepatocellular
carcinoma:
retrospective study.
J Gastroenterol Hepatol 22: 523-7, 200738) Yamashita H, Nakagawa K, Nakamura N,
Koyanagi H, Tago M, Igaki H, Shiraishi K,
Sasano N, Ohtomo K.
Exceptionally high incidence of symptomatic
grade2-5 radiation pneumonitis after stereotactic
radiation therapy for lung tumors.
Radiat Oncol 2: 21, 2007
39) Yamasue H, Abe O, Kasai K, Suga M, Iwanami A,
Yamada H, Tochigi M, Ohtani T, Rogers MA,
Sasaki T, Aoki S, Kato T, Kato N.
Human brain structural change related to acutesingle exposure to sarin.
Ann Neurol 61: 37-46, 200740) Yamazaki T, Suzuki J, Shimamoto R, Tsuji T,
Ohmoto-Sekine Y, Ohtomo K, Nagai R.
A new therapeutic strategy for hypertrophic
nonobstructive cardiomyopathy in humans.
Int Heart J 48: 715-24, 2007

Radiology and Biomedical
Engineering
2. Biomedical Engineering

60

Department of System Physiology
Professor
Joji Ando, M.D.,Ph.D.

Lecturer
Masahiro Shibata, Ph.D.,

Homepage

Kimiko Yamamoto, M.D.,Ph.D.

http://bme-sysphysiol.m.u-tokyo.ac.jp/

Introduction and Organization
Our department originated from the Institute ofMedical Electronics, established in 1961. In 1997, as aresult of the shift to the chair system of the Graduate
School of Medicine, the Institute was replaced withthree departments of Biomedical Engineering: System
Physiology, Bioimaging and Biomagnetics, andBiosystem Construction and Control. The Department
of System Physiology consists of one professor andtwo lecturers.

Teaching activities
We provide lectures of “Early Exposure to
Medicine” for second year students, “Basic Principles
of Biomedical Engineering” for second and third year
students, “Introduction to Biomedical Engineering”
for postgraduate students in the faculty of Medicine,and “Principles of Medicine” for postgraduate
students in the faculty of Engineering. We offer
practical training of biomedical engineering research
to third and fourth year medical students. A weekly
seminar is held in our laboratory bringing together
staff, postgraduate students and research fellows to
discuss journal articles and give updates on
experiments. Our aim is to enhance the research skillsof students.

Research activities
This laboratory has been pursuing the study ofbiomechanics dealing with mechanical phenomena in
the human body, especially focusing on cellularsensing and response mechanisms to mechanicalstimuli. The main theme of our work is therelationships between shear stress, a mechanical force
generated by blood flow, and its target cells, vascularendothelial cells. This would be of benefit not only tounderstanding blood flow-mediated regulation ofvascular functions but also to the elucidation ofclinically important problems such as angiogenesis,
vascular remodeling and atherogenesis which occur ina blood flow-dependent manner.
Original biomedical engineering methods have been
applied, in which cultured endothelial cells are
exposed to controlled levels of shear stress in a fluid–
dynamic flow apparatus and whose responses areanalyzed at the cellular and molecular levels.
Microcirculatory hemodynamics and oxygen transport
are studied by employing opto-electronics technology.
The results of these experiments are listed below.
1. Cell responses to shear stress
2. Shear stress-mediated gene regulation
3. Shear stress signal transduction
4. Oxygen dynamics and microvascular energetics
1. Cell responses to shear stress
Our studies have demonstrated that endothelial cells
have functional responses to shear stress. When acultured endothelial cell monolayer was partiallydenuded, surrounding cells migrated and proliferated
in the denuded area, and covered the denuded area.
Shear stress enhanced the regenerative functions of

61

endothelial cells (Microvasc Res 1987, Biorheology,1990). Shear stress increased the production of nitricoxide, a potent vasodilator, in endothelial cells in adose-dependent manner (BBRC 1994). Shear stressalso increased the expression of thrombomodulin, an
antithrombotic molecule, in endothelial cells (BBRC
1994). In contrast, it decreased the expression ofvascular cell adhesion, which leads to the inhibition ofleukocyte adhesion to vascular cell adhesion
molecule-1 (VCAM-1; BBRC 1993, Am J Physiol
1994). A collaborative study showed that shear stressincreases the levels of adrenomedulin and C-typenatriuretic peptide mRNA which have vasodilating
effects in addition to nitric oxide (Hypertension 1997),
and that it also augmented the expression of lectin likelow density lipoprotein receptor (LOX-1) at theprotein and mRNA level (Circ Res 1998). We revealed
that endothelial progenitor cells (EPCs) circulating inhuman peripheral blood proliferate and differentiate
into mature endothelial cells in response to shear
stress, thereby forming tube-like structures in collagengel (J Appl Physiol 2003). We also found that shear
stress induces the differentiation of murine embryonicstem cells (ES cells) into endothelial cells in vitro(Am J Physiol 2005). Based on these findings, in acollaborative study, a new type of artificial bloodvessel, in which ES cells were cultured in polymer
tubes and exposed to pulsatile shear stress, wasdeveloped (J Artif Organs 2005). Recently, wedemonstrated that cyclic strain induces ES celldifferentiation into smooth muscle cells and that aligand-independent phosphorylation of PDGF receptor
is involved in the effect of cyclic strain (J Appl
Physiol 2008).
2. Shear stress-mediated gene regulation
We have demonstrated that shear stress regulates
endothelial gene expression transcriptionally and/or
posttranscriptionally. Shear stress downregulates
VCAM-1 gene transcription via the double AP-1
binding element (TGACTCA) in the promoter whichfunctions as a shear stress-responsive element (Am J
Physiol 1997). Shear stress has also been shown toincrease the level of granulocyte/macrophase-colony
stimulating factor (GM-CSF) via mRNA stabilization(Circ Res 1988). Differential display analysis showedthat around 600 known and unknown transcripts wereup- or down-regulated in human umbilical vein
endothelial cells exposed to a shear stress of 15
dynes/cm2 for 6 h (BBRC 1996). From these shear
stress-responsive genes, a cDNA encoding an
unknown G-protein coupled receptor was cloned(BBRC 1997). We showed that the transcription factor
SP1 is involved in the shear stress-induced
down-regulation of P2X4 (an ATP-gated cation
channel) gene expression in endothelial cells (Am J
Physiol 2001). DNA microarray analysis revealed thatapproximately 3% of the all endothelial genes, whichcorresponds to about 600 genes, respond to shear
stress (J Athero Thromb 2003). We revealed that
endothelial genes are differentially regulated bylaminar and turbulent shear stress. Laminar shear
stress decreases the gene expression of urokinase
plasminogen activator (uPA), which plays a role infibrinolysis and vascular remodeling, via both
GATA6-mediateddown-regulationofgene
transcription and an acceleration of mRNAdegradation, while turbulent shear stress increases theuPA gene expression through mRNA stabilization (AmJ Physiol 2004). We found that hepatocytes areflow-sensitive. Hepatocyte PAI-1 gene expression was
up-regulated by shear stress through cooperative
Sp1/Ets-1 activation of transcription (Am J Physiol
2006). Recently, we developed a silicon-tube typeflow-loading device and revealed that endothelial
gene responses vary depending on whether cells are
simultaneously exposed to both shear stress and cyclicstrain or subjected to shear stress or cyclic strain alone(J Biotechnol 2008).
3. Shear stress signal transduction
We first showed that Ca2+ signalling plays animportant role in the mechanism by which endothelial
cells recognize the shear stress signal and transmit itinto the cell interior（In Vitro Cell Dev Biol 1988.
Strong shearing forces induced by dragging
endothelial cells with a balloon causes an increase incytoplasmic Ca2+ concentrations (Biorheology 1994).
A relatively weak shearing force like shear stressgenerated by fluid flow needs the presence of
extracellular ATP to induce Ca2+ response, and atseveral hundred nanomolar of ATP, intracellular Ca2+
concentrations increase in a shear stress-dependent

62

manner (BBRC 1991, 1993). Generally, flow-induced
Ca2+ responses are initiated at a locus at the cell edge
and propagate throughout the entire cell in the form ofa Ca2+ wave. The initiation locus corresponded
precisely to caveolae rich cell edges (Proc Natl Acad
Sci 1998). We found that a subtype of ATP-gatedcation channel, the P2X4 receptor, is expressed inhuman vascular endothelial cells (Am J Physiol 2000)
and that P2X4 receptors play a crucial role in theshear stress-dependent Ca2+ response (Circ Res 2000).
Endogeneously released ATP by shear stress isinvolved in the P2X4-mediated Ca2+ responses (Am J
Physiol 2003). We produced P2X4-deficient mice andobserved that the P2X4-deficent mice have impaired
flow-dependent control of vascular tone andremodeling, indicating that shear stress signaltransduction via P2X4 plays a critical role in theregulation of circulatory functions (Nat Med 2006).
Recently, we found that cell surface F1FoATP
synthase located at caveolae/raft is involved in shear
stress-induced ATP release by endothelial cells (Am J
Physiol 2007).
4.Oxygen dynamics and microvascular energetics
For nearly 100 years, the capillary is believed to be
the sole source of oxygen supply to surrounding tissue.
By using an originally developed laser microscopic
system (Med Biol Eng Comput 1999), we found asignificant downstream drop in the arteriolar oxygen
level (J Appl Physiol 2001), and clarified that thisdrop in oxygen was caused by oxygen supply to tissue
from arterioles (Eur J Appl Physiol 2005, 2006).
Furthermore, we have examined the effect of vessel
wall oxygen consumption on the oxygen drop inarterioles. We found that the vascular wall oxygen
consumption in functional arterioles was more than
100 times greater than the values reported in in vitro
experiments, and the oxygen consumption depends on
the total amount of workload of vascular smoothmuscle (Am J Physiol 2005a). We have also studied
the relationship between the endothelium derived
nitric oxide and oxygen transport to tissue, andclarified the physiological role of nitric oxide as amodulator of tissue oxygenation by reducing oxygen
consumption by vessel walls (Am J Physiol 2005b, J
Appl Physiol 2006).

References(1) Shimizu N, Yamamoto K, Obi S, Kumagaya S,
Masumura T, Shimano Y, Naruse K, Yamashita
JK, Igarashi T, and Ando J. Cyclic strain induces
mouse embryonic stem cell differentiation into
vascular smooth muscle cells by activating PDGF
receptor β. J Appl Physiol 2008;104:766-772.
(2) Tsuda T, Toyomitsu E, Komatsu T, Masuda T,
Kunifusa E, Nasu-Tada K, Koizumi S, Yamamoto
K, Ando J, and Inoue K. Fibronectin/integrin
system is involved in P2X4 receptor upregulationin the spinal cord and neuropathic pain after
nerve injury. Glia 2008; 56:579-585.
(3) Toda M, Yamamoto K, Shimizu N, Obi S,
Kumagaya S, Igarashi T, Kamiya A, and Ando J.
Differential gene responses in endothelial cells
exposed to a combination of shear stress andcyclic stretch. J Biothechnol 2008; 133:239-244.
(4) Yamamoto K, Shimizu N, Obi S, Kumagaya S,
Taketani Y, Kamiya A, and Ando J. Involvementof cell surface ATP synthase in flow-induced ATP
release by vascular endothelial cells. Am J
PhysiolHeart
Circ
Physiol
2007;
293:H1646-H1653.
(5) Koshiba N, Ando J, Chen X, and Hisada T.
Multipysics simulation of blood flow and LDLtransport in a porohyperelastic arterial wallmodel. J Biomech Eng 2007; 129:374-385.
(6) Hayashida K, Kanda K, Yaku H, Ando J,
Nakayama Y.
Development of an in vivo
tissue-engineered, autologous heart valve 9thebiovalve): Preparation of a prototype model. J
Throac Cardiovasc Surg 2007; 134:152-159.
(7) Sugiyama S, Yamamoto K, Nishimura N,
Nakagawa M, Maruta Y, Ando J. Adequate designof customized cDNA microarray for convention
multiple gene expression analysis. J Biosci
Bioeng 2007: 103:74-81.
(8) Ichioka S, Ando T, Shibata M, Sekiya N,
Nakatsuka T. Oxygen consumption of keloids andhypertrophic scars. Ann Plast Surg 2007; 60:
194-197.
(9) Shibata M, Ohura N, Sekiya N, Ichioka S,
Yamakoshi T, Yamakoshi K, Kamiya A. Compact
capillaroscopy for human skin using CCD
video-probe. Microvascular Reviews and63

Communications 2007; 1: 4-7.
(10) Nakagami G, Sanada H, Matsui N, Kitagawa A,
Yokogawa H, Sekiya N, Ichioka S, Sugama J,
Shibata M. Effect of vibration on skin blood flowin an in vivo microcirculatory model. BioScience
Trends 2007; 1: 161-166.
(11) Ichioka S, Sekiya N, Shibata M, Nakatsuka T.
Alpha V beta 3 (αvβ3) integrin inhibition reduces
leukocyte-endotheliuminteraction
inapressure-induced reperfusion model. Wound Rep
Reg 2007; 15: 572-576.
(12) Nakatsuka H, Sokabe T, Yamamoto K, Sato Y,
Hatakeyama K, Kamiya A, Ando J. Shear stressinduces hepatocyte PAI-1 gene expression
thorugh cooperative Sp1/Ets-1 activation oftranscription. Am J Phsyiol Gastrointest Liver
Physiol 2006; 291: G26-G34.
(13) Mackley JR, Ando J, Herzyk P, Winder SJ.
Phenotypic responses to mechanical stress infibroblasts from tendon, cornea and skin.
Biochem J 2006; 396:307-316.
(14) Nakamura M, Mie M, Funabashi H, Yamamoto K,
Ando J, Kobatake E. Cell-surface-localized ATP
detection with immobilized firefly luciferase.
Anal Biochem 2006; 352: 61-67.
(15) Yamamoto K, Sokabe T, Matsumoto T,
Yoshimura K, Shibata M, Ohura N, Fukuda T,
Sato T, Sekine K, Kato S, Isshiki M, Fujita T,
Kobayashi M, Kawamura K, Masuda H, Kamiya
A, Ando J. Impaired flow- dependent control ofvascular tone and remodeling in P2X4-deficientmice. Nat Med 2006; 12: 133-137.
(16) Shibata M, Qin K, Ichioka S, Kamiya A. Vascularwall energetics in arterioles during nitric oxide
dependent and independent vasodilation. J Appl
Physiol. 2006; 100: 1793-1798.
(17) Shibata M, Ichioka S, Togawa T, Kamiya A.
Arterioles’ contribution to oxygen supply toskeletal muscles at rest. Eur J Appl Physiol.
2006; 97: 327-331.
(18) Ohura N, Kurita T, Takishima A, Shibata M,
Harii K. Efficacy of a skin-protection power for
use as a dressing for intractable ulcers. J Wound
Care. 2006; 15: 471-478.

64

Department of Biosystem
Construction & Control
Associate Professor
Yusuke Abe, M.D., Ph.D.

Lecturer
Takashi Isoyama, Ph.D.

Homepage http://www.bme.gr.jp/
Introduction and Organization
Institute of Medical Electronics was established in
1963 as the first research institute for medical
engineering in Japan. Department of Clinical
Medicine in the Institute of Medical Electronics wasstarted in 1964 for research and development of theadvanced diagnostic and of the therapeutic medical
engineering technologies in clinical medicine. To
date, medical engineering has grown up not only to avery important academic discipline but also to a very
important means for the clinical medicine. The nameof the department and institute has been changed asshown above since April 1, 1997 with the structuralreformation of the Faculty of Medicine.
The research covers wide area of interdisciplinary andcomprehensive research fields based on the medical
and engineering techniques, we are cooperating withvarious laboratories. Especially, Research Center for
Advanced Science and Technology (RCAST) and
Department of Information Physics and Computing(IPC), Graduate School of Information Science andTechnology have close relations with us, contacting
and performing various cooperative researches. Our
doctor course students have the opportunity toperform research work under the guidance of Prof.
Mabuchi at IPC.

Teaching activities
As for under-graduate education, our department takes

a part in systematic lectures for the 3rd year medical
students, and provides practice in the “free quarter”
course and other short-term course for the 3rd and 4thyear medical students. In systematic lectures, basic
knowledge about the advanced diagnostic andtherapeutic medical engineering technologies andartificial organ technologies are presented. The basic
lectures of medical electronics are included.
As for post-graduate education, our department takes
a part in series of lectures for master course anddoctor course students. In the lectures for mastercourse students, artificial organ technologies arepresented. In the lectures for doctor course students,
philosophy, methodology and basic and special
knowledge about medical engineering for basic andclinical medicine are presented.
The educational practice of the post-graduate students
is performed mainly by on-the-job training method in
the daily research works. Pre-operative management,
anesthesia, surgery, post-operative management,
measurement, data processing, ethical factor, andmany other important information are acquired
through the fabrication and the animal experiment ofartificial hearts. As for the subject of research,
students find by themselves not only from the field ofartificial organs but also from the wide area of
medical engineering fields. On the other hand, theeducation to train the leaders of biomedical engineers
and clinical engineers is another important role.
About half of our students come from medical
departments and other students come from

65

engineering departments of our university and otheruniversities. Students must attend to weekly meeting.
They can learn how to perform the research work andhow to report it through this meeting.

Research activities
Our research field covers advanced diagnostic andtherapeutic medical engineering technologies forclinical medicine. The main themes are artificialorgans (artificial heart, assist circulation, artificial
lung, artificial valve, tissue engineered artificialorgans, regenerative artificial organs, etc). Especially,
artificial heart is the world famous research project
having a long history since 1959 at the University ofTokyo. Almost all the researches and developments
for driving mechanisms, energy converters, blood
pumps, artificial valves, biomaterials, powertransmissions, measurement techniques, control
methods,
anatomicalcompatibility,
hemocompatibility, tissue compatibility, computer
fluid dynamics, physiology, pathology, and so on,
have been studied. All the stuffs and students are
participating in the artificial heart project. In 1995,
we succeeded to survive a goat for 532 days with theparacorporial total artificial heart (TAH), which is still
the longest survival record of TAH animals in theworld.
Our artificial heart research at present is to develop an
implantable TAH. We invented a small continuousflow blood pump with high performance, named
undulation pump, to meet the purpose. We aredeveloping an undulation pump total artificial heart(UPTAH) using undulation pumps. The UPTAH is themost compact implantable TAH with the highest
performance in producing output in the world. ThisTAH is designed to generate pulsatile flow bychanging motor speed periodically. Recently, the newmodel of UPTAH was developed for the purpose of
studying physiology with nonpulsatile TAH. This
UPTAH can switch pulsatile flow to nonpulsatile flow
with a single device easily. We succeeded to survive agoat for 153 days with UPTAH.
How to control the output of TAH is another big
interest. We have developed our original control
method, named 1/R control, in which the cardiac
output is controlled by the cardiovascular center

through the feedback mechanism using changes intotal peripheral resistance and arterial pressure. At thepresent time, 1/R control is the only reported method
to achieve a physiological control of a TAH logically.
With 1/R control, the particular problems of TAH
such as venous hypertension, slight anemia, low
thyroid hormone level, and so on, were not observed
and the output was changed in accordance with ametabolic condition of the animal. 1/R control was
installed in the UPTAH and the pathphysiologicalstudy is being performed.
Concerning the biomaterials, the mechanism ofthrombus formation and calcification on the medical
polymer surfaces have been studied. Recently, wedeveloped tissue engineered insert molding method
for making parts of artificial organs. This method will
be important technique for developing next generation
artificial organs.
An implantable probe for observation of
microcirculation has been developed using CCD chip.
This device is expected to progress the physiology ofthe microcirculation with TAH. The new implantableprobe for observation of angiogenesis in tissue
engineered material using CMOS camera is under thedevelopment.
Nerve interface will be very important technology fordeveloping control mechanism of artificial organs.
The basic study to develop a multiple interface arrayfor single nerve fibers is being studied.

References
1. Abe Y, Isoyama T, Saito I, Mochizuki S, Ono M,
Nakagawa H, Taniguchi N, Mitsumune N, Sugino
A, Mitsui M, Takiura K, Ono T, Kouno A, Chinzei
T, Takamoto S, Imachi K: Development of
mechanical circulatory support device at theuniversity of Tokyo. J Artif Organs, 10:60-70,
2007
2. Mitsumune N, Saito I, Mochizuki S, Abe Y,
Isoyama T, Nakagawa H, Ono T, Kouno A,
Sugino A, Chinzei T: Fundamental study todevelop a fiber-optic gap sensor for a rotary
undulation pump. J Artif Organs, 10:231-235,
2007
3. Imachi K, Mochizuki S, Baba A, Isoyama T, Saito
I, Takiura K, Chinzei T, Shiraishi Y, Yambe T, Abe

66

4.

5.

6.

7.

Y: Development of implantable probe forobservation of microcirculation. Biocybernetics
and Biomed Eng, 27:45-52, 2007
Okamoto E, Nakamura M, Akasaka Y, Inoue Y,
Abe Y, Chinzei T, Saito I, Isoyama T, Mochizuki
S, Imachi K, Mitamura Y: Analysis of heatgeneration of lithium ion rechargeable batteries
used in implantable battery systems for driving
Undulation Pump Ventricular Assist Device. Artif
Organs, 31:538-541, 2007
Fukayama O, Taniguchi N, Saito S, Suzuki T,
Mabuchi K: Control of a Vehicle-formed BMI
system for Rats by Neural Signals Recorded in theMotor Cortex. Proc of the 3rd International IEEE
EMBS Conference on Neural Engineering, 394397, 2007
Taniguchi N, Suzuki T, Mabuchi K:
Biocompatibility of wire electrodes improved by
MPC polymer coating. Proc of the 3rdInternational IEEE EMBS Conference on NeuralEngineering, 122-125, 2007
Vasku J, Wotke J, Dobsak P, Baba A, Rejthar A,
Kuchtickova S, Imachi K, Abe Y, Saito I, Isoyama
T, Nitta S, Yambe T: Acute and chronic
consequences of non-pulsatile blood flow patterninlong-term
total
artificial
heart.
Pathopysiology, 14:87-95, 2007

Neuroscience
1. Basic Neuroscience68

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

Associate Professor
Lecturer
Associate

Homepage
Dr. Iwatsubo’s research group has been pursuing
the pathogenesis of Alzheimer’s disease (AD) andrelated neurodegenerative conditions (especially,
dementia
withLewy
bodies;DLB)
bymultidisciplinary approaches, based on histopathology
and protein biochemistry of postmortem human brains.
They then extended the knowledge derived from thehuman studies in a way to establish cellular models
and to elucidate the key steps in the pathologicalcascade of neurodegeneration. Thus, Dr. Iwatsubo’sgroup has been addressing the pathogenesis ofneurodegenerative disorders from the downstream (i.e.,analysis of aggregated proteins) as well as from the
upstream (i.e., pathogenic effects of pathogenic genes),
covering a number of crucial proteins/genes related to
AD and DLB, i.e., β-amyloid (including its binding
protein CLAC), presenilin/ γ -secretase and α-synuclein. In this way Dr. Iwatsubo’s group has
contributed much to the widely accepted notion that
abnormal misfolding of brain proteins is the common
cause of a variety of neurodegenerative disorders
including AD. Furthermore, Dr. Iwatsubo’s group is
currently working hard to translate the basic findings
into the clinical application of mechanism-based,disease-modifying therapies for AD through theworld-wide ADNI project, in which Dr. Iwatsubo
serves as the PI of Japanese ADNI.

1. Research on β-amyloid and presenilins
Using C-terminal specific monoclonal antibodies
that discriminate amyloid β peptides (Aβ) endingat 40th or 42nd residues (A β 40 and A β 42,
respectively), Dr. Iwatsubo has performed asystematic immunohistochemical studies on autopsied
brain tissues from patients with AD, Down syndrome
and familial AD, and demonstrated that Aβ42, thatmost readily form amyloid fibrils in vitro, is theinitially and predominantly deposited species inhuman cerebral β -amyloidosis (Iwatsubo et al.
Neuron 1994, Ann Neurol 1995). Dr. Iwatsubo’s groupthen established celllar models expressing mutant
forms of presenilin (PS) genes linked to familial AD(FAD), and using their original highly-sensitive
ELISA quantitation system, his group has clearlyshown that an increase in the production of Aβ42 is
the pathogenic mechanism leading to FAD (Tomita etal. Proc Natl Acad Sci USA, 1997). These findings
have provided a firm basis for the currently prevailing
β -amyloid hypothesis. They then focused on themechanisms of γ-secretase complex that cleaves the
C terminus of Aβ, and set out to cell biologicalstudies using RNA interference on the formation andfunction of the γ-secretase complex harboring PS as
the catalytic center, associated with three additional
membrane proteins. They demonstrated that APH-1
and Nicastrin serve as the “stabilizing” co-factor of PS,

69

whereas PEN-2 is the component that confers
proteolytic activity to this complex. They also showedthat PS, APH-1, nicastrin and PEN-2 are the essential
set of proteins that comprise the γ -secretase
complex (Takasugi et al. Nature, 2003). This study ishighlighted as a milestone work that elucidated themechanistic roles of protein cofactors in the formationand function of γ-secretase (see reviews; Iwatsubo
Mol Psychiatr, 2004; Curr Opin Neurobiol, 2004). His
group has also shown by establishing in vitro γ-secretase assays that sulindac sulfide, a major
non-steroidal anti-inflammatory drugs, directly acts on
γ-secretase and selectively reduce Aβ42-generating
activities (Takahashi et al., J Biol Chem, 2003),
providing important implications to the therapeuticstrategies of AD by γ -secretase modulation.
Recently, he has established a novel method for an
efficient in vitro reconstituion of γ -secretase
complex, paving the way towards the structural
analysis of active γ-secretase (Hayashi et al. J Biol
Chem, 2004), and using thus highly purified γ-secretase particles, they have partially unveiled thesubmolecular structure of this complex bysingle-particle EM analysis (Ogura et al. BBRC,
2006). Very recently, his group has established an
elegant strategy to analyze the structure-function
relationship within the catalytic structure of γ
-secretase complex by cystein chemistry, anddemonstrated that γ -secretase harbors awater-permeable catalytic pore (Sato et al. J Neurosci,
2006), and that substrate proteins enter the catalytic
pore through the lateral gate located at the C terminalside of PS (Sato et al. J Neurosci, 2008). Thus, Dr.
Iwatsubo’s group started from an elegant
immunohistochemical analysis of Aβ deposits in AD
brains and extended it to a contemporary
molecular/cellular biology of PS, that proved to play a
key role in the important biological reaction termed“intramembrane proteolysis”.
2. Identification and characterization of α-synuclein as a major component of Lewy bodies.
Using cortical Lewy bodies purified frompostmortem brains of patients with dementia with
Lewy bodies (DLB) by his original method (Iwatsubo
et al. Am J Pathol 1996) as immunogens, Dr.
Iwatsubo’s group, in collaboration with Drs. Virginia

Lee and John Trojanowski at Univ. Penn, performed
an extensive immunochemical search for componentsof Lewy bodies. They have demonstrated by raising a
specific monoclonal antibody that α-synuclein, thatproved to be a product of pathogenic gene for familial
form of Parkinson’s disease, is one of the major
constituent of Lewy bodies in sporadic Parkinson’s
disease and DLB (Baba et al. Am J Pathol 1998). His
group then purified aggregated α -synuclein from
DLB cortices using fine biochemical techniques,purified it to near homogeneity, and demonstratedusing mass spectrometry and specific antibodies thatα-synuclein deposited in synucleinopathy lesions ishighly phosphorylated at a specific serine residue(Fujiwara et al. Nature Cell Biol 2002). This finding
led to a range of studies focusing on the role ofsynuclein phosphorylation in neurodegeneration. Also,
the phospho-specific α-synuclein antibody is widelyused as the most sensitive marker for α-synucleinopathy lesions, and they have characterized
a wide spectrum of α -synuclein pathologies inneurodegenerative disorders.
3. Identification of a non-Aβ Alzheimer amyloid
plaque component CLAC, and its precursor
CLAC-P
The major component of Alzheimer’s amyloid
plaques is Aβ, although there are a number of non-A
β components that potentially affect fibrillizationand degradation of amyloid deposits. Among these,
there has been an enigmatic “missing piece” proteinof molecular masses of 50/100 kDa. Dr. Iwatsubo’sgroup raised a monoclonal antibody against amyloid
fraction that recognizes this protein, and using thisantibody as a probe, they conducted a thoroughbiochemical purification of these antigens and finallycloned a cDNA coding for the precursor of this protein.
This protein turned out to be a novel class ofmembrane-bound collagen, which was named CLAC
(collagen-like Alzheimer amyloid plaque component)
and its precursor CLAC-P (Hashimoto et al. EMBO J
2002). This finding had an immense impact both on
fields of AD research as well as on general biology as
a first discovery of neuron-specific collagen harboringa unique membrane-spanning structure. CLAC has
been highlighted as a protein that may affectfibrillization of Aβ and contribute to amyloid plaque70

formation. Indeed, he has recently shown that
CLAC-positive senile plaques constitute a uniquesubset of plaques distinct from the classical, β-sheet-rich amyloid deposits, underscoring thepathobiological role of CLAC in amyloid formation(Kowa et al. Am J Pathol, 2004), and that CLAC
inhibits fibrillization of Aβ in vitro (Osada et al. J
Biol Chem, 2005). Transgenic mice studies are
confirming the role of CLAC in the morphogenesis ofsenile plaques in vivo.
4. Japanese ADNI: clinical studies for theidentification of surrogate imaging andbiomarkers of AD
Basic studies on the pathomechanism of AD haveboosted the development of mechanism-based drugs
for AD, whereas the bottleneck has been the lack ofsurrogate biomarkers that represent the progression of
AD pathology and are useful in the clinical trial of
disease-modifying drugs. In close collaboration with
Drs. Mike Weiner and Ron Petersen of US-ADNI, Dr.
Iwatsubo has initiated the Japanese ADNI as theprincipal investigator on 2006, recruiting 35 clinicalsites nationwide, and preparing all the infrastructures
required for the large-scale clinical study. The J-ADNI
group is starting to recruit participants on June 2008
(total, 600 cases for 5 years), and the instruments andframework of J-ADNI are being adopted in multiple
global clinical trials in Japan.

References
1) Ito G, Okai T, Fujino G, Takeda K, Ichijo H,
Katada T, Iwatsubo T: GTP binding is essential tothe protein kinase activity of LRRK2, a causative
gene product for familial Parkinson’s disease.
Biochemistry 46:1380-1388, 20072) Hori Y, Hashimoto T, Wakutani Y, Urakami K,
Nakashima K, Condron MM, Tsubuki S, Saido TC,
Teplow DB, Iwatsubo T: The Tottori (D7N) andEnglish (H6R) familial Alzheimer's disease
mutations accelerate Aβ fibril formation without
increasing protofibril formation. J Biol Chem 282:4916-4923, 2007
3) Lippa CF, Duda JE, Grossman M, Hurtig HI,
Aarsland D, Boeve BF, Brooks DJ, Dickson DW,
Dubois B, Emre M, Fahn S, Farmer JM, Galasko

4)

5)

6)

7)

8)

9)

D, Galvin JE, Goetz CG, Growdon JH, GwinnHardy KA, Hardy J, Heutink P, Iwatsubo T,
Kosaka K, Lee VM-Y, Leverenz JB, Masliah E,
McKeith IG, Nussbaum RL, Olanow CW, Ravina
BM, Singleton AB, Tanner CM, Trojanowski JQ,
Wszolek ZK, for the DLB/PDD working Group:
DLB and PDD boundary issues: diagnosis,
treatment, molecular pathology, and Biomarkers.
Neurology 68:812-819, 2007
Isoo N, Sato C, Miyashita H, Shinohara M,
Takasugi N, Morohashi Y, Tsuji S, Tomita T,
Iwatsubo T: Aβ42 overproduction associated withstructural changes in the catalytic pore ofγ-secretase:commoneffectsof
Pen-2
amino-terminal elongation and fenofibrate. J Biol
Chem 282:12388-12396, 2007
Fumimura Y, Ikemura M, Saito Y, Sengoku R,
Kanemaru K, Sawabe M, Arai T, Ito G, Iwatsubo T,
Fukayama M, Mizusawa H, Murayama S:
Analysis of adrenal gland is useful for evaluating
pathology of the peripheral autonomic nervous
system in Lewy body disease. J Neuropathol Exp
Neurol 66: 354-362, 2007
Haleem K, Lippa CF, Wong M, Abdelhak T, Smith
TW, Kowa H, Iwatsubo T: Space-occupying
plaques in PS-1 C410Y Alzheimer’s disease
contain synaptic- terminal specific proteins.
American Journal of Alzheimer’s Disease
22:137-144, 2007
Wakamatsu M, Ishii A, Ukai Y, Sakagami J, Iwata
S, Ono M, Matsumoto K, Nakamura A, Tada N,
Kobayashi K, Iwatsubo T, Yoshimoto M:
Accumulation of phosphorylated α-synuclein in
dopaminergic neurons of transgenic mice that
express human α-synuclein. J Neurosci Res 85:
1819-1825, 2007
Yamamoto R, Iseki E, Murayama N, Minegishi M,
Marui W, Togo T, Katsuse O, Kosaka K, Kato M,
Iwatsubo T, Arai H: Correlation in Lewy
pathology between the claustrum and visual areas
in brains of dementia with Lewy bodies. Neurosci
Lett 415:219-224, 2007
Kan T, Kita Y, Morohashi Y, Tominari Y, Hosoda
S, Tomita T, Natsugari H, Iwatsubo T, Fukuyama
T: Convenient synthesis of photoaffinity probes
and evaluation of their labeling abilities. Org Lett
9:2055-2058, 2007

7110) Fuwa H, Takahashi Y, Konno Y, Watanabe N,
Miyashita H, Sasaki M, Natsugari H, Kan T,
Fukuyama T, Tomita T, Iwatsubo T: Divergent
synthesis of multifunctional molecular probes to
elucidate the enzyme specificity of dipeptidic
γ-secretase inhibitors. ACS Chemical Biology 2:
408-418, 200711) Kato M, Kinoshita H, Enokita M, Hori Y,
Hashimoto T, Iwatsubo T, Toyo'oka T: Analyticalmethod for β-amyloid fibrils using CE-laser
induced fluorescence and its application toscreening for inhibitors of β-amyloid protein
aggregation. Anal Chem 79:4887-4891, 200712) Ishii A, Nonaka T, Taniguchi S, Saito T, Arai, T,
Mann D, Iwatsubo T, Hisanaga S-i, Goedert M,
Hasegawa M: Casein kinase 2 is the major
enzyme in brain that phosphorylates Ser129 ofhuman
α-synuclein:
Implicationforα-synucleinopathies. FEBS letters 581:4711-4717,
200713) Sasakawa H, Sakata E, Yamaguchi Y, Masuda M,
Mori T, Kurimoto E, Iguchi R, Hisanaga S-i,
Iwatsubo T, Hasegawa M, Kato K: 920 MHz
ultra-high field NMR studies of antibody binding
and site-specific phosphorylation of α-synuclein.
Biochem Biophys Res Comm 363:795-799, 2007
14) Kaneko H, Kakita A, Kasuga K, Nozaki H,
Ishikawa A, Miyashita A, Kuwano R, Ito G,
Iwatsubo T, Takahashi H, Nishizawa M, Onodera
O, Sisodia SS, Ikeuchi T: Enhanced accumulationof phosphorylated α-synuclein and elevatedAβ42/40 ratio caused by expression of thepresenilin-1 ΔT440 mutant associated withfamilial Lewy body disease and variant Alzheimer
disease. J Neurosci 27:13092-13, 2007

72

Department of Neurochemistry
Associate Professor and Head
Haruhiko Bito, M.D., Ph.D.

Assistant Professors
Hiroyuki Okuno, Ph.D.
Sayaka Takemoto-Kimura, M.D., Ph.D.

Homepage

http://www.neurochem.m.u-tokyo.ac.jp/Homepage.html

Introduction and Organization
Our Department’s primary goal is to elucidate thebasic signal transduction mechanisms which mediate
key processes underlying various brain functions, suchas learning, memory or emotion. A fundamental
question is how an ensemble behavior of 10~100
billion neurons can possibly give rise to a coherent
and integrated “brain” that controls the whole humanorganism for a period of more than eighty years. Our
central nervous system is physically wired andorganized based on evolutionary and developmental
principles that are primarily encoded into the genome
and that are highly conserved in mammals fromrodents to primates. This neural network, however, isable to recognize and memorize external and internal
events as they occur. And furthermore, brain function,
especially human’s, stands out by its intrinsic capacity
to extract patterns and rules from these events, and to
consciously associate them with abstract meaning andaffective valence, while also unconsciously
facilitating coordinated body responses.
Neurochemistry once used to be a relatively dull
discipline consisting of analyzing substances that form
the brain. However, it has recently become a field of
excitement where we are now (almost) able tomeasure changes in cellular messengers or
modifications in signaling molecules in critical partsof the neurons such as the dendritic spines or the axon
terminals, as the neurons summate synaptic potentials
or fire action potentials.
What are the precise nature and the whole

spectrum of the molecular changes in the neurons that
undergo heavy or patterned electrical activity? What
are the molecular rules that govern these local andglobal changes, both electrical and chemical? How arethese events, in turn, converted into more profoundmodifications of the synaptic wiring mechanisms?
And finally do these alterations genuinely underlie
certain kinds of information processing and storage?
To address these issues, this Department currently
focuses its resources into two basic aims:
1) Molecular investigation (including identification,
characterization and real-time visualization) of
signaling molecules involved in calciumdependent synaptic modification, especiallyduring signaling from synapse-to-nucleus, andback from nucleus-to-synapses.
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on bothsides of the synapses, in the dendritic spines andin axon terminals.
Following the retirement of Professor Tatsuya
Haga (who became the President of Life Sciences
Institute at the Faculty of Science at Gakushuin
Univisersity) in March 2001, and the departure of
Associate Professor David Saffen to initially
University of Minnesota and then to Ohio State
University in August 2001, Associate Professor
Haruhiko Bito was appointed as Head of Department
since January 2003. The Department is located on the
6th floor, in the West wing of the third building of theMedical School. The Department currently enrolls one
associate professor, two assistant professors, three73

postdoctoral scholars, one technical staff member,
three Ph.D. and three M.S.-Ph.D. graduate students,
three rotating medical students, three technicalassistants and one administrative assistant.

Teaching activities
The Department’s teaching activities include:
1) Introductory Neuroscience coursework provided
to pre-medical students in the Komaba campus(one hour);2) Neurochemistry lectures to medical students aspart of the “Biochemistry- Molecular BiologyNutrition” core curriculum (two hours);3) Introductory Molecular and Cellular Neuroscience,
and Basic Neurochemistry lectures to first-year
master degree students (three hours);
4) Organization of the lecture course: “Basic
Neuroscience”(MolecularandCellular
Neuroscience) (a lecture series with fifteen
lectures from outstanding neuroscientists from allover Japan).
Additionally, Neurochemistry Seminars are
frequently and regularly organized under the auspicesof the 21st Century Center of Excellence Program
Grant “Center for Integrated Brain Medical Science”.
This enables direct exposure of Ph.D. graduate
students and postdocs to both young promisingresearchers and established investigators from all over
the world.

Research activities
The Department of Neurochemistry currently focuses
its resources into two core projects:
1) Molecular investigation (including identification,
characterization and real-time visualization) of
signaling molecules involved in calcium-dependent
synaptic modification, especially during signalingfromsynapse-to-nucleus,
and
back
from
nucleus-to-synapses.
Changes in efficacy of synaptic transmission havebeen shown to strongly correlate with functional
plasticity of many brain circuits including the
hippocampus, the amygdala, the striatum, theneocortex, the cerebellum or the spinal cord. An earlyphase of long-term synaptic plasticity is induced byvirtue of specific post- and/or presynaptic
modifications of the biochemical machinery dedicatedto synaptic release and neurotransmitter recognition. It
then is expressed by bistable mechanisms that arestrongly governed and dictated by the pattern ofsynaptic calcium influxes experienced during theinitial conditioning period. While the molecular
identity of the involved synaptic proteins is now(almost) being solved (or is becoming much lesscontroversial than before), several essential questions
remain unanswered.
The “Old” question was: What are the moleculardeterminants that enable these plastic changes to be
induced and maintained locally?
Yet, related issues of critical importance that still
remain wide open questions are:1) What are the full-range of calcium-triggered
molecular signaling cascades which are activatedat and near the potentiated/depressed synapses?
And how do they influence plasticity per se?
2) What is the contribution of activity-dependent
gene expression in prolongation and consolidationof such synapse-restricted changes?
In order to begin to address these issues, we havebeen investigating in particular the role of several
calcium-calmodulin dependent protein kinases.
We previously showed the critical importance of a
CaMKK/CaMKIV
cascadeintriggering
synaptically-stimulated
nuclear
CREB
phosphorylation in hippocampal neurons. The extreme
biochemical efficacy and the relative poor
frequency-dependence of this signaling cascade, in
combination with the robust correlation between
prolonged pCREB response and downstream gene
expression
led
us
to
proposethat
CaMKK/CaMKIV/pCREB cascade was likely to act
as a critical temporal integrator for activity-dependent
gene expression in excitatory neurons (Bito et al., Cell,
1996; Bito et al., Curr. Opin. Neurobiol., 1997; Bito,
Cell Calcium, 1998). This hypothesis has now been
critically tested in various brain systems and indeed
pCREB immunofluorescence is now considered as auniversal marker for integrated synaptic activity thatis more sensitive than that of c-Fos. Furthermore,
CaMKIV-KO, CaMKK-KO and CaMKIV-dominant

74

negative transgenic studies by many laboratories haveconfirmed the critical role for CaMKIV as synaptic
activity-triggered CREB kinase.
We subsequently also showed that CaMKIV in the
cerebellar granule cells played a critical role in tuning
the pCREB response necessary for depolarizationmediated neuronal survival, and that in fact CaMKIV
stability was actively maintained by depolarization.
Loss of depolarizing signal led to a caspase-mediatedproteolytic degradation of CaMKIV. This in turnseverely impaired CREB phosphorylation, facilitating
apoptosis, and conversely rescuing pCREB byoverexpressing an active form of CaMKIV was
sufficient to prevent apoptosis (See et al., FASEB J.,
2001). Consistent with our observation that subtle
CREB regulation may underlie the neuronal cell
survival,
CREB-dependent
gene
expression
mechanisms, especially CBP regulation, have actually
been proposed to be affected in one way or another inmany neurodegenerative disorders such as hereditary
polyglutamine diseases. We thus speculated that if
CREB-opathies (or various defects in CREB-mediatedgene
activation
mechanisms)
werecriticaldeterminants in exacerbating neurodegeneration,certain disease forms may actually accompany deficit
in CaMKIV / pCREB signaling (Bito andTakemoto-Kimura, Cell Calcium 2003). Thishypothesis is now being tested.
One parallel branch of CaMK signaling that has
not been widely studied is the CaMKK/CaMKI
pathway. During the search for potential CaMKIV-like
CREB regulatory kinases (CLICKs) (Ohmae et al., J.
Biol. Chem. 2006), we identified a novel CaMKI
isoform that contained a C-terminal CAAX lipid
modification motif (Takemoto-Kimura, Ageta-Ishihara
et al., J. Biol. Chem., 2003; Takemoto-Kimura et al.
Neuron 2007). This novel membrane-bound CaMK
(CLICK-III/CaMKIγ) is most expressed in the central
nucleus of the amygdala and in the ventral medial
hypothalamus, while also being present at a much
weaker amount in most central neurons. Ongoingbiochemical and cell biological studies indicate acritical role for lipidification of this kinase to beproperly sorted into specific lipid-restricted membrane
microdomains. The function played by this lipidified,membrane-inserted CaMK in circuitry formation andmaturation was scrutinized using RNA interference.

Along with the identification of the criticallipid-modifying enzyme that controls lipid-anchoringof this kinase, we discovered a novel activityregulated mechanism whererby CLICK-III/CaMKIγ isactively sorted into dendritic lipid rafts, where it
specifically regulates Rac-mediated actin remodelingthat is required for BDNF-stimulated dendritogenesis(Takemoto- Kimura, Ageta-Ishihara et al., Neuron,2007).
One further important topic that we have been
focusing for a number of years is the role of gene
expression in prolongation / consolidation of synapsespecific local changes. Neurons undergoing various
stimulus patterns have been followed up in time andthe amount of newly synthesized proteins and the
local distribution of induced gene products have beenmonitored. Using state-of-the-art multi-wavelength
fluorescence imaging techniques, we are now
quantitatively assessing how local distribution of these
newly synthesized gene products affect synaptic
protein complexes (Okuno and Bito, AfCS/Nature
Mol. Pages, 2006).
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sidesof the synapses, in the dendritic spines and in axon
terminals.
Both synaptic maturation and synaptic plasticity
have been shown to include a morphologicalcomponent that is directed by the dynamics of actin
cytoskeleton, a major cytoskeletal component both in
the dendritic spines and at the very proximity ofboutons in the axon terminals. Few studies in the past,
however, had directly addressed what moleculardeterminants regulate actin dynamics in living central
neurons undergoing synaptic activity. This was in part
because actin filament assembly and disassembly wereclassically studied mostly at the moving edges oflamellipodia of large growth cones in large-size
neurons from either mollusc or peripheral nerve cells.
Such visualization turned out to be much moredifficult in seemingly far less mobile spine structures
tightly apposed to presynaptic active zones.
We (and others) used GFP-actin imaging to try tounderstand how neuronal actin cytoskeleton in
hippocampal neurons was organized and reorganizedby exposure to synaptic activity. In our dissociated75

culture system, virtually all spines contained a highamount of GFP-actin and most of them with few
exceptions were apposed to FM4-64-positive active
presynaptic termini. In these cultures, increases insynaptic glutamatergic transmission by repeated burstsof high-frequency synaptic activity clearly induced
several distinct kinds of activity-dependent actin
mobilization, including a slow but sustained synaptic
delivery of GFP-actin in a non-negligible number ofactivated spines and a massive but transientenhancement in cortical actin at the somatic periphery.
The
formerwasentirelydependenton
2+
NMDA-dependent Ca -influx while the latter was
likely to be mediated at least in part by L-type
voltage-gated Ca2+ channel activity. Thus distinct
patterns and sources of Ca2+ influx were likely totrigger a complex spatially segretated patterns of actin
cytoskeletal reorganization, with variable impact oneither neuronal morphology and/or synaptic protein
assembly (Furuyashiki et al., PNAS, 2002).
Similar studies are now ongoing in cerebellar
Purkinje neurons, where spinogenesis is also subject
to complex regulation during development, and where
calcium dynamics is key to pre- and postsynaptic
plasticity.
What are the key signaling pathways controlling
actin dynamics in central neurons? We were especiallykeen to resolve the contribution of the small GTPase
Rho and its downstream effectors, initially in thecontext of developmentally regulated neuronalmorphogenesis. We first established in a model cellline N1E-115 that neurite retraction was directly
linked to Rho/ROCK activity (Hirose et al., J. Cell
Biol., 1998). We subsequently revealed that in central
neurons, in addition to its essential role in regulating
growth cone motility, Rho/ROCK activity in fact acted
as a negative gate that tightly controls the timing withwhich the first processes are initiated out from theround cell soma (Bito et al., Neuron, 2000).
Disruption of Rho/ROCK activity was sufficient toimmediately initiate neuritogenesis. This indicatedthat endogenous Rho activators, by titrating ROCK
activity, continuously antagonized process/ branchformation and that local gradient of Rho activators
might play a crucial role in shaping the timing and theextent of process formation (Bito, J. Biochem., 2003).
Consistent with this idea, we found that in cerebellar

granule cells, a chemokine SDF-1α released from thepia mater was likely to be a predominant Rho
activator via stimulation of a cognate and specific
GPCR CXCR4 (Arakawa et al., J. Cell Biol., 2003).
While a true gradient in SDF-1α still remains to be
demonstrated in vivo, it is intriguing to note that mostactive axonal process formation and elongation
actually occur in the inner zone of EGL that is
opposite and most distant from the interface with the
pia mater (Bito, J. Biochem., 2003). Most strikingly,
we demonstrated that axon elongation could actively
occur in an intermediate Rho activity range thatenables ROCK to be weakened enough while allowing
another Rho effector mDia1 to actively mediate its
effect on actin nucleation and polymerization(Arakawa et al., J. Cell Biol., 2003; Yamana et al.,Mol. Cell Biol. 2006).
Whether similar or distinct mechanisms also
operate during spinogenesis and spine maturation
remains to be determined, though a role for Rho andROCK has already been postulated in control of spinecomplexity and spine stability. However, multiple
small GTPase signaling cascades clearly seem tocontribute together, in a tightly coordinated manner, tospine regulation, since many distinct classes of GEFs
and GAPs have now been shown to be localized in thedendritic spines. We ourselves initially reported thefirst two direct examples for PSD localization for such
Rho small GTPases interacting proteins, Citron(Furuyashiki et al., J. Neurosci., 1999) and
Cupidin/Homer2 (Shiraishi et al., J. Neurosci., 1999).
In an attempt to pin down molecular mechanismsthat link PSD complexes and spine formation, wequantitatively examined the effect of deleting thebinding capacity of single PDZ domains of PSD-95,
one by one, and in combination, by structure-based
amino acid replacements rather than domain deletion.
Such a second-generation structure-function relation
study surprisingly revealed that a quantitative binding
between PSD-95 and synGAP tighly controlled thedegree of PSD protein clustering in a manner that was
inversely correlated with the distance from the spine
head to the shaft. Thus, these results suggest theexistence of a tight coordination between the state of
PSD complex and the morphogenetic activity of eachspine (Nonaka et al. J. Neurosci., 2006).
In parallel with this work, we and others

76

determined that protein-protein interaction was key todetermining the physical distance between thesynaptic vesicles in the active zone and thevoltage-gated calcium channels in its vicinity, theopening of which triggers their release (Kiyonaka etal., Nature Neurosci., 2007).

Publications by lab members(April 2007 - March 2008)
1. Takemoto-Kimura S, Ageta-Ishihara N, Nonaka M,
Adachi-Morishima A, Mano T, Okamura M, Fujii
H, Fuse T, Hoshino M, Suzuki S, M Kojima,
Mishina M, Okuno H, Bito H. Regulation ofdendritogenesis via a lipid raft-associatedproteinkinaseCa2+/calmodulin-dependent
CLICK-III/CaMKIγ. Neuron, 54: 755-770, 2007.
2. Kiyonaka S, Wakamori M, Miki T, Uriu Y,
Nonaka M, Bito H, Beedle AM, Mori E, Hara Y,
De Waard M, Kanagawa M, Itakura M, Takahashi
M, Campbell KP, Mori Y. The active zone protein
RIM1
conferssustained
activityandneurotransmitter vesicle anchoring to presynaptic
Ca2+ channels. Nature Neurosci., 10: 691-701,
2007.
3. Fuse T, Ohmae S, Takemoto-Kimura S, Bito H.
DCLK1. AfCS/Nature Molecule Pages, doi:
10.1038/mp.a003011.01, 2007.
4. Bito H, Takemoto-Kimura S, Okuno H.
Activity-dependent gene regulation: How dosynapses talk to the nucleus and fine-tune
neuronal outputs? in “Molecular Pain“ (M. Zhuo
ed. Springer), 2007.
5. Bito H, Nonaka M, Fuse T, Fujii H,
Takemoto-Kimura S, Okuno H. Molecularmechanisms regulating synapse function and PSD
structure. Protein, Nucleic Acid and Enzyme (inJapanese) 53: 418-423, 2008
6. Okuno H, Fujii H, Bito H. Synapses as unitary
information processing units: structure, function
and role as novel drug targets. p220-233, in
Nanomedicine (ed. T. Urisu, in Japanese), Ohme
Publishing, Tokyo (2008).

Neuroscience
2. Speech and Cognitive Sciences

78

Department of Cognitive
Neuroscience
Associate Professor
Katsuyuki Sakai, M.D., PhD

Associate
Yosuke Morishima, M.D., Ph.D.

Homepage
Introduction and Organization
Speech and language are the most prominentcognitive functions distinguishing human being from
nonhuman animals. The Department of Cognitive
Neuroscience aims at basic, interdisciplinary studies
on human cognitive functions ranging from perception,action, attention, memory, language and thought.
Many studies are conducted in cooperation withother departments, faculties and universities such as in
the field of engineering, physiology, psychology,
education and clinical neuroscience.

Teaching activities
1. Graduate Course
Introduction to Neuroscience
Imaging Neuroscience
2. Undergraduate Course
Introduction to Medical Biology

Research activities
We all know that our perception, action, emotion,
thought and consciousness depend on the activity ofneurons in the brain. But we know very little about
how the neurons do these jobs. The aim of cognitive
neuroscience is to clarify the neural mechanisms ofour mental activity. Conventional and still very
powerful approach is to devise a task paradigm that
represents the psychological phenomenon in question

and measure the brain activity while the experimental
subjects perform the task. Studies to date haveidentified neural correlates for varieties of mental
activities.
Here in this lab, we attempt to go beyond the simple
correlation between brain activity and behavior. The
key questions are the following. .
- Behavioral significance: You've got nice activation
in some parts of the brain. Is the activity truly
associated with the behavior? Is it necessary for the
behavior? In other words we are interested in thecausality of the brain activity to behavior.
- Temporal dynamics: The temporal order of theevents in the brain is not enough to understand theneural mechanisms. Let's clarify the causal
relationships between the activations in different brain
regions. How? Let's discuss.
- System dynamics: Do not be satisfied with pretty
brain images with blobs. Neurons are useless unlessthey transmit impulses to other neurons. It is thebi-directional interactions between multiple brain
areas that make us perceive, feel, and think. I am nowinterested in the dynamics in the transition between
symmetric and asymmetric impulse transmission
between brain areas.
- Information-based analysis: We can tell what aperson is thinking about based solely on his brain
activity. Do not be surprised. Everyone in this field
knows that. But what does this tell us about the brain?
This decoding technique can be used to demonstratethat the brain is the cause of our cognition.

79

To answer these questions we are using various
behavioral paradigms such as selective attention, task
switching, perceptual decision making, masked
priming and so on. We are interested in themechanistic explanation of brain function and students
and younger researchers are free to choose any kind of
behavioral paradigms if we agree that the paradigm isthe best one to answer the questions about the brain.

References
1. Rowe JB, Sakai K, Lund TE, Ramsoy T,
Christensen MS, Baare WFC, Paulson OB , andPassingham RE. Is the prefrontal cortex necessaryfor establishing cognitive sets?, J Neurosci.
2007:27:13303-10.
2. Haynes JD, Sakai K, Rees G, Gilbert S, Frith C,
Passingham RE. Reading hidden intentions in thehuman brain, Curr Biol. 2007:17: 323-8.

Neuroscience
3. Clinical Neuroscience81

Department of Neuropsychiatry
Associate Professor
Nobuo Nakayasu, M.D., Ph.D.,

Yukiko Kano, M.D., Ph.D.

Lecturer
Kiyoto Kasai, M.D., Ph.D.,

Masatoshi Shibayama, M.D., Ph.D.,

KeiIchiro Watanabe, M.D., Ph.D.

Research Associate
Mamoru Tochigi, M.D., Ph.D.,

Toshiyuki Otani, M.D., Ph.D.,

Hitoshi Kuwabara, M.D., Ph.D.,

Nakagami Ryuichi, M.D.,

Hidenori Yamasue, M.D., Ph.D.,

Tsuyoshi Araki, M.D.,

Kenji Otowa, M.D., Ph.D.,

Soo-Yung Kim, M.D., Ph.D.,

Tsuyoshi Okamura, M.D.,

Nishiyama Jun, M.D.

Nishida Takuji, M. D.

Homepage

http://npsy.umin.ac.jp/

Introduction and Organization

Clinical activities

The Department of Neuropsychiatry is Japan's
oldest psychiatric department which was establishedin 1886. "Anti-Psychiatry" movement for the last 3
decades had highly negative effects on the progress inall aspects of our activities. However, since 1994, ourdepartment has been normalized and restarted to playa leading role in psychiatry in Japan. Now the
Department of Neuropsychiatry provides awide-ranged clinical, training, and research services.
Since August 2006, we have been working in the newclosed ward (30 beds) and in the open ward (30 beds).
Moreover, since 2000, we have been supported by agovernment grant for basic and clinical neurosciencein stress-related disorders including posttraumaticstress disorder (PTSD). Since 2005, we have begun tofocus on basic and clinical neuroscience in pervasive
developmental disorders (PDDs).

For outpatient services, we have more than 20 staff
psychiatrists, 4 clinical psychologists, 2 trained nurses,
and 1 psychiatric social worker. Approximately 1100
new patients visited yearly (2007), and the total visits
per year was about 43,000 (140 per day).
The secluded ward has 29 beds including 3
seclusion rooms. We also have 31 beds for the open
general ward. Approximately 470 patients withvarious psychiatric disorders were admitted in a year
(2007), about one-third of whom were referred fromthe emergency unit. Occupational therapy, recreational
therapy, group therapy, and art therapy are performed.
We established Japan’s first child psychiatry day
care unit in national university hospitals in 1967. Aschildren with Down’s syndrome began to be accepted
into nurseries and kindergartens around the year 1975,
the focus of this division shifted to the psychologicalpedagogy of autism. Treatment of autism changed
along with the understanding of the clinical condition,from behavioral therapy to cognitive development

82

based therapy. Since 1997, our division was reducedin size and an improved therapy system,“developmental psychology outpatient clinic” wasestablished. This outpatient clinic encompasses
individual treatment and psychological counseling by
clinical psychologists under the supervision of
psychiatrists. Our staff includes 1 full-time
psychiatrists, 4 part-time psychiatrists, and 3 clinicalpsychologists. We provide care for 260 autistic ordevelopmentally disabled children per year. Since
2000, a short term therapy group program has started.
Parents participated in the treatment program
alongside the staff members. This not only emphasizes
the therapy of the child, but assesses theirdevelopmental level from many directions. The
purpose of the therapy program is to help parents gaina better understanding of children’s disability and tohelp them to acquire a more supportive role for theirchildren in the home environment. Since 2005, wehave established clinical and educational center for
developmental disorders, and provided clinical andeducational activities in pervasive developmental
disorders.

Teaching activities
For psychiatric residents, we have provided: 1)
clinical meetings on patients (every morning); caseconferences on inpatients (every week); 3) a series oflectures by teaching staffs on various aspects ofpsychiatry. For undergraduates, we have provided
neuropsychiatry comprehensive lectures (2nd year),bedside learning (3rd year), and clinical clerkship(elective for 4th-year students). For postgraduate,
currently more than 20 neuropsychiatry Ph.D. students
are studying.

Research activities
Stress- It is well accepted that neuropeptide Y(NPY) is involved in anxiolytic-like effects andanti-stress effects. Pharmacological and behavioral
studies have consistently indicated that these effects
are mainly mediated through an activation of NPY Y1
receptor in the brain. To further elucidate thefunctional role of Y1 receptor, we have evaluated thehistological and behavioral changes in Y1

receptor-deficient mice, after an exposure to 2h ofrestraint stress. Trimethyltin (TMT), a neurotoxic
organotin, has been shown to cause selective loss ofpyramidal neurons in the rat hippocampus, similar tostress-induced hippocampal changes. Several recent
studies in animal models of brain ischemia revealed
the neuroprotective properties of tacrolimus (FK506),
a potent immunosuppressant used in organ transplants.
Therefore, we have investigated the effect of FK-506
on the neuronal death and apoptosis in the
hippocampus after TMT intoxication, using
immunohistochemistry and TUNEL method.
Epilepsy- Systemic injection of kainic acid in rat
causes severe convulsions, increased seizure
susceptibility and seizure-induced neuronal death.
Since precise mechanisms of various anticonvulsants
are still unclear, we have investigated to elucidate
whetherthese
anticonvulsantsdemonstrateneuroprotective effects on kainic acid-induced
neuronal death in the hippocampus.
Environmental endocrine disrupter- Bisphenol-A(BPA), one of environmental endocrine disrupters, isreleased from polycarbonate plastics, and is known to
mimic oestrogens in their action. Recent studies
reported that prenatal and neonatal exposure to
low-dose bisphenol-A modulates the sexual
differentiation of behavior and the central
dopaminargic effects in vivo and in vitro. We examine
the effects of BPA on the behavior, memory and theexpression of estrogen-alpha receptor in the brain ofrats exposed to BPA during the fetal and sucklingperiods at a dosage far less than the
no-observed-adverse-effect level.
Genetic Research- The Genetic Research Group of
the department is investigating genetic as well as
environmental mechanism of psychiatric disorders. A
major focus of the studies is exploration ofsusceptibility genes of the disorders including
schizophrenia, infantile autism, their spectrum
disorders and anxiety disorder (mainly panic disorder).
A number of candidates of the susceptible genes arestudied using case-control and TDT (transmission
disequilibrium test) designs. We are at present
achieving most interesting results in the investigationsof DISC1, Neuregulin1 and other candidate genes inschizophrenia and the chromosome 7 genes in
infantile autism. Another focus is investigation of

83

genes that affect the development of personality.
Neuroimaging- Our group plays a leading role inpsychiatric neuroimaging in Japan. Our research aims
at multi-modality neuroimaging (structural andfunctional MRI, MR spectroscopy, EEG, MEG, nearinfrared spectroscopy (NIRS), PET) in schizophrenia,
mood disorders, pervasive developmental disorders,and posttraumatic stress disorder (PTSD).
Clinical Pharmacology- The atypical neuroleptics
have been widely prescribed in our country. They
contribute to the reduction of uncomfortable side
effects and the improvement of the patient’s QOL. But
the typical neuroleptics still have been used becauseof their sedative effects particularly in acute state of
Schizophrenia. We have been investigating a
voluntary clinical research, which contain thepractical evaluation to the treatment of atypicalneuroleptics for acute psychotic state in
Schizophrenia.
Recently the abnormal glucose tolerance induced byatypical neuroleptics had been reported and some
accidental hyperglycemia had happened in our country,
too. Though there are many reports involving to thisproblem in foreign country, few detailed investigation
was performed in Japan until now. We are preparing to
examine the glucose tolerance of inpatients that aretreated by neuroleptics in collaboration with many
hospitals and expect that the frequency of risk andsome actual factors will be revealed.
Neuropathological study of dementias- Our interestis neuropathological background of dementia,
especially NFT-predominant form of dementia(NFTD). NFTD is a sporadic subset of dementia
pathologically characterized by abundant and almost
exclusive appearance of NFTs in the limbic areas withscarcity of senile plaques. Our study suggests that
pathogenetic background of NFTD may be different
from that of AD and cognitive decline in NFT-SC may
be affected not only by severity of NFT pathology but
also by coexisting vascular lesions and/or argyrophilic
grains.

References1

Abe O, Yamasue H, Aoki S, Suga M, Yamada H,
Kasai K, Masutani Y, Kato N, Kato N, Ohtomo K:
Aging in the CNS: comparison of gray/whitematter volume and diffusion tensor data.
Neurobiol Aging, in press.
2 Abe O, Yamasue H, Kasai K, Yamada H, Aoki S,
Iwanami A, Ohtani T, Masutani Y, Kato N,
Ohtomo K: Voxel-based diffusion tensor analysis
reveals aberrant anterior cingulum integrity inposttraumatic stress disorder due to terrorism.
Psychiatry Res Neuroimaging 146: 231-242, 2006
3 Araki T, Yamasue H, Sumiyoshi T, Kuwabara H,
Suga M, Iwanami A, Kato N, Kasai K:
Perospirone in the treatment of schizophrenia:
effect on verbal memory organization. Prog
Neuropsychopharmacol Biol Psychiatry 30:
204-208, 2006
4 Araki T, Kasai K, Rogers MA, Kato N, Iwanami
A: The effect of perospirone on auditory P300 in
schizophrenia: a preliminary study. Prog
Neuropsychopharmacol Biol Psychiatry 30:
1083-1090, 2006
5 Araki T, Kasai K, Kirihara K, Yamasue H, Kato N,
Kudo N, Nakagome K, Iwanami A: Auditory P300
latency prolongation with age in schizophrenia:
gender and subcomponent effects. Schizophr Res
88: 217-221, 2006
6 Ebisawa T: Circadian rhythms in the CNS andperipheral clock disorders: Human sleep disorders
and clock genes. J Pharmacol Sci, in press
7 Fujimura Y, Ikoma Y, Yasuno F, Suhara T, Ota M,
Matsumoto R, Nozaki S, Takano A, Kosaka J,
Zhang M.-R, Nakao R, Suzuki K, Kato N, Ito H:
Quantitative analyses of [18F]FEDAA1106
binding to peripheral benzodiazepine receptors inliving human brain. Journal of Nuclear Medicine
47: 43-50, 2006
8 Hibino H, Tochigi M, Otowa T, Kato N, Sasaki T:
No association of DRD2, DRD3, and tyrosinehydroxylase gene polymorphisms with personality
traits in the Japanese population. Behav Brain
Funct 2: 32, 2006
9 Ikoma Y, Yasuno F, Ito H, Suhara T, Ota M,
Toyama H, Fujimura Y, Takano A, Maeda J,
Zhang M.-R, Nakao R, Suzuki K: Quantitative
analysis for estimating binding potential of theperipheral
benzodiazepine
receptorwith[11C]DAA1106. J Cereb Blood Flow Metab:
Published online, in press
10 Kaneko N. Kudo K. Mabuchi T. Takemoto K.

84

Fujimaki K. Wati H. Iguchi, H. Tezuka H, Kanba
S: Suppression of cell proliferation by interferonalpha through interleukin-1 production in adult rat
dentategyrus.
Neuropsychopharmacology
advance online publication, in press
11 Kato N, Sadamatsu M, Taeko K, Noriko N,
Fukuyama
Y:
Paroxysmal
Knesigenic
Choreoathetosis: From first discovery in 1892 togenetic linkage with benign familial infantile
convulsions. Epilepsy Research 70S: S174-S184,
2006
12 Kawakubo Y, Kasai K, Rogers MA, Nakagome K,
Iwanami A, Kamio S, Nose T, Kato N, Fukuda M:
Phonetic mismatch negativity predicts social skills
acquisition in schizophrenia. Psychiatry Res, inpress.
13 Kawakubo Y, Kasai K: Support for an association
between mismatch negativity and social
functioninginschizophrenia.
Prog
Neuropsychopharmacol Biol Psychiatry 30:
1367-1368, 2006
14 Kawakubo Y, Rogers MA, Kasai K: Procedural
memory predicts social skills in persons withschizophrenia. J Nerv Ment Dis 194: 625-627,
2006
15 Kawakubo Y, Kasai K, Kudo N, Rogers MA,
Nakagome K, Itoh K, Kato N: Phonetic mismatch
negativity predicts verbal memory deficits inschizophrenia. Neuroreport 17: 1043-1046, 2006
16 Kawashima M, Tamiya G, Oka A, Hohjoh H, JujiT, Ebisawa T, Honda Y, Inoko H, Tokunaga K:
Genomewide association analysis of humannarcolepsy and a new resistance gene. Am J Hum
Genet 79: 252-263, 2006
17 Kazuno A, Munakata K, Nagai T, Shimozono S,
Tanaka M, Yoneda M, Kato N, Miyawaki A, Kato
T: Identification of mitochondrial DNA
polymorphisms that alter mitochondrial matrix pH
and intracellular calcium dynamics. PLoS
Genetics, in press
18 Kikuchi T, Nomura M, Tomita H, Harada N,
Kanai K, Konishi T, Yasuda A, Matsuura M, Kato
N, Yoshiura K, Niikawa N: Paroxysmal
kinesigenic choreoathetosis (PKC): Confirmationof linkage to 16p11-q21 but unsuccessful
detection of mutations among 157 genes at the
PKC-critical region in seven PKC families. J Hum

Genet, in press
19 Kohda K, Jinde S, Iwamoto K, Bundo M, Kato N,
Kato T: Maternal separation stress drasticallydecreases expression of transthyretin in the brains
of
adult
rat
offspring.
Int
J
Neuropsychopharmacol 9: 201-208, 2006
20 Kobayashi S, Nomoto K, Watanabe M, Hikosaka
O, Schultz W, Sakagami M: Influences ofrewarding and aversive outcomes on activity in
macaque lateral prefrontal cortex. Neuron 51:
861-870, 2006
21 Kono T, Matsuo K, Tsunashima K, Kasai K,
Takizawa R, Rogers MA, Yamasue H, Fukuyama
C, Tanaka K, Yano T, Taketani Y, Kato N:
Multiple-time repeatability of near-infrared
spectroscopy
recordingduringprefrontal
activation task in healthy men. Neurosci Res, inpress
22 Kudo N, Kasai K, Itoh K, Koshida I, Yumoto M,
Kato M, Kamio S, Araki T, Nakagome K, Fukuda
M, Yamasue H, Yamada H, Abe O, Kato N,
Iwanami A: Comparison between mismatch
negativity amplitude and magnetic mismatch fieldstrength in normal adults. Biol Psychol 71: 54-62,
2006
23 Kunugi H, Hashimoto R, Okada T, Hori H,
Nakabayashi T, Baba A, Kudo K, Omori M,
Takahashi S, Tsukue R, Anami K, Hirabayashi N,
Kosuga A, Tatsumi M, Kamijima K, Asada T,
Harada S, Arima K, Saitoh O: Possible
association
betweennonsynonymous
polymorphisms of the anaplastic lymphoma
kinase (ALK) gene and schizophrenia in a
Japanese population. J Neural Transm 113:
1569–1573, 2006
24 Kuwabara H, Kasai K, Takizawa R, Kawakubo Y,
Yamasue H, Rogers MA, Ishijima M, Watanabe K,
Kato N: Decreased prefrontal activation during
letter fluency task in adults with pervasive
developmental
disorders:anear-infrared
spectroscopy study. Behav Brain Res 172:272-277, 2006
25 Maeda K, Kasai K, Watanabe A, Henomatsu K,
Rogers MA, Kato N: The relationship between
subjective reasoning for medication adherence
and neurocognition in persons with schizophrenia.
Psychiatr Serv 57: 1203-1205, 2006

85

26 Marui T, Ikuko Funatogawa I, Koishi S,
Yamamoto K, Matsumoto H, Hashimoto O, Nanba
E, Nishida H, Sugiyama T, Kasai K, Watanabe K,
Kano Y, Kato N, Sasaki T: Tachykinin 1 (TAC1)
gene SNPs and haplotypes with autism: a casecontrol study. Brain and Development, in press
27 Matsuo K, Glahn DC, Peluso MA, Hatch JP,
Monkul ES, Najt P, Sanche M, Zamarripa F, Li J,
Lancaster JL, Fox PT, Gao JH, Soares JC:
Prefrontal hyperactivation during working
memory task in untreated individuals with major
depressive disorder. Mol Psychiatry 12: 158-166,
2007
28 Matsumoto R, Haradahira T, Ito H, Fujimura Y,
Seki C, Ikoma Y, Maeda J, Arakawa R, Takano A,
Higuchi M, Suzuki K, Fukui K, Suhara T:
Measurement of Glycine Binding Site of
N-methyl-D-asparate (NMDA) Receptors in
Living Human Brain using 4-Acetoxy derivativeof L-703,717, 4-Acetoxy-7-chloro-3-[3-(4-[11C]
methoxybenzyl)
phenyl]-2(1H)-quinolone(AcL703) with PET. Synapse, in press
29 Matsuo K, Kono T, Hatch JP, Seino K, Ohtani T,
Kato N, Kato T: A near-infrared spectroscopy
study of prefrontal cortex activation during averbal fluency task and carbon dioxide inhalation
in individuals with bipolar disorder. Bipolar
Disord, in press
30 Matsuoka K, Uno M, Kasai K, Koyama K, Kim Y:
Estimation of premorbid IQ in individuals with
Alzheimer’s disease using Japanese ideographic
script (Kanji) compound words: a Japaneseversion of NART. Psychiatry Clin Neurosci 60:
332-339, 2006
31 Minato T, Tochigi M, Kato N, Sasaki T:
Association study between the cholecystokinin A(CCK-A) receptor gene and schizophrenia in theJapanese population. Psychiatr Genet, in press
32 Nishimura T, Imai H, Minabe Y, Sawa A, Kato N:
Beneficial effects of FK506 for experimental
temporal lobe epilepsy. Neurosci Res, in press
33 Nishiyama J, Tochigi M, Itoh S, Otowa T, Kato C,
Umekage T, Kohda K, Ebisawa T, Kato N, Sasaki
T: No association between the CNTF nullmutation and schizophrenia or personality.
Psychiatr Genet 16: 217-219, 2006
34 Ohta M, Kano Y, Nagai Y: Catatonia in

individuals with autism spectrum disorders inadolescence and early adulthood: a long-term
prospective study. Int Rev Neurobiol 72: 41-54,
2006
35 Ohtani T, Kaiya H, Utsumi T, Inoue K, Kato N,
Sasaki T: Sensitivity to seasonal changes in panic
disorder patients. Psychiatr Clin Neurosci 60:
379-383, 2006
36 Okamura T, Kudo K, Sata N, Sameshima T, Doi N,
Kato N: Electroconvulsive therapy after coilembolization of cerebral aneurysm: a case reportand literature review. J ECT 22: 148-149, 2006
37 Otake T, Yoshinaga J, Seki Y, Matsumura T,
Watanabe K, Ishijima M, Kato N: Retrospective inutero exposure assessment of PCBs with thepreserved umbilical cords and its application tocase-control comparison. Environmental Healthand Preventive Medicine 11, 65-68, 2006
38 Otowa T, Tochigi M, Rogers M, Umekage T, Kato
N, Sasaki T: Insertional polymorphism ofendogenous
retrovirus
HERV-K115
inschizophrenia. Neurosci Lett 408: 226-229, 2006
39 Paraguison RC, Higaki K, Sakamoto Y,
Hashimoto O, Miyake N, Matsumoto H,
Yamamoto K, Sasaki T, Kato N, Nanba E:
Polyhistidine Tract Expansions in HOXA1 Resultin Intranuclear Aggregation and Increased Cell
Death. Biochem Biophys Res Commun, in press
40 Rosario-Campos MC, Miguel EC, Quatrano S,
Chacon P, Ferrao Y, Findley D, Katsovich L,
Scahill L, King RA, Woody SR, Tolin D,
Hollander E, Kano Y, Leckman JF: The
Dimensional Yale-Brown Obsessive-Compulsive
Scale (DY-BOCS): An instrument for assessing
obsessive-compulsive symptom dimensions. Mol
Psychiatry 11: 495-504, 2006
41 Salisbury DF, Kuroki N, Kasai K, Shenton ME,
McCarley RW: Progressive and interrelated
functional and structural evidence for post-onset
brain reduction in schizophrenia. Arch Gen
Psychiatry, in press.
42 Shimabukuro M, Sasaki T, Imamura A, Tsujita T,
Fuke C, Umekage T, Tochigi M, Hiramatsu K,
Miyazaki T, Oda T, Sugimoto J, Jinno Y, Okazaki
Y: Global hypomethylation of peripheralleukocyte DNA in male patients withschizophrenia: a potential link between

86

epigenetics and schizophrenia. J Psychiatr Res, inpress
43 Takemura N, Kato N: Adult neurogenesis andsystemic adaptation: animal experiments andclinical perspectives for PTSD. Progress in Brain
Research, in press
44 Tochigi M, Otowa T, Hibino H, Kato C, Otani T,
Umekage T, Utsumi T, Kato N, Sasaki T:
Combined analysis of association between
personality
traitsand
threefunctional
polymorphisms in the tyrosine hydroxylase,monoamine oxidase A, and catechol-Omethyltransferase genes. Neurosci Res 54:
180-185, 2006
45 Tochigi M, Hibino H, Otowa T, Kato C, Marui T,
Ohtani T, Umekage T, Kato N, Sasaki T:
Association between Dopamine D4 Receptor(DRD4) Exon III polymorphism and Neuroticism
in the Japanese Population. Neurosci Lett 398:
333-336, 2006
46 Tochigi M, Hibino H, Otowa T, Ohtani T, Ebisawa
T, Kato N, Sasaki T: No association of 5-HT2C,
5-HT6, and tryptophan hydroxylase-1 gene
polymorphisms with personality traits in theJapanese population. Neurosci Lett 403: 100-102,
2006
47 Tochigi M, Otowa T, Hibino H, Kato C, Marui T,
Ohtani T, Umekage T, Kato N, Sasaki T: No
association between the Clara cell secretory
protein (CC16) gene polymorphism andpersonality traits. Prog Neuropsychopharmacol
Biol Psychiatry 30: 1122-1124, 2006
48 Tochigi M, Kato C, Otowa T, Hibino H, Marui T,
Ohtani T, Umekage T, Kato N, Sasaki T:
Association between the Corticotropin-Releasing
HormoneReceptor
2(CRHR2)Gene
Polymorphism and Personality Traits. Psychiatry
Clin Neurosci 60: 524-526, 2006
49 Tochigi M, Zhang X, Ohashi J, Hibino H, Otowa
T, Rogers M, Kato T, Okazaki Y, Kato N,
Tokunaga K, Sasaki T: Association study of thedysbindin (DTNBP1) gene in schizophrenia fromthe Japanese population. Neurosci Res 56:
154-158, 2006
50 Tochigi M, Otowa T, Suga M, Rogers M, Minato
T, Yamasue H, Kasai K, Kato N, Sasaki T: No
evidence for an association between the BDNF

Val66Met polymorphism and schizophrenia or
personality traits. Schizophr Res 87: 45-47, 2006
51 Tochigi M, Suga M, Ohashi J, Otowa T, Yamasue
H, Kasai K, Kato T, Okazaki Y, Kato N, Sasaki T:
No association between the metabotropic
glutamate receptor type 3 gene (GRM3) andschizophrenia in a Japanese population. Schizophr
Res 88: 260-264, 2006
52 Tochigi M, Zhang X, Ohashi J, Hibino H, Otowa
T, Rogers M, Kato T, Okazaki Y, Kato N,
Tokunaga K, Sasaki T: Association study between
the TNXB locus and schizophrenia in a Japanese
population. Am J Med Genet Part B(Neuropsychiatric Genetics), in press
53 Utsumi T, Sasaki T, Shimada I, Mabuchi M,
Motonaga T, Ohtani T, Tochigi M, Kato N, Nanko
S: Clinical features of soft bipolarity in major
depressive inpatients. Psychiatr Clin Neurosci 60:
611-615, 2006
54 Washizuka S, Kametani M, Sasaki T, Tochigi M,
Umekage T, Kohda K, Kato T: Association of
mitochondrial complex I subunit gene NDUFV2
at 18p11 with schizophrenia in the Japanese
population. Am J Med Genet 141B: 301-304,
2006
55 Wati H, Kudo K, Qiao C, Kuroki T, Kanba S: A
decreased survival of proliferated cells in the
hippocampus is associated with a decline inspatial memory in aged rats: Neurosci Lett 399:
171-174, 2006
56 Yasuno F, Ota M, Ando K, Ando T, Maeda J,
Ichimiya T, Takano A, Doronbekov T.-K,
Fujimura Y, Nozaki S, Suhara T: Role of ventral
striatal dopamine D1 receptor in cigarette craving.
Biological Psychiatry: (Epub) 2006
57 Yoshikawa E, Matsuoka Y, Yamasue H, Inagaki M,
Nakano T, Akechi T, Kobayakawa M, Fujimori M,
Nakaya N, Akizuki N, Imoto S, Murakami K,
Kasai K, Uchitomi Y: Prefrontal cortex andamygdala volume in first minor or major
depressive episode after cancer diagnosis. Biol
Psychiatry 59: 707-712, 2006

87

Department of Neurology
Professor
Shoji Tsuji, M.D., Ph.D.
Associate Professor
Shin Kwak, M.D., Ph.D.

Lecturer
Jun Goto, M.D., Ph.D.
Jun Shimizu, M.D. , Ph.D.

Associate
Yasuo Terao, M.D.,Ph.D.,

Tomotaka Yamamoto, M.D.,Ph.D.,

Yaeko Ichikawa, M.D.,Ph.D.,

Riotsuko Hanajima, M.D., Ph.D.,

Yuji Takahashi, M.D.,PhD.

Homepage http://square.umin.ac.jp/neurotky/
Introduction and Organization
The Department of Neurology was established by
the founder Professor Yasuo Toyokura in 1964 as one
Department in the Brain Research Institute. The
Department of Neurology was succeeded byProfessors Toru Mannen and Ichiro Kanazawa. The
organization of the Brain Research Institute wasreorganized as the Division of Neuroscience of the
Graduate School of Medicine in 1997. We celebrated
40th Anniversary of the Department of Neurology in
2004.

Clinical activities
We offer clinical services in the field of Neurology.
We are putting our effort to provide the patients withhighly advanced clinical practice as well as on clinicalactivities connected to postgraduate education of
Neurology.
We have outpatient clinics covering the broad
fields of Neurology. Furthermore, we also provide
clinics specialized to movement disorders andheadaches.

In the in patient ward, we offer programs forpostgraduate education including the program for the
first stage postgraduate education. We also offer the
excellent training program with the goal to get theboard of Neurologist. In 2005, we initiated deep brain
stimulation for the treatment of movement disorders incooperation with Department of Neurosurgery.
Clinical trials including that for polyglutamine disease
and that based on vestibular nerve stimulation arebeing conducted.

Teaching activities
As for under-graduate education, our Department
takes a part in lectures of Neurology for the 4th and5th grade medical students, and bed-side learning forthe 5th grade medical students, and clinical clerkshipfor the 5th grade medical students.
In the bed-side learning we include small group
lectures covering
neurological examination,neurophysiology, neuroradiology, neuropathology,
neuropsychology,
neuroimmunology,
andneurogenetics. We are also putting our effort for Free
Quarters where we offer various opportunities for88

medical students to be involved in research activities,
and 2-3 medical students are conducting their research
activities in the laboratories.
In postgraduate education we offer the integrated
program including Neurology as the part of the
program of Internal Medicine.
For training of board-certified Neurologists, weoffer the excellent program including patients’care,training in Neurophysiology and Neuropathology,
consultation for Neurology, and supervising of juniortrainees. This program is integrated with clinicalpractice at the affiliated hospitals where richexperience is obtained for numerous cases in Clinical
Neurology.
In Graduate School, we offer highly advanced
research activities based on the interest of graduate
students. In 2003, 21st Century COE program started
in the Neuroscience Division, and we havesuccessfully accomplished the aim of the program.

Research activities
Our research field covers broad fields related toneurological diseases, with the goals to elucidate themechanisms of neurological diseases, and toeventually develop new therapeutic strategies. Our
research activities include molecular genetics,
developmental biology, cell biology, pharmacology,
pathology, and physiology. We aim to integrate thesebroad research fields to better contribute to clinicalneurology.
In the filed of molecular genetics, we havedevelop a high throughput DNA-microarray-based
diagnostic
system.
Thissystemprovidescomprehensive analyses of genes including those for
Alzheimer disease, Parkinson disease, amyotrophic
lateral sclerosis, and familial spastic paraplegia. We
have initiated multicenter-based consortium for
multiple system atrophy. A large-scale genome-wide
analyses are being conducted to identify diseasesusceptibility genes. We have established excellent
animal models for dentatorubral-pallidoluysian
atrophy, and conducting studies for development oftherapeutics. As the new protein degradation pathway,
the role of autophagy was investigated. (Tsuji, S.,
Goto, J., Shimizu, J., Takahashi, Y., Ichikawa, Y.,
Momose, Y., Date, H., Iwata, A., Fukuda, Y., Jin, Y.,

Suzuki, K., Nakahara, Y., Seki, N., Mitsui, J., Deoka,
K., Ishiura, H., Ihara, R.)
We have demonstrated that RNA editing ofglutamate receptor subunit GluR2 was significantly
reduced in motor neurons in sporadic ALS patients ina neuronal class-selective and disease specific manner.
Since this molecular change is the primary causes ofneuronal death, research work on elucidation of theunderlying molecular mechanism and development ofspecific therapy for sporadic ALS is undergoing. We
have been investigating to what extent the vestibular
nerve stimulation is beneficial for alleviating
parkinsonism and orthostatic hypotension in patientswith Parkinson disease and Shy-Drager syndrome.
Validity of a wearable accelerometer in evaluating
anti-parkinsonism medication in outpatient clinic has
been also under investigation. (Kwak, S., Hideyama,T., Yamashita, T., Pan, W., Awabayashi, K.)
The human neurophysiology section has been
studying normal function of the human brain andpathophysiology for neurological disorders using
several non-invasive physiological methods, such as
TMS, EEG, MEG, fMRI, NIRS and ECG. Our final
goal is to develop a new therapeutic method for
intractable disorders. One of them is deep brain
stimulation (DBS) which has been partly established.
We began a physiological approach to elucidate themechanisms for DBS in the patients. We have also
recently developed a new, highly effective TMS
method to induce long-term effects on the humanbrain using repetitive, monophasic magnetic stimuli.
We have just stared a project to treat patients withmovement disorders, intractable pain, epilepsy and soon using that new treatment. (Terao, Y., Hanajima, R.,
Okabe, S., Terada, S., Yugeta, A., Hamada, M.,
Matsumoto, H., Furubayashi, T., Higashihara, M.,
Shirota, Y)
In the field of neuromuscular diseases, we provide
diagnosis of neuromuscular pathology (muscle andnerve biopsies) and autoantibody testing foranti-ganglioside antibodies. Our neuromuscularpathology service evaluates approximately 100
neuromuscular biopsy specimens each year. In
research field, we focus on exploring the mechanismof inflammatory myopathies and immune mediatedneuropathies. We also focus on establishing improved
methods of diagnosis and treatment of these diseases.

89

Using clinical, pathological and molecular techniques,
we aim to increase understanding of the etiology andpathogenesis of neuromuscular diseases. (Shimizu, J.,
Hashimoto, H., Kubota, A.,Tokimura, N., Mashiko,R.)

Publication
1. Hamada M, Hanajima R, Terao Y, Arai N,
Furubayashi T, Inomata-Terada S, Yugeta A,
Matsumoto H, Shirota Y, Ugawa Y. Quadropulse stimulation is more effective than pairedpulse stimulation for plasticity induction of thehuman motor cortex. Clin Neurophysiol. 118:
2672-82, 2007.
2. Hara, K, Shiga, A, Nozaki, H, Mitsui, J, Takahashi,
Y, Ishiguro, H, Yomono, H, Kurisaki, H, Gotom J,
Ikeuchi, T, Tsuji, S, Nishizawa, M, and Onodera,
O. Total deletion and a missense mutation of
ITPR1 in Japanese SCA15 families. Ann Neurol
62: 544-544, 2007
3. Hara, K., Momose, Y., Tokiguchi, S., Shimohata,M., Terajima, K., Onodera, O., Kakita, A.,
Yamada, M., Takahashi, H., Hirasawa, M.,
Mizuno, Y., Ogata, K., Goto, J., Kanazawa, K.,
Nishizawa, M., and Tsuji, S. Multiplex families
with multiple system atrophy Arch. Neurol
64:545-51, 2007
4. Isoo, N, Sato, C, Miyashita, H, Shinohara, M,
Takasugi, N, Morohashi, Y, Tsuji, S, Tomita, T,
and Iwatsubo, T. Aβ42 overproduction associatedwith structural changes in the catalytic pore ofγ-secretase: common effects of Pen-2 aminoterminal elongation and fenofibrate. J. Biol. Chem.
282:12388-96, 2007
5. Kaneko N, Muratake T, Kuwabara H, Kurosaki, T.,
Takei, M., Ohtsuki, T., Arinami, T., Tsuji, S.,
Someya, T. Autosomal linkage analysis of aJapanese single multiplex schizophrenia pedigree
reveals two candidate loci on chromosomes 4q
and 3q. Am J Med Genet Part B-Neuropsych
Genet 144B: 735-742, 2007
6. Martins, S, Calafell, F, Gaspar, C, Wong, VCN,
Silveira, I, Nicholson, GA, Brunt, ER.
Tranebjaerg, L, Stevanin, G, Hsieh, M, Soong, B,
Loureiro, L, Du¨ rr, A, Tsuji, S, Watanabe, M,
Jardim, LB, Giunti, P, Riess, O, Ranum, LPW,

Brice, A, Rouleau, GA, Coutinho, P, Amorim, A,
Sequeiros, J. Asian Origin for the WorldwideSpread Mutational Event in Machado-Joseph
Disease. Arch Neurol. 64:1502-8, 2007.
7. Matsumoto L, Yamamoto T, Higashihara M,
Sugimoto I, Kowa H, Shibahara J, Nakamura K,
Shimizu J, Ugawa Y, Goto J, Dalmau J, Tsuji S.
Severe hypokinesis caused by paraneoplastic
anti-Ma2 encephalitis associated with bilateral
intratubular germ-cell neoplasm of the testes. Mov
Disord. 22:728-31, 2007
8. Pan W, Ohashi K, Yamamoto Y, Kwak S:
Power-law temporal autocorrelation of activity
reflects severity of parkinsonism. Mov Disord 22:1308 -1313, 2007.
9. Sakurai Y, Onuma Y, Nakazawa G, Ugawa Y,
Momose T, Tsuji S, Mannen T Parietal
dysgraphia: characterization of abnormal writing
stroke sequences, character formation andcharacter recall. Behav Neurol 18: 99-114, 2007
10. Sakurai Y, Terao Y, Ichikawa Y, Ohtsu H, Momose
T, Tsuji S, Mannen T Pure alexia for kana.
Characterization of alexia with lesions of theinferior occipital cortex. J. Neurol. Sci. 268:48-59,
2007
11. Shimohata, T, Hara, K, Sanpei, K, Nunomura, J,
Maeda, T, Kawachi, I, Kanazawa, M, Kasuga, K,
Miyashita, A, Kuwano, R, Hirota, K, Tsuji, S,
Onodera, O, Nishizawa, M. and Honma, Y. Novellocus for benign hereditary chorea with adultonset maps to chromosome 8q21.3- q23.3 Brain.
130:2302-9, 2007
12. Takahashi, T., Tada, M., Igarashi, S., Koyama, A.,
Date, H., Yokoseki, A., Shiga, A., Yoshida, Y.,
Tsuji, S., Nishizawa, M., Onodera, O. Aprataxin,causative gene product for EAOH/AOA1, repairs
DNA single-strand breaks with damaged
3'-phosphate and 3'-phosphoglycolate ends.
Nucleic Acids Res 35: 3797-809, 2007
13. Takizawa Y, Kanda H, Sato K, Kawahata K,
Yamaguchi A, Uozaki H, Shimizu J, Tsuji S,
Misaki Y, Yamamoto K Polymyositis associated
with
focal
mesangial
proliferative
glomerulonephritis with depositions of immune
complexes. Clin Rheumatol l26: 792-6, 2007
14. Terao Y, Ugawa Y, Yamamoto T, Sakurai Y,
Masumoto T, Abe O, Masutani Y, Aoki S, Tsuji S.

90Primary face motor area as the motor
representation of articulation Author(s): Source: J.
Neurol. 254 : 442-447 APR 2007
15. Arai, N, Kishino, A, Takahashi, Y, Morita1, D,
Nakamura, K, Yokoyama, T, Watanabe, T, Ida, M.,
Goto, J, Tsuji, S. Familial cases presenting very
early onset autosomal dominant Alzheimer’s
disease with I143T in presenilin-1 gene:
Implication for genotype-phenotype correlation.
Neurogenetics 9:65-7, 2008
16. Abe Y, Miyashita M, Ito N, Shirai Y, Momose Y,
Ichikawa Y, Tsuji S, Kazuma K Attitude ofoutpatients with neuromuscular diseases in Japanto pain and use of analgesics. J Neurol Sci 267:
22-7, 2008
17. Hanajima R, Okabe S, Terao Y, Furubayashi T,
Arai N, Inomata-Terada S, Hamada M, Yugeta A,
Ugawa Y. Difference in intracortical inhibitionof the motor cortex between cortical myoclonus
and focal hand dystonia. Clin Neurophysiol.
119: 1400-7, 2008.
18. Iwata NK, Aoki S, Okabe S, Arai N, Terao Y,
Kwak S, Abe O, Kanazawa I, Tsuji S, Ugawa Y
Evaluation of corticospinal tracts in ALS withdiffusion tensor MRI and brainstem stimulation.
Neurology 70:528-32, 2008
19. Ishiura H, Morikawa M, Hamada M, Watanabe T,
Kako S, Chiba S, Motokura T, Hangaishi A,
Shibahara J, Akahane M, Goto J, Kwak S,
Kurokawa
M,
Tsuji
S.
Lymphomatoid
granulomatosis involving central nervous system
successfully treated with rituximab alone. Arch
Neurol65:662-665, 2008
20. Kwak S, Hideyama T, Yamashita T: AMPA
receptor-mediated neuronal death in motor neuron
diseases. In: Amino Acid Receptor Research, Ed:
Paley BF, Warfield TE, Nova Science Publishers
Inc. NY. pp 293-310, 2008
21. Matsumoto, H, Ohminami, S, Goto, J, Tsuji, S.
Progressive supranuclear palsy with wall-eyedbilateral internuclear ophthalmoplegia syndrome.
Arch Neurol 65: 827-829, 2008
22. Nishimoto Y, Yamashita T, Hideyama T, Tsuji S,
Suzuki N, Kwak S: Determination of editors ofmRNAs with site-selective A-to-I editing
positions, Neurosci Res 61:201-206, 2008
23. Takada K, Shimizu J, Kusunoki S. Apoptosis ofprimary sensory neurons in GD1-induced sensory
ataxic neuropathy. Exp. Neurol. 2008; 209: 279283
24. Flanagan JR, Terao Y, Johansson RS. Gazebehavior when reaching to remembered targets. J
Neurophysiol. 2008 [Epub ahead of print]
25. Furubayashi T, Ushiyama A, Terao Y, Mizuno Y,
Shirasawa K, Pongpaibool P, Simba AY, Kanako
Wake K, Nishikawa M, Miyawaki K, Yasuda A,
Uchiyama M, Kobayashi Yamashita H, Masuda H,
Hirota S, Takahashi M, Okano T, Inomata-Terada
S, Sokejima S, Maruyama E, Watanabe S, Taki M,
Ohkubo C, Ugawa Y. Effects of short-term
exposure to a W-CDMA mobile phone basestation signal: Do they differ between womenwith mobile phone related symptoms and those
without?. Bioelectromagnetics 2008 (in press)
26. Hamada M, Terao Y, Hanajima R, Shirota Y,
Nakatani-Enomoto S, Furubayashi T, Matsumoto
H, Ugawa Y.Bidirectional long-term motor
cortical plasticity and metaplasticity induced byquadripulse transcranial magnetic stimulation. J
Physiol. 2008 [Epub ahead of print]
27. Kwak S, Nishimoto Y, Yamashita T: Newly
identified ADAR2-mediated editing positions as a
useful tool for ALS research. RNA Biology inpress
28. Massie A, Cnops L, Smolders I, McCullumsmith
R, Kwak S, Arckens L, Michotte Y: High-affinity
Na+/K+-dependent glutamate transporter EAAT4
is expressed throughout the rat fore- and midbrain.
J comp Neurol in press.
29. Pan W, Soma R, Kwak S, Yamamoto Y:
Improvement of motor functions by noisy
vestibular stimulation in central neurodegenerative disorders. J Neurol in press.
30. Takahashi, Y, Seki, N, Ishiura, H, Mitsui, J,
Matsukawa, T, Kishino, A, Onodera, O, Aoki, M,
Shimozawa, M, Murayama, S, Itoyama, Y, Suzuki,
Y, Sobue, S, Nishizawa, M, Goto, J and Tsuji, S.
Development of high-throughput microarraybased resequencing system for neurologicaldisorders and its application to molecular genetics
of amyotrophic lateral sclerosis. Arch Neurol (inpress)
31. Tsuji, S, Onodera, O, Goto, J. and Nishizawa, M.
Sporadic Ataxias in Japan -A population-based

91

epidemiological study- Cerebellum (Epub aheadof print)

92

Department of Neurosurgery
Professor
Nobuhito Saito, M.D., Ph.D.

Associate Professor
Nobutaka Kawahara, M.D., Ph.D.

Lecturer
Tomoki Todo, M.D., Ph.D.,

Kensuke Kawai, M.D., Ph.D.,

Yasushi Ino, M.D., Ph.D.

Associate
Kyosuke Kamata, M.D., Ph.D.,

Akira Iijima, M.D.,

Akitake Mukasa, M.D., Ph.D.,

Keisuke Maruyama, M.D., Ph.D.,

Keisuke Takai, M.D,

Takahiro Ohta, M.D.,

Homepage

Masahiro Shin, M.D., Ph.D.,
Tomoyuki Koga, M.D.

http://www.m.u-tokyo.ac.jp/neurosurg/

Introduction and Organization
The Department of Neurosurgery at the Universityof Tokyo Hospital consists of 14 staff neurosurgeons,
who participate in the three major academic activities:
patient care, research and education. The staffs
include a professor/chairman, two associate professors,
three lecturers and nine associates.
Clinical ward for Neurosurgery in our university
hospital was founded in 1951 as the first
Neurosurgical clinic in Japan. Dr. Keiji Sano, as thefounding professor, established the Department of
Neurosurgery in 1962. Dr. Kintomo Takakura and Dr.
Takaaki Kirino served as the second and the third
professor. The incumbent professor, Dr. Nobuhito
Saito, has been serving as the fourth professor since
2006.
Our department provides expertise for patients withbrain tumor, cerebro-vascular disease, spinal lesion,functional disorders, head trauma, etc.

Clinical activities
General and specialized outpatient clinics are open

three days a week (Monday, Wednesday and Friday).
New patient are accepted two days a week (Tuesday
and Thursday). Specialized outpatient clinics are open
for patient with brain tumors, pituitary disease, spinal
disease, cerebrovascular disease, epilepsy, and gamma
knife treatment. From April 2007 through March 2008,
14,024 patients were treated at the outpatient clinics.
The Neurosurgery Ward has about 40 beds on theseventh floor of the new hospital building opened in
Sept. 2001. In 2006 and 2007, 674 and 482 patientswere admitted to the Neurosurgical Ward, respectively.
Three hundred and twenty two and 404 surgicalprocedures were performed with 98 and 147 gamma
knife precedures in each year. Our practice covers awide variety of neurosurgical diseases including
malignant and benign brain tumors, hemorrhagic andocclusive cerebrovascular diseases, spinal disorders,
epilepsy, pain and movement disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional
mapping in epilepsy surgery are frequently used topreserve brain function as much as possible.
State-of-the-art techniques including intraoperative
computer-aided
navigation
andintravascular

93

procedures help our continuous effort to increase thesafety of surgical treatment.
Our department is affiliated with 42 neurosurgicalinstitutions in and around the city of Tokyo including
15 university medical centers, where our residents andstudents are exposed to various pathologies. Surgicalcase volume in all hospitals exceeds 4000cases.

Teaching activities
Medical students take lectures of clinicalneurosurgery in their second year. Clinical casestudies and bedside teaching are scheduled in the thirdand fourth years. The lecturers introduce general
Neurosurgery as well as the state-of-art Neurosurgicalpractice to the students. At the bedside teaching andclinical clerkship, they are offered opportunities tolearn clinical management of Neurosurgical patients in
the hands-on style, and also are exposed to practice invarious subspecialties in neurosurgery through special
seminars given by experts in the fields.
We accepted 5 residents in 2006 as a new residency
program. These residents are trained in the university
hospital and affiliated hospitals to experience every
aspects of neurosurgical practice for five years inaverage. Our residency training is finalized after thesixth year, when the finishing residents serve as seniorresident at the university hospital for 6 months.
Academic training is provided through numerous
intramural clinical and research conference, journal
clubs seminars as well as quarterly regional meetingof Japan Neurosurgical Society. After the residents
finish their training, or during training, they canchoose to be admitted into the Ph.D. course at thegraduate school of Medicine, University of Tokyo, tobe involved in advanced basic research activities for 4
year. After complete training, our graduates stay in thedepartment to be an associate in our or otheruniversity hospitals or become clinical staff in ouraffiliated hospitals.

Research activities
Clinical research in these two years have mainly
focused on treatment of acoustic neurinoma
techniques of skull base surgery, treatment ofmalignant brain tumors, radiosurgery and epilepsy

surgery. The results were presented at domestic andinternational meetings including Annual Meetings of
the Japan Neurosurgical Society and Annual Meetingsof American Association of Neurological Surgeons. .
Our department has been keeping prominent basic
research activities as well. The fields of our current
research are as follows
1) Pathogenesis of cerebral ischemia and neuronal
regeneration after ischemic brain damage
One of the major topics in recent basic science is toregenerate the brain with endogenous neuralprogenitors. Our laboratory has started basic research
to regenerate neurons in vivo following ischemic
insult. We have demonstrated that the 40% of the lost
neurons could be regenerated by administration of
growth factors. We also succeeded in regeneration of
striatal neurons. Molecular mechanisms of adultneurogenesis are currently investigated using various
models to enhance post-ischemic regeneration. By
extending the research into primate model, we are
pursuing clinical application in the future.
2) Development of New Therapeutic Modalities for
Malignant Brain Tumors
Despite advances in microsurgical techniques, thepoor prognoses of malignant glioma patients have not
improved for decades. We develop a new strategy byusing replication-competent herpes simplex viruses(HSV) that are genetically engineered to replicate in
and kill tumor cells but not normal cells. Using athird-generation oncolytic HSV, we currently preparea clinical trial on patients with progressive
glioblastoma. Using our HSV vector construction
system, we further create and test various oncolytic
HSV vectors “armed” with immunostimulatory genes.
We also practice optimized therapy based on the
results of genetic analyses routinely performed ontumor specimens obtained from glioma patients.
Currently, using polymeric micelles, we develop a
new mode of chemotherapeutic drug delivery systemfor brain tumors.
3) Development and evaluation of function-preserving
and less invasive treatment of intractable epilepsy
We have been promoting the research on development,
evaluation and standardization of the novel treatment
for intractable epilepsy. Since our facility is presently
the only one that can provide vagus nerve stimulation
therapy in Japan, we are trying to evaluate its efficacy

94

and establish its significance in epilepsy treatment.
Efficacy evaluation and development of surgicalinstruments has been promoting for novel
function-preserving techniques, multiple subpial
transection and multiple hippocampal transection.
Basic and clinical research on gamma knife treatmentof epilepsy has been performed as well.
4) Research on brain function using non-invasive andinvasive techniques
We have been studying human brain function using
not only non-invasive techniques such as fMRI, MEG,NIRS but also intracranial electrodes implanted inepilepsy patients. The latter is our markedly
advantageous feature that enables us to obtain brain
information with much higher spatial resolution and
SN ratio. We are planning to expand the research on
this field to the study on brain-computer interface incooperation with other brain research laboratories andengineering laboratories.
5) Gamma knife radiosurgery
Our department is the first to introduce gamma knife
radiosurgery in Japan to treat various kinds ofintracranial lesions including skull base tumors or
deep-seated brain arteriovenous malformations withsuccessful clinical result. We have particularly
excellent achievement on treatment of brain
arteriovenous malformations; not only imaging result
but also effect on the risk of hemorrhage was analyzed
and reported in NEJM 352:146-53,2005. Moreover,the integration of diffusion-tensor tractography into
gamma knife treatment enabled us to confirm the doseto the critical white matter fibers inside the brain,
which can be performed only in our department
among the world and can lead to safer treatment.
6) Clinical applications of the functional brain
imaging for neurosurgery
Our department intensively utilizes various kinds offunctional
imaging
modalities
includingmagnetoencephalography, functional MRI and
diffusion tensor imaging-based tractography forpresurgical brain mapping. Combining the results ofthe multi-modalities enables to visualize all corticaland subcortical networks of the motor, language andother cognitive functions in each patient. Furthermore,
we succeeded to import the combined information intoaneuronavigation
system(functional
neuronavigation), which quickly and accurately

indicates the eloquent brain areas.

References
1. Fukuhara H, Todo T: Oncolytic herpes simplex
virus type 1 and host immune responses. Current
Cancer Drug Target 7: 149-155, 2007
2. Furnari FB, Fenton T, Bachoo RM, Mukasa A,
Stommel JM, Stegh A, Hahn WC, Ligon KL,
Louis DN, Brennan C, Chin L, DePinho RA,
Cavenee WK: Malignant astrocytic glioma:
genetics, biology, and paths to treatment. Genes
Dev 21: 2683-2710, 2007
3. Hashiba Y, Tosaka M, Saito N, Imai H, Shimizu T,
Sasaki T: Vasorelaxing effect of the Rho-kinase
inhibitor, Y-27632, in isolated canine basilar
arteries. Neurol Res 29: 485-489, 2007
4. Huang PH, Mukasa A, Bonavia R, Flynn RA,
Brewer ZE, Cavenee WK, Furnari FB, White FM:
Quantitative analysis of EGFRvIII cellularsignaling networks reveals a combinatorial
therapeutic strategy for glioblastoma. Proc Natl
Acad Sci U S A 31: 12867-12872, 2007
5. Iijima A, Ito D, Kunishima K, Aoki S, Saito N:
Elevated volume embolization ratio with
KANEKA extraSoft
coilfor
aneurysm
endovasculartreatment.
Interventional
Neuroradiology 13 suppl.2: 392-393, 2007
6. Inoue T, Tsutsumi K, Yako K, Tanaka S:
Recurrent subarachnoid hemorrhage after
complete occlusion of a ruptured small-necked,
small vertebral artery-posterior inferior cerebellar
artery aneurysm. case illustration. J Neurosurg
106: 514, 2007
7. Ishiuchi S, Yoshida Y, Sugawara K, Aihara M,
Ohtani T, Watanabe T, Saito N, Tsuzuki K, Okado
H, Miwa A, Nakazato Y, Ozawa S:
Ca2+-permiable AMPA receptors regulate growthof human glioblastoma via akt activation. J
Neurosci 27:7987-8001, 2007
8. Kamada K, Sawamura Y, Takeuchi F, Kuriki S,
Kawai K, Morita A, Todo T: Expressive andreceptive language areas determined by a
non-invasive reliable method using functional
magnetic
resonance
imagingandmagnetoencephalography. Neurosurgery 60:
296-306, 2007

95

9. Kamada K, Todo T, Masutani Y, Aoki S, Ino K,
Morita A, Saito N: Visualization of thefrontotemporal language fibers by tractography
combined with functional magnetic resonanceimagingandmagnetoencephalography.
J
Neurosurg 106: 90-98, 2007
10. Maruyama K, Kamada K, Shin M, Itoh D,
Masutani Y, Ino K, Tago M, Saito N: Optic
radiation tractography integrated into gamma
knife surgery. J Neurosurg 107: 721-726, 2007
11. Maruyama K, Shin M, Tago M, Kishimoto J,
Morita A, Kawahara N: Radiosurgery to reduce
the risk of first hemorrhage from brain
arteriovenous malformations. Neurosurgery 60:
453-459, 2007
12. Miyagishima T, Takahashi A, Kikuchi S,
Watanabe K, Hirato M, Saito N, Yoshimoto Y:
Effect of Vim-thalamotomy on the area withinsensorimotor cortex activated by passive hand
movements: fMRI imaging study. Stereotact
Funct Neurosurg 85: 225-234, 2007
13. Nakao K, Watanabe K, Fujishiro Y, Ebihara Y,
Asakage T, Goto A, Kawahara N: Olfactory
neuroblastoma: long-term clinical outcome at asingle institute between 1979-2003. Acta Otolaryngologica 127: 113-117, 2007
14. Nohara H, Furuya K, Kawahara N, Iijima A, Yako
K, Shibahara J, Kirino T: Lymphoplasmacyte-richmeningioma with atypical invasive nature. Neurol
Med Chir (Tokyo) 47: 32-35, 2007
15. Okaji Y, Tsuno NH, Tanaka M, Yoneyama S,
Matsuhashi M, Kitayama J, Saito S, Nagura Y,
Tsuchiya T, Yamada J, Tanaka J, Yoshikawa N,
Nishikawa T, Shuno Y, Todo T, Saito N, Takahashi
K, Nagawa H: Pilot study of anti-angiogenic
vaccine using fixed whole endothelium in patientswith progressive malignancy after failure ofconventional therapy. Eur J Cancer, 2007 (Epubahead of print)
16. Palfi S, Brouillet E, Jarraya B, Bloch J, Jan C,
Shin M, Condé F, Li XJ, Aebischer P, Hantraye P,
Déglon N: Expression of mutated huntingtin
fragment in the putamen is sufficient to produce
abnormal movement in non-human primates. Mol
Ther 15:1444-1451, 2007
17. Sakurai K, Tanaka N, Kamada K, Takeuchi F,
Takeda Y, Koyama T: Magnetoencephalographic

studies of focal epileptic activity in three patientswith epilepsy suggestive of Lennox-Gastautsyndrome. Epileptic Disord 9: 158-163, 2007
18. Sawamura Y, Kamada K, et al.: Role of surgery
for optic pathway / hypothalamic astrocytomas inchildren. Neuro-Oncology, in press
19. Shin M, Lefaucheur JP, Penholate MF, Brugières P,
Gurruchaga JM, Nguyen JP: Subthalamic nucleus
stimulation in Parkinson’s disease: postoperative
CT-MRI fusion images confirm accuracy ofelectrodeplacement
using
intraoperative
multi-unit recording. Neurophysiol Clin 37:
457-466, 2007
20. Shinoura N, Tabei Y, Yamada R, Saito K,
Takahashi M: Continuous intrathecal treatment
with methotrexate via subcutaneous port:
implication for leptomeningeal dissemination ofmalignant tumors. J Neurooncol, 2007
21. Shinoura N, Yamada R, Suzuki Y, Kodama T,
Sekiguchi K, Takahashi M, Yagi K: Functional
magnetic resonance imaging is more reliable thansomatosensory evoked potential or mapping forthe detection of the primary motor cortex inproximity to a tumor. Stereotact Funct
Neurosurg 85:99-105, 2007
22. Takahashi M, Yamada R, Tabei Y, Nakamura O,
Shinoura N: Navigation-guided ommaya reservoir
placement: implications for the treatment of
leptomeningeal metastases. Minim Invasive
Neurosurg 50: 340-345, 2007
23. Todo T: Oncolytic virus therapy using geneticallyengineered herpes simplex viruses. Gene
Therapy 2007: 130-136, 2007
24. Tosaka M, Sato N, Hirato J, Fujimaki H,
Yamaguchi R, Kohga H, Hashimoto K, Yamada M,
Mori M, Saito N, Yoshimoto Y: Assessment ofhemorrhage in pituitary macroadenoma by
T2*-weighhted grandient-echo MR imaging.
AJNR Am J Neuroradiol 28: 2023-2029, 2007

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

97

Department of
Molecular Preventive Medicine
Professor
Kouji Matsushima, M.D., Ph.D.

Associate Professor
Sho Ishikawa, M.D., Ph.D.

Research Associate
Shinichi Hashimoto, Ph.D.,

Makoto Kurachi, M.D., Ph. D.,

Tetsu Nishiwaki, M.D., Ph. D.,

Takeshi Shimaoka, Ph.D.,

Satoshi Ueha, Ph. D.

Homepage

http://www.prevent.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Molecular Preventive Medicine
was originally established in 1885. It was designed tooffer both a high level of hygienic education andfacilities for specialized research. At present, it is our
responsibility to give lectures, seminars and courses
for experiments and practical training on thepreventive medicine to the third and fourth grade
medical students. The professor, several invitedlecturers (including adjunct staff) and research
associates take part in the education as well as
research activities. There are over thirty members
including research fellows, graduate students andguest researchers in our department.

Teaching activities
The field of our department covers the wide area of
preventive medicine. The main scope of education
includes molecular mechanism of host defense
responses to inciting environmental stimuli, free
radical chemistry and the environmental medicine
with special reference to the relation between healthand environment. The education is provided for thethird and fourth grade medical students. The course isconsisted of lectures, seminars, experiments andpractical training which are provided by our own
staffs and also by the experts outside: National
Institute of Infectious Diseases (Dr. Takebe),
Kanazawa University (Dr. Matsugo), Kyoto
University (Dr. Koizumi), Environmental Science
Center of The University of Tokyo (Dr. Karima),
Health Service Center of The University of Tokyo (Dr.
Okubo), Toyama Medical and Pharmaceutical
University (Dr. Inadera), Kyoto Prefectural Universityof Medicine (Dr. Sakai), Shinshu University (Dr.
Fukushima).

Research activities
We focus on several research fields as follows;
1) Establishment of pathophysiological roles ofchemokines in vivo in various animal diseasemodels.
2) Molecular analysis of chemokine receptor
signaling pathway.
3) Genome-wide transcriptome and epigenetic
signature of various types of cells and tissues innormal as well as disease state

984) Development of vaccines against pathogenic
microorganisms and cancer5) Establishment of a novel bio-monitoring systemfor environmental chemicals.

References(1) Ishida, Y., A. Kimura, T. Kondo, T. Hayashi, M.
Ueno, N. Takakura, K. Matsushima, and N.
Mukaida. Essential roles of the CC chemokine
ligand 3-CC chemokine receptor 5 axis inbleomycin-induced pulmonary fibrosis throughregulation of macrophage and fibrocyte infiltration.
Am J Pathol. 2007; 170(3): 843-54.
(2) Ishikawa, S. and K. Matsushima. Aberrant B1 celltrafficking in a murine model for lupus. Front
Biosci. 2007; 12: 1790-803.
(3) Kai, Y., H. Yoneyama, J. Koyama, K. Hamada, H.
Kimura, and K. Matsushima. Treatment withchondroitinase ABC alleviates bleomycin-induced
pulmonary fibrosis. Med Mol Morphol. 2007;
40(3): 128-40.
(4) Kasahara, M., K. Naruse, S. Sasaki, Y. Nakatani, W.
Qu, B. Ahsan, T. Yamada, Y. Nagayasu, K. Doi, Y.
Kasai, T. Jindo, D. Kobayashi, A. Shimada, A.
Toyoda, Y. Kuroki, A. Fujiyama, T. Sasaki, A.
Shimizu, S. Asakawa, N. Shimizu, S. Hashimoto, J.
Yang, Y. Lee, K. Matsushima, S. Sugano, M.
Sakaizumi, T. Narita, K. Ohishi, S. Haga, F. Ohta, H.
Nomoto, K. Nogata, T. Morishita, T. Endo, I.T. Shin,
H. Takeda, S. Morishita, and Y. Kohara. The
medaka draft genome and insights into vertebrate
genome evolution. Nature. 2007; 447(7145): 714-9.
(5) Katsuta, K., H. Namiki, and K. Matsushima.
Development of a modified microtiter plate with aconcave portion in the center. J Immunol Methods.
2007; 323(2): 132-8.
(6) Kitabatake, M., S. Inoue, F. Yasui, S. Yokochi, M.
Arai, K. Morita, H. Shida, M. Kidokoro, F. Murai,
M.Q. Le, K. Mizuno, K. Matsushima, and M.
Kohara. SARS-CoV spike protein-expressing
recombinant vaccinia virus efficiently induces
neutralizing antibodies in rabbits pre-immunizedwith vaccinia virus. Vaccine. 2007; 25(4): 630-7.
(7) Kurachi, M., K. Kakimi, S. Ueha, and K.
Matsushima. Maintenance of memory CD8+ T cell
diversity and proliferative potential by a primary

response upon re-challenge. Int Immunol. 2007;
19(1): 105-15.
(8) Nakamoto, Y., E. Mizukoshi, H. Tsuji, Y. Sakai, M.
Kitahara, K. Arai, T. Yamashita, K. Yokoyama, N.
Mukaida, K. Matsushima, O. Matsui, and S.
Kaneko. Combined therapy of transcatheter hepatic
arterial embolization with intratumoral dendritic cell
infusion for hepatocellular carcinoma: clinicalsafety. Clin Exp Immunol. 2007; 147(2): 296-305.
(9) Nakano, A., H. Yoneyama, S. Ueha, M. Kitabatake,
S. Ishikawa, I. Kawase, H. Sugiyama, and K.
Matsushima. Intravenous administration of
MIP-1alpha with intra-tumor injection of P. acnes
shows
potentanti-tumor
effect.
Int
Immunopharmacol. 2007; 7(6): 845-57.
(10) Nakaya, I., T. Wada, K. Furuichi, N. Sakai, K.
Kitagawa, H. Yokoyama, Y. Ishida, T. Kondo, T.
Sugaya, H. Kawachi, F. Shimizu, S. Narumi, M.
Haino, C. Gerard, K. Matsushima, and S. Kaneko.
Blockade of IP-10/CXCR3 promotes progressive
renal fibrosis. Nephron Exp Nephrol. 2007; 107(1):e12-21.
(11) Shimaoka, T., K. Seino, N. Kume, M. Minami, C.
Nishime, M. Suematsu, T. Kita, M. Taniguchi, K.
Matsushima, and S. Yonehara. Critical role for CXC
chemokine ligand 16 (SR-PSOX) in Th1 response
mediated by NKT cells. J Immunol. 2007; 179(12):8172-9.
(12)Ueha, S., M. Murai, H. Yoneyama, M. Kitabatake, T.
Imai, T. Shimaoka, S. Yonehara, S. Ishikawa, and K.
Matsushima. Intervention of MAdCAM-1 or
fractalkine alleviates graft-versus-host reaction
associated intestinal injury while preserving
graft-versus-tumor effects. J Leukoc Biol. 2007;
81(1): 176-85.
(13) Ueha, S., H. Yoneyama, S. Hontsu, M. Kurachi, M.
Kitabatake, J. Abe, O. Yoshie, S. Shibayama, T.
Sugiyama, and K. Matsushima. CCR7 mediates the
migration of Foxp3+ regulatory T cells to theparacortical areas of peripheral lymph nodes
through high endothelial venules. J Leukoc Biol.
2007; 82(5): 1230-8.
(14) Vasilescu, A., Y. Terashima, M. Enomoto, S. Heath,
V. Poonpiriya, H. Gatanaga, H. Do, G. Diop, T.
Hirtzig, P. Auewarakul, D. Lauhakirti, T. Sura, P.
Charneau, S. Marullo, A. Therwath, S. Oka, S.
Kanegasaki, M. Lathrop, K. Matsushima, J.F.

99

Zagury, and F. Matsuda. A haplotype of the human
CXCR1 gene protective against rapid diseaseprogression in HIV-1+ patients. Proc Natl Acad Sci
U S A. 2007; 104(9): 3354-9.
(15) Wada, T., N. Sakai, K. Matsushima, and S. Kaneko.
Fibrocytes: a new insight into kidney fibrosis.
Kidney Int. 2007; 72(3): 269-73.

100

Department of Public HealthProfessor
Yasuki Kobayashi, M.D., Ph.D.

Associate Professor
Kazuo Inoue, M.D., Ph.D.

Lecturer
Hajime Sato, M.D., M.P.H., Ph.D., D.P.H.

Associate
Satoshi Toyokawa, Ph.D.

Homepage

http://publichealth.m.u-tokyo.ac.jp/

Introduction and Organization

Teaching activities

Public health departments in medical schools inJapan were introduced after the World War II,
following the model of the U.S. systems for publichealth and medical education. The Department of
Public Health was established in 1947, in the Facultyof Medicine, the University of Tokyo. In 1995, theDepartment became a part of the Division of Social
Medicine, Graduate School of Medicine, as the resultof the shift to a graduate school system in the
University of Tokyo.
The objectives of the Department are botheducation and research of public health. The
Department trains graduate and undergraduate
students through lectures, seminars, field practice, andlaboratory work in public health and occupational
medicine, for the degrees of Medical Doctor (MD),Master of Medical Sciences (MSc), and Doctor of
Medical Sciences (equivalent to Ph.D.).
The Department has conducted research on a wide
variety of public health issues, including health policy
and economics, occupational medicine, communityand clinical epidemiology, and so on. In addition, thestaff members of the Department have offered public
and occupational health services to the governments,
industries, and local communities.

1) Graduate Program
The Department offers special lectures, seminars,
field practice, and laboratory work on public healthand occupational medicine to graduate students. In
these training, special emphasis has been placed on
the following points: (1) how to conduct
epidemiologicalstudies,
(2)
how
to
use
epidemiological and statistical methods, (3) how to
use economic concepts and methods in the healthfields, (4) how to establish the collaboration withhealth professionals in the various fields, and (5) how
to read and write original papers.
Part of the seminars described above has beenformally open to all students in the Graduate Schoolof Medicine as an intensive practice course on study
methods in public health. At the same time, theDepartment has provided the students enrolling in the
Master of Medical Science program with a shortcourse on public health.
2) Undergraduate Program
In the winter term of the fourth grade in the Schoolof Medicine (M2), students are provided with thefollowing lectures: (1) current issues in the field of
public health, (2) preventive services, (3)epidemiology, (4) health economics, (5) community

101

health and primary care (6) occupational andenvironmental health, (7) infection and tuberculosis
control, (8) behavioral medicine, (9) international
health, and (10) health policy in Japan. Similarly, inthe sixth grade (M4), a concentration course of publichealth (e.g., health care systems, occupational
medicine, and community health practice) is provided.
All the above lectures are given by faculty members
and part-time lectures including governmental
officials.
Field practice and laboratory work in public healthis due in the spring term of the fifth grade (M3),which is jointly provided by Department of MolecularPreventive Medicine and the other departments related
to public health fields. Averagely four to five students(small group) are assigned to one special topic groupwith a tutor (a faculty member or part-time lecturer).
Each group conducts field practice, review work, orlaboratory work and writes a report in the style oforiginal or review paper. The reports submitted arebound and made available to those students insubsequent years.
The Department also provides those lectures related
to public health and occupational medicine forundergraduate students in the School of Health
Sciences and Nursing, and the Faculty of Engineering.

Research activities
1) Health policy and economics
We are interested in the topics of health care systemand economics in general. We have performed andpublished those studies related to supply and demandsides of health services in Japan; such as supply anddistribution of physicians, the separation ofpharmaceutical dispensing and prescribing in medical
practice, cost studies of outpatient and inpatient
services, and the efficiency and equity issues of theJapan's health insurance system. We have also carriedon several policy studies in terms of public awarenessof medical technology. These studies have been
published in some international policy journals. We
have continued a collaborative study on a system of
HIV/AIDS care with the introduction of highly active
anti-retroviral therapy (HAART) in developing
countries, since such a system involves medical,
behavioral, social, and economic factors, and would

inevitably become an important health policy issue.
2) Occupational health
We have carried on a longitudinal study onlife-style and health status of workers in various
occupational settings for the purpose of preventing
occupational and life-style diseases. We have also
tackled the issues of health effects of lead and otherheavy metals and solvents, and health effects ofpesticides in developing countries.
3) Community and clinical epidemiology
We have done several epidemiological studies incommunity, such as activities of daily living (ADL)
for the community elderly, as well as those studies inclinical epidemiology. Most of these studies have been
carried on in collaboration with local communities orclinical departments.

References
1. Vigeh M, Yokoyama K, Ramezanzadeh F,
Dahaghin M, Sakai T, Morita Y, Kitamura F, Sato
H, Kobayashi Y. Lead and other trace metals in
preeclampsia: A case-control study in Teheran,
Iran. Environmental Reseach 2006; 100: 268-275.
2. Inoue K, Shono T, Toyokawa S, Kawakami M.
Body mass index as a predictor of mortality incommunity-dwelling seniors. Aging Clinical andExperimental Research 2006; 18: 205-210.
3. Inoue K, Shono T, Matsumoto M. Absence of
outdoor activity and mortality risk in older adults
living at home. Journal of Aging and Physical
Activity 2006; 14: 203-211.
4. Inoue K. Venous thromboembolism in earthquake
victims. Disaster Management and Response
2006; 4: 25-27.
5. Matsumoto M, Inoue K, Kaiji E. Fasting plasma
glucose and its relationship to future diabetes
mellitus and white blood cell count: a longitudinal
study in a rural Japanese population. Jichi
Medical University Journal 2006; 29: 115-123.
6. Sato H, Akabayashi A, Kai I. Appraisal of thepolicymaking process in Japan for gene therapy:
Results of the national surveys of academic
societies, hospitals, and medical schools. Medical
Science Monitor 2006; 12: 7-15.
7. Sato H, Akabayashi A, Kai I. The development of

102

public opinion on advanced medical technologies
and experts’ views on their acceptance of thesetechnologies - the case of organ transplant andgene therapy in Japan. Health Care Analysis 2006;
14: 203-214.
8. Shinozaki M, Watanabe T, Sato H, Nagawa H.
Chronic colitis promotes tumor development.
Oncology Reports 2006; 15: 1485-1490.
9. Toyokawa S, Kitajima T, Kobayashi Y, Sato H,
Chaipah W, Thuennadee R. Health insurance
status and access to antiretroviral treatment
among HIV/AID patients in Northeast Thailand A patient-based analysis. Journal of International
Health 2006; 21: 129-135.
10. Nakata A, Ikeda T, Takahashi M, Haratani T,
Hojou M, Fujioka Y, Araki S. Non-fatal
occupational injury among active and passive
smokersinsmallandmedium-scale
manufacturing enterprises in Japan. Social
Science & Medicine 2006; 63: 2452-2463.
11. Nakata A, Ikeda T, Takahashi M, Haratani T,
Hojou M, Fujioka Y, Swanson NG, Araki S.
Impact of psychosocial job stress on non-fatal
occupational injuries in small and medium-sized
manufacturing enterprises. American Journal ofIndustrial Medicine 2006; 49: 658-669.
12. Nakata A, Ikeda T, Takahashi M, Haratani T,
Hojou M, Swanson NG, Fujioka Y, Araki S. The
prevalence and correlates of occupational injuries
in small-scale manufacturing enterprises. Journalof Occupational Health 2006; 48: 366-376.
13. Sabawoon W, Sato H, Inoue K, Kobayashi Y.
Health condition in Afghanistan and the basic
health package of health services. Journal of
Conference for Emergency Medicine in Rural
Areas and Isolated Islands 2006; 7: 57-63.

Social Medicine
2. Forensic Medicine, and Medical
Informatics and Economics

104

Department of Forensic Medicine
Professor
Ken-ichi Yoshida, M.D., Ph.D.

Lecturer
Kazuki Harada, M.D., Ph.D.

Research Associate
Kaori Shintani, Ph.D.

Research Assistant
Kou Takahashi, M.D, Ph.D.

Homepage

http://plaza.umin.ac.jp/~forensic/

Introduction and Organization
Associate Professor Kuniyoshi Katayama lectured“judicial medicine” in University of Tokyo since 1882
before our department was founded as the firstdepartment of forensic medicine in Japan in 1888. He
renamed “judicial medicine” to “forensic medicine” in1891 since the department should cover legislation as
well as general forensic practices. Dr. Katayama
became the first professor of forensic medicine inJapan.
The 2nd Professor Sadanori Mita also founded theserological department (Department of Immunology atpresent). He discovered the antigen-antibody reaction
and complement fixation reaction.
The 3rd Professor Tanemoto Furuhata was thefamous for ABO blood group genetics, and also
contributed the development of criminology. He
autopsied several cases of historical crimes.
The 4th Professor Shokichi Ueno discovered thecomplex III. He helped foundation of national police
academy for death investigators.
The 5th Professor Toshiyuki Miki could not perform
autopsy for four years due to the University of Tokyo
strike. However, he left many achievements in thefield of blood typing and paternity examination.
The 6th Professor Ikuo Ishiyama encouraged
forensic pathology. He also introduced DNA

fingerprinting and PCR technique in the forensic
practices.
The 7th Professor Takehiko Takatori studied thebiochemical changes of the lipid in cadavers. He
dissected five victims of sarin subway attacks inTokyo and identified sarin in tissue by a sophisticatedmethod.
The present Professor Ken-ichi Yoshida has studied
on the mechanism of ischemic heart disease andsudden cardiac death related to psychological stress,
with respect to gap junction, intracellular signaling,
and proteolysis. Additionally, the death investigation
systemonunnaturaldeath
andmedicalpractice-related death is another topic of study.
The department currently has one professor, one
lecturer, one assistant professor, one associate, two
special technicians, six postgraduate students, and one
researcher. Three doctors from this department has
become professors since 1999. It is a nationwide
difficulty to find suitable doctors as forensic
pathologists. However, there are not a few doctors
who want to become the graduate students in our
department. Those who have experience in clinicalpractices, and researchers in biochemistry, physiology,
pathology, and molecular biology are welcome. We
are preparing to teach practice and research for the
future forensic pathologists.

105

Forensic autopsy

Research activities

The determination of precise cause of death is themost important work in our department. We autopsy
80-100 criminal cases in eastern part of Tokyo every
year. We have already autopsied more than 10000
cases since 1889. Some of these cases are very famousin criminology in Japan.
In forensic autopsy, we examine the pathological,
alcohol, toxicological, and blood type testing of eachcase, too. Finally, forensic pathologists in our
department diagnose the cause of death. Official
documents written in our forensic judgments are so
precious that we keep them since first autopsy case in1889. We have serious responsibility in thedetermination of cause of death.
Since 2005, we also performed autopsies on
medical practice-related deaths (MPAD) in
corroboration with Department of Human Pathology.
Both departments lead the pilot study on theinvestigation and analysis of MPAD (supported bygovernment). We also contribute to evolve new way ofpresenting expert opinions for the jury courts that will
be enacted in 2009.

Our research is wide ranged from social issues tomolecular biology. Main research interest in our
department is as follows:More than two thirds of the causes of unusual death
are ischemic heart disease. Psychological stress from
accidents, assaults, and restraint often triggers these
deaths. To diagnose ischemic heart attack and sudden
death due to psychological events, we study on themechanismofmyocardial
death
due
to
ischemia-reperfusion, with respect to intracellularsignaling system and calcium-dependent protease(calpain). We have focused recently on the implicationof the changes in a gap junction (GJ) component
conexin 43 to the development of contraction bandnecrosis (histological sign of early stage of heart
attack)and sudden death in acute myocardial
infarction or under psychological stress (by restraint).
The death investigation system and information
disclosure on “unusual death” and medical
practice-related death have been also studied. For
example, by a questionnaire study on the plaintiff of
medical malpractice litigations or disuptes, we foundthat delayed and insufficient disclosure causes thesedisputes and litigations. The content of thepresentation at the Meeting of Japanese Society ofLegal Medicine was introduced by Asahi Newspaper.
The achievement will be expected to contribute to
the design the new system for death investigation.
We are also contributing to the innovation ofexpert opinion by use of 3D-computor graphic(3DCG). Mr Takahiro Seo a student (M2) produced
several 3DCGs to support visual understanding of theconventional
expertopinionwith difficult
expressions. These 3DCGs were introduced by TV
programs and newspapers. Additionally, the 3DCG
techniques are applied to expert opinions in an actual
case and simulated court cases. Some of the 3DCGs
were referred to by a publication for lawyers,
forensic pathologists, and police to introduce new
methods of delivery of expert opinions.

Teaching activities
As for under-graduate education, our department
provides lectures for the 4th year medical students,
Free Quarter training course for the 3-4th year medical
students, and Clinical Clerkship learning for the 5thyear medical students.
The lectures are based on the autopsy and court
cases for the better understanding of the deathinvestigation and medical law. In the Free Quarter
training course, students experience laboratory
practices (toxicology, DNA typing, histology) or
experiments. In the clinical clerkship, each student
experiences the process from autopsy to presentationof expert opinion. They can also attend the practicesof medical examiner’s activities and the court.
In addition, students of school of public health andlaw school are provided with somewhat practicallectures with exercises.

References(1) Ohno H, Uemura K, Shintani-Ishida K,
Nakamura M, Inomata M, Yoshida K. Ischemia

106

promotes calpain-mediated degradation of
p120-catenin in SH-SY5Y cells. Biochem
Biophys Res Commun. 2007;353(3):547-52.
(2) Saka K, Uemura K, Shintani-Ishida K, Yoshida
K.Acetic acid improves the sensitivity oftheophylline
analysisbygaschromatography-mass
spectrometry.
J
Chromatogr B Analyt Technol Biomed Life Sci.
2007;846(1-2):240-4.
(3) Shintani-Ishida K, Uemura K, Yoshida KI.
Hemichannels in cardiomyocytes open transiently
during ischemia and contribute to reperfusion
injury following brief ischemia. Am J Physiol
Heart Circ Physiol. 2007, H1714-H1720.
(4) Masami
Uji,
Ken-ichi
Yoshida,Kaori
Shintani-Ishida, Keiko MorimotoSex difference in norepinephrine surge in
response to psychological stress through nitricoxide in rats
Life Sciences 2007; 80(9):860-6.
(5) Takako Ito, Kazue Nakajima, Luella Matstunaga,
Takahiro Kiuchi, Ken-ichi Yoshida. National
Patient and Safety Organization in United
Kingdom. Japan Medical News 2007; 4331：76－
80 (in Japanese)(6) Takako Ito, Noriaki Ikeda. The present states oflegal autopsy on medical practice-associateddeaths. Fukuoka Medical Journal 2007; 98：245－252 (in Japanese)(7) Takako Ito, Koh-ichi Noburomo, Ken-ichi
Yoshida. The present states and how theinvestigation system ought to be judging from thecontent of the reports on medical accidents.
Medical Safety 2007; 4: 30－38 (in Japanese).
(8) Ken-ichi Yoshida. The present status and future of
the model project on medical practive related
deaths. From view-points as forensic pathologist
and representative of the project at Tokyo District.
Japanse Journal of Surgery. 2007; 108: 37-40 (inJapanese)(9) Ken-ichi Yoshida. Textbook “Forensic Medicine
learned from autopsy and court cases”.
Yu-uhikaku Publishing Co. (401pages) 2007,
Tokyo (in Japanese)

107

Department of Medical
Informatics and Economics
Professor
Kazuhiko Ohe, M.D.,Ph.D.

Homepage

http://www.m.u-tokyo.ac.jp/medinfo/

Introduction and Organization
The Department of Medical Informatics andEconomics aims to reform medical systems and makesocial contribution by applying information
technology to medical field such as medical
economics and hospital management. The department
develops basic methods that are applicable to medical
information systems in the boundary area of
healthcare and information science, establishes
infrastructures for information environment where
medical information are utilized effectively, andapplies knowledge and technique acquired throughthese efforts to medical and healthcare field.
The main keywords of the target domain are
medicalandclinicalinformation
systems,
next-generation electronic health record systems,
virtualhealthcare
environment,
computerrepresentations and standardization of medical
concepts, ontology, medical knowledge engineering,
hospital epidemiology, quality assessment ofhealthcare, clinical and bioinformatics engineering,privacy protection and encryption, analysis of hospitalmanagement, safety management in healthcare.
The professor of the department also holds the
position of director of the department planning,
information and management (DPIM) in the
University of Tokyo Hospital. DPIM is the departmentthat deals with information analyses and futureplanning for the University of Tokyo Hospital byusing information systems as well as the planning,
design, development, and operation of information
systems for the whole hospital. The DPIM was newly
established on April 1, 2003, after integration of the

Hospital Computer Center and the project team for
hospital development, which separately existed until
the end of March, 2003.
Since the professor runs the Department of Medical
Informatics and Economics with staffs of DPIM, they
are practically the same organization. Therefore,
educations and researches in the graduate course arepromoted together with DPIM activities. Only one
professor is the official faculty member of the
Department of Medical Informatics and Economics,
however, faculty outside the department participatesas teaching staffs of the graduate course: Assoc. prof.
T. Imamura and Lecturer. K. Miyo from DPIM, Prof.
T. Kiuchi from UMIN center, Visiting assoc. prof. S.
Oku from the Department of Healthcare RelatedInformatics that is the affiliated department (April
2004 - ), Visiting assoc. Prof. H. Hashimoto from the
Department of Health Management and Policy that is
also the affiliated department (Oct. 2005 - ), Assoc.
Prof. R.Yamamoto from Interfaculty Initiative inInformation
Studies,
Graduate
SchoolofInterdisciplinary Information Studies, and Prof. H.
Oyama and Assoc. Prof. Y. Onogi from Division ofClinical and Bioinformatics Engineering, Departmentof Clinical Bioinformatics, Graduate School of
Medicine.
The origin of the Department of Medical
Informatics and Economics dates back to 1983 when
the hospital computer center was officially approved
as one of the central clinical service facilities in thehospital. At the same time, the doctor’s course for
medical informatics was established. The first
professor was Dr. Shigekoto Kaihara, who is thefounder of medical informatics inJapan, and he is now

108

a emeritus professor of the University of Tokyo. In
accordance with the reform to the university with
graduate school curriculum in the university of Tokyo,
the Department of Medical Informatics and economics
was established in present division of social medicine
in 1997. Then, one professor and one associate
professor belonging to the hospital computer center
moved to the department. In 2000, medical
informatics field was set up in the Interfaculty
Initiative in Information Studies, Graduate School ofInterdisciplinary Information Studies. One post for
associate professor was transferred from the
Department of Medical Informatics and economics tothe Interfaculty Initiative in Information Studies andthen our department started the wide acceptance ofstudents. Assoc. prof. Y. Onogi assumed the start-up
position, and now Assoc. prof. R. Yamamoto takes
over the post.
The department is located on the fourth floor in
Administration and Research Building in the
University of Tokyo Hospital.

Teaching activities
The department offers the Medical Science
Doctoral course (4-year program). The eligibility foradmission is open to those who graduate from a 6-year
undergraduate program at the School of Medicine andthose who have master’s degrees either in the
University of Tokyo or any other institutions. It does
not need to have a medical license to apply foradmission. Students will receive Doctor’s degree in
Medical Science with completion of required units
and passing a doctoral thesis.
The department is collaborating with the healthinformatics course in the division of Health Sciences
and Nursing at the Graduate School of Medicine.
Although the department formally belongs to theDivision of Social Medicine, it offers the course ofhealth informatics for students in the division of
Health Sciences and Nursing. Therefore most faculty
members in this department also supervise thestudents in the Health Informatics course. The Health
Informatics course offers 2-year master’s course
program and 3-year doctoral course program.
Completing required units and passing thesis, themaster’s course students will receive Master’s degreein Health Science and the doctoral course student will

receive Doctor’s degree in Health Science.
Furthermore our department accepts the students inthe master’s course of Medical Science.
In this master’s course, all students spend the first
four months on the planned coursework, then will
decide which department they wish to be enrolled.
After assignment of each department, students
conduct their researches and complete master’s thesis
over remaining one and half year. Completing therequired units and passing the thesis, they will receive
the Master’s degree in Medical Science.
The enrolled students in FY2006 are seven in
doctor’s course for Medical Informatics andEconomics, two in doctor’s course for Health
Informatics, and two in master’s course for Health
Informatics.
The students’ researches cover various topics. The
main ones are the analysis of medical cost for the DPC
Classification”, development of method for medical
ontology, a study on the communication model
between healthcare professionals and patients, a study
on methods for healthcare safety control, medical
support by electronic description format of chemical
therapy regimen and inference mechanism, and so on.

Research activities
In 2007 F.Y., research staffs are Prof. Kazuhiko Ohe,
Assistant Professor Kengo Miyo, Project Associate
Hiroki Watanabe, Research Associate Izumi
Yamaguchi, hiroo Ide, Hiroyuki Hoshimoto, Hideo
Yasunaga, Katsuya Tanaka, and Project Research
Associate Eiji Aramaki, Takeshi Imai, Takashi
Noguchi, Nobuo Shinohara, Megumi Sato, Yuki
Nittami (Sumita), Shiro Matsuya, and Akihisa
Watanabe.
Our main research domains are 1) application
studies on developments of clinical information
systems as typified by hospital information systemand electronic health records system, 2) studies on
medical safety control systems, 3)medical knowledge
discovery and analysis of medical economics
indicators by using databases of hospital information
system and electronic health records system, 4)
structured representations and standardization of
medical terms and concepts, 5) privacy protection andsecurity in healthcare information systems, 6)
information analysis on food safety, 7) analysis of

109various issues on DPC, 8) application of virtualenvironment for healthcare.
In these domains, major research topics are as listed
below.
1) A study on development methods for large scale
ontology databases of medical terms andconcepts :This research develops the methods to build thelarge scale medical ontology, which is a databasefor hundreds of thousand of clinical terms andconcepts and their relationships. It focuses on thedevelopment of basic methods for making andaccessing databases and will be applied for the
research described in 6).
2) A study on the development of a patient-oriented,
event-driven, and intellectual clinical support
subsystem(Industry-academia
collaboration
project with Fujitsu Limited, 2004-2008)
This research develops autonomic, distributed,
real–time clinical support system. This system will
be tested by being incorporated in the information
system of the university of Tokyo Hospital.
3) Construction of Clinical and Medical Ontology
Database (Industry-academia collaboration projectwith the Japan Anatomy Laboratory, Co, Ltd.,
2004-2008)
This research aims the construction of actuallyavailable clinical and medical ontology withapproximately 200,000 terms. It also develops
application tools for the ontology.

References
1. Yuki Sumita, Mami Takata, Keiju Ishitsuka,
Yasuyuki Tominaga and Kazuhiko OHE: Buildinga reference functional model for EHR systems
International Journal of Medical Informatics,
76(5), 688-700, 2007
2. Hideo Yasunaga, Hiroo Ide, Tomoaki Imamura,
Kazuhiko Ohe: Price Disparity of PercutaneousCoronary Intervention Devices in Japan and theUnited States in 2006. Circulation Journal, 71,
1128-1130, 2007
3. Hideo Yasunaga , Hiroo Ide , Tomoaki Imamura:
Current disparities in the prices of medical
materials between Japan and the United States:
further investigation of cardiovascular medical

devices. The American Journal of Cardiology ,49(2), 77-81,2007
4. Yasunaga H, Ide H, Imamura T, Ohe K. Accuracyof Economic Studies on Surgical Site Infection.
Journal of Hospital Infection, 65(2), 102-107, 2007
5 Yasunaga H, Ide H, Imamura T, Ohe K. Women’s
Anxieties Caused by False Positives in
Mammography
Screening:A
Contingent
Valuation Survey. Breast Cancer Research andTreatment, 101(1), 59-64, 2007
6. Hideo Yasunaga: Risk of authoritarianism:
fibrinogen-transmitted hepatitis C in Japan,
Lancet 2007 Dec15; 370(9604), 2063-2077
7. H. Ide, H. Yasunaga, T. Imamura, K. Ohe: Pricedifferences between Japan and the US for medical
materials and how to reduce them. Health Policy,
82(1), 71-77, 2007
8. Eiji Aramaki: Natural Language Processing andRecent Japanese Art Studies, Inaugural Workshop
on Computational Japanese Studies, 2007
9. Eiji Aramaki, Takeshi Imai, Masayuki Kajino
Kengo Miyo, Kazuhiko Ohe: A Statistical Selectorof the Best among Multiple ICD-coding Methods,
MedInfo, 2007
10. Eiji Aramaki, Takeshi Imai, Kengo Miyo,
Kazuhiko Ohe: UTH: Semantic Relation
Classification using Physical Sizes, theAssociation for Computational Linguistics(ACL2007) Workshop on Semantic Evaluations(SemEval 2007), pp.464-467, 2007
11. Takeshi Imai, Eiji Aramaki, Masayuki Kajino,
Kengo Miyo, Yuzo Onogi, Kazuhiko Ohe: Finding
Malignant Findings from Radiological Reports
using Medical Attributes and Syntactic
Information, Proceedings of MEDINFO2007, pp.
540-544
12. Imamura T, Kanagawa Y, Matsumoto S, Tajima B,
Uenotsuchi T, Shibata S, Furue M. Relationshipbetween clinical features and blood levels of
pentachlorodibenzofuran in patients with Yusho.
Environ Toxicol. 22(2):124-31, 2007
13. Miyo K., Nittami SY, Kitagawa Y, Ohe K. :Development of Case-based Medication Alerting
and Recommender System; A New Approach toPrevention for Medication Error. Proceedings of
MEDINFO 2007, 2007
14. H Hoshimoto, Y S. Nittami, Y Konishi, M
Ohbayashi, E Murakami, T Kubodera, H

110

Watanabe, I Yamaguchi, K Tanaka, K Miyo, R
Yamamoto, K Ohe: Nationwide Standard
Electronic Health-Document-Exchange based on
HL7CDA-Rel.2
in
the
New
National
Health-Checkup-Program
for
Preventing
Metabolic Syndrome in Japan, Proceedings of
MEDINFO 2007, 2007.

Internal Medicine
1. Medicine Ⅰ

112

Department of Cardiovascular
Medicine
Professor
Ryozo Nagai, M.D., Ph.D.

Associate Professor
Yasunobu Hirata, M.D., Ph.D.

Lecturer
Yoshinori Seko, M.D., Ph.D.,

Hiroshi Yamashita, M.D., Ph.D.

Hospital Lecturer
Nobukazu Ishizaka, M.D., Ph.D.,

Homepage

Koji Maemura, M.D., Ph.D.

http://plaza.umin.ac.jp/~utok-card/

Introduction and Organization

Outline of department

The Department of Cardiovascular Medicine isactively involved in clinical medicine, basic researchand teaching. In line with the rapidly evolving andprogressing nature of modern treatment ofcardiovascular diseases, our department has changed
dynamically during the recent years. Not only do wehave the most highly advanced equipment andfacilities (e.g. 24-hour cardiac care unit), but are
personnel are also highly trained to be wellknowledged and expert in the most modern methodsof diagnosis and treatment. As a teaching and researchhospital, we also emphasize the development andincorporation of new treatments if they may benefit
the patient. From a research standpoint, our interests
range throughout all fields of cardiovascular medicine
ranging from molecular biology to clinical research
including genomics. Importantly, our researchinterests are aimed at making possible new diagnostics
and treatment of cardiovascular diseases. Finally, we
have a particular interest in teaching not only for
medical students but also for residents which isimportant for the future of cardiovascular medicine.

Staff: one professor (Ryozo Nagai), 1 associate
professor (Yasunobu Hirata), 2 assistant professors(outpatient clinic Yoshinori Seko and hospital ward
Hiroshi Yamashita), 15 research associates, 9 staff
members, 30 graduate school students, 6 researchers,
1 members on leave and 2 members studying abroad.

Clinical activities
In 2007, 1,467 patients were newly admitted to our
hospital ward of approximately 50 beds. Of thesepatients, approximately 70% were due to ischemic
heart disease. Cardiovascular angiograms wereconducted in 1,783 patients, of which 582 cases wereinterventional procedures. CT coronary angiography
was examined in 351 patients and cardiovascular MRI
in 117. For arrhythmias, there were 61 cases of
implantation of a pacemaker, 51 cases of catheter
ablation, and other specialized pacemaker devices
such as 13 cases of implantation of a cardioverterdefibrillator, and 10 cases of implantation of a cardiac
resynchronization device.
As we are an authorized facility for heart113

transplantation, left ventricular assist device (LVAD)
use for severe heart failure cases has been increasing.
In 2006, the first case of heart failure from ourdepartment underwent a heart transplant procedure atthe Department of Cardiovascular Surgery. The hearts
were transplanted to 2 cases also in 2007. Duration of
hospitalization is on average 12.9 days.
Out-patient clinics are available as part of the
Department of Medicine or as a specialized
department. Patient numbers are increasing each year
to 51,820 in 2007. The profile of diseases includes
ischemic heart disease in main in addition to
hypertension and peripheral artery disease.
Out-patient clinics are open both mornings andafternoons from Monday to Friday. Approximately
203 patients visit each day. Acute cases of coronary
heart disease and aortic disease are also a focus of thedepartment, as emergent catheterization is available
on a 24-hours basis.

Teaching activities

10. Molecular analysis of myosin light chain
mutationsinfamilial
hypertrophic
cardiomyopathy
11. Clock gene in cardiovascular diseases
12. Early diagnosis of ischemic heart disease using
visualization techniques of coronary arteries
13. Immunological basis of myocarditis and dilated
cardiomyopathy
14. Anti-arrhythmia therapy using catheter ablation
15. New treatment for pulmonary hypertension
16. Development of drug eluting stent
17. Clinical application of vasoactive substances for
cardiorenal insufficiency
18. Bone marrow-derived cells in atherosclerosis
19. Regeneration therapy for cardiovascular disease

References
1. Aihara K, Azuma H, Akaike M, Ikeda Y, Sata M,
Takamori N, Yagi S, Iwase T, Sumitomo Y, Kawano
H, Yamada T, Fukuda T, Matsumoto T, Sekine K,
Sato T, Nakamichi Y, Yamamoto Y, Yoshimura K,

As a division of the Department of Medicine,
medical diagnostics training, general cardiovascular
medicine, clinical lectures and bedside teaching arecourses available at the medical school. For bedsideteaching, two students are placed under the guidanceof one research associate allowing for teaching insmall groups. Specialized groups provide lectures. As
for post-graduate education, residents are educatedthrough specialized group conferences, chart rounds,
grand rounds and clinical conferences.

Research activities

Watanabe T, Nakamura T, Oomizu A, Tsukada M,
Hayashi H, Sudo T, Kato S, Matsumoto T.
Strain-dependent

lethality

andexaggerated vascular remodeling in heparin cofactor
II-deficient mice. J. Clin. Invest. 2007;117. 1514-26.
2. Asada K, Hatano M, Takeda N, Higashikuni Y, Saito
K, Ishizaka N, Hirata Y, Nagai R. Giant left
coronary artery aneurysm in a patient with mixed
connective tissue disease. Intern Med. 2007; 46:
1267-8.
3. Fujita M, Yamazaki T, Hayashi D, Kohro T, Okada Y,
Nagai

Areas of interest are as follows:
1. Regulated expression of smooth muscle myosin
heavy chain
2. Mouse genetic models of cardiovascular diseases
and vascular development
3. Differentiation of smooth muscle cells
4. Genetic risk analysis of atherosclerosis
5. Mechanism of post-PTCA restenosis
6. MRI in cardiovascular diseases
7. Gene expression and regulation in cardiomyocytes
8. Nitric oxide and endothelial function
9. Aerobic threshold and cardiac rehabilitationembryonic

R.

The

JCAD

Study

Investigators.

Comparison of cardiovascular events in patientswithangiographically

documented

coronary

narrowing with combined renin-angiotensin system
inhibitor plus statin versus renin-angiotensin system
inhibitor alone versus statin alone (from theJapanese Coronary Artery Disease Study). Am J
Cardiol. 2007; 100: 1750-53.
4. Fukuda D, Sata M. Renin-angiotensin system: apotential modulator of endothelial progenitor cells.
Hypertens Res. 2007; 30:1017-8.
5. Hara K, Yamauchi T, Imai Y, Manabe I, Nagai R,

114

Kadowaki

T.

Reducedadiponectin

level

is

14. Ishizaka N, Nagai R, Ishizaka Y, Toda E, Yamakado

associated with severity of coronary artery disease.

M, Hashimoto H. Comparison of several metabolic

Int Heart J. 2007; 48: 149-53.

syndrome definitions with relation to early carotid

6. Iida H, Kurano M, Takano H, Kubota N, Morita T,
Meguro K, Sato Y, Abe T, Yamazaki Y, Uno K,

atherosclerosis in Japanese men. Atherosclerosis.
2007; 195: e216-7; author reply e218-9.

Takenaka K, Hirose K, Nakajima T. Hemodynamic

15. Ishizaka N, Ishizaka Y, Toda E, Nagai R, Koike K,

and neurohumoral responses to the restriction ofHashimoto H, Yamakado M. Relationship between

femoral blood flow by KAATSU in healthy subjects.

smoking, white blood cell count and metabolic

Eur J Appl Physiol. 2007; 100: 275-85.

syndrome in Japanese women. Diabetes Res Clin

7. Inoue T, Sata M, Hikichi Y, Sohma R, Fukuda D,
Uchida T, Shimizu M, Komoda H, Node K.

Pract 2007; 78: 72-6.
16. Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamakado

MobilizationofCD34-Positivebone

M. Is metabolic syndrome a risk factor for carotid

marrow-derived

cells

after

stent

atherosclerosis in normotensive and prehypertensive

coronary

implantation: impact on restenosis. Circulation
2007; 115: 553-61.

individuals? J Atheroscl Thromb 2007; 14: 72-7.
17. Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamakado

8. Ishizaka N, Ishizaka Y, Nagai R, Toda E, Hashimoto

M. Association between cigarette smoking, white

H, Yamakado M. Association between serum

blood cell count, and metabolic syndrome as definedalbumin, carotid atherosclerosis, and metabolicby the Japanese criteria. Intern Med. 2007; 46:

syndrome in Japanese individuals. Atherosclerosis.

1167-72.

2007; 193: 373-9.

18. Ishizaka N, Matsuzaki G, Saito K, Furuta K, Mori I,

9. Ishizaka N, Ishizaka Y, Toda E, Hashimoto H, Nagai

Nagai R. Downregulation of klotho gene expression

R, Yamakado M. Higher Serum Uric acid isin streptozotocin-induced diabetic rats. Geriatrics

associated with increased arterial stiffness inGerontology International. 2007; 7: 285-92.

Japanese individuals. Atherosclerosis 2007; 192:131-7.
10. Ishizaka N, Ishizaka Y, Toda E, Koike K, Seki G,

19. Ishizaka N, Saito K, Furuta K, Matsuzaki G, Koike
K, Noiri E, Nagai R. Angiotensin II-induced
regulation of the expression and localization of iron

Nagai R, Yamakado M. Association between chronic

metabolism-related

kidney disease and carotid intima-media thickening

Hypertens Res 2007; 3: 195-202.

genes

in

the

rat

kidney.

in individuals with hypertension and impaired

20. Iwata H, Sata M. Potential contribution of bone

glucose metabolism. Hypertension Res 2007; 30:

marrow-derived precursors to vascular repair and1035-41.
11. Ishizaka N. Carotid ultrasonography in general
health screening --- Noninvasive assessment ofearly atherosclerosis. Ningen Dock 2007; 21:
47-49.
12. Ishizaka Y, Ishizaka N, Yamakado M.
Albuminuria in general health screening in Japan--- Relationship with insulin resistance andatherosclerosis. Ningen Dock 2007; 21: 51-5.
13. Ishizaka N, Ishizaka Y, Toda E, Koike K, Seki G,

lesion formation: lessons from animal models of

Nagai R, Yamakado M. Association between obesityand chronic kidney disease in Japanese: Differencein gender and hypertensive status? Hypertens Res
2007; 30:1059-64.

vascular diseases. Frontiers in Bioscience 2007; 12:4157-67.
21. Kada N, Suzuki T, Aizawa K, Matsumura T,
Ishibashi N, Suzuki N, Takeda N, Munemasa Y,
Sawaki D, Ishikawa T, Nagai R. Acyclic retinoid
inhibits neointima formation through retinoic acidreceptorbeta-induced

apoptosis.

Arterioscler

Thromb Vasc Biol. 2007; 27: 1535-41.
22. Kohro T, Hayashi D, Okada Y, Yamazaki T, Nagai R.
The JCAD Investigators. Effects of Medication on
Cardiovascular Events in the Japanese Coronary
Artery Disease (JCAD) Study. Circ J. 2007; 71:

115

1835-40.

607-16.

23. Kojima I, Tanaka T, Inagi R, Kato H, Yamashita T,

31. Nakano K, Okada Y, Saito K, Tanikawa R,

Sakiyama A, Ohneda O, Takeda N, Sata M, Miyata

Sawamukai N, Sasaguri Y, Kohro T, Wada Y,

T, Fujita T, Nangaku M. Protective role ofKodama T, Tanaka Y. Rheumatoid synovial

hypoxia-inducible factor-2alpha against ischemic

endothelial

damage and oxidative stress in the kidney. J Am Soc

colony-stimulating

Nephrol. 2007; 18: 1218-26.

osteoclastogenesis

24. Maemura K, Takeda N, Nagai R. Circadian rhythms

cells

producefactorinmacrophageleadingrheumatoidtoarthritis.

Rheumatology (Oxford). 2007; 46: 597-603.

in the CNS and peripheral clock disorders: role of

32. Nishihira K, Imamura T, Hatakeyama K, Yamashita

the biological clock in cardiovascular diseases. J

A, Shibata Y, Date H, Manabe I, Nagai R, Kitamura

Pharmacol Sci. 2007; 103: 134-8.

K, Asada, Y. Expression of interleukin-18 in

25. Matsumoto S, Miyagishi M, Taira K. Genome-wide

coronary plaque obtained by atherectomy fromsreening by using small-interfering RNA expression

patients with stable and unstable angina. Thromb

libraries. Methods Mol Biol. 2007; 360: 131-42.

Res. 2007; 121: 275-9.

26. Meguro K, Toyama T, Adachi H, Ohshima S,

33. Nishimura S, Manabe I, Nagasaki M, Hosoya Y,

Taniguchi K, Nagai R. Assessment of central

Yamashita H, Fujita H, Ohsugi M, Tobe K,

chemosensitivity and cardiac sympathetic nerve

Kadowaki T, Nagai R, Sugiura S. Adipogenesis in

activity using I-123 MIBG imaging in central sleep

obesityapnea

differentiating adipocytes, stromal cells, and blood

syndromeinpatients

withdilatedcardiomyopathy. Ann Nucl Med 2007; 21: 73-8.

requiresclose

interplay

betweenvessels. Diabetes. 2007; 56: 1517-26.

27. Miyazawa A, Tsujino I, Ako J, Shimada Y, Courtney

34. Nishimura S, Manabe I, Nagasaki M, Hosoya Y,

BK, Sakurai R, Nakamura M, Okura H, Waseda K,

Kadowaki T, Nagai R, Sugiura S. Adipose tissue

Honda Y, Fitzgerald, PJ. Characterization of late

remodeling and malfunctioning in obesity revealed

incomplete stent apposition: A comparison amongby in vivo molecular imaging. Bioimages. 2007; 15:

bare-metal stents, intracoronary radiation and9-15.

sirolimus-eluting stents. J Invasive Cardiol. 2007;
19: 515-8.

35. Ohmoto-Sekine Y, Suzuki J, Shimamoto R,
Yamazaki T, Tsuji T, Nagai R, Ohtomo K.

28. Muto S, Senda M, Akai Y, Sato L, Suzuki T, Nagai

Gender-specific clinical characteristics of deep Q

R, Senda T, Horikoshi M. Relationship between the

waves in hypertrophic cardiomyopathy. Gend Med.

structure of SET/TAF-Ibeta/INHAT and its histone

2007; 4: 274-83.

chaperone activity. Proc Natl Acad Sci U S A. 2007;
104: 4285-90.
29. Nakajima T, Takano H, Kurano M, Iida H, Kubota N,

36. Ohno T, Takamoto S, Ando J, Morita T, Fujita H,
Hirata Y, Shigeeda T, Hirose A, Nagai R. Diabetic
retinopathy

andcoronary

implantationof

Yasuda T, Kato M, Meguro K, Sato Y, Yamazaki Y,

sirolimus-eluting stents. J Interv Cardiol. 2007; 20:

Kawashima S, Ohshima H, Tachibana S, Nagata T,

122-31.

Abe T, Ishii N, Morita T Effects of KAATSU

37. Ohno T, Takamoto S, Motomura N, Ono M, Ando J,

training on haemostasis in healthy subjects. Int. J.

Morita T, Fujita H, Hirata Y, Nagai R, Shigeeda T,

Kaatsu Training Res. 2007; 3: 11-20.

Hirose A. Coronary artery bypass grafting versus

30. Nakamura K, Sata M, Iwata H, Sakai Y, Hirata Y,

coronary implantation of sirolimus-eluting stents in

Kugiyama K, Nagai R. A synthetic small molecule,patients with diabetic retinopathy. Ann Thorac Surg.

ONO-1301, enhances endogenous growth factor

2007; 84: 1474-8.

expression and augments angiogenesis in theischaemic heart. Clin Sci (Lond) . 2007; 112:

38. Sahara M, Sata M, Morita T, Nakamura K, Hirata Y,
Nagai

R.

Diversecontribution

of

bone

116

marrow-derived

cells

to

vascularremodeling

Cardiovasc Res. 2007; 75: 158-67.

associated with pulmonary arterial hypertension and

46. Seko Y, Matsumoto A, Fukuda T, Imai Y, Fujimura T,

arterial neointimal formation. Circulation. 2007;

Taka H, Mineki R, Murayama K, Hirata Y, Nagai

115: 509-17.

R. A case of neonatal lupus erythematosus

39. Sainz J, Sata M. CXCR4, a key modulator ofpresenting delayed dilated cardiomyopathy with

vascular progenitor cells. Arterioscler Thromb Vasc

circulating autoantibody to annexin A6. Int Heart J

Biol. 2007; 27: 263-5.

2007; 48: 407-15.

40. Saito K, Ito T, Asashima N, Ohno M, Nagai R,

47. Shimamoto R, Suzuki J-i, Yamazaki T, Tsuji T,

Fujita H, Koizumi N, Takano A, Watanabe H,

Ohmoto Y, Morita T, Yamashita H, Honye J, Nagai

Kawabata H. Case report: Borrelia valaisiana

R, Akahane M, Ohtomo K. A new method for

infection in a Japanese man associated withmeasuring coronary artery diameters with CT spatial

traveling to foreign countries. Am J Trop Med Hyg

profile curves. Radiography. 2007; 13: 44-50.

2007; 77: 1124-7.

48. Shimamura M, Sato N, Sata M, Wakayama K,

41. Sakurai R, Ako J, Hassan AHM, Bonneau HN,

Ogihara T, Morishita R. Expression of hepatocyte

Neumann FJ, Desmet W, Holmes DRJ, Yock PG,

growth factor and c-Met after spinal cord injury in

Fitzgerald PJ, Honda Y. Neointimal progression andrats. Brain Res. 2007; 1151: 188-94.

luminalnarrowinginsirolimus-eluting

stent

49. Shimamura M, Sato N, Sata M, Kurinami H,

treatment for bare metal in-stent restenosis: A

Takeuchi D, Wakayama K, Hayashi T, Iida H,

quantitative intravascular ultrasound analysis. Am

Morishita R. Delayed post-ischemic treatment with

Heart J. 2007; 154: 361-5.

fluvastatin improved cognitive impairment after

42. Sakurai R, Bonneau HN, Honda Y, Fitzgerald PJ.

stroke in rats. Stroke. 2007; 38: 3251-8.

Intravascular Ultrasound Findings of Endeavor II

50. Shirakawa I, Sata M, Saiura A, Kaneda Y, Yashiro H,

and Endeavor III. Am J Cardiol. 2007; 100(8B):

Hirata Y, Makuuchi M, Nagai R. Atorvastatin

71M-76M.

attenuatestransplant-associatedcoronary

43. Sakurai R, Hongo Y, Yamasaki M, Honda Y,

arteriosclerosis in a murine model of cardiac

Bonneau HN, Yock PG, Cutlip D, Popma JJ,

transplantation. Biomed Pharmacother. 2007; 61:

Zimetbaum P, Fajadet J, Kuntz RE, Wijns W,

154-9.

Fitzgerald PJ. Detailed intravascular ultrasoundanalysisofzotarolimus-eluting

phosphoryl

51. Sugiyama A, Wada Y, Izumi A, Kobayashi M,
Kohro T, Patrick CR, Hamakubo T, Kodama T.

choline-coated cobalt-chromium alloy stent in deTranscriptional

novo

the

low-density lipoprotein loading in cultured vascular

ENDEAVOR II Trial). Am J Cardiol. 2007; 100:smooth muscle cells. J Atheroscler Thromb. 2007;

818-23.

14: 226-34.

coronarylesions(Results

fromactivationbyhypoxiaand

44. Sakurai R, Yamasaki M, Nakamura M, Hirohata A,

52. Sumi M, Sata M, Toya N, Yanaga K, Ohki T, Nagai

Honda Y, Bonneau HN, Luikart H, Yock PG,

R. Transplantation of adipose stromal cells, but not

Fitzgerald PJ, Yeung AC, Valantine HA, Fearon WF.

mature adipocytes, augments ischemia-induced

Determinants of lumen loss between years 1 and 2

angiogenesis. Life Sci. 2007; 80: 559-65.

after cardiac transplantation. Transplantation. 2007;
84: 1097-102.

53. Sumi M, Sata M, Hashimoto A, Imaizumi T, Yanaga
K, Ohki T, Mori T, Nagai R. OPC-28326, a selective

45. Seko Y, Yagita H, Okumura K, Azuma M, Nagai R.

femoral arterial vaso- dilator, augments ischemia-

Roles of programmed death-1 (PD-1)/PD-1 ligands

induced angiogenesis. Biomed Pharmacother. 2007;

pathway in the development of murine acute61: 209-15.

myocarditis

causedbycoxsackievirus

B3.

54. Sumi M, Sata M, Miura S, Rye KA, Toya N,

117

Kanaoka Y, Yanaga K, Ohki T, Saku K, Nagai R.

Kawakami K, Fukuda H, Tomimatsu T, Ogihara T,

Reconstituted high-density lipoprotein stimulates

Morishita

differentiation of endothelial progenitor cells andneurological deficit after mild (30 min) transientenhances

middle cerebral artery occlusion in rats. Brain Res.

ischemia-induced

angiogenesis.

Arterioscler Thromb Vasc Biol. 2007; 27: 813-8.

R.

Quantitative

measurementof

2007; 1130: 181-7.

55. Suzuki T, Nishi T, Nagino T, Sasaki K, Aizawa K,

64. Yamada T, Kondo T, Numaguchi Y, Tsuzuki M,

Kada N, Sawaki D, Munemasa Y, Matsumura T,

Matsubara T, Manabe I, Sata M, Nagai R, Murohara

Muto S, Sata M, Miyagawa K, Horikoshi M, Nagai

T.

R. Functional interaction between the transcription

neointimal hyperplasia through regulation of smoothfactor Kr üppel-like factor 5 and poly (ADP-ribose)

muscle-like progenitor cells." Arterioscler Thromb

polymerase-1 in cardiovascular apoptosis. J Biol

Vasc Biol. 2007; 27: 2363-9.

Chem. 2007; 282: 9895-901.

Angiotensin

II

receptor

blocker

inhibits

65. Yamazaki T, Goto S, Shigematsu H, Shimada K,

56. Suzuki T, Nagai R. Cardiovascular proteomic

Uchiyama S, Nagai R, Yamada N, Matsumoto M,

analysis. J Chromatogr B Analyt Technol Biomed

Origasa H, Bhatt DL, Steg PG, Ikeda Y. Prevalence,

Life Sci. 2007; 855: 28-34.

awareness and treatment of cardiovascular risk

57. Takeda N, Maemura K, Horie S, Oishi K, Imai Y,

factors in patients at high risk of atherothrombosis in

Harada T, Saito T, Shiga T, Amiya E, Manabe I,

Japan -Results from domestic baseline data of the

IshidaaREduction of atherotherombosis for continued

clock-controlled gene in vascular endothelial cells. J

health (REACH) registry-. Circ J. 2007; 71:

Biol Chem. 2007 Nov 9; 282: 32561-7.

995-1003.

N,

Nagai

R. Thrombomodulin

is58. Takeda N, Maemura K. Chronobiology of acute
myocardial

infarction.

Molecular

Biology.

Biological Rhythms Research. 2007; 38: 233-45.
59. Takeda N, Nakajima J, Yamada N, Hiroi Y, Hirata Y,
Nagai R. Rupture of bronchogenic cyst in the
pericardium with high carbohydrate antigen 19-9
production. Respiratory Medicine Extra 2007; 3:
76-8.
60. Takimoto Y, Maeda S, Slingsby BT, Harada K,
Nagase T, Nagawa H, Nagai R, Akabayashi A. A
template for informed consent forms in medical
examination and treatment: an intervention study.
Med Sci Monit. 2007; 13: PH15-8.
61. Tanaka K, Sata M. Therapeutic application of bonemarrow-derived

progenitor

cells

for

vasculardisease: magic bullets having the good without thebad? Int J Gerontol. 2007; 1: 10-21.
62. Tsuji T, Suzuki J-i, Shimamoto R, Yamazaki T,
Ohomoto Y, Iwasawa K, Nagai R. Morbidity
prevalence rate of Kawasaki disease assessed bysingle cross-sectional history-taking. Int Heart J.
2007; 48: 615-21.
63. Wakayama K, Shimamura M, Sata M, Sato N,

66. Yamazaki T, Suzuki J-i, Shimamoto R, Tsuji T,
Ohmoto-Sekine Y, Ohtomo K, Nagai R. A New
Therapeutic

StrategyforHypertrophic

Nonobstructive Cardiomyopathy in Humans. Int
Heart J. 2007; 48: 715-24.

118

Department of Respiratory
Medicine
Professor
Takahide Nagase, M.D.,Ph.D.

Lecturer
Nobuya Ohishi, M.D.,Ph.D.,

Taiji Nagata, M.D.,Ph.D.,

Associate
Tadashi Kohyama, M.D.,Ph.D., Masashi Desaki, M.D.,Ph.D., Kazutaka Takami, M.D.,Ph.D.,
Hitoshi Oonuma, M.D.,Ph.D., Yasuhiro Yamauchi, M.D.,
Reiko Okudaira M.D.,Ph.D.,

Homepage

Goh Tanaka M.D.,Ph.D.,

Hiroshi Kitagawa, M.D.,Ph.D.

http://kokyuki.umin.jp/

Introduction and Organization
The staff of the Department of Respiratory Medicine,
Graduate School of Medicine, University of Tokyo,
consists of 1 professor, 2 lecturers, and 8 research
associates. In the University of Tokyo, affiliatedhospitals and foreign institutions, approximately 50
members belong to the Department. In the Universityof Tokyo Hospital, about 15 respiratory physicians are
doing clinical works.
The Department of Respiratory Medicine wasestablished in April 1998. In June 2003, Takahide
Nagase was appointed to Professor and since thenchairs the Department.
Based on the fact that the number of patients withrespiratory diseases such as primary lung cancer and
COPD is tremendously increasing, advancement andfruitful results of researches on respiratory medicine
are more and more expected in the 21st century. In thisera, we are conducting basic and clinical researches
for wide variety of respiratory disorders including
lung cancer, COPD, asthma and interstitial lungdiseases. Especially, we have been intensively
studying the molecular mechanisms underlying thepathogenesis of lung disorders. Our research goal is todevelop novel diagnostic and therapeutic tools tomanage these pulmonary diseases.

Clinical Activities
The Department of Respiratory Medicine is
responsible for the out-patient care as well as care of
in-patients (40 cases on average), which is taken at the13th floor of the hospital ward A of the University ofTokyo Hospital. Our practice is performed by thethree-member system of a junior resident, a seniorresident and an experienced associate.
Main diseases of in-patients are bronchogenic
carcinoma, respiratory infections, interstitial lungdiseases, COPD, and asthma. There are many
emergency visits and admission due to pneumonia ,respiratory failure, progression of lung cancer, and soon. In cases of sever respiratory failure such as
ARDS, we conduct ventilatory support of suchpatients in collaboration with ICU staff. A specialized
clinical conference for respiratory disease has been
held once a week since over 10 years ago, where staffof our department, department of respiratory surgery
and department of radiology join and discuss together
to make best diagnostic and therapeutic approach to119individual patients. This conference is appreciated as
prototype of Cancer Board of the University of Tokyo
Hospital, which launched this year. Our department
contributes to the pre- and post-surgical evaluation of
respiratory functions, and also receives consultationfrom other departments.
At present, there increase highlighted interests in
respiratory medicine. Primary lung cancer is now
leading cause of cancer death, and is one of the major
medical and social problem to be overcome. In
respiratory diseases, there are several disorders to which
no effective therapeutic modalities are currently
available. For example, ARDS is an acute lung injury
and the mortality rate for ARDS is extremely highdespite of intensive care using currently available tools.
Idiopathic pulmonary fibrosis is a progressive and fatal
inflammatory disorder of the lung parenchyma, while nouseful medications are currently available to treat thedisease. We would like to make every effort to develop
a novel and potential therapeutic approach to these
diseases.
Number of in-patients in 2006
1. Primary lung cancer
3. Interstitial lung disease
2. Respiratory infection
4. COPD
5. Asthma

267
52
47
32
29

A weekly chart round and professor’s round arescheduled for Tuesday afternoon. A specialized
clinical conference for patients with respiratory
diseases is held, together with respiratory surgeons
and radiologists, where radiologicaldiagnosis,
indication of thoracoscopic biopsy, CT-guided biopsy,
and surgical and radiological treatment are discussed,
making it possible to give best care to individual
patients.

Teaching Activities
As for under-graduate education, our department takes
part in systemic lectures and specific learning for
diagnosis and treatment of respiratory diseases for the
4th year medical students, bed-side learning for the 5thyear medical students, and clinical lectures for the 5th
and 6th year medical students. Clinical Clerkship forthe 5th year students is actively performed incollaboration with expert doctors from several leading
affiliated hospitals.
In systemic lectures, comprehensive presentation for
the understanding of basic knowledge about theconcept, pathogenesis, pathology, diagnosis andtreatment of common respiratory diseases isperformed.
In clinical lectures, we present clinical cases ofimportant diseases such as lung cancer, and try to
discuss with the students several important points forplanning the diagnostic evaluation and treatment incollaboration with the Faculty of the Department ofRespiratory Surgery. Recent major advance in therelevant fields are also reviewed.
During the period of bed-side learning, the students
have opportunities to experience the daily clinical carewith junior and senior residents as well as with theFaculty. Each student can learn how to make a
medical interview, check physical findings and makethe actual plans for the diagnosis and treatment.
Several lectures about the specific topics important in
respiratory medicine such as fundamental chest
radiology, oxygen therapy are provided by the
respiratory specialists.
Clinical clerkship at the 5th year of the educational
program is actively performed to facilitate the early
exposure to the clinical practice for a relatively long
period (for one month). Several lecture on thespecialized theme on respiratory disease such as
medical treatment of lung cancer, are also provided.
Each student is expected to learn and acquire theprofessionalism required for a medical doctor during
this period. Our program, in general, is highly
appreciated by the students.
As for the post-graduate education, 8 to 9 juniorresidents join the Department of General Medicine on
the 13th floor simultaneously for one to two months,
and are expected to experience respiratory as well asother diseases. Since the training period is short, theresidents are expected to experience emergency cases
as often as possible.

Research Activities
Our department is conducting basic and clinicalresearches for many respiratory disorders including

120lung cancer, COPD, asthma, interstitial lung diseases,
diffuse panbronchiolitis, respiratory infections, acutelung injury, chronic respiratory failure and others. We
have also been studying the effects of air pollutants
such as diesel exhausts. Epidemiological, clinical,
cellular and molecular biological techniques are
utilized for the elucidation of pathogenetic
mechanisms and for the development of novel
diagnostic and therapeutic modalities in respiratory
medicine. Postgraduate students as well as the Faculty
members make considerable studies about genetic
analysis of lung cancer in collaboration with theFaculty of the Department of Respiratory Surgery, cellbiological analysis using airway epithelial cells,
fibroblast, smooth muscle cells and genetic analysis
about
diffusepanbronchiolitis.
Respiratory
rehabilitation utilizing KAATSUT training shows
promising preliminary results. These results have beenpresented and/or published in the Scientific Meeting
and/or peer-review Journals. Our main research
projects are as follows.
Molecular analysis of airway smooth muscle ionchannels
Exploration of disease-susceptibility genes in
respiratory diseases
Effects of KAATSU training on respiratory
rehabilitation
Analysis of DNA methylation and its clinicalapplication in lung cancer
Analysis of signal transduction through EGF receptor
system in lung cancer and its therapeutic application
Elucidation of molecular mechanisms of diseases
using conditional vectors for siRNA knockdowns
Epidemiological studies of diffuse panbronchiolitis
and interstitial lung diseases
Effects of air pollutants such as diesel exhausts on
airway hyperresponsivenessElucidationofmolecular
mechanismsoftissue-remodeling in respiratory diseases
Roles of chemokines, cytokines and eicosanoids onfunctional regulation of airway epithelial cells,smooth muscles and fibroblasts.
Elucidation of molecular mechanisms underlying thepathogenesis of pulmonary fibrosis
Elucidation of molecular pathogenetic mechanism ofacute lung injury

Analysis of diseaseengineered micemodelsusing

geneticallyTakahide Nagase is an Associate Editor of
Respirology and an Editorial Board Member ofAmerican Journal of Physiology.

References(1) Ito I, Laporte JD, Fiset PO, Asai K, Yamauchi Y,
Martin JG, Hamid Q. Downregulation of adisintegrin and metalloproteinase 33 by IFNgamma in human airway smooth muscle. J
Allergy Clin Immunol 2007;119:89-97.
(2) Ohnishi T, Arnold LL, He J, Clark NM, Kawasaki
S, Rennard SI, Boyer CW, Cohen SM.Inhalationof tobacco smoke induces increased proliferationof urinary bladder epithelium and endothelium infemale C57BL/6 mice.Toxicology 2007; 20:
58-65.
(3) Sugiura H, Liu X, Togo S, Kobayashi T, Shen L,
Kawasaki S, Kamio K, Wang XQ, Mao LJ,
Rennard SI. Prostaglandin E2 protects humanlung fibroblasts from cigarette smoke extractinduced apoptosis via EP2 receptor activation. J
Cell Physiol 2007 ;210:99-110.
(4) Sugiura H, Liu X, Duan F, Kawasaki S, Togo S,
Kamio K, Wang XQ, Mao L, Ahn Y, Ertl RF,
Bargar TW, Berro A, Casale TB, Rennard SI.
Cultured lung fibroblasts from ovalbuminchallenged "asthmatic" mice differ functionallyfrom normal. Am J Respir Cell Mol Biol 2007;37:
424-30.
(5) Kamio K, Liu X, Sugiura H, Togo S, Kobayashi T,
Kawasaki S, Wang XQ, Mao L, Ahn Y,
Hogaboam C, Toews ML, Rennard SI.
Prostacyclin Analogues Inhibit Fibroblast
Contraction of Collagen Gels Through thecAMP-PKA Pathway. Am J Respir Cell Mol Biol
2007;37:113-20.
(6) Liu X, Das AM, Seideman J, Griswold D, Afuh
CN, Kobayashi T, Abe S, Fang Q, Hashimoto M,
Kim H, Wang X, Shen L, Kawasaki S, Rennard
SI. The CC Chemokine Ligand 2 (CCL2)Mediates
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121(7) Ogawa K, Saito A, Matsui H, Suzuki H, Ohtsuka
S, Shimosato D, Morishita Y, Watabe T, Niwa H,
Miyazono K. Activin-Nodal signaling is involvedin propagation of mouse embryonic stem cells. J
Cell Sci 2007;120:55-65.
(8) Goto Y, Nagase T. Correspondence letter, 12-h
pretreatment with methylprednisolone versus
placebo for prevention of postextubation
laryngeal oedema: a randomised double-blind
trial. Lancet 2007;370:25.
(9) Sano A, Kage H, Sugimoto K, Kitagawa H, Aki N,
Goto A, Fukayama M, Nakajima J, Takamoto S,
Nagase T, Yatomi Y, Ohishi N and Takai D. A
second-generation
profilingsystemforquantitative methylation analysis of multiple genepromoters: application to lung cancer. Oncogene
2007;26:6518-25.
(10)Sugimoto K, Kage H, Aki N, Sano A, Kitagawa H,
Nagase T, Yatomi Y, Ohishi N, Takai D. The
Induction of H3K9 Methylation by PIWIL4 at the
p16Ink4a Locus. Biochem Biophys Res Commun
2007;359:497-502.
(11) Yamaguchi Y, Nagase T, Tomita T, Nakamura K,
Fukuhara S, Amano T, Yamamoto H, Ide Y,
Suzuki M, Teramoto S, Asano T, Kangawa K,
Nakagata N, Ouchi Y, Kurihara H. Beta-defensin
overexpression induces progressive muscle
degeneration in mice. Am J Physiol Cell Physiol
2007;292:C2141-9.
(12) Yamamoto H, Nagase T, Shindo T, Teramoto S,
Aoki-Nagase T, Yamaguchi Y, Hanaoka Y,
Kurihara H, Ouchi Y. Adrenomedullin
insufficiency increases allergen-induced airway
hyperresponsiveness in mice. J Appl Physiol
2007;102:2361-8.
(13)Aoki-Nagase T, Nagase T, Oh-hashi Y, Kurihara Y,
Yamaguchi Y, Yamamoto H, Nagata T, Kurihara
H, Ouchi Y. Calcitonin gene-related peptide
mediates acid-induced lung injury in mice.
Respirology 2007;12:807-13.
(14) Tanaka G, Sandford AJ, Burkett K, Connett JE,
Anthonisen NR, Pare PD, He JQ. Tumour
necrosisfactorandlymphotoxinApolymorphisms and lung function in smokers. Eur
Respir J 2007 ;29:34-41.
(15) Nakajima T, Takano H, Kurano M, Iida H,
Kubota N, Yasuda T, Kato M, Meguro K, Sato Y,

Yamazaki Y, Kawashima S, Ohshima H,
Tachibana S, Nagata T, Abe T, Ishii N, Morita T.
Effects of KAATSU training on haemostasis in
healthy subjects. Int J KAATSU Training Res
2007;3:11-20.
(16) Tanaka G, Shojima J, Matsushita I, Nagai H,
Kurashima A, Nakata K, Toyota E, Kobayashi N,
Kudo K, Keicho N. Pulmonary Mycobacterium
avium complex infection: Association with
NRAMP1 polymorphisms. Eur Respir J 2007;30:
90-6.
(17) Mai HN, Hijikata M, Inoue Y, Suzuki K, Sakatani
M, Okada M, Kimura K, Kobayashi N, Toyota E,
Kudo K, Nagai H, Kurashima A, Kajiki A,
Oketani N, Hayakawa H, Tanaka G, Shojima J,
Matsushita I, Sakurada S, Tokunaga K, Keicho N.
Pulmonary Mycobacterium avium complex
infection associated with the IVS8-T5 allele of
the CFTR gene. Int J Tuberc Lung Dis 2007;11:808-13.
(18) Kage H, Kohyama T, Kitagawa H, Takai D,
Kanda Y, Ohishi N, Nagase T. Non-infectious
bronchiolitis as an early pulmonary complicationof hematopoietic stem cell transplantation.
Internal Medicine 2008 (in press).
(19) Makita R, Uchijima Y, Nishiyama K, Amano T,
Chen Q, Takeuchi T, Mitani A, Nagase T, Yatomi
Y, Aburatani H, Nakagawa O, Small EV,
Cobo-Stark P, Igarashi P, Murakami M,
Tominaga J, Sato T, Asano T, Kurihara Y,
Kurihara H. Multiple renal cysts, urinary
concentration
defects,andpulmonaryemphysematous changes in mice lacking TAZ.
Am J Physiol Renal Physiol 2008 (in press).
(20) Shornick LP, Wells AG, Zhang Y, Patel AC,
Huang G, Takami K, Sosa M, Shukla NA,
Agapov E, Holtzman MJ. Airway epithelial
versus immune cell Stat1 function for innate
defense against respiratory viral infection. J
Immunol 2008 (in press).
(21) Li YJ, Kawada T, Takizawa H, Azuma A, Kudoh
S, Sugawara I, Yamauchi Y, Kohyama T. Airway
inflammatory responses to oxidative stressinduced by prolonged low-dose diesel exhaust
particle exposure from birth differ between
mouse BALB/c and C57BL/6 strains. Exp LungRes 2008 (in press).

122

Department of Gastroenterology
Professor
Masao Omata, M.D., Ph.D.

LecturerHaruhiko Yoshida, M.D., Ph.D.
Shuichiro Shiina, M.D., Ph.D.
Minoru Tada, M.D., Ph.D.

Associate
Hiroshi Kanamori, M.D., Ph.D.

Tomoaki Tomiya, M.D., Ph.D.

Naoya Kato, M.D., Ph.D.

Keisuke Hamamura, M.D., Ph.D.

Yutaka Yamaji, M.D., Ph.D.

Goichi Togo, M.D., Ph.D.

Masao Akanuma, M.D., Ph.D.

Hajime Fujie, M.D., Ph.D.

Hiroyuki Isayama, M.D., Ph.D.

Tsuneo Ikenoue, M.D., Ph.D.

Hideaki Ijichi, M.D., Ph.D.

Tadashi Goto, M.D., Ph.D.

Takeshi Tsujino, M.D., Ph.D.

Naoki Sasahira, M.D., Ph.D.

Ryosuke Tateishi, M.D., Ph.D.

Kenji Hirano, M.D., Ph.D.

Mitsuhiro Fujishiro, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/gastro/

Introduction and Organization
The Department of Gastroenterology wasestablished through a reorganization of the
Postgraduate School of Medicine and that of theDivision of Internal Medicine of the University ofTokyo Hospital in 1998. The department is
responsible for clinical services, education andresearch activities in the field of liver,pancreatobiliary and digestive canal. It is now
comprised of a professor, 3 lecturers, 17 associates, 11
fellows, 30 graduates and 11 other visiting researchers
including students from abroad. A number of others
are under a temporary transfer in and outside thecountry. The north and south wings on the 11th floorof Ward A have provided core hospital rooms for the
department. At present, forth and fifth floor of Ward B
also takes important part for providing rooms of

inpatients. Laboratories of the department are
scattered in each floor, mainly of Clinical ResearchCenter and First Research Building as in the otherdepartments.

Clinical Activities
The Department of Gastroenterology is in chargeof about 90 inpatients on average, which is about
2,500 in total per year. We receive about 90 new
patients in and out of the hospital each week, with anaverage hospital stay of 12 days. Resident, junior andsenior staff members bear the responsibility for a
medical management of each inpatient, in
collaboration with subspecialty groups concerned. The
staff members examine about 5,000 outpatients withvarious digestive diseases in a month. Professor’s
ward round is performed on Monday and Wednesday

123mornings. Specialty and subspecialty clinicalconferences are held on Monday evening.
Hepatocellular carcinoma is the most common
disease in patients who are admitted to the department.
(1200 cases in 2007). Number of treatments forhepatocellular carcinoma treatments, represented by
percutaneous radiofrequency ablation, exceeded 900
cases per year, showing one of the greatest
achievements in the field. Number of cases
undergoing radiofrequency ablation for metastatic
liver tumors is also increasing recent years (138 casesin 2007). Fibrosis progression in chronic liver disease
is conventionally assessed by liver biopsy. Recently
we can evaluate the stage of liver fibrosis by
Fibroscan®, newly developed equipment thatmeasures liver stiffness by ultrasound.
ERCP is performed more than 650 cases each year.
The number of patients treated for choledocholithiasis
with endoscopic papillary balloon dilation method
exceed 1,000, which is possibly the largest in theworld. Endoscpic metallic stenting is an effective
palliative care for malignant obstructive jaundice (40patients a year). Covered metallic stent placement has
been performed in a total of 550 cases, which may be
the world’s largest number. Pancreatic interventions
such as pancreatic stenting, cystic drainage,
endoscopic stone extraction and lithotripsy using
ESWL (extracorporeal shock-wave lithotripsy) arealso performed for many challenging cases. ESD(endoscopic submucosal dissection) is performed as a
curative endoscopic treatment for neoplasms inesophagus, stomach or colon (180 patients a year).
Endoscopic variceal ligations for esophageal
varices (50 patients a year) are also frequently done.
Double-ballon endoscopy and capsule endoscopy havebeen introduced recently, which enabled theexamination of whole small intestines. All thoseinterventions are performed by members of thedepartment specially trained for each technique. Our
strategy for the management of malignancies isinterventional therapy and chemotherapy (180 cases
for pancreato-biliary and 50 cases for digestive tract
neoplasms).
On outpatient basis, ultrasonography is performedon 16,000 patients, gastroduodenal endoscopy on
6,500, and colonoscopy on 3,800 patients each year,
leading the detection of about 140 cases of gastriccancer and 170 cases of colorectal cancer annually.
About 50 % of them are treated endoscopically, but
we also aim to perform basic studies using specimen,
and turn these efforts to clinical activities.

Educational Activities
Systematicandclinicallectureson
gastroenterology are regularly given to undergraduate
medical students by staff members of the department.
In addition, several courses of practical teaching areprovided for the students. In particular, theDepartment of Gastroenterology makes much of theimportance of bed-side teaching for the fifth gradestudents, where each student is allotted to an inpatient
by joining the group of physicians and offering theopportunity to learn digestive diseases practically. The
results are reported to the professor at the end of thecourse as an oral examination. Students are also
required to summarize and outline articles in world’s
leading medical journals.
Residents of internal medicine join the
Department of Gastroenterology for 1-6 months inrotation in their first year as a doctor, where they learn
therapeutics and diagnostics in gastroenterology
together with general internal medicine. Giving
presentations at the scientific meeting is highly
encouraged. If they are interested in gastroenterology
in particular, they may learn advanced techniques ingastroenterology in affiliated hospitals for a few years.
Usually, they will come back to the department afterthat period, and improve their clinical skills still
further while at the education course. The majority ofthem also become graduate student, and starts medical
researches either as a basic or clinical researcher.
Currently, the department has 50 students who were
graduated from more than 30 medical schools inJapan.

Research Activities
Since gastroenterology covers various organs anddiseases, everything below the diaphragms except for
the kidneys and the reproductive system, themes of a
research are virtually unlimited as shown in the list of
publication described below. Both basic and clinicalresearchers are equally encouraged, on condition that

124

the results may eventually contribute to the cure ofgastroenterological disorders. For basic researches,the department has been eager to acquire cutting-edge
methodologies, especially those in molecular biology
and genetics. The themes of our recent basic
researches include mRNA expression analysis using
microarray, protein expression analysis using mass
spectrometer, and gene mutation analysis using laser
micro dissection of clinically obtained samples.
Various clinical activities are recorded in databaseand analyzed. Studies oriented for evidence-based
medicine are highly appreciated. Recent randomizedcontrolled trials include interferon to prevent
recurrence of hepatocellular carcinoma, evaluation ofdiagnostic usefulness of angiography with computed
tomography, and radiofrequency ablation for liver
metastasis of colorectal cancer. We have also designed
clinical trials of TSU-68 for advanced hepatocellular
carcinoma, erythropoietin for anemia introduced byinterferon with ribavirin therapy, TS-1 alone or
combined with gemcitabine for pancreatic and bile
duct cancers.
The department is dedicated to pursuing bettermedical services from all facets of the subspecialty ofgastroenterology, which is brought about by bothbasic and clinical researches.

References
1. Arai M, Tejima K, Ikeda H, Tomiya T, Yanase M,
Inoue Y, Nagashima K, Nishikawa T, Watanabe N,
Omata M, Fujiwara K. Ischemic preconditioningin liver pathophysiology. J Gastroenterol Hepatol.
2007;22 Suppl 1:S65-7.
2. Enomoto S, Yahagi N, Fujishiro M, Oka M,
Kakushima N, Iguchi M, Yanaoka K, Arii K,
Tamai H, Shimizu Y, Omata M, Ichinose M.
Novel endoscopic hemostasis technique for use
during endoscopic submucosal dissection.
Endoscopy. 2007;39 Suppl 1:E156.
3. Fujishiro M, Goto O, Kakushima N, Kodashima S,
Muraki Y, Omata M. Endoscopic submucosal
dissectionofstomachneoplasms
after
unsuccessful endoscopic resection. Dig Liver Dis.
2007;39:566-71.
4. Fujishiro M, Nomura S, Yamada K, Kaminishi M,
Omata M. Intensive follow-up may be necessaryfor endoscopically resected esophageal squamouscell carcinoma invading the muscularis mucosae,
at least during the first year. Endoscopy. 2007;39:
1111; author reply 2.
5. Fujishiro M, Yahagi N, Kakushima N, Kodashima
S, Muraki Y, Ono S, Yamamichi N, Tateishi A,
Oka M, Ogura K, Kawabe T, Ichinose M, Omata
M. Outcomes of endoscopic submucosal
dissection for colorectal epithelial neoplasms in
200 consecutive cases. Clin Gastroenterol Hepatol.
2007;5:678-83; quiz 45.
6. Fujiwara K, Yokosuka O, Imazeki F, Miki M,
Suzuki K, Okita K, Tanaka E, Omata M. Analysisof hepatitis A virus protein 2B in sera of hepatitis
A of various severities. J Gastroenterol. 2007;42:560-6.
7. Hirano K, Tada M, Isayama H, Yagioka H, Sasaki
T, Kogure H, Nakai Y, Sasahira N, Tsujino T,
Yoshida H, Kawabe T, Omata M. Long-term
prognosis of autoimmune pancreatitis with andwithout corticosteroid treatment. Gut. 2007;56:
1719-24.
8. Hoshida Y, Moriyama M, Otsuka M, Kato N,
Taniguchi H, Shiratori Y, Seki N, Omata M. Gene
expressions associated with chemosensitivity inhuman hepatoma cells. Hepatogastroenterology.
2007;54:489-92.
9. Hosokawa K, Omata M, Maeda M. Immunoassay
on a power-free microchip with laminar flowassisted dendritic amplification. Anal Chem.
2007;79:6000-4.
10. Ikai I, Arii S, Okazaki M, Okita K, Omata M,
Kojiro M, Takayasu K, Nakanuma Y, Makuuchi M,
Matsuyama Y, Monden M, Kudo M. Report of the
17th Nationwide Follow-up Survey of PrimaryLiver Cancer in Japan. Hepatol Res. 2007;37:
676-91.
11. Ikeda H, Kume Y, Tejima K, Tomiya T, Nishikawa
T, Watanabe N, Ohtomo N, Arai M, Arai C,
Omata M, Fujiwara K, Yatomi Y. Rho-kinase
inhibitor prevents hepatocyte damage in acuteliver injury induced by carbon tetrachloride in rats.
Am J Physiol Gastrointest Liver Physiol. 2007;
293:G911-7.
12. Kakushima N, Fujishiro M, Kodashima S, Muraki
Y, Tateishi A, Yahagi N, Omata M. Technicalfeasibility of endoscopic submucosal dissection

125

for gastric neoplasms in the elderly Japanese
population. J Gastroenterol Hepatol. 2007;22:
311-4.
13. Kodashima S, Fujishiro M, Takubo K, Kammori
M, Nomura S, Kakushima N, Muraki Y, Goto O,
Ono S, Kaminishi M, Omata M. Ex vivo pilot
study using computed analysis of endo-cytoscopic
images to differentiate normal and malignant
squamous cell epithelia in the oesophagus. Dig
Liver Dis. 2007;39:762-6.
14. Koike Y, Yoshida H, Shiina S, Teratani T,
Shuntaro O, Sato S, Akamatsu M, Tateishi R,
Fujishima T, Hoshida Y, Kanda M, Ishikawa T,
Shiratori Y, Omata M. Changes in hepaticfunctional reserve after percutaneous tumor
ablation for hepatocellular carcinoma: long-term
follow up for 227 consecutive patients with asingle lesion. Hepatol Int. 2007;1:295-301.
15. Kondo S, Yamaji Y, Watabe H, Yamada A,
Sugimoto T, Ohta M, Ogura K, Okamoto M,
Yoshida H, Kawabe T, Omata M. A randomized
controlled trial evaluating the usefulness of atransparent hood attached to the tip of thecolonoscope. Am J Gastroenterol. 2007;102:
75-81.
16. Kondo Y, Yoshida H, Tateishi R, Shiina S, Mine N,
Yamashiki N, Sato S, Kato N, Kanai F, Yanase M,
Yoshida H, Akamatsu M, Teratani T, Kawabe T,
Omata M. Health-related quality of life of chronic
liver disease patients with and without
hepatocellular carcinoma. J Gastroenterol Hepatol.
2007;22:197-203.
17. Kuboki M, Iino S, Okuno T, Omata M, Kiyosawa
K, Kumada H, Hayashi N, Sakai T. Peginterferonalpha-2a (40 KD) plus ribavirin for the treatmentof chronic hepatitis C in Japanese patients. J
Gastroenterol Hepatol. 2007;22:645-52.
18. Kubota K, Kuroda J, Origuchi N, Kaminishi M,
Isayama H, Kawabe T, Omata M, Mafune K.
Stomach-partitioning
gastrojejunostomy
forgastroduodenal outlet obstruction. Arch Surg.
2007;142:607-11; discussion 11.
19. Kume Y, Ikeda H, Inoue M, Tejima K, Tomiya T,
Nishikawa T, Watanabe N, Ichikawa T, Kaneko M,
Okubo S, Yokota H, Omata M, Fujiwara K,
Yatomi Y. Hepatic stellate cell damage may leadto decreased plasma ADAMTS13 activity in rats.

FEBS Lett. 2007;581:1631-4.
20. Maeda S, Hikiba Y, Shibata W, Ohmae T, Yanai A,
Ogura K, Yamada S, Omata M. Essential roles ofhigh-mobility group box 1 in the development ofmurine colitis and colitis-associated cancer.
Biochem Biophys Res Commun. 2007;360:394400.
21. Masuzaki R, Tateishi R, Yoshida H, Sato T, Ohki
T, Goto T, Yoshida H, Sato S, Sugioka Y, Ikeda H,
Shiina S, Kawabe T, Omata M. Assessing liver
tumor stiffness by transient elastography Hepatol
Int. 2007;1:394-7.
22. Matsubara S, Arizumi T, Togawa O, Sasaki T,
Yamamoto N, Nakai Y, Sasahira N, Hirano K,
Tsujino T, Isayama H, Toda N, Tada M, Kawabe T,
Omata M. Endoscopic transpapillary approach to
the gallbladder for diagnosing gallbladder cancer.
Can J Gastroenterol. 2007;21:809-13.
23. Nakai Y, Tsujino T, Kawabe T, Kogure H, Sasaki
T, Yamamoto N, Sasahira N, Isayama H, Tada M,
Omata M. Pancreatic tuberculosis with apancreaticobiliary fistula. Dig Dis Sci. 2007;52:
1225-8.
24. Nakamura N, Igaki H, Yamashita H, Shiraishi K,
Tago M, Sasano N, Shiina S, Omata M, Makuuchi
M, Ohtomo K, Nakagawa K. A retrospective studyof radiotherapy for spinal bone metastases fromhepatocellular carcinoma (HCC). Jpn J Clin Oncol.
2007;37:38-43.
25. Nishi H, Tojo A, Onozato ML, Jimbo R, Nangaku
M, Uozaki H, Hirano K, Isayama H, Omata M,
Kaname S, Fujita T. Anti-carbonic anhydrase II
antibody in autoimmune pancreatitis andtubulointerstitialnephritis.
Nephrol
Dial
Transplant. 2007;22:1273-5.
26. Nishikawa T, Tomiya T, Ohtomo N, Inoue Y,
Ikeda H, Tejima K, Watanabe N, Tanoue Y, Omata
M, Fujiwara K. Stimulation by glutamine andproline of HGF production in hepatic stellate cells.
Biochem Biophys Res Commun. 2007;363:97882.
27. Ogura K, Mitsuno Y, Maeda S, Hirata Y, Yanai A,
Shibata W, Ohmae T, Yoshida H, Kawabe T,
Omata M. Efficacy and safety of faropenem in
eradication therapy of Helicobacter pylori.
Helicobacter. 2007;12:618-22.
28. Ohki T, Tateishi R, Shiina S, Sato T, Masuzaki R,

126

Yoshida H, Kanai F, Obi S, Yoshida H, Omata M.
Obesity did not diminish the efficacy of
percutaneous
ablationforhepatocellular
carcinoma. Liver Int. 2007;27:360-7.
29. Omata M, Wakabayashi R, Kudoh S, Kida K.
Correlation
betweenbronchodilator
responsiveness and quality of life in chronic
obstructive pulmonary disease. Allergol Int. 2007;
56:15-22.
30. Omata M, Yoshida H, Toyota J, Tomita E,
Nishiguchi S, Hayashi N, Iino S, Makino I, Okita
K, Toda G, Tanikawa K, Kumada H. A large-scale,multicentre, double-blind trial of ursodeoxycholicacid in patients with chronic hepatitis C. Gut.
2007;56:1747-53.
31. Ono Y, Hino M, Ueda Y, Kamizuru R, Omata M,
Uehara T, Tanaka Y, Soma T, Kudoh S. Phase I
study of paclitaxel, carboplatin and UFT inchemo-naive patients with advanced non-small
cell lung cancer (NSCLC). Med Oncol. 2007;24:
402-6.
32. Sasahira N, Tada M, Isayama H, Hirano K, Nakai
Y, Yamamoto N, Tsujino T, Toda N, Komatsu Y,
Yoshida H, Kawabe T, Omata M. Outcomes after
clearance of pancreatic stones with or without
pancreatic stenting. J Gastroenterol. 2007;42:63-9.
33. Shao RX, Kato N, Lin LJ, Muroyama R,
Moriyama M, Ikenoue T, Watabe H, Otsuka M,
Guleng B, Ohta M, Tanaka Y, Kondo S, Dharel N,
Chang JH, Yoshida H, Kawabe T, Omata M.
Absence of tyrosine kinase mutations in Japanesecolorectal cancer patients. Oncogene. 2007;26:
2133-5.
34. Shibata W, Maeda S, Hikiba Y, Yanai A, Ohmae T,
Sakamoto K, Nakagawa H, Ogura K, Omata M.
Cutting edge: The IkappaB kinase (IKK) inhibitor,
NEMO-binding
domainpeptide,blocksinflammatory injury in murine colitis. J Immunol.
2007;179:2681-5.
35. Shiina S, Tateishi R, Yoshida H, Kanai F, Omata
M. Local ablation therapy for hepatocellular
carcinoma.
Fromethanol
injectiontoradiofrequency ablation. Saudi Med J. 2007;28:
831-7.
36. Takano S, Kanai F, Jazag A, Ijichi H, Yao J,
Ogawa H, Enomoto N, Omata M, Nakao A.
Smad4 is essential for down-regulation ofE-cadherin induced by TGF-beta in pancreaticcancer cell line PANC-1. J Biochem. 2007;141:345-51.
37. Tanaka Y, Imamura J, Kanai F, Ichimura T, Isobe
T, Koike M, Kudo Y, Tateishi K, Ikenoue T, Ijichi
H, Yamaji Y, Yoshida H, Kawabe T, Omata M.
Runx3 interacts with DNA repair protein Ku70.
Exp Cell Res. 2007;313:3251-60.
38. Tejima K, Arai M, Ikeda H, Tomiya T, Yanase M,
Inoue Y, Nishikawa T, Watanabe N, Ohtomo N,
Omata M, Fujiwara K. Induction of ischemic
tolerance in rat liver via reduced nicotinamide
adenine dinucleotide phosphate oxidase in
Kupffer cells. World J Gastroenterol. 2007;13:5071-8.
39. Tomiya T, Nishikawa T, Inoue Y, Ohtomo N,
Ikeda H, Tejima K, Watanabe N, Tanoue Y, Omata
M, Fujiwara K. Leucine stimulates HGF
production by hepatic stellate cells through mTOR
pathway. Biochem Biophys Res Commun. 2007;
358:176-80.
40. Tomiya T, Yamaoka M, Inoue Y, Nishikawa T,
Yanase M, Ikeda H, Tejima K, Nagashima K,
Watanabe N, Omata M, Fujiwara K. Effect of
rapamycin
onhepatocyte
functionandproliferation induced by growth factors.
Chemotherapy. 2007;53:59-69.
41. Tsujino T, Kawabe T, Komatsu Y, Yoshida H,
Isayama H, Sasaki T, Kogure H, Togawa O,
Arizumi T, Matsubara S, Ito Y, Nakai Y,
Yamamoto N, Sasahira N, Hirano K, Toda N, Tada
M, Omata M. Endoscopic papillary balloon
dilation for bile duct stone: immediate andlong-term outcomes in 1000 patients. Clin
Gastroenterol Hepatol. 2007;5:130-7.
42. Tsujino T, Kawabe T, Omata M. Antiproteases inpreventing post-ERCP acute pancreatitis. Jop.
2007;8:509-17.
43. Tsujino T, Kogure H, Sasahira N, Isayama H,
Tada M, Kawabe T, Omata M, Akahane M, Sano
K, Makuuchi M. A huge intra-abdominal mass ina young man. Gut. 2007;56:1372, 93.
44. Tsujino T, Sugawara Y, Kawabe T, Makuuchi M,
Omata M. Foreign body (suture thread) in the bile
duct after living donor liver transplantation. Liver
Transpl. 2007;13:1065-6.
45. Tsujino T, Sugita R, Yoshida H, Yagioka H,

127

Kogure H, Sasaki T, Nakai Y, Sasahira N, Hirano
K, Isayama H, Tada M, Kawabe T, Omata M. Risk
factors for acute suppurative cholangitis causedby bile duct stones. Eur J Gastroenterol Hepatol.
2007;19:585-8.
46. Watanabe N, Ikeda H, Nakamura K, Ohkawa R,
Kume Y, Aoki J, Hama K, Okudaira S, Tanaka M,
Tomiya T, Yanase M, Tejima K, Nishikawa T, Arai
M, Arai H, Omata M, Fujiwara K, Yatomi Y. Bothplasma lysophosphatidic acid and serum autotaxin
levels are increased in chronic hepatitis C. J Clin
Gastroenterol. 2007;41:616-23.
47. Watanabe N, Ikeda H, Nakamura K, Ohkawa R,
Kume Y, Tomiya T, Tejima K, Nishikawa T, Arai
M, Yanase M, Aoki J, Arai H, Omata M, Fujiwara
K, Yatomi Y. Plasma lysophosphatidic acid leveland serum autotaxin activity are increased in liver
injury in rats in relation to its severity. Life Sci.
2007;81:1009-15.
48. Yamaji Y, Mitsushima T, Yoshida H, Watabe H,
Okamoto M, Ikuma H, Wada R, Kawabe T, Omata
M. Right-side shift of metachronous colorectal
adenomasafter
polypectomy.
Scand
J
Gastroenterol. 2007;42:1466-72.
49. Yamamichi N, Inada K, Ichinose M, YamamichiNishina M, Mizutani T, Watanabe H, Shiogama K,
Fujishiro M, Okazaki T, Yahagi N, Haraguchi T,
Fujita S, Tsutsumi Y, Omata M, Iba H. Frequentloss of Brm expression in gastric cancer correlateswith histologic features and differentiation state.
Cancer Res. 2007;67:10727-35.
50. Yamashiki N, Yoshida H, Tateishi R, Shiina S,
Teratani T, Yoshida H, Kondo Y, Oki T, Kawabe T,
Omata M. Recurrent hepatocellular carcinoma has
an increased risk of subsequent recurrence after
curative treatment. J Gastroenterol Hepatol. 2007;
22:2155-60.
51. Yamashita H, Nakagawa K, Shiraishi K, Tago M,
Igaki H, Nakamura N, Sasano N, Siina S, Omata
M, Ohtomo K. Radiotherapy for lymph nodemetastases in patients with hepatocellular
carcinoma: retrospective study. J Gastroenterol
Hepatol. 2007;22:523-7.
52. Yanai A, Maeda S, Hikiba Y, Shibata W, Ohmae T,
Hirata Y, Ogura K, Yoshida H, Omata M. Clinicalrelevance of Helicobacter pylori sabA genotype inJapanese clinical isolates. J Gastroenterol Hepatol.

2007;22:2228-32.
53. Yoshida H, Kato T, Levi DM, Regev A,
Madariaga JR, Nishida S, Martinez EJ, Schiff ER,
Omata
M,
TzakisAG.
Lamivudine
monoprophylaxis for liver transplant recipientswith non-replicating hepatitis B virus infection.
Clin Transplant. 2007;21:166-71.

Internal Medicine
2. Medicine Ⅱ129

Department of Nephrology and
Endocrinology
Professor
Toshiro Fujita, M.D., Ph.D.

Associate Professor
Eisei Noiri, M.D., Ph.D.

Visiting Associate Professor, Project Associate Professor
Keiichi Hishikawa, M.D., Ph.D.,

Akira Ishikawa, M.D., Ph.D.

Takanari Gotoda, M.D., Ph.D.,

Katsuyuki Ando, M.D., Ph.D.

Lecturer
Seiji Fukumoto, M.D., Ph.D.,

George Seki, M.D., Ph.D.,

Akihiro Tojo, M.D., Ph.D.,

Yugo Shibagaki, M.D., Ph.D.

Hospital Lecturer
Taroh Iiri, M.D., Ph.D.,

Koji Takano, M.D., Ph.D.,

Masaomi Nangaku, M.D., Ph.D.

Associate
Katsutoshi Takahashi, M.D., Ph.D.,

Masashi Isshiki, M.D., Ph.D.,

Shigeyoshi Oba, M.D., Ph.D.,

Noriko Makita, M.D., Ph.D.,

Junichi Hirahashi, M.D., Ph.D.,

Yuichi Hori, M.D., Ph.D.,

Hideomi Yamada, M.D., Ph.D.,

Takehiko Wada, M.D., Ph.D.,

Visiting Associate, Project Associate
Takeshi Marumo, M.D., Ph.D.,

Yoshitaka Ishibashi, M.D., Ph.D.,

Miki Nagase, M.D., Ph.D.,

Hiromitsu Matsui, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/˜kid-endo/top.html

Introduction and Organization
The Division of Nephrology and Endocrinology is
one of the major divisions in the Department ofInternal Medicine of the University of Tokyo, which
covers nephrology, hypertension, and endocrinology,
and also renal diseases associated with diabetes
mellitus, cardiovascular diseases, collagen diseases

and so on. We have 18 proper beds on the 12th floorof the Northern part of Ward A in The University ofTokyo Hospital, and ten beds for hemodialysis.
Usually we have up to 30 inpatients in the hospital.
The Professor and each member of the staff have an
active responsibility for all clinical activities. Eachmember has an office and a research laboratory. In our
department, almost all members support the clinical130

works of our residents, and other 2 associates are
involved mainly in the Hemodialysis Unit. We are
intimately working together in all clinical activities
under the supervision of the Professor and the
Associate Professors.

Clinical activities
The residents are in charge of up to 30 patients ofour division and supervised by associates and faculty
staffs. Every Tuesday, we have a clinical conference todiscuss the diagnosis and treatment of our patientswith all members of the staff. Particularly difficult
cases are further discussed with guest specialists fromoutside almost once a month.
Nephritis should be morphologically diagnosed byrenal biopsy and the optimal treatment should bechosen for each patient. In our division, renal biopsy
is actively performed to give the real benefits oftreatment to the patients. We also treat diabetic
patients with proteinuria and end-stage renal failure.
Each staff of our division also works at the
hemodialysis unit, thus we can manage patients inevery stage of renal disease.
In the endocrine unit there is a variety of patients
having disorders in thyroid, parathyroid, pituitary,adrenal and genital glands. It is also our specialty todiagnose and treat secondary hypertension caused byprimary
aldosteronism,
Cushing’s
syndrome,
pheochromocytoma, renal artery stenosis and so on.
We often have consultation from other divisions
concerning disorders of water and mineralmetabolism.

Education
We have responsibility for educating undergraduate,
graduate students and residents. Our staffs take part inseveral lectures for undergraduate and graduate
students. In addition, our members are actively
involved in bed-side learning and clinical clerkship ofundergraduate students, and other clinical practice. In
the ward, we are also educating residents during dailyclinical works and periodical lectures concerningkidney and endocrine diseases.

Research
In our department there are more than 30 studentsof the graduate school. We have research conferences
every Tuesday, to discuss the results of the researchwith the Professor and faculty members. As you see inthe references below, our research topics are various
and cover every field of nephrology, hypertension andendocrinology. We are also actively collaborating with
scientists outside the division and outside theUniversity including foreign countries. Achievementsof our researches are published in world top level
journalsofnephrology,
hypertension
andendocrinology.

Affiliated Endowed Chairs
Department of Clinical Renal
Regeneration
Introduction and Organization
Department of Clinical Renal Regeneration was
founded by a donation from MOCHIDA
Pharmaceutical Co., Ltd. in November 2002 as one ofthe departments of Division of Tissue Engineering in
The University of Tokyo Hospital. The main object of
this department is to contribute to the development ofbetter treatment and drug discovery through tissue
engineering technologies and regenerative medicine.

Research activities
We aim at clinical application of kidney-derived
adult stem cell, clinical application of new scaffold
material and matrix for renal regeneration and clinicalrenal regeneration by using cord blood. To achievethese goals, we are conducting research on adult stem
cell biology in regeneration, comprehensive researchon stem cell dysfunction in renal failure anddevelopment of 3-D culture system for induction ofmetanephros in vitro.

131

Division of Total Renal Care
Medicine
Homepage

http://www.trc.umin.jp

Introduction and Organization
Division of Total Renal Care was established inJune 2004 by courtesy of TERUMO Co., a leading
company in the field of continuous ambulatory
peritoneal dialysis (CAPD), as a part of 22nd Century
Medical and Research Center of The University ofTokyo Hospital. The main object of this division is tomake it possible to provide the best total renal care forpatients with end stage renal disease (ESRD).

Clinical activities

the Graduate School of Medicine, the University ofTokyo. Our department also belongs to the 22nd
Century Medical Center, which partly represents thetranslational research activities of The University ofTokyo Hospital. Our department is established withthe main aim of performing the clinical andepidemiological analysis on the metabolic syndromein the Japanese population, of isolating susceptibilitygene(s) to metabolic syndrome through molecular andgenetic analysis on human and rodent animal models,and of contributing to the development of novel
diagnostic method and therapeutic agents for theprevention and treatment of the cardiovasculardiseases.

Research activities

Two research projects are now ongoing. One is theinvestigation of changes of peritoneal function overtime with special emphasis on histopathologicalalteration of mesothelial cells by peritoneal dialysate.
Another one is to clarify the mechanism of renal
preservation effect of angiotensin-II receptor blockers
using cyclosporine-treated nephrotoxic rats.

Our research field of interest covers the followings.
z Identification and isolation of novel susceptible
genes and related factors to metabolic syndrome
through systemic molecular and biological analysis
on human and rodent animal models of metabolic
syndrome.
z Performance of clinical and epidemiologicalanalysis with regard to metabolic syndrome.
z Development of novel diagnositic method for risk
factors of cardiovascular diseases.
z Contribution to the development of preventive andtherapeutic novel agents to treat patients withmetabolic syndrome.
z Exploration of novel mechanisms of action ofavailable pharmaceutical agents to treat patientswith cardiovascular diseases.

Department of Clinical &Molecular Epidemiology

Division of Molecular Cardiovascular Metabolism

Homepage http://www.h.u-tokyo.ac.
jp/center22/rinsyo_bunshi.html

Homepage http://plaza.umin.ac.jp/˜kid-endo/a-3-13.html

Introduction and Organization

Introduction and Organization

The Department of Clinical & Molecular
Epidemiology was established in June 2004 as anendowed department (Tanabe Seiyaku Co., Ltd.) of

In order to investigate common diseases such as
hypertension
and
their
reno-cardiovascularcomplication, which is induced by deflective lifestyle

We are engaged in the care of patients undergoing
CAPD, the creation of arteriovenous shunt for
hemodialysis, and kidney transplantation incollaboration with nearby medical facilities.

Research activities

132(salt excess, obesity, and so on), Division of
Molecular Cardiovascular Metabolism was started
with donation of Daiichi-Sankyo Company, Ltd. in
2006.

Research activities
In basic research, we are investigating the role ofreactive oxygen species (ROS), the sympathetic
nervous system, and the renin-angiotensinaldosterone system in the pathophysiology of saltsensitive hypertension, metabolic syndrome, and theirreno-cardiovascular complication. We are also
conducting a clinical research investigating thesignificance of sympatholytic effect on antiproteinuric
action using L-/N-type calcium channel blocker(CCB) and L-type CCB.

Publications
1. Nangaku M. The heat is on: an expanding role for
HIFs in kidney transplantation. J Am Soc Nephrol
2007;18:13-15.
2. Kojima I, Tanaka T, Inagi R, Kato H, Yamashita
T, Sakiyama A, Ohneda O, Takeda N, Sata M,
Miyata T, Fujita T, Nangaku M. Protective role ofhypoxia-inducible factor-2alpha against ischemic
damage and oxidative stress in the kidney. J Am
Soc Nephrol 2007;18:1218-26.
3. Eto N, Wada T, Inagi R, Takano H, Shimizu A,
Kato H, Kurihara H, Kawachi H, Shankland SJ,
Fujita T, Nangaku M. Darbepoetin protects
podocytes by preservation of the cytoskeleton andnephrin distribution. Kidney Int 2007;72:455-463.
4. Sakairi T, Hiromura K, Yamashita S, Takeuchi S,
Tomioka M, Ideura H, Maeshima A, Kaneko Y,
Kuroiwa T, Nangaku M, Takeuchi T, Nojima Y.
Increased expression of nestin in the kidney
injured by unilateral ureteral obstruction. Kidney
Int 2007;72:307-318.
5. Wang D, Gill PS, Chabrashvili T, Onozato ML,
Raggio J, Mendonca M, Dennehy K, Li M,
Modlinger P, Leiper J, Vallance P, Adler O,
Leone A, Tojo A, Welch WJ, Wilcox CS.
Isoform-specific regulation by N(G),N(G)dimethylarginine dimethylaminohydrolase of rat
serum asymmetric dimethylarginine and vascularendothelium-derived relaxing factor/NO. Circ Res
2007;101:627-635.
6. Shibata S, Nagase M, Yoshida S, Kawachi H,
Fujita T. Podocyte as the target for aldosterone:roles of oxidative stress and Sgk1. Hypertension
2007;49:355-364.
7. Nagase M, Matsui H, Shibata S, Gotoda T, Fujita
T.
Salt-induced
nephropathyinobese
spontaneously hypertensive rats via paradoxical
activation of the mineralocorticoid receptor: roleof oxidative stress. Hypertension 2007;50:877883.
8. Frishberg Y, Ito N, Rinat C, Yamazaki Y,
Feinstein S, Urakawa I, Navon-Elkan P,
Becker-Cohen R, Yamashita T, Araya K, IgarashiT, Fujita T, Fukumoto S. Hyperostosishyperphosphatemia syndrome: a congenital
disorder of o-glycosylation associated withaugmented processing of fibroblast growth factor
23. J Bone Miner Res 2007;22:235-42.
9. Fukumoto S, Yamashita T. FGF23 is ahormone-regulating
phosphatemetabolismUnique biological characteristics of FGF23. Bone
2007;40:1190-1195.
10. Sato S, Hanada R, Kimura A, Abe T, Matsumoto
T, Iwasaki M, Inose H, Ida T, Mieda M, Takeuchi
Y, Fukumoto S, Fujita T, Kato S, Kangawa K,
Kojima M, Shinomiya K, Takeda S . Central
control of bone remodeling by neuromedin U. Nat
Med 2007;13:1234-1240.
11. Makita N, Sato J, Manaka K, Shoji Y, Oishi A,
Hashimoto M, Fujita T, Iiri T. An acquired
hypocalciuric
hypercalcemia
autoantibody
induces allosteric transition among active humanCa-sensing receptor conformations. Proc Natl
Acad Sci U S A 2007;104:5443-5448.
12. Makita N, Sato J, Rondard P, Fukamachi H,
Yuasa Y, Aldred MA, Hashimoto M, Fujita T, Iiri
I.
Human
Gsα
mutantcausespseudohypoparathyroidism
type
Ia/neonatal
diarrhea, a potential cell-specific role of thepalmitoylation cycle. Proc Natl Acad Sci U S A
2007;104:17424-17429.
13. Liu J, Shimosawa T, Matsui H, Meng F, Supowit
SC, Dipette DJ, Ando K, Fujita T.
Adrenomedullin inhibits angiotensin II-induced
oxidative stress via Csk-mediated inhibition of

133

Src activity. Am J Physiol Heart Circ Physiol
2007;292:H1714-H1721.
14. Fujita T, Ando K, Nishimura H, Ideura T, Yasuda
G, Isshiki M, Takahashi T, on behalf of theCilnidipine versus Amlodipine Randomized Trial
for Evaluation in Renal Disease (CARTER) Study
Investigators. Antiproteinuric effect of thecalcium channel blocker cilnidipine added torenin-angiotensin inhibition in hypertensive
patients with chronic renal disease. Kidney Int
2007;72:1543–1549.
15. Sawada N, Taketani Y, Amizuka N, Ichikawa M,
Ogawa C, Nomoto K, Nashiki K, Sato T, Arai H,
Isshiki M, Segawa H, Yamamoto H, Miyamoto K,
Takeda E. Caveolin-1 in extracellular matrix
vesicles secreted from osteoblasts. Bone 2007;41:
52-58.
16. Yoshikawa M, Hishikawa K, Marumo T, Fujita T.
Inhibition of histone deacetylase activity
suppresses epithelial-to-mesenchymal transition
induced by TGF-beta1 in human renal epithelial
cells. J Am Soc Nephrol 2007;18:58-65.
17. Imai N, Hishikawa K, Marumo T, Hirahashi J,
Inowa T, Matsuzaki Y, Okano H, Kitamura T,
Salant D, Fujita T. Inhibition of histone
deacetylase activates side population cells inkidney and partially reverses chronic renal injury.
Stem Cells 2007; 25:2469-2475.
18. Fijuta M, Ando K, Nagae A, Fujita T.
Sympathoexcitation by oxidative stress in thebrain mediates arterial pressure elevation in salt
sensitive hypertension. Hypertension 2007;50:
360-367.
19. Kawarazaki H, Ishibashi Y, Kawarazaki W,
Shimizu H, Takara Y, Kume H, Sasahira N,
Kaname S, Fujita T. Successful management ofcatheter obstruction by endoscopic nasopancreatic drainage tube. Perit Dial Int 2007;27:
467.
（Total 54 publications）

134

Department of Metabolic Diseases
Professor
Takashi Kadowaki, M.D.,Ph.D.

Associate Professor
Kohjiro Ueki, M.D.,Ph.D.

Lecturer
Kazuhisa Tsukamoto, M.D., Ph.D.

Research Associate
Jun-ichi Osuga, M.D., Ph.D.,

Ken Ohashi, M.D., Ph.D.

Masumi Hara, M.D. Ph.D.,

Hideyuki Sakoda, M.D., PhD.

Midori Fujishiro, M.D., Ph.D.,

Mitsuru Ohsugi, M.D., PhD.

Nobuhiro Shojima, M.D., Ph.D.,

Momoko Horikoshi, M.D., Ph.D.

Homepage

http://dm.umin.jp/

Introduction and Organization
In 1998 the Department of Internal Medicine at the
University of Tokyo was reorganized to the morefunctional units based on clinical specialties of
diseased organs. The physicians specialized in themetabolic diseases from 3 departments of Internal
Medicine were unified to the Department of Metabolic
Diseases. The Department of Metabolic Diseases is
one of the major divisions in the Department ofInternal Medicine at the University of Tokyo, andcovers metabolic diseases including diabetes mellitus,
obesity and dyslipidemia.
Under the supervision and direction of the previous
professors Dr. Satoshi Kimura (1998-2003) and Dr.
Toshiro Fujita (2003) and the present Professor Dr.
Takashi Kadowaki (2003-present), we have provided awide-ranged clinical, teaching and research activities.
Currently, we hold 35 beds mainly on the 12th floor of
the Northern Ward of the Tokyo University Hospital,
and take care of more than 30 patients constantly.
Besides the staffs listed above, our division holds
faculties in branches, for example, Department ofIntegrated Molecular Science on Metabolic Diseases(visiting associate professor, Dr. Toshimasa
Yamauchi), Translational Systems Biology andMedicine Initiative (project associate professor, Dr.
Naoto Kubota) and 21st Century COE Program. With
all these staffs, we intensively instruct and teach theresidents and under-graduate students; annual
evaluation of the teaching skill by the students always
rates our department within the three places of the top.
In addition, there are around 20 students of Graduate
School in our division. With all these members, wevigorously work on the research activities, which leadto the outstanding contributions in the field of
metabolism.

Clinical activities
Based on the update clinical evidences and with theexperienced skills, we provide superior andwarm-hearted medicine to each patient. We haveoutpatient clinics from Monday through Friday, andtake care of more than 4000 patients. In the inpatientcare unit, we not only take care of more than 30
patients in our division as mentioned above, but also
provide a sophisticated management to all patients

135

suffering from metabolic diseases, especially diabetes
mellitus. Diabetes mellitus, metabolic syndrome,
hyperlipidemia and obesity are very popular in Japan,
and cause complications including nephropathy,
retinopathy, neuropathy and cardiovascular diseases.
Thus, in collaboration with other departments, we
optimize the treatment of each patient.
We provide the educational lectures to the patients
every day in the inpatient ward, and also give lectures
twice a week in the outpatient unit. In addition, in
collaboration with co-medical staffs of our hospital,
we provide patients well-reasoned instructions
regarding diet therapy, excise therapy and medication
therapy.
The weekly official activities of our department are
the pre-round case conference and the Ward Round by
the Professor on Monday. We also hold a caseconference by the consultation group staffs on
Tuesday.

Teaching activities
As for under-graduate education, our department takes
a part in systemic lectures for the 4th year medical
students, bed-side learning and clinical clerkship forthe 5th year medical students, and clinical lectures forthe 6th year medical students.
In systemic lectures, comprehensive presentation for
the understanding of basic knowledge about theconcept, pathogenesis, diagnosis and treatment ofcommon metabolic diseases is performed.
In clinical lectures, we present clinical cases ofimportant diseases such as diabetes mellitus, and try
to discuss with the students several points forplanning the diagnosis and treatment in collaboration
with the faculties of the Departments of Nephrology,
Cardiology, and Ophthalmology.
During the period of bed-side learning, the students
have opportunities to experience the daily clinical carewith junior and senior residents as well as with theFaculty members. Each student can learn how to makea medical interview, check physical findings and makethe actual plans for the diagnosis and treatment.
Several lectures that lead to profound understandingsof the metabolic diseases are provided by the staffs.
In clinical clerkship, we arrange the program so thatthe students can experience the clinical practice andlearn the disease itself more profoundly. One faculty
and one senior-resident always instruct one student.
As for the post-graduate education, attending doctor(staff) and senior resident instruct the junior residents.
We provide advanced teaching through the seminars
and grand conference.

Research activities
There are several laboratories in our departments;
collaborating with each other or with otherdepartments, we focus on the molecular mechanismsof the metabolic diseases and the establishment of the
new treatment.
1) Molecular mechanisms of type 2 diabetes
We have been trying to elucidate the mechanisms
underlying the development of type 2 diabetes at themolecular and genetic levels. To this end, we are
exploring the signal transduction pathways andphysiological roles of insulin and adipokines invarious tissues and the secretory mechanism of insulin
under the normal or pathological conditions, such as
diabetes and obesity, using a number of transgenic
and knockout animal models. In particular, we areinterested in the physiological and pathophysiological
functions of some adipokines secreted by adipocytes,
including adiponectin and other adipokines, and thesignal transduction pathway of adiponectin throughthe receptors, AdipoR1 and AdipoR2, that we
identified. In addition, we have been successfully
unraveling the molecular mechanisms of ß cellproliferation. We believe that these will provide
novel therapeutic strategies for diabetes and themetabolic syndrome.
2) Analysis of a glucose transport mechanism ininsulin resistance
We analyze insulin-stimulated and contractioninduced glucose transport with technique of molecularbiology. In addition, we try condition of a patient
elucidation of diabetes and establishment of a newtreatment by analyzing a diabetes model animal andmechanism of insulin resistance in a cultured cell.
3) Pathophysiological roles of lipid storage andatherosclerosis

136

Our aim is to clarify the significance of metabolic risk
factors in the onset and development of
atherosclerosis. We are currently investigating thepathophysiological roles of lipid storage in obesity,
fatty
liver,
diabetes,
hyperlipidemia
andatherosclerosis using strategies of molecular biology
and genetic engineering techniques.
4) Lipid disorders and atherosclerosis
Utilizing the animal models of lipid disorders andmolecular biological technique, we are analyzing theroles of lipid transporters, nuclear receptors and theanti-oxidative proteins on the lipid disorders andatherosclerosis. We are currently interested in thecholesterol and lipid absorption from the intestine andlipid handling in the cells.

References
1. Asano T, Fujishiro M, Kushiyama A, Nakatsu Y,
Yoneda M, Kamata H, Sakoda H. Role ofphosphatidylinositol 3-kinase activation on insulin
action and its alteration in diabetic conditions.
Biol Pharm Bull 30:1610-1616, 2007
2. Ebinuma H, Miida T, Yamauchi T, Hada Y, Hara
K Kadowaki T. Improved ELISA for selective
measurement of adiponetin multimers andidentificationofadiponectininhuman
cerebrospinal fluid. Clin Chem 53: 1541-1544,
2007
3. Hada Y, Yamauchi T, Waki H, Tsuchida A, Hara K,
Yago H, Miyazaki O, Ebinuma H, Kadowaki T.
Selective purification and characterization of
adiponectin multimer species from human plasma.
Biochem Biophys Res Commun 356: 487-493,
2007
4. Hadsell DL, Olea W, Lawrence N, George J,
Torres D, Kadowaki T, Lee AV. Decreased
lactation capacity and altered milk composition in
insulin receptor substrate null mice is associatedwith decreased maternal body mass and reduced
insulin-dependent phosphorylation of mamary Akt.
J Endocrinol 194: 327-336, 2007
5. Hara K, Yamauchi T, Imai Y, Manabe I, Nagai R,
Kadowaki T. Reduced adiponectin level isasociated with severity of coronary artery disease.
Int Heart J 48: 149-153, 2007

6. Hashimoto H, Arai T, Ohnishi Y,Eto T, Ito M,
Suzuki R, Yamauchi T, Ohsugi M, SaitoM,
Ueyama Y, Tobe K, Kadowaki T , Tamaoki N,
Kosaka K. Phenotypes of IRS-2 deficient mice
produced by reproductive technology are stable.
Exp Anim 56: 149-154, 2007
7. Horikoshi M, Hara K, Ito C, Nagai R, Froguel P,
Kadowaki T. A genetic variation of thetranscription factor 7-like 2 gene is associatedwith risk of type 2 diabetes in the Japanese
population. Diabetologia 50:747-751, 2007
8. Horikoshi M, Hara K, Ito C, Shojima N, Nagai R,
Ueki K, Froguel P, Kadowaki T. Variations in the
HHEX gene are associated with increased risk oftype 2 diabetes in the Japanese population.
Diabetologia 50:2461-2466, 2007
9. Ishikawa M, Kitayama J, Yamauchi T, Kadowaki
T, Maki T, Miyato H, Yamashita H, Nagawa H.
Adiponectin inhibits the growth and peritoneal
metastasis of gastric cancer through its specificmembrance receptors AdipoR1 and AdipoR2.
Cancer Sci 98: 1120-1127, 2007
10. Kadowaki T, Yamauchi T, Kubota N, Hara K,
Ueki K. Adiponectin and adiponectin receptors in
obesity-linked insulin resistance. Fatty Acids andLipotoxicity in Obesity and Diabetes. (Novartis
Foundation Symposium 286) , John Wiley & Sons,
Ltd, pp164-182, 2007
11. Kawamori R, Kadowaki T, Onji M, Seino Y,
Akanuma Y on behalf of the PRACTICALStudy
Group. Hepatic safety profile and glycemic
control of pioglitazone in more than 20,000
patients with type 2 diabetes mellitus:
Postmarketing surveillance study in Japan.
Diabetes Res Clin Pract 76: 229-235, 2007
12. Kawamura N, Kugimiya F, Oshima Y, Ohba S,
Ikeda T, Saito T, Shinoda Y, KawasakiY, Ogata N,
Hoshi K, Akiyama T, Tobe T, Kadowaki T, Azuma
Y, Nakamura K, Chung UI, and Kawaguchi H.
Akt1 in osteoblasts and osteoclasts controls bone
remodeling. PLoS ONE 2:e1058, 2007
13. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S,
Kumagai H, Kozono H, Takamoto I, Okamoto S,
Shiuchi T, Suzuki R, Satoh H, Tsuchida A, Moroi
M, Sugi K, Noda T, Ebinuma H, Ueda Y, Kondo T,
Araki E, Ezaki O, Nagai R, Tobe K, Terauchi Y,
Ueki K, Minokoshi Y, Kadowaki T. Adiponectin

137

stimulates AMP-activated protein kinase in the
hypothalamus and increases food intake. Cell
Metabolism 6: 55-68, 2007
14. Kume S, Uzu T, Araki S, Sugimoto T, Isshiki K,
Chin-Kanasaki M, Sakaguchi M, Kubota N,
Terauchi Y, Kadowaki T, Haneda M, Kashiwagi A,
Koya D. Role of altered renal lipid metabolism inthe development of renal injury induced by ahigh-fat diet: lessons from insulin-sensitive PPAR
γ-deficient mice. J Am Soc Nephrol 18: 27152723, 2007
15. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda
H, Asano T, Levine B, Sadoshima J. Distinct
roles of autophagy in the heart during ischemia
and reperfusion: roles of AMP-activated protein
kinase and Beclin 1 in mediating autophagy. Circ
Res 100: 914-922. 2007
16. Matsuzaka T, Shimano H, Yahagi N, Kato T,
Atsumi A, Yamamoto T, Inoue N, Ishikawa M,
Okada S, Ishigaki N, Iwasaki H, Iwasaki Y,
Karasawa T, Kumadaki S, Matsui T, Sekiya M,
Ohashi K, Hasty AH, Nakagawa Y, Takahashi A,
Suzuki H, Yatoh S, Sone H, Toyoshima H, Osuga
JI, Yamada N. Crucial role of a long-chain fatty
acid elongase, Elovl6, in obesity-induced insulin
resistance. Nat Med 13:1193-1202, 2007
17. Nishimura S, Manabe I, Nagasaki M, Hosoya Y,
Yamashita H, Fujita H, Ohsugi M, Tobe K,
Kadowaki T, Nagai R, Sugiura S. Adipogenesis
in obesity requires close interplay between
differentiating adipocytes, stromal cells and bloodvessels. Diabetes 56: 1517-1526, 2007
18. Ochi M, Osawa H, Hirota Y, Hara K, Tabara Y,
Tokuyama Y, Shimizu I, Kanatsuka A, Fujii Y,
Ohashi J, Miki T, Nakamura N, Kadowaki T,
Itakura M, Kasuga M, Makino H. The frequencyof the G/G genotype of resistin single nucleotide
polymorphism at -420 appears to be increased in
vounger onset type 2 diabetes. Diabetes 56: 28342838, 2007
19. Ono H, Sakoda H, Fujishiro M, Anai M,
Kushiyama A, Fukushima Y, Katagiri H, Ogihara
T, Oka Y, Kamata H, Horike N, Uchijima Y,
Kurihara H, Asano T.
Carboxy-terminal
modulator protein induces Akt phosphorylation
and activation, thereby enhancing antiapoptotic,
glycogen synthetic, and glucose uptake pathways.

Am J Physiol Cell Physiol 293: C1576-1585,
2007
20. Sadagurski M, Nofech-Mozes S, Weingarten G,
White MF, Kadowaki T, Wertheimer E. Insulin
receptor substrate 1 (IRS-1) plays a unique role innormal epidermal physiology. J Cell Physiol 213:
519-527, 2007
21. Saheki T, Iijima M, Li MX, Kobayashi K,
Horiuchi M, Ushikai M, Okamura F, Meng XJ,
Inoue I, Tajima A, Moriyama M, Eto K,
Kadowaki T, Sinasac DS, Tsui LC, Tsuji M,
Okano A, Kobayashi T. Citrin/mitochondrial
glycerol 3-phosphate dehydrogenase doubleknockout mice recapitulate features of human
citrin deficiency. J Biol Chem. 282: 25041-25052,
2007
22. Sekiya M, Yahagi N, Matsuzaka T, Takeuchi Y,
Nakagawa Y, Takahashi H, Okazaki H, Iizuka Y,
Ohashi K, Gotoda T, Ishibashi S, Nagai R,
Yamazaki T, Kadowaki T, Yamada N, Osuga J,
Shimano H. SREBP-1-independent regulation of
lipogenic gene expression in adiocytes. J Lipid
Res 48: 1581-1591, 2007
23. Shibayama T, Kobayashi K, Takano A,, Kadowaki
T, Kazuma K. Effectiveness of lifestylecounseling by certified expert nurse of Japan for
non-insulin-treated diabetic outpatients: A 1-year
randomized controlled trial. Diabetes Res Clin
Pract 76: 265-268, 2007
24. Shimazaki T, Kadowaki T, Ohyama Y, Ohe K,
Kubota K. Hemoglobin A1c (HbA1c) predicts
future drug treatment for diabetes mellitus: afollow-up study using routine clinical data in a
Japanese university hospital. Transl Res 149:196204, 2007
25. Takagi H, Matsui Y, Hirotani S, Sakoda H, Asano
T, Sadoshima J. AMPK mediates autophagy
during myocardial ischemia in vivo. Autophagy
3: 405-407. 2007
26. Takeuchi Y, Yahagi N, Nakagawa Y, Matsuzaka T,
Shimizu R, Sekiya M, Iizuka Y, Ohashi K, Gotoda
T, Yamamoto M, Nagai R, Kadowaki T, Yamada
N, Osuga J, Shimano H. In vivo promoter analysis
on refeeding response of hepatic sterol regulatory
element-binding protein-1c expression. Biochem
Biophys Res Commun 363: 329-335, 2007
27. Taniguchi CM, Aleman JO, Ueki K, Luo J, Asano138

T, Kaneto H, Stephanopoulos G, Cantley LC,
Kahn CR. The p85{alpha} Regulatory Subunit of
Phosphoinositide 3-Kinase Potentiates c-Jun
N-Terminal Kinase-Mediated Insulin Resistance.
Mol Cell Biol 27: 2830-2840, 2007
28. Terauchi Y, Takamoto I, Kubota N, Matsui J,
Suzuki R, Komeda K, Hara A, Toyoda Y, Miwa I,
Aizawa S, Tsutsumi S, Tsubamoto Y, Hashimoto S,
Eto K, Nakamura A, Noda M, Tobe K, Aburatani
H, Nagai R, Kadowaki T. Requirement of
glucokinase and Irs2 for compensatory beta-cell
hyperplasia in response to high-fat-diet-induced
insulin resistance. J Clin Invest 117: 246-257,
2007
29. Yamauchi T, Nio Y, Maki T, Kobayashi M,
Takazawa T, Iwabu M, Okada-Iwabu M,
Kawamoto S, Kubota N, Kubota T, Ito Y, Kamon
J, Tsuchida A, Kumagai K, Kozono H, Hada Y,
Ogata H, Tokuyama K, Tsunoda M, Ide T,
Murakami K, Awazawa M, Takamoto I, Froguel P,
Hara K, Tobe K, Nagai R, Ueki K, Kadowaki T.
Targeted disruption of AdipoR1 and AdipoR2
causes abrogation of adiponectin binding andmetabolic actions. Nat Med 13: 332-339, 2007
30. Zhou Y, Cras-Meneur C, Ohsugi M, Stormo GD,
Permutt MA. A global approach to identify
differentially expressed genes in cDNA
(two-color)microarrayexperiments.
Bioinformatics. 23:2073-2079, 2007

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Department of
Hematology and Oncology
Professor
Mineo Kurokawa, M.D., Ph.D.

Lecturer
Yoichi Imai, M.D., Ph.D.

Tsuyoshi Takahashi, M.D., Ph.D.

Special Lecturer (Hospital)
Akira Hangaishi, M.D., Ph.D.

Associate
Takashi Asai, M.D., Ph.D.,

Takuro Watanabe, M.D., Ph.D.,

Motoshi Ichikawa, M.D., Ph.D.,

Go Yamamoto, M.D., Ph.D.,

Yasuhito Nannya, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/hematology/

Introduction and Organization
Department of Hematology and Oncology is
responsible for clinical activities in out-patient as wellas in-patient clinics of hematological disorders,
conducting research activities for hematology andoncology, and are also in charge of teaching activities
for undergraduate medical students and graduate
students. These activities are performed by the unitedefforts of all members who belong to the department.
As of June in 2008, the staff of Department of
Hematology and Oncology consists of thirty members
including one professor, 2 lecturers, one special
lecturer (hospital), and 4 associates.

Clinical activities
On average, 60 patients with hematological diseases
are treated in the ward. Clinical facilities include
patient rooms with high-efficiency particulate air
filtration and filtrated water supply. Patients who are
eligible for the treatment with high-grade infection
prophylaxis are admitted to the facilities. Patient careis provided by team management and three doctors
composed of each one of junior residents, seniorresidents, and associates are assigned to one patient.
Since clinical issues especially for patients withhematological tumors are highly related to thehamatopoietic stem cell transplantation, all clinicalconferences are shared with staff members of the three
departments, Hematology and Oncology, Cell Therapy
and Transplantation, and Pediatrics. A number ofclinical problems involved in the patient management
are discussed in the morning clinical conference held
every other day. Diagnostic and therapeutic issues aswell as pathological aspects are also discussed weekly
in the clinical conferences, each focusing on
hematological diseases, lymphomas, or hematopoietic
stem cell transplantation. All these conferences arealso attended by the staff member of Department of
Cell Therapy and Transplantation because of clinicalsignificance of hamatopoietic stem cell transplantationin the treatment of hematological disorders.
Approximately 130 patients with acute leukemia,
240 with malignant lymphoma, 10 with chronic
leukemia, 30 with multiple myeloma, 40 with

140

myelodysplastic syndrome are annually admitted to
our ward. Out-patient clinical services are provided
daily in the morning and afternoon using three booths.
Approximately 1100 patients are monthly consulted
by our out-patient clinic. One of our final goals in theclinical activities is to cure all patients withhematological malignancies.
Here are some technical aspects on the treatment
strategy:
1. High-dose chemotherapy with or without
autologous stem cell support: High-dose
chemotherapy is administered according to themalignant disease. For the autologous stem cell
support, peripheral blood stem cell is usually
selected as a source of stem cells. Similar
procedures like leukapheresis and preservation areused in the allogeneic stem cell harvest.
2. Allogeneic
hematopoietic
stem
cell
transplantation: Bone marrow cells are operatively
harvested and infused without preservation. For
peripheral blood stem cell transplantation,
leukapheresis is performed with the use of an
automated continuous flow blood cell separator,and harvested cells are preserved in cooperation
with Department of Transfusion Medicine.
Recently, transplantation after pre-conditioning of
reduced intensity (RIST for reduced-intensity stem
cell transplantation) is commonly performed forthe elderly patients and patients with organ
damages. The development of this strategy is
expanding the eligibility of transplant recipients.
Cord blood cells are also used as the sources ofhematopoietic stem cells.

Teaching activities
A lecture course on etiology, pathogenesis, clinicaland laboratory features, differential diagnosis, therapy
and prognosis for all hematological diseases isprovided for the second grade medical students. The
course contents include:
1. Mechanisms of hematopoiesis, transplantation
medicine and cell therapy
2. Acute leukemia and myeloproliferative disorders
3. Bone marrow failure syndrome (aplastic anemia
and myelodysplastic syndrome)
4. Lymphoma and myeloma

5. Hemostasis and thrombosis
6. Hemolytic anemia and anemia of various causes
Courses for bedside learning on diagnostic andtherapeutic issues and arts are given for the third grade
medical students on a man-to-man basis with a seniorfaculty member that are erudite both in generalinternal medicine and in hematology and oncology.
During the one-week case-oriented course, students
learn the basic techniques of medical interview andphysical examination, interpretation of laboratory tests,
and practical medical procedures.

Research activities
The major research projects are focused onmolecular mechanisms of hematopoietic tumors,
hematopoietic
transcription
factors,
signaltransduction mechanisms in hematopoietic cells,
chromosomal
andgenomic
approaches
toleukemogenesis, generation of murine models forleukemias, proliferation and differentiation ofhematopoietic stem cells, and development of
immunotherapy for hematopoietic tumors. Everyeffort has been made to achieve the highest quality inboth clinical and basic medical research. The ultimate
aims of our research are the application of
epoch-making discoveries in research fields to theclinical hematology and oncology. Representative
publications from our departments published in thepast year are listed in the reference.

References
1. Shinohara A, Asai T, Izutsu K, Ota Y, Takeuchi K,
Hangaishi A, Kanda Y, Chiba S, Motokura T, andKurokawa M. Durable remission after theadministration of rituximab for EBV-negative
diffuse large B-cell lymphoma arising after
autologous
peripheral
blood
stem
cell
transplantation for angioimmunoblastic T-cell
lymphoma.
Leukemia and Lymphoma 48:
418-420, 2007.
2. Nitta E, Izutsu K, Sato T, Ohta Y, Takeuchi K,
Kamijo A, Oshima K, Kanda Y, Chiba S,
Motokura T, and Kurokawa M. A high incidenceof late-onset neutropenia following rituximabcontaining chemotherapy as a primary treatment

141

3.

4.

5.

6.

7.

8.

9.

for CD20-positive B-cell lymphoma: a single
institution study.
Annals of Oncology 18:364-349, 2007.
Kako S, Kanda Y, Sato T, Goyama S, Noda N,
Shoda E, Ohsiman K, Inoue M, Izutsu K,
Watanabe T, Motokura T, Chiba S, Fukuyama M,
and Kurokawa M. Early relapse of JAK2
V617F-positive chronic neutrophilic leukemiawith central nervous system infiltration after
unrelatedbonemarrowtransplantation.
American Journal of Hematology 82: 386-390,
2007.
Izumi R, Fujimoto M, Yazawa N, Nakashima H,
Asashima N, Watanabe R, Kurokawa M,
Hashimoto T, and Tamaki K. Bullous pemphigoid
positive for anti-BP180 and anti-laminin 5
antibodies in a patient with graft-vs-host disease.
Journal of the American Academy of Dermatology
56: 94-97, 2007.
Matsumoto A, Haraguchi K, Takahashi T, Azuma
T, Kanda Y, Tomita K, Kurokawa M, Ogawa S,
Takahashi K, Chiba S, and Kitamura T.
Immunotherapy against metastatic renal cell
carcinomawithmaturedendritic
cells.
International Journal of Urology 14: 277-283,
2007.
Sanada M, Uike N, Ohyashiki K, Ozawa K, Lili W,
Hangaishi A, Kanda Y, Chiba S, Kurokawa M,
Omine M, Mitani K, and Ogawa S. Unbalanced
translocation der(1;7)(q10;p10) defines a uniqueclinicopathologicalsubgroupofmyeloid
neoplasms. Leukemia 21: 992-997, 2007.
Kako S, Izutsu K, Arai T, Yokoyama Y, Oshima K,
Sato H, Asai T, Watanabe T, Hangaishi A, Kanda
Y, Motokura T, Chiba S, and Kurokawa M.
Regression of the tumor after withdrawal of
cyclosporine in relapsed extranodal naturalkiller/T cell lymphoma following allogeneic
hematopoietic
stem
cell
transplantation.
American Journal of Hematology 82: 937-939,
2007.
Kako S, Izutsu K, Arai T, Yokoyama Y, Oshima K,
Sato H, Asai T, Watanabe T, Hangaishi A, Kanda
Y, Motokura T, Chiba S, and Kurokawa M.
FDG-PET in T-cell and NK-cell neoplasms.
Annals of Oncology 18: 1685-1690, 2007.
Oshima K, Kanda Y, Asano-Mori Y, Nishimoto N,

Arai S, Nagai S, Sato H, Watanabe T, Hosoya N,
Izutsu K, Asai T, Hangaishi A, Motokura T, Chiba
S, and Kurokawa M. Presumptive treatment
strategyforaspergillosis
inallogeneic
hematopoietic stem cell transplant recipients. The
Journal of Antimicrobial Chemotherapy 60:
350-355, 2007.
10. Ishikawa T, Tohyama K, Nakao S, Yoshida Y,
Teramura M, Motoji T, Takatoku M, Kurokawa M,
Mitani K, Uchiyama T, and Omine M. A
prospective study of cyclosporine A treatment ofpatients with low-risk myelodysplastic syndrome:presence of CD55-CD59- blood cells predicts
platelet response.
International Journal of
Hematology 86: 150-157, 2007.
11. Yamamoto G, Nannya Y, Kato M, Sanada M,
Kawamata N, Hangaishi A, Kurokawa M, Chiba S,
Gilliland G, Koeffler HP, and Ogawa S. Highly
sensitive method for genome-wide detection ofallelic composition in non-paired, primary tumor
specimens using SNP genotyping microarrays.
American Journal of Human Genetics 81: 114-126,
2007.
12. Arai S, Asai T, Uozaki H, Hangaishi A, Kanda Y,
Motokura T, Chiba S, and Kurokawa M. Splenicpeliosis occurred in a patient with aplastic anemia
during danazol therapy. International Journal of
Hematology 86: 329-332, 2007.
13. Nagai S, Ichikawa M, Takahashi T, Sato H,
Yokota H, Morikawa M, Oshima K, Hangaishi A,
Kanda Y, Motokura T, Chiba S, Yatomi Y, andKurokawa M. The origin of neoplastic mast cells
in systemic mastocytosis with AML1/ETO
positive acute myeloid leukemia. Experimental
Hematology 35: 1747-1752, 2007.
14. Saito A, Chiba S, Ogawa S, Kanda Y, Hirai H, andKurokawa M. Long-term sustained mixed
chimerism
after
allogeneic
stem
cell
transplantation in a patient with severe aplastic
anemia. Internal Medicine 46: 1923-1926, 2007.
15. Kawazu M, Yamamoto G, Yoshimi M, Yamamoto
K, Asai T, Ichikawa M, Seo S, Nakagawa M,
Chiba S, Kurokawa M, and Ogawa S. Expression
profiling of immature thymocytes revealed anovel
homeoboxgene
that
regulates
double-negative thymocyte development. The
Journal of Immunology 179: 5335-5345, 2007.

142

Department of Allergy andRheumatology
Professor
Kazuhiko Yamamoto, M.D. ( Rheumatology, Allergology )Lecturer
Fujio Takeuchi, M.D. (Rheumatology)
Yoshikata Misaki, M.D. (Rheumatology)
Makoto Dohi, M.D. (Allergology )Zen-ichiro Honda, M.D. (Rheumatology)

Research Associate
Tetsuji Sawada, M.D. (Rheumatology)
Masao Yamaguchi, M.D. (Allergology )Ryoichi Tanaka, M.D. (Allergology )Hiroko Kanda, M.D. (Rheumatology)
Kimito Kawahata, M.D. (Rheumatology)
Keishi Fujio, M.D. (Rheumatology)

Project Research Associate
Noboru Hagino, M.D. (Rheumatology)
Kanae Kubo, M.D. (Rheumatology)

The Department of Allergy and Rheumatology
presently consists of 10 staff mentioned above, who
preside over 6 medical staff, 15 graduate students for"Doctor of Medical Science" and 3 staff studying
abroad. The outpatient facilities are situated on the
2nd floor of the Outpatient Clinic. The inpatient
facility is mainly located on the 13th floor of the
Hospital Ward A. The physician's office is situated in
the East Hospital Ward and the research rooms arelocated in the East Hospital Ward, the Central Wardand the Internal Medicine Research Ward.

EducationIn

regardtoundergraduate

education,

theDepartment is in charge of internal medicine
diagnosis and systemic lectures for M2 students andclinical lectures and bedside education for M3 and M4
students in cooperation with other departments ofinternal medicine. The systemic lectures and clinicallectures covers clinical immunology, connective tissue
diseases and allergy. Bedside education provides
students with a good opportunity to learn about
patients as well as practical knowledge throughnumerous seminars.
For postgraduate education, internal medicine
trainees are accepted on rotation basis and trained asinternist. Our department accepts students for "Doctorof Medical Science". Our 4-year education covers
clinicalimmunology,
molecular
immunology,

143

rheumatology and allergology.

Medical Care
General and special outpatient clinics are opened from
Monday to Friday. Special outpatients clinics include
clinics for rheumatoid arthritis, connective tissue
diseases, bronchial asthma, allergy, and kidney
disorders. For inpatients, there are presently 25 to 30
beds. Every week on Monday afternoon the charts arerounded and on Tuesday afternoon the professor
makes his rounds. To achieve the highest quality of
medical care, clinical conferences are held. Majorityof patients in the ward are suffered from connective
tissue diseases and usually exhibit multiple organ
involvements. Therefore, a careful, well-rounded
approach to each patient as a whole is required rather
than a limited special approach to a single organsystem.

Research
The Department has 10 research laboratories in whichclinical and basic studies are carried out concerning
mainly rheumatology and allergology. Recently themainstream of research has employed various
techniques of molecular biology and cellularimmunology. The principal research topics are listed
below.
1) Analysis of regulatory T cells.
2) Analysis of the mechanisms of tolerance
breakdown to systemic autoantigens usingtransgenic mice.
3) Analysis of antigen specific T cell clonalities in
immunological disorders.
4) Genetic analysis of rheumatoid arthritis and otherconnective tissue diseases.
5) Development of new gene therapies for
immunological diseases.
6) Analysis of the mechanisms of oral tolerance.
7) Analysis of signal transduction mechanisms in
immunological disorders.
8) Development and analysis of animal models of
bronchial asthma.
9) Study of signal transduction of IgE mediated mastcell activation.
10) Regulation of IgE antibody production.

11) Analysis of cytokines and chemokines in thepathogenesis of allergic conditions.
12) Analysis of interstitial pneumonitis associatedwith connective tissue diseases,13) Mechanism of drug allergy

References
2007(1) Yamamoto K, Okamoto A, Fujio K. Antigenspecific immunotherapy for autoimmune diseases.
Expert Opin Biol Ther. 7:359-367, 2007.
(2) Suzukawa M, Komiya A, Yoshimura-Uchiyama C,
Kawakami A, Koketsu R, Nagase H, Iikura M,
Yamada H, Ra C, Ohta K, Yamamoto K,
Yamaguchi M. IgE- and FceRI-mediatedenhancement of surface CD69 expression inbasophils: role of low-level stimulation. Int Arch
Allergy Immunol. 143:56-59, 2007.
(3) Tanaka Y, Yamamoto K, Takeuchi T, Nishimoto N,
Miyasaka N, Sumida T, Shima Y, Takada K,
Matsumoto I, Saito K, Koike T. A multicenter
phase I/II trial of rituximab for refractory
systemic lupus erythematosus. Mod Rheumatol.
17:191-197, 2007.
(4) Suzuki A, Yamada R, Yamamoto K. Citrullination
by peptidylarginine deiminase in rheumatoid
arthritis. Ann NY Acad Sci. 1108:323-339, 2007.
(5) Takizawa Y, Kanda H, Sato K, Kawahata K,
Yamaguchi A, Uozaki H, Shimizu J, Tsuji S,
Misaki Yoshikata, Yamamoto K. Polymyositis
associated with focal mesangial proliferative
glomerulonephritis with depositions of immune
complexes. Clin Rheumatol. 26: 792-796, 2007.
260. Suzuki A, Yamada R, Yamamoto K.
Citrullination by peptidylarginine deiminase inrheumatoid arthritis. Ann NY Acad Sci.
1108:323-339, 2007.
(6) Tanaka Y, Yamamoto K, Takeuchi T, Nishimoto N,
Miyasaka N, Sumida T, Shima Y, Takada K,
Matsumoto I, Saito K, Koike T. A multicenter
phase I/II trial of rituximab for refractory
systemic lupus erythematosus. Mod Rheumatol.
17:191-197, 2007.
(7) Yamamoto K, Okamoto A, Fujio K. Antigenspecific immunotherapy for autoimmune diseases.
Expert Opin Biol Ther. 7:359-367, 2007.

144(8) Okunishi K, Dohi M, Fujio K, Nakagome K,
Tabata Y, Okasora T, Seki M, Shibuya M,
Imamura M, Harada H, Tanaka R, Yamamoto K.
Hepatocyte growth factor significantly suppresses
collagen-induced arthritis in mice.J Immunol.
179:5504-5513, 2007.
(9) Fujio K, Okamura T, Okamoto A, Yamamoto K. T
cell receptor gene therapy for autoimmune
diseases. Ann N Y Acad Sci. 10:222-232, 2007.
(10) Yamamoto K, Yamada R. Lessons from a
Genomewide Association Study of Rheumatoid
Arthritis. N.Engl.J.Med. 357:1250-1251, 2007.
(11) Fujio K, Okamura T, Okamoto A, Yamamoto K. T
cell receptor and anti-inflammatory gene
modulated T cells as therapy for auto immune
diseases. Expert Rev Clin Immunol. 2007 in press(12) Shoda H, Fujio K, Yamamoto K. Rheumatoid
Arthritis and Interleukin-32. Cell Mol Life Sci.
30:398-403, 2007.
(13) Yamaguchi Y, Fujio K, Shoda H, Okamoto A,
Tsuno NH, Takahashi K, Yamamoto K.
Interleukin-17B
andinterleukin-17C
areassociated with TNF-alpha production andcontribute to the exacerbation of inflammatory
arthritis.J Immunol. 179:7128-36, 2007.

145

Department of Infectious
Diseases (Internal Medicine)
Professor
Kazuhiko Koike, M.D., Ph.D.

Associate Professor
Hiroshi Yotsuyanagi, M.D., Ph.D.

Research Associate
Satoshi Itoyama, M.D., Ph.D.

Homepage

http://infect.umin.jp/

Introduction and Organization
The Department of Infectious Diseases has been
one of the leading academic organizations specialized
for internal medicine, in particular, infectious disease
medicine in Japan since 1998, when the Departmentsof Internal Medicine, established in 1890, wererearranged into new ones according to subspecialty ofinternal medicine. Our department has been chiefly
engaged in clinical, educational and research activities
for infectious diseases including bacterial, fungal andviral infections of all organs including HIV infection,
tuberculosis and viral hepatitis. Our department islocated on 11th floor of the University of Tokyo
Hospital Building, and has well-furnished researchlaboratories including P-2 class laboratory, adepartmental library and a computer room as own
properties. In clinical and research activities, we arecollaborating with the Department of Infection
Control and Prevention. A professor, an associate
professor, 6 guest lecturers, an associate, 8 graduate
students and 15 full-time staff member are all
performing their own duties in clinical, educationaland research activities.

Clinical activities
We have hospital beds on the 11th floor of the Ward

A of University of Tokyo Hospital. Diseases include
HIV infection, viral hepatitis, pneumonia, resistantbacteria infections such as MRSA, BLNAR or VRE,
tuberculosis, EBV infection, CMV infection, parasite
infection, etc. Every effort is made to give patients thebest care and best quality of life. Clinical associates,
full-time staff and residents take care of inpatients.
The case presentation by residents is held on a weekly
basis. Weekly clinical conference is held for
discussing about all cases, in particular, those withproblems difficult to be solved. Consultations are veryfrequent from other departments on the managementof infectious diseases. The general diagnostic,
therapeutic plans and decisions for each patient are
given at the Professor’s round.
Our department offers out-patient care everyday on
infectious diseases and general medicine. We are also
engaged in infection control and prevention of
emerging infectious diseases such SARS or avian
influenza virus, which appeared recently.

Teaching activities
Our department takes a part in clinical lectures andbed-side teaching of the internal medicine forundergraduate medical students according to theeducational programs of the University of Tokyo. For
the fourth year medical students, six lectures of146

infectious diseases are given. In addition, principles of
medical diagnosis are taught at the bedside. During
the bed-side teaching for fifth and sixth year students,
our associates teach them on man-to man basis thebasic way of thinking for correct diagnosis andtherapy, the techniques of interrogation and physicalexamination, the way for interpretations of laboratory
tests and other medical examinations, and the basic
medical procedures on each case. The education ofjunior residents is performed as described in “Clinical
Activities”.

Research activities
Both clinical and basic researches are necessary to
improve the diagnosis and treatment. The members ofour department are doing best to obtain new findings
using highly sophisticated methodologies. A monthly
intramural research conference is held, in which twoto three members present their annual research
progresses to be discussed by all the department staff.
In addition, each laboratory holds its own conference
and/or journal club on a weekly or bi-weekly basis.
The research field covers wide areas of infectious
diseases including HIV infection, viral hepatitis andhepatocarcinogenesis, CMV infection and tuberculosis(Mycobacterium infection). Also, various emerging
and re-emerging infectious diseases are covered.
Following themes are currently being investigated in
the department.
(1) Establishment of effective therapy for HIV
infection: we have made a great contribution in
the establishment of the guideline for treatment of
HIV infection in Japan.
(2) Elucidationofthemechanismofhepatocarcinogenesis in hepatitis viral infection:
the direct involvement of both HBV and HCV in
hepatocarcinogenesis has been demonstratedusing our transgenic mouse systems.
(3) Establishment of effective therapy for HCV and
HBV infection: we have made a great
contribution in the establishment of the guideline
for treatment of hepatitis viral infection in Japan.
(4) Establishment of effective therapy for HCV/HIV
co-infection: we have made a great contribution
in the establishment of the guideline for treatmentof HCV/HIV co-infection in Japan.

(5) Establishment of the criteria for prediction andearly diagnosis of CMV infection associated with
HIV infection.
(6) Innovation of new methods to control viral
hepatitis or prevent the development of
hepatocellular carcinoma in chronic viral
hepatitis.
(7) Establishment of the effective infection control
method of MRSA and other MDRO infection.
(8) Elucidating
the mechanism andsignaltransduction of bacterial infection throughtoll-like receptors.
(9) Analysis of intracellular function and signaling of
the proto-oncogene Cbl.
(10) Establishment of new methods for practical
diagnosis and treatment of respiratory infection.

Members
Kazuhiko Koike, Hiroshi Yotsuyanagi, Yasuo Ota,
Yoshizumi Shintani, Takeya Tsutsumi, Satoshi
Itoyama, Takatoshi Kitazawa, Kuniko Ueda, Shuji
Hatakeyama, Shu Okugawa, Miki Kawada, Shintaro
Yanagimoto, Yohko Nukui, Katsutoshi Abe, Atsuhito
Fukishima, Keita Tatsuno, Sohei Harada, Koji Goto,
Mahoko Kamimura, Yusuke Yoshino, Takahiro Aoki,
Kohji Gotoh, Koh Okamoto.

References
1) Koike K, Tsukada K, Yotsuyanagi H, Moriya K,
Kikuchi Y, Oka S, Kimura S. Prevalence of
Coinfection with Human Immunodeficiency Virusand Hepatitis C Virus in Japan. Hepatol Res 2007;
37:2-5.
2) Bi X, Gatanaga H, Koike K, Kimura S, Oka S.
Reversal periods and patterns from drug resistant
to wild-type HIV-1 after cessation of anti-HIV
therapy. AIDS Res Hum Retro 2007;23:43-50.
3) Miyamoto H, Moriishi K, Moriya K, Murata S,
Tanaka K, Suzuki T, Miyamura T, Koike K,
Matsuura Y. Hepatitis C Virus Core Protein
InducesInsulinResistancethrougha
PA28γ-Dependent
Pathway.
J
Virol
2007;81:1727-1735.
4) Moriishi K, Mochizuki R, Moriya K, Miyamoto H,
Mori Y, Abe T, Murata S, Tanaka K, Suzuki T,
Miyamura T, Koike K, Matsuura Y. Critical role of

147

PA28γ
in
hepatitisCvirus-associatedsteatogenesis and hepatocarcinogenesis. Proc Natl
Acad Sci USA 2007;104:1661-1666.
5) Ishizaka N, Saito K, Furuta K, Matsuzaki G,
Koike K, Noiri E, Nagai R. Angiotensin
II-induced regulation of the expression andlocalization of iron metabolism-related genes in
the rat kidney. Hypertens Res 2007;30:195-202.
6) Suzuki Y, Yotsuyanagi H, Okuse C, Nagase Y,
Takahashi H, Moriya K, Suzuki M, Koike K, Iino
S, Itoh F. Fatal liver failure caused by reactivationof lamivudine-resistant hepatitis B virus: A casereport. World J Gastroenterol 2007;13:964-969.
7) Hatakeyama S, Sugaya N, Ito M, Yamazaki M,
Ichikawa M, Kimura K, Kiso M, Shimizu H,
Kawakami C, Koike K, Mitamura K, Kawaoka Y.
Emergence of Influenza B Viruses With Reduced
Sensitivity to Neuraminidase Inhibitors. JAMA
2007;297:1435-1442.
8) Saito R, Kumita W, Sato K, Chida T, Okamura N,
MoriyaK,
Koike
K.
Detectionofplasmid-mediated quinolone resistance associatedwith qnrA in an Escherichia coli clinical isolate
producing CTX-M-9 beta-lactamase in Japan. Int
J Antimicrob Agents 2007;29:600-602.
9) Ishizaka N, Ishizaka Y, Toda EI, Nagai R, Koike
K, Hashimoto H, Yamakado M. Relationshipbetween smoking, white blood cell count andmetabolic syndrome in Japanese women. Diabetes
Res Clin Pract 2007;78:72-76.
10) Kitazawa T, Nakayama K, Okugawa S, Koike K,
Shibasaki Y, Ota Y. Biphasic regulation oflevofloxacin
onlipopolysaccharide-induced
IL-1beta production. Life Sci 2007;80:1572-1577.
11) Okugawa S, Ota Y, Tatsuno K, Tsukada K,
Kishino S, Koike K. A case of invasive central
nervous system aspergillosis treated withmicafungin with monitoring of micafunginconcentrations in the cerebrospinal fluid. Scand J
Infect Dis 2007;39:344-346.
12) Yotsuyanagi H, Koike K. Mechanisms underlying
drug resistance in antiviral treatment for
infections with hepatitis B and C viruses. J
Gastroenterol 2007;42:329-335.
13) Saito R, Sato K, Kumita W, Inami N, Nishiyama
H, Okamura N, Moriya K, Koike K. Detection ofplasmid-mediated quinolone resistance associatedwith qnrA in Escherichia coli clinical isolate
producing CTX-M-9 beta-lactamase in Japan. Int
J Antimicrob Agents 2007;29:600-602.
14) Tsukada K, Kitazawa T, Fukushima A, Okugawa S,
Yanagimoto S, Tatsuno K, Koike K, Nagase H,
Hirai K, Ota Y. Macrophage tolerance induced bystimulation with Toll-like receptor 7/8 ligands.
Immunol Lett 2007;111:51-56.
15) Misawa Y, Yoshida A, Saito R, Yoshida H,
Okuzumi K, Ito N, Okada M, Moriya K, Koike K.
Applicationofloop-mediatedisothermal
amplification technique to rapid and direct
detection of methicillin-resistant Staphylococcus
aureus (MRSA) in blood cultures. J InfectChemother 2007;13:134-140.
16) Suzuki S, Kitazawa T, Ota Y, Okugawa S, Tsukada
K, Nukui Y, Hatakeyama S, Yamaguchi D,
Matsuse S, Ishii T, Matsubara T, Yamauchi C, Ota
S, Yahagi N, Fukayama M, Koike K. Dengue
Hemorrhagic
Shock
and
DisseminatedCandidiasis. Intern Med 2007;46:1043-1046.
17) Koike K. Hepatitis C virus contributes tohepatocarcinogenesis by modulating metabolic
andintracellularsignaling
pathways.
J
Gastroenterol Hepatol 2007;22:S108-111.
18) Koike K. Pathogenesis of HCV-associated HCC:
dual-pass carcinogenesis through the activation ofoxidative stress and intracellular signaling.
Hepatol Res 2007;37:S38-S43.
19) Aono J, Yotsuyanagi H, Miyoshi H, Tsutsumi T,
Fujie H, Shintani Y, Moriya K, Okuse C, Suzuki
M, Yasuda K, Iino S, Koike K. Amino acidsubstitutions in S region of hepatitis B virus in thesera from patients with acute hepatitis. Hepatol
Res 2007;37:731-739.
20) Ichibangase T, Moriya K, Koike K, Imai K. A
novel proteomics method revealed disease-related
proteins in the liver of hepatitis C mouse model. J
Proteome Res 2007;6:2841-2849. (6.9)21) Ota Y, Tatsuno K, Okugawa S, Yanagimoto S,
Kitazawa T, Fukushima A, Tsukada K, Koike K.
Relationship between the initial dose of
micafungin ansd its efficacy in patients withcandidemia. J Infect Chemother 2007;13:208-212.
22) Kitazawa T, Fukushima A, Okugawa S,
Yanagimoto S, Tsukada K, Tatsuno K, Koike K,
Kimura S, Kishimoto T, Shibasaki Y, Ota Y.

148

Chlamydophilal antigens induce foam cell
formation via c-Jun NH2-terminal kinase.
Microbes Infect 2007;9:1410-1414.
23) Ishizaka N, Ishizaka Y, Toda E, Koike K, Seki G,
Nagai R, Yamakado M. Association between
obesity and chronic kidney disease in Japanese:differences in gender and hypertensive status?
Hypertens Res 2007;30:1059-1064.
24) Ishizaka N, Ishizaka Y, Toda E, Koike K, Seki G,
Nagai R, Yamakado M. Association between
chronic kidney disease and carotid intima-media
thickening in individuals with hypertension andimpaired glucose metabolism. Hypertens Res
2007;30:1035-1041.
25) Okuse C, Yotsuyanagi H, Koike K. Hepatitis C asa Systemic Disease: Virus and Host Immunologic
Responses Underlie Hepatic and Extrahepatic
Manifestations. J Gastroenterol 2007;42:857865.
26) Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Moriya K, Koike K, Makuuchi M.
Impactofnewmethicillin-resistant
Staphylococcus aureus carriage postoperatively
after living donor liver transplantation. Transplant
Proc 2007;39:3271-3275.
27) Saito R, Okugawa S, Kumita W, Sato K, Okamura
N, Moriya K, Koike K. Clinical epidemiology of
ciprofloxacin-resistant Proteus mirabilis isolated
from urine samples in hospitalized patients. Clin
Microbiol Infect 2007;13:1204-1206.
28) Tanaka N, Moriya K, Kiyosawa K, Koike K,
Aoyama T. Hepatitis C virus core protein induces
spontaneous and persistent activation ofperoxisome proliferator-activated receptor alphaintransgenic
mice:
Implicationsfor
HCV-associated hepatocarcinogenesis. Int J
Cancer 2008;122:124-31.
29) Koike K, Kikuchi Y, Kato M, Takamatsu J,
Shintani Y, Tsutsumi T, Fujie H, Miyoshi H,
Moriya K, Yotsuyanagi H. Prevalence of Hepatitis
B Virus Infection in Patients with Human
Immunodeficiency Virus in Japan. Hep Res
2008;38:310-314.
30) Tanaka N, Moriya K, Kiyosawa K, Koike K,
Gonzalez FJ, Aoyama T. PPAR-a is essential forsevere hepatic steatosis and hepatocellular
carcinoma induced by HCV core protein. J Clin

Invest 2008;118:683-694.
31) Ishizaka N, Ishizaka Y, Toda EI, Koike K,
Yamakado
M,
Nagai
R.
Are
Serum
Carcinoembryonic Antigen Levels AssociatedWith Carotid Atherosclerosis in Japanese Men?
Arterioscler Thromb Vasc Biol 2008;28:160-165.
32) Nagase Y, Yotsuyanagi H, Okuse C, Yasuda K,
Kato T, Koike K, Suzuki M, Nishioka K, Iino S,
Itoh F. Effect of treatment with interferonalpha-2b and ribavirin in patients infected withgenotype 2 hepatitis C virus. Hepatol Res 2008;
38:252-258.
33) Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Moriya K, Koike K, Makuuchi M.
Methicillin-resistant
Staphylococcus
aureusinfection after living-donor liver transplantation in
adults. Transpl Infect Dis 2008;10:110-116.
34) Koike K, Tsutsumi T, Miyoshi H, Shinzawa S,
Shintani Y, Fujie H, Yotsuyanagi H, Moriya K.
Molecular Basis for the Synergy between Alcoholand Hepatitis C Virus in Hepatocarcinogenesis. J
Gastroenterol Hepatol 2008;23:S87-91.
35) Newell P, Villanueva A, Friedman SL, Koike K,
Llovet JM. Experimental models of hepatocellular
carcinoma. J Hepatol 2008;48:858-879.
36) Ishizaka N, Ishizaka Y, Toda E, Shimomura H,
Koike K, Seki G, Nagai R, Yamakado M.
Association between cigarette smoking andchronic kidney disease in Japanese men.
Hypertens Res 2008;31:485-92.
37) Ishizaka Y, Ishizaka N, Tani M, Toda A, Toda EI,
Koike K, Yamakado M. Relationship between
Albuminuria,
Low
eGFR,
and
Carotid
Atherosclerosis in Japanese Women. Kidney
Blood Press Res 2008;31:164-170.
38) Ishizaka N, Ishizaka Y, Seki G, Nagai R,
Yamakado M, Koike K. Association between
hepatitis B/C viral infection, chronic kidneydisease and insulin resistance in individuals
undergoing general health screening. Hepatol Res
2008 in press.
39) Matsuzaki G, Ishizaka N, Furuta K, Hongo M,
Saito K, Sakurai R, Koike K, Nagai
R. Comparison of vasculoprotective effects ofbenidipine and losartan in a rat model ofmetabolicsyndrome.
Eur
J
Pharmacol
2008;587:237-42.
40) Koike K. Steatosis, Liver Injury andHepatocarcinogenesis in Hepatitis C Viral
Infection. J Gastroenterol 2008 in press.

149

Department of Stress Science andPsychosomatic Medicine
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Hiroaki Kumano, M.D., Ph.D.

Associate
Kazuhiro Yoshiuchi, M.D., Ph.D.,

Homepage

Yoshiyuki Takimoto, M.D., Ph.D.

http://psmut.umin.ac.jp/

Introduction and Organization
The Department of Stress Science andPsychosomatic Medicine is one of 11 divisions of the
Department of Internal Medicine, the University ofTokyo. It covers eating disorder, panic disorder, andvarious psychosomatic diseases such as chronicheadache, irritable bowel syndrome, functional
dyspepsia, hypertension, diabetes mellitus, andhyperthyroidism. Our teaching staff consists of one
professor, one associate professor, two associates, and5 adjunct professors, and other members are 2 seniorresidents, 7 graduate students, and 7 researchers.

Clinical activities
Our department is responsible for both outpatient
clinic and inpatient ward. The ward is managed as apart of the Division of General Internal Medicine, andsenior residents, an associate, and the associate
professor attend it every day and provide closeside-by-side instruction to junior residents. The
weekly professor’s round is scheduled on Thursday
morning. During 2006 April to 2007 March, 69
patients were admitted to the ward, many of whomwere eating disorder patients. Outpatient clinic is
attended on every morning and afternoon in three
consultation rooms by approximately fifteen

physicians. During 2006 April to 2007 March, thenumbers of the new outpatients and of the overall
outpatients in our department were 320 and 5369,
respectively.

Teaching activities
We are giving 6 methodical lectures on
psychosomatic medicine for fourth grade medical
students, ‘problem-based learning’ lasting 12 weeks(net 24 hours) for 6 or 7 fourth grade students,‘bed-side learning’ for fifth grade students lasting two
weeks, ‘clinical clerkship’ for 3 to 4 fifth gradestudents lasting 4 weeks each, and a clinical lecture on
panic disorder for sixth grade students. We are trying
to teach them not only basic knowledge of specificdiseases, ways of physical examination, orinterpretation of laboratory data, but also relevantways of clinical interview, doctor-patient relationshipbuilding, and behavior modification.
As for education for junior residents, our seniorresidents and an associate provide man-to-man
instruction. In addition, they can learn how to present
the history of newly-admitted patients at the weekly
professor’s round from our teaching staff.

150

Research activities
Targeting stress-related diseases such as not only
those covered by our department but also otherlifestyle-related disease, and cancers, we areinvestigating
theirpathophysiology
andpsychopathology
throughassessingbio-psycho-behavioral time-series data, various
questionnaire data, and autonomic nervous function.
We are also actively conducting basic as well as
clinical research on eating-related substances.
Some representative research methods are as
follows:
1) Ecological momentary assessment (EMA):
Investigation on neurobehavioral basis ofstress-related diseases such as tension-type
headache, eating disorders, insomnia, and panic
disorder using portable computers for real-timeassessmentof
subjective
symptoms
incombination with ambulatory monitors such as
electrocardiogram and actigraphy.
2) Neuroendocrinological and neuroimmunologicalstudiesinanorexia
nervosapatients:
multidisciplinary
investigationonenergymetabolism during a refeeding phase; changes invarious substances such as neuropeptides before
and after treatment; relationship between bonemetabolism and various makers; and explorationof biomarkers for evaluating treatment efficacy.
Ten graduate students and 7 researchers actively
conducted their researches along with our teaching
staff. We have been also collaborating with many
scientists belonging to other departments either inJapan or abroad. Research conferences are held once amonth, where one of the graduate students presents
his/her research for open discussion by all themembers of our department.

References
1. Yoshiuchi K, Cook DB, Ohashi K, Yamamoto Y,
Kumano H, Kuboki T, Natelson BH. A real-timeassessment of the effect of exercise in chronic
fatigue syndrome. Physiol Behav 2007,
92:963-968
2. Kikuchi H, Yoshiuchi K, Ohashi K, Yamamoto Y,

Akabayashi A. Tension-type headache andphysical
activity:anactigraphic
study.
Cephalalgia 2007, 27:1236-1243
3. Nakamura T, Kiyono K, Yoshiuchi K, Nakahara R,
Struzik ZR, Yamamoto Y. Universal scaling law inhuman behavioral organization. Phys Rev Let
2007, 99: 138103-1-4
4. Viernes N, Zaidan ZA, Dorvlo ASS, Kayano M,
Yoshiuchi K, Kumano H, Kuboki T, Al-Adawi S.
Tendency toward deliberate food restriction, fearof fatness and somatic attribution in cross-cultural
samples. Eat Behav 2007, 8:407-417
5. Hojo S, Ishikawa S, Kumano H, Miyata M,
SakabeK.
Clinicalcharacteristicsofphysician-diagnosed patients with multiple
chemical sensitivity in Japan. Int J Hyg Environ
Health (in press)
6. Struzik ZR, Yoshiuchi K, Sone M, Ishikawa T,
Ki-kuchi H, Kumano H, Watsuji T, Natelson BH,
Ya-mamoto Y. “Mobile Nurse” platform for
ubiquitous medicine. Method Inform Med 2007,
46:130-134
7. Akabayashi A, Slingsby BT. Informed consent
re-visited: Japan and the U.S. Am J Bioeth. 2006,
6:9-14.
8. Kikuchi H, Yoshiuchi K, Miyasaka N, Ohashi K,
Yamamoto Y, Kumano H, Kuboki T, Akabayashi
A. Reliability of recalled self-report on headache
inten-sity:
investigationusing
ecologicalmomentary as-sessment technique. Cephalalgia.
2006, 26:1335-43.
9. Moriya J, Takimoto Y, Yoshiuchi K, Shimosawa T,
Akabayashi A. Plasma agouti-related protein
levels in women with anorexia nervosa.
Psychoneuroendo-crinology. 2006, 31: 1057-61.
10. Yoshida NM, Yoshiuchi K, Kumano H, Sasaki T,
Kuboki T. Changes in heart rate with refeeding inanorexia nervosa: a pilot study. J Psychosom Res.
2006, 61:571-5.
11. Sakai Y, Kumano H, Nishikawa M, Sakano Y,
Kaiya H, Imabayashi E, Ohnishi T, Matsuda H,
Yasuda A, Sato A, Diksic M, Kuboki T. Changes
in cerebral glucose utilization in patients withpanic disorder treated with cognitive-behavioral
therapy. Neuroi-mage. 2006, 15;33:218-26
12. Yoshiuchi K, Nakahara R, Kumano H, Kuboki T,
Togo F, Watanabe E, Yasunaga A, Park H,

151

Shephard RJ, Aoyagi Y: Yearlong physical activity
and de-pressive symptoms in older Japanese
adults: cross-sectional data from the Nakanojo
Study. Am J Geriatr Psychiatry. 2006, 14:621-4.
13. Yoshiuchi K, Farkas J, Natelson BH. Patients withchronic fatigue syndrome have reduced absolutecortical blood flow. Clin Physiol Funct Imag 2006,
26:83-86
14. Nakahara R, Yoshiuchi K, Kumano H, et al:
Pro-spective study on influence of psychosocial
factors on glycemic control in Japanese patientswith type 2 diabetes. Psychosomatics. 2006, 47:
240-6.
15. Takimoto Y, Yoshiuchi K, Kumano H, Kuboki T:
Bulimia nervosa andabnormal cardiac
repolarization. J Psychosom Res. 2006, 60:105-7.
16. Yoshida NM, Kumano H, Kuboki T: Does theAging Males' Symptoms scale assess major
depressive dis-order?: a pilot study. Maturitas.
2006, 53:171-5

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

153

Department of Transfusion
Medicine
Professor
Koki Takahashi, M.D., Ph.D.

Associate
Nelson H. Tsuno, M.D., Ph.D., Minoru Tanaka, M.D., Ph.D., Susumu Goyama, M.D, Ph.D.

Homepage

http://172.27.30.16/yuketsu/s-index.html

Introduction and Organization
The Transfusion Medicine service was established in1949, as an internal provisional measure, andofficially established in 1966. In 1984, Professor
Hiroshi Toyama assumed as the first Professor of thedepartment. Professor Toyama greatly contributed to
the field of transfusion medicine, especially by
publishing “Transfusion Medicine” (actually in its 3rd.
edition), which is the bible of transfusion medicine inJapan. Other great contributions from the department
are as follows. Dr. Kazuo Okochi, ex-lecturer of thedepartment, is the pioneer in the field oftransfusion-associated hepatitis research, ex-Professor
Takeo Juji clarified the mechanisms of transfusionassociated graft-versus-host disease (TA-GVHD), a
serious post-transfusional complication, and theprevious professor, Professor Yoichi Shibata
contributed enourmously to the field of platelet
immunology. In 1997, the Department of Transfusion
Medicine was established as a chair of the Division ofInternal Medicine of the Graduate School of Medical
Sciences, the University of Tokyo.
Actually, the department is composed of 6 medical
doctors (4 full-time, and 2 partial-time), 10 laboratory
technicians, 1 nurse and 1 office assistant.

Clinical activities
The main activity of the department of Transfusion
Medicine is the control, preservation, and provision ofsafe blood products and their derivatives. The control
of all blood products in the hospital is centralized tothe department, which, in addition, provides
information and orientation related to bloodtransfusion. Transfusion-related laboratory tests andtests for transfusion-transmitted infectious diseases
are routine practices of the department, which also
actively takes part in the diagnosis, prevention andtreatment of adverse reactions and post-transfusion
complications. Collection, preservation and provisionof autologous blood are also important functions of
the department, where the outpatient clinic forautologous blood was established in January 2006. At
the outpatient clinic, the first established in Japan, thetransfusionist gives consultation to the patients,
prepares the adequate blood collection schedule, takes
the informed consent, and performs the bloodcollection, according to the surgeons’ needs.
Additionally, immunotherapy of cancer patients andpatients with recurrent abortion, and collection andpreservation of peripheral blood stem cells are also
performed.
I. Control and preservation of blood products andits derivatives;
II. Laboratory tests
1) Blood typing and histocompatibility testing;2) Detection of anti-erythrocyte, anti-leukocyte andanti-platelet antibodies;3) Detection of HBV antigens and antibodies, HCV,
HAB, ATLA and HIV antibodies;
4) HLA typing for bone marrow and organ154

transplantation;
III. Clinical work
1) Pre-operative autologous blood collection andpreservation;2) Lymphocyte vaccination therapy for patients withspontaneous recurrent abortion;3) Collection and preservation of peripheral blood
stem cells for transplantation;4) Dendritic cell-based cancer immunotherapy.
5) Anti-angiogenic cancer therapy.

Teaching activities
Sixth-year medical students are provided withpractical courses focusing on clinical practice of bloodtransfusion and laboratory tests. Courses are given insmall groups of 6 students each, in a total of 18 groups
per year. The course lasts 3 days/week, including thefollowing subjects;
1) Visit to the laboratories of the department tounderstand the routine of a laboratory;
2) Introduction to the blood group types and theirimportance in transfusion medicine;3) Methodology of blood typing and compatibility
typing for transfusion;4) Methodology for screening of irregular antibodies,and their importance in transfusion practice;5) Introduction
tothepost-transfusional
complications, their etiology, prevention andtreatment.
6) The indications and techniques of autologous
blood collection and preservation;7) The techniques for peripheral blood stem cells(PBSCs) collection and preservation, as well as
their clinical application;8) The immunotherapy of cancer patients;
9) The recent advances in the field of bloodtransfusion, including the “New Blood Law”, andthe recently revised “Indications of blood
products” and “The principles of transfusion
practice”.
10) One-day visit to the Japanese Red Cross Blood
Center, to learn the general process of blood
donation and transfusion, including the types ofblood products, and their indications.

Research activities
Research on red cells, leukocytes, and platelets, thepost-tranfusional
complications,transplantation
immunology, immunotherapy, and stem cell biology
are the main themes of the department. Typing ofblood cells is performed by serological andDNA-based methods. The HLA typing, which wasintroduced by ex-Professor Takeo Juji, one of thepioneers of this field, is an essential test for stem celland organ transplantations, and still continues as oneof the most important research fields of thedepartment. The mixed-passive hemagglutination(MPHA) method, the most popular methodology forplatelet serology in Japan, was developed by Professor
Yoichi Shibata, the previous professor, and its
applicability is now extended for granulocyte as wellas endothelial cell serology. Transplantation
immunology, including stem cell biology, anddevelopment of immunotherapeutic strategies to treat
cancer patients and patients with recurrent abortion
are also being performed. Recently, development of
new materials for medical use is being researched.
Following are the main themes.
1. Detection of platelet alloantigens and antibodies
and their role in the transfusion practice.
2. Diagnosis and prevention of post-transfusional
complications and thrombocytopenic purpura of
the newborn.
3. Clinical application of refrigerated and frozenstored blood for autologous transfusion in surgicalpatients.
4. Study on the mechanisms of transfusionassociated GVHD and its prevention.
5. Development of a new methodology for plateletcross-match.
6. Detection and characterization of anti-endothelial
cell antibodies, and study on their role in thepathogenesis of inflammatory and autoimmune
diseases, as well as in organ transplantation.
7. HLA and HPA genotyping.
8. Development of a new methodology forevaluation of platelet function.
9. Development of new strategies for the treatmentof cancer patients, by targeting the tumor
vasculature.
10. Dendritic cell-based immunotherapy of cancer

155

patients.
11. Ex-vivo expansion of hematopoietic stem cells
and their clinical application.
12. Development of new materials for medical use.

References
1. Kanhai HH, Porcelijn L, Engelfriet CP, Reesink
HW, Panzer S, Ulm B, Goldman M, Bonacossa I,
Richard L, David M, Taaning E, Hedegaard M,
Kaplan C, Kiefel V, Meyer O, Salama A, Morelati
F, Greppi N, Marconi M, Tassis B, Tsuno NH,
Takahashi K, Oepkes D, Porcelijn L, Kanhai H,
Osnes
LT,
Husebekk
A,
KillieMK,
Kjeldsen-Kragh J, Zupanska B, Muñiz-Diaz E,
Nogués N, Parra J, Urbaniak SJ, Cameron
A.Management of alloimmune thrombocytopenia.
Vox Sang. 2007; 93(4):370-85.
2. Yamada J, Kawai K, Tsuno NH, Kitayama J,
Tsuchiya T, Yoneyama S, Asakage M, Okaji Y,
Takahashi K, Nagawa H. Plaunotol induces
apoptosis of gastric cancer cells. Planta Med.
2007;73(10):1068-73.
3. Aiba-Kojima E, Tsuno NH, Inoue K, Matsumoto
D, Shigeura T, Sato T, Suga H, Kato H, Nagase T,
Gonda K, Koshima I, Takahashi K, Yoshimura K.
Characterization of wound drainage fluids as asource of soluble factors associated with woundhealing: comparison with platelet-rich plasma andpotential use in cell culture. Wound Repair Regen.
2007;15(4):511-20.
4. Aoki S, Yatomi Y, Shimosawa T, Yamashita H,
Kitayama J, Tsuno NH, Takahashi K, Ozaki Y.
The suppressive effect of sphingosine 1-phosphateon monocyte-endothelium adhesion may be
mediated by the rearrangement of the endothelial
integrins alpha(5)beta(1) and alpha(v)beta(3). J
Thromb Haemost. 2007;5(6):1292-301.
5. Yoneyama S, Okaji Y, Tsuno NH, Kawai K,
Yamashita H, Tsuchiya T, Yamada J, Sunami E,
Osada T, Kitayama J, Takahashi K, Nagawa H. A
study of dendritic and endothelial cell interactions
in colon cancer in a cell line and small mammal
model. Eur J Surg Oncol. 2007.
6. Hasebe T, Yohena S, Kamijo A, Okazaki Y, Hotta
A, Takahashi K, Suzuki T.Fluorine doping into
diamond-like carbon coatings inhibits protein

adsorption and platelet activation.J Biomed Mater
Res A. 2007 15;83(4):1192-9.
7. Nitta E, Izutsu K, Sato T, Ota Y, Takeuchi K,
Kamijo A, Takahashi K, Oshima K, Kanda Y,
Chiba S, Motokura T, Kurokawa M.A highincidence of late-onset neutropenia following
rituximab-containing chemotherapy as a primary
treatment of CD20-positive B-cell lymphoma: asingle-institution study.Ann Oncol. 2007;18(2):364-9.
8. Yamaguchi Y, Fujio K, Shoda H, Okamoto A,
Tsuno NH, Takahashi K, Yamamoto K.IL-17B and
IL-17C are associated with TNF-alpha production
and contribute to the exacerbation of
inflammatory arthritis.J Immunol. 2007;179(10):7128-36.

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

157

Department of
Reproductive Endocrinology
Professor
Yuji Taketani

Associate Professor
Tetsu Yano

Lecturer
Koji Kugu

Mikio Momoeda

Yutaka Osuga

Toru Takeuchi

Homepage http://plaza.umin.ac.jp/ivf/index.html
http://square.umin.ac.jp/tkyobgyn/
Organization
The Department of Reproductive Endocrinology isorganized by one professor, one associate professor
and five lecturers. All the staff members are taking
part in both clinical and research activities. For theclinical aspect, we are engaged with in-patient andout-patient care including the activities in the delivery
units.

Activities
In clinical section, we have an out-patient clinic for
infertility, gynecological endocrine diseases, genetic
counseling and assisted reproductive technologies(ART). We also perform minimal access surgery forendometriosis, uterine fibroid, benign tumor and soon.
We have a highly organized infertility clinic, where
every patient is systemically examined and after
diagnosis of underlying infertility factor (s)appropriate treatment is performed following our
protocol. Once it turns out higher level of treatment isnecessary, ART is applied to such cases. We have been
engaged in in vitro fertilization and embryo transfer(IVF-ET) as a main axis of ART for eighteen years.

Conventional IVF-ET is mainly indicated to caseswith tubal factor, mild male factor, immunologicalfactor or of unexplained infertility factor. In case of
severe male factor or other fertilization disorderintracytoplasmic sperm injection (ICSI) is performed.
Now we have about 200 OPU cycles of IVF-ET every
year, which conventional IVF-ET and ICSI sharealmost equally. The clinical pregnancy rate ofconventional IVF-ET is around 30% per embryotransfer cycle, which is comparable with that of ICSI.
Other
ART
techniques
suchasembryocryopreservation and assisted hatching are also
performed.
In the field of gynecological surgery, we have been
constantly trying to minimize surgical invasion topatients as much as possible. With both ofwell-equipped instruments and well-trained expertise,
more than 90% of surgery cases for benign
gynecological disorders are operated endoscopically.
These endoscopic surgeries include laparoscopic or
laparoscopicallyassisted
cyctectomyorsalpingo-oophorectomy (216 cases), laparoscopic
hysterectomy or laparoscopically assisted vaginal
hysterectomy(33
cases),
laparoscopicorlaparoscopically assisted myomectomy (87 cases),diagnostic laparoscopy for infertility (8 cases)

158

laparoscopic surgery for ectopic pregnancy (23 cases),
hysteroscopic surgery (45 cases) and so on, whichmake a total of 386 cases.
[Each number of cases indicates per year base.]
Primary care peri/post-menopausal women is
becoming more important. We have alreadyestablished the primary care system for womenfocusing on climacteric syndrome and osteoporosis.
Hormone replacement therapy (HRT) is employed forthe purpose.
In basic research section, a couple of projects asfollows are under way, some of which have alreadyyielded interesting findings; 1) the mechanism offolliculogenesis and follicular apoptosis in the ovary,2) the functions of gynecologic hormones such as
gonadotropins and ovarian steroids, 3) the analysis ofendometriosis, 4) effect of ovarian steroid hormoneson bone metabolism, and 6) effects of endocrine
disrupters on the reproductive system.

References published in 2007
(1) Hirota Y, Osuga Y, Nose E, Koga K, Yoshino O,
Hirata T, Yano T, Tsutsumi O, Sakuma S,
Muramatsu T, Taketani Y. The presence of
midkine and its possible implication in humanovarian follicles. Am J Reprod Immunol 58(4):367-73, 2007.
(2) Takemura Y, Osuga Y, Yoshino O, Hasegawa A,
Hirata T, Hirota Y, Nose E, Morimoto C, Harada
M, Koga K, Tajima T, Yano T, Taketani Y.
Metformin
suppresses
interleukin(IL)-1beta-induced IL-8 production, aromataseactivation, and proliferation of endometriotic
stromal cells. J Clin Endocrinol Metab 92: 3213-8,
2007.
(3) Hirata T, Osuga Y, Hamasaki K, Hirota Y, Nose E,
Morimoto C, Harada M, Takemura Y, Koga K,
Yoshino O, Tajima T, Hasegawa A, Yano T,
Taketani Y. Expression of toll-like receptors 2, 3,
4, and 9 genes in the human endometrium during
the menstrual cycle. J Reprod Immunol 74(1-2):
53-60, 2007.
(4) Hiroi H, Fujiwara T, Nakazawa M, Osuga Y,
Momoeda M, Kugu K, Yano T, Tsutsumi O,
Taketani Y. High incidence of tubal dysfunction isdetermined by laparoscopy in cases with positive

Chlamydia trachomatis antibody despite negative
finding in prior hysterosalpingography. Reprod
Med & Biol 6(1): 39-43, 2007.
(5) Takemura Y, Osuga Y, Koga K, Tajima T, Hirota
Y, Hirata T, Morimoto C, Harada M, Yano T,
Taketani Y. Selective increase in high molecularweight adiponectin concentration in serum of
women with preeclampsia. J Reprod Immunol73(1): 60-5, 2007.
(6) Takeuchi T, Tsutsumi O, Taketani Y. Impaired
growth hormone secretion after glucose loading
in non-obese women with polycystic ovary
syndrome, possibly related to androgen but not
insulin and free fatty acids. Gynecol Endocrinol
23: 468-73, 2007.
(7) Momoeda M, Fukuta S, Iwamori Y, Taketani Y,
Iwamori M. Prolactin-dependent expression of
GD1 alpha ganglioside, as a component of milk
fat globule, in the murine mammary glands. J
Biochem 142(4): 525-31, 2007.

159

Department of
Gynecologic Oncology
Associate

Professor

Tetsu Yano

Lecturer
Shunsuke Nakagawa

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/a_joseika01.html#d03

Organization
The Department of Gynecologic Oncology isorganized by one associate professor and one lecturer,
being directed practically by Professor Yuji Taketani,
the Chairman of the Department of Obstetrics andGynecology. The staff members are taking part in bothclinical and research activities, as well as teachingactivities, with 18 associates of the University ofTokyo Hospital. For the clinical aspect, they are
engaged with in-patient and out-patient care.

Activities(1) Oncology research
In our division, the pathogenesis of uterine cervical
can-cer has been investigated these two decades. To
identify the risk factors for cervical intraepithelial
neoplasia (CIN), we reanalysed the data from ourprevious case-control study by adjusting for humanpapillomavirus (HPV) antibodies. Unlike our previous
study based only on HPV DNA, smoking andChlamydia trachomatis in-fection were revealed as
significant risk factors for CIN after adjustment for
HPV antibodies. The enhanced on-cogenicity ofparticular human papillomavirus type 16 (HPV16) E6variants is population-dependent, implying the
involvement of additional genetic cofactors. This
study was designed to investigate the association
between E6 variants and human leukocyte antigen(HLA) poly-morphism within a Japanese population.

Fifty-seven women with HPV16-positive cervicalcancer were ana-lyzed for E6 sequence variation andits relationship to HLA class II alleles. Compared withlocal controls (n = 138) and published controls (n =916), DRB1*1501 and DQB1*0602 frequencies weresignificantly increased among patients with HPV16
E6 prototype (n = 11). Ad-ditionally, DRB1*1502 waspositively associated with a particular E6 variant
designated D25E (n = 25), although we could not finda significant association between HLA class II alleles
and L83V variants (n = 16). Our observa-tions suggestthat a specific match between E6 variant proteins andHLA types may contribute to HPV16-related cervicalcarcinogenesis.
Studies of virus neutralization by antibody are
prerequi-site for development of a prophylactic
vaccine strategy against HPVs. To determine whether
neutralizing anti-bodies (NAs) against HPV16 is
responsible for a higher regression rate of low-grade
cervical intraepithelial neo-plasia (CIN1), we
investigated an association between the presence of
the NAs and the fate of the HPV16-related CIN1. The
incidence of the presence of the NAs in the womenwith a non-pathological cervix (85.7%) was
sig-nificantly higher than in the CIN1 cases (21.5%),
the CIN2/3 cases (15.7%), and the cervical cancer
cases (0%) (p<0.0001). The regression of the CIN1
lesion was closely associated with the presence of the
N As (p=0.0002). The presence of the NAs was
associated with low-level copy number of the viral
DNA relative to the NA-negative group (p=0.05). The

160

presence of the NAs against HPV16 was associatedwith a higher regression rate of HPV-related CIN1
lesions. The NAs seem to have a role in deterring
HPV-related cervical lesions from progressing to
CIN2/3 by inhibiting the infection with de novo
replicated
HPV.
Then
we
designedapla-cebo-controlled trial in healthy adults to evaluate
the safety and immunogenicity of a synthetic peptide
con-sisting of the aa 108-120 of HPV16 L2(L2-108/120) region, because this region contains across-neutralization epitope against genital HPV.. A
total of 13 volunteers were given nasal inoculations
with 0.1 (n=5) or 0.5mg (n=5) doses of the peptides orplacebo (n=3) without adjuvant at weeks 0, 4, and 12.
Sera were collected before inoculation and at 6, 16
and 36 weeks. The inoculation caused no serious local
and systemic complications. The inoculation
generated anti-L2 antibodies binding to both HPV16
and 52 L1/L2-capsids in four of the five recipi-ents in
the 0.5mg group. Sera of the four recipients showedneutralizing activities against HPV16 and 52.
Serological responses to the peptides were not foundin the 0.1mg group and the placebo group recipients.
This study suggests the L2-108/120 peptide istolerable in humans and has the potential as abroad-spectrum pro-phylactic vaccine against genital
HPV.
We also investigated interacting proteins with the
HPV E6 protein. Recently, a LAP protein, scribble,
was iden-tified in Drosophila epithelia as a basolateralprotein that controls the apical-basolateral polarity.
Loss of scribble causes disorganisation andovergrowth of the epithelia. Scribble has a humanhomologue, human scribble (hScrib), which is a
substrate of ubiquitin-mediated deg-radation byhuman papillomavirus E6 and the E6AP
ubiquitin-protein ligase. In the present study, we
revealed that hScrib localised to the basolateralregions of the epithelial cell line MDCK and humanuterinecervicalepithelial
tissuesbyimmunofluorescence. Human scrib-ble colocalised
rather with the adherens junction protein E-cadherin,
but not with the tight junction protein ZO-1.
Histochemical analysis showed a dramatic decrease in
the expression of hScrib with the progression of
disease from normal uterine cervical tissues toinvasive cervical can-cers through the precursor

lesions. In contrast, the ex-pression of hScrib was
retained in the throughout epithe-lial layer of the
HPV-negative
cervicalhigh-grade
squamous
intraepithelial lesions (H-SIL). Although quantitative
RT-PCR revealed no significant downregu-lation of
hScrib mRNA expression in the H-SIL, it re-vealed aclear downregulation in the invasive cancers. These
results suggest the possibility that degradation by
HPV E6 is one of the causal roles for the progressive
decrease of hScrib expression during the disease
pro-gression from low-grade squamous intraepithelial
lesions to H-SIL, and a cooperative role ofdownregulation of hScrib mRNA expression andubiquitin-mediated degra-dation of hScrib by E6 andE6AP led to the complete decrease of hScrib
expression during the process of car-cinogenesis from
H-SIL to invasive cancer. These data underscore theimportance of hScrib in the construction of tissue
architecture and prevention of cancer develop-ment.
Another basic research is focused on analysis oftumor suppressor genes in gynecological malignancies
as following.
1 Human Scribble
Recently, a LAP protein, scribble, was identi-fied in
Drosophila epithelia as a basolateral protein that
controls the apical-basolateral polarity. Loss ofscribble causes disorganisation and overgrowth of theepithelia. Scribble has a human homologue, humanscribble (hScrib), which is a substrate ofubiquitin-mediateddeg-radationbyhumanpapillomavirus E6 and the E6AP ubiquitin-protein
ligase. In the present study, we re-vealed that hScrib
localised to the basolateral regions of the epithelial
cell line MDCK and human uterine cervical epithelial
tissues by immunofluorescence. Human scrib-ble
colocalised rather with the adherens junction protein
E-cadherin, but not with the tight junction protein
ZO-1. Histochemical analysis showed a dramatic
decrease in the expression of hScrib with theprogression of disease from normal uterine cervicaltissues to invasive cervical cancers through theprecursor lesions. In contrast, the expression of hScrib
was retained in the throughout epithelial layer of the
HPV-negative
cervicalhigh-grade
squamous
intraepithelial lesions (H-SIL). Although quantitative
RT-PCR revealed no significant downregu-lation of
hScrib mRNA expression in the H-SIL, it re-vealed a161

clear downregulation in the invasive cancers. These
results suggest the possibility that degradation by
HPV E6 is one of the causal roles for the progressive
decrease of hScrib expression during the disease
pro-gression from low-grade squamous intraepithelial
lesions to H-SIL, and a cooperative role ofdownregulation of hScrib mRNA expression andubiquitin-mediated degra-dation of hScrib by E6 andE6AP led to the complete decrease of hScrib
expression during the process of car-cinogenesis from
H-SIL to invasive cancer. These data underscore theimportance of hScrib in the construction of tissue
architecture and prevention of cancer develop-ment.
Drosophila discs large (Dlg) is one of neoplas-tic
tumor suppressors, which genetically links to scribble.
E6 also targets human Dlg (hDlg) for
ubiquitin-mediated degradation. Ubiquitin-protein
ligase involved in this process has not been identified
thus far. Here we inves-tigated mechanism underlying
degradation of three target proteins of E6, hScrib,
hDlg, and p53 by using eighteen HPV 16 E6 mutants
with single amino acid substitution. In vitro
degradation ability of each E6 mutant was equivalent
for these tumor suppressors. We investigated whether
E6AP is involved in ubiquitin-mediated degra-dationof hDlg. In vitro binding assay revealed that hDlg
formed ternary complex with E6-E6AP complex. The
ability of E6 mutants to degrade these tumor
suppressors was correlated with their ability tointeract with E6AP. Furthermore, hDlg was targeted
for in vitro ubiquitina-tion in the presence of both E6
and E6AP. These data revealed that E6AP isextensively involved in the ubiq-uitin-mediateddegradation of E6-dependent substrates as a cellular
E3 ubiquitin-protein ligase.
Human Scribble, classified as a LAP protein
containing leucine-rich repeats and PDZ domains,interacts with E6 through its PDZ domains andC-terminal PDZ do-main-binding motif of E6 protein.
Interaction between human Discs Large (hDlg), which
is a substrate of E6 for the ubiquitin-mediateddegradation, and adenomatous polyposis coli (APC)
has been shown. Here, we investi-gated whether
hScrib and APC interact with each other in vitro andin vivo. Interaction between hScrib and APC ismediated by the PDZ domains 1 and 4 of hScrib andC-terminal PDZ domain-binding motif of APC.

Human Scribble co-localized with APC at the synaptic
sites of hippocampal neuron and at the tip ofmembrane protru-sion in the epithelial cell line.
Interference of the interac-tion between hScrib and
APC caused disruption of ad-herens junction.
Knockdown of hScrib expression by RNAi disrupts
localization of APC at the adherens junc-tion. These
data suggest that hScrib may participate in the
hDlg-APC complex through its PDZ domains andregulate cell cycle and neural function by associatingwith APC.
Drosophila tumor suppressor Scribble has been
identified as an apical-basolateral polarity determinant
in epithelia. A human homolog of Drosophila Scribble,
human Scrib-ble (hScrib), has been identified as aprotein targeted by human papillomavirus E6 for theubiquitin-mediated degradation dependent on E6AP, acellular ubiq-uitin-protein ligase. Human Scribble isclassified as a LAP protein, having leucine-richrepeats (LRRs) and PDZ domains. We investigatedwhether hScrib, which is thought to have a role inpolarity determination based on the data of its
Drosophila homolog, is involved in cell-cycle
regulation and proliferation control of epithe-lia.
Transfection of hScrib inhibits cell-cycle progression
from G1 to S phase, and it up- and down-regulates
ex-pression of adenomatous polyposis coli and cyclins
A and D1, respectively. Knockdown of hScrib
expression by siRNA leads to cell-cycle progression
from G1 to S phase. We explored functional domain
mapping to reveal which domains of hScrib are
critical for its cellular pro-liferation control andlocalization at the basolateral membrane. We foundthat LRRs and PDZ domain 1 are indispensable for
hScrib to inhibit cell growth by block-ing cell-cycle
progression and to keep its proper local-ization. These
data indicate that basolateral membrane localization of
hScrib is closely related to its prolifera-tion control.
Our findings suggest the possibility that hScrib isinvolved in signal transduction to negatively regulate
cell proliferation by localizing at the basolateral
membrane of epithelial cells through LRRs and PDZ
domains.
We also investigated which E3 ubiquitin-protein
ligase is involved in the ubiquitin-mediateddegradation of hDlg. Human scribble (hScrib), which
was identified as sub-strate of human papillomavirus

162(HPV) E6 for ubiq-uitin-mediated degradation
dependent on ubiq-uitin-protein ligase E6AP, is ahuman homolog of Dro-sophila neoplastic tumor
suppressor scribble, in which mutation causes loss ofpolarity and overgrowth of epi-thelia. Drosophila
discs large (Dlg) is one of neoplastic tumor
suppressors, which genetically links to scribble. E6
also targets human Dlg (hDlg) for ubiquitin-mediateddegradation. Ubiquitin-protein ligase involved in thisprocess has not been identified thus far. Here we
inves-tigated mechanism underlying degradation of
three target proteins of E6, hScrib, hDlg, and p53 byusing eighteen HPV 16 E6 mutants with single aminoacid substitution. In vitro degradation ability of each
E6 mutant was equivalent for these tumor suppressors.
We investigated whether E6AP is involved inubiquitin-mediated degra-dation of hDlg. In vitro
binding assay revealed that hDlg formed ternarycomplex with E6-E6AP complex. The ability of E6
mutants to degrade these tumor suppressors wascorrelated with their ability to interact with E6AP.
Furthermore, hDlg was targeted for in vitro
ubiquitina-tion in the presence of both E6 and E6AP.
These data revealed that E6AP is extensively involved
intheubiq-uitin-mediateddegradationof
E6-dependent substrates as a cellular E3
ubiquitin-protein ligase. hScrib, human homologue ofDrosophila neoplastic tumor suppressor, wasidentified as a target of human papillomavirus E6
oncoprotein for the ubiquitin-mediated degradation.
Here, we report that hScrib is a novel death substratetargeted by caspase. Full-length hScrib was cleaved
by caspase during death ligands-induced apoptosis,
which generates a p170 C-terminal fragments in Helacells. In vitro cleavage assay using recombinantcaspases showed that hScrib is cleaved by the
executioner caspases.
DNA damage-induced
apoptosis caused loss of expression of full-length
hScrib, which was recovered by addition of capase-3
inhibitor in HaCat cells. TUNEL positive apoptotic
cells, which were identified 4 hours after UV
irradiation in HaCat cells, showed loss of hScrib
expression at the adherens junction. Mutational
analysis identified the caspase dependent cleavage siteof hScrib at the position of Asp-504. While MDCK
cells transfected with GFP-fused wild type hScrib
showed loss of E-cadherin expression and shrinkage

of cytoplasm by UV irradiation, cells transfected with
hScrib with Ala substitution of Asp-504 showed
resistance to caspase dependent cleavage of hScrib
and intact expression of E-cadherin. These results
indicate that caspase dependent cleavage of hScrib is a
critical step for detachment of cell contact during
process of apoptosis.
2 PTEN
Although the mutation of PTEN, a tumor suppressor, is known to be involved in tumorigenesis of
en-dometrioid adenocarcinomas of the endometrium
and ovary, the role of PTEN alteration in endometrioid
ade-nocarcinoma of the cervix remains to beinvestigated. To elucidate the molecular pathogenesisof cervical adeno-carcinoma and adenosquamous
carcinoma, and in par-ticular to examine the potential
role of PTEN mutation in endometrioid-type cancer ofthe cervix, we analyzed 32 cervical adeno- or
adenosquamous
carcinomas(8
endo-metrioid
adenocarcinomas, 14 mucinous adenocarcino-mas and
10 adenosquamous carcinomas) for PTEN mu-tationsand HPV infections. PTEN mutation was detected in 2
of 8 (25.0%) endometrioid cases, 2 of 14 (14.3%)
mucinous cases, and none of 10 (0%) adenosquamous
cases. HPV DNA was detected in 11 out of 18 (61.1%)
PTEN wild-type adenocarcinomas and 8 out of 10(80.0%) adenosquamous carcinomas. Among 11
HPV-negative adenocarcinomas, 40.0% (2/5) endometrioid cases and 33.3% (2/6) mucinous cases wereshown to be PTEN mutated, while no cases (0/21)
were PTEN-mutant in the remainder (i.e.
adenosquamous car-cinomas and HPV-positive
adenocarcinomas). The cur-rent observations suggestthat PTEN mutation is fre-quently detected in HPVnegative adenocarcinomas of the cervix and the mostprevalent occurrence of PTEN mutation in
endometrioid subtype is keeping with endo-metrial
and ovarian carcinomas.
Next, we analyzed involvement of PTEN intreatment of endometrial cancer. Young patients withcomplex atypical hyperplasia (CAH) or stage Ia, G1
adenocarcinoma (IaG1) of the endometrium, who
desire to preserve fertility, can select the conservative
therapy by oral progestin, medroxyprogesterone
acetate (MPA). However, conservative treatments
involve potential risks of progression and recurrence.
In an attempt to find out molecular markers for163

sensitivity
to
MPA,
we
performed
immunohistochemical analysis of PTEN, phospho-Akt,
p53, ER and PgR in MPA-treated 31 cases with CAH
or IaG1. Eleven of 12 cases (92%) with CAH and 15
of 19 cases (79%) with IaG1 demonstrated an initial
complete response, while five patients underwent
hysterectomy due to no response. Four of 11
responders (36%) with CAH and five of 15 responders(33%) with IaG1 later developed relapse. Five of ninepatients (56%) with CAH and three of 11 patients(27%) with IaG1 became pregnant after infertility
treatment. Immunohistochemi-cal analysis revealed
that phospho-Akt expression was significantly
decreased by MPA administration (p=0.002).
Furthermore, combination of two factors, weak
phosho-Akt or PTEN-null expression, was found to besignificantly associated with receiving hysterectomy(p=0.04), while each factor showed a trend without
sta-tistical significance (p=0.07 and 0.2, respectively).
Strong expression of both ER and PgR significantly
cor-related with successful pregnancy after infertility
treat-ment following complete response to MPA(p=0.02). Our observations in vivo suggest thatanti-tumor action of MPA may be mediated bydephosphorylation
of
Akt,
and
that
immunohistochemical evaluation of phospho-Akt andPTEN may be able to predict the outcome of MPA
therapy.
3 SFRP1 gene
The SFRP1 gene on chromosome 8p11.2 en-codes a
Wnt signaling antagonist, and was recently
demonstrated to be a new tumor suppressor that is
inac-tivated by promoter methylation in human coloncancers. Here, we analyzed promoter methylation of
the SFRP1 gene in human ovarian cancers, in whichloss of het-erozygosity in 8p is frequently observed
and involve-ment of the Wnt signaling pathway has
been suggested. Methylation-specific PCR (MSP)
analysis showed that four of 13 ovarian cancer celllines and two of 17 pri-mary ovarian cancers had
methylated SFRP1, while an immortalized ovarianepithelial cell line, HOSE, and seven ovarian
endometrial cyst samples did not. In the four ovariancancer cell lines with the methylation, SFRP1 was not
expressed at all as determined by quan-titative
RT-PCR analysis. These results show that SFRP1 isinactivated by promoter methylation in human ovariancancers, as well as colon cancers.
4 hMSH2
The DNA mismatch repair gene is a key regu-lator
in the elimination of base-base mismatches andinsertion/deletion loops (IDLs). Human MutS
homo-logue 2 (hMSH2), originally identified as ahuman homologue of the bacterial MutS, is a tumour
suppressor gene frequently mutated in hereditary
non-polyposis
co-lorectal
cancer.
Hereditary
non-polyposis colorectal cancer is characterised by theearly onset of colorectal cancer and the developmentof extracolonic cancers such as endometrial, ovarian,and urological cancers. Oestro-gen receptor (ER)alpha and beta are members of a nu-clear receptor(NR) superfamily. Ligand-dependent transcription of
ER is regulated by the p160 steroid re-ceptor
coactivatorfamily,thethyroidhormonerecep-tor-associatedproteins/thevitaminD
receptor-interacting proteins (TRAP/DRIP) mediator
complex, and the TATA box-binding protein(TBP)-free TBP associated factor complex (TFTC)
type histone acetyltransferase complex. We identified
the interaction between ER al-pha/beta and hMSH2.
Immunoprecipitation and glu-tathione-S-transferase
pull-down assay revealed that ER alpha and hMSH2
interacted in a ligand-dependent manner, whereas ER
beta and hMSH2 interacted in a ligand-independent
manner. Oestrogen receptor al-pha/beta bound tohMSH2 through the hMSH3/hMSH6 interaction
domain of hMSH2. In a transient expression assay,
hMSH2 potentiated the transactivation function ofliganded ER alpha, but not that of ER beta. These
results suggest that hMSH2 may play an importantrole as a putative coactivator in ER alpha dependent
gene expres-sion.
(2) Clinical oncology
To compare treatment outcome results of conventional surgery vs. radiotherapy (RT) for carcinomaof the uterine cervix. A retrospective analysis was
con-ducted of 152 patients with uterine cervicalcancer radi-cally treated with surgery or highdose-rate intracavitary brachytherapy (HDR-ICBT)with or without external RT from June 1991 to May
2004. The median follow-up time was 43.5 months(range, 1.0-130.0 months). The median age was 53
years (range, 25-81 years). There were 13 patients164(9%) in stage IA, 52 (34%) in stage IB, 24 (16%) instage IIA, and 63 (41%) in stage IIB. The
conventional surgery group included 115 patients(76%) who underwent hysterectomy with pelvic
lymph node dissection. Of these, 72 (63%) received
postoperative radiotherapy. Thirty-seven patients(24%) were assigned to the RT group. Of these, 14(38%) received chemora-diotherapy. Three patientswith stage I received ICBT-alone without external
beam
irradiation.
RESULTS:The
5-yearcause-specific survival (CSS) rates for surgery and RT
were 79.9% and 82.3%, respec-tively; the difference
between these two treatments was not statisticallysignificant (P = 0.8524). The differences in thesurvival rates between the two treatments for each of
the stage I or stage II patients were also notstatisti-cally significant (P = 0.8407 for stage I and P =0.6418 for stage II). This retrospective study suggeststhat RT results in compatible survival withconventional surgery for patients with stage I-II
cervical carcinoma.

References published in 2007
(1) Minaguchi T, Nakagawa S, Takazawa Y, Nei T,
Horie K, Fujiwara T, Osuga Y, Yasugi T, Kugu K,
Yano T, Yoshikawa H, Taketani Y. Combined
phospho-Akt and PTEN expressions associatedwithpost-treatment
hysterectomy
afterconservative progestin therapy in complex
atypical hyperplasia and stage Ia, G1
adenocarcinoma of the endometrium. Cancer Lett
248(1): 112-22, 2007.
(2) Tsuruga T, Nakagawa S, Watanabe M, Takizawa
S, Matsumoto Y, Nagasaka K, Sone K, Hiraike H,
Miyamoto Y, Hiraike O, Minaguchi T, Oda K,
Yasugi T, Yano T, Taketani Y. Loss of Hugl-1
expression associates with lymph node metastasis
in endometrial cancer. Oncol Res 16(431-5),
2007.
(3) Arimoto T, Nakagawa S, Yasugi T, Yoshikawa H,
Kawana K, Yano T, Taketani Y. Treatment withpaclitaxel plus carboplatin, alone or with
irradiation, of advanced or recurrent endometrial
carcinoma. Gynecol Oncol 104(1): 32-5, 2007.
(4) Sato K, Takeuchi T, Kukimoto I, Mori S, Yasugi T,
Yano T, Taketani Y, Kanda T. Human

papillomavirus type 16 P670 promoter isnegatively regulated by CCAAT displacement
protein. Virus Genes 35: 473-81, 2007.
(5) Sone K, Nakagawa S, Nakagawa K, Takizawa S,
Matsumoto Y, Nagasaka K, Tsuruga T, Hiraike H,
Hiraike-Wada O, Miyamoto Y, Oda K, Yasugi T,
Kugu K, Yano T, Taketani Y. hScrib, a humanhomologue of Drosophila neoplastic tumor
suppressor, is a novel death substrate targeted by
caspase during the process of apoptosis. Genes
Cells. May 29, 2008.

165

Department of Perinatal Medicine
Associate Professor
Shiro Kozuma

Tomoyuki Fujii

Lecturer
Yoshimasa Kamei

Homepage

http://www.iiosan.umin.jp/index.htm

Organization
The Department of Perinatal Medicine is organizedby two associate professors and one lecturer, being
directed practically by Professor Yuji Taketani, thechairman of the Department of Obstetrics andGynecology. All the staff members are taking part inboth the clinical and research activities, as well as theteaching activities, with 15 associates of the
University of Tokyo Hospital. For the clinical aspect,they are engaged with in-patient and out-patient careincluding the activities in the delivery units.

Activities
The clinical service for perinatology in the
University of Tokyo Hospital consists of out-patient
clinic and the Delivery Unit. [See Delivery Unit of the
University of Tokyo Hospital]
By the advance of the techniques for prenatal
diagnosis of fetal growth and congenital
malformations, the area of fetal medicine is enlarging.
Strict measurement of fetal growth during pregnancy
has made possible the accurate diagnosis of
intrauterine growth retardation. New techniques likefetal blood sampling and three- dimensional
ultrasonography have been introduced into clinicalservice. The subjects of studies were focused on“fetus” and “ultrasound” in perinatology and medical
engineering research group. Fetal behavior,particularly breathing movements and sleepwakefulness cycle were studied with ultrasound in
human fetuses. Studies were done to investigate

mechanism of fetal brain damage by repeated cord
occlusion in sheep. The effect of brain damage on
fetal behavior was also studied.
Recurrent spontaneous abortion (RSA) is diagnosed
by a history of three times or more spontaneousabortions in the first trimester. Our “RSA clinic”
opens once a week. About 200 new couples with RSA
visit our hospital in a year. The patients are checked
several risk factors of RSA, such as anatomical,
chromosomal, hormonal, biological, or autoimmune
factors. To RSA patients with autoimmune factors,
especiallywithantiphospholipid
antibodies,
anticoagulation therapy is performed. For the low risk
group, low dose aspirin is administered. Heparin
injection is performed for the high risk group, forinstance, patients with successive intrauterine fetal
death during the second or third trimester ofpregnancy, or those with beta-2 glycoprotein I
dependent anticardiolipin antibody. Further to RSA
patients with unknown etiology, the immunotherapy
with her husband’s lymphocyte inoculation isindicated. The inoculation is usually performed four to
six times in every two or three weeks. In our clinic,
after the immunotherapy, their pregnancy outcomes
have extremely improved in these 10 years. Now thesuccessful reproductive rate has achieved over 75%.

References published in 2007
(1) Nagamatsu T, Fujii T, Matsumoto J, Kanai T,
Hyodo H, Yamashita T, Kozuma S, Taketani Y.
Theoretical basis for herbal medicines,
Tokishakuyaku-San and Sairei-To, in the166treatment of recurrent abortion: enhancing the
production of granulocyte-macrophage colonystimulating factor in decidual stromal cells. Am J
Reprod Immunol 57(4): 287-93, 2007.
(2) Yamaguchi SI, Kamei Y. Kozuma S. Taketani Y.
Tissue elastography imaging of the uterine cervix
during pregnancy. J Med Ultrasonics 34(4):209-10, 2007.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

168

Department ofPediatrics, Department ofDevelopmental Pediatrics
Professor
Takashi Igarashi, M.D.,Ph.D.

Associate Professor
Akira Oka, M.D., Ph.D.
Takashi Sekine, M.D., Ph.D.

Lecturer
Hiroshi Watanabe, M.D., Ph.D.
Masaru Takamizawa, M.D., Ph.D.
Koumei Ida, M.D., Ph.D.
Junko Takita, M.D., Ph.D. (Department of Cell Therapy and Transplantation Medicine)

Associate
Keiji Goishi, M.D.,
Takayoshi Isoda M.D.,
Hirotsugu Kano, M.D., Ph.D., Tatsuo Katori, M.D.,
Yasuo Kodachi, M.D.,
Takako Matsuoka, M.D.,
Ken-ichirou Miura, M.D.,
Ai Motomura, M.D.,
Hiroshi Ono, M.D.,
Atsuishi Satou, M.D.,
Akihumi Toyoda, M.D.
(As of March 31, 2008)

Homepage

Akio Ishiguro, M.D., Ph.D.,
Katsuyoshi Ko, M.D.,
Masakazu Mimaki, M.D., Ph.D.,
Riki Nishimura, M.D.,
Kan Takahashi, M.D.,

http://square.umin.ac.jp/ped/

Introduction and Organization
The former Department of Pediatrics developed into
Department of Pediatrics and Department ofDevelopmental Pediatrics, which comprise subgroupsof the Group of Reproductive, Developmental andAging Medicines, Graduate School of Medicine, The
University of Tokyo.
Our staff consists of 1 professor, 2 associate
professors, 4 lecturers, 16 associate professors, 13senior residents, 1 research fellow, 11 graduate

students and 2 foreign pediatricians as of May 31,
2008.
The outpatient clinic of our department is locatedon the second floor of the outpatient clinic building.
The inpatient ward and conference rooms are locatedon the second floor of the inpatient clinic building A.
Offices are on the second and third floors of the East
Research Building. Our laboratories are located on thesecond, third and fourth floors of the Research
Building of Internal Medicine and on the second andthird floors of the East Research Building.

169

Clinical activities
We have specialized outpatient clinics covering allpediatric fields in addition to general pediatrics. In
July, 2008, the capacity of the pediatric and pediatricsurgery ward will be increased to 100 beds, including
9 beds in the neonatal intensive care unit (NICU), 16
beds in the growth care unit (GCU) and 6 beds in thepediatric intensive care unit (PICU), and ourinstitution is going to fulfill the designation as
children’s hospital affiliated to the university hospital.
In NICU, we are taking care of small premature babies
weighing from 400g to 3,000g often associated withcongenital disorders requiring invasive interventions.
A variety of patients with diseases, such ashematological/oncological disorders (acute leukemia,
neuroblastoma, Ewing sarcoma, osteosarcoma, brain
tumors, etc.), cardiac disorders (congenital heartdiseases and Kawasaki disease), neuromusculardisorders, immunological/allergic disorders (common
variable immunodeficiency, chronic granulomatous
disease and bronchial asthma), renal and urinary tract
diseases(nephrotic
syndrome,
chronicglomeluronephritis, purpura nephritis and renal and/or
urinary tract anomalies), endocrinological disorders,metabolic disorders and psychosomatic diseases areadmitted in the wards. Approximately 10 patients
received hematopoietic stem cell transplantation every
year. There are patients with severe combined
immunodeficiency, aplastic anemia-myelodysplastic
syndrome, acute lymphocytic leukemia with high-riskfeatures, acute myelogenous leukemia, non-Hodgkin
lymphomas, disseminated neuroblastoma and brain
tumors.
Many patients need to stay long in the hospital. We
provide an official in-hospital school ”Kodama
Gakkyu” where patients receive education and havechances to communicate with other patients as well as
their family members. “Niko-niko Volunteer”
members, an official volunteer group in the hospital,
visit the pediatric ward every weekday to play withthe patients and help their mothers, providing
enormous comfort to both the patients and theirmothers. Various activities are scheduled for thepatients in the hospital such as the Tanabata festival, a
Christmas party and music concerts. All the residents,
fellows and nurses participate in these activities. We

will have a child care specialist in the pediatric ward
in April, 2006.
(As of May 31, 2008)

Teaching activities
The staff members and the visiting lecturers givelectures of general pediatrics and pediatric diagnosis
for 36 hours to the second year students, and clinicalbedside learning in the inpatient ward for 2 weeks to
the third year students. During bedside learning for 2
weeks, specialized teaching sessions, like seminars areheld every day. In the outpatient learning, medical
students take histories and perform physicalexaminations of patients under the supervision of theteaching staff. On the second and third days of theoutpatient clinic, each student visits the local
pediatricians or local hospitals in and around Tokyo.
On the last day of clinical learning, the Professor andan Associate Professor evaluate the students’achievements. We have an elective clinical clerkshipcourse for the third year students.

Research activities
Our departments have the following researchgroups: nephrology, hematology/oncology, neurology,
cardiology, endocrinology, immunology, allergy,
pulmonology and neonatology. We also havemultidisciplinary research groups and laboratories
such as cell biology, genetic molecular biology andepidemiology. The main subjects of research during
the last year are listed as follows.
① Hematology/Oncology group: Using extremely
high grade oligonucleotide array system, many
deletions and amplifications in unreported genes
were identified in solid tumors including
neuroblastoma, rhabdomyosarcoma and Ewing
sarcoma.
② Nephrology group: Genetic and clinical diversityof Dent disease was identified in more than 90
unrelated patients. In the field of podocyte biology,
novel mechanisms underlying the signaltransduction via nephrin and neph1 wasdemonstrated.
③ Cardiology goup: A novel intervention cathether
technique in PDA was applied in several

170

congenital heart disease patients.
④ Immunology group: A therapy using humandendritic cells for children’s cancer patients are
performed.
⑤ Neonatology group: Clinical researches in theregulation of body fluid and circulation are being
conducted.
⑥ Neurology Group: The pathogenetic mechanismof acute encephalopathy as well as genetic basis ofcongenital CNS anomalies are investigated. The
neuropathological studies of perinatal brain
damage,inparticularperiventricularleukomalacia , is also performed.

References
1. Chen Y, Takita J, Mizuguchi M, Ida K, Koh K,
Igarashi T, Hanada R, Tanaka Y, Hayashi Y:
Mutation and expression analyses of the MET and
CDKN2A genes in rhabdomyosarcoma withemphasis on MET overexpression. Gene
Chromosome Cancer 46: 348-358, 2007
2. Hiraiwa R, Maegaki Y, Oka A, Ohno K:
Behavioral and psychiatric disorders in
Prader-Willi syndrome; a population study inJapan. Brain Dev 29:535-542, 2007
3. Inatomi J, Yokoyama Y, Sekine T, Igarashi T: A
case of cerebral salt wasting syndrome associatedwith aseptic meningitis in 8-year-old boy. Pediatr
Nephrol 23: 695-662 2007
4. Ishiguro A, Inagaki M, Kaga M: Stereotypiccircling behavior in mice with vestibular
dysfunction: asymmetrical effects of intrastriatal
microinjection of a dopamine agonist. Int J
Neurosci 117:1049-1064, 2007
5. Khamrin P, Peerakome S, Tonusin S, Malasao R,
Okitsu S, Mizuguchi M, Ushijima H, Maneekarn
N: Changing pattern of rotavirus G genotype
distribution in Chiang Mai, Thailand from 2002 to
2004: decline of G9 and reemergence of G1 andG2. J Med Virol 79: 1775-1782, 2007
6. Khamrin P, Maneekarn N, Peerakome S, Tonusin
S, Malasao R, Mizuguchi M, Okitsu S, Ushijima
H: Genetic diversity of noroviruses andsapoviruses in children hospitalized with acutegastroenteritis in Chiang Mai, Thailand. J Med
Virol 79: 1921-1926, 2007

7. Kitanaka S, Sato U, Igarashi T: Regulation ofhuman insulin, IGF-I, and multidrug resistance
protein 2 promoter activity by hepatocyte nuclear
factor (HNF)-1beta and HNF-1alpha and theabnormality of HNF-1beta mutants. J Endocrinol
192: 141-147, 2007
8. Komuro H, Saihara R, Shinya M, Takita J,
Kaneko S, Kaneko M, Hayashi Y: Identification ofside population cells (stem-like cell population) in
pediatric solid tumor cell lines. J Pediatr Surg 42:
2040-2045, 2007
9. Kunishima S, Yoshinari M, Nishio H, Ida K,
Miura T, Matsushita T, Hamaguchi M, Saito H:
Haemotologicalcharacteristicsof
MYH9
disorders due to MYH9 R702 mutations. Eur J
Haematol 78: 220-226, 2007
10. Nagasawa T, Kimura I, Abe U, Oka A: HHV-6
encephalopathy with clusters of convulsions
during eruptive stage. Pediatr Neurol 33: 98-104,
2007
11. Nanba Y, Matsui K, Aida N, Sato Y, Toyoshima K,
Kawataki M, Hoshino R, Ohyama M, Itani Y,
Goto A, Saito,Y, Oka A: Detection of T1
hyperintensity in region of the corona radiataconnecting with posterior limb of the internal
capsule on magnetic resonance imaging at nearterm is sensitive in predicting gross motor
problems in premature infants Pediatirics 120:e10-19, 2007
12. Nguyen TA, Khamrin P, Takanashi S, Le Hoang P,
Pham le D, Hoang KT, Satou K, Masuoka Y,
Okitsu S, Ushijima H: Evaluation of
immunochromatography tests for detection ofrotavirus and norovirus among Vietnamesechildren with acute gastroenteritis and theemergence of a novel norovirus GII.4 variant. J
Trop Pediatr 53: 264-269, 2007
13. Nozu K, Inagaki T, Fu Jun Xue, Nozu Y, Kaito H,
Kanda K, Sekine T, Igarashi T, Nakanishi K,
Yoshikawa N, Iijima K, Matsuo M: Molecularanalysis of digenic inheritance in Bartter
syndrome with sensorineural deafness. J Med
Genet 45: 182-186, 2007
14. Okame M, Shiota T, Hansman G, Takagi M,
Yagyu F, Takanashi S, Phan TG, Shimizu
Y,Kohno H, Okitsu S, Ushijima H: Anti-norovirus
polyclonal antibody and its potential for171

development of an antigen-ELISA. J Med Virol
79: 1180-1186, 2007
15. Okoshi Y, Mizuguchi M, Itoh M, Oka A,
Takashima, S: Altered nestin expression in the
cerebrum with periventricular leukomalacia.
Pediatr Neurol 36: 170-174, 2007
16. Phan TG, Kaneshi K, Ueda Y, Nakaya S,
Nishimura S, Yamamoto A, Sugita K, Takanashi
S, Okitsu S, Ushijima H: Genetic heterogeneity,
evolution, and recombination in noroviruses. J
Med Viro 79: 1388-1400,2007
17. Phan TG, Khamrin P, Quang TD, Dey SK,
Takanashi S, Okitsu S, Maneekarn N, Ushijima H:
Emergenceof
intragenotype
recombinantsapovirus in Japan. Infect Genet Evol 7: 542-546,
2007
18. Phan TG, Khamrin P, Quang TD, Dey SK,
Takanashi S, Okitsu S, Maneekarn N, Ushijima H:
Detection and genetic characterization of group A
rotavirus strains circulating among children withacute gastroenteritis in Japan. J Virol 81:46454653,2007
19. Phan TG, Trinh QD, Khamrin P, Kaneshi K, Ueda
Y, Nakaya S,Nishimura S, Sugita K, Nishimura T,
Yamamoto A, Takanashi S, Yagyu F, Okitsu S,
Ushijima H: Emergence of new variant rotavirus
G3 among infants and children with acutegastroenteritis in Japan during 2003-2004. Clin
Lab 53: 41-48, 2007
20. Saitoh M, Sakakihara Y, Mizuguchi M, Ito H, M,
Takashima S, Iwamori M, Kamoshita, S, Igarashi
T: Increase of ceramide monohexoside anddipalmitoyl glycerophospholipids in the brain of
Zellweger syndrome. Neurosci Lett 417: 165-170,
2007
21. Saitoh M, Horikawa M, Iwamori Y, Sakakihara Y,
Mizuguchi M, Igarashi T, Fujiki Y, Iwamori M:
Alterations in the molecular species ofplasmalogen phospholipids and glycolipids due toperoxisomal dysfunction in Chinese hamster
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852: 367-373, 2007
22. Sekine T, Nozu K, Iyengar R, Fu XJ, Matsuo M,
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23. Shiota T, Okame M, Takanashi S, Khamrin P,
Takagi M, Satou K, Masuoka Y, Yagyu F, Shimizu
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Recognition of a novel conformational epitope. J
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24. Shimada A, Taketani T, Kikuchi A, Hanada R,
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173

Department of Pediatric surgery
Professor
Tadashi Iwanaka, M.D., Ph.D.

Associate Professor
Yutaka Kanamori, M.D., Ph.D.

Research Associate
Masahiko Sugiyama, M.D.,

Makoto Komura, M.D., Ph.D.

Teturou kodaka, M.D., Ph.D.

Yujirou Tanaka, M.D., Ph.D.

Homepage

http://square.umin.ac.jp/pedsurg/index.html

History and organization
In 1951, a pediatric surgical team was established in
the Department of Second Surgery. Subsequently, in
1961, a pediatric surgical research team, which would
eventually research diaphragmatic hernia, wasestablished with a chief, Dr. Ishida, by Professor
Kimoto.
In 1971, it was authorized as the first clinicaldepartment of Pediatric Surgery in a National
University.
A pediatric intensive care unit was founded with Prof.
Ishida in 1973, and a ward which could accommodate
mainly pediatric surgical patients was completed.
Assistant Prof. Saito assumed office as the first
Director of this Pediatric Surgery clinical department.
Dr. Sumio Saito became Professor of PediatricSurgery in 1983. Professor Saito had enthusiastically
performed clinical studies such as operation
techniques and the use of biliary atresia.
Dr. Nakajo took office as a professor in 1985. Prof.
Nakajo had developed original operative procedures
such as a radical operation for umbilical hernia and ananti-reflex valve for biliary atresia. These original
operative procedures have been inherited by pediatricsurgeons as Nakajo methods.
Our department was authorized as the Department ofPediatric Surgery in 1989 after Kyusyu University by
the Ministry of Education.

Dr. Yoshiaki Tsuchida assumed the role of Professor in1990 and published many highly regarded articles,
mainly concerning neuroblastoma and Wilm’s tumor
from research and clinical work.
In 1995, the department was reorganized as the
Reproductive, Developmental and Aging Science,
Pediatric Science and Pediatric Surgery, due to the
University policy for the Graduate School.
In 1997, Dr Hashizume became Professor in the
Department of Pediatric Surgery. He started
living-related partial liver transplantation (LRPLT) for
children with Professor Makuuchi in the Department
of Second Surgery.
Dr. Tadashi Iwanaka became the sixth Professor in
August 2006. The present staff are the chief professor,
one associate professor, four research associates, two
medical staff and three graduate students. More than
20 members of our department shoulder the clinicalwork as pediatric surgeons.

Clinical activities
Staff higher than research associate level take chargeof the out-patient clinic from Monday through Friday.
The pediatric surgical outpatient clinic takes place inthe same location as the pediatric outpatient clinic andwe closely cooperate with pediatricians to diagnose
and treat patients. We also have specialized outpatient
clinics, liver and biliary tract clinics and a tumor clinic.

174

Recently, a second-opinion clinic has opened withcareful detailed explanations and this has received afavorable reception.
Our ward is on the second floor south of the hospital A
wing. Other pediatric surgical patients are also
admitted to this ward. We have 16 beds in the ward
and about 400 patients a year are hospitalized. Most
operation cases are inguinal hernia, but we have othercases such as respiratory surgery disease, neonatal
digestive organ obstructions, infant malignant tumors
such as Wilms' tumor and neuroblastoma, biliary tract
diseases such as biliary tract dilatation and biliaryatresia, trachea stenosis, and lung cysts.
We compare positively with Pediatric Surgery at otherinstitutions that perform endoscopic surgery(laparoscopic surgery/thorascopic surgery). We havedeveloped an endoscopic surgery technique forpediatric diseases not covered by insurance to apply toadvanced medical care. Furthermore, we surgicallymanage seriously ill mentally and physicallyhandicapped infants and nervous system intractabledisease patients to improve their quality of life, andwe cooperate with pediatricians (neonatologists) totreat patients with prenatal diagnosis

Education
We expose 1st and 2nd year students to our dailyclinical work as well as research work during “Free
Quarter” and “Research Lab Visit” courses. Thesestudents are guided to be concerned with clinical areas
and are in charge of part of the research project. The
students hold a results announcement party at the endof training. For M2 students, general pediatric surgery
and neonatal surgery instruction is given by theprofessor and the lecturer.
An education program is also provided for M3 and M4
students for 5 days.
The bedside education of pediatric surgery consists ofparticipation in clinical conferences, attendance at
operations, and small group lectures concerning
neonatal surgery, pediatric surgical oncology, pediatrichepatobiliary surgery, and pediatric emergency
medicine which include the practice of cardiac
massage and intra-tracheal intubation using
mannequins for practice.
We take charge of the core surgical curriculum in the“super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge about pediatric surgical disease andsurgery, and hemodynamic and respiratory evaluation
as well as basic surgical techniques and patientmanagement.

Research activities
Professor Iwanaka has established a low invasive
operation study group and developed experiments forendscopic surgery using white rabbits in the animal
resources research facilities. This study group tries todevelop endoscopic surgery for infants. Prof. Iwanaka
also provides a training program for infant endscopic
surgery for members of our department. In addition,
he has started the project of robotic surgery to perform
radical operation with laparoscopic surgery techniquefor biliary atresia.
The intestinal tract immunity study group was the firstto start infant digestive organ function activation
medical treatment using a probiotic, Shinbiotic, withgood clinical effects, and also started a fundamental
study using an animal model.
Professor Iwanka. has performed the study of theregenerative medicine positively. He founded a newlaboratory in the Department of Tissue Engineering toperform not only conventional animal experiments but
also human experiments to fabricate a trachea in theclinical course. Furthermore, The differentiation
experiment of stem cells in amniotic fluid was
performed in this laboratory by the obstetrics andgynecology department cooperation in our hospital.
The continuing tumor study group analyzes the genes
related to tumor development. New therapy using avirus is under development.
The hepato-biliary and transplantation groupelucidated the immune system after livertransplantation and small intestinal transplantation.
They also studied the pathophysiology of clinicalpostoperative biliary atresia.

References
1. Iwanaka T, Kawashima H, Uchida H. The
laparoscopic approach of neuroblastoma..
Seminars in Pediatric Surgery. 2007; 16: 259-265.

175

2. Kanamori, Y. Hashizume, K. Sugiyama, M.
Tomonaga, T. Takayasu, H. Ishimaru, T.T erawaki,
K. Suzuki, K. Goishi, K. Takamizawa, M. Longterm survival of a baby with body stalk anomaly:report of a case. Surg Today. 2007; 37: 30-33.
3. Nakanishi H, Ozaki T, Nakamura Y, Hashizume K,
Iwanaka T, Nakagawara A. Purification of humanprimary neuroblastomas by magnetic beads andtheir in vitro culture. Oncology Reports. 2007;
17: 1315-1320.
4. Yamagishi, J. Ishimaru, Y. Takayasu, H. Otani,
Y.Tahara, K.Hatanaka, M.Hamajima, A.Hasumi,
A.Ikeda, H. Visceral coverage with absorbablemesh followed by split-thickness skin graft in
the treatment of ruptured giant omphalocele.
Pediatr Surg Int. 2007; 23: 199-201
5. Takayasu H, Nakazawa N, Montedonico S, ,Paradisi F, Puri P. Impaired alveolar epithelial
cell differentiation in the hypoplastic lung in
nitrofen-induced congenital diaphragmatic
hernia. Pediatr Surg Int. 2007; 23:405-410.
6. Takayasu H, Nakazawa N, Montedonico S, Puri
P. Reduced expression of aquaporin 5 water
channel in nitrofen-induced hypoplastic lungwith congenital diaphragmatic hernia rat model.
Pediatr Surg. 2007; 42:415-419.
7. Takayasu, H. Nakazawa, N. Montedonico, S.
Puri, P. Reduced expression of aquaporin 5
water channel in nitrofen-induced hypoplastic
lung with congenital diaphragmatic hernia rat
model. J Pediatr Surg. 2007; 42: 415-419
8. Takayasu H, Nakazawa N, Montedonico S, Puri
P. Down-regulation of Wnt signal pathway innitrofen-induced hypoplastic lung. J Pediatr
Surg. 2007; 42:426-430.
9. Nakazawa N, Takayasu H, Montedonico S, Puri
P. Altered regulation of retinoic acid synthesis
in nitrofen-induced hypoplastic lung. Pediatr
Surg Int. 2007; 23:391-396.
10. Nakazawa, N. Montedonico, S. Takayasu, H.
Paradisi, F. Puri, P. Disturbance of retinoltransportation causes nitrofen-induced hypoplastic
lung." J Pediatr Surg. 2007; 42: 345-349.
11. Komura M, Kanamori Y, Sugiyama M, Tomonaga
T, Suzuki K, Hashizume K, Goishi K. A female
infant who had both complete VACTERL
association and MURCS association: report of acase. Surg Today. 2007; 37:878-880.
12. Kitano Y. Prenatal intervention for congenital
diaphragmatic hernia. Semin Pediatr Surg. 2007
May; 16:101-108.
13. Yokoyama S, Morioka D, Fukuda A, Honna T,
Kuroda T, Nakagawa S, Shimizu N, Nakagawa A,
Kasahara M. Successful living-donor livertransplantation in a 3-year-old boy with fulminant
hepatic
failureandaplastic
anemia.
Transplantation. 2007 Sep 15; 84:668-9.

Reproductive, Developmental andAging Sciences
3. Aging Sciences

177

Department of Geriatric Medicine
Department of Aging Research
Professor
Yasuyoshi Ouchi, M.D.,Ph.D.

Associate Professor
Masahiro Akishita, M.D., Ph.D.

Lecturer
Shinji Teramoto, M.D., Ph.D.,

Masato Eto, M.D., Ph.D.

Katsuya Iijima, M.D., Ph.D.

Research Associate
Sumito Ogawa, M.D., Ph.D.,

Yasuhiro Yamaguchi, M.D., Ph.D.,

Hiroshi Yamamoto, M.D.

Homepage

http://www.m.u-tokyo.ac.jp/mcm/

Introduction and Organization

Clinical activities

The Department of Geriatrics was established in
1962, as the first geriatric department in Japan.
Since elderly patients usually have multiple organ
disorders, we have to take care the patients as a wholefrom multiple points of view. In addition, in theelderly patients, symptoms, signs and responses to thetreatment are sometimes quite different from theyoung. We have to have a broad knowledge on thephysiological and metabolic changes with aging when
we treat the elderly patients. Quality of life of thepatients is another point of view which should beemphasized.
Our sub-specialty includes respirology, cardiology,
neurology, hematology, endocrinology, and bonemetabolism, besides the general geriatric internal
medicine.
We are trying to elucidate the pathophysiology of
aging process and understand elderly patients fromviewpoints of basic aging science using molecularbiology technique and clinical aspects using the recent
advancement of technology and geriatric assessment.

In the clinical ward, there are around 20 patients
who are taken care of by junior, senior and chief
residents of our staff. Because senior and chief
residents are very experienced, they team up with ajunior resident, give instructions as to the assessmentof the patient's problem, making of future plans, andhelp the resident with various procedures. Very
important issues are discussed and decisions are madein weekly professor's round.
Specialized services are provided to out-patients ona daily basis in all areas of internal medicine.
Approximately 400 new and a total of 18,000 patients
visit the out-patient clinic in a year.

Teaching activities
Clinical education is provided for fifth and sixthyear medical students on a man-to-man basis with afaculty staff member. During the period, the student
studies one or two cases, through which the student
learns the techniques interrogation and physical178

examination, interpretation of laboratory tests, andactual medical procedures. Interpretation of the resultsof geriatric assessment is studied through lectures in acase-oriented manner with an emphasis placed on themultidisciplinary basis of geriatric patients.

3.

Research activities
Pulmonary unit
Lung mechanics, exercise physiology, management
and assessment of dyspnea, sleep study for nocturnal
disturbed breathing, latent virus infection in airways,
animal model of aging lung, prediction and preventionof aspiration pneumonia, pathophysiology ofinterstitial lung disease, role of adhesion molecule inairway disease, role of endothelin, leukotrienes, andneuropeptides
inasthma,proliferationanddifferentiation of lung fibroblasts, proliferation andapoptosis of airway disease, defensin and infectious
disease.
Cardiovascular unit
Research on the mechanism and regulation ofvascular calcification, sex hormone regulation ofvascular function, clinical evaluation of vascularfunction using vascular ultrasound and pulse wave
velocity, metabolic syndrome in the elderly.
Neurology unit
Diagnosis and treatment of the demented patients,
neuro-protective function of Thioredoxin in
Drosophila,
regulationofapoptosisbystress-responsive kinases, etc
Osteoporosis and endocrinology unit
Bone metabolism, mechanism of action nuclear ofreceptors, genetic analysis of osteoporosis, vitamin K
action, hormone dependent cancer.

4.

5.

6.

7.

8.

References
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Iijima K, Eto M, Ouchi Y. Low testosterone levelis an independent determinant of endothelial
dysfunction in men. Hypertens Res. 30; 1029-34,
2007
2. Aoki-Nagase T, Nagase T, Oh-Hashi Y, Kurihara

9.

Y, Yamaguchi Y, Yamamoto H, Nagata T,
Kurihara H, Ouchi Y. Calcitonin gene-related
peptide mediates acid-induced lung injury in mice.
Respirology 12; 807-13, 2007
Arai H, Yamamoto A, Matsuzawa Y, Saito Y,
Yamada N, Oikawa S, Mabuchi H, Teramoto T,
Sasaki J, Nakaya N, Itakura H, Ishikawa Y, Ouchi
Y, Horibe H, Egashira T, Hattori H, Kita T.
Polymorphisms of apolipoprotein E andmethylenetetrahydrofolate reductase in theJapanese population. J Atheroscler Thromb. 14;
167-71, 2007
Asai A, Sahani N, Kaneki M, Ouchi Y, Martyn JA,
Yasuhara SE. Primary role of functional ischemia,
quantitative evidence for the two-hit mechanism,
and phosphodiesterase-5 inhibitor therapy inmouse muscular dystrophy. PLoS ONE 2; e806,
2007
Fujimura T, Takahashi S, Urano T, Kumagai J,
Ogushi T, Horie-Inoue K, Ouchi Y, Kitamura T,
Muramatsu M, Inoue S. Increased expression of
Estrogen-Related Receptor alpha (ERRalpha) is anegative prognostic predictor in human prostatecancer. Int J Cancer 120; 2325-30, 2007
Ghisletti S, Huang W, Ogawa S, Pascual G, Lin M,
Willson TM, Rosenfeld MG, and Glass CK.
Parallel
SUMOylation-dependent
pathways
mediate gene- and signal-specific transrepression
by LXRs and PPARγ. Mol Cell 25; 57-70, 2007
Kano MR, Bae Y, Iwata C, Morishita Y, Yashiro
M, Oka M, Fujii T, Komuro A, Kiyono K,
Kaminishi M, Hirakawa K, Ouchi Y, Nishiyama N,
Kataoka K, Miyazono K. Improvement ofcancer-targeting therapy, using nanocarriers for
intractable solid tumors by inhibition of TGF-beta
signaling. Proc Natl Acad Sci U S A. 104; 3460-5,
2007
Kinoshita H, Nakagawa K, Narusawa K,
Goseki-Sone M, Fukushi-Irie M, Mizoi L,
Yoshida H, Okano T, Nakamura T, Suzuki T,
Inoue S, Orimo H, Ouchi Y, Hosoi T. A functional
single nucleotide polymorphism in the vitamin
K-dependent gamma-glutamyl carboxylase gene(Arg325Glu) is associated with bone mineraldensity in elderly Japanese women. Bone 40;
451-6, 2007
Kumagai J, Fujimura T, Takahashi S, Urano T,

179

Ogushi T, Horie-Inoue K, Ouchi Y, Kitamura T,
Muramatsu M, Blumberg B, Inoue S. Cytochrome
P450 2B6 is a growth-inhibitory and prognostic
factor for prostate cancer. Prostate 67; 1029-37,
2007
10. Ota H, Akishita M, Eto M, Iijima K, Kaneki M,
Ouchi
Y.
Sirt1
modulates
prematuresenescence-like phenotype in human endothelial
cells. J Mol Cell Cardiol. 43; 571-9, 2007
11. Pascual G, Sullivan AL, Ogawa S, Gamliel A,
Perissi V, Rosenfeld MG, Glass CK. Antiinflammatory and antidiabetic roles of PPARγ.
Novartis Found. Symp. 286; 183-96, 2007
12. Son BK, Kozaki K, Iijima K, Eto M, Nakano T,
Akishita M, Ouchi Y. Gas6/Axl-PI3K/Akt
pathway plays a central role in the effect of statins
on inorganic phosphate-induced calcification ofvascular smooth muscle cells. Eur J Pharmacol.
556; 1-8, 2007
13. Takayama K, Kaneshiro K, Tsutsumi S,
Horie-Inoue K, Ikeda K, Urano T, Ijichi N, Ouchi
Y, Shirahige K, Aburatani H, Inoue S.
Identification of novel androgen response genes inprostate cancer cells by coupling chromatin
immunoprecipitation and genomic microarray
analysis. Oncogene 26; 4453-63, 2007
14. Umeda-Kameyama Y, Tsuda M, Ohkura C,
Matsuo T, Namba Y, Ohuchi Y, Aigaki T.
Thioredoxin
suppresses
Pael-R-induced
neurotoxicity and extends longevity in drosophila.
J Biol Chem. 282; 11180-7, 2007
15. Urano T, Narusawa K, Shiraki M, Usui T, Sasaki
N, Hosoi T, Ouchi Y, Nakamura T, Inoue S.
Association of a single nucleotide polymorphismin the WISP1 gene with spinal osteoarthritis in
postmenopausal Japanese women. J Bone Miner
Metab. 25; 253-8, 2007
16. Urano T, Shiraki M, Narusawa K, Usui T, Sasaki
N, Hosoi T, Ouchi Y, Nakamura T, Inoue S. Q89R
polymorphism in the LDL receptor-related protein
5 gene is associated with spinal osteoarthritis in
postmenopausal Japanese women. Spine 32; 25-9,
2007
17. Urano T, Shiraki M, Ouchi Y, Inoue S.
Association of a single nucleotide polymorphismin the steroid and xenobitic receptor (SXR) gene
(IVS1-579A/G) with bone mineral density.

Geriatric Gerontol Int. 7; 104-9, 2007
18. Usui T, Urano T, Shiraki M, Ouchi Y, Inoue S.
Association of a single nucleotide polymorphismin Wnt10b gene with bone mineral density.
Geriatric Gerontol Int. 7; 48-53, 2007
19. Xi H, Akishita M, Nagai K, Yu W, Hasegawa H,
Eto M, Kozaki K, Toba K. Potent free radical
scavenger, edaravone, suppresses oxidative
stress-induced endothelial damage and early
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20. Yamaguchi Y, Nagase T, Tomita T, Nakamura K,
Fukuhara S, Amano T, Yamamoto H, Ide Y,
Suzuki M, Teramoto S, Asano T, Kangawa K,
Nakagata N, Ouchi Y, Kurihara H. Beta-defensin
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21. Yamamoto H, Nagase T, Shindo T, Teramoto S,
Aoki-Nagase T, Yamaguchi Y, Hanaoka Y,
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22. Fujimura T, Takahashi S, Urano T, Kumagai J,
Ogushi T, Horie-Inoue K, Ouchi Y, Kitamura T,
Muramatsu M, Inoue S. Increased expression of
estrogen-related receptor alpha (ERRalpha) is anegative prognostic predictor in human prostatecancer. Int J Cancer. 120:2325-2330, 2007
23. Yu J, Eto M, Akishita M, Kaneko A, Ouchi Y,
Okabe T. Signaling pathway of nitric oxide
production induced by ginsenoside Rb1 in humanaortic endothelial cells: A possible involvement of
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24. Ishii M, Teramoto S, Yakabe M, Yamamato H,
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syndrome. J Am Geriatr Soc. 55; 1891-2, 2007
28. Teramoto S, Yamamoto H, Yamaguchi Y, Hanaoka
Y, Ishii M, Hibi S, Ouchi Y. ACE inhibitors
prevent aspiration pneumonia in Asian, but not
Caucasian, elderly patients with stroke. Eur
Respir J. 29; 218-9, 2007
29. Ishii M, Teramoto S, Yakabe M, Yamamato H,
Yamaguchi Y, Hanaoka Y, Ouchi Y. Small
intestinal intussusceptions caused by percutaneousendoscopic jejunostomy tube placement. J Am
Geriatr Soc. 55; 2093-4, 2007
30. Kinoshita H, Hirano H, Hosoya A, Ninomiya T,
Ozawa H, Sawabe M, Ouchi Y, Yamaguchi M,
Hosoi T. Case of bone Paget's disease with cheekpain, hearing loss and tremor whose histologicalfindings showed peculiar calcified structures.
Geriatr Gerontol Int. 7; 189-94, 2007
31. Kojima T, Ako J, Eto M, Iijima K, Akishita M,
Ouchi Y. Tako-tsubo-like left ventricular
dysfunction in a patient with chronic total
occlusion of the left anterior descending artery. Int
J Cardiol. 119; e19-21, 2007

Surgical Sciences
1. Surgery

182

Thoracic Surgery
Professor
Takamoto, Shinichi

Associate Professor
Nakajima, Jun

StaffsMurakawa, Tomohiro and Fukami, Takeshi

Homepage

http://ctstokyo.umin.ne.jp/

History
Clinical and basic researches of the thoracic surgery
has been performed since the prewar era in thisuniversity, when Professor Masao Tsuduki adopted themodified Coryllos’s thoracoplasty for the treatment of
the pulmonary tuberculosis in 1934. They initiatedthoracoscopy for the treatment of the tuberculosis in
our country. After the successful application of theantituberculous drugs, surgical treatment of thethoracic malignant neoplasms was the major concernof the thoracic surgery.
The Department of Cardiothoracic Surgery, The
University of Tokyo, was established in December 15,
1964 as the first department of this field along withthe cardiovascular surgery in the Japanese national
universities. Since then it has played an internationallyleading role and contributed to development of the
field in our country.
Professors and Chairs in the history of thedepartment are as follows: Kimoto, Seiji (1964.12.15~ 1968.3.31), Saigusa, Masahiro (1968.4.1 ~1981.3.31), Asano, Ken-ichi (1981.4.1 ~ 1986.3.31),
Furuse, Akira (1986.4.1 ~ 1997.3.31) and Takamoto,Shinichi (1997.6.1 ~).
The Department of Cardiothoracic Surgery has been
divided into two departments, Department of
Cardiovascular Surgery and Department of Thoracic
Surgery in 1998.
The mission of the Department of Thoracic Surgery

is to improve the patients with diseases of the thoracic
organs through clinical works, basic and clinicalresearches, and education of the medical students,
postgraduates, and the surgical residents in our
university.

Clinical activities
Three staffs (Nakajima J, Murakawa T, and FukamiT), certificated as members of the Japanese Board ofGeneral Thoracic Surgery, are in charge of the
Department of Thoracic Surgery, University of Tokyo
Hospital. They specialize in surgical treatment of thediseases of the respiratory and the mediastinal organs
and the chest wall, except for diseases of theesophagus and mammary glands. Approximately 250
surgeries are performed in the department in 2007.
Primary lung cancer has been the leading cause ofdeath among the malignant neoplasms in our country.
As the number of the dead patients by the lung cancer
has been increasing, the basic and the clinicalinvestigations for the treatment of the lung cancer arevery important. In our department, the staffs
participate the clinical works, studies and educationsof diagnostics and therapeutics of the lung cancer aswell as other thoracic diseases.
We have performed the modern-style thoracoscopy
for the diagnosis and treatment of the thoracic disease
with less surgical invasiveness since 1992.
Approximately a half of the surgical procedures in our183

department have been safely and successfully
accomplished through thoracoscopy. Researches on
less-invasiveness, oncological advantage of thethoracoscopic surgery have been studied actively.
Pulmonary metastasis represents far advanced
malignant neoplasms of extrathoracic organs.
Pulmonary resection is an option for the treatment of
pulmonary metastasis. We actively perform
pulmonary resection through thoracoscopy on patientswith pulmonary metastasis who are eligible forsurgical therapy.
Thymic epithelial neoplasms, such as thymoma andthymic carcinoma, show broad spectrum in the degreeof malignancy. They also associated withparaneoplastic syndromes, such as the myasthenia
gravis and the pure red cell aplasia. We have sought toestablish the strategies on diagnosis and treatment ofthese diseases, which are still yet to be determined,from our clinical experiences of more than 200 caseswith the diseases in our department.

Academic education
Medical students in the fifth grade have two-weeks’program on the clinical training of the thoracic and the
cardiovascular surgery. They are also able toparticipate the clinical clerkship of the cardiothoracic
surgery, an elective course for 4 weeks. The
Department of Thoracic Surgery also offers the 4-year
postgraduate program for qualified surgeons who arewilling to specialize in the thoracic surgery.

Current researches
Main subjects of current research at present include
basic and clinical studies on the malignant neoplasmsin the thorax, transplantation of the thoracic organs
and the cryopreserved tissues. Recently we conductedclinical studies on the immunotherapy with adopted
gamma- delta- T-cell for the treatment of the advanced
non-small cell lung cancer and the pulmonoary
metastasis from extrathoracic organs.
The following are the major themes under research:(1) New oncogenes or suppressor oncogenes of thelung cancer(2) New methods for quantitative analysis of the
DNA methylation of the lung cancer.

(3) Clinical studies on the less-invasive surgicaltreatment of the thoracic malignancies(4) Analysis of the factors influencing the prognosisof lung cancer or mediastinal neoplasms is also
performed.
(5) Adoptive anticancer immunity of the autologous
gamma-delta-T-cell(6) Mechanisms of acute or chronic rejection of theallogeneic trachea.

Selected publications
1. Nakajima J, Takamoto S, Murakawa T, Fukami T,
Sano A. Interstitial pneumonia caused by collagendiseases: A contraindication for lung cancer surgery?
Surgery Today 37: 14-18, 2007
2. Nakajima J, Goto A, Takamoto S, Murakawa T,
Fukami T, Kusakabe M. Invasive lymphangioma of
the lung presented as a large pulmonary mass andhemoptysis. Surgery Today 37: 418-422, 2007
3. Nakajima J, Morota T, Matsumoto J, Takazawa Y,
Murakawa T, Fukami T, Yamamoto T, Takamoto S.
Pulmonary intimal sarcoma treated by a left
pneumonectomy with pulmonary arterioplasty undercardiopulmonary bypass: Report of a Case. Surgery
Today 37: 496-499, 2007
4. Wang T, Niki T, Goto A, Ota S, Morikawa T,
Nakamura Y, Ohara E, Ishikawa S, Aburatani H,
Nakajima J, Fukayama M. Hypoxia increases the
motility of lung adenocarcinoma cell line A549 via
activation of the epidermal growth factor receptor
pathway. Cancer Science. 98:506-511, 2007
5. Babu AN, Murakawa T, Thurman JM, Miller EJ,
Henson PM, Zamora MR, Voelkel NF, Nicolls MR.
Microvascular destruction identifies murine
allografts that cannot be rescued from airway
fibrosis. The Journal of Clinical Investigation 117:3774-3785, 2007
6. Sano A, Kage H, Sugimoto K, Kitagawa H, Aki N,
Goto A, Fukayama M, Nakajima J, Takamoto S,
Nagase T, Yatomi Y, Ohishi N, Takai D. A
second-generation
profilingsystemforquantitative methylation analysis of multiple genepromoters: application to lung cancer. Oncogene.
26: 6518-25, 2007
7. Nakamura Y, Niki T, Goto A, Morikawa T,
Miyazawa K, Nakajima J, Fukayama M. c-Met

184

activation in lung adenocarcinoma tissues: an
immunohistochemical analysis. Cancer Science
98:1006-13, 2007
8. Nagayama K, Kohno T, Sato M, Arai Y, Minna
JD, Yokota J. Homozygous deletion scanning of
the lung cancer genome at a 100-kb resolution.
Genes Chromosomes Cancer 46:1000-1010, 2007
9. Nakajima J, Murakawa T, Fukami T, Sano A.
Sugiura M, Takamoto S. Is finger palpation at
operationindispensablefor
pulmonarymetastasectomy in colorectal cancer? The Annalsof Thoracic Surgery. 84:1680-1684, 2007

185

Department of
Cardiothoracic Surgery
Professor
Shinichi Takamoto, M.D.

Associate Professor
Arata Murakami, M.D.

Lecturer
Noboru Motomura, M.D.,

Tetsuro Morota, M.D.,

Minoru Ono, M.D.

Associate
Koh Takeuchi, M.D.,

Tetsufumi Yamamoto, M.D.,

Munemoto Endo, M.D.

Yoshihiro Suematsu, MD

Mitsuhiro Kawata, MD

Kan Nawata, MD

Homepage

http://ctstokyo.umin.ne.jp/

Introduction and Organization
Cardiac surgery in the Department was initiated by
Dr. Seiji Kimoto, who performed ligation of patentductus arteriosus in June, aortic arch aneurysm
resection in July and first-in-Japan Blalock-Taussig
operation for Tetralogy of Fallot in October in 1951.
He also started implantation of alcohol-preserved
aortic homograft for abdominal aortic aneurysm in
1952, and closed commissurotomy for mitral valve
stenosis in 1954. The first open heart surgery (atrial
septal defect closure) was performed in 1955, using
selective brain perfusion cooling method that wasdeveloped in the Department.
Establishment of Department of Thoracic Surgery
in the University of Tokyo Hospital was approved by
the government first in Japan December 15, 1964.
Under the leadership of Professor Kimoto excellent
research works were created especially on pacemakerand artificial heart, and many opinion leaders were
produced. Dr. Masahiro Saigusa, the second Professor,

endeavored to make open heart surgery safer byintroducing new- generation heart-lung machines tothe Department. Dr. Kenichi Asano, the third
Professor, started posterior-leaflet preserving mitralvalve replacement first in Japan. He also dramatically
improved surgical results of Tetralogy of Fallot. Dr.
Akira Furuse, the fourth Professor, modernizedmanagement of extremely busy clinical works. During
this time, the Department was divided into two
Divisions, Cardiovascular and General thoracic, due
to the University policy of Graduate-school.
Dr. Shinichi Takamoto assumed the fifth Professor
in June 1997. He rearranged clinical teams into threegroups (adult cardiac disease, thoracic aortic diseaseand congenital heart disease) to adapt the rapid
progress of cardiovascular surgery. Present staffs are
one Chief Professor, one Associate Professor and three
Lecturer and six Associates.

186

Clinical Activities
Clinical conference starts at 7:15 am in weekdays.
Regular surgery is scheduled on Monday, Wednesday
and Friday. Patient round is on Tuesday and Thursday.
Adult patients are hospitalized in the South Wing of
5th floor, and pediatric patients in the South Wing of
2nd floor. Clinics are open Monday through Friday forthe follow-up visit as well as for patient referral.
Case volume in recent years has been about 350,
which is one of the highest in Japan. We are leading inJapan by showing excellent surgical results. There areeight Board- certified surgeons, each of whom has his
own subspecialty among adult cardiac, thoracic aortic
or congenital heart disease. We are famous for aortic
valve sparing root replacement, arch replacement
using retrograde cerebral perfusion, treatment ofextended thoracic aortic aneurysm, ventricular assist
device implantation, off- pump coronary artery bypass
surgery, mitral valve plasty and repair of complex
congenital heart diseases, such as Jatene, Fontan and
Norwood operations.
The University of Tokyo Tissue Bank was founded
in 1997, based on the Department of Cardiovascular
Surgery. The Bank has been actively promoting
procurement, preservation and shipping of humanvalve and blood vessel allograft in Japan. We take thelead in surgical treatment using allograft for severe
active endocarditis or infection of aortic aneurysm or
vascular prosthesis. Surgical treatment using allograft
was approved as advanced medical technology by theGovernment in 2006. As of March 2008, four cases ofheart transplantation were performed in The
University Hospital.

Teaching Activities
We have the chair of systematic review ofcardiovascular surgery in the spring term at the 2nd
grade of medical course. We also take charge inclinical practice on diagnosis of cardiovasculardisease in the autumn term at the 2nd grade. We expose
the students to daily clinical works as well as researchworks during the course of “Free Quarter” and“Research Lab Visit”, which are scheduled in thesummer and spring vacations at 1st and 2nd grade. Joint
lectures with the Cardiology Department arescheduled 3rd through 4th grades. Each student is
assigned one or two cardiovascular surgical cases in
the Bed Side Learning, in which he/she is required tolearn preoperative patient evaluation and management,
surgical treatment and postoperative care, based onparticipatory practice. There are also twelve small
key-lectures on cardiovascular surgery. Hands-on
practice is provided during the “Clinical clerkship”
one-month course in the last months of 3rd grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required four-year general surgicaltraining for General Surgery Board certification. We
have well-developed specialty/ subspecialty training
programs to allow the residents to pass Cardiovascular
Board Examination by 10th postgraduate year.

Research Activities
In order to achieve excellent clinical results and toseek for new possibilities of surgical treatments, it isessential for cardiothoracic surgical department of the
University to have active research programs in clinicaland basic subjects. The cardiothoracic department of
the University of Tokyo has created highly active
research programs in the every field of cardiothoracic
surgery, played an internationally leading role andcontributed to its development. A research meeting isheld every Saturday on a research project for every
member of the department to understand and to makefree thorough discussions of the subject.
Basic and/or clinical research activities are focusedon 1) new effective brain and spinal protection
strategy, 2) intracardiac repair technique on a beatingheart guided by three-dimensional echo, 3) basic andclinical research on cryopreserved allograft, 4)
treatment of end-stage heart failure by ventricularassist device, 5) a new technique of aortic valve
sparing root replacement and its hemodynamic
evaluation, 6) development of intrauterine treatment
for fetal heart disease, 7) application of regenerative
medicine to end-stage heart failure, 8) treatment of

187

acute and chronic rejection after heart transplantation.

References
1. Taketani T, Nawata K, Motomura N, Ono M,
Takamoto S: Acute stenosis of porcine stentless
bioprosthesis caused by infective endocarditis.
Circulation 114:e567-568, 2006
2. Morota T. Takamoto S. Kitamura T. Motomura N.
Ono M: Clinical experience with Cryopreserved
Allografts for Aortic Infection. J Jpn Coll Angiol
46:817-822, 2006
3. Takeuchi K. McGowan FX Jr. Bacha EA. MayerJE Jr. Zurakowski D. Otaki M. del Nido PJ:
Analysis of surgical outcome in complex
double-outlet right ventricle with heterotaxy
syndrome or complete atrioventricular canal
defect. Ann Thorac Surg 82:146-152, 2006
4. Takeuchi K. Murakami A. Takaoka T. Takamoto
S: Evaluation of valved saphenous vein homograftas right ventricle-pulmonary artery conduit inmodified stage I Norwood operation. Interact
CardioVasc Thorac Surg 5:345-348, 2006
5. Takeuchi K. Murakami A. Hirata Y. Kitahori K.
Doi Y. Takamoto S: Surgical Outcome of
Heterotaxy Syndrome in a Single Institution Asian.
Cardiovasc Thorac Ann 14:489-494, 2006
6. Hisagi M. Higuchi K. Koseni K. Inaba H: Total
Anomalous Pulmonary Venous Return in an Adult.
Asian Cardiovasc Thorac Ann 14:e27-29, 2006
7. Ohno T, Ando J, Ono M, Morita T, Motomura N,
Hirata Y, Takamoto S: The Beneficial effect ofcoronary-artery-bypass surgery on survival inpatients with diabetic retinopathy. Eur J
Cardiothorac Surg 30:881-886, 2006
8. Ono T, Ohashi T, Asakura T, Ono N, Ono M,
Motomura N, Takamoto S: Impact of diabetic
retinopathy on cardiac outcome after coronary
artery bypass graft surgery: prospective
observational study. Ann Thorac Surg 81:608-612,
2006
9. Tsukihara H. Takamoto S. Kitahori K. Matsuda K.
Murakami A. Novick RJ. Suematsu Y: Preventionof Postoperative Pericardial Adhesions With a
Novel Regenerative Collagen Sheet. Ann Thorac
Surg 81:650-657, 2006
10. Kawata M, Sekino M, Takamoto S, Ueno S,

Yamaguchi S, Kitahori K, Tsukihara H, Suematsu
Y, Ono M, Motomura N, Morota T, Murakami A:
Retrograde cerebral perfusion with intermittent
pressureaugmentation
providesadequateneuroprotection: diffusion- and perfusionweighted magnetic resonance imaging study in anexperimental canine mode. J Thorac Cardiovasc
Surg 132:933-940, 2006
11. Kawata M, Takamoto S, Kitahori K, Tsukihara H,
Morota T, Ono M, Motomura N, Murakami A,
Suematsu Y: Intermittent pressure augmentation
during retrograde cerebral perfusion undermoderate
hypothermia
providesadequateneuroprotection: an experimental study. J Thorac
Cardiovasc Surg 132:80-88, 2006
12. Kawata M, Takamoto S, Kitahori K, Tsukihara H,
Morota T, Ono M, Motomura N, Murakami A,
Suematsu Y: Erythropoietin protects the central
nervous system during prolonged hypothermic
circulatory arrest: an experimental study in acanine model. J Thorac Cardiovasc Surg 131:
1331-1337, 2006
13. Kawata M., Atsumi N., Nakayama S: Poor
response to a balloon atrial septostomy in TGA
with pulmonary hypertension. Chirurgia 19:169,
2006
14. Kawata M., Atsumi N., Nakayama S: Acuteprolapse of floppy mitral valve in an infant.
Chirurgia 19:41, 2006
15. Higuchi K. Koseni K. Takamoto S.: Graftinsertion technique for distal anastomosis in casesof ascending aortic aneurysm. J Cardiovasc Surg
46: 537-8, 2005
16. Kubota H. Takamoto S. Furuse A. Sato M. Endo
H. Fujiki T. Sudo K.: Epicardial maze procedureon the beating heart with an infrared coagulator.
Ann Thorac Surg 80:1081-6, 2005
17. Kawata M. Takamoto S. Morota T. Ono M.
Motomura N. Murakami A. Suematsu Y.: Is theguideline the cause of structural failure in current
polyester vascular prostheses? An experimental
study. Artif Organs. 29:820-5, 2005
18. Yamamoto T. Sata M. Fukuda D. Takamoto S.:
The angiotensin II type 1 receptor blocker
valsartan attenuates graft vasculopathy. Basic Res
Cardiol 100:84-91, 2005
19. Miyaji K. Murakami A. Takasaki T. Ohara K.

188

Takamoto S. Yoshimura H.: Does a bidirec- tional
Glenn shunt improve the oxygenation of rightventricle-dependent coronary circulation inpulmonary atresia with intact ventricular septum?
J Thorac Cardiovasc Surg 130:1050-3, 2005
20. Kawata M. Morota T. Takamoto S. Kubota H.
Kitahori K.: Non-anastomotic rupture in theguideline of a Dacron thoracic aortic graft. J Vasc
Surg 42:573, 2005
21. Takamoto S.: Managing surgical quality based on
database. Jap J Thorac Cardiovasc Surge 53:337,
2005
22. Kitahori K. Takamoto S. Takayama H. Suematsu
Y. Ono M. Motomura N. Morota T. Takeuchi K.:
A novel protocol of retrograde cerebral perfusion
with intermittent pressure augmentation for brain
protection. J Thorac Cardiovasc Surg 130:363-70,
2005
23. Tanaka K. Sata M. Fukuda D. Suematsu Y.
Motomura N. Takamoto S. Hirata Y. Nagai R.:
Age-associated aortic stenosis in apolipoprotein
E-deficient mice. J Am Coll Cardiol 46:134-41,
2005
24. Miyairi T. Takamoto S. Kotsuka Y. Takeuchi A.
Yamanaka K. Sato H.: Comparison ofneuroncognitive results after coronary artery
bypass grafting and thoracic aortic surgery using
retrograde cerebral perfusion. Eur J CardioThorac Surg 28:97- 101; 2005
25. Omoto R. Kyo S. Nishimura M. Matsuda H.
Matsumiya G. Kitamura S. Nakatani T. Takamoto
S. Ono M. Tabayashi K. Yozu R.: Japanesemulticenter clinical evaluation of the HeartMate
vented electric left ventricular assist system. J
Artif Organs. 8:34-40, 2005
26. Kitamura T. Morota T. Motomura N. Ono M.
Shibata K. Ueno K. Kotsuka Y. Takamoto S.:
Management of infected grafts and aneurysms of
the aorta. Ann Vasc Surg 19:335-42, 2005
27. Kitamura T. Sata M. Motomura N. Takamoto S.:
Seeding of recipient bone marrow cells reduces
neointimal hyperplasia of deendo- thelialized rat
aortic allograft. Int Heart J 46:303-12, 2005
28. Taketani T. Imai Y. Morota T. Maemura K.
Morita H. Hayashi D. Yamazaki T. Nagai R.
Takamoto S.: Altered patterns of gene expression
specific to thoracic aortic aneurysms: microarray

analysis of surgically resected specimens. Int
Heart J 46:265-77, 2005
29. Taketani T. Miyata T. Morota T. Takamoto S.
Surgical treatment of atypical aortic coarctation
complicating Takayasu's arteritis--experience with
33 cases over 44 years. J Vasc Surg 41:597-601,
2005
30. Hashimoto T. Sugawara Y. Kishi Y. Akamatsu N.
Matsui Y. Kokudo N. Motomura N. Takamoto S.
Makuuchi M.: Superior vena cava graft for right
liver and right lateral sector transplantation.
Transplantation. 79:920-5, 2005
31. Hirata Y. Sata M. Motomura N. Takanashi M.
Suematsu Y. Ono M. Takamoto S.: Humanumbilical cord blood cells improve cardiac
function after myocardial infarction. Biochem
Bioph Res Com 327:609-14, 2005
32. Taketani T. Motomura N. Toyokawa S. Kotsuka
Y. Takamoto S.: Beneficial effect of acutenormovolemic hemodilution in cardio- vascularsurgery. Jap J Thorac Cardiovasc Surg 53:16-21,
2005

189

Department of
Gastrointestinal Surgery
Associate Professor
Sachiyo Nomura MD. PhD.

Lecturer
Hirokazu Yamaguchi MD.

Nobuyuki Shimizu MD. PhD.

Associates
Fumihiko Hatao MD. PhD.,
Kazuhiko Mori MD. PhD.,
Masato Nishida MD. PhD.,

Ikuo Wada MD. PhD.,
Kouji Nozaki MD. PhD.,
Daisuke Sakaguchi MD. PhD.

Homepage
General Affairs:
Since 2001, the former Third Department ofSurgery, which was located in a branch hospital of the
University of Tokyo, has been divided into two
departments, the Department of Gastrointestinal
Surgery and the Department of Metabolic Care andEndocrine Surgery, in line with the integration of themain and branch hospitals the elevation to a
department in the graduate school of medicine at ouruniversity. Our research activities in both departments
have been well organized and ultimately successful by
maintaining a close connection. The Department of
Gastrointestinal Surgery presently comprises one
Professor, one Lecturer，one Hospital Lecturer andnine associates.
With the prolongation of life expectancy, there are
increasing numbers of multi-morbid patients requiring
multi-organ treatment, as well as a greater need for
multidisciplinary approaches to the patients. Our
clinical and research activities have for the most partreceived the cooperation of members in the
Department of Metabolic Care and Endocrine Surgery
as well as those in other surgical departments at the
University of Tokyo.
Our fundamental principles of patient treatment arecomprehensive patient care which includes pre-, peri-,and postoperative management of the diseases as wellas patient care over long-term postoperative periods
which often extend to the terminal stage. We believethat patient care encompassing the entire lifespanprovides a wealth of valuable information concerning
the appropriateness of current treatment strategy, theestablishment of new surgical designs, thedevelopment of new basic research activities which
can much contribute to clinical fields, and indicationsof desirable modes of terminal care.
Fostering good surgeons as well as scientists whomeet both clinical and academic needs has always
been the guiding principle of our Department.

Educational Activities:
We educate chief residents and junior residents inrotation．Our educational systems for residents andstudents reflect our aforementioned principles.
Medical students are encouraged to be members ofclinical staffs rather than mere students during their
bedsideLearning. They learn generic patient care which
encompasses not only perioperative management ofdiseases but also non-surgical management of190

postoperative disorders and terminal care. Our
educational system provides medical students with agreat deal of practical information from the medical
point of view as well as better opportunities to ponder
the implications of life and death.
Junior residents rotate every three months. Aftercompletion of their initial training program, they go
into a further clinical training program for several
consecutive years and become a chief resident. We
have also several postgraduate students who aremainly engaged in research work. Their researchworks are under supervision of the Professor.

Research Activities:
The main research activities of the department of
Gastrointestinal Surgery are focused on diagnosis andtherapy for gastrointestinal diseases and clinical andbasic research for gastrointestinal carcinogenesis fromthe view point of “Surgery and Inflammation”. The
department's research activities have focused on awide spectrum of research topics, ranging from basic
research topics to clinical ones. Our research activities
have been well organized and ultimately achieved bymaintaining a close connection between hospital andlaboratory activities. Our medical staffs make every
effort to promote the research activities and obtain
successful results. Current research topics are:1) Carcinogenesis of gastrointestinal cancer- Diversity of gastointestinal carcinogenesis- Gender differences in gastrointestinal cancers- Roles of sex hormones in gastrointetinal
carcinogenesis- Monoclonality of intestinal metaplasia- Roles of Helicobactor pylori infection in gastriccarcinogenesis- Interaction between cancer and interstitial tissue- Experimental
evaluationofpromotive
mechanisms of gastroduodenal reflux anddenervation of the gastric mucosa in gastricremnant carcinogenesis- Preventative roles of PPARr in gastriccarcinogenesis- Clinical and experimental studies on the Barrett
esophagus

2) Molecular mechanisms of gastrointestinal tract
cancer- Role of bone marrow derived progenitor cells ingastric carcinogenesis- Apoptosis-related molecules during multimodal
therapies for esophageal cancer- Angiogenic factors in gastrointestinal tract cancer- Genetic alterations in gastric cancer andcolorectal cancer- Methylation status of gastrointestinal cancers- Lymph node micrometastasis of gastric cancer
3) Minimally invasive surgery for the treatment ofearly cancer of the stomach and large intestine- Endoscopic treatment- Laparoscopic surgery- Optimal scope of lymphadenectomy- Sentinel lymph node navigation surgery for earlygastric cancer- Evaluation of postoperative QOL after pylorus
preserving gastrectomy (PPG) and jejunal
interposition for early gastric cancer4) Alternative surgical design for the improvement of
the patient's postoperative quality of life5) Radical treatment for advanced gastric cancer6) Multimodal treatment for gastrointestinal tract
cancer- Neoadjuvant or definitive chemoradiation therapy
for esophageal cancer- Neoadjuvant or adjuvant chemotherapy for
gastric and colorectal cancer7) Gastrointestinal motility- Mechanism of pepermint oil solution of digestivetract- Role of cytokine and COX-2 in gastrointestinal
motility- Manipulation of the intestine and postoperative
motility

Clinical Activities:
We have outpatient clinics from Monday throughFriday. We have specialized divisions for outpatient191

management of esophageal, gastric, and colorectal
diseases. The ward is divided into four subgroups, andeach of them has one medical staff for supervision,
one assistant supervisor, one chief resident, and one or
two junior residents in rotation. They are on duty fordaily patient care under the supervision of medical
staffs. Ordinary, each subgroup takes care of 10-12
patients.
We have our own multidisciplinary diseaseevaluation systems for inpatients and outpatients, suchas endoscopy and endoscopic ultrasonography for
upper and lower gastrointestinal tracts, ultrasounddiagnosis, and barium roentgenogram. These
multidisciplinary services provide good opportunities
to evaluate the diseases systematically from thesurgeon's standpoint. We also perform endoscopic
treatment, especially mucosal resection for strictly
selected early cancers in the upper and lower
gastrointestinal tract.
The weekly official activities of our department are
Ward Rounds by the Professor on Monday and by the
Associate Professor on Friday. We have post- andpreoperative case conferences on Tuesday, Wednesday
and Thursday morning, respectively, and a journal
club on Monday. We also have a specialized uppergastrointestinal case conference on Tuesday evening.
Nursing-staffs have meetings with medical doctors on
every Friday to ensure a high quality of patient careduring the patients' hospital stay.
Generally, elective surgery is scheduled on Tuesday，
Wednesday and Thursday. The statistics for 20 ５
show more than 250 cases of elective surgery andemergency surgery. All residents and medical
personnel work many extra hours with highmotivation whenever it is necessary for the good of
the patients.

3.

4.

5.

6.

7.

8.

References9.
1. Seto Y, Chin K, Gomi K, Kozuka T, Fukuda T,
Yamada K, Matsubara T, Tokunaga M, Kato Y,
Yahune A, Yamaguchi T. Treatment of thoracic
esophageal
carcinoma
invading
adjacent
structures. Cancer Science 998:937-942,2007
2. Seto Y, Yamada K, Fukuda T, Hosoi N,
Takebayashi R, Chin K, Kozuka T, Gomi K,
Yamaguchi T. Esophgeal bypass using a gastrictube and a cardiostomy for malignant
esophagorespiratory fistula. Am J Surg
193:792-793,2007
Cao L，Mizoshita T，Tsukamoto T，Takenaka Y，Toyoda T，Cao X，Nozaki K，Tatematsu M.
Development of carcinoid tumors of the glandular
stomach and effects of eradication in Helicobacter
pylori-infected Mongolian gerbils. Cancer Sci
98：478-483，2007
Iwata C, Kano MR, Komuro A, Oka M, Kiyono K,
Johansson E, Morishita Y, Yashiro M, Hirakawa K,
Kaminishi M, Miyazono K. Inhibition of
cyclooxygenase-2 suppresses lymph nodemetastasis via reduction of Lymphangiogenesis.
Cancer Res 67：10181-10189，2007
Kaneki M，Shimizu N，Yamada D，Chang K.
Nitrosative stress and pathogenesis of insulin
resistance. Antioxid Redox Signal 9：319-329，
2007
Kodashima S，Fujishiro M，Takubo K，kamimori
M，Nomura S，Kakushima N，Muraki Y，Goto
O，Ono S，Kaminishi M，Omata M. Ex vivo pilot
study using computed analysis of endo-cytoscopic
images to differentiate normal and malignant
squamous cell epithelia in the oesophagus. Dig
Liv Dis 39：762-766，2007
Kubota K，Katayama A，Takeshita Y，Nozaki K，Ueda T ， Imamura K， Hiki N ，Nomura S ，Kaminishi M ， Mafune K. Effect of imatinib
mesylate in a patient with a metastatic
gastrointestinal stromal tumor with a c-kit
mutation in exon 11. Dig Dis Sci 52：1725-1729，
2007
Kubota K，Kuroda J，Origuchi N，Kaminishi M，Isayama H，Kawabe T，Omata M，Mafune K.
Stomach-partitioning
gastrojejunostomy
forgastroduodenal outlet obstruction. Arch Surg
142：607-611，2007
Kuwabara K, Nishishita T, Morishita M, Oyaizu N,
Yamashita S, Kanematsu T, Obara T, Mimura T,
InoueY, Kaminihsi M, Kaga K, Amino N, Kitaoka
M, Ito K, Miyauchi A, Noguchi S, Uchimaru K,
Akagawa E, Watanabe N, Takahashi T, Sato K,
Inazawa T, Nakaoka T, Yamashita N. Results of aphase i clinical study using dendritic cell
vaccinations for thyroid cancer. Thyroid 17：
53-58，2007

192

10. Leys CM，Nomura S，Goldenring JR. Expression
and prognostic significance of prothymosin-alphaand ERp57 in human gastric cancer Surgery
141：41-50，2007
11. Mori K，Suzuki T，Uozaki H，Nakanishi H，Ueda
T，Matsuno Y，Kodera Y，Sakamoto H，Yamamoto
N，Kaminishi M. Detection of minimal gastriccancer cells in peritoneal washings by focusedmicroarray analysis with multiple markers:
clinical implications. Ann Surg Oncol 14 ：
1694-702，2007
12. Kaminishi M. Introductory Remarks. Dig Surg
24：87，2007
13. Nomura S，Kaminishi M. Surgical treatment ofearly gastric cancer in Japan. Dig Surg 24：
96-100，2007
14. Takenaka Y ， Tsukamoto T ， Mizoshita T ，Ogasawara N，Hirano N，Otsuka T，Ban H，Nakamura T，Yamamura Y，Kaminishi M，Tatematsu M. Gastric and intestinal phenotypiccorrelation between exocrine and endocrinecomponents in human stomach tumors. Histol
Histopathol 22：278-284，2007
15. Yoshizawa N，Yamaguchi H，Yamada K，Nozaki
K，Kaminishi M，Mafune K，Nomura S. Early
esophageal cancer in patients with a history ofgastrectomy for gastric cancer. Esophagus 4：
99-102，2007
16. Yoshizawa N，Takenaka Y，Yamaguchi H，Tetsuya
T，Tanaka H，Tatematsu M，Nomura S，Goldenring
JR ， Kaminishi M. Emergence of spasmolytic
polypeptide-expressing metaplasia in Mongolian
gerbils infected with Helicobacter pylori. Lab
Invest 87：1265-1276，2007
17. Kaminishi. Digestive Surgery24, SurgicalTreatment for Digestive Cancer in Japan. Karger
Basel, 2007
18. Mizuno S, Kato K, Ono Y, Yano K, Kurosaka H,
Takahashi A, Abeta H, Kushiro T, Miyamoto S,
Kurihara R, Hiki N, Kaminishi M, Iwasaki A,
Arakawa Y. Oral pepermint oil is a usefulantispasmodic for double-contrast barium meal
examination. J Gastroenterol Hepatol 21:
1297-1301, 2006
19. Takenaka Y, Tsukamoto T, Mizoshita T, Cao X,
Ban H, Ogasawara N, Kaminishi M, Tatematsu T.
Helicobacter
pylori
infection
stimulates

intestinalization of endocrine cells in glandular
stomach of Mongolia gerbils. Cancer Sci 97:
1015-1022, 2006
20. Nomura S, Nakajima A, Ishimine S, Matsuhashi N,
Kadowaki T, Kaminishi M. Differential
expression of peroxisome proliferator-activatedreceptor in histologically different human gastriccancer tissues. J Exp Clin Cancer Res 25: 443-448,
2006
21. Yamashita H, Najagawa K, Tago M, Nakamura N,
Shiraishi K, Mafune K, Kaminishi M, Ohtomo K.
Theintergroup/RTOG
85-01
concurrent
chemoradiation regimen foe Japanese esophageal
cancer. Hepato-Gastroneterology 53: 863-868,
2006
22. Leys CM, Nomura S, Rudzinski E, Kaminishi M,
Montgomery E, Washington MK, Goldenring JR.
Expression of Pdx-1 in human gastric metaplasia
and gastric adenocarcinoma. Human Pathology
37: 1162-1168, 2006
23. Shimada M, Liu L. Nussler N, Jonas S, Langrehr
JM, Ogawa T, Kaminishi M, Neuhaus P, Nussler
AK: Human hepatocytes are protected fromethanol-induced cytotoxicity by DADA via
CYP2E1 inhibition. Toxicology Letters 163(3):242-249, 2006
24. Nozaki K, Nomura S, Shimizu N, Hiki N,
Yoshizawa N, Aiko S, Kubota K, Yamaguchi H,
Kurosaka H, Shinozaki A, Mafune K, Fukyama M,
Kaminishi M. Helicobacter pylori-negative /API2-MALT1 translocation-negative low grade
MALT lymphoma. Gastric Cancer 9: 229-234,
2006
25. Hiki N, Shimoyama S, Yamaguchi H, Kubota K,
Kaminishi M. Laparoscopy-assisted pyloruspreserving gastrectomy with quality controlled
lymph node dissection in gastric cancer operation.
J.Am.Coll.Surg. 203 (2):162-169, 2006
26. Maruyama K, Kaminishi M, Hayashi K, Isobe Y,
Honda I, Katai H, Arai K, Kodera Y, Nashimoto A.
Gastric cancer treated in 1991 in Japan: data
analysis of nationwide registry. Gastric Cancer 9:51-66, 2006
27. Hiki N, Shimizu N, Yamaguchi H, Imamura H,
Hatao F, Kaminishi M. Manipulation of the small
intestine as a cause of the increased inflammatory
response after open compared with laparoscopic

193

surgery. Br. J Surg 93: 195-204 2006
28. Mizoshita T, Tsukamoto T, Yakenaka Y, Cao X,
Kato S, Kaminishi M, Tatematsu M. Gastric andintestinal phenotypes and histogenesis ofadvanced glandular stomach cancers incarcinogen-treated, Helicobacter pylori-infected
Mongolian gerbils. Cancer Sci 97: 38-44, 2006

194

Department of Hepatobiliary
Pancreatic Surgery andDepartment of Artificial Organ
and Transplantation Surgery
Professor
Norihiro Kokudo, MD,

Associate Professor
Yasuhiko Sugawara, MD

Lecturer
Yoshifumi Beck, MD,

Hiroshi Imamura, MD,

Kiyoshi Hasegawa, MD,

Masami Minagawa, MD,

Katsutoshi Naruse, MD,

Wei Tang, MD,

Sumihito Tamura, MD,

Taku Aoki, MD,

Junichi Kaneko, MD,

Yasuji Seyama, MD,

Yuichi Matsui, MD,

Junichi Arita, MD,

Research Associates

Koichi Masuda, MD

Organization
We specialize in hepato-pancreato-biliary surgery andliver transplantation. The Hepatobiliary Pancreatic
Surgery Division and Artificial Organ andTransplantation Surgery Division precede the Second
Department of Surgery, which was established in 1893.
A professor and chairman, two associate professors,
three lecturers, and ten associates take part ininpatient and outpatient care as well as teaching andresearch activities. Department of plastic surgery,anesthesiology and staff of intensive care unit assist
us in performing liver transplantation. Research on
artificial liver is actively performed by Dr. Katsutoshi
Naruse.

Clinical Activities
We shared around 60 beds mainly on the A9 northfloor ward with hepatobiliary pancreatic surgery andtransplantation division, high care unit and intensive
care unit on the A4 floor. Each inpatient is taken careof by senior and junior specialist surgeons and aresident in the field of his or her disease throughout
the pre- and postoperative periods. Staff members are
responsible for the entire care of the patients on a
24-hour-a-day basis. Elective operations are carriedout on Monday, Wednesday and Friday.
Form January 1996 to December 2006, thePediatric Surgery Division and our department
performed around 380 living donor and one deceased
donor liver transplantation. The operative mortality isaround 5%. Clinical conferences are held on everyday
in which the laboratory data and clinical status of thepatients are discussed. staff’s ward round for
inpatients is performed on Tuesday, Thursday andholidays. Out patient clinic is conducted incollaboration with other department of surgery. We

195have both general and special outpatient clinic.
Specialist surgeons in liver transplantation surgery are
in service on Monday, Tuesday and Thursday.

Teaching Activities
We take part in clinical lectures and bed-side teachingfor medical students in cooperation with the otherdepartments. Bed-side teaching is provided to the fifthand sixth grade students on a man-to-man basis withstaff members. During a three-week period each
student learns the basic way of thinking for correct
diagnosis and treatment, fundamental techniques ofradiological examinations and laboratory data, andpre- and postoperative patient care.
Doctor course students are doing research work
under the supervision of the professor and the staff
members. If they think it necessary, they canparticipate in clinical patient care as a junior specialist
surgeon.
Residents learn basic patient care and operative
procedures at the university hospital. Subsequently
they are sent to subsidiary hospitals for two years tolearn further surgical activities. After this postgraduate
training course they decide whether they take a doctor
course.

References (2007)
1: Yuan P, Tang W, Kokudo N, Hasegawa K, Xiang
C, Li QM, Luo H, Wen J, Liang BH, Aoki T,
Zhang KM, Sugawara Y, Imamura H, Sano K,
Makuuchi M. Demographic and clinicalcharacteristics of resectable hepatocellular
carcinoma in China and Japan. Hepatogastroenterology. 2007 Dec;54(80):2343-7.
2: Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Moriya K, Koike K, Makuuchi M.
Impactofnewmethicillin-resistant
Staphylococcus aureus carriage postoperatively
after living donor liver transplantation. Transplant
Proc. 2007 Dec;39(10):3271-5.
3: Akamatsu N, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Makuuchi M. Impact of live
donor age (>or=50) on liver transplantation.
Transplant Proc. 2007 Dec;39(10):3189-93.
4: Zhang K, Kokudo N, Hasegawa K, Arita J, Tang

W, Aoki T, Imamura H, Sano K, Sugawara Y,
Makuuchi M. Detection of new tumors byintraoperative ultrasonography during repeatedhepatic resections for hepatocellular carcinoma.
Arch Surg. 2007 Dec;142(12):1170-5; discussion
1176.
5: Kyoden Y, Tamura S, Sugawara Y, Akamatsu N,
Matsui Y, Togashi J, Kaneko J, Makuuchi M.
Biliary complications in right lateral sector graft
live donor liver transplantation. Transpl Int. 2008
Apr;21(4):332-9. Epub 2007 Dec 5.
6: Shindoh J, Kokudo N, Miura Y, Satoh S,
Matsukura A, Imamura H, Makuuchi M. In situ
hepatic vein graft: a simple new technique forhepatic venous reconstruction. Hepatogastroenterology. 2007 Sep;54(78):1748-51.
7: Hashimoto M, Miki K, Beck Y, Kokudo N,
Makuuchi M, Tanaka H. Femoral neck fracture as
a complication of lipase-secreting pancreaticacinar cell carcinoma. Surgery. 2007 Nov;142(5):779-80. .
8: Sugawara Y, Tamura S, Makuuchi M. Living
donor liver transplantation for hepatocellular
carcinoma: Tokyo University series. Dig Dis.
2007;25(4):310-2.
9: Nagase T, Koshima I, Maekawa T, Kaneko J,
Sugawara Y, Makuuchi M, Koyanagi H,
Nakagami G, Sanada H. Ultrasonographic
evaluation of an unusual peri-anal induration: apossible case of deep tissue injury. J Wound Care.
2007 Sep;16(8):365-7. Review.
10: Saiura A, Yamamoto J, Koga R, Kokudo N, Seki
M, Oya M, Ueno M, Kuroyanagi H, Fujimoto Y,
Natori T, Yamaguchi T, Muto T. Outcome after
hepatic resection of solitary liver metastasis fromcolorectal cancer in the caudate lobe. World J
Surg. 2007 Dec;31(12):2378-83.
11: Akamatsu N, Sugawara Y, Kaneko J, Tamura S,
Makuuchi M. Preemptive treatment of fungal
infection based on plasma (1 --> 3)beta-D-glucan
levels after liver transplantation. Infection. 2007
Oct;35(5):346-51. Epub 2007 Sep 20.
12: Makuuchi M, Sugawara Y. Current status of livertransplantation for hepatocellular carcinoma fromliving donors. Hepatol Res. 2007 Sep;37 Suppl
2:S277-8.
13: Ishizawa T, Hasegawa K, Ikeda M, Aoki T, Sano

196

K, Imamura H, Kokudo N, Makuuchi M.
Transhepatic approach for a small paracaval
tumor in repeat resection. Dig Surg. 2007;24(6):409-12. Epub 2007 Sep 13.
14: Takemura N, Sugawara Y, Tamura S, Makuuchi
M. Liver transplantation using hepatitis B core
antibody-positive grafts: review and university ofTokyo experience. Dig Dis Sci. 2007 Oct;52(10):2472-7. Epub 2007 Mar 16. Review.
15: Hashimoto M, Beck Y, Mise Y, Kokudo N,
Makuuchi M. Celiac axis compression during the
expiratory phase as a cause of hepatic ischemia
during pancreaticoduodenectomy. Surgery. 2007
Sep;142(3):429-30. .
16: Hashimoto T, Kokudo N, Hasegawa K, Sano K,
Imamura H, Sugawara Y, Makuuchi M.
Reappraisal of duct-to-duct biliary reconstructionin hepatic resection for liver tumors. Am J Surg.
2007 Sep;194(3):283-7.
17: Kaneko J, Sugawara Y, Yanhong Q, Makuuchi M.
Education and Imaging. Hepatobiliary andpancreatic: extended directional power Doppler
ultrasonography in liver transplantation. J
Gastroenterol Hepatol. 2007 Aug;22(8):1345. .
18: Hasegawa K, Kokudo N, Makuuchi M. Surgicalmanagement of hepatocellular carcinoma. Liver
resection and liver transplantation. Saudi Med J.
2007 Aug;28(8):1171-9. Review.
19: Sugawara Y, Tamura S. Reconstructing thedrainage vein of the right paramedian sector inright liver grafts. Liver Transpl. 2007 Aug;13(8):1075-7. .
20: Kyoden Y, Sugawara Y, Kaneko J, Kishi Y,
Akamatsu N, Makuuchi M. Hepatofugal portal
flow after living donor liver transplantation.
Hepatogastroenterology. 2007 Jun;54(76):1164-6.
21: Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Moriya K, Koike K, Makuuchi M.
Methicillin-resistant
Staphylococcus
aureusinfection after living-donor liver transplantation in
adults. Transpl Infect Dis. 2008 Apr;10(2):110-6.
Epub 2007 Jul 1.
22: Tsujino T, Sugawara Y, Kawabe T, Makuuchi M,
Omata M. Foreign body (suture thread) in the bile
duct after living donor liver transplantation. Liver
Transpl. 2007 Jul;13(7):1065-6. .
23: Kishi Y, Sugawara Y, Kaneko J, Tamura S, Matsui

Y, Makuuchi M. Blood eosinophilia after living
donor liver transplantation for hepatitis C
virus-related cirrhosis. Transplant Proc. 2007
Jun;39(5):1540-3.
24: Kokudo N, Sasaki Y, Nakayama T, Makuuchi M.
Dissemination of evidence-based clinical practiceguidelines for hepatocellular carcinoma among
Japanese hepatologists, liver surgeons andprimary care physicians. Gut. 2007 Jul;56(7):1020-1. .
25: Yamamoto J, Kosuge T, Saiura A, Sakamoto Y,
Shimada K, Sano T, Takayama T, Sugawara Y,
Yamaguchi T, Kokudo N, Makuuchi M.
Effectiveness of hepatic resection for early-stage
hepatocellular carcinoma in cirrhotic patients:
subgroup analysis according to Milan criteria. Jpn
J Clin Oncol. 2007 Apr;37(4):287-95.
26: Sugawara Y, Tamura S, Makuuchi M. Systematic
grading of surgical complications in live liver
donors. Liver Transpl. 2007 Jun;13(6):781-2. .
27: Hashimoto T, Sugawara Y, Makuuchi M. Impact
of human leukocyte antigen mismatching on
outcomes of living donor liver transplantation forprimary biliary cirrhosis. Liver Transpl. 2007 Jun;
13(6):938-9. .
28: Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Makuuch M. Clostridium
difficile-associated diarrhea after living donorliver transplantation. World J Gastroenterol. 2007
Apr 14;13(14):2072-6.
29: Hashimoto T, Kokudo N, Orii R, Seyama Y, Sano
K, Imamura H, Sugawara Y, Hasegawa K,
Makuuchi M. Intraoperative blood salvage during
liver resection: a randomized controlled trial. Ann
Surg. 2007 May;245(5):686-91.
30: Arita J, Kokudo N, Zhang K, Makuuchi M.
Three-dimensional visualization of liver segmentson contrast-enhanced intraoperative sonography.
AJR Am J Roentgenol. 2007 May;188(5):W464-6.
31: Kishi Y, Sugawara Y, Tamura S, Kaneko J, Matsui
Y, Makuuchi M. Histologic eosinophilia as an aid
to diagnose acute cellular rejection after living
donor liver transplantation. Clin Transplant. 2007
Mar-Apr;21(2):214-8.
32: Inagaki Y, Tang W, Guo Q, Kokudo N, Sugawara
Y, Karako H, Konishi T, Nakata M, Nagawa H,

197

Makuuchi M. Sialoglycoconjugate expression inprimary colorectal cancer and metastatic lymph
node tissues. Hepatogastroenterology. 2007 JanFeb;54(73):53-7.
33: Kokudo N, Hasegawa K, Makuuchi M. Control
arm for surgery alone is needed but difficult toobtain in randomized trials for adjuvant
chemotherapy after liver resection for colorectal
metastases. J Clin Oncol. 2007 Apr 1;25(10):1299-300; author reply 1300.
34: Guo Q, Tang W, Inagaki Y, Kokudo N, Sugawara
Y, Karako H, Nakata M, Makuuchi M. Subcellular
localization of KL-6 mucin in colorectal
carcinoma cell lines: association with metastatic
potential and cell morphology. Oncol Rep. 2007
May;17(5):1057-60.
35: Akamatsu N, Sugawara Y, Tamura S, Togashi J,
Kaneko J, Makuuchi M. Late mortality fromthrombotic
microangiopathy
after
liver
transplantation: report of a case. Surg Today.
2007;37(4):345-8. Epub 2007 Mar 26.
36: Hashimoto M, Beck Y, Hashimoto T, Kokudo N,
Makuuchi M. Preservation of thick middle hepaticvein
tributaryduringright
paramedian
sectoriectomy. Surgery. 2007 Apr;141(4):546-7.
Epub 2007 Mar 9. .
37: Tamura S, Sugawara Y, Makuuchi M. Impact ofrecipient age on the long-term outcome of living
donor liver transplantation for post-kasai biliaryatresia. Am J Transplant. 2007 Mar;7(3):728. .
38: Tang W, Guo Q, Qu X, Inagaki Y, Seyama Y,
Midorikawa Y, Gai R, Kokudo N, Sugawara Y,
Nakata M, Makuuchi M. KL-6 mucin is a usefulimmunohistochemicalmarkerforcholangiocarcinoma. Oncol Rep. 2007 Apr;17(4):737-41.
39: Satou S, Sugawara Y, Tamura S, Kishi Y, Kaneko
J, Matsui Y, Kokudo N, Makuuchi M.
Three-dimensional computed tomography forplanning donor hepatectomy. Transplant Proc.
2007 Jan-Feb;39(1):145-9.
40: Hashimoto T, Sugawara Y, Tamura S, Kaneko J,
Motomura N, Takamoto S, Makuuchi M. One
orifice vein reconstruction in left liver plus
caudate lobe grafts. Transplantation. 2007 Jan 27;
83(2):225-7.
41: Arita J, Kokudo N, Hasegawa K, Sano K,

Imamura H, Sugawara Y, Makuuchi M. Hepatic
venous thrombus formation during livertransection exposing major hepatic vein. Surgery.
2007 Feb;141(2):283-4. Epub 2007 Jan 4. .
42: Tamura S, Sugawara Y, Kaneko J, Matsui Y,
Togashi J, Makuuchi M. Recurrence of primarysclerosing cholangitis after living donor livertransplantation. Liver Int. 2007 Feb;27(1):86-94.
43: Ishizawa T, Hasegawa K, Sano K, Imamura H,
Kokudo N, Makuuchi M. Selective versus total
biliary drainage for obstructive jaundice caused
by a hepatobiliary malignancy. Am J Surg. 2007
Feb;193(2):149-54.
44: Tamura S, Sugawara Y, Makuuchi M.
Choledochotomy in live liver donors. Liver
Transpl. 2007 Jan;13(1):173; author reply 174. .
45: Hashimoto M, Kokudo N, Imamura H, Akahane
M, Makuuch M. Demonstration of the common
hepatic artery coursing in the lesser omentum by
three-dimensional computed tomography. Surgery.
2007 Jan;141(1):121-3. Epub 2006 Sep 25. .
46: Hashimoto M, Miki K, Kokudo N, Beck Y,
Makuuchi M. A long-term survivor of metastatic
acinar cell carcinoma. Pancreas. 2007 Mar;34(2):271-2. .
47: Dulundu E, Sugawara Y, Kaneko J, Kishi Y,
Akamatsu N, Matsui Y, Kokudo N, Makuuchi M.
Short hepatic vein reconstruction in biliary atresia
patients with absent inferior vena cava. Clin
Transplant. 2007 Jan-Feb;21(1):13-7.
48: Sakata H, Sugawara Y, Makuuchi M. Educationand imaging. Hepatobiliary and pancreatic: acute
Budd-Chiari syndrome treated by systemic
thrombolytic therapy. J Gastroenterol Hepatol.
2007 Mar;22(3):444.

198

Department of Urology
Professor
Tadaichi Kitamura, M.D., Ph.D.

Associate Professor
Takumi Takeuchi, M.D., Ph.D.

Kyoichi Tomita, M.D., Ph.D.

Lecturer
Haruki Kume, M.D., Ph.D.

Hiroaki Nishimatsu, M.D., Ph.D.

Yutaka Enomoto M.D., Ph.D.

Hiroshi Fukuhara, M.D., Ph.D.

Research Associate
Tetsuya Fujimura, M.D., Ph.D.,

Motofumi Suzuki, M.D., Ph.D.,

Shinya Matsumoto, M.D.,

Akihiko Matsumoto, M.D., Ph.D.,

Akira Nomiya, M.D.,

Yusuke Sato, M.D.,

Shigenori Kakutani M.D.,

Norio Toyoda, M.D.

Homepage

http:// www.h.u-tokyo.ac.jp/urology/

Introduction and Organization
Urology is a special field of clinical medicine
covering the diseases of the adrenal gland, the kidney,
the urinary tract and the male genital system by meansof a surgical procedure as well as an approach ofinternal medicine. In addition, urology encompasses
pediatric urology, neurourology, female urology, renaltransplantation, renal vascular surgery, endocrine
surgery and geriatric urology. For this reason, urology
requires the scientific background of oncology,
nephrology, endocrinology, andrology, immunology,
pediatrics, histology, microbiology, neurology andgerontology. Now we have commenced to utilize
cellular and molecular biology to develop the researchin urology. It is expected for our department to devote
to the scientific progress in the frontier of urology.
In recent years, we have been taking international
leadership in applying the new and minimally invasive
treatment modalities. They are exemplified byendoscopic management of the diseases in the upper
urinary tract, ESWL, or laser lithotripsy for

urolithiasis, hyperthermic and laser therapies for BPH,
and laparoscopic adrenalectomy, nephrectomy, andprostatectomy substituting open procedures.
The professor, associate professors, instructors andassociates are involved in in-patient and out-patientcares and teaching of the students as well as research
activities. Clinical visiting professors are mainly
engaged in the teaching.

Clinical activities
There are 44 beds in the ward (8th floor of thecentral-ward-building). The residents take care of all
the patients on 24-hour a day basis. Associate staff
members team up with the residents on a man-to-man
basis. The total number of inpatients was 1,500 fromJanuary 2007 to December 2007. More than half ofin-patients
sufferfromurogenitalcancers.
Urolothiasis, benign prostatic hyperplasia, urinary
incontinence and other many diseases are also treated.

199

Elective operations are performed on Tuesday,
Wednesday, and Thursday. A total of 1,450 operations
were performed in 2007. The numbers of main
operations are total cystectomy 14, radical
prostatectomy 80, radical nephrectomy 43,transurethral resection of the bladder tumor (TUR-Bt)
113, transurethral resection of the prostate (TUR-P) 21,
laparoscopic surgery 62.
At the weekly professor’s round on Wednesday,
data of all in patients are presented and appropriate
treatment strategies are recommended for them. On
Wednesday evening, a clinical conference is held for
discussing cases with difficult problems in detail andthe best treatment is chosen for each case.
In out-patient clinic, services are provided from
Monday to Friday. Patients assigned to specialized
services as andrology, neurourology, urolithiasis,kidney transplantation, second opinion, and female
Urology receive sophisticated care on the particularday of the week.
The total number of out-patients was 30,693
patient-days from January 2007 to December 2007.

Teaching activities
Systematic urological lectures are provided forsecond year medical students. Both clinical lecturesand bed side teaching are scheduled for third andfourth year medical students. Thirteen times ofsystematic lectures are performed by professor,
associate professors and instructors concerning their
specialties.
Bed side teaching is concentrated on practical careof the patients. Teachers give lectures mainly
regarding pre- and post-operative management,
indication of operation, surgical anatomy and surgical
techniques.

Research activities
There are 9 research themes for research as below.
The basic principles for research are program insurgical techniques and therapy for incurable diseases,
which include advanced cancer, renal insufficiency,
sexual dysfunction, and interstitial cystitis. We havepublished 25 papers in English every year.

Renal tumor
Urolithiasis
Kidney Transplantation
Prostate diseases
New surgical technique
Urinary disturbance/ Female Urology
Andrology
Virology

References
1. Zeng Y, Wu XX, Homma Y, Yoshimura N, Iwaki
H, Kageyama S, Yoshiki T, Kakehi Y. UroplakinIII-delta4 messenger RNA as a promising marker
to identify nonulcerative interstitial cystitis.J Urol.
2007; 178: 1322-7.
2. Yamaguchi O, Honda K, Nomiya M, Shishido K,
Kakizaki H, Tanaka H, Yamanishi T, Homma Y,
Takeda M, Araki I, Obara K, Nishizawa O, Igawa
Y, Goto M, Yokoyama O, Seki N, Takei M,
Yoshida M.Defining overactive bladder as
hypersensitivity. Neurourol Urodyn. 2007; 26:904-7.
3. Yoshida M, Homma Y, Kawabe K. Silodosin, anovel selective alpha 1A-adrenoceptor selective
antagonist for the treatment of benign prostatic
hyperplasia. Expert Opin Investig Drugs. 2007;
16: 1955-65.
4. Imai N, Hishikawa K, Marumo T, Hirahashi J,
Inowa T, Matsuzaki Y, Okano H, Kitamura T,
Salant D, Fujita T.
Inhibition of histone
deacetylase activates side population cells inkidney and partially reverses chronic renal injury.
Stem Cells. 2007; 25: 2469-75.
5. Yamada Y, Fujimura T, Yamaguchi T, Nishimatsu
H, Hirano Y, Kawamura T, Teshima S, Takeuchi
Lymphoepithelioma-like carcinoma of the renal
pelvis. Int J Urol. 2007; 14: 1093-4.
6. Morikawa T, Goto A, Tomita K, Tsurumaki Y, Ota
S, Kitamura T, Fukayama M. Recurrent prostatic
stromal sarcoma with massive high-grade
prostatic intraepithelial neoplasia. J Clin Pathol.
2007; 60: 330-2.
7. Okamoto N, Aruga S, Tomita K, Takeuchi T,
Kitamura T. Chronic acid ingestion promotes
renal stone formation in rats treated with vitamin
D3. Int J Urol. 2007; 14: 60-6.

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8. Kashibuchi K, Tomita K, Schalken JA, Kume H,
Takeuchi T, Kitamura T. The prognostic value ofE-cadherin, alpha-, beta- and gamma-catenin inbladder cancer patients who underwent radical
cystectomy. Int J Urol. 2007; 14: 789-94.
9. Morikawa T, Sugiyama A, Kume H, Ota S,
Kashima T, Tomita K, Kitamura T, Kodama T,
Fukayama M, Aburatani H. Identification ofToll-like receptor 3 as a potential therapeutictarget in clear cell renal cell carcinoma. Clin
Cancer Res. 2007; 13: 5703-9.
10. Fukuhara H, Todo T. Oncolytic herpes simplex
virus type 1 and host immune responses. Curr
Cancer Drug Targets. 2007; 7:149-55.
11. Kumagai J, Fujimura T, Takahashi S, Urano T,
Ogushi T, Horie-Inoue K, Ouchi Y, Kitamura T,
Muramatsu M, Blumberg B, Inoue S. Cytochrome
P450 2B6 is a growth-inhibitory and prognostic
factor for prostate cancer. Prostate. 2007; 67:1029-37.
12. Fujimura T, Takahashi S, Urano T, Kumagai J,
Ogushi T, Horie-Inoue K, Ouchi Y, Kitamura T,
Muramatsu M, Inoue S. Increased expression of
estrogen-related receptor alpha (ERRalpha) is anegative prognostic predictor in human prostatecancer. Int J Cancer. 2007; 120: 2325-30.
13. Matsumoto, A., K. Haraguchi, T. Takahashi, T.
Azuma, Y. Kanda, K. Tomita, M. Kur okawa, S.
Ogawa, K. Takahashi, S. Chiba and T. Kitamura.
2007. Immunotherapy against metastatic renal cell
carcinoma with ma ture dendritic cells. Int J Urol
14:277.
14. Kaneko T. Re: Is interval from an initial biopsy asignificant predictor of prostate cancer at repeat
biopsies? Int J Urol 14:177, 2007
15. Zhong S, Zheng HY, Suzuki M, Chen Q, Ikegaya
H, Aoki N, Usuku S, Kobayashi N, Nukuzuma S,
Yasuda Y, Kuniyoshi N, Yogo Y, Kitamura T:
Age-related
urinary
excretionofBK
polyomavirusbynonimmunocompromised
individuals. J Clin Microbiol. 2007; 45: 193-198.
16. Suzuki M, Kurosaki T, Arai T, Sawabe M, Hosoi T,
Kitamura T: The Val158Met polymorphism of thecatechol-O-methyltransferase
gene
is
not
associated with the risk of sporadic or latent
prostate cancer in Japanese men. Int J Urol. 2007;
14: 800-804.

17. Teramoto S, Kume H, Yamaguchi Y, Yamamoto H,
Hanaoka Y, Ishii M, Ishii T, Ouchi Y.
Improvement of endothelial function withallopurinol may occur in selected patients with
OSA: effect of age and sex.Eur Respir J. 2007; 29:
216-7.
18. Kawarazaki H, Ishibashi Y, Kawarazaki W,
Shimizu H, Takara Y, Kume H, Sasahira N,
Kaname S, Fujita T. Successful management ofcatheter obstruction by endoscopic nasopancreatic drainage tube. Perit Dial Int. 2007;
27:467.
19. Yokoyama H, Kume H, Niimi A, Tomota K,
Kitamura T. Plasma cell granuloma of urethra in ayoung woman. Am J Obstet Gynecol. 2007;196:
9-10.
20. Teramoto S, Yamaguchi Y, Yamamoto H, Hanaoka
Y, Ishii M, Hibi S, Kume H, Akishita M, Ouchi Y.
Effects of age and sex on plasma adrenomedullin
levels in patients with obstructive sleep apnea
syndrome.J Am Geriatr Soc. 2007; 55: 1891-2.
21. Yogo Y, Zhong S, Suzuki M, Shibuya A, Kitamura
T. Occurrence of the European subgroup of
subtype I BK polyomavirus in JapaneseAmericans suggests transmission outside thefamily. J Virol. 2007;81:13254-8.
22. Nishimoto Y, Zheng HY, Zhong S, Ikegaya H,
Chen Q, Sugimoto C, Kitamura T, Yogo Y. An
Asian origin for subtype IV BK virus based on
phylogenetic analysis. J Mol Evol. 2007; 65:
103-11.
23. Zhong S, Yogo Y, Ogawa Y, Oshiro Y, Fujimoto K,
Kunitake T, Zheng HY, Shibuya A, Kitamura T.
Even distribution of BK polyomavirus subtypes
and subgroups in the Japanese Archipelago. Arch
Virol. 2007; 152: 1613-21.
24. Zheng HY, Nishimoto Y, Chen Q, Hasegawa M,
Zhong S, Ikegaya H, Ohno N, Sugimoto C,
Takasaka T, Kitamura T, Yogo Y. Relationships
between BK virus lineages and humanpopulations. Microbes Infect. 2007; 9: 204-13.
25. Nakamura K, Takeuchi T, Ohkawa R, Okubo S,
Yokota H, Tozuka M, Aoki J, Arai H, Ikeda H,
Ohshima N, Kitamura T, Yatomi Y. Serum
lysophospholipase D/autotaxin may be a new
nutritional assessment marker: study on prostatecancer patients. Ann Clin Biochem. 2007; 44:549-56.

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Department of Surgical Oncology
Professor
Hirokazu Nagawa, M.D., Ph.D.

Lecturer
Joji Kitayama, M.D., Ph.D.

Clinical Lecturer
Shoichi Kaisaki, M.D.

Associate
Yoshiki Takei, M.D., Ph.D.,

Giichiro Tsurita, M.D., Ph.D.,

Hironori Ishigami, M.D.,

Soichiro Ishihara, M.D., Ph.D.,

Sinsuke Saito, M.D., Ph.D.,

Sinsuke Kazama, M.D., Ph.D.,

Takamitsu Kanazawa, M.D.,

Akio Hidemura, M.D., Ph.D.

Homepage http://all-1su.umin.jp/
Introduction and Organization
In 1995, a new system for postgraduate education
was introduced. The First Department of Surgery was
reorganized to form the Department of Surgical
Oncology and the Department of Vascular Surgery.
The staff of the Department of Surgical Oncology
consists of one Professor, two Lecturers and eight
Associates. The outpatient office is located on thethird floor of the Outpatient Building. The ward issituated on the eighth floor of the Ward Building. The
administrative office and research laboratories arelocated in the Administration and Research Building.
Current activities of the Department of Surgical
Oncology in clinical practice, education, and research
are summarized as follows.

Clinical activities
The Department of Surgical Oncology provides
comprehensive evaluation, diagnosis, treatment andmanagement for adult patients with both general andoncologic surgical problems, in the ambulatory as wellas inpatient setting. Additionally, surgical specialities

in the department include the treatment of benign andmalignant disorders of the breast and management ofmalignancies of the gastrointestinal tract (esophageal,
gastric, and colorectal). The department is also wellknown for its innovative therapy for inflammatory
bowel disease. Department specialists have expertisein biological cancer immunotherapy, chemotherapy
for a variety of malignancies, and radiotherapy forrectal cancer. The outpatient clinic is open from
Monday through Friday, and twenty-four-hour
consultation is available for urgent or emergency
problems.
The outpatient clinic is specialized in the upper GI
tract, lower GI tract, and breast diseases. The
Department was responsible for 278 surgically treatedinpatients in the year of 2007. On Monday,
Wednesday and Friday mornings, pre- andpost-surgery conferences are held, and the Professor's
Round takes place after the conference every
Wednesday. Operating days are Monday, Tuesday andThursday. In addition to the clinical conferences,
research conferences are held every Monday andSaturday morning. Each research unit holds its own
conference every week.

202

Teaching activities
The Department of Surgical Oncology also offers afellowship in surgical oncology for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in surgicaloncology. The Department of Surgical Oncology has a
Surgical Oncology Training Program and provides
broad reaching experience in technical aspects ofdiagnosis, treatment and management for adultpatients with both surgical and oncologic problems,development of surgical judgment, and increasing
knowledge about routine and complex conditions. In
addition, the dedicated staff allows multiple
opportunities for academic development both along
clinical and basic scientific lines.
In the undergraduate education program, ourdepartment plays a role in the systemic and clinicallectures and the bedside learning program for 3rd year
medical students, in cooperation with otherdepartments of surgery. In the systemic lectures onsurgery for the fiscal year of 2005, various fields werecovered such as surgical oncology and immunology,
injury, somatic reaction to surgery, infectious diseases,
shock, pre- and post-surgical management andnutrition. In the clinical lectures, we presented many
diseases such as colon cancer, colonic polyp, colonicpolyposis and ulcerative colitis. In the postgraduate
education program, new residents are trained to
become qualified surgeons. In addition to pre- andpost-surgery clinical conferences, the residents are
expected to attend research conferences and seminars,
which are held periodically. They are also asked topresent cases at clinical meetings, which are held
locally such as the local meeting of the JapaneseSociety of Gastroenterology.

Research activities
At present, our department has three major research
units divided according to the members’ special fields.
The clinical and academic interests of our department
are the upper and lower gastrointestinal tract, and thebreast. We also apply the techniques used in molecularand cellular biology to our research. The following are
the major themes under research.
1) Preoperative radiotherapy in lower rectal cancer

2)
3)
4)
5)
6)

Cancer surveillance in ulcerative colitis
Carcinogenesis in ulcerative colitis
Laparoscopically assisted colon surgery
Local immunity in colorectal cancer
Genetic analysis of colorectal cancer andadenoma
7) Prognostic factor of early colorectal cancer8) Surveillance program following colectomy forcolorectal cancer
9) The mechanism of liver metastasis of colorectal
cancer10) Carcinogenesis in superficial early colorectal
cancer11) Genetic alterations in synchronous andmetachronous multiple colorectal cancers12) Microsatellite instability and a risk of developing
multiple colorectal cancers13) Dendritic cell Immunotherapy for advanced
cancer14) Cancer Immunotherapy targeting to the tumor
vessels
15) Angiogenesis inhibition in peritoneal metastasisof gastric cancer16) Role of LPA S1P and Edg receptors in tumor
metastasis17) Lipid metabolism in carcinogenesis and tumor
progression18) Sentinel lymph node identification using
nanobeads
19) Genetic
analysisonsensitivity
tochemotherapeutic agents20) Hemostasis and fibrinolysis in Oncology21) Leptin and adiponectin in Oncology22) Intraabdominal chemotherapy for peritoneal
metastasis of gastric cancer23) Angiogenic progenitor cells and antigen
presentation
24) Fibloblast Growth Factor (FGF) in inflammatory
bowel disease25) Genetic analysis of undifferentiated colorectal
cancer26) High Frequency Ultrasonography (HIFU) for
solid cancer27) Endocannabinoid in acticancer therapy

203

References
1. Konishi T, Watanabe T, Kishimoto J, Kotake K,
Muto T, Nagawa H; Japanese Society for Cancerof the Colon and Rectum. Prognosis and risk
factors of metastasis in colorectal carcinoids:
results of a nationwide registry over 15 years.
Gut. 2007 Jun;56(6):863-8.
2. Yamashita H, Kitayama J, Ishigami H, Yamada J,
Miyato H, Kaisaki S, Nagawa H. Endoscopic
instillation of indigo carmine dye with acetic
acid enables the visualization of distinct marginof superficial gastric lesion; Usefulness inendoscopic treatment and diagnosis of gastriccancer. Dig Liver Dis. 2007 Apr;39(4):389-91.
3. Yoneyama S, Okaji Y, Tsuno NH, Kawai K,
Yamashita H, Tsuchiya T, Yamada J, Sunami E,
Osada T, Kitayama J, Takahashi K, Nagawa H. A
study of dendritic and endothelial cellinteractions in colon cancer in a cell line andsmall mammal model. Eur J Surg Oncol. 2007
Dec;33(10):1191-8.
4. Ishikawa M, Kitayama J, Yamauchi T, Kadowaki
T, Maki T, Miyato H, Yamashita H, Nagawa H.
Adiponectin inhibits the growth and peritoneal
metastasis of gastric cancer through its specificmembrane receptors AdipoR1 and AdipoR2.
Cancer Sci. 2007 Jul;98(7):1120-7.
5. Mori K, Kitayama J, Aoki J, Kishi Y, Shida D,
Yamashita H, Arai H, Nagawa H. Submucosal
connective tissue-type mast cells contribute to
the production of lysophosphatidic acid (LPA) inthe gastrointestinal tract through the secretion of
autotaxin (ATX)/lysophospholipase D (lysoPLD).
Virchows Arch. 2007 Jul;451(1):47-56.
6. Kazama Y, Watanabe T, Kanazawa T, Tanaka J,
Tanaka T, Nagawa H. Microsatellite instability inpoorly differentiated adenocarcinomas of the
colon
and
rectum:relationshiptoclinicopathological features. J Clin Pathol. 2007
Jun;60(6):701-4.
7. Kitayama J, Ishigami H, Ishikawa M, Yamashita
H, Soma D, Miyato H, Nagawa H. Hyaluronic
acid is a useful tool for intraoperative sentinelnode detection in gastric cancer surgery. Surgery.
2007 Jun;141(6):815-20.
8. Yamada J, Kawai K, Tsuno NH, Kitayama J,

Tsuchiya T, Yoneyama S, Asakage M, Okaji Y,
Takahashi K, Nagawa H. Plaunotol induces
apoptosis of gastric cancer cells. Planta Med.
2007 Aug;73(10):1068-73.
9. Kojima T, Watanabe T, Hata K, Nagawa H. Basic
fibroblast growth factor enema improves
experimental
colitisinrats.
Hepatogastroenterology. 2007 Jul-Aug;54(77):1373-7.
10. Tanaka J, Watanabe T, Kanazawa T, Tada T,
Kazama Y, Tanaka T, Nagawa H. Left-Sided
microsatellite unstable colorectal cancers showless frequent methylation of hMLH1 and CpG
island methylator phenotype than right-sided
ones. J Surg Oncol. 2007 Dec 1;96(7):611-8.
11. Kagaya H, Kitayama J, Hidemura A, Kaisaki S,
Ishigami H, Takei J, Kanazawa T, Nagawa H.
Metastatic esophageal tumor from cecal
carcinoma. Jpn J Clin Oncol. 2007 Aug;37(8):628-31.
12. Kiyomatsu T, Watanabe T, Muto T, Nagawa H.
The 4-portal technique decreases adverse effects
in preoperative radiotherapy for advanced rectal
cancer: comparison between the 2-portal and the
4-portal techniques. Am J Surg. 2007 Oct;194(4):542-8.
13. Ishihara S, Kitayama J, Nagawa H. Clinicalchallenges and images in GI. Amoebic
appendicitis. Gastroenterology. 2007 Nov;
133(5):1412.
14. Soma D, Kitayama J, Yamashita H, Miyato H,
Ishikawa M, Nagawa H. Leptin Augments
Proliferation of Breast Cancer Cells via
Transactivation of HER2. 2007 Nov 26. [Epubahead of print]

204

Department of Vascular Surgery
Professor
Hirokazu Nagawa, M.D., Ph.D.

Associate Professor
Tetsuro Miyata, M.D., Ph.D.

Associate
Kunihiro Shigematsu, M.D., Ph.D.,

Juno Deguchi, M.D., Ph.D.,

Hideo Kimura, M.D., Ph.D.,

Seiji Nishikage, M.D.

Homepage http://all-1su.umin.jp/
Introduction and Organization
In 1995, a new system for postgraduate education
was introduced. The First Department of Surgery was
reorganized to form the Department of Vascular
Surgery and the Department of Surgical Oncology.
The staff of the Department of Vascular Surgery
consists of one Professor, one Associate Professor andfour Associates. The outpatient office is located on thethird floor of the Outpatient Building. The ward issituated on the eighth floor of the Ward Building. The
administrative office and research laboratories arelocated in the Administration and Research Building.
Current activities of the Department of Vascular
Surgery in clinical practice, education, and research
are summarized as follows.

Clinical activities
The Department of Vascular Surgery has anextensive clinical program in both primary and tertiarycare for vascular problems, and manages patients with
peripheral arterial occlusion, abdominal and thoracoabdominal aortic aneurysms, peripheral aneurysm,
visceral arterial occlusion, carotid artery disease andcommon disorders of the venous circulation such asvaricose veins and venous leg ulcers. State-of-the-art
techniques of percutaneous transluminal angioplasty,
angioscopy and intraoperative ultrasonography areavailable for the treatment of peripheral arterial
disease. The outpatient clinic is open from Monday
through Friday, and twenty-four-hour consultation isavailable for urgent or emergency problems.
The department was responsible for 217 surgicallytreated inpatients in the year of 2007. Included in thedepartment is the non-invasive Clinical Vascular
Laboratory, which sees over 500 patients per year,with broad reaching expertise in peripheral vasculardiagnostic modalities. Also the department has anactive angiography program, which encompasses all
aspects of diagnostic and therapeutic intervention inover 500 patients per year and a full range of othersupport and collaborative services.
On Monday, Wednesday and Friday mornings, preand post-surgery conferences are held. Operating days
are Monday, Tuesday and Thursday. The vascularclinical conference is held every Tuesday evening.

Teaching activities
The Department of Vascular Surgery also offers afellowship in vascular surgery for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in vascularsurgery. The Department of Vascular Surgery has a
Vascular Surgery Training Program and provides
broad reaching experience in technical aspects ofvascular surgery, development of surgical judgment,

205

and increasing knowledge about routine and complex
conditions. In addition, the dedicated staff offers
multiple opportunities for academic development bothalong clinical and basic scientific lines.
In the undergraduate education program, theDepartment of Vascular Surgery plays a role in thesystemic and clinical lectures and the bedside learning
program for 3rd year medical students, in cooperation
with other departments of surgery. In the postgraduate
education program, new residents are trained to
become qualified surgeons in our department. In
addition to pre- and post-surgery clinical conferences,
the residents are expected to attend research
conferences and seminars, which are held periodically.

Research activities
The Department of Vascular Surgery includes major
research laboratories for academic development bothalong clinical and basic scientific lines. The clinicalvascular laboratories are approaching completely noninvasive testing for vascular disorders, analyzing
essential physiologic information about the specificproblems being addressed. The basic vascularlaboratories are actively performing research on
endothelial biology, the mechanism of intimal
hyperplasia, microcirculation, application of genetherapy to vascular surgery and vascular prosthesis
development. Vascular research meeting is held every
other Saturday morning. The following are the major
themes under research.
1) Three-dimensional visualization abdominal aorta
2) Pathophysiology of the development of theaneurysm
3) Prevention of the anastomotic intimal hyperplasia
4) Pathophysiology of stent restenosis
5) Analyzing the intercellular transmission of thegrowth signal in the vascular smooth muscle cells6) Tissue oxygen dynamics assessed by near infrared
spectroscopy7) Application of near infrared spectroscopy to bloodflow monitoring during carotid endarterectomy8) Lower limb arterial circulation in a patient with
end-stage renal disease assessed by near infrared
spectroscopy9) Microvascular permeability changes induced by
PAF10) Pharmacological analysis of microcirculation in
in-vivo model11) Mechanism of ischemic preconditioning of thelimb12) Development of a new drug delivery system fortherapeutic angiogenesis13) Introduction of gene into vascular wall cells byelectroporation
14) Application of nano technology for in-vivo genetransfer to vascular wall cells
15) Basic research for arterialization of artificial
organ
16) Development of a new method for evaluation oflimb ischemia
17) Develolpment of a new machine for autoevaluation of in-vivo endothelial function

References
1. Akagi D, Arita H, Komiyama T, Ishii S,
Shigematsu K, Nagawa H and Miyata T.
Objective assessment of nerve injury after greater
saphenous vein stripping. Eur J Vasc Endovasc
Surg 33: 625-30, 2007
2. Y Akagi D, Oba M, Koyama H, Nishiyama N,
Fukushima S, Miyata T, Nagawa H and Kataoka
K. Biocompatible micellar nanovectors achieve
efficient gene transfer to vascular lesions without
cytotoxicity and thrombus formation. Gene Ther
14: 1029-38, 2007.
3. Itatani K, Miyata T, Komiyama T, Shigematsu K
and Nagawa H. An ex-situ arterial reconstruction
for the treatment of an infected suprarenal
abdominal aortic aneurysm involving visceralvessels. Ann Vasc Surg 21: 380-3, 2007.
4. Yamamoto K, Miyata T and Nagawa H. Good
correlation
betweencerebraloxygenation
measured using near infrared spectroscopy andstump pressure during carotid clamping. Int
Angiol 26: 262-5, 2007.
5. Yamamoto K, Miyata T and Nagawa H. The highprevalenceofcolorectal
neoplasms
inpreoperative patients with abdominal aortic
aneurysm or peripheral artery disease. Eur J Vasc
Endovasc Surg 33: 397-400, 2007.
6. Yamamoto K, Miyata T, Onozuka A, Koyama H,
Ohtsu H and Nagawa H. Plantar flexion as an206alternative to treadmill exercise for evaluating
patients with intermittent claudication. Eur J Vasc
Endovasc Surg 33: 325-9, 2007.

207

Department of Metabolic Careand Endocrine Surgery
Professor
Michio Kaminishi MD. PhD.

Associate Professor
Toshihisa Ogawa MD. PhD,

Yoshikazu Mimura MD. PhD (Surgical Center)

Lectuler
Hajime Kanauchi MD. PhD.

Associates
Ei-ichi Tsuji MD. Kazuo Shirakawa MD. PhD

Homepage
Organization
Our section is staffed by one professor, one
associate professor, one lecturer and two assistants
and two or three residents. Official activities of oursections are run by same schedule to Department of
Gastrointestinal Surgery.

Clinical Activities
Endocrine Surgery is not familiar with Japanese yet,however, it has been a long time to be studied this area
by top level surgeons in western countries. We havestarted our activities for this area since 1987 and ourdepartment has been established with reconstructionof our hospital structure in 1997. This is a result of thegrowth of demand nationally and internationally and it
is caused by not only treatment for malignant disease
but also functional one or giving more attention toquality of life.
Professional skill and wider knowledge of
endocrine system are required for this area. Diseases
we treat at our department are breast, thyroid,parathyroid, and adrenal gland. In additional totreatment for malignant cases of these diseases, we

perform surgical procedures for hyperfunctional
diseases. We co-work with the department of
endocrinological internal medicine and have about 60
surgical procedures annually in total.
In breast surgery, more than a half of the mammary
cancer patients undergo the breast-preserving surgery.
In addition, sentinel node navigation surgery has been
adopted, resulting in better quality of postoperative
life. Reconstruction surgery for the breast cancer islikely to provide much better QOL. In this field, we
have started collaboration with the Department of
Plastic Surgery. Chemotherapy, hormone therapy andmolecular- targeting therapy play important roles intreatment of the breast cancer. We have accumulated a
lot of experience and achievement in this field.
Our clinical themes are 1) establishment of safe
proceduresfor
endocrine
surgery
without
complications; 2) diagnosis and treatment of
micro-breast lesions under ultrasonographic guides; 3)preoperative diagnosis for thyroid neoplasmas andbreast tumors based on telomerase activity using
Q-Fish.

208

Research Acitivities
Our section has been studying about the mostfundamental issues to surgery, i.e., “surgical stress”
which means postoperative physiological andendocrinological internal reaction and “nutritional
support” for the postoperative patients. These aresubjects to reduce the intra- and post-operative
stresses that would be risky for the patients. Our
section is like a pioneer for this area in Japan and weestablished Japanese Society for Surgical Metabolism
and Nutrition in 1965. Graduate students organize
main study group and we have presentations at someinternational conferences each year.

2.

3.

4.
The focus of our research is “surgical metabolism
and nutrition” and “the body’s adaptive responses
during postoperative recovery”. In addition, we havebeen engaged in the project of chemo-sensitivity ofbreast cancer and of treatment for breast tumors byhigh-energy ultrasound. Research details follow.
1) Mechanisms of cross tolerance among different
stresses (endotoxin - hypoxia/ hypoxia - hypoxia)
after surgery
2) Role of catecholamines in adaptation to surgicalstresses such as endotoxemia3) Bacterialtranslocation
after
anti-cancer
chemotherapy4) Gender difference is a modulating factor for
postoperative morbidity
5) Measurement of endotoxin activity through Tolllike receptor 46) Role of oxygen on local and systemic protein
metabolism after major surgery7) Ischemic
preconditioning
preserves
renal
dysfunction after ischemia-reperfusion
8) Telomere-length and telomere activity in the
thyroid and the breast tumors9) Application of Q-Fish in diagnosis of the thyroid
and the breast tumors10) Chemo-sensitivity in breast cancer

Publications
1. Ogawa T，Kanauchi H，Kammori M，Mimura Y，Ota S ， Kaminishi M. Diffuse large B-cell

5.

6.

7.

lymphoma in the thyroid gland associated withprimary hyperparathyroidism. Int J Clin Oncol
12：48-51，2007
Ogawa T，Kammori M，Tsuji E，Kanauchi H，Kurabayashi R，Terada K，Mimura Y，Kaminishi
M. Preoperative evaluation of thyroid pathology
in patients with primary hyperparathyroidism.
Thyroid 17：59-62，2007
Ogawa T，Tsuji E，Kanauchi H，Yamada K，Mimura Y ， Kaminishi M. Excision ofpostesophageal parathyroid adenoma in posterior
mediastinum with intraoperative 99mTechnetium
sestamibi scanning. Ann Thorac Surg 84 ：
1754-1756，2007
Shimada M, Liu L. Nussler N, Jonas S, Langrehr
JM, Ogawa T, Kaminishi M, Neuhaus P, Nussler
AK: Human hepatocytes are protected fromethanol-induced cytotoxicity by DADA via
CYP2E1 inhibition. Toxicology Letters 163(3):242-249, 2006
Kammori M, Tsuji E, Kaminishi M, et al. Invasive
breast carcinoma in a patient with Behcet’s
disease: The pathological findings existed
vasculitis with carcinoma. Breast Cancer 13：
378-381，2006
Hiki N, Shimizu N, Yamaguchi H, Imamura H,
Hatao F, Kaminishi M. Manipulation of the small
intestine as a cause of the increased inflammatory
response after open compared with laparoscopic
surgery. Br. J Surg 93: 195-204 2006
Kammori M, Fukami T, Ogawa T, Tsuji E, Takubo
K, Nakajima J, Kaminishi M: Giant mediastinal
cystic parathyroid adenoma. J Clin Endocrinol
Metab 91: 1635-1636, 2006

Surgical Sciences
2. Sensory and Motor System Medicine

210

Department of Dermatology
Professor
Kunihiko Tamaki, M.D., Ph.D.
Associate Professor
Kanako Kikuchi, M.D., Ph.D.

Lecturer
Hidehisa Saeki, M.D., Ph.D.

Takafumi Kadono,M.D., Ph.D.

Masahide Kubo, M.D., Ph.D.

Takashi Kakinuma, M.D., Ph.D.

Makoto Sugaya, M.D.,Ph.D

Associate
Yayoi Tada, M.D. Ph.D.

Yuichiro Tsunemi, M.D. Ph.D

Hideki Fujita, M.D., Ph.D

Andre Le Pavoux, M.D.

Ryuichi Ashida, M.D.

Asako Okada, M.D.

Daisuke Yamada, M.D.

Miki Takahashi, M.D.

Umehara Kaichi, M.D.

Home page

http://www.h.u-tokyo.ac.jp/der/Introduction and Organaization

Clinical Activities

The Department of dermatology celebrated its 100th
anniversary in 1990. Originally it was founded as the
Department of dermatology and Urology, which also
encompassed veneology. In 1946 the Department ofdermatology was separated from that of Urology.
Regarding venereology, sexually transmitted diseases
only related to skin manifestations are now dealt inour department.
The professor, one associate professors, fivelecturers and eight associates take part in inpatient andoutpatient cares as well as research and teachingactivities. Twenty doctors who basically belong to ourdepartment are currently out in affiliated hospitals
mainly engaged in clinical works there Additionally,
five staff members are abroad at present, mainly
involved in advanced research activities in cellbiology and molecular biology.

In the out-patient clinic we see around 200 patientsa day. Incisional and excisional biopsies are
frequently performed under local anesthesia at theoutpatient operation facilities belonging to ourdepartment. Daily discussions are made for initiallyconsulted cases when they are rather difficult todiagnose, by all staff members including Professorand Associate Professors. Furthermore, retrospective
clinical and histological discussions are held regularly,
which always gives us invaluable lessons.
Concerning the in-patient clinic, there are about ten
staff members under the supervision of the ward-chief.
Surgical operations such as removal of malignancies
and skin grafting that require general anesthesia arealso performed weekly in the central surgical facilities.

211

Education
We have ten dermatologist and are studying in the
postgraduate course under the guidance of staff
members of our department.
In addition to series of lectures , clinical education
is provided for fifthand six grade medical students, which aims at
giving a general introduction for how makedermatological approaches for diagnosis andtreatment, with a stress on learning how to observeand describe a variety of skin eruptions. Actually thestudents are supposed to see patients in outpatient
clinic every day for an entire week, as well as toparticipate in the inpatient clinic.

References Activities
Each specialized outpatient service reflects its own
research field in a disease-oriented manner. However,those specialized groups performing their own clinicaland research activities are never exclusive, and there
are increasing communications with other departments
such as internal medicine and blood transfusion
service as well as intergroup communications. Recent
advanced techniques in cellular, molecular biology
and our newly established laboratories, will enable us
to organize optimal research conditions.
1) Jinnin M, Ihn H, Mimura Y, Asano Y, Tamaki K:
Involvement of the constitutive complex
formation of c-Ski/SnoN with Smads in the
impaired negative feedback regulation oftransforming growth factor beta signaling inscleroderma fibroblasts. Arthritis Rheum 56:
1694-1705, 2007
2) Passeron T, Valencia JC, Bertolotto C, Hoashi T,
Le Pape E, Takahashi K, Ballotti R, Hearing VJ.
SOX9 is a key player in ultraviolet B-induced
melanocyte differentiation and pigmentation. Proc
Natl Acad Sci U S A 104: 13984-13989, 2007.
3) Asano Y, Czuwara J, Trojanowska M.
Transforming growth factor-b regulates DNA
binding activity of transcription factor Fli1 by
p300/CREB-binding protein-associated factordependentacetylation.
J
BIol
Chem.
2007;282:34672-83.

4) Yamane K, Asano Y, Tamaki K, Ihn H. Epidermal
growth factor up-regulates transforming growth
factor-beta receptor type II in human dermal
fibroblasts via p38 mitogen-activated protein
kinase pathway. Biochem Biophys Res Commun.
2007;352:69-77.
5) Ihn H, Mimura Y, Yazawa N, Jinnin M, Asano Y,
Yamane K, Tamaki K. High-dose intravenous
immunoglobulin infusion as treatment for diffuse
scleroderma. Br J Dermatol. 2007;156:1058-60.
6) Ito Y, Hamazaki TS, Ohnuma K, Tamaki K,
Asashima M, Okochi H: Isolation of murine hairinducing cells using the cell surface marker
prominin-1/CD133. J Invest Dermatol 127:105260, 2007
7) Ohmatsu H, Sugaya M, Kadono T, Tamaki K:
CXCL13 and CCL21 are expressed in ectopic
lymphoidfolliclesincutaneous
lymphoproliferative disorders. J Invest Dermatol
127: 2466-2468, 2007.
8) Yazawa N, Fujimoto M, Tamaki K.Recent
advances on pathogenesis and therapies insystemic sclerosis. Clin Rev Allergy Immunol.
2007;33:107-12.
9) Prazma CM, Yazawa N, Fujimoto Y, Fujimoto M,
Tedder TF. CD83 expression is a sensitive markerof activation required for B cell and CD4+ T cell
longevity in vivo. J Immunol. 2007;179:4550-62.
10) Fujita H, Akihiko Asahina, Mayumi Komine,
Kunihiko Tamaki: The direct action of
1α,25(OH)2-vitamin D3 on purified mouse
Langerhans cells. Cell. Immunol. 245: 70-79,
200711) Ashida R, Ihn H, Mimura Y, Jinnin M, Asano Y,
Kubo M, Tamaki K.Clinical features ofscleroderma patients with contracture ofphalanges.
ClinicalRheumatol.
2007
Aug;26(8):1275-7.
12) Kanda N, Shimizu T, Tada Y, Watanabe S. IL-18
enhances IFN-gamma-induced production of
CXCL9, CXCL10, and CXCL11 in humankeratinocytes. Eur J Immunol. 37:338-350. 2007.
13) Sugaya M, Hartley O, Root MJ, Blauvelt A. C34,
a Membrane Fusion Inhibitor,Blocks HIV
Infection of Langerhans Cells and Viral
Transmission to T Cells. J Invest Dermatol. 2007
Jun;127(6):1436-43.

21214) Nakashima H, Fujimoto M, Asashima N,
Watanabe R, Kuwano Y, Tada Y, Maruyama N,
Okochi H, Tamaki K: Serum chemokine profile inpatients with bullous pemphigoid. Br J Dermatol
156: 454-459, 2007.
15) Kuwano Y, Prazma CM, Yazawa N, Watanabe R,
Ishiura N, Kumanogoh A, Okochi H, Tamaki K,
Fujimoto M, Tedder TF: CD83 influences cellsurface MHC class II expression on B cells andother antigen-presenting cells. Int Immunol. 19:
977-92, 2007.
16) Kuwano Y, Fujimoto M, Watanabe R, Ishiura N,
Nakashima H, Komine M, Hamazaki TS, Tamaki
K, Okochi H: The involvement of Gab1 and PI 3kinase in beta1 integrin signaling in keratinocytes.
Biochem Biophys Res Commun. 361: 224-9, 2007.
17) Kuwano Y, Fujimoto M, Watanabe R, Ishiura N,
Nakashima H, Ohno Y, Yano S, Yazawa N,
Okochi H, Tamaki K: Serum chemokine profiles
in patients with alopecia areata. Br J Dermatol.
157: 466-73, 2007.
18) Ishiura N, Komine M, Kadono T, Kikuchi K,
Tamaki K. A case of milia en plaque successfully
treated with oral etretinete. Br J Dermatol 2007;
157(6): 1287-919) Komine M, Karakawa M, Takekoshi T, Sakurai N,
Minatani Y, Mitsui H, Tada Y, Saeki H, Asahina A,
Tamaki K. Early inflammatory changes in the"perilesional skin" of psoriatic plaques: is thereinteraction between dendritic cells andkeratinocytes? J Invest Dermatol. 2007
Aug;127(8):1915-22.
20) Watanabe R, Fujimoto M, Ishiura N et al. CD19
expression in B cells is important for suppressionof contact hypersensitivity. Am J Pathol 2007;
171: 560-70.

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Department of Plastic andReconstructive Surgery
Professor
Isao Koshima, M.D.

Lecturer
Kotaro Yoshimura, M.D.

Research Associate
Koichi Gonda, M.D.,

Gentaro Uchida, M.D.,D.D.S

Takuya Iida, M.D.,

Noriyuki Aoi, M.D.

Mitsunaga Narushima, M.D.

Homepage
Organization
The present faculty of the Department of Plastic andReconstructive Surgery consists of 1 professor, 1
associate professor, 1 lecturer, 5 associates and 6
physicians. There are about 100 doctors in thedepartment, including 16 medical trainees, 8 graduate
school students, but most are serving in rotation ataffiliated hospitals.
The outpatient clinic is located on the 3rd floor of
the outpatients building, while there are wards with
about 25 available beds on the 10th floor in the New
Ward. Our faculty room is located in the Medical
Laboratory Building and laboratory rooms in the East
Laboratory Building.
The present status of the educational, research andclinical activities of the department is as follows.

Clinical Activities
The outpatient clinic is opened every morning from
Monday to Friday. There are several specialized
clinics for trauma, scars and keloids, facial paralysis,
hand, replantation, microsurgery, breasts, head andneck reconstruction, cleft lip and palate, craniofacial

malformation,congenital
anomalies,
vascularmalformations, lymphedema, and cosmetic surgery
including cosmetic dermatology. There are about
2,500 new patients and the total number of revisiting
patients are about 25,000 in a year. In the operating
theater over 350 operations are achieved under generalanesthesia, while in the outpatient clinic about 350
operations are achieved under local anesthesia in ayear. Each week, the professor goes the round of
inpatients on Wednesday morning. Preoperative andpostoperative conferences and seminar that all
members of the department should attend are held at
6pm on Wednesday. The Journal club are also held at
8am on Wednesday and Thursday. Research
conferences are held on every Monday and Friday
evening.

Teaching Activities
In regard to pregraduate education, the department
has the duty of lecturing to 2nd, 3rd and 4th year
medical students, and also of instructing 4th medical
students in bed side practice. The subjects taken up in
the lectures include general concepts of plastic surgery,wound healing, congenital malformations, skin grafts

214

and flaps, microsurgery, head and neck reconstruction,
hand surgery, craniomaxillofacial surgery, burn andtrauma, cosmetic surgery, and regenerative medicine.
In the bed side practice the students have theopportunity of seeing various diseases and disorders in
the field of plastic surgery and attending outpatient
clinics, surgical operations and clinical lectures byfaculty members. For graduate school students,
microsurgical training program is undertaken in thelaboratory room. In the postgraduate course, after
completing the 6-year training program, a trainee cansit for the board examination of the Japan Society of
Plastic and Reconstructive Surgery. We have acceptedover ten foreign visitors (in a year) who desire to learn
our new surgical techniques, “supermicrosurgery”.

Research Activities
Basic and clinical researches are performed ingroups. The major research subjects are as follows:
1) Studies on cell isolation from human tissue suchas adipose, amnion, and placenta.
2) Studies on mechanism of hypermelanogenesis of
the skin.
3) Studies on differentiation induction of humanadult stem cells from adipose, amnion, andplacenta4) Characterization of human adult stem cells anddermal papilla cells.
5) Studies on hair regrowth using epidermal stem
cells and dermal papilla cells.
6) Clinical studies on fat regeneration using
suctioned fat tissue and adipose stromalprogenitor cells.
7) Studies on biological function of extracellularmatrix taken from human adipose tissue.
8) Studies on angiogenesis using human adult stem
cells from adipose.
9) Studies on chondrogenesis and osteogenesis using
human fibrin and adipose stromal cells.
10) Studies
onmolecular
mechanismsofvasculogenesis and angiogenesis in the mouseembryo.
11) Studies
onmolecular
pathogenesisofholoprosencephaly using a mouse model.
12) Studies on MMPs and TIMPs expressed in keloid.

13) Studies on the cultured epidermal cells and thecell adhesive function.
14) Studies on clinical application and growth factor
extraction of a fluid from continuous suction
drainage.
15) Studies on mechanism of biological effects ofretinoids on epidermis and dermis.
16) Studies on regeneration of peripheral nerves17) Studies on regeneration of muscles
18) Studies on vascularized nerve flaps
19) Studies on microsurgery for lymphedema
20) Studies on preservation of cancer fertility

References (2007)
1: Koshima I, Narushima M, Mihara M, Nakai I,
Akazawa S, Fukuda N, Watanabe Y, Nakagawa M.
Island medial plantar artery perforator flap forreconstruction of plantar defects. Ann Plast Surg.
2007 Nov;59(5): 558-62.
2: Ogata F, Narushima M, Mihara M, Azuma R,
Morimoto
Y,KoshimaI.
Intraoperative
lymphography using indocyanine green dye fornear-infrared fluorescence labeling in lymphedema.
Ann Plast Surg. 2007 Aug;59(2):180-4.
3: Aiba-Kojima E, Tsuno NH, Inoue K, Matsumoto D,
Shigeura T, Sato T, Suga H, Kato H, Nagase T,
Gonda K, Koshima I, Takahashi K, Yoshimura K.
Characterization of wound drainage fluids as asource of soluble factors associated with woundhealing: comparison with platelet-rich plasma andpotential use in cell culture. Wound Repair Regen.
2007 Jul-Aug;15(4):511-20.
4: Ogata F, Azuma R, Kikuchi M, Koshima I,
Morimoto Y. Novel lymphography using
indocyanine
green
dye
for
near-infrared
fluorescence labeling. Ann Plast Surg. 2007
Jun;58(6):652-5.
5: Nagase T, Hisatomi T, Koshima I, Hattori N,
Koyanagi H, Sanada H. Heterotopic ossification in
the sacral pressure ulcer treated with basic fibroblast
growth factor: coincidence or side effect? J Plast
Reconstr Aesthet Surg. 2007;60(3):327-9.
6: Matsumoto D, Shigeura T, Sato K, Inoue K, Suga H,
Kato H, Aoi N, Murase S, Gonda K, Yoshimura K.
Influences of preservation at various temperatureson liposuction aspirates. Plast Reconstr Surg. 2007

215

Nov;120(6):1510-7.
7: Sato K, Matsumoto D, Iizuka F, Aiba-Kojima E,
Machino C, Suga H, Watanabe-Ono A, Inoue K,
Gonda K, Yoshimura K. A clinical trial of topicalbleaching treatment with nanoscale tretinoin
particles and hydroquinone for hyperpigmented skinlesions. Dermatol Surg. 2007 Aug;33(8):937-44.
8: Miyamoto S, Takushima A, Momosawa A, Iida T,
Ozaki M, Harii K. Camouflaging a cleft lip scar withsingle-hair transplantation using a Choi hairtransplanter. Plast Reconstr Surg. 2007 Aug;120(2):517-20.
9: Okazaki M, Asato H, Takushima A, Sarukawa S,
Okochi M, Suga H, Harii K. Reconstruction withrectus abdominis myocutaneous flap for total
glossectomy with laryngectomy. J Reconstr
Microsurg. 2007 Jul;23(5):243-9.
10: Suga H, Asato H, Okazaki M, Okochi M, Narushima
M. Combination of costal cartilage graft and riblatissimus dorsi flap: a new strategy for secondary
reconstruction of the maxilla. J Craniofac Surg.
2007 May;18(3):639-42.
11: Suga H, Okazaki M, Sarukawa S, Takushima A,
Asato H. Free jejunal transfer for patients with ahistory of esophagectomy and gastric pull-up. Ann
Plast Surg. 2007 Feb;58(2):182-5.
12: Narushima M, Koshima I, Mihara M, Uchida G,
Gonda K. Intravascular stenting (IVaS) for safeand precise supermicrosurgery. Ann Plast Surg.
2008 Jan;60(1):41-4
13: Mihara M, Nakanishi M, Nakashima M,
Narushima M, Gonda K, Koshima I. J Plast
Reconssstr Aesthet Surg. 2008;61(1):88-93. Epub
2007 Apr 5.

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Department ofOral-Maxillofacial Surgery
Professor
Tsuyoshi Takato, M.D.,Ph.D.

Associate Professor
Takafumi Susami, D.D.S., Ph.D.

Mitsuyoshi Iino, D.D.S., Ph.D

Lecturer
Yoshiyuki Mori, D.D.S., Ph.D.

Hisako Hikiji, D.D.S., Ph.D.,

Toru Ogasawara, D.D.S., Ph.D.

Meiko Ohki, D.D.S., Ph.D.

Associate
Jun-ichi Kuroe, D.D.S.

Yukiko Suzuki, D.D.S.

Nobuhiko Kumazawa, D.D.S.

Gen-ichiro Takagi, D.D.S.

Katsumi Ohhashi, D.D.S.

Daichi Chikazu, D.D.S., Ph.D.

Masako Matsuzaki, D.D.S., Ph.D.

Kazumi Ohkubo, D.D.S., Ph.D.

Hideto Saijo, D.D.S., Ph.D.

Homepage

http://plaza.umin.ac.jp/%7Eoralsurg/

Introduction and Organization
Department of Oral and Maxillofacial Surgery,commenced by Dr. Hisashi Ishihara in 1900, is one ofthe oldest departments in Graduate School of
Medicine, the University of Tokyo. This department
consists of wide variety of specialists, such as oral
surgeons, orthodontists and prosthodontists. We
handle all diseases in the oral-maxillofacial region,such as congenital anomalies, jaw deformities, benign
and malignant tumors, trauma and inflammation.
Dental care for the patients who have systemic
disorders or under medical control is another field ofour department. Multidisciplinary treatment teamedby these specialists is characteristic and has performed
excellent results in clinical works. In research fields,
all staffs participate in the clinical and basic researchto support the treatment scientifically and to develop
new treatment protocols, and we have mainly

performed the experimental studies on theregenerative abilities of tissues such as bone,
periosteum, cartilage, perichondrium, vessels, nerve,and skin. At present, we are focusing on tissue
engineering in research works especially in bone,cartilage and vessels. Professor Takato had establishedTissue Engineering Division in the University ofTokyo Hospital and our department has two
endowment departments: Department of Cartilage andBone Regeneration (FUJI SOFT Inc.) and Departmentof Clinical Vascular Regeneration (Daiichi SankyoCo., Ltd.) in Tissue Engineering Division. Eachdepartment has 1 associate professor, 1 assistantprofessor, and several graduate students respectively.
These staffs are focusing on translational researchworks in maxillofacial regions.

217

Clinical activities

Education

In the outpatient clinic, we have 12 dental treatment
booths, one operation room and one speech therapy
room. Average number of patients treated at outpatient
clinic is approximately 100 per day.
Our department has two sections mainly; one is oral
and maxillofacial surgery and another is dental andorthodontic dentistry.
In outward dispensary, oral surgery section
performs dental surgeries such as extraction of
impacted teeth, amputation of infected dental root andgingivoplasty in the operation room. Patients who had
been performed surgical treatment are also followed
up after release from the hospital.
Dentistry and orthodontic dentistry performs facial
growth control and tooth movements for patients withcongenital orofacial anomalies such as cleft lip andpalate, jaw deformities and other congenital
deformities. Speech therapy for the patients with cleft
lip and palate is also performed by speech therapists inour department.
Special section for patients of congenital
deformities is on Monday afternoon examined byplastic surgeon, oral and maxillofacial surgeons,orthodontists and prosthetists. Special section for
temporomandibular arthrosis is on Wednesday
afternoon.
In the ward, we have approximately 400 new
inpatients and surgical treatment is performed on
approximately 300 cases per year. The main surgicaltreatments are chiloplasty and plateplasty for cleft lip
and palate patients, bone grafting in alveolar cleft,orthognatic surgery of orofacial deformities, fixationof orofacial fractures, resection of malignant tumors
combined with reconstruction surgery.
Peculiarity of our treatment strategy is teamapproach in consists of oral and maxillofacial
surgeons, orthodontists and prosthodontists. In our
department, patients with congenital dento-facial
deformity are treated by utilizing several techniquessuch as distraction technique, autologous bone graft
technique, and the original artificial bone graft
technique in addition to orthognatic surgery. The
original bone graft is made from patient’s three
dimensional images of CT data and this technique is
now applied for patent.

Teaching activities are divided into two parts; forundergraduate medical students and for postgraduate
dental students. For undergraduate students, we make5 systematic lectures in their second year of
specialized course, and one lecture and one week
bedside learning in final year. Through thesecurriculums, we demonstrate the characteristics andtreatments of the diseases in oral-maxillofacial region.
Teaching is focused on following points; congenital
anomalies such as cleft lip and palate and branchialarch syndromes, dentofacial deformities caused bydevelopmental and acquired problems, surgicalresection and functional reconstruction of benign andmalignant tumors, temporomandibular joint disorders,
inflammation and maxillofacial trauma. Minimum
dental knowledge concerning jaw movement, toothpain, periodontal disease, malocclusion and dental
restorations are instructed.
For postgraduate dental students, we have two-yearresident course. This course aims to train for a wide
range of dental treatments and to learn about medical
cares. Various specialists instruct dental treatments forthem in outpatient clinic. Carious treatments,
periodontal cares and applications of dentures are
instructed by prosthodontists. Tooth extractions andorthodontic treatment are instructed by oral surgeons
and orthodontists. Medical cares in the ward aretaught by medical doctors and oral surgeons.
After two-year residential course, research training at
postgraduate school is positively recommended. Ouraim for education of clinician is to raise up specialists
mastered both clinic and research skills.

Research
Our research project is consists of clinic and basic
sections. Each research themes are closely related on
the aim of clinical improvement.
The main projects are as follows.
Clinical research:
1） Multidisciplinary treatment of facial deformities
in patients with cleft lip and palate or othercongenital maxillofacial anomalies
2） Multidisciplinary treatment of dentomaxillofacial

218

deformities, trauma and temporomandibulardiseases
3） Multidisciplinary treatment of malignant tumors
in head and neck region4） Distraction technique of orofacial osteogenesis
5） Treatment for oforofacial dysplasia with cleft lip
and palate patients
6） Speech therapy for cleft lip and palate patients
7） Advancement therapy for congenital orofacial
dysplasia
8） Evaluation of therapy for cleft lip and palatepatients
9） Surgery, chemotherapy and irradiation therapy formalignant tumors10) development of dental implant made of newmaterials
11) Advancement of orthognatic surgery for orofacial
dysplasia
12) Evaluation of treatment for temporomandibular
disorders13) Evaluation of mastication function14) Non-surgical treatment system for orofacial
trauma15) Reconstructive treatment utilizing custom-madeartificial bone from our original technique
Basic and experimental research:
1) Contribution of periosteum to bone regeneration
2) Chondrogenic potential of the perichondrium3) Bone regeneration using growth plate chondrocyte
4) Distribution of cell cycle related factors in
regulation of osteo-chondrocyte differentiation
5) Osteochondrogenic differentiation of bonemarrow derived mesenchymal stem cells by
spheroid culture6) Periodontal tissue regeneration around dental
implants
7) Reconstruction of bone and cartilage of oro-facial
region using tissue engineering technique
Tissue engineering:
Clinical section
1) Clinical application of artificial bone that displace
into bone2) Implant type artificial bone generated from tissue
engineered human chondrocyte
3) Therapy of regeneration blood vessel using

AGHM-ßFGF
Research section1) Development of intelligent type of artificial bone
invested with osteogenic differentiation factors2) Development of tetra pod type micro artificial
bone unit
3) Development of neo wound-care dressings4) Three dimensional cell culture of autologous
chondrocyte

Publications
1. Abe M., Westermann F., Nakagawara A., Takato
T., Schwab M., Ushijima T.: Marked andindependent prognostic significance of the CpG
island methylator phenotype in neuroblastomas.
Cancer Lett. 247: 253-258, 2007.
2. Yamagami S, Yokoo S, Mimura T, Takato T,
Araie M, Amano S.: Distribution of precursors inhuman corneal stromal cells and endothelial cells.
Ophthalmology. 114(3):433-9, 2007.
3. Chikazu D, Tomizuka K, Ogasawara T, Saijo H,
Koizumi T, Mori Y, Yonehara Y, Susami T,
Takato T.: Cyclooxygenase-2 activity is essential
for the osseointegration of dental implants. Int J
Oral Maxillofac Surg. 36(5):441-6, 2007.
4. Ohba S, Nakajima K, Komiyama Y, Kugimiya F,
Igawa K, Itaka K, Moro T, Nakamura K,
Kawaguchi H, Takato T, Chung UI.: A novel
osteogenic helioxanthin-derivative acts in a
BMP-dependent manner. Biochem Biophys Res
Commun. 357(4):854-60, 2007.
5. Liu, G., Kawaguchi, H., Ogasawara, T., Asawa, Y.,
Kishimoto, J., Takahashi, T., Chung, UI, Yamaoka,
H., Asato, H., Nakamura, K., Takato, T., Hoshi,
H.: Optimal combination of soluble factors fortissue engineering of permanent cartilage from
cultured human chondrocytes. J Biol Chem. 282(28):20407-20415, 2007.
6. Takahashi, T., Ogasawara, T., Asawa, Y., Mori, Y.,
Uchinuma, E., Takato, T., Hoshi, K.
Three-dimensional microenvironments retainchondrocyte phenotypes during proliferation
culture. Tissue Eng.13(7):1583-92,2007.
7. Ohba S., Ikeda T., Kugimiya F., Yano F., Lichtler
AC., Nakamura K., Takato T., Kawaguchi H.,

219

Chung UI.: Identification of a potent combinationof osteogenic genes for bone regeneration using
embryonic stem (ES) cell-based sensor. FASEB J
21(8):1777-87, 2007.
8. Itaka K, Ohba S, Miyata K, Kawaguchi H,
Nakamura K, Takato T, Chung UI, Kataoka K.:
Bone regeneration by regulated in vivo genetransferusing
biocompatible
polyplex
nanomicelles. Mol Ther. 15(9):1655-62, 2007.
9. Chikazu D., Mori Y., Saijo H., Hasegawa Y.,
Fujihara H., Suenaga H., Ko E.C, Yonehara Y.,
Takato T.: Intraoral Reconstruction of soft palate
with the greater palatine vessels-supplying
mucoperiosteal flap following the resection of thetumor. Asian J Oral Maxillofac. Surg. 19 (4):203206, 2007.
10. Jang K, Sato K, Igawa K, Chung U, Kitamori T.
Development of an osteoblast cell-based 3D
continuous perfusion microfluidic system for drug
screening. Analytical Bioanalytical Chemistry390: 825-832, 2007.
11. Kawamura N, Kugimiya F, Oshima Y, Ohba S,
Iakeda T, Saito T, Shinoda Y, Kawasaki Y, Ogata
N, Hoshi K, Akiyama T, Tobe T, Kadowki T,
Azuma Y, Tanaka S, Nakamura K, Chung UI, andKawaguchi H. Akt1 in osteoblasts and osteoclasts
controls bone remodeling. PLoS ONE 2007 inpress.
12. Itaka K, Ohba S, Chung U, Kataoka K. Bone rege
neration by regulated in vivo gene transfer using
biocompatible polyplex nanomicelles. Mol Ther
15: 1655-1662, 2007.
13. Tanaka Y, Ogasawara T, Asawa Y, Yamaoka H,
Nishizawa S, Mori Y, Takato T, Hoshi K. Factor
contents of autologous human sera prepared bydifferent production methods and their biologicaleffects on chondrocytes. Cell Biol Int in press.

220

Department ofOrthopaedic Surgery
Professor
Kozo Nakamura, M.D., Ph.D.

Associate Professors
Hiroshi Kawaguchi, M.D., Ph.D.,

Sakae Tanaka, M.D., Ph.D.

Lecturers
Isao Ohnishi, M.D., Ph.D.,

Katsushi Takeshita, M.D., Ph.D.,

Tatsuro Karita, M.D., Ph.D.,

Hirotaka Kawano, M.D., Ph.D.

Associates
Takumi Nakagawa, M.D., Ph.D.,

Toshiki Miura, M.D., Ph.D.,

Hideya Itoh, M.D.,

Yuho Kadono, M.D., Ph.D.,

Hirotaka Chikuda, M.D., Ph.D.,

Nobuhiro Hara, M.D.,

Yusuke Shinoda, M.D., Ph.D.,

Takashi Ono, M.D.,

Jun Hirose, M.D.,

Hideki Takeda, M.D.,

Satoshi Ogihara, M.D.,

Yusuke Nakao, M.D.,

Yutaka Morizaki, M.D.

Homepage

http://www.h.u-tokyo.ac.jp/ortho/

Introduction and Organization
In 1906 our department was established as the firsteducational institute of orthopedic surgery in Japan,
by the first Professor Yoshinori Tashiro who hadlearned orthopedic surgery in German and Austria.
Initially, the department treated patients with
infectious disorders and congenital malformations,such as poliomyelitis, tuberculosis of the spine,congenital clubfoot and hip dislocation. The numberof outpatients visiting our department in 1910 was
estimated to be no more than 3.3% that of the twosurgical departments in the University of Tokyo
Hospital.
The number and characteristics of the patients,
however, have changed dramatically in these 100

years. This is because our department addressed theacute needs of society from the beginning. Prof.
Tashiro believed that trauma should be treated byorthopedists, so he provided his pupils with thistraining. Since 1950’s, the department has
increasingly been involved in the treatment of traffic
and industrial accident victims. Prof. Tashiro and his
successor Professor Kenji Takagi devoted themselvesto the establishment of an institute for children withdisabilities. The arthroscope was developed by Prof.
Takagi, and is now considered to represent a
breakthrough in the development of minimallyinvasive surgery. We have recently been conducting
many studies related to the ossification of spinal
ligaments (OPLL), rheumatoid arthritis, biomechanics,
and the degenerative skeletal disorders such as221

osteoporosis and osteoarthritis in response to theprogressive aging of our society.
Our department is now adept in the entire field of
medical science and medical practice related to thehuman locomotor system, the importance of which is
now clearly recognized not only in Japan, but also all
over the world. To meet the expanding needs ofsociety, we have been conducting the teaching,clinical, and research activities described below.
Faculty members of the department are the top
professor, two associate professors, four lecturers, 13
associates, 10 medical staff members, and 12
part-time teachers.

Teaching activities
As for undergraduate education, our department
provides a comprehensive series of lectures, physicalassessment classes and problem-based learning (PBL)
program to 4th year medical students, bedsidelearning and clinical clerkship programs to 5th year
students and clinical lectures to 6th year medical
students.
A comprehensive series of lectures provides basic
knowledge of the physiology, pathology, diagnosis
and treatment of various musculoskeletal disorders.
Twelve consecutive lectures in total cover a whole
field of orthopaedics: basic science, pediatricdisorders, rheumatic diseases, metabolic bone diseases,
musculoskeletal neoplasms, trauma and regional
disorders of the musculoskeletal system (spine,
shoulder, elbow, hand, hip, knee, ankle and foot). In
the physical assessment classes, we have provided
physical diagnostic maneuvers and the radiologicalassessment of a variety of musculoskeletal diseases.
PBL has been introduced to a small group of students
to learn medical humanity and to develop a practicalmethodology to resolve clinical problems.
During the 10-day period of bed-side learning,
students have opportunities to experience patient careand orthopaedic practice with residents and faculty
members. We have developed an original text for the
students to learn orthopedics effectively. They areencouraged to participate in clinical conferences andsurgeries. They are also required to submit reportson the cases they are involved in. They learn how to
conduct a medical interview, check physical findings

and draw up actual plans for a diagnosis and treatment
including surgery.
Clinical Clerkship provides 4 weeks of early
exposure to the clinical practice. The students areattached to a clinical team and are involved in most of
the clinical activities performed by the team.
In clinical lectures, we present the clinical aspectsof important skeletal diseases, and discuss with thestudents several points for reaching a diagnosis andplanning a treatment. Metastatic bone tumors andsports injuries were focused on in 2006 and 2007,
respectively.
For postgraduate education, junior residents join
our department for 5-8 months. Since the training
period is short, the residents are encouraged toexperience emergency cases as often as possible. A
postgraduate seminar and a basic research conference
are held weekly.
Including the postgraduate training, a ten-year
course has been adopted with clinical and researchtraining taking place either in the University of Tokyo
Hospital or in our 50 affiliated hospitals.

Clinical activities
We have the outpatient clinic open from Monday
through Friday, with specialized divisions for spine,
hip, rheumatoid arthritis, tumor, scoliosis, limb
reconstruction and bone lengthening, knee, hand,elbow, shoulder, sports, peripheral nerves, and bonesystemic disorders. A total of 38,153 patients visitedthe outpatient clinic from April 2007 through March
2008.
The ward has approximately 55 to 65 beds available
and is divided into the subgroups above. The members
are on duty for daily patient care under the supervisionof faculty members. The weekly official activities ofour department are ward rounds by the professor on
Tuesday. We have post- and preoperative caseconferences on Monday evening, Tuesday morning
and Thursday evening.
Eight hundred and forty-eight operations were
performed in 2007. These include 102 cervical andthoracicspine
surgeries(including
29
computer-assisted surgeries (CAS)), 54 lumbar spine
surgeries, 24 scoliosis surgeries (including 21 CAS),
63 surgeries for rheumatoid arthritis patients, 99 hip

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surgeries, 63 knee surgeries (including 19 CAS), 12
shoulder surgeries, 97 hand surgeries, 12 limb
lengthening and reconstruction surgeries using
external fixators, 71 surgeries for bone and soft tissue
tumor and 90 trauma surgeries.
The main disorders of cervical spine surgery weremyelopathy due to spondylosis or OPLL. We
successfully adopted double-door open laminoplasty
by splitting the spinal processes for most of thesecases. This procedure was invented and developed inour department and is now used nationwide. The
present professor Kozo Nakamura has also been thechief investigator of a national project to investigate
OPLL. Difficult operations such as subluxation of thecervical spine due to rheumatoid arthritis, Down’s
syndrome or cerebral palsy were treated using anavigation system that has been officially approved asa high-level advanced medical treatment.
The lumbar spine group developed a new posterior
decompression technique which preserves the spinous
processes and interspinous ligaments, and successfully
uses it for lumbar spinal canal stenosis. Randomized
clinical trials are now ongoing by this group.
Main operations performed by the rheumatoid
arthritis clinic group were total joint arthroplasty.
They are using image-free navigation system in total
knee arthroplasty operation, which is useful for theaccurate placement of the implants.
The hip surgery group treated mainly acetabular
dysplasia and osteoarthritis of the hip joint. They
performed not only total hip replacements, but also
several osteotomies including rotational acetabularosteotomy (RAO). The RAO was originated andestablished in our department. They have started aclinical trial for a new artificial hip joint using the
MPC polymer in collaboration with the Department ofMaterials Engineering in Tokyo University.
The knee clinic group developed a new endoscopic
anterior cruciate ligament reconstruction techniqueusing the navigation system based on fluoroscopic
images to realize ideal graft placement.
The peripheral nerve clinic group has developed"costal nerve transfer to the musculocutaneous nerve"
for brachial plexus injury.
Limb reconstruction operations using external
fixators included non-union, leg lengthening anddeformity correction. One of the main interests of thisgroup is the development of a system to analyze themechanical properties of a skeletal system. During
this period of analysis, the mechanical properties ofthe fracture site in vivo are to be evaluated bymonitoring the motion of a dynamic pin clamp during
simulated walking.

Research activities
Our research activities cover the full range of themusculoskeletal system medicine, using the in-depthsciences of biology and technology. Especially in thefield of molecular biology of bone and cartilage
metabolism, we are regarded as being on the leadingedge in the world. Basic research is performed under
the supervision of the faculty staff members. The main
research topics we have focused on are as follows.
1) Molecular backgrounds of bone and joint diseases
using forward and reverse genetics approaches
2) Signaling of differentiation and apoptosis ofosteoclasts
3) Etiology of OPLL
4) Molecular background underlying the joint
destruction by rheumatoid arthritis
5) Molecular background of osteoarthritis using amouse genomics approach6) Non-invasive evaluation of bone strength using afinite element method
7) In vivo bone formation by cytokines and its
clinical application
8) Molecular mechanism of age-related bone andcartilage disorders
9) Molecular mechanism of glial cell differentiation
In addition, four endowment departments take anactive role in research activities in close collaboration
with our Department. Two were established in the 22th
Century Medical Center. They deal with clinicalresearch, which houses the largest clinical database of
osteoarthritis patients in the world for the pursue ofgenomic and etiological research. One department isin the Division of Tissue Engineering, which seeks todevelop epochal bone and cartilage regenerative
medicine. The fourth is founded in the Graduate
School of Medicine and the researchers aredeveloping durable artificial joints in cooperation with
the Ishihara & Takai Laboratory of the Graduate
School of Engineering. Furthermore, we collaborate

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with the Center for Disease Biology and Integrative
Medicine (CDBIM), and are developing nonviral genedelivery vectors (polyion complex micelles).

References
1. Bessho M, Ohnishi I, Matsuyama J, Matsumoto T,
Imai K, Nakamura K. Prediction of strength andstrain of the proximal femur by a CT-based finite
element method. J Biomech 2007;40: 1745-53.
2. Fijita T, Orimo H, Inoue T, Kaneda K, Sakurai M,
Morita R, Yamamoto K, Sugioka Y, Inoue A,
Takaoka K, Yamamoto I, Hoshino Y, andKawaguchi H: Clinical effect of bisphosphonate
and vitamin D on osteoporosis: reappraisal of amulticemter double-blind clinical trial comparing
etidronate and alfacalcidol. J Bone Miner Metab
2007; 25: 130-137.
3. Fukui M, Chiba K, Kawakami M, Kikuchi S,
Konno S, Miyamoto M, Seichi A, Shimamura T,
Shirado O, Taguchi T, Takahashi K, Takeshita K,
Tani T, Toyama Y, Wada E, Yonenobu K, Tanaka T,
Hirota Y. Japanese Orthopaedic Association BackPain
Evaluation
Questionnaire.
Part
2.
Verification of its reliability: The Subcommittee
on Low Back Pain and Cervical Myelopathy
Evaluation of the Clinical Outcome Committee of
the Japanese Orthopaedic Association. J Orthop
Sci 2007;12:526-32.
4. Fukui M, Chiba K, Kawakami M, Kikuchi S,
Konno S, Miyamoto M, Seichi A, Shimamura T,
Shirado O, Taguchi T, Takahashi K, Takeshita K,
Tani T, Toyama Y, Wada E, Yonenobu K, Tanaka T,
Hirota Y. JOA Back Pain Evaluation
Questionnaire: initial report. J Orthop Sci 2007;
12:443-450.
5. Fukui M, Chiba K, Kawakami M, Kikuchi S,
Konno S, Miyamoto M, Seichi A, Shimamura T,
Shirado O, Taguchi T, Takahashi K, Takeshita K,
Tani T, Toyama Y, Wada E, Yonenobu K,Tanaka T,
Hirota Y. Japanese Orthopaedic Association
Cervical Myelopathy Evaluation Questionnaire(JOACMEQ): Part 3. Determination of reliability.
J Orthop Sci 2007;12:321-326.
6. Fukui M, Chiba K, Kawakami M, Kikuchi S,
Konno S, Miyamoto M, Seichi A, Shimamura T,
Shirado O, Taguchi T, Takahashi K, Takeshita K,

Tani T, Toyama Y, Wada E, Yonenobu K,Tanaka T,
Hirota Y. Japanese Orthopaedic Association
Cervical Myelopathy Evaluation Questionnaire(JOACMEQ): Part 2. Endorsement of thealternative item. J Orthop Sci 2007;12:241-248.
7. Fukui M, Chiba K, Kawakami M, Kikuchi S,
Konno S, Miyamoto M, Seichi A, Shimamura T,
Shirado O, Taguchi T, Takahashi K, Takeshita K,
Tani T, Toyama Y, Wada E, Yonenobu K,Tanaka T,
Hirota Y. An outcome measure for patients withcervical myelopathy: Japanese Orthopaedic
Association Cervical Myelopathy Evaluation
Questionnaire (JOACMEQ): Part 1. J Orthop Sci
2007;12:227-240.
8. Hikita A, Tanaka S. Ectodomain shedding ofreceptor activator of NF-kappaB ligand. Adv Exp
Med Biol. 2007;602:15-21.
9. Hiramatsu K, Asaba Y, Takeshita S, Nimura Y,
Tatsumi S, Katagiri N, Niida S, Nakajima T,
Tanaka S, Ito M, Karsenty G, Ikeda K.
Gamma-glutamyltransferase as a pathogenic
factor of bone and joint disease. Endocrinology
2007, 48:2708-2715.
10. Ikeda T, Saito T, Ushita M, Yano F, Kan A, Itaka
K, Moro T, Nakamura K, Kawaguchi H, andChung UI: Identification and characterization of
the human SOX6 promoter. Biochem Biophys Res
Commun 2007; 357: 383-390.
11. Itaka K, Ohba S, Miyata K, Kawaguchi H,
Nakamura K, Takato T, Chung UI, and Kataoka
K: Bone regeneration by regulated in vivo genetransferusing
biocompatible
polyplex
nanomicelles. Mol Ther 2007; 15: 1655-1662.
12. Kawaguchi H, Jingushi S, Izumi T, Fukunaga M,
Matsushita T, Nakamura T, Mizuno K, Nakamura
T, and Nakamura K: Local application ofrecombinant human fibroblast growth factor-2 onbone repair: a dose-escalation prospective trial on
patients with osteotomy. J Orthop Res 2007; 25:480-487.
13. Kawamura N, Kugimiya F, Oshima Y, Ohba S,
Ikeda T, Saito T, Shinoda Y, Kawasaki Y, Ogata N,
Hoshi K, Akiyama T, Chen WS, Hay N, Tobe T,
Kadowaki T, Azuma Y, Tanaka S, Nakamura K,
Chung UI, and Kawaguchi H: Akt1 in osteoblasts
and osteoclasts controls bone remodeling. PLoS
ONE 2007; 2: e1058.

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14. Kimura M, Konno T, Takai M, Ishiyama N, Moro
T, Ishihara K. Prevention of tissue adhesion by aspontaneously formed phospholipid polymerhydrogel. Key Engineering Materials 2007; 342343: 777-780.
15. Konno S, Hayashino Y, Fukuhara S, Kikuchi S,
Kaneda K, Seichi A, Chiba K, Satomi K, Nagata
K, Kawai S. Development of a clinical diagnosis
support tool to identify patients with lumbar
spinal stenosis. Eur Spine J 2007; 16:1951-1957.
16. Kono SJ, Ohshima Y, Hoshi K, Bonewald LF, Oda
H, Nakamura K, Kawaguchi H, and Tanaka S: Erk
pathwaysnegatively
regulate
matrixmineralization. Bone 2007; 40: 68-74.
17. Kosaki N, Takaishi H, Kamekura S, Kimura T,
Okada Y, Minqi L, Amizuka N, Chung UI,Nakamura K, Kawaguchi H, Toyama Y, andD'Armiento J: Impaired bone fracture healing inmatrix metalloproteinase-13 deficient mice.
Biochem Biophys Res Commun 2007; 354:846-51.
18. Koyama Y, Miyashita M, Irie S, Takatori Y,
Yamamoto M, Karita T, Kazuma K. A study of thereality of daily life among patients withosteoarthritis of the hip undergoing conservative
treatment. J Orthop Nurs. 2007; 11: 81-90.
19. Koyama Y, Miyashita M, Irie S, Takatori Y,
Yamamoto M, Karita T, Kazuma K. A study of thereality of daily life among patients withosteoarthritis of the hip undergoing conservative
treatment. J Orthop Nursing 2007; 11(2): 81-90.
20. Kugimiya F, Kawaguchi H, Ohba S, Kawamura N,
Hirata M, Chikuda H, Azuma Y, Woodgett JR,
Nakamura K, and Chung UI: GSK-3β controls
osteogenesis through regulating Runx2 activity.
PLoS ONE 2007; 2: e837.
21. Kyomoto M, Iwasaki Y, Moro T, Konno T, Miyaji
F, Kawaguchi H, Takatori Y, Nakamura K, andIshihara K: High lubricious surface of
cobalt-chromium-molybdenum alloy prepared bygraftingpoly(2-methacryloyloxyethyl
phosphorylcholine). Biomaterials 2007; 28:
3121-3130.
22. Kyomoto M, Iwasaki Y, Moro T, Konno T, Miyaji
F, Kawaguchi H, Takatori Y, Nakamura K,
Ishihara K. High lubricious surface of
cobalt-chromium-molybdenum alloy prepared bygraftingpoly(2-methacryloyloxyethyl
phosphorylcholine). Biomaterials. 2007; 28:
3121-3130.
23. Kyomoto M, Moro T, Konno T, Takadama H,
Kawaguchi H, Takatori Y, Nakamura K,
Yamawaki N, and Ishihara K: Effects ofphoto-induced
graft
polymerizationof
2-methacryloyloxyethyl phosphorylcholine on
physical properties of cross-linked polyethylene in
artificial hip joints. J Mater Sci Mater M 2007;
18: 1809-1815.
24. Kyomoto M, Moro T, Konno T, Takadama H,
Kawaguchi H, Takatori Y, Nakamura K,
Yamawaki N, Ishihara K. Effects ofphoto-induced
graft
polymerizationof
2-methacryloyloxyethyl phosphorylcholine on
physical properties of cross-linked polyethylene in
artificial hip joints. J Mater Sci Mater Med. 2007;
18: 1809-1815.
25. Kyomoto M, Moro T, Konno T, Takadama H,
Yamawaki N, Kawaguchi H, Takatori Y,
Nakamura K, and Ishihara K: Enhanced wear
resistance of modified cross-linked polyethylene
by grafting with poly (2-methacryloyloxyethyl
phosphorylcholine). J Biomed Mater Res A 2007;
82: 10-17.
26. Kyomoto M, Moro T, Konno T, Takadama H,
Yamawaki N, Kawaguchi H, Takatori Y,
Nakamura K, Ishihara K. Enhanced wear
resistance of modified cross-linked polyethylene
by grafting with poly(2-methacryloyloxyethyl
phosphorylcholine). J Biomed Mater Res A.
2007; 82: 10-17.
27. Liu G, Kawaguchi H, Ogasawara T, Asawa Y,
Kishimoto JI, Takahashi T, Chung UI, Yamaoka H,
Asato H, Nakamura K, Takato T, and Hoshi K:
Optimal combination of soluble factors for tissue
engineering of permanent cartilage from cultured
human chondrocytes. J Biol Chem 2007; 282:
20407-20415.
28. Maruyama Z, Yoshida CA, Furuichi T, Amizuka N,
Ito M, Fukuyama R, Miyazaki T, Kitaura T,
Nakamura K, Fujita T, Kanatani N, Moriishi T,
Yamana K, Liu W, Kawaguchi H, Nakamura K,
and Komori T: Runx2 determines bone maturity
and turnover rate in postnatal bone development
and is involved in bone loss in estrogen deficiency.

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Dev Dynam 2007; 236: 1876-1890.
29. Miyamoto Y, Mabuchi A, Shi D, Kubo T, Takatori
Y, Saito S, Fujioka M, Sudo A, Uchida A,
Yamamoto S, Ozaki K, Takigawa M, Tanaka T,
Nakamura Y, Jiang Q, Ikegawa S. A functional
polymorphism in the 5' UTR of GDF5 isassociated with susceptibility to osteoarthritis. Nat
Genet. 2007; 39: 529-533.
30. Miyazaki T, Yamamoto S, Tanaka S. Molecularmechanism of bone destruction in rheumatoid
arthritis. Future Rheumatology 2007, 2:61-72.
31. Muraki S, Yamamoto S, Ishibashi H, Oka H,
Yoshimura N, Kawaguchi H, and Nakamura K:
Diet and lifestyle associated with increased bonemineral density: cross-sectional study of Japaneseelderly women at an osteoporosis outpatient clinic.
J Orthop Sci 2007; 12: 317-320.
32. Nakagawa T, Hiraoka H, Fukuda A, Kuribayashi S,
Nakayama S, Matsubara T, Nakamura K.
Fluoroscopic-based navigation-assisted placementof the tibial tunnel in revision anterior cruciate
ligament
reconstruction.
Arthroscopy,
2007;23:443.e1-443.e4
33. Ogata N, Kawaguchi H, Chung UI, Roth SI, andSegre GV: Continuous activation of Gαq in
osteoblasts results in osteopenia through impaired
osteoblast differentiation. J Biol Chem 2007; 282:
35757-64.
34. Ohashi S, Ohnishi I, Kageyama T, Imai K,
Nakamura K. Distraction osteogenesis promotes
angiogenesis in the surrounding muscles. Clin
Orthop Relat Res. 2007 Jan;454:223-9.
35. Ohba S, Ikeda T, Kugimiya F, Yano F, Lichtler AC,
Nakamura K, Takato T, Kawaguchi H, and Chung
UI: Identification of a potent combination of
osteogenic genes for bone regeneration using
embryonic stem (ES) cell-based sensor. FASEB J
2007; 21: 1777-1787.
36. Ohba S, Nakajima K, Komiyama Y, Kugimiya F,
Igawa K, Itaka K, Moro T, Nakamura K,
Kawaguchi H, Takato T, and Chung UI: A novel
osteogenic helioxanthin-derivative acts in a
BMP-dependent manner. Biochem Biophys Res
Commun 2007; 357: 854-860.
37. Saito T, Ikeda T, Nakamura K, Chung UI, andKawaguchi H: S100A1 and B, transcriptionaltargets of SOX trio, inhibit terminal

differentiation of chondrocytes. EMBO Rep 2007;
8: 504-509.
38. Shimizu S, Asou Y, Itoh S, Cung UI, Kawaguchi
H, Shinomiya K, and Muneta T: Prevention of
cartilage destruction with intraarticular osteoclastogenesis inhibitory factor / osteoprotegerin ina murine model of osteoarethritis. Arthritis
Rheum 2007; 56: 3358-3365.
39. Suematsu A, Tajiri Y, Nakashima T, Taka J, Ochi
S, Oda H, Nakamura K, Tanaka S, Takayanagi H.
Scientific basis for the efficacy of combined useof antirheumatic drugs against bone destruction inrheumatoid arthritis. Mod Rheumatol 2007, 17:
17-23.
40. Tanaka S. Signaling axis in osteoclast biology andtherapeutic targeting in the RANKL/RANK/OPG
system. Am J Nephrol 2007, 27:466-478.
41. Wakeyama H, Akiyama T, Nakamura K, Tanaka S.
Posttranslational regulation of Bim by Caspase-3
in the osteoclast. Ann N Y Acad Sci. 2007, 1116:
271–280.
42. Wakeyama H, Akiyama T, Takahashi K, Amano H,
Kadono Y, Nakamura M, Oshima Y, Itabe H,
Nakayama KI, Nakayama K, Nakamura K, Tanaka
S. Negative feedback loop in the Bim-caspase-3
axis regulating apoptosis and activity ofosteoclasts. J Bone Miner Res 2007,
22:1631-1639.

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Department of Ophthalmology
Professor
Makoto Araie, M.D., Ph.D.

Associate Professor
Satoru Kato, M.D., Ph.D.,

Yasuhiko Tamaki, M.D., Ph.D.

Lecturer
Makoto Aihara, M.D., Ph.D.,

Atsushi Tomidokoro, M.D., Ph.D.,

Miyuki Nagahara, M.D., Ph.D., Toshikatsu Kaburaki, M.D., Ph.D,
Ryuichi Ideta, M.D

Research Associate
Tomohiko Usui, M.D., Ph.D.,

Yasuo Yanagi, M.D., Ph.D.,

Yasuo Noda, M.D., Ph.D.,

Yuji Inoue, M.D., Ph.D.,

Koichi Mishima, M.D., Ph.D.,

Keiko Hayashi, M.D.,

Takashi Shigeeda, M.D.,

Akira Hirose, M.D.,

Kenji Sugisaki, M.D.,

Takuya Atarashi, M.D.,

Shinsuke Konno, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/ophl

Introduction and Organization
The Department of Ophthalmology, University ofTokyo School of Medicine, was founded in 1989.
Since then, the department has contributed to Japanese
ophthalmology not only by educating a large numberof eminent ophthalmologists in Japan, but also byproducingsignificant
basic
researchinophthalmology.
The department has been active in collaboration with
ophthalmologists around the world, sponsoring
international ophthalmological meetings, educating
fellows from foreign countries and sending our staff
and fellows abroad.

Clinical activities
Altogether, approximately 4000 new outpatients areseen every year in our hospital, which has a total of 44
beds. Residents work in the ambulatory section andtake care of inpatients. Special services are provided

in units devoted to ophthalmic subspecialities such as
cornea,glaucoma,
retina,uveitis,neuroophthalmology, orthoptics, diabetic retinopathy, andgenetic and color blindness problems. The staff
members supervise the ambulatory and special
services depending on each one’s speciality.
Most of the inpatients suffer from cataract, glaucoma,
corneal diseases, retinal detachment, diabetic
retinopathy, uveitis and strabismus. Surgeries are
performed in the operating theater of the hospital
under operating microscopes. Approximately 2400
cases underwent operations in our department.
Surgeries can be monitored by TV system which ismounted on operating microscopes. Since multiple
observers can watch the same images and sharefindings, this system has a great potential in training
and promoting discussion.

Teaching activities
As an undergraduate course, we give lectures on

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corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged inpractical training for medical students on
ophthalmological examinations at the outpatient clinic.
As a postgraduate course, we give lectures on topics
concerning corneal transplantation, corneal diseases
and new medical therapies.

Research activities
Research topics in our department cover a variety offields in ophthalmology; e.g. ocular pharmacology,
regenerative medicine in the cornea and retina,
aqueous humour dynamics, immunology andmolecular biology. Special laboratories for physiology,
pharmacology and genetic engineering have been
established. Specific fields of research in our
department are as follows.
1. Analysis with laser-speckle method of vascularflow in retina and iris
2. Clinical investigation of normal tension glaucoma
3. Analysis of dynamics of aqueous flow
4. Drug effect on glaucoma
5. Screening method of glaucoma
6. Tissue engineering of the cornea
7. Clinical investigation of corneal shape
8. Gene therapy in corneal transplantation
9. Role of advanced glycation endproducts in oculardiseases
10. Clinical and basic research of excimer laser
refractive surgery
11. Molecular analysis of retinal degenerative
diseases
12. Color blindness and visual function
13. Electrophysiological analysis of the effect ofdrugs on the retina
14. Biocompatibility of intraocular lenses
15. Immuno-hereditary analysis of Harada’s disease
and Bechet’s disease
16. Immunosuppressive reagents on Bechet’s disease
17. Pathophysiology and molecular mechanisms of
diabetic retinopahty

References
1. Chen YN, Aihara M, Mao W, Yamada H,
Matsuyama S, Araie M. Effects of Bax-inhibiting

peptides in retinal ganglion cell death induced byglutamate or oxidative stress in vitro. Brain Res
1148:28-37, 2007.
2. Ebihara N, Yamagami S, Yokoo S, Amano S,
Murakami A. Involvement of CCL2-CCR2
interaction in monocyte-lineage cell recruitmentof normal human corneal stroma. J Immunol 178:
3288-3292, 2007
3. Ebihara N, Yamagami S, Chen L, Tokura T,
Iwatsu M, Ushio H, Murakami A. The expression
and function of Toll-like receptor-3 and -9 inhuman corneal myofibroblasts. Invest Ophthalmol
Vis Sci 48:3069-3076, 2007
4. Fujisawa K, Shimizu K, Uga S, Suzuki M,
Nagano K, Murakami Y, Goseki H: Changes in
the crystalline lens resulting from insertion of aphakic IOL (ICL) into the porcine eye. Graefe'sArch Clin Exp Ophthalmol 245:114-122, 2007
5. Fukuoka S, Aihara M, Iwase A, Araie M.
Intraocular pressure in an ophthalmologicallynormal Japanese population. Acta Ophthalmol
Scand. 2007 Nov 26 [Epub ahead of print]
6. Hamrah P, Yamagami S, Liu Y, Zhang Q, Vora S,
Lu B, Gerard C, Dana MR. Deletion of thechemokine receptor CCR1 prolongs corneal
allograft survival. Invest Ophthalmol Vis Sci 48:
1228-1236, 2007
7. Harada T, Harada C, Nakamura K, Quah H-M.A,
Okumura A, Namekata K, Saeki T, Aihara M,
Yoshida H, Mitani A, Tanaka K. The potential roleof glutamate transporters in the pathogenesis ofnormal tension glaucoma. Journal of Clinical
Investigation 117:1763-1770, 2007
8. Hirasawa H, Yanagi Y, Tamaki Y, Inoue Y,
Kadonosono K. Indocyanine green and trypan
blue: intracellular uptake and extracellular bindingby human retinal pigment epithelial cells. Retina
27:375-378, 2007
9. Inoue Y, Iriyama A, Ueno S, et al. Subretinal
transplantation of bone marrow mesenchymal
stem cells delays retinal degeneration in the RCS
rat model of retinal degeneration. Exp Eye Res
85:234-241, 2007
10. Inoue Y, Yanagi Y, Matsuura K, Takahashi H,
Tamaki Y, Araie M. Expression of hypoxiainducible factor 1alpha and 2alpha in choroidal
neovascular membranes associated with age-

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related macular degeneration. Br J Ophthalmol
91:1720-1721, 2007
11. Iriyama A, Chen YN, Tamaki Y, Yanagi Y. Effectof anti-VEGF antibody on retinal ganglion cells in
rats. Br J Ophthalmol 91:1230-1233, 2007
12. Joko T, Nanba D, Shiba F, Miyata K, Shiraishi A,
Ohashi Y, Higashiyama S: Effects ofpromyelocytic leukemia zinc finger protein on the
proliferation of cultured human corneal
endothelial cells. Mol Vis 27: 649-658, 2007
13. Kaji Y, Usui T, Ishida S, Yamashiro K, Moore
TCB, Moore J, Yamamoto Y, Yamamoto H,
Adamis AP. Inhibition of diabetic leukostasis andblood-retinal barrier b reakdown with a soluble
form of a receptor for advanced glycation end
products. Invest Ophthalmol Vis Sci 48: 858-865,
2007
14. Kaji Y, Nagai R, Amano S, Takazawa Y,
Fukayama M, Oshika T. Advanced glycation end
product deposits in climatic droplet keratopathy.
Br J Ophthalmol 91:85-88, 2007
15. Kawaguchi T, Mochizuki M, Miyata K, Miyata N:
Phacoemulsification cataract extraction andintraocular lens implantation in patients withuveitis. J Cataract Refract Surg 33:305-309, 2007
16. Mimura T, Yamagami S, Usui T, Yokoo S, Ono K,
Honda N, Kaneda A, Sugisaki K, Sayegh RR,
Amano S. Preoperative evaluation of cultured
human corneal limbal epithelium on amniotic
membrane by confocal microscopy. Curr Eye Res
32:407-411, 2007
17. Mimura T, Yamagami S, Honda N, Usui T, Yokoo
S, Amano S. Necessary prone position time forhumancornealendothelial
precursor
transplantation in a rabbit endothelial deficiency
model. Curr Eye Res 32:617-623, 2007
18. Mimura T, Usui T, Amano S, Yamagami S, Ono
K, Noma H, Funatsu H. Retinal vasculitis andvitreous hemorrhage associated with mixed
connective tissue disease. Retinal vasculitis in
MCTD. Int Ophthalmol 26;159-161, 2007
19. Miyai T, Yonemura T, Nejima R, Otani S, Miyata
K, Amano S. Interlamellar flap edema due tosteroid-induced ocular hypertension after laser insitu keratomileusis. Jpn J Ophthalmol 51:228-230,
2007
20. Miyanaga M, Kawaguchi T, Shimizu K, Miyata K,

Mochizuki M: Influence of early cerebrospinal
fluid-guided diagnosis and early high-dose
corticosteroid therapy on ocular outcomes ofVogt-Koyanagi-Harada disease. Int Ophthalmol
27:183-188, 2007
21. Miyata K, Kato S, Nejima R, Miyai T, Honbo M,
Ohtani S: Influences of optic edge design on
posterior capsular pacity and anterior capsulecontraction. Acta Ophthalmol Scand, 85:99-102,
2007
22. Murata H, Kato S, Fukushima H, Tsutsumi A,
Numaga J, Amano S. Corneal endothelial celldensity reduction: A complication of retinal
photocoagulation
withanindirectophthalmoscopy contact lens. Acta Ophthalmol
Scand 85:407-408, 2007
23. Murata H, Tomidokoro A, Matsuo H, Tomita G,
Araie M: Frequency doubling technology
perimetry in open-angle glaucoma eyes withhemifield visual field damage: comparison ofhigh-tension and normal-tension groups. J
Glaucoma 16:9-13, 2007
24. Obata R, Iriyama A, Inoue Y, Takahashi H,
Tamaki Y, Yanagi Y. Triamcinolone acetonide
suppresses early proangiogenic response in retinal
pigment epithelial cells after photodynamic
therapy in vitro. Br J Ophthalmol 91:100-104,
2007
25. Obata R, Tamaki Y, Yanagi Y, Kami J.
Relationship between intensity of reflected lightand temperature increase: assessment of fundus
pigmentation for transpupillary thermotherapy.
Jpn J Ophthalmol 51:462-469, 2007
26. Ono K, Yokoo S, Mimura T, Usui T, Miyata
K, Araie M, Yamagami S, Amano S. Autologoustransplantation of conjunctival epithelial cells
cultured on amniotic membrane in a rabbit model.
Mol Vis 13:1138-1143, 2007
27. Oshika T, Sugita G, Miyata K, Tokunaga T,
Samejima T, Okamoto C, Ishii Y. Influence of tilt
and decentration of scleral-sutured intraocularlens on ocular higher-order wavefront aberration.
Br J Ophthalmol 91:185-188, 2007
28. Saito H, Suzuki M, Asakawa T, Kato S.
Retinopathy in a multiple sclerosis patientundergoing interferon-therapy. Mult Scler 13:939940, 2007

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29. Sakata N, Tokunaga T, Miyata K, Oshika T:
Changes in contrast sensitivity function andocular higher order aberration by conventional
myopic photorefravtive keratectomy. Jpn J
Ophthalmol 51:347-352, 2007
30. Sakata R, Yanagi Y. Expression of immature andmature retinal cell markers in retinoblastoma. Eye2007 Feb 2 [Epub ahead of print]
31. Shimazaki J, Amano S, Uno T, Maeda N, Yokoi N,
and the Japan Bullous Keratopathy Study Group.
National survey on bullous keratopathy in Japan.
Cornea 26:274-278, 2007
32. Shimazawa M, Inokuchi Y, Ito Y, Murata H,
Aihara M, Miura M, Araie M, Hara H
Involvement of ER stress in retinal cell death. Mol
Vision 13:578-587, 2007
33. Suzuki M, Usui T, Kinoshita N, Yamagami S,
Amano S. A case of sterile corneal perforation
after bone marrow transplantation. Eye 21:114116, 2007
34. Suzuki M, Amano S, Honda N, Usui T, Yamagami
S, Oshika T. Longitudinal changes in corneal
irregular astigmatism and visual acuity in eyeswith keratoconus. Jpn J Ophthalmol 51:265-269,
2007
35. Suzuki S: A case of malignant solotary fibroustumor presenting with exophthalmos. Jpn J Clin
Oncol 37:401, 2007
36. Takamoto M. Kaburaki T. Numaga J. Fujino Y.
Kawashima H. Long-term infliximab treatment
for Behcet's disease. Jpn J Ophthalmol 51:239-40,
2007.
37. Takezawa S, Yokoyama A, Okada M, Fujiki R,
Iriyama A, Yanagi Y, Ito H, Takada I, Kishimoto
M, Miyajima A, Takeyama K, Umesono K,
Kitagawa H, Kato S. A cell cycle-dependent
co-repressor mediates photoreceptor cell-specificnuclear receptor function. Embo J 26:764-774,
2007
38. Tanimoto K, Kaneko A, Suzuki S, Sekiguchi N,
Watanabe T, Kobayashi Y, Kagami Y, Maeshima
AM, Matsuno Y, Tobinai K: Primary ocularadnexal MALT lymphoma: a long-term follow up
study of 114 patients. Jpn J Clin Oncol 37:337344, 2007
39. Toda J, Fukushima H, Kato S: Injection oftriamcinolone acetonide into the posterior

sub-tenon capsule for treatment of diabetic
macular edema. Retina 27:764-769, 2007
40. Toda J, Kato S, Oshika T, Sugita G: Posterior
capsule opacification after combined cataract
surgery and vitrectomy. J Cataract Refract Surg,
33:104-107,2007
41. Tomidokoro A, Araie M, Iwase A; Tajimi Study
Group.Corneal thickness and relating factors in a
population-based study in Japan: the Tajimi study.
Am J Ophthalmol 144:152-154, 2007
42. Usui T, Yamagami S, Kishimoto S, Yokoo S,
Nakayama T, Amano S. Role of macrophagemigration
inhibitory
factorincornealneovascularization. Invest Ophthalmol Vis Sci 48:
3545-3550, 2007
43. Yamagami S, Yokoo S, Mimura T, Araie M,
Amano S. Distribution of precursors in humancorneal stromal cells and endothelial cells.
Ophthalmology 114:433-439, 2007
44. Yamagami S, Yokoo S, Amano S, Ebihara N.
Characterization of bone marrow-derived cells inthe substantia propria of the human conjunctiva.
Invest Ophthalmol Vis Sci 48:4476-4481, 2007
45. Yanagi Y, Iriyama A, Jang WD, Kadonosono K.
Evaluation of the safety of xenon/bandpass lightin vitrectomy using the A2E-laden RPE model.
Graefes Arch Clin Exp Ophthalmol 245:677-81,
2007
46. Yoneya H, Kato S, Sugita G, Oshika T:
Spontaneous regression of Elschnig pearl
posterior capsule opacification. J Cataract Refract
Surg 33:913-914, 2007
47. Yu ZK, Chen YN, Aihara M, Mao W, Uchida S,
Araie M: Effects of beta-adrenergic receptor
antagonists on oxidative stress in purified rat
retinal ganglion cells. Mol Vis 13:833-839, 2007

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Department ofOtorhinolaryngology andHead & Neck Surgery
Professor
Tatsuya Yamasoba, M.D, Ph.D.

Associate Professor
Mitsuya Suzuki, MD.PhD, Takahiro Asakage, M.D.,Ph.D,

Lecturer
Ken Ito, M.D.,Ph.D,

Kazunari Nakao, M.D, Ph.D

Shinichi Iwasaki, M.D., Ph.D

Research Associate
Kenji Kondo, M.D, Ph.D,

Takashi Sakamoto, M.D. PhD.

Takaharu Nito, M.D,

Shotaro Karino, M.D, Ph.D,

Yasuhiro Ebihara, M.D,

Kenta Watanabe, M.D,

Miho Hagisawa, M.D,

Yasuhiro Chirara, M.D.,

Keigo Suzukawa, M.D.,

Akinori Kashio, M.D,

Homepage

http://www.h.u-tokyo.ac.jp/orl /Introduction and Organization
The Department of Otorhinolaryngology was
founded in 1899 by Prof.Waichiro Okada who studiedin Germany. This is the first department ofotorhinolaryngology of the national university inJapan.
Our
department
coversallotorhinolaryngological diseases and associatedsystemic diseases, and has specialized clinics in
middle ear and inner ear diseases, hearing impaired
infant and children, adult and elderly patients, facialparesis, vertigo and balance disorders, olfactory
disorders and paranasal diseases, voice and speechdisorders, taste and swallowing respiratory disorders,aphasia, central auditory disorders and head & neckcancers.
A professor, associate professors, lecturers(assistant professors) and associates participate insurgery, out-patient and in-patient care as well as
research and educational activities. One assistantprofessor is abroad at present for basic and clinicalresearch in the U.S.A. Moreover eight Japanese
graduate students and one Chinese foreign graduate
student participate in basic research.
Weekly preoperative and postoperative conferences
are held to discuss surgical cases in detail. Special
lectures on leading research activities are presented byinvited guests on a regular basis. A weekly journal
club is held to introduce current research papers.

Clinical activities
In the out-patient clinic, general and special

231

services are provided to approximately 150
out-patients on a daily basis in all areas ofotorhinolaryngology and related specialties, andapproximately 300 new patients visit monthly.
In the new inpatient hospital, 44 beds are preparedfor patients under the supervision of lecturers andsenior residents from each subspecialty group
including head & neck surgery, middle ear surgery andcochlear
implant
surgery;
voice
andbronchoesophagological surgery, and paranasal
surgery and other minor surgery. Peroperative andpostoperative problems are checked and discussed byeach group, the professor’s and associate professor’s
rounds. Approximately 810 operations are performed
annually.
Cochlear implant surgery over 150 cases has been
actively performed for infants, children and adultpatients with profound hearing loss and is very
successful to provide new hearing. Head and necksurgery is performed to extirpate malignant tumor
with neighboring tissues and reconstruct upper
respiratory and swallowing functions at one stage
operation cooperating with plastic surgeons.
Reconstructive surgery of microtia and atresia toreconstruct external ear is routinely performed withplastic surgeons.
Auditory brainstem response is routinely examinedin order to diagnose peripheral and central deafness inneonates, infants and children.
Treatment of acoustic tumor using an ɤ-knife andauditory brainstem implant are performed inconsultation with neurosurgons.

Teaching activities
For the fourth year medical students’ serial lecturesand for the fifth and sixth year medical students
special lectures on current topics are provided by theprofessor and associate professor.
Clinical training is provided for the sixth year classof medical students on a one-to-one basis with staff
doctors. They are requested to write reports on aclinical case or a clinical problem. The students
participate to see surgery, special clinics and clinicalexaminations such as otoscope, fiberscope, auditory
brainstem response, and caloric test. Interview withpatient is encouraged. They are questioned many

aspects of clinical problems in seminars by professor
and associate professor. During half and a week period,
the students participate in surgery special clinics andpractice of clinic examination such otoscope,
fiberscope auditory brainstem, caloric test and so on.

Research activities
Clinical and basic research activities are highly
encouraged. Clinical research, which is supervised bysenior doctors, is very actively pursued even by young
residents. Case reports presentation and writing skills
are regarded as important experience in order todevelop young doctors’ research activity andinvestigate important findings in patients. The clinicalresearch is related to ear surgery, neurotology,
audiology,
head
&
neck
surgery,
bronchoesophagology and rhinology and is related tocase resersch, clinical statistics and clinicalelectrophysiology. Basic research is also encouraged
to solve essence of clinical problems and to elucidate
basic phenomena or anatomical and cellular structures.
Our research topics cover:1) Morphology and neurophysiology of the inner ear
focusing on sensory neural deafness: human
temporal bone pathology, electron microscopic
study in animal models, gene therapy, protein
tranasduction, and nanotechnology
2) Clinical application of otoacoustic emissions andauditory brainstem responses.
3) Histochemistry of olfactory epithelium indevelopment and aging.
4) Clinical neurophysiology of the facial nerves
focusing on degeneration and regeneration inpatients.
5) Histochemistry of head and neck cancer
pathology.
6) The central auditory cortex research using MEG.
7) Auditory brainstem response and speech andhearing after the new born hearing screening.
8) Pathology and electrophysiology of the larynx.
9) Vestibular research on the oculomotor and balancesystems in the brain.
10) Vestibular myogenic evoked potentials in cochlear
implant and inner ear anomaly.
11) Hair cell physiology in the vestibular end organ.
12) Newborn hearing screening and language

232

development in deaf childen.
13) Physiology bone conduction innovation of bone
conduction hearing and bilateral hearing.
14) Embryology of middle, inner ear and central
auditory system.
Various clinical and basic research are conducted bystaffs, residents, postgraduate doctors and seniordoctors at affiliated hospitals.

References
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2. Asakage T, , et al. Acta Otolaryngol 127 (Suppl559):118-122, 2007
3. Chihara Y, et al. Neurological complications after
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factors based on long-term follow-up. Acta
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5. Ebihara Y, et al. Carcinoid tumor of the larynx:
clinical analysis of 33 cases in Japan. Acta
Otolaryngol 127 (Suppl 559):145-150, 2007
6. Egami N, et al. Vocal cord abductor paralysis in
multiple system atrophy: a case report. Acta
Otolaryngol 127 (Suppl 559):164-167, 2007
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116:897-901, 2007
9. Fujishiro Y, et al. A new aspect of tri-modal
therapywithsuperselective
intra-arterial
chemotherapy in maxillary sinus carcinoma. Acta
Otolaryngol 127 (Suppl 559):151-156, 2007

10. Ishimoto S. et al. Hearing levels in patients withmicrotia: correlation with temporal bonemalformation. Laryngoscope 117:461-5, 2007
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with various IAM deformities in Children. Ann
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12. Ito K, et al. Successful cochlear implantation inpatient with bilateral thalamic infarction. Arch
Otolaryngol Head Neck Surg 133:192-3, 2007
13. Ito K, et al. Effect of head position on vestibular
evoked myogenic potentials with toneburst
stimuli. Acta Otolaryngol 127: 57-61, 2007.
14. Iwasaki S, et al. Head taps evoke a crossed
vestibulo-ocular reflex. Neurology 68:1227-1229,
2007
15. Iwasaki S, et al. Migraine-associated vertigo:
clinical characteristics of Japanese patients andeffect of lomerizne, a calcium channel antagnist.
Acta Otolaryngol 127 (Suppl 559):45-49, 2007
16. Kaga K, et al. Changes in auditory behaviors ofmultiply handicapped children with deafness
after hearing aid fitting. Acta Otolaryngol 127(Suppl 559):9-12, 2007
17. Kaga K, Asakage T. Medical education by
bedside learning - helping medical students tointeract with patients who have head and neckcancer. Acta Otoraryngol 127:408-10, 2007
18. Kuan C-C, et al. Tuberculous meningitis-induced
unilateral sensorineural hearing loss: a temporalbone study. Acta Otolarygol 127:553-557, 2007
19. Shinjo Y, et al. Assessment of vestibular functionof infants and children with congenital andacquired deafness using the ice-water caloric test,
rotational chair test and vestibular-evoked
myogenic potential recording. Acta Oto-Laryngol.
126:736-747, 2007
20. Asenov D.R, et al. Changes in the audiograms ofa nasopharyngeal cancer patient during thecourseoftreatment:atemporalbone
histopathological study. Acta Otoraryngol
127:1105-1110, 2007
21. Takahashi H, et al. Multiple neural origins ofearly auditory evoked potential in rats.
Neuroscience 148:845-856, 2007
22. Takahashi H, et al. Intra-oral pressure based
voicing control of electrolaryngeal speech withintra-oral vibrator. Journal of Voice 15, 2007

233

23. Kashio A, et al. A protein derived from the fusion
of TAT peptide and FNK, a Bcl-xL derivative,
prevents cochlear hair cell death fromaminoglycoside ototoxicity in vivo. J Neurosci
Res. 15 :1403-12, 2007
24. Kikuchi S et al. Neuro-otological findings inpatients with very small (border zone) cerebellar
infarcts. Acta Otolaryngol 127 (Suppl 559):56-60,
2007
25. Kikuta S, et al. Factors associated with thepresence of drug-resistant bacteria and recurrent
acute otitis media in children- a study in a private
clinic .Acta Otolaryngol 127 (Suppl 559):5-8,
2007.
26. Kimura M, et al. Tonsillar cyst of the false vocal
cord. Auris Nasus Larynx 34:111-113, 2007.
27. Kondo K, et al. Reconstruction of theintratemporal facial nerve using interposition
nerve graft: time course of recovery in facial
movement and electrophysiological findings.
Acta Otolaryngol 127 (Suppl 559):85-90, 2007
28. LePrell CG, et al. Mechanisms of noise-induced
hearing loss indicate multiple methods ofprevention. Hearing Research 226:22-43, 2007
29. Miyajima C, et al. Otosclerosis associated with
Ehlers-Danlos syndrome: report of a case. Acta
Otolaryngol 127 (Suppl 559):157-159, 2007
30. Mizuochi T, et al. Latency variation of auditory
N1m responses to vocal and nonvocal sounds.
Neuroreport 18:1945-1949, 2007
31. Mochiki M, et al. Prognostic factors ofhypopharyngeal cancer: a univariate andmultivariate study of 142 cases. Acta Otolaryngol
127 (Suppl 559):136-144, 2007
32. Monobe H, et al. Peritonsillar abscess withparapharyngeal and retropharyngeal involvement:
incidence and intraoral approach. Acta
Otolaryngol 127 (Suppl 559):91-94, 2007
33. Murofushi T, et al. Tone burst-galvanic ratio ofvestibular evoked myogenic potential amplitudes:a new parameter of vestibular evoked myogenic
potential?. Clin Neurophysiol 118:1685-1690,
2007
34. Nakao K, et al. Olfactory neuroblastoma: longterm clinical outocome in a single institutebetween 1979 and 2003. Acta Otolaryngol 127(Suppl 559):113-117, 2007

35. Nakaya M, et al. Prolonged allergen challenge inmurine nasal allergic rhinitis: nasal airway
remodeling and adaptation of nasal airway
responsiveness. Laryngoscope 117:881-885, 2007
36. Nito T, et al. Parathyroid adenoma causing
spontaneous cervical hematoma: a case report.
Acta Otolaryngol 127 (Suppl 559):160-163, 2007
37. Okada K, Ito K, Yamasoba T, Ishii M, Iwasaki S,
Kaga K. Benign mass lesions deep inside thetemporal bone: imaging diagnosis for proper
management. Acta Otolaryngol 127 (Suppl 559):
71-77, 2007
38. Otake R, et al. The effect of eye position on theorientation of sound lateralization. Acta
Otolaryngol 127 (Suppl 559):34-37, 2007
39. Ozeki H, et al. Development and regeneration of
hair cells. Acta Otolaryngol 127 (Suppl 559):3844, 2007
40. Sakamoto T, et al. Methimazole- induced cell
death in rat olfactory receptor neurons occurs via
apoptosis triggered through mitochondrial
cytochrome c-mediated caspase-3 activation
pathway. J Neurosci Res 85:548-557, 2007.
41. Sano M, et al. Influence of Chronic Middle Ear
Diseaseson
Gustatory
Function:
An
Electrogustometric Study. Otol Neurotol.
28:44-47, 2007
42. Sano M, et al. Early myelination patterns in thebrainstem auditory nuclei and pathway: MRI
evaluation study. Int J Pediatr Otorhinolaryngol.
71:1105-1115, 2007
43. Sasaki T, et al. Results of hearing tests after total
middle ear reconstruction. Acta Otolaryngol. 127:474-9, 2007
44. Someya S, et al. Genes encoding mitochondrial
respiratory chain components are profoundly
down-regulated with aging in the cochlea of
DBA/2J mice. Brain Res 1182:26-33, 2007
45. Someya S, et al. Caloric restriction suppresses
apoptotic cell death in the mammalian cochlea
and leads to prevention of presbycusis. Neurobiol
Aging 28:1613-1622, 2007
46. Suzukawa K, et al. Surgical treatment of medial
meatal fibrosis. Report of four cases. Auris Nasus
Larynx 34:365-368, 2007.
47. Suzuki M, et al. Vestibulo-ocular reflex (VOR)
preserved in bilateral severe vestibular

234

malformations with internal auditory canalstenosis. Acta Otolaryngol 127:1226-1230, 2007
48. Suzuki M, et al. Clinicopathological factors
related to cervical lymph node metastasis in apatient with carcinoma of the oral floor. Acta
Otolaryngol 127 (Suppl 559):129-135, 2007
49. Takegoshi H, et al. Aplasia and displacement of
the horizontal portion of the petrous carotid
artery in mandibulofacial dysostosis. Acta
Otolaryngol 127 (Suppl 559):50-55, 2007
50. Toma-Hirano M, et al. Type I interferon regulates
pDC maturation and Ly49Q expression. Eur J
Immunol. 37:2707-2014, 2007
51. Tsunoda A, et al. Head torsion technique fordetailed observation of larynx and hypopharynx.
J Laryngol Otol. 121:489-90, 2007
52. Tsunoda K, et al. An effective management
regimen for laryngeal granuloma caused by
gastro-esophageal reflux: combination therapy
with suggestions for lifestyle modifications.
Acta Otolaryngol 127:88-92, 2007
53. Ushio M, et al. Subjective visual horizontal inpatients with posterior canal benign paroxysmal
positional vertigo. Acta Otolaryngol 127:836-838,
2007
54. Ushio M, et al. Long-lasting deviation of thesubjective visual horizontal after complete
unilateral vestibular deafferentation by subtotal
resection of the temporal bone. Otol Neurotol28:
369-371, 2007
55. Ushio M, et al. Prediction of the prognosis ofbell’s palsy using multivariate analyses. Otology& Neurotology 29:69-72, 2007
56. Watanabe K, et al. Musashi-1 expression in
postnatalmouseolfactoryepithelium.
Neuroreport 18:641-644, 2007
57. Watanabe K, et al. Age-related change in theaxonal diameter of the olfactory nerve in mouselamina propria. Acta Otolaryngol 127 (Suppl559):108-112, 2007
58. Yamasoba T, et al. Role of mitochondrial
dysfunction and mitochondrial DNA mutations in
age-related hearing loss. Hear Res 226:185-193,
2007
59. Yamasoba T, et al. Isolated hearing loss
associatedwith
T7511C
mutationinmitochondrial DNA. Acta Otolaryngol 127(Suppl 559):13-18, 2007
60. Yasui T, Yamasoba T. Acute sensorineural
hearing loss associated with aortitis syndrome.
Acta Otolaryngol 127 (Suppl 559):29-33, 2007
61. Yoshimoto S, et al. Treatment results for 84
patients with base of tongue cancer. Acta
Otolaryngol 127 (Suppl 559):123-128, 2007

235

Department of
Rehabilitation Medicine
Professor
Nobuhiko Haga, M.D.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The Department of Rehabilitation Medicine wasestablished by Ministry of Education, Culture, Sports,
Science and Technology in April 2001. It is one of thenewest fields in Graduate School of Medicine, theUniversity of Tokyo. It belongs to the Sensory andMotor System Science Course of the Surgical Science
Division. Current authorized staff is only one
professor.
This department derives from the establishment of
the physical therapy room in the central diagnostic
and therapeutic sections in order to develop theclinical practice of rehabilitation medicine in 1963.
The chair of professor was set up as a full-time
director of the central rehabilitation service in 1984,
but the formal title remained a physical therapy
department.
Rehabilitation medicine is a newly establishedclinical section which was born in development of themodern principle of the medical health service bywhich it came to value the enhancement of not only
adding years of patient's life but also adding life to theyears. Regardless of the rapid expansion of needs,
acknowledgment of rehabilitation medicine wasdelayed in the frame of the old-fashioned clinicaldepartments. In our country, it was 1996 when the
rehabilitation specialty was authorized as formal
clinical practice by the former Ministry of Health andWelfare.
On the other hand, it was positioned as an
assistance instructor in the sensory and motor system
medicine department with shifting to the graduate

school course systems since 1995 to 97 in the
University of Tokyo. Finally, the rehabilitation
medicine field was installed in the sensory and motor
system medicine department by a budget step of 2001.
We have accepted the graduate school student
formally since fiscal year 2001. However, thearrangement of additional teaching staff is not stillmaterialized. Therefore, the staff of the graduate
school is only one professor. Nine students haveentered the graduate school by 2006, and three ofthem were granted Ph.D.

Clinical activities
There is not enough doctors arranged for the
department of rehabilitation medicine, and we cannot
run own beds for rehabilitation patients at present. The
professor serves as a director of Central Rehabilitation
Service Department of the University of Tokyo
Hospital. Both departments are united and engage inclinical practice. We have at present no charged ward,
and treat about 1,000 new referrals annually fromalmost all the departments of the university hospital.
We always take charge of about 150 patients
corresponding about 15% of the whole number of
inpatients. We also see 15 people per day at theoutpatient rehabilitation setting. The numerical ratioof outpatient is being reduced in order to give priority
to the clinical service corresponding to needs
expansion of service to inpatients.

236

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year
medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such ascerebrovascular disturbances, spinal cord injuries andspina bifida, neuromuscular diseases, bone and joint
diseases, and cerebral palsy as well as on outline ofrehabilitation, welfare system, and prostheses /orthoses . We have provided a clinical practice insmall group, so-called bedside learning for 5th year
students from Wednesday to Friday every other week.
They experience a few patients and learn how to takea patients’ history, physical findings, functional
evaluation, and how to plan rehabilitation programs.
We have introduced a few of elective students forclinical clerkship to our collaborating hospitals withspecialized rehabilitation ward.
In addition, we have provided the training of comedical students including physical therapy andoccupational therapy. Twenty students or more comeand stay at the university hospital annually as along-term clerkship from several PT/OT training
schools.
Nine graduate school students entered by 2006 andthree of them acquired a degree of Ph.D. andgraduated.

Research activities
Our research activities are growing up. In 2006, theCentral Rehabilitation Service Department moved to
the new building and a research laboratory wasprovided for the first time. As the motion analysis
system was partially renewed, we are planning ourresearches mainly in the field of musculoskeletal
disabilities. In addition, we are planning collaborating
researches with other departments in our hospital,
other faculties in our university, and institutions
outside the University of Tokyo. The ongoing andscheduled projects are as follows.
1) 3D-motion analysis of patients with joint
disorders in the lower extremities
2) Estimation of supported motion by humanmachine coadaptation system

3) Analysis of effects on body by vibration stimulus
4) Estimation of standing balance and the effect bypassive stimulation
5) Analysis of motion and energy expenditure in theactivities of daily living in the physically disabled
6) Non-invasive evaluation of lower limb motor
function in spina bifida
7) Prevention of requiring long-time care withphysical exercise
8) Disabilities and handicaps in patients with skeletal
dysplasias
9) Mechanism of physical therapy on the change ofpain and perceptional threshold10) Evaluation of higher brain dysfunction

References
1. Imahashi K, Kawagoe M, Eto F, Haga N: Clinicalstatus and dependency of the elderly requiringlong-term care in Japan. Tohoku J Exp Med 2007;
212: 229-238.
2. Miyamoto Y, Matsuda T, Kitoh H, Haga N,
Ohashi H, Nishimura G, Ikegawa S: A recurrent
mutation in type II collagen gene causes
Legg-Calve-Perthes disease in a Japanese family.
Hum Genet 2007; 121: 625-629.
3. Nakajima M, Haga N, Takikawa K, Manabe N,
Nishimura G, Ikegawa S: The ACVR1 617G>A
mutation is also recurrent in three Japanesepatients with fibrodysplasia ossificans progressiva.
J Hum Genet 2007; 52: 473-475.
4. Nishimura A, Sakai H, Ikegawa S, Kitoh H, Haga
N, Ishikiriyama S, Nagai T, Takada F, Ohta T,
Tanaka F, Kamasaki H, Saitsu H, Mizuguchi T,
Matsumoto N: FBN2, FBN1, TGFBR1, andTGFBR2 analyses in congenital contracturalarachnodactyly. Am J Med Genet A 2007; 143:694-698.
5. Yamasaki S, Yamasue H, Abe O, Yamada H,
Iwanami A, Hirayasu Y, Nakamura M, Furukawa
S, Rogers MA, Tanno Y, Aoki S, Kato N, Kasai K:
Reduced planum temporale volume and delusional
behaviour in patients with schizophrenia. Eur
Arch Psychiatry Clin Neurosci 2007; 257: 318324.

Surgical Sciences
3. Vital Care Medicine

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Department of Anesthesiology
Professor
Yoshitsugu Yamada, M.D., Ph.D.

Associate Professor
Tomoki Nishiyama, M.D., Ph.D.

Lecturer
Ryo Orii, M.D., Ph.D.

Kyung-Ho Chang, M.D., Ph.D. Takami Komatsu, M.D., Ph.D.

Sou Suzuki, M.D., Ph.D.

Instructor
Hiroshi Sekiyama, M.D., Makoto Ogawa, M.D.,

Nobuko Ito, M.D., Ph.D.,

Yuichiro Saito, M.D.,

Nobuhide Kin, M.D.,

Takayuki Kitamura, M.D.,

Kenichi Kishida, M.D.,

Toshiya Tomioka, M.D., Ph.D.,

Makoto Ogawa, M.D.,

Gaku Kawamura, M.D.,

Junichi Ninagawa, M.D.,

Miho Asahara, M.D.,

Yoshie Suzuki, M.D.,

Nagara Ono, M.D.,

Atsuko Satou, M.D.,

Kaori Fujita, M.D.,

Hiroko Tsujihara, M.D.,

Yoshiteru Mori, M.D.

Kanako Sato, M.D.,

Masahiko Sumitni,M.D.,PhD.,

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/aprc_md.html/
http://www.anes.umin.ne.jp/
Introduction and Organization
The Department of Anesthesiology was establishedin 1952. Our department has residents, chief residents
besides the members above. We introduce theactivities about Teaching, Research and Clinical workof our department.

Clinical activities
Our clinical activities can be divided into two areas;
surgical anesthesia in the operating theater and a pain
clinic.
Anesthesia service including pre and post-operative
care is given every day for elective and emergency
surgery. We provide general anesthesia for various
kinds of surgeries including open heart surgery (adults

and pediatrics) and liver transplant, spinal/epidural
anesthesia and monitored anesthetic care forelectro-convulsion therapy. Recently, the number ofhigh risk or geriatric patents is increasing. In addition,
more than 20% of the surgery (about 8000 cases intotal per year) spends more than eight hours. A new
operating theater opened in January 2007 and thedemand for sufficient number of competentanesthesiologists is increasing.
Pain clinic services are provided for out-patients(including patients in the ward of the otherdepartment) on a daily basis in all areas of painful
diseases. We also provide preoperative anesthetic
consult service for patients who have various medical
diseases. From April 2006 to April 2007, the numberof ambulatory patients was about ten thousand; four
hundred and forty of those were newcomer patients.

239

Currently we have three beds in the ward. Annually,
we provide inpatient service for sixty patients in ourward as well as for seven hundred and twenty patientsin other wards. Preoperative anesthetic consults weredone for nine hundred and fifty patients last year.

Teaching activities
We give lectures for fourth year medical students
and provide clinical education for fifth and sixth year
medical students on a man-to-man basis with ourfaculty staff members. The lectures of the last year
were the history of anesthesia and the preliminary
consideration, the mechanisms of anesthesia,
inhalational anesthesia, intravenous anesthesia andcirculation, the balance of body fluid, acid-basebalance, muscle relaxants, the management of thepatient during anesthesia, monitoring, resuscitation,
pain clinic and the physiology and the management ofpain.
The curriculum of bedside learning consists of threemajor contents: learning a practice of anesthetic
management for patients undergoing surgeries,
observing a practice of pain management for
outpatients suffering from intractable pain, andinteractive lectures on specific topics. During thepractice of anesthetic management, we teach students
technique of examinations and physiological- andpharmacological-knowledge which are essential forthe management of patients in the peri-operative
period. Through the practice of pain management, weteach students causes of intractable pain as well asprocedures of nerve block. We schedule 5 lectures
entitled “introduction to anesthesiology”, “airway
management”, “central venous catheterization”,“spinal anesthesia” and “pain clinic”. These 5 lectures
cover fundamental knowledge of basic procedures
which medical students should acquire. Moreover,students can experience procedures of tracheal
intubation, central venous catheterization and spinal
anesthesia using simulators. Each student is required
to prepare a case report of anesthetic management anda paper on anesthetics and cardiovascular drugs inperi-operative use. We discuss the contents of thereports and papers with students at the end of bedsidelearning, for further comprehension.

Research activities
We have seven research groups and their fields
include respiration, circulation, pain, immune systemand shock.
These are recent major subjects of our research.
1) A role of cytokine signaling in acute lung injury2) Evaluation of optimal ventilatory strategy for
respiratory failure3) Modification of immune system by anesthetics
4) Signal transduction pathway related to apoptosis
activated by sepsis or ischemia-reperfusion insult5) investigation of pathophysiology of shock6) A role of lipid mediators in organ damage
mediated by ischemia-reperfusion injury of amouse lower limb
7) A role of lipid mediators in the formation of
hyperalgesia
8) Antihyperalgesic and antipruritic effects of alpha2-adrenergic agonists
9) A role of spinal microglial cells in thedevelopmentof
inflammation-mediatedneuropathic pain10) spinal contribution for analgesic pathway11) Mechanism of Pruritoceptive and Neurogenic Itch
12) Dose-escalation of sublingual buprenorphine inpatients with chronic pain13) Analysis of electroencephalography during
general anesthesia
14) Invention and evaluation of a new airway device15) Clinical evaluation of neurological sequelae after
cardiac surgery16) Development and assessment of the system fortreating waste anesthetic gases: against global
warming

References
1. Shu H, Arita H, Hayashida M, Chiba S, Sekiyama
H, Hanaoka K.. Inhibition of morphine tolerance
by processed Aconiti tuber is mediated bykappa-opioid receptors. J Ethnopharmacol. 2006
Jun 30;106(2):263-71.
2. Chi Li, Hiroshi Sekiyama, Masakazu Hayashida,Toshinobu Sumida, Hideko Arita, Kazuo
Hanaoka,Effect of repeated topical application ofclonidine cream in a rat model of postoperative

240

pain , PAIN RESEARCH, 21 : 25-32, 2006.
3. Mizuno J, Gauss T, Suzuki M, Hayashida M, Arita
H, Hanaoka K . Encephalopathy andrhabdomyolysis induced by iotrolan during
epiduroscopy. CAN J ANESTH.2007 54:49-53.
4. Hashimoto T, Okudo N, Orii R et al. Intraoperative blood salvage during liver resection,
RCT. Annals of Surgery (in press, 2007)
5. Nishiyama T. Antithrombin can modulate
coagulation, cytokine production, and expressionof adhesion molecules in abdominal aortic
aneurysm repair surgery. Anesth Analg 2006.102(4):1007-11
6. Nishiyama T, Matsukawa T, Yamashita K.
Comparison
betweenneurotropin
andmepivacaine for stellate ganglion injection. J
Anesth 2006. 20 (3): 240-2
7. Nishiyama T, Yokoyama T, Yamashita K. Effects
of protease inhibitor, ulinastatin, on coagulationand fibrinolysis in abdominal surgery. J Anesth
2006. 20 (3) :179-82
8. Nishiyama T. Analgesic effects of systemic
midazolam:comparison
withintrathecal
administration.
Can
J
Anesth2006.53(10) :1004-9
9. Nishiyama T, Nakamura S, Yamashita K. Effectsof the electrode temperature of a new monitor,
TCM4TM on the measurement of transcutaneous
oxygen and carbon dioxide tension. J Anesth 2006.
20 (4 ):331-4
10. Nishiyama T, Nakamura S, Yamashita K.
Comparison of the transcutaneous oxygen andcarbon dioxide tension in different electrodelocations during general anaesthesia. Eur J
Anaesthesiol 2006.23 (12) :1049-54
11. Mizuno J, Yoshiya I, Yokoyama T, Yamada Y,
Arita H, Hanaoka K: Age and sex-relateddifferences in dose-dependent hemodynamic
response to landiolol hydrochloride during generalanesthesia. Eur J Clin Pharm. 2007 (in press)
12. Mizuno J, Muroya M, Gauss T, Yamada Y, Arita H,
Hanaoka K. Effect of 2.5% sevoflurane at PaCO2
30 mm Hg for epileptic focus resection on
hemodynamics and hepatic and renal function. J
Anesth. 2007 (in press)
13. Mizuno J, Gauss T, Suzuki M, Hayashida M, Arita
H,
HanaokaK.
Encephalopathy
andrhabdomyolysis induced by iotrolan during
epiduroscopy. Can J Anesth. Jan; 54(1): 2007 (inpress)
14. Mizuno J, Mohri S, Shimizu J, Suzuki S, Mikane
T, Araki J, Matsubara H, Morita T, Hanaoka K,
Suga H. Starling-effect-independent lusitropism
index in canine left ventricle: Logistic time
constant. Anesth Analg. 2006 Apr;102(4): 1032-9.
15. Xue F, Zhang G, Liu J, Li X, Sun H, Wang X, Li C,
Liu K, Xu Y, Liu Y. A clinical assessment of the
Glidescope videolaryngoscope in nasotracheal
intubation with general anesthesia. J Clin Anesth.
2006 Dec;18(8):611-5.
16. Ong BY, Arneja A, Ong EW. Effects of anesthesia
on pain after lower-limb amputation. J Clin
Anesth. 2006 Dec;18(8):600-4.
17. Ito N, Hirota K, Momoeda K, Iwamori M. Change
in the concentration of neutrophil elastase inbronchoalveolar lavage fluid during anesthesia
and its inhibition by cholesterol sulfate. Transl
Res. 2006 Aug;148(2):96-102.

241

Department of Emergency andCritical Care Medicine
Professor
Naoki Yahagi, M.D.

Lecturer
Yukio Tanaka, M.D., Ph.D.

Associate
Takeshi Ishii, M.D.,

Kyoko Komatsu, M.D.,

Yoichi Kitsuta, M.D.,

Susumu Nakajima, M.D., Ph.D., Tsuneo Suzuki, M.D.,

Masataka Gunshin, M.D.,

Daisuke Yamaguchi, M.D.,

Toshihiro Morita, M.D.

Yasushi Imai, M.D.,

Staff
Takehiro Matsubara, M.D.

Homepage
Introduction and Organization
Department of Emergency and Critical Care
Medicine was established in 1965, as the emergency
service within the Central Clinical Service Facilitiesof the University of Tokyo Hospital and at the sametime as the intensive care service for in-hospitalpatients, it became a tertiary emergency care andcritical care center in the metropolitan Tokyo and also
became the principal teaching facility of the
University of Tokyo. It is a designated Level I Trauma
Center, and also the home of one of the newest Life
Flight aeromedical services in the country.
The Emergency Center sees approximately 17,000
patients per year. It contains major trauma and cardiac
resuscitation rooms complete with STAT X-ray andfull monitoring and resuscitation equipment. There are
9 treatment spaces including space for orthpedics,
gynecology, and Optho-ENT evaluations.
10overnight-stay monitored beds, X-ray, rapid spiral CT,
ultrasound, angiography and STAT Lab are locatedadjacent to the Emergency Center.
In September, 2001, the University of Tokyo

Hospital opened the In-patient Ward A and ourdepartment has necessarily extended services for
management of Critical patients in the new Critical
Care Center now containing adult ICU/CCU of 16
beds, high care unit (ICU2) of 24 beds, pediatricintensive care unit (PICU) of 6 beds and neonatal
intensive care unit (NICU) of 6 beds.
The Emergency Care Center and the Critical Care
Center see an excellent mix of multiple trauma,
high-acuity medical, surgical, pediatric, andgynecologic patients. The Life Flight service provides
another opportunity for exposure to critically illpatients. Consult services are available from all of theclinical departments of the Medical School.

Clinical activities
Our clinical activities are divided into four
categories as follows:
1) Emergency medicine
Our department is responsible for not only
tertiary emergency but also primary and secondary

242

emergency care on 24-hour-a-day basis. In the 2004,
we had about 6,000 ambulance patients out of total
17,000 ER outpatients.
The new ER, four times the size of the present
ER was built in November, 2006. The facility has 5
consultation rooms, 4 specialized consultation
rooms
for
dentistry,
ophthalmology,
otorhinolaryngology
andgynecology,2
resuscitation bays, 1 operating room and 4
observation beds.
2) Intensive care
Staff members specialized in internal medicine,cardiovascular medicine, orthopedic surgery,
surgery, neurosurgery or anesthesiology create “thesemi-closed ICU” model. We are responsible for theentire care of the critically ill patients (i.e. patientswith respiratory insufficiency such as ARDS, withsepsis, with MOF, with shock), post-operative
patients, and tertiary emergency patients, placing anemphasis on evidence-based medical therapy. We
had 1,000 ICU/CCU patients in the 2007. In 2007,
the number of beds in ICU/CCU increased to 16
and the facility included the 24 beds for the highcare ICU2.
3) Bed management
The objective of bed management services is toprovide a timely and appropriate bed allocation for
all the patients. In our hospital, patients areallocated to three types of wards, that is, generalward, ICU2 and ICU/CCU in accordance with theircritical condition. The ICU2 undertakes the leading
bed management in the hospital to ensure maximum
performance as an acute hospital.
4) Risk management
It is split into two categories – in-hospital andout-hospital disasters. In regard to in-hospital risk
management, including “code blue emergency”, weare responsible for patient safety on 24-hour/
365-day basis. And in regard to out-hospital risk
management, our hospital has been authorized by
the Tokyo Metropolitan Government as a disasterbase hospital, and also the Government hasrequested the formation of Disaster Medical
Assistant Team (DMAT) from us. We are now

proceeding with a drastic revision of in-hospitalmanual for disaster control, holding seminars on
disaster medicine, and enforcing the disastertraining. We have oxygen and medical suction
equipment on the passageways in the new ER since2006 fiscal year in case treating the large number ofdisaster patients.

Teaching activities
1) Six hours of lecture for the 2nd year medical
student, the topics include the prehospitalemergency care, the initial evaluation of emergency
patients, disaster medicine, serious infections
disease, and medical equipment. Four hours ofsimulation training of Basic Life Support.
2) One month of clinical clerkship and 1 week of
bed-side training for the 3rd year. ACLS Basiccourse (ICLS) is held for the participants in theclinical clerkship program, and successful
completion of this course will enable students to be
ICLS certified.
3) Clinical integrated lecture for the 4th year students
includes diagnosis and treatment of serious patientsusing case studies of shock, conscious disorder,
trauma, intoxication, infections disease, burns,
hypothermia, and convulsion. After learning a
ACLS course, students experience the real practiceof emergency medicine as fellow passengers in theambulance and as 2.5-day trainees in affiliatedhospitals’ emergency centers.
In conformity with the guideline by Ministry of
Health, Labour and Welfare, all residents learn andpractice emergency medicine and primary care at
every level, primary, secondary and tertiary. The
residents are trained in the ACLS Basic (ICLS)
during resident year to obtain the knowledge andskills in CPR.
Junior residents are also assigned to ICU services
to gain the knowledge of intensive care from
pathophysiological and internal medicine’s point ofview.
In the senior resident program in 2006, we willtrain the new residents to be skilled in advanced
critical care medicine including primary caretrauma, MOF, shock, and equipment support.
As medical aspects of disaster management, we243

provide the residents with lectures based on
MIMMS (Major Incident Medical Management andSupport) program, triage training, and risk
communication techniques using wireless network.
In addition, we produce the seminar for nurses suchas medical support in the big earthquake.

Research activities
The on-going researches include “the Vital Care
Network System” which manages the great number ofhigh-risk people continually, electrolyzed water,elucidation of peripheral neural regulation of heart,and brain resuscitation. In collaboration with
Department of Pharmacy, Department of ClinicalLaboratory Medicine, Department of Infectious
Diseases, we focus on several clinical research on
issues including intra-nuclear transcription of β-D-glucan in blood products .

References
1) Kitsuta Y, Suzuki N, Sugiyama M, Yamamoto
Changes is consciousness level and association
with hyperglycemia as tool for predicting andpreventing
re-bleedingafter
spontaneous
subarrachnoid hemorrhage Pre-hospital anddisaster medicine, 2006; 21(3), 190-195.
2) Toru Sasaki, Sayaka Toriumi, Takahiro Asakage,
Kimitaka Kaga, Daisuke Yamaguchi, Naoki
YahagiThe Toothbrush; A Rare but Potentially Life
Threatening Cause of Penetrating
Pediatrics 2006(118), 1284-1286
3) Kobayashi K, Ikeda H, Higuchi R, Nozaki M,
Yamamoto Y, Urabe M, Shimazaki S, Sugamata N,
Aikawa N, Ninomiya N, Sakurai H, Hamabe Y,
Yahagi N, Nakazawa H. Epidemiological andoutcome characteristics of major burns in Tokyo.
Burns 2005; 31S: S3-11.
4) Hale SI, Kloner RA, Katada S, Obayashi T, Ishii T,
Nakajima S, Yahagi N. Myocardical ischemia
and infarction. In Tisherman SA and Sterz F,
editors. Therapeutic Hypothermia. New York:
Springer; 2005. pp191-209.

Health Sciences and Nursing
1. Health Sciences

Health Sciences and Nursing
2. Preventive and Administrative Nursing

246

Department of Nursing
Administration / Advanced
Clinical Nursing
Professor
Katsuya Kanda, R.N., P.H.N., Ph.D.

Lecturer
Minako Sasaki, R.N., P.H.N., Ph.D.

Assistant Professor
Hideyuki Kobayashi, R.N., P.H.N., B.S.N.,

Homepage

Mami Onishi, R.N., P.H.N., M.S.N.

http://nurs-adm.m.u-tokyo.ac.jp/2004activities.htm

Introduction and Organization
Nursing Administration department provides broad
opportunities to learn about societal issues related tonursing
education,
nursing
ethics,nursingadministration, and safety and quality issues innursing.
Advanced Clinical Nursing department provides 1)
critical analysis and synthesis of conceptual
frameworks, nursing theories and models foradvanced practice, and 2) generation and utilization ofevidence related to practice, understanding of clients,and fundamental skills.
As we expect much of the graduates to develop
their professional carriers in various settings, we areconstantly exploring new issues to make students beable to take wide and long viewpoints.

Teaching activities
A. Graduate courses
1. Nursing Administration 1 (2 credits, Lecturers)
Prof. Kanda and Affiliates
Exploration of political and administrative
functional role in nursing. The course offers
critical analysis of theories in nursing

administration related to quality assurance/
improvement and cost- effective/efficient caredelivery systems. Discussions include concepts
and structures in organization, decision/policy
making process, and application of management
theory and nursing process to nursing
administration. Theory and practice in nursing
education is also explored.
2. Nursing Administration 2 (2 credits, Lecturers)
Prof. Kanda and Affiliates
Studies on application of management theory tonursing administration. Focuses are on 1) issues innursing management such as budgetary
management, nursing informatics, patientclassification systems, staffing, and quality
improvement, and 2) issues in staff management
such as staff development and continuing
education. Students will learn concepts and skills
essential to solving economic issues in health careand nursing to meet professional demands in thecomplexity of health care systems.
3. Advanced Clinical Nursing 1 (2 credits ,Lecturers)
Prof. Kanda and Affiliates
An overview on models and theories in nursing,conceptual frameworks in nursing research, and247

clients' potential and actual physiological andpsychosocial responses to health problems.
Focuses are on 1) conceptual frameworks ofclients' potential and actual physiological andpsychosocial responses to health problems, 2)
health assessment skills in nursing practice, 3)
measurement of clients' health and nursing
intervention outcome. Students will establish theirown theoretical knowledge and practical skills
essential to advanced clinical nursing.
4. Advanced Clinical Nursing 2 (2 credits, Lecturers
and practice)Prof. Kanda and Affiliates
This course explores issues related to advanced
clinical practice, research, and education with anemphasis on specific theoretical perspectives,
methodologies,
practiceandeconomic
implications.
B. Undergraduate Courses
1. First Aid & CPR (1 credit Lecturers & practice)Prof. Kanda and Affiliates
Students will understand the EMS (Emergency
Medical Services) system and learn how to act inemergency situations. The practicum includes
following
subjects;
1)
observationandmeasurement of vital signs, 2) first aid to thevictim with bleeding, intoxication, or burn, 3)
how to carry an injured person, and 4) CPR(cardiopulmonary resuscitation).
2. Fundamental Nursing 1 (2 credits, Lecturers)
Prof. Kanda and Affiliates
This course offers fundamental knowledge ofnursing, such as history and theory in nursing,concepts of professional nursing practice, nursing
service and care delivery systems, nursing
administration,
andnursing
education.
Discussions include contemporary challenging
issues and future strategies in nursing.
3. Fundamental Nursing 2 (2 credits, Lecturers)
Prof. Kanda and Affiliates
This course offers fundamentals in understanding
interpersonal relationships and assessing clients'
health. Students will learn 1) theory and practicein communication, 2) knowledge necessary for
identifying health problems and care priorities, 3)
skills essential to health assessment, 4) nursing

4.

5.

6.

7.

process and nursing diagnosis, and 5) current
ethical issues in nursing and health.
Fundamental Nursing 3 (4 credits, Lecturers andlaboratory practicum)
Prof. Kanda and Affiliates
This course provides theory and practice offundamental nursing skills, which are essential toproviding clients with: 1) safe and effective careenvironment, 2) physiological and psychosocial
integrity, and 3) health promotion andmaintenance.
Clinical Practicum in Fundamental Nursing (2credits, practice)Prof. Kanda, Staffs and Affiliates
Under instructors' supervision, students haveopportunity to apply their fundamental knowledge
and skills of nursing in a variety of settings.
Students will assess clients' health and needs
through application of nursing process.
Nursing Administration (1 credit, Lecturers)
Prof. Kanda and Affiliates
This course prepares students for nurse
administrators/managers of all types of health caresettings such as institutions, organizations,community and politics. Students will learn
fundamental theory and practice in nursing
administration/management through analyzing
current issues in health care and nursing.
Nursing Administration Practicum (1 credit,
practice)
Prof. Kanda and Staffs
Students
haveadministrative/management
practicum in units or divisions in hospitals.
Students will learn care delivery systems such asstaffing and patient classification systems, nursing
informatics, and budgetary issues including costeffectiveness and quality improvement.

Research activities
Nursing research starts with an approach to addressa variety of complex problems related to healthexperience of human beings' daily life. Philosophicalorientations and research methodologies may include
natural scientific (or biomedical, quantitative,
statistical) approaches, or social and human scientific(or narrative, qualitative) approaches, or combination

248

of both approaches.
1. Issues of Nursing Administration
Critical analysis and international comparative
study of administrative, socioeconomic andpolitical issues in contemporary nursing. Focuses
are on 1) patient classification systems andnursing
caredeliverysystems,2)
cost-effectiveness of nursing services, 3) nursing
case management, and 4) nursing policy andstrategies to meet the professional demands.
2. Quality Improvement, Safety Issues, and Risk
Management in Nursing
This work examines 1) quality of nursing care, 2)
outcome management for nursing practice, 3) risk
management in acute care settings, 4)
occupational safety and health of health care
workers, and 5) infection control.
3. PhysiologicalandPsychological
Human
Responses to Stimulus
This area of study aims at exploring the nature, or
determining various effects of physiological andpsychologicalstimulustoparticipants'
physiological bio-information and psychologicalmeasurements. Research scenarios include; 1)patient' daily activities, 2) caregivers' workload
and sleep deprivations, or 3) nurses focus ofattention,eyemovement,
andelectroencephalography
activities.
Data
collections take place through field studies orlaboratory/experimental settings.
4. Nursing Assessment and Intervention
Exploration of structure of existing discipline anddevelopment of new nursing theories in clinicalpractice. Emphases are on 1) explorations ofstructure of nursing theories and models in
nursing, 2) development of clinical and scholarly
knowledge for the identification of healthproblems and assessment of care priorities, and 3)
testing hypotheses effective for nursing
interventions
5. Studies of Nursing Education
Exploration of nursing education systems andfunctional roles of professional nurses in various
settings in advanced countries and developing
countries as well. Higher education for theadvanced practice nurses in Japan is also

explored.

References
1. Sato, R., Kanda, K. & Anan, M. Sleep patterns of
middle-aged and older females who are providing
home care for their ventilator-dependent spouses.
Journal of Japan Academy of Home Health Care,
10(2): 43-50, 2007. (in Japanese)
2. Ozawa, M. Effect of light environment forpreterm infant in NICU and GCU. Journal ofJapan Academy of Neonatal Nursing, 13(3): 6-17,
2007. (in Japanese)
3. Kobayashi, H., Takemura, Y. & Kanda, K.
Patients' perception of nursing service in Japan:
differences amongst degrees of dependence on
daily living care. 7th Conference on Advances in
Health Care Science Research, p30, 2007.
4. Sasaki, M. Workplace violence for health care
workers in U.S.A. Journal of Safety Managementfor Medical Practices, 4(4), 20-23, 2007. (inJapanese)
5. Kanda, K. Benchmarking for quality improvementof nursing service: Nursing quality and its
evaluation. EBNURSING 7(1):102-108, 2007. (inJapanese)

249

Department of Family Nursing
Professor
Associate Professor
Kiyoko Kamibeppu, R.N., P.H.N., Ph.D.

Lecturer
Akemi Yamazaki, R.N., R.M., P.H.N., Ph.D.

Research Associate
Shiho Murayama, R.N., R.M., M.S.
Kafumi Sugishita, R.N., R.M., M.H.S.

Homepage

http://park.itc.u-tokyo.ac.jp/fn/

Introduction and Organization
This Department was established in 1992. The
Japanese Association for Research in Family Nursing
was founded by this department in 1994. Currently, it
has four faculty members: an associate professor, alecturer, two research associates, and a technicalspecialist. Also it has six doctoral students, six
master’s course students, a research student, andtwelve visiting scholars.

Education
1. Graduate Courses, School of Health Sciences andNursing
Advanced Family Nursing I
Advanced Family Nursing II
Laboratory and/or Field Work on Family
Nursing
2. Undergraduate Courses, School of Health
Sciences and Nursing
Family Nursing
Pathophysiologic Immunology
3. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
Pediatric Nursing
Clinical Practicum in Pediatric Nursing

4. Undergraduate Courses of Midwifery, School of
Health Sciences and Nursing
Midwifery III
Clinical Practicum in Midwifery

Research
Topics of our current research projects are as follows:
1. Studies of Post Traumatic Stress Disorder (PTSD)
and other late complication among persons who
experienced childhood cancer
2. Studies of perinatal mental health and childrearing
support
3. Childrearing and self care of persons with mental
disorders
4. The development of an instrument measuring thequality of life for children
5. Qualitative research to explore childbearing
family formation process
6. A study of mourning work in the family bereaved
children
7. Psychosocial factors related to symptom
management of children with cancer
8. Families/siblings of children with chronic illness

250

Publications
1. Kamibeppu K, Nishigaki K, Yamashita H,
Suzumiya H, Yoshida K. Factors associated withskills of health visitors in maternal-infant mental
health in Japan. BioScience Trends. 2007; 1(3):149-155.
2. Yamazaki A. Family Synchronizers: Predictors of
sleep-wake rhythm for Japanese first-time
mothers. Sleep and Biological Rhythms. 2007; 5:
217-224.
3. Chen X, Origasa H, Ichida F, Kamibeppu K, Varni
JW. Reliability and validity of the PediatricQuality of Life InventoryTM (PedsQLTM) ShortForm 15 Generic Core Scales in Japan. Quality ofLife Research. 2007; 16: 1239-1249.
4. Nonaka J, Kamibeppu K. Grieving process insiblings of children who died of cancer. PediatricBlood & Cancer. 2007; 49(4): 558-559.
5. Wakimizu R, Ozeki S, Kamibeppu K.
Psychological distress and related factors duringhospitalization among young patients undergoingminor surgery in a Japanese suburban hospital.
Japanese Journal of Research in Family Nursing.
2007; 12(3): 112-124.
6. Kamibeppu K. Childhood cancer and PTSD. The
Japanese Journal of Child Nursing. 2006; 29(12):1637-1641. (in Japanese)
7. Kamibeppu K, Sato I, Hoshi Y. The narratives ofadolescents after losing siblings to pediatriccancer: a qualitative analysis. 2006; 21:13-27. (inJapanese)
8. Kamibeppu K, Yamashita H, Kurihara K,
Suzumiya H, Ei T, Yoshida, K. Training
community health professionals to improve
interventional skills in the field of maternal andmental health: an evaluation. The Journal of Child
Health. 2007; 66(2): 299-306. (in Japanese)
9. Wakimizu R, Kamibeppu K. Effects on emotional
upset in hospitalized pediatric surgery patients ofrepeated viewing of a promotional video at homeprior to hospitalization: a randomized controlled
trial. Iryo To Shakai. 2006; 16(2):183-202. (inJapanese)
10. Wakimizu R, Kuroki H, Igarashi M. Literature
review of physician-patient relationship inpediatric primary care. The Journal of Ambulatory

and General Pediatrics. 2006; 9:24-32. (inJapanese)
11. Shimodaira K, Kamibeppu K, Sugishita C. The
effects of nurses’ emotions for terminally illpatients and their families. Journal of Japan
Academy of Nursing Science. 2007; 27(3): 57-65.
(in Japanese)
12. Nishigaki K. Special feature: History and current
status of qualitative research. Gairai Shounika.
2007; 10(3): 270-276. (in Japanese)
13. Chen J. Child rearing circumstances in China andJapan experienced by a young foreign scientist
from China. Hoken no Kagaku. 2007; 49(12):826-830. (in Japanese)

251

Department ofCommunity Health Nursing
Public Health Nursing
Professor
Sachiyo Murashima, D.H.S., R.N., P.H.N.

Lecturer
Satoko Nagata, D.H.S., R.N., P.H.N.

Associate
Atsuko Taguchi, M.H.S., R.N., P.H.N.
Azusa Arimoto, D.H.S., R.N., P.H.N.
Yuka Dai, M.S.N., R.N., P.H.N.

Homepage

http://park.itc.u-tokyo.ac.jp/chn/

Introduction and Organization
Department of Community Health Nursing wasestablished in June 1992. Department of Public HealthNursing was established related to opening of mastercourse for public health nurses in 2006. At present,
there are three faculty members introduced above and
20 graduate course students (15 in master course, 5 indoctoral course) in the department. Also, we accept
many visiting researchers from other colleges andinstitutions.

Teaching activities
1. Undergraduate program, in the School of Health
Sciences and Nursing
1) Community Health Nursing (4 credits, lectures)
Community health nursing is a study to develop
the caring techniques and the method toevaluate the effectiveness of care not only for a
person but also for a whole community. This
class is to study, the concepts and functions ofcommunity health nursing, developing processof community health nursing, community
assessment and activities of community healthnurses.
2) Home Health Nursing (2 credits, lectures)
The aim of this class is to have a deep
understanding of the social context around thehome care patients and the medical, health andwelfare system. Students learn the basics ofcare management, home health care service, andhealth care system.
3) Health Guidance (2 credits, lectures)This class is to study the methodology andpractice of health guidance, which is the
supporting technique to promote health of thepeople living in the community.
4) Community Health Nursing Practice (2 credits,
practice)This program is intended to understand thesystem of health promotion and prevention byattending the actual community health nursing
activities at health center. Students are expected
to realize the principle and the common
technique of community health nursing

252

activities by observing the activities of publichealth nurses.
5) Home Health Nursing Practice (1 credits,
practice)This program offers opportunities to learn thebasis of home nursing and understand the life ofhome care patients and their family at
home-visit nursing station and hospital’s
department of discharge planning. Basictechniques and the role of nursing throughcollaboration with other profession are
mastered.
2. Graduate program, in the Graduate School of
Health Sciences and Nursing
1) Advanced Community Health Nursing I (2credits, lectures)This program is to study the health at thecommunity-level and theory and application of
the community organization.
2) Advanced Community Health Nursing II (2credits, lectures)This program is to study the research issues onhome care and methodology of qualitative
research for community health nursing.
3) Advanced Public Health Nursing I (2 credits)
This program is to study the methodology ofcommunity
assessmentfor
advancedcommunity health nursing practice using the
textbook for master course students in westerncountries.
4) Advanced Public Health Nursing II (2 credits)
This program is to understand policymaking of
national and local government, method tooperate and evaluate the systems, and approach
to policy development as public health nurses
through lectures by experts of public policy andsocial welfare.
5) Advanced Community Health Nursing Seminar
I, II and Practice I, II
Especially in Public Health Nursing course,
practices for sequential home visiting,community assessment / activity, andcommunity health nursing management are
given.
In addition to these programs, we have department
meeting (journal reading and research introduction) on

every Tuesday, and monthly seminar on every 3rd
Friday.

Research activities
Our research focuses on the development andevaluation of health care programs, establishment ofcommunity health care systems, and standardizationof skills of public health nurses, in response to thehealth care needs of individuals, families, aggregates
and the communities. We are conducting researches
on Grant-in –Aid for Scientific Research of Ministryof Education, Culture, Sports, Science and Technology,
Health Science research Grants of Ministry of Health,Labour and Welfare, and grants from somefoundations.
Research projects which are undergoing in our
department are listed below.
1. Developing activity model of public health nurse
and terminology of community health nursing
We intend to standardize the terms used in community
health nursing and develop the activity model forcommunity health nursing (primarily for public healthnurses). Through review and brainstorming, we will
systematize the terms which explain the activity of
public health nurses, develop the activity model, andverify the validity of the model.
2. Skills of public health nurses
For the purpose of health maintenance andimprovement of the community residents, publichealth nurses provide services (i.e. “personal
support”) to each resident and family with healthproblems. On the other hand, they play a role todevelop new services to provide more effective andefficient support to more residents with same kinds ofproblems and influence the administrative decision.
These activities are called “development of program,”
which lately had been recognized as an importantfunction of public health nurses. We are conducting
researches to clarify the techniques used by the publichealth nurse’s in program development.
3. Establishment and evaluation of community
health care systems

253

The project has been designed to reform service
systems and currently being evaluated. The aroundthe-clock in-home care system and discharge planningsystem are examples of these researches which are
now being conducted.
Furthermore, we are conducting the research topromote community organization and interorganizational network.
Especially about the around-the-clock in-home caresystem, through the model project at visiting nurse
services stations, we clarify the effects of the services
and the methods to establish the system. Also we aredeveloping and validating the check sheet to detect thepatients who have the potential need of visiting nurse
services.
4. Expansion and enforcement of visiting nursing
activities
We are conducting researches to develop and expand
the field of visiting nurse services, through evaluationof the model projects to deliver the visiting nurse
services to group-homes for elderly, and research
project on the remuneration system and supplement
system of visiting nurse services.
5. Discharge planning
Discharge planning is an interdisciplinary process thatshould be available to aid patients and their families indeveloping a feasible plan for the next place of care,and there is an increasing demand for it. We are trying
to standardize discharge planning activities, todevelop the outcome indicator of discharge planning,
and to produce the educational program of dischargeplanning for ward nurse. And we are conducting the
research about discharge planning system.
6. Support for families with babies and children
We are conducting researches covering two fields,
community health and occupational health. The
former researches are aimed to prevent and reduce
anxieties of mothers and the latter is to support
mothers and fathers balance their work with child-care.
For example, we compare the work-family conflicts ofworking mothers and fathers with small children inorder to reduce their stress and burden. Also, thenetwork for childrearing was investigated to avoid
child abuse.

7. Support for people with diseases or disabilities
We are making researches for people with diseases ordisabilities to improve their QOL.
The research themes in 2007 are 1) Self care ability ofthe members of cardiac disease patients after
operation and social support and 2) Acceptance todiseases and experiences in hospitalization fortuberculosis patients

References
1. Murayama H ， Taguchi A ， Murashima S.
Differences in Psychosocial Factors among
Novice ， Experienced ， and Veteran Health
Promotion Volunteers in Japan. Public HealthNursing (in press)
2. Arimoto A，Murashima S. Child-rearing Anxiety
and Its Correlates among Japanese Mothers
Screened at 18-month Infant Health Checkups.
Public Health Nursing，24(2), 101-110, 2007
3. Saeki K, Izumi H, Uza M, Murashima S. Factors
Associated With the Professional Competencies of
Public Health Nurses Employed by Local
Government Agencies in Japan: Public HealthNursing, 24(5), 449-457, 2007
4. Murayama H，Taguchi A，Murashima S， Ryu S.
The Condition and the Consciousness of the
Activities among Health Promotion Volunteers –Comparison Based on the Recognition of theRelationship between the Organization andMunicipal Administrative Officer. Journal ofJapan Health Nursing,10(1)，113-121，2007
5. Yamamoto A, Murayama H ， Taguchi A ，
Kobayashi S, Murashima S. The Characteristics
and the Significance of the Activities of Public
Health Nurses belonging to Public Sector andPrivate Sector – Interviews with Public Health
NursesWorking at Nonprofit Organizations after
Retiring from Public Sector. Journal of Japan
Health Nursing, 10(2)，79-84，2008
6. Yoshioka K， Murashima S. Factors related toexperience of project development processes bymulticipal public health nurses in Japan. Japanese
Journal of Public Health, 54(4), 217-225, 2007
7. Murayama H，Taguchi A，Murashima S， Ryu S.
Levels of the consciousness of activities among
health promotion volunteers – Comparison by254

years of volunteer’s experience. Japanese Journalof Public Health, 54(9)，633-643，2007
8. Nagahiro K, Kobayashi S, Murashima S.
Significance of directly observed treatment,
short-course (DOTS) for homeless males withtuberculosis – Interviews with patients in
Kotobuki district, Japan. Japanese Journal of
Public Health, 54(12)，857-866，2007
9. Nagata S, Murashima S. Anxieties and Problemsof Elderly Patients Discharged from the Hospital.
Hospital Administration，44(4)，323-335，2007
10. Murashima S. How can master course training
develop the skills for public health nurses. HealthCare, 49(4) 259-264, 2007

Health Sciences and Nursing
3. Clinical Nursing

256

Department of Adult Nursing /Palliative Care Nursing
Professor
Keiko Kazuma, R.N., Dr.Hlth.Sci.

Lecturer
Mitsunori Miyashita, R.N., Dr.Hlth.Sci.

Research Associate
Naomi Ito, R.N., Dr.Hlth.Sci. (-2007.11)
Makoto Tanaka, R.N., Dr.Hlth.Sci.
Masakazu Nishigaki, R.N., Dr.Hlth.Sci. (2007.11-)

Project Research Associate
Naomi Ito, R.N., Dr.Hlth.Sci. (2007.11-)

Homepage http://www.adng.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Adult Nursing / Palliative Care
Nursing originated as the “Department of Adult
Health” in the School of Health Sciences (1965-1992),
later becoming the “Department of Adult Health andNursing” in the School of Health Sciences & Nursing(1992-).
From 1995 to 1997, the Graduate School of
Medicine shifted to a Graduate School chair system,and our two newest departments were established. The
members of these two departments cooperate ineducational and research projects.
Our department also takes charge of the Certified
Nurse Specialist course newly established in 2008.

Education
In undergraduate courses, our departments have thechair of Lecturer and school- and hospital-based
practicums in adult nursing. In addition, ourdepartments have the educational responsibility ofteaching students about “disease in adult populations I

and II”, which is a basic discipline for adult nursing.
In graduate courses, the two departments cooperatein education and research. In particular, during thefirst term of the doctoral course (master’s course), in
which students learn basic research skills, the focus ison the effective and efficient management of bothfields.
Graduate students prepare their dissertations by
developing research question from their own scientificinterests or by participating in departmental projects.
Since we consider that the process itself is a part ofthe educational training of researchers, we focus ourenergy on seminars for developing master’s anddoctoral theses.

Research
Our department conducts research on adult nursing
from various points of view. One such perspective
focuses on the course of a disease, in which not only
the periods of recovery and terminal treatment but
also the upstream preventive steps, before disease
onset, are assessed with the chronic phase in the257

center; therefore, such nursing comprises an extremely
wide range of periods of practice. We have been
conducting studies which are expected to allow us tounderstand the state of individuals who requirenursing in those periods, and investigations on
effective and efficient nursing care for suchindividuals.
Another theme regarding nursing systems is how
care should be provided for individuals in the mostappropriate ways. We have been investigating how
nursing should be provided, and the continuity ofnursing care in various settings, such as outpatient
clinics, at home, and in palliative care facilities, by
focusing on individuals before disease onset, in thechronic phase, in the recovery period, and in theterminal period. We consider that it is essential toeliminate and/or improve the difficulties nurses inthese settings must confront, since they are associatedwith the improvement of care; therefore, such issues
have also been investigated.
Furthermore, one of our research themes is thedevelopment of evaluation measures and scales, which
are required in such studies.
Herein, we describe our current research areas. You
may refer to our homepage for more information, suchas the details of our research achievements, and theacquisition of research funds. The resources that havebeen developed in our research, such as evaluation
scales, are freely available to the public via our
homepage.
1) Nursing for Patients with Chronic Illnesses
It is necessary for individuals with chronic illnesses
to conduct self-management for symptom control intheir daily lives. Nursing has the important role ofsupporting patients to maintain their lifestyle bycontinuing self-management in their daily life.
We have developed various instruments formeasuring the difficulties that patients with chronic
illnesses experience in their daily lives, and havedescribed actual situations of difficulties using these
instruments. Furthermore, we have conducted a study
regarding support for controlling symptoms in order toreduce such difficulties.
The summaries of these studies, including sometheses in preparation for publication, are briefly
described below.

Diabetes (DM): We have developed preventive
strategies for adult offspring of diabetes patients andconfirmed its effectiveness. Now we are planning toengage this strategy more widely, especially on thehealth testing system. Meanwhile we have beendeveloping diabetes diet / physical activity-related
QOL Scale.
Cardiovasular diseases: We have developed andvalidated Japanese version of the European Heart
Failure Self-Care Behavior scale and Coronary
revascularisation
outcomequestionnaire,andinvestigated the factors associated with each outcomes
which were measured by them. Furthermore, afollow-up study, evaluating the influence of theself-care on the rehospitalization has been conducted.
We are on the process of developing a disease
management program aimed to facilitate patients’ self
management. We also conducted a study about adultcongenital heart disease.
Liver / pancreas diseases: To improve Quality ofLife (QOL) of patients with pancreatic or primaryliver cancer, we are starting the development ofJapanese version of the disease-specific QOL
questionnaires of EORTC designed for use in cancer
clinical trials internationally. After the development ofJapanese version, we will explore the factors relating
to their QOL.
Neuromuscular diseases: In neurological conditions,pain is an extremely common feature but is often lessprecisely described. We showed apart of the actual
conditions of pain and management of pain in patientswith neuromuscular disease.
HIV/AIDS: We are on the process of researchwhich investigates structure and barriers of HIV/AIDS
related self care aimed to develop self care support
tool.
2) Nursing for Recipients and Donors in Advanced
Medicine (organ transplantation)
In a transplantation therapy in advanced medicine,both recipients and donors experience various
difficulties, which have not been observed inconventional medicine. Reduction of such difficulties
is also important in nursing. The University of Tokyo
Hospital is a medical facility that provides one of thehighest levels of treatment in living donor livertransplantation and bone marrow transplantation in the258

world. Therefore, we have conducted the following
studies on cases at the hospital:
We have described the QOL of patients who
underwent adult living donor liver transplantation, andthe experiences of donors before and after
transplantation. In addition, we initiated a study
regarding difficulties in the chronic stage followingbone marrow transplantation and support for reducing
such difficulties.
We have also contributed to establish donor
coordination system in the hematopoietic stem celltransplantation (HSCT) thorough the project whichdevelops donor coordination guideline about related
HSCT.
3) Nursing Care System for Outpatients
Recently, the role of nursing in hospital outpatientcare and home care has changed dramatically due tothe decrease in the duration of hospitalization, theincrease of chronic diseases, and the increase of theelderly population. In the field of adult nursing, we
focus on consultation and guidance in outpatient carein order to support self-management of chronic
diseases by nurses who are specialized in each diseasecategories.. We have performed nation-wide surveys
which aim to clarify the effectiveness of nurse
specialist assignment, and have been conducting
educational activities regarding the promotion ofnursing activity in outpatient care.
4) Evaluation of Specialized Palliative Care andQuality Assurance
Palliative care services in Japan are primarily
provided by palliative care teams in general wards, inpalliative care units, and at home. We have conducted
research on methods for evaluating palliative careservices by focusing on various categories, such as
symptom control and communication. We havedeveloped a Japanese version of the STAS-J, which isan evaluation scale developed in the U.K., and areattempting to promote its utilization. We haveparticipated in the development of a care evaluation
scale for bereaved families. Furthermore, we areconducting a survey on the current status of palliative
care teams, and research regarding the evaluation. We
are also strongly motivated to evaluate palliative carefor patients with hematological cancers, which remain

uncommon in Japan.
5) Continuity of the Palliative Care System
End-stage cancer patients receive care in generalwards, palliative care units, and at home. We haveconducted a study on the preparation of a system fortransition in the care setting. Actual research goals
include the identification of preference in care settings
and related factors, and the factors that facilitate asmooth transition from general wards or palliative
units to the patient’s home.
6) Good Death in Japan
Recently, the conceptualization of good death,
which is one of the goals of palliative care, andinvestigations of the current status are being
conducted in Western countries. We haveconceptualized good death in Japan by conducting
qualitative research, followed by quantitative research,on groups comprised of the general public andbereaved families. Furthermore, we have establishedintervention measures by investigating the attainmentof good death and possible barriers. We also consider
that it is important to provide education for thegeneral public.
7) Palliative Care at HomeA large number of patients wish to receiveend-stage care at home; however, many difficulties are
involved in the realization of such requests. Thus, it is
one of the most important problems in palliative carein Japan.
We have conducted a study regarding the actualcare provided at home based on a survey of patientsand their families, and a study that described andevaluated the experiences of bereaved families who
attended the home death. We also take part in the
project which aims to establish regional palliative caresystem.

Publications[1] Miyashita M, Nakai Y, Sasahara T, Koyama Y,
Shimizu Y, Tsukamoto N, Kawa M. Nursing
autonomy plays an important role in nurses'
attitudes toward caring for dying patients. Am J
Hosp Palliat Care. 2007;24(3):202-10.

259[2] Miyashita M, Sanjo M, Morita T, Hirai K,
Kizawa Y, Shima Y, Shimoyama N, Tsuneto S,
Hiraga K, Sato K, Uchitomi Y. Barriers toproviding palliative care and priorities for future
actions to advance palliative care in Japan: anationwide expert opinion survey. J Palliat Med.
2007;10(2):390-9.
[3] Miyashita M, Nishida S, Koyama Y, Kimura R,
Sasahara T, Shirai Y, Kawa M, Society of
Palliative Care for a, University H. The current
status of palliative care teams in Japanese
university hospitals: a nationwide questionnaire
survey. Support Care Cancer. 2007;15(7):801-6.
[4] Miyashita M, Morita T, Shima Y, Kimura R,
Takahashi M, Adachi I. Physician and nurse
attitudes toward artificial hydration for
terminally ill cancer patients in Japan: results of
2 nationwide surveys. Am J Hosp Palliat Care.
2007;24(5):383-9.
[5] Miyashita M, Sanjo M, Morita T, Hirai K,
Uchitomi Y. Good death in cancer care: anationwide quantitative study. Ann Oncol. 2007;
18(6):1090-7.
[6] Tanaka M, Iwao Y, Sasaki S, Okamoto S, Ogata
H, Hibi T, Kazuma K. Moderate dietary
temperance effectively prevents relapse of
Crohn disease: a prospective study of patients inremission. Gastroenterol Nurs. 2007;30(3):202-10.
[7] Tanaka M, Shibayama T, Sato E, Sasaki S,
Kazuma K. Dietary intake and body compositionof Japanese ulcerative colitis patients inremission. Gastroenterol Nurs. 2007;30(5):357-62.
[8] Nishigaki M, Kobayashi K, Hitomi T, Yokomura
T, Yokoyama M, Seki N, Kazuma K. Perceptionof offspring risk for type 2 diabetes among
patients with type 2 diabetes and their adultoffspring. Diabetes Care. 2007;30(12):3033-4.
[9] Nishigaki M, Shimada M, Ikeda K, Kazuma K,
Ogane M, Takeda K, Yamada Y, Fukuyama Y, Ito
S, Kishigami F, Kimura S. Process and contents
of telephone consultations between registerednurses and clients with HIV/AIDS in Japan. J
Assoc Nurses AIDS Care. 2007;18(6):85-96.
[10] Nishigaki M, Kazuma K, Oya M, Ueno M, Arai
M, Yamaguchi T, Muto T. The influence of life

stage on psychosocial adjustment in colorectal
cancer patients. J Psychosoc Oncol. 2007;25(4):71-87.
[11] Sanjo M, Miyashita M, Morita T, Hirai K, Kawa
M, Akechi T, Uchitomi Y. Preferences regarding
end-of-life cancer care and associations with
good-death concepts: a population-based survey
in Japan. Ann Oncol. 2007;18(9):1539-47.
[12] Sano T, Maeyama E, Kawa M, Shirai Y,
Miyashita M, Kazuma K, Okabe T. Family
caregiver's experiences in caring for a patientwith terminal cancer at home in Japan. Palliat
Support Care. 2007; 5(4): 389-95.
[13] Ota K, Ota A, Kitae S. Analysis of the sleeping
habits of young children in relation toenvironmental factors and their psychologicalstate. Sleep Biol Rhythms. 2007;5(4):284-7.
[14] Koyama Y, Miyashita M, Irie S, Takatori Y,
Yamamoto M, Karita T, Kazuma K. A study of
the reality of daily life among patients withosteoarthritis of the hip undergoing conservative
treatment. J Orthop Nurs. 2007;11(2):81-90.
[15] Shibayama T, Kobayashi K, Takano A,
Kadowaki T, Kazuma K. Effectiveness oflifestyle counseling by certified expert nurse of
Japan
for
non-insulin-treateddiabetic
outpatients: a 1-year randomized controlled trial.
Diabetes Res Clin Pract. 2007;76(2):265-8.
[16] Hirabayashi Y, Miyashita M, Kawa M, Kazuma
K, Yamashita K, Okamoto N. Factors relating toterminally ill cancer patients' willingness tocontinue living at home during the early phase ofhome care after discharge from clinical cancer
centers in Japan. Palliat Support Care. 2007;
5(1):19-30.
[17] Marugame T, Katanoda K, Matsuda T,
Hirabayashi Y, Kamo K, Ajiki W, Sobue T. The
Japan Cancer Surveillance Report: Incidence ofChildhood, Bone, Penis and Testis Cancers. Jpn
J Clin Oncol. 2007;37(4):319-23.
[18] Kinoshita S. Respecting the wishes of patients in
intensive care units. Nurs Ethics. 2007;14(5):651-64.
[19] Miyashita M, Shirai Y, Sanjo M, Hasada T, SatoK, Misawa T. Association between prefectural
home death proportion and medical, social
factors in 2004, Japan [in japanese]. Journal of

260

Health and Welfare Statistics. 2007; 54(11):44-9.
[20] Sato K, Miyashita M, Morita T, Suzuki M. The
Japanese perception of feasibility of end-of-life
home care until death and related factors [inJapanese]. Palliative Care Research. 2007; 2(1):101-11.
[21] Miyashita M, Sato K, Morita T, Hamashima C,
Sobue T. Quality indicator in palliative care: A
review [in Japanese]. Palliative Care Research.
2007;2(2):231-8.
[22] Shibayama T. Chronicity of illness andcontinuity of life from nursing viewpoint [inJapanese]. Journal of Japanese Society for
Chronic Illness and Condition Nursing. 2007;
1(1):10-19.

261

Department of Midwifery and
Women's HealthProfessor
Sachiyo Murashima, Ph.D., P.H.N., R.N.
(Concurrent office: Community Health Nursing)

Lecturer
Megumi Haruna, Ph.D., R.N.M., P.H.N.
Ryoko Murayama, MS., R.N.M.

Research associate
Etsuko Watanabe, MS., R.N.M., P.H.N.

Homepage

http://park.itc.u-tokyo.ac.jp/midwifery/index.html

Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002.
Currently, it has 4 faculty members introduced
above and 7 part-time lecturers, 7 graduate students (4in master course, 3 in doctoral course), and 2 research
students.

Teaching activities
We teach graduate and undergraduate courses for
midwifery and maternal care, and women's health.
1. Graduate Courses, School of Health Sciences andNursing1) Advanced Midwifery and Women’s Health 1 (2credits, lectures)
2) Advanced Midwifery and Women’s Health 2 (2credits, lectures)
2. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
1) Maternity Care and Nursing(2 credits, lectures)
2) Maternity Care and Nursing Practice(2 credits, practice)
3. Undergraduate Advanced Courses for Midwifery,
School of Health Sciences and Nursing1) Midwifery 1 (1 credit, lectures)
2) Midwifery 2 (1 credit, lectures)
3) Midwifery 4 (3 credits, lectures)
4) Administration for Midwifery(1 credit, lectures)
5) Clinical Practice of Midwifery 1(1 credit, practice)6) Clinical Practice of Midwifery 2(7 credits, practice)

Research activities
Our research activities focus on maternal-child healthcare as well as health promotion and quality of life of
women in each life cycle.
Current research projects are as follows.
1) Effectiveness of an exercise program forpromoting mental health in postnatal women:
a randomized controlled trial
To evaluate the effective of the postpartum exercise
program on mental health.

2622) Sleeping posture and sleep problems of pregnant
women
To study the relationship of sleeping posture with
the quality of sleep, the state of respiration and thecirculatory system.
3) Change of posture and the local muscle system
during pregnancy and postpartum
To study the state of local muscle system is relatedwith posture during pregnancy and postpartum, and todevelop a perinatal physical self-care program.
4) Lifestyle and oxidative stress during pregnancy
To find the biochemical parameters such asoxidative stress markers for the assessment of ahealthy lifestyle during pregnancy.
5) Physical activity during pregnancy
To assess the reliability and validity of the Japaneseand Vietnamese version of the pregnancy physicalactivity questionnaire (PPAQ)．
6) Maternal body composition during pregnancy andinfant birth weight
To identify optimal weight control method andlifestyle during pregnancy for the prevention of lowbirth weight via the measurement of weight, bodycomposition, lipid metabolic biomarker, daily lifestyle,and nutritional intakes.
7) Nutrition and weight management during
pregnancy and postpartum
To examine the guidance of pregnant women in
outpatient care and to investigate the method of themother's body weight control, pregnancy nutritional
intakes, physical activities, and weight change in orderto facilitate the review of the management system.
The association between pregnancy weight gain
among Vietnamese women of varying prepregnancy
body mass index and the risk factors for adverse
perinatal outcome is studied.
8) Changes of prostaglandin levels in saliva during
pregnancy, labor and the postpartum period
To examine the change by labor progression of
prostaglandin levels in saliva during pregnancy, laborand the postpartum period.

References
1. Watanabe E, Lee JS, Kawakubo K, Marui E.
Correlation between change in body weight andlifestyle behavior before and after childbirth. The
Japanese Journal of Health and Human Ecology.
2008; 74(1): 3-12. (in Japanese)
2. Ota E, Haruna M, Yanai H, Suzuki M, Anh DD,
Matsuzaki M, Tho LH, Ariyoshi K, Yeo SA,
Murashima S. Reliability and validity of theVietnamese version of the pregnancy physicalactivity questionnaire (PPAQ). Southeast Asian
Journal of Tropical Medicine and Public Health.
In press.
3. Matsuzaki M, Haruna M, Ota E, Sasaki S, Nagai Y,
Murashima S. Dietary folate intake, use of folate
supplements, lifestyle factors, and serum folate
levels among pregnant women in Tokyo, Japan.
The Journal of Obstetrics and Gynaecology
Research. In press.
4. Haruna M, Watanabe E, Ota E. Healthcare forpregnant women. In: Kabeyama K, Taketani Y,
editors. Josangakukouza 6, Tokyo: Igakushoin;2007. p. 200-72. (in Japanese)
5. Murayama R, Matuzaki M. Intrapartum care (careof a woman in labour). In: Kabeyama K, Taketani
Y, editors. Josangakukouza 7, Tokyo: Igakushoin;2007. p.152-83. (in Japanese)
6. Matsuzaki M, Tanizaki T, Haruna M, Hasumi Y,
Sekine K, Murashima S. Ubiquinol andUbiquinone levels in Umbilical cord blood of
healthy newborn and venous blood of theirmothers. 5th Congress of the International
Coenzyme Q10 Association; 2007 Nov 9-12 ；Kobe, Japan; 2007. p.106-7.
7. Haruna M, Matsuzaki M, Ota E, Tanizaki T,
Sekine K, Murashima S. Increased serum
Coenzyme Q10 during pregnancy correlates tobirthweight. 5th Congress of the International
Coenzyme Q10 Association; 2007 Nov 9-12；
Kobe, Japan; 2007. p.108-9.
8. Ota E, Haruna M, Matsuzaki M, Honda Y, Nagai
Y, Murashima S. Risk factors of healthy pregnant
women associated with occurrence of low birthweight infants in Japan, 11th East Asian Forum on
Nursing Science Annual Conference in Taiwan;
2008 Feb 27-29; Kaoshung, Taiwan; 2008. p.

263

a-30.
9. Matsuzaki M, Shimizu M, Yajima Y, Sakata K,
Iketa M, Hirade M, Haruna M. Midwives’
activities and women’s voice at one maternity
house in Japan. 28th Congress of the International
Confederation of Midwives; 2008 Jun 1-5;
Glasgow, Scotland; 2008. p.72.

264

Department of
Psychiatric Nursing
Professor
Norito Kawakami, M.D., Ph.D.

Lecturer
Yuki Miyamoto, R.N., P.H.N., P.S.W., Ph.D.

Homepage

http://plaza.umin.ac.jp/heart/

Introduction and Organization
Our department was firstly established as
Department of Fourth Clinical Medical Nursing in
School of Health Care and Nursing in 1957. When the
School of Health Care and Nursing was reorganized as
the School of Health Sciences in 1965, the department
was renamed Department of Mental Health. In 1992,
as School of Health Sciences became The School of
Health Science and Nursing, Department of Mental
Health became Department of Mental Health andPsychiatric Nursing. As the result of the shift to thechair system of the Graduate School of Medicine in
1996, two departments were established, Departmentof Mental Health and Department of PsychiatricNursing. Faculty, staff, and students of two
departments have been working cooperatively eversince.
Our department currently has two faculty members
introduced above, part-time lecturers, visiting research
fellows, 5 doctoral course students, 4 master course
students, and research associates.
Our department’s mission comprises two elements.
One is to provide education and research training inmental health and psychiatric nursing toundergraduate and graduate students in order toprepare students to assume leadership roles in nursing
clinical practice, administration, teaching, andresearch in this field. The other is to conduct clinicalresearch in the fields of psychiatric nursing andadvance knowledge and theory through research.

All of the activities of our department are
conducted in collaboration with staff members in the
Department of Mental Health.

Education
Our department is responsible for giving lectures on
psychiatric nursing to undergraduate students. Other
than lectures, our department provides students
opportunities to practice psychiatric nursing activities
in several relevant facilities.
Our department is also obliged to educate graduate
students in master and doctor programs in psychiatricnursing. To accomplish this objective, our department
has a specialized lecture course on psychiatric nursing,and seminars on mental health and psychiatric nursing
for graduate students. These activities are conducted
and supervised by the faculty. In collaboration withthe department of mental health, we also have thedepartment seminar every Wednesday evening, where
members provide the actual plans for their own
research and discuss the topic.
We also have monthly journal clubs and study
clubs.

Research
Our research field covers mental health andpsychiatric nursing. Our department has many
research projects across diverse fields as follows:
study of community support system for the people

265

with mental health needs; issues of caregiver burdenin family caregivers; psychiatric clinical pathways;
behavioral and psychological symptoms of dementia;
patient satisfaction with psychiatric services; practiceand evaluation of home visiting psychiatric nursing;illness self-management in mental health; andrecovery for people with mental health difficulties. We
are conducting studies in collaboration withresearchers in other institutions and universities.

Publications
1. Furukawa TA, Kawakami N, Saitoh M, Ono Y,
Nakane Y, Nakamura Y, Tachimori H, Iwata N, Uda
H, Nakane H, Watanabe M, Naganuma Y, Hata Y,
Kobayashi M, Miyake Y. The performance of theJapanese version of the K6 and K10 in the World
Mental Health Survey Japan. International Journalof Methods in Psychiatric Research (in press).
2. Fukutome A, Watashi K, Kawakami N and Ishikawa
H: Mathematical modeling of severe acuterespiratory syndrome nosocomial transmission in
Japan: The dynamics of incident cases and prevalent
cases. Microbiol Immunol 2007; 51(9): 823-832.
3. Nakanishi M, Setoya Y, Kodaka M, Makino H,
Nishimura A, Yamauchi K, Mimura M, Sato H,
Arata H, Yukumi H, Amagasa T, Ueno H, Miyamoto
Y, Sugie T, Anzai N. Symptom dimensions andneeds of care among patients with schizophrenia in
hospital and the community. Psychiatry Clin
Neurosci. 2007 Oct;61(5):495-501.
4. Funakoshi A, Miyamoto Y, Kayama M. Managerial
support of community mental health nurses. J Adv
Nurs. 2007 May;58(3):227-35.
5. Tadaka E, Kawagoe H, Miyamoto Y, Ogata Y,
Kadota N. Development of quality indicators toassess the quality of home-visit nursing thatspecializes in dementia care. Journal of Japan
Academy of Gerontological Nursing. 2007 March;
11(2): 64-73 [in Japanese]
6. Kessler, R.C., Angermeyer, M., Anthony, J.C., de
Graff, R., Demyttenaere, K., Gasquet, I., deGirolamo, G., Gluzman, S., Guereje, O., Haro, J.M.,
Kawakami, N., Karam, A., Levinson, D., MedinaMora, M.E., Oakley Browne, M.A., Posada-Villa, J.,
Stein, D.J., Tsang, C.H.A., Aguilar-Gaxiola, S.,
Alonso, J., Lee, S., Heeringa, S., Pennell, B-E.,

Berglund, P.A., Gruber, M., Petukhova, M., Chatterji,S., Ustun, T.B. Lifetime prevalence and age-of-onset
distributions of mental disorders in the World HealthOrganization's World Mental Health Surveys. World
Psychiatry 2007;6:168-176.
7. Yoshikawa T, Kawakami N, Kogi K, Tsutsumi A,
Shimazu M, Nagami M, Shimazu A. Developmentof a mental Health Action Checklist for improving
workplace environment as means of job stressprevention. Sangyo Eiseigaku Zasshi, 2007; 49,
127-142. [in Japanese]
8. Hiro H, Kawakami N, Tanaka K, Nakamura K:
Japan Work Stress and Health Cohort Study Group.
Association between job stressors and heavy
drinking: age differences in male Japanese workers.
Ind Health. 2007; 45(3): 415-25.
9. Umehara K, Ohya Y, Kawakami N, Tsutsumi A,
Fujimura M. Association of Work-Related Factors
with Psychosocial Job Stressors and Psychosomatic
Symptoms among Japanese Pediatricians. Journal of
Occupational Health. 2007; (49): 467-481.
10. Geshi M, Hirokawa K, Taniguchi T, Fujii Y,
Kawakami N. Effects of Alcohol-related Health
Education on the Knowledge of Alcohol andDrinking Behavior among Japanese Junior College
Students: A Randomized Controlled trial. Acta Med
Okayama (in press).
11. Tsutsumi A, Iwata N, Wakita T, Kumagai R,
Noguchi H, Kawakami N. Improving the
Measurement Accuracy of the Effort-Reward
Imbalance Scales. International Journal of
Behavioral Meicine (in press).
12. Choi BK, Kawakami N, Chang SJ, Koh SB, Bjorner
J, Punnett L, Karasek R. A Cross-National Study on
the Multidimensional Characteristics of the FiveItem Psychological Demands Scale of the Job
Content Questionnaire. International Journal of
Behavioral Meicine (in press).
13. Taniguchi T, Hirokawa K, Tsuchiya M, Kawakami
N. The immediate effects of 10-minute relaxation
training on salivary immunoglobulin A (s-IgA) andmood state for Japanese female medical co-workers.
Acta Med Okayama. 2007; 61(3): 139-45.
14. Ormel J, Von Korff M, Burger H, Scott K,
Demyttenaere K, Huang YQ, Posada-Villa J, Pierre
Lepine J, Angermeyer MC, Levinson D, deGirolamo G, Kawakami N, Karam E, Medina-Mora

266

ME, Gureje O, Williams D, Haro JM, Bromet EJ,
Alonso J, Kessler R. Mental disorders among
persons with heart disease - results from World
Mental Health surveys. Gen Hosp Psychiatry. 2007;
29(4): 325-34.
15. Nishiuchi K, Tsutsumi A, Takao S, Mineyama S,
Kawakami N. Effects of an education program forstress reduction on supervisor knowledge, attitudes,
and behavior in the workplace: a randomized
controlled trial. J Occup Health. 2007; 49(3): 190-8.
16. Mineyama S, Tsutsumi A, Takao S, Nishiuchi K,
Kawakami N. Supervisors' attitudes and skills for
active listening with regard to working conditions
and psychological stress reactions among
subordinate workers. J Occup Health. 2007; 49(2):81-87.
17. Tsutsumi A, Kayaba K, Ojima T, Ishikawa S,
Kawakami N, Jichi Medical School Cohort Study
Group. Low control at work and the risk of suicidein Japanese men: a prospective cohort study.
Psychother Psychosom. 2007; 76(3): 177-85.
18. Yorifuji T, Tsuda T, Kawakami N. Age standardized
cancer mortality ratios in areas heavily exposed tomethylmercury. Int Arch Occup Environ Health.
2007; 80: 679-688.
19. Tsutsumi A, Umehara K, Ono H, Kawakami N.
Types of psychosocial job demands and adverse
events due to dental mismanagement: a crosssectional study. BMC Oral Health. 2007; 7:3.

267

Department ofGerontological Nursing /Wound Care Management
Professor
Hiromi Sanada, R.N., Ph.D., P.H.N., WOCN.

Assistant Professor
Atsuko Kitagawa, R.N., Ph.D.
Noriko Matsui, R.N., M.H.S., P.H.N.
Miho Oba, R.N., M.H.S., P.H.N.

Project Assistant Professor
Ai Kinoshita, M.T., PhD.

Homepage

http://www.rounenkango.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Gerontological Nursing wasestablished in June 2003, followed by theestablishment of the Department of Wound CareManagement in April 2006. These two departments
are currently headed by one professor and assisted bythree assistant professors, and five part-time lecturers.
The student body consists of three doctoral course
students, thirteen master course students, and two
research students. The basic course for theundergraduates is “Evidence-based Practice forGerontological Nursing” where we wish to create asociety that respects the beauty of aging andrecognizes it to be a joyful process in life.

Teaching activities
1.Undergraduate course
1) Gerontological Nursing (3-4th yr/ 4 credits)
The aim of the 3rd year course is for students tounderstand the physical, psychological and social
characteristics of the elderly population. The main

themes in the 2007 curriculum were as follows;a) Practical Simulation for Gerontological Nursingb) Physical, Psychological & Social Characteristicsof the Elderlyc) Social, Health and Medical Policies for a healthy
life of the elderlyd) Long-term Care Insurance System and Caring for
the Elderlye) End-of-Lifes of the Elderly and the Ethical Issuesf) Patients with dementia in Japan: State of the artg) Features of Health and Illness in the Elderly
The aim of the 4th year course is to understand theailments and conditions required to provide propercare to the elderly. The main themes in the 2007
curriculum were as follows;a) Pharmacologic Management of the Elderlyb) Nutritional Management of the Elderlyc) Feeding and Swallowing Difficulty of the Elderlyd) Age-related Changes in the Physiologic Systeme) Aging and Respiratory Disordersf) Common Urinary Disorders of the Elderlyg) Cognitive Disorders of the Elderly

268h) Cardiovascular Disorders of the Elderlyi) Osteoporosis of the Elderly
The above lectures were developed under thecooperation by the Department of Geriatric Medicine
and The University of Tokyo Hospital.
2) Clinical Practice in Gerontological Nursing(4th yr/ 3 credits)
The aim of this practicum is to learn the skills
essential for the elderly care in a long-term carefacility. This program was supported by the long-termcare facility owned by Medical Corporation Tatsuoka.
3) Bachelor’s thesis
The research theme in 2007 was as follows;‘Evaluation of Comfortableness in the Supine
Position’2. Graduate course
1) Gerontological Nursing I (Summer course/ 2
credits)
2) Gerontological Nursing II (Winter course/ 2
credits)
This program focuses on studying the latest
developments related to gerontological nursing.
Gerontological NursingⅠoffers review and criticalanalysis of recent world-wide research aroundgerontological nursing. The main theme in 2007 was
the topics on Geriatric Palliative Care (Oxford
University Press, 2003) edited by Morrison RS andMeier DE.
Gerontological Nursing Ⅱ provides lectures anddiscussion regarding the recent topics aroundgerontological nursing, in which the main themes in2007 were as follows;a) New Style of Home Care for the Highly Impaired
Elderlyb) Elderly Needs during a Natural Disasterc) Nursing Care for the Younger Demented People
and Their Familyd) Physical assessment of the elderlye) Influence of Moving to the Health Condition of
the Elderlyf) The Roles of Home Visiting Nurse Stations for theCommunity Dwelling Elderlyg) Strategy of Treatment and Care for the Elderlywith Dementia

3) Wound Care Management I (Summer course/ 2
credits)
4) Wound Care Management II (Winter course/ 2
credits)
The course program focuses on understanding andthe development of the practice,research, education,and perspectives in advanced Wound CareManagement.
Wound Care Management I offers review andcritical analysis of recent world-wide research
involving wound care management. The main theme
in 2007 was the topics on Lymphoedema Framework:
Best Practice for the Management of Lymphoedema.
International Consensus. (London: MEP Ltd, 2006)edited by Dr. Moffatt CJ.
Wound Care Management II provides lectures anddiscussion regarding the recent topics involving
wound care management, and the main themes in2007 were as follows;a) Wound Care Treatment and Pressure Ulcer:
State-of-the Art，b) Practice of Lymphoedema Care and Their Social
Environmentc) Strategy of Pressure Ulcer Management: Based onExperiments of 1,000 Patientsd) The Principle of Ultrasonic Waves and the Image
Assessment of Surface Echography.
e) Development of Methods for Measuring theAdhesive Force of Skin Barriers and Effects of theAdhesive Force of Skin Barriers on Skinf) Wound Healing and Bacterium5) Master’s thesis
The followings were research themes in 2007;‘Continuous Monitoring of Interface Pressure
Distribution in Intensive Care Patients for Pressure
Ulcer Prevention’‘Cross-sectional Observational Study of Callus in
Diabetic Patients’‘A Study of Absorbent Pads and Skin Lesions inJapanese Elderly Incontinence Patients at a Long-term
Medical Facility’‘Evaluating the Quality Indicators for the Pressure
Ulcer Management in the Special Functioning
Hospitals’‘Histological Examination of Pressure-induced
Ischemic Wound Healing in Diabetic Rats’2695) Doctoral thesis
The following was a research theme in 2007;’Competency Development Process for Wound,
Ostomy, and Continence Nurses Providing Pressure
Ulcer Management in Japan’Research activities
1. Activity policy
Our main activity involves the “Evidence-based
Practice for Gerontological Nursing” where we are
striving to develop new nursing techniques andinstruments to fulfill the needs of those elderly
wishing to maintain their independence.
Specifically, we are trying to improve the prediction,
prevention, diagnosis, and treatment of elderly
suffering with geriatric syndrome, pressure ulcers,
diabetic foot ulcers, incontinence, malnutrition, pain,
depression, and dementia. Most research is conductedunder industry-academia cooperation. We hopethrough such researches to be able to increase physicalactivity and enhance self-esteem of the elderly inorder to maintain their independent lifestyles.
2. Research fields and themes
1) Basic experimental studies
・ Infection control of pressure ulcers
・ Histological studies of terminally-ill patientsskin・ Effect of vibration on blood circulation
・ Cutaneous wound healing and DM
・ Infection control based on quorum sensing
signaling regulation
・ Modeling of deep tissue injury in rats
2) Nursing engineering・ Effect of vibration on blood flow acceleration
・ Development of new air-mattress equipped withinterface pressure sensing system
・ Development of self-regulating alternating air
pressure cushion
・ Quantitative evaluation of skin texture based oncomputed image analysis3) Clinical studies
・ Evaluation of low frictional dressing forpressure ulcer prevention

・ Cross-sectional study of diabetic foot ulcerationand its risk factors
・ Evaluation of new diaper for elderly people forincontinence related dermatitis management
・ Cross-sectional study of skin vulnerability ofelderly patients requiring 24-hour diaper・ Qualitative analysis of competency and carrier
development of WOC nurse
・ Quality assessment of nursing ward in tertiary
hospitals using pressure ulcer prevalence as anindicator
・ Nutritional status and mutable associatedfactors in the free-living elderly

References(1) Nakagami G, Sanada H, Matsui N, Kitagawa A,
Yokogawa H, Sekiya N, Ichioka S, Sugama J,
Shibata M. Effect of vibration on skin blood flowin an in vivo microcirculatory model. BioScience
Trends. 2007; 1: 161-166.
(2) Hohashi N, Nakagami G. Results of removal oforal bacteria among infants brushing their own
teeth: using α-hemolytic Streptococcus count on
the tooth surface as the indicator. Jpn J HealthHum Ecol. 2007; 73: 183-192.
(3) Suriadi, Sanada H, Sugama J, Kitagawa A,
Thigpen B, Kinosita S, Murayama S. Risk factors
in the development of pressure ulcers in an
intensive care unit in Pontianak, Indonesia.Int
Wound J. 2007; 4:208-215. .
(4) Nagase T, Koshima I., Maekawa T, Kaneko J,
Sugawara Y, Makuuchi,M, Koyanagi H,
Nakagami G, Sanada H. Ultrasonographic
evaluation of an unusual peri-anal induration: apossible case of deep tissue injury. J Wound Care.
2007; 16: 365- 367.
(5) Nakagami G, Sanada H, Konya C, Kitagawa A,
Tadaka E, Matsuyama Y. Evaluation of a newpressure ulcer preventive dressing containing
ceramide 2 with low frictional outer layer. J Adv
Nurs. 2007; 59: 520-529.
(6) Sugama J, Matsui Y, Sanada H, Konya C, Okuwa
M, Kitagawa A. A study of the efficiency
convenience of an advanced portable WoundMeasurement System (VISITRAKTM), J Clin Nurs.
2007; 16: 1267-1269.

270(7) Tanaka A, Tanaka S, Miyamoto K, Yi SQ,Nakatani T. Gross anatomical study of thesympathetic cardiac nerves in the house musk
shrew (Suncus murinus). Anat Rec (Hoboken).
2007; 290: 468-476.
(8) Nagase T, Hisatomi T, Koshima I, Hattori N,
Koyanagi H, Sanada H. Heterotopic ossificationin the sacral pressure ulcer treated with basic
fibroblast growth factor: coincidence or side
effect? J Plast Reconstr Aesthet Surg. 2007; 60:
327-329.

International Health
1. International Social Medicine

272

Department of
Health Policy and Planning
Associate Professor
Chushi Kuroiwa, M.D., Ph.D.

Research Associate
Ali Moazzam, M.D., Ph.D., Yoshihisa Shirayama, Ph.D.

Homepage

http://www.sih.m.u-tokyo.ac.jp/english/index.html

Introduction and Organization
In the past 20 years, globalization together withmarked-oriented economy established by the
Neoliberalism has been continuously gaining huge
power and the poor appear to be pushed farther awayfrom reaping its benefits. Besides, our planet has
faced enormous challenges such as global warming,
famine, scarcity of clean water, growing number of
population and environment degradation, which poseworrying health risks.
Industrializedcountries
have
developed
sophisticated health policies for developing countries,
yet many issues remain when considering thesustainability. Our mission is to educate students from
Asian countries to become leaders in the field ofinternational health and to carry out researches toaddress challenges and hidden realities in health forvulnerable people.
By pursuing alternative richness or happiness
instead of economic growth, we would like to achieve
real health through respecting existing health systems,
indigenous cultures, and nature.

Previous Major Research Activities- EPI and measles control at post-polio eradication
period (International Cooperation Research Grant)- Monitoring & evaluation of multi-bi cooperation(Grant from Ministry of Health)- Problems of EPI in developing countries in Laosand Mongolia (Grant from Ministry of Education,
Science)- Monitoring & evaluation on IMCI (Integrated
Management of Childhood Illness) in Laos/
Mongolia (Grant from international medical centerof Japan, Ministry of Health)- Health Policy and Health-Care Waste Managementin Asia (ongoing) (Grant from Ministry ofEnvironment)

Major Research Activities- International health policy and system analysis:
MDGs, IMCI, ODAs/NGOs, Health damages andreal poverty caused by globalization- Child Health: EPI, IMCI, Nutrition by Brest
Feeding- Environment Health (Medical waste management
and international health policy, safety injection, aid
and environmental damage)- Reproductive Health. Gender (violence)- Infectious Diseases: Malaria prevention; HIV/
AIDS; Tuberculosis.
- Allergic Diseases and Asthma Epidemiology- Emergency Medicine

Integrated Activities
Health Policy Discussion with International
Medical Center of Japan, University of Nagoya
Health projects in IMCJ and researches.

273Managing
editorfor
BioScience
Trend(International Academic journal)
Visiting professor at Public Health in Shandong
University in China.
ASNET (Asian Studies Network in University ofTokyo) lecture for master students on Asian crisis andinfectious diseases.
Board member of the NPO: International Emerging
Medicine and Health Support, Japan (IEMS Japan).
Communication
with
NGOs
preserving
environment such as Mekong Watch, Namakemono
club.
Universities and research institutions in Laos,
Mongolia, Shandong and Dairen in China, Thailand,
Pakistan, etc

Education
Students from Japan, Laos, Mongolia, China, India,
Bangladesh, Indonesia, Taiwan, Iran
Health Policy and Planning I and II (2 credits each)
The followings are the main topics covered in theacademic year 2007;
1. Introduction: Child survival in the world such as
IMR150 and Japan’s Health System
2. ODA in the world, Japanese aid and trend
3. World aid trend: GO, PPP, NGOs, etc
4. Policy Advocacy and Roles of Civil Society
Actors – Applicability of Lessons Learnt fromODA Reform for Health Policies
5. Infectious diseases eradication (smallpox, polio,
measles, etc) and EPI, expanded programme on
immunization
6. PKO and SDF, disaster medicine
7. Risk in Asia: Infection (global warming, emerging
diseases, bio-weapon), and medical waste
8. Risk in Asia: Health System of UN in the
globalization or neoliberalism
9. Health Policy, an introduction to process andpower
10. Health sector reform, SWAP
11. Innovative Health Policy by students
12. Green revolution (game for experiencing thereality of aid world)
13. Poverty reduction, Global Fund
14. HIV, Malaria, TB control and health policy

15. Infectious disease surveillance in Japan
16. Nutrition programme and health policy

Department meeting
Department meeting is held every Monday (1-3pm):
1) Journal reading; 2) Presentation of research planand results
Open seminar on Health Policy discussion based onfield experience by guest speakers: every 3rd Monday
of each month (6-7:40pm)

Publications
1. Kuroiwa C (2007). Alternatives must be sought tohelp the poor. Point of view, Opinion: In The
Asahi International Herald Tribune. September
19: 29..
2. Kuroiwa C (2007). Dams causing algae-induced
ill health and poverty? Stories from the Mekong.
BioScience Trends; 1(3): 119-120.
3. Nozue M, Miyoshi M, Okumura J, Sanchez H,
Andreu J, Kuroiwa C (2007). Prevalence anddeterminants of obesity and dietary habits among
adults in rural area, Chile. BioScience Trends;
1(3): 140-8.
4. Kuroiwa C (2007). Risk of radiation exposure
from genbaku and genpatsu: The 1945 atomic
bombings and the 2007 Kashiwazaki nuclear
power plant leak. BioScience Trends; 1(2): 69-71.
5. Kakimoto K, Sasaki Y, Kuroiwa C, Vong S, Kanal
K (2007). Predicting factors for the experience of
HIV testing among women who have given birthin Cambodia. BioScience Trends; 1(2):97-101.
6. Masuno K, Kuroiwa C (2007). Measles outbreakin Japan: Why now? BioScience Trends; 1(1):13.
7. Maekawa M, Douangmala S, Taskahashi K,
Kuroiwa C (2007). Factors affecting routine
immunization among children 12-59 months in
Lao PDR after regional polio eradication.
BioScience Trends; 1(1): 43-51.
8. Gai RY, GU XJ, Kuroiwa C, Tang W (2007). GMP
implementation in China: A double-edged sword
for the pharmaceutical industry. Drug Discoveries& Therapeutics;1(1): 12-13.
9. Ali M, Kuroiwa C (2007). Accurate record

274

keeping in referral hospitals in Pakistan's NorthWest Frontier Province and Punjab: a crucial stepneeded to improve maternal health. Journal of the
Pakistan Medical Association; 57(9): 443-446.
10. Ozaki, Ali M, Kuroiwa C (2007). Economic
burden of diseases and cost benefit analysis of
emergency medical service (EMS) system in
Rumania. Journal of Japan Evaluation Society;7(1): 117-129.
11. Phathammavong O, Ali M, Kuroiwa C (2007).
Parasitic Infestation and Nutrintional Statusamong Schoolchildren in Vientiane, Lao PDR.
Journal of Paediatrics and Child Health; 43:
689-694.
12. Gai R, Huang Y, Xu L, Tang W, Kuroiwa C (2007).
Strengthening national public health system on
bio-terrorism alert and response. Journal of
Pathogen Biology; 2: 401-3.
13. Ali M, Rizwan H, Ayaz Bhatti AM, Kuroiwa C(2007). Women's rights equal women's lives: Thecase of Pakistan. Journal of International Health;22 (1):35-45.
14. Shirayama Y, Phompida S, Kuroiwa C, Miyoshi
M, Okumura J, Kobayashi J (2007). Maintenancebehavior and long-lasting insecticide-treated nets
(LLITNs) previously introduced into Bourapar
district, Khammouane province, Lao PDR. Public
Health; 121(2):122-129.
15. Takada S, Oudavong B, Kuroiwa C (2007). The
successes and challenges of the IMCI training
course in Lao PDR. Southeast Asian J Trop Med
Public Health; 28(1):178-87.
16. Phengxay M, Ali M, Yagyu F, Soulivanh P,
Kuroiwa C, Ushijima H (2007). Risk factors forprotein-energy malnutrition in children under 5
years: Study from Luangprabang Province, Laos.
Pediatric International; 49(2):260-265.
17. Tanimura S and Kuroiwa C, Mizota T (2007).
Auxilary Cartographic Functions in R: North
Arrow, Scale Bar, and Label with Leader Arrow.
Journal of Statistical Software; 19 (Code Snippet
1).

275

Department of International
Community HealthProfessor
Masamine Jimba, MD, PhD, MPH

Lecturer
Krishna C. Poudel, PhD, MHSc

Research Associate
Junko Yasuoka, DSc, MPH
Kayako Sakisaka, PhD, MHSc, MA

Homepage: http://www.sih.m.u-tokyo.ac.jp
Introduction and Organization
The department of international community healthhas been headed by four professors since 1993;
Professors Gen Oi (1993-1996), Som-Arch
Wongkhomthon (1996-1999), Susumu Wakai (19992005), and Masamine Jimba (2006-present).
The mission of the department is to seek equity andsocial justice in health within and across the nations.
Our aim is to bring together the clinical, public healthand social science research to address the broad issuesof pubic health in the world. The goals are to:
1. Investigate how to improve health status of themost vulnerable people, in particular, indeveloping countries,
2. Undertake research on the influences of‘globalization’ and ‘free market’ system on
health and social development,

Visiting Lecturers(8), PhD course students (18),Master’s course students (24), Research students (5),and Visiting researchers (17).

International Cooperation
Activities
Our department has conducted a variety ofinternational cooperation activities through JICA andnon-governmentalorganizations. The target countries have been
Nicaragua, Lao PDR, Cambodia, Thailand, Vietnam,
and Brazil.

Teaching Activities
The objectives of our teaching activities are
summarized as follows.
1. Train those who are willing to work forinternational cooperation in future,

3. Investigate the mechanisms to reduce inequalities
between and within nations on health anddevelopment.

2. Train those who are willing to contribute to carryout research in international health,The organization of the department is as follows:
Professor (1), Lecturer(1), Research Associate (2),3. Teach general students who are interested ininternational health.

276

The major topics for teaching is as follows: 1) Whatis international health? 2) Health promotion indeveloping countries, 3) Health economics, 4)Research ethics, 5) Project management, 6)
Reproductive health
Our department has accepted students of various
disciplines: medical doctors, nurses, co-medical
workers, social scientists and others. The academic
year of Master Course (MA, 2 years) and Doctor
Course (PhD, 3 years) starts in April and ends in
March every year. All the lectures and seminars are
conducted in English.

Research activities
We have carried our research by working together
with different international organizations, NGOs,
universities in developing countries. The major focusof research has been primary health care, healthpromotion, school health, health and human rights(including migrants’ health), conflict and health,injury prevention, HIV/AIDS, tuberculosis, leprosy,
etc. The target countries have been those in SouthAsia, South East Asia, and Brazil. We will startresearch activities in some African countries. The
outcomes of our research are listed in the next section.

References
2008
Sakisaka K, Jimba M. International nutrition training
for local action. Lancet. 2008;371:1752
Poudel-Tandukar K, Poudel KC, Yasuoka J, Eto T,
Jimba M. Domestic violence against women in
Nepal .Lancet. 2008 ;371:1664.
Nonaka D, Kobayashi J, Jimba M, Vilaysouk B,
Tsukamoto K, Kano S, Phommasack B,
Singhasivanon P, Waikagul J, Tateno S, Takeuchi
T.Malaria education from school to community in
Oudomxay province, Lao PDR. Parasitol Int.
2008 ;57:76-82.
2007
Kobayashi J, Jimba M, Okabayashi H, Singhasivanon
P, Waikagul J. Beyond deworming: the promotion ofschool-health-based interventions by Japan. Trends
Parasitol. 2007; 23: 25-9.
Poudel KC, Jimba M, Poudel-Tandukar K, Wakai S.
Reaching hard-to-reach migrants by letters: an
HIV/AIDS awareness programme in Nepal. HealthPlace. 2007; 13: 173-8.
Iriyama S, Nakahara S, Jimba M, Ichikawa M, Wakai
S. AIDS health beliefs and intention for sexual
abstinence among male adolescent students in
Kathmandu, Nepal: a test of perceived severity andsusceptibility. Public Health. 2007; 121: 64-72.
Acharya S, Yoshino E, Jimba M, Wakai S.
Empowering women through a community
development approach in Nepal. Community Dev J.
2007; 42:34-46.
Fujiya R, Jimba M, Giacaman R, Nakahara S,
Ichikawa M, Wakai S. The influence of economic
factors on the location of birth among Palestinian
women in Bethlehem during the second Palestinian
uprising. Trop Doct. 2007; 37: 13-7.
Kanamori S, Jimba M. Compensation for avian
influenza cleanup. Emerg Infect Dis. 2007; 13: 341-2.
Nomura Y, Poudel KC, Jimba M. Hard-to-reach
populations in Japan.
Southeast Asian J Trop Med Public Health. 2007;
38:325-7.
Jimba M, Aitken IW, Joshi AB, Ohashi T, Poudyal AK,
Wakai S.
A challenge for monitoring iodine
deficiency disorders in rural Nepal. Trop Doct. 2007;
37:106-7.
Singh S, Sharma SP, Mills E, Poudel KC, Jimba M.
Conflict induced internal displacement in Nepal.
Med Confl Surviv. 2007; 23:103-10.
Poudel KC, Poudel-Tandukar K, Yasuoka J, Jimba M.
HIV superinfection: another reason to avoid
serosorting practice. Lancet 2007; 370:23.
Poudel-Tandukar K, Nakahara S, Ichikawa M, Poudel

277

KC, Jimba M. Risk perception, road behavior andpedestrian injury among adolescent students in
Kathmandu, Nepal. Inj Prev. 2007; 13:258-63.
Zaman K, Takeuchi H; Md Yunus, El Arifeen S,
Chowdhury HR, Baqui AH, Wakai S, Iwata T.
Asthma in rural Bangladeshi children. Indian J
Pediatr. 2007; 74:539-43.
Aikawa R, Jimba M, Nguen KC, Binns CW.
Prenatal iron supplementation in rural Vietnam.
Eur J Clin Nutr. (In press)
Poudel KC, Nakahara S, Poudel-Tandukar K, Jimba
M. Perceptions towards preventive behaviours against
HIV transmission among people living with
HIV/AIDS in Kathmandu, Nepal. Public Health2007; 121; 958-61.
Joshi AB, Banjara MR, Bhatta LR, Rikimaru T, Jimba
M. Insufficient level of iodine content in household
powder salt in Nepal.
Nepal Med Coll J.2007; 9:75-8.
Yasuoka J, Poudel K, Jimba M. Towards sustainablemalaria control. Lancet 2007; 370: 1684.
Yasuoka J, Levins Impact of deforestation andagricultural development on anopheline ecology andmalaria epidemiology.
Am J Trop Med Hyg. 2007 ;76:450-60.
Yasuoka J, Levin Ecology of vector mosquitoes in Sri
Lanka--suggestions for future mosquito control inrice ecosystems.
Southeast Asian J Trop Med Public Health. 2007
Jul;38(4):646-57.
Maekawa M, Douangmala S, Sakisaka K , Takahashi
K, Phathammavong O, Xeuatvongsa A, Kuroiwa C.
Factors affecting routine immunization coverageamong children aged 12-59 months in Lao PDR after
regional polio eradication in Western Pacific Region.
BioScience Trends.2007 ;1:43-51
Poudel KC, Jimba M, Poudel-Tandukar K, Wakai
S.Reaching hard-to-reach migrants by letters: an

HIV/AIDS awareness programme in Nepal.
Health Place. 2007 ;13:173-8.

International Health
2. International Biomedical Sciences

279

Department of Human Genetics
Professor
Katsushi Tokunaga, Ph.D.

Associate Professor
Akihiko Mabuchi, M.D., Ph.D. (May 2007-)

Research Associate
Jun Ohashi, Ph.D., Hiroko Miyadera, Ph.D.

Project Research Associate
Nao Nishida, Ph.D.

Homepage

http://www.humgenet.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Human Genetics wasestablished in 1992. Currently, the department has one
professor, one associate professor, three research
associates, 11 graduate students, 2 research fellows,
and 9 research assistants/technicians. We also accept a
few graduate students from clinical departments fortheir PhD studies.

Teaching activities
For students at the Graduate School of International
Health, courses that cover basic principles as well as
the clinical application of human genetics areprovided.
As to undergraduate students, a series of lectures isgiven to each of the sophomore (Human Genetics I,
compulsory) and junior (Human Genetics II, elective)classes at the School of Health Sciences. A series oflectures is also provided to the first year (M0) students
at the School of Medicine (compulsory).

Research activities
The Department of Human Genetics is broadlyinterested in the human genome diversity, especiallyin the Asian populations. Specifically, we are using

genomic research tools including SNP andmicrosatellite analyses, as well as gene expression
profiling, to better understand the genetic backgroundof a variety of complex diseases, especially sleep
disorders and infectious diseases,.
Major research projects:
1) Theoretical and experimental analyses on thege-netics of complex diseases, including the development of statistical approaches for susceptibility
gene mapping in complex diseases, genomic
studies for the understanding of genetic
background and pathogenesis of autoimmune
diseases, sleep disorders, hypertension, diabetes, aswell as for host susceptibility factors to infectious
diseases.
2) Development of new methodologies for genome
polymorphism and gene expression analyses.
3) Analysis on the genome diversity of Asia-Pacificpopulations.
4) Development of methodologies for the analysis ofprotein interactions.
5) Genetic analyses combined with epidemiologicalstudies for bone and joint diseases. This study
fo-cuses on the elucidation of genetic susceptibility
to those, based on four cohorts established inJapan.

280

References
1. Nakajima F, Tokunaga K, and Nakatsuji N:
Human leukocyte antigen matching estimations ina hypothetical bank of human embryonic stem celllines in the Japanese population for use in celltransplantation therapy. Stem Cells 25(4):983-985, 2007.
2. Ueta M, Sotozono C, Tokunaga K, Yabe T, andKinoshita S: Strong association between
HLA-A*0206 and Stevens-Johnson syndrome inJapanese. Am. J. Ophthalmol. 143(2): 367-368,
2007.
3. Ogata S, Shi L, Matsushita M, Yu L, Huang XQ,
Shi L, Sun H, Oahashi J, Muramatsu M, Tokunaga
K, and Chu JY: Polymorphisms of HLA genes in
Maonan people in China. Tissue Antigens 69(2):154-160, 2007.
4. Hitomi Y, Tsuchiya N, Hasegawa M, Fujimoto M,
Takehara K, Tokunaga K, and Sato S: Associationof CD22 gene polymorphism with susceptibility
to limited cutaneous systemic sclerosis. Tissue
Antigens 69(3): 242-249, 2007.
5. Tochigi M, Zhang X, Ohashi J, Hibino H, Otowa
T, Rogers M, Kato T, Okazaki Y, Kato N,
Tokunaga K, and Sasaki T: Association study
between the TNXB locus and schizophrenia in a
Japanese population. Am. J. Med. Genet. B
Neuropsychiatr. Genet. 144(3): 305-309, 2007.
6. Hananantachai H, Patarapotikul J, Ohashi J, Naka
I, Looareesuwan S, and Tokunaga K: Significant
association between TNF-α (TNF) promoter allele(-1031C, -863C, and –857C) and cerebral malaria
in Thailand. Tissue Antigens 69(3): 277-280,
2007.
7. Kawasaki A, Tsuchiya N, Ohashi J, Murakami Y,
Fukazawa T, Kusaoi M, Morimoto S, Matsuta K,
Hashimoto H, Takasaki Y, and Tokunaga K: Roleof APRIL (TNFSF13) polymorphisms in thesusceptibility to systemic lupus erytematosus in
Japanese. Rheumatology 46(5): 776-782, 2007.
8. Nishida N, Tanabe T, Takasu M, Suyama A, andTokunaga K: Further development of multiplex
SNP typing method, DigiTag2 assay. Anal.
Biochem. 364: 78-85, 2007.
9. Naka I, Ohashi J, Patarapotikul J, Hananantachai
H, Wilaiatana P, Looareesuwan S, and Tokunaga

K: The genotype of GYPA and GYPB carrying the
MNSs antigens are not associated with cerebral
malaria. J. Hum. Genet. 52(5): 476-479, 2007.
10. Kimura R, Fujimoto A, Tokunaga K, and Ohashi
J: A practical genome scan for population-specificstrong selective sweeps that have reached fixation.
PLoS ONE. 2(3): e286, 2007.
11. Mai HN, Hijikata M, Inoue Y, Suzuki K, Sakatani
M, Okada M, Kimura K, Kobayashi N, Toyota E,
Kudo K, Nagai H, Kurashima A, Kajiki A,
Oketani N, Hayakawa H, Tanaka G, Shojima J,
Matsushita I, Sakurada S, Tokunaga K, andKeicho N: Pulmonary Mycobacterium avium
complex infection associated with the IVS8-T5 of
the CFTR gene. Int. J. Tubers. Lung Dis. 11(7):808-813, 2007.
12. Takasu M, Hayashi R, Maruya E, Ota M, Imura M,
Kougo K, Kobayashi C, Saji H, Ishikawa Y, AsaiT, and Tokunaga K: Deletion of entire HLA-A
gene accompanied by an insertion of a
retrotransposon. Tissue Antigens 70(2): 144-150,
2007.
13. Furuya T, Hakoda M, Ichikawa N, Higami K,
Nanke Y, Yago T, Kobashigawa T, Tokunaga K,
Tsuchiya N, Kamatani N, and Kotake S:
Differential association of HLA-DRB1 alleles inJapanese patients with early rheumatoid arthritis
in relationship to autoantibodies to cyclic
citrullinated peptide. Clin. Exp. Rheumatol. 25(2):219-224, 2007.
14. Miyamoto Y, Mabuchi A, Shi D, Kubo T, Takatori
Y, Saito S, Fujioka M, Sudo A, Uchida A,
Yamamoto S, Ozaki K, Takigawa M, Tanaka T,
Nakamura Y, Jiang Q, Ikegawa S. A functional
polymorphism in the 5' UTR of GDF5 isassociated with susceptibility to osteoarthritis. Nat
Genet. 39(4): 529-533, 2007.
15. Arai H, Otagiri T, Sasaki A, Hashimoto T, Umetsu
K, Tokunaga K, and Hayasaka K: De novo
polyalanine expansion of PHOX2B in congenital
central hypoventilation syndrome: Unequal sister
chromatid
exchangeduringpaternal
gametogenesis. J. Hum. Genet. 52(11): 921-925,
2007.
16. Ohashi J, Naka I, Kimura R, Natsuhara K,
Yamauchi T, Furusawa T, Nakazawa M, Ataka Y,
Patarapotikul J, Nuchnoi P, Tokunaga K, Ishida281

T, Inaoka T, Matsumura Y, and Ohtsuka R: FTO
polymorphisms in Oceanic populations. J. Hum.
Genet. 52(12): 1031-1035, 2007.
17. Hoa B.K., Hang N.T.L., Kashiwase K, Ohashi J,
Lien L.T., Horie J, Shojima J, Hijikata M, Satake
M, Tokunaga K, Sasazuki N, and Keicho K:
HLA-A, B, C, DRB1 and DQB1 alleles andhaplotaypes in the Kinh population in Vietnam.
Tissue Antigens 71: 127-134, 2007.
18. Shi Li, Ogata S, Yu JK, Ohashi J, Yu L, Shi L, Sun
H, Lin K, Huang XQ, Matushita M, Horai S,
Muramatsu M, Chu JY, and Tokunaga K:
Distribution of HLA alleles and haplotypes inJinuo and Wa populations in Southwest China.
Hum. Immunol. 69(1): 58-65, 2007.
19. Nakano K, Sakai N, Yamazaki Y, Watanabe H,
Yanada N, Sezaki K, Sugami T, Tokunaga K,
Takato T, and Uchinuma E: Novel mutations of
the HOXD13 gene in hand and footmalformations. Int. Surg. 92(5): 287-295, 2007.
20. Doi K, Noiri E, Maeda R, Nakao A, Kobayashi S,
Tokunaga K, and Fujita T: Functional
polymorphism of the myeloperoxidase gene in
hypertensive nephrosclerosis dialysis patients.
Hypertens. Res. 30(12): 1193-1198, 2007

282

Department of Developmental
Medical Sciences
Professor
Masashi Mizuguchi, M.D., Ph.D.

Associate Professor
Teruyuki Tanaka, M.D., Ph.D.

Research Associate
Masaaki Oda, Ph.D.,

Homepage

Makiko Saitoh, M.D., Ph.D.

http://www.sih.m.u-tokyo.ac.jp/devt.html

Introduction and Organization
Founded in 1996 as the Department of Maternal andChild Health, our department was the first one
established in Japan. With the subsequent expansionof research activities and the foundation of the
Graduate School of Medicine, it was renamed in 1992
as the Department of Developmental Medical
Sciences. Up to now, it has been engaged inexperimental and epidemiologic studies to provide thescientific bases for all the activities to promote thephysical and mental health of mothers and children.
The experimental studies include those on the nervousand endocrine systems, infection, immunity andmetabolism, whereas the epidemiologic studies deal
with development, mother-to-child relationship andhealth promotion. In 2007, joined by new members,
the department has just entered a new era, putting
more emphasis than ever on the research on
developmental disorders of the nervous system.
At present, our department consists of one professor,
one associate professor, two associates, one assistantclerk, one technical assistant, eleven visiting lecturers,
twelve visiting researchers, sixteen graduate students(including eight overseas students) and two research
fellows.
Our department gives lectures to undergraduate andpostgraduate students, have weekly meetings of thewhole department and of individual research groups,
communicate with other investigators inside oroutside the University of Tokyo, and have seminars
and meetings with researchers invited from abroad.
We have collaborated with many laboratories in the
United States, Canada, Germany, Greece, China,
Taiwan, Korea, Thailand, Viet Nam, Laos, Malaysia,
Bangladesh, Pakistan, Sri Lanka and Russia, in orderto promote the mothers’ and children’s health all over
the world. We also have accepted many young
students from these countries, for the purpose ofbringing up professionals who either perform medical
research or lead local health policies.

Teaching activities
1. Undergraduate course, Faculty of Medicine, Schoolof Health Science and Nursing1) Human growth and development
2) Medical microbiology and zoology
3) Maternal and child diseases
4) Immunology
5) Maternal and child health6) School health and nursing7) International health
2. Graduate course, the Graduate School of Medicine,283

School of International Health Sciences
In addition to lectures and laboratory courses by ourown staff, special lectures are given by experts both
inside and outside the University.

Research activities(1) Molecular pathologic studies on developmental
brain
disorders:Abnormalneuronaldifferentiation and size control in tuberous
sclerosis.
(2) Molecular genetic and cell biologic studies
combined with post-genomic approaches onmolecules regulating neuronal migration, such as
Doublecortin and Cdk5.
(3) Studies of inflammation, cell death and plasticity
in perinatal brain damage.
(4) Clinical, genetic and pathologic studies of acuteencephalopathies:
Acutenecrotizing
encephalopathy and acute encephalopathy withfebrile convulsive status epilepticus.
(5) Molecular genetics and biochemistry of inheritedmetabolic disorders, such as peroxisomal
disorders, and of neurodegenerative diseases,
such as spinal muscular atrophy.
(6) Epidemiologic studies on nutrition (breast
feeding) and child growth, and on care of infants.
(7) Molecular epidemiology of infectious diseases,in particular viral diarrheal diseases.
(8) Epidemiology
andmolecular
genetics(epigenetics) of the fetal origin of adult diseases.
(9) Studies on immune responses using componentsof Bordetella pertussis.
(10) Effects of high-rise living on physical and mental
development of children.
(11) Studies to improve health education at schools.
(12) Studies on the health of mothers and children ofminority races.
(13) Studies on the mental health of schoolchildren,and of mothers and children living abroad

References
1. Chen Y, Takita J, Mizuguchi M, Ida K, Koh K,
Igarashi T, Hanada R, Tanaka Y, Hayashi Y.
Mutation and expression analyses of the MET and

CDKN2A genes in rhabdomyosarcoma withemphasis on MET overexpression. Genes
Chrromosomes Cancer. 2007; 46(4): 348-358.
2. Dey SK, Phan TG, Nguyen TA, Nishio O, Salim
AFM, Yagyu F, Okitsu S, Ushijima H. Prevalenceof sapovirus infection among infants and children
with acute gastroenteritis in Dhaka City,
Bangladesh during 2004-2005. J Med Virol. 2007;
79(5): 633-638.
3. Dey SK, Nguyen TA, Phan TG, Nishio O, Salim
AFM, Rahman M, Yagyu F, Okitsu S, Ushijima H.
Molecular and epidemiological trend of norovirus
associated gastroenteritis in Dhaka City,
Bangladesh. J Clin Virol. 2007; 40(3):218-223.
4. Kawata K, Ushijima H, Environmental Lead
Exposure-Perspectives on global and mother andchild health-. J Int Health. 2007; 22: 47-52.
5. Khamrin P, Nguyen TA, Phan TG, Satou K,
Masuoka Y, Okitsu S, Maneekarn N, Nishio O,
Ushijima
H.
Evaluationoftheimmunochromatography test and commercial
enzyme-linked immunosorbent assay kit for rapid
detection of norovirus antigen in stool samples. J
Virol Methods. 2008; 147(2): 360-363.
6. Khamrin P, Maneekarn N, Peerakome S, Tonusin
S, Malasao R, Mizuguchi M, Okitsu S, Ushijima
H. Genetic diversity of noroviruses andsapoviruses in children hospitalized with acutegastroenteritis in Chiang Mai, Thailand. J Med
Virol. 2007; 79(12): 1921-1926.
7. Khamrin P, Peerakome S, Tonusin S, Malasao R,
Okitsu S, Ushijima H, Maneekarn N. Changing
pattern of rotavirus G genotype distribution in
Chiang Mai, Thailand from 2002 to 2004: declineof G9 and reemergence of G1 and G2. J Med Virol.
2007; 79(11): 1775-1782.
8. Khamrin P, Maneekarn N, Peerakome S, Tonusin
S, Phan TG, Okitsu S, Ushijima H. Molecularcharacterization of rare G3P[9] rotavirus strains
isolated from children hospitalized with acutegastroenteritis. J Med Virol. 2007; 79(6): 843-851.
9. Khamrin P, Maneekarn N, Peerakome S, Chan-it
W, Yagyu F, Okitsu S, Ushijima H. Novel porcine
rotavirus of the genotype P[27] shares new
phylogenetic lineage with G2 porcine rotavirus
strain. Virology. 2007; 361(2): 243-252.
10. Kominami M, Kawata K, Ali M, Meena H,

284

Ushijima H. Factors determining prenatal HIV
testing for prevention of mother to childtransmission in Dar Es Salaam, Tanzania. Pediatr
Int. 2007; 49(2): 286-292.
11. Li Y, Hotta M, Shi A, Li Z, Yin J, Guo G, Kawata
K, Ushijima H. Malnutrition improvement for
infants under 18 months old of Dai minority in
Luxi, China. Pediatr Int. 2007; 49(2): 273-279.
12. Mizuguchi M. Abnormal giant cells in the cerebral
lesions of tuberous sclerosis complex. Congenit
Anom (Kyoto). 2007; 47(1): 2-8.
13. Mizuguchi M, Yamanouchi H, Ichiyama T, Shiomi
M. Acute encephalopathy associated with
influenza and other viral infections. Acta Neurol
Scand. 2007; 115(4): 45-56.
14. Mizuguchi M, Itoh M, Ozawa H, Morikawa Y. A
2-year-old boy with hypoactivity of neonatal onset
andprofounddevelopmental
delay.
Neuropathology. 2007; 27(2): 145-149.
15. Nguyen TA, Yagyu F, Okame M, Phan TG, Trinh
QD, Yan H, Hoang KT, Cao AT, Hoang PL, Okitsu
S, Ushijima H. Diversity of viruses associatedwith acute gastroenteritis in children hospitalizedwith diarrhea in Ho Chi Minh City, Vietnam. J
Med Virol. 2007; 79(5): 582-590.
16. Nguyen TA, Khamrin P, Takanashi S, Hoang PL,
Pham LD, Hoang KT, Satou K, Masuoka Y,
Okitsu S, Ushijima H. Evaluation of
immunochromatography tests for detection ofrotavirus and norovirus among Vietnamesechildren with acute gastroenteritis and theemergence of a novel GII.4 norovirus variant. J
Trop Pediatr. 2007; 53(4): 264-269.
17. Nguyen TA, Khamrin P, Trinh QD, Phan TG,
Hoang PL, Pham LD, Hoang KT, Yagyu F, Okitsu
S, Ushijima H. Sequence analysis of VietnameseP[6] rotavirus strains suggests evidence ofinterspecies transmission. J Med Virol. 2007;
79(12): 1959-1965.
18. Okame M, Shiota T, Hansman G, Takagi M,
Yagyu F, Takanashi S, Phan TG, Shimizu Y,
Kohno H, Okitsu S, Ushijima H. Anti-norovirus
polyclonal antibody and its potential fordevelopment of an antigen-ELISA. J Med Virol.
2007; 79(8): 1180-1186.
19. Okoshi Y, Mizuguchi M, Itoh M, Oka A,
Takashima S. Altered nestin expression in the

cerebrum with periventricular leukomalacia.
Pediatr Neurol. 2007; 36(3): 170-174.
20. Ozeki N, Mizuguchi M. Japanese mothers living
in New York with young children: Transculturaland child rearing stress factors and mental health.
J Jpn Soc Psychosomat Obstetr Gynecol. 2007;12(3): 506-508.
21. Pham NT, Khamrin P, Nguyen TA, Dey SK, Phan
TG, Okitsu S, Ushijima H. Isolation and molecularcharacterization of Aichi viruses from fecal
specimens collected in Japan, Bangladesh,
Thailand and Vietnam. J Clin Microbiol. 2007;
45(7): 2287-2288.
22. Phan TG, S Okitsu, Maneekarn N, Ushijima H.
Evidence of recombination in VP7 genes ofrotaviruses. J Virol. 2007; 81 (18): 10188-10194.
23. Phan TG, Khamrin P, Quang TD, Dey SK,
Takanashi S, Okitsu S, Maneekarn N, Ushijima H.
Detection and genetic characterization of group A
rotavirus strains circulating among children withacute gastroenteritis in Japan. J Virol. 2007; 81(9): 4645-4653.
24. Phan TG, Trinh QD, Khamrin P, Kaneshi K, Ueda
Y, Nakaya S, Nishimura S, Sugita K, Nishimura T,
Yamamoto A, Takanashi S, Yagyu F, Okitsu S,
Ushijima H. Emergence of new variant G3
rotavirus among infants and children with acutegastroenteritis in Japan during 2003-2004. Clin
Lab. 2007; 53 (1-2): 41-48.
25. Phan TG, Trinh QD, Yagyu F, Okitsu S, Ushijima
H. Emergence of rare sapovirus genotype among
infants and children with acute gastroenteritis inJapan. Eur J Clin Microbiol Infect Dis. 2007; 26(1): 21-27.
26. Phan TG, Khamrin P, Trinh DQ, Dey SK, Yagyu F,
Okitsu S, Nishio O, Ushijima H. Genetic
characterization of group A rotavirus strains
circulating
among
childrenwith
acutegastroenteritis in Japan in 2004-2005. InfectGenet Evol. 2007; 7 (2): 247-253.
27. Phan TG, Khamrin P, Quang TD, Dey SK,
Takanashi S, Okitsu S, Maneekarn N, Ushijima H.
Emergenceof
intragenotype
recombinantsapovirus in Japan. Infect Genet Evol. 2007; 7 (4):542-546.
28. Phan TG, Khamrin P, Akiyama M, Yagyu F,
Okitsu S, Maneekarn N, Nishio O, Ushijima H.

285

Detection and genetic characterization of
norovirus in oysters from China and Japan. Clin
Lab. 2007; 53 (7-8): 405-412.
29. Phan TG, Kaneshi K, Ueda Y, Nakaya S,
Nishimura S, Yamamoto A, Sugita K, Takanashi S,
Okitsu S, Ushijima H. Genetic heterogeneity,
evolution and recombination in noroviruses. J
Med Virol. 2007; 79 (9): 1388-1400.
30. Phan TG, Okitsu S, Maneekarn N, Ushijima H,
Duan ZJ. Possible misidentification of G3P[6]rotavirus as a novel strain detected in humans forthe first time. J Clin Microbiol. 2007; 45(6): 2098.
31. Phan TG, Okitsu S, Maneekarn N, Ushijima H.
Genetic
heterogeneity,
evolutionandrecombination in emerging G9 rotaviruses. InfectGenet Evol. 2007; 7(5): 656-663.
32. Phengxay M, Ali M, Yagyu F, Phengxay S,
Kuroiwa C, Ushijima H. Risk factors forprotein-energy malnutrition of children under 5
years: A study from Luangprabang province, Lao
PDR; Child health in Asia and Africa; Pediat Int.
2007; 49(2): 260-265.
33. Saito M, Horikawa M, Iwamori Y, Sakakihara Y,
Mizuguchi M, Igarashi T, Fujiki Y, Iwamori M.
Alterations in the molecular species ofplasmalogen phospholipids and glycolipids due toperoxisomal dysfunction in Chinese hamster
ovary-mutant Z65 cells by FABMS method. J
Chromatogr B Analyt Technol Biomed Life Sci.
2007; 852(1-2): 367-373.
34. Saitoh M, Sakakihara Y, Mizuguchi M, Ito, M,
Takashima S, Iwamori M, Kamoshita, S, Igarashi
T. Increase of ceramide monohexoside anddipalmitoyl glycerophospholipids in the brain of
Zellweger syndrome. Neurosci Lett. 2007; 417(2):165-170.
35. Shiota T, Okame M, Takanashi S, Khamrin P,
Takagi M, Satou K, Masuoka Y, Yagyu F, Shimizu
Y, Kohno H, Mizuguchi M, Okitsu S, Ushijima H.
Characterization of a broadly reactive monoclonal
antibody against norovirus genogroups I and II:recognition of a novel conformational epitope. J
Virol. 2007; 81(22): 12298-12306.
36. Takahashi K, Saitoh M, Hoshino H, Mimaki M,
Yokoyama Y, Takamizawa M, Mizuguchi M, Lin
Z-M, Yang Y, Igarashi T. A case of primary
erytermalgia,
wintryhypothermia
andencephalopathy. Neuropediatrics. 2007; 38(3):157-159.
37. Tanaka T, Gleeson JG. Subcortical laminar (band)
heterotopia. Handbook of Clinical Neurology (3rdseries) 87, Malformations of the Nervous System.
Elsevier; 2007, pp. 191-204.
38. Trinh QD, Nguyen TA, Phan TG, Khamrin P, Yan
H, Hoang PL, Maneekarn N, Li Y, Yagyu F,
Okitsu S, Ushijima H. 2007. Sequence analysis of
the VP7 gene of human rotavirus G1 isolated inJapan, China, Thailand, and Vietnam in thecontext of changing distribution of rotavirus
G-types. J Med Virol. J Med Virol. 79(7):1009-1016.
39. Trinh QD, Pham NT, Nguyen TA, Phan TG,
Khamrin P, Yan H, Hoang PL, Maneekarn N, Li Y,
Kozlov V, Kozlov A, Okitsu S, Ushijima H. 2007.
Amino acid substitutions in the VP7 protein ofhuman rotavirus G3 isolated in China, Russia,
Thailand, and Vietnam during 2001-2004. J Med
Virol. 2007; 79(10): 1611-1616.

286

Department of Human Ecology
Professor
Chiho WATANABE, D. Hlth Sc.

Associate Professor
Masahiro UMEZAKI, Ph.D.

Research Associate
Hana SHIMIZU, Ph.D.
Shoko FUKUYAMA、Ph.D.
Jiang Hong-Wei, Ph.D. (Project)

Homepage

http://www.humeco.m.u-tokyo.ac.jp/index-e.html

Introduction and Organization
We had four research/teaching faculties in FY2007.
Apart from the faculty staffs, two secretaries, two
doctoral candidates (two foreign students), eightmaster course students (including three foreign
students), and two research fellows are working in thedepartment. There are nine extra-university lecturersdelivering lectures in either graduate or undergraduate
course.

Teaching activities
The department is one of the six departments of the
School of International Health. Human Ecology
Special Lecture I focused on the basic components of
Human Ecology such as demography, nutrition, andenvironment. In “Human Ecology Special Lecture II”,emphases were on recent topics and ongoing
researches in the field of Human Ecology and relatedareas. With these classes for the Graduate Students,
we tried to describe Human Ecology as a basic
component of International Health, and gave examplesof the recent issues that have been dealt with andapproaches used in this field. The lectures for the
Graduate Course were given in English.
In the undergraduate course, the department is incharge of a part of the School of Health Sciences andNursing, providing the lectures on “Human Ecology”,“Environmental
Health”,“Demography”,“International Health”. We were also responsible fororganizing“Pharmacology
andToxicology”,“Physiology”, “Anatomy”, as well as “Environmental
Engineering/ Human Engineering” ． At theundergraduate level, our emphases were in
introducing global-scale issues such as population
explosion, food security, and environmental issues inrelation to the problems that Asia-Pacific region(including Japan) has been facing. Another emphasis
was on the relation between human activities andchemical contamination of the environment.

Research activities
Most of our researches focused on the field of“Environmental Health” and/or “Population ecology[of human]”, and we utilized both fieldwork andexperimental approach. The areas for the field studies
were mainly Asian-Oceanian rural communities,
focusing on population, nutrition/growth, andenvironment. Experimental studies focusing on theeffects of perinatal exposures to heavy metals havebeen conducted, emphasizing the factors that modify
the effects. What follows is a list of major projects

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conducted in the past two years.
1. Neurodevelopmental effects of perinatal exposure
to environmental chemicals:
Modern human societies, regardless developed ordeveloping, consume and are exposed to a variety ofchemical substances, which would be regarded as a
substantial part of the environment. Since often thefetus/newborn is said to be relatively sensitive to thesechemicals, we focused on the exposure to chemicals
during perinatal period. Collaborating with several
institutes/universities, we have conducted studies on
the effects of heavy metals (mercury and cadmium),toxicity of which were still being debated in Japan andother countries, as well as those of so called endocrine
disrupters. Toxicity was evaluated at cellular as wellas organism levels, and major findings included
susceptibility of metallothionein knock-out mice tothe neurodevelopmental toxicity of metals. In thisfiscal year, the effects of low-dose mercury andcadmium were reported, focusing on the contributionof thyroid hormone metabolism to the observed
toxicities. The effects of estrogenic compounds at low
doses were also examined; non- monotonous
dose-effect relationships were found and reported.
2. Evaluation and Alleviation of Environmental
Burden due to Subsistence Transition in
Asia-Pacific –Elucidation of Health Impact:
Most communities in Asia-Pacific undergo a very
rapid transition from traditional subsistence to casheconomy agriculture. Such transition entails
introduction and release-accumulation of chemical
substances, such as pesticides and food additives(through the purchase of processed foods), into the
local ecosystem, which in turn would affect not only
the health and survival of the inhabitants, but also thesafety of local produce. Choosing six regions that
represent diversified environments in Asia-Pacific, we(1) describe such transition and their environmental
consequences in detail, (2) investigate theinterrelationship between the transitions and thechanges of local chemical environments, and (3)examine their health impact among the individuals in
the target areas. Final goal of the study will be to
make a policy recommendation to minimize
unnecessary adverse effects of such transition. In thisfiscal year, our main task was to conduct the fieldsurvey and collect samples to be analyzed. At least
one survey in each of the targeted countries has been
conducted, and the analyses of the collected samples
has been started. Many unexpected chemicals were
found in the biological samples, demonstrating the“invasion” of industrial potentially hazardous
chemicals to rural communities of developing
countries. In addition, substantial between-community
difference in the chemical exposures was revealed.
Laboratory analyses and data analyses will be
continued in the next fiscal year.
3. Development and subsistence activity, subsistencetransition and adaptation:
In many Asian and Oceanean countries, various
types of developmental projects have been undertaken
aiming at economic development, procurement of
natural resources, or accelerating tourism. Suchdevelopmental projects brought about drastic changes
in the subsistence activity of people, availability ofnatural resources, or ecosystem, and in turn, causedchanges in lifestyle and health status, disease patternsof the people. Attempts to describe such changes fromthe viewpoint of political ecology were made in China
as well as Papua New Guinea. Adaptive strategy athousehold level was analyzed in China, wheresubsistence transition has been taking place, andpossible determinant of the difference in the strategy
was identified. In some studies, spatial information
technology, such as Geographical Information System(GIS)/GPS, and spatial statistical methods wereapplied for analyzing the relationship between thesubsistence transition and land-use.
4. Studies on nutrition, growth, and physicalactivities (energetics) in developing countries:
In rural Bangladesh, arsenic contamination of thedrinking water has been creating a huge problem.
Effects of arsenic on children was examined andanalyzed with regard to the relationship between
arsenic toxicity and nutritional status. In the lowland
Nepal, located upper-stream of the Bangladesh,
relationship between the nutritional status and thearsenic toxicity was also examined. From both ofthese surveys, a distinct sex-related difference and theeffect of nutritional status on the arsenic toxicity were288

observed and reported.

References(1) Andoh, S.Y., Umezaki, M., Nakamura, K., Kizuki,M., and Takano, T. (2007) Association ofhousehold demographic variables with childmortality in Cote d'Ivoire. Journal of biosocial
Science, 39: 257-265.
(2) Ishitobi H, Mori K, Yoshida K, Watanabe C(2007) Effects of perinatal exposure to low-dose
cadmium on thyroid hormone-related and sex
hormone receptor gene expressions in brain ofoffspring Neurotoxicology 28, 790-7(3) Maharjan M, Watanabe C, Ahmad SA, Umezaki
M, Ohtsuka R. (2007) Mutual interaction between
nutritional status and chronic arsenic toxicity due
to groundwater contamination in an area of Terai,
lowland Nepal. J Epidemiol Community Health.
61(5):389-94.
(4) Mean-Heang, N.G.Y., Nakamura, K., Ohnishi, M.,
Kizuki, M., Suyama, S., Seino, K., Inose, T.,
Umezaki, M., Watanabe, M., and Takano, T.
(2007) Improved Perinatal Health throughQualified Antenatal Care in Urban Phnom Penh,
Cambodia.
Environmental Health andPreventive Medicine, 12: 193-201.
(5) Mori K, Yoshida K, Nakagawa Y, Hoshikawa S,
Ozaki H, Ito S, and Watanabe C ． (2007)
Methyl-mercury inhibition of type II 5 ’-deiodinase activity resulting in a decrease in
growth hormone production in GH3 cells
Toxicology 237，203-9．
(6) Sekiyama M., Tanaka M., Gunawan B.,
Abdoellah O., Watanabe C. (2007) Pesticide
usage and its association with health symptoms
among farmers in rural villages in west Java,
Indonesia. Environmental Sciences 14, suppl.
23-33.
(7) Umezaki M, Sengebau-Kinzio MJ, Nakamura K,
Ridep E, Watanabe M, TakanoT (2007)
Household risk factors associated withdengue-like illness, Republic of Palau, 2000-2001.
BioScience Trends, 1: 33-37.
(8) Watanabe C, Matsui T, Inaoka T, Kadono T,
Miya-zaki K, Bae MJ, Ono T, Ohtsuka R, A.T.M.
Bokul(2007)
DermatologicalandNutritional/growth Effects among Children
Living in Arsenic-contaminated Communities in
Rural Bangladesh ． Journal of environmental
science and health, part a vol. A42, 1835-41.
(9) Yamauchi, T., Midorikawa, T., Hagihara, J.,
Sasaki, K. (2007) Quality of life, nutritional
status,physical
activity,
andtheirinterrelationships of elderly living on anunderpopulated island in Japan. Geriatrics andGerontology International, 7: 26-33.
(10) Yokosuka M, Ohtani-Kaneko R, Yamashita K,
Muraoka D, Kuroda Y, Watanabe C. (2007)
Estrogen and environmental estrogenic chemicals
exert developmental effects on rat hypothalamic
neurons and glias. Toxicol In Vitro. 22,1-9.
(11) Zhou H, Watanabe C, Ohtsuka R. (2007) Impacts
of dietary intake and helminth infection on
diversity in growth among schoolchildren in rural
south China: a four-year longitudinal study. Am
J Hum Biol. 19(1):96-106.
(12) Yoshida M, Watanabe C, Kishimoto M, Yasutake
A, M. S, Sawada M (2007) Behavioral changes inmetallothionein-null mice after the cessation
oflong-term, low-level exposure to mercury vapor.
Toxicol Lett 161:210-218.
(13) Fukuyama S，Umezaki M., Watanabe C Levels
and Sources of energy and nutrient intake among
Tongan adults. The 39th Conference of the
Asia-Pacific Academic Consortium for Public
Health (APACPH), November 23-25, 2007,
Sakato.
(14) Ichimaru, N., Yamauchi, T., Weng, C.C., Kim,
S.N., Jaw, S.P., Kim, S.W., Ishii, M Obesity andphysical fitness among urban school children in
Korea and Taiwan. The 4th Asia-Oceania
Conference on Obesity. 2007, Seoul (Korea).
(15) Parajuli R, M Umezaki, M Sekiyama, C
Watanabe. Socio-economic status, dietary intake,helminthiasis, and their relation with nutritional
status of Mushar in lowland Terai, Nepal. The
39th Conference of the Asia-Pacific Academic
Consortium for Public Health (APACPH),
November 23-25, 2007, Sakato.
(16) Sekiyama M, Roosita K, Ohtsuka R, Watanabe C
Snack consumption among children in rural
In-donesia under nutrition transition. The 39th
Con-ference of the Asia-Pacific Academic

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Consortium for Public Health (APACPH),
November 23-25, 2007, Sakato.
(17) Umezaki M. Impact of Poplation Pressure on
Food Production in Papua New Guinea Highlands.
The 21th Pacific Science Congress, 12-18 June,
2007, Okinawa.
(18) Watanabe C, Islam R, Inaoka T, Yoshinaga J,
Tagami K Arsenic exposure and nutritional status
in communities in Bangladesh, June 27, 2007
Second meeting of IAEA-Coordiated Research
Project, Wien, Austria.
(19) Watanabe C.
Evaluation and alleviation ofenvironmental burden due to economic
development in Asian rural areas International
Conference on Emerging Issues on Research andDevelopment April 4-6, 2007, Kathmandu, Nepal

290

Department of
Biomedical Chemistry
Professor
Kiyoshi Kita, Ph.D.

Associate Professor
Yoh-ichi Watanabe, Ph.D.

Associate
Kimitoshi Sakamoto, Ph.D.,

Homepage

Shigeo Yoshinari, Ph.D.

http://www.sih.m.u-tokyo.ac.jp/departments-J.html#Anchor-33869

Introduction and Organization
Aim of our department is to contribute to global
health and welfare from basic research. Our
department, formerly named Biochemistry andNutrition was renamed on April 1st, 1996 to The
Department of Biomedical Chemistry as newly
affiliating with Biomedical Science Division ofInternational Health, Graduate School of Medicine,
The University of Tokyo. Prof. Kita has moved fromThe Institute of Medical Science, The University ofTokyo on March 1st, 1998.

Teaching activities
Teaching activity in our department cover a broad
spectrum of biochemistry-oriented life sciences frompremise to frontiers and in either conceptual orexperimental point of view
Graduate Course: Biochemistry and Nutrition I, IIThis course is comprised of lectures and seminars
to provide basic concepts and newer vistas forunderstanding nutrition with special reference tobiochemistry and molecular biology. These include
the structure and function of biomolecules,
metabolism, its regulation, and underlying mechanism
at either molecular, cellular and systemic level.

Undergraduate Course: Biochemistry, Molecular
Biology, Laboratory Method in Health Science,
Physiological
Chemistry,
Nutrition,
MedicalChemistry, Practice on Medical Chemistry,Parasitology.

Research activities
Energy metabolism is essential for the survival,continued growth and reproduction of livingorganisms. From the standpoint of biological
adaptation, we have been studying on the molecularmechanism of energy transducing systems such as
mitochondrial and bacterial respiratory chain. In
addition, we are interested in the basic biologicalreactions such as protein synthesis. Our research havebeen focusing on
I. Human mitochondria
1) succinate-ubiquinone reductase
2) mitochondrial myopathy
II. Ascaris suum and Caenorhabditis elegans
1) molecular mechanism of adaptation to low
oxygen tension (regulation of gene expressionof mitochondrial proteins)2) mitochondrial fumarate reductase (structure
function relationship, enzyme evolution)

2913) C. elegans as a model system of parasitic
nematode (expression of foreign genes or
cDNAs, gene knockout)
III. Parasitic protozoa (Plasmodium falciparum ,Trypanosoma
brucei,
Trypanosoma
cruzi,
Cryptosporidium)1) characterization of mitochondria as a target forthe chemotherapy2) molecular biology of mitochondrial DNA3) structure based drug design (SBDD)
IV. Protein synthesis
1) Mitochondrial protein synthesis
2) Biogenesis of cytoplasmic ribosomes

References
1. Mitochondria and apicoplast of Plasmodium
falciparum: behaviour on subcellular fractionationand the implication. Kobayashi T., Sato, S.,
Takamiya, S., Komaki-Yasuda, K., Yano, K.,
Hirata, A., Onitsuka, I., Hata, M., Mi-ichi, F.,
Tanaka, T., Hase, T., Miyajima, A., Kawazu, S.,
Watanabe, Y., Kita, K. (2007) Mitochondrion 7,
125-132
2. Independent
evolutionofpyrimethamine
resistance in Plasmodium falciparum in Melanesia.
Mita,T., Tanabe, K., Takahashi, N., Tsukahara, T.,
Eto, H., Dysoley, L., Ohmae, H., Kita, K.,
Krudsood, S., Looareesuwan, S., Kaneko, A.,
Bjokman, A., and Kobayakawa, T. (2007)
Antimicrob. Agents. Chemother. 51, 1071-1077
3. Parasitology in Japan: Advances in drug discovery
and biochemical studies. Kita, K., Shiomi K.,
and Õmura, S. (2007) Trends in Parasitol. 23,
223-229
4. Relationship between reactive oxygen species andheme metabolism during the differentiation of
Neuro2a cells. Shinjyo N., and Kita K, (2007)
Biochem. Biophys. Res. Commun. 358, 130-135
5. Decursin and decursinol angelate selectively
inhibits NADH-fumarate reductase of Ascarissuum. Shiomi K., Hatano H., Morimoto H., Ui H.,
Sakamoto K., Kita K., Tomoda H., Lee E. W.,
Heo T. W., Kawagishi H., and Omura S. (2007)
Planta Medica 73, 1478-1481

6. Anaerobic NADH-Fumarate Reductase System Is
Predominant in the Respiratory Chain of
Echinococcus multilocularis, Providing a Novel
Target for the Chemotherapy of Alveolar
Echinococcosis. Matsumoto J., Sakamoto K.,
Shinjyo N., Kido Y., Yamamoto N., Yagi K.,
Miyoshi H., Nonaka N., Katakura K., Kita K. andOku Y. (2008) Antimicrob. Agents. Chemother. 52,
164-170
7. Change of subunit composition of mitochondrialcomplex II (Succinate-ubiquinone reductase/
Quinol-fumarate reductase) in Ascaris suum
during the migration in the experimental host.
Iwata F., Shinjyo N., Amino H., Sakamoto K.,
Islam M. K., Tsuji N. and Kita K. (2008) Parasitol.
Int. 57, 54-61
8. Mutation underlying resistance of Plasmodium
berghei to atovaquone in the quinone binding
domain 2 (Qo2) of the cytochrome b gene. Siregar
J. E., Syafruddin D., Matsuoka H, Kita K., andMarzuki S. (2008) Parasitol. Int. 57, 229-232
9. Coinfection with nonlethal murine malaria
parasites suppresses pathogenesis caused by
Plasmodium berghei NK65. Niikura M., Kamiya
S., Kita K. and Kobayashi F. (2008) J. Immunol.
in press
10. A cryptic algal group unveiled: a plastid
biosynthesis pathway in the oyster parasite
Perkinsus marinus. Matsuzaki M., Kuroiwa H.,
Kuroiwa T., Kita K. and Nozaki H. (2008) Mol.
Biol. Evolution in press
11. Malaria parasites reproduce with the same manneras flowering plants. Hirai M., Arai M., Mori T.,
Kawai S., Kita K., Kuroiwa T. and Matsuoka H.
(2008) Current Biol. in press
12. Gramicidin S identified as a potent inhibitor forcytochrome bd-type quinol oxides. Mogi T., Ui T.,
Shiomi K., Ōmura S. and Kita K. (2008) FEBS
Lett. in press
13. Structures of Trypanosoma cruzi dihydroorotate
dehydrogenase complexed with substrates andproducts: Atomic resolution insights intomechanisms of dihydroorotate oxidation andfumarate reduction. Inaoka, D. K., Sakamoto, K.,
Shimizu, H., Shiba, T., Kurisu, G., Nara,T., Aoki,
T., Kita, K. and Harada, S. (2008) Biochemistry
in pressSchool of Public Health
1. Epidemiology and Health Sciences

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Department of Biostatistics
Professor
Yasuo Ohashi, Ph.D.

Associate Professor
Yutaka Matsuyama, Ph.D.

Research Associate
Ayano Takeuchi

Project Research Associate
Akiko Harada, Ph.D.
Satoshi Iimuro, Ph.D.

Homepage

http://www.epistat.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Epidemiology and Biostatistics
changed the name from “Epidemiology” in 1992 andhas responsibility for providing educational courses
on epidemiology and biostatistics to undergraduate
students as well as graduate ones. As compared to thesituation in the United States, the education ofbiostatistics and methodological aspects of
epidemiology is poor in Japanese universities andgraduate schools, although the necessity forcollaboration with biostatisticians in clinical research(especially clinical trials) is recently being to beclaimed by clinical researchers and pharmaceuticalindustry. One mission of our educational courses is toprovide detailed knowledge and experiences inbiostatistics/ epidemiology to students who are
expected to take part in clinical/epidemiologicalresearch as experts and the other mission is to provide
basic principles of biostatistics/epidemiology tostudents who will work in many health-related fields
including nursing. Our main research project is thedevelopmentof
methodology
forclinical/epidemiological research and it requires
keeping touch with real clinical/epidemiologicalproblems. For these purposes and researchcoordination, a non-profit organization titled ‘The
Japan Clinical Research Support Unit’ was establishedby the faculty members in 2001, and the organization
is providing research support in design, data
management and statistical analysis in many projects
inside/outside the university.
The faculty of the department provided lectures in aseries of educational courses organized by ‘The
Clinical Bioinformatics Research Unit’ in 2002-2007.

Teaching activities
1. Undergraduate courses
1) Epidemiology and Biostatistics (2 credits)
2) Applied Mathematics (2 credits)
3) Statistical Methods and Information Processing(2 credits, practice)4) Design and Analysis of EpidemiologicalResearch (2+1 credits, 1 practice)5) Medical Data analysis (2 credits)
6) Biostatistics (2 credits; for the School of
Medicine)
2. Garduate courses
1) Biostatistics (4 credits)
2) Epidemiology and Preventive Health Sciences(4 credits)2943) Introduction to Medical Statistics (2 credits; for
the School of Medicine)
3. School of public health
1) Statistical Analysis of Medical Research (2credits)
2) Practice of Biostatistics (2 credits)3) Design of medical Research (2 credits)

Research activities
1) Biostatistics and Theoretical Epidemiology
Analysis of longitudinal missing /incomplete data
Analysis of multiple events data
Analysis of QOL data
Causal analysis
Analysis of micro/macro array data
Meta analysis of epidemiological studies
2) Methodology and Information Systems forClinical Trials
Design of clinical trials
Data management of large-scale clinical trials3) Pharmacoepidemiology4) Coordination of collaborative epidemiological/
clinical research
Japan Arteriosclerosis Longitudinal StudyJapan Diabetes Collaborative Study
5) Consultation Works with Corporate SponsoredResearch Program ‘Clinical Data Management’

4.

5.

6.

7.

References
1. Morita S. Nakata B. Tsuji A. Mitachi Y. Shirasaka
T. Saji S. Ohashi Y. Sakamoto J. Hirakawa K. A
phase I study of combination therapy of the oral
fluorinated pyrimidine compound S-1 with
low-dose cisplatin twice-a-week administration(JFMC27-9902 Step2) in patients with advanced
gastric cancer using a continual reassessment
method. Japanese Journal of Clinical Oncology
2007; 37(12):924-9.
2. Ikai I, Arii S, Okazaki M, Okita K, Omata M,
Kojiro M, Takayasu K, Nakanuma Y, Makuuchi M,
Matsuyama Y, Monden M, and Kudo M. Report ofthe 17th nationwide follow-up survey of primaryliver cancer in Japan. Hepatology Research 2007;
37(9):676-691.
3. Saito K. Sone H. Kawai K. Tanaka S. Kodama S.

8.

9.

Shu M. Suzuki E. Kondo K. Yamamoto S.
Shimano H. Ohashi Y. Yamada N. Risk imparted
by various parameters of smoking in Japanese
men with type 2 diabetes on their development of
microalbuminuria: analysis from the Tsukuba
Kawai Diabetes Registry. Diabetes Care 2007.
30(5):1286-8.
Funatogawa I. Funatogawa T. Ohashi Y. An
autoregressive linear mixed effects model for the
analysis of longitudinal data which show profiles
approaching asymptotes. Statistics in Medicine
2007. 26(9):2113-30
Kurita M. Shimozuma K. Morita S. Fujiki Y.
Ishizawa K. Eguchi H. Saito Y. Ushirozawa N.
Wasada I. Ohashi Y. Eguchi K. Clinical validity of
the Japanese version of the Functional Assessmentof Cancer Therapy-Anemia Scale. Supportive
Care in Cancer 2007. 15(1):1-6.
Usuki K. Urabe A. Ikeda Y. Ohashi Y. Mizoguchi
H. Takaku F. Japan IL-11 Study Group. A
multicenter randomized, double-blind, placebocontrolled late-phase II/III study of recombinanthuman interleukin 11 in acute myelogenous
leukemia. International Journal of Hematology
2007. 85(1):59-69.
Saeki T. Nomizu T. Toi M. Ito Y. Noguchi S.
Kobayashi T. Asaga T. Minami H. Yamamoto N.
Aogi K. Ikeda T. Ohashi Y. Sato W. Tsuruo T.
Dofequidar fumarate (MS-209) in combination
with cyclophosphamide, doxorubicin, andfluorouracil for patients with advanced orrecurrent breast cancer. Journal of ClinicalOncology 2007. 25(4):411-7.
Ohe Y. Ohashi Y. Kubota K. Tamura T. Nakagawa
K. Negoro S. Nishiwaki Y. Saijo N. Ariyoshi Y.
Fukuoka M. Randomized phase III study ofcisplatin plus irinotecan versus carboplatin plus
paclitaxel, cisplatin plus gemcitabine, andcisplatin plus vinorelbine for advanced
non-small-celllungcancer:Four-Arm
Cooperative Study in Japan. Annals of Oncology
2007. 18(2):317-23.
Sakamoto J. Hamada C. Yoshida S. Kodaira S.
Yasutomi M. Kato T. Oba K. Nakazato H. Saji S.
Ohashi Y. An individual patient datameta-analysis of adjuvant therapy withuracil-tegafur (UFT) in patients with curatively

295

resected rectal cancer. British Journal of Cancer
2007. 96(8):1170-7.
10. Kodama S. Tanaka S. Saito K. Shu M. Sone Y.
Onitake F. Suzuki E. Shimano H. Yamamoto S.
Kondo K. Ohashi Y. Yamada N. Sone H. Effect ofaerobic exercise training on serum levels ofhigh-density lipoprotein cholesterol: a metaanalysis. Archives of Internal Medicine 2007.
167(10):999-1008.
11. Yamashita K. Ougolkov AV. Nakazato H. Ito K.
Ohashi Y. Kitakata H. Yasumoto K. Omote K. Mai
M. Takahashi Y. Minamoto T. Adjuvant
immunochemotherapy
withprotein-boundpolysaccharide K for colon cancer in relation to
oncogenic beta-catenin activation. Diseases of theColon & Rectum 2007. 50(8):1169-81.
12. Minagawa, M, Yamamoto J, Kosuge T,
Matsuyama Y, Miyagawa S, and Makuuchi M.
Simplified staging system for predicting the
prognosis of patients with resectable liver
metastasis: Development and validation. Archivesof Surgery 2007; 142(3):269-276.
13. Shimizu F, Matsuyama Y, Tominaga T, Ohashi Y,
and Fujime M. Inadequacy of prostate-specificantigen doubling time estimates calculated using
an ultrasensitive assay of prostate-specific antigen
for biochemical failure after radical prostatectomy.
Urologia Internationalis 2007; 79: 356-360.
14. Shimizu F, Tanaka S, Matsuyama Y, Tominaga T,
Ohashi Y, and Fujime M. Efficiency ofultrasensitive prostate-specific antigen assay indiagnosing biochemical failure after radical
prostatectomy. Japanese Journal of ClinicalOncology 2007; 37: 446-451.
15. Sone H. Yoshimura Y. Tanaka S. Iimuro S. Ohashi
Y. Ito H. Seino H. Ishibashi S. Akanuma Y.
Yamada N. Japan Diabetes Complications Study(JDCS) Group. Cross-sectional association
between BMI, glycemic control and energy intake
in Japanese patients with type 2 diabetes. Analysis
from the Japan Diabetes Complications Study.
Diabetes Research & Clinical Practice 2007. 77
Suppl 1:S23-9.
16. Yoshida M, Matsuyama Y, and Ohashi Y for the
MEGA Study Group. Estimation of treatment
effect adjusting for dependent censoring using the
IPCW method: an application to a large primaryprevention study for coronary events (MEGA
study). Clinical Trials 2007; 4: 318-328.
17. Tanaka S, Matsuyama Y, Shiraki M, Ohashi Y.
Estimating the effect of time-varying treatments:
Incidence of fractures among postmenopausal
Japanese women. Epidemiology 2007; 18: 529536.
18. Ishii M. Ohashi Y. Influence of an educational
videotape on attitudes toward participating incohort studies--results of a randomized controlled
trial. Nippon Koshu Eisei Zasshi - Japanese
Journal of Public Health 2007. 54(7):419-26.
19. Saito AM. Kami M. Mori S. Kanda Y. Suzuki R.
Mineishi S. Takami A. Taniguchi S. Takemoto Y.
Hara M. Yamaguchi M. Hino M. Yoshida T. Kim
SW. Hori A. Ohashi Y. Takaue Y. Prospective
phase II trial to evaluate the complications andkinetics of chimerism induction following
allogeneic hematopoietic stem cell transplantation
with fludarabine and busulfan.
AmericanJournal of Hematology 2007. 82(10):873-80.
20. Nakagami G, Sanada H, Konya C, Kitagawa A,
Tadaka E, and Matsuyama Y. Evaluation of a newpressure ulcer preventive dressing containing
ceramide 2 with low frictional outer layer. Journalof Advanced Nursing 2007; 59(5): 520-529.
21. Sakuramoto S. Sasako M. Yamaguchi T. Kinoshita
T. Fujii M. Nashimoto A. Furukawa H. Nakajima
T. Ohashi Y. Imamura H. Higashino M.
Yamamura Y. Kurita A. Arai K. ACTS-GC Group.
Adjuvant chemotherapy for gastric cancer with
S-1, an oral fluoropyrimidine. New England
Journal of Medicine 2007. 357(18):1810-20.
22. Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y,
and Makuuchi M. Staging of hepatocellular
carcinoma: Assessment of the Japanese TNM and
AJCC/UICC TNM systems in a cohort of 13,772
patients in Japan. Annals of Surgery 2007;
245(6):909-922.
23. Shimizu F. Igarashi A. Fukuda T. Kawachi Y.
Minowada S. Ohashi Y. Fujime M. Decision
analyses in consideration of treatment strategies
for patients with biochemical failure after curative
therapy on clinically localized prostate cancer inthe prostate-specific antigen era. Japanese Journalof Clinical Oncology 2007. 37(10):763-74.
24. Nakajima T. Kinoshita T. Nashimoto A. Sairenji

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M. Yamaguchi T. Sakamoto J. Fujiya T. Inada T.
Sasako M. Ohashi Y. on behalf of the National
Surgical Adjuvant Study of Gastric Cancer Group.
Randomized controlled trial of adjuvant
uracil-tegafur
versussurgery
alone
forserosa-negative, locally advanced gastric cancer.
British Journal of Surgery 2007. 94(12):1468-76.
25. Miyabara Y. Onoe Y. Harada A. Kuroda T. Sasaki
S. Ohta H. Effect of physical activity and nutrition
on bone mineral density in young Japanesewomen. [Journal Article] Journal of Bone &Mineral Metabolism 2007. 25(6):414-8.

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Department of Social andPreventive Epidemiology
Professor
Satoshi Sasaki, M.D.,Ph.D.

Associate Professor
Lecturer
Associate
Kentaro Murakami, M.Sc.

Homepage

http://www.nutrepi.m.u-tokyo.ac.jp/

Introduction and Organization
The Department of Social and Preventive
Epidemiology is a new department which wasestablished at the same time of the establishment of
the School of Public Health, the University of Tokyo(April 2007).
Epidemiology is a study of quantitatively assessing
health status and disease development in populations
and statistically analyzing the relationship of risk
factors with the development of certain disease. In
addition to traditional risk factors including alcohol
drinking, smoking, nutrition, and physical activity,
gene and factors controlling gene and socioeconomic
factors are recently important topics in epidemiologic
research. Epidemiologic data are of course needed for
conducting the assessment of certain treatment
including medicine and estimating situation of diseasedevelopment.
Epidemiology
notonly
providesresearchmethodology in the field of public health but also is
considered a practical study for public health and thus
a central field of health science. However, botheducation and research systems have long been
insufficient in Japan.

Social and preventive epidemiology is a study of
epidemiologically clarifying the relationship between
various phenomena in human society (including
individual lifestyle) and certain disease.
The Department of Social and Preventive
Epidemiology particularly focuses on nutrition, whichis essential for individual and population health, as amain research topic and epidemiologically researches
various issues related to nutrition (nutritional
epidemiology), playing a central role in this research
field in Japan.
The Department currently consists of one professor
and one associate.

Teaching activities
We have the following two lectures in the School of
Public Health.
Epidemiological research and practice
Practice and assessment in public health
Both are strongly associated with practical tasks inpublic health field, aiming at giving students
opportunities for acquiring abilities of conducting

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public health activities and tasks based on theory of
epidemiology.
We have also several lectures for students in otherschools.

Research activities
Our main topic is basic research for development andapplication of research methodology in the field of
nutritional epidemiology. Based on this basic research,
we also conduct a wide range of epidemiologic
research for investigating the relationship of nutrition
with health and disease. As a characteristic of thisresearch field, we conduct many multi-center studies
with various kinds of disease.
Another characteristic is collection of researchfindings(scientificpapers)derivedfromepidemiologic research all over the world on theassociation of nutrition with health and disease, which
is applied for health control through nutrition
improvement and disease control.

References
1. Murakami K, Sasaki S, Okubo H, Takahashi Y,
Hosoi Y, Itabashi M, the Freshmen in Dietetic
Courses Study II Group. Food intake andfunctional constipation: a cross-sectional study of
3,835 Japanese women aged 18-20 years. J Nutr
Sci Vitaminol (Tokyo) 2007; 53: 30-6.
2. Murakami K, Sasaki S, Okubo H, Takahashi Y,
Hosoi Y, Itabashi M, the Freshmen in Dietetic
Courses Study II Group. Association between
dietary fiber, water and magnesium intake andfunctional constipation among young Japanesewomen. Eur J Clin Nutr 2007; 61: 616-22.
3. Tanaka M, Iwao Y, Sasaki S, Okamoto S, Ogata H,
Hibi T, Kazuma K. Moderate dietary temperance
effectively prevents relapse of Crohn's disease:
Prospective study of patients in remission.
Gastroenterol Nurs 2007; 30: 202-10.
4. Murakami K, Sasaki S, Okubo H, Takahashi Y,
Hosoi Y, Itabashi M, the Freshmen in Dietetic
Courses Study II Group. Dietary fiber intake,dietary glycemic index and load, and body massindex: a cross-sectional study of 3931 Japanesewomen aged 18-20 years. Eur J Clin Nutr 2007;

61: 986-95.
5. Murakami K, Sasaki S, Okubo H, Takahashi Y,
Hosoi Y, Itabashi M. Monetary costs of dietaryenergy reported by young Japanese women:
association with food and nutrient intake and bodymass index. Public Health Nutr 2007; 10: 1430-9.
6. Miyamoto S, Miyake Y, Sasaki S, Tanaka K, Ohya
Y, Matsunaga I, Yoshida T, Oda H, Ishiko O,
Hirota Y; Osaka Maternal and Child Health Study
Group. Fat and fish intake and asthma in Japanesewomen: baseline data from the Osaka Maternaland Child Health Study. Int J Tuberc Lung Dis
2007; 11: 103-9.
7. Murakami K, Sasaki S, Takahashi Y, Uenishi K,
Yamasaki M, Hayabuchi H, Goda T, Oka J, Baba
K, Ohki K, Kohri T, Muramatsu K, Furuki M.
Hardness (difficulty of chewing) of the habitual
diet in relation to body mass index and waist
circumference in free-living Japanese women
aged 18-22 y. Am J Clin Nutr 2007; 86: 206-13.
8. Okubo H, Sasaki S, Murakami K, Kim MK,
Takahashi Y, Hosoi Y, Itabashi M, the Freshmen
in Dietetic Courses Study II Group. Dietary
patterns associated with functional constipation
among Japanese women aged 18 to 20 years: across-sectional study. J Nutr Sci Vitaminol(Tokyo) 2007; 53: 232-8.
9. Murakami K, Sasaki S, Takahashi Y, Uenishi K,
Yamasaki M, Hayabuchi H, Goda T, Oka J, Baba
K, Ohki K, Watanabe R, Sugiyama Y. Nutrientand food intake in relation to serum leptin
concentration among young Japanese women.
Nutrition 2007; 23: 461-8.
10. Kanno Y,Sasaki S,Suzuki H. Nutritional
assessment by a new method for patients withrenal disease. Contrib Nephrol 2007; 155: 29-39.
11. Yoneyama S, Miura K, Sasaki S, Yoshita K,
Morikawa Y, Ishizaki M, Kido T, Naruse Y,
Nakagawa H. Dietary intake of fatty acids andserum C-reactive protein in Japanese. J Epidemiol
2007; 17(3): 86-92.
12. Yoshida M, Takashima Y, Inoue M, Iwasaki M,
Otani T, Sasaki S, Tsugane S; for the JPHC Study
Group. Prospective study showing that dietary
vitamin C reduced the risk of age-related cataracts
in a middle-aged Japanese population. Eur J Nutr
2007; 46: 118-24.

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13. Okubo H, Sasaki S, Rafamantanantsoa HH,
Ishikawa-Takata K, Okazaki K, Tabata I.
Validation of self-reported energy intake by aself-administered diet history questionnaire using
the doubly labeled water method in 140 Japanese
adults Eur J Clin Nutr 2007; : (in press).
14. Miyake Y, Ohya Y, Tanaka K, Yokoyama T, Sasaki
S, Fukushima W, Ohfuji S, Saito K, Kiyohara C,
Hirota Y; for the Osaka Maternal and Child HealthStudy Group. Home environment and suspected
atopic eczema in Japanese infants: The Osaka
Maternal and Child Health Study. Pediatr Allergy
Immunol 2007; 18(5): 425-32.
15. Miyake Y, Arakawa M, Tanaka K, Sasaki S, Ohya
Y. Cross-sectional study of allergic disorders
associated with breastfeeding in Japan: The
Ryukyus Child Health Study. Pediatr Allergy
Immunol 2007; 18(5): 433-40.
16. Miyake Y, Sasaki S, Tanaka K, Ohya Y, Miyamoto
S, Matsunaga I, Yoshida T, Hirota Y, Oda H; theOsaka Maternal and Child Health Study Group.
Fish and fat intake and prevalence of allergic
rhinitis in Japanese females: the osaka maternaland child health study. J Am Coll Nutr 2007;
26(3): 279-87.
17. Murakami K, Sasaki S, Takahashi Y, Uenishi K,
the Japan Dietetic Students' Study for Nutrition
and Biomarkers Group. Dietary energy density is
associated with body mass index and waist
circumference, but not with other metabolic risk
factors, in free-living young Japanese women.
Nutrition 2007; 23: 798-806.
18. Okamoto K, Kihira T, Kondo T, Kobashi G,
Washio M, Sasaki S, Yokoyama T, Miyake Y,
Sakamoto N, Inaba Y, Nagai M. Nutritional status
and risk of amyotrophic lateral sclerosis in Japan.
Amyotrophic Lateral Sclerosis 2007; 8: 300-4.
19. Otsuka R, Tamakoshi K, Yatsuya H, Wada K,
Matsushita K, Ouyang P, Hotta Y, Takefuji S,
Mitsuhashi H, Sugiura K, Sasaki S, Kral JG,
Toyoshima H. Eating fast leads to insulin
resistance: Findings in middle-aged Japanese men
and women. Prev Med 2007; 46: 154-9.
20. Miyabara Y, Onoe Y, Harada A, Kuroda T, Sasaki
S, Ohta H. Effect of physical activity and nutrition
on bone mineral density in young Japanesewomen. J Bone Miner Metab 2007; 25: 414-8.

21. Kamao M, Suhara Y, Tsugawa N, Uwano M,
Yamaguchi N, Uenishi K, Ishida H, Sasaki S,
Okano T. Vitamin k content of foods and dietary
vitamin k intake in Japanese young women. J Nutr
Sci Vitaminol (Tokyo) 2007; 53(6): 464-70.
22. Tanaka K, Miyake Y, Sasaki S, Ohya Y,
Matsunaga I, Yoshida T, Hirota Y, Oda H.
Relationship between Intake of Vegetables, Fruit,and Grains and the Prevalence of Tooth Loss inJapanese Women. J Nutr Sci Vitaminol (Tokyo)
2007; 53: 522-8.
23. Tanaka K, Miyake Y, Arakawa M, Sasaki S, Ohya
Y. Prevalence of asthma and wheeze in relation topassive smoking in Japanese children. Ann
Epidemiol 2007; 17: 1004-10.
24. Watanabe S, Morita A, Aiba N, Miyachi M,
Sasaki S, Morioka M, Noda M, Takebayashi T,
Kimira M, for SCOP. Study Design of the Saku
Control Obesity Program (SCOP) Anti-Aging
Med 2007; 4(2): 70-3.

300

Department of Health Economics
and Epidemiology Research
Professor
Hideki Hashimoto, M.D.,D.PH.

Associate Professor
Takashi Fukuda, Ph.D.

Homepage

to be prepared

Introduction and Organization
The Department of Health Economics andEpidemiology Research is a new department
established since April 2007, as a part of Master of
Public Health (MPH) program under the new Schoolof Public Health (SPH). The Department is alsoaffiliated with the Division of Social Medicine for
doctoral education. The mission of the Department
is two folds; to help health professionals obtain
scientifically
sound
basis
and
skillsforevidence-based practice, and to empirically evaluate
the health care system/policy for further improvementof the quality of health care in this country. For thispurpose, the Department puts a unique emphasis onquantitative analytic methods and inter-disciplinary
theories across economics, epidemiology, and othersocial sciences.

cost-effective analysis, technology assessment ofsurgical treatment, and hospital management. In theapplied course, the students are required to set a
research hypothesis, design a study, and prepare an
own study protocol for fund proposal. The lecture
course on health economics provides an overview ofhealth care systems in this country and a systematic
review on basic micro-economic theories and costeffectiveness analysis. The applied course offers thestudents an opportunity for hands-on training of actual
economic evaluation of health care and technologies.
The Department has not yet accepted a doctoral
student for the fiscal years of 2007-8, though two
department faculties already contribute as thesis
advisors for students in other tracks. The Department
will be open to doctoral students who are interested inhealth economics and health services research since
the year of 2009.

Teaching activities

Research activities

Under the MPH program, the Department is
responsible for 4 courses, two on clinicalepidemiology and the other two on health economics.
The lecture course on clinical epidemiology provides
a quick review on elementary to intermediate levels of
epidemiology such as research design, bias and error,and statistical inference. Then, the course requires
participating students to apply the provided
knowledge to empirical examples such as evaluationof effectiveness of screening tests, pharmaceutical

Current activities in this Department cover a broad
range of health services research, including clinicalstudies, economic evaluation of health technology andhealth policy, quality of life research, hospitaladministration and quality assurance, and social
epidemiology research.
Consultation for design, data collection, and analysisof clinical studies are provided for several clinicalstudies, mainly in cardiovascular arena. Several
questionnaire tools for evaluating patient’s quality of

301

life have been developed and validated in the area oforthopedic surgery. In the collaboration with the
Department of Health Management and Policy in 22nd
Medical Research Center in the University of Tokyo
Hospital, the Department also contributes to thedevelopment and refinement of Japanese original
patient classification system, Diagnosis Procedure
Combination (DPC). DPC database allows a uniqueand detailed analysis on the process of care in acutecare hospitals in this country. DPC database also
provides resource diagnosis in hospital levels as well
as regional levels, when combined with other data
sources such as the Patient Survey, and hospitalfinancial statement. Socioeconomic status affects
people’s health, which is another research focus in thisDepartment. The association between income
distribution and regional health status are widely
acknowledged across countries including this country,
yet the mechanism is still a matter of debate. The
Department has contributed to an ongoing research ofsocioeconomic status and health among elderly
population in the collaboration with the School of
Economics of the University of Tokyo and the
Research Institute of Economic, Industry, andTechnology.
Since health care services should be delivered
efficiently under the publicly funded health caresystem, economic evaluation of new health caretechnologies is one of the research topics in the
Department. Molecular target therapies of cancer,
which are effective but costly, attract the great concern.
Based on the modeling of therapies and efficacy data
in clinical trials, cost effectiveness of the therapies
have been evaluated. Preventive services such as
smoking cessation therapies are also important field
for economic evaluation. We also contribute for the
piggy bag style data collection for economic
evaluation in the clinical trials and epidemiologicalprospective studies. Standardized methods of datacollection for both costs and outcomes in economic
evaluations should be established through these
activities. If the result of economic evaluation would
be used as the reference for coverage decision of newtechnologies under publicly funded health care system,
acceptable thresholds of payment must be discussed.
International comparative survey was conducted to see
people’s willingness to pay for additional year of life

in perfect condition.

References
1: Hashimoto H, Sase T, Arai Y, Maruyama T, IsobeK, Shouno Y. Validation of a Japanese version of
the Scoliosis Research Society-22 Patient
Questionnaire among idiopathic scoliosis patientsin Japan. Spine. 2007 Feb 15;32(4):E141-6.
2: Fushimi K, Hashimoto H, Imanaka Y, Kuwabara
K, Horiguchi H, Ishikawa KB, Matsuda S.
Functional mapping of hospitals by diagnosisdominant case-mix analysis. BMC Health Serv
Res. 2007 Apr 10;7:50.
3: Ishizaka N, Ishizaka Y, Toda E, Hashimoto H,
Nagai R, Yamakado M. Higher serum uric acid is
associated with increased arterial stiffness inJapanese individuals. Atherosclerosis. 2007 May;
192(1):131-7.
4: Ishizaka N, Ishizaka Y, Nagai R, Toda E,
Hashimoto H, Yamakado M. Association between
serum albumin, carotid atherosclerosis, andmetabolic syndrome in Japanese individuals.
Atherosclerosis. 2007 Aug;193(2):373-9.
5: Ishizaka N, Nagai R, Ishizaka Y, Toda E,
Yamakado M, Hashimoto H. Comparison ofseveral metabolic syndrome definitions withrelation to early carotid atherosclerosis inJapanese men. Atherosclerosis. 2007 Dec;195(2):e216-7.
6: Shimizu F, Igarashi A, Fukuda T, Kawachi Y,
Minowada S, Ohashi Y, Fujime M. Decision
analyses in consideration of treatment strategies
for patients with biochemical failure after curative
therapy on clinically localized prostate cancer inthe prostate-specific antigen era. Japanese Journalof Clinical Oncology 2007; 37(10): 763-74.
7: Shiroiwa T, Fukuda T, Tsutani K. Costeffectiveness analysis of bevacizumab combinedwith chemotherapy for the treatment of metastatic
colorectal cancer in Japan. Clinical Therapeutics
2007; 29(10): 2256-2267.

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Department of HealthCommunication
Professor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Noriaki Aoki, M.D., Ph.D., M.S., M.B.A.

Homepage

http://www.umin.ac.jp/hc

Introduction and Organization
The Department of Health Communication wasestablished as part of the newly developed School of
Public Health (professional graduate school) in April
2007, which was derived from the University Hospital
Medical Information Network (UMIN) Center. It
consists of two faculty groups: professors and associate
professors.
Whereas health communication is a major discipline in
the USA and there are many such graduate programs,
our department offers one of only two healthcommunication programs in Japan. However, theimportance of the health communication discipline isgradually becoming recognized academically andthroughout society.

Teaching Activities
The Department of Health Communication, within the
School of Public Health, is a newly developed
professional graduate program that aims to foster thedevelopment of medical and public health professionals
as well as researchers. We strive to make the most of
our professional activities and experience at UMIN
Center. We provide lectures and practical instruction in
the program. The following is the current curriculum:[Health Communication Lectures]
1. General Aspects of Health Communication

2. Social Marketing
3. Mass Media and Communication
4. Internet Communication
5. Edutainment
6. Science Communication
7. Hospital Management and Communication
8. Public Health Informatics
9. Communication During Emergency and Disaster10. Publicity in Healthcare organizations
11. Provider-patient Communication
12. Communication Among Healthcare Consumers[Health Communication Practice]
1. Research, Analysis and Evaluation of Websites
2. Website Development
3. Practice of Media Publicity
4. Evaluation of News
5. MBTI (Myers-Briggs Type Indicator)
6. Image / Film Development
We also provide lectures and practical instruction in
medical informatics / economics as part of the PhD
program of the Faculty of Medicine.
In theundergraduate program, Professor Kiuchi presents a
lecture entitled “Medical Literature Informatics.”

Research Activities
The two main characteristics of research studies

303

conducted through the Department of HealthCommunication, which distinguish them from studies atother medical informatics programs, are the following:(1) A focus on health informatics and communication
The Department of Health Communication is the only
research institute in Japan that carries out healthinformatics and communication-related research,
addressing areas such as the Internet and satellite
communications.
(2) Targeting health information science, not healthcare
information practiceCurrently, main topics of research studies at mostmedical informatics programs in Japan focus on
information for healthcare practice, such as hospital
information systems, electronic medical record systems,
telemedicine, and electronic billing systems. In contrast,
the Department of Health Communication has focusedon information systems for medical science, such as
medical literature databases, data registries for clinicalstudies, and information systems for medical education.
The following are current research topics at the
Department of Health Communication:(1) Research in Health Communication
Currently, “health communication” is becoming animportant concept in the distribution of clinical results
for the improvement of population-based clinicaloutcomes. We have conducted health communication
research focusing on knowledge and skills in“informatics” and “communication.”(2) Technological Assessment of Health Information
and Communication Technologies
Although information technology is expected to play animportant role in healthcare, its comprehensive
usefulness, including cost-effectiveness, has been rarely
evaluated. We conducted a literature review in 2003
and concluded that there were few cost-effectivenessanalyses for telemedicine programs even though many
telemedicine programs have been implemented
throughout many developed countries, including the
USA and Japan. Based on the review, we have done a

cost-effectivenesstechnologies.

analysisforinformation(3) Edutainment Research
To disseminate clinical knowledge and information tolaypersons, it is important to consider standards such as“easy to understand” and “acceptable byunknowledgeable persons.” We focus on studies related
to media, entertainment, and interface design. For
example, we have conducted the development andevaluation of edutainment tools for health education
aimed at type-1 diabetes patients, as a concrete
application.
(4) Research Regarding Medical Management
It is important to make proper judgments and decisions
in order to achieve optimal outcomes, a process whichis termed “management.” However, scientific researchand evaluations related to patient safety, quality
improvement and medical management have not been
well established in Japan. We focus on the Theory ofConstraint (TOC) as a tool for medical managementfrom a perspective of information utilization, andconducted research on medical error prevention andquality improvement.
(5) Research Related to UMIN Activities
Most systems developed at the UMIN Center have been
subjects for research. In particular, we published andreported systems utilizing advanced technologies andhaving scientifically meaningful concepts at academic
conferences.
(6) Information Systems for Clinical Epidemiologic
Studies
We have developed and applied information systems
for clinical epidemiological studies. Recently, we havefocused on research in electronic formats andstandardization that are related to clinical research, suchas the Clinical Data Interchange Standards Consortium(CDISC). We utilized the achievements attained by the
medical research data center at the UMIN.
(7) Research Regarding the Security of an Information
Network

304

The study addresses a Virtual Private Network (VPN),
and secure transactions with electronic mail(encryption), which have been also utilized for systemmanagement at the UMIN Center.
(8) Research Plan Development; A Statistical Analysisof Clinical Studies
In cooperation with clinicians, we have developed
clinical research plans and support statistical analysis.
In addition, we have done data mining research for
information extraction, knowledge discovery andprognostic modeling. Furthermore, we have conducted
research and development for decision support systems
to utilize the results in clinical practice.
(9) Patient Registry System for Quality Improvement
Many data have been accumulated in the existing
hospital information system, such as electronic record
systems; however, these data have not been utilized
significantly for quality improvement, patient safety or
medical management.
We have deployed aninteractive web-based patient registry system with areal-time feedback system of quality indicators (QIs).

References
1. Aoki N, Kiuchi T. UMIN Online Abstract andPaper Entry System for Biomedical Academic
Meetings - An Overview of and its Impact on theDistribution of Digitalized Academic Informationin Japan. Methods of Information in Medicine
46(6); 671-678: 2007.
2. Aoki N, Demsar J, Zupan B. Letter .to the Editor.
J Trauma 2007; 63: 452.
3. Aoki N, Sakai M, Nakayama T, Fukuhara S, Ohta S,
Kikuchi N, Oishi M, Kiuchi T, Nozaki K,
Hashimoto N. Web-based Decision Support / Risk
Communication Tool for Healthcare Consumers
with Unruptured Intracranial Aneurysms, MedInfo
2007; 12: 1012-1016.
4. Aoki N, Demsar J, Zupan B, Mozina M, Pretto EA,
Oda J, Tanaka H, Sugimoto K, Yoshioka T, Fukui T.
Predictive model for estimating risk of crush
syndrome: a data mining approach. J Trauma 2007;
62: 940-5.

5. Motomura N, Takamoto S, Miyata H, Tsukihara T,
Okada M, Kiuchi T. The Risk of Model of Thoracic
Surgery in 4707 Cases from Single Race
Nationalwide Population, via Web-based Data
Entry System: a First Report of 30-day andOperative Outcome Risk Model on Thoracic Aortic
Surgery. Proceedings of American Heart
Association Scientific Sessions 2007, 2007
(Accepted for presentation)
6. Aoki N, Kiuchi T. UMIN - its History and Current
Status. Proceedings of the 12th World Congress on
the Internet in Medicine (MEDNET 2007) , Leipzig,
2007 (Accepted for presentation)
7. Koide D, Matsuba H, Furukawa H, Kubota K,
Kiuchi T. Pharmaceutical Safety Reporting System
on UMIN. MEDINFO 2007, IOS Press, P131, 2007
(CD-ROM)
8. Sato T, Kiuchi T, Aoki N, Watanabe H, Kubota K.
Risk Management of Unapproved Drugs in Japan:
An Academic Activity for Safety Data Exchange
via the Internet. Pharmacoepidemioloy and Drug
Safety (Supplement) 16: S182, 2007

School of Public Health
2. Behavioral Health Sciences

306

Department of Mental HealthProfessor
Norito Kawakami, M.D., Ph.D.

Assosicate Professor
Akihito Shimazu, Ph.D.

Assistant Professor
Toshio Mori, Ph.D.

Homepage http://plaza.umin.ac.jp/heart/
Introduction and Organization
The department was firstly established as
Department of Fourth Clinical Medical Nursing in
School of Health Care and Nursing in 1957. When
the School of Health Care and Nursing was
reorganized as the School of Health Sciences in 1965,
the department was renamed Department of Mental
Health. In 1992, as School of Health Sciences became
The School of Health Science and Nursing,
Department of Mental Health became Department of
Mental Health and Psychiatric Nursing. As the resultof the shift to the chair system of the Graduate Schoolof Medicine in 1996, two departments were
established, Department of Mental Health andDepartment of Psychiatric Nursing. Faculty, staff, andstudents of two departments have been working
cooperatively ever since.
The department currently has faculty members
introduced above, part-time lecturers, a technicalspecialist, visiting research fellows, 10 doctoral course
students, 7 master course students, research associates,and secretaries.
The department has two major objectives: one is toteach mental health to undergraduate and graduate
students in order to produce leading practitioners andclinical researchers in the field. The other is toconduct clinical research in the fields of mental
health.
All of the activities of the department are

conducted in collaboration with staff members in thedepartment of psychiatric nursing.

Teaching activities
The department is responsible for giving lectures
on mental health; mental disorders; clinicalpsychology; and psychometry and behavior evaluation
to undergraduate students. Other than lectures, thedepartment provides students opportunities to practicemental health activities in several relevant mental
health facilities.
The department provides special courses onmental health I and II, featuring occupational mental
health and research methodology of epidemiology inmental health, respectively, in the fiscal year of 2006.
The department also provided a 1.5 hour seminar
every Wednesday evening for 20 weeks in eachsemester (40 weeks per year) for graduate students
and research students, inducing presentation ofliterature review and lectures by guest speakers. The
seminar included presentation of a research plan byeach graduate student and relevant discussion, as well.

Research activities
The department conducts research on mental
health and psychosocial stress and provides
education/training of professionals in related fields
from global perspectives. The World Mental Health307

Japan survey, which is part of a WHO international
collaboration, is a largest epidemiologic study ofcommon mental disorders in the community in Japan.
Assessment of health effects of job stressors andeffectiveness of interventions to reduce job stress arealso core research activities of the department.
Research in the department also includes various othertopics, such as psychiatric rehabilitation, clinicalpsychology, psychotherapy, child and adolescent
psychiatry; and developmental disorders. Most of theresearch has been conducted in a close collaboration
with researchers in other domestic and foreign
institutions/universities.

References (Jan.-Dec., 2007)
1. Kessler, R.C., Angermeyer, M., Anthony, J.C., de
Graff, R., Demyttenaere, K., Gasquet, I., deGirolamo, G., Gluzman, S., Guereje, O., Haro,
J.M., Kawakami, N., et al. Lifetime prevalence
and age-of-onset distributions of mental disorders
in the World Health Organization's World Mental
Health Surveys. World Psychiatry 2007; 6:
168-176.
2. Shimazu A, Schaufeli WB. Does distraction
facilitate problem-focused coping with job stress?
A one year longitudinal study. J Behav Med,
2007; 30, 423-434.
3. Yamagishi M, Kobayashi T, Kobayashi T, Nagami
M, Shimazu A, Kageyama T: Effect of web-based
assertion training for stress management ofJapanese nurses. J Nursing Management, 2007; 15,603-607.
4. Hiro H, Kawakami N, Tanaka K, Nakamura K:
Japan Work Stress and Health Cohort Study
Group. Association between job stressors andheavy drinking: age differences in male Japanese
workers. Ind Health. 2007; 45: 415-25.
5. Umehara K, Ohya Y, Kawakami N, Tsutsumi A,
Fujimura M. Association of Work-Related Factors
with
Psychosocial
Job
StressorsandPsychosomatic Symptoms among JapanesePediatricians. J Occup Health. 2007; 49: 467-481.
6. Niekawa N, Sakuraba Y, Uto H, Kumazawa Y,
Matsuda O. The relationship between financial
competence and cognitive function in patientswith schizophrenia. Psychiatry Clin Neurosci.

2007; 61: 455-461.
7. Taniguchi T, Hirokawa K, Tsuchiya M, Kawakami
N. The immediate effects of 10-minute relaxation
training on salivary immunoglobulin A (s-IgA)
and mood state for Japanese female medical
co-workers. Acta Med Okayama. 2007; 61:
139-45.
8. Ormel J, Von Korff M, Burger H, Scott K,
Demyttenaere K, Huang YQ, Posada-Villa J,
Pierre Lepine J, Angermeyer MC, Levinson D, deGirolamo G, Kawakami N, et al. Mental disorders
among persons with heart disease - results fromWorld Mental Health surveys. Gen Hosp
Psychiatry. 2007; 29: 325-34.
9. Nishiuchi K, Tsutsumi A, Takao S, Mineyama S,
Kawakami N. Effects of an education program forstress reduction on supervisor knowledge,
attitudes, and behavior in the workplace: arandomized controlled trial. J Occup Health.
2007; 49: 190-8.
10. Mineyama S, Tsutsumi A, Takao S, Nishiuchi K,
Kawakami N. Supervisors' attitudes and skills for
active listening with regard to working conditions
and psychological stress reactions among
subordinate workers. J Occup Health. 2007; 49:
81-87.
11. Tsutsumi A, Kayaba K, Ojima T, Ishikawa S,
Kawakami N, Jichi Medical School Cohort Study
Group. Low control at work and the risk ofsuicide in Japanese men: a prospective cohort
study. Psychother Psychosom. 2007; 76(3):177-85.
12. Tsutsumi A, Umehara K, Ono H, Kawakami N.
Types of psychosocial job demands and adverse
events due to dental mismanagement: a crosssectional study. BMC Oral Health. 2007; 7:3.

308

Department of Health Sociology/ Health Sociology and Health
Education
Associate Professor
Yoshihiko Yamazaki, Ph.D. (Dr.Hlth.Sc.)

Homepage

http://www.hlthsoc.m.u-tokyo.ac.jp/indexj.htm/

Introduction and Organization
The Department of Health Sociology is one of thetwo departments which ex-Department of HealthSociology was devided into in 1997, when mostdepartments in the University of Tokyo werereorganized into the Graduate School of the
University of Tokyo. The department of HealthSociology is one of sixteen departments in the
Graduate School of Health Sciences and Nursing. In
2007, Master Course only in the Division of Health
Sciences was reorganized into the newly establishedschool, the Graduate School of Public Health. The
department where the master course students in the
Department of Health Sociology get affiliated isnamed as the Department of Health Sociology and
Health Education. The department consists of one
Associate Professor (Head of Health Sociology /Health Sociology and Health Education), 34 graduate
students (15 master course students and 19 doctor
course students) including 2 international students and
18 students qualified with nurse, and 3 research
students. More than forty visiting researchers areaffiliated with the department.

Teaching activities
In Graduate Courses, School of Health Sciences andNursing, Dr. Yamazaki, A. prof. and Head of HealthSociology, runs runs two seminars every year: HealthSociology(I) in summer semester, and HealthSociology(II) in winter semester, with a lecturer, prof.
Nakayama from St. Luca Nursing College.
The purpose of Health Sociology(I) is for students
to obtain a basic understanding of the healthsociological approach through a quick overview ofmajor concepts, principles, and research in sociologyof health and medicine.
Health Sociology(II) introduces students to basic
methods and techniques in designing and conducting
social research- in general, both quantitative andqualitative- in the health field. For these years, thisseminar has been provided as Introduction toMultivariate Statistical Methods, and designed to learn
the basic statistical methods such as factor analysis,
analysis of variance/covariance, multiple regression
analysis, multiple logistic regression analysis, andstructural equation modeling.
For the graduate students and the other members in
Dept. of Health Sociology, a workshop and a journal
club are held every week. In the former, a student’s
research proposal or paper is to be reported anddiscussed. In the latter, a student is supposed to
introduce an English article in the recent issue of aninternational refereed journal.
In our department in the fiscal 2007, 4 MC students
submitted Master Thesis and gained Master’s Degree.
Two DC students submitted Doctoral Dissertation and
got Doctor’s Degree.
In Undergraduate Courses, School of Health
Sciences and Nursing, our department is in charge ofthe following subjects as: Health Sociology (with a309

lecturer, Dr. Tamura), Social Welfare and Social
Security (with two lecturers, Dr. Sakano from
Okayama Prefectural University and Prof. Takagi
from Keio University), Social Research Method
Practice, Social and Human Relations, Graduation
Thesis (many graduate students the last three subjects
are shared with many graduate students in Dept.of
Health Sociology), and the other two.

Research activities
Our department studies social and psychologicalfactors related to health problems and health caresystems, through developing and applying theories,
concepts and methods, which have been developed insociology, psychology, and social and behavioral
sciences.
We have been conducting the following 7 research
projects on going.
1. Studies on Antonovsky’s Salutogenesis and Sense
of Coherence (SOC) Concept
We have introduced Antonovsky’s Salutogenesis
and its core concept ‘Sense of Coherence (SOC)’
to Japanese fields of health and stress. The
objective of this project is to develop and apply
Japanese version Antonovsky’s SOC scale toexamine SOC and correlates among different
population, people with chronic illness/disability,
and so on.
2. Study on People with Medically Induced HIV
Nearly 1,500 hemophilia patients were infectedwith HIV through blood products in the mid
1980’s in Japan, and so far more than five hundred
patients have died of AIDS and others. They are
suffering not only from health damage but also
various types of stigma and discrimination. In thisproject, several research studies are being
conduced in order to explore the problems of theirlives, and to suggest the needed social supports
3. Studies on Social Differences and Inequalities in
HealthThis project is designed to explore evidence aboutsocio-economic differences in health, especiallyamong the middle-aged, in Japan. Anotherpurpose of this project is to cinsider possible
explanations for these differences and the

4.

5.

6.

7.

implications for policy.
Studieson
Changing
Professional-Patient
Relationship and Patient Autonomy
The aim of this project is to examine the current
situation of professional-patient relationship andpatient autonomy in Japan, and to derive newtheories. Both empirical and theoretical studies
have been conducted from various perspectives.
Studies on “Way of Working and Living” andFatigue/Stress of Working People
Recently Japanese industrial society has been
subjected to the never-experienced structuralchanges. The aims of this project are to explore
the effects of these changes on “ways of working
andliving”,
work-familybalanceandfatigue/stress of working people, and to clarify themechanism of the effects.
Studies on Characteristics of the Physical andPsychological Distresses in Human Service Work
Human service work is spread over the many
fields including medicine, nursing and caring. The
aims of this project is to examine thecharacteristics of the psychological and physicaldistress of human service workers and theirrelated factors.
Studies on the Onset of Pneumoconiosis among
Tunnel Construction Workers
In Japan, many tunnel construction workers
suffered from the onset of severe pneumoconiosis
in 1970’s. It is still continuing in 1990’s. The
purpose of this research project is to reveal theprocess and the related factors on the onset ofpneumoconiosis in recent years.

References
1. Isono F, Suzuki M, Yamazaki Y. The correlationof work environment and low back pain andsymptoms of neck, The Journal of Child Health,
2007; 66(6): 789-796. (in Japanese)
2. Fujimura K, Yoshida T, Yamamoto T, Yamazaki Y.
Prevalence of domestic violence against womenand its risk factors in Gunma, Japan. The Japanese
Journal Health and Human Ecology. 2007; 73(6):225-241.
3. Kawai K, Yamazaki Y, Nakayama K.
Development and formative evaluation of a

310

4.

5.

6.

7.

Web-based stress management program topromote Psychological Well-being. The Japanese
Journal of Health and Human Ecology, 2007;
73(4): 137-152.
Togari T, Yamazaki Y, Nakayama K, Shimizu J.
Development of a short version of the Sense of
Coherence Scale (SOC3-UTHS) for population
survey. Journal of Epidemiology and Community
Health. 2007; 61: 921-930.
Tsuno YS, Yamazaki Y. A comparative study ofSense of Coherence (SOC) and related
psychosocial factors among urban versus rural
residents in Japan. Personality and Individual
Differences.2007; 43: 449-461.
Hirano Y, Yamazaki Y, et al. The Herth Hope
Index (HHI) and related factors in the Japanesegeneral urban population. The Japanese Journal of
Health and Human Ecology. 2007; 73(1): 31-42.
Yamazaki Y, Asakura T, editors. Health Sciences
for Ways of Living. 4th Edition, Yushindo
Publisher. 2007. (in Japanese)

311

Department ofSocial Gerontology
Professor
Ichiro Kai, M.D., M.P.H.

Lecturer
Miyako Takahashi, M.D., Dr.Hlth.Sc.

Associate
Tami Saito, M.Hlth.Sc.

Homepage

http://www.sg.m.u-tokyo.ac.jp

Introduction and Organization
It is often voiced from the general public that recent
advancement of medicinal technology would notnecessarily lead to the happiness of people: Life
prolongation technology enables even the terminally
ill to live for a considerable period. How to use thetechnology is a serious problem in clinical practice.
Also, there is evidence that the prolongation of life
expectancy for the elderly does not mean the
prolongation of health and productivity, but that ofmorbidity. Taking another example, we areexperiencing ethical dilemmas with the application of
medical technology such as genetic screenings andorgan transplantation. When we turn to the worldwide
situation regarding health, we will find poverty andunequal distribution in terms of health resources andoutcomes.
The department is studying these health-related
problems from social perspective, many of which areoften difficult to decide upon. Major topics include
elderly health, terminal care, medical ethics andinternational health among others. We are currently
conducting several research projects as described
below.
Our educational activities include lectures, practicaltraining and supervision of writing theses for students
in graduate level as well as undergraduate level. The

department consists of one professor, one lecturer, one
associate, 24 visiting researchers and 14 graduate
students (including three international students from
Nepal, Korea and Philippines).

Teaching activities
1. Graduate Courses, School of Health Sciences andNursing
1) Social Gerontology: The course is to provide
the students with the basic understanding ofsocial sciences in the field of gerontology. The
topics include (1) the concept andmeasurements of quality of life, (2) the
influences of psychosocial factors on healthstatus, health behavior and health belief, and (3)policy considerations for medical care andprevention.
2. Undergraduate Courses, School of Health
Sciences and Nursing
1) Health Education: This course provides
fundamental understanding in health educationand health promotion in various settings such ascommunity, workplace, school and clinics.
Emphasis is put upon preparing students to
conduct heath education in their future career asa health professional.
2) Practice in Social Surveys: This is for practicing

312

to
conductsocialsurveysusing
questionnaire/interview method. The students
are divided into several groups, and each groupis given a survey area. They will go through all
the processes of a health sociological survey,
from planning the survey to writing a reportbased on the survey. They have the opportunity
to report and discuss their surveys with eachother.
3) Health Behavior: This seminar aims to help thestudents to practice the basic research methods
related to health behaviors. Final product will
be a research proposal and the review of
relevant literature.
4) Decision-making in Health: This course
introduces students to recent developments inmedical and health decision-making. Topics
include the definition and measurement ofquality of life (QOL), cost-effectiveness andcost-benefit analysis, technology assessmentand optimal allocation of scarce medical
resources. Readings are selected from extensive
range of literature in behavioral sciences,economics and philosophy as well as medical
decision-making.

Research activities
1) Reciprocity of Social Support on Subjective
Well-being of the Elderly: Traditional support
study emphasizes the importance of receiving
support. We examine the pattern of support
exchange (i.e., receiving and providing) and its
effects on the subjective well-being of the elderly
in rural Japan as well as a number of Asian
countries such as Korea, Nepal, Malaysia, andIndonesia.
Intervention
studiesregardingintergeneration exchanges and targeting therelocated elderly are now in progress.
2) Disability-free Life Expectancy in Japan: We
calculate disability-free expectancy using alarge-scale cohort of the residents in Nagano
Prefecture and examine variables influencing thelife expectancy.
3) Multi-disciplinary
CollaborationinthePsychosocial Care for the People with Cancer in
Clinical Setting: The survey we performed

indicated that Japanese surgeons consideredthemselves mainly responsible for medical aspectsof patient care and paid less attention topsychosocial issues. We examine the possibilities
of integrating other support resources such as
clinical psychologists, psychiatrists and medicalsocial workers in the clinical practices of cancer
in Japan.
4) Activities of Cancer Self-help Groups in Japan:
Although cancer self-help groups are growing
presence in Japan, they do not attract as many
patients as they do in other countries such as US.
Through semi-structured interviews and aquestionnaire survey, we revealed how Japanesecancer survivors and surgeons view peer support
activities implemented by cancer survivors.
5) Socio-cultural Analysis of Sexuality after Cancer:
Researchers have long neglected sexuality aftercancer. Through intensive semi-structured
interviews with Japanese women with breast
cancer, we examine how the cancer diagnosis andthe following treatments have affected theirsexuality and the whole relationship with theirpartners. Based on the findings of the qualitative
approach, we intend to perform a large-scale
survey on sexual complications among Japanesecancer survivors.
6) Role and Function of Ethics Committees in Japan:
In this project, we surveyed and analyzed the roleand function of ethics committees at various
levels, from hospital level to national level.

References
1. Houde SC, Gautam R, Kai I. Long-term careinsurance in Japan: implications for U.S. longterm care policy. J Gerontol Nurs. 2007 Jan;33(1):7-13.
2. Miyata H, Aita K, Shiraishi H, Kai I.
Understanding
treatment
attitudes
towarddementia: differences among community residents
and health care professionals. Nippon Koshu Eisei
Zasshi. 2007 Apr;54(4):254-61.
3. Chalise HN, Saito T, Takahashi M, Kai I.
Relationship specialization amongst sources andreceivers of social support and its correlations
with loneliness and subjective well-being: a cross313

sectional study of Nepalese older adults. Arch
Gerontol Geriatr. 2007 May-Jun;44(3):299-314.
4. Akabayashi A, Slingsby BT, Nagao N, Kai I, Sato
H. An eight-year follow-up national study of
medical school and general hospital ethics
committees in Japan. BMC Med Ethics. 2007 Jun
29;8:8(8pages).
5. Chalise HN, Saito T, Kai I. Correlates ofloneliness among older Newar adults in Nepal.
Nippon Koshu Eisei Zasshi. 2007 Jul;54(7):427-33.
6. Ohta M, Kai I. The cross-validity of the filial
obligation scale. Arch Gerontol Geriatr. 2007
Jul-Aug;45(1):1-8.
7. Varona R, Saito T, Takahashi M, Kai I. Caregivingin the Philippines: a quantitative survey on adultchild caregivers' perceptions of burden, stressors,and social support. Arch Gerontol Geriatr. 2007
Jul-Aug;45(1):27-41.
8. Aita K, Takahashi M, Miyata H, Kai I, Finucane
TE. Physicians' attitudes about artificial feeding inolder patients with severe cognitive impairment inJapan: a qualitative study. BMC Geriatr. 2007 Aug
17;7:22(9pages).
9. Saito T, Lee H, Kai I. Health and motivation ofelderly relocating to a suburban area in Japan.
Arch Gerontol Geriatr. 2007 Sep-Oct;45(2):217-32.
10. Gautam R, Saito T, Kai I. Leisure and religious
activity participation and mental health: genderanalysis of older adults in Nepal. BMC Public
Health. 2007 Oct 22;7(147):299(11pages).
11. Aragaki M, Saito T, Takahashi M, Kai I. Hospitalvolunteer's role and accident-prevention systems:
a nationwide survey of Japanese hospitals. HealthServ Manage Res. 2007 Nov;20(4):220-6.
12. Kono A, Kai I, Sakato C, Rubenstein LZ.
Frequency of going outdoors predicts long-rangefunctional change among ambulatory frail elders
living at home. Arch Gerontol Geriatr. 2007
Nov-Dec;45(3):233-42.
13. Chalise HN, Saito T, Kai I. Self-rated health: astudy of older adults from a developing country Nepal. BioScience Trends. 2007;1(2):102-7.

314

Department of Biomedical
Ethics & Department of
Health Promotion Sciences
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Jung Su Lee, Ph.D.

Lecturer
Satoshi Kodama, Ph.D.

Research Associate
Kenji Matsui, M.D., Ph.D.

Homepage

http:// www.ethps.m.u-tokyo.ac.jp/

Introduction and Organization
The former Department of Health Administration
was established in 1967 and Dr. Tsuneo Tanaka
became its first professor in 1974. He devoted himself
to the development of the community health caresystem in Japan and published numerous papers
concerning the social theory of health administrationand data management systems for community healthcare. He also contributed to the establishment of the
School of Health Sciences. In 1985, Dr. Atsuaki Gunji
became the second professor of the department.
During Dr. Gunji’s tenure, two major research projects
were undertaken. One was “The effects of physicalactivity and inactivity on health.” From 1990, a20-day bed rest human experimental study was
conducted every year in the context of an international
cooperative research project that was supported bygovernment grants. The other project concerned healthcare systems, especially health care economics and thequality of hospital care.
In 1996, the Department of Health Administration
developed into two departments: the Department of

Health Economics and the Department of Health
Promotion Sciences. Both were established as
departments of the Graduate School of Medicine. In
1998, Dr. Yasuki Kobayashi became the professor of
the Department of Health Economics. He conducted
research into health care delivery systems in Japan. In
2001, he moved to the Department of Public Health.
From 1996 to 2002, Dr. Kiyoshi Kawakubo tookcharge of the Department of Health Promotion
Sciences as the associate professor.
In June 2002, Dr. Akira Akabayashi became
professor of the Department of Health Economics.
Professor Akabayashi’s area of research is biomedical
ethics. In April 2003, the Department of Health
Economics was restructured and named theDepartment of Biomedical Ethics.
Staff members of the two departments include a
professor, an associate professor, a lecturer, anassociate, and a technical specialist. All five members,
a total of ten lecturers from other organizations andnine visiting researchers contribute to department
teaching and research activities.
Department graduate students included four master315

program students and three doctoral program students.
In this annual report, the organization and teachingactivities are reviewed followed by an explanation ofresearch activities.

Teaching activities
Our departments highly prioritize the teaching andguidance of graduate students and their research
activities. Five bachelor theses, seven master thesis,
and six doctoral dissertations were completed between
April 2004 and March 2008. Our departments’ staff
members are also responsible for the following
undergraduate and graduate courses.
Undergraduate Courses
Required courses
1) Health Administration (2 credits, lecture)2) Biomedical Ethics (2 credits, lecture)3) Occupational Health and Law (1 credit, lecture)
Elective courses
4) Health Care & Welfare Ⅰ & Ⅱ (2 credits,
lecture)5) Field Work for Health Administration (2 credits,
practicum)6) Health Promotion Sciences (1 credit, lecture)7) Health Policy & Administration (2 credits,
lecture)8) Introduction to Health Economics (2 credits,
lecture)Graduate Courses
1) Biomedical Ethics Ⅰ
2) Biomedical Ethics Ⅱ
3) Health Promotion Sciences Ⅰ
4) Health Promotion Sciences Ⅱ
Graduate level courses in Biomedical Ethics focus
on the analytical study of ethical theories and on thereview of several empirical studies within the field
and its related areas. The main foci in the graduate
courses of Health Promotion Sciences are theassessment and design of the health promotion
projects in the community and at the work place, thedevelopment of preventive health strategies and healthpromotion related to life-style related disease.

Research activities
Department of Biomedical Ethics
The Department of Biomedical Ethics is interested
in the current topics of health care ethics. We are
currently conducting studies in the fields ofbiomedical ethics, research ethics and clinical ethics.
Methodology is two-folded – theoretical and empirical.
While conducting theoretical research on ethics andphilosophy of health care, we also have adopted a
descriptive approach.
We have recently established the Center for
Biomedical Ethics and Law (CBEL) adjunct to the
Department of Biomedical Ethics (http://square.umin.
ac.jp/CBEL). The Center is funded by a ministry grant
and is aimed to provide educational opportunities bothto students and healthcare professionals outside theuniversity. The Center holds 10 faculty positions andhas started several public activities as of October 2003.
In December 2007, an international collaboration
resulted in a joint conference with University ofPennsylvania (The Global Challenge of Vaccination:
Legal Challenges, Ethical Conundrums).
Specific research topics include;
1) Study of methods for promoting social consensus
on topics related to advanced medical technology
2) Study of the function and responsibilities of ethics
committees in Japan
3) Acceptability of advance directives in Japanesesociety4) Development of evaluative methods forbiomedical ethics education
5) Ethical and psychosocial aspects of living relatedorgan transplantation
6) Publication of a medical ethics case book forJapan7) Comparative study of clinical ethics in the Asian
region8) Historical analyses for the term “bioethics” in theJapanese context
Department of Health Promotion Sciences
The main research activity of the Department of
Health Promotion Sciences is making health policy
proposals concerning health promotion in thecommunity and work place through experimental and316

survey research. The main research fields are healthbehavior and life-style related disease. The main focusof health behaviors are physical activity including
exercise, diet and nutrition, and obesity. Our
department is providing lectures and practical training
with the aim of helping students to understand themethod of planning, implementation and evaluation of
the health promotion programs in the community andwork place.
Specific research topics include;1) Development of effective health promotion
programs
2) Assessment of and supporting methods for healthbehavior, and the impact on health status
3) Short and long term effects of behavior change
4) Influence of behavior change on medical costs,
and cost effectiveness analysis
5) Determinants in the social and physicalenvironment on the adherence to behavior change
6) Survey of health promotion resources in thecommunity and at the work place
7) The development of a physical activity
questionnaire for the Japanese8) Multiple risk factors and health behavior
9) Glycemic index as a tool for nutritional education
10) Dietary patterns among overweight men andwomen

Publications
1. Akabayashi A, Slingsby BT, Nagao N, Kai I, Sato
H. An eight-year follow-up national study of
medical school and general hospital ethics
committees in Japan. BMC Medical Ethics 2007;
8:8.
2. Amano Y, Sugiyama M, Lee JS, Kawakubo K,
Mori K, Tang AC, Akabayashi A. Glycemic
index-based nutrition education improves blood
glucose control in Japanese adults: a randomized
controlled
trial.
DiabetesCare
2007;30(7):1874-1876.
3. Fujita T, Hayashi K, Kataoka K, Matsumura Y,
Lee JS, Takagi H, Suzuki S, Mizunuma H, Aso T.
Prevalence of disease and Statistical power of theJapanese Nurses’Health Study. Industrial Health2007; 45:687-694.

4. Kawakubo K, Lee JS, Mori K. Relative
contribution of walking steps to weight reduction
in overweight women. Movement & Health 2007;
paper CD No.20:1-5.
5. Kondo K, Lee JS, Kawakubo K, Mori K, Kataoka
Y, Asami Y, Akabayashi A, Umezaki M, Yamauchi
T, Takagi H, Shimomitsu T, Inoue S, Sunagawa H.
Relationship between physical activity andneighborhood environment in two different rural
areas in Japan. Movement & Health 2007; paper
CD No.21:1-6.
6. Lee JS, Kawakubo K, Mori K. Akabayashi A.
Effective cutoff values of waist circumference
detecting the clustering of cardiovascular risk
factors of metabolic syndrome in Japanese men
and women. Diabetes and Vascular Disease
Research 2007; 4(4):340-345.
7. Lee JS, Kawakubo K, Kondo K, Akabayashi A,
Kataoka Y, Asami Y, Mori K, Umezaki M,
Yamauchi T, Takagi H, Shimomitsu T, Inoue S,
Sunagawa H. Neighborhood environment andleisure-time physical activity in residents of theTokyo Metropolitan area. Movement & Health2007; paper CD No.25:1-6.
8. Matsui K, Lie RK, Kita Y. Two Methods of
Obtaining Informed Consent in a Genetic
Epidemiological Study: Effects on Understanding.
Journal of Empirical Research on Human
Research Ethics 2007; 2(3):39-48.
9. Matsui K, Lie RK. Privacy shakes Japan ’ sstatistics on health & welfare. Eubios Journal of
Asian and International Bioethics 2007;
17(2):41-49.
10. Matsushima T, Akabayashi A, Slingsby BT,
Nishitateno K. Evaluation of program to cerebrateseasonal events in Japanese hospice patients.
PalliativeandSupportive
Care
2007;
5(3):251-254.
11. Nakade M, Lee JS, Kawakubo K, Amano Y, MoriK, Akabayashi A. Correlation between food intakechange patterns and body weight loss in
middle-aged women in Japan. Obesity Researchand Clinical Practice 2007; 1(2):79-89.
12. Nakade M, Lee JS, Kondo K, Kawakubo K, MoriK, Akabayashi A. The effect of walking steps on
body weight loss. Movement & Health 2007;
paper CD No.32:1-6.

317

13. Slingsby BT, Plotnikoff GA, Mizuno T,
Akabayashi A. Physician strategies for addressing
patient adherence to prescribed psychotropic
medications in Japan: a qualitative study. Journalof Clinical Pharmacy and Therapeutics 2007;
32(3):241-245.
14. Takimoto Y, Maeda S, Slingsby BT, Harada K,
Nagase T, Nagawa H, Nagai R, Akabayashi A. A
template for informed consent forms in medical
examination and treatment: an intervention study.
Medical Science Monitor 2007; 13(8):PH15-8.
15. The J-MICC Study Group (Kenji Matsui is one ofthecontributing
authors).
The
Japan
Multi-institutional Collaborative Cohort Study(J-MICC Study) to Detect Gene-environment
Interactions for Cancer. Asian Pacific Journal ofCancer Prevention 2007; 8:317-23.

School of Public Health
3. Health Services Sciences

319

Department of Public Health/
Department of Health Policy
Professor
Yasuki Kobayashi, M.D., Ph.D.

Associate Professor
Kazuo Inoue, M.D., Ph.D.

Lecturer
Hajime Sato, M.D., M.P.H., Ph.D., D.P.H.

Associate
Satoshi Toyokawa, M.S., Ph.D.

Homepage

http://publichealth.m.u-tokyo.ac.jp/

Introduction and Organization
Public health departments in medical schools inJapan were introduced after the World War II,
following the model of the U.S. systems for publichealth and medical education. The Department of
Public Health was established in 1947, in the Facultyof Medicine, the University of Tokyo. In 1995, theDepartment became a part of the Division of Social
Medicine, Graduate School of Medicine, as the resultof the shift to a graduate school system in the
University of Tokyo. In 2007, School of Public
Health was established in the University of Tokyo,
and the Department became a part of School of Public
Health (Department of Health Policy) and remained
being a part of the Division of Social Medicine(Department of Public Health).
The objectives of the Department are botheducation and research of public health. The
Department trains graduate and undergraduate
students through lectures, seminars, field practice, andlaboratory work in public health and occupational
medicine, for the degrees of Medical Doctor (MD),Master of Public Health (MPH), and Doctor of
Medical Sciences (equivalent to Ph.D.).
The

Department has conducted research on a wide varietyof public health issues, including health policy andeconomics, occupational medicine, community andclinical epidemiology, and so on. In addition, the staff
members of the Department have offered public andoccupational health services to the governments,
industries, and local communities.

Teaching activities
1) Undergraduate Program (Medical School)
In the winter term of the fourth grade in the Schoolof Medicine (M2), students are provided with thefollowing lectures; current issues in the field of publichealth, preventive services, epidemiology, healtheconomics, community health and primary care,occupational and environmental health, infection andtuberculosis control, mental health, international
health, current health policy in Japan, and so on.
Similarly, in the sixth grade (M4), a concentration
course of public health (e.g., health care systems,
occupational medicine, and community healthpractice) is provided. All the above lectures are given
by faculty members and part-time lectures including
governmental officials.

320

Field practice and laboratory work in public healthis due in the spring term of the fifth grade (M3),which is jointly provided by Department of MolecularPreventive Medicine and the other departments related
to public health fields. Averagely four to five students(small group) are assigned to one special topic groupwith a tutor (faculty member or part-time lecturer).
Each group conducts field practice, review work, orlaboratory work and writes a report in the style oforiginal or review paper. The reports submitted arebound and made available to those students insubsequent years.
The Department also provides those lectures related
to public health and occupational medicine forundergraduate students in the School of Health
Sciences and Nursing, and the Faculty of Engineeringin the University of Tokyo.
2) MPH Program
The Department offers two lectures and one fieldpractice;“HealthPolicy,”“Public
HealthPreparedness,” and “Public Health Practice.” The
Department also provides a research course forindividual students.
3) Doctoral Program (PhD Program)
The Department offers special lectures, seminars,
field practice, and laboratory work on public healthand occupational medicine to graduate students. In
these training, special emphasis has been placed on
the following points: (1) how to conduct
epidemiologicalstudies,
(2)
how
to
use
epidemiological and statistical methods, (3) how to
use economic concepts and methods in the healthfields, (4) how to establish the collaboration withhealth professionals in the various fields, and (5) how
to read and write original papers.

Research activities
1) Health policy and economics
We are interested in the topics of health care systemand economics in general. We have performed andpublished those studies related to supply and demandsides of health services in Japan; such as supply anddistribution of physicians, the separation ofpharmaceutical dispensing and prescribing in medical

practice, cost studies of outpatient and inpatient
services, and the efficiency and equity issues of theJapan's health insurance system. We have also carriedon several policy studies in terms of public awarenessof medical technology. These studies have been
published in some international policy journals.
We have continued a collaborative study on asystem of HIV/AIDS care with the introduction ofhighly active anti-retroviral therapy (HAART) in
developing countries, since such a system involves
medical, behavioral, social, and economic factors, andwould inevitably become an important health policy
issue.
2) Occupational health
We have carried on a longitudinal study onlife-style, occupational stress, and health status ofworkers in various occupational settings for the
purpose of preventing occupational and life-stylediseases.
3) Community preventive measures
We have done several studies on preventive
measures in a community, such as child immunization
programs in rural China and maternal and child healthcare programs in Afghanistan.

References
1. Inoue K, Matsumoto M, Sawada T: Evaluation ofa medical school for rural doctors. Journal of
Rural Health 23: 183-187, 2007.
2. Inoue K, Matsumoto M, Shono T, Toyokawa S,
Moriki A: Increased intima media thickness andatherosclerotic plaques in the carotid artery as risk
factors for silent brain infarcts. Journal of Stroke
and Cerebrovascular Disease 16: 14-20, 2007.
3. Inoue K, Matsumoto M, Kobayashi Y: The
combi-nation of fasting plasma glucose andglycosylated hemoglobin predict type 2 diabetes
in Japanese workers. Diabetes Research andClinical Practice 77: 451-458, 2007.
4. Matsumoto M, Inoue K, Moriki A: Associationsof brachial-ankle pulse wave velocity and carotid
atherosclerotic lesions with silent cerebral lesions.
Hypertension Research 30: 767-773, 2007.
5. Matsumoto M, Inoue K: Predictors of institutiona-321

lization in elderly people living at home: theimpact of incontinence and commode use inrural Japan.
Journal of Cross-cultural
Gerontology 22: 421-432, 2007.
6. Takayashiki A, Inoue K, Okayama M, Nakamura
Y, Matsumoto M, Otaki J, Kajii E: Primary careeducation for undergraduates in Japan: Is it
enough to increase student interest in and career
preference for primary care? Education forPrimary Care 19: 156-164, 2007.
7. Waza K, Inoue K, Matsumura S: Symptoms
associated with parvovirus B19 infection in
adults: A pilot study. The Japanese Society ofInternal Medicine 46: 1975-1978,2007.
8. Maeno T, Inoue K, Yamada K, Sato H: Indicatorsof a major depressive episode in primary carepatients with a chief complaint of headache.
Headache 47(9): 1303-1310, 2007.
9. You X, Kobayashi Y, Yang J, Zhu X, Liang X:
Qua-litative study of knowledge and behaviours
related to tetanus toxoid immunization among
women of childbearing age in rural China.
Public Health 121: 227-230, 2007.
10. Sugiyama T, Xie D, Graham-Maar RC, Inoue K,
Kobayashi Y, Stettler N: Dietary and lifestylefactors associated with blood pressure among U.S.
adolescents. Journal of Adolescent Health 40:
166-172, 2007.
11. Akabayashi A, Slingsby BT, Nagao N, Kai I, Sato
H: An eight-year follow-up national study of
medical school and general hospital ethics committees in Japan. BMC Medical Ethics 8: 1-8,
2007.
12. Miyaji K, Kohira S, Nakajima K, Sato H, Ohara K,
Yoshiyama H: Pediatric cardiac surgery without
homologous blood transfusion using low priming
volume extracorporeal circulation. The Journalof Thoracic and Cardiovascular Surgery 134:284-289, 2007.
13. Inoue M, Toyokawa S, Miyoshi Y, Miyano Y,
Su-zuki T, Suyama Y, Inoue K, Kobayashi Y:
Degree of agreement between weight perception
and body mass index of Japanese workers: MY
Health Up Study. Journal Occupational Health
49: 376-381, 2007.

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Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D.,Ph.D.

Homepage:

http://cbie-cancerprev.cie.m.u-tokyo.ac.jp:8090/Plone1

Introduction and Organization
Information engineering in Japan places a great dealof weight on computer hardware, software, and dataprocessing. It is a discipline that seeks objective dataand emphasizes the conception of new methods ofdata transfer, storage, processing, and input/output. It
also targets research on developing computer devices
and systems.
Reviewing the history of the application of computersin medicine, calculating machines for supporting
scientists and technologists first appeared in the 1950s.
In the 1960s, computers were used for accounting andvarious statistics. The personal computer appeared in
the 1980s and was adopted for personal use in many
professions. The systematization of large hospitals,
such as university hospitals, pushed ahead rapidly. In
the 1990s, the computer began to be used as a tool tohelp human thinking, such as in presentations, design,and discovery. When computers became connected toeach other through the internet, the distribution of
information became very easy and rapid, not only
within organizations, but also internationally. In 2003,
a high-quality, "finished" sequence of the humangenome was completed. At the dawn of thetwenty-first century, bioinformatics appeared as a new
discipline, one that uses applied mathematics,
informatics, statistics, computer science, andbiochemistry to solve biological problems. In
medicine, advanced information technologies havebeen applied to health information infrastructures,electrical clinical guidelines, and knowledge
navigation systems.

In response to the needs of the time, the Departmentof Clinical Information Engineering (CIE) wasestablished at the School of Public Health in April
2007. Its predecessor was the clinical informationengineering division of clinical bioinformatics, using
Special Coordination Funds for Promoting Scienceand Technology from the Ministry of Education,
Culture, Sports, Science, and Technology, of Japan.

Teaching activities
The purpose of the Department of Clinical
Information Engineering is to nurture talented people
who have special knowledge and skills at aninternational level in order to apply advanced
information technologies to practical projects inclinical medicine and the health sciences. It offers
courses on information system design, development
methodology, evaluation and project management inbiomedicine, health care and public health in the
School of Public Health, and data mining and virtual
reality for clinical decision-making in social medicine.
At present, the department has only one faculty
member: Prof. Hiroshi Oyama, M.D., Ph.D. However,famous visiting lecturers and researchers from the
National Cancer Center and other universities havegiven lectures here, furthering our hope of becoming aworld leader in this field.
The education of graduate students is based on weekly
conferences at which the students present the progresson their own research projects and discuss their future
directions.

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Research activities
Our research covers the biomedical computer
applications that focus on
biomedical data(collection, analysis, and representation). It constitutes
a combination of information science, computerscience, and clinical science designed to assist in the
management and processing of data, information, andknowledge to support the practice and delivery ofclinical care. Our laboratory is engaged in thefollowing research activities:(1) Medical Decision-making: We focus on how to
improve health outcomes by advancing
systematic approaches to clinical decisionmaking and policy formation in health care using
information engineering methodology (IEM),
especially electrical clinical guidelines andencoded knowledge.
(2) Data Mining & Knowledge Discovery from
Databases: It is necessary to collate
heterogeneous information, such as the clinicalindications for a drug, drug side effects,
pharmacokinetics, metabolic pathways, and drug
response
genes
forsinglenucleotide
polymorphisms (SNPs). These data are
distributed and managed in various clinicaldatabases. We are studying ways to integrate
distributed biomedical data and knowledge
mining with virtualized database technologies,
such as auto-indexing and technical term
identification algorithms.
(3) Computer Graphics & Virtual Reality (VR) for
Medical Science: Our research has three goals:(1) to improve the living conditions of in-patientswith limited physical activity by providing virtual
experiences; (2) to develop new diagnostic
methods using medical imaging; and (3) todevelop a surgical edutainment and preoperative
surgical planning support system in virtual space.
The advantages of simulating surgical procedures
using VR techniques include: (1) practicing thesurgical procedure and image-based training; (2)planning the surgical procedure for individual
patients preoperatively using VR images modeledfrom the patient's preoperative computed
tomography (CT) or magnetic resonance (MR)images, in collaboration with the Department of

Neurosurgery; (3) allowing supervisors toevaluate a procedure objectively; and (4) helping
patients and their families to better understand thesurgical procedure before and after the operation.
(4) Social Information Engineering for Public Health(Public Health Informatics): Our laboratory
researches new tools and methodologies for
applying information and computer science andtechnology to public health practice, research,and learning. This has just started. At present, weare studying differences in the computerization of
public health in the US and Japan.

References
1. Imamura T, Matsumoto S, Kanagawa Y, Tajima B,
Matsuya S, Furue M, Oyama H. A technique for
identifying three diagnostic findings using
association analysis. Med Biol Eng Comput. 2007
Jan;45(1):51-9.
2. Katsumura Y, Yasunaga H, Imamura T, Oyama H,
Ohe K. Quality evaluation of economic studies for
medical safety management. Nippon Koshu Eisei
Zasshi. 2007 Jul;54(7):447-53. Japanese.

Endowment Department

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Department of Integrated
Traditional Medicine
Project Associate Professor
Tetsuro Okabe, M.D., Ph.D.

Project Associate
Jing Yu, Ph.D.

Homepage

http://square.umin.ac.jp/seitai/

Introduction and Organization
In an attempt to investigate the Japanese traditional
herbal medicine, the Department of Integrated
Traditional Medicine was established in 1996 as the
Department of Bioregulatory Function affiliated with
the Department of Medicine and Physical Therapy.
In 1999, the Department of Geriatric Medicine joinedusasan
anotheraffiliatedDepartment.
Pharmacological actions by medicinal herbs have been
intensively investigated not only on allergic or
autoimmune diseases, but also the disorders associatedwith aging process. Therapeutic experiments ofherbal medicine have been carried out by using animal
disease models to clarify the mechanisms of thepharmacological actions. In additions, the biologicalactions of the herbs have been investigated at cellularlevels to clarify the intracellular signaling pathways
induced by the medicinal herbs.
In 2003, traditional medicine was introduced into corecurriculum of medical education program. Since 2004,
lecture of traditional medicine has been
started in this university as an essential study. The
lectures have been served by this department. For
postgraduate education, seminars of traditional
medicine have been held at the university.
To avoid the confusion of similar names in western
medicine, the name of this department “Department of
Bioregulatory Function” was changed to “Department
of Integrated Traditional Medicine” in 2005.
Together with the change in the department name, westarted the translational studies on the physiology andpathology of the traditional medicine to translate thetraditional medicine into scientific medicine. It
required not only the chemical or pharmacologicalstudies but also the biophysical approaches. In
addition, translation from scientific medicine into the
traditional medicine has been also required for better
understanding the integration of both medicine. For
this purpose, free seminars “traditional medicine as alife science” have been started, in which we analyze
and translate the scientific data into the traditional
medicine and also try to integrate both medicines.
Another research interest has been focused on theanti-aging medicine used in ancient traditional
medicine. Recently, hormone supplemented therapy
has been tried for disorders associated with aging inWestern medicine. Some herbs have been shown toexert their pharmacological actions through receptors
for certain hormones. The studies on this theme havebeen intensively performed at the department.
Postgraduate students have been also engaged in bothbasic and clinical sciences. The department provides awide-ranged clinical, training, and research services.
The weekly official activities of our department are ajournal club on Tuesday and research conferences on
Thursday.

Clinical activities
We have outpatient clinics on Tuesday, Wednesday,and Friday in the Department of General Medicine.

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The diagnosis is made by the western medicine using
blood examinations and imaging studies. After thescientific diagnosis, patients are diagnosed based on
the instructions of the traditional herbal medicine, andtreated mainly with the medicinal herbs.

Teaching activities
As for under-graduate student education, ourdepartment takes a part in systemic lectures for the 4thyear medical students. In systemic lectures,comprehensive presentation for the understanding ofbasic knowledge about the concept, pathogenesis,
pathology, diagnosis and treatment is performed.
In systemic lectures, we also present clinical cases ofrepresentative cases, and try to discuss with thestudents several points for planning the diagnosis andtreatment. Demonstration of some herbs and typical
recipes is also served during the lectures.
Free seminars “traditional medicine as a life science”
are served, in which we analyze and translate thescientific data into the traditional medicine and also
try to integrate the idea from both medicines.
For international experimental educations, a special
lecture on traditional herbal medicine anddemonstration of acupuncture were given for foreign
students from over 40 countries at Harvard Project for
Asian and International Relations Tokyo Conference.
Postgraduate students are served with scientificeducation of molecular cell biology and biophysics.
As for the post-graduate clinical education, we
provide clinical lectures regularly on the use of
traditional herbal medicine.

Research activities
Our
researchfield
coversfromclinical,
pharmacological, biological, and biophysical activitiesof traditional medicinal herbs. We focus on themolecular mechanisms of cell functions andintracellular signaling pathways.
Traditional medicinal herbs such as Ginseng has long
been used as an anti-aging agent in Asian countries.
Our laboratory studies molecular mechanisms ofaction by such anti-aging herbs. Ginsenoside Rb1, amajor constituent of Ginseng
has been demonstrated to exert the biological action asa phytoandrogen. Endocrinological activities ofanti-aging herbs are investigated using various
molecular cell biological approaches including
biochemistry, immunochemistry, molecular biology,
molecular genetics such as gene targeting andtransgenic mouse approaches, molecular biophysics.
Much current interest is focused on the therapeuticpotential of hormone replacement therapy (HRT).
However, one of the major adverse reactions of HRT
is considered to promote cancer growth. It is urgent
for us to elucidate the mechanisms of action by theanti-aging herbs and to compare them with those ofhormones. Subsequently, we compare the biologicalactivities of the anti-aging herbs and their counterpart
hormones. We have demonstrated ginsenoside Rb1
exerts the biological activity through its non-genomic
action. Our studies are focused on endocrinologicalactivities of anti-aging herbs which are through theirgenomic or non-genomic actions.
Spinocerebellar ataxia type 6 (SCA6) has been
demonstrated to be an autosomal dominant cerebellar
ataxia associated with small polyglutamine-dependent
expansions in the alpha 1A-voltage calcium channel.
Long-term remission of this genetic disease has been
attained with medicinal herbs. The findings of ourstudy imply the therapeutic potential of herbal
medicine for this hereditary neurodegenerative
disorder. Extensive investigations are under way toclarify the mechanisms.
Physiology, pathology and therapy of traditional
herbal medicine is based on the principle of thecharacteristic systems biology. According to theguideline of the traditional herbal medicine, we haveexamined the clinical effect by systems therapy withmedicinal herbs in patients with bronchial asthma andessential hypertension. Long- term remission has beenobtained in both disorders. Extensive studies are under
way to elucidate the mechanisms by which systems
therapy exerts the therapeutic activities.

References
1. Yu, J., Eto. M., Akishita, M.,Kaneko, A., Ouchi,
Y.and Okabe, T. Signaling pathway of nitricoxide production by ginsenoside Rb1 in humanaortic endothelial cells: A possible involvement of
androgen receptor. Biochem Biophys Res

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2.

3.

4.

5.

Commun. 2007;353:764-9.
Okabe, T., Fujisawa, M., Sekiya, T., Ichikawa, Y.,
and Goto, J. Successful treatment ofspinocerebellar ataxia 6 with medicinal herbs.
Geriatr Gerontol Int.2007:195-7.
Okabe, T. Differential diagnosis of arterial
hypertension by systems review and treatment
with medicinal herbs: A preliminary report.
International Medical Journal (IMJ).2007; 7:
113-6.
Okabe, T. Differential diagnosis of bronchialasthma by systems review and induction ofsymptom-free remission with medicinal herbs: An
alternative therapeutic approach. International
Medical Journal (IMJ). 2007;14; 117-21.
Okabe T. Remission induction by systems therapy
with medicinal herbs of inhaled steroid resistantasthma. International Medical Journal (IMJ).2007;
14: 211-4.

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Department of Metabolome
Professor
Ryo Taguchi, Ph.D.

Associate Professor
Yaoshiya Oda, Ph.D.

Homepage

http://metabo.umin.ac.jp /Introduction and Organization

Teaching activities

Lipidomics became one of the prominent research
fields in metabolomics trough recent advances in mass
spectrometry.
Lipids are classes of molecules
thought to be very important, not only as energy
source or constituents of biological membrane, butalso as functional molecules concerning the many
regulation steps in biological process. Furthermore,
recent research has revealed the roles of lipids, such as
mediators of signal transduction and ligands ofreceptors. Thus analyses of these metabolites seem tobe extremely important to understand global and basic
biological system in the life in combination with other-omics data such as genomics, transcriptomics andproteomics.
Under such circumstances, Department ofMetabolome was settled at February 1st, 2003 by the
donation from Ono Pharmaceutical Company andShimadzu Corporation. And this laboratory has beentightly supported by the Department of cellularsignaling (Prof. Takao Shimizu). At 2008 it was
decided to be expanded for additional three years.
Adding to Prof. Taguchi, Dr. Oda, who is one of theprominent readers in the international proteomics field,
is engaged as an associate professor. Six research
associates are engaged in lipidomics research and one
gradient student is engaged in proteomics work
especially on post-translational modification. Adding
to them, 6 collaborating researchers from otheruniversities, institutes or companies, occasionallyengaged in metabolomics research in our laboratory.

Lectures on mass spectrometry, proteomics andmetabolomics were given to 2nd year of undergraduate,
master course for medicine, and graduate students.
Also special lectures for graduate students of otherfaculty in this university have been occasionallyoperated.
Further, several technical seminars, and academic
meetings on mass spectrometry in proteomics andmetabolomics have been operated in The Tokyo
University, The Faculty of Medicine. And we havebeen trying to advertise global analytical methods bymass spectrometry through consulting for faculty
stuffs on every technical problems in this field.

Research activities
In lipidomics, techniques of mass spectrometry
become very important. Furthermore, recent advances
in mass spectrometry make it possible to getcomprehensive analyses of lipid metabolites within
the cells and tissues. Studies on lipidomics are
essential to get further understanding of eachphysiological and biological function of proteinsconcerning lipid metabolism. In this process, studies
on comprehensive profiling on lipid metabolites in thecells should be inevitable. In particularly, to identify
real lipid substrates for enzyme proteins, lipid ligands
for receptor proteins, and lipid metabolites for its
carrier proteins, lipidomics by mass spectrometry isvery useful.
Another aim of lipidomics is to identify lipid
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molecules from MS data and get profiling patterns ofalteration of these molecules under specificcircumstances.
In these analytical processes of
profiling, elucidation of unknown pathway or exact
lipid substrate specificity of new enzyme proteins canbe investigated.
Molecular diversity of glycerophospholipids arises
from the nature of the linkage and from the identity of
the fatty acyl chain that is linked to the sn-1and sn-2
carbon atom. In the analytical methods in lipidomic
comprehensive s by mass spectrometry, adding to theand untargeted analysis, focused or targeted analyses
for categorical components are very important.
It is very difficult to obtain exact identification of
all metabolites even in the limited classes ofmolecules such as lipid metabolites. This is causedby different extraction efficiency of individual
metabolites, different solubility in analytical solvents,
different ionic efficiency and broad dynamic ranges of
their existence in biological samples. Even in thecase of proteomics, it is very difficult to detect small
amounts of peptides or proteins in mammalian plasma
because of very wide dynamic ranges of protein
contents in plasma. This is exactly the same in lipid
metabolites in most of biological samples.
For detecting minor but physiologically important
lipid molecules, specified technical strategies should
be appliedin selecting the detection methods
including choice of HP LC system with most effective
columns and that of the most suitable MS systemand collision conditions.
Since electrospray ionization (ESI) is a soft
ionization method, each molecule in a mixture can bedetected without any fragmentation. However, ingeneral only the major peaks will be detected if thesample is injected as a mixture without any LC
separation. One of the solutions to this problem is touse specific detecting methods, such as precursor ion
scanning and neutral loss scanning; these scanningmodes are often used for measurement of particularfocused phospholipids.
Soft ionization in mass spectrometry has induced
some paradigm changes in the applications of mass
spectrometry in biological studies.
Effective
insight can be obtained by comprehensive analyses ofmetabolic molecules under genetically,
environmentally or physiologically different

conditions. Matrix assisted laser desorption/ionization(MALDI) is essentially used as off-line methods,
while ESI can be used as a flow system, and is easily
combined with on-line separation systems such as
HPLC or capillary electrophoresis (CE). Sensitivityof detection by ESI essentially depends on theconcentration of molecules in the sample solution.
Thus, for obtaining a highest sensitivity, it is very
important to use low elution rate with small size ofcolumn. For this purpose, capillary or nana LC
system combined with ESI has been used.
Concerning metabolic molecules as target of
metabolome, individual molecular structures aremostly known and relations of each metabolite are
well studied. Thus we can easily imagine their
metabolic linkage from our former knowledge. Fromthese circumstances, we will be able to get effective
data from comprehensive analysis of metabolites bymass spectrometric analyses, for elucidating new
function of enzyme proteins including substratespecificities.
By ESIMS, selective analyses ofindividual molecules in the mixture can be effectively
obtained.
To elucidate the function of lipids, it is necessary toanalyze not only their classes but also their molecularspecies. Thus, the application of mass spectrometry(MS) has become increasingly popular in thelipidomics. As analytical methods for lipidomics, weselected several different approaches in theidentification of lipid molecular species. First one is a
shotgun LC-MS/MS analysis with data dependent
scanning for global identification of lipid molecularspecies, the second one is a structure-related focusedmethod such as precursor ion scanning or neutral loss
scanning. The third one is a sort of targeted method in
combination with theoretically constructed MS/MS
database of lipid search using multiple reaction
monitoring. We constructed this method for detecting
minor lipid metabolites such as oxidized lipids. Even,in this case structural isomers with same m/z value canbe separately detected with partially comprehensive
manner. The choice of these three different types ofmethods seems to be very important for detecting
different class of lipid metabolites. Data from both
first and second types of analyses can be subjected tooursearchengine,“LipidSearch”(http://lipidsearch.jp), and most probable molecular
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species can be obtained with their compensated ion
intensities. And identified individual molecularspecies can be automatically profiling according totheir compensated ion intensities.
Recently, the global analysis of the oxidized fatty
acid was also established in our laboratory, using
theoretically expanded multiple reaction monitoringwith reversed-phase liquid chromatography/tandem
mass spectrometry. And this system has beeneffectively applied several biological samples, such as
in the acute peritonitis model and the bronchialasthma model, for analyzing a quantitative variationof the oxidized fatty acid.
Our recent projects are clarifying the changes in
profiling of lipid metabolites in obesity andinflammation.

3. Houjou T, Hayakawa J, Watanabe R, Tashima Y,
Maeda Y, Kinoshita T, Taguchi R.. Changes inmolecular species profiles of glycosylphosphatidylinositol anchor precursors in early stagesof biosynthesis. J Lipid Res. 48:1599-606, 2007
4. Maeda Y, Tashima Y, Houjou T, Fujita M,
Yoko-o T, Jigami Y, Taguchi R, Kinoshita T.
Fatty acid remodeling of GPI-anchored proteins isrequired for their raft association. Mol Biol Cell.
18:1497-506. 2007
5. Nakashima H, Hamamura K, Houjou T, Taguchi
R, Yamamoto N, Mitsudo K, Tohnai I, Ueda M,
Urano T, Furukawa K, Furukawa K..
Overexpression of caveolin-1 in a humanmelanoma cell line results in dispersion of
ganglioside GD3 from lipid rafts and alteration ofleading edges, leading to attenuation of malignant
properties. Cancer Sci.; 98:512-20, 2007
6. Nakano-Kobayashi A, Yamazaki M, Unoki T,
Hongu T, Murata C, Taguchi R, Katada T,
Frohman MA, Yokozeki T, Kanaho Y. Role ofactivation of PIP5Kgamma661 by AP-2 complex
in synaptic vesicle endocytosis. EMBO J.; 26:1105-16, 2007
7. Shindou H, Hishikawa D, Nakanishi H, Harayama
T, Ishii S, Taguchi R, Shimizu T. A single
enzyme catalyzes both PAF production andmembrane biogenesis of inflammatory cells:cloningandcharacterizationofacetyl-CoA:lyso-PAF acetyltransferase. J Biol
Chem. 282, 6532-6539, 2007
8. Taguchi R, Nishijima M, Shimizu T. Basic
analytical systems for lipidomics by mass
spectrometry in Japan. Methods Enzymol.; 432:
185-211, 2007

Instruments for mass spectrometry
We have been using several ESI-MS instruments formetabolomics and proteomics; as triple stage
quadrupole MS, 4000Qtrap and Quantum Ultra, and as
iontrap, LCQ and LTQ, then as hybrid type-MS, LTQ
Orbitrap, Q-TOF micro and LCMS-IT-TOF. Further as
MALDI MS, we have been using AXIMA-CFR. Also
at 2007, we started to prepare several new techniques
for the elucidation of analysis in localization of lipid
metabolites, such as razor microdissection, DESI and
MALDI mass imaging.

References
1. Tsumoto H, Murata C, Miyata N, Kohda K,
Taguchi R. Efficient identification andquantification of proteins using isotope-coded
1-(6-methylnicotinoyloxy)
succinimidesbymatrix-assisted laser desorption/ionization timeof-flight mass spectrometry. Rapid Commun Mass
Spectrom.; 21(23):3815-24, 2007
2. Shindou H, Hishikawa D, Nakanishi H, Harayama
T, Ishii S, Taguchi R, Shimizu T. A single
enzyme catalyzes both PAF production andmembrane biogenesis of inflammatory cells:cloningandcharacterizationofacetyl-CoA:lyso-PAF acetyltransferase. J Biol
Chem. 282, 6532-6539, 2007
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Department of Clinical
Epidemiology and Systems
Professor
Tutomu Yamazaki, M.D.,Ph.D.

Associate Professor
Daisuke Koide, R.Rh., HIM, Ph.D.

Homepage

http://cbi.umin.ne.jp/dces/index_e.html

Introduction and Organization
The Department of Clinical Epidemiology and
Systems was established in 2007, supported by Banyu
pharmaceutical company. Our department took overand enhanced the function and infrastructures of theClinical Epidemiology Division in the Clinical
Bio-Informatics Research Unit (CBI) which had beenlead by Professor Ryozo Nagai at the Department of
Cardiovascular Medicine, because the unit had been
terminated its five-year program supported by theJapan Science and Technology Agency in 2007 asscheduled.
Our objectives are to develop standards for thetransfer of clinical information and improve thequality of clinical epidemiologic researches in the areaof life-style related diseases and preventive medicine,
because large and longitudinal data are necessary.
Through these activities, we evaluate such standards
and establish academic foundations of “Clinical
Epidemiology and Systems” as well as contribute toprofessional training in this field which will be more
and more required in the future.
In order to facilitate our broad activities, ourorganization is subordinate to the Department of
Cardiovascular Medicine, and works with close
collaboration with the staffs in the Center for
Epidemiology and Preventive Medicine which wasestablished in 2007 because professor Yamazaki isconcurrently the head of the both sections. The staffs
of this center overlap with faculty members in the

Department of Ubiquitous Preventive Medicine which
also took over and enhanced the function andinfrastructures of the Genomic Science Division in the
CBI. Furthermore, these departments work with the
Department of Clinical Trial Data Management in the
22nd Century Medical and Research Center, andprovide consultation on biostatistics and clinicalresearch. Since associate professor Koide has abackground of medical informatics, he develops andsystemizes the standards of information in the area ofclinical epidemiology in collaboration with the
DepartmentofPlanning,
Information
andManagement, the University Hospital Medical
Information
Network(UMIN)
Center,theDepartments of Epidemiology and Biostatistics, andPharmacoepidemiology.
In addition, our department has been incollaboration with many institutions within andoutside the university, since the times of the CBI.

Teaching activities
The basic lectures of Medical Writing had anenrollment of 223 participants at the Testumon
memorial auditorium on every Tuesdays (5 series)
from September 4 to October 2 in 2007, hosted by the
non-profit organization of Japan Medical andScientific Communicators Association, and under thejoint auspices of the three departments of Clinical
Epidemiology and Systems, Clinical Trial DataManagement, and Ubiquitous Preventive Medicine.

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In addition, the public lectures for the Initiative of
Health Business (7 series) had an enrollment of 267
participants at the Testumon memorial auditoriumfrom October 29, 2007 to February 27, 2008, hosted
by the department of Pharmaco-Business Innovationin the graduate school of pharmaceutical science, andunder the joint auspices of the two departments ofClinical Epidemiology and Systems, and Ubiquitous
Preventive Medicine.
Furthermore, the intensive course that was entailed“the principles of Medical Research – Basic
Epidemiology –” was presented by Professor Moonsfrom the department of clinical epidemiology at
Utrecht University, the Netherlands. From inside andoutside our university, 80 people attended thisintensive course at the clinical auditorium in our
university from November 23 through 25 (three days)in 2007. This was hosted by the Master of Clinical
Biomedical Science in Tokai University, and under thejoint auspices of the four departments of Biostatistics,
Clinical
Trial
DataManagement,
Clinical
Epidemiology and Systems, and Ubiquitous
Preventive Medicine.

Research activities
1) Studies of Clinical Epidemiology (Clinical trials,
prospective cohort studies)
Our department facilitates large-scale clinical trials
by executing the data management with computer
servers in our department and in the Japan ClinicalResearch Assist Center. In particular, our department
was in charge of the secretariat for JCAD study which
was comparison of cardiovascular events between
combined and normal therapy for patients withcoronary narrowing.
And studies for clinical epidemiology, such as
monitoring blood pressure at home by using IT andinvestigational researches into new bio-markers forarteriosclerosis have been carried out by analyzing thedatabase in the Center for Epidemiology andPreventive Medicine.
2) Improving Quality of Health Care
As a core member of the quality improvement andassessment committee and chairs of the clinicalpathway working group (WG) and the WG for quality

care at our university hospital, our department
contributes to develop clinical indicators andcomparative studies. Since an electronic clinicalpathway system is supposed to implement in 2008,
standardization and improvement of health care arealso under way based upon EBM.
3) Standardization of Information in Clinical
Epidemiology
As attending the International Conference on
Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH)and Health Level Seven which is one of theinternational standards development organizations, westudy on electronic standards for the transfer
pharmaceutical regulatory information, especially
focusing on electronic standards for safety reporting.
Also, through activities of participating in Clinical
Data Interchange Standards Consortium (CDISC), we
tackle the interoperability of information on clinical
trials.

References
1. Yamazaki T, Goto S, Shigematsu H, Shimada K,
Uchiyama S, Nagai R, et al. Prevalence,
Awareness and Treatment of Cardiovascular Risk
Factors in Patients at High Risk ofAtherothrombosis in Japan Results From
Domestic Baseline Data of the REduction of
Atherothrombosis for Continued Health (REACH)
Registry. Circulation J. 2007; 71: 995-1003.
2. Kohro T, Hayashi D, Okada Y, Yamazaki T, Nagai
R, The JCAD Investigators. Effects of medication
on cardiovascular events in the Japanese Coronary
Artery Disease (JCAD) Study. Circulation J.
2007; 71: 1835-1840.
3. Fujita M, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R, et al. Comparison of
Cardiovascular Events in Patients With
AngiographicallyDocumented
Coronary
Narrowing With Combined Renin-Angiotensin
System Inhibitor Plus Statin Versus ReninAngiotensin System Inhibitor Alone Versus Statin
Alone. The American Journal of Cardiology.
2007; 100(12):1750-3.
4. Koide D, Matsuba H, Furukawa H, Kubota K,

333

Kiuchi T. Pharmaceutical Safety Reporting
System on UMIN. Medinfo 2007. 2007;(CD):131.
5. Otieno GO, Toyama H, Asonuma M, Koide D,
Naitoh K. Sophistication of information
technology in healthcare: A comparison among asample of hospitals in Japan. Electronic Journal of
Health Informatics. 2007; 2(2) e12: 1-13.

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Department of Ubiquitous
Preventive Medicine
Associate Professor
Toru Suzuki, M.D., Ph.D.

Associate
Kenichi Aizawa, M.D., Ph.D.

Homepage:

http://plaza.umin.ac.jp/upm/

Introduction and Organization
As an official department in the Graduate School of
Medicine of the University of Tokyo, the Departmentof Ubiquitous Preventive Medicine was inaugurated inAugust 1st, 2007 (Heisei 19), with a generous
donation from three pharmaceutical companies,
Toa-Eiyo Ltd., Shionogi & Co., Ltd. and NEC
Corporation to the University. Its predecessor is theClinical Bio-Informatics Research Unit in the
Graduate School of Medicine of the University ofTokyo (Director: Ryozo Nagai) which was establishedin 2002 (Heisei 14) as a government-funded program(Bio-Informatics Training Program supported by the
Ministry of Education, Culture, Sports, Science andTechnology [MEXT] through Special Coordination
Funds for Promoting Science and Technology). When
the Clinical Bio-Informatics Research Unit completed
its program tenure in 2007, its academic mission andservices were continued by the Department of
Ubiquitous Preventive Medicine and the Departmentof Clinical Epidemiology and Systems, both affiliatedwith the Department of Cardiovascular Medicine in
the Graduate School of Medicine of the University ofTokyo.
The first head of the Department of Ubiquitous
Preventive Medicine is Toru Suzuki, appointed inAugust 1st, 2007, as Associate Professor. Kenichi
Aizawa serves as Research Associate.
Our objectives are to develop diagnostic biomarkers
and diagnostic/therapeutic systems for prevention andearly detection of disease.
For this purpose,advanced and highly efficient techniques of proteome
analysis are used with potential clinical application topreventive medicine. We are also committed todeveloping surrogate biomarkers for the discovery ofdrugs used in the treatment of cardiovascular diseases
as well as the optimization of their efficacy, and todevelop information infrastructure technologies foradvancing personalized medicine by clinically
applying the techniques of proteome analysis in aneffort to promote preventive medicine for healthpromotion. Our mission is to ultimately establish theacademic basis for Ubiquitous Preventive Medicine.
Our department provides diagnostic/therapeutic aswell as academic support for the Department of
Epidemiology and Preventive Medicine established in2007 within the University of Tokyo Hospital. In
collaboration with our department, the Department ofClinical Epidemiology and Systems also support the
management of the Department of Epidemiology andPreventive Medicine.

Research Activities
The principal objective of our research is to develop
diagnostic technologies for prevention and early
detection of disease by using advanced and highly
efficient techniques of proteome analysis, focusing on
the development of diagnostic biomarkers anddiagnostic/therapeutic systems. A typical example is335

metabolic syndrome which if left untreated may resultin lifestyle-related diseases including cardiovasculardiseases. While cardiovascular diseases have a very
long incubation period, protein modifications such asprocessing and denaturation play a leading role on thedevelopment of the diseases. Prevention is thereforeof utmost importance. To this end, we are in theprocess of developing methods for the measurementof protein modifications in cardiovascular diseases
and other new bio-tools for early detection oflifestyle-related diseases.
Specifically, the development of diagnostic
biomarkers and diagnostic/therapeutic systems byusing the techniques of proteome analysis is pursued
on an ongoing basis with its main research projects
being Industrial Technology Development for the New
Energy and Industrial Technology Development
Organization (NEDO) under the Ministry of Economy,
Trade and Industry (METI) and an AcademicIndustrial Research Collaboration (joint research with
Shimadzu Corporation).
In addition to the development of proteomics-based
diagnostic methods, we also are developing
information infrastructure technologies for advancing
personalized medicine by clinically applying thesemethods to preventive medicine, as in comprehensive
medical examinations. In this way, Ubiquitous
Preventive Medicine is an applied science, based on
which a comprehensive system is to be developed inan effort to promote preventive medicine andparticipatory medicine for health promotion.

Clinical activities
The Department of Ubiquitous Preventive Medicine
is involved in the management of the Department of
Epidemiology and Preventive Medicine in the
University of Tokyo Hospital and provides diagnostic/
therapeutic as well as academic support for the
department.

Teaching activities
The Department of Ubiquitous Preventive Medicine
offers education and research supervision to graduate
students and post-doctoral fellows in the affiliate
Department of Cardiovascular Medicine.

References
Academic Papers in English
1. Muto S, Senda M, Akai Y, Sato L, Suzuki T,
Nagai R, Horikoshi M. Senda T: Relationshipbetween the structure of SET/TAF-Ibeta/INHAT
and its histone chaperone activity. Proc Natl Acad
Sci USA 104:4285-90, 2007
2. Suzuki T, Nishi T, Nagino T, Sasaki K, Aizawa K,
Kada N, Sawaki D, Munemasa Y, Matsumura T,
Muto S, Sata M, Miyagawa K, Horikoshi M,
Nagai R: Functional interaction between thetranscription factor Krüppel-like factor 5 andPoly(ADP-ribose) polymerase-1 in cardiovascularapoptosis. J Biol Chem 282:9895-9901, 2007
3. Kada N, Suzuki T, Aizawa K, Matsumura T,
Ishibashi N, Suzuki N, Takeda N, Munemasa Y,
Sawaki D, Ishikawa T, Nagai R. Acyclic retinoid
inhibits neointima formation through retinoic acidreceptor beta-induced apoptosis. Arterioscler
Thromb Vasc Biol 27:1535-41, 2007
4. Suzuki T, Nagai R. Cardiovascular proteomic
analysis. J Chromatogr B Analyt Technol Biomed
Life Sci 855: 28-34, 2007
5. Tsai TT, Evangelista A, Nienaber CA, Myrmel T,
Meinhardt G, Cooper JV, Smith DE, Suzuki T,
Fattori R, Llovet A, Froehlich J, Huchison S,
Distante A, Sundt T, Beckman J, Januzzi JL Jr,
Isselbacher EM, Eagle KA; International Registryof Acute Aortic Dissection. Partial thrombosis of
the limen in patients with acute type B aortic
dissection. N Engl J Med. 357:349-359, 2007
6. Pape LA, Tsai TT, iiselbacher EM, Oh JK, O’gara
PT, Evangelista A, Fattori R, Meinhardt G,
Trimarchi S, Bossonr E, Suzuki T, Cooper JV,
Froenhlich JB, Nienaber CA, Eagle KA; on behalfof the International Registry of Acute Aortic
Dissection (IRAD) Investigators. Aortic diameter>=5.5cm Is Not a good predictor of type A aortic
dissection: observations from the international
registry of acute aortic dissection (IRAD).
Circulation. 116:1120-7, 2007
Academic Papers in Japanese
1. Suzuki T and Nagai R, Biochemical diagnosis ofaortic dissection, Japanese Journal of Intensive
Care Medicine, 31 (extra edition 8): 615-620,
2007

336

2. Fujimoto H and Suzuki T, Determination of risk
factors and treatment effects (basic research):
proteomics in cardiovascular disease, Journal of
Clinical and Experimental Medicine, 221 (extra
edition 13): 1058-1062, 2007
3. Suzuki T and Nagai R, Diagnostic significance ofoxidized LDL, The Lipid 18 (extra edition 1):
22-25, 2007
4. Suzuki T and Fujimoto H, Proteomic analysis ofcardiovasculardisease,Cell
technology,
Shujunsha, pp. 120-127, 2007
Books
1. Suzuki T, Sangiorgi G, Bossone E. Future
directions of aortic dissection. Baliga RR,
Nienaber CA, Isselbacher EM, Eagle KA eds. In:
Aortic dissection and related syndromes.
Springer pp.317-332, 2007
2. Suzuki T, The University of Tokyo Open Lecture
DVD Series; 1. Topics in Clinical Medicine vol.
09: Proteomics (editorial supervisor, Nagai R),
SCICUS K.K., 2007
Reviews
Suzuki T, Elucidation of the mechanisms ofvascular oxidative stress using proteomic methods,
Research Report of Takeda Medical Research
Foundation 34: 101-109, 2007
International Conferences
1. Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Kada N, Mizuno Y, Munemasa Y, Nagai R.
Krüppel-like factor 5 promotes vascularremodeling in biphasic ways; inhibition ofvascular smooth muscle cell (VSMC) apoptosis
and stimulation of cell growth. American Heart
Association, Scientific Sessions 2007 (Orlando,
FL, USA: November 4-7, 2007)
2. Aizawa K, Suzuki T, Matsumura T, Kada N,
Sawaki D, Zhan H, Nagai R: Proteome analysis ofa regulatory pathway of pathologic vascular injury
as mediated by KLF5 and its transcriptional
complexes.
AmericanHeart
Association,
Scientific Sessions 2007 (November 4-7, 2007,
Orlando, Florida, U.S.)
3. Suzuki T, Distante A, Sabino F, Sizza A, Villani M,
Fazzi V, Trimarchi S, Donato SP, Salerno J,
Fracell S, Ignone G, Rinaldis G, Nowak R,
Birkhahn R, Hollander J, Counselman F, Bossone
E, Eagle K. A Biomarker for Diagnosing Acute

Aortic Dissection: Preliminary Experience with
the Smooth Muscle Troponin-Like Protein,Calponin. (American College of Cardiology, 56th
Annual Scientific Session, March 24-27, 2007,
New Orleans, USA）
National Conferences
1. Suzuki T. Proteomic analysis in search of new
cardiovascular pathophysiological factors andmechanism. (New Approaches to Heart Failure:
From Pharmacogenomics to Drug Development).
Plenary Session 4. The 71st Annual Scientific
Meeting of the Japanese Circulation Society(March 15-17, 2007, Kobe, Japan)
2. Aizawa K, Suzuki T, MatsumuraT, Sawaki D,
Kada N, Nagai R. Angiotensin II activates the
DNA damage response through nitric oxide invascular endothelial cells. The 71st Annual
Scientific Meeting of the Japanese Circulation
Society (March 15-17, 2007, Kobe, Japan)
3. Aizawa K, Suzuki T, Matsumura T, Sawaki D,
Kada N, Nagai R. A novel regulatory pathway of
DNA damage response to pathologic vascular
injury as mediated by KLF5 and its transcriptional
complexes. The 71st Annual Scientific Meeting of
the Japanese Circulation Society (March 15-17,
2007, Kobe, Japan)
4. Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Kada N, Mizuno Y, Munemasa Y, Nagai R.
Krüppel-like factor 5 directly stimulates cell
growth in vascular lesions. The 71st Annual
Scientific Meeting of the Japanese Circulation
Society (March 15-17, 2007, Kobe, Japan)
5. Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Kada N, Mizuno Y, Munemasa Y, Nagai R.
Modulation of ubiquitin-proteasomal degradationof KLF5 influences vascular remodeling. The
71st Annual Scientific Meeting of the Japanese
Circulation Society (March 15-17, 2007, Kobe,
Japan)
6. Kada N, Suzuki T, Aizawa K, Matsumura T,
Takeda N, Sawaki D, Nagai R. Acyclic retinoid
inhibits neointima formation through retinoic acidreceptor beta-induced apoptosis. The 71st Annual
Scientific Meeting of the Japanese Circulation
Society (March 15-17, 2007, Kobe, Japan)
7. Kada N, Suzuki T, Aizawa K, Matsumura T,
Sawaki D, Munemasa Y and Nagai R, Acyclic

337

retinoid inhibits neointima formation through
RARbeta-induced apoptosis, The University ofTokyo
ClinicalDevelopment
Research
Symposium (Tokyo; March 2, 2007)
8. Sawaki D, Suzuki T, Nagai R. The effects of
adenovirus-mediated overexpression of the
cardiovascular transcription factor KLF5 on
vascular remodeling, The University of Tokyo
Clinical Development Research Symposium(Tokyo; March 2, 2007)
9. Munemasa Y, Suzuki T, Aizawa K, Miyamoto S,
Imai Y, Matsumura T, Mizuno Y, Kada N, Sawaki
D and Nagai R, Promoter region-specific histone
incorporation by histone chaperone p32 andDNA-binding factor KLF5, BMB2007 (the 30th
Annual Meeting of the Molecular Biology Societyof Japan and the 80th Annual Meeting of theJapanese Biochemical Society; Tokyo; December
11-14, 2007)
Lectures
1. Suzuki T, lecture entitled “Which is better as
clinical data on heart failure, echocardiography or
BNP?” in the "Fireside Seminar" of the 11th
Annual Scientific Meeting of the Japanese Heart
Failure Society (September 9, 2007; Hilton TokyoBay)
2. Suzuki T, lecture entitled “Cardiovascularbiomarkers and proteomic discovery” in the 21stCentury COE Program Academic Lecture, The
University of Tokyo, "Meet The Specialist 2007"(August 24, 2007; Conference Room on the 7th
floor of Central Care 2, The University of Tokyo
Hospital)338

Hospital Logistics by Sagawa
Express Co., Ltd.
Visiting Professor
Hirohito Kuse, Dr.Eng.

Project Research Associate
Tomoyasu Ishikawa
Teppei Osada, Ph.D.

Homepage

http://hpt-logi.umin.jp/

Introduction and Organization

Teaching activities

In the current study, hospital logistics has only
pointed out the goods movement in and inside a
hospital, such as the supply of ethical medicines ormedical materials. However, the medical environment- the shortening the duration of hospital stays, theexternal consignment of inspection, etc. - has changed.
Therefore, it is necessary to consider not only goods
movement in and inside hospital but also thecomprehensive hospital logistics including goods
movement from /to a hospital.
“Hospital Logistics by Sagawa Express Co., Ltd”
was established as a part of 22nd Century Medical andResearch Center in 2004 by the contribution from
Sagawa Express Co., Ltd.
Our main purpose is to develop hospital logistics
and logistics services for patients and medical staffs.
This laboratory consists of five members who are
the visiting professor, two project research associates,
and two assistant clerks. We research in cooperation
with the hospital staffs and the delivery company
staffs.
Our research activities cover not only the academic
field but also the development of logistics services
related to medical treatment and patients.

We hosted the symposium “The newest trend andthe future of the hospital logistics” in December,
2007.
In this symposium, the specialists from many fields,
including hospital management, medical informatics,
hospital architecture and logistics, gave their lectures.

Research activities
Our research activities are divided into following
three parts.
First is to improve supply and distribution methods
for ethical medicines and medical materials. For
example, we conducted the goods movement survey inthe hospital. The other example is that we estimate theethical medicine volume in a hospital after huge
earthquakes to continue providing medical andnursing care activities.
Second is to develop logistics services for patients.
Two examples of the trial logistics service in thehospital that we conducted were “Delivery service forthe patients’ baggage between home and the hospital”
and “Home delivery service for the ethicalmedicines”.
Third is to improve procurement and management
method for hospital management. In this part, weanalyzed the effect of changing the procurement and339

management methods at a hospital.
We show the specific themes of research as follows.
1. Improve supply and distribution methods for ethicalmedicines and medical materials.
i) Investigate a situation of vehicles movement in
the hospital.
We found out the peak time of arrival
vehicles. Arrival vehicles are including thewholesalers’ and the retailers’ of medical
supplies, the companies’ of medical waste.
ii) Investigate a situation of goods movement in
the hospital.
We conducted the survey to identify each
person who enters the hospital to see what kindof goods he/she brings in, where he/she takes
them to, what kind of vehicles he/she comes
and what time he/she comes.
iii) Investigate a situation of people and goods
movement inside the hospital.
We investigated a situation of goods
movement in the hospital using RFID. During
the 2-week-survey, we attached the RFID tag
on the person who takes medical supplies andthe other goods. As the result, we identified thesituation of goods movement by following the
movement of people in the hospital.
iv) Estimate a method of the medicine volume in a
hospital after huge earthquakes.
In case of a disaster, the hospital should
continue providing medical and nursing care
activities for a certain amount of time without
outside assistance. We developed the method
how to estimate the ethical medicine volume
when a disaster occurs. This method isavailable for the hospital to measure the ethicalmedicine volume for the disaster.
2. Develop logistics services for patients.
i) Development of the delivery service for thepatients’ baggage between home and a hospital.
We provided the delivery service for patients’baggage between their home and the hospital.
ii) Development of the procurement service forgoods to the hospital room.
We developed the procurement service for
personal items to the hospital room.
iii) Development of the home delivery service forthe ethical medicines.
We developed the home delivery service fordischarged patients to deliver their ethicalmedicine from a hospital to their home.
iv) Development of the home delivery service forthe medical treatment food.
We proposed the home delivery service ofwell-balanced diet for the discharged patientsfor their recovery at home.
3. Improve procurement and management method for
hospital management.

References
1. Ishikawa T, Osada T, Ebihara K, Ide H, Kuse
H：A basic study on the estimate method of the
medicine volume for emergency care in hospital
after huge earthquakes, Journal of Japan Logistics
Society, 2007;15:129-36(Japanese)
2. Ishikawa T, Osada T, Kuse H：A Survey in thelogistics of medical ward using Noncontact Active
IC-TAG（RFID）,The 45th Annual Meeting Japan
Society on Hospital Administration,2007;44:194(Japanese)

340

Department of
Immunotherapeutics (Medinet)
Project Associate Professor
Kazuhiro Kakimi, M.D., Ph.D.

Project Research Associate
Kiminori Kimura, M.D, Ph.D.

Homepage http://immunoth.umin.jp/
Introduction and Organization
The Department of Immunotherapeutics (Medinet)
was established on June 1, 2004 as one of the first of
22 departments of the 22nd Century Medical andResearch Center in the University of Tokyo Hospital.
This Center is a research complex of departments
endowed by the Business-Academia partnership. The
Department of Immunotherapeutics (Medinet) was
contributed by Medinet Co. Ltd., the leading company
in this field in Japan. The aim of our department is to
execute basic and clinical research on cancer
immunology and immunotherapy and to establish itsrole in the treatment of cancer.
Research on cancer immunotherapy is directedby Dr. Kazuhiro Kakimi. Dr. Makoto Kurachi
who participated in the starting-up period of thedepartment from 2004 to March 2007 as an
associate. Dr. Kiminori Kimura joined our team in
April, 2007. Our focus remains the study of cancer
immunology and promotion of translational
research for the development of improved cancer
immunotherapy.
When the new building (Central Diagnosis andTreatment Building 2) of the University of Tokyo
Hospital became available in July 2006, we moved
our department to its 9th floor in September 2006. It
is particularly worth noting that the GMP-level Cell
Processing Center (CPC) was installed in thedepartment at the same time. A CPC is a criticalfacility to prepare cells for clinical applications.

Cancer immunotherapy requires the expansion offunctional T cells and/or dendritic cells (DC) thatare responsible for the anti-tumor immune response
in vivo. Peripheral blood mononuclear cells(PBMC) are isolated from the patients andprocessed in the CPC to ensure that they maintain
optimal functionality, or for triggering new
functions in vitro prior to clinical application.
Autologous cells derived from cancer patients areprocessed for therapeutic use in our CPC in
accordance with all current regulations and ethicalobligations. We began the outpatient program
specializing in cancer immunotherapy in February
2007.
To perform reliable high quality translational
research, we designed our Department’s facilities
literally from the bench to the bedside. The
Department consists of three divisions, (1)laboratory for basic and pre-clinical research (2)Cell Processing Center and (3) outpatient clinic.
Because these three divisions are situated side-byside on the same floor, close cooperation between
the members of each group can be more easily andbetter organized. As soon as blood is drawn fromthe patient at the outpatient clinic, it is directlytransferred to the CPC through the pass-box
between the two. The cells processed and cultured
in the CPC are scrutinized in the laboratory nextdoor to the clinic and CPC regarding their quality
and function. Those cultured cells which areapproved following this examination are transferred

341

back to the clinic and administered to the patient.
The patients are followed-up at regular intervals by
the research staff at the laboratory to monitor theirimmune responses to evaluate the impact of theimmunotherapy.
All protocols for cancer immunotherapy performedin our department are submitted to the institutional
review board (IRB). Once approved, the protocols areregistered in the UMIN clinical research registration
system to provide open access to any interested
parties. Because the cells used for treatment arederived from each individual patient, it is reallydifficult to guarantee consistent quality. However,
we do everything possible to provide the cultured
cells with the best conditions, by means of welltrained specialist staff following standard operatingprocedures. All these efforts allow us to reliably
perform cancer immunotherapy clinical trials incooperation with many clinical departments of the
University of Tokyo Hospital system.
In addition to cancer immunology and immunotherapy, our activities include tissue transplantationand transplantation immunology, the developmentof novel vaccination strategies and identification ofunique anti-infectious agents in collaboration with
the Department of Cardiothoracic Surgery (Professor
Shin-ichi Takamoto).

Clinical activities
We provide outpatient services for cancer patients.
All interventions performed in the department are
defined by the protocols of the particular clinical trial
approved by the IRB. The following clinical trials
are underway in our department:
1) Clinical study on safety and efficacy of adoptive
transfer of autologous γδ T lymphocytes in patientswith non-small cell lung cancer (IRB approval
number 1290).
2) A study to evaluate the safety and efficacy ofinfusions of ex vivo expanded autologous γδ T cells
following zoledronic acid sensitization in patients who
received radiotherapy for bone metastases (IRB
approval number 1511).
3) Clinical trial of the efficacy and safety ofautologous γδ T cell transfer therapy after pulmonary
metastasectomy of colorectal cancer (IRB approval

number 1781).
4) Clinical trial to investigate safety and efficacy ofthe combination of gemcitabine and autologous
adoptive γδ T cell transfer after resection of pancreaticcancer (IRB approval number 1810).
5) A phase I study of vaccination with NY-ESO-1f
peptide mixed with OK-432 (Picibanil®) andMontanide® ISA-51 in patients with cancers
expressing the NY-ESO-1 antigen (IRB approval
number 1935).
Furthermore, we support the following clinicalstudies in corporation with the Department of
Gastroenterology and Hematology, The Tokyo
Medical University:
1) Clinical trial of intratumoral DC injection afterradiofrequency ablation (RFA) therapy for thetreatment of hepatitis C virus-related hepatocellular
carcinoma (HCC) (C000000451, UMIN00000971).
2) Clinical trial of DC therapy for unresectableadvanced pancreatic cancer (UMIN000001135).
As part of the above clinical trials, 7 lung cancer,
5 bone metastasis, and 3 metastatic lung tumor
patients (15 patients in total) have thus far received
infusions of autologous γδT cells. The safety andthe efficacy of these treatments were evaluated.

Teaching activities
Research guidance in molecular immunology isprovided to postgraduate students. Because
knowledge of and techniques for evaluation of
immune response are important for clinicians andmedical researchers, we also provide many
opportunities to postgraduate students to learn how
to analyze in vivo immune responses by means ofexperiments using animal models and by the
immunological monitoring of the patientsthemselves in clinical research.

Research activities
All of our research activities are directed atunderstanding the dynamics of the immune
response in vivo at the molecular, cellular andorganismal levels and to develop more effective
immunotherapy against cancer. To this end, we
perform both clinical immunology in humans and342

basic preclinical immunology using animal models.
We especially focus on the spatiotemporal analysisof anti-tumor immunity in both humans andexperimental animals. During the course of eachtrial, many samples from the clinic are delivered to
the research laboratory to monitor immune
responses in patients. Tumor-specific immunity isevaluated using standardized immunological assays,
such as ELISA, ELISPOT and flow cytometry.
To develop novel immunological interventions,tumor-bearing mice are used to confirm principles
believed to be the basis for the new immunotherapy.
Using many different TCR-transgenic and human
MHC class I-bearing mice we can provide clear
answers regarding the antigen-specific immune
response. As described above, we pursue a researchstrategy of going back and forth from the bench tothe bedside and from basic to clinical immunology
in order to maximize benefit to patients via therapid application of new knowledge to clinicalpractice.

References
1. Isogawa M, Kakimi K, Kamamoto H, Protzer U,
Chisari FV. Differential dynamics of theperipheral and intrahepatic cytotoxic T
lymphocyte response to hepatitis B surface
antigen. Virology, 2005, Mar 15: 333(2): 293-300.
2. Tokuyama, H., S. Ueha, M. Kurachi, K.
Matsushima, F. Moriyasu, R.S. Blumberg, and K.
Kakimi. The simultaneous blockade of chemokine
receptors CCR2, CCR5 and CXCR3 by anon-peptide chemokine receptor antagonist
protects mice from dextran sodium sulfatemediated colitis. Int Immunol. 2005, 17:10231034.
3. Furuichi, Y., H. Tokuyama, S. Ueha, M. Kurachi,
F. Moriyasu, and K. Kakimi. Depletion ofCD25(+)CD4(+)T cells (Tregs) enhances the
HBV-specific CD8(+) T cell response primed by
DNA immunization. World J Gastroenterol. 2005,
11:3772-3777
4. Takai S, Kimura K, Nagaki M, Satake S, Kakimi
K, Moriwaki H.Blockade of neutrophil elastaseattenuates severe liver injury in hepatitis B transgenic mice. J Virol. 2005 Dec;79(24):15142-50.

5. Uno K, Suginoshita Y, Kakimi K, Moriyasu F,
Hirosaki M, Shirakawa T, Kishida T. Impairment
of IFN-alpha production capacity in patients with
hepatitis C virus and the risk of the developmentof hepatocellular carcinoma. World J Gastroenterol. 2005; 11(46):7330-4.
6. Saito A, Motomura N, Kakimi K, Ono M, Takai D,
Sumida S, Takamoto S. Cryopreservation does notalter the allogenicity and development of vasculopathy in post-transplant rat aortas. Cryobiology.
2006; 52(2):251-60.
7. Saito A, Kakimi K, Motomura N, Takamoto S.
Restriction of methicillin-resistant Staphylococcus
aureus growth in allogeneic vascular grafts byindoleamie 2’3-dioxygenase. J.Immunol. 2006;
176:S97.
8. Sasawatari S, Tadaki T, Isogai M, Takahara M,
Nieda M and Kakimi K. Efficient priming andexpansion of antigen-specific CD8+ T cells by anovel cell-based artificial antigen presenting cell.
Immunology and Cell Biology. 2006. 84:512-521
9. Matsuda Y, Toda M, Kato T, Kuribayashi K, andKakimi K. Fulminant liver failure triggered bytherapeutic antibody treatment in a mouse model.
International Journal of Oncology. 2006. 29:
1119-1125.
10. Uno K, Suginoshita Y, Kakimi K, Moriyasu F,
Nakano K, Nakamura N, Fujita T, Horino Y, Sato
T and Kishida T. Clinical utility of 2',5'-oligoadenylate synthetase activity measurement: Using whole blood as a highly sensitive
method to detect the effect of IFN. Journal of
Virological Methods. 2006. 136: 185-192
11. Kurachi M, Kakimi K, Ueha S and Matsushima K.
Maintenance of memory CD8+T cell diversity andproliferative potential by a primary response uponre-challenge. International Immunology 2007. 19(1): 105-115
12. Uno K, Hirosaki M, Kakimi K, Tominaga M,
Suginoshita Y, Hasegawa G, Fukui M, Nakamura
N, Shirakawa T, Kishida T.Impaired IFN-alphaproduction and the risk of cancer development. J
Interferon Cytokine Res. 2007.27: 1013-1017.

343

Department of Integrated
Molecular Science on Metabolic
Diseases
Project Associate Professor
Toshimasa Yamauchi, M.D.,Ph.D.

Project Research Associate
Naoto Kubota, M.D.,Ph.D., Hironori Waki, M.D.,Ph.D.

Homepage
Introduction and Organization
The Department of Integrated Molecular Science on
Metabolic Diseases (DIMSMD) is devoted toclarifying the mechanisms of onset of lifestyle-relateddiseases resulting from interactions between genetic
and environmental factors in the Japanese population
as well as to contributing to the prophylaxis, diagnosis
and treatment of these diseases, in response to thedrastic increase in the number of diabetic patients
which is becoming a major social issue of current
interest. In this regard, the DIMSMD strives toestablish an accurate method through which to predictrisk for the onset of lifestyle-related diseases bytapping into a comprehensive database for genetic andenvironmental factors for these diseases which is
being developed to integrate “Informatics on Genetic
Predisposition to Lifestyle-related Diseases” asgenerated by cutting-edge advances such as single
nucleotide polymorphism analyses with “Informatics
on Environmental Factors for Lifestyle-relatedDiseases” that draw on surveys including detailed
questionnaires on diet intake. The DIMSMD istherefore expected to make significant scientific andsocial contributions by providing effective modalities
for primary prevention of diabetes, moleculardiagnosis of onset of diabetes and its pathology, andoptimal treatment of diabetes, and to play a major role

in reducing the number of newly onset diabetes aswell as in raising the treatment standard for diabetes.
The DIMSMD also aims to develop a system thatallows formulas to be developed to predict therapeutic
response to drugs as well as their safety to be
developed based on information available onenvironmental and genetic factors including gene
expression from patients being treated at University ofTokyo Hospital, and which allows safe and effective
use of drugs being developed in patients withlifestyle-related diseases.
The DIMSSMD has set as its final goal the
installment of a human metabolic disease tissue bankat University of Tokyo Hospital, which draws on an“integrated database” that offers comprehensive
information on gene expression in human hepatic andadipose tissue samples, electronic charts, SNP andlifestyle habits, which will allow validation ofmolecular targets in actual human diseases, design ofa clinical trial system based on SNP and gene
expression profiles, development of models forprediction of therapeutic response based on
environmental and genetic interactions, identificationof molecular targets, discovery of novel therapeutic
agents and safe and effective use of drugs thus
developed in time.
The DIMSMD is thus engaged in daily research
activities and clinical care aimed at contributing to the344

advancement of health and medical care in the future.

Research activities
The DIMSMD Research Laboratory aims to elucidate
the molecular mechanisms of lifestyle-related diseases
such as the metabolic syndrome, diabetes andcardiovascular disease associated with obesity and to
put relevant molecular targets identified in the process
to effective use in the treatment of these diseases. Of
note, the DIMSMD Research Laboratory has animpressive track record in research in this area,
including identification of multiple “key molecules”
implicated in lifestyle-related diseases, such as
adiponectin receptors, which led to an elucidation ofsome of the processes through which lifestyle-relateddiseases develop and progress, based on functional
analyses that tap into developmental engineering and
RNA engineering. The DIMSMD ResearchLaboratory has also been credited with discoveringthat adiponectin is highly active in its high molecularweight form as a ligand to the adiponectin receptors
and that its quantitative measurement is useful in the
diagnosis of insulin resistance and the metabolic
syndrome. Not only that, the DIMSMD ResearchLaboratory has found that, via the adiponectin
receptors, the plant-derived peptide osmotin activates
the AMPK pathway which has a critical role inprotecting against lifestyle-related diseases. Currently,
the DIMSMD Research Laboratory is proactively
engaged in the development of definitive treatments
for lifestyle-related diseases that draw on ligands
specific for the adiponectin receptors.

References
1. Hara K, Yamauchi T, Imai Y, Manabe I, Nagai R,
Kadowaki T. Reduced adiponectin level isasociated with severity of coronary artery disease.
Int. Heart. J.2007; 48: 149-153.
2. Hashimoto H, Arai T, Ohnishi Y,Eto T, Ito M,
Suzuki R, Yamauchi T, Ohsugi M, Saito M,
Ueyama Y, Tobe K, Kadowaki T , Tamaoki N,
Kosaka K: Phenotypes of IRS-2 deficient mice
produced by reproductive technology are stable.
Exp. Anim. 2007;56: 149-154.

3. Ishikawa M, Kitayama J, Yamauchi T, Kadowaki
T , Maki T, Miyato H, Yamashita H, Nagawa H:
Adiponectin inhibits the growth and peritoneal
metastasis of gastric cancer through its specificmembrance receptors AdipoR1 and AdipoR2.
Cancer Sci. 2007;98: 1120-1127.
4. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh
S, Kumagai H, Kozono H, Takamoto I, Okamoto
S, Shiuchi T, Suzuki R, Satoh H, Tsuchida A,
Moroi M, Sugi K, Noda T, Ebinuma H, Ueda Y,
Kondo T, Araki E, Ezaki O, Nagai R, Tobe K,
Terauchi Y, Ueki K, Minokoshi Y, Kadowaki T:
Adiponectin stimulates AMP-activated protein
kinase in the hypothalamus and increases foodintake. Cell Metabolism 2007; 6: 55-68.
5. Kadowaki T, Yamauchi T, Kubota N, Hara K,
Ueki K: Adiponectin and adiponectin receptors in
obesity-linked insulin resistance. Fatty Acids andLipotoxicity in Obesity and Diabetes (Novartis
Foundation Symposium 286), John Wiley & Sons,
Ltd, 2007: pp164-182.
6. Kadowaki T, Yamauchi T, Kubota N: The
physiological and pathophysiological role ofadiponectin and adiponectin receptors in the
peripheral tissues and CNS. FEBS Letters 2008;
582: 74-80.
7. Kubota N, Kubota T, Itoh S, Kumagai H, Kozono
H, Takamoto I, Mineyama H, Ogata H, Tokuyama
K, Ohsugi M, Sasago T, Moroi M, Sugi K, Kakuta
S, Iwakura Y, Noda T, Ohnishi S, Nagai R, Tobe
K, Terauchi Y, Ueki K, Kadowaki T: Dynamic
functional relay between insulin receptor
substrate-1 and -2 in hepatic insulin signaling
during fasting and feeding. Cell Metabolism 2008,
8: 49-64.

345

Department of Translational
Research for Healthcare andClinical Science
Project Associate Professor
Hiroyuki Morita, M.D.,Ph.D.

Project Research Associate
Takahide Kohro, M.D.,Ph.D.

Homepage

http://www.trhcs.org/en/

Introduction and Organization
Our department was open in January 2005,
contributed by Hitachi, Ltd. and Hitachi Medical
Corporation. Since then, the construction of clinicalinformation database has been performed incollaboration with the Department of Cardiovascular
Medicine of this University (Professor and Chairman;
Dr. Ryozo Nagai). In January 2008, our new missions
have started under the contribution of Theravalues
Corporation and Hitachi, Ltd. The aim of ourdepartment is to improve the clinical information
database to the better one and put that into practicaluse in developing the clinical research.
Our department belongs to the 22nd century medical
center in the University of Tokyo Hospital, which was
founded as the front line of university-industry
partnerships. As our research foothold is located in thehospital, we could keep the close connection with thebedside. Our department is thought to be suited for
obtaining the maximum output in clinical research.

Research activities
The onset and progression of the disease are thought
to be caused by the environmental and/or genetic
factors. What is the best way to identify thepathogenesis and the factors predicting the prognosis?

The answer should be the filing of the clinicalinformation.
We are constructing the effective framework to makethe relevant clinical data available for research andperforming the investigation to resolve the clinicalquestions, followed by the translation of its fruits tothe bedside.
Another mission is to confer the explicit scientificre-evaluation on the health issues (e.g. eating habits,
exercise, lifestyle) which have been believed to be
empirically effective. This mission has to be followedby the prompt publicity of the “accurate” data led byour re-evaluation.
The realization of these missions above could becompleted in a close collaboration with the academic
groups and private enterprises. In this regard, we areready to discuss and think together with anybody
anytime.
In summary, our research field covers the issues asfollows;
1. Development of information analysis system andsystematization of clinical information
2. Clinical and/or genomic research utilizing theclinical information analysis system
3. Scientific verification of eating habits, exercise andlifestyle
4. Analysis on the current state of the medical system
5. Spread of accurate medical information to society

346

utilizing the information technology
Research Grant
A Grant from the Ministry of Health, Labour andWelfare (2005-2007)
Mochida Memorial Foundation for Medical andPharmaceutical Research (2007)
Research Grant of Mitsubishi Pharma Research
Foundation (2007)

References
1. Luptak I, Shen M, He H, Hirshman MF, Musi N,
Goodyear LJ, Yan J, Wakimoto H, Morita H, Arad
M, Seidman CE, Seidman JG, Ingwall JS, Balschi
JA, Tian R. Aberrant activation of AMP-activatedprotein kinase remodels metabolic network infavor of cardiac glycogen storage. J Clin Invest.
2007;117: 1432-1439.
2. Fujita M, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R; JCAD Study Investigators.
Comparison of cardiovascular events in patientswith angiographically documented coronary
narrowing with combined renin-angiotensin
system inhibitor plus statin versus reninangiotensin system inhibitor alone versus statin
alone (from the Japanese Coronary Artery Disease
Study). Am J Cardiol. 2007;100:1750-1753.
3. Kohro T, Hayashi D, Okada Y, Yamazaki T, Nagai
R. The JCAD Investigators. Effects of Medication
on Cardiovascular Events in the JapaneseCoronary Artery Disease (JCAD) Study. Circ J.
2007;71:1835-1840.
4. Sugiyama A, Wada Y, Izumi A, Kobayashi M,
Kohro T, Patrick CR, Hamakubo T, Kodama T.
Transcriptional activation by hypoxia andlow-density lipoprotein loading in cultured
vascular smooth muscle cells. J Atheroscler
Thromb.2007;14:226-234.
5. Okada Y, Okimoto M, Katsumata M, Takeuchi S.
Temporary Perfusion for Mesenteric Ischemia
With Acute Type A Aortic Dissection. Ann
Thorac Surg. 2007; 83:293-294.
6. Fujita M, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R; The JCAD Study Investigators.
Pleiotropic effects of statins on cardiovascular
events in the Japanese Coronary Artery Disease

study. Int J Cardiol. 2007 in press.
7. Nishiyama T, Hayashi D. Electrostatic field canpreserve red blood cells in stored blood
preparations. J Anesth. 2007; 21:42-46.

347

Department of Joint Disease
Research
Project Associate Professor
Noriko Yoshimura, M.D., Ph.D.

Project Research Associate
Hiroyuki Oka, M.D.

Homepage

http://kansetsu.umin.jp

Introduction and Organization
The department of Joint Disease Research wasestablished in 22nd Century Medical and ResearchCenter in 2005, which is an endowment department
supported by Chugai Pharmaceutical Co., Ltd. and inclose collaboration with department of Orthopaedic
Surgery. Our department has been established for the
epidemipological study to clarify the frequencies andrisk factors for bone and joint system.

(Research on Osteoarthritis/osteoporosis Against
Disability) in 2005, of which aims at the elucidationof an environmental and genetic background for boneand joint diseases, represented by OA and OP.
We have completed the baseline study on three
population-based cohorts with total 3,040 participantsin urban, mountainous and seacoast communities ofJapan. A second comprehensive clinic visit isscheduled for October 2008 after a follow-up periodof 3 years.

Research activities

Publications

Osteoarthritis (OA) and osteoporosis (OP) are two
major public health problems in the elderly that affectactivities of daily life (ADL) and quality of life (QOL),
leading to increased morbidity and mortality. As the
proportion of the aging population is expanding inJapan, there is an urgent need for a comprehensive andevidence-based
prevention
strategy
formusculoskeletal diseases, including OA and OP.
However, few prospective, longitudinal studies havebeen undertaken, and little information is available
regarding the prevalence and incidence of OA and OP
as well as pain and disability in the Japanese
population. It is difficiult to design rational clinicaland public health approaches for the diagnosis,
evaluation, and prevention of OA and OP without such
epidemiological data.
We therefore established a large-scale nationwide
osteoarthritis/osteoporosis cohort study called ROAD

1. Kanis JA, Oden A, Johnell O, Johansson H, De
Laet C, Brown J, Burckhardt P, Cooper C,
Christiansen C, Cummings S, Eisman JA,
Fujiwara S, Gluer C, Goltzman D, Hans D, Krieg
MA, La Croix A, McCloskey E, Mellstrom D,
Melton LJ III, Pols H, Reeve J, Sanders K, Schott
M, Silman A, Torgerson D, van Staa T, Watts NB,
Yoshimura N. The use of clinical risk factors
enhances the performance of BMD in theprediction of hip and osteoporotic fractures inmen and women, Osteoporos Int 18: 1033-1046,
2007
2. Muraki S, Yamamoto S, Ishibashi H, Oka H,
Yoshimura N, Kawaguchi H, Nakamura K. Dietand lifestyle associated with increased bonemineral density: cross-sectional study of Japaneseelderly women at an osteoporosis outpatient clinic.
J Orthop Sci 12: 317-320, 2007

348

3. Yoshimura N, Kinoshita H, Oka H, Muraki S,
Mabuchi A, Kawaguchi H, Nakamura K,
Nakamura T. Association between height loss andbone loss, cumulative incidence of vertebral
fractures and future QOL: The Miyama Study.
Osteoporos Int 19, 21-28, 2008
4. Yanaoka K, Oka M, Mukoubayashi C, Yoshimura
N, Enomoto S, Iguchi M, Magari H, Utsunomiya
H, Tamai H, Arii K, Ohata H, Fujishiro M,
Takeshita T, Mohora O, Ichinose M: Cancer
high-risk subjects identified by serum pepsinogentests: outcomes after 10-year follow-up in
asymptomatic middle-aged males. Cancer
Epidemiol Biomarkers Prev 17, 838-845, 2008
5. Yanaoka K, Oka M, Yoshimura N, Mukoubayashi
C, Enomoto S, Iguchi M, Magari H, Utsunomiya
H, Tamai H, Arii K, Ysmsmichi N, Fujishiro M,
Takeshita T, Mohora O, Ichinose M: Risk ofgastric cancer in asymptomatic, middle-aged
Japanese subjects based on serum pepsinogen andHelicobacter pylori antibody levels. International
J Cancer, 917-926, 2008
6. Oka H, Muraki S, Akune T, Mabuchi A, Suzuki T,
Yoshida H, Yamamoto S, Nakamura K, Yoshimura
N, Kawaguchi H.: Fully automatic quantificationof knee osteoarthritis severity on standard
radiographs. Osteoarthritis and Cartilage, in press,
2008

349

Department of Health Management
and Policy
Associate Professor
Hideo Yasunaga, M.D., Ph.D.

Research Associate
Hiromasa Horiguchi, Ph.D.

Homepage

http://plaza.umin.ac.jp/~hmp/cgi-bin/wiki/wiki.cgi

Introduction and Organization

Teaching Activities

The Department of Health Management and Policy isan endowed department affiliated with the “22ndCentury Medical and Research Center,” which is a
new center of industry-academia collaboration
established by the University of Tokyo Hospital. With
donations from Nissay Information Technology Co.,
Ltd., the Department launched its first courses on
April 1, 2005. The cooperative department is the
Department of Medical Informatics and Economics,
Division of Social Medicine, Graduate School of
Medicine, University of Tokyo.
The objective of the Department’s activities is topromote interdisciplinary research designed to
improve the quality and efficiency of systems related
to health, medicine and nursing care. The mission of
our research activities is as follows:
1) Conduct research on evidence-based healthmanagement and policy
2) Bring the fruits of our research to society
Our strategies for fulfilling this mission are as
follows:
1) Develop and utilize a national database of Japan’s
Diagnosis Procedure Combination (DPC)
2) Collaborate with outside researchers in eachresearch project3) Promote industry-academia collaboration with
Nissay Information Technology Co., Ltd.

The Department has achieved success in providing ourresearch students and others with education and thesis
guidance on health policy studies and healtheconomics.
We also participated as a key member in the “Training
Program for Hospital Managers,” which was aprogram for doctors held by the University of Tokyo
Hospital in October 2007. We were in charge of the
training program in cooperation with the Hospital
Planning and Management department.

Research Activities(1) Research activities of the DPC Research TeamOver the past three years, the Department has
participated in the DPC Research Team at the Ministryof Health, Labour and Welfare. In addition toproviding support for the processing and analysis of
DPC data, we have announced the results of these
efforts. Since 2006, we have been responsible forresearch into the functional categories of medical
facilities, linking financial accounting informationfrom hospitals with DPC data. In 2007, we also
contributed to developing an integrated database ofclinical data and DPC data related to acuterehabilitation. Since 2007, we have also been
preparing a system using the Department’s server tomanage a database of five years’ worth of data
accumulated by the DPC Research Team to date,

350

which contains in excess of 3 million discharged
cases.

(2) Other research activities
We have also put the following research into
practice.
(a) Research into cases of large-scale health hazards,
such as drug-induced sufferings(b) Research into the existence of, and chief causes
for, regional and departmental disparities in the
supply of doctors(c) Research into the links between the volume andoutcomes of surgical operations(d) Research into government regulations and thedisparity between domestic and overseas prices of
medical equipment(e) Research into the economic evaluation ofhealthcare services(f) Research into risk communication in food hygiene(g) Research into the policy evaluation ofoccupational health, such as measures to prevent
karoshi (death from overwork)(h) Research on systems that contribute to medical
safety(i) Research for the sustainable development ofregional healthcare systems(3) Industry-academia collaboration
Ever since the inauguration of the Department, wehave exchanged information regarding the DPC
research and strengthened our cooperation with the
Health and Nursing Care Solutions Development
Team of Nissay Information Technology Co., Ltd. In
2006-2007, we promoted collaborative research on thefollowing two themes:(a) Establishment of an integrated regional databaseof health, medicine and nursing care information,and utilization of this for regional policy(b)Standardization of disease information, anddevelopment of a risk prediction model.
In 2008, we will further promote this research, and we
aim to build a new management and operating system
for insurance systems which combines clinicalepidemiology techniques with insurance theory.

References
1. Fushimi K, Hashimoto H, Imanaka Y, Kuwabara
K, Horiguchi H, Ishikawa KB, Matsuda S.
Functional mapping of hospitals by diagnosisdominant case-mix analysis. BMC Health ServRes 2007; 10:50.
2. Yasunaga H, Ide H, Imamura T, Ohe K. Women’sanxieties caused by false positives inmammography screening: a contingent valuation
survey. Breast Cancer Research and Treatment
2007; 101: 59-64.
3. Ide H, Yasunaga H, Imamura T, Ohe K. Pricedifferences between Japan and the US for medical
materials and how to reduce them. Health Policy
2007; 82: 71-7.
4. Yasunaga H, Ide H, Imamura T. Current
disparities in the prices of medical materials
between Japan and the United States: further
investigation of cardiovascular medical devices.
Journal of Cardiology 2007; 49: 77-81.
5. Yasunaga H, Ide H, Imamura T, Ohe K. Pricedisparity of percutaneous coronary intervention
devices in Japan and the United States in 2006.
Circulation Journal 2007; 71: 1128-30.
6. Yasunaga H, Ide H, Imamura T, Ohe K. Accuracyof economic studies on surgical site infection.
Journal of Hospital Infection 2007; 65: 102-7.
7. Imamura T, Ide H, Yasunaga H. History of publichealth crises in Japan. Journal of Public Health
Policy 2007; 28: 221-37.
8. Yasunaga H. Risk of Authoritarianism:
Fibrinogen-transmitted Hepatitis C in Japan.
Lancet 2007; 370: 2063-7.

357

Department of Clinical Motor
System Medicine
Project Associate Professor
Toru Akune, M.D., Ph.D.

Project Research Associate
Shigeyuki Muraki, M.D., Ph.D.

Homepage

http://rinsho.umin.jp

Introduction and Organization
The department of Clinical Motor System Medicine
was established in 22nd Century Medical andResearch Center in 2005, which is an endowment
department supported by Eisai Co., Ltd. and in close
collaboration with department of Orthopaedic Surgery.
Our department has been established for the study oflocomotor system medicine.

Research activities
Our research field covers observational and genomic
epidemiology and main target diseases are
osteoarthritis,
spondylosis
andosteoporosis.
Osteoarthritis and osteoporosis are major public healthissues in the elderly that cause impairment of
ADL/QOL. The number of patients with these
diseases is rapidly increasing in Japan, however, few
epidemiologic indices have been established and there
is an urgent need for a comprehensive andevidence-based prevention strategy. We set up alarge-scale nationwide osteoarthritis/osteoporosis
cohort study called ROAD (Research on
Osteoarthritis/osteoporosis Against Disability) in 2005
for the pursue of genomic and etiological evidence.
We have to date created a baseline database withdetailed clinical and genomic information on three
population-based cohorts with total 3,040 participantsin urban, mountainous and seacoast communities ofJapan. Recruitment and baseline visits began in

October 2005 and were completed over a 1.5-year
period, with the last visit in March 2007. A second
comprehensive clinic visit is scheduled for October
2008 after a follow-up period of 3 years.

References
1. Muraki S, Yamamoto S, Ishibashi H, Oka H,
Yoshimura N, Kawaguchi H, Nakamura K. Dietand lifestyle associated with increased bonemineral density: cross-sectional study of Japaneseelderly women at an osteoporosis outpatient clinic.
J Orthop Sci. 2007 Jul;12(4): 317-20.
2. Yoshimura N, Kinoshita H, Oka H, Muraki S,
Mabuchi A, Kawaguchi H, Nakamura K.
Association between height loss and bone loss,
cumulative incidence of vertebral fractures andfuture QOL: The Miyama Study Osteoporosis Int.
2008 Jan;19(1):21-8.
3. Oka H, Muraki S, Akune T, Mabuchi A, Suzuki T,
Yoshida H, Yamamoto S, Nakamura K, Yoshimura
N, Kawaguchi H. Fully automatic quantificationof knee osteoarthritis severity on plainradiographs
Osteoarthritis
andCartilage
Osteoarthritis Cartilage 2008.

352

Department of Clinical Trial DataManagement
Project Associate Professor
Takuhiro Yamaguchi, Ph.D.

Project Assistant Professor
Hiroshi Ohtsu, M.S.

Homepage

http://ctdm.umin.jp/

Introduction and Organization
Why we discuss Clinical Data Management (CDM)?
The reason why the concept of CDM is important has
not been fully discussed and educated in Japan. Our
department was established to answer this question.
The Department of Clinical Trial Data Management
was established in 2007 and carries out educationaland research activities on CDM in collaboration withThe Department of Biostatistics and The ClinicalResearch Center in University of Tokyo.
As compared to the situation of CDM in the UnitedStates and Europe, technical aspects (data collection,
entry, check…) have been mainly focused in Japan but
the essence of CDM is to ensure quality of clinicaldata to appropriate level for fair and scientificevaluation. This has not been recognized in manyeducational activities. CDM should be defined as atechnical system to conduct clinical trials scientifically,
ethically and efficiently and to draw correctconclusion and also as a research discipline withtheory and practice that applies statistics, quality
control and clinical knowledge. It can optimize thewhole clinical trial process, keep the level of data
quality appropriately and calculate the trial cost.
One of our missions is to activate researches on CDM
aimed at improving the quality of clinical trials. The
other is to produce data managers trained under the
new education system which can look around all theclinical trial process to adapt rapid change of medical
environment and recent increase of e-clinical trials in

the world.

Teaching activities
1. Development of systematic educational programsof CDM and holding of seminars, which include¾ Design of clinical trials¾ CDM¾ Protocol development¾ Regulatory science¾ Ethics¾ IT¾ Safety information and PMS¾ Translational research methodology¾ …
2. Acceptance of clinical trial staffs from other sites,that is, conducting an on-the-job training (OJT)
3. Support to clinical researchers, especially those in
the University of Tokyo Hospital, in collaboration
with the Department of Clinical and Genetic
Informatics and the Department of Clinical
Epidemiology and Systems¾ Consultation works on medical statistics andresearch methodology¾ Data center is working at our department
and stuffs are included as a biostatistician ora clinical data manager

Research activities
In addition to activities described above, we are353

developing common tool for clinical research such as
Standardized Operating Procedures (SOPs) in
conducting clinical research.
Research on Clinical Data Interchange Standards
Consortium (CDISC) in collaboration with University
Hospital Medical Information Network (UMIN) is
actively ongoing. The mission of CDISC is to develop
and support global, platform-independent data
standards
thatenableinformation
systeminteroperability to improve medical research andrelated areas of healthcare and we are challenging toconvert several academic clinical trial data to CDISC
Standards formats.

References
1. Takahashi S, Ooi J, Tomonari A, Konuma T,
Tsukada N, Oiwa-Monna M, Fukuno K,
Uchiyama M, Takasugi K, Iseki T, Tojo A,
Yamaguchi T, Asano S. Comparative singleinstitute analysis of cord blood transplantationfrom unrelated donors with bone marrow or
peripheral blood stem cell transplantation from
related donors in adult patients withhematological malignancies after myeloablative
conditioning regimen. Blood . 2007;109(3):132230.
2. Matsuyama Y, Yamaguchi T. Estimation of themarginal survival time in the presence ofdependent competing risks using inverse
probability of censoring weighted (IPCW)
methods. Pharmaceutical Statistics. In press 2007.
3. Miyakoshi S, Kami M, Tanimoto T, Yamaguchi T,
Narimatsu H, Kusumi E, Matsumura T, Takagi S,
Kato D, Kishi Y, Murashige N, Yuji K, Uchida N,
Masuoka K, Wake A, Taniguchi S. Tacrolimus
as prophylaxis for acute graft-versus-host disease
in reduced intensity cord blood transplantation for
adult patients with advanced hematologic diseases.
Transplantation. 2007;84(3):316-22.
4. Tomonari A, Takahashi S, Ooi J, Tsukada N,
Konuma T, Kato S, Kasahara S, Iseki T,
Yamaguchi T, Tojo A, Asano S. Impact ofcytomegalovirus serostatus on outcome ofunrelated cord blood transplantation for adults: asingle-institute experience in Japan. Eur J
Haematol. 2008 Mar;80(3):251-7.

5. Ushio M, Kondo K, Takeuchi N, Tojima H,
Yamaguchi T, Kaga K. Prediction of the prognosis
of Bell's palsy using multivariate analyses. Otol
Neurotol. 2008 Jan;29(1):69-72.
6. Miura Y, Yamaguchi T, Azuma T, Hamaki T,
Kodama Y, Kusumi E, Matsumura T, Nakamura T,
Kami M, Komatsu T. Regional differences exist inallogeneic stem cell transplantation rates for acuteleukemia. Int J Hematol. 2008 Feb;87(2):236-8.
7. Ushio M, Murofushi T, Chihara Y, Iwasaki S,
Yamaguchi T, Kaga K. Testing of vibratory
thresholds as a clinical examination for patientswith unsteadiness due to somatosensory disorders.
Gait Posture. 2008 May 2.
8. Narimatsu H, Miyakoshi S, Yamaguchi T, Kami
M, Matsumura T, Yuji K, Murashige N, Kusumi E,
Kodama Y, Komatsu T, Sakamaki H, Kouzai Y,
Okada M, Osugi Y, Kobayashi R, Inoue M,
Takahashi S, Kai S, Kato K, Inoue-Nagamura T,
Taniguchi S, Kato S. Chronic graft-versus-hostdisease following umbilical cord bloodtransplantation: retrospective survey involving
1,072 patients in Japan. Blood. 2008 Jun 23.
9. Yamagishi A, Morita T, Miyashita M, Akizuki N,
Kizawa Y, Shirahige Y, Akiyama M, Hirai K,
Kudo T, Yamaguchi T, Fukushima A, Eguchi K.
Palliative Care in Japan: Current Status and a
Nationwide Challenge to Improve Palliative Careby the Cancer Control Act and the Outreach
Palliative Care Trial of Integrated Regional Model(OPTIM) Study. Am J Hosp Palliat Care. 2008 Jul
3.
10. Bergmann L, Aamdal S, Marreaud S, Lacombe D,
Herold M, Yamaguchi T, Wilhelm-Ogunbiyi K,
Lentzen H, Zwierzina H. Phase I trial of r
viscumin(INN:
aviscumine)
given
subcutaneously in patients with advanced cancer:
A study of the European Organisation for
Research and Treatment of Cancer (EORTC
protocol number 13001). Eur J Cancer. 2008 Jul 2.
11. Nito T, Ushio M, Kimura M, Yamaguchi T,
Tayama N. Analyses of risk factors for
postoperative airway compromise following
arytenoid adduction. Acta Otolaryngol. 2008 May
21:1-6.
12. Homma Y, Yamaguchi T, Yamaguchi O. A
randomized, double-blind, placebo-controlled354

phase II dose-finding study of the novelanti-muscarinic agent imidafenacin in Japanesepatients with overactive bladder. Int J Urol. 2008
Jul 10.

355

Department of Computational
Diagnostic Radiology andPreventive Medicine
Project Associate Professor
Naoto Hayashi, M.D., Ph.D.,

Kansei Uno, M.D., Ph.D.,

Project Research Associate
Takeharu Yoshikawa, M.D., Ph.D.,

Mika Nagasaki, M.D., Ph.D.,

Eriko Maeda, M.D.

Homepage: http://www.h.u-tokyo.ac.jp/center22/computer.html
http://square.umin.ac.jp/cdrpm/
Introduction and Organization
The Department of Computational Diagnostic
Radiology and Preventive Medicine (CDRPM) has
been established in May 2005. It is under thesupervision of the Department of Radiology, and isfunded by Himedic Co. Ltd. and GE Yokogawa
Medical Systems, Ltd.
The aim of our research project is 1) to create alarge database of health screening clinical data
including medical images, 2) to develop methods toanalyze large volumes of medical images and to
search for algorithms to detect subtle abnormal
findings in these images, 3) to evaluate the clinicalusefulness of such image processing methods and to
apply the system in clinical settings.
The department consists of two project associate
professors and three project research associates, alongwith almost 40 people as medical staffs in thehealth-screening center

Clinical activities
CDRPM is responsible for the clinical activities in the
CDRPM Health Screening Center. In this healthscreening center, the following diagnostic imaging

modalities are installed to facilitate high level ofdiagnostic accuracy: positron emission computed
tomography / X-ray computed tomography (PET/CT),
3-tesla magnetic resonance imaging systems (3T-MRI),
ultrasound imaging systems, digital mammography

Teaching activities
At present, CDRPM do not accept students of any
kind. However, CDRPM participates in education of
the students and the residents in the Department ofRadiology. CDRPM endeavor to help students thathave research themes on image analysis such as
computer-assisted detection, or on epidemiologic
studies employing health-screening data.

Research activities
1) Health screening database
We have developed a unique health screening
information system in order to facilitate daily
management of the health screening activities and to
input the health screening data. This information
system is still under constant revision. The medical
images acquired in the health screening are stored in
the hospital PACS for clinical use. Medical images

356

used solely for research purposes are stored in an
independent PACS installed inside the CDRPM
department.
2) Image processing software development
We have structured an integrated software developing
system to facilitate the production of image processing
soft wares. The system is divided into the clinical partand the research part, with the data in the latter being
anonymized. The clinical part consists of case entry
for soft ware development, and clinical application of
the developed soft ware. The research part consists ofan interface to obtain the images of the representative
cases to develop the software, and an interface to test
the developed software with the accumulated cases.
3) Clinical evaluation and application of software,
epidemiological studies
Researches based on the health-screening database arecarried out in collaboration with other researchers ofvarious specialties. Images are analyzed employing
the developed software.

References
1) Nishimura S, Seo K, Nagasaki M, Hosoya Y,
Yamashita H, Fujita H, Nagai R, Sugiura S.
Responses of single ventricular myocytes todynamic axial stretching. Progress in Biophysics& Molecular Biology, 2008 in publication.
2) Nishimura S, Manabe I, Nagasaki M, Seo K,
Yamashita H, Hosoya Y, Ohsugi M, Tobe K,
Kadowai T, Nagai R, Sugiura S. In vivo imaging
im mice reveals local cell dynamics andinflammation n obese adipose tissue. J Clin Invest.
2008, 118(2): 710-721.
3) Sonoda M, Aoyagi T, Takenaka K, Uno K, Nagai
R. A One-Year Study of the Antiatherosclerotic
Effect of the Angiotensin-II Receptor Blocker
Losartan in Hypertensive Patients. Int Heart J.
2008 Jan;49(1):95-103.
4) Sonoda M, Takenaka K, Uno K, Ebihara A, Nagai
R. A larger aortic annulus causes aortic regurgitation and a smaller aortic annulus causes aortic
stenosis in bicuspid aortic valve. Echocardiography. 2008 Mar;25(3):242-8.
5) Nishimura S, Manabe I, Nagasaki M, Hosoya Y,
Yamashita H, Fujita H, Ohsugi M, Tobe K,
Kadowaki T, Nagai R, Sugiura S. Adipogenesis in

obesity requires close interplay between
differentiating adipocytes, stromal cells and bloodvessels. Diabetes. 2007,56:1517-1526.
6) Nishimura S, Manabe I, Nagasaki M, Hosoya Y,
Kadowaki T, Nagai R, Sugiura S. Adipose Tissue
Remodeling and Malfunctioning in Obesity
Revealed by in vivo Molecular Imaging Bioimages 2007,15:9-15.
7) Iida H, Kurano M, Takano H, Kubota N, Morita T,
Meguro K, Sato Y, Abe T, Yamazaki Y, Uno K,
Takenaka K, Hirose K, Nakajima T. Hemodynamic
and neurohumoral responses to the restriction offemoral blood flow by KAATSU in healthy
subjects. Eur J Appl Physiol. 2007 Jun;100(3):275-85. Epub 2007 Mar 7.
8) Kabasawa H, Masutani Y, Aoki S, Abe O,
Masumoto T, Hayashi N, Ohtomo K. 3T
PROPELLER diffusion tensor fiber tractography:
a feasibility study for cranial nerve fiber tracking.
Radiat Med 2007;25(9):462-6.
9) Kiryu S, Takeuchi K, Shibahara J, Uozaki H,
Fukayama M, Tanaka H, Maeda E, Akahane M,
Ohtomo K. Epstein-Barr Virus-positive Inflammatory
Pseudotumour
andInflammatory
Pseudotumour-like Follicular Dendritic Cell
Tumour: case report and review of the literature
British Journal of Radiology, in press.

University Hospital
Central Clinical Facilities

University Hospital
Clinical Divisions

359

Department of Clinical Laboratory
Professor
Yutaka Yatomi, M.D.

Associate Professor
Hitoshi Ikeda, M.D.

Lecturer
Katsu Takenaka, M.D.,

Tatsuo Shimosawa, M.D.

Daiya Takai, M.D.,

Masato Yumoto, M.D.

Associate
Yukako Koike, M.D.,

Aya Ebihara, M.D.,

Makoto Kaneko, M.D.

Chief Technologist
Hiromitsu Yokota, Ph.D.

Homepage

http://lab-tky.umin.jp/

Introduction and Organization
Clinical Laboratory Center consists of 11 doctors, achief technologist, 63 technicians, and 2 nurses, and isdivided into the following sections. The second generation Laboratory Automation System is in fulloperation, and ordering of laboratory tests, the flow ofsamples, operation of laboratory analyzers, quality
control of analysis, and data reporting are allcontrolled by the Laboratory Automation computer
system.
This system has greatly improved thequality, safety, and efficiency of the laboratory andcontributed to both patients and doctors by providing
rapid and high-quality laboratory testing.
The 1st Section
This section deals mainly with the maintenance oflaboratory system and blood and urine sampling. In
2007, 224,184 outpatient blood sampling were
performed in this section.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2007, over 3,998,852

serum enzyme tests (such as AST and ALT), and441,042 immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology and
DM-related tests, gene analysis tests and urinalysis.
In 2007, 937,180 samples were examined forcomplete blood cell counts, cell surface marker
analysis, prothrombin time, fibrinogen, glucose, and
HbAIC tests, and 207,166 urine samples were
examined.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2007, 41,363 ECG, 20,239
pulmonary function tests, 18,207 echocardiography
tests, 14,539 abdominal echography tests, and 10,352
EEG were performed.
The Hospital Ward Section
This section has been recently founded and is incharge of laboratory tests, mainly ECG, forseriously-ill, hospitalized patients. In the future, this

360

section is going to be further expanded since there isso much demand from clinical doctors.

Teaching activities
Lectures are given to the fourth and fifth grade
medical students on clinical tests including
hematology, chemistry, endocrinology, immunology,
bacteriology, cardiology, and pulmonary function.
The reversed CPC program is presented to the fifthand sixth grade students. Laboratory practice teachingis provided for the fifth year medical students, insmall groups of 6-7 students for one-week duration.
In this course, students learn clinical and practicalknowledge and techniques on various laboratory tests.
Students from professional schools also study
laboratory medicine under the guidance of members inClinical Laboratory Center.

3.

4.

5.
Research activities
The main goal of our research projects is thedevelopment of new and useful laboratory tests, andelucidation of pathophysiology of diseases throughlaboratory tests. The areas included are: i)(Patho)physiological roles of lysophospholipid
mediators and its application into laboratory medicine,ii) platelet biology, iii) the clinical significance ofreticulated platelets and immature platelet fraction, iv)
hepatic fibrosis and ischemic reperfusion injury of theliver, v) genetic testing, vi) bioactive peptides,
especially adrenomedullin, vii) oxidative stress andorgan injury, viii) analysis of cardiac functions using
ultrasound, ix) elucidation of abnormality inepigenetics in cancer and its clinical application, andx)analysisofbrainfunctionusing
magnetoencephalographyandnear-infrared
spectroscopy.

6.

7.

8.

References
1. Aoki, S., Osada, M., Kaneko, M., Ozaki, Y., andYatomi, Y. Fluid shear stress enhances thesphingosine 1-phosphate responses in cell-cellinteractions between platelets and endothelial
cells. Biochem. Biophys. Res. Commun. 358:
1054-1057, 2007.
2. Aoki, S., Yatomi, Y., Shimosawa, T., Yamashita,

9.

H., Kitayama, J., Tsuno, N.H., Takahashi, K., andOzaki, Y. The suppressive effect of sphingosine
1-phosphate on monocyte-endothelium adhesion
may be mediated by the rearrangement of theendothelial
integrinsalpha(5)beta(1)andalpha(v)beta(3). J. Thromb. Haemost. 5: 12921301, 2007.
Arai, M., Tejima, K., Ikeda, H., Tomiya, T.,
Yanase, M., Inoue, Y., Nagashima, K., Nishikawa,T., Watanabe, N., Omata, M., and Fujiwara, K.
Ischemic preconditioning in liver pathophysiology.
J. Gastroenterol. Hepatol. 22 Suppl 1: S65-67,
2007.
Cuyun-Lira, O., Kaneko, M., Takafuta, T., Satoh,K., Ohnishi, M., Yatomi, Y., and Ozaki, Y.
Inhibitory effects of ticlopidine on platelet
function as assessed by three different methods.
Eur. J. Pharm. Sci. 30: 21-25, 2007.
Hirano, Y., Tsunoda, M., Shimosawa, T., Fujita, T.,
and Funatsu, T. Measurement of catecholO-methyltransferase activity in the brain of Dahl
salt-sensitive rats. Biol. Pharm. Bull. 30:
2178-2180, 2007.
Hirano Y, Tsunoda M, Shimosawa T, Matsui H,
Fujita T, Funatsu T. Suppression of COMT
activity through blunting alpha2-adrenoceptor can
explain hypertension in Dahl salt-sensitive rats.
Hypertens. Res. 30: 269-278, 2007.
Iida, H., Kurano, M., Takano, H., Kubota, N.,
Morita, T., Meguro, K., Sato, Y., Abe, T.,
Yamazaki, Y., Uno, K., Takenaka, K., Hirose, K.,andNakajima,
T.
Hemodynamic
andneurohumoral responses to the restriction offemoral blood flow by KAATSU in healthy
subjects. Eur. J. Appl. Physiol. 100: 275-285,
2007.
Ikeda, H., Kume, Y., Tejima, K., Tomiya, T.,
Nishikawa, T., Watanabe, N., Ohtomo, N., Arai,
M., Arai, C., Omata, M., Fujiwara, K., and Yatomi,
Y. Rho-kinase inhibitor prevents hepatocyte
damage in acute liver injury induced by carbon
tetrachloride in rats. Am. J. Physiol. Gastrointest.
Liver Physiol. 293: G911-917, 2007.
Kawanabe, T., Kawakami, T., Yatomi, Y., Shimada,S., and Soma, Y. Sphingosine 1-phosphate
accelerates wound healing in diabetic mice. J.
Dermatol. Sci. 48: 53-60, 2007.

361

10. Kimura, A., Ohmori, T., Ohkawa, R., Madoiwa, S.,
Mimuro, J., Murakami, T., Kobayashi, E.,
Hoshino, Y., Yatomi, Y., and Sakata, Y. Essential
Roles of Sphingosine 1-Phosphate/S1P1 Receptor
Axis in the Migration of Neural Stem Cells
Toward a Site of Spinal Cord Injury. Stem Cells
25: 115-124, 2007.
11. Kume, Y., Ikeda, H., Inoue, M., Tejima, K.,
Tomiya, T., Nishikawa, T., Watanabe, N.,
Ichikawa, T., Kaneko, M., Okubo, S., Yokota, H.,
Omata, M., Fujiwara, K., and Yatomi, Y. Hepatic
stellate cell damage may lead to decreased plasma
ADAMTS13 activity in rats. FEBS Lett. 581:
1631-1634, 2007.
12. Lin, J.C., Jeong, S., Liang, G., Takai, D., Fatemi,M., Tsai, Y.C., Egger, G., Gal-Yam, E.N., andJones, P.A. Role of nucleosomal occupancy in theepigenetic silencing of the MLH1 CpG island.
Cancer cell 12: 432-444, 2007.
13. Liu, J., Shimosawa, T., Matsui, H., Meng, F.,
Supowit, S.C., Dipette, D.J., Ando, K., and Fujita,
T. Adrenomedullin inhibits angiotensin II-induced
oxidative stress via Csk-mediated inhibition of
Src activity. Am. J. Physiol. Heart Circ. Physiol.
292: H1714-1721, 2007.
14. Marumo, T., Hishikawa, K., Matsuzaki, Y., Imai,N., Takase, O., Shimosawa, T., Okano, H., andFujita, T. Angiotensin II type 1 receptor blockade
prevents decrease in adult stem-like cells inkidney after ureteral obstruction. Eur. J.
Pharmacol. 573: 216-220, 2007.
15. Nagai, S., Ichikawa, M., Takahashi, T., Sato, H.,
Yokota, H., Oshima, K., Izutsu, K., Hangaishi, A.,
Kanda, Y., Motokura, T., Chiba, S., Yatomi, Y.,
and Kurokawa, M. The origin of neoplastic mastcells
insystemic
mastocytosis
with
AML1/ETO-positive acute myeloid leukemia.
Exp. Hematol. 35: 1747-1752, 2007.
16. Nakamura, K., Kishimoto, T., Ohkawa, R., Okubo,
S., Tozuka, M., Yokota, H., Ikeda, H., Ohshima,N., Mizuno, K., and Yatomi, Y. Suppression oflysophosphatidic acid and lysophosphatidylcholine formation in the plasma in vitro: Proposalof a plasma sample preparation method forlaboratory testing of these lipids. Anal. Biochem.
367: 20-27, 2007.
17. Nakamura, K., Ohkawa, R., Okubo, S., Tozuka,

M., Okada, M., Aoki, S., Aoki, J., Arai, H., Ikeda,
H., and Yatomi,Y.
Measurementoflysophospholipase D/autotaxin activity in humanserum samples. Clin. Biochem. 40: 274-277,
2007.
18. Nakamura, K., Takeuchi, T., Ohkawa, R., Okubo,
S., Yokota, H., Tozuka, M., Aoki, J., Arai, H.,
Ikeda, H., Ohshima, N., Kitamura, T., and Yatomi,
Y. Serum lysophospholipase D/autotaxin may be a
new nutritional assessment marker: study on
prostate cancer patients. Ann. Clin. Biochem. 44:
549-556, 2007.
19. Nishikawa, T., Tomiya, T., Ohtomo, N., Inoue, Y.,
Ikeda, H., Tejima, K., Watanabe, N., Tanoue, Y.,
Omata, M., and Fujiwara, K. Stimulation by
glutamine and proline of HGF production in
hepatic stellate cells. Biochem. Biophys. Res.
Commun. 363: 978-982, 2007.
20. Osada, M., Yatomi, Y., Ohmori, T., Aoki, S.,
Hosogaya, S., and Ozaki, Y. Involvement of
sphingosine 1-phosphate, a platelet-derived
bioactive lipid, in contraction of mesangium cells.
J. Biochem. 142: 351-355, 2007.
21. Sano, A., Kage, H., Sugimoto, K., Kitagawa, H.,
Aki, N., Goto, A., Fukayama, M., Nakajima, J.,
Takamoto, S., Nagase, T., Yatomi, Y., Ohishi, N.,
and Takai, D. A second-generation profilingsystem for quantitative methylation analysis ofmultiple gene promoters: application to lungcancer. Oncogene 26: 6518-6525, 2007.
22. Satoh, Y., Ohkawa, R., Nakamura, K., Higashi, K.,
Kaneko, M., Yokota, H., Aoki, J., Arai, H., Yuasa,
Y., and Yatomi, Y. Lysophosphatidic acidprotection against apoptosis in the humanpre-B-cell line Nalm-6. Eur. J. Haematol. 78:
510-517, 2007.
23. Shimosawa, T., Gohchi, K., Yatomi, Y., and Fujita,
T. Effectiveness of add-on low-dose diuretics incombination
therapyfor
hypertension:
losartan/hydrochlorothiazide vs. candesartan/
amlodipine. Hypertens. Res. 30: 831-837, 2007.
24. Sugimoto, K., Kage, H., Aki, N., Sano, A.,
Kitagawa, H., Nagase, T., Yatomi, Y., Ohishi, N.,
and Takai, D. The induction of H3K9 methylation
by PIWIL4 at the p16(Ink4a) locus. Biochem.
Biophys. Res. Commun. 359: 497-502, 2007.
25. Suzuki-Inoue, K., Hughes, C.E., Inoue, O.,362

Kaneko, M., Cuyun-Lira, O., Takafuta, T., Watson,
S.P., and Ozaki, Y. Involvement of Src kinases and
PLCgamma2 in clot retraction. Thromb. Res. 120:251-258, 2007.
26. Suzuki-Inoue, K., Kato, Y., Inoue, O., Kaneko,
M.K., Mishima, K., Yatomi, Y., Yamazaki, Y.,
Narimatsu, H., and Ozaki, Y. Involvement of the
Snake Toxin Receptor CLEC-2, in Podoplaninmediated Platelet Activation, by Cancer Cells. J.
Biol. Chem. 282: 25993-26001, 2007. “Paper ofthe Week”
27. Tejima, K., Arai, M., Ikeda, H., Tomiya, T.,
Yanase, M., Inoue, Y., Nishikawa, T., Watanabe,N., Ohtomo, N., Omata, M., and Fujiwara, K.
Induction of ischemic tolerance in rat liver via
reduced nicotinamide adenine dinucleotide
phosphate oxidase in Kupffer cells. World J.
Gastroenterol. 13: 5071-5078, 2007.
28. Tomiya, T., Nishikawa, T., Inoue, Y., Ohtomo, N.,
Ikeda, H., Tejima, K., Watanabe, N., Tanoue, Y.,
Omata, M., and Fujiwara, K. Leucine stimulates
HGF production by hepatic stellate cells throughmTOR pathway. Biochem. Biophys. Res.
Commun. 358: 176-180, 2007.
29. Tomiya, T., Yamaoka, M., Inoue, Y., Nishikawa,T., Yanase, M., Ikeda, H., Tejima, K., Nagashima,K., Watanabe, N., Omata, M., and Fujiwara, K.
Effect of rapamycin on hepatocyte function andproliferation induced by growth factors.
Chemotherapy 53: 59-69, 2007.
30. Yamauchi, Y., Fujikura, T., and Shimosawa, T.
The Effect of H1 Antagonists Carebastine andOlopatadine on Histamine Induced Expression of
CC Chemokines in Cultured Human Nasal
Epithelial Cells. Allergol. Int. 56: 171-177, 2007.
31. Watanabe, N., Ikeda, H., Nakamura, K., Ohkawa,
R., Kume, Y., Aoki, J., Hama, K., Okudaira, S.,
Tanaka, M., Tomiya, T., Yanase, M., Tejima, K.,
Nishikawa, T., Arai, M., Arai, H., Omata, M.,
Fujiwara, K., and Yatomi, Y. Both Plasma
Lysophosphatidic Acid and Serum Autotaxin
Levels are Increased in Chronic Hepatitis C. J.
Clin. Gastroenterol. 41: 616-623, 2007.
32. Watanabe, N., Ikeda, H., Nakamura, K., Ohkawa,
R., Kume, Y., Tomiya, T., Tejima, K., Nishikawa,T., Arai, M., Yanase, M., Aoki, J., Arai, H., Omata,M., Fujiwara, K., and Yatomi, Y. Plasma

lysophosphatidic acid level and serum autotaxin
activity are increased in liver injury in rats inrelation to its severity. Life Sci. 81: 1009-1015,
2007.

363

Surgical Center
Director (Professor)
Hiroshi Yasuhara M.D., Ph.D.

Associate Professor
Yoshikazu Mimura, M.D., Ph.D.
Yushi Uetera, M.D., Ph.D.

Lecturer
Takami Komatsu, M.D., Ph.D.
Ryoji Fukushima, M.D., Ph.D.

Associate
Toshihiko Obayashi, M.D., Ph.D.
Saito Yuhei, Ph.D.

Homepage
Introduction and Organization
Operating rooms were centralized for the first timein Japan in the University of Tokyo Hospital on July
1955. Surgical center was located in the surgical ward
building till December 1987. The center moved to the
new central building on January 1988, when the surgical center had 14 operating rooms, including one
bio-clean room. The administration staffs consisted of
5 doctors, 54 nurses, 6 technical officials, 6 part-time
employees. The surgical center became to afford services to 18 clinical departments after the new surgicalcenter started.
The total number of operations did not apparently
increase between 1999 and 2000, partly because of theshortage in the number of operating rooms and nursing staffs.
In July 2001, the branch hospital, which was located in Mejiro, merged to the University of Tokyo
Hospital in Hongo and a new ward building opened in
October 2001. Then, the number of operations remarkably increased and became over 7500. Anothermanagement effort was made to enforce the availability of the operating rooms. Two new operating rooms

were tentatively used to overcome the tremendous
increase in the number of operations. The one is on
the ICU/CCU/HCU floor in the new ward building
and the other room was in the outpatient building,which had been used for the orthopedic patients. This
operating room was used for the short-stay and day
surgery of orthopedics as well.
Until September 2001, the elective operations had
been performed daily in 9 operating rooms on average.
Then after October 2001, 12 operating rooms began to
be used for elective operations. The number of operations annually increased thereafter. Some 8,013 (1,129
emergency cases) were performed in 2005.
Most recently, in the year 2007, most newest central
building, which had 11 operating rooms, is open tosolve the problem of the chronic shortage of theavailable operating rooms. As a result, the total number of operating rooms became 23, and then the number of operations has been dramatically increased. A
total of 8,322 and 9,374 operations, which is 1.5 times
comparing to those in 2001, were performed in oursurgical center in 2006 and 2007, respectively.
Recently, we have been concerned about the an apparent increase in the patients with positive results of

364

the preoperative microbiological test such as tuberculosis, MRSA, pseudomonas aeruginosa, HBV, HCV
and HIV. Those patients have been increasing by
5-18% per year over the last 4 years. More and moreadministrative efforts might be needed to protect thestaffs as well as the patients as the new infectious
agent such as prion may be found in the near future.

Activities of Surgical Center
Our work covers from the management of operation
schedule to the teaching and research.

Management of Surgical CenterAll operations of in-patients are performed in 23
operating rooms of the surgical center. Computer system has been introduced in order to deal with the information on the operation. In May 1999, on-line
computer system was introduced for ordering systemof the elective and emergency operations. Then, all theoperations have been ordered through the computer
terminal set up at each clinical department since May
l999. The doctors and nurses became to be able tomanage postoperative information as well through thecomputer system since March 2000.
For the efficient management of operation, the information on the status of the operations has been displayed on the computer monitor screen since May
1997. This monitor screen also gives the every hospital staff the information whether there are any operating rooms available on the next day. Furthermore,since November 2000, the hospital staffs became to beable to see how each clinical department plans to use
the operating rooms on the next week through thehospital computer network.
Digitalized visual information such as photographsof operative fields and resected organs has been distributed to each clinical department through hospitalcomputer network since February 1997. Moreover,real-time monitoring visual information of the operative fields has been distributed to each clinical department through the hospital computer network sinceJune 1999.
In the new ward building SPD and progressive patient care system started for the management of our
hospital in October 2001. Then, the SPD system wasintroduced for the surgical center in September 2002.
The complicated surgical procedures including organ transplantation microvascular surgery, cardiovascular surgery, minimally invasive surgery and orthopedic surgery have recently increased dramatically. In
addition, more and more patients recently underwent
surgery using artificial implants such as vascular
prosthesis, joint prosthesis and intraocular lenses.
The advanced techniques have been employed in
the operating rooms. Those include navigation surgery
in neurosurgical, orthopedic and ENT (ear, nose andthroat) operations, and arterial stent for the thoracic
aortic aneurysms. The minimally invasive surgery
such as MIDCAB operations is also performed in the
CABG as well as a in the treatment of heart anomalies
such as ASD and VSD. In addition, organ transplantation and intraoperative three-dimensional echo-guided
surgery are performed in the surgical center.
Another recent trend is the presence of emergenceand re-emergence infectious diseases such as HIV andtuberculosis among the operated patients. Therefore, it
is mandatory to educate how to prevent nosocomial
and occupational infections in the surgical center. For
instance, the principles of standard precautions andtransmission-based precautions should be taught to all
health care staffs in the surgical center.
The number of immune-compromised hosts andcomplex surgical procedures will continue to increase
throughout the 21 century. Therefore, the surgicalcenter ought to be playing an important role because
the improvement of the management skill is mandatory to meet the increase in the perioperative healthcare services for those patients.

Teaching Activities
The following lectures are given to the undergraduates and postgraduates: aseptic techniques, sterilization methods, disinfection methods, prevention of perioperative infections, humoral and cellular responses
to trauma and shock, training of scrubbing and gown
techniques, Curriculum is updated every year. For
example, introductory course for disinfection, sterilization and preservation of surgical instruments andmedical devices was added in the training courses in
1998, which gained interest and popularity among
students.

365

In the surgical center, the innovative surgical instruments and medical devices are recently introduced
to perform highly advanced operations such as in thenavigation surgery, transplantation surgery, cardiovascular surgery and so forth. Consequently, education
has become one of the most important activities in thesurgical center. The lectures of advanced technologies
are in the curriculum for the surgeons, nursing staffs
and medical electronics engineers so that they canunderstand how to use them properly.
Lectures for the nursing staffs consist of a freshmancourse and an advanced course. The freshman course
is a basic training course as a scrub nurse and a circulating nurse. It consists of lectures of aseptic techniques, de-contamination methods, sterilization methods, prevention of perioperative infections, andtraining of scrubbing and gown techniques as wall as
aseptic preparation of surgical instruments in the operating room. An advanced course is also prepared tothe experienced nurses. The purpose of this course is
to upgrade their perioperative nursing skills so thatthey can afford full nursing skills in the complex surgical procedures such as transplantation surgery,open-heart surgery and neurosurgery.
There is also a training course to medical electronics engineers and students of medical electronics. This
training course consists of introduction on the medical
electronic instruments and devices, precautions ofaccidental troubles in handling surgical instruments
and medical devices, development of new surgicalinstruments and medical devices, cardiopulmonary
bypass techniques and illumination techniques in theoperating fields. The contents of this course are summarized in the manual for the nursing staffs and contribute to decrease the number of accidents in handling surgical instruments and medical devices.
The on-job training are given to the non-nursing
staffs such as technical officials and temporary employees and performed when they start their careers inthe surgical center. They are lectured on aseptic techniques, sterilization methods, disinfection methods,
prevention of perioperative infections and how tocheck the faults in the reusable surgical instruments
such as forceps, scissors and clamps. These contents
are summarized in the manual. Lectures are also given
to senior technical officers and temporary employees
to upgrade their technical knowledge and skills.

Research Activitiesl)Safety management of the surgical treatments inthe operation center2) Introduction of IT technology in the managementof surgical center3) Improvement of cost-effectiveness in the management of surgical center and international comparison of effectiveness in the management ofsurgical center
4) Precautions of accidental troubles in the handlingsurgical instruments and medical devises5) Introduction of aseptic environment in the operating theaters
6) Perioperative infection control of patients undergoing operations and prevention of occupational
infection of medical staffs working in the surgicalcenter7) Development of new sterilization methods8) Improvement of cost-effectiveness in sterilizationand preservation of medical instruments and introduction of international standardization of sterilization methods8) Cost-effectiveness analysis of disposable and reusable surgical instruments
9) Development of new surgical instruments andmedical devisesl0) Improvement of minimally invasive surgery andmicrosurgery11) Three dimensional processing of visual information
12) Computer assisted surgery13) Computer assisted anesthesia
14) Inter-hospital visual communications via satellite
systemReferences（2005-2006）
1. Hayashida M, Kin N, Tomioka T, Orii R, Sekiyama H, Usui H, Chinzei M, Hanaoka K: Cerebral
ischaemia during cardiac surgery in children detected by combined monitoring of BIS and nearinfrared spectroscopy. Br J Anaesth 92: 662-9,
2005
2. Hatao F, Hiki N, Mimura Y, Ogawa T, Kojima J,
Mafune K, Hawkins LD, Muroi M, Tanamoto K,
Kaminishi M: The induction of super-resistance366

using synthetic lipopolysaccharide receptor agonist rescues fatal endotoxemia in rats without excessive immunosuppression. Shock 23: 365-370,
2005
3. Uetera Y, et al. A simple method to perform vacuum leak test in the prevacuum autoclave without
the automatic test mode. PDA Journal of GMP
and Validation in Japan 7, pp146-149, 2005
4. Yasuhara H. Acute mesenteric ischemia: The
challenge of gastroenterology. Surgery today 35:
185-95, 2005
5. Yasuhara H, Niwa H, Takenoue T, Naka S. Factors
influencing mortality of acute intestinal infarction
associated with SIRS. Hepatogastroenterology 52:
1474-8, 2005
6. Yasuhara H, Ohara N, Hattori T, Shigeta O. Importance of combination of persistent underlying
factors in deep vein thrombosis. Int Angiol 26(suppl) 79, 2007.
7. Furuya Y, Yasuhara H, Yanagie H, Naka S, Takenoue T, Shinkawa H, Niwa H, Kikuchi T, Nagao.
Role of Ganglion Cells in Sigmoid Volvulus.
World J Surg 29:88-91, 2005
8. Sotome K, Onishi T, Hirano A, Nakamaru M, Furukawa A, Miyazaki H, Morozumi K, Tanaka Y,
Iri H, Mimura Y. A rare case of anaplastic transformation within the metastatic site of the retroperitoneal region in a patient 17 years after total
thyroidectomy for papillary carcinoma of the thyroid beginning with multiple bone metastases.
Thyroid 17: 1309-1311, 2007
9. Kuwabara K, Nishishita T, Morishita M, Oyaizu N,
Yamashita S, Kanematsu T, Obara T, Mimura Y,
Inoue Y, Kaminishi M, Kaga K, Amino N, Kitaoka M, Ito K, Miyauchi A, Noguchi S, Uchimaru K, Akagawa E, Watanabe N, Takahashi TA,
Sato K, Inazawa T, Nakaoka T, Yamashita N. Results of a phase I clinical study using dendritic
cell vaccinations for thyroid cancer. Thyroid 17:
53-58, 2007
10. Ogawa T, Tsuji E, Kanauchi H, Yamada K, Mimura Y, Kaminishi M. Excision of postesophageal
parathyroid adenoma in posterior mediastinum
with intraoperative 99mTechnetium sestamibi
scanning. Ann Thorac Surg 84: 1754-1756, 2007
11. Ogawa T, Kammori M, Tsuji E, Kanauchi H, Kurabayashi R, Terada K, Mimura Y, Kaminishi M.

Preoperative evaluation of thyroid pathology inpatients with primary hyperparathyroidism. Thyroid 17: 59-62, 2007

367

Department of Clinical Radiology
Professor (department manager)
Kuni Ohtomo, M.D.,Ph.D.

Lecturer (vice manager)
Tomohiko Masumoto, M.D.,Ph.D.

Research Associate
Shinichi Inoh, M.D.

Homepage

http://www.ut-radiology.umin.jp/

Introduction and Organization
In the Department of Clinical Radiology, clinicalservices on Diagnostic Radiology (imaging and intervention), Radiation Oncology (radiotherapy), Nuclear
Medicine and the Radiation Safety Control System areprovided in cooperation with radiology technologists
and nurses. Present constituent members are as follows: three medical doctors, 52 radiological technicians, 2 assistants, 18 nurses, and 1 technical officialof the radiation control. The staff members of the Department of Radiology (teachers, the graduate school
students, medical staffs, and the clinical trainees) join
this. In addition, the doctors and the nurses of otherclinical departments cooperate and are also engaged in
the clinical radiology activities. The educational
training and registration of the radiation engaging
persons are controlled according to the University ofTokyo Hospital Ionizing Radiation Injury Prevention
Rules.
Department of Clinical Radiology covers four major fields: (1) Diagnostic Radiology, (2) Radiation
Oncology, (3) Nuclear Medicine and (4) the Radiation
Safety Control System. The Diagnostic Radiology
Section is mainly operated at the first floor in theCentral Clinic Building 1. Parts of the diagnostic activities are done at the Central Clinic Building 2 (theMR rooms, the operation rooms, and the emergency
department) and some other clinical departments. The

services provided are X-ray imaging, fluoroscopic
imaging, computed tomography (CT), magnetic resonance imaging (MRI) and angiography. Radiation
Oncology Section is operated at third basement floorof the Central Clinic Building 2. The outpatient clinic
is also located here and not in the Outpatient Clinic
building. The methods of therapy provided are linear
accelerator (LINAC), gamma-knife, Remote After
Loading System (RALS) and Brachytherapy (Radioactive Seed Implantation Therapy). Nuclear Medicine
Section is operated at the basement floor of the Central Clinic Building 1. The methods of examination
provided are conventional scintigram, SPECT and
PET. The office of Radiation Safety Control System islocated at the third floor of the old Central Clinic
Building.
Department of Clinical Radiology is actively participating in the following projects. 1) PACS: We haverecently developed a radiology information system(RIS) networking with hospital information system(HIS) and PACS (picture archiving and communicating system). The PACS of the whole hospital (thefilm-less imaging system) was established in 2003.
The new reporting system was installed in 2002. 2)
Radiation Safety Control: Stimulated by the need forevaluating the individual accumulated exposure doseby medical radiation, we have started a working group
to solve this problem. We aim to provide the accumulated exposure dose data on RIS. 3) Image Computing

368& Analysis Laboratory: The clinical section of thisproject is located at the reading room in the Diagnostic Radiology Section. The main services are processing of volume image data into clinical 3D-images andanalysis of imaging data. 4) Researches on new radiology techniques: Ongoing collaborative researches
are as follows: image-guided radiation therapy, clinical PET, multi-detector row CT, 3-Tesla MRI, flat
panel detector.

Clinical activities
1) Diagnostic Radiology:
The section of diagnostic radiology is responsible
for all the clinical examinations of CT, MRI, and angiography and vascular interventional procedures except for cardiac and peripheral arterial studies. All ofthese examinations are performed under the requests
of clinicians. Over one hundred and fifty CT examinations are performed using five MDCT scanners eachday. Interventional procedure such as percutaneous
biopsy and abscess drainage are also done by CT
guidance. About fifty MR examinations are done using 1.5-Tesla and 3-Tesla scanners every day. About
six angiographies, most of which are interventional
procedures including arterial embolization, arterial
infusion therapy, arterial infusion port placement, andangioplasty, are done by the radiologists using two
angiographic units.
In clinical research works, efficacy of MDCT has
been investigated in all parts from the head to extremities. New three-dimensional approaches havebeen also developed. Clinical research and basic animal experiments are in progress in the field of functional MR imaging and diffusion and perfusion MR
techniques.
2) Radiation Oncology:
The radiation therapy is performed with two linear
accelerators, an intracavitary irradiation device(RALS), and a gamma knife for radiosurgery. The
network system connecting these radiotherapy equipments, CT/MR devices, and treatment planning systems was already constructed. Each year, over 700
new patients receive radiation therapy in the Radiation
Oncology section. Highly accurate 3D radiation therapy is the most outstanding feature. We have devel-

oped a new linear accelerator with C-arm and multileaf collimator systems, which is utilized mainly for
non-coplanar radiation therapy in many patients especially with brain tumor or head and neck tumor. The
rate of the non-coplanar radiation therapy is over 25%
and surpasses those of other institutions. Recently, a
new linear accelerator system with cone-beam CT
technology was introduced to our hospital, which enabled image-guided radiation therapy.
3) Nuclear medicine:
Positron Emission Tomography (PET) and Single
Photon Emission Computed Tomography (SPECT) are
the main activities in the clinical and research work.
These nuclear imaging procedures are chiefly performed and reported by radiologists and cardiologists.
Cerebral blood flow, glucose metabolism and neuralsynaptic functions are measured for the understandingof normal and pathophysiological states of CNS disorders, using a variety of positron-emitter radiotracer,such as [O-15] H2O, CO2, O2, CO, [F-18] FDG, [C-11]
methionine, [F-18] Dopa, [C-11] NMSP, NMPB and[C-11] raclopride. The study of dementia using
SPECT and the standard brain atlas has made it possible to categorize the type of dementia. Evaluation of
dopaminergic function by PET is very important in the
differential diagnosis of Parkinsonism. Cardiac PET
and SPECT are also active fields. Myocardial viability,
vascular reserve and sympathetic nerve denervation in
the ischemic heart disease are evaluated with [F-18]
FDG, [N-13] NH3, Tl-201 and [I-123] MIBG. Higher
brain functions such as reading, speech and thinking
have been studied with PET by comparing blood flow
and receptor binding potential (BP) under various
tasks and at rest. For the precise localization of activated brain function, computer processing and reconstruction of composite images of function and anatomy is an essential subject for investigation. Wholebody FDG-PET is one of the most promising studies
for exploring metastatic lesions of cancer patients.
Combination display of SPECT/PET with XCT/MRI
would be a routine job and anatomo-functional images
would play an important role in the clinical management of the patients.
In conclusion, the department of clinical radiology
is a service section to all clinical departments. Main

369

supporter as the doctor is a radiologist. However, thecooperation with the radiation diagnosis and treatment
engaging persons of other clinical departments, technicians and nurses must be reinforced. We want tomake still more effort to achieve the cooperation andimprove clinical activities in the department of clinical radiology.

References
See the corresponding part of the department ofRadiology.

370

Delivery Unit
Professor
Takashi Igarashi

Lecturer
Yoshimasa Kamei

Homepage

http://www.iiosan.umin.jp/index.html

Organization
The Delivery Unit of the University of Tokyo Hospital is organized by one professor, one associate, and5-10 fellows. All the staff members are taking part inresearch activities of reproductive endocrinology, gynecologic oncology, or perinatal medicine, as well as
being engaged with in-patient and out-patient care forpregnant women including the activities in the delivery units.

Activities
Total number of delivery cases was 797 in 2007,
617 in 2006.
Recently, cases of obstetrical emergencies like abruptio placentae, eclampsia and uterine rupturestransported from neighboring hospitals have been increasing. Two or three doctors and three midwives areon duty every night. Our service is an important partof Tokyo Metropolitan Service System for Maternal
Welfare and Perinatal Medicine.

References from April 2005 to
March 2007
[See Department of Perinatal Medicine.]

371

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Associate
Takashi Maeno, M.D.,

Shun-ichi Furukawa, M.D.

Toshihiro Arao, M.D.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The physical therapy service started in 1963 at the
University of Tokyo Hospital, and then expanded toinclude occupational therapy and social work section.
In 1966 this service was converted to the central rehabilitation service department as a part of the Central
Diagnostic and Therapeutic Service Department. The
Central Rehabilitation Service became an independent
unit in 1970. After the reorganization of the Universityof Tokyo Hospital according to major organic classification in 1998, outpatient clinic as rehabilitation
medicine was installed. The formal title of our unit
was changed from the Physical Therapy Department
to the Rehabilitation Department by the budget measures in the fiscal year 2001, and we integrated the related personnel categories, which belonged to the orthopedic surgery department and the physical medicine department.
At the present time our department consists of four
sections. Rehabilitation physicians’ section includes
three full-time doctors and two other part-time doctors.
They work chiefly for clinical practice in medical rehabilitation service, but also have to engage in teaching activities for medical students. Fourteen physicaltherapists and five acupuncture therapists are working
in the physical therapy section. In the occupational
therapy section, three occupational therapists work forthe general rehabilitation service and the other two
therapists work for the psychiatric rehabilitation. In
the Day-care Unit, a clinical psychologist and a nurse
also work. In 2006, speech therapists and orthoptists

who belong to other departments in the University ofTokyo Hospital are going to be included in our department.

Clinical activities
There is not enough doctors arranged for the department of rehabilitation medicine, and we cannot
run own beds for rehabilitation patients at present. The
professor serves as a director of Central Rehabilitation
Service Department of the University of Tokyo Hospital. Both departments are united and engage in clinical practice. We have at present no charged ward, andtreat about 1,000 new referrals annually from almost
all the departments of the university hospital. We always take charge of about 150 patients corresponding
about 15% of the whole number of inpatients. We also
see 15 people per day at the outpatient rehabilitation
setting. The numerical ratio of outpatient is being reduced in order to give priority to the clinical service
corresponding to needs expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year
medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such as cerebrovascular disturbances, spinal cord injuries andspina bifida, neuromuscular diseases, bone and joint372

diseases, and cerebral palsy as well as on outline ofrehabilitation, welfare system, and prostheses / orthoses . We have provided a clinical practice in small
group, so-called bedside learning for 5th year students
from Wednesday to Friday every other week. Theyexperience a few patients and learn how to take a patients’ history, physical findings, functional evaluation,and how to plan rehabilitation programs. We have introduced a few of elective students for clinical clerkship to our collaborating hospitals with specialized
rehabilitation ward.
In addition, we have provided the training of comedical students including physical therapy and occupational therapy. Twenty students or more come andstay at the university hospital annually as a long-term
clerkship from several PT/OT training schools.
Nine graduate school students entered by 2006 andthree of them acquired a degree of Ph.D. and graduated.

Research activities
Our research activities are growing up. In 2006, theCentral Rehabilitation Service Department moved to
the new building and a research laboratory was provided for the first time. As the motion analysis system
was partially renewed, we are planning our researches
mainly in the field of musculoskeletal disabilities. In
addition, we are planning collaborating researcheswith other departments in our hospital, other faculties
in our university, and institutions outside the University of Tokyo. The ongoing and scheduled projects are
as follows.
1) 3D-motion analysis of patients with joint disorders in the lower extremities
2) Estimation of supported motion by humanmachine coadaptation system
3) Analysis of effects on body by vibration stimulus
4) Estimation of standing balance and the effect bypassive stimulation
5) Analysis of motion and energy expenditure in theactivities of daily living in the physically disabled
6) Non-invasive evaluation of lower limb motor
function in spina bifida
7) Prevention of requiring long-time care with physical exercise
8) Disabilities and handicaps in patients with skeletal

dysplasias
9) Mechanism of physical therapy on the change ofpain and perceptional threshold10) Evaluation of higher brain dysfunction

References
1. Imahashi K, Kawagoe M, Eto F, Haga N: Clinicalstatus and dependency of the elderly requiringlong-term care in Japan. Tohoku J Exp Med 2007;
212: 229-238.
2. Miyamoto Y, Matsuda T, Kitoh H, Haga N, Ohashi H,
Nishimura G, Ikegawa S: A recurrent mutation in
type II collagen gene causes Legg-Calve-Perthes disease in a Japanese family. Hum Genet 2007; 121:625-629.
3. Nakajima M, Haga N, Takikawa K, Manabe N, Nishimura G, Ikegawa S: The ACVR1 617G>A mutation is also recurrent in three Japanese patients withfibrodysplasia ossificans progressiva. J Hum Genet
2007; 52: 473-475.
4. Nishimura A, Sakai H, Ikegawa S, Kitoh H, Haga N,
Ishikiriyama S, Nagai T, Takada F, Ohta T, Tanaka F,
Kamasaki H, Saitsu H, Mizuguchi T, Matsumoto N:
FBN2, FBN1, TGFBR1, and TGFBR2 analyses incongenital contractural arachnodactyly. Am J Med Genet A 2007; 143: 694-698.
5. Yamasaki S, Yamasue H, Abe O, Yamada H, Iwanami A, Hirayasu Y, Nakamura M, Furukawa S,
Rogers MA, Tanno Y, Aoki S, Kato N, Kasai K:
Reduced planum temporale volume and delusional
behaviour in patients with schizophrenia. Eur Arch
Psychiatry Clin Neurosci 2007; 257: 318-324.

373

Division of Diagnostic Pathology
Professor (Director)
Masashi Fukayama, M.D., Ph.D.*

Associate Professor (Deputy Director)
Noriyoshi Fukushima, M.D., Ph.D.*

Lecturer
Hiroshi Uozaki, M.D., Ph.D.,

Satoshi Ohta, M.D., Ph.D.*

Lecturer (Hospital)
Yutaka Takazawa, M.D., Ph.D.,

Toru Motoi, M.D., Ph.D.

Kenji Kashima, M.D., Ph.D. (visiting researcher, UK)

AssociateJunji Shibahara, M.D., Ph.D.,

Tetsuo Ushiku, M.D., Ph.D.,

Takashi Sakatani, M.D., Ph.D. *,Shunpei Ishikawa, M.D., Ph.D.*,

Rumi Hino, M.D., Ph.D. *,Teppei Morikawa, M.D., Ph.D.*,

Takeo Nakaya, M.D., Ph.D.* (Human Resource Development for Cancer)

Clinical Fellow
Naoko Yamauchi, M.D., Ph.D.,

Hideki Miyazaki, M.D.,

Kazuki Kaji, M.D., Hiroto Kato, M.D., Ph.D.

Homepage

http://pathol.umin.ac.jp/

Introduction and Organization
Department of Pathology and Diagnostic Pathology(*) and Division of Diagnostic Pathology of
University Hospital have been united to function as aunit. This union is responsible for the pathologic
practice of the University Hospital (autopsy andsurgical pathology), as well as for education andresearch of human pathology.
The proper staffs were 1 lecturer, two lecturers(hospital), two associates, and two clinical staffs.

Clinical activities (diagnostic
pathology and autopsy)
Annual statistics of the pathologic practice in 2007
fiscal year are 13,090 cases of biopsy, 17,676 ofcytology, 658 of frozen histology, 558 of intraoperative cytology and 78 of autopsy (16% as autopsyrate). Clinico-pathological conferences (CPCs) for
the two autopsy cases are held every month in thehospital. In 2006, 126th – 136th CPC were held.
Furthermore, surgical pathological conferences are
regularly held with each clinical division, anddiscusses the cases of various tumors, including
thorax, upper gastrointestinal tract, neurosurgery, liver,pancreato-biliary
tract,
urology,
gynecology,
mammary gland, and orthopedics, as well as biopsy

374

cases of liver, kidney and skin.
Our aim of the pathologic practice is to provide
the correct diagnosis as soon as possible. We are
addressing ‘one-day pathology’ using a newly
developed rapid-histoprocessing machinery. Furthermore, a virtual slide scanner has been installed, whichenabled us to save the consultation specimens as
digital information. We are setting out a future
providing system of pathologic images for clinicaldivisions. Lecturer Uozaki is mainly in charge of thisproject.
We continued to participate the autopsy
assessment for “The Model Project for Inspection andAnalysis of the Death Associated with Medical
Practice” of Health, Labor and Welfare Ministry,.

Teaching activities
The lectures and exercise course of systemic
pathology are for the 2nd grade–students. Clinicalclerkship and bed-side learning (BSL) course of
autopsy and surgical pathology are for the 3rd and 4th
grade students, respectively.
The new system of internship has started since2004, and all interns are required to submit at least
one report of CPC case. The Division of Diagnostic
Pathology received seven interns in 2007 for thesecond year program of their internship.

Research activities
We are developing the tumor specific antibodies incollaboration with Genome Science Division,
Research Center for Advanced Science andTechnology, the University of Tokyo. Based on the
DNA array data of various human neoplasms,
monoclonal antibodies against candidate geneproducts are generated. In addition, we are in theprocess of constructing the tissue array of neoplastic
and non-neoplastic tissues in order to facilitate thescreening process of immunohistochemistry,.

References
See the corresponding section of Department of
Pathology and Diagnostic Pathology

375

Department of Corneal
Transplantation
Associate Professor
Shiro Amano, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kakumaku.html

Introduction and Organization
The department of corneal transplantation wasestablished in 1976 as one of clinical sections in the
University of Tokyo Hospital. The purpose of theestablishment of this section is to carry out andpromote corneal transplantation and to perform
clinical and basic research in the corneal diseases andcorneal transplantation. The section is composed of adirector (associate professor).

Clinical activities
The clinical activities of this section include corneal
transplantation and outpatient clinics for various
corneal diseases as a consulting corneal service. The
director is responsible not only for corneal
transplantation but also for general ophthalmologicalpractice as a senior staff member of Department ofOphthalmology, University of Tokyo. The corneal
service is held every Wednesday. At the corneal
service, we determine indication for corneal
transplantation and follow up patients after the surgery.
We also diagnose and treat various corneal diseases.
The corneal service is conducted by the director anddoctors from related hospitals. The patients who
enrolled in the corneal service have exceeded 5000.
The total number of corneal transplantation hasreached 1500 cases since we started keratoplasties in
1971. Approximately 50 corneal transplantations havebeen performed annually.
The other important activities of the section include
mediation of donor eyes to other university hospitals

and medical institutes that need donor eyes for corneal
transplantation.
Followings are our main clinical themes to be pursued
to improve the safety and prognosis of corneal
transplantation.
1) Thorough examination of donor eyes not only byslit-lamp biomicroscope but also by specular
microscope.
2) Positive proof that donors were free of such
infectious diseases as viral hepatitis, syphilis,
AIDS and acute T-cell leukemia to prevent
transmission to recipient patients through grafting.
3) Introduction of sclero-corneal preservation ofdonor eyes, because sclero-corneal preservation ismore suitable for longer preservation thanconventional whole eye preservation.
4) The long-term natural course of keratoconus has
been investigated with corneal topography.

Teaching activities
As an undergraduate course, we give lectures on
corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged inpractical training for medical students on
ophthalmological examinations at the outpatient clinic.
As a postgraduate course, we give lectures on topics
concerning corneal transplantation, corneal diseases
and new medical therapies.

376

Research activities

References

1. Regenerative medicine for corneal diseases.
We have pursued to apply regenerative medicine tocorneal diseases. In patients with chemical burn ofocular surface and Stevens-Johnson syndrome, we try
to reconstruct the ocular surface with autologous
cultivated limbal, conjunctival or oral epithelial cells.
We also use cultured human corneal endothelial cells,
collagen sheet and amniotic membrane to construct
sheets with corneal endothelial cells. These sheets
have the same degree of pump function as corneal
endothelium. We have investigated the potentiality ofcollagen extracted from animal dermis forreconstruction of corneal stroma. We also examined
the potential clinical usefulness of acellularized
porcine corneal stroma.

1. Ebihara N, Yamagami S, Yokoo S, Amano S,
Murakami A. Involvement of CCL2-CCR2
interaction in monocyte-lineage cell recruitmentof normal human corneal stroma. J Immunol 178:
3288-3292, 2007
2. Suzuki M, Usui T, Kinoshita N, Yamagami S,
Amano S. A case of sterile corneal perforation
after bone marrow transplantation. Eye 21:114116, 2007
3. Kaji Y, Nagai R, Amano S, Takazawa Y,
Fukayama M, Oshika T. Advanced glycation end
product deposits in climatic droplet keratopathy.
Br J Ophthalmol 91:85-88, 2007
4. Yamagami S, Yokoo S, Mimura T, Araie M,
Amano S. Distribution of precursors in humancorneal stromal cells and endothelial cells.
Ophthalmology 114:433-439, 2007
5. Shimazaki J, Amano S, Uno T, Maeda N, Yokoi N,
and the Japan Bullous Keratopathy Study Group.
National survey on bullous keratopathy in Japan.
Cornea 26:274-278, 2007
6. Murata H, Kato S, Fukushima H, Tsutsumi A,
Numaga J, Amano S. Corneal endothelial celldensity reduction: A complication of retinal
photocoagulation
withanindirectophthalmoscopy contact lens. Acta Ophthalmol
Scand 85:407-408, 2007
7. Ono K, Yokoo S, Mimura T, Usui T, Miyata K,
Araie M, Yamagami S, Amano S. Autologoustransplantation of conjunctival epithelial cells
cultured on amniotic membrane in a rabbit model.
Mol Vis 13:1138-1143, 2007
8. Miyai T, Yonemura T, Nejima R, Otani S, Miyata
K, Amano S. Interlamellar flap edema due tosteroid-induced ocular hypertension after laser insitu keratomileusis. Jpn J Ophthalmol 51:228-230,
2007
9. Mimura T, Yamagami S, Usui T, Yokoo S, Ono K,
Honda N, Kaneda A, Sugisaki K, Sayegh RR,
Amano S. Preoperative evaluation of cultured
human corneal limbal epithelium on amniotic
membrane by confocal microscopy. Curr Eye Res
32:407-411, 2007
10. Usui T, Yamagami S, Kishimoto S, Yokoo S,
Nakayama T, Amano S. Role of macrophage

2. Tissue stem cells in the cornea.
Using neurosphere method, we successfully isolated
tissue stem cells in the corneal epithelium, stroma andendothelium. Each tissue stem cells show
multipotency and self-renewality. We try to utilize
these tissue stem cells in corneal regenerative
medicine.
3. Meibomian gland dysfunction.
Meibomian glands secrete lipids into the tear film andprevent excessive evaporation of the tear film byforming a thin oily layer on the tear film. Meibomian
gland dysfunction (MGD) is a major cause of dry eye
syndrome. We have developed a non-contact, lesstime-consuming, and patient-friendly meibographymethod that employs an infrared filter and an infrared
charge-coupled device (CCD) video camera. Using
this meibography system, the structure of the
meibomian glands can be easily observed in both theupper and lower eyelids within 1 minute withoutcausing any discomfort to the patients. Using thismeibography, we are examining the morphologicchanges in meibomian glands associated with aging
and sex and assessed their relation with slit-lamp
findings of eyelids and tear film function in a normal
population.

377

migration
inhibitory
factorincornealneovascularization. Invest Ophthalmol Vis Sci 48:
3545-3550, 2007
11. Suzuki M, Amano S, Honda N, Usui T, Yamagami
S, Oshika T. Longitudinal changes in corneal
irregular astigmatism and visual acuity in eyeswith keratoconus. Jpn J Ophthalmol 51:265-269,
2007
12. Mimura T, Yamagami S, Honda N, Usui T, Yokoo
S, Amano S. Necessary prone position time forhumancornealendothelial
precursor
transplantation in a rabbit endothelial deficiency
model. Curr Eye Res 32:617-623, 2007
13. Yamagami S, Yokoo S, Amano S, Ebihara N.
Characterization of bone marrow-derived cells inthe substantia propria of the human conjunctiva.
Invest Ophthalmol Vis Sci 48:4476-4481, 2007

378

Department of Cell Therapy andTransplantation Medicine
Associate Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Junko Takita, M.D., Ph.D. (Pediatrics/Hematology-Oncology)

Associate
Keiki Kumano, M.D., Ph.D. (Hematology-Oncology)

Homepage

http://www.h.u-tokyo.ac.jp/mukin/index.htm

Introduction and Organization
Department of Cell Therapy and Transplantation
Medicine was institutionally established in 1995, andformally organized in 1996. At present, the staff consists of three medical doctors listed above. Clinicalfacilities include 8 single-patient rooms withhigh-efficiency particulate air filtration and other highstandards. Patients who are eligible for the treatment
with high-grade infectious prophylaxis are admitted to
the facilities.

Clinical activities
Allogeneic hematopoietic stem cell transplantation:
Bone marrow cells are operatively harvested and infused without preservation. For peripheral blood stem
cell transplantation, leukapheresis is performed withthe use of an automated continuous flow blood cell
separator, and harvested cells are preserved at -196°C
in cooperation with Department of Transfusion Medicine. Recently, transplantation after pre-conditioningof reduced intensity (RIST for reduced-intensity stem
cell transplantation or NST for non-myeloabrative
stem cell transplantation) is commonly performed forthe elderly patients and patients with organ damages,
etc. The development of this strategy is expanding theeligibility of transplant recipients.

Several clinical studies with allogeneic stem celltransplantation have been also conducted. These include transplantation from a donor with mismatched
HLA at two loci or more. All these studies are approved by the ethical committee of the Faculty of
Medicine.
High-dose chemotherapy with or without autologous stem cell support: High-dose chemotherapy isadministered according to the malignant disease. For
the autologous stem cell support, peripheral blood
stem cell is usually selected as a source of stem cells.
Similar procedures used in the allogeneic stem cell
harvest are performed for leukapheresis and preservation.
Clinical conference for hematopoietic stem celltransplantation : The conference is held monthly, inwhich the members of Department of Hematology/Oncology and Hematology/Oncology group in the
Department of Pediatrics, and some members of Department of Transfusion Medicine routinely participate and discuss on the patients receiving hematopoietic stem cell transplantation.

Teaching activities
Together with the members of Department of He-

379

matology/Oncology and Hematology/Oncology groupin the Department of Pediatrics, lecture courses on
etiology, pathogenesis, clinical and laboratory features,
differential diagnosis, therapy and prognosis for all
hematological diseases are provided for the second
grade medical students. Courses for bedside learning
on diagnostic and therapeutic issues and arts are given
for the third grade medical students on a man-to-man
basis with a senior faculty member. Clinical clerkshipcourses are given to the fourth grade medical students,
who join the patient care teams consisting of juniorand senior medical doctors and learn medical practices
and patient management, through playing a role as a
junior member of the team, as well as through discussions and presentations.

Research activities
The major research projects are focused on clinicalstudies such as development of improved/new methods for hematopoietic stem cell transplantation, immunotherapy for hematopoietic tumors, and basic
studies on hematopoietic stem cells and leukemogenesis. In the area of pediatric oncology, we continue the studies on molecular mechanisms of pediatric malignancies, such as neuroblastoma, rhabdomyosarcoma, and infant leukemia. Representative publications from our department published in the past two
years are listed in the references.

3.

4.

5.

6.

7.

References
1. Shinohara A, Asai T, Izutsu K, Ota Y, Takeuchi K,
Hangaishi A, Kanda Y, Chiba S, Motokura T, andKurokawa M. Durable remission after the administration of rituximab for EBV-negative diffuse
large B-cell lymphoma arising after autologous
peripheral blood stem cell transplantation for angioimmunoblastic T-cell lymphoma. Leukemia
and Lymphoma 48: 418-420, 2007.
2. Nitta E, Izutsu K, Sato T, Ohta Y, Takeuchi K,
Kamijo A, Oshima K, Kanda Y, Chiba S, Motokura T, and Kurokawa M. A high incidence oflate-onset neutropenia following rituximabcontaining chemotherapy as a primary treatment
for CD20-positive B-cell lymphoma: a single institution study. Annals of Oncology 18: 364-349,

8.

9.

2007.
Kako S, Kanda Y, Sato T, Goyama S, Noda N,
Shoda E, Ohsiman K, Inoue M, Izutsu K, Watanabe T, Motokura T, Chiba S, Fukuyama M, andKurokawa M. Early relapse of JAK2
V617F-positive chronic neutrophilic leukemiawith central nervous system infiltration after unrelated bone marrow transplantation. American
Journal of Hematology 82: 386-390, 2007.
Izumi R, Fujimoto M, Yazawa N, Nakashima H,
Asashima N, Watanabe R, Kurokawa M, Hashimoto T, and Tamaki K. Bullous pemphigoid positive for anti-BP180 and anti-laminin 5 antibodies
in a patient with graft-vs-host disease. Journal of
the American Academy of Dermatology 56: 94-97,
2007.
Matsumoto A, Haraguchi K, Takahashi T, Azuma
T, Kanda Y, Tomita K, Kurokawa M, Ogawa S,
Takahashi K, Chiba S, and Kitamura T. Immunotherapy against metastatic renal cell carcinoma
with mature dendritic cells. International Journalof Urology 14: 277-283, 2007.
Sanada M, Uike N, Ohyashiki K, Ozawa K, Lili W,
Hangaishi A, Kanda Y, Chiba S, Kurokawa M,
Omine M, Mitani K, and Ogawa S. Unbalanced
translocation der(1;7)(q10;p10) defines a uniqueclinicopathological subgroup of myeloid neoplasms. Leukemia 21: 992-997, 2007.
Kako S, Izutsu K, Arai T, Yokoyama Y, Oshima K,
Sato H, Asai T, Watanabe T, Hangaishi A, Kanda
Y, Motokura T, Chiba S, and Kurokawa M. Regression of the tumor after withdrawal of cyclosporine in relapsed extranodal natural killer/Tcell lymphoma following allogeneic hematopoietic stem cell transplantation. American Journalof Hematology 82: 937-939, 2007.
Kako S, Izutsu K, Arai T, Yokoyama Y, Oshima K,
Sato H, Asai T, Watanabe T, Hangaishi A, Kanda
Y, Motokura T, Chiba S, and Kurokawa M.
FDG-PET in T-cell and NK-cell neoplasms.
Annals of Oncology 18: 1685-1690, 2007.
Oshima K, Kanda Y, Asano-Mori Y, Nishimoto N,
Arai S, Nagai S, Sato H, Watanabe T, Hosoya N,
Izutsu K, Asai T, Hangaishi A, Motokura T, Chiba
S, and Kurokawa M. Presumptive treatment
strategy for aspergillosis in allogeneic hematopoietic stem cell transplant recipients. The Journal

380

of Antimicrobial Chemotherapy 60: 350-355,
2007.
10. Ishikawa T, Tohyama K, Nakao S, Yoshida Y,
Teramura M, Motoji T, Takatoku M, Kurokawa M,
Mitani K, Uchiyama T, and Omine M. A prospective study of cyclosporine A treatment of patientswith low-risk myelodysplastic syndrome: presence of CD55-CD59- blood cells predicts platelet
response. International Journal of Hematology 86:
150-157, 2007.
11. Yamamoto G, Nannya Y, Kato M, Sanada M,
Kawamata N, Hangaishi A, Kurokawa M, Chiba S,
Gilliland G, Koeffler HP, and Ogawa S. Highly
sensitive method for genome-wide detection ofallelic composition in non-paired, primary tumor
specimens using SNP genotyping microarrays.
American Journal of Human Genetics 81: 114-126,
2007.
12. Arai S, Asai T, Uozaki H, Hangaishi A, Kanda Y,
Motokura T, Chiba S, and Kurokawa M. Splenicpeliosis occurred in a patient with aplastic anemia
during danazol therapy. International Journal of
Hematology 86: 329-332, 2007.
13. Nagai S, Ichikawa M, Takahashi T, Sato H,
Yokota H, Morikawa M, Oshima K, Hangaishi A,
Kanda Y, Motokura T, Chiba S, Yatomi Y, andKurokawa M. The origin of neoplastic mast
cells in systemic mastocytosis with AML1/ETO
positive acute myeloid leukemia. Experimental
Hematology 35: 1747-1752, 2007.
14. Saito A, Chiba S, Ogawa S, Kanda Y, Hirai H, andKurokawa M. Long-term sustained mixed chimerism after allogeneic stem cell transplantation
in a patient with severe aplastic anemia. Internal
Medicine 46: 1923-1926, 2007.
15. Kawazu M, Yamamoto G, Yoshimi M, Yamamoto
K, Asai T, Ichikawa M, Seo S, Nakagawa M,
Chiba S, Kurokawa M, and Ogawa S. Expression profiling of immature thymocytes revealed anovel homeobox gene that regulates doublenegative thymocyte development. The Journalof Immunology 179: 5335-5345, 2007.
16. Komuro H, Saihara R, Shinya M, Takita J,
Kaneko S, Kaneko M, Hayashi Y. Identification ofside population cells (stem-like cell population) in
pediatric solid tumor cell lines. Journal of Pediatric Surgery 42: 2040-2045, 2007.

17. Chen Y, Takita J, Mizuguchi M, Tanaka K, Ida K,
Koh K, Igarashi T, Hanada R, Tanaka Y, Park MJ,
Hayashi Y. Mutation and expression analyses ofthe MET and CDKN2A genes in rhabdomyosarcoma with emphasis on MET overexpression.
Genes, Chromosomes and Cancer 46: 348-358,
2007.

381

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Takao Kawabe, Ph.D.

Introduction and Organization
Department of Endoscopy and Endoscopic Surgery
was established in April 1997. Although the present
staff of our department is only an associate professor,
about 80 doctors of other departments, including thedepartment of internal medicine, surgery, gynecology
andotorhinolaryngology,
participate
theexaminations.The examination rooms moved to thenew building in Oct. 2006.

polyps, endoscopic biliary stone removal, andendoscopic stenting for biliary malignant diseases, arerecently increasing. Our recent clinical activities are
summarized in Table 1.
Another important activity of our department is thedisinfection and maintenance of endoscopic
apparatuses used in other units including outpatient
clinic, radiolographic procedure rooms, surgery rooms
or intensive care units. All endoscopes are collectedin our department after use and disinfected.

Clinical activities

Teaching activities

Endoscopic
examinations,
includinguppergastrointestinalendoscopy,colonoscopy,
bronchoscopy, otorhinolaryngological examinations
and gynecologycal examinations, are performed from
Monday to Friday. Therapeutic endoscopies, including
endoscopic variceal ligation, endoscopic resection
including submucosal dissection for esophageal,
gastric and colorectal tumors, polypectomy for colonic

We participate in under-graduate education as a part ofsystemic lectures and bed-side learning by thedepartment of gastroenterology, surgery and otherdepartments. As for post-graduate education, training
opportunities for endoscopy and endoscopic surgery
are given to resident or young doctors in a program ofeach department.

Table 1. Enoscopic examinations in Depatment of Endoscopy and Endoscooic Surgery
1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

UGI endoscopy

4384

5555

5667

5923

6346

7324

7920

7597

8265

8131

8796

Colonoscopy

1398

2415

2472

2799

3212

3529

3873

3728

4084

4327

4360

Bronchoscopy

*

190

239

282

233

194

220

207

194

212

201

201

**

347

562

569

470

479

583

586

476

461

438

484

Laparoscopy

19

7

2

0

-

-

-

-

-

-

Otophino-laryngologicalexamination

131

96

99

115

154

93

68

61

89

127

91

Gynecological examination

272

213

153

149

181

103

124

139

88

58

117

Total

6741

9087

9244

9689

10566

11852

12778

12195

13199

13282

14043

EUS

*UGI; upper gastrointestinal, **Endoscopic ultarasonography

382

Research activities
Our researches cover a variety of fields including theupper and lower gastrointestinal tract and thepancreatobilialy system. They are mainly performedincooperation
withthedepartment
ofGastroenterology.

References
1. Tsujino T, Kawabe T, Isayama H, Sasaki T,
Kogure H, Togawa O, Arizumi T, Ito Y, Matsubara
S, Yamamoto N, Nakai Y, Sasahira N, Hirano K,
Toda N, Komatsu Y, Tada M, Yoshida H, Omata
M. Efficacy and safety of low-pressured andshort-time dilation in endoscopic papillary balloon
dilation for bile duct stone removal. J
Gastroenterol Hepatol 2007; 23: 867-71.
2. Yamada A, Sugimoto T, Kondo S, Ohta M,
Watabe H, Maeda S, Togo G, Yamaji Y, Ogura K,
Okamoto M, Yoshida H, Kawabe T, Kawase T,
Omata M. Assessment of the risk factors forcolonic diverticular hemorrhage. Dis Colon
Rectum 2007; 51: 116-20.
3. Matsubara S, Arizumi T, Togawa O, Sasaki T,
Yamamoto N, Nakai Y, Sasahira N, Hirano K,
Tsujino T, Isayama H, Toda N, Tada M, Kawabe T,
Omata M. Endoscopic transpapillary approach to
the gallbladder for diagnosing gallbladdercancer. Can J Gastroenterol 2007; 21: 809-13.
4. Yamashiki N, Yoshida H, Tateishi R, Shiina S,
Teratani T, Yoshida H, Kondo Y, Oki T, Kawabe T,
Omata M. Recurrent hepatocellular carcinoma has
an increased risk of subsequent recurrence after
curative treatment. J Gastroenterol Hepatol 2007;
22: 2155-60.
5. Ogura K, Mitsuno Y, Maeda S, Hirata Y, Yanai A,
Shibata W, Ohmae T, Yoshida H, Kawabe T,
Omata M. Efficacy and safety of faropenem in
eradication therapy of Helicobacter pylori.
Helicobacter 2007; 12: 618-22.
6. Tsujino T, Kogure H, Sasahira N, Isayama H,
Tada M, Kawabe T, Omata M, Akahane M, Sano
K, Makuuchi M. A huge intra-abdominal mass ina young man. Gut 2007; 56: 1372, 1393.
7. Yamaji Y, Mitsushima T, Yoshida H, Watabe H,
Okamoto M, Ikuma H, Wada R, Kawabe T, Omata

M. Right-side shift of metachronous colorectal
adenomasafter
polypectomy.
Scand
J
Gastroenterol 2007; 42: 1466-72.
8. Tsujino T, Kawabe T, Omata M. Antiproteases inpreventing post-ERCP acute pancreatitis. JOP
2007; 8: 509-17.
9. Tanaka Y, Imamura J, Kanai F, Ichimura T, Isobe
T, Koike M, Kudo Y, Tateishi K, Ikenoue T, Ijichi
H, Yamaji Y, Yoshida H, Kawabe T, Omata M.
Runx3 interacts with DNA repair protein Ku70.
Exp Cell Res 2007; 313: 3251-60.
10. Kubota K, Kuroda J, Origuchi N, Kaminishi M,
Isayama H, Kawabe T, Omata M, Mafune K.
Stomach-partitioning
gastrojejunostomy
forgastroduodenal outlet obstruction. Arch Surg
2007; 142: 607-112.
11. Tsujino T, Sugawara Y, Kawabe T, Makuuchi M,
Omata M. Foreign body (suture thread) in the bile
duct after living donor liver transplantation. Liver
Transpl 2007; 13: 1065-6.
12. Tsujino T, Sugita R, Yoshida H, Yagioka H,
Kogure H, Sasaki T, Nakai Y, Sasahira N, Hirano
K, Isayama H, Tada M, Kawabe T, Omata M. Risk
factors for acute suppurative cholangitis causedby bile duct stones. Eur J Gastroenterol Hepatol
2007; 19: 585-8.
13. Hirano K, Tada M, Isayama H, Yagioka H, Sasaki
T, Kogure H, Nakai Y, Sasahira N, Tsujino T,
Yoshida H, Kawabe T, Omata M. Long-term
prognosis of autoimmune pancreatitis with andwithout corticosteroid treatment. Gut 2007; 56:
1719-24.
14. Fujishiro M, Yahagi N, Kakushima N, Kodashima
S, Muraki Y, Ono S, Yamamichi N, Tateishi A,
Oka M, Ogura K, Kawabe T, Ichinose M, Omata
M. Outcomes of endoscopic submucosal dissection for colorectal epithelial neoplasms in
200 consecutive cases. Clin Gastroenterol Hepatol
2007; 5: 678-83.
15. Nakai Y, Tsujino T, Kawabe T, Kogure H, Sasaki
T, Yamamoto N, Sasahira N, Isayama H, Tada M,
Omata M. Pancreatic tuberculosis with apancreaticobiliary fistula. Dig Dis Sci 2007; 52:1225-8.
16. Okamoto M, Yamaji Y, Togo G, Kawabe T, Omata
M. Significance of the screening test for colon
neoplasms. Nippon Naika Gakkai Zasshi 2007;

383

96: 239-44.
17. Sasahira N, Tada M, Isayama H, Hirano K, Nakai
Y, Yamamoto N, Tsujino T, Toda N, Komatsu Y,
Yoshida H, Kawabe T, Omata M. Outcomes after
clearance of pancreatic stones with or without
pancreatic stenting. J Gastroenterol 2007; 42:
63-9.
18. Kondo Y, Yoshida H, Tateishi R, Shiina S, Mine N,
Yamashiki N, Sato S, Kato N, Kanai F, Yanase M,
Yoshida H, Akamatsu M, Teratani T, Kawabe T,
Omata M. Health-related quality of life of chronic
liver disease patients with and without
hepatocellular carcinoma. J Gastroenterol Hepatol
2007; 22: 197-203.
19. Guleng B, Tateishi K, Ohta M, Asaoka Y, Jazag A,
Lin LJ, Tanaka Y, Tada M, Seto M, Kanai F,
Kawabe T, Omata M. Smoothened gene mutations
found in digestive cancer have no aberrant
Hedgehog signaling activity. J Gastroenterol
2007; 41: 1238-9.
20. Tsujino T, Kawabe T, Komatsu Y, Yoshida H,
Isayama H, Sasaki T, Kogure H, Togawa O,
Arizumi T, Matsubara S, Ito Y, Nakai Y,
Yamamoto N, Sasahira N, Hirano K, Toda N, Tada
M, Omata M. Endoscopic papillary balloon
dilation for bile duct stone: immediate andlong-term outcomes in 1000 patients. Clin
Gastroenterol Hepatol 2007; 5: 130-7.
21. Kondo S, Yamaji Y, Watabe H, Yamada A,
Sugimoto T, Ohta M, Ogura K, Okamoto M,
Yoshida H, Kawabe T, Omata M. A randomized
controlled trial evaluating the usefulness of atransparent hood attached to the tip of thecolonoscope. Am J Gastroenterol 2007; 102:
75-81.
22. Shao RX, Kato N, Lin LJ, Muroyama R,
Moriyama M, Ikenoue T, Watabe H, Otsuka M,
Guleng B, Ohta M, Tanaka Y, Kondo S, Dharel N,
Chang JH, Yoshida H, Kawabe T, Omata M.
Absence of tyrosine kinase mutations in Japanesecolorectal cancer patients. Oncogene 2007; 26:
2133-5.

384

Department of Hemodialysis &Apheresis
Director,
Toshiro Fujita, MD, PhD

Vice Director,
Head, Eisei Noiri, MD, PhD
Noiri Hanafusa, MD, PhD

Introduction
Hemodialysis and related blood purification therapy
had been individually performed in their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for
Hemodialysis in 2000 at the University Hospital. The
Center for Hemodialysis was further renovated andstarted operations in Fall of 2006. This new Center for
Hemodialysis is equipped with one pressure control
unit in addition to 12 hemodialysis machines under astate-of-the-art hemodialysis control system. Ourconcept of a hemodialysis controlling system is a hub
to transfer all digital and analog data from patientsand to monitor machines, including blood purification
machines, to the host computer in our hospital,
centralizing all data and administering medical coding
and billing robustly. Blood purification machines in
the ICU are also connectable to this system, which
was developed collaboratively with Nihon Kohden
Corp. Blood purification machines are selected
uniformly to secure patients’ safety while avoiding
human error and increasing the overall educational
quality of staff members.

Education
1. A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acuteand chronic renal failure including diabetic
nephropathy.
2. Technical development course for medical
engineers and nurses.
3. Tutorial course for clinical fellows applying to thespeciality of blood purification therapy.
4. Exposure in hemodialysis & apheresis course to
second year residents on request.

Medical Care
1. Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
2. Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does
not accept holiday dialysis.
3. Emergency hemodialysis and hemodiafiltration
for ICU patients.
4. Plasma exchange for neurodegenerative diseases,
SLE, TTP, TMA, and pre/post-liver transplantpatients.
5. DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
6. LDL apheresis for nephrotic syndrome and ASO
patients.
7. White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.

Research
1. Prognostic analysis for post-liver transplant

385

2.
3.
4.
5.
6.
7.
8.

patients received plasma exchange therapy.
Development and application of a non-invasive
pulse hemoglobin meter.
Candidate gene analysis for CKD; whole genome
analysis for CKD.
Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
Pathophysiology of acute renal failure and its
applicability for renal regenerative study.
Development of a mouse CKD model.
Renal
biomarker
todetermine
clinicalactionability in CKD and type-2 DN.
The potentiality of urine biomarker tests fordeveloping country.

References
1. Negishi K, Noiri E, Maeda R, Portilla D, Sugaya
T, Fujita T: Renal L-type fatty acid-binding
protein mediates the bezafibrate reduction of
cisplatin-induced acute kidney injury. Kidney Int
73:1374, 2008
2. Yamamoto T, Noiri E, Ono Y, Doi K, Negishi K,
Kamijo A, Kimura K, Fujita T, Kinugawa T,
Taniguchi H, Nakamura K, Goto M, Shinozaki N,
Ohshima S, Sugaya T: Renal L-type fatty acidbinding protein: possible stress reducer andbiomarker for human renal microcirculation. J Am
Soc Nephrol 18:2894, 2007
3. Negishi K, Noiri E, Sugaya T, Li S, Megyesi J,
Nagothu K, Portilla D: A role of liver fatty
acid-binding protein in cisplatin-induced acuterenal failure. Kidney Int 72:348, 2007
4. Tanaka T, Noiri E, Yamamoto T, Sugaya T,
Negishi K, Maeda R, Nakamura K, Portilla D,
Goto M, Fujita T: Urinary human L-FABP is apotential biomarker to predict COX-inhibitorinduced renal injury. Nephron Exp Nephrol 108:e19, 2007
5. Hanafusa N, Kondo Y, Suzuki M, Nakao A, Noiri
E, Fujita T: Double filtration plasmapheresis candecrease factor XIII activity. Ther Apher Dial 11:165, 2007
6. Noiri E, Nagano N, Negishi K, Doi K, Miyata S,
Abe M, Tanaka T, Okamoto K, Hanafusa N,
Kondo Y, Ishizaka N, Fujita T: Efficacy ofdarbepoetin in doxorubicin-induced cardiorenal

injury in rats. Nephron Exp Nephrol 104:e6, 2006
7. Doi K, Noiri E, Fujita T, Tokunaga K: Nonassociation of VEGF genetic polymorphism inpromoter—5’ UTR with end-stage renal disease.
Nephrol Dial Transplant 21:1124, 2006
8. Doi K, Noiri E, Nakao A, Fujita T, Kobayashi S,
Tokunaga K: Functional polymorphisms in thevascular endothelial growth factor gene areassociated with development of end-stage renal
disease in males. J Am Soc Nephrol 17:823, 2006
9. Doi K, Okamoto K, Negishi K, Suzuki Y, Nakao
A, Fujita T, Toda A, Yokomizo T, Kita Y, Kihara Y,
Ishii S, Shimizu T, Noiri E: Attenuation of folic
acid-induced renal inflammatory injury inplatelet-activating factor receptor-deficient mice.
Am J Pathol 168:1413, 2006
10. Nishi H, Hanafusa N, Kondo Y, Nangaku M,
Sugawara Y, Makuuchi M, Noiri E, Fujita T:
Clinical outcome of thrombotic microangiopathy
after living-donor liver transplantation treatedwith plasma exchange therapy. Clin J Am Soc
Nephrol 1:811, 2006
11. Hanafusa N, Noiri E, Yamashita T, Kondo Y,
Suzuki M, Watanabe Y, Kanai T, Miyashita E,
Tsuno NH, Fujii T, Kozuma S, Takahashi K,
Taketani Y, Nakao A, Fujita T: Successfultreatment by double filtrate plasmapheresis in apregnant woman with the rare P blood group and ahistory of multiple early micharges. Ther Apher
Dial 10:498, 2006
12. Okamoto K, Kobayashi S, Noiri E: Longer
treatment time and slower ultrafiltration inhemodialysis: associations with reduced mortality
in the Dialysis Outcomes and Practice Patterns
Study. Kidney Int 70:1877, 2006
13. Noiri E, Kobayashi N, Takamura Y, Iijima T,
Takagi T, Doi K, Nakao A, Yamamoto T, Takeda S,
Fujita T: Pulse total-hemoglobinometer provides
accurate noninvasive monitoring. Crit Care Med
33:2831, 2005
14. Noiri E and Tsukahara H: Parameters formeasurement of oxidative stress in diabetes
mellitus:
applicabilityofenzyme-linked
immunosorbent assay for clinical evaluation. J
Invest Med 53:167, 2005
15. Doi K, Noiri E, Nakao A, Fujita T, Kobayashi S,
Tokunaga K: Haplotype analysis of NAD(P)H386

oxidase p22 phox polymorphism in end-stage
renal disease. J Hum Genet 50:641, 2005
16. Goligorsky MS, Brodsky SV, Noiri E: NO
bioavailability, endothelial dysfunction, and acuterenal failure: new insights into pathophysiology.
Semin Nephrol 24:316, 2004
17. Doi K, Noiri E, Tokunaga K: The association ofNAD(P)H oxidase p22phox with diabetic
nephropathy is still uncertain: response to
Hodgkinson, Millward, and Demaine. Diabetes
Care 27:1518, 2004
18. Doi K, Suzuki Y, Nakao A, Fujita T, Noiri E:
Radical scavenger edaravone developed forclinical use ameliorates ischemia/reperfusion
injury in rat kidney. Kidne Int 65:1714, 2004

387

Clinical Research Center
Professor
Masao Omata, M.D., Ph.D.

Associate Professor
Yoshihiro Arakawa, Ph.D.

Research Associate
Keiji Ogura, M.D., Ph.D. (Appointed on June 2007)

Homepage

http://www.crc.h.u-tokyo.ac.jp/index.html

Introduction and Organization
The Clinical Research Center was established in
April 2001 as one of the regular departments in thecentral division in our hospital. The Center not only
took over the duties of the former provisional Clinical
Trial Research Center, which dealt industry-initiatedclinical trials, but also newly-incorporated the commission to support investigator-initiated clinical trials.
The staff of the center as of March, 2008, is comprisedof one professor, one associate professor, one research
associate, seven pharmacists, five nurses, one clinicalpsychologist and three officials, of which three pharmacist and three nurses were full-time workers withthree years' tenure and two officials and one clinicalpsychologist were part-time workers. The center consists of four subdivisions: a division of consultation on
protocol development (one associate professor and
one research associate), a division of pharmaceuticaladministration (three pharmacists), a division of clinical research coordination (five nurses, four pharmacists and one clinical psychologist) and a division ofclerkship (three officials).

Clinical activities
The duties of the center are wide-ranging fromserving as a secretariat for the institutional review
board (IRB) to supporting the conduct of clinical trials.
Clinical trials that we dealt with covered all regulatory

clinical trials for approval and investigator-initiatedclinical trials concerned with medicinal treatments.
As an IRB secretariat, to which all the staffs are responsible, we dealt 45 new protocols and 56 ongoingprotocols for industry-initiated clinical trials in fiscal
2007. We also dealt with 1 new protocol for investigator-initiated regulatory clinical trials and 39 investigator-initiated non-regulatory clinical trials, which
include the ethical use of non-approved drugs. A protocol hearing was held every month for applications of
new industry-initiated protocols to facilitate a review
with meaningful discussion in the IRB and to givepractical advice in carrying out the protocols properly.
The meeting was held with the attendance of applicant
company representatives, principal and sub investigators and the staffs of the center. We also dealt applications for changes in the initial application documents(463applications), safety information (588 reports),
and other reports in fiscal 2007.
To solve a so-called ‘un-approved drugs issue’ or‘drug lag issue’, participation to global trials was a
key issue. For this purpose, University Hospital Clinical Trial Alliance (UHCT Alliance) comprised of 7
national university hospitals (Tokyo University, Niigata University, Gunma University, Shinshu University, Tsukuba University, Tokyo Medical and Dental
University and Chiba University) was established in2006 and is collaborating with each other in continuing improvement of our clinical trial environments. In
fiscal 2007, 11 protocols were introduced to the alli-388

ance including 4 multi-national trials.
As for pharmaceutical administration, we tookcharge of 103 clinical trial drugs and medical devices
and filled 1165 prescriptions in fiscal 2007. Pharmacists in the division are also in charge of the primary
review of safety information about clinical trial drugs
and the database management in the Center. Our databases concerning protocols and subjects were transferred to a new system as a part of the hospital clinicalinformation system in March 2006, allowing the directaccess to the clinical trial information from the hospital system.
Clinical research coordinators (CRC) support theimplementation of all regulatory clinical trials. The
coordination covered all aspects in pursuing clinical
trials: preparation for the trials, screening for patients,
assistance to obtain patients’ informed consent, coordinating outpatients’ visit, assistance with inspections,assistance in the preparation of case report forms(CRF), arrangements for monitoring and audits, andarrangements for medical accounting. There were atotal of 4853 times of coordination of outpatients' visits and medical treatments of inpatients in fiscal 2007.
CRCs also support the implementation of some of theinvestigator-initiated non-regulatory clinical trials. In
2005, we introduced a principle that beneficiaries
should pay for part of a personnel cost of CRCs andadopted three investigator-initiated protocols for the
CRC support on this principle.
Publicity activity has been continued including theprovision of the information about the protocols undersubject recruitment both in our internet home pageand in our takeaway leaflets.
The outpatient clinic dedicated for clinical trials
moved new building in Nov. 2006 and was newly
equipped with consultation counters and a waitingroom.
The consultation division started in May 2002 to
support the investigator-initiated clinical trial. The
mission of the division is to help investigators to
conduct clinical research under the ethically and scientifically reviewed protocols. Namely, the division
supports protocol development, application to IRB
and monitoring of the progress and amendment ofclinical trials. As for educational programs of clinicalresearch for investigators, the division also gives a
training course 3 times a year and a symposium every

year. The division dealt with 39 new investigator-initiated clinical trials which include the ethicaluse of non-approved drugs in fiscal 2007.

Teaching activities
The Center accepted 40 fourth grade students fortraining in collaboration with the Pharmaceutical Department. Arakawa is taking charge of one half-year
lecture on clinical pharmacology for the graduate
course students in the Faculty of Pharmaceutical Sciences every year. One graduate student belonged toour research labs in fiscal 2007.
The Center is involved as an on-the-job training institution in CRC training programs. In fiscal 2007, we
accepted 1 one-week trainee and 3 three-week trainees
from the program operated by Pharmacist Training
Center.

Research activities
We performed the publication of 6 original papers
written in English, 3 review papers in Japanese andthe 36 presentations in academic conferences in 2006.
Ms. Yamada et al. received the Most Excellent Poster
Presentation Award from the Conference on How
CRC and Clinical Trials Should Be (Nov. 2007).

References(1) Yanai A, Maeda S, Hikiba Y, Shibata W, Ohmae T,
Hirata Y, Ogura K, Yoshida H, Omata M.: Clinical relevance of Helicobacter pylori sabA genotype in Japanese clinical isolates. J Gastroenterol
Hepatol. 2007; 22(12):2228-32.
(2) Ogura K, Mitsuno Y, Maeda S, Hirata Y, Yanai A,
Shibata W, Ohmae T, Yoshida H, Kawabe T,
Omata M.: Efficacy and safety of faropenem in
eradication therapy of Helicobacter pylori. Helicobacter. 2007; 12(6):618-22.
(3) Shibata W, Maeda S, Hikiba Y, Yanai A, Ohmae T,
Sakamoto K, Nakagawa H, Ogura K, Omata M.:
Cutting edge: The IkappaB kinase (IKK) inhibitor,
NEMO-binding domain peptide, blocks inflammatory injury in murine colitis. J Immunol. 2007;
179(5):2681-5.
(4) Maeda S, Hikiba Y, Shibata W, Ohmae T, Yanai A,389

Ogura K, Yamada S, Omata M.: Essential roles ofhigh-mobility group box 1 in the development ofmurine colitis and colitis-associated cancer. Biochem Biophys Res Commun. 2007; 360(2):394400.
(5) Fujishiro M, Yahagi N, Kakushima N, Kodashima
S, Muraki Y, Ono S, Yamamichi N, Tateishi A,
Oka M, Ogura K, Kawabe T, Ichinose M, Omata
M.: Outcomes of endoscopic submucosal dissection for colorectal epithelial neoplasms in 200
consecutive cases. Clin Gastroenterol Hepatol.
2007; 5(6):678-83.
(6) Kondo S, Yamaji Y, Watabe H, Yamada A, Sugimoto T, Ohta M, Ogura K, Okamoto M, Yoshida
H, Kawabe T, Omata M.: A randomized controlled trial evaluating the usefulness of a transparent hood attached to the tip of the colonoscope.
Am J Gastroenterol. 2007; 102(1):75-81.

390

University hospital Medical
Information Network (UMIN)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Noriaki Aoki, M.D., Ph.D., M.S., M.B.A.

Homepage

http://www.umin.ac.jp/umin/

Introduction and Organization
The University hospital Medical Information Network(UMIN) (the original name was the University
Medical Information Network), was established in
1989. While general-use computer systems were
implemented at all national university hospitals
around the end of the Showa era (late 1980s), Dr.
Shigekoto Kaihara, chair and professor at the HospitalComputer Center, University of Tokyo Hospital, led aproject to connect these computer systems in a
network in order to share information for better
communication. Finally, the Ministry of Education,
Culture, Sports, Science and Technology approved abudget to initiate the UMIN Center. The UMIN Center
was founded within the Hospital Computer Center,
University of Tokyo Hospital, and was officiallyopened in March 1989.
Dr. Tsunetaro Sakurai
became an associate professor as the first full-time
UMIN staff. The following are the objectives of the
UMIN Center, as initially outlined in 1989 (No.6 wasadded later):
1. Provide up-to-date information for healthcare
professionals
2. Promote digitalized communication among
healthcare professionals
3. Support collaborative projects among university

hospitals
4. Support collaborative medical research
5. Standardize data format and support datacollection
6. Support medical education and clinical training
The original UMIN system utilized an N1 protocol,
which was developed in Japan and was the only
solution at the time to connect general-use computersof the five major computer vendors in Japan, although
it was poor in function, supporting only line-mode,character-based terminals.
In 1994, we launched a service through the Internet,
and it began to spread in those days. The number of
UMIN users gradually increased, mainly in the E-mailservice.
In 1996, Dr. Takahiro Kiuchi took up a new post while
Dr. Sakurai was promoted to professor at Hokkaido
University. Dr, Kiuchi updated the system to be
web-based. With the rapid spread of the Internet in
Japan, UMIN users dramatically increased.
The UMIN Center subsequently started to provide
three major information services: (1) the ELBIS(Electronic Library for Biomedical Sciences) as of1997, (2) the INDICE (Internet Data and Information
Center of Clinical Research) as of 2000, and (3) the
EPOC (Evaluation System of Postgraduate ClinicalTraining) as of 2004.

391

In April 2002, the UMIN Center became an
independent entity, with the adjusted name of
University Hospital Medical Information Network
Center, as per an internal arrangement at the
University of Tokyo Hospital. In 2003, a budget for
a new professor position was officially approved by
the Ministry of Education, Culture, Sports, Scienceand Technology. Then, Dr. Kiuchi was promoted to
become the first professor of the UMIN Center on
April 1, 2004. On October 1, 2004, Ms. Hisako
Matsuba arrived to take on the position of research
associate that is a lower part diverted the associate
professor position She resigned from her position at
the end of March, 2006, and Dr. Noriaki Aoki,
formerly an assistant professor at the School of Health
Information Sciences, University of Texas Health
Science Center at Houston, became associate
professor at the Center. The UMIN Center became
part of the Faculty of Medicine, as the Department of
Health Communication, School of Public Health,which was established in April 2007.

Clinical Activities
Although the UMIN Center is one of the central
medical examination and treatment institutions of the
University of Tokyo Hospital, the center does notprovide direct patient care services, but provides
services for medical researchers and practitioners
throughout Japan. We currently have about 290,000
registrants, and approximately 40,000,000 monthly
website accesses, which is currently in the scale of theworld’s highest access rates. The service extends tostudy / education / medical examination and treatment/ hospital duties and encompasses many divergences
as indicated below:
 Research: http://www.umin.ac.jp/research
AC:
Information for Academic Conferences
ELBIS:
Electronic Library for Biomedical
Sciences
FIND:
Fund Information Database
INDICE: Internet Data and Information Center ofClinical Research
ROCOLS: Recruiting System for Our Colleagues’
and Students’ Education:
http://www.umin.ac.jp/education/

A Web-QME:
Web-based Quality Management System
for Education
SUPERCOURSE:
Online Lectures Compiled by Pittsburgh
Univ., U.S.A
VHP:
Visible Human Project Image Data
EPOC:
Evaluation System of Postgraduate
Clinical Training
Debut:
Dental Training Evaluation andTabulation System
 Medical Examination and Treatment
http://www.umin.ac.jp/uhosp/• Intoxication database• HIV treatment manual• Medical supplies and materials database• Drug information text database for patients• Drug information text database forpharmacists• Standardized nursing procedures database• Ministry of Education, Culture, Sports,
Science and Technology document public
information system• Basic hospital statistics database• National university hospital-related medical
dispute report• Collection of advanced medical procedures
application• Lists for people and committees• Various government official appointments,
administrative websites and ML
 General Services(1) General information and search•••

Medical / biology related websites
Medical terminology
A medical research organization / medical
institution database(2) Services for information providers••••

Web service for public
Web service for members
Website preservation service
Video-on-demand (VOD) and streaming
service392(3) Communication support
•
•
•
•
•

E-mailListserv
News group
Discussion board
File exchange

Teaching Activities
We provide briefing sessions and symposiums todisseminate and promote services offered by the
UMIN center. In 2005, the UMIN Center held briefing
sessions and symposiums for medical supplies adverse
event report system, thalidomide registration system,
clinical test registration system, and dental training
evaluation system. In 2006, we held briefing sessions
and symposiums for Safety Management System for
Unapproved Drugs, Individual Case Safety Reports.
These sessions and symposiums were broadcasted
through the MINCS system, and can be downloaded
as VOD from the UMIN server. Please refer
Department of Health Communication for detail
information about graduate and undergraduate
education.

Research Activities
Please refer to the Department ofCommunication about research activities.

References
See Department of Health Communication page

Health393

Organ Transplantation Service
Director Professor
Norihiro Kokudo

Homepage
Organ Transplant Service started to function since2003. In the Western countries the solid organtransplantation is widely performed. In contrast,
deceased donor organs are extremely rare in the East
due to religious and cultural traditions. In Japan thenumber of the recipients from the deceased donors has
been limited. The University of Tokyo Hospital has
aggressively performed organ transplantation. In 1966,
kidney transplantation for chronic renal failure was
firstly performed in Japan. In 1996 the living donorliver transplantation was performed and totally 406
patients underwent liver transplantation until
December, 2007. The 5-year survival rate is around
85% which is much superior to the national average(~70%). The University of Tokyo Hospital has been
one of the authorized institutions for hearttransplantation.

References (2007)
1. Yuan P, Tang W, Kokudo N, Hasegawa K, Xiang
C, Li QM, Luo H, Wen J, Liang BH, Aoki T,
Zhang KM, Sugawara Y, Imamura H, Sano K,
Makuuchi M. Demographic and clinicalcharacteristics of resectable hepatocellular
carcinoma in China and Japan. Hepatogastroenterology. 2007 Dec;54(80):2343-7.
2. Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Moriya K, Koike K, Makuuchi M.
Impact of new methicillin-resistant Staphylococcus aureus carriage postoperatively after living
donor liver transplantation. Transplant Proc. 2007
Dec;39(10):3271-5.
3. Akamatsu N, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Makuuchi M. Impact of live
donor age (>or=50) on liver transplantation.

Transplant Proc. 2007 Dec;39(10):3189-93.
4. Zhang K, Kokudo N, Hasegawa K, Arita J, Tang
W, Aoki T, Imamura H, Sano K, Sugawara Y,
Makuuchi M. Detection of new tumors byintraoperative ultrasonography during repeatedhepatic resections for hepatocellular carcinoma.
Arch Surg. 2007 Dec;142(12):1170-5; discussion
1176.
5. Kyoden Y, Tamura S, Sugawara Y, Akamatsu N,
Matsui Y, Togashi J, Kaneko J, Makuuchi M.
Biliary complications in right lateral sector graft
live donor liver transplantation. Transpl Int. 2008
Apr;21(4):332-9. Epub 2007 Dec 5.
6. Shindoh J, Kokudo N, Miura Y, Satoh S,
Matsukura A, Imamura H, Makuuchi M. In situ
hepatic vein graft: a simple new technique forhepatic venous reconstruction. Hepatogastroenterology. 2007 Sep;54(78):1748-51.
7. Hashimoto M, Miki K, Beck Y, Kokudo N,
Makuuchi M, Tanaka H. Femoral neck fracture as
a complication of lipase-secreting pancreaticacinar cell carcinoma. Surgery. 2007 Nov;142(5):779-80. .
8. Sugawara Y, Tamura S, Makuuchi M. Living
donor liver transplantation for hepatocellular
carcinoma: Tokyo University series. Dig Dis.
2007;25(4):310-2.
9. Akamatsu N, Sugawara Y, Kaneko J, Tamura S,
Makuuchi M. Preemptive treatment of fungal
infection based on plasma (1 --> 3)beta-D-glucan
levels after liver transplantation. Infection. 2007
Oct;35(5):346-51. Epub 2007 Sep 20.PMID:
17885729
10. Makuuchi M, Sugawara Y. Current status of livertransplantation for hepatocellular carcinoma fromliving donors.Hepatol Res. 2007 Sep;37 Suppl 2:

394

S277-8.
11. Tsujino T, Kogure H, Sasahira N, Isayama H,
Tada M, Kawabe T, Omata M, Akahane M, Sano
K, Makuuchi M. A huge intra-abdominal mass ina young man.Gut. 2007 Oct;56(10):1372, 1393. .
12. Ishizawa T, Hasegawa K, Ikeda M, Aoki T, Sano
K, Imamura H, Kokudo N, Makuuchi M.
Transhepatic approach for a small paracaval
tumor in repeat resection. Dig Surg. 2007;24(6):409-12. Epub 2007 Sep 13.
13. Takemura N, Sugawara Y, Tamura S, Makuuchi
M. Liver transplantation using hepatitis B core
antibody-positive grafts: review and university ofTokyo experience. Dig Dis Sci. 2007 Oct;52(10):2472-7. Epub 2007 Mar 16
14. Hashimoto M, Beck Y, Mise Y, Kokudo N,
Makuuchi M. Celiac axis compression during the
expiratory phase as a cause of hepatic ischemia
during pancreaticoduodenectomy. Surgery. 2007
Sep;142(3):429-30.
15. Torzilli G, Donadon M, Palmisano A, Del Fabbro
D, Spinelli A, Makuuchi M, Montorsi M.
Back-flow bleeding control during resection ofright-sided liver tumors by means of ultrasoundguided finger compression of the right hepaticvein at its caval confluence. Hepatogastroenterology. 2007 Jul-Aug;54(77):1364-7.
16. Hashimoto T, Kokudo N, Hasegawa K, Sano K,
Imamura H, Sugawara Y, Makuuchi M.
Reappraisal of duct-to-duct biliary reconstructionin hepatic resection for liver tumors. Am J Surg.
2007 Sep;194(3):283-7.
17. Kaneko J, Sugawara Y, Yanhong Q, Makuuchi M.
Education and Imaging. Hepatobiliary andpancreatic: extended directional power Doppler
ultrasonography in liver transplantation. J Gastroenterol Hepatol. 2007 Aug;22(8):1345. .
18. Hasegawa K, Kokudo N, Makuuchi M. Surgicalmanagement of hepatocellular carcinoma. Liver
resection and liver transplantation. Saudi Med J.
2007 Aug;28(8):1171-9. Review.
19. Kyoden Y, Sugawara Y, Kaneko J, Kishi Y,
Akamatsu N, Makuuchi M. Hepatofugal portal
flow after living donor liver transplantation.
Hepatogastroenterology. 2007 Jun;54(76):1164-6.
20. Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Moriya K, Koike K, Makuuchi M.

Methicillin-resistant
Staphylococcus
aureusinfection after living-donor liver transplantation in
adults. Transpl Infect Dis. 2008 Apr;10(2):110-6.
Epub 2007 Jul 1.
21. Tsujino T, Sugawara Y, Kawabe T, Makuuchi M,
Omata M. Foreign body (suture thread) in the bile
duct after living donor liver transplantation. Liver
Transpl. 2007 Jul;13(7):1065-6.
22. Kishi Y, Sugawara Y, Kaneko J, Tamura S,
Matsui Y, Makuuchi M. Blood eosinophilia after
living donor liver transplantation for hepatitis C
virus-related cirrhosis. Transplant Proc. 2007 Jun;
39(5):1540-3.
23. Kokudo N, Sasaki Y, Nakayama T, Makuuchi M.
Dissemination of evidence-based clinical practiceguidelines for hepatocellular carcinoma among
Japanese hepatologists, liver surgeons andprimary care physicians. Gut. 2007 Jul;56(7):1020-1.
24. Yamamoto J, Kosuge T, Saiura A, Sakamoto Y,
Shimada K, Sano T, Takayama T, Sugawara Y,
Yamaguchi T, Kokudo N, Makuuchi M.
Effectiveness of hepatic resection for early-stage
hepatocellular carcinoma in cirrhotic patients:
subgroup analysis according to Milan criteria. Jpn
J Clin Oncol. 2007 Apr;37(4):287-95.
25. Sugawara Y, Tamura S, Makuuchi M. Systematic
grading of surgical complications in live liver
donors. Liver Transpl. 2007 Jun;13(6):781-2.
26. Hashimoto T, Sugawara Y, Makuuchi M. Impact
of human leukocyte antigen mismatching on
outcomes of living donor liver transplantation forprimary biliary cirrhosis. Liver Transpl. 2007 Jun;
13(6):938-9.
27. Seyama Y, Makuuchi M. Current surgicaltreatment for bile duct cancer. World J Gastroenterol. 2007 Mar 14;13(10):1505-15. Review.
28. Midorikawa Y, Makuuchi M, Tang W, Aburatani
H. Microarray-based analysis for hepatocellular
carcinoma: from gene expression profiling to newchallenges. World J Gastroenterol. 2007 Mar 14;
13(10):1487-92. Review.
29. Hashimoto T, Kokudo N, Orii R, Seyama Y, Sano
K, Imamura H, Sugawara Y, Hasegawa K,
Makuuchi M.Intraoperative blood salvage during
liver resection: a randomized controlled trial.Ann
Surg. 2007 May;245(5):686-91.

395

30. Arita J, Kokudo N, Zhang K, Makuuchi M.
Three-dimensional visualization of liver segmentson contrast-enhanced intraoperative sonography.
AJR Am J Roentgenol. 2007 May;188(5):W4646.
31. Kishi Y, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Makuuchi M. Histologic eosinophilia
as an aid to diagnose acute cellular rejection after
living donor liver transplantation. Clin Transplant.
2007 Mar-Apr;21(2):214-8.
32. Inagaki Y, Tang W, Guo Q, Kokudo N, Sugawara
Y, Karako H, Konishi T, Nakata M, Nagawa H,
Makuuchi M. Sialoglycoconjugate expression inprimary colorectal cancer and metastatic lymph
node tissues. Hepatogastroenterology. 2007 JanFeb;54(73):53-7.
33. Kokudo N, Hasegawa K, Makuuchi M. Control
arm for surgery alone is needed but difficult toobtain in randomized trials for adjuvant
chemotherapy after liver resection for colorectal
metastases. J Clin Oncol. 2007 Apr 1;25(10):1299-300; author reply 1300.
34. Guo Q, Tang W, Inagaki Y, Kokudo N, Sugawara
Y, Karako H, Nakata M, Makuuchi M.
Subcellular localization of KL-6 mucin incolorectal carcinoma cell lines: association withmetastatic potential and cell morphology. Oncol
Rep. 2007 May;17(5):1057-60.
35. Akamatsu N, Sugawara Y, Tamura S, Togashi J,
Kaneko J, Makuuchi M.Late mortality fromthrombotic microangiopathy after liver transplantation: report of a case. Surg Today. 2007;
37(4):345-8. Epub 2007 Mar 26.
36. Hashimoto M, Beck Y, Hashimoto T, Kokudo N,
Makuuchi M. Preservation of thick middle hepaticvein
tributary during
rightparamedian
sectoriectomy. Surgery. 2007 Apr;141(4):546-7.
Epub 2007 Mar 9.
37. Khan AZ, Makuuchi M. Trends in the surgicalmanagement of Klatskin tumours.Br J Surg. 2007
Apr;94(4):393-4.
38. Tamura S, Sugawara Y, Makuuchi M. Impact ofrecipient age on the long-term outcome of living
donor liver transplantation for post-kasai biliaryatresia. Am J Transplant. 2007 Mar;7(3):728.
39. Tang W, Guo Q, Qu X, Inagaki Y, Seyama Y,
Midorikawa Y, Gai R, Kokudo N, Sugawara Y,

Nakata M, Makuuchi M. KL-6 mucin is a usefulimmunohistochemical marker for cholangiocarcinoma. Oncol Rep. 2007 Apr;17(4):737-41.
40. Hashimoto M, Miki K, Kokudo N, Beck Y,
Makuuchi M.A long-term survivor of metastatic
acinar cell carcinoma. Pancreas. 2007 Mar;34(2):271-2.
41. Dulundu E, Sugawara Y, Kaneko J, Kishi Y,
Akamatsu N, Matsui Y, Kokudo N, Makuuchi M.
Short hepatic vein reconstruction in biliary atresia
patients with absent inferior vena cava. Clin
Transplant. 2007 Jan-Feb;21(1):13-7.
42. Sakata H, Sugawara Y, Makuuchi M. Educationand imaging. Hepatobiliary and pancreatic: acute
Budd-Chiari syndrome treated by systemic
thrombolytic therapy. J Gastroenterol Hepatol.
2007 Mar;22(3):444.
43. Satou S, Sugawara Y, Tamura S, Kishi Y, Kaneko
J, Matsui Y, Kokudo N, Makuuchi M.Threedimensional computed tomography for planning
donor hepatectomy. Transplant Proc. 2007 JanFeb;39(1):145-9.
44. Hashimoto T, Sugawara Y, Tamura S, Kaneko J,
Motomura N, Takamoto S, Makuuchi M. One
orifice vein reconstruction in left liver plus
caudate lobe grafts. Transplantation. 2007 Jan
27;83(2):225-7.
45. Arita J, Kokudo N, Hasegawa K, Sano K,
Imamura H, Sugawara Y, Makuuchi M.Hepatic
venous thrombus formation during livertransection exposing major hepatic vein. Surgery.
2007 Feb;141(2):283-4. Epub 2007 Jan 4.
46. Tamura S, Sugawara Y, Kaneko J, Matsui Y,
Togashi J, Makuuchi M. Recurrence of primarysclerosing cholangitis after living donor livertransplantation. Liver Int. 2007 Feb;27(1):86-94.
47. Ishizawa T, Hasegawa K, Sano K, Imamura H,
Kokudo N, Makuuchi M. Selective versus total
biliary drainage for obstructive jaundice caused
by a hepatobiliary malignancy. Am J Surg. 2007
Feb;193(2):149-54.
48. Tamura S, Sugawara Y, Makuuchi M.
Choledochotomy in live liver donors. Liver
Transpl. 2007 Jan;13(1):173; author reply 174.
49. Torzilli G, Del Fabbro D, Palmisano A, Marconi
M, Makuuchi M, Montorsi M. Salvage hepatic
resection after incomplete interstitial therapy for396

primary and secondary liver tumours. Br J Surg.
2007 Feb;94(2):208-13.
50. Nakamura N, Igaki H, Yamashita H, Shiraishi K,
Tago M, Sasano N, Shiina S, Omata M, Makuuchi
M, Ohtomo K, Nakagawa K. A retrospective
study of radiotherapy for spinal bone metastases
from hepatocellular carcinoma (HCC). Jpn J Clin
Oncol. 2007 Jan;37(1):38-43. Epub 2006 Dec 1

397

Department of Epidemiology andPreventive Medicine
Director & Professor
Tsutomu Yamazaki, M.D., Ph.D. (Department of Clinical Epidemiology and Systems)

Associate Professor
Toru Suzuki, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Associates
Yumiko Oike, M.D., Ph.D.,
Yoshinari Asaoka, M.D., Ph.D.
Kenichi Aizawa, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Homepage:

http://www.h.u-tokyo.ac.jp/patient/depts/kenshin.html

Introduction and Organization
Following the inauguration of a new Central Clinical
Service Building (Central Care 2) in November 2006
(Heisei 18) in the University of Tokyo Hospital, theDepartment of Epidemiology and Preventive
Medicine was established on January 1, 2007, within
the Central Clinical Facilities and the relevant
regulations were revised. On January 9, the Working
Group for the Establishment of the Department of
Epidemiology and Preventive Medicine wasorganized; on April 1, Steering Committee for the
Establishment of the Department of Epidemiology andPreventive Medicine was organized; preparation foroffering its services continued until May 31; on June 4,
the department started offering its services on a trial
basis (in-hospital services) and was officiallyinaugurated in July, starting to provide public
services.
The principal objectives of the establishment of
the Department of Epidemiology and Preventive
Medicine are 1) to scientifically demonstrate theutility and effectiveness of examinations andpreventive interventions, 2) to integrate a vast amountof clinical data and health-related information todevelop more efficient models for disease
management, 3) by doing the above 1) and 2), topromote preventive medicine and medicine for healthpromotion in an effort to contribute to theimprovement of public health, and 4) to train medical
personnel who can put the above 1), 2) and 3) into
practice.
In the administrative organization of the
Department of Epidemiology and Preventive
Medicine, its Director directly under the Director of
the Hospital is responsible for the entire organization.
The management of the Department is also supportedby the Department of Clinical Epidemiology and
Systems and the Department of Ubiquitous Preventive
Medicine. In addition, examinations in the
Department are administered in collaboration withthree Central Clinical Facilities (Clinical Laboratory
Center, Radiological Center, and Department ofEndoscopy and Endoscopic Surgery) and four Clinical
Divisions(Breastand
Endocrine
Surgery,
Gynecologic Surgery, Ophthalmology and VisionCollection, and Oral-Maxillofacial Surgery, Dentistry
and Orthodontics).
The staff of the Department of Epidemiology andPreventive Medicine is composed of five physicians

398(two regular physicians and three physicians from therelated departments). One of the regular physiciansalso performs upper gastrointestinal endoscopy andcolonoscopy in the Department of Endoscopy andEndoscopic Surgery. Our department also has three
regular nurses and three regular secretaries (from theMedical Affairs Department). When our department
was established, the number of staff was increased inother divisions. Among our staff, one nurse (fulltime), three radiological technologists (full-time) andthree medical technologists (full-time) are assigned
respectively to the Department of Endoscopy andEndoscopic Surgery, the Radiological Center and theClinical Laboratory Center.

Clinical activities
In addition to basic examinations which are open
to the public, our department provides these nine
options: 1) comprehensive cardiovascular examinations, 2) comprehensive cerebrovascular examinations,3) colorectal cancer screening, 4) uterine cancer
screening, 5) breast cancer screening, 6) lung cancer
screening, 7) tumor marker diagnosis, 8) estimation ofgastric cancer risk, and 9) oral/dental examinations.
While meeting the needs of examinees, we haveincreased the number of the optional examinations andprovided higher levels of examinations.
The physicians of our department are responsible
for analyzing the results of examinations andscreenings, performing overall evaluations, andconsultations with examinees. One of our important
services is that we take approximately 30 minutes per
examinee to perform comprehensive medical
examinations. Formally, the examinee is notified inwriting of the results within approximately two weeks
after the examination. We also offer each examinee afree 20-minute consultation so that we can help
him/her understand the results or decide whether or
not to have further work-up.

Teaching activities
Although our department has no students directly
under our supervision being a clinical service, weoffer education in epidemiology to graduate students
in the Department of Clinical Epidemiology and

Systems and the Department of Ubiquitous Preventive
Medicine.

Research activities
The University of Tokyo Hospital is expected not only
to provide its service of comprehensive medical
examinations but also to promote evidence-based
practice and scientific examinations, which is themission of our department. Academically, we aim toestablish a database from clinical data and to promoteepidemiological research. This will enable us toprevent disease based on scientific data. In 2007, thefirst year of our department, we collected data on
examinees and designed a pilot database. From 2008
onward, we continue to collect data and conduct theircross-sectional and longitudinal analysis.

Past activities
In the fiscal year (FY) 2007 from July 1, 2007 to
March 31, 2008, the total number of examinees (whohad basic examinations and optional examinations)was 2,603, including 838 in basic examinations, 294
in complete cardiovascular examinations, 113 incomplete cerebrovascular examinations, 155 incolorectal cancer screening, 185 in uterine cancer
screening, 205 in breast cancer screening, 282 in lungcancer screening, 324 in tumor marker diagnosis, 99
in estimation of gastric cancer risk, and 108 in
oral/dental examinations. In addition, in the 20 dayperiod from June 4 to 29, during which we offeredservices on a trial basis, the total number of examinees
was 130.
When examinees visit other departments in our
hospital for a work-up or treatment, we write a letterof referral by request. In the FY 2007, we issued 281
letters of referral to other departments in our hospitaland 20 to other hospitals.
We have expanded our public relations efforts andduring the FY 2007 our brochure has reached its
seventh edition and 20,000 copies were delivered. We
also prepared posters which were placed within our
hospital and on the campus of the University of Tokyo
as well (60 posters). Our homepage (the above URL)
has been constantly updated to provide the latest
information for examinees. The Department of399

Epidemiology and Preventive Medicine has attracted
much media attention and was covered by the press
including the well-known magazine, Yomiuri Weekly.

References
Academic Papers in English
1. Yamazaki T, Goto S, Shigematsu H, Shimada K,
Uchiyama S, Nagai R, et al. Prevalence,
Awareness and Treatment of Cardiovascular Risk
Factors in Patients at High Risk ofAtherothrombosis in Japan Results From
Domestic Baseline Data of the REduction of
Atherothrombosis for Continued Health (REACH)
Registry. Circulation J. 2007; 71: 995-1003.
2. Kohro T, Hayashi D, Okada Y, Yamazaki T, Nagai
R, The JCAD Investigators. Effects of medication
on cardiovascular events in the Japanese Coronary
Artery Disease (JCAD) Study. Circulation J.
2007; 71: 1835-1840.
3. Fujita M, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R, et al. Comparison of
Cardiovascular Events in Patients With
AngiographicallyDocumented
Coronary
Narrowing With Combined Renin-Angiotensin
System Inhibitor Plus Statin Versus ReninAngiotensin System Inhibitor Alone Versus Statin
Alone (from the Japanese Coronary Artery
Disease Study).
The American Journal of
Cardiology. 2007; 100(12):1750-3.
4. Muto S, Senda M, Akai Y, Sato L, Suzuki T,
Nagai R, Horikoshi M. Senda T: Relationshipbetween the structure of SET/TAF-Ibeta/INHAT
and its histone chaperone activity. Proc Natl Acad
Sci USA 104:4285-90, 2007
5. Suzuki T, Nishi T, Nagino T, Sasaki K, Aizawa K,
Kada N, Sawaki D, Munemasa Y, Matsumura T,
Muto S, Sata M, Miyagawa K, Horikoshi M,
Nagai R: Functional interaction between thetranscription factor Krüppel-like factor 5 and Poly
(ADP-ribose) polymerase-1 in cardiovascularapoptosis. J Biol Chem 282:9895-9901, 2007
6. Kada N, Suzuki T, Aizawa K, Matsumura T,
Ishibashi N, Suzuki N, Takeda N, Munemasa Y,
Sawaki D, Ishikawa T, Nagai R. Acyclic retinoid
inhibits neointima formation through retinoic acidreceptor beta-induced apoptosis. Arterioscler

Thromb Vasc Biol 27:1535-41, 2007
7. Suzuki T, Nagai R. Cardiovascular proteomic
analysis. J Chromatogr B Analyt Technol Biomed
Life Sci 855: 28-34, 2007
8. Tsai TT, Evangelista A, Nienaber CA, Myrmel T,
Meinhardt G, Cooper JV, Smith DE, Suzuki T,
Fattori R, Llovet A, Froehlich J, Huchison S,
Distante A, Sundt T, Beckman J, Januzzi JL Jr,
Isselbacher EM, Eagle KA; International Registryof Acute Aortic Dissection. Partial thrombosis of
the limen in patients with acute type B aortic
dissection. N Engl J Med. 357:349-359, 2007
9. Pape LA, Tsai TT, iiselbacher EM, Oh JK, O’gara
PT, Evangelista A, Fattori R,
Meinhardt G,
Trimarchi S, Bossonr E, Suzuki T, Cooper JV,
Froenhlich JB, Nienaber CA, Eagle KA; on behalfof the International Registry of Acute Aortic
Dissection (IRAD) Investigators. Aortic diameter>=5.5cm Is Not a good predictor of type A aortic
dissection: observations from the international
registry of acute aortic dissection (IRAD).
Circulation. 116:1120-7, 2007
Academic Papers in Japanese
1. Suzuki T and Nagai R, Biochemical diagnosis ofaortic dissection, Japanese Journal of Intensive
Care Medicine, 31 (extra edition 8): 615-620,
2007
2. Fujimoto H and Suzuki T, Determination of risk
factors and treatment effects (basic research):
proteomics in cardiovascular disease, Journal of
Clinical and Experimental Medicine, 221 (extra
edition 13): 1058-1062, 2007
3. Suzuki T and Nagai R, Diagnostic significance ofoxidized LDL, The Lipid 18 (extra edition 1):
22-25, 2007
4. Suzuki T and Fujimoto H, Proteomic analysis ofcardiovasculardisease,Cell
technology,
Shujunsha, pp. 120-127, 2007
Books
1. Suzuki T, Sangiorgi G, Bossone E. Future
directions of aortic dissection. Baliga RR,
Nienaber CA, Isselbacher EM, Eagle KA eds. In:
Aortic dissection and related syndromes.
Springer pp.317-332, 2007
2. Suzuki T, The University of Tokyo Open Lecture
DVD Series; 1. Topics in Clinical Medicine vol.
09: Proteomics (editorial supervisor, Nagai R),

400

SCICUS K.K., 2007
Reviews
Suzuki T, Elucidation of the mechanisms ofvascular oxidative stress using proteomic methods,
Research Report of Takeda Medical Research
Foundation 34: 101-109, 2007
International Conferences
1. Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Kada N, Mizuno Y, Munemasa Y, Nagai R.
Krüppel-like factor 5 promotes vascularremodeling in biphasic ways; inhibition ofvascular smooth muscle cell (VSMC) apoptosis
and stimulation of cell growth. American Heart
Association, Scientific Sessions 2007 (Orlando,
FL, USA: November 4-7, 2007)
2. Aizawa K, Suzuki T, Matsumura T, Kada N,
Sawaki D, Zhan H, Nagai R: Proteome analysis ofa regulatory pathway of pathologic vascular injury
as mediated by KLF5 and its transcriptional
complexes.
AmericanHeart
Association,
Scientific Sessions 2007 (November 4-7, 2007,
Orlando, Florida, U.S.)
3. Suzuki T, Distante A, Sabino F, Sizza A, Villani M,
Fazzi V, Trimarchi S, Donato SP, Salerno J,
Fracell S, Ignone G, Rinaldis G, Nowak R,
Birkhahn R, Hollander J, Counselman F, Bossone
E, Eagle K. A Biomarker for Diagnosing Acute
Aortic Dissection: Preliminary Experience with
the Smooth Muscle Troponin-Like Protein,Calponin. (American College of Cardiology, 56th
Annual Scientific Session, March 24-27, 2007,
New Orleans, USA)
4. Asaoka Y, Tateishi K, Lin L, Seto M, Ohta M,
Tada M, Tanaka Y, Kanai F, Isayama H, Tada M,
Kawabe T, Omata M: Absence of EGFR Hotspot
Mutation in Intrahepatic Cholangiocarcinoma inJapanese Patients. 17th APASL Conference（March 27-30,2007, Kyoto, Japan.）
5. Akishita M, Ohike Y, Hashimoto M, Iiijima K,
Eto M, Teramoto S, Ouchi Y: Obstructive Sleep
Apnea Exacerbates Endothelial Dysfunction In
Patients With Metabolic Syndrome. American
Heart Association, Scientific Session 2007
(November 4-7, 2007, Orlando, Florida, U.S.)
National Conferences
1. Suzuki T. Proteomic analysis in search of new
cardiovascular pathophysiological factors and

2.

3.

4.

5.

6.

7.

8.

mechanism. (New Approaches to Heart Failure:
From Pharmacogenomics to Drug Development).
Plenary Session 4. The 71st Annual Scientific
Meeting of the Japanese Circulation Society(March 15-17, 2007, Kobe, Japan)
Aizawa K, Suzuki T, MatsumuraT, Sawaki D,
Kada N, Nagai R. Angiotensin II activates the
DNA damage response through nitric oxide invascular endothelial cells. The 71st Annual
Scientific Meeting of the Japanese Circulation
Society (March 15-17, 2007, Kobe, Japan)
Aizawa K, Suzuki T, Matsumura T, Sawaki D,
Kada N, Nagai R. A novel regulatory pathway of
DNA damage response to pathologic vascular
injury as mediated by KLF5 and its transcriptional
complexes. The 71st Annual Scientific Meeting of
the Japanese Circulation Society (March 15-17,
2007, Kobe, Japan)
Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Kada N, Mizuno Y, Munemasa Y, Nagai R.
Krüppel-like factor 5 directly stimulates cell
growth in vascular lesions. The 71st Annual
Scientific Meeting of the Japanese Circulation
Society (March 15-17, 2007, Kobe, Japan)
Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Kada N, Mizuno Y, Munemasa Y, Nagai R.
Modulation of ubiquitin-proteasomal degradationof KLF5 influences vascular remodeling. The 71st
Annual Scientific Meeting of the Japanese
Circulation Society (March 15-17, 2007, Kobe,
Japan)
Kada N, Suzuki T, Aizawa K, Matsumura T,
Takeda N, Sawaki D, Nagai R. Acyclic retinoid
inhibits neointima formation through retinoic acidreceptor beta-induced apoptosis. The 71st Annual
Scientific Meeting of the Japanese Circulation
Society (March 15-17, 2007, Kobe, Japan)
Kada N, Suzuki T, Aizawa K, Matsumura T,
Sawaki D, Munemasa Y and Nagai R, Acyclic
retinoid inhibits neointima formation through
RARbeta-induced apoptosis, The University ofTokyo
ClinicalDevelopment
Research
Symposium (Tokyo; March 2, 2007)
Sawaki D, Suzuki T, Nagai R. The effects of
adenovirus-mediated overexpression of the
cardiovascular transcription factor KLF5 on
vascular remodeling, The University of Tokyo401

Clinical Development Research Symposium(Tokyo; March 2, 2007)
9. Munemasa Y, Suzuki T, Aizawa K, Miyamoto S,
Imai Y, Matsumura T, Mizuno Y, Kada N, Sawaki
D and Nagai R, Promoter region-specific histone
incorporation by histone chaperone p32 andDNA-binding factor KLF5, BMB2007 (the 30th
Annual Meeting of the Molecular Biology Societyof Japan and the 80th Annual Meeting of theJapanese Biochemical Society; Tokyo; December
11-14, 2007)
10. Asaoka Y, Lin L, Tada M, Kawabe T, Omata M.
High-Resolution Genomic Profiling in Human
Pancreatic Cancer Cell Lines Using Single
Nucleotide Polymorphism Array. The 38th Annual
Meeting of the Japan Pancreas society (June28-29, 2007, Fukuoka)
11. Nomura K, Akishita M, Nakamura T, Yamada Y,
Kojima T, Ohike Y, Iijima K, Araki A, Eto M,
Ouchi Y. A clinical study about the effect ofvisceral fat to multiplication of risk factors foratherosclerosis of the elderly. The 104th Annual
Meeting of Internal Medicine (April 3-5, 2007,
Osaka)
12. Ohike Y, Akishita M, Yamamoto H, Yamaguchi Y,
Kojima T, Ogawa S, Teramoto S, Iijima K, Eto M,
Ouchi Y. Gender differences and age-relatedchanges of depressive state and cognitive functionof geriatric inpatients. The 49th Annual Meetingof the Japan Geriatric Society (June 20-22, 2007,
Sapporo)13. Kojima T, Akishita M, Ohike Y, Iijima K, Eto M,
Nakamura T, Toba K, Ouchi Y. The effects oflifestyle-related diseases and medication to therisk of fall of the elderly. The 49th Annual
Meeting of the Japan Geriatric Society (June20-22, 2007, Sapporo)
14. Kojima T, Akishita M, Ota H, Nomura K, Ohike Y,
Ogawa S, Iijima K, Eto M, Ouchi Y. The
efficacy and safety of the change of medicationfrom ARB alone to a combination of ARB andantihypertensive diuretics of the patients ofelderly hypertension. The 49th Annual Meeting of
the Japan Geriatric Society (June 20-22, 2007,
Sapporo)15. Nomura K, Akishita M, Nakamura T, Kojima T,
Ohike Y, Iijima K, Eto M, Ouchi Y. An

investigation of the relationship between
calcification of abdominal aorta and renal
dysfunction. The 39th Annual Meeting of Japan
Atherosclerosis Society(July 13-14, 2007,
Osaka)
16. Kojima T, Akishita M, Nakamura T, Ohike Y,
Nomura K, Ogawa S, Iijima K, Eto M, Ouchi Y.
The effects of medication and hypertension status
to the risk of fall of the elderly. The 30th Annual
Scientific Meeting of the Japanese Hypertension
Society (October 25, 2007, Okinawa)
Lectures
1. Suzuki T, lecture entitled “Which is better as
clinical data on heart failure, echocardiography or
BNP?” in the "Fireside Seminar" of the 11th
Annual Scientific Meeting of the Japanese Heart
Failure Society (September 9, 2007; Hilton TokyoBay)
2. Suzuki T, lecture entitled “Cardiovascularbiomarkers and proteomic discovery” in the 21stCentury COE Program Academic Lecture, The
University of Tokyo, "Meet The Specialist 2007"(August 24, 2007; Conference Room on the 7th
floor of Central Care 2, The University of Tokyo
Hospital)

402

Division of Tissue Engineering
Director & Professor
Tsuyoshi Takato, M.D., Ph.D.

Vice Director & Visiting Professor
Ung-il Chung, M.D., Ph.D.

Visiting Associate Professors
Keiichi Hishikawa, M.D., Ph.D.,

Kazuto Hoshi, M.D., Ph.D.,

Hiroyuki Koyama, M.D., Ph.D.,

Seishi Ogawa, M.D., Ph.D.,

Satoru Yamagami, M.D., Ph.D.

Visiting Research Associates
Yuko Fujihara, D.D.S., Ph.D.,

Toshiyuki Ikeda, M.D.,

Takeshi Marumo, M.D., Ph.D.,

Naoshi Ogata, M.D., Ph.D.,

Makoto Ohba, Ph.D.,

Seiichi Yokoo, Ph.D.

Homepage

http://square.umin.ac.jp/t-e/

Introduction and Organization
Division of Tissue Engineering was established as a
special medical office in The University of Tokyo
Hospital, in October 2001 and has a fully equipped
800 m2 laboratory on the 8th floor of the Inpatient
Word B. Division of Tissue Engineering consists of
Department of Bone & Cartilage Regenerative
Medicine, Department of Vascular Regeneration,
Department
ofRegeneration
Medicine
forHematopoiesis, Department of Corneal Tissue
Regeneration, Department of Clinical Renal
Regeneration, Department of Cartilage & BoneRegeneration. We have invited talented personnel ofvarious fields from home and abroad. One visiting
associate professor and one or two visiting research
associates who are assigned to each department are
conducting research with many post graduate students.
Aiming at clinical application within a few years, theresearchers continue their studies to make the center
function as a translational research center.
Tie-up with companies, technical transfer, patenting

developed technologies, producing materials fortreatment at a GMP level, safety evaluation studies
and organization for clinical trials are necessary inorder to realize regenerative medicine, which is now
recognized as a national project. As foundation andoperation of venture companies as well as
industry-university-government
cooperationisessential to the success, it seems that state-level
efforts are necessary. It is expected that broad progressin tissue engineering technologies and regenerative
medicine contributes to treatment and drug discoveryof all medical fields regardless of specialties.
October, 2001 Division of Tissue Engineeringfounded as special medical office in the Universityof Tokyo Hospital.
June, 2002 Department of Corneal Tissue
Engineering founded by a donation from HOYA healthcare CO., Ltd.
July, 2002 Department of Vascular Regeneration
founded by a donation from Daiichi PharmaceuticalCo., Ltd.

403

July, 2002 Department of Bone & Cartilage
Regenerativen Medicine founded by a donation from
TAKEDA Chemical Industries., Ltd.
September, 2002 Department of Regeneration
medicine for Hematopoiesis founded by a donationfrom KIRIN Brewery Co., Ltd.
November, 2002 Department of Clinical Renal
Regeneration founded by a donation from MOCHIDA
Pharmaceutical Co., Ltd.
November, 2002 Department of MENICON
Cartilage & Bone Regeneration founded by a donationfrom MENICON Co., Ltd.
March, 2003 The Cell Processing Center set up on
the 8th floor of the Inpatients Ward B.
June, 2005 Department of Corneal Tissue
Regeneration was renewed by a donation fromAMNIO TEC Co., Ltd (now ArBlast Co., Ltd.)
July, 2005 Department of Bone & Cartilage
Regenerative Medicine was renewed by a donationfrom TAKEDA Chemical Industries, Ltd.
September, 2005 Department of Regeneration
Medicine for Hematopoiesis was renewed by adonation from KIRIN Brewery Co., Ltd.
November, 2005 Department of Clinical Renal
Regeneration was renewed by a donation fromMOCHIDA Pharmaceutical Co., Ltd.
November, 2005 By a donation from FUJISOFTABC Co., Ltd. Department of MENICON Cartilage &Bone Regeneration was renewed to Department ofFuji Software ABC Cartilage & Bone Regeneration.
July, 2007 Department of Bone & Cartilage
Regenerativen Medicine was renewed by a donationfrom Eli Lilly Japan K.K.

Research activities
As for corneal regeneration, we aim at constructionof regenerated cornea, clinical application of corneal
epithelial sheet transplantation for ocular surface
reconstruction and establishment and clinicalapplication of corneal endothelium transplantation. To
achieve these goals, we are conducting functional
analysis on cultured corneal cells, reconstruction of
cornea with cultured epithelium and endothelium, andartificial stroma, research on adult stem cell biology incorneal tissues and immunological analysis on
amniotic membrane for ocular surface reconstruction

As for vascular regeneration, we aim atestablishment of effective and safe “therapeutic
angiogenesis” and its clinical application, developmentof non-invasive soft-tissue reconstruction techniqueassisted by induction of angiogenic reactions anddevelopment of the techniques to induce
microcirculation to regenerated organs. To achievethese goals, we are conducting research on angiogenic
gene therapy using adenovirus vector, research on
angiogenic gene therapy using non-viral vector,
development of drug delivery method for therapeutic
angiogenesis and research on induction of angiogenic
reactions in soft-tissue.
As for bone and cartilage regeneration, we aim todevelop easy, precise, non-invasive systems to detect
osteoblastic and chondrocytic differentiation, todetermine a finite set of signaling factors sufficient for
induction of osteoblasts and chondrocytes, to develop
a cell-sheet culture system for bone and cartilage, todevise a method to induce osteogenesis andangiogenesis simultaneously, to screen for compounds
that induce bone and cartilage regeneration, todevelop non-viral gene transfer methods bynano-micelle technology and to generate andtransplant regenerated bone and cartilage. To achievethese goals, we are conducting research on bone andcartilage biology, developmental biology, stem cellbiology and regenerative medicine.
As for renal regeneration, we aim at clinicalapplication of kidney-derived adult stem cell, clinicalapplication of new scaffold material and matrix forrenal regeneration and clinical renal regeneration byusing cord blood. To achieve these goals, we areconducting research on adult stem cell biology inregeneration, comprehensive research on stem cell
dysfunction in renal failure and development of 3-D
culture system for induction of metanephros in vitro.
As for regenerative medicine for hematopoiesis, we
aim to develop effective systems for in vitro
expansion of cord blood hematopoietic stem cells(CB-HSCs) and its clinical application to humanhematopoietic stem cell transplantation, and for
inducing various hematopoietic components from
HSCs and embryonic stem cells. To achieve thesegoals, we are conducting research on the regulatory
mechanisms of proliferation, self-renewal, anddifferentiation of human hematopoietic stem cells

404(HSCs), plasticity of HSCs and clinical application of
the in vitro expansion and differentiation system of
HSCs.
In the department donated by FUJISOFT ABC, we
aim to produce regenerated cartilage and bone withhigh safety and usefulness, to realize production
system and establish practical quality control and topromote the application of regenerated cartilage andbone. To achieve these goals, we are conducting
research on adult stem cell biology in mesenchymal
tissues, application of molecular biology on cartilage
repair for regenerative medicine, development ofnovel scaffolds in cartilage and bone regeneration,
development of 3-D reconstruction system forregenerated tissues, evaluation on biochemical andbiophysical properties of regenerated tissues in vivo
and clinical trials and application of regenerated
cartilage and bones.
Basic Research on human ES cells
Besides, to promote basic research on humanembryonic stem cells with our eyes set on applicationsin the future, Department of Clinical Renal
Regeneration and Department of Bone and Cartilage
Regenerative Medicine are carrying forward theapplication procedures to obtain human ES cells from
Institute for Frontier Medical Sciences, Kyoto
University, which will be approved shortly.
Clinical Studies
Of particular note is clinical studies started in thefour departments as a result of basic research. In
Department
ofRegenerative
Medicine
forHematopoiesis, clinical study on expansion of human
cord blood hematopoietic cells (Institutional Review
Board approval number #351) has been started. In
Department of Vascular Regeneration, clinical studies
on claudication limbs and severe ischemic limbs
caused by peripheral vascular diseases (IRB approval
number #825 and #826) have been started andcontinued without causing major side effects. In
Department of Corneal Tissue Regeneration, clinicalstudies on transplantation of cultured autologous oral
mucous epithelial sheet on amniotic membrane forocular surface reconstruction, and corneal endothelial
stem cell transplantation for decrease in number ofcorneal endotheliums (IRB approval number #363 and#898) have been started. In Department of Bone &Cartilage Regenerative Medicine, clinical study onbone implants into non-loading parts (IRB approval
number #1310) will be started by the end of March.
As stated above, we are proceeding translational
research aiming at clinical application of tissue
engineering and regenerative medicine.
Contribution to the Hospital
Division of Tissue Engineering, as a cooperative
research facility in the Hospital, opens expensive
special machines that each laboratory cannot afford toequip with, such as a confocal laser scanningmicroscope, a cell analyzer and a cell sorter to the
Hospital staff, letting them use with cost sharing.
Department of Plastic Surgery is conducting researchusing this facility.

References
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Murakami A. Involvement of CCL2- CCR2
interaction in monocyte-lineage cell recruitmentof normal human corneal stroma. J Immunol.
2007;178:3288-92.
2. Yamagami S, Yokoo S, Mimura T, Araie M,
Amano S. Distribution of precursors in humancorneal stromal cells and endothelial cells.
Ophthalmology. 2007;114:433-9.
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Lu B, et al. Deletion of the chemokine receptor
CCR1 prolongs corneal allograft survival. Invest
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4. Ebihara N, Yamagami S, Chen L, Tokura T,
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Honda N, et al. Preoperative Evaluationof Cultured Human Corneal Limbal Epitheliumon Amniotic Membrane by Confocal Microscopy.
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2007;48:3545-50.
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Araie M, et al. Autologous transplantation of
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8. Suzuki M, Amano S, Honda N, Usui T, Yamagami
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13. Oba M, Fukushima S, Kanayama N, Aoyagi K,
Nishiyama N, Koyama H, et al. Cyclic RGD
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14. Nakanishi M, Joon-Sik P, Woo-Dong J, Oba M,
Kataoka K. Study of quantitative aminolysis
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Uchinuma E, Takato T, et al. Three-dimensional

microenvironments
retainchondrocyte
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16. Liu G, Kawaguchi H, Ogasawara T, Asawa Y,
Kishimoto J, Takahashi T, et al. Optimal
combination of soluble factors for tissue
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Yoshiba K, Yoshiba N, et al. Hard tissue
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18. Kono SJ, Oshima Y, Hoshi K, Bonewald LF, Oda
H, Nakamura K, Kawaguchi H, Tanaka S. Erk
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Ikeda T, Saito T, et al. Akt1 in osteoblasts andosteoclasts controls bone remodeling. PLoS ONE.
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21. Cotta-de-Almeida V, Westerberg L, Maillard MH,
Onaldi D, Wachtel H, Meelu P, et al. Wiskott
Aldrich syndrome protein (WASP) and N-WASP
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GV. Continuous activation of Gαq in osteoblasts
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differentiation. J Biol Chem. 2007;282: 35757-64.
23. Kugimiya F, Kawaguchi H, Ohba S, Kawamura N,
Chikuda H, Azuma Y, et al. GSK-3β controls
osteogenesis through regulating Runx2 activity.
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24. Masago K, Itaka K, Nishiyama N, Chung U,
Kataoka K. Gene delivery with biocompatible
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H, Shinomiya K, et al. Prevention of cartilage
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406

model of osteoarthritis. Arthritis Rheum. 2007;56:3358-65.
26. Itaka K, Ohba S, Chung U, Kataoka K. Boneregeneration by regulated in vivo gene transfer
using biocompatible polyplex nanomicelles. Mol
Ther. 2007;15: 1655-62.
27. Ohba S, Nakajima K, Kugimiya F, Igawa K, Itaka
K, Moro T, et al. A novel compound, TH, induces
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357: 854-60.
28. Ikeda T, Saito T, Ushita M, Yano F, Kan A, Itaka
K, et al.Identification and characterization of thehuman SOX6 promoter. Biochem Biophys Res
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Nakamura K, et al. Identification of a potent
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407

Hospital Planning andManagement
Lecturer
Soichi Koike M.D., M.P.H., M.B.A., Ph.D.

Assistant Professor
Hiroki Watanabe, M.D., Hiroo Ide, M.A., Yusuke Inoue, M.P.H., Kento Doi, M.D, Ph.D.

Homepage

http://www.cc.h.u-tokyo.ac.jp/mulins/kikakushitsu/index.htm

Introduction and Organization

Clinical activities

In recent years, the medical system in Japan has
been experiencing times of major change. University
hospitals, as well, have been under pressure forsweeping reforms. There are demands, greater thanever before, for the development and practical application of high-quality advanced medical treatment,
and for the efficient promotion of graduate and postgraduate education, and of clinical research. And there
are demands for those results to be expressed clearly
to Japanese citizens in specific terms. In April 2004,
as the University of Tokyo was incorporated under the
National University Corporation Law, the Universityof Tokyo Hospital underwent drastic organizational
restructuring. In addition to the establishment of Hospital Executives, there was also the launch of fourorganizations that support hospital management (Hospital Planning and Management; Personnel Administration and Human Resources; Performance Monitoring, Risk Management, and Staff Development; andEducation and Research Support) and three organizations that support clinical management (Inpatient Service Administration; Outpatient Service Administration; and Central Hospital Service Administration).
Hospital Planning and Management is a key working organization in the management of the hospital. It
has three full-time faculty members from the Department of Planning, Information and Management, andboasts a team of two pharmacists, three nurses, one
engineering staff member, and 12 administrative staff.

Hospital Planning and Management is responsible
for all of the organizational and strategic business affairs of the University of Tokyo Hospital. It conducts
the following kinds of clinical-management duties.
(1) Analysis of hospital management
The division manages and analyzes hospital accounting information, and conducts hospitalmanagement analyses by utilizing management
information and standardized hospital information.
(2) Planning
Based on the hospital management analyses, thedivision designs short-term management planningand strategy, and provides effective support for
the Hospital Executives to make swift management decisions. The division is also responsible
for formulating medium- and long-term plans.
Following is a list of hospital management
achievements in which Hospital Planning andManagement was deeply involved.
・ Launched the “22nd Century Medical Center”
・ Launched the new central hospital building
・ Enhanced functions in the inpatient ward (expansion of ICU/CCU, increase in number ofbeds in the Psychiatry Department)
・ Reduced the average length of hospital stays,
and improved the bed occupancy rate
・ Achieved reductions in drug costs and costs for
medical materials

408

In addition to these achievements, the division
has also strived to improve innovative patient
services, such as introducing a credit card forpatients, attracting commercial stores in thehospital, and illuminating the hospital buildings. At the same time, the division has worked
to develop an environment in which medicalcare staff can provide high-quality and safe
medical treatment in a more composed fashion.
(3) Medical policy recommendations
The division is not just restricted to the management of the University of Tokyo Hospital. It also
actively implements policy recommendations
aimed at improving the medical system in Japanand at deregulating medical care.
Furthermore, we point out issues related to Japan’s medical insurance system based on evidence, and we constantly issue messages for theirimprovement.

Teaching activities
Turning to postgraduate education, the division accepts 1 doctoral student from the Department of Medical Informatics and Economics at the Graduate
School of Medicine, and 1 research student from the
Graduate School of Medicine.
Postgraduate students and research students pursue
their own research projects, not just from the researchareas of healthcare management and hospital management, but also from such areas as healthcare economics and healthcare policy. The students review
previous literature and materials, and they are actively
engaged in developing research designs and the collection of data. The students present regular research
progress reports, they are given thorough instruction
on writing academic papers, and they also follow arigid schedule of academic presentations.

Research activities
The research activities of the division are not limited to merely healthcare management and hospitalmanagement, but cover a broader area, including
health policy and health economics.
（1） Research in healthcare management
In the past, the division analyzed the impact thata prospective payment system, which is based on
Diagnosis Procedure Combination (DPC), has on
the healthcare workplace, and it conducted research to estimate the effects that this system hason the length of hospital stays. The division also
conducted research related to the efficient use of
medical facilities, by studying the relationshipbetween the running of operating rooms and thenumber of hospital beds.
In an attempt to systemize healthcare management, the division edited a standard textbook. The
division is also conducting research into the development of an education program for healthcare
management, and educates students working in
health sector since 2007.
(2) Research in healthcare policy
The division undertook comparative studies between medical systems in Japan and other developed countries. Empirical studies related to thedisparity in domestic and imported prices of
medical materials among multi countries, andstudies into the career paths of medical doctors
and health workers’ migration are ongoing.
The division carried out assessments related toJapan’s medical insurance system, and in particular, conducted research into improvements tothe prospective payment system based on DPC,
and the effectiveness of such improvements.
(3) Research in healthcare economics
In cooperation with hospitals providing cares for
HIV/AIDS patients, the division is conducting
cost-accounting study in HIV/AIDS care. Recently, we began cost-effectiveness analysis forhepatitis B prevention strategies.
(4) Other research topic
The division commits a research project regarding socio-economic impacts on childhood obesity
using a large panel data set, with other research
institutes

References
1. Yasunaga H, Ide H, Imamura T, Ohe K. Price
Disparity of Percutaneous Coronary Intervention
Devices in Japan and the United States in 2006.
Circulation Journal 2007;71:1128-30
2. Imamura T, Ide H, Yasunaga H. History of public

409

3.

4.

5.

6.

health crisis in Japan. Journal of Public Health
Policy 2007 2007;28(2):221-237
Yasunaga H, Ide H, Imamura T. Current disparities in the prices of medical materials between
Japan and the United States：Further investigationof cardiovascular medical devices. Journal of
Cardiology 2007;49(2):77-81
Ide H, Yasunaga H, Imamura T, Ohe K. Price differences between Japan and the U.S. for medical
materials and how to reduce them. Health Policy
2007;82:71-77
Ishikawa T, Osada T, Ebihara K, Ide H, Kuse H.A
basic study on the estimate method of the medicine volume for emergency care in hospital after
huge earthquakes. Journal of Japan logistics society 2007:15;129-1336 (in Japanese)
Imamura T, Yasunaga H, Ide H. Iryo-Keiei-Gaku.
(in Japanese) Tokyo: Igaku-Shoin; 2006

410

Department of Child Psychiatry
Professor
Takashi Igarashi, M.D.,Ph.D.

Specially Appointed Associate Professor
Yukiko Kano, M.D.,Ph.D.

Specially Appointed Lecturer
Keiichiro Watanabe, M.D., Ph.D.

Specially Appointed Associate
Soo-Yung Kim, M.D.

Homepage

http://kokoro.umin.jp/

Introduction and Organization

Clinical activities

The Department of Child Psychiatry was established in April 2005 as the clinical counterpart to theClinical Education Center of Mental Development,
both of which are funded by the special grant for faculty development. The major aim of the Clinical Education Center is to train mental health specialists invarious fields with a fundamental grounding in childpsychiatry and neurosciences. Much of the services
provided are based on the 37 years of experience inintervention and treatment for developmentally disabled children established in the former child psychiatry division of Department of Neuropsychiatry.
The department uses a multidisciplinary approach byworking in collaboration not only with the Departmentof Neuropsychiatry, Department of Pediatrics andGraduate School of Education in the University ofTokyo but also several other educational and/or clinical facilities on mental development or developmental
disorders. The Department of Child Psychiatry complements the Clinical Education Center by providing
fieldwork for clinical training. It also offers clinicalservices to patients with various development problems and places an emphasis on research to provide
evidence-based clinical and educational activities.

In the year 2007, the Department of Child Psychiatry consisted of 8 psychiatrists including 3 full-timechild psychiatrists and 8 psychologists (full-time andpart-time). Although patients with various disorders
are seen, the focus of the department is mainly on patients with developmental disorders. We offer services
to patients with a broad range of developmental disorders including Pervasive Developmental Disorders(PDD), Attention-Deficit/Hyperactivity Disorder(AD/HD), Learning Disabilities (LD), Mental Retardation (MR), tic disorders and child ObsessiveCompulsive Disorders (OCD).
The number of new patients in the year 2006 and2007 was more than 470, in contrast to 300 in the yearof 2005. This indicates an increase of about 50%
compared with that of the previous year. Among thenew patients, 45% were patients with disorders of
psychological development including LD, with PDD
being the most prevalent diagnosis. The second mostprevalent diagnosis was tic disorders (15%), followed
by AD/HD (10%) and stress-related disorders (10%).
The age group of these patients was distributed widelyfrom early infancy to adulthood, and the largest number of patients being those in the late infancy to earlychildhood group.
The number of follow-up patients has been in-411

creasing consistently and doubled since the year of
2005. Among follow-up patients, disorders of psychological development were again the most prevalentat 45%, followed by tic disorders, stress-related disorders, AD/HD and mood disorders. About half of thepatients at follow-up were adult patients, especiallyhigh in number were patients in their twenties, constituting a total of 20%. This highlights the need forlong-term follow-up in patients with developmental
disabilities.
Clinical activities are largely divided into two areasof general child psychiatry outpatient services andinterventions for children with developmental disabilities.
Services for the general child psychiatry outpatientsare provided by psychiatrists in the areas of pharmacotherapy, psychotherapy, psychoeducation and also
work closely with the schools and community.
Interventions for developmentally disabled children
consist of “developmental psychology outpatient services” and “short-term group therapy”. Patients involved in interventions are children with developmental disabilities, and individualized cognitive developmental therapy is planned for each child. “Developmental psychology outpatient clinic” provides
services in the following areas: (1) evaluation of cognitive and behavioral development, (2) individual
treatment of the child (3) counseling of parents andproviding information to the child’s support network(relatives, schools). “Short-term group therapy” is a
10 session group therapy for a small group of children
with similar developmental levels. These services areprovided mainly by psychologists under the supervision of child psychiatrists.

Education
As part of the Clinical Education Center of Mental
Development, two training courses (Course A and B)
are offered for graduate level students and various
mental health professionals including psychiatrists
and pediatricians. Course A is a lecture course which
incorporates an interactive component with role-playexercises and case conferences. Course B is an intensive training course, which includes more clinical experience through participation in intervention andpsychological assessment.

Course A is composed of 11 sessions of 3 hour lectures and is offered twice a year, with a total of approximately 120 trainees per year. Trainees consistedof a wide range of professionals, including those in
the medical field, such as physicians, psychologists,
educators and social workers. This mixture of a variety of professions laid the groundwork for creating a
multidisciplinary network for professionals involved
in issues related to mental development. Feedback
from questionnaires indicated that 80% of the trainees
found the course useful.
Course B is offered for a duration of 6 months, with
3 days per week of clinical training. Trainees haveincluded pediatricians, nurses, and school teachers.
A seminar and symposium is held annually in orderto facilitate understanding of mental development anddevelopmental disorders among the general public. In
the year 2007, a seminar entitled “Towards fruitfuladolescence and adulthood of developmental disorders” and a symposium entitled “Understanding andsupport for developmental disorders” each attracted an
audience of about 200 and 1,100 people respectively.
Undergraduates and psychiatry residents from the
University of Tokyo have opportunities to observe
evaluations and outpatients services as part of theircourse. They are also required to actively participate
in “short-term group therapy”.

Research
We participate in investigation of etiology and development of effective treatment on PDD and AD/HD,
which are organized in collaboration with the Department of Neuropsychiatry and other research, educational and clinical facilities. In addition, research
related specifically to the clinical activities in the Department of Child Psychiatry is currently being investigated.
Clinical evaluation and treatment
The reexamination of reliability and validity of Ohta Staging (an evaluation system using symbol development for cognitive developmental therapy developed in the former child division of the Department of
Neuropsychiatry) and investigation of the effectiveness of present interventions for children with PDD
are being conducted.

412

A comparison study of the effectiveness of individual treatment and “short-term group therapy” in arandomized control study is being undertaken.
In another study, the possible relations among clinical characteristics such as tics and obsessivecompulsive symptoms in Tourette syndrome (chronictic disorder with multiple motor tics and one or more
vocal tics) and child OCD are being evaluated.

3.

4.
Neuropsychological research
Neuropsychological data on PDD, AD/HD andTourette syndrome are being collected. Analysis of therelations among neuropsychological findings and theclinical evaluation as well as comparisons between
patients and their healthy siblings are being conducted.
5.
Genetic research
Research exploring susceptibility genes of PDD inchromosome 2, long arm of chromosome 7 and longarm of chromosome 15 are conducted. As we are interested in gene-environment interaction, we are examining influence of endocrinologic change including
thyroid hormone in PDD. In addition to the molecular
genetic study, investigation of specific family and environment of Tourette syndrome is being undertaken.
Neuroimaging
Studies include structural MRI, MEG and NearInfrared Spectroscopy (NIRS) and exploration of thepathogenesis of developmental disorders such as PDD.
The main focus is the examination of prefrontal bloodflow in PDD and Tourette syndrome by NIRS which is
non invasive and easily applicable to children and developmentally disabled individuals.

6.

7.

References8.
1. Kawakubo Y, Kamio S, Nose T, Iwanami A,
Nakagome K, Fukuda M, Kato N, Rogers MA,
Kasai K. Phonetic mismatch negativity predicts
social skills acquisition in schizophrenia. Psychiatry Res. 152(2-3): 261-265, 2007
2. Kawakubo Y, Kasai K, Okazaki S, Hosokawa M,
Watanabe K, Kuwabara H, Ishijima M, Yamasue
H, Iwanami A, Kato N, Maekawa H. Electrophysiological abnormalities of spatial attention in

9.

adults with autism during the gap overlap task.
Clin Neurophysiol. 118:1 464-1471, 2007
Marui T, Funatogawa I, Koishi S, Yamamoto K,
Matsumoto H, Hashimoto O, Nanba E, Nishida H,
Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato
N, Sasaki T: Tachykinin 1 (TAC1) gene SNPs
and haplotypes with autism: a case-control study.
Brain and Development, 29(8): 510-513, 2007
Marui T, Koishi S, Funatogawa I, Yamamoto K,
Matsumoto H, Hashimoto O, Ishijima M, Nanba E,
Nishida H, Sugiyama T, Kasai K, Watanabe K,
Kano Y, Kato N, Sasaki T: No association between the Neuronal Pentraxin II gene polymorphism and autism. Progress in NeuroPsychopharmacology & Biological Psychiatry, 31(4): 940-943, 2007
Kato C#, Tochigi M#, Ohashi J, Koishi S, Kawakubo Y, Yamamoto K, Matsumoto H, Hashimoto
O, Kim S-Y, Watanabe K, Kano Y, Nanba E, Kato
N, Sasaki T (#:equal contribution) Association
study of the 15q11-q13 maternal expression domain in Japanese autistic patients. Am J Med Genet Part B (Neuropsychiatric Genet) (in press).
Kato C#, Tochigi M#,, Koishi S, Kawakubo Y,
Yamamoto K, Matsumoto H, Hashimoto O, Kim
S-Y, Watanabe K, Kano Y, Nanba E, Kato N, Sasaki T (#:equal contribution) Association study ofthe commonly recognized breakpoints in chromosome 15q11-q13 in Japanese autistic patients.
Psychiatric Genet (in press)
Tochigi M, Kato C, Koishi S, Kawakubo Y, Yamamoto K, Matsumoto H, Hashimoto O, Kim SY,
Watanabe K, Kano Y, Nanba E, Kato N, Sasaki T.
No evidence for significant association between
GABA receptor genes in chromosome 15q11-q13
and autism in a Japanese population. J Hum Genet.;52(12):985-989, 2007
Tochigi M#, Kato C#, Ohashi J, Koishi S, Kawakubo Y, Yamamoto K, Matsumoto H, Hashimoto
O, Kim S-Y, Watanabe K, Kano Y, Nanba E, Kato
N, Sasaki T. (#equal contribution) No association
between the ryanodine receptor 3 gene and autism
in a Japanese population. Psychiatry and Clinical
Neurosciencse (in press).
Takizawa R, Kasai K, Kawakubo Y, Marumo K,
Kawasaki S, Yamasue H, Fukuda M. 「Reduced
frontopolar activation during verbal fluency task

413

in schizophrenia: A multi-channel near-infrared
spectroscopy study Schizophre Res (in press)

414

Department of Palliative Medicine
http://www.h.u-tokyo.ac.jp/patient/depts/pailiative.html
History and outline of organization
Half of the cancer patients die of original cancer inspite of the advanced cancer treatment technology.
The success or failure of the first treatment against
cancer results in its cure or non-cure. Almost all thepatients who underwent unsuccessful initial treatment
die after the struggle against disease within several
years. It is sure to need the proper medical care only
for such patients.
However, most attention has been entirely paid to theimprovement of cure rates of cancer patients in Japanso far. Therefore, the sense of palliative care is very
poor and immature consequentially.
Palliative care means active treatment approach and a
total human care for the patients who do not respondto any treatment. In addition, pain relief, othersymptomatic controls, psychiatric, social and mental
care are as a top priority for these patients. However,palliative care is necessary to be applied in the cancer
treatment even for patient in early stage of the disease
as well as the progressive disease.
In Department of Palliative Medicine of The
University of Tokyo Hospital, our palliative care teamtakes a leading role not only to control physicalsymptoms of patients but also to care for the mind andsocial support at the same time, and to improve theoverall QOL (Quality of life) of patients. Moreover, italso becomes base of the education and palliative
medicine research for medical students.
Palliative care is described clearly in "Fundamental
law of the cancer measures" passed in the National
Diet on June 2006, "The medical treatment to aim atrelieving pains according to the condition of cancer
patient is appropriate from the early stage of thedisease". In a word, palliative care is provided by thelaw as a medical treatment that should be offered at

the early stage when the patient receives the cancer
treatment.

Consultation
In The University of Tokyo Hospital, the palliative
care team is composed of a lot of specialists such as
one full-time staff doctor, one full-time doctor, andthe designated hospice care nurse who take an
initiative in working. They visited the general ward
and offer palliative care to the patient who hasreceived the cancer care in cooperation withpatients’ attending doctors and ward staff andrehabilitation staff, etc.
Hereafter, we concretely show the consultation
situation in fiscal year 2007.
The cumulative number of patients who consulted our
palliative care team was 7,426 (20.3 average daily
patients). The maximum monthly patients was 895 ofDecember (28.9 daily patients), and minimum was
383 of June (12.8 daily patients). According to site of
the cancer, 292 cancers were divided into 40 stomachs,
29 pancreas, 28 lungs, 28 large intestines, 25
esophagus, 18 livers and 13 breasts and so on. We
visited almost all the ward in the hospital. According
to gender, a total of 295 patients were divided into 194
males and 101 females. Males were almost two times
females. According to the age group, there were 31%,
25%, 23%, and 7% in sixties, seventies, fifties, and 80
years old or more, respectively. These figures proved
significantly the importance of the palliative care.

Education
In the training at the Department of Palliative
Medicine, medical students of the first and second
year can learn the basic knowledge of palliative care415

by selecting an optional subject for one, two, four oreight months. And then they can participate in thepalliative care team and attend the daily conference ofpalliative care on weekdays.
1) Palliative care training program
The training course (selection) for two months ( or *for one month )･ Program to acquire basic knowledge andtechnology of palliative care for targeting all
resident physicians. * Only in "Comprehensive
Internal Medicine” selection.
The training course (selection) for four or eightmonths･ Program to acquire basic knowledge, basic
technology, and communications skills for doctor
who aims at medical oncologists or palliative caredoctor.
2) Curriculum
Resident physician arrangement and content oftraining･ All resident physicians are assigned to the palliative
care team. They chiefly participate in ward
palliative care as a member of the team, and also
learn the cancer registry of palliative care.
･ In the course for four and eight months, they makepalliative care program for patients in charge,
discuss their palliative care with patients’ attending
doctors, ward staff, and execute their palliative careprogram.
Content of training and attainment goal･ The ward palliative care (3-5 patients in charge permonth and around 20 consultation patients a day):
They acquire the outline of control of physical andpsychiatric symptoms of the patients with common
disease in Japan such as digestive cancers in thegeneral ward. They also acquire the outline of
spiritual and family care.
･ Cancer registry: In The University of Tokyo
Hospital, it is not unusual that the patient whom thepalliative care team treats is often in an end stage,and his or her condition changes physically andmentally day by day. Residents should input theconcise and plain content of the offered palliative
care for such a patient to the data base. Theyacquire the outline of data management of thepalliative care connected directly to a clinicalresearch.
･ The communications skills: The clinician shouldtell "Bad news" time after time by all the processesof examining the patient. It is very difficult for theclinician to explain the accurate information ofdiagnosis, progression and prognosis of cancer tothe patient. This is a lot of work of the stress to theclinician. The clinician should deal with patient's
disappointment or failure feeling when treatment
does not go well while should do the balance of"Bad news" and "The patient's hope andexpectation". We introduce Protocol (SPIKES) of
the communications skills that psychiatricallysupport the patient in Department of Palliative
Medicine of The University of Tokyo Hospital.
Resident can make the palliative care execution
program based on this Protocol, and intend toobtain the communications skills in the course offour or eight months.
Event concerning education･ Concerning the intensive course to the first stage
resident physicians, following lectures are done by
the staff.
O pain control
O delirium control
O Introduction of the guideline and its use
O Basic drug therapy for palliative care
O Spiritual care for Japanese
Clinical training schedule･ Conference: Monday - Friday (every day)9:00-10:30･ Ward consultation: Monday - Friday (every day);up to the end of request patient's consultation after
conference.
･ The cancer registry: They input data in the ward
round with the HIS (Hospital information system)
terminal on each floor.
System of guidance･ The ward consultation: Resident participate in the
consultation team (or palliative care team) thatconsists of two guidance medical doctors (oneassistant or lecturer, one designated hospice carenurse, and one resident physician). A palliative careteam examines about 20 – 30 in-patients a day.
･ The conference: Psychiatrist, Chinese medicine
specialist, morphine special pharmacist, and nurse

416

of The Tokyo University Graduate School of
Medicine and others participate in the daily
conference besides the regular member of thepalliative care team in the ward round. They discuss
the multidisciplinary palliative care program thatthe palliative care team offers. They also guide theresident's palliative care program from their special
viewpoints.

Research
The content accumulated from the palliative careconsultation is input to the data base concise andplainly, and submitted to the international medical
journal such as "International Journal of Radiation
Oncology Biology Physics", "American Journal of
Hospice & Palliative Medicine" and "Biomed" as aresult of a clinical research.
The following fields of investigations are the one that
had been executed in our Department of Palliative
Medicine. Please refer to the homepage for results indetails and acquisition of the research fund.
1) Evaluation and quality assurance of special
palliative care team2) Development of the scale to measure execution ofpreferable death and its nationwide investigation
3) Development of target system in extracranialstereotactic radiotherapy4) Home care of cancer patients in terminal stage andregional liaison
5) Palliative care supporting metastatic breast cancer
patient6) Chinese medicine in palliative care

Publications etc.
1. Nakagawa K; Yamashita H, Shiraishi K, Igaki H,
Terahara A, Nakamura N, Ohtomo K, Saegusa S,
Shiraki T, Oritate T, and Yoda K: Verification ofin-treatment tumor position using Kilovoltage
cone-beam computed tomography: a preliminary
study. Int. J. Radiat. Oncol. Biol. Phys. 2007, inpress
2. Nakagawa K, Yoda K et al.: Radiophotoluminescence dosimetry using a small sphericalglass: a preliminary phantom study. Radiat. Prot.
Dosimetry 123: 254-256, 2007

3. Nakagawa K, Yoda K et al.: Rod matrix
compensator for small-field intensity modulated
radiation therapy: a preliminary phantom study.
IEEE Trans. Biomed. Eng. 54: 943-946, 2007
4. Iwase S, Murakami T, Saitou Y, Nakagawa K:
Preliminary Stastical Assessment of Intervention
by a Palliative Care Team Working in a Japanese
General Inpatient Unit. American Journal of
Hospice & Palliative Medicine. 24(1): 1-7, March2007
5. Yanagie H, Sakurai Y, Ogura K, Kobayashi T,
Furuya Y, Sugiyama H, Kobayashi H, Ono K,
Nakagawa K, Takahashi H, Nakazawa M,
Eriguchi M: Evaluation of neutron dosimetry on
pancreatic cancer phantom model for applicationof intraoperative boron neutron-capture therapy.
Biomed Pharmacother. 61(8): 505-14, Sep. 2007;
Epub 2007 Feb 27.
6. Aoyama H, Tago M, Kato N, Toyoda T, Kenjyo M,
Hirota S, Shioura H, Inomata T, Kunieda E,
Hayakawa K, Nakagawa K, Kobashi G, Shirato H:
Neurocognitive function of patients with brain
metastasis who received either whole brain
radiotherapy plus stereotactic radiosurgery orradiosurgery alone. Int J Radiat Oncol Biol Phys.
68(5): 1388-95, Aug. 1 2007
7. Nishino T, Miyatake A, Inoue K, Katsuta S,
Gomi-Miyagishi T, Kohno R, Kameoka S,
Nakagawa K, Ogino T.: “ Experimental
verification of proton beam monitoring in ahuman body by use of activity image of
positron-emitting nuclei generated by nuclear
fragmentation reaction," Radiat. Phys. Tech.
accepted.
8. Yamashita H, Nakagawa K, Shiraishi K, Tago M,
Igaki H, Nakamura N, Sasano N, Shiina S, Omata
M, Ohtomo K: Radiotherapy for lymph nodemetastases in patients with hepatocellular
carcinoma: retrospective study. J. Gastroenterol.
Hepatol. 22(4): 523-7, Apr. 2007
9. Igaki H, Nakagawa K, Uozaki H, Akahane M,
Hosoi Y, Fukayama M, Miyagawa K, Akashi M,
Ohtomo K, Maekawa K: Pathological changes in
the gastrointestinal tract of a heavily radiation-e
xposed worker at the Tokai-mura criticality
accident J Radiat Res 2007 in press.
10. Kaneko A, Okabe T, Iwase S, Nakagawa K:

417

Palliative care ‐ current state and view in the
future. Chinese Medicine Current Therapy in the
Palliative Care.
25(11): 909-912, 2007 (inJapanese)
11. Iwase S, Murakami T, Yasuda E, Nakagawa K:
Palliative care ‐ Home care and regional
network, staring at the enforcement offundamental law of the cancer measures – 8.
Regional network in cancer treatment ‐ A casestudy of The Tokyo University Hospital ‐Medicine and Drug Journal 43(8): 2035-2037,
2007 (in Japanese)
12. Shiraishi S, Tago M, Nakagawa K, Iwase S,
Yamakawa S: Palliative care supporting patientswith metastatic breast cancer. Radiotherapy formetastatic breast cancer. ‐ Special reference tothe brain metastasis and the bone metastasis ‐ .
Palliative Care 17(4): 300-303, 2007(in Japanese)
13. Nakagawa K, Iwase S, and Yamakawa S: Cancer
palliative treatment (Palliative cancer therapy).
Japanese J Clinical Medicine Vol.65 No.1, Page.
93-97, 2007(in Japanese)418

Clinical Genomics
Director & Professor
Shoji Tsuji, M.D., Ph.D.

Vice-director & Lecturer
Jun Goto, M.D., Ph.D.

Organization
The Department of Clinical Genomics started as a
special unit conducting genomic medicine or clinicalhuman genetics services in 2003. Our department
functions as the core unit to accomplish an appropriate
and efficient application of results of recently
advanced human genetics and genomics to clinicalpractice in the hospital and as the unit of training andeducating specialists of human genetics practice. It
consists of one professor and many different
specialties participate in the department. They include
pediatricians, obstetricians, internist (cardiologists,diabetologists, and neurologists),dermatologists,and staffs of the Departments of Clinical Laboratory
Medicine, Human Genetics and Nursing Science.

Activities
The exclusive consultation room (Room 200) is
allocated in the outpatient clinic. Consultation andcounseling is performed by a team of medical doctor
and non-M.D. staffs. All cases are reviewed anddiscussed at the conference which is held on the 1st
Monday every month.
Counseling of participants in researches including
genome or gene analysis is a duty with which thehospital and the faculty charge the department.
To build suitable clinical systems including modern
genomic medicine we are cooperating with otherdepartments. We are participating in Marfan’sSyndrome Clinic which is managed collaboratively by
the Departments of Cardiovascular Surgery,
Cardiovascular Medicine, Pediatrics, Spinal Surgery
and Ophthalmology. We are also collaborating with

Clinical Laboratory Center, Pharmaceutical Services,
DepartmentsofPlanning
Information
andManagement,
Gastroenterology,
Cardiovascular
Medicine and Neurology and started a clinicalpharmacogenetics service for proton pump inhibitors
and warfarin in 2006.

References
1. Shimohata, T, Hara, K, Sanpei, K, Nunomura, J,
Maeda, T, Kawachi, I, Kanazawa, M, Kasuga, K,
Miyashita, A, Kuwano, R, Hirota, K, Tsuji, S,
Onodera, O, Nishizawa, M. and Honma, Y. Novellocus for benign hereditary chorea with adultonset maps to chromosome 8q21.3- q23.3 Brain.
130:2302-9, 2007
2. Hara, K., Momose, Y., Tokiguchi, S., Shimohata,M., Terajima, K., Onodera, O., Kakita, A.,
Yamada, M., Takahashi, H., Hirasawa, M.,
Mizuno, Y., Ogata, K., Goto, J., Kanazawa, K.,
Nishizawa, M., and Tsuji, S. Multiplex families
with multiple system atrophy Arch. Neurol 64:
545-51, 2007
3. Martins, S, Calafell, F, Gaspar, C, Wong, VCN,
Silveira, I, Nicholson, GA, Brunt, ER.
Tranebjaerg, L, Stevanin, G, Hsieh, M, Soong, B,
Loureiro, L, Du¨ rr, A, Tsuji, S, Watanabe, M,
Jardim, LB, Giunti, P, Riess, O, Ranum, LPW,
Brice, A, Rouleau, GA, Coutinho, P, Amorim, A,
Sequeiros, J. Asian Origin for the WorldwideSpread Mutational Event in Machado-Joseph
Disease. Arch Neurol. 64:1502-8, 2007.
4. Hara, K, Shiga, A, Nozaki, H, Mitsui, J, Takahashi,
Y, Ishiguro, H, Yomono, H, Kurisaki, H, Gotom J,
Ikeuchi, T, Tsuji, S, Nishizawa, M, and Onodera,

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Koyama, A., Date, H., Yokoseki, A., Shiga, A.,
Yoshida, Y., Tsuji, S., Nishizawa, M., Onodera, O.
Aprataxin,causative
gene
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for
EAOH/AOA1, repairs DNA single-strand breaks
withdamaged3'-phosphate
and3'-phosphoglycolate ends. Nucleic Acids Res 35:
3797-809, 2007
Kaneko N, Muratake T, Kuwabara H, Kurosaki, T.,
Takei, M., Ohtsuki, T., Arinami, T., Tsuji, S.,
Someya, T. Autosomal linkage analysis of aJapanese single multiplex schizophrenia pedigree
reveals two candidate loci on chromosomes 4q
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Arai, N, Kishino, A, Takahashi, Y, Morita1, D,
Nakamura, K, Yokoyama, T, Watanabe, T, Ida, M.,
Goto, J, Tsuji, S. Familial cases presenting very
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disease with I143T in presenilin-1 gene:
Implication for genotype-phenotype correlation.
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Takahashi, Y, Seki, N, Ishiura, H, Mitsui, J,
Matsukawa, T, Kishino, A, Onodera, O, Aoki, M,
Shimozawa, M, Murayama, S, Itoyama, Y, Suzuki,
Y, Sobue, S, Nishizawa, M, Goto, J and Tsuji, S.
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Sporadic Ataxias in Japan -A population-based
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Cooperative Unit of Medicine andEngineering Research
Organization
The University of Tokyo Hospital
Cardiovascular Medicine, Nutrition and Metabolism, Surgical Oncology, Vascular Surgery,
Artificial Organ and Transplantation, Cardiac Surgery, Thoracic Surgery, Neurosurgery,
Urology, Orthopaedic Surgery, Oral and maxillofacial Surgery, Radiology, Tissue Engineering Unit, Department of Clinical Epidemiology & Systems, Clinical Vascular Regeneration,
Bone & Cartilage Regenerative Medicine, Cartilage of Bone Regeneration, Department of
Immunotherapeutics (Medinet)

Engineering and Pharmaceutical Research
Chemical System Engineering, Mechanical Engineering, Precision Engineering, Quantum
Engineering and System Science, Nuclear Engineering and Management, Chemistry andBiotechnology, Material Engineering, Information Science and Technology, Frontier Sciences, Pharmaceutical Sciences Laboratory of Chemistry and Biology, Center for Disease
Biology and Integrative Medicine, Center for Disease Biology and Integrative Medicine
Regenerative Medical Engineering, Center for Disease Biology and Integrative Medicine
Clinical Biotechnology, Research Center for Advanced Science and Technology, Institute ofIndustrial Science

Homepage

http://plaza.umin.ac.jp/~ikourenk/

Introduction and Organization
The application of an advanced bioscience to a newtechnical development of clinical medicine has become an important subject for research in the 21st
century. We’ve established Cooperative Unit of Medicine and Engineering Research at The University ofTokyo Hospital to create a new research and education
center, which cross-sectionally unites medicine withengineering research for the development of a next
generation medical technology.
2002 June. The establishment of Cooperative Unitof Medicine and Engineering Research was approvedby a hospital administration committee as a special

practice unit that belongs to The University of Tokyo
Hospital.
2002 September. A steering committee of Cooperative Unit of Medicine and Engineering Research wasorganized by representative members of relevant clinical departments. The committee made a decision of
the following basic principles; recruitment for the participation to this unit should be, as a general rule, an
open call for a joint project of clinical department andengineering or pharmaceutical research group in The
University of Tokyo, an equipment/administration
expense of a laboratory should be a responsibility of
the user, and a basic participation period to this unit
should be three years and for the continued participation in the unit, a review and approve of the steering421

committee is indispensable.
2002 October. An open call for participants to thisunit started. There were 18 applications and the steering committee approved all projects after review. A
liaison conference of Cooperative Unit of Medicine
and Engineering Research was organized by a representative member of each project. Configuration ofeach project in a space of 554.4m2 that is consisted ofa portion of the first floor and the basement of an administration building came to a decision by the conference.
2003 May. The construction of Cooperative Unit ofMedicine and Engineering Research was completed.
The cost of the construction was shared by the participation groups.
2003 May 22. The first research meeting of Cooperative Unit of Medicine and Engineering Research
took place and research activities started.
2004 September 3. The second research meeting of
Cooperative Unit of Medicine and Engineering Research took place.
2005 September 13. The third research meeting of
Cooperative Unit of Medicine and Engineering Research took place.
2006 December 21. The fourth research meeting of
Cooperative Unit of Medicine and Engineering Research took place.
2007 December 13. The fifth research meeting of
Cooperative Unit of Medicine and Engineering Research will take place.

Research activities
Development of Advanced Sterotactic Rediation
Cancer Rherapy System
Department of Radiation Oncology
Nuclear Professional school, Department of Nuclear
Engineering and Management
Department of Chemical System Engineering
High Precision Stereotactic X-ray Cancer Theraoy
System. Development of Advanced Compact Electron
Linear Accelerator for Cancer Inspection and Therapy
Laboratory of Nano-crystals in Oncology
Department of Chemical System Engineering
Department of Surgical Oncology
To develop an exact diagnosis and treatment system

for the micro-metastasis of neoplasm by using nano-crystal particles, and to introduce it to clinical use.
To visualize peritoneum metastases (peritonitis) andmicro-metastasis of neoplasm which cannot bechecked in naked eye, and apply it to an operation or
the determination of a medical treatment plan. To
search for the new method for treating neoplasm byusing biological changes of the cells after up taking
nano-crystal particles.
Laboratory of Medical Ultrasound with Microbubbles in Oncology
Department of Mechanical Engineering, Fluids Engineering Laboratory
Department of Surgical Oncology
To develop easy, precise, non-invasive systems to treat
human disease. To devise a method to induce microbubbles effectively to treat human tumors in deep situ.
To make a precise assessment on tumor invasion inμm order by injecting microbubbles into tumor arteries. To develop a non-invasive treatment system using
HIFU devise and microbubble contrast agents.
Medico-engineering Laboratory for Microsurgical
Robotics and Virtual Simulation Laboratory (MRVLabo)
Laboratories of A Morita, Neurosurgery
Dept. Engineering Synthesis, M Mitsuishi
To develop Microsurgical robotic system and 3D visual system for telesurgery
Laboratory of Cavitation & Lithotripsy
Department of Urology, Faculty of Medicine
Department of Mechanical Engineering, School ofEngineering
Development of a new method of lithotripsy using
high intensity focused ultrasound induced cavitation.
Development of Support Systems for Risk Reduction in the Clinical Process
Department of Pharmacoepidemiology
Chemical System Engineering
Department of Clinical Epidemiology & Systems
Our specific targets are research and education on the
integration of biological and clinical information including genome. In particular, they consist of establishment of personalized medicine as translational

422

research, selection of drug targets by proteomics, interpretation of transcriptional regulations and drug
development by targeting transcription factors in cardiovascular diseases (arteriosclerosis, cardiac hypertrophy, cardiac failure, etc.). Other analyses and development are also quite active, such as creation oftransgenic animals, analyses of genomic functions,clinical safety monitoring by clinical database andassessments of clinical information systems.
Surgical Robot System Lab.
Robotics, Dynamics, and Control Laboratory
Department of Mechano-Informatics
University of Tokyo
Development of motion synchronization technology
for in-vivo molecular imaging of small animals, basedon robot systems for endoscopic cardiac surgery.
Neuro-musculo-skeletal model and its parameter identification for diagnosis and rehabilitation of neuromuscular disorders.
Vascular Biomebical Engineering Laboratory
Department of Vascular Surgery
Department of Tissue Engineering, The University ofTokyo Hospital
Bio-Medical Precision Engineering Laboratory, Department of Precision Engineering , The University ofTokyo
Development of minimally invasive diagnostic andtherapeutic technologies for vascular surgery throughcollaboration research.
Orthopedic clinical biomechanics laboratory
The Department of Orthopaedic Surgery, The University of Tokyo.
Graduate School of Information Science and Technology, The University of Tokyo.
To develop a non-invasive method for predicting bonestrength by finite element method analysis.
To develop a new method for evaluation of fracture
healing by echo tracking.
To develop a non-invasive method for morphologicalevaluation.
Minimally invasive cardiac surgery with the integral videography system
Department of Cardiothoracic Surgery, Graduate

School of Medicine, University of Tokyo
Advanced Therapeutic and Rehabilitation Engineering
Laboratory, Department of Mechano-Informatics,
Graduate School of Information Science and Technology, University of Tokyo
To develop: real-time three-dimensional echocardiography, suture device with liner probe, integral
videography, and minimal invasive cardiac surgery
monitored by real-time three-dimensional echocardiography without cardiopulmonary bypass
Division of Neutron Capture Therapy & Immunotherapy for Cancer
Department of Cardiothoratic Surgery, Graduate /School of Medicine
Department of Radiology, University of Tokyo Hospital
Department of Quantum Engineering and System Science, School of Engineering
Department of Nuclear Engineering and Management,
School of Engineering
Research Center for Advanced Science & Technology
Endowment Department, Department of Immunotherapeutics (Medinet)
In order to control and eliminate human cancers, wedevelop the neutron capture therapy (BNCT) using
small neutron accerelator equipped to hospital andalso develp more effective immumotherapeutic approaches.
Molecular Imaging Laboratory, Cooperative Unitof Medicine, Engineering and Pharmaceutical Reserch
Tetsuo Nagano, Laboratory of Chemistry and Biology,
Graduate School of Pharmaceutical Sciences
Yasunobu Hirata, Department of Cardiovascular
Medicine
To develop chemical probes for imaging of biomolecules To elucidate mechanisms and to establish
cures of arteriosclerosis
Laboratory of Artificial Organs
Division of Artificial Organs & Transplantation: Katsutoshi Naruse and Lei Guo
Institute of Industrial Science and Center for Disease
Biology and Integrative Medicine, Graduate School of
Medicine: Yasuyuki Sakai

423

Laboratory of Artificial Organs consists of researchers
belonging to Division of Artificial Organs & Transplantation, and Sakai Laboratory. We have been collaborating in the research of bioartificial liver support
systems in the past 10 years. Our current specialization is, development of artificial liver support, clinicaluse of new apheresis therapy, development of transgenic pig producing human serum albumin, and development of implantable liver tissue equivalents.

of Tokyo Hospital
Biomechanics Laboratory, Graduate School of Frontier Sciences, The University of Tokyo
We are developing multi-scale, multi-physics heart
simulator for the in-silico diagnosis and treatment ofheart diseases by the synergistic effort of cellular physiology and computational mechanics. For collecting
quantitative data for the simulator, mechanical analysis of cardiomyocytes is performed.

Laboratory of Applied Metabolic Biotechnology
Department of Cardiovascular Medicine, Graduate
School of Medicine
Department of Metabolic Diseases, Graduate Schoolof Medicine
Department of Chemistry and Biotechnology, Schoolof Engineering
To establish the system and methods for engineering
the novel model mice of life style-related diseases
using RNAi technology and biotechnology. To elucidate the mechanisms by which adipose tissue derived
factors, adipokines, contribute to the development of
the metabolic syndrome. To explore the signal transduction pathways of major adipokines including adiponectin

Laboratory of Hard-Tissue Nanomedicine
Kataoka & Yamasaki Lab, Department of Materials
Science, Graduate School of Engineering, The University of Tokyo
Department of ″Menicon″ Cartilage & Bone Regeneration, Graduate School of Medicine, The Universityof Tokyo
Department of Bone & Cartilage Regenerative Medicine, Graduate School of Medicine, The University ofTokyo
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo Department of Oral andMaxillofacial Surgery, Faculty of Medicine, The University of Tokyo
Division of Clinical Biotechnology, Center for Disease
Biology and Integrative
Medicine, Graduate School of Medicine, The University of Tokyo
Division of Tissue Engineering, The University of Tokyo Hospital
Development of a non-viral gene delivery system bysupramolecular nanotechnology. Development of anon-viral siRNA delivery system by supramolecular
nanotechnology. Production of regenerated cartilage
and bone with high safety and usefulness . Establishment of practical production and quality control systems. Promotion of the clinical application of regenerated cartilage and bone. Development of easy, precise, non-invasive systems to detect osteoblastic andchondroocytic differentiation. Determination of a finite set of signaling factors sufficient for induction of
osteoblasts and chondrocytes. Development of amethod to induce osteogenesis and angiogenesis simultaneously . Development of a cell-sheet culture
system for bone and cartilage. Screening for compounds that induce bone and cartilage regeneration

Laboratory of Biomaterial Science
Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo
Ishihara & Takai Lab, Department of Materials Science, Graduate School of Engineering, The Universityof TokyoLaboratory of Regenerative Medical Engineerin,
Center for Disease Biology and Integrative Medicine,
Faculty of Medicine, The University of Tokyo
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, The University of Tokyo
Inhibition of aseptic loosening of artificial joints bynano-grafting of a novel biocompatible polymer MPC.
Creation of biocompatible biomaterials optimized forbone, cartilage and vascular regeneration. Regeneration of bone and cartilage tissue in vitro promoted byphysical stimulation
Molecular and cellular mechanics laboratory forthe development of multi-scale heart simulator
Department of Cardiothoracic Surgery, The University

424

Cooperative Unit of Kataoka Laboratory and Department of Vascular Regeneration
Department of Vascular Regeneration, Division of
Tissue Engineering, The University of Tokyo Hospital
Kataoka Laboratory, Department of Materials Scienceand Engineering, Graduate School of Engineering,
The University of Tokyo
To achieve effective and safe in vivo gene therapy ofcardiovascular and vascular diseases, we are developing non-viral gene vectors based on nano-scaled polymer assemblies (polymeric micelles). Polymeric
micelles, which are spontaneously formed from block
copolymers, have a core containing packaged genes
surrounded by biocompatible poly(ethylene glycol)(PEG) palisades, and a variety of pilot molecules canbe installed on the surface of polymeric micelles. This"virusmimicking" nanoparticles might achieve efficient gene transfer to the targeted tissues or cells because of protection of the loaded DNA from nucleaseattack, their lowered non-specific interaction withproteins and cells and facilitated internalization by thetargeted cells through specific interaction of the pilot
molecules. Currently, our research has been focusedon in vivo gene transfer to artery walls and muscles
using polymeric micelles incorporated genes.

References
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14 (13), 1029–1038 (2007).
2. Muri Han, Younsoo Bae, Nobuhiro Nishiyama,
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13. Jiang Meiling, Kazue Mizuno, Mitsuru Uesaka,
Fumito Sakamoto, Noritaka Yusa, Nobuhiro Nishiyama, Kazunori Kataoka, Keiichi Nakagawa.
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Ohtomo K. A rod matrix compensator forsmall-field intensity modulated radiation therapy:
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17. Igaki H, Nakagawa K, Uozaki H, Akahane M,
Hosoi Y, Fukayama M, Miyagawa K, Akashi M,
Ohtomo K, Maekawa K. Pathological Changes in
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18. Sasano N, Enomoto A, Hosoi Y, Katsumura Y,
Matsumoto Y, Shiraishi K, Miyagawa K, Igaki
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19. Nakagawa K, Yamashita H, Shiraishi K, Igaki H,
Terahara A, Nakamura N, Ohtomo K, Saegusa S,
Shiraki T, Oritate T, Yoda K. Verification ofin-treatment tumor position using kilovoltage
cone-beam computed tomography: a preliminary
study. Int J Radiat Oncol Biol Phys. 2007 Nov
15;69(4):970-3.
20. Huang H, Oizumi S, Kojima N, Niino T, Sakai Y.
Avidin-biotin binding–based cell seeding andperfusion culture of liver-derived cells in a porous
scaffold with a three-dimensional interconnectedflow-channel network. Biomat. 2007;28:38153823.
21. Nakayama H, Kimura H, Komori K, Fujii T, Sakai
Y. Development of a multi-compartment microcell culture device as a future on-chip human: fabrication of a three-compartment device and immobilization of rat mature adipocytes for theevaluation of chemical distributions. J Robotics
Mechatr. 2007;19: 544-549.
22. Kimura H, Nishikawa M, Yamamoto T, Sakai Y,
Fujii T, Microfluidic perfusion culture of humanhepatocytes. J Robotics Mechatr. 2007;19:550556.
23. Naruto H, Huang H, Nishikawa M, Kojima N,
Mizuno A, Ohta K, Sakai Y. Feasibility of direct
oxygenation of primary-cultured rat hepatocytes
using polyethylene glycol decorated liposomeencapsulated hemoglobin (LEH). J Biosci Bioeng.
2007;104:343-346.
24. Nishimura S, Nishimura M, Hosoya Y, Fujita H,
Katoh M, Yamashita H, Manabe I, Tobe K, Kadowaki T, Nagai R, Sugiura S Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells and blood vessels
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suitable for ratiometric fluorescence imaging of
neuronal zinc. J Am Chem Soc 2007; 129:1344713454
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fluorescence probe for hypochlorous acid and its
application to real-time imaging of phagocytosis.

J Am Chem Soc 2007; 129:7313-7318
37. Sunahara H, Urano Y, Kojima H, Nagano T: Design and synthesis of a library of BODIPY-based
environmenta polarity sensors utilizing photoinduced electron transfer-controlled fluorescence
ON/OFF switching J Am Chem Soc 2007; 129:5597-5604
38. Yuki Maeda, Nobuhiko Sugano, Masanobu Saito,
Kazuo Yonenobu, Ichiro Sakuma, Yoshikazu Nakajima, Shinichi Warisawa, Mamoru Mitsuishi:
Robot-assisted femoral fracture reduction: Preliminary study in patients and healty volunteers,
Computer Aided Surgery 13(3):pp148-156,2008
39. Hiromasa Yamashita, Kiyoshi MAtsumiya, Ken
MAsamune, Etsuko Kobayashi, Ichiro Sakuma,
Hongen Liao, Makoto Hashizume, Takeyoshi Dohi:Development of a Miniature 2-DOFs Bending
Manipulator with Bipolar Coagulator, J JSCAS
vol.9 no.2:pp91-101,2007
40. Kosuke Kishi, Hidekazu Nakamoto, Makoto Hashizume, Masakatsu G. Fujie, Ichiro Sakuma, Takeyoshi Dohi:Compact Manipulator System for
Guilding Needle with Real-time Navigation Basedon MR Images, J JSCAS vol.9 no.2:pp103-111,
2007
41. Shinya Onogi, Hongen Liao, Shigeru Watanabe,
Etsuko Kobayashi, Ichiro Sakuma:Tracking Method of Small Receiver Coil Using MR Scanner,
Transactions of the Japanese Society for Medical
and Biological Enineering Vol.45 No.3:pp177-184,
2007
42. Koji Nishizawa, Yoshihiko Muragaki, Masakatsu
G. Fujie, Ichiro Sakuma, Hiroshi Iseki:
Development ofManipulator Systems to Support
Precise and Minimally-Invasive Surgery in a
Small Operative field, J JSCAS vol.9 no.1:pp7-14,
2007
43. Eisuke Aoki, Masafumi Noguchi, Jae-Sung Hong,
Etsuko Kobayashi, Ryoichi Nakamura, Takashi
Maruyama, Yoshihiro Muragaki, Hiroshi Iseki,
and Ichiro Sakuma: Development of an Intraoperative Information Integration System and Implementation for Neurosurgery, Journal of Robotics and Mechatronics, Vol.19 No.3,pp. 339-352,
2007
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E.Kobayashi,
X.Chen,T.Hisada,
I.Sakuma, Transversery isotropic properties of427

porcine liver tissue, Med Bio Eng Comput 45:
pp99-106,2007
45. S.O. Lee, Y. Nakamura, K. Yamane, T. Toujo, S.
Takahashi, Y. Tanikawa, and H. Takahashi: “Image Stabilization for In vivo Microscopy by High
Speed Visual Feedback Control,” IEEE Transactions on Robotics, vol. 24, no. 1, pp. 45-54, 2008.
46. G. Venture, Y. Nakamura, K. Yamane, and M. Hirashima: “A Painless and Constraint-free Method
to Estimate Viscoelastic Passive Dynamics ofLimbs' Joints to Support Diagnosis of Neuromuscular Diseases,” IEEE/EMBS International Conference on Engineering in Medicine and Biology,
pp 5362-5365, 2007.
A. Murai, K. Yamane, and Y. Nakamura: “Modelingand identifying the somatic reflex network of thehuman neuromuscular system” IEEE/EMBS International Conference on Engineering in Medicine and Biology, pp. 2717-2721, 2007.
47. G. Venture, Y. Nakamura, K. Yamane, and M. Hirashima: “Identification of Limbs Joint Passive
Visco-Elasticity: A Comparison of Two Experimental Methods,” International Symposium on
Skill Science, pp. 31-37, 2007.
48. K. Yamane and Y. Nakamura: “Robot Kinematics
and Dynamics for Modeling the Human Body,”International Symposium on Robotics Research,
pp. 77-88, Hiroshima, Japan, 2007.
49. G. Venture, Y. Nakamura, K. Yamane, and M. Hirashima: “Estimating Viscoelastic Properties of
Human Limb Joints Based on Motion Capturing
and Robotic Identification Technologies,”
IEEE/RSJ International Conference on Intelligent
Robot System, pp. 624-629, 2007.
50. S.O. Lee, T. Ozaki, K. Yamane, and Y. Nakamura:“In vivo Motion Estimation for Image Stabilization in Optical Imaging through a Contact-type
Sensor Device,” Joint Molecular Imaging Conference, #0427, 2007.

University Hospital
Pharmaceutical Service

429

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Associate Professor
Kousei Ito, Ph.D.

Research Associate
Tomonobu Uchino, Ph.D.,

Yuko Sekine, Ph.D.,

Tappei Takada, Ph.D.,

Kazuo Takayama,

Masashi Honma,

Yoshitsugu Yanagihara, Ph.D.,

Takehito Yamamoto

Homepage

http://square.umin.ac.jp/todaiyak/index.html

Introduction and Organization
We have nine faculty members, 53 pharmacy staffs,
27 pharmacy residents, and 14 graduate students and 5
undergraduate students from the faculty ofpharmaceutical sciences (as of December 1st, 2007).
In addition, project associate professor (Akihiro
Hisaka,Ph.D.)
fromPharmacology
andPharmacokinetics department, and project research
associate (Shogo Miura, Ph.D.) from Cancer
Professional Training Plan are involved in our work..

Clinical activities
Department of Pharmacy consists of the following
six sections:1) Drug information and research section
This section offers drug information for questions
from the medical person, executes and supports
the medicine management to inpatients. In
addition, the section prepares materials forpharmaceutical affair committee, where each
medicine is discussed whether it should be
adopted or deleted. Preparation of several
periodicals regarding drug information forclinicians is also included.
2) The dispensing sectionAfterinspecting
allprescriptionsforcontraindications or improper use, medications
are dispensed. Drug information is given to
outpatients from this section, using a private room
if necessary. The computerized order system islinked with automatic packaging machines fororal medicines, bar code label printer, andautomatic dispensing system for injection drugs.
3) Pharmaceutical section
This section sterilizes formulations of apharmaceutical such as injection medicines,
instillation medicines and decontaminatingchemicals. They prepare capsule medicines,
ointment medicines, suppositories, central vein
nutrition (IVH) for inpatients and in-home carepatients. After strict inspection of prescriptions,they also dispense anti- malignant tumor medicine(database is constructed based on the submitted
protocols and the patient information). They also
do mixing of injections at each staff station of
ICU, CCU, HCU (both the surgical department
and internal department), internal medicines forhematology and oncology. In order to support
advanced medical care, they develop and check
formulations (characterization of the uniformity,
stability and so on) of the medicine which is quite
necessary for certain patients, but is not marketed.
4) Drug matters and drug management section
Drug matter section manages the adoption of

430

medical supplies (in-hospital and out-hospital),
periodically reconsiders the adopted medicines,
and also manages the accountings of all the
medicines and other materials used in our
department. This section also takes statistics ofevery information of drug affairs. Drugmanagement section takes care of supplying andsafekeeping of all the in-hospital medicines(approx. 2,150 items), out-patient medicines,
anesthetics, muscle relaxation drugs, psychotropic
drugs, poison medicines.
5) Narcotic section
Under the supervision of authorized manager fornarcotics (the director of the pharmacy
department), narcotics are properly managed,
recorded, reported, inspected and directed.
Narcotics are properly arranged and managed at
the dispensing section and each medical caresection.
6) Ward section
They contribute to the team medical care byproviding specialized drug information andsharing them with all the staffs involved in thetreatment as follows;① Supporting the proper use of medication bypharmacists stationed at 1st and 2nd ICU section.
② Arrangement and mixing of injections forpatients at the staff station of HCU for internaldiseases, and for Hematology and Oncology.
③ Investigation of carrying medicines and the side
effect histories, allergy histories etc. at the timeof hospitalization. Participation for conferences.
Procurement and appraisal of patient’s basic
information about the disease, compilation of
the medicine history. Monitoring of medication
guidance and the side effect for the patient, andcompilation of guidance record. Offering thedoctor with drug information, prescription
design support and detailed contents ofmedication guidance to each patient.
④ Investigation and management of ward stock
medicine.
⑤ Nutrient support of the patients as a member of
NST.
⑥ Management of proper use of narcotics as amember of palliative care team.
⑦ Management of proper use of antibiotics,

rounds of a hospital ward, and training of thestaffs as a member of ICT
Statistical Data (fiscal year 2007)
Number of items on in-hospital formulary:
approx. 2,227
Number of prescriptions filled (annual)out-patients:
476,050(outside:402,773)(inside:73,317)(chemotherapy:
4,808)
in-patients:
444,534(oral and external: 209,346)(injection drugs: 216,593)(IVH:
18,595)(chemotherapy:
6,855)
TDM consultations (annual):
14,161
Numbers of hospital pharmaceutical cares (annual):
2,556

Educational Activities
The department of pharmacy takes various
responsibilities of education with regard to clinicalpharmacy, pharmacology, and pharmacokinetics forstudents and graduate students in the faculty of
medicine, in the faculty of pharmacy, and in theschool of health sciences and nursing. We also have
our own one-year post-graduate training course
optimized for new pharmacists.
For students in the faculty of medicine, we are in
charge of "Pathogenetic and Pathology" as an optionalcourse lecture. We are providing a free quarter
practice course for some M1 and M2 students for 2
weeks and teach basic molecular and biochemical
techniques as well as the pharmacokinetic theory tothem. We are providing a 3-days practice course as apart of compulsory clinical practice for the M3 andM4 students and teach clinical pharmaceutics andpractical knowledge of prescription and risk
management to them. For the students in the healthsciences and nursing, we are in charge of clinicalpharmacokinetics lectures as a part of a compulsory
subject, "Pharmacology and Toxicology".
For students in the faculty of pharmacy, we are in
charge of two series of lectures for the undergraduate
students: "Clinical Pharmacy I" (compulsory subject)431

and "Clinical Pharmacy II" (an optional course).
They are educated for the clinical pharmacology andpharmacokinetics. For the graduate students, we arein charge of "Advanced Course of Medical Pharmacy"(every other year) as a cooperator of the ClinicalPharmacokinetic. Recent trends of the medical
pharmacy as well as the practical developments andfuture visions of the department of pharmacy arepresented in this lecture. We are responsible for thehospital practice courses (10 days in total) and teachpractical techniques of pharmacists such as drug
preparations and patient consultation. In addition tothese, we educate 4th year students and graduate
students who moved to the Clinical Pharmacokinetics.
In 2007, 27 pharmacists completed our one-year
post-graduate training course. They learned various
practical knowledge and techniques necessary for
hospital pharmacists. This course takes a role of
6-years education of the faculty of pharmacy inadvance which will start in 2009. In addition, we arepromoting life-long education of pharmacists in thelocal area by holding monthly regular technicalworkshop.

Research activities
A proper medication requires scientific evidences.
However, it is not fully understood that what the target
for main and side-effect of the drug is, as well as the
enzymes and transporters involved in the dispositionof drugs. Moreover, a number of patients are waitingfor development of new pharmacotherapy. We aretrying to clarify basic mechanisms of the genetic or
acquired diseases to develop useful pharmacotherapy
for an individual patient. Our research fields include
the regulation of the expression and function oftransporters related to the pharmacotherapy,
polymorphism of drug metabolizing enzymes andtransporters governing the drug disposition, and drug
information research.
Followings are the topics of our recent research:
1) Regulation of transcription and function oftransporters in the liver and intestine involved incholesterol homeostasis.
2) Intracellular trafficking and dynamic rearrangementof transporter complexes.
3) Regulation of intracellular trafficking andtranscription of signaling molecules involved inbone homeostasis
4) Polymorphism of drug metabolizing enzymes andtransporters. Quantitative prediction of clinicaleffects.
5) Clinical data analysis and utilization of drug
package insert, information on drug-druginteraction, and patient data for the development ofsafer and better medications for patients.

References
Original Article(1) Fujiyama N, Shitara Y, Ito K, Masubuchi Y, Horie
T. Down-regulation of hepatic transporters for
BSP in rats with indomethacin-induced intestinal
injury. Biol Pharm Bull 30: 556-561, (2007).
(2) Ohno Y, Hisaka A, Suzuki H. General framework
for the quantitative prediction of CYP3A4mediated oral drug interactions based on the AUC
increase by coadministration of standard drugs.
Clin Pharmacokinet 46: 681-696, (2007).
(3) Okada K, Shoda J, Kano M, Suzuki S, Ohtake N,
Yamamoto M, Takahashi H, Utsunomiya H, Oda
K, Sato K, Watanabe A, Ishii T, Itoh K, Yamamoto
M, Yokoi T, Yoshizato K, Sugiyama Y, Suzuki H.
Inchinkoto, a herbal medicine, and its ingredientsdually exert Mrp2/MRP2-mediated choleresis andNrf2-mediated antioxidative action in rat livers.
Am J Physiol Gastrointest Liver Physiol 292:
G1450-1463, (2007).
(4) Okuwaki M, Takada T, Iwayanagi Y, Koh S,
Kariya Y, Fujii H, Suzuki H. LXR alphatransactivates mouse organic solute transporter
alpha and beta via IR-1 elements shared with FXR.
Pharm Res 24: 390-398, (2007).
(5) Shoda J, Okada K, Inada Y, Kusama H,
Utsunomiya H, Oda K, Yokoi T, Yoshizato K,
Suzuki H. Bezafibrate induces multidrugresistance P-Glycoprotein 3 expression in cultured
human hepatocytes and humanized livers ofchimeric mice. Hepatol Res 37: 548-556, (2007).
(6) Yamamoto T, Ito K, Honma M, Takada T, Suzuki
H. Cholesterol-lowering effect of ezetimibe in
uridinediphosphate
glucuronosyltransferase
1A-deficient (Gunn) rats. Drug Metab Dispos 35:
1455-1458, (2007).

432(7) Yamanashi Y, Takada T, Suzuki H. Niemann-Pick
C1-like 1 overexpression facilitates ezetimibesensitive cholesterol and beta-sitosterol uptake in
CaCo-2 cells. J Pharmacol Exp Ther 320: 559-564,(2007).
International Meeting(1) Hisaka A, Ohno Y, Suzuki H. Systematic
prediction of drug-drug interactions mediated by
CYP3A4 from in vivo pharmacokinetics;
considerations on intestinal metabolism andtransport. . 4th World conference on Drug
Absorption, Transport and Delivery (WCDATD)(2007, June).
(2) Kozawa M, Honma M, Suzuki H. Prediction of
the time profiles for the human in vivo inductionof CYP enzymes from in vitro data. 8thinternational ISSX meeting 60: 39-40, (2007,
October).
(3) Takada T, Yamanashi Y, Narushima K, Suzuki H.
Construction of NPC1L1 expression system andevaluation of its transport properties. Biomedical
Transporters 2007 Bern, Switzerland: (2007,
August).
(4) Yoshikado T, Takada T, Ito K, Suzuki H.
Characterization of cholestatic ABCB4 mutants
using in vitro adenovirus expression system 8th
International ISSX Meeting Sendai, Japan: (2007,
October).

Center for Disease Biology andIntegrative Medicine

434

Division of Basic Medical
Sciences(I)Professor
Toru Miyazaki, M.D., Ph.D.

Lecturer/Associate Professor
Satoko Arai, Ph.D.

Endowment Assistant Professor
Nobuya Kurabe, Ph.D.

Research Fellow
Miki Miyazaki-Kondo, M.D., Ph.D.

Homepage

http: //tmlab.m.u-tokyo.ac.jp/

Research
Our laboratory will focus on clarification of thepathogenesis of various diseases and the related
physiological machineries in cellular and molecular
aspects. Based on our technical advantage in genemanipulation via gene knockout and transgenesis, wewill give high priorities to in vivo analyses. This willdefinitively contribute to the direct therapeutic
application of our findings. Since our rationale is tochallenge to uncharacterized disease mechanisms andphysiologies, we will not restrict our interest, strategy
or technique employed, in certain specific field.
Rather, we will expand our research area by
establishing different collaborations with a broad
spectrum of investigators. We believe this fits to thepolicy of the CDBIM, which aims the development of
a comprehensive science including the fundamental
and clinical medicines, and the biotechnology. Overall,
we will attempt to discover novel biological insights
rather than to study details of previously characterized
physiologies, by targeting molecules newly identified
by ourselves. The major specific aims during the next
five years are as follows:

1. Role of Apoptosis Inhibitor expressed byMacrophages(AIM)inatherosclerosis
development.
AIM, which we initially identified as a soluble
apoptosis inhibitory factor, is largely produced bytissue macrophages. Recently, we found that AIM
expression induction is highly correlated to
hyperlipidemia; and that expression of AIM is criticalin progression of atherosclerosis as assessed in AIM
knockout mice. We will isolate the putative receptor
for AIM, and elucidate the entire signaling pathway of
how AIM inhibits apoptosis. In addition, bygenerating functional antibodies against human AIM,we will develop a potential treatment of
atherosclerosis by suppressing AIM activity in thebody.
2. Epigenetical regulation of Genome-Stability via
Polycomb and its relevance to oncogenesis.
Recently, we discovered a novel Polycomb groupprotein MBT-1, which specifically dictates thematurational transition of immature myeloid
progenitor cells. We will clarify the definitive
molecular mechanism of how MBT-1 regulates the
myelopoiesis, which may open avenues for the further

435

understanding of the mechanisms responsible forleukemogenesis. In addition, we will perform a large
scale screening of leukemia patients for the mutation
and/or the translocation of the MBT-1 gene (locus).
3. Regulation of mitosis progression by DEDD and
its influence on cell & body sizing andoncogenesis.
It has been suggested that the regulation of
apoptosis is crucially involved in tumor development.
Our recent analysis of knockout mice of the deatheffector domain (DED) containing element DEDD-1
has implied an important role of DEDD-1 in tumor
progression. We will further determine theinvolvement of DEDD-1 in tumorgenesis in thecontext of apoptosis as well as of other potentialmachineries. We will also study the function of asimilar molecule DEDD-2 both in vivo and in vitro.
These studies will not only provide a novel insight
into the influence of apoptosis in tumorgenesis, butalso suggest a potentiality of tumor manipulation bymodulating expression of DEDD molecules.
4. Analysis of pathogenesis for IDDM via genetargeting in NOD-derived ES cells.
Insulin dependent diabetes mellitus (IDDM) is an
autoimmune disease that is characterized by the
specific destruction of the insulin-producing β-cells of
the Langerhans islets within the pancreas. An
important animal model for IDDM is the non-obese
diabetic (NOD) mouse. Since humans and the NOD
mouse share most of the fundamental characteristics
of IDDM, the NOD mouse has been extensively
studied in order to better understand the etiology andpathogenesis of the disease. To date, more than twenty
insulin-dependent diabetes (Idd) genes that influence
the disease have been mapped in the NOD mouse. In
collaboration with Dr. Nagafuchi in Kyushu
University, we have established the experimental
conditions that provide a high germline transmission
efficiency of NOD-derived ES cells, which enabled us
to create gene manipulated mice for specific diseaseresponsible genes on a pure NOD genetic background.
We will clarify the precise involvement of various Idd
genes in IDDM by targeting these genes in the
NOD-ES cells.

5. Towards the development of a definitive
therapy for Propionic Acidemia.
Propionic acidemia (PA) is the most frequent inborn
error of organic acid metabolism in humans. It iscaused by a deficiency of propionyl-CoA carboxylase(PCC), which results in accumulation of toxic
propionic acid, leading to furious acceleration of
ketoacidosis. We generated a mouse model for thesevere-type PA by disrupting the PCCA (α-subunit of
PCC) gene, and successfully rescued the mice bycomplementation of a partial PCC-activity restrictedly
in the liver or in the skin via a transgene. Having thisresult, we will establish a novel therapy for PA that isbased on an idea of developing “chimeric” organs via
transplantation of hepatic stem cells or fibroblast cells
into newborns or early infants.

Lab Activities
DBELS（Disease Biology Excellent Lecture Series）
We present a lecture series by top scientists in avariety of research fields related to disease biology. Sofar, eleven lecturers have been invited from many
places including Kyoto Univ., Hokkaido Univ., Riken
Institute, Tokyo Univ. of Science, Washington Univ.
(USA), Univ. of Basel (Switzerland), and Weill
Medical College of Cornell University (USA).

DBELS-EXTRAAs a daughter series of DBELS, we started atechnical lecture series for young scientists. We invite
various scientists from not only universities but also
research institutes or industries.
DBELS WORKSHOPThis summer (2007), we had a workshop at Unzen,
a great resort place in Nagasaki prefecture. Along thepolicy for DBELS, we invited 8 top-scientists from
Kyoto, Tokyo, Hokkaido, Okinawa, and Boston as
lecturers, and many young participants as audiences.
Staying in a beautiful resort hotel, we all had ascientifically and culturally fruitful time. The next
workshop is scheduled to be held in Switzerland,
probably in 2009 summer.
Music and ScienceAs an opening ceremony of our lab, we invited

436

Maestro Christian Zimerman (Pianist), for a concert
by him, and a discussion (with Prof. Miyazaki) on
Music and Science, at the Yasuda memorial
auditorium (June 2006). More than 800 audiences
have participated.
Visiting Professors
So far, Profs. Edward K. Wakeland (Univ. of Texas
Southwestern Medical Center at Dallas) (2007), Diane
Mathis and Christophe Benoist (Harvard Univ.
Medical School) (2008) visited our lab for 3 months,
and had many activities.

Publications
1. Jayachandran,R.,
Sundaramurthy,
V.,
Combaluzier, B., Korf, H., Huygen, K., Miyazaki,T., Albrecht, I., Massner, J. & Pieters, J. Survival
of Mycobacteria in macrophages is mediated byCoronin 1-dependent activation of calcineurin.
Cell 130: 1-14 (2007).
2. Miyazaki, T. & Arai, S. Two distinct controls of
mitotic Cdk1/cyclin B1 requisite for cell growthprior to cell division. Cell Cycle 6: 1419 - 1425
(2007).
3. Arai, S., Miyake, K., Voit, R., Nemoto, S.,
Wakeland, E.K., Grummt, I. & Miyazaki, T. The
death-effector domain containing protein DEDD
is a novel mitotic inhibitor requisite for cell
growth. Proc. Natl. Acad. Sci. USA 104: 22892294 (2007).
4. Koltsova, E.K, Ciofani, M., Benezra, R.,
Miyazaki, T., Clipstone, N., Zuniga-Pflucker, J.C.,
Wiest, D.L. Early Growth Response 1 and
NF-ATc1 Act in Concert to Promote Thymocyte
Development
beyondthebeta-Selection
Checkpoint. J. Immunol. 179: 4694-4703 (2007).
5. Arai, S., Shelton, J.M., Chen, M., Bradley, M.N.,
Castrillo, A, Bookout, A.L., Mak, P.A., Edwards.
P.A., Mangelsdorf, D.J., Tontonoz, P. & Miyazaki,
T. A role of the apoptosis inhibitory factor
AIM/Spα/Api6 in atherosclerosis development.
Cell Metabolism 1: 201-213 (2005).
6. Arai, S. & Miyazaki, T. Impaired maturation of
myeloid progenitor cells exhibiting normal
proliferative activity in mice lacking the novel
Polycomb group protein MBT-1. EMBO J. 24:

1863-1873 (2005).
7. Haks, M.C., Lefebvre, J.M., Lauritsen, J.P.H.,
Carleton, M., Rhodes, M., Miyazaki, T., Kappes,
D.J. & Wiest, D.L. Attenuation of γδTCRsignaling efficiently diverts thymocytes to the αβlineage. Immunity 22: 595-606 (2005).
8. Kroll, J., Shi, X., Caprioli, A., Liu, H.H., Waskow,
C., Lin, K.M., Miyazaki, T., Rodewald, H.R. &Sato, T.N. The BTB-kelch protein, KLHL6, isinvolved in B-lymphocyte antigen receptor
signaling and germinal center formation. Mol.
Cell. Biol. 25: 8531-8540 (2005).
9. Arai, S., Minjares, C., Nagafuchi, S. & Miyazaki,
T. Improved experimental procedures for NODderived embryonic stem cells to achieve an
efficient transmission into mouse germ line. Exp.
Diab. Res. 5: 219-226 (2004).
10. Kuwata, K., Watanabe, H., Jiang, S-Y., Yamamoto,T., Miyaji, C., Abo, T., Miyazaki, T. & Naito, M.
AIM inhibits apoptosis of T cells and NKT cellsinCorynebacterium-induced
Granuloma
formation in mice. Am. J. Pathol 162: 837-847(2003).
11. Ito, Y., Arai, S., van Oers, N.S.C., Aifantis, I., vonBoehmer, H. & Miyazaki, T. Positive selection by
the pre-TCR yields mature CD8+ T cells. J.
Immunol. 169: 4913-4919. (2002).
12. Miyazaki, T., Ohura, T., Kobayashi, M.,
Shigematsu, Y., Yamaguchi, S., Suzuki, Y., Hata,
I., Aoki, Y., Yang, X., Minjares, C., Haruta, I., Uto,
H., Ito, Y. & Muller, U. Fatal propionic acidemia
in mice lacking propionyl-CoA carboxylase andits
rescuebypostnatal,liver-specificsupplementation via a transgene. J. Biol. Chem.
276: 35995-35999 (2001).
13. Haruta, I., Kato, Y., Hashimoto, E., Minjares, C.,
Kennedy, S., Uto, H., Yamauchi, K., Kobayashi,M., Yusa, S., Müller, U., Hayashi, N. & Miyazaki,
T. Association of AIM with hepatitis via
supporting macrophage survival and enhancing
phagocytotic function of macrophages. J. Biol.
Chem. 276: 22910-2914 (2001).
14. Miyazaki, T., Hirokami, Y., Matsuhashi, N.,
Takatsuka, H. & Naito, M. Increased
susceptibility of thymocytes to apoptosis in micelacking AIM, a novel murine macrophage-derived
soluble factor belonging to the scavenger receptor

437

cysteine-rich domain superfamily. J. Exp. Med.
189:413-422 (1999).
15. Miyazaki, T. & Lemonnier, F.A. Modulation ofthymic selection by expression of animmediate-early gene, early growth response 1(Egr-1). J. Exp. Med. 188:715-723 (1998).
16. Miyazaki, T. Two distinct steps during thymocyte
maturation from CD4-CD8- to CD4+CD8+
distinguished in the early growth response (Egr)-1transgenic mice with a recombinase-activating
gene deficient background. J. Exp. Med. 186:877-885. (1997).
17. Miyazaki, T., Müller, U. & Campbell, K.S.
Normal development but differentially alteredproliferative responses of lymphocytes in micelacking CD81. EMBO. J. 16: 4217-4225. (1997).
18. Miyazaki, T., Wolf, P., Tourne, S., Waltzinger, C.,
Dierich, A., Barois, N., Ploegh, H., Benoist, C. &Mathis, D. Mice lacking H2-M complexes,
enigmatic elements of the MHC class II
peptide-loading pathway. Cell 84: 531-541(1996).
19. Miyazaki, T., Dierich, A., Benoist, C. & Mathis D.
Independentmodesofnaturalkilling
distinguished in mice lacking Lag3. Science 272:405-408 (1996).
20. Miyazaki, T., Matsuda, Y., Toyonaga, T., Miyazaki,J., Yazaki, Y. & Yamamura, K. Prevention of
autoimmune insulitis in non-obese diabetic miceby expression of major histocompatibility
complex class I Ld molecules. Proc. Natl. Acad.
Sci. USA. 89: 9519-9523 (1992).
21. Miyazaki, T., Uno, M., Uehira, M., Kikutani, H.,
Kishimoto, T., Kimoto, M., Nishimoto, H.,
Miyazaki, J. & Yamamura, K. Direct evidence forthe contribution of the unique I-ANOD to thedevelopment of insulitis in non-obese diabetic
mice. Nature 345: 722-724 (1990).

438

Division of
Basic Medical Sciences (II)Professor
Haruo Kasai, M.D.,Ph.D.

Lecturer
Noriko Takahashi, M.D., Ph.D.

Research Associate
Masanori Matsuzaki, Ph.D.,

Homepage

Jun Nogichi, Ph.D.,

Junichi Tanaka, Ph.D.

http://www.bm2.m.u-tokyo.ac.jp/

Introduction and Organization
The Center for Disease Biology and Integrative
Medicine (CDBIM) has been established in 2003, andelected Dr. Kasai as the professor of the Division of
Basic Medical Sciences (2) of CDBIM in July of 2004.
Dr. Kasai was in the National Institute for Physiological Sciences at that time, and officially took officein the University of Tokyo in November, 2005. The
Kasai laboratory has moved to the first building ofFaculty of Medicine in January, 2006. Our division
belongs to the Section of Functional Biology in the
Graduate School of Medicine, and our division isnamed the Division of Biophysics in the graduate
school.

Teaching activities
In 2007, we were involved in undergraduate education of Physiology. Particularly, we taught endocrine
physiology and was responsible for student experiments.
We have four graduate students in our own
laboratory.

Research activities
Functional imaging is a central theme in modern
biology and medicine. All biological functions involvea multitude of interactions at the molecular, cellular,
and system levels, and it is ultimately desirable toperform molecular and cellular imaging in intact
preparations in which the original in vivo functions
are preserved. We have been exploring two-photon
excitation microscopy with a new type of laser, an
infrared femtosecond-pulse laser, as a means toachieve this goal. The two-photon microscope has theability to penetrate deep into tissues and is the only
imaging instrument that allows investigations of intact
tissues at the cellular and molecular levels.
Two-photon microscopy can also be readily combinedwith molecular biological and other physiologicalmethods, and it promises to provide important insight
into various biological processes in the coming years.
Our research interests have two main focuses: (1) the
dynamics of synapses in the cerebral cortex and (2)exocytosis in both neurons and secretory cells. We
welcome multidisciplinary collaborations to promote
our research goals and to help to adapt the new microscopic techniques and lasers to a wide range of
biomedical applications.
1) Dynamics of synapses in the cerebral cortex. We
have developed a method to stimulate and control
single synapses in the cerebral cortex with the useof two-photon excitation of photoactive glutamate
analogs. Our investigations have revealed that the439

major functions of synapses depend on theirstructure. We have thus shown that small synapses
are ready to learn, enlarging rapidly (within 10 s)after stimulation, whereas large synapses are
structurally stable and act as long-term memory
traces. These observations suggest that learning,memory, and other activities of the brain are mediated by changes in synaptic structure, and thatthey can be directly visualized. Moreover, we are
now in a position to manipulate synaptic plasticity
with a laser beam at the level of the individual
synapse. Such notions and methodology will befurther exploited to understand brain functions
and disorders.
2) Exocytosis is the most essential function of synaptic terminals and secretory cells. Knowledge ofthe mechanisms of and the ability to control exocytosis artificially have been limited, however.
With the use of two-photon excitation-based simultaneous multicolor imaging of various tracers,
we have, for the first time, visualized exocytosis
in intact islets of Langerhans, pancreatic acini, theadrenal medulla, and synaptic preparations. Byfurther extending our approaches, we aim to develop new methods for imaging and control of secretory functions and their molecular processes in
the cerebral cortex and secretory tissues.

References
1. Augustine GJ & Kasai H. B ernard Katz, quantaltransmitter release, and the foundations of presynaptic physiology, J. Physiol. (Lond.) 2007;
578:623-625.
2. Wang H, Peca J, Matsusaki M, Matsuzaki K, Noguchi J, Qiu L, Wang D, Zhang F, Boyden E,
Deisseroth K, Kasai H, Hall WC, Feng G & Augustine GJ. Activation and high-speed mappingof brain circuitry using photostimulation in
Channelrhodopsin-2 transgenic mice. PNAS
2007; 104:8143-8.
3. Ellis-Davies GCR, Matsuzaki M, Paukert M, Kasai H & Bergles DE. CDNI-Glu: an improved
caged glutamate for expeditious ultraviolet and2-photon photolysis in brain slices. J. Neurosci.

2007; 27:6601-4.
4. Hatakeyama H, Takahashi N, Kishimoto T, Nemoto T, & Kasai H. Two cAMP-dependent
pathways differentially regulate large-dense coreand small vesicles in mouse β cells. J. Physiol.
(Lond.) 2007; 582:1087-1098.
5. Takahashi N. & Kasai H. Two-photon excitation
imaging of insulin exocytosis. In “ Pancreatic beta
cell in health and disease,” Springer Verlag, New
York, 2007; pp195-211.
6. Takahashi N & Kasai H. Exocytic process analyzed with two-photon excitation imaging in endocrine pancreas. Endocrine J. 2007; 54:337347.

440

Division of Regenerative Medical
Engineering
Professor
Takashi Ushida, Ph.D.

Associate Professor
Yasuyuki Sakai, Ph.D.

Homepage

http://www.cdbim.m.u-tokyo.ac.jp/

Introduction and Organization
The Division is composed of two laboratories, Ushidalaboratory and Sakai Laboratory. The Division tightly
collaborates with Faculty of Engineering. Prof. Ushidais also charged at Department of MechanicalEngineering, where the laboratory members include
Assistant Professor, two Associates and 15 graduate
students (as of April 1, 2004). Prof. Sakai also holds a
position in Institute of Industrial Science (IIS),
University of Tokyo.
The current laboratory
members at IIS (as of April 1, 2004) include one
research associate, one JSPS postdoctoral fellow, one
technical assistant, and six graduate students from
Department of Chemical System Engineering,
Graduate School of Engineering. In addition, four
graduate students who belong to other universities do
research in our laboratory.

Teaching activities
Prof. Ushida and Prof. Sakai are sharing duties forundergraduate and graduate students of both Graduate
School of Medicine and Graduate School ofEngineering. They give lectures on biomedical
engineering at Graduate School of Medicine. Prof.
Ushida has also lectures on tissue engineering,
advanced biomaterials and biomechanics at Graduate
School of Engineering. Prof. Sakai gives a lecture
concerning biosystem engineering at the Chemical
System Engineering course and Bioengineering course

at Graduate School of Engineering School.

Research activities
Prof. Ushida’s laboratory aims to establish key
technologies for regenerative medicine. One of the
projects of our research targets the hard tissue
regeneration, such as cartilage or bone by tissue
engineering technology. Hard tissue engineering
requires the control of its shape in addition to the cell
accumulation and scaffold play a key role in meeting
this requirement. We focus on the development of
biocompatible materials such as synthetic polymer orinorganic materials combined with stem cellbiotechnology. Secondly, we try to elucidate
mechanisms of cellular responses to physicalstimulations such as hydrostatic pressure, shear stress,
stretch, through observing intracellular signaling, andto adopt those effects to tissue engineering.
1) Tissue engineering of cartilage or bone defect- Design and development of biocompatible
materials for cartilage or bone using synthetic
polymer, inorganic materials or those combination.
- Development of osteoinductive biomaterials
hybridized with bioactive substances.
- Order made shaping of scaffolds by router system
according to the graphical images of tissue defects- Establishment of vascular rich graft bed bybiomaterials that spur new blood vessel growth.

4412) Cellular signal transduction induced by physicalstimulations- Hydrostatic pressure loading to chondrocytes orarticular cartilage- Shear stress loading to endothelial cells- Stretch loading to endothelial cells, smooth muscle
cells
The general objective of Prof. Sakai’s laboratory is toorganize experimentally human systems or its
subsystems such as organ or tissue using cultured
human cells for fundamental understanding ofsystemic responses of a human body or organs andbiomedical or environmental applications. At present,
we need several different technologies to achieve thegoal in addition to usual cell culture technologies.
These include in vitro control of the growth anddifferentiation of organ stem or progenitor cell
populations, cultivation technologies ranging frommicro- to clinically significant-sizes, threedimensional microfabrication of biodegradable organ
templates, etc. About such topics, we are actively
doing collaborative research with other institutes
outside Univ. of Tokyo. The most important thing is toorganize these technologies originally derived fromdifferent academic background from engineering pointof view.
3) Engineering of human large internal organs- Design, preparation and in vitro maturation of
implantable liver tissue for humans- In vitro control of growth and differentiation ofhepatocyte progenitors- Semi-bottom-up tissue engineering4) Development of in vitro models for human organs
and their applications- Micro-organ model devices- 2D and 3D micro-patterning of cultured cells- Cell-based simulator (on-chip human) for humanmetabolism

References
1. Yasuhisa Urita, Hiroaki Komuro, Guoping Chen,
Miki Shinya, Setsuko Kaneko, Michio Kaneko,
Takashi Ushida,, Regeneration of the esophagus
using gastric acellular matrix: an experimental

2.

3.

4.

5.

6.

7.

study in a rat model, Pediatr Surg Int , 23:21-26(2007)
Kawanishi M, Oura A, Furukawa K, Fukubayashi
T, Nakamura K, Tateishi T, Ushida ,Redifferentiation of dedifferentiated bovine
articular chondrocytes enhanced by cyclichydrostatic pressure under a gas-controlled system,
T., Tissue Eng. ;13(5):957-964 (2007)
Miyata S, Numano T, Homma K, Tateishi T,
Ushida T.,, Feasibility of noninvasive evaluationof biophysical properties of tissue-engineered
cartilage by using quantitative MRI, J Biomech 40,
2990-2998 (2007)
H. Huang, S. Oizumi, N. Kojima, T. Niino, Y.
Sakai, Avidin-biotin binding–based cell seeding
and perfusion culture of liver-derived cells in a
porous scaffold with a three-dimensional
interconnectedflow-channel
network,
Biomaterials, 28, 3815-3823 (2007).
H. Nakayama, H. Kimura, K. Komori, T. Fujii,
and Y. Sakai, Development of a multicompartment micro-cell culture device as a future
on-chip human: fabrication of a threecompartment device and immobilization of rat
mature adipocytes for the evaluation of chemical
distributions, J. Robotics Mechatronics, 19(5),544-549 (2007).
H. Kimura, M. Nishikawa, T. Yamamoto, Y. Sakai,
and T. Fujii, Microfluidic perfusion culture ofhuman hepatocytes, J. Robotics Mechatronics, 19(5), 550-556 (2007).
H. Naruto, H. Huang, M. Nishikawa, N. Kojima,
A. Mizuno, K. Ohta, Y. Sakai, Feasibility of direct
oxygenation of primary-cultured rat hepatocytes
using polyethylene glycol decorated liposomeencapsulated hemoglobin (LEH), J. Biosci &Bioengineering, 104, 343-346 (2007).

442

Division of Clinical Biotechnology
Professor
Kazunori Kataoka, Ph.D.

Lecturer
Keiji Itaka, M.D., Ph.D.
Nobuhiro Nishiyama, Ph.D.

Assistant Professor
Joon-Sik Park , Ph.D.

Homepage: http://www.cdbim.m.u-tokyo.ac.jp/research/01_04.html
http://www.bmw.t.u-tokyo.ac.jp/
Introduction and Organization
Division of Clinical Biotechnology in The Center for
Disease Biology and Integrative Medicine (CDBIM)
was established in April 2003. This Division wishes
to contribute to the realization of nanomedicine,which is one of major goals for Research Cluster for
Frontier Medicine Development at The University ofTokyo Hospital and The Center for NanoBio
Integration (CNBI) at The University of Tokyo. We
actively collaborate and have an interchange of
graduate students with Graduate Schools ofEngineering & Medicine at The University of Tokyoand Division of Tissue Engineering at The Universityof Tokyo Hospital. Our division also plays a majorrole in the Nano-Bioengineering Education Program(NBEP), which started in 2004 as a novel medicineengineering interdisciplinary program, and tries tocontribute to the production of medical ventures bypromoting liaison with the industrial sector and to the
production of professionals who understand bothadvanced medicine and nanotechnology. The divisionconsists of one professor, one associate professor, two
lecturers and several project staff members belonging
to the CNBI and NBEP.
Our division focuses on the realization of
nanomedicine. Nanotechnology, which has recently
been attracting tremendous attention as a leading

scientific field in the 21st century, attempts to process
and assemble materials with precision at theatomic/molecular level to produce units withsophisticated functions. Nanodevices produced bynanotechnology integrate materials and systems on ananometer scale, and hold the key to realizing thefuturistic medical system that can serve the needed
function at the right time and the right place withminimal invasiveness. Furthermore, nanodevices are
expected to become an important interface between
basic biomedical science and clinical medicine byfacilitating the translation of basic achievements into
clinical applications. Our division wishes to produce
revolutionary medical nanodevices based on
nanotechnology and thereby to spread the idea of"Nanomedicine" intranationally and internationally.

Teaching activities
Traditional medicine-engineering interdisciplinary
programs have focused on the exchange of researchers
and the promotion of collaborative researches between
these two different academic areas. However, the next
generation medicine such as "minimum-invasive
diagnosis-treatment"
and"targeting
medicaltreatment" and nanotechnologies are developing soquickly with increasing complexity that scholars inboth areas find it hard to understand each other. For443

this reason, it is becoming increasingly difficult for
medical doctors to locate technological seeds meeting
their medical needs and for engineers to find ways ofapplying their technological seeds to corresponding
medical needs. This situation prevents the effective
development of revolutionary medical diagnosticaland therapeutic inventions. Division of Clinical
Biotechnology intends to create an optimal milieu
where undergraduate and graduate students from the
medical and engineering fields can respect eachother's background, ignores the boundary and study
the fusion area in order to achieve the common goal ofdeveloping intelligent nanodevices for the futuristic
medical system.

Research activities
Drug delivery to the targeted site is strongly desired toenhance the drug function and minimize the side
effects. In this regard, drug delivery systems basedon self-assemblies of block copolymers (i.e.,
polymeric micelles) recently draw much attention as
one of the medical applications of the nanotechnology.
Block copolymers spontaneously form polymeric
micelles, which are characterized by the core-shellstructure and the size of ~100 nm, in aqueous media.
The core of the micelles behaves as a nanoreservoir
for drugs, while the coronal shell providing thebiocompatible surface.
Polymeric micelles can
incorporate a variety of drugs including hydrophobic
drugs, metal complex drugs, and macromolecular
drugs such as proteins and DNA, and release them in asustained manner or in response to environmental
changes such as pH. The site-specific drug delivery
can be achieved by conjugation of the pilot moleculeson the surface of polymeric micelles.
Thus,
polymeric micelles behave as intelligent chemical
nanomachines for the drug targeting.
The long-circulation of drug carriers is a requisite
for the successful drug targeting. The main obstacles
to long-circulatio are considered to be glomerular
excretion in the kidney and recognition by thereticuloendothelial system (RES) located at the liver,spleen and lung. Polymeric micelles can escapefrom those barriers in the body, resulting in stable
blood circulation.
Another advantage of using
polymeric micelles is their preferential accumulation

in solid tumors, which might be due to microvascular
hyperpermeability and immature lymphatic system intumor tissues. We have succeeded in the tumorselective delivery of several antitumor drugs including
adriamycin (ADR) and cisplatin (CDDP) by
polymeric micelles, and observed enhanced antitumor
activity with reduced side effects. These micellar
formulations are currently being tested in clinical
trials.
Recently, plasmid DNA (pDNA) and siRNA are
receiving much attention as promising tools for thetreatment of genetic and intractable diseases. One of
the major requirements for therapeutic use of pDNA
and siRNA is the development of gene vectors, which
can safely and effectively deliver them into specificcells and regulate their expressions. Recently, we
have prepared polymeric micelles incorporating
pDNA through the electrostatic interaction between
DNA and positively charged block copolymers. The
polymeric micelles protected the loaded DNA fromdegradation by nuclease attack and showed efficientgene transfer to a variety of cells. Also, various
smart functions such as the targeting ability andenvironmental sensitivity can be integrated withpolymeric micelles, offering the opportunities todevelop effective synthetic vectors resembling viralfunctions. Recently, we have developed the lightresponsive gene carriers, and have achieved in vivo
gene transfer in a light-specific manner. Further,polymeric micelles can be used for the tissue
engineering without cell transplantation. Recently,
polymeric micelles carrying pDNA encoding
osteogenic factors were implanted to mouse calvaria
bone defects in the form of calcium phosphate paste,
resulting in rapid induction of bone regeneration.
Thus, polymeric micelles are expected as useful
nanocarriers of pDNA and siRNA for in vivo use.

References
1. Y. Lee, K. Miyata, M. Oba, T. Ishii, S. Fukushima,
M. Han, N. Nishiyama, K. Kataoka, Chargeconversional ternary polyplex with endosome
disruption moiety: a new paradaigm for theefficient and safe gene delivery. Angew. Chem. Int.
Ed., in press.
2. S. Wu, N. Nishiyama, M. R. Kano, Y. Morishita,

444

K. Miyazono, K. Itaka, U. Chung, K. Kataoka
Enhancementofangiogenesis
throughstabilization of hypoxia inducible factor-1 bysilencing prolyl hydroxylase domain 2 gene.
Molecular Ther., in press.
3. S. Takae, K. Miyata, M. Oba, T. Ishii, N.
Nishiyama, K. Itaka, Y. Yamasaki, H. Koyama, K.
Kataoka, PEG-detachable polyplex micelles basedondisulfide-linked
block
catiomers
asbioresponsive nonviral gene vectors. J. Am. Chem.
Soc. 130 (18) 6001-6009 (2008)
4. K. Sugisaki, T. Usui, N. Nishiyama, W-D Jang, Y.
Yanagi, S. Yamagami, S. Amano, K. Kataoka,
Photodynamic
therapyforcornealneovascularization using polymeric micelles
encapsulating dendrimer porphyrins. Invest.
Ophth. Vis. Sci. 49 (3): 894-899 (2008)
5. A. Harada, K. Kataoka, Selection between blockand homo-polyelectrolytes through polyion
complex formation in aqueous medium. Soft
Matter 4 (1) 162-167 (2008)
6. Y. Imai, E. Kaneko, T. Asano, M. Kumagai, M.
Ai, A. Kawakami, K. Kataoka, K. Shimokado, A
novel contrast medium detects increased
permeability of rat injured carotid arteries inmagnetic resonance T2 mapping imaging. J
Athero. Throm. 14 (2) 65-71 (2007)
7. S. Hiki, K. Kataoka, A facile synthesis of
azido-terminated heterobifunctional poly(ethylene
glycol)s for "Click" conjugation. Bioconjugate.
Chem. 18 (6) 2191-2196 (2007)
8. Y. Li, W. -D. Jang, N. Nishiyama, A. Kishimura,S. Kawauchi, Y. Morimoto, S. Miake, T.
Yamashita, M. Kikuchi, T. Aida, K. Kataoka,
Dendrimer generation effects on photodynamic
efficacy of dendrimer porphyrins and dendrimerloaded supramolecular nanocarriers. Chem. Mater.
19 (23) 5557-5562 (2007)
9. K. Masago, K. Itaka, N. Nishiyama, U. Chung, K.
Kataoka, Gene delivery with biocompatible
cationic polymer:Pharmacogenomic analysis on
cell bioactivity. Biomaterials 28 (34) 5169-5175(2007)
10. M. Nakanishi, J. -S. Park, W. -D. Jang, M. Oba, K.
Kataoka, Study of the quantitative aminolysis
reaction of poly(beta-benzyl L-aspartate) (PBLA)

as a platform polymer for functionality materials.
React. Funct. Polym. 67 (11) 1361-1372 (2007)
11. M. P. Xiong, Y. Bae, S. Fukushima, M. L. Forrest,
N. Nishiyama, K. Kataoka, G. S. Kwon,
pH-responsive multi-PEGylated dual cationic
nanoparticles enable charge modulations for safe
gene delivery. ChemMedChem 2 (9) 1321-1327(2007)
12. M. Oishi, Y. Nagasaki, N. Nishiyama, K. Itaka, M.
Takagi, A. Shimamoto, Y. Furuichi, K. Kataoka,
Enhanced
growthinhibition ofhepatic
multicellular tumor spheroids by lactosylated poly
(ethylene glycol)-siRNA conjugate formulated in
PEGylated polyplexes. ChemMedChem 2 (9)1290-1297 (2007)
13. K. Miyata, S. Fukushima, N. Nishiyama, Y.
Yamasaki, K. Kataoka, PEG-based block
catiomers possessing DNA anchoring andendosomal escaping functions to form polyplex
micelles with improved stability and hightransfection efficacy. J. Control. Release 122 (3)252-260 (2007)
14. M. Oba, S. Fukushima, N. Kanayama, K. Aoyagi,
N. Nishiyama, H. Koyama, K. Kataoka, Cyclic
RGD peptide-conjugated polyplex micelles as atargetable gene delivery system directed to cells
possessing alphavbeta3 and alphavbeta5 integrins.
Bioconjugate Chem. 18 (5) 1415-1423 (2007)
15. H. Cabral, N. Nishiyama, K. Kataoka,
Optimizationof(1,2-diamino-cyclohexane)
platinum(II)-loaded polymeric micelles directed
to improved tumor targeting and enhanced
antitumor activity. J. Control. Release 121 (3)146-155 (2007)
16. M. Han, Y. Bae, N. Nishiyama, K. Miyata, M.
Oba, K. Kataoka, Transfection study using
multicellular tumor spheroids for screening
non-viral polymeric gene vectors with low
cytotoxicity and high transfection efficiencies. J.
Control. Release 121 (1-2) 38-48 (2007)
17. S. Takae, Y. Akiyama, Y. Yamasaki, Y. Nagasaki,
K. Kataoka, Colloidal Au replacement assay forhighly sensitive quantification of low molecularweight analytes by surface plasmon resonance.
Bioconjugate Chem. 18(4) 1241-1245 (2007)
18. Y. Bae, N. Nishiyama, K. Kataoka, In vivo
antitumor activity of the folate-conjugated445

pH-sensitive polymeric micelle selectively
releasing adriamycin in the intracellular acidic
compartments. Bioconjugate Chem. 18(4) 11311139 (2007)
19. A. Kishimura, A. Koide, K. Osada, Y.Yamasaki,
K.Kataoka, Encapsulation of myoglobin in
PEGylated polyion complex vesicles made from apair of oppositely charged block ionomers: aphysiologically available oxygen carrier. Angew.
Chem. Int. Ed. 46(32) 6085-6088 (2007)
20. K. Itaka, S. Ohba, K. Miyata, H. Kawaguchi, K.
Nakamura, T. Takato, U. -I. Chung, K. Kataoka,
Bone regeneration by regulated in vivo genetransferusing
biocompatible
polyplex
nanomicelles. Mol Ther. 15 (9) 1655-1662 (2007)
21. T. Satomi, Y. Nagasaki, H. Kobayashi, H. Otuka,
K. Kataoka, Density control of poly(ethylene
glycol) layer to regulate cellular attachment.
Langmuir 23(12) 6698-6703 (2007)
22. M. Oishi, H. Hayashi, K. Itaka, K. Kataoka, Y.
Nagasaki, pH-Responsive PEGylated nanogels astargetable and low invasive endosomolytic agentsto induce the enhanced transfection efficiency ofnonviral gene vectors. Colloid. Polym. Sci. 285
1055-1060 (2007)
23. D. Akagi, M. Oba, H. Koyama, N. Nishiyama, S.
Fukushima, T. Miyata, H. Nagawa, K. Kataoka,
Biocompatible micellar nanovectors achieve
efficient gene transfer to vascular lesions without
cytotoxicity and thrombus formation. Gene Ther.
14 (13) 1029-1038 (2007)
24. J. K. Oh, D. J. Siegwart, H. -I Lee, G. Sherwood,
L. Peteanu, J. O. Hollinger, K. Kataoka, K.
Matyjaszewski, Biodegradable nanogels preparedby atom transfer radical polymerization as
potential drug delivery carriers: synthesis,
biodegradation,invitro
release,andbioconjugation. J. Am. Chem. Soc. 129 (18) 59395945 (2007)
25. J. -S. Park, K. Kataoka, Comprehensive andaccurate control of thermosensitivity ofpoly(2-alkyl-2-oxazoline)svia
well-defined
gradient
or
randomcopolymerization.
Macromolecules 40 (10) 3599-3609 (2007)
26. Y. Lee, S. Fukushima, Y. Bae, S. Hiki, T. Ishii, K.
Kataoka, A protein nanocarrier from charge-

conversion polymer in response to endosomal pH.
J. Am. Chem. Soc. 129 (17) 5362-5363 (2007)
27. I. A. Khalil, K. Kogure, S. Futaki, S. Hama, H.
Akita, M. Ueno, H. Kishida, M. Kudoh, Y.
Mishina, K. Kataoka, M. Yamada, H. Harashima,
Octaarginine-modified multifunctional envelopetype nanoparticles for gene delivery. Gene Ther.
14 (8) 682-689 (2007)
28. M. R. Kano, Y. Bae, C. Iwata, Y. Morishita, M.
Yashiro, M. Oka, T. Fujii, A. Komuro, K. Kiyono,
M. Kamiishi, K. Hirakawa, Y. Ouchi, N.
Nishiyama,K.
Kataoka,K.
Miyazono,
Improvement of cancer-targeting therapy, using
nanocarriers for intractable solid tumors by
inhibition of TGF-beta signaling. P. Natl. Acad.
Sci. USA. 104 (9) 3460-3465 (2007)
29. M. Kumagai, Y. Imai, T. Nakamura, Y. Yamasaki,
M. Sekino, S. Ueno, K. Hanaoka, K. Kikuchi, T.
Nagano, E. Kaneko, K. Shimokado, K. Kataoka,
Iron hydroxide nanoparticles coated withpoly(ethylene glycol)-poly(aspartic acid) block
copolymer as novel magnetic resonance contrast
agents for in vivo cancer imaging. Colloids Surf.,
B Biointerfaces 56 174-181 (2007)
30. J.-S. Park, Y. Akiyama, Y. Yamasaki, K. Kataoka,
Preparation and characterization of polyion
complex micelles with a novel thermosensitivepoly(2-isopropyl-2-oxazoline) shell via thecomplexation of oppositely charged blockionomers. Langmuir 23 (1) 138-146 (2007)

446

Division of Environmental Health
Sciences
Professor
Chiharu Tohyama, Ph.D., Dr.Med.Sci.

Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Assistant Professor
Masaki Kakeyama, Ph.D.

Project Research Associate
Wataru Yoshioka, Ph.D.

Homepage

http://env-health.m.u-tokyo.ac.jp

Introduction and Organization
Laboratory of Environmental Health Sciences is alaboratory established as a part of the Center for
Disease Biology and Integrative medicine, andcomprises of Professor, Associate Professor, andAssistant Professor and other staff members as well as
postdoctoral fellows, graduate and undergraduate
students. The laboratory settings have been renovated,which makes it possible to start research andeducational activities in full capacity as of January,
2006. Staff members have been engaged inenvironmental toxicology for many years at the
National Institute for Environmental Studies, Tsukuba,
and the mission of this division for research andeducation is described below.

Research activities
Humans are exposed in our environment to various
hazardous chemicals via food, air, and water. Whenthese chemicals are absorbed, distributed andmetabolized in the body, perturbation of homeostasis
and adverse signs and symptoms of toxicity may occur.
At the Laboratory of Environmental Health Sciences,

the adverse effects caused by exposure to anindividual chemical or to mixtures of chemicals are
identified, the dose response relationship for causing
the adverse effects is determined, and the precise
mechanism by which the toxicity is produced at themolecular and cellular level is elucidated by using two
approaches.
The first approach is based on ‘forward toxicology’.
Here we start from a specific disease or healthproblem humans are facing in the real world thatmight be caused by exposure to certain chemicals in
our environment and we determine if the adverse
effects caused by exposure to the particular chemicalor mixture of chemicals are similar to the adverse
effects associated with the human disease or humanhealth problem. This is done by exposing laboratory
animals and cultured cells to increasing doses of thechemical or chemical mixture and identifying adverse
effects, called ‘endpoints of toxicity’, at each dose.
The other approach is ‘reverse toxicology’. In thisapproach we utilize a particular laboratory animalmodel in which a specific adverse effect can be
reproducibly observed, and we attempt to clarify thephysiological significance of altered expression ofgenes and proteins in causing the adverse effect. In

447

this ‘reverse toxicology’ approach we use modern,molecular biology based technologies such as global
gene analysis and genetic engineering to identify themechanism of toxicity at the molecular and cellularlevels.
The primary goal of the Laboratory’s research
program is to elucidate toxicity mechanisms forvarious environmentally hazardous chemicals. To
achieve this goal, ‘forward and reverse toxicology’
approaches are used to determine how adverse
responses of laboratory animals, which are used as anexperimental substitute for humans, to a particularchemical are similar to or different from the adverse
responses of humans.
The outcomes of our research provide not only
fundamental information for human health risk
assessment that can lead to the establishment ofadequate margins of safety for human exposure toenvironmental chemicals. They give the generalpublic a greater sense of security in their surroundings
and they provide clinical medicine and the basic life
sciences new knowledge that is human health relevant.
Laboratory’s Research Themes
1. Elucidation of mechanisms of toxicity at themolecular and cellular level for adverse effects ofenvironmentally hazardous chemicals (dioxin,
PCBs, and heavy metals).
2. Identification of differences in susceptibility to
the toxicity caused by a particular environmentally hazardous chemical between different animal
species and between different genetic strains of
the same species.
3. Determination of the cause of such species andstrain differences in sensitivity to an environmental toxicant at the molecular and cellular level.

Teaching activities
Unfortunately, ‘environmental health’ is not fairly
placed in the curriculum of medicine, pharmacy,
nursing, and other allied health sciences at most
universities. In addition to its research mission, theLaboratory of Environmental Health Sciences has anequally important education mission. The Laboratoryis actively involved in educating graduate students andtraining postdoctoral fellows to become promisingscientist leaders in the field of environmental healthsciences in the future.
The Laboratory will be responsible for a full credit
course on ‘Principles and Applications of Environmental Health Sciences’. In addition, several lectures
are to be given to graduate students for Master’s
degree as well as to undergraduate students at Schoolof Medicine and School of Health Sciences andNursing.

Publications
1. Miyazaki1 W, Iwasaki T, Takeshita A, Tohyama C,
and Koibuchi N. Identification of functional
domain of thyroid hormone receptor responsible
for polychlorinated biphenyl-mediated suppression of its action. Environ. Health Perspect. 116,
2008
2. Nishimura N, Matsumura F, Vogel CFA,
Nishimura N, Yonemoto J, Yoshioka W, andTohyama C. Critical role of cyclooxygenase-2
activation in pathogenesis of hydronephrosis
caused by lactational exposure of mice to dioxin.
Toxicol. Appl. Pharmacol. 231:374-383 (2008)
3. Kakeyama M, Sone H and Tohyama C. Perinatal
exposureoffemalerats
to2,3,7,8tetrachlorodibenzo-p-dioxin
induces
centralprecocious puberty in the offspring. J Endocrinol,(in press).
4. Nohara K, Ao K, Miyamoto Y, Suzuki T,
Imaizumi S, Tateishi Y, Omura S, Tohyama C, andKobayashi T. Arsenite-induced thymus atrophy is
mediated by cell cycle arrest: A characteristic
down-regulation of E2F-related genes revealed bya microarray approach. Toxicol Sci, (in press)
5. Wu Q, Suzuki JS, Zaha H, Lin T-M, Peterson RE,
Tohyama C, and Ohsako S. Differences in gene
expression and benzo[a]pyrene-induced DNA
adduct formation in the liver of three strains offemale mice with identical AhRb2 genotype
treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin
and/or benzo[a]pyrene. J Applied Toxicol, (inpress)
6. Hojo R, Kakeyama M, Kurokawa Y, Aoki Y,
Yonemoto J and Tohyama C. Learning behavior in
rat offspring after in utero and lactational
exposure to either TCDD or PCB126. Environ.

448

Health Prevent. Med., 13:169-180, 2008
7. Hozumi I., Suzuki J.S., Kanazawa H., Hara A.,
Saio M., Inuzuka T., Miyairi S., Naganuma A.,
and Tohyama C. Metallothionein-3 is expressed in
the brain and various peripheral organs of the rat.
Neurosci. Lett, 438:54-58, 2008
8. Tse D, Langston RF, Kakeyama M, Bethus I,
Spooner PA, Wood E, Morris RGM. Schemas andmemory consolidation. Science, 316:76-82.2007
9. Sakata Y., Yoshioka W., Tohyama C., and Ohsako
S. Internal genomic sequence of human CYP1A1
gene is involved in superinduction of dioxininduced CYP1A1 transcription by cycloheximide.
Biochem Biophys Res Comm 355, 687-692, 2007.
10. Kobayashi K, Kuroda J, Shibata N, Hasegawa T,
Seko Y, Satoh M, Tohyama C, Takano H, Imura N,
Sakabe K, Fujishiro H, Himeno S. Induction of
metallothionein by manganese is completelydependent on interleukin-6 production. J
Pharmacol Exp Ther. 320:721-727, 2007
11. Ishimura R., Kawakami T., Ohsako S., Nohara K.
and Tohyama C. Suppressive effect of
2,3,7,8-tetrachlorodibenzo-p-dioxin on vascularremodeling that takes place in the normal
labyrinth zone of rat placenta during late gestation.
Toxicol. Sci., 91: 265-274, 2006
12. Tsukahara S, Kakeyama M, Toyofuku Y. Sex
differences in the level of Bcl-2 family proteinsand caspase-3 activation in the sexually dimorphic
nuclei of the preoptic area in postnatal rats. J
Neurobiol. 66:1411-1419, 2006
13. Nakajima D, Tin-Tin-Win-Shwe, Kakeyama M,
Fujimaki H, Goto S. Determination of toluene inbrain of freely moving mice using solid-phasemicroextraction technique. Neurotoxicology, 27:
615-618, 2006
14. Shwe TT, Yamamoto S, Kakeyama M, Kobayashi
T, Fujimaki H. Effect of intratracheal instillationof ultrafine carbon black on proinflammatory
cytokine and chemokine release and mRNA
expression in lung and lymph nodes of mice.
Toxicol Appl Pharmacol. 209:51-61, 2006
15. Tin-Tin-Win-Shwe, Yamamoto S, Ahmed S,
Kakeyama M, Kobayashi T, Fujimaki H. Braincytokine and chemokine mRNA expression inmice induced by intranasal instillation withultrafine carbon black. Toxicol Lett. 163:153-160,

2006.
16. Nishimura N, Yonemoto J, Nishimura H, Tohyama
C. Localization of cytochrome P450 1A1 in a
specific region of hydronephrotic kidney of rat
neonates lactationally exposed to 2,3,7,8tetrachlorodibenzo-p-dioxin.
Toxicology. 227:117-126,2006.
17. Mitsui T, Sugiyama N, Maeda S, Tohyama C,
Arita J. Perinatal exposure to 2,3,7,8tetrachlorodibenzo-p-dioxin suppresses contextual
fear conditioning-accompanied activation of
cyclic AMP response element-binding protein in
the hippocampal CA1 region of male rats.
Neurosci Lett. 398: 206-210, 2006
18. Nohara K, Ao K, Miyamoto Y, Ito T, Suzuki T,
Toyoshiba H, Tohyama C. Comparison of the
2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)induced CYP1A1 gene expression profile inlymphocytes from mice, rats, and humans: Most
potent induction in humans. Toxicology. 225: 204213, 2006
19. Kawakami T., Ishimura R., Nohara K., Takeda K.,
Tohyama, C. and Ohsako, S. Differential
susceptibilities of Holtzman and Sprague-Dawley
rats to fetal death and placental dysfunction
induced by 2,3,7,8-teterachlorodibenzo-p-dioxin(TCDD) despite the identical primary structure of
the aryl hydrocarbon receptor. Tox. Appl.
Pharmacol. 212: 224-236, 2006
20. Shiizaki K., Ohsako, S., Koyama, T., Nagata R.,
Yonemoto, J. and Tohyama, C. Lack of CYP1A1
expression is involved in unresponsiveness of thehuman hepatoma cell line SKHEP-1 to dioxin.
Toxicol. Lett. 160: 22-33, 2005
21. Inouye K, Pan X, Imai N, Ito T, Takei T, Tohyama
C, Nohara K.:cell-derived IL-5 production is asensitive target of 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD) Chemosphere 60: 907-913,
2005
22. Nishimura N, Yonemoto J, Miyabara Y,
Fujii-Kuriyama Y, Tohyama C.: Altered thyroxin
and retinoid metabolic response to 2,3,7,8tetrachlorodibenzo-p-dioxin in aryl hydrocarbon
receptor-null mice. Arch Toxicol 79: 260-267,
2005
23. Ikeda M, Mitsui T, Setani K, Tamura M,
Kakeyama M, Sone H, Tohyama C, Tomita T.: In449

utero and lactational exposure to 2,3,7,8
tetrachlorodibenzo-p-dioxin in rats disrupts brain
sexual differentiation. Toxicol Appl Pharmacol.
205: 98-105, 2005.
24. Nohara K, Pan X, Tsukumo S, Hida A, Ito T,
Nagai H, Inouye K, Motohashi H, Yamamoto M,
Fujii-Kuriyama Y, Tohyama C.: Constitutively
active aryl hydrocarbon receptor expressed
specifically in T-lineage cells causes thymus
involution and suppresses the immunizationinduced increase in splenocytes. J Immunol. 174:
2770-2777, 2005.
25. Nishimura N, Yonemoto J, Nishimura H, Ikushiro
S, Tohyama C.: Disruption of thyroid hormone
homeostasis at weaning of Holtzman rats bylactational but not in utero exposure to
2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci.
85: 607-614. 2005.

450

Section of Animal Research,
Division of Research Resources
and Support
Professor
Akio Nomoto, Ph.D.

Research Associate
Ken-Ichi Hanaki, D.V.M., Ph.D.,

Homepage

Haruyuki Hirata, D.V.M., Ph.D.

http:// www.cdbim.m.u-tokyo.ac.jp/research/01_06.html

Introduction and Organization
Section of Animal Research was established as
Animal Center for Biomedical Research in April 1971
to provide laboratory animal husbandry and veterinary
consultation services for the investigators in the Faculty of Medicine. The first full-time teaching staff, aveterinarian, was employed in April 1972. The building was completed in March 1973, and the center began to provide services for animal experimentation in
April 1973. Animal Center for Biomedical Research
was at first a facility attached to the faculty. Today the
animal center is one of sections, Division of Research
Resources and Support, the Center for Disease Biology and Integrative Medicine (CDBIM).
The members of this section are 3 teaching staffs, 2technical support staffs, the assistant manager of
CDBIM, a teaching assistant, 3 assistant laboratory
animal technicians, and 4 assistance clerks. In addition,
about 10 contracted employees work together with us
in the building to maintain the facilities; animal care,
air-conditioning, cage-washing, etc.
The laboratory animals breeding in the building aremacaque monkeys, dogs, swine, rabbits, guinea pigs,
rats, mice, and chickens. All investigators in the University of Tokyo are able to use facilities in our building after the registration. The number of registered
patrons was 301 at the end of 2007 academic year. The

most of them were the investigators in the Graduate
School of Medicine.

Supporting activities
One of our missions is to provide quality care for
all animals breeding in our building. The other is toassist the registered patrons in their mission of quality
research with respect to the use of laboratory animals.
In particular, research associates have overall responsibility for the health and welfare of animals used inresearch. The office of this section is in charge of thesecretariat of the Animal Care and the Use Committeeof Graduate School of Medicine, the University ofTokyo (IACUC). We check submitted animal experiment plans to the committee whether the plans would
be carried out in consideration of animal welfare, andthen give comment and/or advice to respective principal investigators. The committee (Chair, Prof. Akio
Nomoto) will review the latest plans and will approve,
withhold approval, or require modifications to secure
approval in accordance with law, regulations andUniversity policies governing the use of animals.

Teaching activities
Our teaching responsibility is to give lectures on
Laboratory Animal Science to the 2nd-year students

451(M0) at the School of Medicine. The teaching staff
lectured on the following subjects.
(i) Animal Welfare, Law, Rules and Regulations(ii) Refinement of Animal Experiments (Anesthesia
and Euthanasia)(iii) Animal Breeding and Animals Used in Medical
Science(iv) Infectious Diseases of Laboratory Animals andZoonoses
The teaching staff gave lectures to the laboratory
animal managers, researchers and animal techniciansat the Graduate School of Medicine on the following
contents.
(i) Items related to pertinent laws and ordinances,bylaws, guidelines(ii) Items related to animal experiments and the handling of laboratory animals(iii) Items related to the care and management of laboratory animals(iv) The elements of Laboratory Animal Science

Research activities
Each research associate has own research themes,
and they are responsible for the research in this section. Followings are the research profiles.
(i) Detection of a trace amount of antigen in tissue.
The purpose of this research is the development of asignal amplification technique suitable for the detection of antigen in tissue. We have developed a newsignal amplification technique using nucleic acid thatwould be suitable for the detection of immobilized
antigen on protein chip or tissue. Now we try to adapt
the technique for the detection of infectious agents intissue. This study is collaboration with National Institute of Infectious Diseases (NIID).
(ii) Elucidation of the mechanisms to escape hostimmunity by pathogen in parasitic infections.
We expect this investigation will be helpful for thedevelopment of new therapeutic approaches anddrugs.
(iii) Development of the techniques for the microbiological monitoring for SPF mice in individual
cages.

References
No publication

452

Section of Radiation Biology,
Center for Disease Biology andIntegrative Medicine
Professor
Kiyoshi Miyagawa, M.D.,Ph.D.

Associate Professor
Yoshio Hosoi, M.D.,Ph.D.

Lecturer
Takahiko Suzuki, Ph.D.

Associate
Atsushi Enomoto, Ph.D.,

Mari Katsura, M.D.,Ph.D.,

Noriko Hosoya, M.D.,Ph.D.

Homepage http://www.cdbim.m.u-tokyo.ac.jp/
Introduction and Organization
The Section of Radiation Biology belongs to theDivision of Research Resources and Support in Center
for Disease Biology and Integrative Medicine. The
main duty of the section is to support the use ofradioisotope at Graduate School of Medicine.
Historically, in 2003, the Department of Radiation
Oncology and the Radiation Research Institute werejoined to form a new department.
To maintain the facility of radiation research,
responsible staffs at two facilities are elected from ourdepartment. There is no remarkable change in themaintenance system and frequency of the use ofradioisotope this year.
Although the supportive work is very important,education and research on effects of radiation onhuman bodies are the most important duties in thissection. We cannot deny the fact that individual works
have not been integrated thus far, the present staffs areconstructing a new group that plays a leading role inradiation biology.

Teaching activities
We are responsible for the education of basic radiation
medicine for the 2nd year medical students. The
students are expected to start with understanding of
the physics and the chemistry for radiation and thenunderstand the basic biology of radiation. After that,they learn how to handle radioactive materials by the
2-day practical course.
In addition to these courses, the 4th year medical
students are expected to learn how to use clinicalradiation technology safely in hospitals. The
background for this addition is that clinical problems
arising from the lack of knowledge of radiation effects
have been increasing. Furthermore, the education ofradiation casualty medicine is included in this new
course. Even though radiation casualty is rare, allclinicians should know how to treat patients exposed
to radiation.

453

We also take part in the education of radiation
health science for the 3rd year students specialized inhealth science. Radiation protection is emphasized inthis course.
At Graduate School of Medicine, molecular biology
of DNA damage response to radiation is moreemphasized.
In addition, education courses for users ofradioactive materials frequently take place.

Research activities
Before the present professor took the position, a vide
range of radiation biology, including biological effectsof low-dose irradiation, nonhomologous end joining(NHEJ) for DNA double-strand breaks, apoptosis that
responds to DNA damage, and radio-sensitization had
been topics in this department. Since 2005,
homologous recombinational repair has been the main
subject.
RecA in E. coli and its homolog Rad51 in budding
yeast play a central role in homologous
recombinational repair. Historically, mechanism ofhomologous recombination was extensively studied inthese organisms, whereas homologous recombination
had been recognized as a minor pathway of DNA
double-strand break repair in higher organisms.
However,
subsequentstudiesrevealedthathomologous recombination as well as NHEJ plays animportant role in DNA double-strand break repair inhigher organisms. There are two major differences
between these two pathways. NHEJ functions at any
stages of the cell cycle, whereas homologous
recombination is restricted to the S to M phases.
Another difference is that NHEJ is an error-prone
repair pathway and homologous recombination is anerror-free repair pathway.
We have been studying on the functions of Rad51
paralogs, which share structural similarity with Rad51.
There are five genes that belong to this paralog family
in mitotic cells. Although they share structuralsimilarity with each other, there is no functional
redundancy. To clarify their roles, we have generated
their mutant human cells by gene targeting and RNAinterference.
Rad51B dysfunction due to chromosomal translocations has been found in some benign tumors,particularly in uterine leiomyomas. In Rad51B mutant
cells, the Rad51-dependent recombinational repair
pathway is impaired. In addition, centrosome
aberrations and aneuploidy were found to be increasedin these cells. Haploinsufficiency of the gene causes
these aberrations. Thus, Rad51B plays a role incentrosome and chromosome integrity.
In contrast to early stages of homologous
recombination, little is known about the mechanismsof homologous recombination at late stages. The
Mus81-Eme1 complex has been shown to resolve
recombination intermediates. Subsequent studies
revealed that this enzyme plays a role in the resolutionof stalled replication forks. We have studied on thefunction of this complex in human cells. Unexpectedly,
the mutant cells are hypersensitive to DNA crosslinking agents rather than to replication inhibitors.
Cisplatin and its analogs are widely used in current
cancer treatment. Because these drugs induce DNA
cross-linking, we are trying to understand the role ofMus81-Eme1 from the viewpoint of cancer therapy.
The impaired recombinational repair pathway is
associated with numerous chromosomal aberrations. It
is established that some breast cancers arise fromdefective recombination. It is also possible that othercancers are caused by the similar processes.
Furthermore, we hypothesize that non-cancerous
diseases can be associated with DNA damage
responses. The study on homologous recombination
also contributes to the development of radiation
therapy.
RadiationandDNA-damaging
chemotherapeutic agents induce DNA double-strand
breaks, which can be normally repaired by the
intrinsic repair pathways. The induced breaks
therefore do not always lead to apoptosis. If we will
understand the details of the repair pathways, themolecules in this pathway will be the therapeutictargets. From the clinical point of view, we will
establish the basic science of homologous
recombinational repair.

References
1. Nakai-Murakami C, Shimura M, Kinomoto M,
Takizawa Y, Tokunaga K, Taguchi T, Hoshino
S, Miyagawa K, Sata T, Kurumizaka H, Yuo A,
Ishizaka Y. HIV-1 Vpr induces ATM-dependent

454

2.

3.

4.

5.

cellular signal with enhanced homologous
recombination. Oncogene. 2007; 26:477-486.
Suzuki T, Nishi T, Nagino T, Sasaki K, Aizawa K,
Kada N, Sawaki D, Munemasa Y, Matsumura T,
Muto S, Sata N, Miyagawa K, Horikoshi M,
Nagai R. Functional interaction between thetranscription factor Kruppel-like factor 5 andpoly(ADP-ribose) polymerase-1 in cardiovascularapoptosis. J Biol Chem. 2007; 282:9895-9901.
Lee Motoyama JP, Kim-Motoyama H, Kim P,
Nakagama H, Miyagawa K, Suzuki K.
Identification of dermcidin in human gestational
tissue and characterization of its proteolytic
activity. Biochem Biophys Res Commun. 2007;
357:828-833.
Ikura T, Tashiro S, Kakino A, Shima H, Jacob N,
Amunugama R, Yoder K, Izumi S, Kataoka I,
Tanaka K, Kimura H, Ikura M, Nishikubo S, Ito T,
Muto A, Miyagawa K, Takeda S, Fishel R,
Igarashi K, Kamiya K. DNA damage-dependentacetylation and ubiquitination of H2AX enhances
chromatin dynamics. Mol Cell Biol. 2007;27:7028-7040.
Sasano N, Enomoto A, Hosoi Y, Katsumura Y,
Matsumoto Y, Shiraishi K, Miyagawa K, Igaki H,
Nakagawa K. Free radical scavenger edaravone
suppresses X-ray-induced apoptosis through p53
inhibition in MOLT-4 cells. J Radiat Res. 2007;
48:495-503.

455

Section of Bioinformatics
AssociateKenji Hatano, M.D.

Homepage

http://www.cdbim.m.u-tokyo.ac.jp/

Organization
Section of Bioinformatics started in 2003 as a divisionof Research and Support of the Center for Disease
Biology and Integrative Medicine. Targeting
biomedical research support using information
technologies, this division performs management andmaintenance of the research network and information
servers working with the Information Promoting
Office of the Graduate School of Medicine.

Research activities
Medical terminology and ontology:
Standardization and systematization of medical
vocabularies are major issue for appropriate utilizationof medical information implied in various medical
terms. We are committed the working group for theJapanese standard disease code master (standard
vocabulary of Japanese disease names) and studying
about the strategies for perform the standardization ofJapanese medical vocabularies for electronic medical
records. Using current techniques of systematizationof terms and concepts, such as terminology or
ontology, we are testing systematization of Japanese
medical terms and concepts and automaticclassification system for free medical words.
Distributed processing system for medical terms:
As an efficient method for the distribution of medical
term information and promotion of the standard
vocabularies, we focused distributed processing
system using the network and are developing
distributed methods service system in the internet forevaluation of utilities and effectiveness of the system.

Main targets of our research are:z Standardization of medical vocabularies andcoding systemz Biomedical terminology and ontology
z Distributed processing system for medical
information using the internetz Security of biomedical research networkz Privacy and anonymization of personal data inclinical researchz Digitalization and indexing of old Japanese
medical libraries.

References
1. Hatano K., Ohe K. Information Retrieval System
for Japanese Standard Disease-Code Master Using
XML Web Service. J. American Medical
Informatics Association. Symposium Suppl. 597,
2003.

456

Office ofInternational Academic Affairs
Head
Tatsuya Yamasoba

Assistant Professor
Joseph Green
Toshiyuki Maruyama
Christopher Holmes

Homepage:

http://square.umin.ac.jp/koryu/homepage10.html

Status and functions
The Office of International Academic Affairs is under the direct authority of the Dean of the Faculty of
Medicine. Its three most important roles, as defined by
the Committee on International Academic Affairs, arei) international educational exchange, ii) international
contacts in research and scientific fields, and iii) international cooperation in health care and medicine.

Activities
This document reports on the office's activities inthese areas over the academic year 2007 (April to
March).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2007, there were 154 foreign students (34 countries) officially registered in the Graduate School of
Medicine. Many inquiries were received during thisperiod from prospective applicants for foreign student
and trainee status: responses were sent to 86 such inquiries.
Many currently enrolled foreign students received
counseling at this office concerning their studies andlife at the University of Tokyo and the requirementsfor obtaining scholarships and degrees.

In addition, a large number of University of Tokyo
students wish to supplement their training with basic
clinical experience overseas before graduation, as wellas the type of short-term training (1-3 months) frequently called clinical electives overseas. Inquiries
from these students were either answered by this office or referred to appropriate centers.
Every year, 20 or more University of Tokyo students go overseas to study, and the office makes its
best efforts to accommodate their needs.
It has become a tradition to hold a Spring
get-together of foreign students and University of Tokyo students who will study or have studied abroad.
This event is attended by the Dean of the Faculty of
Medicine, teaching staff, administrative staff, andstudents: about 80 people attended in 2006, at the
Sanjo Kaikan, a reception hall on the Hongo campus.
The annual Ryugakusei Ronbun Contest was first
held in 1999. As in previous years, in the 2007 Contest foreign students gave oral presentations based on
their research papers to interested fellow students andfaculty, and the five best speakers were given awards.
A formal agreement for academic exchange between the University of Pennsylvania and the University of Tokyo was renewed in May 2004. Since thattime, eight University of Tokyo students have taken
research electives at the University of Pennsylvania
every year, and one student from the University of457

Pennsylvania has taken a clinical elective at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the University of Tokyo and Johns Hopkins University inDecember 2002. Since the start of the program in
2002, twelve University of Tokyo students visited toattend clinical electives at Johns Hopkins University,and four student from Johns Hopkins University havetaken clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the University of Tokyo and the University of Michigan
Medical School in January 2005. Since the start of the
program in 2005, five University of Tokyo students
have attended clinical electives at the University ofMichigan Medical School, and two students from the
University of Michigan have taken clinical electives at
the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the University of Tokyo and Munich University in February
2005. Since the start of the program in 2005, two
University of Tokyo student visited to attend research
electives at Munich University, and two students from
Munich University have taken clinical electives at the
University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the University of Tokyo and the University of Washington
Medical School in November 2005. Since the start ofthe program in 2005, four University of Tokyo students have attended clinical electives at the Universityof Washington Medical School, and one student fromthe University of Washington Medical School hastaken clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the University of Tokyo and Taipei Medical University inNovember 2005. Since the start of the program in
2005, two University of Tokyo students visited to attend clinical electives at Taipei Medical University
and two students from Taipei Medical University havetaken clinical electives at the University of Tokyo.
An agreement on academic cooperation was signed
between the Graduate School of Medicine of the University of Tokyo and Mahidol University in September

2006. Since the start of the program in 2006, three
University of Tokyo students visited to attend research
electives at Mahidol University, and three students
from Mahidol University have taken clinical electives
at the University of Tokyo.
1.2 Counseling University of Tokyo medical students
and researchers about short-term and longer overseas
study programs
Every year, about 30 requests from students forcounseling regarding pre-graduation or postgraduation studies abroad are received by the Officeof International Academic Affairs. The office responds
to these requests by providing information, advice,and letters of recommendation.
2. International contacts in research and scientific fields
2.1 Promotion of academic exchange between Japanand Thailand
Through the good offices of the Japan Society for
the Promotion of Science, a 10-year program of scientific exchange with Mahidol University in Thailand
began in 1999. Quite unlike previous forms of academic exchange, this one is designed from the start toachieve results by focusing clearly on one area of research and on specific outcomes. The focus is on infectious diseases and related fields, within which research projects are underway in HIV, in new andre-emerging infections, and in other related areas. A
total of 19 researchers were invited to Japan (847 researcher-days) and 17 Japanese researchers were sent
abroad (124 researcher-days) in 2007.
3. New project (International Training Program)This project (total budget: 100,000,000 yen/5 years)
provides opportunities for young researchers from the
Graduate School of Medicine at the University of Tokyo to receive instruction and training at partner institutions in the USA, with the goal of helping themexcel not only as scientists, but also as educators forthe next generation and as administrators of their research groups.
The details of the plans for the young researchers at
the partner institution in USA are as follows.
(1) They should carry out highly advanced medical
research.

458(2) They should observe and experience participatory,
student-centered forms of education (tutorials,etc.) used with medical students.
(3) They should observe and experience the management of research laboratories, particularly withregard to the importance of the activities of graduate students and postdoctoral fellows.
(4) They should observe how teaching assistants contribute in education and research, and how teaching assistants are trained to become leaders andmentors.
In 2007, four young researchers from the Graduate
School of Medicine at the University of Tokyo began
studying at the partner institutions in the USA.
4. Education and research
3.1 Education
In 2007, Dr. Joseph Green and Dr. Toshiyuki Maruyama taught a course open to all students in the
Graduate School of Medicine: Introduction to Clinical
Epidemiology Research.
In 2007, Dr. Green taught a course open to all students in the Graduate School of Medicine: Introduction to Scale Development.
Dr. Green also taught two other graduate-levelclasses: International Epidemiology 1 and 2.
Mr. Christopher Holmes taught Medical English 1,
2, and 3, the first two of which are required for all
medical students. The Office also organized classes inEnglish for the Health Sciences.
In 2007, Dr. Green and Mr. Holmes led ad hoc sessions in Oral Presentation Training. These sessions
were open to all students and teaching staff in the
Graduate School of Medicine and the Faculty of
Medicine.
3.2 References
1. Fukuhara S, Yamazaki S, Hayashino Y, Green J.
Measuring health-related quality of life in patientswith end-stage renal disease: why and how. NatClin Pract Nephrol. 2007 Jul;3(7):352-3.
2. Yamazaki S, Nitta H, Ono M, Green J, Fukuhara S.
Intracerebral haemorrhage associated with hourly
concentration of ambient particulate matter:case-crossover analysis. Occup Environ Med
2007;64:17–24.

459

The International Research Center
for Medical Education (IRCME)
Director & Professor
Kazuhiko Yamamoto, M.D., Ph.D.

Professor
Kiyoshi Kitamura, M.D., Ph.D.

Lecturer
Hirotaka Onishi, M.D., M.H.P.E.

Research Associate
Hiroshi Nishigori, M.D.

Homepage

http://www.ircme.u-tokyo.ac.jp

History and organization
The University of Tokyo has established International Research Center for Medical Education(IRCME) in 2000. The Ministry of Education (in2001 reformed to Ministry of Education, Culture,
Science and Sports), the University of Tokyo, and the
Graduate School of Medicine positioned IRCME as abase for promoting international cooperative studiesof medical education.
IRCME consists of three departments of International Cooperative Study for Medical Education,
Planning & Coordination for International Cooperative Projects and Information on Medical Education,and visiting professor from abroad. We hope that the
research in medical education carried out by IRCME
will improve medical education and health care inmany countries.
The mission of IRCME includes research ininternational cooperation in medical education,
research in medical education, and development of
human resource in medical education. Promotion ofand contribution to education in the Faculty of
Medicine, University of Tokyo and University ofTokyo Hospital is also our fundamental role.

International Cooperative Study in
Medical Education
The University of Tokyo, especially the Faculty of
Medicine, takes pride in its academic excellence not
only in Japan but also other foreign countries.
Compared with other Western big-name universities,
however, activities and research in international
cooperation area have been weak. The strength of
IRCME is to implement educational cooperation
projects in health area supported by official development assistance. Such an approach takes longer time
but will influence people in developing countries withsustainability and independence.
To fulfill the mission, faculty and staff in IRCME
conduct research on a wide range of topics inundergraduate and postgraduate medical education.
One of our objectives is to establish a new methodology of effective and efficient implementation of
medical education reform by the information obtained
from the practice of international cooperation in
medical education.
IRCME also makes important contributions toundergraduate and postgraduate medical curricula of
the Faculty of Medicine to raise awareness of460

international cooperation and help Japanese medical
practitioners develop interest in international
activities.

Planning & Cooperation forInternational Cooperative Projects
and Information on Medical
Education
Department of Planning & Coordination forInternational Cooperative Projects and Information on
Medical Education is responsible for developing
international cooperation in health professions
education area (medicine, dentistry, pharmacy, nursing,public health, rehabilitation, etc) facilitated by the
Ministry of Education, Culture, Sports, Science, andTechnology. This department should lead any
international cooperation projects in health professions education area in Japan and aim at face-to-faceand heart-to-heart international cooperation. Activities
are listed below.
1． Japan International Cooperation Agency (JICA)
appointed IRCME as the cooperative agency for
JICA Medical Education Project, Afghanistan(2005 Jul-2008 Jun). Counterpart of the project
has been Ministry of Higher Education and Kabul
Medical University. IRCME will also contributeto the follow-up activities.
2． Japan Bank for International Cooperation
entrusted joint venture team including members
from IRCME with the survey on Special
Assistance for Project Formation regarding
Republic of Indonesia: Special Assistance for
Project Formation for the Development of WorldClass University at University of Indonesia (2007
Sep-Dec).
3． JICA entrusted Joint Venture of University ofTokyo and System Science Consultants with the
Project for Medical Education and Research for
the Setthathirath Hospital, the Lao People’s
Democratic Republic (2007 Dec-2010 Nov)

Visiting Professors
IRCME invites specialists from abroad withexpertise in medical education and international

cooperation to be visiting professors. They advise andinstruct IRCME on planning and on educational
activities, and collaborate with IRCME faculty andstaff on educational research.
Through IRCME-sponsored lectures and seminars,
they also provide intellectual stimulation to medical
students, interns, and residents, and introduce new
information on medical education and international
cooperation to a wider audience.
In 2007, we accepted one visiting professor, Linda
Snell, MD, MHPE, FRCPC, FACP (McGill
University: October 2006-April 2007). She offered
several seminars, lectures for international trainees,and many suggestions.

References
1.

Iain Robbe, Hiroshi Nishigori, Hirotaka Onishi,
Makoto Kikukawa. Medical Professionalism: an
exploration of international similarities anddifferences in teaching and learning about
professionalism. AMEE2007 Pre-Conference
Workshop. 25 September 2007. Trondheim,
Norway.

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本誌の一部または全部を当編集委員会の許可なく転載または複製す
ることは著作権法によって禁じられています。

Copyright ©2008

The Tokyo Society of Medical Sciences, The University of Tokyo Medical
Society & The University of Tokyo Faculty of Medicine (Printed in Japan)

東

京

医

編集・発行者

学第 117 巻

平成 20 年 10 月 31 日発行

東京都文京区本郷７-３-１

東京大学医学部内（〒113-0033）
財団法人

印

刷

者

ナカバヤシ株式会社

東 京 医 学 会

東京都板橋区東坂下 2-5-1