ISSN 1883-9606

Vol.119

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2008 ---- March 2009

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2008-March 2009

Introduction
This is the report of the University of Tokyo’s Faculty of Medicine and Graduate School of Medicine forthe years 2008. Here we document each department’s research and education activities.
The University of Tokyo has a historically unique role as the leading force in medicine within Japan. It
is only natural to expect that we well also be in the forefront of medicine worldwide. We take it as our
mission to be an internationally recognized source of important research results, and a center for training
outstanding medical scientists and clinicians.
In the 20th century, medicine was dominated by the West, but we are confident that in the 21st century
much greater contributions will come from Asia. In that context the role of Japan, and in particular that of
the Graduate School of Medicine at the University of Tokyo, will become even more important. Always
conscious of our mission, we should continue pursuing our educational and scientific interests
enthusiastically.
As we create the future, let us strive to achieve the best in medical research and teaching, and to provide
the best possible clinical care.
Takao Shimizu
Dean, Faculty of medicine and Graduate School of Medicine
The University of Tokyo
March, 2009

i

CONTENTS
Introduction
History
Organization Chart
Teaching, Research, Secretarial and Administrative Staffs
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 ····································································································

25

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

26

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

29

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

32

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

33

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

37

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

41

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

42

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

44

ii

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

47

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

48

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

51

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

52

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

58

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

59

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

63

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

66

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

67

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

71

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

76

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

78

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

79

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

81

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

82

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

88

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

93

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

97

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

98

Department of Public Health ／ Department of Health Policy ············································

101

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

104

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

105

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

109

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

112

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

113

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

119

iii

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

124

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

131

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

132

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

137

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

143

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

148

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

151

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

155

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

158

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.377] )Department of Transfusion Medicine ·········································································

159

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

162

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

163

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

165

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

171

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

173

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

174

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

179

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

183

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

184

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

187

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

188

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

191

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

195

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

200

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

202

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

206

Department of Vascular Surgery ···············································································

209

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

211

iv

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

213

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

214

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

217

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

220

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

225

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

231

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

236

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

240

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

242

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

243

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

246

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

249

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

250

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

253

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

256

Department of Social Gerontology(See Department of Social Gerontology [P.319] )Department of Biomedical Ethics & Department of Health Promotion Sciences ·······················

259

2. Preventive and Administrative Nursing ·······································································

262

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

263

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

266

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

268

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

272

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

273

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

278

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

281

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

283

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

287

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

288

Department of Community and Global Health ·······························································

291

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

294

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

295

v

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

299

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

302

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

305

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

307(See Department of Biostatistics [P.256] )Department of Social and Preventive Epidemiology ························································

308

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

312

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

315

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

318

Department of Mental Health(See Department of Mental Health [P.253] )Department of Health Sociology / Health Sociology and Health Education(See Department of Health Sociology/Health Sociology and Health Education [P.250] )Department of Social Gerontology ············································································

319

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.259] )3. Health Services Sciences ·························································································

322

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.101] )Department of Healthcare Informatics (See Department of Medical Informatics and Economics [P.109] )Department of Clinical Information Engineering ·····························································

323

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.105] )Endowed Department ···································································································

325

Department of Pharmacoepidemiology ·······································································

326

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

329

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

332

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

336

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

339

Department of Advanced Skin Care (Miss Paris) ····························································

342

Department of Chronic Kidney Disease (CKD) ·····························································

344

Department of Immunotherapeutics (Medinet) ······························································

346

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

349

Department of Advanced Clinical Science and Therapeutics ··············································

351

Department of Ischemic Circulatory Physiology, KAATSU training ·········································

353

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

355

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

357

vi

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

359

Department of Hospital Environment ·········································································

362

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

363

Department of Medical Safety Management ···································································

365

Division of Molecular Cardiovascular Metabolism (Daiichi-Sankyo Company, Limited) ·················

368

Department of Anti-Aging Medicine ··········································································

370

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

372

vii

University Hospital
Clinical Divisions ····································································································
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.113] )Respiratory Medicine (See Department of Respiratory Medicine [P.119] )Gastroenterology (See Department of Gastroenterology [P.124] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.132] )Metabolic Diseases (See Department of Metabolic Diseases [P.137] )Hematology and Oncology (See Department of Hematology and Oncology [P.143] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.148] )Infectious Diseases (See Department of Infectious Diseases [P.151] )Neurology (See Department of Neurology [P.88] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.184] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.155] )Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.195] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.206] )Hepatobiliary Pancreatic Surgery(See Department of Hepatobiliary Pancreatic Surgery [P.200] )Vascular Surgery (See Department of Vascular Surgery [P.209] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.211] )Artificial Organ and Transplantation Surgery(See Department of Artificial Organ and Transplantation Surgery [P.200] )Cardiovascular Surgery (See Department of Cardiothoracic Surgery [P.191] )Thoracic Surgery (See Department of Thoracic Surgery [P.188] )Neurosurgery (See Department of Neurosurgery [P.93] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.243] )Urology and Andrology (See Department of Urology [P.202] )Gynecologic Surgery (See Department of Obstetrics and Gynecology [P.162] )Dermatology and Photolaser Medicine (See Department of Dermatology [P.214] )Ophthalmology and Vision Correction (See Department of Ophthalmology [P.231] )Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.225] )Otorhinolaryngology, and Auditory and Voice Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.236] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.240] )

375

viii

Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.217] )Oral-Maxillofacial Surgery Dentistry and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.220] )Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.174] )Pediatrics Surgery (See Department of Pediatrics Surgery [P.179] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.163, 165, 171] )Neuropsychiatry (See Department of Neuropsychiatry [P.82] )Radiology (See Department of Radiology [P.52] )Central Clinical Facilities ···························································································

376

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

377

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

380

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

385

Department of Emergency Services(See Department of Emergency and Critical Care Medicine [P.246] )Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.159] )Delivery Unit ·····································································································

388

Rehabilitation Center ····························································································

389

Department of Intensive Care Unit
(See Department of Emergency and Critical Care Medicine [P.246] )Division of Diagnostic Pathology ··············································································

391

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

393

Department of Cell Therapy and Transplantation Medicine ···············································

396

Department of Endoscopy and Endoscopic Surgery ························································

400

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

403

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

406

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.44] )Department of Planning, Information, and Management(See Department of Medical Informatics and Economics [P.109] )University Hospital Medical Information Network (UMIN) Center ······································

409

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

412

Center for Epidemiology and Preventive Medicine ·························································

414

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

419

ix

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

425

Department of Child Psychiatry ················································································

428

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

431

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

435

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

437

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

448

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

449

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

453

Laboratory of Molecular Biomedicine for Pathogenesis ·····················································

454

Laboratory of Structural Physiology ············································································

458

Laboratory of Regenerative Medical Engeneering ····························································

461

Laboratory of Clinical Biotechnology ··········································································

463

Laboratory of Environmental Health Sciences ································································

466

Laboratory of Animal Research ················································································

469

Laboratory of Molecular Radiology ···········································································

472

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

475

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

478

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009x

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. 119, October 2009

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.

xi

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. 119, October 2009

xii

2004

Apr.

All the National Universities owned by the Japanese Government becameNational University
Corporations, and the University of Tokyo was renamed the University of Tokyo National
University Corporation.

2007

Apr.

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

2008

May.

The University of Tokyo Faculty of Medicine and the University of Tokyo Hospital celebrated
their 150th anniversary.

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009

xiii

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

xiv

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009

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. 119, October 2009

xv

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

Global Health Policy
Community and Global 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

Laboratory of Molecular Biomedicine for Pathogenesis
Laboratory of Structural Physiology
Laboratory of Regenerative Medical Engineering
Center for Disease Biology
and Integrative medicine

Laboratory of Clinical Biotechnology
Laboratory of Environmental Health Sciences
Laboratory of Animal Resources
Division of Research Resources and Support

Section of Animal Research
Section of Radiation Biology
Section of Bioinformatics

xvi

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009

Office of International Academic Affairs
Institution

Medical Library
Medical Scientist Training Program
Pharmacoepidemiology
Integrated Traditional Medicine (Tsumura)
Clinical Vascular Regeneration (Daiichi Sankyo Co.,Ltd.)
Bone & Cartilage Regenerative Medicine
Cartilarge &Bone Regeneration(Fujisoft)
Metabolome
Clinical Renal Regeneration
Hospital Logistics by Sagawa Express Co. Ltd.
Clinical Molecular Epidemiology (Mitsubishi Tanabe Pharma Corporation.)
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
Translational Research for Healthcare and Clinical Science

Endowed Department

Joint Disease Research
Health Care Management and Policy
Computational Diagnostic Radiology and Preventive Medicine
Hospital Environment
Clinical Motor System Medicine
Medical Safety Management(Tokio Marine & Nichido)
Molecular Cardiovascular Metabolism (Daiichi-Sankyo Company, Limited)
Healthcare Quality Assessment
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
Molecular Research for Vascular Deseases
Advanced Skin Care(Miss Paris)
Therapeutic Strategy for Heart
Molecular Physiology on Energy Metabolism

General Affairs Office

Molecular Neuroscience on Neurodegeneration

Personnel Office

Chronic Kidney Disease

Research Liaison

Molecular Structure and Dynamics(JEOL/Zeiss)

Educational Affairs

Molecular Vascular Endocrinology

Graduate Student Affairs
Buget Office

Administrative office

Purchasing Office

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009

Faculty of Medicine
Graduate School of
Medicine

xvii

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xviiiThe Tokyo Journal of Medical Sciences. Vol. 119, October 2009

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
Hepatobiliary 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 Correction
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
Administrative Department
Nursing Department
Management Department
Administration Office
Management Strategy Department
Clinical Laboratory Center
Medical Affairs Department
Surgical Center
Radiological Center

Central Clinical Facilities

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

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009

xix

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
Cancer Resource Center
Center for Liaison and Public Relations
The Database Center for the National University Hospitals
Outpatient Chemotherapy Department
Neonatal and Pediatric Intensive Care Unit
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

Translational Research Center

Personnel Administrationand Human Resources

Hospitality Center

Performance Monitoring,
Risk Management, and Staff
Development

Education andResearch support

Performance Monitoring
Medical Safety management
Center
General Education Center
Infection Control Center
Patient Help and Clinical
Ethics Center

Inpatient Services
Administration

Cancer Board

Hospital Planning andManagement

Outpatient Services
Administration
Central HospitalServices
Administration

22nd Century Medical and Research Center

Pediatric Medical Center

Vascular Board

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009ix

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

Kiyoshi kita

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. 119, October 2009x

Department of Clinical Neuroscience

professor

Kiyoto Kasai

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

Department of Obstetrics and Gynecology

professor

Yuji Taketani

Department of Pediatric Science

professor

Takashi Igarashi

professor

Tadashi Iwanaka

professor

Yasuyoshi Ouchi

professor

Shinichi Takamoto

professor

Yasuyuki Seto

professor

Norihiro Kokudo

professor

Yukio honma

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 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. 119, October 2009xi

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

professor

Yasuo Ohashi

professor

Satoshi Sasaki

professor

Hideki Hashimoto

professor

Takahiro Kiuchi

professor

Norihito Kawakami

professor

Ichiro Kai

professor

Akira Akabayashi

professor

Yasuki Kobayashi

professor

Kazuhiko Ohe

professor

Hiroshi Oyama

professor

Kenichi Yoshida

Health Sciences and Nursing
Department of Health Sciences

Department of Preventive and Administrative Nursing

Department of Clinical Nursing

International Health

School of Public Health
Department of Epidemiology and Health Sciences

Department of Behavioral Health Sciences

Department of Health Services Sciences

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009

xii

Center for Disease Biology and Integrative Medicine
Laboratory of Molecular Biomedicine for pathogenesis

professor

Toru Miyazaki

Laboratory of Structural Physiology

professor

Haruo Kasai

Laboratory of Regenerative Medical Engineering

professor

Takashi Ushida

Laboratory of Clinical Biotechnology

professor

Kazunori Kataoka

Laboratory of Environmental Health Sciences

professor

Chiharu Tohyama

Laboratory of Animal Resources

professor

Atsuo Ogura

Laboratory of Molecular Radiology

professor

Kiyoshi Miyakawa

professor

Kazuhiko Yamamoto

Associate professor

Kiyoshi Kubota

Associate professor

Tetsuro Okabe

Associate professor

Satoru Yamagami

Division of Research Resources and Support
International Academic Affairs
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

Department of Bone & Cartilage Regenerative Medicine

professor

Yuichi Tei

Department of

Associate professor

Kazuto Hoshi

Department of Clinical Renal Regeneration

Associate professor

Keiichi Hishikawa

Department of Metabolome

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

Sato Sports Plaza Co., Ltd Kaatsu Training

Associate professor

Toshiaki Nakajima

Translational Research Based on the Clinical Database

Associate professor

Hiroyuki Morita

Department of Joint Disease Research

Associate professor

Noriko Yoshimura

Health Care Management and Policy

Associate professor

Hideo Yasunaga

Computational Diagnostic Radiology and Preventive Medicine

Associate professor

Naoto Hayashi

Associate professor

Kansei Uno

Hospital Environment

Associate professor

Yushi Uetera

Clinical Motor System Medicine

Associate professor

Toru Akune

Cartilage of Bone Regeneration(Fujisoft)

Department of Advanced Clinical Science and Therapeutics

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009

xiii

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

Ubiquitous Preventive Medicine

Associate professor

Toru Suzuki

Science for joint reconstruction

professor

Yoshio Takatori

Associate professor

Toru Moro

Department of Molecular Research for Vascular Diseases

Associate professor

Daisuke Nagata

Department of Advanced Skin Care (Miss Paris)

professor

Junko Sugama

Department of Therapeutic Strategy for Heart Failure

professor

Shunei Kyo

Associate professor

Satoshi Gojo

Laboratory of Molecular Physiology on Energy Metabolism

Associate professor

Naoya Yahagi

Department of Molecular Neuroscience on Neurodegeneration

Associate professor

Atsushi Iwata

Director

Kazuhiko Yamamoto

professor

Kiyoshi Kitamura

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

Head

Hirokazu Nagawa

Stomach and Esophagus Surgery

Head

Yasuyuki Seto

International Research Center for Medical Education

University Hospital
Clinical Divisions

xiv

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009

Colon and Rectal Surgery

Head

Hirokazu Nagawa

Hepatobiliary Pancreatic Surgery

Head

Norihiro Kokudo

Vascular Surgery

Head

Tetsuro Miyata

Breast and Endocrine Surgery

HeadToshihisa Ogawa

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

Yukio Honma

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

Neuropsychiatry

Head

Kiyoto Kasai

Radiology

Head

Kuni Ohtomo

Department of Clinical Laboratory

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

Central Clinical Facilites

The Tokyo Journal of Medical Sciences. Vol. 119, October 2009xv

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

Department of Child Psychiatry

Head

Takashi Igarashi

Tissue Bank

Head

Shinichi Takamoto

Center for Epidemiology and Preventive Medicine

Head

Tsutomu Yamazaki

Cancer Resource Center

Head

Shoichi Kaisaki

Center for Liaison and Public Relations

Head

Kazuhiko Ohe

The Database Center of the National University Hospitals

Head

Hiroshi Kushiyama

Division of Tissue Engineering

Head

Tsuyoshi Takato

Department of Clinical and Genetic Informatics

Head

Ryozo Nagai

Department of Palliative Medicine

Head

Keiichi Nakagawa

Department of Clinical Genomics

Head

Shoji Tsuji

Cooperative Unit of Medicine and Engineering Research

Head

Tetsuro Miyata

Translational Research Center

Head

Ryozo Nagai

22nd Century Medical and Research Center

Head

Kozo Nalamura

Pharmaceutical Department

Head

Hiroshi Suzuki

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 molecular mechanisms of cell morphogenesis and intracellulartransports.
Our laboratory studies molecular architecture, dynamics and function of the neuronal cytoskeleton using various new molecular cell biological approaches
including new electron microscopy such as the quick
freeze deep etch electron microscopy, cryoelectron
microscopy at atomic resolution, and cryoultramicrotomy, biochemistry, immunocytochemistry, molecular biology, molecular genetics such as gene targeting and transgenic mouse approaches, molecular biophysics and structure biology including X ray crystallography and cryoelectron 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 morphology
composed of dendrites, cell body and a long axon

3along 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 organelle transports in the cells. Namely it works as rails andmotor molecules to transport materials from cell
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 and molecular genetics
and X-ray crystallography.

References(1) Guillaud, L., R. Wong and N. Hirokawa. Disruptionof KIF17-Mint1 interation by CamKII-dependent
phosphorylation: a molecular model of kinesin-cargo release. Nature Cell Biology 10: 19-29,
2008.
(2) Hirokawa, N. and Y. Noda. Intracellular transportand Kinesin superfamily proteins, KIFs: structure,function, and dynamics. Physiological Review 88:
1089-1118, 2008.
(3) Nitta, R., Y. Okada and N. Hirokawa. Structuralmodel for strain-dependent microtubule activation of
Mg-ADP release from kinesin via microtubule-sensor.
Nature Structural and Molecular Biology 15:1067-1075, 2008.
(4) Niwa, S. Y. Tanaka and N. Hirokawa. KIF1B beta/KIF1A- mediated axonal transport of presynaptic
regulator Rab3 in GTP-dependent manner via
DENN/MADD.

NatureCell

Biology11:1270-1276, 2008.
(5) 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 41, 53-72,
2009.
(6) Hirokawa, N. Y. Noda, Y. Tanaka, and S. Niwa.
Kinesin superfamily motor proteins and intracellular transport. Nature Review Molecular Cell Biology. (in press) 2009.
(7) Hirokawa, N. and R. Nitta, and Y. Okada. The mechanism of motility of Kinesin motors: Lessons
from monomeric motor KIF1A. Nature Review
Molecular Cell Biology. (in press) 2009.
(8) Zhou R. S. Niwa, N. Homma, Y. Takei, and Hirokawa N. Novel Kinesin superfamily protein 26A: a
key regulator of GDNF-Ret signaling in entericneuronal development. Cell (in press) 2009.

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. 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.
2. 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.
3. 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.
4. 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.
5. Maruo, T., Ebihara, T., Sato, E., Kondo, S., Okabe, S.
Cre complementation with variable dimerizers for
inducible expression in neurons. J. Med. Dent. Sci.,
55, 247-254, 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, Ph.D., Kenji Ito, Ph.D., Shiho Arakawa, Ph.D.

Homepage

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 that
two 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. Another ubiquitin ligase islikely to be responsible for degrading at least
Cyclin A during anchorage deprivation andseemingly requires p53 for its activity. Its identity
and the mechanism by which it requires p53 forits 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 appears to mediate an anchorage signal
and controls 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. Search for the factor that links
integrins and this pathway is underway and acandidate for it has already been found.
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

Our current studies indicate that Cdc6 might
have two additional functions promoting S phase
onset and progression.
4. Inductionofanchorage-independent
proliferation of NRK cells by manipulation offour cell cycle and related 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. Last year we succeeded in
inducing anchorage-independent proliferation ofmouse embryonic fibroblasts by overexpression of
Cdk6, cyclin D3 and Cdc6. But theanchorage-independent proliferation was transientand lasted only one week. This year we have
found
the
way
to
obtaincontinued
anchorage-independent proliferation of embryonic
fibroblasts. It can be achieved by additional
expression of constitutively active mutant Rheb,
which is a positive regulator of mTOR complex 1.

Education
To medical students, we give lectures on DNA andrelated. DNA replication, transcription, nuclear export
of mRNA, translation, gene engineering, mobile DNA
and metabolism of nuclei acids are the topics coveredby the lectures. To graduate course students, thegenetic engineering course consisting of lectures andexperiments is provided.

References(1) Kan, Q., Jinno, S., Kobayashi, K., Yamamoto, H.,
and Okayama, H. Cdc6 Determines Utilization of
p21WAF1/CIP1-dependent Damage Checkpoint in S
Phase Cells. 2008, J. Biol. Chem. 283,
17864-17872.
(2) Kan, Q., Jinno, S., Yamamoto, H., Kobayashi, K.,
and Okayama, H. ATP-dependent activation of

p21WAF1/CIP1-associated Cdk2 by Cdc6. 2008,
Proc. Natl. Acad. Sci. USA. 105, 4757-4762.

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
In addition to the above 5 faculty members, we have 9
graduate students (9 doctor course students including
1 PhD-MD course students), and 4 undergraduate
medical students (Free Quarter). Several clinicalscientists and a research fellow from pharmaceuticalcompany are also our members. We have two foreignscientists (one postdoc from Germany and one
graduate student from Taiwan). Ms Toshie Takahashi(Assistant belongs to the Dean of the Faculty), Ms
Fumie Hamano (Research associate) and Mr Shinji
Ichihara (Technical staff) are in charge of maintenanceand education of various instruments for common use.
Professor Takao Shimizu has been awarded Japan
Academy Prize in June 2009.

Education
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 2008 is over17.
For graduate course students, we havethree-month lecture series (Lecture on receptor andsignal transduction), and an eight-week laboratory
course for clinical scientists.

Research
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 intracellulartrafficking and signaling mechanisms; and (3) target
disruption or overexpression of the gene of interest in
mice, and identification of the in viv o role of eachmolecule by examining phenotypes of these mice. In
the last several years we have cloned several key
enzymes of phospholipid metabolism and receptors forlipid mediators. Recently, we have successfully
identified several lysophospholipid acyltransferases
involving in Lands’ cycle. Thus, we are able toexplain the molecular mechanism and biological11significance of diversity and asymmetry of membrane
lipids.
Several lines of transgenic mice andknock-out mice were established and their phenotypes
were analyzed. We found that these mediators are
involved in inflammation, 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 and Mr Harayama
are in charge of the 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.
These research are supported by Grant-in-Aids,
Nanobio Integration Program of the University ofTokyo, and a global COE program.

Publications
1. Hikiji, H., Takato, T., Shimizu, T., and Ishii, S. The
roles
of
prostanoids,
leukotrienes,andplatelet-activating factor in bone metabolism anddisease. Prog. Lipid Res. 2008; 47: 107-26.
2. 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.
3. Harayama, T*., Shindou, H*. (*, equal
contribution), Ogasawara, R., Suwabe, A, andShimizu,T.
Identification
of
a
novel
non-inflammatory biosynthetic pathway ofplatelet-activating factor. J Biol Chem. 2008; 283:
11097-106.
4. Tsujimura, Y., Obata, K., Mukai, K., Shindou, H.,
Yoshida, M., Nshikado, H., Kawano, Y., Minegishi,Y., Shimizu, T., and Karasuyama, H. Basophils

12play a pivotal role in IgG-, but not IgE-mediatedsystemic anaphylaxis in contrast to mast cells.
Immunity 2008; 28: 581-9.
5. 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.
6. 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.
7. 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.
8. Ito, S., Ito, Y., Katagiri, H., Suzuki, T., Hoka, S.,
Yokomizo, T., Shimizu, T., and Majima, M.
Leukotriene B4/Leukotriene B4 Receptor Pathway
Is Involved in Hepatic Microcirculatory
Dysfunction Elicited by Endotoxin. Shock 2008;
30: 87-91.
9. Mashimo, M., Hirabayashi, T., Murayama, T., andShimizu, T. Cytosolic PLA2a activation in Purkinje
neurons and its role in AMPA-receptor trafficking J
Cell Sci. 2008; 121: 3015-3024.
10. Uozumi, N., Kita, Y., and Shimizu, T. Modulationof lipid and protein mediators of inflammation bycytosolicphospholipase
A2alphaduringexperimental sepsis. J Immunol. 2008; 181:3558-3566.
11. Kihara, Y., Yanagida, K., Masago, K., Kita, Y.,
Hishikawa, D., Shindou, H., Ishii, S., and Shimizu,
T. Platelet-Activating Factor Production in the
SpinalCordof
Experimental
Allergic
Encephalomyelitis Mice via the Group IVA
Cytosolic PLA2-LysoPAFAT Axis. J Immunol.
2008; 181: 5008-5014.
12. Moos, M. P. W., Mewburn, J. D., Kan, F. W. K.,
Ishii, S., Abe, M., Sakimura, K., Noguchi, K.,
Shimizu, T., and Funk, C. D. Cysteinyl leukotriene
2 receptor-mediated vascular permeability via
transendothelial vesicle transport. FASEB J. 2008;
22: 4352-4362.

13. Ikeda, K., Shimizu, T., and Taguchi, R. Targeted
analysis of ganglioside and sulfatide molecularspecies by LC/ESI-MS/MS with theoretically
expanded multiple reaction monitoring. J Lipid Res.
2008; 49: 2678-2689.
14. Lopes-Vales, R., Navarro, X., Shimizu, T..,
Baskakis, C., Kokotos, G., Constanious- Kokotou,
V., Stephen, D., Dennis, E. A., and David, S.
Intracellular phospholipase A2 group IVA andgroup VIA play important roles in Walleriandegeneration and axon regeneration after peripheral
nerve injury. Brain 2008; 131: 2620-2631.
15. Prevost, N., Mitsios, J., Kato, H., Burke, J. E.,
Dennis, E.A., Shimizu, T. and Shattil, S. J. Group
IVA cytosolic phospholipase A2 (cPLA2) andintegrin a IIbb3 reinforce each other's functions
during IIb3 signaling in platelets. Blood 2008; 113:447-457.
16. Shindou H. and Shimizu T. Acyl-CoA:lysophospholipid acyltransferases. J Biol Chem.
2009; 284: 1-5.
17. Welch, E. J., Naikawadi, R. P., Li, Z., Lin, P., Ishii,S., Shimizu, T., Tiruppathi, C., Du, X., Subbaiah, P.
V., and Ye, R. D. Opposing Effects ofPlatelet-activating
FactorandLyso-Platelet-activating Factor on Neutrophil andPlatelet Activation. Mol Pharmacol. 2009; 75:
227-234.
18. Mogi, C., Tobo, M., Tomura, H., Murata, N., He,
X.-d., Sato, K., Kimura, T., Ishizuka, T., Sasaki, T.,
Sato, T., Kihara, Y., Ishii, S., Harada, A., andOkajima, F. Involvement of proton-sensing
TDAG8 in extracellular acidification-induced
inhibition of pro-inflammatory cytokine productionin peritoneal macrophages. J Immunol. 2009; 182:
3243-3251.
19. Yasuda, D., Okuno, T., Yokomizo, T., Hori, T.,
Hirota, N., Hashidate, T., Miyano, M., Shimizu, T.,
and Nakamura, M. Helix 8 of leukotriene B4 type-2
receptor is required for the folding to pass the ER
quality control. FASEB J., 2009; 23: 1470-1481.
20. Yuki, K., Shindou, H., Hishikawa, D., and Shimizu,
T. Characterization of mouse lysophosphatidic acidacyltransferase 3: An enzyme with dual functionsin the testis. J Lipid Res. 2009; 50: 860-869.
21. Shimizu, T. Lipid mediators in health and diseases.
Ann. Rev. Pharmacol. Toxicol. 2009; 49: 123-150.

13

22. Shindou, H., Eto, M., Morimoto, R., and Shimizu,
T. Identification of membrane O-acyltransferase
family motifs. Biochem. Biophys. Res. Commun.,2009; 383: 320-325
23. Shindou, H., Hishikawa, D., Harayama, T., Yuki,
K., and Shimizu, T. Recent progress on
Acyl-CoA:lysophospholipid
acyltransferase
research. J Lipid Res. 2009; 50: S46-S51.
24. Harayama, T., Shindou, H., and Shimizu, T.
Biosynthesis of phosphatidylcholine by humanlysophosphatidylcholine acyltransferase 1. J Lipid
Res. 2009; , in press
25. Yanagida, K., Masago, K., Nakanishi, H., Kihara,Y., Hamano, F., Tajima, Y., Taguchi, R., ShimizuT., and Ishii, S. Identification and characterizationof a novel lysophosphatidic acid receptor,
p2y5/LPA6. J Biol Chem. 2009; in press
26. Ishii, S., Noguchi, K., and Yanagida, K. Non-Edg
family lysophosphatidic acid (LPA) receptors.
Prostaglandins Other Lipid Mediat. 2009; in press

14

Department 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, 2 postdoctoral fellows, 6 graduate students, 2technical staffs and 1 secretary.

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 proteinthat binds to and coactivates Pax3, a key
transcription factor in neural crest development andits role in the organogenesis of the kidney and lung15

as 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) Sato, T., Kurihara, Y., Asai, R., Kawamura, Y.,
Tonami, K., Uchijima, Y., Heude, E., Ekker, M.,
Levi, G. and Kurihara, H. An endothelin-1 switch
specifies maxillomandibular identity. Proc. Natl.
Acad. Sci. U. S. A. 2008; 105: 18806-18811.
(2) 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.
(3) 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.
(4) 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.
(5) Horike, N., Sakoda, H., Kushiyama, A., Ono, H.,
Fujishiro, M., Kamata, H., Nishiyama, K.,
Uchijima, Y., Kurihara, Y., Kurihara, H. andAsano,T.
AMPK
activation
increases
phosphorylation of GSK3beta and thereby reduces
CRE transcriptional activity and PEPCK-C gene
expression in the liver. J. Biol. Chem. 2008; 283:
33902-33910.
(6) Watanabe, T., Sato, T., Amano, T., Kawamura, Y.,
Kawamura, N., Kawaguchi, H., Yamashita, N.,
Kurihara, H. and Nakaoka, T. Dnm3os, a noncoding RNA, is required for normal growth andskeletal development in mice. Dev. Dyn. 2008;
237: 3738-3748.
(7) 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 and restoresinsulin resistance in K/KAy mice. Am. J. Physiol.
Endocrinol. Metab. 2008; 294: E719-E725.
(8) 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.
(9) Egawa, M., Kudo, Y., Kamata, H., Kushiyama, A.,
Sakoda, H., Fujishiro, M., Horike, N., Yoneda, M.,
Nakatsu, Tsuchiya, Y., Takata, K., Kurihara, H.
and Asano, T. Long-term forskolin stimulationinduces AMPK activation and thereby enhances
tight-junction formation in human placental
trophoblast BeWo cells. Placenta 2008; 29: 10031008.
(10) Toda, M., Suzuki, T., Hosono, K., Hayashi, I.,
Hashiba, S., Onuma, Y., Amano, H., Kurihara, Y.,16

Kurihara, H., Okamoto, H., Hoka, S. and Majima,
M. Neuronal system-dependent facilitation oftumor angiogenesis and tumor growth bycalcitonin gene-related peptide. Proc. Natl. Acad.
Sci. U. S. A. 2008; 105: 13550-13555.
(11) 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.
(12) 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.
(13) Harada, N., Okajima, K., Narimatsu, N., Kurihara,
H. and Nakagata, N. (2008). Effect of topicalapplication of raspberry ketone on dermal
production of insulin-like growth factor-I in miceand on hair growth and skin elasticity in humans.
Growth Horm. IGF Res. 2008; 18: 335-344.
(14) 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.

Functional Biology
1. Physiology

18

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

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

Research Associate
Toshiyuki Hirabayashi, Ph.D.,

Homepage

Masaki Takeda, Ph.D.,

Takahiro Osada, Ph.D.

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, in teachingactivities for undergraduate courses and the nursing
school. The fields in which our laboratory specializes
span the entire spectrum of animal functions 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, S. Kaname, S. Sugiura
and Y. Shibagaki) take part in giving lectures and laboratory courses to the undergraduate students of theMedical School. The lectures are aimed at providing aclear understanding of the hierarchical functional organizations of living systems. The curriculum is updated every year. For example, a new electrocardiogram experiment in humans was introduced to thelaboratory course, in which students learned humanphysiology of electrocardiogram, its practical procedure in clinical settings and its cellular physiologicalorigins. This practice gained popularity and interest
among students. We accept Free-Quarter students
every year. Usually these students' activities are notlimited to one Quarter, and 2 students (M3 and M4)continued to enjoy their researches from 2008 through2009. Some of these students completed their own
projects, and gave oral presentations in international
meetings and published original papers in top-rankinternational journals. It is not rare that students 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 of Pharmacology, Department of Psychology in Faculty of Letters and Department of Biophysics in Faculty of
Science. As part of a teaching activity for the graduate
students, we have another weekly English seminar, in19which the graduate students learn how to give presentations and hold discussions and debates in English.

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 the temporal
lobe of the monkey. In the inferotemporal cortex,
which we propose to be the storehouse of visual
long-term memory, we discovered a group of
neurons which encode object-object association.
We found that the backward signal from themedial temporal lobe to the inferotemporal cortex
mediates formation of the mnemonic neural circuits for the association. Recently we also foundthat the top-down signal from the prefrontal cortex to the inferotemporal cortex plays a central
role in retrieval of the mnemonic associative
neural code stored in the inferotemporal cortex.
Since association is a basic mechanism for constructing the human memory-based knowledge
system, our finding provides a key to understanding the basic organization of the primate cerebral
cortex.
(2) The recent explosion of new technologies fornoninvasive measurements of human brain activities, especially of functional magnetic resonanceimaging (fMRI), allows us to observe parallel activation of functional brain modules in humans
engaged in various mental tasks. We contributed
to development of a new method called“event-related fMRI”, which enables to utilize thetime resolution of fMRI. We applied this“event-related fMRI” method to the analysis ofhuman 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. Thisapproach provides us a new approach that bridges
a gap between the human non-invasive studies
and the various invasive studies in animals, including intra-cortical electrical microstimulation
and reversible functional inactivation with GABA
agonist drug injections.

References
1. Yamashita, K., Hirose, S.,

2.

3.

4.

Kunimatsu, A.,
Aoki, S., Chikazoe, J., Jimura, K., Masutani, Y.,
Abe, O., Ohtomo, K., Miyashita,Y. and Konishi, S. : Formation of Long-Term Memory Representation in Human Temporal Cortex Related to Pictorial Paired Associates.
J. Neurosci. 29, 10335-10340, 2009.
Kamigaki, T., Fukushima, T., and Miyashita,Y. : Cognitive set reconfiguration signaled bymacaque posterior parietal neurons. Neuron 61,
941-951, 2009.
Chikazoe, J., Jimura. K., Asari, T., Yamashita, K.,
Morimoto, H., Hirose, S., Miyashita, Y. and Konishi, S. : Functional dissociation in right inferior
frontal cortex during performance of go/no-gotask. Cereb. Cortex 19, 146-152, 2009.
Jimura, K., Yamashita, K., Chikazoe, J., Hirose, S.
Miyashita, Y. and Konishi, S. : A critical component that activates left inferior prefrontal cortex during interference resolution.
Eur. J. Neurosci. 29, 1915-1920, 2009.

5. Konishi, S., Morimoto, H., Jimura, K., Asari, T.,

6.

Chikazoe, J., Yamashita, K-I., Hirose, S. andMiyashita, Y. : Differential superior prefrontal
activity on initial versus subsequent shifts innaïve subjects. NeuroImage 4, 575-580, 2008.
Morimoto, H.M., Hirose, S., Chikazoe, J., Jimura,K., Asari, T., Yamashita, K., Miyashita. Y. and

20

7.

8.

Konishi, S. : On verbal/nonverbal modality dependence of left and right inferior prefrontal activation during performance flanker interferencetask. J. Cogn. Neurosci. 20, 2006-2014, 2008.
Asari, T., Konishi, S., Jimura, K., Chikazoe, J.,
Nakamura, N. and Miyashita, Y. : Right temporopolar activation associated with unique perception. NeuroImage 41, 145-152, 2008.
Osada, T., Adachi, Y., Kimura, H.M. and Miyashita, Y. : Toward understanding of the cortical
network underlying associative memory. Philos.
Trans. R. Soc. Lond., B, Biol. Sci. 363,
2187-2199, 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, 4
postdoctoral researchers, 2 visiting scientist, 9
graduate students and 1 secretary stuff.

Using multidisciplinary approaches including electrophysiology, optical imaging, molecular and cellularbiology, and molecular genetics, we at the Department
of Cellular and Molecular Physiology aim at understanding neuronal mechanism for the perception of
sensory inputs and for the emotional states induced by
the sensory inputs. Our recent focus includes olfactory
cortical mechanisms for recognizing food odors andfor judging their edibility.
We have been investigating also the neuronal mechanisms for the incorporation of adult-born interneurons into the pre-existing neuronal circuit in theolfactory bulb, and the contact-mediated interactions
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 teach electrophysiological methods and cell and molecular physiology 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 and molecular and cellular neurobiology. Seminars, progress
reports, and journal club for graduate students areroutinely 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 fromdistinct categories of food-born odorants. These22

results suggest that the olfactory cortical neurons
detect the odorant-category profile of foods in order to distinguish distinct food odors.
Individual neurons in the anterior olfactory nucleus also showed odorant category profile selectivity. Furthermore, for individual cortical neurons
odorant category profile selectivity of left-nasal
input was nearly equivalent with that of theright-nasal input.
We found also that neuronal circuit in the olfactory bulb can actively prolong the odor induced
spike responses and thus keep the specific odor
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 the olfactory bulb.
In addition, we found functional modularizationin the odor maps of the olfactory bulb.
(2) Cellular and molecular mechanisms for the contact-mediated interactions between neurons andimmune cells in physiological and pathologicalconditions.
We are currently focusing on telecncephalonspecific cell adhesion molecule, telencephalin. We
are investigating the telencephalin-mediated signals between neurons and immune cells especially
microglia during recovery from the neuronaldamage.
(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 newlygenerated neurons in the adult neuronal circuit.
We are studying cellular and molecular mechanisms that segregate the fate of new neurons between successful incorporation and apoptotic elimination into/from the neuronal circuit. Recently
we noted the feeding-related time window of fatedecision of newly-generated granule cells in theolfactory bulb, and current focus of our study includes the reorganization of the olfactory bulb
circuit during and after the eating time.

Publications (2008)
1

Haddad, R., Khan, R., Takahashi, Y. K., Mori, K.,
Harel, D. and Sobel, N. A metric for odorantcomparison.

2

3

4

Nature Methods, 5: 425-429(2008).
Ishikawa, M., Nakamura, A., Fujiki A., Ide, J andMori, K. Improving the taste of artificial sweeteners using flavors. In D. K. Weerasinghe andG. E. DuBois (Eds), Sweetness and sweetners,
biology,chemistry,andpsychophysics,(pp420-429) Oxford Univ. Press (2008)
Imayoshi, I., Sakamoto, M., Ohtsuka T., Takao,K., Miyakawa, T., Yamaguchi, Y., Mori, K., Ikeda,
T., Itohara, S. and Kageyama, R. Long-term labeling and ablation reveal requirement of continuous neurogenesis for the structural and functional integrity of the adult forebrain.
Nature Neuroscience, 11:1153-1161 (2008)
Tsuno, Y., Kashiwadani, H. and Mori, K.

Beha-vioral state regulation of dendrodendritic synaptic
inhibition in the olfactory bulb.
J. Neurosci. 28:9227-9238
5(2008).

Kikuta, S., Kashiwadani, H. and Mori, K.
Compensatory Rapid Switching of Binasal Inputs
in the Olfactory Cortex
11997 (2008)

J Neurosci. 28: 11989-

23

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

Associate Professor
Kouichi Hashimoto, 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 including electrophysiology, pharmacology,
morphology, genetic engineering of mouse and opticalimaging of functional molecules in living neurons. We
particularly focus on observing neuronal activities inreal time in intact neurons. We use whole-cell patch
clamp recording, calcium imaging, two-photon imaging

24

and their combinations in various preparations (cultured
neurons, brain slices and intact animals) and investigate
molecular mechanisms of synaptic transmission andplasticity.
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 inan activity-dependent manner, act retrogradely onto
presynaptic cannabinoid receptors and suppress
transmitter release. Since then, we have been
investigating the mechanisms of this retrograde
modulation. We are also interested in elucidating thephysiological significance of this phenomenon
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 vi vo two-photon imaging and whole-cell recording.
We also develop new methods to implement theseexperiments.

References
1.

2.

Hashimoto K, Yoshida T, Sakimura K, Mishina
M, Watanabe M, Kano M. Influence of parallel
fiber-purkinje cell synapse formation on postnatal
development of climbing fiber-purkinje cell
synapses in the cerebellum. Neuroscience. Dec
31. [Epub ahead of print]
Kano M, Hashimoto K, Tabata T. Type-1
metabotropic glutamate receptor in cerebellar
Purkinje cells: a key molecule responsible forlong-term depression, endocannabinoid signalling

3.

4.

5.

6.

and synapse elimination. Philos Trans R Soc
Lond B Biol Sci. 2008 Jun 27;363(1500):217386.
Kano M, Ohno-Shosaku T, Hashimotodani Y,
Uchigashima M, Watanabe M. Endocannabinoidmediated control of synaptic transmission.
Physiol Rev. 2009 Jan;89(1):309-80.
Ohnami S, Endo M, Hirai S, Uesaka N, Hatanaka
Y, Yamashita T, Yamamoto N. Role of RhoA in
activity-dependent cortical axon branching. J
Neurosci. 2008 Sep 10;28(37):9117-21.
Sato T, Miura M, Yamada M, Yoshida T, WoodJD, Yazawa I, Masuda M, Suzuki T, Shin RM,
Yau HJ, Liu FC, Shimohata T, Onodera O, Ross
CA, Katsuki M, Takahashi H, Kano M, Aosaki, T,
Tsuji S. Severe neurological phenotypes of Q129
DRPLA transgenic mice serendipitously createdby en masse expansion of CAG repeats in Q76
DRPLA mice. Hum Mol Genet. 2009 Feb 15;18(4):723-36.
Uesaka N, Nishiwaki M, Yamamoto N. Single
cell electroporation method for axon tracing in
cultured slices. Dev Growth Differ. 2008 Aug;50(6):475-7.

Functional Biology
2. Pharmacology

26

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

Research Associate
Toshiko Yamazawa, Ph. D.,

Yohei Okubo, Ph. D.,

Kazunori Kanemaru, Ph. D.,

Hiroshi Sekiya, M.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
eight 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27

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 (both 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 ofCa2+oscillation,dephosphorylated
NFAT
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.
Furthermore, we generated a nitric oxide (NO)indicator based on the heme-binding domain ofsoluble 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 theactivated synapse and generate 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. Using this fluorescentglutamate indicator, we have succeeded in imaging
spatiotemporal dynamics of glutamate in theextrasynaptic space in brain slices. This study will
provide the basis for the research of extrasynaptic
glutamate transmission that is involved in many
critical brain functions.
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

28

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 regulatingcell-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 thatN-cadherin is involved in the regulation of neural
growth. There seems to be more molecules thatare involved in this mechanism, and we aresearching for the new molecular mechanisms.
4) Cell-to-cell variability in Ca2+ signals
Cell-to-cell phenotypic variability within clonal
populations has attracted considerable attention.
We found that human embryonic kidney 293 cells
exhibit all-or-none phenotypic variability in Ca2+
response upon agonist application: only
approximately 40% of the cells respond to caffeine.
Using a systems-biological approach thatcombines
time-lapse
Ca2+
imagingandmathematical modeling, we are now analyzing thebasis of the cell-to-cell variability. It is expectedthat the study may provide a conceptual basis of
the cell-to-cell phenotypic variability in
mammalian cells.

References1.

Fujiwara, A., Kakizawa, S. and Iino, M. Inductionof cerebellar long-term depression requires activationof calcineurin in Purkinje cells. Neuropharmacology
52, 1663-1670, 2007.

2.

Kanemaru, K., Okubo, Y., Hirose, K. and Iino, M.
Regulation of neurite growth by spontaneous Ca2+
oscillations in astrocytes.

J. Neurosci. 27,

8957-8966, 2007.
3.

Yogo, T., Urano, Y., Mizushima, A., Sunahara, H.,
Inoue, T., Hirose, K., Iino, M., Kikuchi, K. andNagano, T.

Selective photoinactivation ofprotein function through environment-sensitive
switching of singlet oxygen generation byphotosensitizer. Proc. Nat. Acad. Sci. U.S.A. 105,
28-32, 2008.
4.

Iino, M. Identification of new functions of Ca2+
release from intracellular stores in central
nervoussystem.

Biochem.

Biophys.

Res.

Commun. 369, 220-224, 2008
5.

Kakizawa, S., Moriguchi, S., Ikeda, A., Iino, M.
and Takeshima, H. Functional crosstalk between
cell-surface and intracellular channels mediatedby junctophilins essential for neuronal functions.
Cerebellum 7, 385-391, 2008.

29

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

Research Associate
Tomonori Takeuchi, Ph.D.,

Tomoyuki Yoshida, Ph.D.,

Takashi Uemura, Ph.D.,

Misato Yasumura, 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 GluR1 by genetargeting resulted in the increase of thresholds for bothhippocampal LTP induction and contextual learning.
Furthermore, cerebellar Purkinje cell (PC)-specific
GluR2 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 GluR2 and GluR1 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 GluR2 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 GluR2mutant 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.

30

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 GluR2 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
GluR2 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
GluR2-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 vi vo. 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) Brigman, J. L., Feyder, M., Saksida, L. M.,
Bussey, T. J., Mishina, M. and Holmes, A. Impaired discrimination learning in mice lacking
the NMDA receptor NR2A subunit. Learn.
Mem. 15, 55-54. (2008).
(2) Kakegawa, W., Miyzaki, T., Emi, K., Matsuda,K., Kohda, K., Motohashi, J., Mishina, M.,
Kawahara, S., Watanabe, M. and Yuzaki, M.
Differential regulation of synaptic plasticity andcerebellar motor learning by the C-terminal
PDZ-binding motif of GluR2. J. Neurosci. 28,
1460-1468 (2008).
(3) Watanabe, F., Miyazaki, T., Takeuchi, T., Fukaya, M., Nomura, T., Noguchi, S., Mori, H.,
Sakimura, K., Watanabe, M. and Mishina, M.
Effects of FAK ablation on cerebellar foliation,
Bergmann glia positioning and climbing fiber
territory on Purkinje cells. Eur. J. Neurosci. 27,
836-854 (2008).
(4) Yasumura, M., Uemura, T., Yamasaki, M., Sakimura, K., Watanabe, M. and Mishina, M.
Role of the internal Shank-binding segment ofglutamate receptor 2 in synaptic localizationand cerebellar functions. Neurosci. Lett. 433,
146-151 (2008).
(5) Takeuchi, T., Ohtsuki, G., Yoshida, T., Fukaya,
M., Wainai, T., Yamashita, M., Yamazaki, Y.,31Mori, H., Sakimura, K., Kawamoto, S., Watanabe, M., Hirano, T. & Mishina, M.

En-hancement of both long-term depression induction and optokinetic response adaptation inmice lacking Delphilin. PLoS ONE 3, e2297(2008).
(6) Palachick, B., Chen, Y.-C., Enoch, A. J.,
Karlsson, R.-M., Mishina, M. & Holmes, A.
Role of major NMDAR or AMPA receptor
subunits in MK-801 potentiation of ethanol intoxication. Alcoholism: Clinical and Experimental Research, 32, 1479-1492 (2008).
(7) Yoshida, T. & Mishina, M. Zebrafish orthologue of mental retardation protein IL1RAPL1
regulates presynaptic differentiation. Mol. Cell.
Neurosci., 39, 218-228 (2008).
(8) Uemura, T., & Mishina, M. The amino-terminal
domain of glutamate receptor delta2 triggers
presynaptic differentiation. Biochem. Biophys.
Res. Commun., 377, 1315-1319 (2008).
(9) Fukushima, F., Nakao, K., Shinoe, T., Fukaya,
M., Muramatsu, S., Sakimura, K., Kataoka, H.,
Mori, H., Watanabe, M., Manabe, T., & Mishina,
M. Ablation of NMDA receptors enhances theexcitability of hippocampal CA3 neurons. PLoS
ONE, 4, e3993 (2009).
(10) Kishioka, A., Fukushima, F., Ito, T., Kataoka,
H., Mori, H., Ikeda, T., Itohara, S., Sakimura,K., & Mishina, M. A novel form of memory forauditory fear conditioning at a low-intensity
unconditioned stimulus. PLoS ONE, 4, e4157(2009).
(11) Hashimoto, K., Yoshida, T., Sakimura, K., Mishina, M., Watanabe, M., & Kano, M. Influenceof parallel fiber-purkinje cell synapse formation
on postnatal development of climbing fiber-purkinje cell synapses in the cerebellum.
Neuroscience, in press.
(12) Longordo, F., Kopp, C., Mishina, M., Lujan, R.
and Luthi, A. NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal
plasticity to sleep loss. J. Neurosci., in press.

Pathology, Immunology andMicrobiology
1. Pathology

33

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.
Yutaka Takazawa, M.D., Ph.D.
Hiroshi Uozaki, M.D., Ph.D. (Division of Diagnostic Pathology)

Lecturer (Hospital)
Junji Shibahara, M.D., Ph.D.
Kenji Kashima, M.D., Ph.D., (visiting researcher, UK)

Associate
Shunpei Ishikawa, M.D., Ph.D., Rumi Hino, M.D., Ph.D.
Yoshinao Kikuchi, D.D.S., Ph.D.
Takashi Sakatani, M.D., Ph.D., Tetsuo Ushiku, M.D., Ph.D.,
Teppei Morikawa, M.D., Ph.D. (Division of Diagnostic Pathology)
Akiteru Goto, M.D., Ph.D. (visiting researcher, USA)
Takeo Nakaya, M.D., Ph.D. (Cancer Profession Training Program)
Naoko Yamauchi, M.D., Ph.D. (Global COE Program)Technical Support Specialist
Yasuyuki Morishita, M.T., Shinichi Harada, Kei Sakuma

Homepage

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

Introduction and Organization
Department of Pathology and Diagnostic Pathology is
responsible for the practice of diagnostic pathology,
education, and research in conjunction with Divisionof Diagnostic Pathology of the University Hospital.
Our aim is the construction of “pathology as clinicalmedicine” as well as “next-generation pathology fortranslational research”.
“Diagnostic Pathology” has been officiallyadmitted in the fiscal year 2009 as the name of clinicaldepartment that can be shown to the patients. It was agreat delight for us pathologists as indicating a general
acceptance of the importance of pathology diagnosis.
Dr. Motoi moved to Teikyo University, School of
Medicine as an Associate Professor. Drs. Sakatani and34

Morikawa moved to the Division of Diagnostic
Pathology, and Dr. Kikuchi was a new member of
Associates. Dr. Takazawa and Dr. Shibahara were
promoted to be Lecturer and Lecturer (Hospital),
respectively. Dr. Yamauchi was employed by the
global COE program, Chemical Biology of the
Diseases, on September.
Two postgraduate students finished the course
and received Ph.D. In the new fiscal year, 2009, four
new students will enter the course, and there are 13
postgraduates (including one foreign student).
We are responsible for the pathology practice of
The University Hospital, and carry forward themorphology-based research targeting human diseases.
On the other hand, we take charge of General
Pathology course for the 1st grade students incollaboration with Department of Molecular Pathology,
and also Systemic Pathology, Clinical Clerkship, andBedside-learning (BSL) for the 2nd –4th grade students.

Clinical activities (diagnostic
pathology and autopsy)
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).
Surgical pathology conferences are regularly heldwith each clinical division, and the cases of various
tumors, including thorax, brain, liver, pancreatobiliary tract, urology, gynecology, breast, andorthopedics, as well as biopsy cases of liver, kidneyand skin are discussed.
Clinico-pathological conferences (CPCs) for two
autopsy cases are held every month in the hospital.
They are useful forthe education of clinicalresidents, in addition to the weekly autopsy
conferences.
A model project for the survey analysis of deaths
related to medical treatment (DRMT) has been in
operation since September 2005. We have participatedin the autopsy inspection in corporation with
Department of Legal Medicine. We have also started
the two-year project, “Feasibility of post mortem
imaging as a method assisting the autopsy inspectionof DRMT” (Grants-in-Aid from Ministry of Health,labor and Welfare). The report 2008 is now open to
the public and available at the website of the study
group (http:://humanp.umin.jp/).

Teaching activities
We take on General Pathology course for the 1st gradeof undergraduate students, especially in its
morphological field. The course program and lecturenotes are open to the public and available in UT OpenCourse Ware（http://ocw.u-tokyo.ac.jp/）.
Each class of Systemic Pathology course andexercise is held in parallel with that of Systemic
Medicine course. Handouts are available in every halfcourse of the pathological exercises, and all slides
used in the course are accessible on our website as
virtual slides (digital images of the slides). All of the
microscopes will be renewed and the virtual
microscopy system will be introduced in thelaboratory of the 2nd Building, partially by means ofa financial aid from the head office of the university as
one of its Education and Research Programs.
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 a case presentation for paired students,
surgical pathologic practices using various tumor
sections, and a tour of the pathology laboratory.
The past examinations for the second gradestudents and for graduation are also referred to thewebsite.
We have started the lecture series of tumor
pathology for the Cancer Profession Training Programin postgraduate school, and the key slides are
distributed as DVD to the students.

Research activities
The firsrt major theme is “chronic inflammation andneoplasms”, for which various investigations aredeveloped, in the fields of Epstein-Barr virus (EBV)
associated gastric carcinoma (GC), lung carcinoma
and scar formation, and carcinogenesis in pulmonary
fibrosis. We clarified the role of latent membraneprotein 2A in the development and progression of
EBV-associated GC.
The second main theme is the search of target

35

molecules for cancer therapy by global analysis ofexpression profiles of various cancers, in collaboration
with Research Center for Advanced Science andTechnology (RCAST), the University of Tokyo. Drs.
Ota and Shibahara carried out immunohistochemical
studies with newly-developed monoclonal antibodies
using the tissue microaaray of various carcinomas.
Dr. Ishikawa developed a new method foranalyzing the precise copy number of genes in genome
wide (EG-method) in corporation with Prof. Aburatani(RCAST). It is the essential method for the medical
research of the diseases, and he is expected to develop
a new field of genome pathology. His method also getsa lot of attention from industries as a new method
available for identifying the patients susceptible toadverse effects of a drug.

References
1.

2.

3.

4.

5.

6.

Amemiya S, Shibahara J, Aoki S, Takao H,
Ohtomo K. Recently established entities ofcentral nervous system tumors: review ofradiological findings. J Comput Assist Tomogr.
2008 Mar-Apr;32(2):279-85.
Fu DX, Tanhehco Y, Chen J, Foss CA, Fox JJ,
Chong JM, Hobbs RF, Fukayama M, Sgouros G,
Kowalski J, Pomper MG, Ambinder RF.
Bortezomib-induced enzyme-targeted radiation
therapy in herpesvirus-associated tumors. Nat
Med. 2008 Oct;14(10):1118-22.
Fukayama M, Hino R, Uozaki H. Epstein-Barrvirus and gastric carcinoma: virus-hostinteractions leading to carcinoma. Cancer Sci.
2008 Sep;99(9):1726-33.
Fukayama M. A model project for survey analysis
of deaths related to medical treatment. JMAJ
2008 Jul-Aug; 51(4):262-6
Fukushima N, Kikuchi Y, Nishiyama T, Kudo A,
Fukayama M. Periostin deposition in the stromaof invasive and intraductal neoplasms of thepancreas. Mod Pathol 2008 Aug;21(8):1044-53.
Hino R, Uozaki H, Inoue Y, Shintani Y, Ushiku
T, Sakatani T, Takada K, Fukayama M. Survival
advantage of EBV-Associated gastric carcinoma.
survivin up-regulation by viral latent membraneprotein 2A. Cancer Res. 2008 Mar; 68(5):1427-1435.

7.

8.

9.

10.

11.

12.

13.

14.

Hruban RH, Fukushima N. Cystic lesions of thepancreas. Diagnostic Histopathology. 2008
Jun:14(6):260-5.
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-exposed worker at the Tokai-mura
criticality accident. J Radiat Res (Tokyo). 2008
Jan;49(1):55-62.
Ikemura M, Saito Y, Sengoku R, Sakiyama Y,
Hatsuta H, Kanemaru K, Sawabe M, Arai T, Ito
G, Iwatsubo T, Fukayama M, Murayama S. Lewy
body pathology involves cutaneous nerves. J
Neuropathol Exp Neurol, 2008 Oct;67(10):94553.
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
Neurol. 2008 May;65(5):662-5.
Itoh Y, Kamata-Sakurai M, Denda-Nagai K,
Nagai S, Tsuiji M, Ishii-Schrade K, Okada K,
Goto A, Fukayama M, Irimura T. Identificationand expression of human epiglycanin/MUC21: a
novel transmembrane mucin. Glycobiology. 2008
Jan;18(1):74-83.
Kikuchi Y, Kashima GT, Nishiyama T, Shimazu
K, Morishita Y, Shimazaki M, Kii I, Horie H,
Nagai H, Kudo A, Fukayama M. Periostin isexpressed in pericryptal fibroblasts and cancerassociated fibroblasts in the colon. J Histochem
Cytochem 2008 Aug;56(8):753-764.
Komura M, Kanamori Y, Sugiyama M, Nakahara
S, Kawashima H, Hatanaka A, Takazawa Y,
Goishi K, Igarashi T, Iwanaka T. Antenatallydiagnosed giant multicystic dysplastic kidney
resected during the neonatal period. J Pediatr
Surg. 2008 Nov;43(11):2118-20
Li CP, Goto A, Watanabe A, Murata K, Ota S,
Niki T, Aburatani H, Fukayama M. AKR1B10 inusual interstitial pneumonia: expression insquamous metaplasia in association with smoking
and lung cancer. Pathol Res Pract. 2008 May;204(5):295-304.

36

15. Mimura I, Hori Y, Matsukawa T, Uozaki H, Tojo
A, Fujita T. Noncrescentic ANCA-associatedrenal crisis in systemic sclerosis. Clin Nephrol.
2008 Aug;70(2):183-5.
16. Mimura I, Tojo A, Uozaki H, Fujita T.
Erythrophagocytosis by renal tubular cells.
Kidney Int. 2008 Aug;74(3):398.
17. Nakamura Y, Matsubara D, Goto A, Ota S,
Sachiko O, Ishikawa S, Aburatani H, Miyazawa
K, Fukayama M, Niki T. Constitutive activationof c-Met is correlated with c-Met overexpression
and dependent on cell-matrix adhesion in lungadenocarcinoma cell lines. Cancer Sci. 2008 Jan;
99(1):14-22.
18. Oshiro H, Miyagi Y, Kawaguchi Y, Rino Y, Arai
H, Asai-Sato M, Nakayama H, Yamanaka S,
Inayama Y, Fukushima N. Endometrial
Adenocarcinoma without Myometrial Invasion
Metastasizing to the Pancreas and Masqueradingas Primary Pancreatic Neoplasm. Pathol Int. 2008
Jul;58(7):456-61.
19. Sato N, Fukushima N, Hruban RH, Goggins M.
CpG island methylation profile of pancreatic
intraepithelial neoplasia. Modern Pathol. 2008
Mar;21(3):238-44.
20. Shimazaki M, Nakamura K, Kii I, Kashima T,
Amizuka N, Li M, Saito M, Fukuda K,
Nishiyama T, Kitajima S, Saga Y, Fukayama M,
Sata M, Kudo A. Periostin is essent ial for
cardiac healing after acute myocardial infarction.
J Exp Med. 2008 Feb 18;205(2):295-303.
21. Shinozaki A, Nagao T, Endo H, Kato N,
Hirokawa M, Mizobuchi K, Komatsu M, Igarashi
T, Yokoyama M, Masuda S, Sano K, Izumi M,
Fukayama
M,
Mukai
K.
Sebaceousepithelial-myoepithelial carcinoma of the salivary
gland:
clinicopathologic
andimmunohistochemical analysis of 6 cases of a
new histologic variant. Am J Surg Pathol. 2008
Jun;32(6):913-23.
22. Suzuki H, Suzuki T, Kamijo A, Oota S, Sato H,
Hangaishi A, Takahashi T, Kanda Y, Motokura T,
Chiba S, Kurokawa M. Antileukemic immunity
associatedwithantineutrophil
antibody
production after allogeneic hematopoietic SCT
for myeloid/NK-cell precursor acute leukemia.
Bone Marrow Transplant. 2008 Aug;42(4):285-7.

23. Suzuki T, Izutsu K, Kako S, Ohta S, Hangaishi A,
Kanda Y, Motokura T, Chiba S, Kurokawa M. A
case of adult Langerhans cell histiocytosis
showing successfully regenerated osseous tissueof the skull after chemotherapy. Int J Hematol.
2008 Apr;87(3):284-8.
24. Takemura N, Kokudo N, Imamura H, Takazawa
Y, Sano K, Sugawara Y, Nakagawa K, Ohtomo K,
Makuuchi M. Eleven-year survivor ofunresectable intrahepatic cholangiocarcinoma
treatedusing
long-term
UFTtherapy.
Hepatogastroenterology. 2008 Nov-Dec;55(88):1997-9.
25. Tanaka T, Watanabe T, Konishi T, Shibahara J,
Kanazawa T, Kazama S, Nagawa H. Unusualpressure-induced rupture of colonic volvulus in apatient with long-term corticosteroid therapy.
Acta Gastroenterol Belg. 2008 Jul-Sep;71(3):339-41.
26. Yamamoto K, Kimura H, Murayama T, Kashima
T, Kikuchi Y, Akiyama T, Kawano H, Miyata T,
Nagawa H. Chronic expanding hematoma in
combination with a pseudoaneurysm: a casereport. Int Angiol 2008 Jun;27(3):266-268.
27. Yoneda K, Tomimoto A, Endo H, Iida H,
Sugiyama M, Takahashi H, Mawatari H, Nozaki
Y, Fujita K, Yoneda M, Inamori M, Nakajima N,
Wada K, Nagashima Y, Nakagama H, Uozaki H,
Fukayama M, Nakajima A. Expression of
adiponectin receptors, AdipoR1 and AdipoR2, in
normal colon epithelium and colon cancer tissue.
Oncol Rep. 2008 Sep;20(3):479-83.
28. Yoshimi A, Kumano K, Motokura T, Takazawa
Y, Oota S, Chiba S, Takahashi T,Fukayama M,
Kurokawa M. ESHAP therapy effective in apatient with Langerhans cell sarcoma. Int J
Hematol. 2008 Jun;87(5):532-7.

37Department of MolecularPathology
Professor
Kohei Miyazono, M.D., D.M.S.

Associate Professor
Keiji Miyazawa, Ph.D.

Research Associates
Tetsuro Watabe, Ph.D., Shogo Ehata, M.D., Ph.D.

Homepage

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 is working as the professor of the
Department of Molecular Pathology from August
2000. Now, the Department consists of a professor, anassociate professor, a lecturer, two research associates,
4 technicians, and several research fellows, including
19 graduate students, 3 master course students, 2
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 staff of the Department of Human Pathology.
Teaching responsibilities include lectures on General
Pathology related to the mechanisms of diseases.
Since we believe 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 for students from molecular pathologicalpoints 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- meeting in Sweden every spring, and somegraduate students participate in the meeting and orally
present their results.
We are currently supported by the Global Centerof Excellence (COE) Program for "Integrative Life
Science Based on the Study of Biosignaling
Mechanisms" from the Ministry of Education, Culture,
Sports, Science and Technology of Japan. This
program stimulates interaction with students andscientists in the program as well as those from otherlaboratories.
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.

38

Research activities
Our major research interest is to elucidate how
members of the TGF (transforming growth
factor)-beta family transduce signals, and how they
regulate growth, differentiation, and apoptosis ofvarious cells. We are also interested in the regulationof angiogenesis and lymphangiogenesis using
embryonic stem (ES) cell-derived vascular progenitor
cells and other endothelial cells.
Smad2 and Smad3 (Smad2/3) are primarily
involved in the transmission of TGF-beta signalingfrom the cytoplasm to the nucleus. Many transcription
factors have been reported to cooperate with Smad2/3
in regulation of the transcription of target genes. We
have identified more than 1,700 Smad2/3 binding sites
in the promoter regions of over 25,500 genes bychromatin immunoprecipitation on microarray(ChIP-chip) in human HaCaT keratinocyte cells.
Binding elements for ETS1 and TFAP2A wereenriched in the Smad2/3 binding sites, and knockdownof either ETS1 or TFAP2A resulted in alteration of
TGF-beta-induced transcription. These findings
suggest general roles of ETS1 and TFAP2A in thetranscription induced by TGF-beta-Smad signaling
pathways. We identified novel Smad binding sites in
the CDKN1A gene where Smad2/3 binding wasregulated by ETS1 and TFAP2A. Moreover, we
showed that siRNAs for ETS1 and TFAP2A affected
TGF-beta-induced growth arrest. We have also
analyzed genes specifically regulated by Smad2 or
Smad3, and found that their specificity was not solely
dependent on the amounts of the Smad2 or Smad3
proteins bound to the promoters. These findings reveal
novel regulatory mechanisms of Smad2/3-induced
transcription in TGF-beta signaling pathways(Koinuma et al., Mol. Cell. Biol. 2009).
Epithelial-to-mesenchymal transition (EMT) is a
crucial event for cancer cells to acquire invasive andmetastatic properties and is induced by TGF-beta. We
found the mechanism whereby Snail, a key
transcriptional regulator of EMT, is induced by
TGF-beta in cancer cells. Snail induction by TGF-beta
was highly dependent on cooperation with active Ras
signals, and knockdown of Ras abolished induction of
Snail by TGF-beta in a pancreatic cancer cell line
Panc-1. Exogenous expression of active Ras into

HeLa cells resulted in induction of Snail by TGF-beta,
while expression of other target genes of TGF-beta,
e.g. Smad7 and PAI-1, was not affected by Ras
signaling. We found that phosphorylation at the linker
region of Smad2 or Smad3 by MAP kinases was notessential for the induction of Snail by TGF-beta. Ourfindings indicate that Ras and TGF-beta signaling
cooperate in the induction of Snail, which occurs in a
Smad-dependent manner (Horiguchi et al., J. Biol.
Chem. 2009).
Thyroid transcription factor-1 (TTF-1, also
known as Nkx2.1) is expressed in lung cancer, but its
biological functions are unknown. We have found anovel function of TTF-1 that inhibits TGF-betainduced EMT and restores epithelial phenotype inseveral lung adenocarcinoma cells. The effect of
TTF-1 was accompanied by down-regulation of some
TGF-beta target genes, including above-mentioned
EMT regulators, such as Snail and Slug. Silencing of
TTF-1 enhanced TGF-beta-induced EMT, and thus,
TTF-1 exerts a tumor-suppressive effect withabrogation of cellular response to TGF-beta. Moreover,
we have found that TTF-1 reduces TGF-beta2
production in lung adenocarcinoma A549 cells andthat TGF-beta conversely decreases TTF-1 expression.
These findings suggest that enhancement of autocrine
TGF-beta signaling facilitates the decrease of TTF-1
expression and vice versa, and that regulation of
TTF-1 expression can be a novel therapeutic strategy
for treatment of lung adenocarcinoma (Saito et al.,Cancer Res. 2009).
We previously reported the use of TGF-beta
inhibitor on tumor neovasculature in stroma-richtumor models (such as pancreatic cancer models) toincrease the intra-tumoral distribution of nanoparticles.
We compared the effects of two other protein kinase
inhibitors, imatinib and sorafenib, with TGF-beta
inhibitor (LY364947) on extravasation of a modelled
nanoparticle, i.e. 2 MDa dextran. We first used a
Matrigel plug assay to compare neovasculature
formed inside of and around Matrigel plugs(intra-plug and peri-plug regions, respectively).
Intra-plug neovasculature was more abundantly
covered by pericytes, while peri-plug neovasculature
was less covered. TGF-beta inhibitor showed the mostpotent effect on intra-plug neovasculature inincreasing the extravasation of dextran, while39

sorafenib showed the most potent effect on peri-plug
neovasculature. Next, these findings were confirmed
by using two tumor models, i.e. the CT26 coloncancer and the BxPC3 pancreatic cancer models. The
neovasculature phenotype in CT26 was similar to thatin the peri-plug region, while that in BxPC3 wassimilar to that in the intra-plug region. Consistently,
sorafenib potently enhanced the accumulation of
nanoparticles in the CT26 tumors, while TGF-beta
inhibitor did so in the BxPC3 tumors. Thus, thestrategy for optimization of tumor neovasculature fornanoparticles may be different, depending on tumor
types (Kano et al., Cancer Sci. 2009).
During the process of embryonic lymphatic
development, a homeobox transcription factor, Prox1,
is expressed in a subset of venous blood endothelial
cells (BECs) in which an orphan nuclear receptor,
COUP-TFII, is highly expressed. Prox1 induces
differentiation of BECs into lymphatic endothelial
cells (LECs) by inducing the expression of various
molecules responsible for LEC differentiation,
including vascular endothelial growth factor receptor
3(VEGFR3).
However,mechanisms
howtranscriptional activities of Prox1 are regulated remain
to be studied. We have found that Prox1 induces theproliferation and migration of BECs and LECs toward
VEGF-C by inducing the expression of cyclin E1 and
VEGFR3, respectively. Gain-of-function studies
showed that COUP-TFII negatively regulates theeffects of Prox1 in BECs and LECs. We also showedthat Prox1 and COUP-TFII physically interact witheach other in LECs and that they both bind to thecyclin E1 promoter. These findings suggest that
COUP-TFII physically and functionally interact
during differentiation and maintenance of lymphatic
vessels (Yamazaki et al., Gene Cells, 2009).
We have organized Sapporo Cancer Seminar“TGF-beta signaling and cancer” on June 26-27, 2009
in Sapporo (supported by the Global COE Program).
More than 150 scientists and students participated in
the Seminar, and exchanged their most recent data.

References
1. Hayashi, M., Maeda, S., Aburatani, H., Kitamura,K., Miyoshi, H., Miyazono, K., and Imamura, T.
(2008)

Pitx2

transdifferentiation

preventsofosteoblastic

myoblasts

by

bone

morphogenetic proteins. J. Bi ol. Chem. 283 (1):565-571.
2. Suzuki, Y., Montagne, K., Nishihara, A., Watabe,T., and Miyazono, K. (2008) BMPs promote
proliferation and migration of endothelial cells via
stimulationofAngiopoietin-1/Tie2

VEGF-A/VEGFR2
signalling.

andJ. Biochem.

(Tokyo) 143 (2): 199-206.
3. Asagiri, M., Hirai, T., Kunigami, T., Kamano, S.,
Gober, H.J., Okamoto, K., Nishikawa, K., Latz, E.,
Golenbock, D.T., Aoki, K., Ohya, K., Imai, Y.,
Morishita, Y., Miyazono, K., Kato, S., Saftig, P.,
andTakayanagi,

K-dependentH.

toll-like(2008)
receptor

Cathepsin
9

signaling

revealed in experimental arthritis. Science 319(5863): 624-627.
4. Kawasaki, K., Watabe, T., Sase, H., Hirashima, M.,
Koide, H., Morishita, K., Yuki, K., Sasaoka, T.,
Suda, T., Katsuki, M., Miyazono, K., andMiyazawa, K. (2008) Ras signaling directs
endothelial specification of VEGFR2+ vascularprogenitor cells. J. Cell Biol. 181 (1): 131-141.
5. Oka, M., Iwata, C., Suzuki, H.I., Kiyono, K.,
Morishita, Y., Watabe, T., Komuro, A., Kano,
M.R., and Miyazono, K. (2008) Inhibition ofendogenous

TGF-beta

signalingenhances

lymphangiogenesis. Blood, 111 (9): 4571-4579.
6. Monzen, K., Ito, Y., Naito, A.T., Kasai, H., Hiroi,
Y., Hayashi, D., Shiojima, I., Yamazaki, T.,
Miyazono, K., Asashima, M., Nagai, R., andKomuro, I. (2008) A crucial role of a highmobility group protein HMGA2 in cardiogenesis.
Nat. Cell Biol. 10 (5): 567-574.

40

7. Wu, S., Nishiyama, N., Kano, M.R., Morishita, Y.,

14. Miyazono K. (2008) Shear activates platelet-

Miyazono, K., Itaka, K., Chung, U.I., and Kataoka,

derived latent TGF-beta. Blood. 112 (9): 3533-

K. (2008) Enhancement of angiogenesis through3534.

stabilization of hypoxia-inducible factor-1 bysilencing prolyl hydroxylase domain-2 gene. Mol.
Ther. 16 (7): 1227-1234.
8. Kamiya, Y., Miyazono, K., and Miyazawa, K.
(2008) Specificity of the inhibitory effects of Dad
on TGF-beta family type I receptors, Thickveins,
Saxophone, and Baboon in Drosophila. FEBS Lett.
582 (17): 2496-2500.
9. Katsuno, Y., Hanyu, A., Kanda, H., Ishikawa, Y.,
Akiyama, F., Iwase, T., Ogata, E., Ehata, S.,
Miyazono, K., and Imamura, T. (2008) Bonemorphogenetic

proteinsignalingenhances

invasion and bone metastasis of breast cancer
cells through Smad pathway. Oncogene 27 (49):6322-6333
10. Kokudo, T., Suzuki, Y., Yoshimatsu, Y., Yamazaki,T., Watabe, T., and Miyazono, K. (2008) Snail isrequiredformesenchymal

TGF-beta-induced
transitionofendothelial-embryonic

stem

cell-derived endothelial cells. J Cell Sci. 121 (20):3317-3324.
11. Nonaka, H., Watabe, T., Saito, S., Miyazono, K.,andMiyajima,A.

(2008)

stabilin2+

endothelial

embryonic

stem

cells

Development

cells
by

from

of

mouse

inhibition

of

TGFbeta/activin signaling. Biochem. Biophys. Res.
Commun. 375 (2): 256-260.
12. Ikushima, H., Komuro, A., Isogaya, K., Shinozaki,
M., Hellman, U., Miyazawa, K., and Miyazono, K.
(2008)

An

Id-likemolecule,

HHM,

is

a

synexpression group-restricted regulator of TGFbeta signaling. EMBO J. 27 (22): 2955-2965.
13. Miyazono, K., Kamiya, Y., and Miyazawa, K.
(2008) SUMO amplifies TGF-beta signalling. Nat.
Cell Biol. 10 (6): 635-637.

Pathology, Immunology andMicrobiology
2. Microbiology

42

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) andlaboratory courses (36 hr), the following subjects arecovered.
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.

43

8. Molecular basis for HCV pathogenesis
Munakata, T., Hayase, N., and Nomoto, A.
9. Development of novel inhibitors of HCV
replication
Munakata, T., and Nomoto, A.

Publications
1.

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.,
31: 435-448, 2008.

44

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
Takatoshi Kitazawa, M.D., Ph.D.
Katsutoshi Abe, M.D., Ph.D.

Homepage http://www.cc.h.u-tokyo.ac.jp/mulins/kansen/index.html (inside thehospital only)
Introduction and Organization
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, 11 laboratory
technicians, and two office assistants. For isolationand identification of microorganisms from clinicalspecimens, 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 au reus andother drug-resistant microbes.
2) Investigation of trends in weekly bases andmonthly reports to all departments; Screening ofcolonization; monitoring of appropriate use ofantibiotics such as mupirocin and vancomycin.
3) Microbiological investigation of wards andenvironment (at request or need).
4) Detection, investigation, intervention and control of
the hospital infection outbreak.
5) Offering of information and advice on HIV-infectedpatients’ management.
6) 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45

education of graduate students as well as hospital
staff.
For postgraduate education, we have been committed
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)

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.
2)
Tanaka N, Moriya K, Kiyosawa K, Koike K,
Aoyama T. Hepatitis C virus core protein induces
spontaneous and persistent activation ofperoxisome proliferator-activated receptor alpha intransgenic mice: Implications for HCV-associatedhepatocarcinogenesis. Int J Cancer 2008;122:124131.
3)
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 humanimmunodeficiency virus in Japan. Hepatol Res
2008;38:310-314.
4)
Ishizaka N, Ishizaka Y, Toda EI, Koike K,
Yamakado
M,
Nagai
R.
Are
serum
carcinoembryonic antigen levels associated withcarotid atherosclerosis in Japanese men?
Arterioscler Thromb Vasc Biol 2008;28:160-165.
5)
Nagase Y, Yotsuyanagi H, Okuse C, Yasuda
K, Kato T, Koike K, Suzuki M, Nishioka K, Iino S,
Itoh F. Effect of treatment with interferon alpha-2b
and ribavirin in patients infected with genotype 2
hepatitis C virus. Hepatol Res 2008;38:252-258.
6)
Hashimoto M, Sugawara Y, Tamura S,
Kaneko J, Matsui Y, Moriya K, Koike K,
Makuuchi M. Methicillin-resistant Staphylococcus
aureus infection after living-donor livertransplantation in adults. Transpl Infect Dis
2008;10:110-116.
7)
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.
8)
Newell P, Villanueva A, Friedman SL, Koike
K, Llovet JM. Experimental models of
hepatocellular
carcinoma.
J
Hepatol
2008;48:858-879.
9)Ishizaka N, Ishizaka Y, Toda E, Shimomura
H, Koike K, Seki G, Nagai R, Yamakado M.
Association between cigarette smoking and chronic
kidney disease in Japanese men. Hypertens Res
2008;31:485-92.
10) 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.
11) 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;38:775-783.
12) Matsuzaki G, Ishizaka N, Furuta K, Hongo M,
Saito K, Sakurai R, Koike K, Nagai
R. Comparison of vasculoprotective effects of

46

benidipine and losartan in a rat model of metabolic
syndrome. Eur J Pharmacol 2008;587:237-42.
13) Okada H, Kitazawa T, Harada S, Itoyama S,
Hatakeyama S, Ota Y, Koike K. Combined
treatment with oral kanamycin and parenteralantibiotics for a case of persistent bacteremia andintestinal carriage with Campylobacter coli. Intern
Med 2008;47:1363-1366.
14) Yotsuyanagi H, Kikuchi Y, Tsukada K, Nishida K,
Kato M, Sakai H, Takamatsu J, Hige S, Chayama K,
Moriya K, Koike K. Chronic hepatitis C in patientscoinfected with human immunodeficiency virus in
Japan: a retrospective multicenter analysis.
Hepatol Res 2009;39:657-663.
15) Ishizaka Y, Ishizaka N, Tani M, Toda A, Toda EI,
Koike K, Nagai R, Yamakado M.
Association between changes in obesity parameters
and incidence of chronic kidney disease inJapanese individuals. Kidney Blood Press Res
2009;32:141-149.
16) Murata M, Matsuzaki K, Yoshida K, Sekimoto G,
Uemura Y, Sakaida N, Fujisawa J, Seki T, Koike K,
Okazaki K. Hepatitis B virus X protein shifts
hepatic
Smad3-mediatedsignalingfromtumor-suppression to oncogenesis in chronic
hepatitis B. Hepatology 2009;49:1203-1217.
17) Kumita W, Saito R, Sato K, Ode T, Moriya K,
Koike K, Chida T, Okamura N. Molecularcharacterizations of carbapenem and ciprofloxacin
resistance in clinical isolates of Pseudomonas
putida. J Infect Chemother 2009;15:6-12.
18) Hongo M, Ishizaka N, Furuta K, Yahagi N, Saito
K, Sakurai R, Matsuzaki G, Koike K, Nagai R.
Administration of angiotensin II, but notcatecholamines, induces accumulation of lipids inthe rat heart. Eur J Pharmacol 2009;604:87-92.
19) Yanagimoto S, Tatsuno K, Okugawa S, Kitazawa
T, Tsukada K, Koike K, Kodama T, Kimura S,
Shibasaki Y, Ota Y. A single amino acid of
toll-like receptor 4 that is pivotal for its
signaltransduction and subcellular localization. J
Biol Chem 2009;284:3513-3520.
20) Ishizaka N, Ishizaka Y, Yamakado M, Toda E,
Koike K, Nagai R. Association between metabolic
syndrome and carotid atherosclerosis in individuals
without diabetes based on the oral glucose
tolerance test. Atherosclerosis 2008 Oct 30. [Epubahead of print]21) Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Moriya K, Koike K,
Makuuchi M. Colonization and/or infection withmethicillin-resistant Staphylococcus a ureus after
living donor liver transplantation: a case control
study. BMC Infectious Diseases 2008;8:155.
22) Togo M, Hashimoto Y, Iso-O N, Kurano M, Hara
M, Kadowaki T, Koike K, Tsukamoto K.
Identification of a novel mutation for
phytosterolemia. Genetic analysis of two cases.
Clin Chim Acta 2009;401:165-169.
23) Koike K. Steatosis, Liver injury andhepatocarcinogenesis in hepatitis C viral infection.
J Gastroenterol 2009;44supl:82-88.
24) Ichibangase T, Moriya K, Koike K, Imai K.
Limitation of immunoaffinity column for theremoval of abundant proteins from plasma inquantitativeplasmaproteomics.
BiomedChromatogr 2009;23:480-487.
25) Seki G, Yamada H, Li Y, Horita S, Ishizakaa N,
Koike K, Fujita T. Roles of MEK/ERK pathway invascular and renal tubular actions of angiotensin II.
Vasucular Dis Prevent 2009;6:154-159.

Pathology, Immunology andMicrobiology
3. Immunology

48

Department of Immunology
Professor
Tadatsugu Taniguchi, Ph.D.

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

Assistant Professor
Hideyuki Yanai, Ph.D.; Makoto Nakasato, Ph.D.; Hideo Negishi, Ph.D.; David Savitsky, Ph.D.

Homepage

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

Introduction and Organization
The history of the Department of Immunology,
formerly the Department of Serology, dates back to1918. The department’s adopted its present namewhen Dr. Tomio Tada, now Professor Emeritus of The
University of Tokyo, took his position in 1977 as
professor and chair of the department. Through hisinnovative research and great contributions to theinternational community of immunologists, Dr. Tadaraised the stature of the department to aworld-renowned status. After his retirement in 1994,
Dr. Taniguchi had tried to follow and improve the highstandards of the department established by Dr. Tadaby providing a first-rate education to students as wellas performing cutting-edge, internationally recognizedresearch in the field of immunology.
In the late 1970s and early 1980s, Prof. Taniguchi’s
research was the first to identify and subsequentcharacterize two cytokine genes, interferon (IFN)-β
and interleukin (IL)-2. These initial studies led to theexperimental dissection of the cytokine systems in thecontext of the regulation of immunity and oncogenesis.
One of our major contributions resulting from these
efforts was the discovery and characterization of a
new family of transcription factors, termed interferon
regulatory factors (IRFs).
While the core of our current research is aimed atclarifying the functions of IRF family members in thecontext of immunity, the broad scope of our scientificinterests encompass a number of areas including thosepertaining to innate immune system activation,
autoimmunity, oncogenesis, and others.

Teaching activities
All members of our department take our
responsibilities to teach and train the next generationof scientists very seriously. Our department provides
class work instruction through lectures on
immunobiology, immunochemistry and molecularimmunology to the undergraduate students of thefaculty, as well as practical training by way oflaboratory courses on basic immunology experimental
techniques. The education of graduate students isbased on weekly seminars during which time students
present the progress of their own research projects,
discuss the future directions of their own and theresearch of others, and are exposed to the latest,
cutting-edge research question confronting the field of
immunology. We also offer a special training course(called ‘free quarter’) of basic and advanced
biological and immunological techniques to medical
students. In addition to lectures and laboratory courses
provided by our own staff members, special seminars
on leading research activities are also given byinternationally recognized scientists from all over theworld, such as Jeffrey V. Ravetch (Professor of The
Rockefeller University).

49

Research activities
Our research interests within the fields of cellularand molecular immunology involve the extensive
analysis of the mechanisms that underlie theregulation of gene expression and signal transduction
in host defense systems, with a focus on the molecularmechanisms of the host defense against viral andbacterial infections. Among these mechanisms, theinterferon (IFN) system is one of the most importantin the control of such infections. During the course of
our studies, we have identified members of theinterferon regulatory factor (IRF) family to play anumber of critical roles in immunity. In total, ourstudies on IRFs have revealed a remarkable functional
diversity and serve as key regulators in the control of
innate immune responses. For example, we haveshown that the transcription factor IRF-7 is essential
for type I IFN production upon virus- and
TLR-activated signaling pathways. Furthermore,
IRF-5 was demonstrated by us to be critical for the
induction of pro-inflammatory cytokines andchemokine genes, which are typically activated by
TLRs in response to infections.
The exposure of DNA within the cytoplasm of acell, which can occur during the course of viral andbacterial infections, evokes strong, TLR-independent
immune responses. Recently, we have identified aprotein that functions as a cytosolic DNA sensor inthese responses. DNA-dependent activator of IRFs
(DAI) upon recognition of cytosolic DNA associateswith TBK1 kinase and IRF3 transcription factor toinduce transcription of type I IFN genes. We further
identified several important domains of DAI, andrevealed that DAI forms a multimer upon DNA
recognition to activate the down-stream signaling
pathways. We have established DAI-deficient miceand plan to investigate the physiological role of DAI.
With respect to IRF-mediated regulation of
apoptosis, we have shown that IRF-5, previously
shown by us to be important cytokine gene induction,
also regulates cellular susceptibility to apoptosis
triggered by various stimuli such as virus, DNAdamage, and death receptor Fas. In addition, we havedemonstrated that IRF-5 has tumor suppressive
activity. Therefore, IRF-5 is important for two main

aspects of immune homeostasis and host defense,
namely in generating immune responses to invading
pathogens and suppression of tumor development.
Another recent, critical finding is that IRF-1
transactivates the IL-12 receptorβ gene, thereby
supporting Th1 differentiation. These are just a small
subset of the scientific questions related to the IRF
family of transcription factors, which serves toillustrate the important role they serve in host defense
system. Future studies by our and other labs willcontinue to reveal their functions.
In addition to their roles during pathogen challenge,
type I IFNs are known to be produced at low levels in
the absence of infection. Recently, we demonstratethat a weak signal by these constitutively produced
type I IFNs plays a preventive role in cellulartransformation. IFN receptor AR1 (IFNAR1)-deficient(Ifnar1–/–) MEF, which are unable to receive signals
by type I IFNs, undergo spontaneous cellulartransformation during long-term cell culture without
any abnormal growth properties. Furthermore,
Ifnar1–/– mice develop chemically induced skinpapilloma more severely than wild-type mice and theexpression of IFNAR1 mRNA are significantly
decreased in human gastric cancer tissues.
Collectively, these findings suggest a cell-intrinsicrole of the weak signal by constitutively produced
type I IFN to prevent cells from transformation.
In addition to advancing a basic understanding of
the principles of immunology, we are also trying toestablish therapeutic strategies for the treatment ofcancer. The selective elimination of tumor cells is oneof the most important issues in cancer therapy. In thiscontext, we recently revealed that Noxa, a BH3-onlyprotein with proapoptotic activity, selectively induces
apoptosis in human tumor cells. Upon infection of arecombinant adenovirus contrived to express the Noxa
gene, apoptosis was induced in several human breast
cancer cell lines, but not in normal mammary
epithelial cells. Furthermore, intratumoral injection of
the Noxa-expressing adenovirus resulted in marked
shrinkage of the transplanted tumor without any
notable adverse effect on the surrounding normal
tissue. These data provide a new prospect for cancer
therapy by the Noxa-mediated selective elimination ofmalignant cells.

50

References(1)

Taniguchi, T.; Aimez-vous Brahms? A story capriccioso from the discovery of a cytokine family andits regulators. (2009) Nat. Immunol., 10, 447-449(2)

Yanai, H., Savitsky, D., Tamura, T. and Taniguchi,T.; Regulation of the cytosolic DNA-sensing system in innate immunity: a current view. (2009)
Curr. Opin. Immunol., 1, 17-22(3)

Suzuki, S., Nakasato, M., Shibue, T., Koshima, I.
and Taniguchi, T.; Therapeutic potential of proapoptotic molecule Noxa in the selective eliminationof tumor cells. (2009) Cancer Sci., 100, 759-769(4)Chen, H.M., Tanaka, N., Mitani, Y., Oda, E., Nozawa, H., Chen, J.Z., Yanai, H., Negishi, H., Choi,
M.K., Iwasaki, T., Yamamoto, H., Taniguchi, T. andTakaoka, A.; Critical role for constitutive type I interferon signaling in the prevention of cellulartransformation. (2009) Cancer Sci., 100, 449-456(5)

Yanai, H., Savitsky, D., Tamura, T. and Taniguchi,T.; Regulation of the cytosolic DNA-sensing system in innate immunity: a current view. (2009)
Curr. Opin. Immunol., 1, 17-22(6)

Negishi, H., Osawa, T., Ogami, K., Ouyang, X.,
Sakaguchi, S., Koshiba, R., Yanai, H., Seko, Y.,
Shitara, H., Bishop, K., Yonekawa, H., Tamura, T.,
Kaisho, T., Taya, C., Taniguchi, T. and Honda, K.;
A critical link between Toll-like receptor 3 and type
II interferon signaling pathways in antiviral innate
immunity. (2008) Proc. Natl. Acad. Sci. USA., 105,
20446-20451(7)

柳井秀元・谷口維紹, IRF ファミリー転写因子と生体防御シグナル，蛋白質核酸酵素 (2008)
53, 1231-1238, 共立出版

(8)

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.

(9)

Takaoka, A., Tamura T., and Taniguchi, T.; IRF
family transcription factors and regulation of oncogenesis. (2008) Cancer Sci. 99, 467-478.

(10) 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.
(11) 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.
(12) Takaoka, A., and Taniguchi, T.; Cytosolic DNA
recognition for triggering innate immune responses. (2008). Adv. Drug Deliv. Rev. 60,
847-57.
(13) 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 other DNA-sensing
molecules. (2008) Proc. Natl. Acad. Sci. USA 105,5477-5482.

Radiology and Biomedical
Engineering
1. Radiology

52

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

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

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

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

Masaaki Akahane, M.D.

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

Yoshitaka Masutani, Ph.D.,

Akira Kunimatsu, M.D.,Ph.D.,

Harushi Mori, M.D.

Assisstant Professor
Syuhei Komatsu, M.D.,

Shinichi Inoh, M.D.,

Kenshirou Shiraishi, M.D., Ph.D.,

Hideomi Yamashita, M.D., Ph.D.,

Jiro Sato, M.D.,

Miwako Takahashi, M.D., Ph.D.,

Soichiro Miki, 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 in cooperation with
Department of Radiology in The Research Institute ofMedical Science, which has three (1 associate professor, 1 lecturer, and 1 assistant professor) positions. In
addition, Department of Radiology mainly takes careof 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 by diagnostic 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 and reported 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
such as interventional radiology (IVR), angiography
and myelography. There are two special beds for ra-

53

dionuclide (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 and nuclear medicine. Professor, associate professors and lecturers as well as specialists assigned as part time lecturers 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 in radiation therapy against cancer. Postgraduate students arealso welcome to each of subspecialties of radiology
according to their interests.

Research activities
Research activities in our department include clinical research, animal experiments and development of
instruments as well as computer-based new technology. Diagnostic Radiology group in the department
promotes research activities aiming at efficacy improvement of diagnostic imaging and expansion of its
application. Multi-row detector helical computed tomography (MDCT) enables us to take tomographic
images in three-dimensional (3D) fashion. Using thedata acquired by MDCT various kinds of diseases inalmost all parts of the body, from cerebral diseases tomusculoskeletal diseases, can be displayed in 3D images. New 3D software developed in 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 the Faculty of Engineering,

the University of Tokyo. This section will contributeto development of novel software to abstract clinicallyuseful information from the 3D imaging data moresophisticatedly. In the field of magnetic resonance(MR) imaging, MR digital subtraction angiography,
perfusion imaging, and diffusion tensor imaging are
the foci of research. These techniques are aggressively
applied to the investigation of vascular and neoplastic
diseases of the brain. Application of an open-type MR
imaging unit to interventional radiology is anotherfield of clinical research. In our section, MR imaging
is specifically used to the treatment of vascular malformation. 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 physical engineering aspect of radiotherapy and the other is reduction of
injuries due to radiation exposure. With the purpose ofachieving 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 necktumor. Dynamic conical conformal radiotherapy (Dyconic therapy) for metastatic brain tumors using theaccelerator 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 is under investigation in collaboration
with accelerator makers. Novel approach to terminal
care of patients with various cancers has been investigated and implemented as the palliative care team incooperation 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,
University of Tokyo, and through taste tests in clinicalsetting. Radiation injuries in many tissues in the critically accident in Tokai-mura were also investigated.
Nuclear Medicine group promote clinical research

54

on images of function by the application of radioisotope-labeled tracer technology. In particular, emission
tomography (PET and SPECT) is applied for theevaluation of cerebral blood flow and metabolism inpatients with dementia, epilepsy, and cerebrovasculardiseases. Cerebral blood flow, glucose metabolism andneural synaptic functions are measured for the understanding of normal and pathophysiological states of
CNS disorders, using a variety of positron-emitterradiotracer, 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 bycomparing 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 offunction and anatomy is an essential subject for investigation. At present, whole body FDG-PET is one of
the most effective tool for exploring metastatic lesionsof 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.

References
1) Arai N, Yokochi F, Ohnishi T, Momose T,
Okiyama R, Taniguchi M, Takahashi H, Matsuda
H, Ugawa Y.
Mechanisms of unilateral STN-DBS in patientswith Parkinson's disease.
J Neurol 255: 1236-43, 2008
2) Gooya A, Liao H, Matsumiya K, Masamune K,
Masutani Y, Dohi T.
A variational method for geometric regularizationof vascular segmentation in medical images.
IEEE Trans Image Process 17: 1295-312, 20083) Hori M, Ishigame K, Shiraga N, Kumagai H, Aoki
S, Araki T.
Mean diffusivity, fractional anisotropy maps, andthree-dimensional white-matter tractography bydiffusion tensor imaging. Comparison between
single-shot fast spin-echo and single-shot echoplanar sequences at 1.5 Tesla.
Eur Radiol 18: 830-4, 2008
4) 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 tractof a heavily radiation-exposed worker at the Tokai-mura criticality accident.
J Radiat Res 49: 55-62, 2008
5) Igaki H, Maruyama K, Tago M, Shin M, Murakami N, Koga T, Nakagawa K, Kawahara N, Ohtomo K.
Cyst formation after stereotactic radiosurgery for
intracranial meningioma: a report of two cases.
Stereotact Funct Neurosurg 86: 231-6, 2008
6) Igaki H, Nakagawa K, Shiraishi K, Shiina S, Kokudo N, Terahara A, Yamashita H, Sasano N,
Omata M, Ohtomo K.
Three-dimensional conformal radiotherapy forhepatocellular carcinoma with inferior vena cava
invasion.
Jpn J Clin Oncol 38: 438-44, 2008
7) Inoue Y, Izawa K, Kiryu S, Kobayashi S, Tojo A,
Ohtomo K.
Bioluminescent evaluation of the therapeutic effects of total body irradiation in a murine hematological malignancy model.
Exp Hematol 36: 1634-41, 2008
8) 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 Neurol 65: 662-5, 2008
9) 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

5510) Kabasawa H, Masutani Y, Abe O, Aoki S, Ohtomo
K.
Quantitative diffusion tensor analysis using multiple tensor ellipsoids model and tensor field interpolation at fiber crossing.
Acad Radiol 15: 84-92, 2008
11) Kondo M, Sakuta K, Noguchi A, Ariyoshi N, Sato
K, Sato S, Sato K, Hosoi A, Nakajima J, Yoshida
Y, Shiraishi K, Nakagawa K, Kakimi K.
Zoledronate facilitates large-scale ex vivo expansion of functional gammadelta T cells from cancer
patients for use in adoptive immunotherapy.
Cytotherapy: 10: 842-56, 200812) Kunimatsu N, Aoki S, Kunimatsu A, Yoshida M,
Abe O, Yamada H, Masutani Y, Kasai K, Yamasue
H, Ohtsu H, Ohtomo K.
Tract-specific analysis of the superior occipitofrontal fasciculus in schizophrenia.
Psychiatry Res 164: 198-205, 2008
13) Kunishima K, Takao H, Kato N, Inoh S, Ohtomo
K.
Transarterial embolization of a nonpuerperal
traumatic vulvar hematoma.
Radiat Med 26: 168-70, 200814) Maruyama K, Kamada K, Ota T, Koga T, Itoh D,
Ino K, Aoki S, Tago M, Masutani Y, Shin M, Saito
N.
Tolerance of pyramidal tract to gamma knife radiosurgery based on diffusion-tensor tractography.
Int J Radiat Oncol Biol Phys 70: 1330-5, 200815) Maruyama K, Koga T, Shin M, Igaki H, Tago M,
Saito N.
Optimal timing for Gamma Knife surgery after
hemorrhage from brain arteriovenous malformations.
J Neurosurg 109(suppl): 73-6, 200816) Morooka M, Kubota K, Murata Y, Shibuya H, Ito
K, Mochizuki M, Akashi T, Chiba T, Nomura T,
Ito H, Morita T.
(18)F-FDG-PET/CT findings of granulocyte colony stimulating factor (G-CSF)-producing lungtumors.
Ann Nucl Med 22: 635-9, 200817) Nagai S, Asai T, Watanabe T, Oshima K, Hangaishi A, Kanda Y, Motokura T, Chiba S, Aoki S,
Ohtomo K, Kurokawa M.
Simultaneous appearance of central nervous sys-

tem relapse and subarachnoid hemorrhage during
the treatment for acute promyelocytic leukemia.
Ann Hematol 87: 593-5, 200818) Nakagawa K, Yamashita H, Nakamura N, Igaki H,
Tago M, Hosoi Y, Momose T, Ohtomo K, Muto T,
Nagawa H.
Preoperative radiation response evaluated by
18-fluorodeoxyglucose positron emission tomography predicts survival in locally advanced rectal
cancer.
Dis Colon Rectum 51: 1055-60, 200819) Nakagawa K, Kanda Y, Yamashita H, Nakagawa S,
Sasano N, Ohtomo K, Oshima K, Kumano K, Ban
N, Minamitani Y, Kurokawa M, Chiba S.
Ovarian shielding allows ovarian recovery andnormal birth in female Hematopoietic SCT recipients undergoing TBI.
Bone Marrow Transplant 42: 697-9, 200820) Nakagawa K, Yamashita H, Igaki H, Terahara A,
Shiraishi K, Yoda K.
Contrast medium-assisted stereotactic image-guided radiotherapy using kilovoltage
cone-beam computed tomography.
Radiat Med 26: 570-2, 200821) Nakamura N, Sasano N, Yamashita H, Igaki H,
Shiraishi K, Terahara A, AsakagT, Nakao K, Ebihara Y, Ohtomo K, Nakagawa K.
Oral pilocarpine (5mg t.i.d.) used for xerostomia
causes adverse effects in Japanese.
Auris Nasus Larynx, Epub ahead of print, 200822) Nakata Y, Sato N, Abe O, Shikakura S, Arima K,
Furuta N, Uno M, Hirai S, Masutani Y, Ohtomo K,
Aoki S.
Diffusion abnormality in posterior cingulate fiber
tracts in Alzheimer's disease: tract-specific analysis.
Radiat Med 26: 466-73, 200823) Oishi M, Miki K, Morita A, Fujioka K, Aoki S,
Nishino I, Nonaka I, Goto Y, Mizutani T.
Mitochondrial encephalomyopathy associatedwith diabetes mellitus, cataract, and corpus callosum atrophy.
Intern Med 47: 441-4, 200824) Sakai M, Aoki S, Inoue Y, Ashida R, Yamada H,
Kiryu S, Inano S, Mori H, Masutani Y, Abe O,
Ohtomo K, Nakamura H.
Silent white matter lesion in linear scleroderma en

56

coup de sabre.
J Comput Assist Tomogr 32: 822-4, 200825) Sakurai Y, Terao Y, Ichikawa Y, Ohtsu H, Momose
T, Tsuji S, Mannen T.
Pure alexia for kana. Characterization of alexia
with lesions of the inferior occipital cortex.
J Neurol Sci 268: 48-59, 200826) Sato N, Ota M, Yagishita A, Miki Y, Takahashi T,
Adachi Y, Nakata Y, Sugai K, Sasaki M.
Aberrant mid-sagittal fiber tracts in hemimegalencephaly patients.
AJNR Am J Neuroradiol 29: 823-7, 200827) 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 human homologue of Drosophila neoplastic tumor suppressor, is a novel death substratetargeted by caspase during the process of apoptosis.
Genes Cells 13: 771-85, 200828) Takao H, Shimizu S, Doi I, Watanabe T.
Primary malignant melanoma of the anterior mediastinum: CT and MR findings.
Clin Imaging 32: 58-60, 200829) Takao H, Nojo T, Ohtomo K.
Treatment of ruptured intracranial aneurysms: adecision analysis.
Br J Radiol 81: 299-303, 200830) Takao H, Nojo T, Ohtomo K.
Screening for familial intracranial aneurysms: decision and cost-effectiveness analysis.
Acad Radiol 15: 462-71, 200831) Takao H, Nojo T, Ohtomo K.
Cost-effectiveness of treatment of unruptured intracranial aneurysms in patients with a history ofsubarachnoid hemorrhage.
Acad Radiol 15: 1126-32, 200832) Takei K, Yamasue H, Abe O, Yamada H, Inoue H,
Suga M, Sekita K, Sasaki H, Rogers M, Aoki S,
Kasai K.
Disrupted integrity of the fornix is associated with
impaired memory organization in schizophrenia.
Schizophr Res 103: 52-61, 2008
33) Yamada M, Momoshima S, Masutani Y, Fujiyoshi
K, Abe O, Nakamura M, Aoki S, Tamaoki N,
Okano H.

Diffusion-tensor neuronal fiber tractography andmanganese-enhanced MR imaging of primate
visual pathway in the common marmoset: preliminary results.
Radiology 249: 855-64, 2008
34) Yamashita H, Nakagawa K, Yamada K, Kaminishi
M, Mafune K, Ohtomo K.
A single institutional non-randomized retrospective comparison between definitive chemoradiotherapy and radical surgery in 82 Japanese patients with resectable esophageal squamous cell
carcinoma.
Dis Esophagus 21: 430-6, 200835) Yamashita H, Nakagawa K, Asari T, Murakami N,
Igaki H, Ohtomo K.
Radiotherapy for 41 patients with stages I and IIMALT lymphoma: a retrospective study.
Radiother Oncol 87: 412-7, 2008
36) Yamashita H, Nakagawa K, Hosoi Y, Kurokawa A,
Fukuda Y, Matsumoto I, Misaka T, Abe K.
Umami taste dysfunction in patients receiving radiotherapy for head and neck cancer.
Oral Oncol, Epub ahead of print, 200837) Yamashita H, Kadono T, Tamaki K, Nakagawa K.
Interesting response to concurrent chemoradiation
in metastatic eccrine porocarcinoma.
J Dermatol 35: 606-7, 200838) Yamasue H, Abe O, Suga M, Yamada H, Inoue H,
Tochigi M, Rogers M, Aoki S, Kato N, Kasai K.
Gender-common and -specific neuroanatomicalbasis of human anxiety-related personality traits.
Cereb Cortex 18: 46-52, 2008
39) Yamasue H, Kakiuchi C, Tochigi M, Inoue H,
Suga M, Abe O, Yamada H, Sasaki T, Rogers M A,
Aoki S, Kato T, Kasai K.
Association
betweenmitochondrialDNA
10398A>G polymorphism and the volume of
amygdala.
Genes Brain Behav 7: 698-704, 200840) Yamasue H, Abe O, Suga M, Yamada H, Rogers
M A, Aoki S, Kato N, Kasai K.
Sex-linked neuroanatomical basis of human altruistic cooperativeness.
Cereb Cortex 18: 2331-40, 200841) Yasmin H, Nakata Y, Aoki S, Abe O, Sato N, Nemoto K, Arima K, Furuta N, Uno M, Hirai S,
Masutani Y, Ohtomo K.

57

Diffusion abnormalities of the uncinate fasciculus
in Alzheimer's disease: diffusion tensor
tract-specific analysis using a new method tomeasure the core of the tract.
Neuroradiology 50: 293-9, 200842) Yokoyama I, Inoue Y, Kinoshita T, Itoh H, Kanno
I, Iida H.
Heart and brain circulation and CO2 in healthymen.
Acta Physiol 193: 303-8, 2008
43) Yoshikawa T, Aoki S, Abe O, Hayashi N, Masutani Y, Masumoto T, Mori H, Satake Y, Ohtomo K.
Diffusion tensor imaging of the brain: effects ofdistortion correction with correspondence tonumbers of encoding directions.
Radiat Med 26: 481-7, 200844) Yoshimi A, Izutsu K, Takahashi M, Kako S,
Oshima K, Kanda Y, Motokura T, Chiba S, Momose T, Ohtomo K, Kurokawa M.
Conventional allogeneic hematopoietic stem celltransplantation for lymphoma may overcome thepoor prognosis associated with a positive
FDG-PET scan before transplantation.
Am J Hematol 83: 477-81, 200845) Yoshioka H, Horikoshi T, Aoki S, Hori M, Ishigame K, Uchida M, Sugita M, Araki T, Kinouchi
H.
Diffusion tensor tractography predicts motor
functional outcome in patients with spontaneous
intracerebral hemorrhage.
Neurosurgery 62: 97-103, 2008

Radiology and Biomedical
Engineering
2. Biomedical Engineering

59

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

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

Homepage

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 and
one lecturer.

Teaching activities
We provide lectures of “Early Exposure to
Medicine” for first year students, “Basic Principles ofBiomedical Engineering” for second and third year
students, “Introduction to Biomedical Engineering”
for postgraduate students, “Introduction to Medical
Science: Medical Engineering” for master’s students,
in the faculty of Medicine, and “Principles ofMedicine” for postgraduate students in the faculty ofEngineering. 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 andresearch fellows to discuss journal articles and give
updates on experiments. Our aim is to enhance theresearch skills of 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
to understanding 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
are analyzed 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
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 ofendothelial cells (Microvasc Res 1987, Biorheology,601990). 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
stress increases the levels of adrenomedulin andC-type natriuretic peptide mRNA which havevasodilating effects in addition to nitric oxide(Hypertension 1997), and that it also augmented theexpression of lectin like low density lipoprotein
receptor (LOX-1) at the protein and mRNA level (Circ
Res 1998). Recently, we revealed that endothelial
progenitor cells (EPCs) circulating in humanperipheral blood proliferate and differentiate into
mature endothelial cells in response to shear stress,
thereby forming tube-like structures in collagen gel (JAppl Physiol 2003). We also found that shear stressinduces the differentiation of murine embryonic stem
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). More recently, we
revealed that shear stress increased the gene
expression of the arterial EC marker ephrinB2 in
EPCs, while it decreased the gene expression of thevenous EC marker EphB4, suggesting that shear stressaffects arterial-venous differentiation of EPCs (J Appl
Physiol 2009).

(Circ Res 1988).
Differential display analysis
showed that around 600 known and unknown
transcripts were up- or down-regulated in humanumbilical vein endothelial cells exposed to a shear
stress of 15 dynes/cm2 for 6 h (BBRC 1996). Fromthese 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
that approximately 3% of the all endothelial genes,
which corresponds to about 600 genes, respond toshear stress (J Athero Thromb 2003). Recently, we
revealed that endothelial genes are differentiallyregulated by laminar and turbulent shear stress.
Laminar shear stress decreases the gene expression of
urokinase plasminogen activator (uPA), which plays arole in fibrinolysis 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 demonstrated that shear stress
up-regulates the gene expression of plasminogenactivator inhibitor-1 (PAI-1) through activation oftranscription factors Sp-1 and Ets-1 in humanhepatocytes (Am J Physiol 2006). We developed acompliant tube-type flow-loading device that allows
simultaneous application of physiological levels ofshear stress and cyclic strain to cultured cells andobserved that the response of endothelial genes toshear stress or cyclic strain depends on whether thetwo forces are applied separately or together (JBiotechnology 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

3. Shear stress signal transduction
We first showed that Ca2+ signaling 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 stress61

generated 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
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 Nat’l 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 miceand observed 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).
Our recent study revealed that cell surface ATPsynthase localized in caveolae/lipid rafts are involvedin the shear-stress-induced ATP release by ECs (Am J
Physiol 2007).

References(1) Obi S, Yamamoto K, Shimizu N. Kumagaya T,
Masumura T, Sokabe T, Asahara T, and Ando J.
Fluid shear stress induces arterial differentiation ofendothelial progenitor cells. J Appl Physiol 2009;
106:203-211.
(2) Huang H, Zhou Y-M, Takamizawa K, Ishibashi-Ueda H, Ando J, Kanda K, Yaku H, and Nakayama Y. In vitro maturation of “Biotube” vascular grafts induced by a 2-day pulsatile flow loading. J Niomed Mat Res. (in press)(3) Koga M, Sudo R, Abe Y, Yamamoto K, Ando J,
Ikeda M, and Tanishia K. Contribution of rat endothelial progenitor cells on three-dimensional
network formation in vitro.

Tissue Eng.

(inpress)(4) 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.
(5) 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.
(6) 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.
(7) 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.
(8) 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.
(9) 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.
(10) 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.
(11) Ichioka S, Ando T, Shibata M, Sekiya N,
Nakatsuka T. Oxygen consumption of keloids andhypertrophic scars. Ann Plast Surg 2007; 60:
194-197.
(12) 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 andCommunications 2007; 1: 4-7.
(13) Nakagami G, Sanada H, Matsui N, Kitagawa A,
Yokogawa H, Sekiya N, Ichioka S, Sugama J,
Shibata M. Effect of vibration on skin blood flow

62

in an in vivo microcirculatory model. BioScience
Trends 2007; 1: 161-166.
(14) 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.

63

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. Our doctor course students havethe opportunity to perform research work under theguidance of Prof. Mabuchi at Department ofInformation Physics and Computing, Graduate Schoolof Information Science and Technology.

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 for the 3rd and 4th year medical students. In
systematic lectures, basic knowledge for the advanced
diagnostic and therapeutic medical engineering

technologies are presented. The basic lectures ofartificial organ technologies 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 hightechnologies for basic and clinical medicine arepresented.
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, andmuch 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.
Students must attend to weekly meeting. They canlearn how to perform the research work and how toreport it through this meeting.

Research activities
Our research field covers advanced diagnostic andtherapeutic medical engineering high technologies for64

clinical 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, anatomical compatibility, hemocompatibility,
tissue compatibility, computer fluid dynamics,
physiology, pathology, and so on, have been studied.
All the stuffs and students are participating in theartificial heart project. In 1995, we succeeded tosurvive a goat for 532 days with the paracorporeal
total artificial heart (TAH), which is still the longest
survival record of TAH animals in the world.
Our artificial heart research at present is to develop an
implantable
TAH.
We
inventedasmall
continuous-flow blood pump with high performance,
named undulation pump, to meet the purpose. We
are developing an undulation pump total artificial
heart (UPTAH) using undulation pumps. The UPTAH
is the most 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 suchas venous hypertension, slight anemia, low thyroid
hormone level, and so on, were not observed and theoutput was changed in accordance with a metabolic
condition of the animal.
1/R control was installed in the UPTAH and thepathphysiological study was performed with
nonpulsatile TAH. The result showed that 1/R control
could be possible not only with a pulsatile TAH, butalso with a nonpulsatile TAH. The general conditionand organ function were not changed by theapplication of the nonpulsatile mode. Cardiac output
and arterial pressure changed with the condition of thegoat in pulsatile and also in nonpulsatile modes, which
seemed almost identical. However, the sucking effectof atria was very significant in the nonpulsatile mode,
resulted in hemolysis. Therefore, nonpulsatile TAH
with 1/R control was considered to be inadequate,
unless some pulsatility would be introduced to avoid
fatal sucking effect for ensuring sufficient inflow
condition.
A project of ELSS (Emergency Life Support System)that is a compact PCPS (Percutaneous cardio
pulmonary support) device for emergency use has
been started in 2004. The device consists of blood
pump, oxygenator, drive and control unit and battery
unit. A new membrane oxygenator and a new bloodpump were designed and fabricated in one piece. An
experimental model exhibited good performance.
The whole system components are packed in a casehaving 180 mm in diameter and 390 mm long. The
whole weight will be less than 10 Kg.
Concerning the biomaterials, the mechanisms ofthrombus formation and calcification on the medical
polymer surfaces have been studied. Recently, wedeveloped the new hybrid technique. In general, it was
not easy to develop the mechanical components of
implantable artificial organs from the components ofliving tissue because strength and durability are notenough. To overcome the problem, a tissue engineered
insert molding method for making parts of artificialorgans was introduced. In the method, the mold inwhich the artificial material is inserted was implantedin the animal, and the tissue grew into the mold to
make the hybrid parts. The method was applied to the
Jellyfish valve. The hybrid Jellyfish valve
demonstrated a possibility of the method for practicaluse. This hybrid biomaterial technique will be
important technology 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 of

65

the microcirculation with TAH. This device has madea remarkable progress to make a next generation
device. The new implantable probe can observe
angiogenesis in tissue-engineered material using
CMOS camera. In this method a scaffold was attachedto the camera and implanted in the animal. The
camera succeeded to observe the real-time growth oftissue and micro vessels in the scaffold. This
technique will give important information for thestudies of tissue engineering and regenerative
medicine as well as implantable artificial organs.
Nerve interface will be very important technology fordeveloping control mechanism of artificial organs.
The basic study to develop a multiple interface arrayfor brain machine interface is being studied.

References
1. Abe Y, Saito I, Isoyama T, Miura H, Shi W,
Yamaguchi S, Inoue Y, Nakagawa H, Ono M,
Kishi A, Ono T, Kouno A, Chinzei T, Imachi K. A
nonpulsatile total artificial heart with 1/R control.
J Artif Organs. 2008;11:191-200.
2. Saito I, Chinzei T, Isoyama T, Miura H, Kouno A,
Ono T, Nakagawa H, Yamaguchi-Sekino S, Shi W,
Inoue Y, Kishi A, Abe Y. Implementation of the
Natural Heartbeat Synchronize Control for the
Undulation Pump Ventricular Assist Device Using
the Inflow Pressure. IFMBE Proceedings.
2008;19:62-65.
3. Shi W, Saito I, Chinzei T, Isoyama T, Miura H,
Kouno A, Ono T, Nakagawa H, Yamaguchi S,
Inoue Y, Kishi A, Abe Y. Development of anauto-calibration method for the implantable bloodpressure sensor in the undulation pumpventricular assist device (UPVAD). IFMBE
Proceedings. 2008;19:66-69.
4. Kishi A, Isoyama T, Saito I, Miura H, Inoue Y,
Yamaguchi S, Shi W, Abe Y, Imachi K, Noshiro M.
Artificial organ made in vivo Jellyfish valve,
valve leaflet. ISBPE Proceedings. 2008;339-342.
5. Inoue Y, Nakagawa H, Saito I, Isoyama T, Miura
H, Kouno A, Ono T, Yamaguchi S, Shi W, Kishi A,
Abe Y, Imachi K. In Vivo Observation of Tissue
Induction within an Animal Body. ECSTransaction. 2008;16(17):21-27
6. Fukayama O, Taniguchi N, Suzuki T, Mabuchi K.

A flexible parylene neural probe combined with amicrodialysis membrane. Proc. of 30th Annual
International Conference of the IEEE EMBS.
2008;5322-5325

Neuroscience
1. Basic Neuroscience67

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

Associate Professor
Lecturer
Associate
Genta Ito, M.Sc.
Tomoko Wakabayashi, Ph.D.

Homepage
Dr. Iwatsubo’s research group has been pursuing
the pathogenesis of Alzheimer’s disease (AD) andrelated neurodegenerative conditions (especially, dementia with Lewy bodies; DLB) by multidisciplinary
approaches, based on histopathology and protein biochemistry of postmortem human brains. They thenextended the knowledge derived from the human studies in a way to establish cellular models and to elucidate the key steps in the pathological cascade ofneurodegeneration. Thus, Dr. Iwatsubo’s group has
been addressing the pathogenesis of neurodegenerative 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 thisway Dr. Iwatsubo’s group has contributed much to thewidely accepted notion that abnormal misfolding of
brain proteins is the common cause of a variety ofneurodegenerative disorders including AD. Furthermore, Dr. Iwatsubo’s group is currently working hardto translate the basic findings into the clinical application of mechanism-based, disease-modifying therapies
for AD through the world-wide ADNI project, inwhich 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) ending at
40th or 42nd residues (Aβ40 and Aβ42, respectively),
Dr. Iwatsubo has performed a systematic immunohistochemical studies on autopsied brain tissues frompatients with AD, Down syndrome and familial AD,
and demonstrated that Aβ42, that most readily form
amyloid fibrils in vitro, is the initially and predominantly deposited species in human cerebral
β-amyloidosis (Iwatsubo et al. Neuron 1994, Ann
Neurol 1995). Dr. Iwatsubo’s group then establishedcelllar 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 clearly shown that an increasein the production of Aβ42 is the pathogenic mechanism leading to FAD (Tomita et al. Proc Natl Acad Sci
USA, 1997). These findings have provided a firm basis for the currently prevailing β-amyloid hypothesis.
They then focused on the mechanisms of γ-secretase
complex that cleaves the C terminus of Aβ, and set out
to cell biological studies using RNA interference on
the formation and function of the γ-secretase complex

68

harboring PS as the catalytic center, associated withthree additional membrane proteins. They demonstrated that APH-1 and Nicastrin serve as the “stabilizing” co-factor of PS, whereas PEN-2 is the component that confers proteolytic activity to this complex.
They also showed that PS, APH-1, nicastrin and
PEN-2 are the essential set of proteins that comprisethe γ-secretase complex (Takasugi et al. Nature, 2003).
This study is highlighted as a milestone work that elucidated the mechanistic roles of protein cofactors in
the formation and function of γ-secretase (see reviews;
Iwatsubo Mol Psychiatr, 2004; Curr Opin Neurobiol,2004). His group has also shown by establishing invitro 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 therapeutic strategies 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 the submolecular structure of thiscomplex by single-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 ofγ-secretase complex by cystein chemistry, and demonstrated that γ-secretase harbors a water-permeable
catalytic pore (Sato et al. J Neurosci, 2006), and that
substrate proteins enter the catalytic pore through thelateral gate located at the C terminal side of PS (Satoet 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, thatproved to play a key role in the important biologicalreaction termed “intramembrane proteolysis”.
2. Identification and characterization of α-synuclein asa major component of Lewy bodies.
Using cortical Lewy bodies purified from postmortem brains of patients with dementia with Lewy
bodies (DLB) by his original method (Iwatsubo et al.
Am J Pathol 1996) as immunogens, Dr. Iwatsubo’sgroup, in collaboration with Drs. Virginia Lee andJohn Trojanowski at Univ. Penn, performed an extensive immunochemical search for components of Lewy
bodies. They have demonstrated by raising a specificmonoclonal antibody that α-synuclein, that proved 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 thenpurified aggregated α-synuclein from DLB cortices
using fine biochemical techniques, purified it to near
homogeneity, and demonstrated using mass spectrometry and specific antibodies that α-synuclein deposited in synucleinopathy lesions is highly phosphorylated at a specific serine residue (Fujiwara et al. Nature Cell Biol 2002). This finding led to a range ofstudies focusing on the role of synuclein phosphorylation in neurodegeneration. Also, the phospho-specificα-synuclein antibody is widely used as the most sensitive marker for α-synucleinopathy lesions, and they
have characterized a wide spectrum of α-synuclein
pathologies in neurodegenerative 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-Aβ
components that potentially affect fibrillization anddegradation of amyloid deposits. Among these, there
has been an enigmatic “missing piece” protein of molecular masses of 50/100 kDa. Dr. Iwatsubo’s groupraised a monoclonal antibody against amyloid fractionthat recognizes this protein, and using this antibody as
a probe, they conducted a thorough biochemical purification of these antigens and finally cloned a cDNA
coding for the precursor of this protein. This protein
turned out to be a novel class of membrane-boundcollagen, 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 ofAD research as well as on general biology as a first
discovery of neuron-specific collagen harboring aunique membrane-spanning structure. CLAC has beenhighlighted as a protein that may affect fibrillizationof Aβ and contribute to amyloid plaque formation.
Indeed, he has recently shown that CLAC-positive

69

senile plaques constitute a unique subset of plaques
distinct from the classical, β-sheet-rich amyloid deposits, underscoring the pathobiological 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 micestudies are confirming the role of CLAC in the morphogenesis of senile plaques in vivo.
4. Japanese ADNI: clinical studies for the identification of surrogate imaging and biomarkers 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 the principal investigator on 2006, recruiting 35 clinical sites
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) Takatori S. Ito G, Iwatsubo T: Cytoplasmic localization and proteasomal degradation of
N-terminally cleaved form of PINK1. Neurosci
Lett 430:13-17, 2008
2) Kumano K, Masuda S, Sata M, Saito T, Lee S-Y,
Sakata-Yanagimoto M, Tomita T, Iwatsubo T,
Natsugari H, Kurokawa M, Ogawa S, Chiba S.
Both Notch1 and Notch2 contribute to the regulation of melanocytehomeostasis. Pigment Cell &Melanoma Research 21:70-78, 2008
3) Wakamatsu M, Ishii A, Iwata S, Sakagami J, Ukai
Y, Ono M, Kanbe D, Muramatsu S-i, Kobayashi K,
Iwatsubo T, Yoshimoto M: Selective loss of nigral
dopamine neurons induced by overexpression oftruncated human α-synuclein in mice. Neurobiol
Aging 29:574-585, 2008
4) Ikeuchi T, Kakita A, Shiga A, Kasuga K, Kaneko

H, Tan C-F, Idezuka J, Wakabayashi K, Onodera
O, Iwatsubo T, Nishizawa M, Takahashi H, Ishikawa A: Homozygous and heterozygous patientsfor SNCA duplication in family with parkinsonism and dementia. Arch Neurol 65:514-519, 2008
5) Perry G, Zhu X, Babar AK, Siedlak SL, Yang Q,
Ito G, Iwatsubo T, Smith MA, Chen SG: Leucine-rich repeat kinase 2 colocalizes with
α-synuclein in Parkinson's disease, but not
tau-containing deposits in tauopathies. Neurodegener Dis 5: 222-224, 2008
6) Akanuma SI, Ohtsuki S, Doi Y, Tachikawa M, Ito
S, Hori S, Asashima T, Hashimoto T, Yamada K,
Ueda K, Iwatsubo T, Terasaki T: ATP-binding
cassette transporter A1 (ABCA1) deficiency does
not attenuate the brain-to-blood efflux transport ofhuman amyloid-β peptide (1-40) at the bloodbrain barrier. Neurochem Int 52:956-961, 2008
7) Yoshihara T, Takiguchi S, Kyuno A, Tanaka K,
Kuba S, Hashiguchi S, Ito Y, Hashimoto T, Iwatsubo T, Tsuyama S, Nakashima T, Sugimura K:
Immunoreactivity of phage library-derived humansingle-chain antibodies to amyloid β conformers
in vitro. J Biochem 143:475-486, 20088) Obi, K Akiyama H, Kondo H, Shimomura Y, Hasegawa M, Iwatsubo T, Mizuno Y, Mochizuki H:
Relationship of phosphorylated α-synuclein andtau accumulation to Aβ deposition in the cerebral
cortex of dementia with Lewy bodies. Exp Neurol
210:409-420, 20089) Ichibangase T, Saimaru H, Takamura N, Kuwahara T, Koyama A, Iwatsubo T, Imai K: Proteomics
of Caenorhabditis elegans overexpressing human
α-synuclein analyzed by FD-LC-MS/MS method:
actin and several ribosomal proteins were identified as negative markers at early Parkinson’s disease stages. Biomedical Chromatography 22:232234, 2008
10) Sato C, Takagi S, Tomita T, Iwatsubo T: The
C-terminal PAL motif and transmembrane domain
9 of presenilin 1 are involved in the formation of
the catalytic pore of the γ-secretase. J Neurosci
28: 6264-6271, 2008
11) Cheung K-H, Shineman D, Muller M, Cardenas C,
Mei L, Yang J, Tomita T, Iwatsubo T, Lee VM-Y,
Foskett K: Mechanism of Ca2+ disruption in
Alzheimer’s disease by presenilin regulation of

70

InsP3 receptor channel gating. Neuron 58:871-883,
200812) Laras Y, Pietrancosta N, Tomita T, Iwatsubo T,
Kraus JL: Synthesis and biological activity ofN-substituted
spiro[benzoxazepine-piperidine]Aβ-peptide production inhibitors. J Enzyme Inhib
Med Chem 7:1, 200813) Lo Bianco C, James Shorter C, Régulier E, Lashuel H, Iwatsubo T, Lindquist S, Aebischer P:
Hsp104 antagonizes α-synuclein aggregation andreduces dopaminergic degeneration in a rat modelof Parkinson’s disease. J Clin Invest 118:30873097, 2008
14) Beach TG, White CL, Hamilton RL, Duda JE,
Iwatsubo T, Dickson DW, Leverenz JB, Roncaroli
F, Buttini M, Hladik CL, Sue LI, Noorigian JV,
Adler CH: Evaluation of α-synuclein immunohistochemical methods used by invited experts. Acta
Neuropathol 116:277-288, 2008
15) Kuwahara T, Koyama A, Koyama S, Yoshina S,
Ren C-H, Kato T, Mitani S, Iwatsubo T: Alarge-scale RNA interference screen identifies
endocytic pathway genes as modifiers of
α-synuclein toxicity in transgenic Caenorhabditis
elegans. Human Molecular Genetics 17:29973009, 200816) Ikemura M, Saito Y, Sengoku R, Sakiyama Y,
Hatsuta H, Kanemaru K, Sawabe, M, Arai T, Ito G,
Iwatsubo T, Fukayama M, Murayama S: Lewy
body pathology involves cutaneous nerves. J
Neuropathol Exp Neurol 67:945-953, 200817) Yamada K, Hashimoto T, Yabuki C, Nagae Y, Tachikawa M, Strickland DK, Liu Q, Bu G, BasakJM, Holtzman DM, Ohtsuki S, Terasaki T, Iwatsubo T: The low density lipoprotein receptor-related protein 1 mediates uptake of amyloid β
peptides in an in vitro model of the blood-brain
barrier cells. J Biol Chem 283: 34554-34562,
200818) Qiao L, Hamamichi S, Caldwell KA, Caldwell
GA, Yacoubian TA, Wilson S, Xie ZL, Speake LD,
Parks R, Crabtree D, Liang Q, Crimmins S,
Schneider L, Uchiyama Y, Iwatsubo T, Zhou Y,
Peng L, Lu YM, Standaert DG, Walls KC, Shacka
JJ, Roth KA, Zhan J: Lysosomal enzyme cathepsin D protects against α-synuclein aggregation andtoxicity. Molecular Brain 1:17, 2008

71

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 spectrumof the molecular changes in the neurons that undergo
heavy or patterned electrical activity? What are themolecular rules that govern these local and globalchanges, both electrical and chemical? How are these
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, especially during
signaling from synapse-to-nucleus, and back from
nucleus-to-synapses.
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on bothsides of the synapses, in the dendritic spines and inaxon terminals.
Following the retirement of Professor Tatsuya Haga
(who became the President of Life Sciences Instituteat 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 inAugust 2001, Associate Professor Haruhiko Bito was
appointed as Head of Department since January 2003.
The Department is located on the 6th floor, in the Westwing of the third building of the Medical School. The
Department currently enrolls one associate professor,
two assistant professors, two postdoctoral scholars,

72

one technical staff member, two Ph.D. and two
M.S.-Ph.D. graduate students, three rotating medical
students, three technical assistants 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 (onehour);
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 calciumdependent synaptic modification, especially during
signaling from synapse-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 cascade in triggering synapticallystimulated nuclear CREB phosphorylation in
hippocampal neurons. The extreme biochemical
efficacy and the relative poor frequency-dependenceof this signaling cascade, in combination with therobust correlation between prolonged pCREB
response and downstream gene expression led us topropose that CaMKK/CaMKIV/pCREB cascade was
likely to act as a critical temporal integrator for
activity-dependent gene expression in excitatoryneurons (Bito et al., Cell, 1996; Bito et al., Curr. Opin.
Neurobiol., 1997; Bito, Cell Calcium, 1998). Thishypothesis has now been critically tested in various
brain
systems
andindeedpCREBimmunofluorescence is now considered as a universal
marker for integrated synaptic activity that is moresensitive than that of c-Fos. Furthermore,
CaMKIV-KO, CaMKK-KO and CaMKIV-dominant

73

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 and TakemotoKimura, Cell Calcium 2003). This hypothesis is now
being tested.
One parallel branch of CaMK signaling that has notbeen 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; Fuse et al. in press), we identified anovel CaMKI isoform that contained a C-terminal
CAAX lipid modification motif (Takemoto-Kimura etal., J. Biol. Chem., 2003). This novel membranebound CaMK (CLICK-III/CaMKI) is most expressedin the central nucleus of the amygdala and in theventral medial hypothalamus, while also being present
at a much weaker amount in most central neurons.
Ongoing biochemical and cell biological studies
indicate a critical role for lipidification of this kinase
to be properly sorted into specific lipid-restricted
membrane microdomains. The function played by thislipidified, membrane-inserted CaMK in circuitry
formation and maturation was scrutinized using RNAinterference. Along with the identification of thecritical lipid-modifying enzyme that controls
lipid-anchoring of this kinase, we discovered a novel
activity-regulated
mechanism
whererby
CLICK-III/CaMKI is actively sorted into dendritic
lipid rafts, where it specifically regulates
Rac-mediated actin remodeling that 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 ofsynapse-specific local changes. Neurons undergoing
various stimulus patterns have been followed up intime and the amount of newly synthesized proteins
and the local distribution of induced gene products
have been monitored. Using state-of-the-art multiwavelength fluorescence imaging techniques, we are
now quantitatively assessing how local distribution ofthese 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 bothsides of the synapses, in the dendritic spines and inaxon 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74

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 former was entirely dependent on NMDAdependent Ca2+-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 to trigger a complex spatiallysegretated patterns of actin cytoskeletal reorganization,with variable impact on either 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-1 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-1 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 determined

75

that protein-protein interaction was key to determining
the physical distance between the synaptic vesicles in
the active zone and the voltage-gated calcium
channels in its vicinity, the opening of which triggers
their release (Kiyonaka et al., Nature Neurosci.,2007).

Publications by lab members(April 2006 - March 2007)
1. Ohmae S, Takemoto-Kimura S, Okamura M,
Adachi-Morishima A, Nonaka M, Fuse T, Kida S,
Tanji M, Furuyashiki T, Arakawa Y, Narumiya S,
Okuno H, Bito H. Molecular identification andcharacterization of a family of kinases withhomology to Ca2+/calmodulin-dependent protein
kinases I/IV. J. Biol. Chem. 281: 20427-20439,
2006.
2. Uemura K, Kihara T, Kuzuya A, Okawa K,
Nishimoto T, Bito H, Ninomiya H, Sugimoto H,
Kinoshita A, Shimohama S. Activity-dependent
regulation of -catenin via -cleavage ofN-cadherin. Biochem Biophys Res Commun.
345: 951-958, 2006
3. Kuriu T, Inoue A, Bito H, Sobue K, Okabe S.
Differential control of postsynaptic density
scaffolds via actin-dependent and independent
mechanisms. J. Neurosci. 26: 7693-7706, 2006.
4. Yamana N, Arakawa Y, Nishino T, Kurokawa K,
Tanji M, Itoh RE, Monypenny J, Ishizaki T, Bito
H, Nozaki K, Hashimoto K, Matsuda M,
Narumiya S. Rho-mDia1 pathway regulates cell
polarity and focal adhesion turnover in migrating
cells through mobilizing APC and c-Src. Mol.
Cell Biol. 26: 6844-6858, 2006.
5. SatoK,
Suematsu
A,
Nakashima
T,
Takemoto-Kimura S, Aoki K, Morishita Y,
Asahara H, Ohya K, Yamaguchi A, Takai T,
Kodama T, Chatila TA, Bito H, Takayanagi H.
Regulation of osteoclast differentiation andfunction by the CaMK-CREB pathway. NatureMed. 12: 1410 - 1416, 2006.
6. 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.
7. 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-associated Ca2+/
calmodulin-dependent protein kinase CLICK-III/
CaMKI. Neuron, 54: 755-770, 2007.

76

Department of Neurobiology
Professor
Kenzo Hirose, M.D.,Ph.D.

Homepage http:// www.neurobiol.m.u-tokyo.ac.jp/
Introduction and Organization
The forerunner of Department of Neurobiology is
Department of psychology in Institute of Brain
Research, Faculty of Medicine, University of Tokyo.
Department of psychology was changed to
Department of Neurobiology in 1984. In 2008, Dr.
Kenzo Hirose from Department of Cell Physiology in
Nagoya University was appointed as a new professor.

Teaching activities
We accept Free-Quarter students. Students are
expected to experience various experimental
techniques including basic fluorescence imaging
techniques in living cells as well as cutting-edge
technologies developed in our lab, based on theirinterests. For the training of Master and Ph.D. course
graduated school students, we have a monthly
progress report for discussing current research
activities by each member who summarizes his/her
recent experimental data. Further, we have a weekly
journal club to present papers closely related tomember’s research field. Moreover, we have aseminar by domestic and foreign guest researchers toextend our knowledge.

Research activities
A goal of our research is to elucidate regulation
mechanisms of cell function through newdevelopment of novel technologies.
The mainsubjects of our research are as follows
1) Development of novel strategy for generating
fluorescent probes for live cell imaging

Imaging techniques which visualize signaling
molecules in living cells is a powerful method tounderstand the mechanism underling physiological
functions. To facilitate this process, we developed ahigh-throughput screening system based on 96-wellplate format protocol. After screening, we obtained
glutamate indicators consisting of many combinationsof the cysteine mutant and the fluorescent dye
showing large fluorescence changes upon glutamate
binding. This result suggests that our screening systemshould be applicable to develop the fluorescentindicator for other signaling molecules as well as forglutamate in short periods.
2) Study of synapse physiology by glutamate
imaging technique
In mammalian central nervous system, direct imagingof neurotransmission should greatly contribute toclarify exocytosis dynamics at synapses and improve
our understanding of the mechanisms in synaptictransmission. Aiming at imaging glutamate, wedeveloped a novel optical glutamate probe by our
high-throughput screening system. We successfully
visualized released glutamate following presynaptic
firing with a single synapse resolution. These results
indicate that our glutamate probe is useful to study
presynaptic modulation and plasticity. To clarify the
dynamics of exocytosis in an excitatory synapse, we
tried to quantitatively analyze released glutamate atindividual synapses. Our results suggest that single
hippocampal synapses contain several release units.
3) Study of regulation mechanism of cell movementby fluorescent imaging of Rho family proteins
We have constructed new fluorescent indicators for
Rho family, including Rho, Rac and Cdc42, which

77

function as molecular switches in many signalingcascades. These indicators revealed spatial-temporal
dynamics of Rho family activation in randomly
migrating HT1080 cells. In contrast to previous
studies, Rho and Cdc42 were activated in broad areasof the plasma membrane in motile cells. Therefore,
our probes can be used for more effective andquantitative study for cell movement.
4) Novel technology for construction of genomewide RNAi library
RNA interference(RNAi)

using

short

hairpinRNA-expressing vectors (shRNA vectors) is a
powerful maneuver for functional genomics. We havepreviously

reportedamethodcalledEPRIL(enzymatic production of RNAi library) by whichshRNA vectors are produced from a cDNA fragment
through multiple enzyme reactions. Recently, we have
tried to improve the original EPRIL method to enable
constructing a genome-wide RNAi library. The
improved EPRIL method was successfully adapted to
96-well plate format which allows high-throughput
production of shRNA vectors. we concluded that
improved EPRIL method was applicable to productionof genome-wide RNAi library.

References
Yogo T, Urano Y, Mizushima A, Sunahara H, Inoue T,
Hirose K, Iino M, Kikuchi K, Nagano T. Selective
photoinactivation of protein function throughenvironment-sensitive switching of singlet oxygen
generation by photosensitizer. Proc Natl Acad Sci U S
A. 105, 28-32, 2008

Neuroscience
2. Speech and Cognitive Sciences

79

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 prominent cognitive functions distinguishing human being from nonhuman animals. The Department of Cognitive Neuroscience aims at basic, interdisciplinary studies onhuman 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 have identified 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 the causalityof 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 a person 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 demonstrate that thebrain is the cause of our cognition.
To answer these questions we are using various beha-

80

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

References
1. Sakai K. Task set and prefrontal cortex. Annual
Review of Neuroscience 31:219-245, 2008.

Neuroscience
3. Clinical Neuroscience82

Department of Neuropsychiatry
Professor
Kiyoto Kasai, M.D., Ph.D.

Associate Professor
Nobuo Nakayasu, M.D., Ph.D.,

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

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

Lecturer
Chihiro Kakiuchi, M.D., Ph.D.,

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

Research Associate
Seiichiro Jinde, M.D., Ph.D.,

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

Tsuyoshi Araki, M.D., Ph.D.,

Takuji Nishida, M.D.,

Tsuyoshi Okamura, M.D., Ph.D.,

Kenji Kirihara, M.D., Ph.D.,

Motomu Suga, M.D.

Junichi Terai, M.D.

Satisgu Ogura, M.D.,

Norichika Iwashiro, M.D.

Yuko Okada, M. D.

Ayako Todokoro, 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
Departmentof
Neuropsychiatry
providesawide-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,

83

from behavioral therapy to cognitive development
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 end ocrine di srupter- 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 Res earch- 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84

infantile autism. Another focus is investigation ofgenes 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 P harmacology- 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
stateinSchizophrenia.
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:

2

3

4

5

6

7

8

9

Aging in the CNS: comparison of gray/whitematter volume and diffusion tensor data.
Neurobiol Aging, in press.
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
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
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
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
Ebisawa T: Circadian rhythms in the CNS andperipheral clock disorders: Human sleep disorders
and clock genes. J Pharmacol Sci, in press
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
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
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
11[ C]DAA1106. J Cereb Blood Flow Metab:
Published online, in press

85

10 Kaneko N. Kudo K. Mabuchi T. Takemoto K.
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.

86

Psychiatr Serv 57: 1203-1205, 2006
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 with

87

schizophrenia: a potential link between
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

88

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 establishedby 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 thepatients with highly advanced clinical practice as wellas on clinical activities 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 forthe 4th and 5th grade medical students, and bed-side
learning for the 5th grade medical students, andclinical clerkship for 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89

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 ofthe 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 completed the program. Following the
21st Century COE program, we started “Global Centerof Education and Research for Chemical Biology of
the Diseases” as a Global COE program, in 2008.

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 discovered that glucocerebrosidase gene (GBA)
confers a strong risk with an odds ratio of 28.0 forsusceptibility to Parkinson disease. We have initiatedmulticenter-based consortium for multiple system
atrophy. A large-scale genome-wide analyses arebeing conducted to identify disease susceptibility
genes. We have established excellent animal models

fordentatorubral-pallidoluysian
atrophy,andconducting studies for development of therapeutics.
As the new protein degradation pathway, the role ofautophagy 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., Hahimoto, A)
We have demonstrated that RNA editing ofglutamate receptor subunit GluR2 due to underactivityof ADAR2, an RNA editing enzyme, 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.
(Kwak, S., Hideyama, T., Yamashita, T.,Awabayashi,K., Ymada Y.)
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 thetherapeutic mechanisms for DBS in the patients. We
have also recently developed a new, highly effective
TMS method to induce long-term effects on thehuman brain using repetitive, monophasic magnetic
stimuli. We have just stared a project to treat patientswith movement disorders, intractable pain, epilepsy
and so on using that new treatment. (Terao, Y.,
Hanajima, R., Okabe, S., Terada, S., Yugeta, A.,
Hamada, M., Matsumoto, H., Furubayashi, T.,
Higashihara, M., Shirota, Y, Ohminami, S.)
In the field of neuromuscular diseases, we
provide pathological diagnosis of biopsied materials
from patients with myopathy or neuropathy. We also
provide autoantibody testing for anti-gangliosideantibodies,musclespecific
antibodies
andparaneoplastic neurological antibodies. In research
field, using biopsied muscles and collected serum
samples, we have been studying the mechanisms ofinflammatory myopathies especially in polymyositis,

90cancer associated myositis, dermatomyositis, collagendisease associated myositis and myositis withautoantibodies. We have also been studying themechanism of muscle fiber regeneration in various
myopathies including inclusion body myositis. We
aim to increase understanding of the etiology andpathogenesis of neuromuscular diseases. (Shimizu, J.,
Hashimoto, H., Kubota, A.,Tokimura, N., Sagishima,M., Mashiko, R.).

Publication
1. 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
2. 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
3. Buckingham SD, Kwak S, Jones AK, Blackshaw
SE, Sattelle DB: Edited GluR2, a gatekeeper for
motor neuron survival? BioEssays 30:1185-1192,
2008.
4. Flanagan JR, Terao Y, Johansson RS. Gazebehavior when reaching to remembered targets. J
Neurophysiol. 100:1533-43, 2008.
5. Fukuda Y, Nakahara Y, Date H, Takahashi Y, GotoJ, Miyashita A, Kuwano R, Adachi H, Nakamura
E, and Tsuji S. SNP HiTLink: a high-throughput
linkage analysis system employing dense SNP
data. BMC Bioinformatics 10:121 doi:10.1186/
1471-2105- 10-121, 2009
6. Furubayashi T, Terao Y, Arai N, Okabe S,
Mochizuki H, Hanajima R, Hamada M, Yugeta A,
Inomata-Terada S, Ugawa Y. Short and long
duration transcranial direct current stimulation(tDCS) over the human hand motor area. Exp
Brain Res. 185:279-86, 2008.
7. Furubayashi T, Ushiyama A, Terao Y, Mizuno Y,
Shirasawa K, Pongpaibool P, Simba AY, Wake K,
Nishikawa M, Miyawaki K, Yasuda A, Uchiyama
M, Yamashita HK, 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 W-CDMA mobile
phone base station exposure on women with orwithout mobile phone related symptoms.
Bioelectromagnetics. 30:100-13, 2009.
8. 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. 586:3927-47, 2008
9. Hanajima R, Okabe S, Terao Y, Furubayashi T,
Arai N, Inomata-Terada S, Hamada M, Yugeta A,
Ugawa Y. Difference in intracortical inhibition of
the motor cortex between cortical myoclonus andfocal hand dystonia. Clin Neurophysiol. 119:1400-7, 2008.
10. Hara K, Shiga A, Fukutake T, Nozaki H,
Miyashita A, Yokoseki A, Kawata H, Koyama A,
Arima K, Takahashi T, Ikeda M, Shiota H, Tamura
M, Shimoe Y, Hirayama M, Arisato T, Yanagawa
S, Tanaka A, Nakano I, Ikeda S, Yoshida Y,
Yamamoto T, Ikeuchi T, Kuwano R, Nishizawa M,
Tsuji S, Onodera O. Familial Ischemic Cerebral
Small-Vessel Disease, Alopecia, and Spondylosis
Caused by Mutations in the HTRA1 Gene. New
Engl J Med 360:, 1729-1739, 2009
11. Hara K, Kokubo Y, Ishiura H, Fukuda Y,
Miyashita A, Kuwano R, Sasaki R, Goto J,
Nishizawa M, Kuzuhara S, and Tsuji S. TRPM7 is
not associated with amyotrophic lateralsclerosis-parkinsonism dementia complex in theKii peninsula of Japan. Am. J. Med. Genet. (inpress)
12. 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
13. Iwata A, Nagashima Y, Matsumoto L, Suzuki T,
Yamanaka T, Date H, Deoka K, Nukina N, Tsuji S.
J Biol Chem. (in press) 2009 Feb 13. [Epub aheadof print]
14. Iwata NK, Aoki S, Okabe S, Arai N, Terao Y,

91

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
15. Dick Krueger KA, Tsuji S, Fukuda Y, Takahashi Y,
Goto J, Mitsui J, Ishiura H, Dalton JC, Miller MB,
Day JD, Ranum LPW. SNP Haplotype Mapping in
a Small ALS Family. PLoS ONE. 4:e5687, 2009.
16. Kubota, A, Hida, A, Ichikawa, Y, Momose, Y,
Goto, J, Igeta, Y, Hashida, H, Yoshida, K, Ikeda, S,
Kanazawa, I, and Tsuji, S. A novel ferritin lightchain gene mutation in a Japanese family withneuroferritinopathy: description of clinicalfeatures and implications for genotype-phenotype
correlations. Mov. Disord. (in press)
17. 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
18. Kwak S, Nishimoto Y, Yamashita T: Newly
identified ADAR2-mediated editing positions as a
useful tool for ALS research. RNA Biology 5:193197, 2008
19. 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 511:155-172, 2008.
20. Matsumoto H, Hanajima R, Hamada M, Terao Y,
Yugeta A, Inomata-Terada S, Nakatani-Enomoto S,
Tsuji S, Ugawa Y. Double-pulse magnetic
brainstem stimulation: mimicking successive
descending volleys. J Neurophysiol 100:3437-44,
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. Matsumoto H, Octaviana F, Hanajima R, Terao Y,
Yugeta A, Hamada M, Inomata-Terada S,
Nakatani-Enomoto S, Tsuji S, Ugawa Y. Magnetic
lumbosacral motor root stimulation with a flat,
large round coil. Clin Neurophysiol 120: 770-5,
2009.
23. Matsumoto H, Octaviana F, Terao Y, Hanajima R,
Yugeta A, Hamada M, Inomata-Terada S,

Nakatani-Enomoto S, Tsuji S, Ugawa Y. Magnetic
stimulation of the cauda equina in the spinal canalwith a flat, large round coil. J Neurol Sci. 2009
Apr 30. [Epub ahead of print]
24. Mitsui, J, Mizuta, I, Toyoda, A, Ashida, R,
Takahashi, Y, Goto, J, Fukuda, Y, Date, H, Iwata,A, Yamamoto, M, Hattori, N, Murata, M, Toda,
Miyagawa T, Kawashima M, Nishida N, Ohashi J,
Kimura R, Fujimoto A, Shimada M, Morishita S,
Shigeta T, Lin L, Hong SC, Faraco J, Shin YK,
Jeong JH, Okazaki Y, Tsuji S, Honda M, Honda Y,
Mignot E, Tokunaga K. Variant between CPT1B
and CHKB associated with susceptibility to
narcolepsy. Nat Genet. 40:1324-8, 2008.
25. Miyagawa T, Kawashima M, Nishida N, Ohashi J,
Kimura R, Fujimoto A, Shimada M, Morishita S,
Shigeta T, Lin L, Hong SC, Faraco J, Shin YK,
Jeong JH, Okazaki Y, Tsuji S, Honda M, Honda Y,
Mignot E, Tokunaga K. Variant between CPT1B
and CHKB associated with susceptibility to
narcolepsy. Nat Genet. 40:1324-8, 2008.
26. Miyagawa T, Nishida N, Ohashi J, Kimura R,
Fujimoto A, Kawashima M, Koike A, Sasaki T,
Tanii H, Otowa T, Momose Y, Nakahara Y, Gotoh
J, Okazaki Y, Tsuji S, Tokunaga K. Appropriate
data cleaning methods for genome-wide
association study. J Hum Genet. 53:886-93, 2008
27. Mizuno Y, Moriguchi Y, Hikage T, Terao Y,
Ohnishi T, Nojima T, Ugawa Y. Effects of
W-CDMA 1950 MHz EMF emitted by mobile
phones on regional cerebral blood flow in humans.
Bioelectromagnetics. 2009 [Epub ahead of print]
28. Nakamura K, Igarashi K, Ohkawa R, Okubo S,
Yokota H, Kishimoto T, Ide K, Masuda A,
Yamamoto T, Saito N, Kurokawa M, Tsuji S,
Okudaira S, Ikeda H, Aoki J, Yatomi Y. Autotaxin
enzyme immunoassay in human cerebrospinal
fluid samples. Clin. Chim. Acata (in press)
29. 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
30. Pan W, Soma R, Kwak S, Yamamoto Y:
Improvement of motor functions by noisy
vestibular stimulation in central neurodegenerative disorders. J Neurol 255:1657-1661,
2008.

92

31. 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,
2008.
32. Sato, T, Miura, M, Yamada, M, Yoshida, T, Wood,JD, Yazawa, I, Masuda, M, Suzuki, S, Shin, R-M,
Yau,H-J, Liu, F-C, Shimohata, T, Onodera, O,
Ross, CA, Katsuki, M, Takahashi, H, Kano, M,
Aosaki, T and Tsuji, S. Severe neurologicalphenotypes of Q129 DRPLA transgenic mice
serendipitously created by en masse expansion of
CAG repeats in Q76 DRPLA mice. Hum. Mol.
Genet. 18:723-736, 200933. Sawada J, Yamashita T, Aizawa H, Aburakawa Y,
Hasebe N, Kwak S: Effects of antidepressants on
GluR2 Q/R site-RNA editing in a modified HeLa
cell line. Neurosci Res 64:251-258, 2009.
34. Sidransky E, Aasly JO, Aharon-Peretz J, Annesi G,
Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A,
Chen C-M, Clark ON, Condroyer C, De Marco
EV, Dürr A, Eblan MJ, Fahn S, Farrer M, Fung
H-C, Gan-Or Z, Gasser T, Gershoni-Baruch R,
Giladi N, Griffith A, Gurevich T, Januario C,
Kropp R, Lang AE, Lee-Chen G-J, Lesage S,
Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta
I, Nalls MA, Nicoletti G, Oliveira C, Ottman R,
Orr-Urtreger A, Pereira LV, Quattrone A, Rogaeva
E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A,
Samaddar T, Schulte C, Sharma M, Singleton A,
Spitz M, Tan E-K, Tayebi N, Toda T, Troiano A,
Tsuji S, Wittstock M, Wolfsberg TG, Wu Y-R,
Zabetian CP, Zhao Y, Ziegler SG. International
multi-center analysis of glucocerebrosidase
mutations in Parkinson disease. New Engl J. Med.
(in press)
35. Takada K, Shimizu J, Kusunoki S. Apoptosis ofprimary sensory neurons in GD1-induced sensory
ataxic neuropathy. Exp. Neurol. 2008; 209:279-283
36. 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
65:1326-1332, 2008.
37. Takei N, Miyashita A, Tsukie T, Arai H, Asada T,
Imagawa M, Shoji M, Higuchi S, Urakami K,
Kimura H, Kakita A, Takahashi H, Tsuji S,
Kanazawa I, Ihara Y, Odani S, Kuwano R. Genetic
association study on in and around the APOE in
late-onset Alzheimer disease in Japanese.
Genomics (in press)
38. Tsuji, S, Onodera, O, Goto, J. and Nishizawa, M.
Sporadic Ataxias in Japan -A population-based
epidemiological study-. Cerebellum. 7:189-197,
2008
39. Wang K, Takahashi Y, Gao Z-L, Wang GX, Chen
XW, Goto J, Lou J-N, Tsuji S*. Mitochondrial
ND3 as the Novel Causative Gene for Leber
Hereditary Optic Neuropathy and Dystonia.
Neurogenetics (in press)

93

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

Associate Professor
Kensuke Kawai, M.D., Ph.D.

Lecturer
Kyosuke Kamata, M.D., Ph.D.,

Masahiro Shin, M.D., Ph.D.,

Akira Iijima, M.D., Ph.D.,

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

Associate
Keisuke Maruyama, M.D., Ph.D.,
Tomoyuki Koga, M.D.,

Keisuke Takai, M.D,

Soich Oya, M.D., Ph.D.,

Takahiro Ohta, M.D.,

Sou Nishido, M.D.

Homepage 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 2008 through March 2009,
14,447 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 2007 and 2008, 482 and 731 patientswere admitted to the Neurosurgical Ward, respectively.
Four hundred and four and 367 surgical procedures
were performed with 147 and 135 gamma knife
precedures in each year. Our practice covers a wide
variety of neurosurgical diseases including malignant
and benign brain tumors, hemorrhagic and occlusive
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-ofthe-art techniques including intraoperative computeraided navigation and intravascular procedures help
our continuous effort to increase the safety of surgicaltreatment.

94

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 5500cases.

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 6 residents in 2008 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
and establish its significance in epilepsy treatment.
Efficacy evaluation and development of surgical95

instruments has been promoting for novel functionpreserving techniques, multiple subpial transection
and multiple hippocampal transection. Basic andclinical research on gamma knife treatment of
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 (2008)
1.

Chen Y, Ito A, Takai K, Saito N: Blocking
pterygopalatine arterial blood flow decreases
infarct volume variability in a mouse model of
intraluminal suture middle cerebral artery
occlusion. J Neurosci Methods. 174:18-24, 2008
2. Egawa K, Asahina N, Shiraishi H, Kamada K,
Takeuchi F, Nakane S, Sudo A, Kohsaka S,
Saitoh S: Aberrant somatosensory-evoked
responses imply GABAergic dysfunction in
Angelman syndrome. Neuroimage 39: 593-599,
2008
3. Igaki.H,
Maruyama.K,
Tago.M,
Shin.M,
Murakami.N, Koga.T, Nakagawa.K, Kawahara.N,
Ohtomo.K: Cyst formation after stereotactic
radiosurgery for intracranial meningioma.
Stereotact Funct Neurosurg 86: 231-236, 2008
4. Kawahara N, Sasaki T, Asakage T, Nakao K,
Sugasawa M, Asato H, Koshima I, Saito N:
Long-term outcome following radical temporalbone resection for lateral skull basemalignancies: a neurosurgical perspective. J
Neurosurg 108:501-510, 2008
5. Kubota.M, Shin.M, Taniguchi.M, Terao.T,
Nakauchi.J, Takahashi.H: Syringomyelia caused
by intrathecal remnants of the oil-based contrast
medium. J Neurosurg spine 8:169-173, 2008
6. Lefaucheur.JP, Gurruchaga.JM, Pollin.B, vonRaison.F, Mohsen.N, Shin.M, Jnard-Lefaucheur.I,
Oshino.S, Kishima.H, Jnelon.G, Jmy.P, Cesaro.P,
Gabriel.I, Brugi.P, Keravel.Y, Nguyen.JP:
Outcome of bilateral subthalamic nucleus
stimulation in the treatment of Parkinson disease:correlation with intra-operative multi-unit
recordings but not with the type of anaesthesia.
Eur Neurol 60: 186-199, 2008
7. Maruyama K, Kamada K, Ota T, Koga T, Itoh T,
Ino K, Aoki S, Tago M, Masutani Y, Shin M,
Saito N: Tolerance of pyramidal tract to gamma
knife radiosurgery based on diffusion-tensor
tractography. Int J Radiat Oncol Biol Phys
70:1330-1335, 2008
8. Maruyama K, Koga T, Kamada K, Ota T, Itoh D,
Ino K, Igaki H, Aoki S, Masutani Y, Shin M,
Saito N: Arcuate fasciculus tractography
integrated into Gamma Knife surgery. J
Neurosurg [Epub ahead of print]
9. Maruyama K, Koga T, Shin M, Igaki H, Tago M,
Saito N: Optimal timing to apply gamma knife
surgery
after
hemorrhage
from
brain
arteriovenous malformations. J Neurosurg 109(Suppl):73-76, 2008
10. 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,

96

11.

12.

13.

14.

15.

16.

17.

18.

19.

Takahashi K, Nagawa H: Pilot study ofanti-angiogenic vaccine using fixed wholeendothelium in patients with progressive
malignancy after failure of conventional therapy.
Eur J Cancer 44:383-390, 2008
Oya S, Yoshikawa G, Takai K, Tanaka J,
Higashiyama S, Saito N, Kirino T,Kawahara N:
Region-specific proliferative response of neuralprogenitors to exogenous stimulation by growth
factors following ischemia. Neuroreport 19:805-809, 2008
Sawamura Y, Kamada K, Aoyama H, Shirato H:
Role of Surgery for Optic pathway /Hypothalamic Astrocytomas in Children. Neuro
Oncol 10: 725-733, 2008
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 83: 309-316,
2008
Tanaka Y, Imai H, Konno K, Miyagishima T,
Kubota C, Puentes S, Aoki T, Hata H, Takata K,
Yoshimoto Y, Saito N: Experimental Model of
Lacunar Infarction in the Gyrencephalic Brain of
the Miniature Pig: Neurological Assessment andHistological,
Immunohistochemical,
andPhysiological
EvaluationofDynamic
Corticospinal Tract Deformation. Stroke 39:
205-212, 2008
Terao T, Yokochi F, Taniguchi M, Kawasaki T,
Okiyama R, Hamada I, Nishikawa N, Izawa N,
Shin M, Kumada S, Takahashi H: Microelectrodefindings and topographic reorganization of
kinaesthetic cells after gamma knife thalamotomy.
Acta Neurochir (Wien) 150: 823-827, 2008
Todo T: “Armed” oncolytic herpes simplex
viruses for brain tumor therapy. Cell Adhesion &Migration 2: 208-213, 2008
Todo T: Oncolytic virus therapy using geneticallyengineered herpes simplex viruses. Frontiers in
Bioscience 13: 2060-2064, 2008
Tosaka M, Sato N, Fujimaki H, Tanaka Y,
Kagoshima K, Takahashi A, Saito N, Yoshimoto
Y: Diffuse pachymeningeal hyperintensity andsubduraleffusion/hematoma
detectedbyfluid-attenuated inversion recovery MR imaging
in patients with spontaneous intracranial
hypotension. Am J Neuroradiol 29:1164-70,
2008
Ushio M, Iwasaki S, Chihara Y, Kawahara N,
Morita A, Saito N, Murofushi T: Is the nerve
origin of the vestibular schwannoma correlatedwith vestibular evoked myogenic potential,
caloric test and auditory brainstem response?
Acta Otolaryngol 26:1-6, 2008

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

98

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.,

Satoshi Ueha, Ph. D.,

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

Tetsu Nishiwaki, M.D., 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 state4) Development of vaccines against pathogenic
microorganisms and cancer5) Establishment of a novel bio-monitoring systemfor environmental chemicals.

99

References
(1)

(2)

(3)

(4)

(5)

(6)

(7)

Yasui F, Kai C, Kitabatake M, Inoue S, Yoneda
M, Yokochi S, Kase R, Sekiguchi S, Morita K,
Hishima T, Suzuki H, Karamatsu K, Yasutomi Y,
Shida H, Kidokoro M, Mizuno K, Matsushima K
and Kohara M. Prior immunization with severe
acute respiratory syndrome (SARS)-associatedcoronavirus (SARS-CoV) nucleocapsid proteincauses severe pneumonia in mice infected with
SARS-CoV. J Immunol. 181(9): 6337-6348,
2008
Wu Y, Li Y Y, Matsushima K, Baba T and
Mukaida N. CCL3-CCR5 axis regulates
intratumoral accumulation of leukocytes andfibroblasts and promotes angiogenesis in murine
lung metastasis process. J Immunol. 181(9):6384-6393, 2008
Wada T, Matsushima K and Kaneko S. The roleof chemokines in glomerulonephritis. Front
Biosci. 13: 3966-3974, 2008
Suzukawa M, Koketsu R, Iikura M, Nakae S,
Matsumoto K, Nagase H, Saito H, Matsushima
K, Ohta K, Yamamoto K and Yamaguchi M.
Interleukin-33 enhances adhesion, CD11b
expression and survival in human eosinophils.
Lab Invest. 88(11): 1245-1253, 2008
Suzukawa M, Iikura M, Koketsu R, Nagase H,
Tamura C, Komiya A, Nakae S, Matsushima K,
Ohta K, Yamamoto K and Yamaguchi M. An
IL-1 cytokine member, IL-33, induces humanbasophil activation via its ST2 receptor. J
Immunol. 181(9): 5981-5989, 2008
Shiraishi K, Ishiwata Y, Nakagawa K, Yokochi S,
Taruki C, Akuta T, Ohtomo K, Matsushima K,
Tamatani T and Kanegasaki S. Enhancement ofantitumor radiation efficacy and consistentinduction of the abscopal effect in mice by
ECI301, an active variant of macrophageinflammatory protein-1alpha. Clin Cancer Res.
14(4): 1159-1166, 2008
Shawkat S, Karima R, Tojo T, Tadakuma H,
Saitoh S, Akashi-Takamura S, Miyake K,
Funatsu T and Matsushima K. Visualization of
the molecular dynamics of lipopolysaccharide
on the plasma membrane of murine macrophages
by total internal reflection fluorescencemicroscopy. J Biol Chem. 283(34): 22962-22971,
2008(8) Sawanobori Y, Ueha S, Kurachi M, Shimaoka T,
Talmadge J E, Abe J, Shono Y, Kitabatake M,
Kakimi K, Mukaida N and Matsushima K.
Chemokine-mediatedrapid
turnoverof
myeloid-derived
suppressor
cells
in
tumor-bearing mice. Blood. 111(12): 5457-5466,
2008(9) Sakai N, Wada T, Matsushima K, Bucala R, Iwai
M, Horiuchi M and Kaneko S. The
renin-angiotensin system contributes to renal
fibrosis through regulation of fibrocytes. J
Hypertens. 26(4): 780-790, 2008(10) Nanno M, Kanari Y, Naito T, Inoue N,
Hisamatsu T, Chinen H, Sugimoto K,
Shimomura Y, Yamagishi H, Shiohara T, Ueha S,
Matsushima K, Suematsu M, Mizoguchi A, Hibi
T, Bhan A K and Ishikawa H. Exacerbating roleof gammadelta T cells in chronic colitis of T-cell
receptor alpha mutant mice. Gastroenterology.
134(2): 481-490, 2008(11) Komatsu K, Miyazaki D, Morohoshi K, Kuo C H,
Kakimaru-Hasegawa A, Komatsu N, Namba S,
Haino M, Matsushima K and Inoue Y.
Pathogenesis of Herpetic Stromal Keratitis in
CCR5- and/or CXCR3-Deficient Mice. Curr Eye
Res. 33(9): 736-749, 2008(12) Inadera H, Tachibana S, Takasaki I, Tabuchi Y,
Matsushima K, Uchida M and Shimomura A.
Expression profile of liver genes in response to
hepatotoxicants identified using a SAGE-based
customized DNA microarray system. Toxicol
Lett. 177(1): 20-30, 2008(13) Iida N, Nakamoto Y, Baba T, Kakinoki K, Li Y Y,
Wu Y, Matsushima K, Kaneko S and Mukaida N.
Tumor cell apoptosis induces tumor-specificimmunity in a CC chemokine receptor 1- and5-dependent manner in mice. J Leukoc Biol.
2008(14) Hashimoto S and Matsushima K. SAGE
application in hematological research. Curr
Pharm Biotechnol. 9(5): 383-391, 2008(15) Guo Z, Jang M H, Otani K, Bai Z, Umemoto E,
Matsumoto M, Nishiyama M, Yamasaki M,
Ueha S, Matsushima K, Hirata T and Miyasaka
M. CD4+CD25+ regulatory T cells in the small

100

intestinal
laminapropriashow
aneffector/memory phenotype. Int Immunol.
20(3): 307-315, 2008(16) Gamo K, Kiryu-Seo S, Konishi H, Aoki S,
Matsushima K, Wada K and Kiyama H.
G-protein-coupled receptor screen reveals a rolefor chemokine receptor CCR5 in suppressing
microglial neurotoxicity. J Neurosci. 28(46):11980-11988, 2008(17) Furuichi K, Wada T, Kitajikma S, Toyama T,
Okumura T, Hara A, Kawachi H, Shimizu F,
Sugaya T, Mukaida N, Narumi S, Matsushima K
and Kaneko S. IFN-inducible protein 10(CXCL10) regulates tubular cell proliferation inrenal ischemia-reperfusion injury. Nephron Exp
Nephrol. 109(1): c29-38, 2008(18) Ahsan B, Kobayashi D, Yamada T, Kasahara M,
Sasaki S, Saito T L, Nagayasu Y, Doi K,
Nakatani Y, Qu W, Jindo T, Shimada A, Naruse
K, Toyoda A, Kuroki Y, Fujiyama A, Sasaki T,
Shimizu A, Asakawa S, Shimizu N, Hashimoto S,
Yang J, Lee Y, Matsushima K, Sugano S,
Sakaizumi M, Narita T, Ohishi K, Haga S, Ohta F,
Nomoto H, Nogata K, Morishita T, Endo T, Shin
I T, Takeda H, Kohara Y and Morishita S.
UTGB/medaka: genomic resource database formedakabiology.
Nucleic
Acids
Res.
36(Database issue): D747-752, 2008(19) Abe J, Ueha S, Suzuki J, Tokano Y, Matsushima
K and Ishikawa S. Increased Foxp3(+) CD4(+)
regulatory T cells with intact suppressive
activity but altered cellular localization inmurine lupus. Am J Pathol. 173(6): 1682-1692,
2008

101

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
Modern concepts of public health originated in the
Industrial Revolution era in the UK, and since thendeveloped in Western countries. In Japan, theseconcepts became important and popular in the 1880s,
when the Japan Private (non-governmental)
Association for Hygiene (a synonym of public healthin that age) was established to fight against repeatedoutbreaks of cholera in Japan.
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 PhD).
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 of public health,preventive services, epidemiology, health economics,
community health and primary care, occupational andenvironmental health, infection and tuberculosis

102

control, mental health, international health, current
health policy in Japan, and so on. Similarly, in thesixth 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 and public health practitioners.
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 Faculty of Arts andSciences, the School of Health Sciences and Nursing,and the Faculty of Engineering in the University ofTokyo.
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 delivery of healthservices in Japan; such as supply and distribution ofphysicians, the separation of pharmaceuticaldispensing and prescribing in medical practice, coststudies of outpatient and inpatient services, and theefficiency and equity issues of the Japan's healthinsurance system. We have also carried on several
policy studies in terms of public awareness of medical
technology. These studies have been published ininternational 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 health,and infectious disease control programs in
Afghanistan.

References
1. Hao L, Toyokawa S, Kobayashi Y: Poisson-model
analysis of the risk of vaccine-associated paralytic
poliomyelitis in Japan between 1971 and 2000.
Japanese Journal of Infectious Diseases 61:
100-103, 2008.
2. Akabayashi A, Slingsby BT, Nagao N, Kai I, Sato
H: A five year follow-up national study of ethics
committees in medical organizations in Japan.

103

HEC Forum 20(1): 49-60, 2008.
3. Shono T, Inoue K, Moriki A, Kobayashi Y:
Cost-effectiveness analysis of a hypotheticalscreening system for detecting silent cerebral
infarction in Japanese employees. Ningen Dock
22(6): 9-14, 2008.
4. Senba T, Kobayashi Y, Inoue K, Kaneto C, Inoue
M, Toyokawa S, Suyama Y, Suzuki T, Miyano Y,
Miyoshi Y: The association between self-reported
periodontitis and coronary heart disease-from MY
Health Up Study-. Journal of Occupational Health50(3): 283-287, 2008.
5. Kinoshita H, Kobayashi Y, Fukuda T: Duplicative
medications in patients who visit multiple medical
institutions among the insured of a corporate
health insurance society in Japan. Health Policy
85: 114-123, 2008.
6. Matsumoto M, Inoue K, Kajii E: Characteristics
of medical students with rural origin: Implications
for selective admission policies. Health Policy 87:
194-202, 2008.
7. Inoue K, Matsumoto M, Miyoshi Y, Kobayashi Y:
Elevated liver enzymes in women with a family
history of diabetes. Diabetes Research andClinical Practice 79: 4-7, 2008.
8. Matsumoto M, Inoue K, Kajii E: Long-term effectof the home prefecture recruiting scheme of Jichi
Medical University, Japan. Rural and Remote
Health (e-Journal) 8(930): 1-15, 2008.
9. Inoue K, Matsumoto M, Akimoto K: Fasting
plasma glucose and HbA1c as risk factors for type2 diabetes. Diabetic Medicine 25: 1157-1163,
2008.
10. Matsumoto M, Inoue K, Kajii E: A Contract-based
training system for rural physicians: Follow-Up of
Jichi Medical University graduates (1978-2006).
Journal of Rural Health 24(4): 360-368, 2008.
11. Nakata A, Takahashi M, Haratani T, Ikeda T,
Hojou M, Fujioka Y, Araki S: Association ofactive and passive smoking with sleep
disturbances and short sleep duration among
Japanese working population. International
Journal of Behavioral Medicine 15: 81-91, 2008.
12. Gunji T, Matsuhashi N, Sato H, Fujibayashi K,
Okumura M, Sasabe N, Urabe A: Helicobacter
pylori infection is significantly associated withmetabolic syndrome in the Japanese population.

American Journal of Gastroenterology 103:
3005-3010, 2008.
13. Kaneko Y, Kobayashi J, Yamamoto Y, Yoda H,
Kanetaka Y, Nakajima Y, Endo D, Tsuchiya K, Sato
H, Kawakami T: Intensive cardiac management inpatients with trisomy 13 or trisomy 18. American
Journal of Medical Genetics (Part A) 146A:
1372-1380, 2008.
14. Miyaji K, Miyamoto T, Kohira S, Nakashima K,
Inoue N, Sato H, Ohara K: Miniatuarized
cardiopulmonary bypass system in naonates andsmall infants. Interactive Cardio Vascular andThoracic Surgery 7: 75-79, 2008.

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

105

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

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

Assistant Professor
Kaori Shintani, Ph.D.,

Takashi Kobayashi, M.D., Ph.D.

Associate
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 first department 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 in Japan.
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, two assistant professor, one associate, two
special technicians, nine postgraduate students, andone researcher. Three doctors from this department
have 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.

106

Forensic autopsy

Research activities

The determination of precise cause of death is themost important mission of 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
famous in 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. Expert
opinions expresses the cause of death and forensic
judgment for each case. We have kept them since first
autopsy case in 1889. We have serious responsibility
in the determination 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 has
been enacted in 2009.

Our mission is to determine the cause of death inunnatural deaths through autopsy and various
examinations. We have also tried to find problems inlegal-social systems related to death investigation,
court procedure, and patient safety. To improve deathinvestigation and related legal-social systems, we
conducted
varietyofresearches
including
cardiovascular basic sciences, legal-social medicine,forensic
pathology,
toxicology,
andDNA
polymorphism as described below.

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 and(undergraduate & graduate) law school are provided
with somewhat practical lectures with exercises.

1. Molecular mechanisms underlying sudden cardiac
deaths due to ischemia or emotional stress
The Gap Junction（GJ）that is comprised ofConnexin
43(Cx43)
contributes
tosynchronization of contraction and propagation of
injury from cell to adjacent cell. It has beenthought that down-regulation, translocation, or
dephosphorylation of Cx43 is involved in the
impaired conduction and arrhythmias.
1) Involvement of GJ in myocardial injury andlesion development in ischemic heart diseasemodels … We found that contraction bands,
frequently found in sudden cardiac death, arepropagated from cell to cell through GJs withenhanced activity after enhanced incorporationof Cx43.
2) GJ formation and the contribution of its
ischemic change to the development of injury
and arrhythmias in cultured cardiomyocytes…
Cultured cardiomyocytes are aligned intandem with intercalated discs composed oftranslocated Cx43. In the system, we haveundertaken to investigate the molecularmechanism of Cx43 turnover under baseline
and ischemic conditions, and the contributionof Cx43-based GJ to injury propagation andarrhythmias.
3) Changes in GJ and its contribution toarrhythmogenesis in a restraint model…When
excited persons are restrained, some of themsuddenly die. We found that restraint induces
Cx43 translocation to GJs in rats with a peak at
60 minutes, and that some portions of rats
suddenly die of ventricular tachycardia/

107

fibrillation.
4) Changes in GJ and its contribution toarrhythmogenesis in pressure overloaded(perfused) heart model, and changes in theinteraction of extracellular matrix (ECM),
adhesion molecules, and cytoskeletons and its
contribution to contractile failure in the samemodel…By use of the pressure overload modelof perfused heart, we have tested whetherpressure overload, related to accident orviolence, induces arrhythmias. In fact, Cx43 isdown-regulated in the pressure overload model.
On the other hand, myocardial contraction isenhanced by pressure-overload. It has beenthought that signal transduction andprotein-protein interaction between ECM
proteins, adhesion molecules, and cytoskeletal
proteins contribute to the “enhanced
contraction”. We aimed to clarify themechanisms underlying the arrhythmias andcontractile failure under pressure-overload andemotional stress.
5) Contributionofoxidative
stresstocardiovascular risks and arrhythmogenesis in
the models of sleep apnea syndrome (SAS),and manic-depressive disease (MDD)…SASand MDD have been a focus of research
related to cardiovascular risks, but themechanisms are largely unknown. We haveundertaken to produce animal models, andinvestigate how SAS or MDD generates
cardiovascular risks with reference tooxidative stress.
2. Investigation of legal-social systems related todeath investigation system and patient safely
1) Study on disclosure of autopsy information
and bereavement services…In order to resolve
the disputes due to restricted disclosure of
information on forensic autopsies, we have
performed questionnaire studies, submited
recommendation from the study results, andadopted practical measures.
2) Study on investigation of medical practiceassociated deaths…The Department of Health,Welfare, Labor, and Sports has promoted themodel project on the investigation of medical

practice-associated deaths (MPADs), and been
trying to establish the new investigative
system for MPADs. We have contributed to thereview of the model project, and submitted
reports on review and recommendations. For
the new investigation system, we are trying tooffer evidence and recommendation.
3) Study on presentation of expert opinions injury (saiban-in) system…We have investigated
how juries can understand the expert opinion
without influence by emotional stress throughcomputer graphic or other tactics.
3. Improvement of examinations in forensic practices
While examining each case, we have developed
or applied new methods in our practices described
below.
1) Development of new toxicological analyses2) Development of new technique for racial or
personal identification based on DNA
polymorphism3) Studies on estimation of weapon, and planktonchorology
4. Forensic pathology
We have reported rare cases related to clinicalpractices or medical practice associated deaths.
Additionally, to explore how cardiovascularlesions develop and develop new diagnostic
methods, we performed immunohistochemistry toconfirm the experimental findings or findphenomena that initiate experimental studies.
1) Report and analysis of rare diseases or injuries
2) Study on histopathological diagnosis

References(1) Shintani-Ishida K, Zhu BL, Maeda H, Uemura K,
Yoshida K. A new method for ABO genotyping
to avoid discrepancy between genetic andserological determinations. Int J Legal Med.
2008;122:7-9.
(2) Saka K, Uemura K, Shintani-Ishida K, Yoshida
K.
Determinationofamobarbital
andphenobarbital
in
serum
by
gas
chromatography-mass spectrometry with addition

108

of formic acid to the solvent. J Chromatogr B.
2008;869:9-15.
(3) Ito T, Nobutomo K, Lefler LB, Yoshida K.
Limited disclosure of autopsy information leads
bereaved families to sue physicians. J Med Saf.
2008;Oct:34-42.
(4) Uemura K, Shintani-Ishida K, Saka K, Nakajima
M, Ikegaya H, Kikuchi Y, Yoshida
K.Biochemical blood markers and sampling sites
in forensic autopsy. J Forensic Leg Med.
2008;15:312-317.
(5) Uemura K, Takahashi S, Shintani-Ishida K,
Nakajima M, Saka K, Yoshida K. A death due toperirenal hematoma complicating extracorporeal
shockwave lithotripsy. J Forensic Sci. 2008;53:
469-471.
(6) Uemura K, Ueyama T, Shintani-Ishida K, Unuma
K, Yoshida K. An autopsy report on four sudden
cardiac death cases by Immobilization. Int Med J.
2008;15:301-305.
(7) Morimoto K, Morikawa M, Kimura H, Ishii N,
Takamata A, Hara Y, Uji M, Yoshida K. Mental
stress induces sustained elevation of bloodpressureandlipidperoxidationinpostmenopausal women. Life Sci. 2008;82:
99-107.
(8) Kimura H, Mukaida M, Watanabe M, Hashino K,
Nishioka T, Tomino Y, Yoshida K, Matsumoto K.
Quantitativeevaluationoftime-resolved
fluorescence microscopy using a new europium
label: Application to immunofluorescenceimaging of nitrotyrosine in kidneys. Anal
Biochem. 2008;372:119-121.
(9) Nara A, Uchida K, Ochiai E, Yoshida K, Uemura
K. An autopsy case of six-month-old baby who issuspected to have died of asphyxia on a baby bed
with her hand down. Practice and research offorensic medicine 2008;51:143-148.
(10) Nakajima N, Takeichi H, Yoshida K. Tasks to beaddressed learned from the questionnaire study
on hospital persons who applied to the model
project. Japan Medical News 2008;4399:77-83(in Japanese).
(11) Yoshida K. Interpretation of unnatural deaths
related to medical practices, and the near-future
outlook of “The Medical Safety Committee”.
Guide to Medical Court Cases. 2008;15:16-26 (inJapanese).
(12) Yoshida K. From “the model project on medical
practice

associateddeaths”

to

“the

new

investigative system” Progress in Medicine.
2008; 227: 139-142 (in Japanese).

109

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.
S. Koike and Lecturer. K. Miyo from DPIM, Prof. T.
Kiuchi from UMIN center, Assoc. Prof. S. Oku fromthe Department of Healthcare Related Informatics thatis the affiliated department, Assoc. Prof. H. Yasunaga
from the Department of Health Management andPolicy, Assoc. Prof. R.Yamamoto from Interfaculty
Initiative in Information Studies, Graduate School ofInterdisciplinary Information Studies.
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 in Japan, and he is
now 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

110

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 position.
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 FY2008 are five indoctor’s course for Medical Informatics andEconomics, one in doctor’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 2008 F.Y., research staffs are Prof. Kazuhiko Ohe,
Assistant Professor Kengo Miyo, Project Associate
Hiroki Watanabe, Research Associate Izumi
Yamaguchi, hiroo Ide, Takashi Noguchi, Katsuya
Tanaka, and Project Research Associate Takeshi Imai,
Megumi Sato, Shiro Matsuya, and Project Research
Assistant Yuichi Yoshida, and Masayuki Kajino.
Our main research domains are 1) application
studies on developments of clinical information
systems, hospital information system and electronic
health records system, 2) studies on medical safety
infromation
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 ofvarious issues on DPC.
In these domains, major research topics are as listed
below.
1) A study on development methods for large scale

111

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.
2) A study on the development of a patient-oriented,
event-driven, and intellectual clinical support
subsystem(Industry-academia
collaboration
project with Fujitsu Limited, 2004-2009)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.

References
1. Eiji Aramaki, Takeshi Imai, Kengo Miyo, Kazuhiko
Ohe: Orthographic Disambiguation Incorporating
Transliterated Probability, International Joint
Conference on Natural Language Processing(IJCNLP2008), pp.48-55, 2008.
2. Yasunaga H, Matsuyama Y, Ohe K: Risk-adjusted
analyses of the effects of hospital and surgeon
volumes on postoperative complications and themodified Rankin scale after clipping of unruptured
intracranial aneurysms in Japan. Neurol Med Chir
(Tokyo). 48(12): 531-8, 2008.
3. Yasunaga H, Yanaihara H, Fuji K, Matsuyama Y,
Deguchi N, Ohe K.: Influence of hospital andsurgeon volumes on operative time, blood loss andperioperative complications in radical nephrectomy.
Int J Urol. 15(8):688-93, 2008.
4. Katsumura Y, Yasunaga H, Imamura T, Ohe K,
Oyama H.: Relationship between risk information
on total colonoscopy and patient preferences forcolorectal cancer screening options: analysis using
the analytic hierarchy process. BMC Health Serv
Res. 21;8:106, 2008.
5 Kohro T, Furui Y, Mitsutake N, Fujii R,
Morita H, Oku S, Ohe K, Nagai R.: The
Japanese national health screening andintervention program aimed at preventing
worsening of the metabolic syndrome. Int

Heart J, 49(2):193-203. 2008.
6. Kawazoe Y, Ohe K.: An ontology-based mediatorof clinical information for decision support
systems: a prototype of a clinical alert system forprescription.
Methods
InfMed.
47(6),
549-59,2008.

Internal Medicine
1. Medicine Ⅰ

113

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

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

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

Nobukazu Ishizaka, M.D., Ph.D.

Hospital Lecturer
Kohsuke Ajiki, M.D., Ph.D.,

Homepage

Koichiro Kinugawa

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 Nobukazu Ishizaka and hospitalward Hiroshi Yamashita), 15 research associates, 9
staff members, 23 graduate school students, 3
researchers, 1 members on leave and 2 members
studying abroad.

Clinical activities
In 2008, 1,723 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 2,001 patients, of which 586 cases wereinterventional procedures. CT coronary angiography
was examined in 328 patients and cardiovascular MRI
in 99. For arrhythmias, there were 79 cases of
implantation of a pacemaker, 84 cases of catheter
ablation, and other specialized pacemaker devices
such as 17 cases of implantation of a cardioverterdefibrillator, and 12 cases of implantation of a cardiac
resynchronization device.

114

As we are an authorized facility for hearttransplantation, 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 4 cases also in 2008. Duration of
hospitalization is on average 12.3 days.
Out-patient clinics are available as part of the
Department of Medicine or as a specialized
department. The profile of diseases includes ischemic
heart disease in main in addition to hypertension andperipheral artery disease. Out-patient clinics are open
both mornings and afternoons from Monday to Friday.
Approximately 200 patients visit each day. Acutecases of coronary heart disease and aortic disease arealso a focus of the department, as emergent
catheterization is available on a 24-hours basis.

Teaching activities
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.

mutationsinfamilial
hypertrophic
cardiomyopathy
11. Clock gene in cardiovascular diseases
12. Early diagnosis of ischemic heart disease using
visualization techniques of coronary arteries
13. Anti-arrhythmia therapy using catheter ablation
14. New treatment for pulmonary hypertension
15. Development of drug eluting stent
16. Clinical application of vasoactive substances for
cardiorenal insufficiency
17. Bone marrow-derived cells in atherosclerosis
18. Regeneration therapy for cardiovascular disease
19. Diagnosis and treatment of Marfan syndrome
20. Mechanisms for cardiorenal association
21. Ischemic heart disease in patients with diabetic
retinopathy

References
1.

Hashimoto H, Kobayashi H, Ogasawara K, Aizawa
T, Yamakado M, Nagai R, Ohno M. Manganesesuperoxide dismutase polymorphism affects theoxidized low-density lipoprotein-induced apoptosisof macrophages and coronary artery disease. Eur
Heart J. 2008; 29: 1267-74.
2.

Fujita M, Yamazaki T, Hayashi D, Kohro T, Okada
Y, Nagai R; JCAD Study Investigators. Pleiotropic
effects of statins on cardiovascular events in theJapanese Coronary Artery Disease study. Int J

Research activities

Cardiol. 2008; 129: 294-6.
3.

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 and CT in cardiovascular diseases
7. Gene expression and regulation in cardiomyocytes
8. Nitric oxide and endothelial function
9. Aerobic threshold and cardiac rehabilitation
10. Molecular analysis of myosin light chain

Fujimoto H, Taguchi J, Imai Y, Ayabe S,

Fukuda D, Sata M, Ishizaka N, Nagai R. Criticalrole of bone marrow angiotensin II type 1 receptor
inthepathogenesisofatherosclerosis

inapolipoprotein E deficient mice. Arterioscler
Thromb Vasc Biol. 2008; 28: 90-6.
4.

Harada K, Nagai R. Efforts to improve medical
safety in a University Hospital. (Research andReviews). JMAJ. 2008; 51: 119-24.

5.

Higashikuni Y, Ishizaka N, Ishizaka Y, Toda E,
Nagai R, Yamakado M. Relationship between
blood pressure and chronic kidney disease in theJapanese population: The lower the better even in

115

6.

7.

individuals without hypertension? Hypertens Res.

carotid

2008; 31: 213-9.

Arterioscler Thromb Vasc Biol. 2008; 28: 160-5.

Higashikuni

Y,

NagashimaT,

IshizakaN,

11.

J Cardiol. 2008; 130: e53-5.

chronic kidney disease in Japanese men. Hypertens

Higashikuni Y, Tanabe K, Tanimoto S, Aoki J,

Res. 2008; 31: 485-92.
15.

Ishizaka Y, Ishizaka N, Tani M, Toda A, Toda E,

Ohtsuki S, Yagishita A, Yachi S, Nakajima H, Hara

Koike K, Yamakado M. Relationship between

K. Impact of culprit plaque composition on thealbuminuria,

no-reflow phenomenon in patients with acuteatherosclerosis in Japanese women. Kidney Bloodcoronary syndrome: an intravascular ultrasoundPress Res. 2008; 31: 164-70.
16.

low

eGFR,

and

carotid

Iwata H, Ako J, Nagai R. Recurrence ofHirata Y, Kiyosue A, Takahashi M, Satonaka H,

late-acquired incomplete stent apposition following

Nagata D, Sata M, Suzuki E, Nagai R. Progression

sirolimus-eluting stent implantation. J Invasiveof renal dysfunction in patients with cardiovascular

Cardiol. 2008; 20: e265-8.
17.

Kada N, Suzuki T, Aizawa K, Munemasa Y,

Hiroi Y, Guo Z, Li Y, Beggs AH, Liao JK.

Matsumura T, Sawaki D, Nagai R. Acyclic retinoid

Dynamic regulation of endothelial NOS mediatedinhibits functional interaction of transcription

by competitive interaction with α-actinin-4 andfactors Krüppel-like factor 5 and retinoic acidcalmodulin. FASEB J. 2008; 22: 1450-7.

receptor-α. FEBS Lett. 2008; 582: 1755-60.

Huang PH, Sata M, Nishimatsu H, Sumi M, Hirata

18.

Kariya T, Imai Y, Murakami A, Minegishi S,

Y, Nagai R. Pioglitazone ameliorates endothelial

Katori T, Kato H, Ajiki K, Hirata Y, Nagai R.

dysfunction

andrestoresischemia-induced(Images in cardiovascular medicine.) Markedly

angiogenesis

indiabetic

mice.

dilated right heart 17 years after initial treatment

BiomedPharmacother. 2008; 62: 46-52.

repaired by total right ventricular exclusion andIchikawa-Shindo Y, Sakurai T, Kamiyoshi A,

total

Kawate H, Iinuma N, Yoshizawa T, Koyama T,

2008; 118: e133-5.
19.

cavopulmonary

connection.

Circulation.

Kato N, Ito N, Kinugawa K, Kazuma K. Validity

Murata T, Kangawa K, Nagai R, Shindo T. The

and reliability of the European heart failure

GPCR modulator protein RAMP2 is essential for

self-care behavior scale Japanese version. Eur J

angiogenesis and vascular integrity. J Clin Invest.

Cardiovasc Nurs. 2008; 7: 284-9.
20.

2008; 118: 29-39.

Kohro T, Furui Y, Mitsutake N, Fujii R, Morita H,

Ishizaka N, Ishizaka Y, Seki G, Nagai R, Yamakado

Oku S, Ohe K, Nagai R. The Japanese national

M, Koike K. Association between hepatitis B/C

health screening and intervention program aimed

viral infection, chronic kidney disease and insulin

atresistance in individuals undergoing general healthsyndrome. Int Heart J. 2008; 49: 193-203.

screening. Hepatol Res. 2008; 38: 775-83.
13.

Ishizaka N, Ishizaka Y, Toda E, Shimomura H,
Association between cigarette smoking with

Fukuchi J, Iimuro S, Moriyama N, Kawakami H,

12.

men?

with mirror image branching and vascular ring. Int

disease. Curr Cardiol Rev. 2008; 4: 198-202.

10.

Japanese

Koike K, Seki G, Nagai R, Yamakado M.

radiofrequency analysis. Circ J. 2008; 72: 1235-41.

9.

inKinugawa K, Hirata Y, Nagai R. Right aortic arch

Yamamoto H, Nakazawa G, Chihara R, Onuma Y,

8.

14.

atherosclerosis

21.

preventing

worseningofthemetabolic

Kohro T, Hayashi D, Okada Y, Yamazaki T, Nagai

Ishizaka N, Ishizaka Y, Toda E, Koike K,

R;

Yamakado

serumchanges in medical/interventional treatment ofcarcinoembryonic antigen levels associated withcoronary artery disease patients over a 3.5-year

M,

Nagai

R.

Are

JCAD

Investigators.

Demographics

and

116

22.

period in Japan: the Japanese Coronary Artery

Okada Y, Yamazaki T; JCADII investigators.

Disease study: trend examination. Circ J. 2008; 72:

Rationale and design of a study to examine lower

1397-402.

targets for low-density lipoprotein-cholesterol andKubota N, Takano H, Tsutsumi T, Kurano M, Iida

blood pressure in coronary artery disease patients.

H, Yasuda T, Meguro K, Morita T, Sato Y,

Circ J. 2008; 72: 515-20.

Kawashima S, Yamazaki Y, Ohshima H, Tachibana

23.

T, Meguro K, Sato Y, Yamazaki Y, Kawashima S,

combined

Ohshima H, Tachibana S, Ishii N, Abe T.

withKAATSUduringsimulatedweightlessness Int J KAATSU Training Res. 2008;

Hemodynamic

4: 9-18.

weightlessness of 24-h head-down bed rest andMatsumoto M, Sata M, Fukuda D, Tanaka K,

KAATSU blood flow restriction.Eur J Appl

Soma M, Hirata Y, Nagai R. Orally administered

Physiol. 2008; 104: 727-37.

27.

Nakajima T, Jo T, Meguro K, Oonuma H, Ma J,
NagataMatsuzaki G, Ishizaka N, Furuta K, Hongo M,

voltage-gated Na+ channel in cultured human

Saito K, Sakurai R, Koike K, Nagai R.

bronchial smooth muscle cells. Life Sci. 2008; 82:

Comparison

1210-5.

ofvasculoprotective

effects

of
32.

T.

Nakamura

EffectK,

ofKoibuchidexamethasone

N,

NishimatsuonH,

syndrome. Eur J Pharmacol. 2008; 587: 237-42.

Higashikuni Y, Hirata Y, Kugiyama K, Nagai R,

Monzen K, Ito Y, Naito AT, Kasai H, Hiroi Y,

SataHayashi D, Shiojima I, Yamazaki T, Miyazono K,

dysfunction observed in angiotensin-converting

Asashima M, Nagai R, Komuro I. A crucial role ofenzyme 2-deficient mice. Hypertens Res. 2008; 31:

a high mobility group protein HMGA2 in

1953-61.

MoritaH,

Hayashi

D,

Nagai

R.

33.

M.

Candesartan

ameliorates

cardiac

Nishimatsu H, Suzuki E, Takeda R, Takahashi M,
Oba S, Kimura K, Nagano T, Hirata Y. Blockade of

CTGF

polymorphism associated with systemic sclerosis.

endogenous

N Engl J Med. 2008; 358: 308.

ameliorates endothelial dysfunction in obese

Morita H, Rehm HL, Menesses A, McDonough B,

zucker rats. Hypertens Res. 2008; 31: 737-43.
34.

proinflammatory

cytokines

Nishimura S, Manabe I, Nagasaki M, Seo K,

JG, Seidman CE. Shared genetic causes of cardiac

Yamashita H, Hosoya Y, Ohsugi M, Tobe K,

hypertrophy in children and adults. N Engl J Med.

Kadowaki T, Nagai R, Sugiura S. In vivo imaging

2008; 358: 1899-908.

inMunemasa Y, Suzuki T, Aizawa K, Miyamoto S,

inflammation in obese adipose tissue. J Clin Invest.

Imai Y, Matsumura T, Horikoshi M, Nagai R.

2008; 118: 710-21.

Promoter region-specific histone incorporation by29.

simulated

Atherosclerosis. 2008; 197: 524-33.

Roberts AE, Kucherlapati R, Towbin JA, Seidman

28.

to

Kubota N, Imuta H, Takano H, Iida H, Nagase T,

cardiogenesis. Nat Cell Biol. 2008; 10: 567-74.
26.

31.

responses

atherosclerotic lesions in ApoE-deficient mice.

benidipine and losartan in a rat model of metabolic
25.

Nakajima T, Iida H, Kurano M, Takano H, Morita

S, Ishii N, Abe T, Nakajima T. Resistance exercise

eicosapentaenoic acid reduces and stabilizes

24.

30.

35.

mice

reveals

local

cell

dynamics

andNishimura S, Seo K, Nagasaki M, Hosoya Y,

the novel histone chaperone ANP32B andYamashita H, Fujita H, Nagai R, Sugiura S.

DNA-binding factor KLF5. Mol Cell Biol. 2008;

Responses of single-ventricular myocytes to

28: 1171-81.

dynamic axial stretching. Prog Biophys Mol Biol.

Nagai R, Izumi T, Kurabayashi M, Daida H, Tojo T,

2008; 97: 282-97.

Hasegawa A, Miyauchi K, Hayashi D, Kohro T,

36.

Ohnuki Y, Nishimura S, Sugiura S, Saeki Y.

117

Phosphorylation status of regulatory proteins and

R. The relation of mitral valve morphology tofunctional characteristics in myocardium of dilated

severe mitral regurgitation complicated with mitralcardiomyopathy of syrian hamsters. J Physiol Sci.

valve prolapse. J Echocardiogr. 2008; 6: 1-8.
44.

2008; 58: 15-20.
37.

38.

Oishi Y, Manabe I, Tobe K, Ohsugi M, Kubota T,

M, Salerno Uriarte JA, de Luca Tupputi SchinosaFujiu K, Maemura K, Kubota N, Kadowaki T,

L, Renzulli A, Sabino F, Nowak R, Birkhahn R,

Nagai

Krüppel-likeHollander JE, Counselman F, Bossone E, Eagle K;

transcription factor 5 acts as a molecular switch inInternational Registry of Acute Aortic Dissection

transcriptional programs of lipid metabolism

substudy on Biomarkers (IRAD-Bio) Investigators.

involving PPAR-δ. Nat Med. 2008; 14: 656-66.

Preliminary experience with the smooth muscle

Parisi S, Passaro F, Aloia L, Manabe I, Nagai R,

troponin-like protein, calponin, as a novel

Pastore L, Russo T. Klf5 is involved inbiomarker for diagnosing acute aortic dissection.

self-renewal of mouse embryonic stem cells. J Cell

Eur Heart J. 2008; 29: 1439-45.

R.

SUMOylation

of

45.

Sci. 2008; 121: 2629-34.
39.

cardiovascular disease: cardiovascular biomarkers

S, Tanaka H, Yoshikawa J, Kohro T, Hayashi D,

to proteomic discovery. Nat Clin Pract Cardiovasc

Okada Y, Yamazaki T, Nagai R; The JCAD

Med. 2008; 5: 295.

coronary artery disease (JCAD) study. Circ J.

Hirata Y. Angiotensin II and tumor necrosis factor-

2008; 73: 78-85.

αShinoda Y, Ogata N, Higashikawa A, Manabe I,

chemoattractant protein-1 expression: roles of NF

Shindo T, Yamada T, Kugimiya F, Ikeda T,κ B, p38 and reactive oxygen species. Am J

Kawamura N, Kawasaki Y, Tsushima K, Takeda N,

Physiol Heart Circ Physiol. 2008; 294: H2879-88.
47.

synergisticallypromotemonocyte

Takeda N, Seko Y, Oriuchi N, Nagai R.

Kawaguchi H. Krüppel-like factor 5 causes

Gamma-deltacartilage degradation through transactivation ofcardiomyopathy. Int J Cardiol. 2008; 125: 130-2.
48.

T-cell-mediateddilatedTakeda R, Suzuki E, Takahashi M, Oba S,

283; 24682-9.

Nishimatsu H, Kimura K, Nagano T, Nagai R,

Sonoda M, Aoyagi T, Takenaka K, Uno K, Nagai R.

Hirata Y. Calcineurin is critical for sodium-induced

A one-year study of anti-atherosclerotic effect of

neointimal

angiotensin-II

receptor

blocker

hypertensive rats. Am J Physiol Heart Circ Physiol.

hypertensive

patients.

A

Losartancomparison

informationinnormotensive

and2008; 294: H2871-8.

withangiotensin-converting enzyme inhibitors. Int

49.

Tanaka K, Sata M. Contribution of circulating

Heart J. 2008; 49: 95-103.

vascular progenitors in lesion formation and

Sonoda M, Takenaka K, Uno K, Ebihara A, Nagai

vascular healing: lessons from animal models. Curr

R.

Opin Lipidol. 2008; 19: 498-504.

A largeraorticannuluscausesaorticregurgitation and a smaller aortic annulus causes
aortic43.

Takahashi M, Suzuki E, Takeda R, Oba S,
Nishimatsu H, Kimura K, Nagano T, Nagai R,

matrix metalloproteinase 9. J Biol Chem. 2008:

42.

46.

levels predict cardiovascular events in the JapaneseNagai R, Hoshi K, Nakamura K, Chung UI,

41.

Suzuki T, Nagai R. Molecular markers for

Shimada K, Fujita M, Tanaka A, Yoshida K, Jisso

Investigators. Elevated serum C-reactive protein

40.

Suzuki T, Distante A, Zizza A, Trimarchi S, Villani

stenosisinbicuspid

aorticvalve.

50.

Tanaka K, Sata M, Natori T, Kim-Kaneyama JR,
Nose K, Shibanuma M, Hirata Y, Nagai R.

Echocardiography 2008; 25: 242-8.

Circulating

Sonoda M, Takenaka K, Uno K, Ebihara A, Nagai

neointimal formation in non-irradiated chimeric

progenitor

cells

contribute

to

118

mice. FASEB J. 2008; 22: 428-36.
51.

Tanaka K, Sata M. Potential role of statins in
re-endothelialization. Immun, Endoc. & Metab
Agents in Med Chem. 2008; 8: 151-5.

52.

Tanaka Y, Sato K, Shimizu T, Yamato M, Okano T,
Manabe I, Nagai R, Kitamori T. Demonstration ofa bio-microactuator powered by vascular smoothmuscle cells coupled to polymer micropillars. Lab
Chip. 2008; 8: 58-61.

53.

Wang G, Watanabe M, Imai Y, Hara K, Manabe I,
Maemura K, Horikoshi M, Kohro T, Amiya E,
Sugiyama T, Fujita T, Kadowaki T, Yamazaki T,
Nagai R. Genetic variations of Mrf-2/ARID5B
confer risk of coronary atherosclerosis in theJapanese population. Int Heart J. 2008; 49: 313-27.

54.

Yamazaki T, Suzuki J-i, Shimamoto R, Tsuji T,
Ohmoto-Sekine Y, Morita T, Yamashita H, Honye J,
Nagai R, Komatsu S, Akahane M, Ohtomo K.
Diagnostic efficacy for coronary in-stent patency
with parameters defined on Hounsfield CT
value-spatial profile curves. Radiography. 2008;
14: 98-104.

119

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., Goh Tanaka M.D.,Ph.D., Reiko
Okudaira M.D.,Ph.D., Hiroshi Kitagawa, M.D.,Ph.D.

Homepage 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
sever pneumonia and ARDS, we conduct ventilatory
support of such patients in collaboration with ICU
staff. A specialized clinical conference for respiratory
disease has been held once a week since over 10 years
ago, where staff of our department, department of
thoracic surgery and department of radiology join anddiscuss together to make best diagnostic and120

therapeutic approach to individual patients. Thisconference is appreciated as prototype of Cancer
Board of the University of Tokyo Hospital, which
launched two years ago. Our department contributes tothe pre- and post-surgical evaluation of respiratory
functions, and also receives consultation from otherdepartments.
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
only a few medications are currently available to treat
the disease. We would like to make every effort todevelop a novel and potential therapeutic approach tothese diseases.
Number of in-patients in 2008
1. Primary lung cancer
3. Respiratory infection
2. Interstitial lung disease
4. COPD
5. Asthma

278
113
44
39
29

A weekly chart round and professor’s round arescheduled for Tuesday afternoon. A specialized
clinical conference for patients with respiratory
diseases is held as Respiratory Cancer Board on every
Tuesday evening, together with thoracic surgeons andradiologists, 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 ofThoracic 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.
Lecture on fundamental chest radiology is provided by
the respiratory specialists as one ofessential
elements in bed-side learning.
Clinical clerkship at the 5th year of the educational
program is actively performed to facilitate the early
exposure to the clinical practice both at Tokyo
University Hospital and at one of the affiliatedhospitals for a relatively long period (each for two
weeks) . Several lectures on the specialized theme
on respiratory disease such as medical treatment oflung cancer are also provided. Each student is
expected to learn and acquire the professionalism
required for a medical doctor during this period. Our
program, in general, is highly appreciated by thestudents.
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.

121

Research Activities
Our department is conducting basic and clinicalresearches for many respiratory disorders including
lung cancer, COPD, asthma, interstitial lung diseases,
respiratory infections, acute lung injury, chronic
respiratory failure and others. We have also been
studying the effects of air pollutants such as diesel
exhausts. Epidemiological, clinical, cellular andmolecular biological techniques are utilized for the
elucidation of pathogenetic mechanisms and for thedevelopment of novel diagnostic and therapeuticmodalities in respiratory medicine. Postgraduate
students as well as the Faculty members makeconsiderable studies about genetic analysis of lungcancer in collaboration with the Faculty of the
Department of Thoracic Surgery, cell biologicalanalysis using airway epithelial cells, fibroblast,smooth muscle cells and lung cancer cells.
Respiratory rehabilitation utilizing KAATSU trainingshows promising preliminary results. These results
have been presented and/or published in the Scientific
Meeting and/or peer-review Journals. Our main
research projects are as follows.
Molecular analysis of ion channels expressed on
airway smooth muscle cells and lung cancer cells
Exploration of disease-susceptibility genes in
respiratory diseases
Effects of KAATSU training on respiratory
rehabilitation
Analysis of DNA methylation and miRNA in lungcancer and its clinical application
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
Effects of air pollutants such as diesel exhausts on
airway hyperresponsivenessElucidationofmolecular
mechanismsoftissue-remodeling, especially in relation to epithelial
mesenchymal transition, 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 disease models using geneticallyengineered mice.
Takahide Nagase is an Associate Editor of
Respirology and an Editorial Board Member ofAmerican Journal of Physiology.

References
1.

2.

3.

4.

5.

6.

Togo S, Holz O, Liu X, Sugiura H, Kamio K,
Wang X, Kawasaki S, Ahn Y, Fredriksson K,
Skold CM, Mueller KC, Branscheid D, Welker L,
Watz H, Magnussen H, Rennard SI. Lung
fibroblast repair functions in patients withchronic obstructive pulmonary disease are alteredby multiple mechanisms. Am J Respir Crit CareMed. 2008;178: 248-60.
Tamaoka M, Hassan M, McGovern T, RamosBarbón D, Jo T, Yoshizawa Y, Tolloczko B,
Hamid Q, Martin JG. The epidermal growth
factor receptor mediates allergic airway
remodelling in the rat. Eur Respir J. 2008 Nov;32(5):1213-23.
Nakajima T, Jo T, Meguro K, Oonuma H, Ma J,
Kubota N, Imuta H, Takano H, Iida H, Nagase T,
Nagata T. Effect of dexamethasone on voltagegated Na+ channel in cultured human bronchialsmooth muscle cells. Life Sci. 2008 Jun 6;82
(23-24):1210-5.
Martin JG, Jo T. Genetic differences in airway
smooth muscle function. Proc Am Thorac Soc.
2008 Jan 1;5(1):73-9. Review.
Shojima J, Tanaka G, Keicho N, Tamiya G, AndoS, Oka A, Inoue Y, Suzuki K, Sakatani M, Okada
M, Kobayashi N, Toyota E, Kudo K, Kajiki A,
Nagai H, Kurashima A, Oketani N, Hayakawa H,
Takemura T, Nakata K, Ito H, Morita T,
Matsushita I, Hijikata M, Sakurada S, Sasazuki T,
Inoko H. Identification of MICA as asusceptibility gene for pulmonary
Mycobacterium avium complex infection. J
Infect Dis 2009;199:1707-1715.
Kage H, Kohyama T, Kitagawa H, Takai D,
Kanda Y, Ohishi N, Nagase T. Non-infectious
bronchiolitis as an early pulmonary complication

122

7.

8.

9.

10.

11.

12.

13.

of hematopoietic stem celltransplantation.
Intern Med. 2008;47:61-4.
Kamio K, Sato T, Liu X, Sugiura H, Togo S,
Kobayashi T, Kawasaki S, Wang X, Mao L, Ahn
Y, Holz O, Magnussen H, Rennard SI.
Prostacyclin analogs stimulate VEGF production
from human lung fibroblasts in culture. Am J
Physiol Lung Cell Mol Physiol. 2008; 294:
L1226-32.
Hashimoto M, Wang X, Mao L, Kobayashi T,
Kawasaki S, Mori N, Toews ML, Kim HJ,
Cerutis DR, Liu X, Rennard SI. Sphingosine
1-phosphate potentiates human lung fibroblast
chemotaxis through the S1P2 receptor. Am J
Respir Cell Mol Biol. 2008; 39: 356-63.
Asai K, Foley SC, Sumi Y, Yamauchi Y, Takeda
N, Desrosiers M, Lavigne F, Hamid Q. Amb a
1-immunostimulatory
oligodeoxynucleotide
conjugate
immunotherapy
increases
CD4+CD25+ T Cells in the nasal mucosa of
subjects with allergic rhinitis. Allergol Int. 2008;
57(4):377-381.
Li YJ, Takizawa H, Azuma A, Kohyama T,
Yamauchi Y, Kawada T, Kudoh S, Sugawara I.
The effects of oxidative stress induced byprolonged low-dose diesel exhaust particle
exposure on the generation of allergic airway
inflammation differ between BALB/c and
C57BL/6
mice.
Immunopharmacol
Immunotoxicol. 2008 Sep 12:1-15.
Kohyama T, Yamauchi Y, Takizawa H, Itakura S,
Kamitani S, Kato J, Nagase T. Clarithromycin
inhibits fibroblast migration. Respir Med. 2008;
102:1769-1776
Li YJ, Takizawa H, Azuma A, Kohyama T,
Yamauchi Y, Takahashi S, Yamamoto M, Kawada
T, Kudoh S, Sugawara I. Disruption of Nrf2
enhances susceptibility to airway inflammatory
responses induced by low-dose diesel exhaust
particles in mice. Clin Immunol. 2008; 128(3):366-373
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 Lung

14.

15.

16.

17.

18.

19.

20.

21.

22.

Res. 2008; 34(3):125-39.
Shannon J, Ernst P, Yamauchi Y, Olivenstein R,
Lemiere C, Foley S, Cicora Rt L, Ludwig M,
Hamid Q, Martin JG. Differences in airway
cytokine profile in severe asthma compared tomoderate asthma. Chest. 2008; 133(2):420-6.
Kikuchi K, Kohyama T, Yamauchi Y, Kato J,
Takami K, Okazaki H, Desaki M, Nagase T,
Rennard SI, Takizawa H. C reactive protein
modulates human lung fibroblast migration. Exp
Lung Res 35:48-58, 2009.
Saito RA, Watabe T, Horiguchi K, Kohyama T,
Saitoh M, Nagase T, Miyazono K. Thyroidtranscription factor-1 inhibits transforming
growthfactor-beta-mediatedepithelial-tomesenchymal transition in lung adenocarcinoma
cells. Cancer Res. 69:2783-91, 2009.
Kawakami M, Matsuo Y, Yoshiura K, Nagase T,
Yamashita N. Sequential and quantitative
analysis of a murine model of elastase-induced
emphysema. Biol Pharm Bull 2008; 31: 1434-38.
Makita R, Uchijima Y, Nishiyama K, Amano T,
Chen Q, Takeuchi T, Mitani A, Nagase T, Yatomi
Y, Aburatani H, Nakagawa O, Cobo-Stark P,
Igarashi P, Murakami M, Tominaga J, Sato T,
Asano T, Kurihara Y, Kurihara H. Multiple renal
cysts with concentration defects and pulmonary
emphysema in mice lacking TAZ. Am J Physiol
2008; 294: F542-53.
Goto Y, Katsumata N, Nakai S, Sasajima Y,
Yonemori K, Kouno T, Shimizu C, Ando M,
Fujiwara Y. Leptomeningeal metastasis fromovarian carcinoma successfully treated by the
intraventricular administration of methotrexate.
Int J Clin Oncol 2008;13:555-558.
Goto Y, Sekine I, Yamada K, Nokihara H,
Yamamoto N, Kunitoh H, Ohe Y, Tamura T.
Influence of previous chemotherapy on theefficacy of subsequent docetaxel therapy inadvanced non-small cell lung cancer patients. J
Thorac Oncol 2008;3:412-416.
Goto Y, Sekine I, Tamura T. Reply: Higher
intensity does not necessary yield better survival
in second-line chemotherapy for NSCLC. J
Thorac Oncol 2008 3(9):1079-1080,
Ono M, Watanabe T, Shimizu C, Hiramoto N,
Goto Y, Yonemori K, Kouno T, Ando M, Tamura

123

K, Katsumata N, et al. Therapy-related acutepromyelocytic leukemia caused by hormonal
therapy and radiation in a patient with recurrent
breast cancer. Jpn J Clin Oncol 2008;38:567-570.
23. Mitani A, Nagase T, Fukuchi K, Aburatani H,
Makita R, Kurihara H. Transcriptional
coactivator with PDZ-binding motif is essential
for normal alveolarization in mice. Am J Respir
Crit Care Med 2009 in press.
24. Nakajima T, Kubota N, Tsutsumi T, Oguri A,
Imuta H, Jo T, Oonuma H, Soma M, Meguro K,
Takano H, Nagase T, Nagata T. Eicosapentaenoic
acid inhibits voltage-gated sodium channels andinvasiveness in prostate cancer cells. Br J
Pharmacol 2009 in press
25. Kikuchi Y, Tateda K, Fuse ET, Matsumoto T,
Gotoh N, Fukushima J, Takizawa H,Nagase T,
Standiford TJ, Yamaguchi K. Hyperoxia
exaggerates bacterial dissemination and lethality
in Pseudomonas aeruginosa pneumonia. Pulm
Pharmacol Ther 2009 in press

124

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.

Shin Maeda, M.D., Ph.D.

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

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

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

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

Keisuke Tateishi, M.D., Ph.D.

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

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

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

Yoshihiro Hirata, M.D., Ph.D.

Motoyuki Otsuka, M.D., Ph.D.

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

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

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

Yousuke Nakai, 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 comprisedof a professor, 3 lecturers, 17 associates, 11 fellows,
30 graduates and 11 other visiting researchers
including students from abroad (March, 2009). A
number of others are under a temporary transfer in andoutside the country. The north and south wings on the
11th floor of Ward A have provided core hospitalrooms for the department. At present, forth and fifth

floor of Ward B also takes important part forproviding rooms of inpatients. Laboratories of thedepartment are scattered in each floor, mainly ofClinical Research Center and First Research Building
as in the other departments.

Clinical Activities
The Department of Gastroenterology is in chargeof about 97 inpatients on average, which is about
2,700 in total per year. We receive about 110 new
patients in and out of the hospital each week, with anaverage hospital stay of 12.9 days. Resident, juniorand senior staff members bear the responsibility for a
medical management of each inpatient, in
collaboration with subspecialty groups concerned. The
staff members examine about 5,600 outpatients with

125

various digestive diseases in a month. Professor’s
ward round is performed on Monday and Wednesday
mornings. Specialty and subspecialty clinicalconferences are held on Monday evening.
Hepatocellular carcinoma is the most common
disease in patients who are admitted to the department.
(1217 cases in 2008). 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 (108 casesin 2008). 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 750 cases eachyear. The number of patients treated forcholedocholithiasis with endoscopic papillary balloon
dilation method exceed 1,000, which is possibly thelargest in the world. Endoscpic metallic stenting is aneffective palliative care for malignant obstructive
jaundice (40 patients a year). Covered metallic stentplacement has been performed in a total of 550 cases,
which may be the world’s largest number. Pancreaticinterventions such as pancreatic stenting, cystic
drainage, endoscopic stone extraction and lithotripsy
using ESWL (extracorporeal shock-wave lithotripsy)
are also performed for many challenging cases. ESD(endoscopic submucosal dissection) is performed as a
curative endoscopic treatment for neoplasms inesophagus, stomach or colon (240 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
performed on 16,000 patients, gastroduodenalendoscopy on 6,700, and colonoscopy on 3,500
patients each year, leading the detection of about 140
cases of gastric cancer and 170 cases of colorectal
cancer annually. About 50 % of them are treatedendoscopically, but we also aim to perform basic
studies using specimen, and turn these efforts toclinical 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

126

research are virtually unlimited as shown in the list of
publication described below. Both basic and clinicalresearchers are equally encouraged, on condition thatthe 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 indatabase and analyzed. Studies oriented forevidence-based medicine are highly appreciated.
Recent randomized-controlled trials include interferon
to prevent recurrence of hepatocellular carcinoma,
evaluation of diagnostic usefulness of angiography
with computed tomography, and radiofrequency
ablation for liver metastasis of colorectal cancer. We
have also designed clinical trials of TSU-68 foradvanced hepatocellular carcinoma, erythropoietin foranemia introduced by interferon with ribavirin therapy,
TS-1 alone or combined with gemcitabine forpancreatic and bile duct cancers, additional mosapridein therapy of gastroesophageal reflux disease, andinvestigation and treatment trial of the small intestinal
lesions in NSAID users by capsule endoscopy.
The department is dedicated to pursuing bettermedical services from all facets of the subspecialty ofgastroenterology, which is brought about by bothbasic and clinical researches.

3:

4:

5:

6:

7:

References
1:

2:

Masuzaki R, Yoshida H, Tateishi R, Shiina
S, Omata M. Hepatocellular carcinoma inviral hepatitis: improving standard therapy.
Best Pract Res Clin Gastroenterol. 2008;
22:1137-51.
Li Y, Tanaka Y, Tada M, Hua R, Seto M,
Asaoka Y, Ohta M, Kanai F, Yoshida H,
Kawabe T, Sano T, Motojima T, Yokosuka O,
Omata M. Absence of the AKT1 pleckstrin
homology domain mutation in Japanese
gastrointestinal and liver cancer patients.
APMIS. 2008;116:931-3.

8:

9:Tomiya T, Omata M, Imamura H, Fujiwara
K. Impaired liver regeneration in acuteliver
failure:thesignificanceofcross-communication of growth associatedfactors in liver regeneration. Hepatol Res.
2008;38 (s1The 6 Japan Society of
Hepatology Single Topic Conference: Liver
Failure: Recent Progress and Pathogenesis
to Management. 28-29 September 2007,
Iwate, Japan): S29-S33.
Fujishiro M, Kodashima S, Goto O, Ono S,
Muraki Y, Kakushima N, Omata M.
Technical
feasibilityofendoscopic
submucosal dissection of gastrointestinal
epithelial neoplasms with a splash-needle.
Surg Laparosc Endosc Percutan Tech.
2008;18:592-7.
Imamura J, Tateishi R, Shiina S, Goto E,
Sato T, Ohki T, Masuzaki R, Goto T,
Yoshida H, Kanai F, Hamamura K, Obi S,
Yoshida H, Omata M. Neoplastic seedingafter
radiofrequency
ablationforhepatocellular
carcinoma.
Am
J
Gastroenterol. 2008;103:3057-62.
Goto O, Fujishiro M, Kodashima S, Ono S,
Omata M. Is it possible to predict theprocedural time of endoscopic submucosal
dissection for early gastric cancer? J
Gastroenterol Hepatol. 2009;24:379-83.
Fujiwara K, Kojima H, Yonemitsu Y, Yasui
S, Imazeki F, Miki M, Suzuki K, Sakaida I,
Okita K, Tanaka E, Omata M, Yokosuka O.
Phylogenetic analysis of hepatitis A virus
in sera from patients with hepatitis A ofvarious severities. Liver Int. 2008 Nov 25.
Ohta M, Seto M, Ijichi H, Miyabayashi K,
Kudo Y, Mohri D, Asaoka Y, Tada M,
Tanaka Y, Ikenoue T, Kanai F, Kawabe T,
Omata M. Decreased expression of the
RAS-GTPase activating protein RASAL1 is
associatedwithcolorectal
tumor
progression. Gastroenterology. 2009;136:
206-16.
Ikeda H, Watanabe N, Ishii I, Shimosawa T,
Kume Y, Tomiya T, Inoue Y, Nishikawa T,
Ohtomo N, Tanoue Y, Iitsuka S, Fujita R,
Omata M, Chun J, Yatomi Y. Sphingosine

1271-phosphate regulates regeneration andfibrosis after liver injury via sphingosine
1-phosphate receptor 2. J Lipid Res. 2009;
50:556-64.
10: Nakai Y, Isayama H, Kawabe T, Tsujino T,
Yoshida H, Sasaki T, Tada M, Arizumi T,
Yagioka H, Kogure H, Togawa O, Ito Y,
Matsubara S, Hirano K, Sasahira N,
Omata M. Efficacy and safety of metallic
stents in patients with unresectablepancreatic cancer receiving gemcitabine.
Pancreas. 2008;37:405-10.
11: Masuzaki R, Tateishi R, Yoshida H, Goto E,
Sato T, Ohki T, Goto T, Yoshida H, Kanai F,
Sugioka Y, Ikeda H, Shiina S, Kawabe T,
Omata M. Comparison of liver biopsy andtransient elastography based on clinicalrelevance. Can J Gastroenterol. 2008;22:753-7.
12: Hirano K, Tada M, Isayama H, Yashima Y,
Yagioka H, Sasaki T, Kogure H, Togawa O,
Arizumi T, Matsubara S, Nakai Y, SasahiraN, Tsujino T, Kawabe T, Omata M. Clinicalfeatures of primary sclerosing cholangitis
with onset age above 50 years. J
Gastroenterol. 2008;43:729-33.
13: Yamaji Y, Okamoto M, Yoshida H, Kawabe
T, Wada R, Mitsushima T, Omata M. The
effect of body weight reduction on theincidence of colorectal adenoma. Am J
Gastroenterol. 2008;103:2061-7.
14: Watabe H, Mitsushima T, Derakhshan MH,
Yamaji Y, Okamoto M, Kawabe T, Omata M,
McColl KE. Study of association between
atrophic gastritis and body mass index: across-sectional study in 10,197 Japanese
subjects. Dig Dis Sci. 2009;54:988-95.
15: Lin LJ, Asaoka Y, Tada M, Sanada M,
Nannya Y, Tanaka Y, Tateishi K, Ohta M,
Seto M, Sasahira N, Tada M, Kawabe T,
Zheng CQ, Kanai F, Ogawa S, Omata M.
Integrated analysis of copy number
alterations and loss of heterozygosity inhuman pancreatic cancer using ahigh-resolution,
singlenucleotide
polymorphism array. Oncology. 2008;75:
102-12.

16: Masuzaki R, Omata M. Treatment of
hepatocellular
carcinoma.
IndianJ
Gastroenterol. 2008;27:113-22.
17: Nakai Y, Kawabe T, Isayama H, Sasaki T,
Yagioka H, Yashima Y, Kogure H, Arizumi
T, Togawa O, Ito Y, Matsubara S, Hirano K,
Sasahira N, Tsujino T, Tada M, Omata M.
CA 19-9 response as an early indicator of
the effectiveness of gemcitabine in patientswith advanced pancreatic cancer. Oncology.
2008;75:120-6.
18: Yamashiki N, Sugawara Y, Tamura S,
Kaneko J, Matsui Y, Togashi J, Kokudo N,
Omata M, Makuuchi M. Double-dose
double-phase use of second generation
hepatitis B virus vaccine in patients after
living donor liver transplantation: Not aneffective measure in transplant recipients.
Hepatol Res. 2009;39:7-13.
19: Ito Y, Tsujino T, Togawa O, Yamamoto N,
Isayama H, Nakata R, Kawabe T, Omata M.
Endoscopic papillary balloon dilation forthe management of bile duct stones inpatients 85 years of age and older.
Gastrointest Endosc. 2008;68:477-82.
20: Tanaka Y, Kanai F, Tada M, Tateishi R,
Sanada M, Nannya Y, Ohta M, Asaoka Y,
Seto M, Shiina S, Yoshida H, Kawabe T,
Yokosuka O, Ogawa S, Omata M. Gain of
GRHL2 is associated with early recurrenceof hepatocellular carcinoma. J Hepatol.
2008;49:746-57.
21: Kanda M, Tateishi R, Yoshida H, Sato T,
Masuzaki R, Ohki T, Imamura J, Goto T,
Yoshida H, Hamamura K, Obi S, Kanai F,
Shiina S, Omata M. Extrahepatic
metastasis of hepatocellular carcinoma:
incidence and risk factors. Liver Int.
2008;28:1256-63.
22: Kondo S, Yamamoto N, Nakai Y, Sasahira
N, Hirano K, Tsujino T, Isayama H, Toda N,
Komatsu Y, Tada M, Yoshida H, Kawabe T,
Otomo K, Omata M. Preservation ofpapillary relaxation after endoscopic
papillaryballoondilation.
Hepatogastroenterology. 2008;55:855-8.
23: Nakagawa H, Maeda S, Hikiba Y, Ohmae T,

128

Shibata W, Yanai A, Sakamoto K, Ogura K,
Noguchi T, Karin M, Ichijo H, Omata M.
Deletion of apoptosis signal-regulating
kinase 1 attenuates acetaminopheninduced liver injury by inhibiting c-Jun
N-terminal
kinaseactivation.
Gastroenterology. 2008;135:1311-21.
24: Tada M, Arizumi T, Nakai Y, Sasaki T,
Kogure H, Togawa O, Matsubara S, Tsujino
T, Hirano K, Sasahira N, Isayama H,
Kawabe T, Omata M. Efficacy of
gemcitabineforlocallyadvancedpancreaticcancer:comparison
with
5-fluorouracil-based
chemoradiotherapy.
Chemotherapy. 2008;54:302-8.
25: Yamaji Y, Okamoto M, Yoshida H, Kawabe
T, Wada R, Mitsushima T, Omata M.
Cholelithiasis is a risk factor for colorectal
adenoma. Am J Gastroenterol. 2008;103:2847-52.
26: Masuzaki R, Tateishi R, Yoshida H,
Yoshida H, Sato S, Kato N, Kanai F,
Sugioka Y, Ikeda H, Shiina S, Kawabe T,
Omata
M.
Risk
assessmentof
hepatocellular carcinoma in chronic
hepatitisC
patients
bytransientelastography. J Clin Gastroenterol. 2008;
42:839-43.
27: Ono S, Fujishiro M, Goto O, Kodashima S,
Omata M. En bloc resection of cardia
cancer and lipoma with endoscopic
submucosal dissection. Dig Liver Dis.
2009;41:237.
28: Fujishiro M, Kodashima S, Goto O, Ono S,
Muraki Y, Kakushima N, Omata M.
Successful en bloc resection of superficial
esophageal cancer treated by endoscopic
submucosal dissection with a splash needle.
Endoscopy. 2008;40 Suppl 2:E81-2.
29: Hasegawa K, Makuuchi M, Takayama T,
Kokudo N, Arii S, Okazaki M, Okita K,
Omata M, Kudo M, Kojiro M, Nakanuma Y,
Takayasu K, Monden M, Matsuyama Y,
Ikai I. Surgical resection vs. percutaneous
ablation for hepatocellular carcinoma: apreliminary report of the Japanesenationwide survey. J Hepatol. 2008;49:

589-94.
30: Ohta M, Sugimoto T, Seto M, Mohri D,
Asaoka Y, Tada M, Tanaka Y, Yamaji Y,
Kanai F, Kawabe T, Omata M. Genetic
alterations in colorectal cancers withdemethylation of insulin-like growth factor
II. Hum Pathol. 2008;39:1301-8.
31: Hua R, Tanaka Y, Fukai K, Tada M, Seto M,
Asaoka Y, Ohta M, Goto T, Kanai F, Kato N,
Yoshida H, Kawabe T, Yokosuka O, Omata
M. Rapid detection of the hepatitis B virus
YMDD mutant using TaqMan-minor
groove binder probes. Clin Chim Acta.
2008;395:151-4.
32: Otani K, Kitayama J, Kaisaki S, Ishigami
H, Hidemura A, Fujishiro M, Omata M,
Nagawa H. Early gastric cancer showsdifferent associations with adipose tissue
volume depending on histological type.
Gastric Cancer. 2008;11:86-95.
33: Shibata W, Maeda S, Hikiba Y, Yanai A,
Sakamoto K, Nakagawa H, Ogura K, Karin
M, Omata M. c-Jun NH2-terminal kinase 1
is a critical regulator for the developmentof gastric cancer in mice. Cancer Res.
2008;68:5031-9.
34: Takagi H, Sasaki S, Suzuki H, Toyota M,
Maruyama R, Nojima M, Yamamoto H,
Omata M, Tokino T, Imai K, Shinomura Y.
Frequent epigenetic inactivation of SFRP
genes in hepatocellular carcinoma. J
Gastroenterol. 2008;43:378-89.
35: Kondo Y, Yoshida H, Tateishi R, Shiina S,
Kawabe T, Omata M. Percutaneousradiofrequency ablation of liver cancer inthe hepatic dome using the intrapleural
fluid infusion technique. Br J Surg. 2008;
95:996-1004.
36: Tada M, Kanai F, Tanaka Y, Tateishi K,
Ohta M, Asaoka Y, Seto M, Muroyama R,
Fukai K, Imazeki F, Kawabe T, Yokosuka O,
Omata M. Down-regulation of hedgehoginteracting protein through genetic andepigenetic
alterations
inhuman
hepatocellular carcinoma. Clin Cancer Res.
2008;14:3768-76.
37: Suzuki F, Toyoda J, Katano Y, Sata M,

129

Moriyama M, Imazeki F, Kage M, Seriu T,
Omata M, Kumada H. Efficacy and safetyof entecavir in lamivudine-refractorypatients with chronic hepatitis B:
randomized controlled trial in Japanesepatients. J Gastroenterol Hepatol. 2008;23:
1320-6.
38: Yoshikumi Y, Ohno H, Suzuki J, Isshiki M,
Morishita Y, Ohnishi H, Yasuda H, Omata
M, Fujita T, Mashima H. Up-regulation of
JAM-1 in AR42J cells treated with activin
A and betacellulin and the diabetic
regenerating islets. Endocr J. 2008;55:
757-65.
39: Igaki H, Nakagawa K, Shiraishi K, Shiina
S, Kokudo N, Terahara A, Yamashita H,
Sasano N, Omata M, Ohtomo K.
Three-dimensional conformal radiotherapy
for hepatocellular carcinoma with inferior
vena cava invasion. Jpn J Clin Oncol. 2008;
38:438-44.
40: Ogura K, Okamoto M, Sugimoto T, Yahagi
N,
Fujishiro
M,
Kakushima
N,
KodashimaS, Kawabe T, Omata M.
Efficacy
andsafetyofendoscopic
submucosal dissection for gastric cancer inpatients with liver cirrhosis. Endoscopy.
2008;40:443-5.
41: Ogura M, Hikiba Y, Maeda S, Matsumura
M, Okano K, Sassa R, Yoshida H, Kawabe T,
Omata M. Mortality from gastric cancer inpatients
followedwithupper
gastrointestinalendoscopy.
Scand
J
Gastroenterol. 2008;43:574-80.
42: Nakai Y, Isayama H, Tsujino T, Kawabe T,
Yashima Y, Yagioka H, Kogure H, Sasaki T,
Togawa O, Arizumi T, Ito Y, Matsubara S,
Hirano K, Sasahira N, Tada M, Omata M.
Intraductal US in the assessment of tumor
involvement to the orifice of the cystic ductbymalignantbiliary
obstruction.
Gastrointest Endosc. 2008;68:78-83.
43: Sermasathanasawadi
R,
Kato
N,
Muroyama R, Dharel N, Shao RX, Chang
JH, Li CZ, Kawabe T, Omata M.
Associationofinterferon
regulatory
factor-7 gene polymorphism with livercirrhosis in chronic hepatitis C patients.
Liver Int. 2008;28:798-806.
44: Goto O, Fujishiro M, Kodashima S,
Kakushima N, Ono S, Yahagi N, Omata M.
Feasibility of electrocautery snaring as the
final step of endoscopic submucosal
dissection for stomach epithelial neoplasms.
Dig Liver Dis. 2009;41:26-30.
45: Ohki T, Tateishi R, Sato T, Masuzaki R,
Imamura J, Goto T, Yamashiki N, Yoshida
H, Kanai F, Kato N, Shiina S, Yoshida H,
Kawabe T, Omata M. Obesity is anindependent risk factor for hepatocellular
carcinomadevelopmentinchronic
hepatitis C patients. Clin Gastroenterol
Hepatol. 2008;6:459-64.
46: Eguchi S, Kanematsu T, Arii S, Okazaki M,
Okita K, Omata M, Ikai I, Kudo M, Kojiro
M, Makuuchi M, Monden M, Matsuyama Y,
Nakanuma Y, Takayasu K; Liver Cancer
Study Group of Japan. Comparison of theoutcomes
betweenananatomical
subsegmentectomy and a non-anatomical
minor
hepatectomy
forsinglehepatocellular carcinomas based on a
Japanese nationwide survey. Surgery.
2008;143:469-75.
47: Mashima H, Suzuki J, Hirayama T,
Yoshikumi Y, Ohno H, Ohnishi H, Yasuda
H, Fujita T, Omata M. Involvement ofvesicle-associated membrane protein 7 inhuman gastric epithelial cell vacuolationinduced by Helicobacter pylori-produced
VacA. Infect Immun. 2008;76:2296-303.
48: Togawa O, Kawabe T, Isayama H, Nakai Y,
Sasaki T, Arizumi T, Matsubara S, Ito Y,
Yamamoto N, Sasahira N, Hirano K,
Tsujino T, Toda N, Tada M, Yoshida H,
Omata M. Management of occluded
uncovered metallic stents in patients withmalignant distal biliary obstructions using
coveredmetallic
stents.
J
Clin
Gastroenterol. 2008;42:546-9. 49: Maeda S,
Omata M. Inflammation and cancer: role ofnuclear factor-kappaB activation. Cancer
Sci. 2008;99:836-42.
50: Fujishiro M, Kodashima S, Takubo K,

130

Kakushima N, Omata M. Detailed
comparison between endocytoscopy andhorizontal histology of an esophageal
intraepithelial squamous cell carcinoma.
Dis Esophagus. 2008;21:181-5.
51: Ogura K, Hirata Y, Yanai A, Shibata W,
Ohmae T, Mitsuno Y, Maeda S, Watabe H,
Yamaji Y, Okamoto M, Yoshida H, Kawabe
T, Omata M. The effect of Helicobacter
pylori eradication on reducing theincidence of gastric cancer. J Clin
Gastroenterol. 2008;42:279-83.
52: Dharel N, Kato N, Muroyama R, Taniguchi
H, Otsuka M, Wang Y, Jazag A, Shao RX,
Chang JH, Adler MK, Kawabe T, Omata M.
Potential contribution of tumor suppressor
p53 in the host defense against hepatitis C
virus. Hepatology. 2008;47:1136-49.
53: Tsujino T, Isayama H, Tada M, Sugawara Y,
Kawabe T, Omata M. Intraductal US in
biliary cast after living donor livertransplantation (with video). Gastrointest
Endosc. 2008;67:540-1.
54: Goto O, Fujishiro M, Kakushima N,
Kodashima S, Ono S, Yamaguchi H,
Nomura S, Kaminishi M, Omata M.
Endoscopic submucosal dissection as astaging measure may not lead to worse
prognosis in early gastric cancer patientswith additional gastrectomy. Dig Liver Dis.
2008;40:293-7.
55 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 andsafety of low-pressured and short-time
dilation in endoscopic papillary balloon
dilation for bile duct stone removal. J
Gastroenterol Hepatol. 2008;23:867-71.
56: 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 therisk factors for colonic diverticularhemorrhage. Dis Colon Rectum. 2008;51:
116-20.

57: Yamada G, Iino S, Okuno T, Omata M,
Kiyosawa K, Kumada H, Hayashi N, Sakai
T. Virological response in patients with
hepatitis C virus genotype 1b and a highviral load: impact of peginterferonalpha-2a plus ribavirin dose reductions andhost-related factors. Clin Drug Investig.
2008;28:9-16.
58: Liao G, Wang Y, Chang J, Bian T, Tan W,
Sun M, Li W, Yang H, Chen J, Zhang X, Bi
S, Omata M, Jiang S. Hepatitis B virus
precoreproteinaugments
genetic
immunizations of the truncated hepatitis C
virus core in BALB/c mice. Hepatology.
2008;47:25-34.
59: Yanai A, Maeda S, Shibata W, Hikiba Y,
Sakamoto K, Nakagawa H, Ohmae T,
Hirata Y, Ogura K, Muto S, Itai A, Omata
M. Activation of IkappaB kinase and
NF-kappaB is essential for Helicobacter
pylori-induced
chronic
gastritisin
Mongolian gerbils. Infect Immun. 2008;76:
781-7.
60: Makuuchi M, Kokudo N, Arii S, Futagawa
S, Kaneko S, Kawasaki S, Matsuyama Y,
Okazaki M, Okita K, Omata M, Saida Y,
Takayama T, Yamaoka Y. Development ofevidence-based clinical guidelines for the
diagnosis and treatment of hepatocellular
carcinoma in Japan. Hepatol Res. 2008;38:
37-51.
61: Kogure H, Tsujino T, Yagioka H, Sasaki T,
Nakai Y, Hirano K, Sasahira N, Isayama H,
Tada
M,
KawabeT,
Omata
M.
Self-expandable
metallic
stentsformalignant biliary obstruction with ananomalous pancreaticobiliary junction.
Surg Endosc. 2008;22:787-91.

Internal Medicine
2. Medicine Ⅱ132

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.,

Norio Hanafusa, 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. Usually we have up to 30 inpatients in thehospital. The Professor and each member of the staff
have an active responsibility for all clinical activities.
Each member has an office and a research laboratory.
In our department, almost all members support theclinical works of our residents, and other 2 associates
are involved mainly in the Hemodialysis Unit. We are
intimately working together in all clinical activities

133

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 gonadal 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.

134

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

Ltd.) of the Graduate School of Medicine, theUniversity of Tokyo. Our department also belongs to
the 22nd Century Medical Center, which partly
represents the translational research activities of The
University of Tokyo Hospital. Our department isestablished with the main aim of performing theclinical and epidemiological analysis on the metabolic
syndrome in the Japanese population, of isolating
susceptibility gene(s) to metabolic syndrome throughmolecular and genetic analysis on human and rodent
animal models, and of contributing to the developmentof novel diagnostic method and therapeutic agents forthe prevention 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.
 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.
 Performance of clinical and epidemiologicalanalysis with regard to metabolic syndrome.
 Development of novel diagnositic method for risk
factors of cardiovascular diseases.
 Contribution to the development of preventive andtherapeutic novel agents to treat patients withmetabolic syndrome.
 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 Mitsubishi Seiyaku Co.,

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

135(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 therenoprotective
effect
of
some
types
of
antihypertensives such as calcium channel blockers
and aldosterone antagonists.

Publications
1. Suzuki M, Vaisbich M, Yamada H, Horita S, Li Y,
Sekine T, Moriyama N, Igarashi T, Endo Y,
Cardoso T, de Sá L, Koch H, Seki G, Fujita, T.
Functional analysis of a novel missense NBC1
mutation and of other mutations causing proximal
renal tubular acidosis. Pflugers Arch 2008 ；455:583-593.
2. Li Y, Yamada H, Kita Y, Kunimi M, Horita S,
Suzuki M, Endo Y, Shimizu T, Seki G, Fujita T.
Roles of ERK and cPLA2 in the angiotensin
II-mediated biphasic regulation of Na+-HCO3transport. J Am Soc Nephrol 2008;19: 252-259.
3. Yamazaki O, Hanafusa N, Shirai A, Hanamura K,
Kinugasa S, Hamasaki Y, Mimura I, Endo Y,
Satonaka H, Shibagaki Y, Noiri E, Yamada A,
Omata M, Fujita T. Recurrent intestinal bleeding
successfully treated by means of double-balloon
endoscopy in a hemodialysis patient. J Jpn Soc
Dial Ther 2008;41: 445-49.
4. Eto N, Miyagishi M, Inagi R, Fujita T, Nangaku
M. Suppression of MAP3 kinase 6 mediates
anti-angiogenic and tumor-suppressive effects via
VEGF expression. Am J Pathol 2009;174:15531563.
5. Kojima I, Tanaka T, Inagi R, Nishi H, Aburatani H,
Kato H, Miyata T, Fujita T, Nangaku M.
Metallothionein is up-regulated by hypoxia andstabilizes HIF in the kidney. Kidney Int 2009;75:
268-277.
6. Nishi H, Inagi R, Kato H, Tanemoto M, Kojima I,
Son D, Fujita T, Nangaku M. Hemoglobin isexpressed as anti-oxidant factor by mesangial cell.
J Am Soc Nephrol 2008;19:1500-1508.
7. Inagi R, Kumagai T, Miyata T, Fujita T, Nangaku
M. Preconditioning of endoplasmic reticulum(ER)
stressameliorated
anti-Thy1
glomerulonephritis of rats. J Am Soc Nephrol
2008;19:915-922.
8. Ohtomo S, Nangaku M, Izuhara Y, Mori T, Ito S,
van Ypersele de Strihou C, Miyata T. The role ofmegsin, a serine protease inhibitor, in diabetic
mesangial matrix accumulation. Kidney Int
2008;74:768-774.
9. Onozato ML, Tojo A, Leiper J, Fujita T, Palm F,
Wilcox CS. Expression of DDAH and PRMT
isoforms in the diabetic rat kidney; effects ofangiotensin II receptor blocker. Diabetes 2008;57:
172-180.
10. Mimura I, Tojo A, Uozaki H, Fujita T.
Erythrophagocytosis by renal tubular cells.
Kidney Int 2008;74:398.
11. Takase O, Minto AW, Puri TS, Cunningham PN,
Jacob A, Hayashi M, Quigg RJ. Inhibition of
NF-kappaB-dependent Bcl-xL expression byclusterin promotes albumin-induced tubular cell
apoptosis. Kidney Int 2008;73:567-577.
12. Marumo T, Hishikawa K, Yoshikawa M, Fujita T.
Epigenetic regulation of BMP7 in the regenerative
response to ischemia. J Am Soc Nephrol 2008;19:
1311-1320.
13. Kido M, Ando K, Onozato ML, Tojo A,
Yoshikawa M, Ogita T, Fujita T. Protective effectof dietary potassium against the vascular injury insalt-sensitive hypertension. Hypertension 2008;
51:225-231.
14. Matsui H, Ando K, Kawarazaki H, Nagae A,
Fujita M, Shimosawa T, Nagase M, Fujita T. Salt
excesscausesleft
ventricular
diastolicdysfunction in rats with metabolic disorder.
Hypertension 2008;52:287-294.
15. Wang H, Shimosawa T, Matsui H, Kaneko T,
Ogura S, Uetake Y, Takenaka K, Yatomi Y, Fujita
T.
Paradoxicalmineralocorticoid receptor
activation and left ventricular diastolic

136

dysfunction under high oxidative stress conditions.
J Hypertens 2008;26:1453-1462.
16. Mutoh A, Isshiki M, Fujita T. Aldosterone
enhances
ligand-stimulated
nitricoxide
production in endothelial cells. Hypertens Res
2008;31:1811-20.
17. Shibata S, Nagase M, Yoshida S, Kawarazaki W,
Kurihara H, Tanaka H, Miyoshi J, Takai Y, Fujita
T. Modification of mineralocorticoid receptor
function by Rac1 GTPase: implication inproteinuric kidney disease. Nat Med 2008;14:1370-1376.
18. Nagae A, Fujita M, Kawarazaki H, Matsui H,
Ando K, Fujita T. Sympathoexcitation byoxidative stress in the brain mediates arterialpressureelevationinobesity-induced
hypertension. Circulation 2009;119:978-986.
19. Yamazaki Y, Tamada T, Kasai N, Urakawa I, Aono
Y, Hasegawa H, Fujita T, Kuroki R, Yamashita T,
Fukumoto S, Shimada T. Anti-FGF23 neutralizing
antibodies demonstrate the physiological role andstructural features of FGF23. J Bone Miner Res
2008;23:1509-1518.
20. Morita K, Takano K, Yasufuku-Takano J, Yamada
S, Teramoto A, Fujita T. Expression of
pituitary-tumor-derived isoform of fibroblast
growth factor receptor 4 (ptd-FGFR4) in humanGH-secreting pituitary adenomas correlates withtumor invasiveness, not with gsp mutation. Clin
Endocrinol 2008;68:435-441.
21. Takano K, Yasufuku-Takano J, Morita K, Mori S,
Takei M, Osamura RY, Teramoto A, Fujita T.
Evidence that PKA activity is constitutively
activated in human GH-secreting adenoma cells ina patient with Carney complex harbouring a
PRKAR1A
mutation,
Clin
Endocrinol
2009;70:769–775.
(Total 66 publications)

137

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.

Assistant Professor
Ken Ohashi, M.D., Ph.D.,
Midori Fujishiro, M.D., Ph.D.,
Nobuhiro Shojima, M.D., Ph.D.,
Motohiro Sekiya, M.D., Ph.D.,
Motoharu Awazawa, M.D., Ph.D.

Homepage

Hideyuki Sakoda, M.D., PhD.
Mitsuru Ohsugi, M.D.,
Momoko Horikoshi, M.D., Ph.D.
Yusuke Hada, M.D., Ph.D.

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. The
physicians specialized in the metabolic diseases from
3 former 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 of Internal Medicine at
the University of Tokyo, and covers metabolic
diseases including diabetes mellitus, obesity anddyslipidemia.
Under the supervision and direction of the previous
professors Dr. Satoshi Kimura (1998-2003) and Dr.
Toshiro Fujita (2003) and currently Professor Dr.
Takashi Kadowaki (2003-present), we have been
providing a wide-ranged clinical, teaching andresearch activities. Currently, we hold 35 beds
mainly on the 12th floor of the North Wing Ward A
and the 4th floor of the Ward B of the Tokyo
University Hospital, and take care of more than 30
inpatients constantly. Besides the staffs listed above,
our division holds faculties in branches, for example,

Department of Integrated Molecular Science on
Metabolic Diseases (Associate Professor, Dr.
Toshimasa Yamauchi and Assistant Professor, Dr.
Yukiko Okazaki), Department of Molecular
Physiology on Energy Metabolism (Associate
Professor, Dr. Naoya Yahagi and Assistant Professor,
Dr. Hironori Waki), Department of Translational
Systems Biology and Medicine Initiative (Associate
Professor, Dr. Naoto Kubota), The Clinical Training
Center (Lecturer, Dr. Kazuo Hara), Department ofPatient Safety & Risk Management (AssistantProfessor, Dr. Kenji Harada), Division of Biophysics,
Center for Disease Biology and Integrative Medicine(Lecturer, Dr. Noriko Takahahsi), and Division for
Health Service Promotion, The University of Tokyo(Assistant Professor, Dr. Takayoshi Sasako). With
all these staffs, we actively instruct and teach theresidents and medical school 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, we
enthusiastically work on the research activities, whichlead to the outstanding contributions in the field of

138

metabolism.

Clinical activities
Based on the update clinical evidences and with theexperienced skills, we provide patient-centered
medical services in the highest quality. We haveoutpatient clinics from Monday through Friday, andhave been following more than 4000 patients. On theinpatient ward, 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
suffering from metabolic diseases, especially diabetes
mellitus. Diabetes mellitus, metabolic syndrome,
dyslipidemia and obesity are becoming moreprevalent in Japan, and lead to complications
including nephropathy, retinopathy, neuropathy andcardiovascular diseases. Thus, in collaboration withother departments, we optimize the treatment of eachpatient.
We provide the educational classes 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 ancillary staffs of our hospital, we
provide patients well-reasoned instructions regarding
nutritional management, excise therapy and medical
therapy.
The weekly official activities of our department
consist of the pre-round case conference and the Ward
Round by the Professor on Monday. We also hold aweekly case conference by the consultation group
staffs.

Teaching activities
As for medical student education, our department
takes a part in systemic lectures for the 4th year
medical students, bed-side learning and clinicalclerkship for the 5th year medical students, andclinical lectures for the 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 dohistory taking, perform physical examinations andmake the actual plans for the diagnosis and treatment.
Lectures that lead to profound understandings of themetabolic diseases are regularly provided by the staff
physicians.
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 attempting 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 mechanisms of insulin
secretion under the normal or pathological conditions,such as diabetes and obesity, using a number oftransgenic and knockout animal models.
In
particular, we are interested in the physiological andpathopysiological functions of adipokines secreted byadipocytes, including adiponectin, and the signaltransduction pathway of adiponectin through thereceptors, AdipoR1 and AdipoR2, that we discovered
and characterized.
In addition, we have beensuccessfully unraveling the molecular mechanisms of
β cell proliferation. We believe that these findings

139

will lead to novel therapeutic strategies for diabetes
and the metabolic 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
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. Arai T, Hashimoto H, Kawai K, Mori A, Ohnishi Y,
Hioki K, Ito M, Saito M, Ueyama Y, Ohsugi M,
Suzuki R, Kubota N, Yamauchi T, Tobe K,
Kadowaki T, Kosaka K. Fulminant type 1 diabetes
mellitus observed in insulin receptor substrate 2
deficient mice. Clin Exp Med. 2008;8:93-99.
2. Davies BS, Waki H, Beigneux AP, Farber E,
Weinstein MM, Wilpitz DC, Tai LJ, Evans RM,
Fong LG, Tontonoz P, Young SG. The expressionof GPIHBP1, an endothelial cell binding site forlipoprotein lipase and chylomicrons, is induced byperoxisome proliferator-activated receptor-gamma.
Mol Endocrinol. 2008;22:2496-2504.
3. Doi T, Obayashi K, Kadowaki T, Fujii H, Koyasu
S. PI3K is a negative regulator of IgE production.
International Immunology.2008;20:499-508.
4. Egawa M, Kudo Y, Kamata H, Kushiyama A,

Sakoda H, Fujishiro M, Horike N, Yoneda M,
Nakatsu Y, Ying G, Jun Z, Tsuchiya Y, Takata K,
Kurihara H, Asano T. Long-term Forskolin
Stimulation Induces AMPK Activation and
Thereby Enhances Tight Junction Formation in
Human Placental Trophoblast BeWo Cells.
Placenta. 2008;29:1003-8.
5. Freude S, Leeser U, Muller M, Hettich MM,
Udelhoven M, Schibach K, Tobe K, Kadowaki T,
Kohler C, Schroder H, Krone W, Bruning JC,
Schubert M. IRS-2 branch of IGF-1 receptor
signaling is essential for appropriate timing of
myelination. J Neurochem. 2008;107:907-17.
6. Fruchart JC, Sacks F, Hermans MP, Assmann G,
Brown WV, Ceska R, Chapman MJ, Dodson PM,
Fioretto P, Ginsberg HN, Kadowaki T, Lablanche
JM, Marx N, Plutzky J, Reiner Z, Rosenson RS,
Staels B, Stock JK, Sy R, Wanner C, Zambon A,
Zimmet P. The residual risk reduction initiative: acall to action to reduce residual vascular risk inpatients with dyslipidemia. Am J Cardiol.
2008;102: 1K-34K.
7. Fruchart JC, Sacks F, Hermans MP, Assmann G,
Brown WV, Ceska R, Chapman MJ, Dodson PM,
Fioretto P, Ginsberg HN, Kadowaki T, Lablanche
JM, Marx N, Plutzky J, Reiner Z, Rosenson RS,
Staels B, Stock JK, Sy R, Wanner C, Zambon A,
Zimmet P. The residual risk reduction initiative: acall to action to reduce residual vascular risk indyslipidemic patients. Diab Vasc Dis Res
2008;5:319-335.
8. Fujio J, Kushiyama A, Sakoda H, Fujishiro M,
Ogihara T, Fukushima Y, Anai M, Horike N,
Kamata H, Uchijima Y, Kurihara H, Asano T.
Regulation of gut-derived resistin-like moleculebeta expression by nutrients. Diabetes Res Clin
Pract. 2008;79:2-10.
9. Fujisawa T, Endo H, Tomimoto A, Sugiyama M,
Takahashi H, Saito S, Inamori M, Nakajima N,
Watanabe M, Kubota N, Yamauchi T, Kadowaki T,
Wada K, Nakagama H, Nakajima A. Adiponectin
Suppresses Colorectal Carcinogenesis under theHigh-fat Diet Condition. Gut. 2008;57:1531-1538.
10. Fujisawa T, Sugiyama M, Tomimoto A, Wada K,
Endo H, Takahashi H, Yoneda K, Yoneda M,
Inamori M, Saito S, Terauchi Y, Kadowaki T,
Tsuchiya
N, Nakagama H, Nakajima A.

140

Inhibition of peroxisome proliferator-activatedreceptor gamma promotes tumorigenesis throughactivation of the beta-catenin/TCF pathway in themouse intestine. J Pharmacol Sci. 2008;108:535544.
11. Fujisawa T, Nakajima A, Fujisawa N, Takahashi H,
Ikeda I, Tomimoto A, Yonemitsu K, Nakajima N,
Kudo C, Wada K, Kubota N, Terauchi Y,
Kadowaki T, Nakagama H, and Blumberg RS.
Peroxisome proliferator-activated receptor γ(PPARγ) suppresses colonic epithelial cell
turnover and colon carcinogenesis throughinhibition of the β-catenin/T cell factor (TCF)
pathway. J Pharmacol Sci 2008;106: 627-638.
12. Hashimoto H, Eto T, Kamisako T, Hoya N,
Hatakeyama T, Arai T, Yokosuka M, Ohnishi Y, Ito
M, Hioki K, Suzuki R, Ohsugi M, Saito M,
Ueyama Y, Yamauchi T, Kubota N, Tobe K,
Kadowaki T, Tamaoki N, Nomura T, Kosaka K.
An Efficient reproductive method for Irs2-/- micewith C57BL/6JJcl genetic background. Exp Anim.
2008;57: 407-411.
13. Horike N, Sakoda H, Kushiyama A, Ono H,
Fujishiro M, Kamata H, Nishiyama K, Uchijima Y,
Kurihara Y, Kurihara H, Asano T. AMPK
activation increases phosphorylation of GSK3beta
and thereby reduces CRE transcriptional activity
and PEPCK-C gene expression in the liver. J Biol
Chem. 2008;283:33902-10.
14. Kato M, Takahashi Y, Inoue M, Tsugane S,
Kadowaki T, Noda M; JPHC Study Group.
Comparisons between anthropometric indices forpredicting the metabolic syndrome in Japanese.
Asia Pan J Clin Nutr. 2008;17:223-228.
15. 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.
16. 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,
Asano T. Hepatic overexpression of a dominantnegative form of raptor enhances Akt
phosphorylation and restores insulin sensitivity in
K/KAy mice. Am J Physiol Endocrinol Metab.
2008;294:E719-25.

17. Kubota N, Kubota T, Itoh S, Kumagai H, Kozono
H, Takamoto I, Mineyama T, Ogata H, Tokuyama
K, Ohsugi M, Sasako 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.
18. Miyake K, Horikawa Y, Hara K, Yasuda K, Osawa
H, Furuta H, Hirota Y, Yamagata K, Hinokio Y,
Oka Y, Iwasaki N, Iwamoto Y, Yamada Y, Seino Y,
Maegawa H, Kashiwagi A, Yamamoto K,
Tokunaga K, Takeda J, Makino H, Nanjo K,
Kadowaki T, Kasuga M. Association of TCF7L2
polymorphisms with susceptibility to type 2
diabetes in 4,087 Japanese subjects. J Hum Genet.
2008;53:174-80.
19. Nishimura S, Manabe I, Nagasaki M, Seno K,
Yamashita H, Hosoya Y, Ohsugi M, Tobe K,
Kadowaki T, Nagai R, Sugiura S: In vivo
imaging in mice reveals local cell dynamics andinflammation in obese adipose tissue. J Clin Invest.
2008;118: 710-721.
20. Oishi Y, Manabe I, Tobe K, Ohsugi, M, Kubota, T,
Fujiu K, Maemura K, Kubota N, Kadowaki T,
Nagai R: SUMOylation of Kruppel-like
transcription factor 5 acts as a molecular switch intranscriptional programs of lipid metabolism
involving PPAR-δ. Nature Medicine. 2008;14:656-666.
21. Okamoto M, Ohara-Imaizumi M, Kubota N,
Hashimoto S, Eto K, Kanno T, Kubota T, Wakui M,
Nagai R, Noda M, Nagamatsu S, Kadowaki T,:
Adiponectin induces insulin secretion in vitro andin vivo at a low glucose concentration
Diabetologia 2008;51:827-835.
22. Okazaki H, Igarashi M, Nishi M, Sekiya M,
Tajima M, Takase S, Takanashi M, Ohta K,
Tamura Y, Okazaki S, Yahagi N, Ohashi K,
Amemiya-Kudo M, Nakagawa Y, Nagai R,
Kadowaki T, Osuga J, and Ishibashi S.
Identification of neutral cholesterol esterhydrolase, a key enzyme removing cholesterol
from macrophages. J Biol Chem. 2008;283:3335733364.
23. Ono H, Pocai A, Wang Y, Sakoda H, Asano T,

141

Backer JM, Schwartz GJ, Rossetti L. Activation of
hypothalamic S6 kinase mediates diet-induced
hepatic insulin resistance in rats. J Clin Invest.
2008;118:2959-68.
24. Park KW, Waki H, Villanueva CJ, Monticelli LA,
Hong C, Kang S, MacDougald OA, Goldrath AW,
Tontonoz P. Inhibitor of DNA binding 2 is a small
molecule-inducible modulator of peroxisome
proliferator-activated receptor-gamma expression
and adipocyte differentiation. Mol Endocrinol.
2008;22:2038-2048.
25. Seike N, Noda M, Kadowaki T. Alcohol
consumption and risk of type 2 diabetes mellitus
in Japanese: a systematic review. Asia Pac J Clin
Nutr 2008;17:545-551.
26. Sekiya M, Osuga J, Yahagi N, Okazaki H, Tamura
Y, Igarashi M, Takase S, Harada K, Okazaki S,
Iizuka Y, Ohashi K, Yagyu H, Okazaki M, Gotoda
T, Nagai R, Kadowaki T, Shimano H, Yamada N,
and Ishibashi S. Hormone-sensitive lipase isinvolved in hepatic cholesteryl ester hydrolysis. J
Lipid Res. 2008:49;1829-1838.
27. Takamoto I, Terauchi Y, Kubota N, Kubota T,
Ohsugi M, Ueki K, Kadowaki T. Crucial role ofIRS-2 in compensatory β-cell hyperplasia in
responsetohigh-fat-diet-induced
insulinresistance. Diabetes Obes Metab. 10 S4: 147-156,
2008
28. Takasawa K, Kubota N, Terauchi Y, Kadowaki T.
Impact of increased PPARγ activity in adipocytes
in vivo on adiposity, insulin sensitivity and theeffects of rosiglitazone treatment. Endocr J. 55:
767-776, 2008.
29. Tazoe F, Yagyu H, Okazaki H, Igarashi M, Eto K,
Nagashima S, Inaba T, Shimano H, Osuga J, andIshibashi S. Induction of ABCA1 byoverexpression of hormone-sensitive lipase in
macrophages. Biochem Biophys Res Commun.
2008;376;111-115
30.Tsukamoto K, Ohta K, Suzuki R, Hara M, Osuga J,
Tobe K, and Kadowaki T. Glimepiride-Induced
Bronchial Asthma: Case Report. Diabetes Care
2008;31: e91.
31. Uchida-Kitajima S, Yamauchi T, Takashina Y,
Okada-Iwabu M, Iwabu M, Ueki K, Kadowaki T.
5-Hydroxytryptamine 2A receptor signalingcascade modulates adiponectin and plasminogenactivator inhibitor 1 expression in adipose tissue.
FEBS Letters. 2008;582:3037-3044.
32. Unoki H, Takahashi A, Kawaguchi T, Hara K,
Horikoshi M, Andersen G, Ng DPK, Holmkvist J,
Borch-Johnson K, Jorgensen T, Sandbaek A,
Lauritzen T, Hansen T, Nurbaya S, Tsunoda T,
Kubo M, Babazono T, Hirose H, Hayashi M,
Iwamoto Y, Kashiwagi A, Kaku K, Kawamori R,
Tai ES, Pedersen O, Kamatani N, Kadowaki T,
Kikkawa R, Nakamura Y, Maeda S. SNPs in
KCNQ1 are associated with susceptibility to type2 diabetes in East Asian and European populations.
Nature Genetics. 2008;40:1098-1102.
33. Wang G, Watanabe M, Imai Y, Hara K, Manabe I,
Maemura K, Horikoshi M, Kohro T, Amiya E,
Sugiyama T, Fujita T, Kadowaki T, Yamazaki T,
Nagai R. Genetic variations of Mrf-2/ARID5B
confer risk of coronary atherosclerosis in theJapanese population. Int. Heart J. 2008;49:
313-327
34. Watanabe K, Ohnishi S, Manabe I, Nagai R,
Kadowaki T. KLF6 in non-alcoholic fatty liverdisease: Role of fibrogenesis and carcinogenesis.
Gastroenterology. 2008;135:309-312.
35. Yamauchi T, Kadowaki T. Physiological andpathophysiological roles of adiponectin andadiponectin receptors in the integrated regulationof metabolic and cardiovascular disease. Int. J.
Obes. 2008;32 Suppl 7: S13-18.
36. Yano W, Kubota N, Itoh S, Kubota T, Awazawa M,
Moroi M, Sugi K, Takamoto I, Ogata H,
Tokuyama K, Noda T, Terauchi Y, Ueki K,
Kadowaki T. Molecular mechanism of moderate
insulin resistance in adiponectin-knockout mice,
Endocr. J. 2008;55:515-522.
37. Yasuda K, Miyake K, Horikawa y, Hara K, Oswa
H, Furuta H, Hirota Y, Mori H, Jonsson A, Sato Y,
Yamagata K, Hinokio Y, Wang HY, Tanahashi T,
Nakamura N, Oka Y, Iwasaki N, Iwamoto Y,
Yamada Y, Seino Y, Maegawa H, Kashiwagi A,
Takeda J, Maeda E, Shin HD, Cho YM, Park KS,
Lee HK, Ng MCY, Ma RCW, So WY, Chan YM,
Lyssenko V, Tuomi T, Nilsson P, Groop L,
Kamatane N, Sekine A, Nakamura Y, Yamamoto K,
Yoshida T, Tokunaga K, Itakura M, Makino H,
Nanjo K, Kadowaki T, Kasuga M. Variants in
KCNQ1 are associated with susceptibility to type

142

2 diabetes mellitus. Nature Genetics. 2008;40:
1092-1097.

143

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
Toshiki Saito, M.D., Ph.D.,
Sachiko Seo, 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, graduate students.
We are also engaged in post-graduate, continued
education to develop many hematologists of eminent
distinction. These activities are performed by theunited efforts of all members who belong to thedepartment. As of March in 2009, the staff ofDepartment of Hematology and Oncology consists ofthirty members including one professor, 2 lecturers,
one special lecturer (hospital), and 5 associates.

Clinical activities
On average, 60-70 patients with hematologicaldiseases are treated in the ward. Clinical facilities
include patient rooms with high-efficiency particulate
air filtration and filtrated water supply. Patients whoare 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 hematopoietic stem cell transplantationin the treatment of hematological disorders.
Approximately 40 patients with acute leukemia,

144

150 with malignant lymphoma, 40 with chronic
myelogenous leukemia, 20 with multiple myeloma, 80
with 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.
We perform various kinds of genetic or molecularanalyses to detect, characterize, and monitor
malignant cells and make use of them for diagnosis
and planning of treatments.
Here are some technical aspects on the treatment
strategy:
1. High-dose chemotherapy with or without
autologous stem cell support: Adequate high-dose
chemotherapy is administered for the treatment ofmalignant disease. For the autologous stem cell
support, peripheral blood stem cell is usually
selected as a source of stem cells.
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.
Allogeneic
hematopoietic
stem
cell
transplantations for the elderly are performed
under the admission of ethical committee of theFaculty of Medicine. Cord blood cells are also
used as the sources of hematopoietic 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.
Undergraduate students are educated to become
independent researchers both in basic and clinicalresearch.
Education of clinical fellows to train heamtologists
is also performed. They are trained to achieveknowledge
andtechniques
necessaryforhematologists in our hospital and encouraged topresent clinical studies at academic meetings.

Research activities
The major research projects are as follow: (1)molecular mechanisms of hematopoietic tumors, (2)hematopoietic transcription factors, (3) signaltransduction in hematopoietic cells, (4) chromosomal
and genomic approaches to leukemogenesis, (5)generation of murine models for leukemias, (6)proliferation and differentiation of hematopoietic stem
cells. Translational research to develop novel methods
for diagnosis and treatment based on basic research isalso performed. Every effort has been made to achieve
the highest quality in both clinical and basic medical
research. The ultimate aims of our research are theapplication of epoch-making discoveries in research
fields to the clinical hematology and oncology.
Representative publications from our departments
published in the past year are listed in the reference.

145

References(1) Kako S, Kanda Y, Oshima K, Nishimoto N, Sato H,
Watanabe T, Hosoya N, Motokura T, Miyakoshi S,
Taniguchi S, Kamijo A, Takahashi K, Chiba S, andKurokawa M.
Late onset of autoimmune
hemolytic anemia and pure red cell aplasia after
allogeneic
hematopoietic
stem
cell
transplantation using in vivo alemtuzumab.
American Journal of Hematology 83: 247-249,
2008.
(2) Oshima K, Kanda Y, Nakasone H, Arai S,
Nishimoto N, Sato H, Watanabe T, Hosoya N,
Izutsu K, Asai T, Hangaishi A, Motokura T, Chiba
S, and Kurokawa M. Decreased incidence ofacute graft-versus-host disease by continuous
infusion of cyclosporine with a higher target bloodlevel. American Journal of Hematology 83: 226232, 2008.
(3) Asano-Mori Y, Kanda Y, Oshima K, Kako S,
Shinohara A, Nakasone H, Kaneko M, Sato H,
Watanabe T, Hosoya N, Izutsu K, Asai T,
Hangaishi A, Motokura T, Chiba S, andKurokawa
M.
False-positive
Aspergillus
galactomannan antigenemia after hematopoietic
stem cell transplantation. The Journal of
Antimicrobial Chemotherapy 61: 411-416, 2008.
(4) Kumano K, Masuda S, Sata M, Saito T, Lee SY,
Yanagimoto-Sakata M, Tomita T, Iwatsubo T,
Natsugari H, Kurokawa M, Ogawa S, and Chiba S.
Both Notch1 and Notch2 contribute to theregulation of melanocyte stem cells. Pigment
Cell Melanoma Research 21: 70-78, 2008.
(5) Ichikawa M, Goyama S, Asai T, Kawazu M,
Nakagawa M, Takeshita M, Chiba S, Ogawa S,
and Kurokawa M. AML1/Runx1 negatively
regulates quiescent hematopoietic stem cells in
adult hematopoiesis. The Journal of Immunology
180: 4402-4408, 2008.
(6) Suzuki H, Asai T, Tamaki Z, Yoshimi A,
Hangaishi A, Kanda Y, Motokura T, Chiba S, andKurokawa M. Drug-induced hypersensitivity
syndrome with rapid hematopoietic reconstitution
during treatment for acute myeloid leukemia.
Haematologica 93: 469-470, 2008.
(7) Suzuki H, Asai T, Okada K, Kazuyama Y,
Kanda Y, Motokura T, Chiba S, and Kurokawa M.

Disseminated adenovirus disease by multiple
adenovirus
serotypes
following
allogeneic
hematopoietic stem cell transplantation. Biologyof Blood and Marrow Transplantation 14: 353-355,
2008.
(8) Yoshimi A, Izutsu K, Takahashi M, Oshima K,
Kako S, Kanda Y, Motokura T, Chiba S, Momose T,
Ohtomo K, and Kurokawa M.
Conventional
allogeneic
hematopoietic
stem
cell
transplantation for lymphoma may overcome poor
prognosis associated with positive FDG-PET scan
before transplantation.
American Journal of
Hematology 83: 477-481, 2008.
(9) Asano-Mori Y, Kanda Y, OshimaK, Kako S,
Shinohara A, Nakasone H, Sato H, Watanabe T,
Hosoya N, IzutsuK, Asai T, Hangaishi A,
Motokura T, Chiba S, and Kurokawa M.
Long-term ultra-low-dose acyclovir against
varicella-zoster virus reactivation after allogeneic
hematopoietic
stem
cell
transplantation.
American Journal of Hematology 83: 472-476,
2008.
(10) Asano-Mori Y, Kanda Y, Oshima K, Kako S,
Shinohara A, Nakasone H, Sato H, Watanabe T,
Hosoya N, Izutsu K, Asai T, Hangaishi A,
Motokura T, Chiba S, and Kurokawa M．Clinicalfeatures of late cytomegalovirus infection after
hematopoietic
stem
cell
transplantation.
International Journal of Hematology 87: 310-318,
2008.
(11) Suzuki T, Izutsu K, Kako S, Ohta S,
Hangaish A, Kanda Y, Motokura T, Chiba S, andKurokawa M. A case of adult Langerhans cellhistiocytosis showing successfully regenerated
osseous tissue of the skull after chemotherapy.
Internatinal Journal of Hematology 87: 284-288,
2008.
(12) 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, and Tsuji S.
Lymphomatoid Granulomatosis involving central
nervous system successfully treated withrituximab alone. Archives of Neurology 65: 662655, 2008.
(13) Nakamoto T, Seo S, Sakai R, Kato T, Kutsuna
H, Kurokawa M, Noda M, Miyasaka N, and146

Kitagawa
S.
Expression
andtyrosine
phosphorylation of Crk associated substrate
lymphocyte type (Cas-L) protein in humanneutrophils. J Cellular Biochemistry 105: 121-128,
2008.
(14) Nagai S, Asai T, Watanabe T, Oshima K,
Hangaishi A, Kanda Y, Motokura T, Chiba S, Aoki
S, Ohtomo K, and Kurokawa M. Simultaneous
appearance of central nervous system relapse andsubarachnoid hemorrhage during or aftertargeted therapies for acute promyelocytic
leukemia. Annals of Hematology 87: 593-595,
2008.
(15) Takeshita M, Ichikawa M, Nitta E, Goyama S,
Asai T, Ogawa S, Chiba S, and Kurokawa M.
AML1-Evi-1
specificallytransforms
hematopoietic stem cells through fusion of theentire Evi-1 sequence to AML1. Leukemia 22:1241-1249, 2008.
(16) Kataoka K, Yamamoto G, Nannya Y, Yoshimi
A, Okada S, Asai T, Kumano K, Hangaishi A,
Takahashi T, Chiba S, and Kurokawa M.
Successful
engraftment
following
HLAmismatched cord blood transplantation forpatients with anti-HLA antibodies. Bone Marrow
Transplantation 42: 129-130, 2008.
(17) Yoshimi A, Kumano K, Motokura T,
Takazawa Y, Oota S, Chiba S, Takahashi T,
Fukayama M, and Kurokawa M. ESHAP therapy
was very effective for a patient with Langerhans
cell sarcoma.
International Journal of
Hematology 87: 532-537, 2008.
(18) Kataoka K, Izutsu K, Nagai S, Hangaishi A,
Motokura T, Takahashi T, and Kurokawa M.
Elevated serum levels in interleukin-2 receptor inchronic eosinophilic leukemia / hypereosinophilic
syndrome with FIP1L1-PDGFRα fusion gene.
International Journal of Hematology 87: 440-441,
2008.
(19) Yoshimi A, Asai T, Hangaishi A, Takahashi T,
Chiba S, and Kurokawa M. Hemorrhagic cystitis
in a patient receiving gemtuzumab ozogamicin forrelapsed acute promyelocytic leukemia after cord
blood transplantation. Annals of Hematology 87:
851-852, 2008.
(20) Suzuki H, Izutsu K, Nagai S, Watanabe T,
Oshima K, Kanda Y, Motokura T, Chiba S, andKurokawa M. Late onset pneumatosis cystoides
intestinalis
associatedwithnon-infectious
pulmonarycomplications
after
allogeneic
hematopoietic
stem
cell
transplantation.
International Journal of Hematology 88: 116-118,
2008.
(21) Suzuki H, Hangaishi A, Hosoya N, Watanabe
T, Kanda Y, Motokura T, Chiba S, and Kurokawa
M. Herpes simplex encephalitis and subsequentcytomegalovirus
encephalitis
after
chemoradiotherapy for central nervous system
relapse of diffuse large B-cell lymphoma: a casereport and literature review. International
Journal of Hematology 42: 285-287, 2008.
(22) Sato T, Goyama S, Nitta E, Takeshita M,
Yoshimi M, Nakagawa M, Nakagwa M, Kawazu M,
Ichikawa M, and Kurokawa M. Evi-1 promotes
para-aortic
splanchnopleural
hematopoiesis
through up-regulation of GATA-2 and repressionof TGF-β signaling. Cancer Science 99: 1407-1413,
2008.
(23) Sakata-Yanagimoto M, Nakagami-Yamaguchi
E, Saito T, Kumano K, Yasutomo K, Ogawa S,
Kurokawa M, and Chiba S. Coordinatedregulation of transcription factors throughNotch2 is an important mediator of mast cell fate.
Proceedings of National Academy of Science U S A
105: 7839-7844, 2008.
(24) Suzuki H, Suzuki T, Kamijo A, Ohta S, Sato
H, Hangaishi A, Takahashi T, Kanda Y, Motokura
T, Chiba S, and Kurokawa M. Antileukemic
immunity
associatedwithantineutrophil
antibody
production
after
allogeneic
hematopoietic stem cell transplantation for
myeloid/NK-cell precursor acute leukemia. Bone
Marrow Transplantation 42: 285-287, 2008.
(25) Yoshimi A, Nannya Y, Sakata-Yanagimoto M,
Oshima K, Takahashi T, Kanda Y, Motokura T,
Chiba S, and Kurokawa M. A myeloablative
conditioning regimen for patients with impaired
cardiac function undergoing allogeneic stem celltransplantation:
reducedcyclophosphamide
combined with etoposide and total body
irradiation. American Journal of Hematology
83: 635-639, 2008.
(26) Nannya Y, Yokota H, Sato Y, Yamamoto G,
Asai T, Ichikawa M, Watanabe T, Kumano K,

147

Hangaishi A, Takahashi T, Chiba S, andKurokawa M. Molecular and cytogenetic responseof chronic myelogenous leukemia treated withimatinib mesylate: one institutional experience inJapan. International Journal of Hematology 88:
159-164, 2008.
(27) Oshima K, Kanda Y, Kako S, Asano-Mori Y,
Watanabe T, Motokura T, Chiba S, Shiraki K, andKurokawa
M.
Case
Report:Persistentcytomegalovirus(CMV)
infection
after
haploidentical
hematopoietic
stem
cell
transplantation using in vivo alemtuzumab:
emergence of resistant CMV due to mutations in
the UL97 and UL54 genes. Journal of Medical
Virology 80: 1769-1775, 2008.
(28) Goyama S, Yamamoto G, Shimabe M, Sato T,
Ichikawa M, Ogawa S, Chiba S, and Kurokawa M.
Evi-1 is a critical regulator for hematopoietic
stem cells and transformed leukemic cells. Cell
Stem Cell 3: 207-220, 2008.
(29) Fukuo W, Yoshiuchi K, Takimoto Y, Sakamoto
N, Kikuchi H, Hachizuka M, Inada S, Nannya Y,
Kumano K, Takahashi T, Kurokawa M, andAkabayashi A. Comparison of temporal changesof psychological distress during hematopietic
stem cell transplantation among underlying
diseasesinJapaneseadultpatients.
BioPsychoSocial Medicine 2: 24, 2008.
(30) Masuda A, Nakamura K, Izutsu K, Igarashi
K, OhkawaR, Jona M, Higashi K, Yokota H,
Okudaira S, Kishimoto T, Watanabe T, Koike Y,
Ikeda H, Kozai Y, Kurokawa M, Aoki J, andYatomi Y. Serum autotaxin measurement inhaematological malignancies: a promising marker
for follicular lymphoma.
British Journal of
Haematology, 143: 60-70, 2008.
(31) Nakagawa K, Kanda Y, Yamashita H,
Nakagawa S, Sasano N, Ohtomo K, Oshima K,
Kumano K, Ban N, Minamitani Y, Kurokawa M,
and Chiba S. Ovarian shielding allows ovarianrecoveryandnormalbirthinfemalehematopoietic SCT recipients undergoing TBI.
Bone Marrow Transplantation, 42: 697-699, 2008.
(32) Kanda Y, Okamoto S, Tauchi T, Kizaki M,
Inokuchi K, Yabe M, Yokoyama K, Ito Y, Kimura Y,
Higashihara M, Bessho M, Ando K, Chiba S,
Kurokawa M, Oshimi K, Dan K, Ohyashiki K, andIkeda Y. Multicenter prospective trial evaluating
the tolerability of imatinib for Japanese patientswith chronic myelogenous leukemia in the chronic
phase: Does body weight matter?
AmericanJournal of Hematology, 83: 835-839, 2008.

148

Department of Allergy andRheumatology
Professor
Kazuhiko Yamamoto, M.D. ( Rheumatology, Allergology )Lecturer
Fujio Takeuchi, M.D. (Rheumatology)
Makoto Dohi, M.D. (Allergology )Masao Yamaguchi, M.D. (Allergology )Zen-ichiro Honda, M.D. (Rheumatology)

Research Associate
Ryoichi Tanaka, M.D. (Allergology )Hiroko Kanda, M.D. (Rheumatology)
Kimito Kawahata, M.D. (Rheumatology)
Keishi Fujio, M.D. (Rheumatology)
Noboru Hagino, M.D. (Rheumatology)
Kanae Kubo, M.D. (Rheumatology)

Project Research Associate
Tomohisa Okamura
Akiko Okamoto

Homepage
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.

Education
In regard to undergraduate 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.

149

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,
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
2008(1) Suzuki A,Yamada R, Kochi Y, Sawada T, Okada Y,
Matsuda K, Kamatani Y, Mori M, Shimane K,
Takahashi A, Tsunoda T, Miyatake A, Kubo M,
Kamatani N, Nakamura Y, Yamamoto K
Functional SNPs in CD244 gene increase the riskof rheumatoid arthritis in a Japanese population.
Nat Genet. 40:1224-9, 2008.
(2) Kawakami A, Koketsu R, Suzukawa M, Nagao M,
Hiraguchi Y, Tokuda R, Fujisawa T, Nagase H,
Ohta K, Yamamoto K, Yamaguchi M. Blocking
antibody is generated in allergic rhinitis patientsduring specific immunotherapy using standardized
Japanese cedar pollen extract. Int Arch Allergy
Immunol. 1:54-60, 2008.
(3) Kawakami A, Suzukawa M, Koketsu R, Komiya A,
Ohta K, Yamamoto K, Yamaguchi M.
Enhancement of basophil apoptosis by olopatadine
and theophylline. Allergy Asthma Proc. 29:322-8,
2008.
(4) Kawahata K, Yamaguchi M, Kanda H, Komiya A,
Tanaka R, Dohi M, Misaki Y, Yamamoto K.
Severe airflow limitation in two patients withsystemic lupus erythematosus:effect of inhalationof anticholinergics. Mod Rheumatol. 18:52-6,
2008.
(5) Suzukawa M, Koketsu R, Iikura M, Nakae S,
Matsumoto K, Nagase H, Saito H, Matsushima K,
Ohta K, Yamamoto K, Yamaguchi M.
Interleukin-33
enhances
adhesion,
CD11b
expression and survival in human eosinophils. Lab
Invest. 88:1245-53, 2008.
(6) Suzukawa M, Iikura M, Koketsu R, Nagase H,
Tamura C, Komiya A, Nakae S, Matsushima K,

150

Ohta K, Yamamoto K, Yamaguchi M. An IL-1
cytokine member, IL-33, induces human basophil
activation via its ST2 receptor. J Immunol. 181:5981-9, 2008.
(7) Okada Y, Mori M, Yamada R, Suzuki A,
Kobayashi K, Kubo M, Nakamura Y, Yamamoto K.
SLC22A4 polymorphism and rheumatoid arthritis
susceptibility: a replication study in a Japanese
population and a metaanalysis. J Rheumatol. 35:
1723-8, 2008.
(8) Okamoto A, Fujio K, van Rooijen N, Tsuno NH,
Takahashi K, Tsurui H, Hirose S, Elkon KB,
Yamamoto K. Splenic phagocytes promoteresponses to nucleosomes in (NZB x NZW) F1
mice. J Immunol. 15;181:5264-71, 2008.

151

Department of Infectious
Diseases (Internal Medicine)
Professor
Kazuhiko Koike, M.D., Ph.D.

Associate Professor
Hiroshi Yotsuyanagi, M.D., Ph.D.

Research Associate
Shuji Hatakeyama, M.D., Ph.D.

Homepage http://infect.umin.jp/
Introduction and Organization
The Department of Infectious Diseases has been oneof the leading academic organizations specialized forinternal medicine, in particular, infectious disease
medicine in Japan since 1998, when the Departments ofInternal Medicine, established in 1890, were rearranged
into new ones according to subspecialty of internal
medicine. Our department has been chiefly engaged inclinical, educational and research activities for
infectious diseases including bacterial, fungal and viral
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, educational and research activities.

Clinical activities
We have hospital beds on the 11th floor of the Ward Aof University of Tokyo Hospital. Diseases include HIV

infection, viral hepatitis, pneumonia, resistant bacteria
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 with problems difficult tobe solved. Consultations are very frequent from otherdepartments on the management of 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 ofinfectious diseases are given. In addition, principles of
medical diagnosis are taught at the bedside. During the

152

bed-side teaching for fifth and sixth year students, ourassociates teach them on man-to man basis the basic
way of thinking for correct diagnosis and therapy, thetechniques of interrogation and physical examination,
the way for interpretations of laboratory tests and othermedical examinations, and the basic medical
procedures on each case. The education of juniorresidents 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 two to
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 andre-emerging infectious diseases are covered. Following
themes are currently being investigated in thedepartment.
(1) Establishment of effective therapy for HIV
infection: we have made a great contribution in theestablishment 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 demonstrated using
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 treatmentof 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 treatment of
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 and signal transductionof bacterial infection through toll-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, Yoshizumi
Shintani, Takeya Tsutsumi, Shuji Hatakeyama, Satoshi
Itoyama, Takatoshi Kitazawa, Kuniko Ueda, Shu
Okugawa, Miki Kawada, Shintaro Yanagimoto, Yohko
Nukui, Katsutoshi Abe, Atsuhito Fukishima, Keita
Tatsuno, Sohei Harada, Koji Goto, Mahoko Kamimura,
Yusuke Yoshino, Takahiro Aoki, Koh Okamoto.

References
1) 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.
2) Tanaka N, Moriya K, Kiyosawa K, Koike K,
Aoyama T. Hepatitis C virus core protein induces
spontaneous and persistent activation ofperoxisome proliferator-activated receptor alpha intransgenic mice: Implications for HCV-associatedhepatocarcinogenesis. Int J Cancer 2008;122:124131.
3) 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. Hepatol Res 2008;38:310-314.
4) Ishizaka N, Ishizaka Y, Toda EI, Koike K,
Yamakado
M,
Nagai
R.
Are
serum
carcinoembryonic antigen levels associated withcarotid atherosclerosis in Japanese men?
Arterioscler Thromb Vasc Biol 2008;28:160-165.

1535) Nagase Y, Yotsuyanagi H, Okuse C, Yasuda K,
Kato T, Koike K, Suzuki M, Nishioka K, Iino S,
Itoh F. Effect of treatment with interferon alpha-2b
and ribavirin in patients infected with genotype 2
hepatitis C virus. Hepatol Res 2008;38:252-258.
6) 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.
7) 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.
8) Newell P, Villanueva A, Friedman SL, Koike K,
Llovet JM. Experimental models of hepatocellular
carcinoma. J Hepatol 2008;48:858-879.
9) Ishizaka N, Ishizaka Y, Toda E, Shimomura H,
Koike K, Seki G, Nagai R, Yamakado M.
Association between cigarette smoking and chronic
kidney disease in Japanese men. Hypertens Res
2008;31:485-92.
10) 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.
11) Ishizaka N, Ishizaka Y, Seki G, Nagai R, Yamakado
M, Koike K. Association between hepatitis B/Cviral infection, chronic kidney disease and insulin
resistance in individuals undergoing general healthscreening. Hepatol Res 2008;38:775-783.
12) 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 of metabolic
syndrome. Eur J Pharmacol 2008;587:237-42.
13) Okada H, Kitazawa T, Harada S, Itoyama S,
Hatakeyama S, Ota Y, Koike K. Combined
treatment with oral kanamycin and parenteralantibiotics for a case of persistent bacteremia andintestinal carriage with Campylobacter coli. Intern
Med 2008;47:1363-1366.
14) Yotsuyanagi H, Kikuchi Y, Tsukada K, Nishida K,
Kato M, Sakai H, Takamatsu J, Hige S, Chayama K,
Moriya K, Koike K. Chronic hepatitis C in patientscoinfected with human immunodeficiency virus in
Japan: a retrospective multicenter analysis.
Hepatol Res 2009;39:657-663.
15) Ishizaka Y, Ishizaka N, Tani M, Toda A, Toda EI,
Koike K, Nagai R, Yamakado M.
Association between changes in obesity parameters
and incidence of chronic kidney disease in Japaneseindividuals. Kidney Blood Press Res 2009;32:141149.
16) Murata M, Matsuzaki K, Yoshida K, Sekimoto G,
Uemura Y, Sakaida N, Fujisawa J, Seki T, Koike K,
Okazaki K. Hepatitis B virus X protein shifts
hepatic Smad3-mediated signaling from tumorsuppression to oncogenesis in chronic hepatitis B.
Hepatology 2009;49:1203-1217.
17) Kumita W, Saito R, Sato K, Ode T, Moriya K,
Koike K, Chida T, Okamura N. Molecularcharacterizations of carbapenem and ciprofloxacin
resistance in clinical isolates of Pseudomonas
putida. J Infect Chemother 2009;15:6-12.
18) Hongo M, Ishizaka N, Furuta K, Yahagi N, Saito K,
Sakurai R, Matsuzaki G, Koike K, Nagai R.
Administration of angiotensin II, but notcatecholamines, induces accumulation of lipids inthe rat heart. Eur J Pharmacol 2009;604:87-92.
19) Yanagimoto S, Tatsuno K, Okugawa S, Kitazawa T,
Tsukada K, Koike K, Kodama T, Kimura S,
Shibasaki Y, Ota Y. A single amino acid of toll-likereceptor 4 that is pivotal for its signaltransduction
and subcellular localization. J Biol Chem 2009;284:
3513-3520.
20) Ishizaka N, Ishizaka Y, Yamakado M, Toda E,
Koike K, Nagai R. Association between metabolic
syndrome and carotid atherosclerosis in individuals
without diabetes based on the oral glucose tolerance
test. Atherosclerosis 2008 Oct 30. [Epub ahead ofprint]
21) Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Moriya K, Koike K, Makuuchi
M. Colonization and/or infection with methicillinresistant Staphylococcus a ureus after living donorliver transplantation: a case control study. BMC
Infectious Diseases 2008;8:155.
22) Togo M, Hashimoto Y, Iso-O N, Kurano M, Hara M,
Kadowaki T, Koike K, Tsukamoto K. Identificationof a novel mutation for phytosterolemia. Genetic
analysis of two cases. Clin Chim Acta 2009;401:

154

165-169.
23) Koike
K.
Steatosis,
Liverinjuryandhepatocarcinogenesis in hepatitis C viral infection.
J Gastroenterol 2009;44supl:82-88.
24) Ichibangase T, Moriya K, Koike K, Imai K.
Limitation of immunoaffinity column for theremoval of abundant proteins from plasma inquantitativeplasmaproteomics.
BiomedChromatogr 2009;23:480-487.
25) Seki G, Yamada H, Li Y, Horita S, Ishizakaa N,
Koike K, Fujita T. Roles of MEK/ERK pathway invascular and renal tubular actions of angiotensin II.
Vasucular Dis Prevent 2009;6:154-159.

155

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, 6 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 close sideby-side instruction to junior residents. The weekly
professor’s round is scheduled on Thursday morning.
During 2008 January to 2008 December, 43 patientswere admitted to the ward, many of whom were eating
disorder patients. Outpatient clinic is attended on
every morning and afternoon in three consultation
rooms by approximately fifteen physicians. During

2008 January to 2008 December, the numbers of the
new outpatients and of the overall outpatients in our
department were 181 and 4294, 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.

Research activities
Targeting stress-related diseases such as not only

156

those covered by our department but also otherlifestyle-related disease, and cancers, we areinvestigating
theirpathophysiology
andpsychopathology through assessing bio-psychobehavioral 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 of stressrelated diseases such as tension-type headache,eating disorders, insomnia, and panic disorderusing portable computers for real-time assessmentof subjective symptoms in combination withambulatory monitors such as electrocardiogramand 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.
Six 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. Ishizawa T, Yoshiuchi K, Takimoto Y, Yamamoto
Y, Akabayashi A. Heart rate and blood pressure
variability and baroreflex sensitivity in patientswith anorexia nervosa. Psychosom Med 2008;
70:695-700
2. Sakamoto N, Yoshiuchi K, Kikuchi H, Takimoto Y,
Kaiya H, Kumano H, Yamamoto Y, Akabayashi A.
Panicdisorderandlocomotor
activity.
BioPsychoSoc Med 2008;2:23

3. Yoshiuchi K, Yamamoto Y, Akabayashi A.
Application of ecological momentary assessment
in stress-related diseases. BioPsychoSoc Med
2008;2:13
4. Fukuo W, Yoshiuchi K, Takimoto Y, Sakamoto N,
Kikuchi H, Hachizuka M, Inada S, Nannya Y,
Kumano K, Takahashi T, Kurokawa M,
Akabayashi A. Comparison of temporal changesin psychological distress after hematopoietic stem
cell transplantation among underlying diseases inJapanese adult patients. BioPsychoSoc Med 2008;
2:24
5. Otani M, Takimoto Y, Moriya J, Yoshiuchi K,
Akabayashi A. Plasma intact fibroblast growth
factor 23 levels in women with anorexia nervosa.
BioPsychoSoc Med 2008;2:10
6. Kayano M, Yoshiuchi K, Al-Adawi S, Vierbes N,
Dorvlo ASS, Kumano H, Kuboki T, Akabayashi A.
Eating Attitudes and Body Dissatisfaction in
Adolescents: a Cross-Cultural Study. Psychiatr
Clin Neurosci 2008;62:17-25
7. Takimoto Y, Yoshiuchi K, Akabayashi A. The
effect of mood states on QT interval and QT
dispersion in eating disorder patients. Psychiatr
Clin Neurosci 2008;62:185-189
8. Hashizume M, Yamada U, Sato A, Hayashi K,
Amano Y, Makino M, Yoshiuchi K, Tsuboi K.
Stress and psychological factors before a migraine
attack: a time-based analysis. BioPsychoSoc Med
2008;2:14
9. Nakamura T, Takumi T, Takano A, Aoyagi N,
Yoshiuchi K, Struzik ZR, Yamamoto Y. Of miceand men - universality and breakdown of
behavioral organization. PLoS ONE 2008;3:e2050-1-8
10. Park S, Park H, Togo F, Watanabe E, Yasunaga A,
Yoshiuchi K, Shephard RJ, Aoyagi Y. Yearlong
physical activity and metabolic syndrome in older
Japanese adults: cross-sectional data from
Nakanojo Study. J Gerontol Med Sci 2008;63A:
1119-1123
11. Sugaya N, Kaiya H, Kumano H, Nomura S.
Relationship between subtypes of irritable bowel
syndrome and severity of symptoms associatedwith panic disorder. Scand J Gastroenterol 2008;
43:675-681
12. Namiki M, Akaza H, Shimazui T, Ito N, Iwamoto

157

T, Baba K, Kumano H, Koh E, Tsujimura A,
Matsumiya K, Horie S, Maruyama O, Marumo K,
Yanase T, Kumamoto Y; Working Committee on
Clinical Practice Guidelines for Late-onset
Hypogonadism; Japanese Urological Association/
Japanese Society for Study of Aging Male.
Clinicalpractice
manualforlate-onset
hypogonadism syndrome. Int J Urol 2008;15:
377-388
13. Hojo S, Ishikawa S, Kumano H, Miyata M,
Sakabe K. Clinical characteristics of physiciandiagnosed patients with multiple chemicalsensitivity in Japan. Int J Hyg Environ Health2008;211:682-689

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

159

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

Clinical activities

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.

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

1601) 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 organtransplantation;
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 and DNAbased 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. Clinicalapplicationofrefrigerated
andfrozen-stored blood for autologous transfusion in
surgical patients.
4. Study on the mechanisms of transfusionassociated GVHD and its prevention.
4’. Study on the mechanisms of transfusion related
acute lung injury (TRALI) 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.

161

7. HLA and HPA genotyping.
8. Development of a new methodology for evaluationof platelet function.
9. Development of new strategies for the treatment ofcancer patients, by targeting the tumor
vasculature.
10. Dendritic cell-based immunotherapy of cancer
patients.
11. Ex-vivo expansion of hematopoietic stem cells andtheir clinical application.
12. Development of new materials for medical use.

References
1: Shuno Y, Tsuno NH, Okaji Y, Tsuchiya T, Sakurai
D, Nishikawa T, Yoshikawa N, Sasaki K, Hongo K,
Tsurita G, Sunami E, Kitayama J, Tokunaga K,
Takahashi K, Nagawa H. Id1/Id3 Knockdown
Inhibits Metastatic Potential of Pancreatic Cancer.
J Surg Res. 2008.
2: Nishikawa T, Tsuno NH, Shuno Y, Sasaki K,
Hongo K, Okaji Y, Sunami E, Kitayama J,
Takahashi K, Nagawa H. Antiangiogenic Effect ofa Selective 5-HT4 Receptor Agonist. J Surg Res.
2008.
3: Okamoto A, Fujio K, van Rooijen N, Tsuno NH,
Takahashi K, Tsurui H, Hirose S, Elkon KB,
Yamamoto K. Splenic phagocytes promoteresponses to nucleosomes in (NZBx NZW) F1
mice. J Immunol. 2008;181(8):5264-71.
4: Tsuchiya T, Tsuno NH, Asakage M, Yamada J,
Yoneyama S, Okaji Y, Sasaki S, Kitayama J,
Osada T, Takahashi K, Nagawa H. Apoptosis
induction by p38 MAPK inhibitor in human coloncancer cells. Hepatogastroenterology. 2008;55(84):930-5.
5: Yamada J, Kitayama J, Tsuno NH, Yamashita H,
Miyato H, Soma D, Otani K, Kamei T, Ishigami H,
Hidemura A, Kaisaki S, Takahashi K, Nagawa H.
Intra-peritoneal administration of paclitaxel with
non-animal stabilized hyaluronic acid as avehicle--a new strategy against peritoneal
dissemination of gastric cancer. Cancer Lett. 2008
Dec 18;272(2):307-15.
6: 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. 2008
Feb;44(3):383-90.
7: Stafford P, Garner SF, Huiskes E, Kaplan C,
Kekomaki R, Santoso S, Tsuno NH, Watkins NA,
Ouwehand
WH.
Three
novel
beta3
domain-deletion peptides for the sensitive andspecific detection of HPA-4 and six low frequency
beta3-HPA antibodies. J Thromb Haemost. 2008
Feb;6(2):376-83.
8: Yoneyama S, Kawai K, Tsuno NH, Okaji Y,
Asakage M, Tsuchiya T, Yamada J, Sunami E,
Osada T, Kitayama J, Takahashi K, Nagawa H.
Epigallocatechin gallate affects human dendritic
cell differentiation and maturation. J Allergy Clin
Immunol. 2008 Jan;121(1):209-14.
9. Kako S, Kanda Y, Oshima K, Nishimoto N, Sato H,
Watanabe T, Hosoya N, Motokura T, Miyakoshi S,
Taniguchi S, Kamijo A, Takahashi K, Chiba S,
Kurokawa M. Late onset of autoimmune
hemolytic anemia and pure red cell aplasia after
allogeneic hematopoietic stem cell transplantation
using in vivo alemtuzumab. Am J Hematol. 2008;
83(3): 247-9.

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

163

Department of
Reproductive Endocrinology
Professor
Yuji Taketani

Associate Professor
Tetsu Yano

Lecturer
Koji Kugu

Mikio Momoeda

Yutaka Osuga

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 three 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 that higher level oftreatment is necessary, ART is applied to such cases.
We have been engaged in in v itro fertilization andembryo transfer (IVF-ET) as a main axis of ART for
nineteen years. Conventional IVF-ET is mainly

indicated to cases with tubal factor, mild male factor,
immunological factor or of unexplained infertility
factor. In case of severe male factor or otherfertilization disorder intracytoplasmic sperm injection(ICSI) is performed. Now we have about 200 OPU
cycles of IVF-ET every year, which conventional
IVF-ET and ICSI share almost equally. The clinicalpregnancy rate of conventional IVF-ET is around 30%
per embryo transfer cycle, which is comparable withthat of ICSI. Other ART techniques such as embryo
cryopreservation 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
laparoscopically assisted cyctectomy or salpingooophorectomy (226 cases), laparoscopic hysterectomy
or laparoscopically assisted vaginal hysterectomy (37cases), laparoscopic or laparoscopically assisted
myomectomy (97 cases), diagnostic laparoscopy for
infertility (15 cases) laparoscopic surgery for ectopic
pregnancy (20 cases), hysteroscopic surgery (52cases) and so on, which make a total of 418 cases.

164[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 2008
(1) Osuga Y, Hirota Y, Taketani Y. Basic andtranslational research on proteinase -activatedreceptors: proteinase-activated receptors infemale reproductive tissues and endometriosis. J
Pharmacol Sci. 108(4): 422-5, 2008.
(2) Hirota Y, Tranguch S, Daikoku T, Hasegawa A,
Osuga Y, Taketani Y, Dey SK. Deficiency of
immunophilin FKBP52 promotes endometriosis.
Am J Pathol 173(6): 1747-57, 2008.
(3) Yanai Y, Hiroi H, Osuga Y, Fujimoto A,
Momoeda M, Yano T, Taketani Y. Androgen
insensitivity syndrome with serous gonadal cyst.
Fertil Steril. 90(5):2018, 2008.
(4) Takeuchi T, Tsutsumi O, Taketani Y. Abnormal
response of insulin to glucose loading andassessment of insulin resistance in non-obese
patients with polycystic ovary syndrome.
Gynecol Endocrinol 23(7):385-91, 2008.
(5) OuYang Z, Hirota Y, Osuga Y, Hamasaki K,
Hasegawa A, Tajima T, Hirata T, Koga K,
Yoshino O, Harada M, Takemura Y, Nose E,
Yano T, Taketani Y. Interleukin-4 stimulates
proliferation of endometriotic stromal cells. A m
J Pathol 173(2):463-9, 2008.
(6) Tsutsumi R, Hiroi H, Momoeda M, Hosokawa Y,
Nakazawa F, Koizumi M, Yano T, Tsutsumi O,
Taketani Y. Inhibitory effects of cholesterol
sulfate on progesterone production in humangranulosa-like tumor cell line, KGN. Endocr J
55(3):575-81, 2008.
(7) Hiroi H, Momoeda M, Nakazawa F, Koizumi M,
Tsutsumi R, Hosokawa Y, Osuga Y, Yano T,
Tsutsumi O, Taketani Y. Expression andregulation of periostin/OSF-2 gene in rat uterus
and human endometrium. Endocr J 55(1):183-9,
2008.
(8) Ohno T, Hiroi H, Momoeda M, Hosokawa Y,
Tsutsumi R, Koizumi M, Nakazawa F, Yano T,
Tsutsumi O, Taketani Y. Evidence for the
expression of alcohol dehydrogenase class I genein rat uterus and its up-regulation byprogesterone. Endocr J 55(1): 83-90, 2008.
(9) Harada T, Momoeda M, Taketani Y, Hoshiai H,
Terakawa N. Low-dose oral contraceptive pill fordysmenorrhea associated with endometriosis: aplacebo-controlled, double-blind, randomized
trial. Fertil Steril 90(5):1583-8, 2008.
(10) Hirata T, Osuga Y, Hamasaki K, Yoshino O, Ito
M, Hasegawa A, Takemura Y, Hirota Y, Nose E,
Morimoto C, Harada M, Koga K, Tajima T, Saito
S, Yano T, Taketani Y. Interleukin (IL)-17A
stimulates IL-8 secretion, cyclooxygensase-2
expression,andcellproliferationofendometriotic stromal cells. Endocrinology
149(3):1260-7, 2008.
(11) Osuga Y, Koga K, Hirata T, Hiroi H, Taketani Y.
A case of hydrosalpinx associated with themenstrual cycle. Fertil Steril 90(1):199, 2008.
(12) Hasegawa A, Yoshino O, Osuga Y, Hirata T, Yano
T, Taketani Y. High soluble CD44 concentrationin peritoneal fluid in endometriosis. Fertil Steril
89(5):1267-8, 2008.

165

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 cervicalcancer 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 infection were revealed as
significant risk factors for CIN after adjustment for
HPV antibodies. The enhanced oncogenicity 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) polymorphism within a Japanese population.

Fifty-seven women with HPV16-positive cervicalcancer were analyzed 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). Additionally, 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 observations suggestthat a specific match between E6 variant proteins andHLA types may contribute to HPV16-related cervicalcarcinogenesis.
Studies of virus neutralization by antibody are
prerequisite 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 neoplasia (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
significantly 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

166

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
designedaplacebo-controlled trial in healthy adults to evaluate
the safety and immunogenicity of a synthetic peptide
consisting 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 recipients 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 prophylactic vaccine against genital
HPV.
We also investigated interacting proteins with the
HPV E6 protein. Recently, a LAP protein, scribble,
was identified 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 degradation by humanpapillomavirus E6 and the E6AP ubiquitin-protein
ligase. In the present study, we revealed that hScrib
localised to the basolateral regions of the epithelial
cell line MDCK and human uterine cervical epithelial
tissues by immunofluorescence. Human scribble
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 downregulation of
hScrib mRNA expression in the H-SIL, it revealed 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 degradation of hScrib by E6 andE6AP led to the complete decrease of hScrib
expression during the process of carcinogenesis 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 identified 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-mediateddegradationbyhumanpapillomavirus 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 scribble
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 revealed aclear downregulation in the invasive cancers. These167

results suggest the possibility that degradation by
HPV E6 is one of the causal roles for the progressive
decrease of hScrib expression during the diseaseprogression from low-grade squamous intraepithelial
lesions to H-SIL, and a cooperative role ofdownregulation of hScrib mRNA expression andubiquitin-mediated degradation of hScrib by E6 andE6AP led to the complete decrease of hScrib
expression during the process of carcinogenesis 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 neoplastic
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 investigated 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 degradationof 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 ubiquitination in the presence of both E6
and E6AP. These data revealed that E6AP isextensively involved in the ubiquitin-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 investigated whether hScrib
and APC interact with each other in vitro and in vivo.
Interaction between hScrib and APC is mediated by
the PDZ domains 1 and 4 of hScrib and C-terminal
PDZ domain-binding motif of APC. Human Scribble
co-localized with APC at the synaptic sites ofhippocampal neuron and at the tip of membrane
protrusion in the epithelial cell line. Interference of
the interaction between hScrib and APC caused
disruption of adherens junction. Knockdown of hScrib
expression by RNAi disrupts localization of APC at
the adherens junction. These data suggest that hScrib
may participate in the hDlg-APC complex through its
PDZ domains and regulate cell cycle and neuralfunction by associating with APC.
Drosophila tumor suppressor Scribble has been
identified as an apical-basolateral polarity determinant
in epithelia. A human homolog of Drosophila Scribble,
human Scribble (hScrib), has been identified as aprotein targeted by human papillomavirus E6 for theubiquitin-mediated degradation dependent on E6AP, acellular ubiquitin-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 epithelia.
Transfection of hScrib inhibits cell-cycle progression
from G1 to S phase, and it up- and down-regulates
expression 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 proliferation control andlocalization at the basolateral membrane. We foundthat LRRs and PDZ domain 1 are indispensable for
hScrib to inhibit cell growth by blocking cell-cycle
progression and to keep its proper localization. These
data indicate that basolateral membrane localization of
hScrib is closely related to its proliferation 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(HPV) E6 for ubiquitin-mediated degradation
dependent on ubiquitin-protein ligase E6AP, is a

168human homolog of Drosophila neoplastic tumor
suppressor scribble, in which mutation causes loss ofpolarity and overgrowth of epithelia. Drosophila discs
large (Dlg) is one of neoplastic 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 investigatedmechanism underlying degradation of three target
proteins of E6, hScrib, hDlg, and p53 by usingeighteen HPV 16 E6 mutants with single amino acidsubstitution. In vitro degradation ability of each E6
mutant was equivalent for these tumor suppressors.
We investigated whether E6AP is involved inubiquitin-mediated degradation 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
ubiquitination in the presence of both E6 and E6AP.
These data revealed that E6AP is extensively involvedintheubiquitin-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 ofendometrioid adenocarcinomas of the endometrium
and ovary, the role of PTEN alteration in endometrioid
adenocarcinoma of the cervix remains to beinvestigated. To elucidate the molecular pathogenesisof cervical adenocarcinoma and adenosquamous
carcinoma, and in particular to examine the potential
role of PTEN mutation in endometrioid-type cancer ofthe cervix, we analyzed 32 cervical adeno- or
adenosquamous
carcinomas(8
endometrioid
adenocarcinomas, 14 mucinous adenocarcinomas and
10 adenosquamous carcinomas) for PTEN mutationsand 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 carcinomas and HPV-positive
adenocarcinomas). The cur-rent observations suggestthat PTEN mutation is frequently detected in HPVnegative adenocarcinomas of the cervix and the mostprevalent occurrence of PTEN mutation in
endometrioid subtype is keeping with endometrial andovarian 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 forsensitivity
to
MPA,
we
performed
immunohistochemical analysis of PTEN, phospho-Akt,169p53, 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. Immunohistochemical 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
statistical 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 isinactivated by promoter methylation in human coloncancers. Here, we analyzed promoter methylation of
the SFRP1 gene in human ovarian cancers, in whichloss of heterozygosity in 8p is frequently observed andinvolvement of the Wnt signaling pathway has beensuggested. Methylation-specific PCR (MSP) analysis
showed that four of 13 ovarian cancer cell lines andtwo of 17 primary ovarian cancers had methylated
SFRP1, while an immortalized ovarian epithelial cellline, HOSE, and seven ovarian endometrial cyst
samples did not. In the four ovarian cancer cell lines
with the methylation, SFRP1 was not expressed at all
as determined by quantitative RT-PCR analysis. These
results show that SFRP1 is inactivated by promoter
methylation in human ovarian cancers, as well ascolon cancers.
4 hMSH2

The DNA mismatch repair gene is a key regulator
in the elimination of base-base mismatches andinsertion/deletion loops (IDLs). Human MutS
homologue 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. Oestrogen receptor (ER) alphaand beta are members of a nu-clear receptor (NR)superfamily. Ligand-dependent transcription of ER is
regulated by the p160 steroid receptor coactivatorfamily, the thyroid hormone receptor-associatedproteins/the vitamin D 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
alpha/beta and hMSH2. Immunoprecipitation andglutathione-S-transferase pull-down assay revealed
that ER alpha and hMSH2 interacted in aligand-dependent manner, whereas ER beta andhMSH2 interacted in a ligand-independent manner.
Oestrogen receptor alpha/beta bound to hMSH2
through the hMSH3/hMSH6 interaction domain ofhMSH2. In a transient expression assay, hMSH2
potentiated the transactivation function of liganded
ER alpha, but not that of ER beta. These results
suggest that hMSH2 may play an important role as aputative coactivator in ER alpha dependent gene
expression.
(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 radically treated with surgery or high dose-rate
intracavitary brachytherapy (HDR-ICBT) with orwithout 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 (9%) instage IA, 52 (34%) in stage IB, 24 (16%) in stage IIA,
and 63 (41%) in stage IIB. The conventional surgery

170group 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 chemoradiotherapy. Three patients with stage I received
ICBT-alone without external beam irradiation.
RESULTS: The 5-year cause-specific survival (CSS)
rates for surgery and RT were 79.9% and 82.3%,
respectively; the difference between these twotreatments was not statistically significant (P =0.8524). The differences in the survival rates between
the two treatments for each of the stage I or stage II
patients were also not statistically significant (P =0.8407 for stage I and P = 0.6418 for stage II). This
retrospective study suggests that RT results incompatible survival with conventional surgery forpatients with stage I-II cervical carcinoma.

References published in 2008
(1) OdaK,
Okada
J,Timmerman
L,
Rodriguez-Viciana P, Stokoe D, Shoji K, Taketani
Y, Kuramoto H, Knight ZA, Shokat KM,
McCormick F. PIK3CA cooperates with otherphosphatidylinositol 3'-kinase pathway mutations
to effect oncogenic transformation. Cancer Res.
68(19): 8127-36, 2008.
(2) 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 13(7):771-85, 2008.
(3) Kawana K, Matsumoto J, Miura S, Shen L,
Kawana Y, Nagamatsu T, Yasugi T, Fujii T, Yang
H, Quayle AJ, Taketani Y, Schust DJ. Expressionof CD1d and ligand-induced cytokine production
are tissue specific in mucosal epithelia of thehuman lower reproductive tract. Infect Immun.
76(7):3011-8, 2008.
(4) Tomio A, Schust DJ, Kawana K, Yasugi T,
Kawana Y, Mahalingaiah S, Fujii T, Taketani Y.
Prolactin can modulate CD4+ T-cell response
through receptor-mediated alterations in theexpression of T-bet. Immunol Cell Biol. 86(7):616-21, 2008.
(5) Zhao L, Yano T, Osuga Y, Nakagawa S, Oishi H,
Wada-Hiraike O, Tang X, Yano N, Kugu K,
Schally AV, Taketani Y. Cellular mechanisms ofgrowth inhibition of human endometrial cancer
cell line by an antagonist of growth hormonereleasing hormone. Int J Oncol. 32(3):593-601,
2008.

171

Department of Perinatal Medicine
Professor
Shiro Kozuma

Associate Professor
Tomoyuki Fujii

Lecturer
Yoshimasa Kamei

Homepage

http://www.iiosan.umin.jp/index.htm

Organization
The Department of Perinatal Medicine is organized
by one professor and one associate professor and one
lecturer, being directed practically by Professor Yuji
Taketani, the chairman of the Department of
Obstetrics and Gynecology. All the staff members aretaking part in both the clinical and research activities,
as well as the teaching activities, with 15 associates of
the University of Tokyo Hospital. For the clinicalaspect, they are engaged with in-patient andout-patient care including 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 fetal
growth restriction. New techniques like fetal blood
sampling and three-dimensional ultrasonography havebeen introduced into clinical service. The subjects ofstudies were focused on “fetus” and “ultrasound” inperinatology and medical engineering research group.

Fetal behavior, particularly breathing movements andsleep-wakefulness cycle were studied with ultrasoundin 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 had been
indicated. The inoculation was usually performed fourto six times in every two or three weeks. In our clinic,
after the immunotherapy, their pregnancy outcomes
had extremely improved. The successful reproductive
rate had achieved about 75%.

172

References published in 2008
(1) Kikuchi A, Unno N, Shiba M, Sunagawa S, Ogiso
Y, Kozuma S, Taketani Y. Multifractal descriptionof the maternal surface of the placenta. Gynecol
Obstet Invest. 66(2):127-33, 2008.
(2) Matsumoto J, Kawana K, Nagamatsu T, SchustDJ, Fujii T, Sato H, Hyodo H, Yasugi T, Kozuma
S, Taketani Y. Expression of surface CD1d in theextravillous trophoblast cells of early gestational
placenta is downregulated in a manner dependent
on trophoblast differentiation. Biochem Biophys
Res Commun. 371(2):236-41, 2008.
(3) Kikuchi A, Unno N, Kozuma S, Taketani Y.
Detrended fluctuation analysis of heart ratevariability in normal and growth-restrictedfetuses. Gynecol Obstet Invest 65(2):116-22,
2008.

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

174

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
Hiroshi Ono, M.D., Hirotsugu Kano, M.D., Ph.D., Tatsuo Katori, M.D.,
Keiji Goishi, M.D., Katsuyoshi Ko, M.D., Yasuo Kodachi, M.D.,
Masakazu Mimaki, M.D., Ph.D., Kazuhiro Takahashi, M.D., Naoki Itoh, M.S.,
Kan Takahashi, M.D., Ken-ichirou Miura, M.D., Akifumi Toyoda, M.D.,
Riki Nishimura, M.D., TakakoMatsuoka, M.D., Atsushi Satoh, M.D.,
Ai Motomura, M.D. (As of March 31, 2009)

Homepage

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 associates, 13 seniorresidents, 1 research fellow, and 13 graduate students
on March 31, 2009.

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.

175

Clinical activities

April, 2006.
(As of March 31, 2009)

We have specialized outpatient clinics covering allpediatric fields in addition to general pediatrics. In
July, 2008, the capacity of the pediatric and pediatricsurgery ward was increased to 100 beds, including 9
beds in the neonatal intensive care unit (NICU), 15
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
have two child care specialists in the pediatric ward in

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. We identified over-expression of ALK
gene in advanced stages of neuroblastoma.
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 were
investigated.
③ Cardiology group: A novel intervention catheter
technique in PDA was applied in several

176

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 is investigated. The
neuropathological studies of perinatal brain
damage,inparticularperiventricularleukomalacia , is also performed.

Referencess
1. Abe Y, Negasawa T, Monma C, Oka A: Infantile
botulism caused by Clostridium butyricum type E
toxin. Pediatr Neurol 38: 55-57, 2008
2. Amemiya S, Akahane M, Takita J, Igarashi T,
Ohtomo K: Imaging findings of upper abdominal
involvement by acute megakaryoblastic leukemia.
Pediatr Radiol 38: 457-461, 2008
3. Chen Y, Takita J, Choi YM, Kato M, Ohira M,
Sanada M, Wang L, Soda M, Kikuchi A, Igarashi
T, Nakagawara A, Hayashi Y, Mano H, Ogawa S:
Oncogenic mutations of ALK kinase inneuroblastoma. Nature 455: 971-975, 2008
4. Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine
T, Igarashi T, Hattori S: Neph1, a component of
the kidney slit diaphragm, is tyrosine
phosphorylated by Src-family tyrosine kinase andmodulates intracellular signaling by binding to
Grb2 J Biol Chem. 283: 9177-9186, 2008
5. Inatomi J, Yokoyama Y, Sekine T, Igarashi T: A
case of cerebral salt-wasting syndrome associatedwith aseptic meningitis in an 8-year-old girl.
Pediatr Nephrol 23: 659-662, 2008
6. Itoh M, Suzuki Y, Sugai K, Ozuka N, Ohsawa M,
OtsukiT,
Goto
Y:
Progressive
leukoencephalopathy associated with aluminum
deposits in myelin sheath. J Child Neurol 23:
938-943, 2008
7. Kanamori Y, Iwanaka T, Nakahara S, Kawashima
H, Komura M, Sugiyama M, Kamei Y, Hyodo H,
Yamaguchi SI, Kohzuma S, Taketani Y, Goishi K,
Ishiguro S, Takamizawa M, Igarashi T: Survival ina neonate with complete urorectal malformtion
sequence after fetal vesico-amniotic shunting for a
prominently dilated cloacae. Fetal Diagn Ther 24:
458-461, 2008
8. Kawamata N, Ogawa S, Zimmermann M, Kato M,
Sanada M, Hemminki K, Yamatomo G, Nannya Y,
Koehler R, Flohr T, Miller CW, Harbott J, Ludwig
WD, Stanulla M, Schrappe M, Bartram CR,
Koeffler HP: Molecular allelokaryotyping ofpediatric acute lymphoblastic leukemias byhigh-resolution single nucleotide polymorphism
oligonucleotide genomic microarray. Blood 111:776-784, 2008
9. Kobayashi S, Murayama S, Takanashi S,
Takahashi K, Miyatsuka S, Fujita T, Ichinohe S,
Koike Y, Kohagizawa T, Mori H, Deguchi Y,
Higuchi K, Wakasugi H, Sato T, Wada Y, Nagata
M, Okabe N, Tatsuzawa O: Clinical features andprognoses of 23 patients with chronic
granulomatous disease followed for 21 years by asingle hospital in Japan. Eur J Pediatr 167:
1389-1394, 2008
10. Komura M, Kanamori Y, Sugiyama M, Nakahara
S, Kawashima H, Hatanaka A, Takazawa Y,
Goishi K, Igarashi T, Iwanaka T: Antenatallydiagnosed giant multicystic dysplastic kidney
resected during the neonatal period. J Pediatr Surg
43: 2118-2120, 2008
11. Manabe A, Ohara A, Hasegawa D, Koh K, Saito T,
Kiyokawa N, Kikuchi A, Takahashi H, Ikuta K,
Hayashi Y, Hanada R, Tsuchida M; Tokyo
Children's Cancer Study Group. Significance ofthe complete clearance of peripheral blasts after 7
days of prednisolone treatment in children withacute lymphoblastic leukemia: the Tokyo
Children's Cancer Study Group Study L99-15.
Haematologica 93: 1155-1160, 2008
12. Nozu K, Inagaki T, Fu XJ, Nozu Y, Kaito H,
Kanda K, Sekine T, Igarashi T, Nakanishi N,
Yoshikawa N, Iijima K, Matsuo M: Molecularanalysis of digenic inheritance in Bartter
syndrome with sensorineural deafness. J Med
Genet 45: 182-186, 2008
13. Ogawa S, Matsubara A, Onizuka M, Kashiwase K,
Sanada M, Kato M, Nannya Y, Akatsuka Y, Satake
M, Takita J, Chiba S, Saji H, Maruya E, Inoko H,
Morishima Y, Kodera Y, Takehiko S: Japan

177

Marrow Donation Program (JMDP): Explorationof the genetic basis of GVHD by genetic
association studies. Biol Blood Marrow
Transplant 15(Suppl): 39-41, 2008
14. Ohnishi H, Taki T, Yoshino H, Takita J, Ida K,
Ishii M, Nishida K, Hayashi Y, Taniwaki M,
Bessho F, Watanabe T: A complex t(1;22;11)(q44;q13;q23) translocation causing MLL-p300
fusion gene in therapy-related acute myeloid
leukemia. Eur J Haematol 81: 475-480, 2008
15. Okazaki S, Ohsawa M, Kuki I, Kawawaki H,
Koriyama T, Ri S, Ichiba H, Hai E, Inoue T,
Nakamura H, Goto Y, Tomiwa K, Yamano T,
Kitamura K, Itoh M: Aristaless-related homeobox
gene disruption leads to abnormal distribution of
GABAergic interneurons in human neocortex:
evidence based on a case of X-linked
lissencephaly with abnormal genitalia (XLAG).
Acta Neuropathol 116: 453-462, 2008
16. Saeki H, Watanabe A, Tada Y, Kakinuma T,
Komine M, Ihn H, Asahina A, Etoh T, Ktanaka S,
Sato U, Kano H, Igarashi T, Tamaki K: Juvenile
pustular psoriasis associated with steroid
withdrawal syndrome due to topical corticosteroid.
J Dermatol 35: 601-603, 2008
17. Saito Y, Toyoshima M, Oka A, Zhuo L, Moriwaki
SI, Yamamoto O, Kanzaki S, Hanaki KI,
Ninomiya H, Nanba E, Kondo A, Maegaki Y,
Ohno K: Mental retardation, spasticity, basal
ganglia calcification, cerebral white matter lesions,multiple endocrine defects, telangiectasia andatrophic skin: A new syndrome? Brain Dev 30:
221-225, 2008
18. Sakata R, Usui T, Mimaki M, Araie M.
Developmental glaucoma with chromosomal
abnormalities of 9q deletion and 13t duplication.
Arch Ophthalmol 126: 431-432, 2008
19. Seki G, Yamada H, Horita S, Suzuki M, Sekine T,
Igarashi T, Fujita T: Activation and inactivation of
Na+H/HCO3- cotransporter NBC1. J Epitheal
Biol and Pharmacol 1:35-39, 2008
20. Shimizu N, Yamamoto K, Obi S, Kumagaya S,
Masumura T, Shimano Y, Naruse K, Yamashita JK,
Igarashi T, Ando J: Cyclic strain induces mouseembryonic stem cell differentiation into vascularsmooth muscle cells by activating PDGF receptor
β. J Appl Physiol 104:766-772, 2008.

21. Shinmura K, Suzuki M, Yamada H, Tao H, Goto
M, Kamo T, Nagura K, Kageyama S, Kato M,
Ogawa S, Maekawa M, Takamochi K, Suzuki K,
Nakamura T, Sugimura H: Characterization of
adenocarcinoma of the lung in a familial
adenomatous polyposis patient. Pathol Int 58:
706-712, 2008
22. Suzuki M, Kato M, Yuyan C, Takita J, Sanada M,
Nannya Y, Yamamoto G, Takahashi A, Ikeda H,
Kuwano H, Ogawa S, Hayashi Y: Whole-genome
profiling of chromosomal aberrations inhepatoblastoma using high-density singlenucleotide polymorphism genotyping microarrays.
Cancer Sci 99: 564-570, 2008
23. Suzuki M, Vaisbich MH, Yamada H, Horita S, Li
Y, Sekine T, Moriyama N, Igarashi T, Endo Y,
Cardoso TP, de Sa LC, Koch VH, Seki G, Fujita T:
Functional analysis of a novel missense NBC1
mutation and of other mutations causing proximal
renal tubular acidosis.
Pflugers Arch-Eur J
Physiol 455: 583-593, 2008
24. Takanashi S, Okame M, Shiota T, Takagi M,
Yagyu F, Tung PG, Nishimura S, Katsumata N,
Igarashi T, Okitsu S, Ushijima H: Development ofa rapid immunochromtographic test fornoroviruses genogroups I and II. J Viral Methods
148: 1-8, 2008
25. Takano K, Shimono M, Shiota N, Kato A,
Tomioka S, Oka A, Ohno K, Sathou H: Infantile
neuronal ceroid lipofuscinosis. The first reported
case in Japan diagnosed by palmitoyl-protein
thioesterase enzyme activity deficiency. Brain
Dev 30: 370-373, 2008
26. Tauchi
H,
Tomizawa
D,
EguchiM,
Eguchi-Ishimae M, Koh K, Hirayama M,
Miyamura N, Kinukawa N, Hayashi Y, Horibe K,
Ishii E: Clinical features and outcome of MLL
gene rearranged acute lymphoblastic leukemia in
infantswithadditional
chromosomal
abnormalities other than 11q23 translocation.
Leuk Res 32: 1523-1529, 2008
27. Toda M, Yamamoto K, Shimizu N, Obi S,
Kumagaya S, Igarashi T, Kamiya A, Ando J:
Differential gene responses in endothelial cells
exposed to a combination of shear stress andcyclic stretch. J Biotechnol 133: 239-244, 2008
28. Yanagisawa A, Namai Y, Sekine T, Igarashi T:

178

Ischemic colitis as a complication in a patientwith steroid-dependent nephrotic syndrome.
Pediatr Nephrol 23: 655-657, 2008
29. Zhu W, Shiojima I, Ito Y, Li Z, Ikeda H, Yoshida
M, Naito AT, Nishi J, Umezawa A, Minamino T,
Nagai T, Kikuchi A, Asashima M, Komuro I:
IGFBP-4 is an inhibitor of canonical Wnt
signalling required for cardiogenesis. Nature 454:
345-349, 2008

179

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.

Kan Terawaki, 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

180

and treat patients. We also have specialized outpatient
clinics, liver and biliary tract clinics and a tumor clinic.
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 multiple functional forceps 3
mm in a diameter is developing for robotic surgery
system at first.
The intestinal tract immunity study group was thefirst to 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 thegenes related to tumor development. New therapy
using a virus 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.

181

References
1. Komura M, Komura H, Kanamori Y, Tanaka Y,
Suzuki K, Sugiyama M, Nakahara S, Kawashima
H, Hatanaka A, Hoshi K, Ikada Y, Tabata Y,
Iwanaka T. An animal model study fortissue-engineered trachea fabricated from abiodegradable scaffold using chondrocytes toaugment repair of tracheal stenosis. J Pediatr Surg.
2008; 43: 2141-2146.
2. Kanamori Y, Iwanaka T, Nakahara S, Kawashima
H, Komura M, Sugiyama M, Kamei Y, Hyodo H,
Yamaguchi S, Kohzuma S, Taketani Y, Goishi K,
Ishiguro A, Tsuchida S, Takamizawa M, Igarashi
T. Survival in a neonate with complete urorectal
septum malformation sequence after fetal
vesico-amniotic shunting for a prominently
dilated cloaca. Fetal Diagn Ther. 2008; 24: 458461..
3. Komura M, Kanamori Y, Sugiyama M, Nakahara
S, Kawashima H, Hatanaka A, Takazawa Y,
Goishi K, Igarashi T, Iwanaka T. Antenatallydiagnosed giant multicystic dysplastic kidney
resected during the neonatal period. J Pediatr
Surg. 2008;43: 2118-2120.
4. Kanamori Y, Iwanaka T, Shibuya K. Congenital
lobar emphysema caused by a very rare great
vessel anomaly (left aortic arch, rightdescending aorta and left ligamentum
arteriosum). Pediatr Int. 2008; 50:594-596.
5. Komura M, Komura H, Tanaka Y, Kanamori Y,
Sugiyama M, Nakahara S, Kawashima H,
Suzuki K, Hoshi K, Iwanaka T. Human tracheal
chondrocytes as a cell source for augmenting
stenotic tracheal segments: the first feasibility
study in an in vivo culture system. Pediatr Surg
Int. 2008; 24:1117-1121.
6. Morikawa N, Honna T, Kuroda T, Watanabe K,
Tanaka H, Takayasu H, Fujino A, Tanemura H,
Matsukubo M. High dose intravenous
methylprednisolone
resolves
esophageal
stricture resistant to balloon dilatation withintralesional injection of dexamethasone.
Pediatr Surg Int. 2008; 24:1161-4.
7. Morikawa N, Kuroda T, Honna T, Kitano Y,
Takayasu H, Ito Y, Nakamura T, Nakagawa S,
Hayashi S, Sago H. The impact of strict

infection control on survival rate of prenatallydiagnosed isolated congenital diaphragmatic
hernia. Pediatr Surg Int. 2008; 24:1105-1109.
8. Sugimoto K, Takayasu H, Nakazawa N,
Montedonico S, Puri P. Prenatal treatment withretinoic acid accelerates type 1 alveolar cellproliferation of the hypoplastic lung in thenitrofen model of congenital diaphragmatic
hernia. J Pediatr Surg. 2008; 43:367-372.
9. Takayasu H, Sato H, Sugimoto K, Puri P.
Downregulation of GATA4 and GATA6 in the
heart
of
rats
with
nitrofen-induced
diaphragmatic hernia. J Pediatr Surg. 2008; 43:
362-366.
10. Sato H, Murphy P, Giles S, Bannigan J, Takayasu
H, Puri P. Visualizing expression patterns of Shhand Foxf1 genes in the foregut and lung buds by
optical projection tomography. Pediatr Surg Int.
2008; 24:3-11.
11. Tanaka Y, Nakamura S, Shibata H, Kishi Y, Ikeda
T, Masuda S, Sasaki K, Abe T, Hayashi S, Kitano
Y, Nagao Y, Hanazono Y. Sustained macroscopic
engraftment of cynomolgus embryonic stem cells
in xenogeneic large animals after in uterotransplantation. Stem Cells Dev. 2008; 17:367381.
12. Fujinaga S, Hirano D, Hara S, Uchida H, Kitano Y,
Kobayashi K, Tada M, Someya T, Ohtomo Y,
Shimizu T. Seminal vesicle abscesses associatedwith ipsilateral multicystic dysplastic kidney in an
infant. Pediatr Nephrol. 2008;23:1551-1554.
13. Kitano Y, Sago H, Hayashi S, Kuroda T, Honna T,
Morikawa N. Aberrant venous flow measurement
may predict the clinical behavior of a fetal
extralobar pulmonary sequestration. Fetal Diagn
Ther. 2008; 23: 299-302.
14. Morikawa N, Honna T, Kuroda T, Kitano Y,
Fuchimoto Y, Kawashima N, Kawasaki K.
Resolution of hepatopulmonary syndrome after
ligation of a portosystemic shunt in a pediatricpatient with an Abernethy malformation. J Pediatr
Surg. 2008; 43: e35-38.
15. Mori Y, Kato T, Kodaka T, Kanagawa EM, Hori S,
Kanagawa O. Protection of IFN-gamma signalingdeficient NOD mice from diabetes by
cyclophosphamide. Int Immunol. 2008; 20:12311237.

182

16. Maki T, Carville A, Stillman IE, Sato K, Kodaka T,
Minamimura K, Ogawa N, Kanamoto A,
Gottschalk R, Monaco AP, Marr-Belvin A,
Westmoreland SV, Sehgal P. SV40 infection
associated with rituximab treatment after kidneytransplantationinnonhumanprimates.
Transplantation. 2008; 85:893-902.
17. Kishi Y, Tanaka Y, Shibata H, Nakamura S,
Takeuchi K, Masuda S, Ikeda T, Muramatsu S,
Hanazono Y. Variation in the incidence ofteratomas after the transplantation of nonhumanprimate ES cells into immunodeficient mice. Cell
Transplant. 2008; 17:1095-1102.
18. Kishi Y, Inoue M, Tanaka Y, Shibata H, Masuda S,
Ikeda T, Hasegawa M, Hanazono Y. Knockout
serum replacement (KSR) has a suppressive effecton Sendai virus-mediated transduction ofcynomolgus ES cells. Cloning Stem Cells. 2008;
10: 307-312.

Reproductive, Developmental andAging Sciences
3. Aging Sciences

184

Department of Geriatric Medicine
Department of Aging Research
Professor
Yasuyoshi Ouchi, M.D.,Ph.D.

Associate Professor
Masahiro Akishita, M.D., Ph.D.

Lecturer
Masato Eto, M.D., Ph.D.,

Katsuya Iijima, M.D., Ph.D.

Sumito Ogawa, M.D., Ph.D.

Research Associate
Yasuhiro Yamaguchi, M.D., Ph.D.,

Hiroshi Yamamoto, M.D., Ph.D.

Kotaro Azuma, M.D., Ph.D.

Homepage

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

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 the elderly 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 the patients is another point of view which should be emphasized.
Our sub-specialty includes respirology, cardiology,
neurology, hematology, endocrinology, and bone metabolism, 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 25 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 a junior resident, give instructions as to the assessment of the patient's problem, making of future plans, and help theresident with various procedures. Very important issues are discussed and decisions are made in weekly
professor's round.
Specialized services are provided to out-patients ona daily basis in all areas of internal medicine. Approximately 368 new and a total of 19,820 patients
visit the out-patient clinic in a year.

Education
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 of interrogation and physical185

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.

Research
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 of interstitial lung disease, role of adhesion molecule in airway
disease, role of endothelin, leukotrienes, and neuropeptides in asthma, proliferation and differentiation oflung fibroblasts, proliferation and apoptosis of airway
disease, defensin and infectious disease.
Cardiovascular unit
Research on the mechanism and regulation of vascular calcification, sex hormone regulation of vascularfunction, clinical evaluation of vascular function using
vascular ultrasound and pulse wave velocity, metabolic syndrome in the elderly.

3.

4.

5.

6.

Neurology unit
Diagnosis and treatment of the demented patients,
neuro-protective function of Thioredoxin in Drosophila, regulation of apoptosis by stress-responsive
kinases, etc

7.

Osteoporosis and endocrinology unit
Bone metabolism, mechanism of action of nuclear
receptors, genetic analysis of osteoporosis, vitamin K
action, hormone dependent cancer.

8.

Publications
1.

2.

Akishita M, Hashimoto M, Ohike Y, Ogawa S,
Iijima K, Eto M, Ouchi Y. Association of plasma
dehydroepiandrosterone-sulfate
levelswithendothelial function in postmenopausal womenwith coronary risk factors. Hypertens Res. 31;
69-74, 2008.
Hirao T, Urata Y, Kageyama K, Ikezaki M,

9.

Kawakatsu M, Matsuse M, Matsuo T, Akishita
M, Nagata I, Kondo T. Dehydroepiandrosterone
augments sensitivity to gamma-ray irradiation inhuman H4 neuroglioma cells throughdown-regulation of Akt signaling. Free Radic
Res. 42; 957-65, 2008.
Ishii M, Yamaguchi Y, Yamamoto H, Hanaoka Y,
Ouchi Y. Airspace enlargement with airway cell
apoptosis in klotho mice: a model of aging lung.
J Gerontol A Biol Sci Med Sci. 63; 1289-98,
2008.
Kawashima Y, Akishita M, Hasegawa H, Kozaki
K, Toba K. Stress-induced blood pressure
elevation in subjects with mild cognitive
impairment: effects of the dual-type calcium
channel blocker, cilnidipine. Geriatr Gerontol
Int. 8; 278-83, 2008.
Okamoto T, Okamoto L, Lisanti MP, Akishita M.
Switch to oral hypoglycemic agent therapy frominsulin injection in patients with type 2 diabetes.
Geriatr Gerontol Int. 8; 218-26, 2008.
Ota H, Eto M, Kano MR, Ogawa S, Iijima K,
Akishita M, Ouchi Y. Cilostazol inhibits
oxidative stress-induced premature senescence
via upregulation of Sirt1 in human endothelial
cells. Arterioscler Thromb Vasc Biol. 28;
1634-39, 2008.
Shiraki M, Urano T, Kuroda T, Saito M, Tanaka
S, Miyao-Koshizuka M, Inoue S: The synergistic
effect of bonemineraldensity andmethylenetetrahydrofolate reductase (MTHFR)
polymorphism (C677T) on fractures. J Bone
Miner Metab 26; 595-602, 2008.
Son BK, Akishita M, Iijima K, Kozaki K,
Maemura K, Eto M, Ouchi Y. Adiponectin
antagonizes stimulatory effect of tumor necrosis
factor-alpha on vascular smooth muscle cell
calcification: regulation of growth arrest-specificgene 6-mediated survival pathway by adenosine5'-monophosphate-activated protein kinase.
Endocrinology. 149; 1646-53, 2008.
Sonohara K, Kozaki K, Akishita M, Nagai K,
Hasegawa H, Kuzuya M, Yokote K, Toba K.
White matter lesions as a feature of cognitive
impairment, low vitality and other symptoms ofgeriatric syndrome in the elderly. Geriatr
Gerontol Int. 8; 93-100, 2008.

186

10. Takayama K, Horie-Inoue K, Ikeda K, Urano T,
Murakami K, Hayashizaki Y, Ouchi Y, Inoue S.
FOXP1 is an androgen-responsive transcription
factor that negatively regulates androgen
receptor signaling in prostate cancer cells.
Biochem Biophys Res Commun. 374; 388-93,
2008.
11. 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 insulin-like growth factor-1 receptor genewith spinal disc degeneration in postmenopausal
Japanese women. Spine. 33; 1256-61, 2008.
12. Yamamoto Y, Watari Y, Brydun A, Yoshizumi M,
Akishita M, Horiuchi M, Chayama K, Oshima T,
Ozono R. Role of the angiotensin II type 2
receptor in arterial remodeling after wire injury
in mice. Hypertens Res. 31; 1241-9, 2008.
13. Yu J, Eto M, Kozaki K, Akishita M, Okabe T,
Ouchi Y. Raloxifene analogue LY117018
suppresses oxidative stress-induced endothelial
cell apoptosis through activation of ERK1/2
signaling pathway. Eur J Pharmacol. 589; 32-6,
2008.
14. Son BK, Akishita M, Iijima K, Eto M, Ouchi Y.
Mechanism of Pi-induced vascular calcification.
J Atheroscler Thromb. 15; 63-8, 2008.
15. Kojima T, Akishita M, Iijima K, Eto M, Ouchi Y.
Nocturia in elderly people with hypertension--noinfluence of low-dose thiazide added to losartan.
J Am Geriatr Soc. 56; 2155-6, 2008.
16. Teramoto S, Ishii T, Ishii M, Yamamoto H,
Yamaguchi Y, Hibi S, Ouchi Y. Variation in thetumour necrosis factor-alpha gene is not
associated with susceptibility to Asian COPD.
Eur Respir J. 31; 682-3, 2008.
17. Teramoto S, Yamaguchi Y, Yamamoto H,
Hanaoka Y, Ishii M, Hibi S, Ishii T, Kume H,
Ouchi Y. Cardiovascular and metabolic effects of
CPAP in obese obstructive sleep apnoea patients.
Eur Respir J. 31; 223-5, 2008.
18. Teramoto S, Yamaguchi Y, Yamamoto H,
Hanaoka Y, Ishii M, Hibi S, Kume H, Akishita
M, Ouchi Y. Increase in oxidative stress levels inelderly patients with obstructive sleep apnea
syndrome: effects of age and sex. J Am Geriatr
Soc. 56; 569-71, 2008.

19.

20.

Teramoto S, Yamamoto H, Yamaguchi Y,
Hanaoka Y, Ishii M, Hibi S, Kume H, Ouchi Y.
Lower respiratory tract infection outcomes are
predicted better by an age >80 years than by
CURB-65. Eur Respir J. 31; 477-8, 2008.
Teramoto S, Yamamoto H, Yamaguchi Y, Ishii
M, Hibi S, Kume H, Ouchi Y. Antiplatelet
cilostazol,aninhibitor
of
type
III
phosphodiesterase,
improves
swallowing
function in patients with a history of stroke. J
Am Geriatr Soc. 56; 1153-4, 2008.

Surgical Sciences
1. Surgery

188

Department of Thoracic Surgery
Professor
Takamoto, Shinichi

Associate Professor
Nakajima, Jun

StaffsMurakawa, Tomohiro, Fukami, Takeshi, and Inoue, Yuuta

Homepage http://ctstokyo.umin.ne.jp/
History
Clinical and basic researches of the thoracic surgery
have 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 ~ 2008.3.31).
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 280
surgeries are performed in the department in 2008.
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
department have been safely and successfully
accomplished through thoracoscopy. Researches on

189

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.
Adoptive immunotherapy with activated autologous
gammadelta T-cell for the patients with recurrent lungcancer or pulmonary metastasis from colorectal cancer
is performed as a clinical study to investigate thesafety and anticancer effect of this immunotherapy.
We are now preparing for clinical lungtransplantation for the patients suffering fromadvanced stage of diffuse lung diseases that are
refractory to conventional treatments.

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) Minimally invasive surgeries for thoracic
malignant neoplasms.
(2) Analysis of the factors influencing the prognosis oflung cancer or mediastinal neoplasms.
(3) New methods for quantitative analysis of the
DNA methylation of the lung cancer.
(4) Adoptive anticancer immunity of the autologous
gamma-delta-T-cell for the treatment of therecurrent primary lung cancer or pulmonary
metastasis from colorectal cancer.
(5) Vaccine immunotherapy for the recurrent
non-small cell lung cancer.
(6) Mechanisms of acute or chronic rejection of theallogeneic lung and trachea.

Selected publications(1) Nakajima J, Murakawa T, Fukami T, Takamoto S. Is
thoracoscopic surgery justified to treat pulmonary
metastasis from colorectal cancer? Interact
Cardiovasc Thorac Surg. 7: 212-216, 2008.
(2) Kawamura M, Nakajima J, Matsuguma H, Horio H,
Miyoshi S, Nakagawa K, Fujisawa T, Kobayashi K;
The Metastatic Lung Tumor Study Group ofJapan.Surgical outcomes for pulmonary metastases
from hepatocellular carcinoma.Eur J Cardiothorac
Surg. 34: 196-199, 2008
(3) Nakajima J, Murakawa T, Fukami T, Sano A,
Takamoto S, Ohtsu H. Postthymectomy Myasthenia
Gravis:Relationshipwiththymomaandantiacetylcholine receptor antibody. Ann Thorac Surg
86: 941-945, 2008
(4) Babu AN, Murakawa T, Voelkel NF, Zamora MR,
HensonPM,
NicollsMR.
Functional
microcirculation is lost in early airway fibrosis. Proc
Am Thorac Soc 5: 371, 2008
(5) Shiono S, Kawamura M, Sato T, Nakagawa K,
Nakajima J, Yoshino I, Ikeda N, Horio H, Akiyama
H, Kobayashi K; Metastatic Lung Tumor Study
Group of Japan.Disease-free interval length
correlates to prognosis of patients who underwent
metastasectomy for esophageal lung metastases.J
Thorac Oncol. 3: 1046-1049, 2008.
(6) Kondo M, Sakuta K, Noguchi A, Ariyoshi N, Sato K,

190

Sato S, Sato K, Hosoi A, Nakajima J, Yoshida Y,
Shiraishi K, Nakagawa K, Kakimi K. Zoledronate
facilitates large-scale ex vivo expansion of functional
gammadelta T cells from cancer patients for use in
adoptive immunotherapy. Cytotherapy 10:842-856,
2008

191

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.,

Tetsuhiro Takaoka, M.D.,

Munemoto Endo, M.D.

Takayuki Ohno, MD

Tsuyoshi Taketani, MD

Kazuo Kitahori, 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.

192

Clinical Activities
Clinical conference starts at 7:15 am in weekdays.
Regular surgery is scheduled on Monday, Wednesday,Thursday and Friday. Patient round is on Tuesday andThursday. 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 throughFriday for the follow-up visit as well as for patientreferral.
Case volume in recent years has been about 400,
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 2009, eight casesof heart 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 three-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)establishment of recovery and weaning protocols ofleft ventricular assist device, 5) a new technique ofaortic valve sparing root replacement and its
hemodynamic evaluation, 6) development of
intrauterine treatment for fetal heart disease, 7)

193application of regenerative medicine to end-stage
heart failure, 8) development of new heart preserving
solution .

small infants. Interact Cardiovasc Thorac Surg
7:75-78, 2008
10 Miyamoto T Sinzobahamvya N, Photiadis J,

References1

cardiopulmonary bypass system in neonates andBrecher AM, Asfour B.: Survival after Surgery
with Cardiopulmonary Bypass in Low Weight

Abe Y Saito I, Isoyama T, Miura W, Shi W,

Patients. Asian Cardiovasc Thorac Ann 15:116-

Yamaguchi S, Inoue Y, Nakagawa H, Ono M, Kishi
T, Ono T, Kouno A, Chinzei T, Imachi K.: A
nonpulsatile total artificial heart with 1/R control. J
Artif Organs 11: 191-200, 2008
2

Chikada M Murakami A, Takeuchi K, Takamoto S.:
Communication between the right pulmonary arteryand left atrium with aneurysm formation. Gen
Thorac Cardiovasc Surg 56:177-179, 2008

3

He H Poutias D, Kitahori K, Kawata M, Campbell P,
Cowan D, Friehs I, Del Nido P, McGowan F.:
Mitochondrial oxidative stress promotes failure ofthepressure-loaded

infantright

ventricle.

Circulation 118:S752, 2008
4

Imanaka K Asakura T, Yamabi H.: When a snappedsternal wire stab the aorta. Eur J Cardio-thorac Surg
34:904, 2008

5

Inaba H Higuchi K, Koseni K, Osawa H,
Kinoshita O.: Surgical closure of adult patentductus arteriosus using a pursestring suture.
Asian Cardiovasc Thorac Ann 16:59-61, 2008

6

Kaneko Y Kobayashi J, Yamamoto Y, Yoda H,
Kanetaka Y, Nakajima Y, Endo D, Tsuchiya K,
Sato

H,

Kawakami

T.:

Intensive

cardiacmanagement in patients with trisomy 13 or trisomy
18. Am J Med Genet A 146A: 1372-1380, 2008
7

Kaneko Y Kobayashi J, Yamamoto Y, Tsuchiya
K.: Light-guided surgery to repair coronary sinus
orifice atresia with left superior vena cava. Eur J
Cardio-thorac Surg 33:939-941, 20088

Kariya T Imai Y, Murakami A, Minegishi S, Katori
T, Kato H, Ajiki K, Hirata Y, Nagai R.: Markedly
dilated right heart 17 years after initial treatment
repaired by total right ventricular exclusion andtotal cavopulmonary connection. Circulation 118:
e133-135, 2008

9119, 200811

Miyamoto T Miyaji K, Okamoto H, Kohira S,
Tomoyasu T, Inoue N, Ohara K.: Higher cerebral
oxygen saturation may provide higher urinary
outputduringcontinuous

regional

cerebral

perfusion. J Cardiothorac Surg 3:58, 2008
12 Miyata H Hashimoto H, Horiguchi H, Matsuda S,
Motomura N, Takamoto S.: Performance of
in-hospital mortality prediction models for acutehospitalization: Hospital Standardized Mortality
Ratio in Japan. BMC Health Serv Res 8:229, 200813 Miyata H Motomura N, Ueda Y, Matsuda H,
Takamoto S.: Effect of procedural volume on
outcome of coronary artery bypass graft surgery inJapan: implication toward public reporting andminimal volume standards. J Thorac Cardiovasc
Surg 135:1306-1312, 2008
14 Motomura N Miyata H., Tsukihara H, Takamoto S.:
First report on 30-day and operative mortality inrisk model of isolated coronary artery bypass
grafting in Japan. Ann Thorac Surg. 86:1866-1872,
2008
15 Motomura N Miyata H., Tsukihara H, Takamoto S.:
Risk model of thoracic aortic surgery in 4707 cases
from a nationwide single-race population through a
web-based data entry system: the first report of
30-day and 30-day operative outcome risk models
for thoracic aortic surgery. Circulation 118:S153159, 200816 Ohno T Takamoto S, Motomura N.: Diabetic
retinopathy and coronary artery disease: From thecardiac surgeon’s perspective. Ann Thorac Surg 85:
681-689, 200817 Saito A Motomura N, Kakimi K, Narui K, Noguchi

Miyaji K Miyamoto T, Kohira S, Nakashima K,

N, Sasatsu M, Kubo K, Koezuka Y, Takai D, Ueha

Inoue N, Sato H, Ohara K.: Miniaturized

S, Takamoto S.: Vascular Allografts are Resistant to194

Methicillin- resistant Staphylococcus aureus via
Indoleamine 2,3-Dioxygenase in Murine Model. J
Thorac Cardiovasc Surg139:159-167, 2008
18 Takayama H Salerno CT, Aldea GS, Verrier ED.:
Characteristics of extracoronary vascular disease inheart transplant recipient. J Cardiothorac Surg 23:459-463, 2008
19 Tanaka S Miyairi T, Shimada S, Miura S, Kigawa I,
Fukuda S. Off-pump coronary artery bypass
grafting in a patient with Werner's syndrome. Gen
Thorac Cardiovasc Surg 56:592-594, 2008

195

Department of
Gastrointestinal Surgery
Professor
Yasuyuki

Seto MD. PhD.

Associate Professor
Sachiyo Nomura MD. PhD.

Nobuyuki Shimizu MD. PhD.

Associates
Ikuo Wada MD. PhD.

Masashi Abe MD.

Fumihiko Hatao MD. PhD.

Kouji Nozaki MD. PhD.

Takashi Fukuda MD. PhD.

Souya Nunobe MD. PhD.

Masato Nishida MD. PhD.

Takashi Kiyokawa 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196

bedsideLearning. They learn generic patient care which
encompasses not only perioperative management ofdiseases but also non-surgical management of
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

197

Clinical Activities:
2.
We have outpatient clinics from Monday throughFriday. We have specialized divisions for outpatientmanagement 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.

9.

References
1.

Seto Y, Fukuda T, Yamada K, Matsubara T, Hiki
N, Fukunaga T, Oyama S, Yamaguchi T,
Nakajima T, Kato Y. Celiac lymph nodes: distantor regional for thoracic esophageal carcinoma?

10.

Dis Esophagus 21(8):704-7,2008
Nunobe S, Hiki N, Fukunaga T, Tokunaga M,
Ohyama S, Seto Y, Yamaguchi T. Previous
laparotomy is not a contraindication tolaparoscopy-assisted gastrectomy for earlygastric cancer. World J Surg 32(7):1466-72,2008
Nunobe S, Ohyama S, Sonoo H, Hiki N,
Fukunaga T, Seto Y, Yamaguchi T. Benefit ofmediastinal
andpara-aortic
lymph-nodedissection for advanced gastric cancer withesophageal invasion. J Surg Oncol 97(5):392-5,
2008
Nunobe S, Ohyama S, Miyata S, Matsuura M,
Hiki N, Fukunaga T, Seto Y, Ushijima M,
Yamaguchi T. Incidence of gastric cancer in theremnant stomach after proximal gastrectomy.
Hepatogastroenterology 55(86-87):1855-8, 2008
Nunobe S, Hiki N, Ohyama S, Fukunaga T, Seto
Y, Yamaguchi T. Survival benefits ofpancreatoduodenectomy for gastric cancer:
relationship to the number of lymph nodemetastases. Langenbecks Arch Surg 393(2):157-62, 2008
Hatao F, Yamamoto M, Muroi M, Kaminishi M,
Tanamoto K. MyD88-induced downregulation of
IRAK-4 and its structural requirements. FEMS
Immunol Med Microbiol 53(2): 260-4, 2008
Nozaki K, Ogawa M, Williams JA, Lafleur BJ,
Ng V, Drapkin RI, Mills JC, Konieczny SF,
Nomura S, Goldenring JR. A molecular signatureof gastric metaplasia arising in response to acuteparietal cell loss. Gastroenterology 134(2):511-22, 2008
Fukuda T, Seto Y, Yamada K, Hiki N, Fukunaga
T, Oyama S, Yamaguchi T. Can immuneenhancing nutrients reduce postoperativecomplications in patients undergoing esophageal
surgery? Dis Esophagus 21(8):708-11, 2008
Hiki N, Yamamoto Y, Fukunaga T, Yamaguchi T,
Nunobe S, Tokunaga M, Miki A, Ohyama S,
Seto Y. Laparoscopic and endoscopic
cooperative surgery for gastrointestinal stromal
tumor dissection. Surg Endosc 22(7):1729-35,
2008
Hiki N, Fukunaga T, Yamaguchi T, Nunobe S,
Tokunaga M, Ohyama S, Seto Y, Yoshiba H,
Nohara K, Inoue H, Muto T. The benefits of

198

11.

12.

13.

14.

15.

16.

17.

standardizing the operative procedure for theassistant in laparoscopy-assisted gastrectomy for
gastric cancer. Langenbecks Arch Surg 393(6):963-71,2008
Hiki N, Fukunaga T, Yamaguchi T, Nunobe S,
Ohyama S, Tokunaga M, Miki A, Kuroyanagi H,
Seto Y, Muto T. Cut-and-Screw Insertion: A
Method for Safe and Speedy Secondary Trocar
Insertion in Laparoscopic Surgery. Surg TechnolInt. 17:121-5,2008
Tokunaga M, Hiki N, Fukunaga T, Miki A,
Ohyama S, Seto Y, Yamaguchi T. Does age
matter in the indication for laparoscopy-assisted
gastrectomy? J Gastrointest Surg 12(9):1502-7,
2008
Tokunaga M, Ohyama S, Hiki N, Hoshino E,
Nunobe S, Fukunaga T, Seto Y, Yamaguchi T.
Endoscopic evaluation of reflux esophagitis after
proximal gastrectomy: comparison between
esophagogastric anastomosis and jejunal
interposition. World J Surg32(7):1473-7, 2008
Nagano H, Ohyama S, Fukunaga T, Hiki N, Seto
Y, Yamaguchi T, Kato Y, Yamaguchi A. Two rarecases of node-positive differentiated gastriccancer despite their infiltration to sm1, theirsmall size, and lack of lymphatic invasion into
the submucosal layer. Gastric Cancer 11(1):53-7,
2008
Yamashita H, Nakagawa K, Yamada K,
Kaminishi M, Mafune K, Ohtomo K. A single
institutional
non-randomized
retrospective
comparison
betweendefinitive
chemoradiotherapy and radical surgery in 82
Japanese patients with resectable esophageal
squamous cell carcinoma. Dis Esophagus 21(5):430-6, 2008
Goto O, Fujishiro M, Kakushima N, Kodashima
S, Ono S, Yamaguchi H, Nomura S, Kaminishi
M, Omata M. Endoscopic submucosal dissection
as a staging measure may not lead to worse
prognosis in early gastric cancer patients withadditional gastrectomy. Dig Liver Dis 40(4):293-7,2008
Raher MJ, Thibault HB, Buys ES, Kuruppu D,
Shimizu N, Brownell AL, Blake SL, Rieusset J,
Kaneki M, Derumeaux G, Picard MH, Bloch KD,
Scherrer-Crosbie M. A short duration of high-fat

18.

19.

20.

21.

22.

23.

24.

25.

diet induces insulin resistance and predisposes toadverse left ventricular remodeling afterpressure overload. Am J Physiol Heart Circ
Physiol 295: H2495 - H2502,2008
Kaneki M, Sakai M, Shimizu N, Chang K. Is
normalized mean blood glucose level goodenough for the intensive care unit?-Glycemic
variability as a new independent predictor ofmortality.Crit Care Med 36: 3104-3106,2008
Seto Y, Chin K, Gomi K, Kozuka T, Fukuda T,
Yamada K, Matsubara T, Tokunaga M, Kato Y,
Yafune A, Yamaguchi T. Treatment of thoracic
esophageal carcinoma invading adjacentstructures. Cancer Sci 98:937-42, 2007
Seto Y, Yamada K, Fukuda T, Hosoi N,
Takebayashi R, Chin K, Kotsuka T, Gomi K,
Yamaguchi T. Esophageal bypass using a gastrictube and a cardiostomy for malignamt
esophagorespiratory fistula. Am J Surg 193:
792-93 2007
Cao L, Mizoshita T, Tsukamoto T, Takenaka Y,
Toyoda T, Cao X, Nozaki K, Tatematsu M.
Development of carcinoid tumors of theglandular 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 node metastasis via reduction of
Lymphangiogenesis. Cancer Res 67: 1018110189,2007
Kaneda A, Wang CJ, Cheong R, Timp W,
Onyango P, Wen B, Iacobuzio-Donahue CA,
Ohlsson R, Andraos R, Pearson MA, Sharov AA,
Longo DL, Ko MS, Levchenko A, Feinberg AP.
Enhanced sensitivity to IGF-II signaling links
loss of imprinting of IGF2 to increased cellproliferation and tumor risk. Proc Natl Acad Sci
104: 20926-20931,2007
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,

199

26.

27.

28.

29.

30.

31.
32.

33.

Ono S, Kaminishi M, Omata M. Ex vivo pilot
study using computed analysis of endocytoscopic images to differentiate normal andmalignant squamous cell epithelia in theoesophagus. 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 for
gastroduodenal 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 a phase i clinical study
using dendritic cell vaccinations for thyroid
cancer. Thyroid 17: 53-58, 2007
Leys CM, Nomura S, Goldenring JR. Expression
and prognostic significance of prothymosinalpha and ERp57 in human gastric cancer
Surgery 141: 41-50, 2007
Mori K, Suzuki T, Uozaki H, Nakanishi H, Ueda
T, Matsuno Y, Kodera Y, Sakamoto H,
Yamamoto N, Kaminishi M. Detection ofminimal gastric cancer cells in peritoneal
washings by focused microarray analysis withmultiple markers: clinical implications. Ann
Surg Oncol 14: 1694-702, 2007
Kaminishi M. Introductory Remarks. Dig Surg
24: 87, 2007
Nomura S, Kaminishi M. Surgical treatment ofearly gastric cancer in Japan. Dig Surg 24:
96-100, 2007
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 endocrine

34.

35.

36.

37.

38.

components in human stomach tumors. Histol
Histopathol 22: 278-284,2007
Toyoda T, Tsukamoto T, Mizoshita T, Nishibe S,
Deyama T, Takenaka Y, Hirano N, Tanaka H,
Takasu S, Ban H, Kumagai T, Inada K,
Utsunomiya H, Tatematsu M. Inhibitory effectof nordihydroguaiaretic acid, a plant lignan, on
Helicobacter
pylori-associatedgastric
carcinogenesis in Mongolian gerbils. Cancer Sci
98: 1689-1695, 2007
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
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
Shimoyama S. Angiogenin in gastric cancer andits roles in malignancy Handbook of
immunohistochemistry and in situ hybridizationof human cancers. (Hayat ed) Academic Press
New York: 195-203, 2007
Kaminishi. Digestive Surgery24, SurgicalTreatment for Digestive Cancer in Japan. Karger
Basel, 2007

200

Department of Hepatobiliary
Pancreatic Surgery andDepartment of Artificial Organ
and Transplantation Surgery
Professor
Norihiro Kokudo, MD,

Associate Professor
Yasuhiko Sugawara, MD

Lecturers
Yoshifumi Beck, MD, Kiyoshi Hasegawa, MD, Taku Aoki, MD,

Homepage
Organization

Teaching Activities

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 in1893.

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.

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.

References (2008)
1.

2.

Makuuchi M, Kokudo N, Arii S, Futagawa S,
Kaneko S, Kawasaki S, Matsuyama Y, Okazaki
M, Okita K, Omata M, Saida Y, Takayama T,
Yamaoka Y. Development ofevidence-based
clinical guidelines for the diagnosis andtreatment of hepatocellular carcinoma in Japan.
Hepatol Res. 2008 Jan;38(1):37-51.
Hasegawa K, Imamura H, Ijichi M, Matsuyama Y,
Sano K, Sugawara Y, Kokudo N, Makuuchi M.

201

Inclusion of tumor markers improves thecorrelation of the Milan criteria with vascularinvasion and tumor cell differentiation in patientswith hepatocellular carcinoma undergoing liverresection. J Gastrointest Surg. 2008 May;12(5):858-66.
3. Ishizawa T, Kokudo N, Makuuchi M. Right
hepatectomy for hepatocellular carcinoma: is theanterior approach superior to the conventional
approach? Ann Surg. 2008 Feb;247(2):390-1;
author reply 391-2.
4. Kyoden Y, Tamura S, Sugawara Y, Yamashiki N,
Matsui Y, Togashi J, Kaneko J, Kokudo N,
Makuuchi M. Outcome of living donor livertransplantation for post-Kasai biliary atresia in
adults. Liver Transpl. 2008 Feb;14(2):186-92.
5. Hasegawa K, Kokudo N, Sano K, Seyama Y,
Aoki T, Ikeda M, Hashimoto T, Beck Y, Imamura
H, Sugawara Y, Makuuchi M. Two-stage
pancreatojejunostomy
inpancreaticoduodenectomy: a retrospective analysis of short-term
results. Am J Surg. 2008 Jul;196(1):3-10.
6. Hasegawa K, Kokudo N, Makuuchi M. Surgery
or ablation for hepatocellular carcinoma? Ann
Surg. 2008 Mar;247(3):557-8.
7. Hashimoto T, Miki K, Imamura H, Sano K, SatouS, Sugawara Y, Kokudo N, Makuuchi M.
Sinusoidal perfusion in the veno-occlusive regionof living liver donors evaluated by indocyanine
green and near-infrared spectroscopy. Liver
Transpl. 2008 Jun;14(6):872-80.
8. Ishizawa T, Hasegawa K, Aoki T, Takahashi M,
Inoue Y, Sano K, Imamura H, Sugawara Y,
Kokudo N, Makuuchi M. Neither multiple
tumors nor portal hypertension are surgicalcontraindications for hepatocellular carcinoma.
Gastroenterology. 2008 Jun;134(7):1908-16.
9. Matsui Y, Sugawara Y, Yamashiki N, Kaneko J,
Tamura S, Togashi J, Makuuchi M, Kokudo N.
Living donor liver transplantation for fulminant
hepatic failure. Hepatol Res. 2008 Oct;38(10):987-96.
10. Hasegawa K, Makuuchi M, Takayama T, Kokudo
N, Arii S, Okazaki M, Okita K, Omata M, Kudo
M, Kojiro M, Nakanuma Y, Takayasu K, Monden
M, Matsuyama Y, Ikai I. Surgical resection vs.
percutaneous
ablationforhepatocellular

11.

12.

13.

14.

15.

16.

17.

carcinoma: a preliminary report of the Japanesenationwide survey. J Hepatol. 2008 Oct;49(4):589-94.
Hashimoto T, Minagawa M, Aoki T, Hasegawa K,
Sano K, Imamura H, Sugawara Y, Makuuchi M,
Kokudo N. Caval invasion by liver tumor islimited. J Am Coll Surg. 2008 Sep;207(3):383-92.
Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Kokudo N, Omata M,
Makuuchi M. Double-dose double-phase use of
second generation hepatitis B virus vaccine inpatients after living donor liver transplantation:
Not an effective measure in transplant recipients.
Hepatol Res. 2009 Jan;39(1):7-13.
Kyoden Y, Tamura S, Sugawara Y, Matsui Y,
Togashi J, Kaneko J, Kokudo N, Makuuchi M.
Portal vein complications after adult-to-adultliving donor liver transplantation. Transpl Int.
2008 Dec;21(12):1136-44.
Tamura S, Sugawara Y, Kaneko J, Togashi J,
Matsui Y, Yamashiki N, Kokudo N, Makuuchi M.
Recurrence of cholestatic liver disease after
living donor livertransplantation. World J
Gastroenterol. 2008 Sep 7;14(33):5105-9.
Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Kokudo N, Makuuchi M. Pseudomonas
aeruginosa infection after living-donor livertransplantation in adults. Transpl Infect Dis. 2009
Feb;11(1):11-9.
Takemura N, Kokudo N, Imamura H, Takazawa Y,
Sano K, Sugawara Y, Nakagawa K, Ohtomo K,
Makuuchi M. Eleven-year survivor ofunresectable intrahepatic cholangiocarcinoma
treatedusing
long-term
UFTtherapy.
Hepatogastroenterology. 2008 Nov-Dec;55(88):1997-9.
Xu H, Inagaki Y, Tang W, Guo Q, Wang F,
Seyama Y, Midorikawa Y, Gai R, Kokudo N,
Sugawara Y, Nakata M, Makuuchi M. Elevationof serum KL-6 mucin levels in patients withcholangiocarcinoma.
Hepatogastroenterology.
2008 Nov-Dec;55(88):2000-4.

202

Department of Urology
Professor
Yukio Homma, M.D., Ph.D.

Associate Professor
Takumi Takeuchi, M.D., Ph.D.

Haruki Kume, M.D., Ph.D.

Lecturer
Hiroaki Nishimatsu, M.D., Ph.D.

Yutaka Enomoto, M.D., Ph.D.

Hiroshi Fukuhara, M.D., Ph.D.

Tetsuya Fujimura, M.D., Ph.D.

Research Associate
Motofumi Suzuki, M.D., Ph.D.

Shinya Matsumoto, M.D.

Akira Nomiya, M.D.

Atsuko Takahashi, M.D.

Tohru Sugihara, M.D.

Yumiko Okuno, M.D.

Atsushi Kanatani, M.D.

Waki Tsukui, M.D.

Hiroshi Watanabe, 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 minimum incision endoscopic or laparoscopic
adrenalectomy, nephrectomy, and prostatectomy
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 2008 to December 2008.
Elective operations are performed on Tuesday,
Wednesday, and Thursday. A total of 1,400 operations

203

were performed in 2008. The numbers of main
operations are adrenalectomy 12, radical nephrectomy
31, partial nephrectomy 15, radical cystectomy 15,
radical prostatectomy 82, transurethral resection of the
bladder tumor (TUR-Bt) 113, transurethral resectionof the prostate (TUR-P) 21, and laparoscopic surgery
61.
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 approximately
30,700 patient-days from January 2008 to December
2008.

Renal tumor
Urolithiasis
Kidney Transplantation
Prostate diseases
New surgical technique
Urinary disturbance/ Female Urology
Andrology
Virology

References(1) Inowa T, Hishikawa K, Takeuchi T, Kitamura T,
Fujita T. Isolation and potential existence of side
population cells in adult human kindney. Int J Urol.
2008; 15: 272-275.
(2) Homma Y, Yamaguchi T, Yamaguchi O. A
randomized, double-blind, placebo-controlled phase
Ⅱ dose-finding study of the novel anti-muscarinic
agent imidafenacin in Japanese patients withoveractive bladder. Int J Urol. 2008; 15: 809-815.
(3) Mori S, Takeuchi T, Enomoto Y, Kondo K, Sato K,
Ono F, Sata T, Kanda T. Tissue distribution ofTeaching activities

cynomolgus

adeno-associatedvirusesAAV10,

AAV11, and AAVcy.7 in naturally infected
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

monkeys. Arch Virol. 2008; 153: 375-80.
(4) Huang PH, Sata M, Nishimatsu H, Sumi M, Hirata
Y, Nagai R. Pioglitazone ameliorates endothelial
dysfunction

andrestoresischemia-induced

angiogenesis

indiabetic

mice.

BiomedPharmacother. 2008; 62: 46-52.
(5) Takahashi M, Suzuki E, Takeda R, Oba S,
Nishimatsu H, Kimura K, Nagano T, Nagai R,
Hirata Y. Angiotensin II and Tumor Necrosis
Factor-{alpha} Synergistically Promote Monocyte
Chemoattractant Protein-1 Expression: Roles of
NF{kappa}B, p38 and Reactive Oxygen Species.
Am J Physiol Heart Circ Physiol. 2008; 294:
H2879-88.

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.

(6) Takeda R, Suzuki E, Takahashi M, Oba S,
Nishimatsu H, Kimura K, Nagano T, Nagai R,
Hirata Y. Calcineurin is critical for sodium-induced
neointimal

formationinnormotensive

andhypertensive rats. Am J Physiol Heart Circ Physiol.
2008; 294: H2871-8.

204(7) Yamada Y, Takahashi S, Fujimura T, Nishimatsu H,

2008; 18: 593-614.

Ishikawa A, Kume H, Tomita K, Takeuchi T,(15) Ikegaya H, Zhong S, Shimizu H, Sekiya M,

Kitamura T. The effect of combined androgen

Soemantris A, Ishida T, Nakazawa M, Ohtsuska R,

blockade on bone turnover and bone mineral

Takasaka T, Shibuya A, Kitamura T, Yogo Y. The

density in men with prostate cancer. Osteoporos Int.

Pacific lineage (2E) of JC polyomavirus is2008; 19: 321-7.

prevalent in Sumba Island, Eastern Indonesia.

(8) Nishimatsu H, Suzuki E, Takeda R, Takahashi M,

Anthropol Sci. 2008; 116: 183-186.

Oba S, Kimura K, Nagano T, Hirata Y. Blockade of(16) Yogo Y, Zhong S, Xu Y, Zhu M, Chao Y, Sugimoto

endogeneous proinflamatory cytokines ameliorates

C, Ikegaya H, Shibuya A, Kitamura T. Conserved

endothelial dysfunction in obese zucker rats.

archetypal configuration of the transcriptional

Hypertens Res. 2008; 31: 737.

control(9) Homma Y, Yoshida M, Yamanishi T, Gotoh M.
Core Lower Urinary Tract Symptom score (CLSS)

regionduringthecourseof

BK

polyomavirus evolution. J Gen Virol. 2008; 89:
1849-56.

questionnaire: a reliable tool in the overall(17) Teramoto S, Yamamoto H, Yamaguchi Y, Ishii M,

assessment of lower urinary tract symptoms. Int J

Hibi S, Kume H, Ouchi Y. Antiplatelet cilostazol,

Urol. 2008; 15: 816-20.

an inhibitor of type III phosphodiesterase, improves(10) Homma Y, Yamaguchi O. Long-term safety,

swallowing function in patients with a history oftolerability, and efficacy of the novel anti-

stroke. J Am Geriatr Soc. 2008; 56: 1153-4.

muscarinic agent imidafenacin in Japanese patients(18) Teramoto S, Yamaguchi Y, Yamamoto H, Hanaokawith overactive bladder. Int J Urol. 2008; 15:

Y, Ishii M, Shinichiro H, Kume H, Akishita M,

986-91.

Ouchi Y. Increase in oxidative stress levels in(11) Yogo Y, Zhong S, Shibuya A, Kitamura T, Homma

elderly patients with obstructive sleep apnea

Y. Transcriptional control region rearrangements

syndrome: effects of age and sex. J Am Geriatr Soc.

associated with the evolution of JC polyomavirus.

2008; 56: 569-71.

Virology. 2008; 380: 118-23.

(19) Teramoto S, Yamamoto H, Yamaguchi Y, Hanaoka(12) Nakamura K, Igarashi K, Ide K, Ohkawa R, Okubo

Y, Ishii M, Hibi S, Kume H, Ouchi Y. Lower

S, Yokota H, Masuda A, Oshima N, Takeuchi T,

respiratory tract infection outcomes are predicted

Nangaku M, Okudaira S, Arai H, Ikeda H, Aoki J,

better by an age >80 years than by CURB-65. Eur

Yatomi Y. Validation of an autotaxin enzyme

Respir J. 2008; 31: 477-8; author reply 478.

immunoassay in human serum samples and its(20) Teramoto S, Yamaguchi Y, Yamamoto H, Hanaoka

application to hypoalbuminemia differentiation.

Y, Ishii M, Hibi S, Ishii T, Kume H, Ouchi Y.

Clin Chim Acta. 2008; 388: 51-58.

Cardiovascular and metabolic effects of CPAP in(13) Makita R, Uchijima Y, Nishiyama K, Amano T,
Chen Q, Takeuchi T, Yatomi Y, Aburatani H,

obese obstructive sleep apnoea patients. Eur Respir
J. 2008; 31: 223-5.

Nakagawa O, Igarashi P, Murakami M, Tominaga(21) Homma Y. Lower urinary tract symptomatology －J, Sato T, Kurihara Y, Asano T, Kurihara H.

its definition and confusion. Int J Urol. 2008; 15:

Multiple renal cysts, urinary concentration defects,

35-43.

and pulmonary emphysematous changes in mice(22) Yamada Y, Tomita K, Fujimura T, Nishimatsu H,

lacking TAZ. Am J Physiol, Renal Physiol. 2008;

Takeuchi T, Kitamura T. Metachronous testicular

294: F542-553.

tumor developing eight years after retroperitoneal(14) Miyamura-Ideta A, Tanaka G, Takeuchi T, Aihara K.
A mathematical model of intermittent androgen
suppression for prostate cancer. J Nonlinear Sci.

extragonadal germ cell tumor. Int J Urol. 2008; 15:267-269.
(23) Mori E, Ishibashi Y, Kume H, Ishikawa A, Toshiro

205

F. Two cases of catheter obstruction caused by
subcutaneous catheter kinking. Perit Dial Int. 2008;
28: 677-8.
(24) Kume H, Nishimura S, Teramoto S, Niimi A,
Tomita K, Kitamura T. An [123 I]MIBG-positive
malignant lymphoma involving the adrenal glandwith hypercatecholaminaemia. Clin Radiol. 2008;
63: 475-7.
(25) Kume H, Kakutani S, Tomita K, Kitamura T.
Salvage combination chemotherapy with docetaxel,
ifosfamide and cisplatin (DIP): successful treatmentof a case with metastatic testicular immature
teratoma. Jpn J Clin Oncol. 2008; 38: 143-5.
(26) Homma Y. Re: Validation of the overactive bladder
symptom score J. G. Blaivas, G. Panagopoulos, J. P.
Weiss And C. Somaroo J Urol 2007; 178: 543-547.
J Urol. 2008; 179: 791; author reply 791.
(27) Kume H. Reviewers of the year 2007. Int J Urol.
2008; 15: 563.
(28) Enomoto Y. Editorial comment. Int J Urol. 2008;
15: 51.

206

Department of Surgical Oncology
Professor
Hirokazu Nagawa, M.D., Ph.D.

Associate professor
Joji Kitayama, M.D., Ph.D.

Associate
Eiji Sunami, M.D., Ph.D.,

Hiroaki Nozawa, M.D., Ph.D.,

Hironori Ishigami, M.D.,

Masahiro Kato, M.D., Ph.D.,

Sinsuke Saito, M.D., Ph.D.,

Sinsuke Kazama, M.D., Ph.D.,

Takamitsu Kanazawa, M.D.,

Hironori Yamaguchi, 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 283 surgically treatedinpatients in the year of 2008. 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.

Teaching activities
The Department of Surgical Oncology also offers a207

fellowship 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) Cancer surveillance in ulcerative colitis
3) Carcinogenesis in ulcerative colitis
4) Laparoscopically assisted colon surgery

5) Local immunity in colorectal cancer
6) 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) Role of peripheral nerve on the growth og
gastrointestinal cancer19) 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

References
1. Tabuchi
M.
Kitayama
J.
NagawaH
Hyperglycemia and hypertriglyceridemia may
associate with the adenoma-carcinoma transition

208

2.

3.

4.

5.

6.

7.

8.

9.

in colorectal epithelial cells. Journal of
Gastroenterology & Hepatology. 23(6):985-7,
2008
Otani K. Kitayama J. Kaisaki S. Ishigami H.
Hidemura A. Fujishiro M. Omata M. Nagawa H.
Early gastric cancer shows different associations
with adipose tissue volume depending on
histological type. Gastric Cancer. 11:86-95, 2008
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. European Journal of Cancer.
44:383-90, 2008
Soma D. Kitayama J. Yamashita H. Miyato H.
Ishikawa M. Nagawa H.
Leptin augments
proliferation of breast cancer cells via
transactivation of HER2. Journal of SurgicalResearch. 149:9-14, 2008
Tsuchiya T. Tsuno NH. Asakage M. Yamada J.
Yoneyama S. Okaji Y. Sasaki S. Kitayama J.
Osada T. Takahashi K. Nagawa H. Apoptosis
induction by p38 MAPK inhibitor in human coloncancer cells Hepato- Gastroenterology. 55(84):930-5, 2008
Yamada J. Kitayama J. Tsuno NH. Yamashita H.
Miyato H. Soma D. Otani K. Kamei T. Ishigami H.
Hidemura A. Kaisaki S. Takahashi K. Nagawa H.
Intra-peritoneal administration of paclitaxel with
non-animal stabilized hyaluronic acid as avehicle--a new strategy against peritoneal
dissemination of gastric cancer. Cancer Letters.
272(2):307-15, 2008 Dec 18.
Soma D, Kitayama J, Ishigami H, Kaisaki S,
Nagawa H. Different Tissue Distribution of
Paclitaxel With Intravenous and Intraperitoneal
Administration. Journal of Surgical Research.
2008 Aug 13
Ohnishi T. Watanabe T. Nozawa H. Kitayama J.
Nagawa H. Telomerase activity of blood samples
and recurrence of colorectal cancer. HepatoGastroenterology. 55(86-87):1513-8, 2008
Ishigami H. Kitayama J. Otani K. Kamei T. Soma
D. Miyato H. Yamashita H. Hidemura A. Kaisaki

S. Nagawa H. Phase I pharmacokinetic study ofweekly intravenous and intraperitoneal paclitaxel
combined with S-1 for advanced gastric cancer.
Oncology. 76(5):311-4, 2009
10. Nishikawa T. Tsuno NH. Tsuchiya T. Yoneyama S.
Yamada J. Shuno Y. Okaji Y. Tanaka J. Kitayama J.
Takahashi K. Nagawa H. Sulforaphane stimulates
activation of proapoptotic protein bax leading to
apoptosis of endothelial progenitor cells. Annalsof Surgical Oncology. 16(2):534-43, 2009
11. Kitayama J. Tabuchi M. Tsurita G. Ishikawa M.
Otani K. Nagawa H.
Adiposity andgastrointestinal malignancy. Digestion. 79 Suppl
1:26-32, 2009
12. Kitayama J, Kaisaki S, Ishigami H, Hidemura A,
Nagawa H.
Angleplasty in gastric tube
reconstruction
after
esophagectomy.
Dis
Esophagus. 2009 Jan 9.
13. Yamada J. Tsuno NH. Kitayama J. Tsuchiya T.
Yoneyama S. Asakage M. Okaji Y. Shuno Y.
Nishikawa T. Tanaka J. Takahashi K. Nagawa H.
Anti-angiogenic property of zoledronic acid byinhibition of endothelial progenitor celldifferentiation. Journal of Surgical Research.
151(1):115-20,2009

209

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.,

Hiroyuki Okamoto, M.D., Ph.D.,

Hideo Kimura, M.D., Ph.D.,

Seiji Nishikage, 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 Vascular
Surgery and the Department of Surgical Oncology.
The staff of the Department of Vascular Surgery
consists of one Professor, one Associate Professor, one
Assintant Professor, and three Associates. The
outpatient office is located on the third floor of the
Outpatient Building. The ward is situated on theeighth floor of the Ward Building. The administrative
office and research laboratories are located in the
Administration and Research Building. Current
activities of the Department of Vascular Surgery inclinical practice, education, and research aresummarized 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 197 surgicallytreated inpatients in the fiscal year of 2008. Includedin the department 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 of210

vascular surgery, development of surgical judgment,
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) Development of a minimally invasive treatment
modality for varicous veins of lower extremity
using high frequency ultrasound.
9) Genome
wide-association
studiesforarteriosclerosis.
10) Pharmacological analysis of microcirculation in
in-vivo model11) Mechanism of arteriogenesis in ischemic limb.
12) 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 function18) Creating strategy for diagnosis of acute aortic
syndrome.

References(1) Hashimoto T, Deguchi J, Endo H, and Miyata T
Successful treatment tailored to each splanchnicarterial lesion due to segmental arterial
mediolysis (SAM): report of a case J Vasc Surg
48: 1338-1341, 2008
(2) Takayama T, Miyata T, Shirakawa M, andNagawa H. Isolated spontaneous dissection of thesplanchnic arteries. J Vasc Surg 48: 1338-1341,
2008.
(3) Yamamoto K, Kimura H, Murayama T, Kashima
T, Kikuchi Y, Akiyama T, Kawano H, Miyata T,
and Nagawa H. Chronic expanding hematoma in
combination with a pseudoaneurysm: a casereport. Int Angiol 27: 366-268, 2008.
(4) Shigematsu K, Choudhury NA, Kanetaka T, Saito
T, Takazawa Y, Miyata T, Shigematsu H.
Aneurysm of gastroepiploic artery and vein withan arteriovenous fistula after partial gastrectomy
in a patient with abdominal aortic aneurysm-report of a case. Ann Vasc Disease 1: 52-55,
2008.

211

Department of Metabolic Careand Endocrine Surgery
Professor
Yasuyuki Seto MD. PhD.

Associate Professor
Toshihisa Ogawa MD. PhD.

Yoshikazu Mimura MD. PhD (Surgical Center)

Lectuler
Keiichiro Tada MD. PhD.

Associates
Ei-ichi Tsuji MD.

Kotoe Nishioka 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.

212

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: 17541756, 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

214

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.

Takashi Kakinuma, M.D., Ph.D.

Makoto Sugaya, M.D., Ph.D.

Yayoi Tada, M.D.,Ph.D

Associate
Toshihiko Hoashi, M.D. Ph.D.

Yuichiro Tsunemi, M.D. Ph.D

Hideki Fujita, M.D., Ph.D

Hanako Ohmatsu, M.D. Ph.D

Ryuichi Ashida, M.D.

Yosaku Minatani, M.D.

Mayuko Araki, M.D.

Asako Okada, M.D.

Miki Takahashi, M.D.

Akie Miyamoto, 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.

215

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) Asahina A, Fujita H, Omori T, Kai H, Yamamoto
M, Mii K: Proteus syndrome complicated bymultiple spinal meningiomas. Clin Exp Dermatol
33: 729-32, 2008.
2) Asahina A, Fujita H, Tada Y: Langerhans cells:
unique character in dendritic cells. Expert Rev
Dermatol 3: 293-306, 2008.
3) Fujimoto S, Uratsuji H, Saeki H, Kagami S,
Tsunemi Y, Komine M, Tamaki K: CCR4 andCCR10 are expressed on epidermal keratinocytes
and are involved in cutaneous immune reaction.
Cytokine 44: 172-8, 2008.
4) Fujita H, Iguchi M, Kenmochi Y, Fukunaga Y,
Asahina A: Milia en plaque on the forehead. J
Dermatol 35: 39-41, 2008.
5) Fujita H, Kai H, Yamamoto M, Mitomi H,
Asahina A: Giant apocrine cystadenoma of thescalp. Eur J Dermatol 18: 468-9, 2008.

6) Hoashi T, Kikuchi K, Watanabe S, Nanko H,
Tamaki K: Matrix metalloproteinase-9 expression
in desmoplastic melanoma. J Dermatol 35: 122-3,
2008.
7) Hoashi T, Okochi H, Kadono T, Tamaki K,
Nishida M, Futami S, Maekawa K. A case of
acute radiation syndrome from the dermatologicalaspect. Br J Dermatol 158: 597-602, 2008.
8) Ishiura N, Fujimoto M, Watanabe R, Nakashima
H, Kuwano Y, Yazawa N, Echigo T, Okochi H,
Tamaki K: Serum levels of IgE anti-BP180 andanti-BP230 autoantibodies in patients withbullous pemphigoid. J Dermatol Sci 49: 153-61,
2008.
9) Kagami S, Asahina A, Watanabe R, Mimura Y,
Shirai A, Hattori N, Watanabe T, Tamaki K: Laser
treatment of 26 Japanese patients with Mongolian
spots. Dermatol Surg 34: 1689-94, 2008.
10) Kagami S, Saeki H, Tsunemi Y, Nakamura K,
Kuwano Y, Komine M, Nakayama T, Yoshie O,
Tamaki K: CCL27-transgenic mice showenhanced contact hypersensitivity to Th2, but not
Th1 stimuli. Eur J Immunol 38: 647-57, 2008.
11) Kikuchi K, Seto Y, Matsubara T, Yamada K,
TamakiK:
Amyopathic
dermatomyositis
associated with esophageal cancer. Int J Dermatol
47: 310-1, 2008.
12) Kikuchi K, Wakamatsu K, Tada Y, Komine M, Ito
S, Tamaki K: Serum 5-S-cysteinyldopa levels inpatients with psoriasis undergoing narrowband
ultraviolet B phototherapy. Clin Exp Dermatol
33: 750-3, 2008.
13) Kuwano Y, Fujimoto M, Watanabe R, Ishiura N,
Nakashima H, Ohno Y, Yano S, Yazawa N,
Okochi H, Tamaki K: Serum BAFF and APRIL
levels in patients with alopecia areata. J DermatolSci 2008 50: 236-9, 2008.
14) Masui Y, Komine M, Kadono T, Ishiura N,
Maekawa T, Ihn H, Kikuchi K, Tamaki K:
Proliferating tricholemmal cystic carcinoma: acase containing differentiated and dedifferentiatedparts. J Cutan Pathol 35 Suppl 1: 55-8, 2008.
15) Nakamura K, Tsuchida T, Tsunemi Y, Saeki H,
Tamaki K: Serum thymic stromal lymphopoietin
levels are not elevated in patients with atopic
dermatitis. J Dermatol 35: 546-7, 2008.
16) Ohmatsu H, Tada Y, Yazawa N, Kadono T, Tamaki

216

K:
Generalized
morpheapositivefor
anticentromere antibody. Eur J Dermatol 18:
718-9, 2008.
17) Pannu J, Asano Y, Nakerakanti S, Smith E,
Jablonska S, Blaszczyk M, ten Dijke P,
Trojanowska M: Smad1 pathway is activated insystemic sclerosis fibroblasts and is targeted byimatinib mesylate. Arthritis Rheum 58: 25282537, 2008.
18) Saeki H, Kadono T, Le Pavoux A, Mori E, Tamaki
K: Dermatofibrosarcoma protuberans with
COL1A1-PDGFB fusion transcript arising on ascar due to a previous drainage tube insertion. J
Dermatol 35: 686-8, 2008.
19) Saeki H, Tamaki K: Role of TARC/CCL17 andCTACK/CCL27 in the pathogenesis of atopic
dermatitis. Curr Immunol Rev 4: 221-9, 2008.
20) Saeki H, Watanabe A, Tada Y, Kakinuma T,
Komine M, Ihn H, Asahina A, Etoh T, Kitanaka S,
Sato U, Kano H, Igarashi T, Tamaki K: Juvenile
pustular psoriasis associated with steroid
withdrawal syndrome due to topical corticosteroid.
J Dermatol 35: 601-3, 2008.
21) Sakai M, Aoki S, Inoue Y, Ashida R, Yamada H,
Kiryu S, Inano S, Mori H, Masutani Y, Abe O,
Ohtomo K, Nakamura H: Silent white matterlesion in linear scleroderma en coup de sabre. J
Comput Assist Tomogr 32: 822-4, 2008.
22) Sugaya M, Murai T, Tamaki K: Anaplastic large
cell lymphoma associated with parapsoriasis en
plaques. Acta Derm Venereol 88: 308-9, 2008.
23) Tamaki Z, Kubo M, Yazawa N, Mimura Y, Ashida
R, Tomita M, Tada Y, Kawashima T, Tamaki K:
Serum levels of soluble CD26 in patients withscleroderma. J Dermatol Sci 52: 67-9, 2008.
24) Tsunemi Y, Saeki H, Tamaki K: Blue naevus withpigment network-like structure on dermoscopy.
Acta Derm Venereol 88: 412-3, 2008.
25) Tsunemi Y, Saeki H, Tamaki K: Labial melanotic
macule diagnosed by dermoscopy. Acta Derm
Venereol 88: 524-5, 2008.
26) Watanabe T, Tamaki K: Cidofovir diphosphateinhibits molluscum contagiosum virus DNA
polymerase activity. J Invest Dermatol 128:
1327-9, 2008.
27) Yamashita H, Kadono T, Tamaki K, Nakagawa K:
Interesting response to concurrent chemoradiation

in metastatic eccrine porocarcinoma. J Dermatol
35: 606-7, 2008.
28) Yokobayashi H, Sugaya M, Miyagaki T, Kai H,
Minatani Y, Tamaki T: Serum chemokine levels ina case of angio-oedema associated witheosinophilia. Br J Dermatol 159: 738-40, 2008,
2008.

217

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.,

Takuya Higashino, 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 every evening and Wednesday morning.
Preoperative and postoperative conferences andseminar 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 andFriday 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

218

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 accepted
11 foreign and 32 Japanese visitors (in 2008) who
desire
to
learn
our
new
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 (2008)
1.

2.

3.

4.

5.

6.

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
Mihara M, Nakanishi, Nakashima M, Narushima
M, Gonda K. Koshima I. Distal phalanx replantation using the delayed venous method: a highsuccess rate in 21 cases without specialised technique. J Plast Reconstr Aest Surg. 2008;61(1):88-93. Epub 2007 Apr 5.
Inoue K, Kato H, Sato T, Osada A, Aoi N, Suga
H, Eto H, Gonda K, Yoshimura K. Evaluation ofAnimal Models for the air-Inducing Capacity of
Cultured Human Dermal Papilla Cells. Cells
Tissues Organs. 2008 Nov 26. [Epub ahead ofprint]Suga H, Eto H, Shigeura T, Inoue K, Aoi N, Kato
H, Nishimura S, Manabe I, Gonda K, Yoshimura
K. IFATS collection: Fibroblast growth factor-2-by adipose-derived stromal cells inhibits
postinjury fibrogenesis through a c-Jun
N-terminal kinase-dependent mechanism. StemCells. 2009 Jan;27(1):238-49.
Kurita M, Aiba-Kojima E, Shigeura T, Matsumoto D, Suga H, Inoue K, Eto H, Kato H, Aoi N,
Yoshimura K. Differential effects of three preparations of human serum on expansion of various
types of human cells. Plast Reconstr Surg. 2008
Aug;122(2):438-48.
Suga H, Matsumoto D, Inoue K, Shigeura T, Eto
H, Aoi N, Kato H, Abe H, Yoshimura K. Numer-

219

7.

8.

9.

10.

11.

12.

13.

14.

ical measurement of viable and nonviable adipocytes and other cellular components in aspirated
fat tissue. Plast Reconstr Surg. 2008 Jul; 122(1):103-14.
Yoshimura K, Aoi N, Suga H, Inoue K, Eto H,
Sato K, Kurita M, Harii K, Hirohi T. Ectopic fibrogenesis induced by transplantation of adipose-derived progenitor cell suspension immediately after lipoinjection. Transplantation. 2008
Jun 27;85(12):1868-9.
Yoshimura K, Sato K, Aoi N, Kurita M, Inoue K,
Suga H, Eto H, Kato H, Hirohi T, Harii K.
Cell-assisted lipotransfer for facial lipoatrophy:
efficacy of clinical use of adipose-derived stem
cells. Dermatol Surg. 2008 Sep;34(9):1178-85.
Epub 2008 May 29.
Kurita M, Kato H, Yoshimura K. A therapeuticstrategy based on histological assessment ofhyperpigmented skin lesions in Asians. J Plast
Reconstr Aesthet Surg. 2008 May 2. [Epub aheadof print]
Kurita M, Matsumoto D, Shigeura T, Sato K,
Gonda K, Harii K, Yoshimura K. Influences ofcentrifugation on cells and tissues in liposuction
aspirates: optimized centrifugation for lipotransfer and cell isolation. Plast Reconstr Surg. 2008
Mar;121(3):1033-41; discussion 1042-3.
Inoue K, Sato K, Matsumoto D, Gonda K, Yoshimura K. Arterial embolization and skin necrosis of the nasal ala following injection of dermal
fillers. Plast Reconstr Surg. 2008 Mar;121(3):127e-128e.
Gonda K, Shigeura T, Sato T, Matsumoto D, Suga H, Inoue K, Aoi N, Kato H, Sato K, Murase S,
Koshima I, Yoshimura K. Preserved proliferative
capacity and multipotency of human adipose-derived stem cells after long-term cryopreservation. Plast Reconstr Surg. 2008 Feb;121(2):401-10.
Yoshimura K, Sato K, Aoi N, Kurita M, Hirohi T,
Harii K. Cell-assisted lipotransfer for cosmeticbreast augmentation: supportive use of adipose-derived stem/stromal cells. Aesthetic Plast
Surg. 2008 Jan;32(1):48-55; discussion 56-7.
Epub 2007 Sep 1.
Mihara M, Nakanishi M, Nakashima M, Narushima M, Koshima I. Utility and anatomical ex-

amination of the DIEP flap's three-dimensional
image with multidetector computed tomography.
Plast Reconstr Surg. 2008 Jul;122(1):40e-41e.
15. Koshima I, Narushima M, Mihara M, Uchida G,
Nakagawa M. Short pedicle thoracodorsal artery
perforator (TAP) adiposal flap for threedimensional reconstruction of contracted orbital
cavity. J Plast Reconstr Aesthet Surg. 2008
Dec;61(12):e13-7. Epub 2008 Apr 25.
16. Kawahara N, Sasaki T, Asakage T, Nakao K, Sugasawa M, Asato H, Koshima I, Saito N.
Long-term outcome following radical temporalbone resection for lateral skull base malignancies: a neurosurgical perspective. J Neurosurg.
2008 Mar;108(3):501-10.
17. Koshima I. Atypical arteriole anastomoses forfingertip replantations under digital block. J Plast
Reconstr Aesthet Surg. 2008;61(1):84-7. Epub
2007 Jan 31.

220

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
Gen-ichiro Takagi, D.D.S.

Daichi Chikazu, D.D.S., Ph.D.

Hideto Saijo, D.D.S., Ph.D.

Kazumi Ohkubo, D.D.S., Ph.D.

Yoko Koga, D.D.S., Ph.D.

Masanobu Abe, D.D.S., Ph.D.

Hideyuki Suenaga, D.D.S., Ph.D.

Kohei Nagahama, D.D.S., Ph.D.

Yuko Fujihara, 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.

221

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

222

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., Watanabe N., McDonell N., Takato T.,
Ohira M., Nakagawara A. and Toshikazu
Ushijima.:Identification of genes targeted by CpG
island methylator phenotype in neuroblastomas,
and their possible integrative involvement in poor
prognosis. Oncology; 74:50-60, 2008.
2. Chikazu D., Mori Y., Saijo H., Fujihara H., Ko
E.C., Hikiji H., Yonehara Y., Takato T.: A case oftumoural calcinosis in the temporomandibular
joint associated with systemic sclerosis. Int J Oral
Maxillofac Surg 37(2):190-193, 2008.
3. Chikazu D., Mori Y., Saijo H., Hasegawa Y.,
Fujihara H., Suenaga H., Ko EC., Yonehara Y.,
Takato T.: Intraoral reconstruction of the soft
palate following tumor resection using a
mucoperiosteal flap supplied by the greater
palatine vessels. Asian J Oral Maxillofac Surg
19:203-206, 2008.
4. Fujihara Y., Koyama H., Ohba M., Tabata Y.,
Fujihara H., Yonehara Y., Takato T.: Controlled
delivery of bFGF to recipient bed enhances thevascularization and viability of an ischemic skinflap. Wound Repair Regen 16(1):125-１31, 2008.
5. Hojo H., Igawa K., Ohba S., Yano F., Nakajima K.,
Komiyama Y., Ikeda T., Lichtler AC., Woo JT.,
Yonezawa T., Takato T., Chung UI.:Developmentof high-throughput screening system forosteogenic drugs using a cell-based sensor.
Biochem Biophys Res Commun 14; 376(2):375-9,
2008.
6. Iino M., Yamada H., Ishikawa H., Mami S.,
Shomura E., Ide F., Saito I., Mori Y.: Carcinoma
ex pleomorphic adenoma of the submandibular
gland: Report of a case with an unusual malignant
component of clear cell squamous cell carcinoma.

223

Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 106: e30-e34, 2008.
7. Hikiji H., Takato T., Shimizu T., Ishii S.: The rolesof prostanoids, leukotrienes, and plateletactivating factor in bone metabolism and disease.
Progress Lipid Res 47:107-126, 2008.
8. Kawasaki Y., Kugimiya F., Chikuda H., KamekuraS., Ikeda T., Kawamura N., Saito T., Shinoda Y.,
Higashikawa A., Yano F., Ogasawara T., Ogata N.,
Hoshi K., Hofmann F., Woodgett JR., Nakamura
K., Chung UI., Kawaguchi H.: Phosphorylationof GSK-3beta by cGMP-dependent protein kinase
II promotes hypertrophic differentiation of murinechondrocytes. J Clin Invest 118(7):2506-15, 2008.
9. Ohba, S., Kawaguchi, H., Kugimiya, F.,
Ogasawara, T., Kawamura, N., Saito, T., Ikeda, T.,
Fujii, K., Miyajima, T., Kuramochi, A., Miyashita,T., Oda, H., Nakamura, K., Takato, T. and Chung,U.I.: Patched1 haploinsufficiency increases adultbone mass and modulates Gli3 repressor activity.
Dev Cell 14, 689-69, 2008
10. Saijo H., Chikazu D., Mori Y., Hikiji H., YoneharaY., and Takato T. :Metastasis of prostate cancer tothe mandibular condyle.
Asian J Oral
Maxillofac Surg 20:86-88, 2008.
11. Saijo H., Chung UI., Igawa K., Mori Y., Chikazu
D., IinoM., and Takato T. :Clinical application of
artificial bone in the maxillofacial region. J Artif
Organs 11:171-176, 2008.
12. Tamiya H., Ikeda T., Jeong JH., Saito T., Yano F.,
Jung YK., Ohba S., Kawaguchi H., Chung UI.,
Choi JY.: Analysis of the Runx2 promoter inosseous and non-osseous cells and identificationof HIF2A as a potent transcription activator. Gene
15;416 (1-2):53-60, 2008.
13. Tanaka Y., Ogasawara T., Asawa Y., Yamaoka H.,
Nishizawa S., Mori Y., Takato T., Hoshi K.:
Growth factor contents of autologous human sera
prepared by different production methods andtheir biological effects on chondrocytes. Cell Biol
Int 32(5):505-14, 2008.
14. Yasuda Y., Koyama H., Tabata Y., Fujihara Y.,
Oba M., Uchinuma E., Takato T.: Controlled
Delivery of bFGF Remodeled Vascular Networkin Muscle Flap and Increased Perfusion Capacity
Via Minor Pedicle. J Surg Res; 147(1):132-7,
2008.

15. Yonehara Y., Mori Y., Chikazu D., Saijo H.,
Takato T.:Secondary correction of bilateral cleft
lip

and

nasal

deformitybysimultaneousplacement of an Abbe flap, septal cartilage graft,and cantilevered iliac bone graft. Journal of Oraland Maxillofacial Surgery, Vol.66(3):581-588,
2008.
16. Asawa, Y., Ogasawara, T., Takahashi, T., Yamaoka,
H., Nishizawa, S., Matsudaira, K., Mori, Y.,
Takato, T. and Hoshi, K.: Aptitude of Auricular
and Nasoseptal Chondrocytes Cultured under aMonolayer or Three-Dimensional Condition for
Cartilage Tissue Engineering. Tissue Eng Part A(in press)
17. Fujihara Y., Asawa Y., Takato T., Hoshi K. Tissue
Reactions to Engineered Cartilage Based on
Poly-L-Lactic Acid Scaffolds. Tissue Eng Part A(in press)
18. Hirata M., Kugimiya F., Ohba S., Kawamura N.,
Ogasawara T., Kawasaki Y., Fukai A., Ikeda T.,
Nakamura K., Chung UI., and Kawaguchi H:
C/EBPβ promotes transition from proliferation to
hypertrophic differentiation of chondrocytes
through transactivation of p57Kip2. PLoS ONE(in press)
19. Iino M., Fukuda M., Nagai H., Hamada Y.,
Yamada H., Nakaoka K., Mori Y., Chikazu D.,
Saijo H., Seto I., Ohkubo K., Takato T. Evaluationof 15 mandibular reconstructions with Dumbach
Titan Mesh-System and particulate cancellous
bone and marrow harvested from bilateralposterior ilia. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod (in press)
20. Liu G., Iwata K., Ogasawara T., Watanabe J.,
Fukazawa K., Ishihara K., Asawa Y., Fujihara Y.,
Chung UI., Moro T., Takatori Y., Takato T.,
Nakamura K., Kawaguchi H., Hoshi K. :Selectionof highly osteogenic and chondrogenic cells frombone marrow stromal cells in biocompatible
polymer-coated plates. J Biomed Mater Res A(in press)
21. Mori Y., Saijo H., Fujihara H., Tanaka Y., Maeda
Y., Hayashi N., Chikazu D., Iino M., Takato
T. :Dermoid cyst with fistula formation on thedorsum of the tongue – A case report. Asian J Oral
Maxillofac Surg (in press)

224

22. Ogasawara T., Ohba S., Fujihara Y., Takahashi T.,
Liu G., Chikazu D., Suenaga H., Chung U.I., Yoda
T., Mori Y., Susami T., Takato T., and Hoshi K. :Effects of transforming growth factor (TGF)-1 in
combination with fibroblast growth factor(FGF)-2 and insulin-like growth factor (IGF)-I on
chondrocytes proliferation culture for the cartilage
regenerative medicine. Asian J Oral Maxillofac
Surg (in press)
23. Suenaga H., Furukawa K.S., Takato T., Ushida T.,
and Tateishi T. Cell condensation and threedimensional dynamic environment in rotation
culture up-regulates osteogenic differentiation ofmesenchymal stromal cells. Asian J Oral Maxillofac Surg (in press)
24. Suenaga H., Saijo H., Chikazu D., Fujihara H.,
Sugiyama M., Ohkubo K., Seto I., Mori Y., Iino
M., Takato T.: A case of necrotizing ulcerative
stomatitis in a neutropenic patient with malignant
lymphoma. Asian J Oral Maxillofac Surg (inpress)
25. Huang Z., Kawase-Koga Y., Zhang S., Visvader J.,
Toth M., Christopher A. Walsh and Tao Sun.
Transcription factor Lmo4 defines the shape offunctional areas in developing cortices and regulates sensorimotor control. Dev Biol (in press)

225

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.,

Yuichi Nagase, M.D., Ph.D.,

Yasushi Ohshima, M.D., Ph.D.,

Sei Terayama, M.D.,

Tomotake Okuma, M.D.,

Shuji Taketomi, M.D.,

Naoto Tokuyama, M.D.

Homepage

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

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226

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, six medical staff members, two visiting
fellows, seven senior residents, and 12 part-timeteachers.

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.
For postgraduate education, junior residents join
our department for 1-4 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 36,891 patients visitedthe outpatient clinic from April 2008 through March
2009.
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 eighty-nine operations were
performed in 2008. These include 72 cervical andthoracicspine
surgeries(including
19
computer-assisted surgeries (CAS)), 90 lumbar spine
surgeries, 21 scoliosis surgeries (including 18 CAS),
68 surgeries for rheumatoid arthritis patients, 91 hip
surgeries, 63 knee surgeries (including 19 CAS), 6
shoulder surgeries, 97 hand surgeries, 12 limb
lengthening and reconstruction surgeries using
external fixators, 122 surgeries for bone and soft
tissue tumor and 90 trauma surgeries.

227

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 anterior
cruciate ligament reconstruction technique using thenavigation
systembasedonintraoperative
three-dimensional fluoroscopic image to realize ideal
graft placement.
The peripheral nerve clinic group has developed"costal nerve transfer to the musculocutaneous nerve"
for brachial plexus injury.
The tumor group managed multidisciplinary
treatment for musculoskeletal sarcoma including
chemotherapy, limb sparing surgery and radiotherapy
in coorporation with other departments.
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

228

with the Center for Disease Biology and Integrative
Medicine (CDBIM), and are developing nonviral genedelivery vectors (polyion complex micelles).
In addition, we take part in National Database of
Rheumatic Diseases by iR-net in Japan (NinJa), a
nationwide observational cohort database of rheumatic
disease.

References
1.

2.

3.

4.

5.

6.

Yamakawa K, Kamekura S, Kawamura N,
Saegusa M, Kamei D, Murakami M, Kudo I,
Uematsu S, Akira S, Chung UI, Nakamura K, andKawaguchi H: Association of microsomal
prostaglandin E synthase 1 deficiency with
impaired fracture healing, but not with bone loss
or osteoarthritis, in mouse models of skeletal
disorders. Arthritis Rheum 2008; 58: 172-183.
Yoshimura N, Kinoshita H, Takijiri T, Oka H,
Muraki S, Mabuchi A, Kawaguchi H, Nakamura
K, and Nakamura T: Association between heightloss and bone loss, cumulative incidence ofvertebral fractures and future quality of life: The
Miyama Study. Osteoporosis Int 2008; 19: 21-8.
Kyomoto M, Moro T, Miyaji F, Konno T,
Hashimoto M, Kawaguchi H, Takatori Y,
Nakamura K, and Ishihara K: Enhanced wear
resistance of orthopaedic bearing due to thecross-linking of poly (MPC) graft chains induced
by gamma-ray irradiation. J Biomed Mater Res B
2008; 84: 320-327.
Tamiya H, Ikeda T, Jung JH, Saito T, Jung YK,
Kawaguchi H, Ohba S, Chung UI, and Choi JY:
Analysis of the Runx2 promoter in osseous andnon-osseous cells and identification of HIF2A as
a potent transcriptional activator. Gene 2008;
416: 53-60.
Ohba S, Kawaguchi H, Kugimiya F, Ogasawara T,
Kawamura N, Saito T, Ikeda T, Fujii K, Miyajima
T, Kuramochi A, Miyashita T, Oda H, Nakamura
K, Takato T, and Chung UI: Patched1
haploinsufficiency increases adult bone mass andmodulates Gli3 repressor activity. Dev Cell 2008;
14: 689-699.
Kawasaki Y, Kugimiya F, Chikuda H, Kamekura
S, Ikeda T, Kawamura N, Saito T, Shinoda Y,
Higashikawa A, Yano F, Ogasawara T, Ogata N,

Hoshi K, Hofmann F, Woodgett JR, Nakamura K,
Chung UI, and Kawaguchi H: Phosphorylation of
GSK-3β by cGMP-dependent protein kinase IIpromotes hypertrophic differentiation of murinechondrocytes. J Clin Invest 2008; 118: 25062515.
7. Kyomoto M, Moro T, Miyaji F, Hashimoto M,
Kawaguchi H, Takatori Y, Nakamura K, andIshihara K: Effect of 2-methacryloyloxyethyl
phosphorylcholine concentration on photoinduced graft polymerization of polyethylene inreducing the wear of orthopaedic bearing surface.
J Biomed Mater Res A 2008; 86: 439-47.
8. Sato S, Kimura A, Ozdemir J, Asou Y, Miyazaki
M, Jinno T, Ae K, Liu X, Osaki M, Takeuchi Y,
Fukumoto S, Kawaguchi H, Haro H, Shinomiya
K, Karsenty G, and Takeda S: The Distinct role of
the Runx proteins in chondrocyte differentiationand intervertebral disc degeneration: Findings inmurine models and in human disease. Arthritis
Rheum 2008; 58: 2764-2775.
9. Shinoda Y, Ogata N, Higashikawa A, Manabe I,
Shindo T, Yamada T, Kugimiya F, Ikeda T,
Kawamura N, Kawasaki Y, Tsushima K, Takeda
N, Nagai R, Hoshi K, Nakamura K, Chung UI,
and Kawaguchi H: Krüppel-like factor 5 causes
cartilage degradation through transactivation of
matrix metalloproteinase 9. J Biol Chem 2008;
283: 24682-24689.
10. Oka H, Muraki S, Akune T, Mabuchi A, Suzuki T,
Yoshida H, Yamamoto S, Nakamura K,
Yoshimura N, and Kawaguchi H: Fully automaticquantification of knee osteoarthritis severity on
plain radiographs. Osteoarthritis Cartilage 2008;
16: 1300-1306.
11. Watanabe T, Sato T, Amano T, Kawamura Y,
Kawamura N, Kawaguchi H, Yamashita N,
Kurihara H, and Nakaoka T: Dnm3os, a
non-coding RNA, is required for normal growthand skeletal development in mice. Dev Dynam2008; 237: 3738-3748.
12. Yamashita T, Kobayashi Y, Mizoguchi T, Yamaki
M, Miura T, Tanaka S, Udagawa N, Takahashi N.
MKK6-p38 MAPK signaling pathway enhances
survival but not bone-resorbing activity ofosteoclasts. Biochem Biophys Res Commun
2008; 365:252-257.

229

13. Koyama Y, Miyashita M, Irie S, Yamamoto M,
Karita T, Moro T, Takatori Y, Kazuma K. A studyof disease management activities of hip
osteoarthritis patients under conservative
treatment. J Orthop Nur 2008; 12: 75-83.
14. Ajima R, Akiyama T, Usui M, Yoneda M,
Yoshida Y, Nakamura T, Minowa O, Noda M,
Tanaka S, Noda T, Yamamoto T. Osteoporoticbone formation in mice lacking tob2;
involvement of Tob2 in RANK ligand expression
and osteoclasts differentiation. FEBS Lett 2008;
582:1313-1318.
15. Okuma-Yoshioka C, Seto H, Kadono Y, Hikita A,
Oshima Y, Kurosawa H, Nakamura K, Tanaka S.
Tumor
necrosisfactor-alphainhibitschondrogenic
differentiationofsynovial
fibroblasts through p38 mitogen activating
protein kinase pathways. Mod Rheumatol 2008;
18:366-378.
16. Oshima Y, Akiyama T, Hikita A, Iwasawa M,
Nagase Y, Nakamura M, Wakeyama H,
Kawamura N, Ikeda T, Chung UI, Hennighausen
L, Kawaguchi H, Nakamura K, Tanaka S. Pivotal
role of Bcl-2 family proteins in the regulation ofchondrocyte apoptosis. J Biol Chem 2008; 283:
26499-26508.
17. Eun-Ju Chang, Jeongim Ha, Frank Oerlemans,
You Jin Lee, Soo Woong Lee, Jiyoon Ryu, Hyung
Joon Kim, Youngkyun Lee, Hyun-Man Kim,
Je-Yong Choi, Jin Young Kim, Chan Soo Shin,
Youngmi Kim Pak, Sakae Tanaka, Bé Wieringa,
Zang Hee Lee, Hong-Hee Kim. Brain-type
creatine kinase has a crucial role inosteoclast-mediated bone resorption. Nature Med
2008; 14:966-972.
18. Hoshikawa S, Ogata T, Fujiwara S, Nakamura K,
Tanaka S.A novel function of RING finger
protein 10 in transcriptional regulation of the
myelin-associated glycoprotein gene and myelin
formation in Schwann cells. PLoS ONE 2008;
3:e3464.
19. Okuma C, Kaketa T, Hikita A, Matsuda K,
Nakamura M, Nagase Y, Oshima Y, Iwasawa M,
Nakamura Y, Kurosawa H, Nakamura K, Tanaka
S. Potential involvement of p53 in ischemia/
reperfusion-induced osteonecrosis. J Bone Miner
Metab 2008; 26:576-585.

20. Imai K, Ohnishi I, Yamamoto S, Nakamura K. In
vivo assessment of lumbar vertebral strength inelderly women using CT-based nonlinear finite
element model. Spine 2008; 33, 27-32.
21. Matsuyama J, Ohnishi I, Sakai R, Bessho M,
Matsumoto T, Miyasaka K, Harada A, Ohashi S,
Nakamura K. A new method for evaluation of
fracture healing by echo tracking. Ultrasound in
Med Biol 2008; 34: 775-783.
22. Joung S, Kamon H, Liao H, Iwaki J, Nakazawa T,
Mitsuishi M, Nakajima Y, Koyama T, Sugano N,
Maeda Y, Bessho M, Ohashi S, Matsumoto T,
Ohnishi I, Sakuma I. A robot assisted hip fracture
reduction with a navigation system. Med Image
Compu Comput-Ass Interv 2008; : 11: 501-8.
23. Akaha H, Matsudaira K, Takeshita K, Oka H,
Hara N, Nakamura K Modified measurement offlexion for lumbar impairment -Self-assessment
bending scale- J Lumbar Spine Disord 2008; 14:
164-169
24. 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
Back Pain Evaluation Questionnaire. Part 3.
Validity study and establishment of themeasurement scale: Subcommittee on Low Back
Pain and Cervical Myelopathy Evaluation of theClinical Outcome Committee of the Japanese
Orthopaedic Association, Japan. J Orthop Sci
2008; 13: 173-9.
25. Maruyama T, Takeshita K, Kitagawa T.
Milwaukee brace today. Disab Rehabil: Assist
Tech 2008; 3: 136.
26. Maruyama T, Takeshita K. Surgical treatment ofscoliosis: a review of techniques currently
applied. Scoliosis 2008; 3: 6.
27. Matsumoto M, Chiba K, Toyama Y, Takeshita K,
Seichi A, Nakamura K, Arimizu J, Fujibayashi S,
Hirabayashi S, Hirano T, Iwasaki M, Kaneoka K,
Kawaguchi Y, Ijiri K, Maeda T, Matsuyama Y,
Mikami Y, Murakami H, Nagashima H, Nagata K,
Nakahara S, Nohara Y, Oka S, Sakamoto K,
Saruhashi Y, Yutaka Sasao Y, Shimizu K, Taguchi
T, Takahashi M, Tanaka Y, Tani T, Tokuhashi Y,
Uchida K, Yamamoto K, Yamazaki M, Yokoyama

230

28.

29.

30.

31.

32.

33.

34.

35.

T, Yoshida M, Nishiwaki Y. Surgical Results andRelated Factors for Ossification of PosteriorLongitudinal Ligament of the Thoracic Spine: A
Multi-Institutional Retrospective Study. Spine
2008; 33: 1034-41.
Maruyama T, Takeshita K, Kitagawa T. Side-shift
exercise and hitch exercise. Stud Health Technol
Inform 2008; 135: 246-9.
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, Yonenobu K, Wada E, Tanaka
T, Hirota Y. Japanese Orthopaedic Association
Cervical Myelopathy Evaluation Questionnaire(JOACMEQ): part 4. Establishment of equations
for severity scores: Subcommittee on low backpain and cervical myelopathy, evaluation of theclinical outcome committee of the Japanese
Orthopaedic Association. J Orthop Sci 2008;13:
25-31.
Akiyama T, Yamamoto A, Kashima T, Ishida T,
Shinoda Y, Goto T, Nakamura K, and Kawano H:
Juxtacortical chondroma of the sacrum. J Orthop
Sci. 2008; 13: 476-80.
Matsumoto T, Shiina H, Kawano H, Sato T, andKato S: Androgen receptor functions in male andfemale physiology. J Steroid Biochem Mol Biol.
2008; 109: 236-41.
Akiyama T, Dass CR, Choong PF: Noveltherapeutic strategy for osteosarcoma targeting
osteoclast differentiation, bone-resorbing activity,
and apoptosis pathway. Mol Cancer Ther. 2008;
7: 3461-9.
Miura T, Osuka K, Itoh S, Nakagawa T, Kawano
H, Nakamura K: Early functional improvement
after a modified ligament reconstruction tendon
interposition arthroplasty for thumb basal joint
arthritis. Hand Surg. 2008; 3: 153-8.
Higashikawa A, Saito T, Ikeda T, Kamekura S,
Kawamura N, Kan A, Oshima Y, Ohba S, Ogata
N, Takeshita K, Nakamura K, Chung UI, andKawaguchi H: Identification of the core element
responsive to runt-related transcription factor 2 inthe promoter of human type x collagen gene.
Arthritis Rheum 2009; 60: 166-178.
Chikuda H, Seichi A, Takeshita K, Shoda N, Ono
T, Matsudaira K, Kawaguchi H, and Nakamura

36.

37.

38.

39.

40.

K: Radiographic analysis of the cervical spine inpatients with retro-odontoid pseudotumors. Spine
2009; 34: E110-114.
Hirata M, Kugimiya F, Fukai A, Ohba S,
Kawamura N, Ogasawara T, Kawasaki Y, Saito T,
Yano F, Ikeda T, Nakamura K, Chung UI, andKawaguchi H: C/EBPβ promotes transition fromproliferation to hypertrophic differentiation ofchondrocytes through transactivation of p57Kip2.
PLoS ONE 2009; 4: e4543.
Moro T, Kawaguchi H, Ishihara K, Kyomoto M,
Karita T, Ito H, Nakamura K, and Takatori Y:
Wear resistance of artificial hip joints withpoly(2-methacryloyloxyethyl phosphorylcholine)
grafted polyethylene: Comparisons with theeffect of polyethylene cross-linking and ceramic
femoral heads. Biomaterials 2009; 30: 29953001.
Muraki S, Akune T, Oka H, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Nakamura K, Kawaguchi H,
and Yoshimura N: Association of occupational
activity with radiographic knee osteoarthritis andlumbar spondylosis in elderly patients of
population-based
cohorts:A
large-scale
population-based study. Arthritis Rheum 2009;
61: 779-786.
Shoda N, Seichi A, Takeshita K, Chikuda H, Ono
T, Oka H, Kawaguchi H, and Nakamura K: Sleep
apnea in rheumatoid arthritis patients withoccipitocervical lesions: the prevalence andassociated radiographic features. Eur Spine J
2009; 18: 905-910.
Nakajima K, Kakihana W, Nakagawa T, Mitomi
H, Hikita A, Suzuki R, Akai M, Iwaya T,
Nakamura K, Fukui N: Addition of an arch
support improves the biomechanical effect of alaterally wedged insole. Gait Posture. 2009; 29:
208-213.

231

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,

Research Associate
Tomohiko Usui, M.D., Ph.D., Yasuo Yanagi, M.D., Ph.D.,
Takashi Shigeeda, M.D.,

Shinsuke Konno, M.D., Ph.D.

Chihiro Mayama., M.D., Ph.D., Tanabe Tatsuro, M.D.,

Tatsuya Mimura, M.D., Ph.D., Kohei Muranaka, M.D., Ph.D., Koichi Mishima,M.D.,Ph.D.,
Kenji Sugisaki, M.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
corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged in

232

practical 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.

Aihara M, Miyanaga M, Minami K, Miyata K,
Eguchi S, Shiroma H, Sawaguchi S. A
comparison of fluoroquinolone penetration into

human conjunctival tissue. J Ocul Pharmacol
Ther 2008 Dec 2.
2. Aihara M, Lindsey JD, Weinreb RN. Effect on
diurnal intraocular pressure variation ofeliminating the alpha-2 adrenergic receptor
subtypes in the mouse. Invest Ophthalmol Vis Sci
49:929-933, 2008.
3. Amano S, Shimomura N, Yokoo S, Yamagami S,
Araki-Sasaki K. Decellularizing corneal stroma
using N2 gas. Mol Vis 14:878-882, 2008
4. Amano S, Nakai Y, Ko A, Inoue K, Wakakura M.
A case with keratoconus progression during theuse of topical latanoprost. Jpn J Ophthalmol 52:
334-336, 2008
5. Arita R, Itoh K, Inoue K, Amano S. Non-contact
infrared meibography to document age-relatedchanges of the meibomian glands in a normal
population. Ophthalmology 115:911-915, 2008
6. Dimitrova G, Kato S, Fukushima H, Yamashita
H: Circulatory parameters in the retroulbar
central retinal artery and vein of patients withdiabetes and medically treated systemic
hypertension. 7th International Symposium on
Ocular Pharmacology and Therapeutis: Budapest.
105-109,2008
7. Fukuoka S, Honda N, Usui T, Inoue K,
Yamagami S, Araie M, Amano S. Penetrating
keratoplasty for bullous keratopathy after
trabeculectomy. Eye [Epub ahead of print]
8. Fukuoka S, Aihara M, Iwase A, Araie M.
Intraocular pressure in an ophthalmologicallynormal Japanese population. Acta Ophthalmol
86:434-439, 2008
9. Hayashi K, Tomidokoro A, Aihara M, Tsuji H,
Shirato S, Araie M. Long-term follow-up of
superior segmental optic hypoplasia. Jpn J
Ophthalmol 52:412-414, 2008
10. Hayashi T, Yamagami S, Usui T, Amano S,
Mizuki. A mouse model of allogeneic corneal
endothelial cell transplantation. Cornea 27; 699705, 2008
11. Hitani K, Yokoo S, Honda N, Usui T, Yamagami
S, Amano S. Transplantation of a sheet of humancorneal endothelial cell in a rabbit model. Mol
Vis 14; 1-9, 2008
12. Iriyama A, Obata R, Inoue Y, Takahashi H,
Tamaki Y, Yanagi Y. Effect of posterior

233

13.

14.

15.

16.

17.

18.

19.

20.

21.

juxtascleral triamcinolone acetonide on theefficacy and choriocapillaris hypoperfusion ofphotodynamic therapy. Graefes Arch Clin Exp
Ophthalmol 246:339-344, 2008
Iriyama A, Fujiki R, Inoue Y, Takahashi H,
Tamaki Y, Takezawa S, Takeyama K, Jang WD,
Kato S, Yanagi Y. A2E, a pigment of thelipofuscin of retinal pigment epithelial cells, is an
endogenous ligand for retinoic acid receptor. J
Biol Chem 283:11947-1153, 2008
Iriyama A, Iriyama T, Tamaki Y, Yanagi Y.
Effects of white light on beta-catenin signaling
pathway in retinal pigment epithelium. Biochem
Biophys Res Commun 375:173-177, 2008
Ito M, Murayama K, Deguchi T, Takasu M, Gil T,
Araie M, Peyman G, Yoneya S. Oxygen
saturation levels in the juxta-papillary retina ineyes with glaucoma. Exp Eye Res 86:512- 518,
2008
Ito Y, Shimazawa M, Inokuchi Y, Fukumitsu H,
Furukawa S, Araie M, Hara H. Degenerative
alterations in the visual pathway after
NMDA-induced retinal damage in mice. Brain
Res 1212:89 -101, 2008
Ito Y, Nakamura S, Tanaka H, Shimazawa M,
Araie M, Hara H. Memantine protects against
secondary neuronal degeneration in lateralgeniculate nucleus and superior colliculus after
retinal damage in mice. CNS Neurosci Therap
14:192-202, 2008
Kadonosono K, Yamakawa T, Uchio E,
Watanabe Y, Yanagi Y, Tamaki Y, Araie M.
Fibrovascular membrane removal using ahigh-performance 25-gauge vitreous cutter.
Retina 28:1533-1535, 2008
Kami J, Muranaka K, Yanagi Y, Obata R,
Tamaki Y, Shibuya M: Inhibition of choroidal
neovascularizationbyblocking
vascularendothelial growth factor receptor tyrosine kinase.
Jpn J Ophthalmol 52:91-98, 2008
Kawase K, Tomidokoro A, Araie M, Iwase A,
Yamamoto T; Tajimi Study Group; Japan
Glaucoma Society. Ocular and systemic factors
related to intraocular pressure in Japanese adults:
the Tajimi study. Br J Ophthalmol 92:1175-1179,
2008
Koseki N, Araie M, Tomidokoro A, Nagahara M,

22.

23.

24.

25.

26.

27.

28.

29.

Hasegawa T, Tamaki Y, Yamamoto S. A placebocontrolled 3-year study of a calcium blocker onvisual field and ocular circulation in glaucoma
with low-normal pressure. Ophthalmology 115:2049-57, 2008
Kunimatsu S, Tomidokoro A, Saito H, Aihara M,
Tomita G, Araie M. Performance of GDx VCC ineyes with peripapillary atrophy: Comparison of
three circle sizes. Eye 22:173-178, 2008
Mimura T, Amano S, Yokoo S, Uchida S, Usui T,
Yamagami S: Isolation and distribution of rabbit
keratocyte precursors. Mol Vis 14:197-203, 2008
Mimura T, Yamagami S, Usui T, Honda N, Araki
F, Amano S. In vivo confocal microscopy ofhuman cornea covered with human amniotic
membrane. Jpn J Ophthalmol 52; 493-496, 2008
Mimura T, Amano S, Fukuoka S, Honda N, Arita
R, Ochiai M, Yanagisawa M, Usui T, Ono K,
Araki F, Yamagami S, Araie M, Awaya Y. In vivo
confocal microscopy of hereditary sensory andautonomic neuropathy. Cur Eye Res 33; 940-945,
2008
Mimura T, Amano S, Yokoo S, Uchida S,
Yamagami S, Usui T, Kimura Y, Tabata Y. Tissue
engineering of corneal stroma with rabbit
fibroblast precursors and gelatin hydrogels. Mol
Vis; 14: 1819-1828, 2008
Miyai T, Maruyama Y, Osakabe Y, Nejima R,
Miyata K, Amano S. Karyotype changes incultured human corneal endothelial cells. Mol
Vis 14:942-950, 2008
Miyai T, Miyata K, Nejima R, Honbo M,
Minami K, Amano S. Comparison of laser in situ
ketatomileusis and photorefractive keratectomy
in long-term follow-up. J Cataract Ref Surg 34:
1527-1531, 2008
Mochimaru H, Usui T, Yaguchi T, Nagahama Y,
Hasegawa G, Usui Y, Shimmura S, Tsubota K,
Amano S, Kawakami Y, Ishida S. Suppression ofalkali burn-induced corneal neovascularization
by dendritic cell vaccination targeting VEGF
receptor 2. Invest Ophthalmol Vis Sci 49:21722177, 2008

30. Murata H, Aihara M, Chen YN, Ota T, Numaga J,
Araie M. Imaging mouse retinal ganglion cells
and their loss in vivo by a fundus camera in the234

normal and ischemia-reperfusion model. Invest
Ophthalmol Vis Sci 49:5546-5552, 2008
31. Noma H, Funatsu H, Yamasaki M, Tsukamoto H,
Mimura T, Sone T, Hirayama T, Tamura H,
Yamashita H, Minamoto A, Mishima HK:
Aqueous humour levels of cytokines arecorrelated to vitreous levels and severity ofmacular oedema in branch retinal vein occlusion.
Eye 22:42-8, 2008
32. Ohashi M, Aihara M, Saeki T, Araie M. Efficacyof TonoLab in detecting physiological andpharmacological changes in rat intraocularpressure: Comparison of TonoPen andmicroneedle manometry. Jpn J Ophthalmol 52:
399-403, 2008
33. Osakabe Y, Amano S, Fukuoka S, Yamagami S.
Histologic evaluation of a cornea in a patientwith apolipoprotein A-I deficiency. Cornea 27:
372-373, 2008
34. Saeki T, Aihara M, Ohashi M, Araie M. The
efficacy of TonoLab in detecting physiologicaland pharmacological changes of mouse
intraocular pressure-comparison with TonoPen
and microneedle manometery. Curr Eye Res 33:
247-252, 2008
35. Saito H, Tomidokoro A, Yanagisawa M, Aihara
M, Tomita G, Araie M. Scanning laser
polarimetry with enhanced corneal compensationin patients with open-angle glaucoma. J
Glaucoma 17:24-29, 2008
36. Saito H, Tomidokoro A, Tomita G, Araie M,
Wakakura M. Optic disc and peripapillarymorphology in unilateral nonarteritic anterior
ischemic optic neuropathy and age- andrefraction-matched normals. Ophthalmology 115:
1585-1590, 2008
37. Sakata R, Usui T, Mimaki M, Araie M.
Developmental glaucoma with chromosomal
abnormalities of 9p deletion and 13q duplication.
Arch Ophthalmol. 126; 431-432, 2008
38. Sakata R, Yanagi Y. Expression of immature andmature retinal cell markers in retinoblastoma.
Eye 22:678-683, 2008
39. Sasaoka M, Nakamura K, Shimazawa M, Ito Y,
Araie M, Hara H. Changes in Visual fields andlateral geniculate nucleus in monkey laserinduced high intraocular pressure model. Exp

40.

41.

42.

43.

44.

45.

46.

47.

Eye Res 86:770-782, 2008
Sawada A, Tomidokoro A, Araie M, Iwase A,
Yamamoto T; Tajimi Study Group. Refractive
errors in an elderly Japanese population: theTajimi study. Ophthalmology 115:363-370, 2008
Shibuya E, Meguro A, Ota M, Kashiwagi K,
Mabuchi F, Iijima H, Kawase K, Yamamoto T,
Nakamura M, Negi A, Sagara T, Nishida T,
Inatani M, Tanihara H, Aihara M, Araie M,
Fukuchi T, Abe H, Higashide T, Sugiyama K,
Kanamoto T, Kiuchi Y, Iwase A, Ohno S, Inoko
H, Mizuki N. Association of toll-like receptor 4
gene polymorphisms with normal tension
glaucoma. Invest Ophthalmol Vis Sci 49:44534457, 2008
Sugisaki K, Usui T, Nishiyama N, Jang WD,
Yanagi Y, Yamagami S, Amano S, Kataoka K.
Photodynamic
therapyforcornealneovascularization using polymeric micelles
encapsulating dendrimer porphyrins. Invest
Ophthalmol Vis Sci 49: 894-899, 2008
Suto C, Hori S, Kato S: Management of type 2
diabetics requiring panretinal photocoagulation
and after cataract surgery. J Cataract Refract Surg
34:1001-1006, 2008
Takahashi H, Ishizaki H, Tahara H, Tamaki Y,
YanagiY.
Suppressionofchoroidal
neovascularization by vaccination with epitope
peptide derived from human VEGF receptor 2 inan animal model. Invest Ophthalmol Vis Sci
49:2143-2147, 2008
Takahashi H, Tamaki Y, Ishii N, Oikawa N,
Mizuguchi E, Francis JH, Inoue Y, Iriyama A,
Obata R, Yanagi Y. Identification of a novel
vascular endothelial growth factor receptor 2
inhibitor and its effect for choroidal
neovascularization in vivo. Curr Eye Res 33:
1002-1010,2008
Tanihara H, Inatani M, Honjo M, Tokushige H,
Azuma J, Araie M. Intraocular pressure-lowering
effects and safety of topical administration of a
selective ROCK inhibitor, SNJ-1656, in normal
volunteers. Arch Ophthalmol 126：309-315, 2008
Tomidokoro A, Iwase A, Araie M, Yamamoto T,
Kitazawa Y. Population-based prevalence of optic
disc haemorrhages in elderly Japanese. Eye 2008
Aug 1. [Epub ahead of print]

235

48. Ueda A, Araie M, Kubota S. Polyamine depletioninduces G1 and S phase arrest in humanretinoblastoma Y79 cells. Cancer Cell Int 8:2,
2008
49. Ueta T, Iriyama A, Francis J, Takahashi H,
Adachi T, Obata R, Inoue Y, Tamaki Y, Yanagi
Y. Development of typical age-related maculardegenerationandpolypoidal
choroidal
vsculopathy in fellow eyes of Japanese patientswith exudative age-related macular degeneration.
Am J Ophthalmol 146:96-101, 2008
50. Usui T. Sugisaki K, Iriyama A, Yokoo S,
Yamagami S, Nagai N, Ishida S, Amano S.
Inhibition of corneal neovascularization byblocking the angiotensin II type 1 receptor. Invest
Ophthalmol Vis Sci 49; 4370-4376, 2008
51. Yamaguchi Y, Shirakawa Y, Sugita N, Ueta T,
Tamaki Y, Mitsuishi M. Microsurgical robotic
system for vitreoretinal surgery. Int J CARS 3(Suppl 1) :S289-S290,2008.
52. Yanagi Y: Role of peoxisome proliferator
activator receptor gamma on blood retinal barrier
breakdown. PPAR Res 2008, 2008:679237
53. Yanagisawa M, Tomidokoro A, Saito H, Mayama
C, Aihara M, Tomita G, Shoji N, Araie M.
Atypical retardation pattern in measurements ofscanning laser polarimetry and its relating factors.
Eye 2008 Dec 12. [Epub ahead of print]
54. Yokoo S, Yamagami S, Shimada T, Sato T, Usui T,
Amano S, Araie M, Hamuro J. A novel isolation
technique of progenitor cells in humancorneal epithelium using uncoated dishes. StemCells 26; 1743-1748, 2008
55. Yokoo S, Yamagami S, Usui T, Amano S, Araie
M. Human corneal epithelial equivalents forocular surface reconstruction in complete serum
free culture system without unknown factors.
Invest Ophthalmol Vis Sci 49:2438-2443, 2008

236

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

Kenji Kondo, M.D, Ph.D

Research Associate
Takashi Sakamoto, M.D. PhD.

Takaharu Nito, M.D,

Shotaro Karino, M.D, Ph.D,

Yasuhiro Ebihara, M.D,

Munetaka Ushio, M.D., Ph.D,

Mizuki Ando, M.D.

Yasuhiro Chirara, M.D.,

Keigo Suzukawa, M.D.,

Masahiro Yoshida, M.D,

Tsuyoshi Yoshida, 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.

237

Clinical activities
In the out-patient clinic, general and special
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

238

implant and inner ear anomaly.
11) Hair cell physiology in the vestibular end organ.
12) Newborn hearing screening and language
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.

10.

11.

12.

References
13.
1.

2.

3.

4.

5.
6.

7.

8.

9.

Ando M et al. Mucoepidermoid carcinoma of the
thyroid gland showing marked ciliationsuggestive of its pathogenesis. Pathology
International. 58: 741-744, 2008
Fujii R et al. Safe, complete resection of
epiglottic cysts with phono-ultra-microsurgical
technique. J Laryngol Otol. 122: 201-203, 2008
Fujimoto C et al. Existence of Possible
Functional Interaction between the Saccule and
the Posterior Semicircular Canal in Humans. An
Evaluation Using VEMPs. Audiol Neurotol. 14:
232-239, 2008
Hiramatsu T et al. Role of primate cerebellar
lobulus petrosus of paraflocculus in smooth
pursuit eye movement control revealed bychemical lesion. Neurosci Res. 60: 250-258, 2008
Ishimoto S et al. Objective and non-invasive
evaluation of dry mouth. ANL. 35: 89-93, 2008
Ito K et al. Rotating computed tomographic
movie for evaluating partially ossified cochlea.
Otol Neurotol. 29: 124-130, 2008
Iwasaki S et al. Low-voltage activated potassiumchannels underlie the regulation of intrinsic firingproperties of rat vestibular ganglion cells. J
Neurophysiol. 100: 2192-2204, 2008
Iwasaki S et al. Ocular vestibular evoked
myogenic potentials to bone conducted vibrationof the midline forehead at Fz in healthy subjects.
Clin Neurophysiol. 119: 2135-2147, 2008
Iwasaki S et al. A new indicator of unilateralotolithic loss-ocular vestibular evoked myogenic
potentials (oVEMPs) in response to bone

14.

15.

16.

17.

18.

19.

20.

21.

22.

conducted vibration of the midline forehead at Fz.
Audiol Neurotol. 13: 396-404, 2008
Jin Y et al. Vestibular evoked myogenic
potentials evoked by multichannel cochlear
implant. Influence of C levels. Acta Otolaryngol(Stockh). 128: 284-290, 2008
Karino S et al. Breastfeeding and prevalence ofallergic diseases in Japanese university students.
Ann Allergy Asthma Immunol. 101: 153-159,
2008
Kawahara N et al. Long-term outocome
following radical temporal bone resection forlateral skull base malignancies: a neurosurgicalperspective. J Neurosurg. 108: 501-510, 2008
Kikuta S et al. Compensatory rapid switching ofbinasal inputs in the olfactory cortex. J Neurosci.
28: 11989-11997, 2008
Kikuta S et al. The aggravating factors ofhyperammonemia related to 5-fluorouracil
infusion areport of two cases. ANL. 35: 295-299,
2008
Kimura M et at. Collagen Injection as a
Supplement to Arytenoid Adduction for Vocal
Fold Paralysis. Ann Otol Rhinol Laryngol. 117:430-436, 2008
Kimura M et al. Clinical experience withcollagen injection of the vocal fold: a study of
155 patients. ANL. 35: 67-75, 2008
Monobe H et al. Primary laryngeal naturalkiller/T-cell lymphoma-report of a rare case.
Head Neck. 30: 1527-1530, 2008
Murofushi T et al. Periodic alternating nystagmus
in Meniere’s disease: the peripheral type? Acta
Otolaryngol (Stockh). 128: 824-827, 2008
Nito T et al. Analyses of risk factors for
postoperative airway compromise following
arytenoid adduction. Acta Otolaryngol (Stockh).
128: 1342-1347, 2008
Orita Y et al. Can narrow-band imaging be used
to determine the surgical margin of superficial
hypopharyngeal cancer? Acta Med Okayama. 62:
205-208, 2008
Ozeki H et al. Vestibular drop attack secondary toMeniere’s disease results from unstable otolithic
function. Acta Otolaryngol (Stockh). 128: 887891, 2008
Saito Y et al. Highly malignant submandibular

239

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

extraskeletal osteosarcoma in a young patient.
ANL. 35: 576-578, 2008
Sano M et al. Early myelination patterns in thecentral auditory pathway of the higher brain:
MRI evaluation. Int J Pediatr Otorhinolaryngol.
10: 1479-1486, 2008
Someya S et al. The role of mtDNA mutations in
the pathogenesis of age-related hearing loss inmice carrying a mutator DNA polymerase γ.
Neurobiol Aging. 29: 1080-1092, 2008
Suzuki M et al. Time course of apoptotic cell
death in guinea pig cochlea following
intrarympanic gentamicin application. Acta
Otolaryngol (Stockh). 128: 724-731, 2008
Suzuki M et al. Analysis of vestibular testing inpatients with vestibular schwannoma based on
the nerve of origin, the localization and the sizeof the tumor. Otol Neurotol. 29: 1029-1033, 2008
Ushio M et al. Abnormal deviation of subjective
visual horizontal in patients with vestibular
schwannoma. Ann Otol Rhinol Laryngol. 117:641-644, 2008
Ushio M et al. Testing of vibratory thresholds asa clinical examination for patients with
unsteadiness due to somatosensory disorders.
Gait Posture. 28: 552-558, 2008
Ushio M et al. Modified nasal specula andflexible holder for endoscopic nasal surgery.
Laryngoscope. 118: 1293-1294, 2008
Ushio M et al. Wall-eyed bilateral internuclear
ophthalmoplegia (WEBINO) in a patient with
progressive supranuclear palsy. J Neurophthalmol.
28: 93-96, 2008
Ushio M et al. Prediction of the prognosis ofBell’s palsy using multivariate analyses. Otol
Neurotol. 29: 69-72, 2008
Yuba T et al. Advancement in singing ability
using The YUBA Method in patients withcochlear implants. Acta Otolaryngol (Stockh).
128: 465-472, 2008
Watanabe K et al. Planned simultaneous cervicalskin reconstruction for salvage total. Jpn J Clin
Oncol. 38: 167-171, 2008

240

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. Eleven students haveentered the graduate school by 2008, and six of themwere 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 Rehabilitation Center,the University of Tokyo Hospital. Both departments
are united and engage in clinical practice. We have atpresent no charged ward, and treat about 1,000 newreferrals annually from almost all the departments of
the university hospital. We always take charge ofabout 150 patients corresponding about 15% of thewhole number of inpatients. We also see 15 people per
day at the outpatient rehabilitation setting. The
numerical ratio of outpatient is being reduced in orderto give priority to the clinical service corresponding toneeds expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on

241rehabilitation 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 a longterm clerkship from several PT/OT training schools.
Eleven graduate school students entered by 2006
and six of them acquired a degree of Ph.D. andgraduated.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with otherdepartments in our hospital, other faculties in our
university, and institutions outside the University ofTokyo. The ongoing and scheduled projects are as
follows.
1) Motion analysis of patients with joint disorders in
the lower extremities
2) Motion analysis of motor development in children
3) Early detection, diagnosis, and progression
prevention of musculoskeletal disorders
4) Analysis of motion and energy expenditure in theactivities of daily living in the physically disabled
5) Non-invasive evaluation of lower limb motor

function in spina bifida6) Evaluation of higher brain function in patientswith spina bifida7) Disabilities and handicaps in patients with skeletal
dysplasias
8) Influence of physical therapy to skeletal muscles

References
1. Chiba Y, Nishihara K, Yamaguchi A, Haga N:
Midpoint
fixationtask:
Quantitative
assessment of visual neglect. J Clin Neurosci
15: 647-649, 2008.
2. Chiba Y, Haga N: Analyzing non-motor bias inunilateral neglect with a new variant of the line
bisection task. Brain Injury 22: 952-959, 2008.
3. Fukuda T, Kanomata K, Nojima J, Kokabu S,
Akita M, Ikebuchi K, Jimi E, Komori T, Maruki
Y, Matsuoka M, Miyazono K,
Nakayama
K, Nanba A, Tomoda H, Okazaki Y, Ohtake A,
Oda H, Owan I, Yoda T, Haga N, Furuya, H,
Katagiri T: A unique mutation of ALK2, G356D,
found in a patient with fibrodysplasia ossificans
progressiva is a moderately activated BMP type
I receptor. Biochem Biophys Res Commun 377:
905-909, 2008.
4. Jigjid E, Kawashima N, Ogata H, Nakazawa K,
Akai M, Eto F, Haga N: Effects of passive leg
movement on the oxygenation level of lower
limb muscle in chronic stroke patients.
Neurorehabil Neural Repair 22(1): 40-49, 2008.
5. Takikawa K, Haga N, Tanaka H, Okada K:
Characteristic factors of ankle valgus withmultiple cartilaginous exostoses. J Pediatr
Orthop 28: 761-765, 2008.
6. Yu E, Abe M, Masani K, Kawashima N, Eto F,
Haga N, Nakazawa K: Evaluation of posturalcontrol in quiet standing using the center ofmass acceleration: comparison among the young,the elderly, and people with stroke. Arch Phys
Med Rehabil 89: 1133-1139, 2008.

Surgical Sciences
3. Vital Care Medicine

243

Department of Anesthesiology
Professor
Yoshitsugu Yamada, M.D., Ph.D.

Lecturer
Ryo Orii, M.D., Ph.D.

Kyung-Ho Chang, M.D., Ph.D. Takami Komatsu, 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., Sayaka Shibama, M.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.,

Kanji Uchida, M.D., Ph.D
Yoshiteru Mori, M.D.

Homepage

Hiroko Tsujihara, M.D.,
Kanako Sato, M.D.,

Masahiko Sumitni,M.D.,PhD.,

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 for electroconvulsion therapy. Recently, the number of high risk
or geriatric patents is increasing. In addition, morethan 20% of the surgery (about 8000 cases in total peryear) spends more than eight hours. A new operating
theater opened in January 2007 and the demand forsufficient number of competent anesthesiologists isincreasing.
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 2007 to April 2008, the numberof ambulatory patients was about ten thousand; four
hundred and forty of those were newcomer patients.
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.

244

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.

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

References1.

Kaneki M, Sakai M, Shimizu N, Chang K. Is
normalized mean blood glucose level good enoughfor the intensive care unit?--glycemic variability as
a new independent predictor of mortality. Crit CareMed. 2008;36:3104-6.

2.

Toshiya Tomioka 、 Nobuhide Kin 、 Yoshitsugu
Yamada：Anesthetic management for non-cardiac
surgery in an infant patient with critical aortic

Research activities

stenosis．Anesth Resus．44．44-46．2008．
3.

We have seven research groups and their fields
include respiration, circulation, pain, immune systemand shock.
These are recent major subjects of our research.

Sumitani M, Miyauchi S, McCabe CS, Shibata M,
Maeda L, Saitoh Y, Tashiro T, Mashimo T. Mirror
visual feedback alleviates deafferentation pain,
depending on qualitative aspects of the pain: apreliminary report. Rheumatology 2008;47:1038-43

245

4.

Mittnacht AJ, Thanjan M, Srivastava S, Joashi U,
Bodian C, Hossain S, Kin N, Hollinger I, Nguyen K.
Extubation in the operating room after congenital
heart surgery in children. J Thorac Cardiovasc Surg.
2008 Jul;136(1):88-93.

246

Department of Emergency andCritical Care Medicine
Professor
Naoki Yahagi, M.D.

Lecturer
Yukio Tanaka, M.D., Ph.D.

Associate
Takeshi Ishii, M.D.,
guchi, M.D.,

Kyoko Komatsu, M.D.,

Jiro Ando, M.D.,

Yoichi Kitsuta, M.D.,

Masataka Gunshin, M.D.,

Daisuke Yama-

Takehiro Matsubara, M.D.

Staff
Rei Ito, 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
emergency care on 24-hour-a-day basis. In the 2004,
we had about 6,000 ambulance patients out of total

247

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/365day 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
provide the residents with lectures based on
MIMMS (Major Incident Medical Management and248

Support) 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-Dglucan in blood products .

References
1)

2)

3)

4)

5)

Sakai K, Sanada H, Matsui N, Nakagami G,
Su-gama J, Komiyama C, Yahagi N.
Continuous monitoring of interface pressure
distribution in intensive care patients for pressure
ulcer prevention. J Adv Nur 65, 809-17, 2009
Kitsuta Y, Suzuki N, Sugiyama M, Yamamoto
Changes is consciousness level and association
with hyperglycemia as tool for predicting andpreventing re-bleeding after spontaneous
subarrachnoid hemorrhage Pre-hospital anddisaster medicine, 2006; 21(3), 190-195.
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
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 and outcome characteristics ofmajor burns in Tokyo. Burns 2005; 31S: S3-11.
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. pp191209.

Health Sciences and Nursing
1. Health Sciences

250

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 (Chair of Health Sociology /Health Sociology and Health Education), 32 graduate
students (14 master course students and 18 doctor
course students) including 2 international students and
19 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 2008, 7 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

251

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
and living”, work-family balance and fatigue/
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.

2.

3.

YoshihikoYamazaki. The implications andChallenges of Sense of Coherence (SOC) as
Stress Coping Ability for Health and Medical
Sociology, The Japanese Journal of Health andMedical Sociology 19(2) 2008 ； 43-55 ． (inJapanese)
Royko Ebina , Yoshihiko Yamazaki．Sense ofcoherence and coping in adolescents directly
affected by the 1991-5 war in Croatia，Promotion
and Education, 15(4), 2008；5-10．
Michiyo Ito, Taisuke Togari,Min Jeong Park,

252

Yoshihiko Yamazaki ． Difficulties at work
experienced by patients with inflammatory bowel
disease (IBD) and factors relevant to work
motivation and depression Japanese Journal of
Health & Human Ecology, 74(6), 2008; 290-310．
4. Yoshihiko Yamazaki. Support and Life
Reconstruction for Living with HIV-infected
Hemophilia in Japan. The Journal of AIDS
Research, 10(3), 2008;144-155. (in Japanese)
5. Chikako Yamaki, Yoshihik Yamazak. Social
Regards towards Persons with Disabilities:
Concept and Characteristics The Japanese
Journal of Health and Medical Sociology 19(1)2008;13-25．(in Japanese)
6. Ayako Ide (Okochi), Yoshihiko Yamazaki Social
support networks and health-oriented behaviors
among skid row residents with disabilities
utilizing social rehabilitation services in
Kotobuki, Japan Japanese Journal of Health &Human Ecology, 74(5)，2008;250-266
7. Ryoko Taguchi, Yoshihiko Yamazaki, Tomoko
Takayama, Mitsue Saito. Life-Lines of relapsed
breast cancer patients: A study of post-recurrence
distress and coping strategies Japanese Journal of
Health & Human Ecology, 74(5),2008;217-235
8. Yoshihiko Yamazaki, Taisuke Togari, Junko
Sakano ed. Introduction to the Sense of
Coherence in the Salutogenic Model, 2008 1-228(in Japanese)
9. Taisuke Togari, Yoshihiko Yamazaki, Kazuhiro
Nakayama et al. Follow-up Study on the Effects
of Sense of Coherence on Well-being after Two
Years in Japanese University Undergraduate
Students Personality and Individual Difference
44 2008;1335-1347
10. Fumiko Isono, Miyuki Suzuki, Yoshihiko
Yamazaki. Work Motivation and Mental Healthof Nursery School Teachers and Relevant Factors
The Journal of Child Health 67(2) 2008;367-374.
(in Japanese)
11. Taisuke Togari, Yoshihiko Yamazaki, Kazuhiro
Nakayama et al. Construct validity ofAntonovsky’s sense of coherence scale: Stabilityof factor structure and predictive validity withregard to the well-being of Japanese
undergraduate students from two-year follow-up
data, Jpn J Health & Human Ecology, 74(2),2008; 71-86.
12. YoshihikoYamazaki, Yoji Inoue ed. University ofTokyo Press, QOL in Bereaved Families ofMedically Induced HIV-Positive Victims 2008;
1-277. (in Japanese)
13. Miho Sato, Yoshihiko Yamazaki, Mayumi Sakita,
Thomas J. Bryce.Benefit-finding among people
with rheumatoid arthritis in Japan, Nursing &Health Sciences, 10(1), 2008; 51-58

253

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 isto teach 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 2008.
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, including presentation of a
research plan by each graduate student and relevant
discussion, presentation of literature review, andlectures by guest speakers.

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 Japan survey,

254

which is part of a WHO international collaboration, isa largest epidemiologic study of common mental
disorders in the community in Japan. Assessment ofhealth effects of job stressors and effectiveness ofinterventions to reduce job stress are also coreresearch activities of the department. Current issues
around occupational mental health (e.g., work
engagement, workaholism, organizational justice,bullying, and work-life balance) are also actively
investigated. Furthermore, research in the department
includes various other topics, such as psychiatricrehabilitation, clinical psychology, psychotherapy,
child and adolescent psychiatry; and developmental
disorders. Most of the research has been conducted ina close collaboration with researchers in otherdomestic and foreign institutions/universities.

References (Jan.-Dec., 2008)
1.

2.

3.

4.

5.

6.

Kobayashi Y, Kaneyoshi A, Yokota A, Kawakami
N. Effects of a worker participatory program for
improving work environments on job stressors
and mental health among workers: a controlled
trial. J Occup Health. 2008; 50: 455-70.
Ishizaki M, Nakagawa H, Morikawa Y, Honda R,
Yamada Y, Kawakami N; Japan Work Stress and
Health Cohort Study Group. Influence of job
strain on changes in body mass index and waist
circumference--6-year longitudinal study. Scand
J Work Environ Health. 2008; 34: 288-96.
Tsutsumi A, Nagami M, Morimoto K, Kawakami
N.
Motivation,
overcommitment
andpsychological health at work: a path analytic
approach. J UOEH. 2008; 30: 279-92.
Sono T, Oshima I, Ito J. Family Needs andRelated Factors in caring for a Family Member
with Mental Illness: Adopting Assertive
Community Treatment in Japan where Family
Caregivers play a Large Role in Community Care.
Psychiat Clin Neuros 2008; 62: 584–90.
Suzuki E, Tsuchiya M, Hirokawa K, Taniguchi T,
Mitsuhashi T, Kawakami N. :Evaluation of anInternet-Based Self-Help Program for Better
Quality of Sleep among Japanese Workers: A
Randomized Controlled Trial. J Occup Health.
2008; 50: 387-99.
Shimazu A, Schaufeli W B, Kosugi S, Suzuki A,

Nashiwa H, Kato A, Sakamoto M, Irimajiri H,
Amano S, Hirohata K, Goto R, KitaokaHigashiguchi K. Work engagement in Japan:
Validation of the Japanese version of Utrecht
Work Engagement Scale. Appl Psychol: Int Rev
2008; 57: 510-23.
7. Fukuoka E, Hirokawa K, Kawakami N, Tsuchiya
M, Haratani T, Kobayashi F, Araki S. Doi H.: Job
strain and smoking cessation among Japanesemale employees: A two-year follow-up study.
Acta Medica Okayama 2008; 62: 83-91.
8. Ono Y, Kawakami N, Nakane Y, Nakamura Y,
Tachimori H, Iwata N, Uda H, Nakane H,
Watanabe M, Naganuma Y, Furukawa TA, Hata Y,
Kobayashi M, Miyake Y, Tajima M, Takeshima
T, Kikkawa T. Prevalence of and risk factors for
suicide-related outcomes in the World HealthOrganization World Mental Health Surveys Japan.
Psychiatry Clin Neurosci. 2008; 62: 442-9.
9. Takasaki Y, Kawakami N, Tsuchiya M, Ono Y,
Nakane Y, Nakamura Y, Tachimori H, Iwata N,
Uda H, Nakane H, Watanabe M, Naganuma Y,
Furukawa T, Hata Y, Kobayashi M, Miyake Y,
Takeshima T, Kikkawa T. Heart disease, othercirculatory diseases, and onset of major
depression among community residents in Japan:
results of the World Mental Health Survey Japan
2002-2004. Acta Med Okayama. 2008; 62: 241-9.
10. Ormel J, Petukhova M, Chatterji S,
Aguilar-Gaxiola S, Alonso J, Angermeyer MC,
Bromet EJ, Burger H, Demyttenaere K, deGirolamo G, Haro JM, Hwang I, Karam E,
Kawakami N, Lepine JP, Medina-Mora ME,
Posada-Villa J, Sampson N, Scott K, Ustun TB,
Von Korff M, Williams DR, Zhang M, Kessler
RC. Disability and treatment of specific mental
and physical disorders across the world. Br J
Psychiatry. 2008; 192: 368-75.
11. Shimazu A, De Jonge J, Irimajiri H. Lagged
effects of active coping within the DemandControl Model: A three-wave panel study among
Japanese employees. Int J Behav Med 2008; 15:
44-53.
12. Furukawa T, 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, Takeshima T,

255

Kikkawa T. The performance of the Japaneseversion of the K6 and K10 in the World Mental
Health Survey Japan. Int J Methods Psychiatr
Res. 2008; 17: 152-8.
13. Choi B, Kawakami N, Chang S, Koh S, Bjorner J,
Punnett L, Karasek R. A cross- national study
on the multidimensional characteristics of the
five-item psychological demands scale of the Job
Content Questionnaire. Int J Behav Med. 2008;
15: 120-32.
14. Tsutsumi A, Iwata N, Wakita T, Kumagai R,
Noguchi H, Kawakami N. Improving themeasurement accuracy of the effort-reward
imbalance scales. Int J Behav Med. 2008; 15:
109-19.

256

Department of Biostatistics
Professor
Yasuo Ohashi, Ph.D.

Associate Professor
Yutaka Matsuyama, Ph.D.

Research Associate
Ayano Takeuchi, MS

Project Research Associate
Satoshi Iimuro, Ph.D.
Yukari Tanaka, MS

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
andmethodological 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 touchwith real clinical/epidemiological problems. For these
purposes and research coordination, a non-profit

organization titled ‘The Japan Clinical Research
Support Unit’ was established by the faculty members
in 2001, and the organization is providing researchsupport in design, data management and statisticalanalysis 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. Graduate courses
1) Biostatistics (4 credits)
2) Epidemiology and Preventive Health Sciences(4 credits)
3) Introduction to Medical Statistics (2 credits; for257

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’

References(1) Mizuno K. Nakaya N. Tajima N. Ohashi Y. et al:Usefulness of Pravastatin in Primary Preventionof Cardiovascular Events in Women: Analysis of
the Manage- ment of Elevated Cholesterol in thePrimary Prevention Group of Adult Japanese(MEGA Study). Circu- lation 2008; 117:494-502(2) Japan Arteriosclerosis Longitudinal Study(JALS) Group: Japan Arterio- sclerosis
Longitudinal Study- Existing Cohorts Combine(JALS- ECC).-Rationale, Design, and Population
Characteristics-Circulation Journal 2008;72(10):1563-1568.
(3) Shinohara Y. Gotoh F. Tohgi H. Ohashi Y et al:
Antiplatelet Cilostazolls Is Beneficial in Diabetic
and/or Hypertensive Ischemic Strike Patients.
Cerebrovascular Diseases 2008;26: 63-70.
(4) Kubozono T. Itoh H. Oikawa K. Ohashi Y et al:

Peak VO is More Potent Than B-Type
Natriuretic Peptide as a Prognostic Parameter in
Cardiac Patients. Circulation Journal 2008;72(4):575-581.
(5) Toi M. Nakamura S. Kuroi K. Ohashi Y et al(JBCRG): Phase Study of Preoperative
Sequential FEC and Docetaxel Predicts of
Pathological Response and Disease Free Survival.
Breast Cancer Research and Treatment 2008;110:531-539.
(6) Arai Y. Akaza H. Deguchi T. Ohashi Y. et al:
Evaluation of Quality of Life in Patients with
Previously Untreated Advanced Prostate Cancer
Receiving Maximum Androgen Blockade
Therapy or LHRHa Monotherapy: A Multicenter, Randomized, Double- Blind, Comparative
Study. Journal of Cancer Research and ClinicalOncology 2008;134(12): 1385-1396.
(7) Shimizu F. Ito M Yoichi. Fujino K. Ohashi Y. et
al: Factors Associated with Variation in Utility
Scores among Patients with Prostate Cancer.
Value in Health 2008; 11(7): 1190-1193.
(8) Funatogawa I. Funatogawa T. Ohashi Y: A
Bivariate Autoregressive Linear Mixed Effects
Model for the Analysis of Longitudinal Data.
Statistics in Medicine 2008;27: 6367-6378.
(9) Teramoto T. Nakaya N. Yokoyama S. Ohashi Y.
et al; Practical Risk Prediction Tools forCoronary Heart Disease in Mild to Moderate
Hypercholesterolemia in Japan -Originated From
the MEGA Study Data-. Circulation Journal
2008; 72:1569-1575.
(10) Ishikawa T. Mizuno K. Nakaya N. Ohashi Y. et
al: The Relationship Between the Effect ofPravastatin and Risk Factors for Coronary Heart
Diseasein
Japanese
Patients
withHypercholestero- lemia.
Circulation Journal
2008; 72:1576-1582.
(11) Tajima N. Kurata H. Nakaya N. Ohashi Y. et al;
Pravastatin Reduces the Risk for Cardiovascular
Diseasein
Japanese
Hypercholesterolemic Patients with Impaired
Fasting Glucose or Diabetes: Diabetes
Subanalysis of the Management of Elevated
Cholesterol in the Primary Prevention Group of
Adult Japanese (MEGA) Study. Atherosclerosis
2008;199 (2):455- 462.

258(12) Okada K. Matsuo F. Uno S. Ohashi Y. et al:
Effectiveness of An Acellular Pertussis Vaccine
in Japanese Children During A Non-Epidemic
Period: A Matched Case-Control Study.
Epidemiology and Infection 2009;137: 124-130.
(13) Makuuchi M, Kokudo N, Arii S, Futagawa S,
Kaneko S, Kawasaki S, Matsuyama Y, Okazaki
M, Okita K, Omata M, Saida Y, Takayama T, andYamaoka Y. Development of evidence-based
clinical guidelines for the diagnosis andtreatment of hepatocellular carcinoma in Japan.
Hepatology Research 2008 38: 37-51.
(14) Eguchi S, Kanematsu T, Arii S, Okazaki M,
Okita K, Omata M, Ikai I, Kudo M, Kojiro M,
Makuuchi M, Monden M, Matsuyama Y,
Nakanuma Y, Takayasu K for the Liver Cancer
Study Group of Japan. Comparison of theoutcomes between an anatomical subsegmentectomy and a non-anatomical minor
hepatectomy for single hepatocellular carcinomas
based on a Japanese nationwide survey. Surgery
2008; 143: 469-475.
(15) Hasegawa K, Imamura H, Ijichi M, Matsuyama
Y, Sano K, Sugawara Y, Kokudo N, andMakuuchi M. Inclusion of tumor markers
improves thecorrelation of the Milan criteria with
vascular invasion and tumor cell differentiationin patients with hepatocellular carcinoma undergoing liver resection. Journal of Gastrointestinal
Surgery 2008; 12(5):858-866.
(16) Tateishi R, Yoshida H, Matsuyama Y, Mine N,
Kondo Y, and Omata M. Diagnostic accuracy oftumor markers for hepatocellular carci- noma: asystematic review. Hepatology International
2008; 2: 17-30.
(17) Uemura K, Matsuyama Y, and Ohashi Y. A
modified conditional power approach forincreasing the sample size based on an interim
estimate of treatment difference. Japanese
Journal of Biometrics 2008; 29: 19-34.
(18) Hasegawa K, Makuuchi M, Taka- yama T,
Kokudo N, Arii S, Okazaki M,Okita K, Omata M,
Kudo M, Kojiro M, Nakanuma Y, Takayasu K,
Monden M, Matsuyama Y, and Ikai I for theLiver Cancer Study Group of Japan. Surgicalresection vs. percutaneous ablation forhepatocellular carcinoma: A pre- liminary reportof the Japanese nationwide survey. Journal of
Hepatology 2008; 49: 589-594.
(19) Yasunaga H, Yanaihara H, Fuji K, Matsuyama Y,
Deguchi N, and Ohe K. Influence of hospital andsurgeon volumes on operative time, blood loss,
and perioperative compli- cations in radical
nephrectomy. International Journal of Urology
2008; 15: 688-693.
(20) Matsuyama Y and Yamaguchi T. Estimation of
the marginal survival time in the presence ofdependent competing risks using inverse
probability of censoring weighted (IPCW)
methods. Pharmaceutical Statistics 2008; 7:
202-214.
(21) Yasunaga H, Matsuyama Y, Ohe K for the Japan
Neurosurgical Society. Risk-adjusted analyses ofthe effects of hospital and surgeon volumes on
postoperative complications and the modified
Rankin scale after clipping of unruptured
intracranial aneurysms in Japan. Neurologia
Medico -Chirurgica 2008; 48: 531-538.
(22) Yoshida S, Matsuyama Y, Ohashi Y, and Ueshima
H. A Poisson mixed effects model forinvestigating the exposure-by-cohort interaction:
A Gibbs sampling approach. Japanese Journal of
Biometrics 2008; 29: 61-74.
(23) Tanaka Y, Matsuyama Y, and Ohashi Y. for the
MEGA Study Group. Estimation of treatment
effect adjusting for treatment changes using theintensity score method: an application to a large
primary prevention study for coronary events(MEGA study). Statistics in Medicine 2008;
27:1718-1733.
(24) Suzuki Y. Tokuda Y. Fujiwara Y. Ohashi Y et al:
Weekly Epoetin Beta Maintains Haemoglobin
Levels and Improves Quality of Life in Patientswith Non-Myeloid Malignancies Receiving
Chemo- therapy. Japanese Journal of ClinicalOncology 2008; 38(3): 214-221.

259

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
Misao Fujita, MPH, 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. From 2007, Dr. Lee
became the associate professor and took charge of the
Department of Health Promotion Sciences.
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 eleven lecturers from other organizations,and fifteen visiting researchers contribute to260

department teaching and research activities.
Department graduate students included four masterprogram 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. Seven bachelor theses, eight master theses,
and six doctoral dissertations were completed between
April 2004 and March 2009. 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 & Education (2 credits, lecture)5) Health Care & Welfare Ⅰ & Ⅱ (2 credits,
lecture)6) Field Work for Health Administration (2 credits,
practicum)7) Health Promotion Sciences (1 credit, lecture)8) Health Policy & Administration (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, andthe development of preventive health strategies andhealth promotion 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 University ofTokyo Center for Biomedical Ethics and Law(UT-CBEL) ― a new interdisciplinary andinternational education research center aimed toaddress bioethical issues relevant to Japan and theinternational community. Our center will form aninternational network by establishing partnerships
with research centers overseas (GABEX: Global
Alliance of Biomedical Ethics Centers Project).
Through these efforts, we will foster the next
generation of bioethics experts in policy-making,research, and clinical medicine who are capable ofprovidinginternational
leadershipinthefuture(http://square.umin.ac.jp/CBEL/index.html).
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

261

proposals concerning health promotion in thecommunity and work place through experimental andsurvey 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 evaluationof the health promotion programs in the community
and the work 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) Dietary patterns among overweight men andwomen

Publications
1.

2.

3.

4.

Akabayashi A, Kodama S, Slingsby BT. Is Asianbioethics really the solution? Camb Q Healthc
Ethics 2008, Summer; 17(3):270-2.
Akabayashi A, Slingsby BT, Nagao N, Kai I, Sato
H. A five year follow-up national study of
ethics committees in medical organizations inJapan. HEC Forum 2008 Mar, 20(1):49-60.
Kawakubo K and Lee JS. Effects of healthpromotion program on the waist circumference,
body weight, and BMI. The practice of education
for diet and physical activity ． Occupational
Health Journal 2008; 31: 22-27. (in Japanese)
Kawakubo K, Lee JS. Dislipidemia. Guideline
for Diagnosis and Prevention of Atherosclerotic
Cardiovascular Disease 2007. Japanese Journalof Nutrition and Dietetics 2008；66(1):39-45. (inJapanese)
5. Lee JS, Lee WC, Lee KS, K KW, Choi EJ, Park
CM. The new health promotion strategy in Japan.
Focusing on life-style related diseases. Korean J
Health Educ & Promot 2008, 9:167-181.
6. Lee JS 、 Mori K, Kawakubo K. Proposal ofeffective health education program for
modification on lifestyle behaviors. Short andlong term effects on the Metabolic Syndrome in acommunity setting. Kenko Kanri Organization
Research Grant Theses ⅩⅩⅣ2008: 19-31.(inJapanese)
7. Matsui K, Lie RK, Kita Y, Ueshima H. Ethics offuture disclosure of individual risk information ina genetic cohort study: A survey of donor
preferences. Journal of Epidemiology 2008;
18(5):217-224.
8. Nagao N, Aulisio MP, Nukaga Y, Fujita M,
Kosugi S, Youngner S, Akabayashi A. Clinical
Ethics Consultation: Examining how Americanand Japanese experts analyze an Alzheimer's case.
BMC Med Ethics 2008, 9:2.
9. Fujita M, Kodama S, Akabayashi A. Ten years
after the organ transplant act: Current situation in
Japan. IAB News 20, 5, 2008.
10. Watanabe E, Lee JS, Kawakubo K, Marui E.
Correlation between change in body weight andlifestyle behavior before and after children.
Japanese Journal of health and Human ecology
2008; 74 (1):3-12. (in Japanese)Health Sciences and Nursing
2. Preventive and Administrative Nursing

263

Department of Nursing
Administration / Advanced
Clinical Nursing
Professor
Katsuya Kanda, Ph.D., R.N.

Lecturer
Minako Sasaki, Ph.D., R.N.

Assistant Professor
Mami Onishi, M.S.N., R.N., Ayako Nagata, M.A., R.N.

Homepage

http://nurs-adm.umin.jp/

Introduction and Organization
Nursing Administration department provides broad
opportunities to learn about societal issues related to;1) nursing administration, nursing policy, nursing
education, nursing ethics, and 2) safety and quality
issues in nursing.
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, Lectures)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, Lectures)Prof. Kanda and Affiliates
Studies on application of management theory tonursing administration. Focuses are on; 1) issues
in nursing 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 , Lectures)Prof. Kanda and Affiliates
An overview on models, theories and research innursing. Focuses are on; 1) conceptual
frameworks of clients' potential and actual

264

physiological and psychosocial responses tohealth problems, 2) health assessment skills in
nursing practice, 3) measurement of clients' healthand nursing intervention outcome. Students will
establish their own theoretical knowledge andpractical skills essential to advanced clinicalnursing.
4. Advanced Clinical Nursing 2 (2 credits, Lecturesand practicum)
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, Lectures & practicum)
Prof. Kanda and Affiliates
Students will understand the emergency medical
system and learn how to act in emergency
situations. The practicum includes following
subjects; 1) observation and measurement of vital
signs, 2) first aid to the victim with bleeding,intoxication, or burn, 3) how to carry an injured
person,and
4)CPR(cardiopulmonary
resuscitation).
2. Fundamental Nursing 1 (2 credits, Lectures)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, Lectures)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
process and nursing diagnosis, and 5) current
ethical issues in nursing and health.
4. Fundamental Nursing 3 (4 credits, Lectures 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.
5. Clinical Practicum in Fundamental Nursing (2credits, practicum)
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.
6. Nursing Administration (1 credit, Lectures)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.
7. Nursing Administration Practicum (1 credit,
practicum)
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 combinationof both approaches.
1. Issues of Nursing Administration
Critical analysis and international comparative

265

2.

3.

4.

5.

study of administrative, socioeconomic andpolitical issues in contemporary nursing. Focuses
are on; 1) patient classification systems andnursing care delivery systems, 2) costeffectiveness of nursing services, 3) nursing casemanagement, and 4) nursing policy and strategies
to meet the professional demands.
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.
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 takeplace through field studies or laboratory/
experimental settings.
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
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. Sasaki M, Nagata A, Ohnishi M, Matsutani C,
Kanda K. Experiences of nurses during a hospitalmanagement transfer. International J ournal of
Knowledge, Culture an d Ch ange Management
2008; 8(6): 97-100.
2. Onishi M, Sasaki M, Nagata A, Kanda K.
Development of nurses with specialties: the nurse
administrators' perspective. Journal of Nursing
Management 2008; 16(7): 795-803.
3. Kataoka J, Sasaki M, Kanda K. Visual behavior
differences by clinical experience and alarming
sound during infusion pump operation. Japan
Journal of Nursing Science 2008; 5(2): 123-129.
4. Kondo A, Nishibayashi K, Kadowaki R, Anai K,
Kanda K. The relationship between living withfamily and discharging to home after hip fracture
surgery in Japan. Journal of Japan So ciety fo r
Health Care Management 2008; 8(4): 534-542.
5. Kamijo Y, Kanda K. Estimating nurses' workload
using the Diagnosis Procedure Combination in
Japan. International Nursing Review 2008; 55(3):281-287.
6. Sakaki H, Nishioka M. Evaluation of umbilicalcord care regimens for preventing omphalitis andpromoting cord detachment and wound healing indeveloped countries. Journal of Nu rsing S tudies
NCNJ. 2008; 7(1): 26-32. (in Japanese)
7. Onishi M, Mashimo A, Kanda K. The trend of
education for advanced nursing practice in the
United States. Japanese J ournal o f N ursing
Education 2008; 49(6): 530-533. (in Japanese)
8. Kanda K. Benchmarking for quality improvement of nursing service: Evaluation ofquality of nursing service based on patient
outcomes. EB NUR SING 2008; 8(1): 88-93. (inJapanese)266

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.
Hiroe Yamamoto, R.N., R.M., M.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 five faculty members: an associate professor, alecturer three research associates and a technicalspecialist. Also it has seven doctoral students, four
master’s course students, two research student, andthirteen 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

267

8. Families/siblings of children with chronic illness

Publications
1. Ueno, R., Kamibeppu, K.: Narratives by Japanesemothers with chronic mental illness in the Tokyo
metropolitan area: their feelings toward theirchildren and perceptions of their children's
feelings, Journal of Nervous and Mental Disease,196(7): 522-530, 2008.
2. Kamibeppu, K., Kobayashi, K.: Self-reported
depressive symptoms in school-children:A surveyof three schools in Metropolitan Tokyo, Japanese
Journal of Child and Ado lescent Psych iatry, 49(Suppl.): 9-22, 2008.
3. Omine. F., Nakamura, M., Gima, T., Tamashiro,Y., Uza, M., Kamibeppu, K.: The efficacy of
employing full-time midwives in community
maternal and child health services, The J apanese
Journal of Health and Hu man Eco logy, 74(4) :192-203, 2008.
4. Kobayashi.K., Kamibeppu.K: The Process How
Mothers and Nurses Adjust the Daily Life ofChildhood Cancer Survivors after Their Therapy
Were Finished, Journal of J apanese So ciety ofPediatric Onco logy Nursing.3:45-53.2008. (inJapanese)
5. Ikeda,M., Inoue,K., Kamibeppu,K.: Goals andpotential career advancement of licensed practicalnurse in Japan, Journal of Nursing Ma nagement,
16:821-828,2008.
6. Kamibeppu, K., Furuta, M., Yamashita, H.,
Sugishita, K., Suzumiya, H., Yoshida, K.:Training
health professionals to detect and support mothersat risk of postpartum depression or infant abuse in
the community: A cross-sectional and a before andafter study, BioScience Trends, 3(1):17-24, 2009.
7. Ikeda, T., Nakata, A., Takahashi, M., Hojou, M.,
Haratani, T., Nishikido, N., Kamibeppu, K.:
Correlates of depressive symptoms among
workers
in
small
and
medium-scale
manufacturing enterprises in Japan. Journal of
Occupational Health, 51,:26-37, 2009.
8. Wakimizu, R., Kamagata, S., Kuwabara,T.,Kamibeppu,K.: A randomized controlled trialof an at-home preparation programme forJapanese preschool children: effects on children’sand caregivers’ anxiety associated with surgery,
Journal of Evaluation in Clinica l Pra ctice, 15:393-401, 2009．
9. Sato.I., kamibeppu.K.: Provision and Sharing ofInformation with Siblings of Children with
Cancer - A Review of Explanations Provided -,Japanese J ournal o f Pediatric On cology, 46(1):31-38, 2009. (in Japanese)
10. Murakami.K., Nishigaki.K., Kamibeppu.K. : The
Survey of the Health Care Activities and Nurses’
Role in Nursery Schools in 23 Special Wards ofTokyo ,The Jo urnal of Ch ild Health, 68(3):387-394. 2009.(in Japanese)268

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.

Research Associate
Atsuko Taguchi, M.H.S., R.N., P.H.N.
Azusa Arimoto, D.H.S., R.N., P.H.N.

Homepage http://park.itc.u-tokyo.ac.jp/chn/
Introduction and Organization2)
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
26 graduate course students (18 in master course, 8 indoctoral course) in the department. Also, we accept
many visiting researchers from other colleges andinstitutions.

3)

Teaching activities
4)
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 to evaluate
the effectiveness of care not only for a person but
also for a whole community. This class is to
study, the concepts and functions of community
health nursing, developing process of community
health nursing, community assessment and5)

activities of community health nurses.
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 of caremanagement, home health care service, andhealth care system.
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.
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 activities
by observing the activities of public healthnurses.
Home Health Nursing Practice (1 credits,269

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 ofdischarge planning. Basic techniques and the roleof nursing through collaboration with otherprofession 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 assessment for advanced community
health nursing practice using the textbook formaster course students in western countries.
4) Advanced Public Health Nursing II (2 credits)
This program is to understand policymaking of
national and local government, method to operate
and evaluate the systems, and approach to policy
development as public health nurses throughlectures by experts of public policy and social
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, and community
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 standardization ofskills of public health nurses, in response to the healthcare needs of individuals, families, aggregates and thecommunities. We are conducting researches on Grant-in-Aid for Scientific Research of Ministry of Education,
Culture, Sports, Science and Technology, Health
Science research Grants of Ministry of Health, Labourand Welfare, and grants from some foundations.
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
We aim to clarify and standardize the skills of publichealth nurses especially focusing on “personal support”,“policy making” and “support towards tuberculosis
patients”. In concrete, we are analyzing the interviewsby experienced PHNs and extract their support skills,
compare their practice with existing theory, conduct
surveys, and explore elements related to support. Also,
we are developing health guidance solution for
individuals/groups/community by literature review andfield study.
3. Establishment and evaluation of community healthcare systems
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 topromotecommunityorganization
andinterorganizational network.
Especially about the around-the-clock in-home caresystem, through the model project at visiting nurse

270

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. 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, to develop
the outcome indicator of discharge planning, and to
produce the educational program of discharge planningfor ward nurse. We are conducting research about
discharge planning system, making guidelines for
multisectoral and interagency cooperation amongnurses by investigation of actual situation..
5. 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 ofmothers and the latter is to support mothers and fathers
balance their work with child-care. Our interest is
specially on health concern and action in child raisingfamilies, mother’s loneliness and their relationship withthe society, children’s easiness of going to sleep andmother’s fatigue. Also, the network for childrearing wasinvestigated to avoid child abuse.
6. Support for people with diseases or disabilities
We are making researches for people with diseases ordisabilities to improve their QOL.
The research themes in 2008 are 1) Care for older
people with dementia at mealtimes in group-home, 2)Knee joint pain in older people and their health action,3) Self care ability of the members of cardiac disease
patients after operation and social support and 4)
Acceptance to diseases and experiences in
hospitalization for tuberculosis patients

References
1. Arimoto A, Murashima S. Utilization of parenting
groups and consultation services as parenting
support services by Japanese mothers of 18 monthold children. Japan Journal of Nursing Science, 5(2),73-82, 2008
2. Kobayashi S, Yamamoto-Mitani N, Nagata S,
Murashima S. End-of-life care for older adults withdementia living in group-home in Japan. Japan
Journal of Nursing Science, 5, 31-40, 2008
3. Murayama M, Taguchi A, Murashima S.
Differences in Psychosocial Factors Among Novice,
Experienced, and Veteran Health Promotion
Volunteers in Japan. Public Health Nursing, 25(3),253-260, 2008
4. Watai I, Nishikido N, Murashima S.
Gender Difference in Work-Family conflict among
Japanese Information Technology Engineers withPreschool Children. J Occup Health, 50, 317-327,
2008
5. 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.
J.Obstet. Gynaecol. Res, 34(6), 971-979, 2008
6. Ota E, Haruna M, Matsuzaki M, Honda Y, Sasaki S,
Yeo S, Murashima S. Comparison of body fat masschanges during the third trimester and at one month
postpartum between lactating and nonlactating
Japanese women. BioScienceTrends, 2(5), 200-205,
2008
7. Takeuchi N, Murashima S. Relationships between
Characteristics, Beliefs, and Self-care in
Hemodialysis Patients. Japan Journal of Nursing
Science, 28(4), 37-45, 2008
8. Nakanishi M, Nagae H, Nagata T, Hattori K, Niino
Y. Implementation of discharge planning in the careof hospitalized older adults. － Focus on
involvement of home care providers at
hospitals-Japanese Journal of Public Health, 55(7),456-464, 2008
9. Ohshima H, Murashima S. A Literature Review on
Functional Prognosis in Stroke Patients with
Neglect. Japan Journal of Nursing Science, 28(2),62-69, 2008
10. Murashima S, Taguchi A. Special Feature Article
Health Care System for the Elderly, Commentary
Nurising at home for older people―Preparation ofVisiting Nursing System as a strategy of local
government.―. Gekkan Jichi Forum (Monthly
Local Autonomy Forum), 584, 17-24, 2008

271

11. Murashima S. Creating Nursing Science That
Supports Health and Welfare of the People:From theViewpoint of Community Health Nursing. Japan
Journal of Nursing Science, 28(1), 52-61, 2008
12. Koike T, Yamada M, Nagata S, Horii T, Muramatu
S. Syposium I New Designs for Home Care:
Connecting People, Community, and Nursing.
Japan Journal of Nursing Science, 28(1), 73-39,
2008

Health Sciences and Nursing
3. Clinical Nursing

273

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
Makoto Tanaka, R.N., Dr.Hlth.Sci.
Masakazu Nishigaki, R.N., Dr.Hlth.Sci.

Project Research Associate
Naomi Ito, R.N., Dr.Hlth.Sci.
Yasuko Oyagi, R.N., M.N.

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274

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.
Cardiovascular diseases: We have developed andvalidated Japanese version of the European Heart
Failure Self-Care Behavior scale and Coronary
revascularization
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275

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, Sato K, Morita T, Suzuki M. Effectof a population-based educational intervention
focusingon

end-of-life

home

care,

life-

prolonging treatment, and knowledge about

276

2.

3.

4.

5.

palliative care. Palliat Med. 2008; 22(4): 376-82.

living donors about adult-to-adult living donor

Miyashita M, Morita T, Tsuneto S, Sato K, Shimaliver transplantation. Gastroenterology Nursing.

Y. The Japan HOspice and Palliative care2008; 31(4): 263-72.

Evaluation study (J-HOPE study): Study design

11. Abe Y, Miyashita M, Ito N, Shirai Y, Momose Y,

and characteristics of participating institutions.

Ichikawa Y, Tsuji S, Kazuma K. Attitude of

Am J Hosp Palliat Med. 2008; 25(3): 223-32.

outpatients with neuromuscular diseases in Japan

Miyashita M, Morita T, Sato K, Hirai K, Shima Y,

to pain and use of analgesics. J Neurol Sci. 2008;

Uchitomi Y. Factors contributing to evaluation of267(1-2): 22-7.

a good death from the bereaved family member's

12. Kato N, Ito N, Kinugawa K, Kazuma K. Validity

perspective. Psychooncology. 2008; 17(6): 612-

and reliability of the Japanese version of the20.

European Heart Failure Self-Care Behavior Scale.

Miyashita M, Morita T, Sato K, Hirai K, Shima Y,

Eur J Cardiovasc Nurs. 2008; 7(4): 284-89.

Uchitomi Y. Good Death Inventory: A measure

13. Sato K, Miyashita M, Morita T, Sanjo M, Shimafor evaluating good death from the bereaved

Y, Uchitomi Y. Reliability assessment andfamily member's perspective. J Pain Symptom

findings

Manage. 2008; 35(5): 486-98.

measurement instrument: quality indicators ofMiyashita M, Nakamura A, Morita T, Bito S.

end-of-life cancer care from medical chart review

Identification of quality indicators of the end-of-

at a Japanese regional cancer center. Journal oflife cancer care from medical chart review using

palliative medicine. 2008; 11(5): 729-37.

modified Delphi method in Japan. Am J Hosp
6.

9.

newly

developed

quality

14. Sato K, Miyashita M, Morita T, Sanjo M, Shima
Y, Uchitomi Y. Quality of end-of-life treatment

Miyashita M, Hirai K, Morita T, Sanjo M,

for cancer patients in general wards and the

Uchitomi Y. Barriers to referral to inpatient

palliative care unit at a regional cancer center inpalliative care units in Japan: A qualitative

Japan: a retrospective chart review. Support Caresurvey with content analysis. Support Care

Cancer.

2008; 16(2): 113-22.

15. Hagiwara A, Ito N, Sawai K, Kazuma K. Validity

Miyashita M, Morita T, Shima Y, Kimura R,

and reliability of Physical Activity Scale for the

Takahashi M, Adachi I. Nurse views of theElderly (PASE) in Japanese elderly people.

adequacy of decision-making and nurse distress

Geriatrics and Gerontology International. 2008;

regarding artifical hydration for terminally ill8(3): 143-51.

cancer patients: a nationwide survey. Am J Hosp
8.

aPalliat Med. 2008; 25(1): 33-8.

Cancer. 2008; 16(3): 217-22.
7.

of

16. Sanjo M, Miyashita M, Morita T, Hirai K, Kawa

Palliat Med. 2008; 24(6): 463-9.

M, Ashiya T, Ishihara T, Matsubara T, Miyoshi I,

Miyashita M, Misawa T, Abe M, Nakayama Y,

Nakaho T, Nakajima N, Onishi H, Ozawa T,

Abe K, Kawa M. Quality of life, day hospice

Suenaga K, Tajima T, Hisanaga T, Uchitomi Y.

needs, and satisfaction of community-dwelling

Perceptions of specialized inpatient palliativeadvanced cancer patients and their caregivers incare: a population-based survey in Japan. J Pain

Japan. J Palliat Med. 2008; 11(9): 1203-7.

Symptom Manage. 2008;35(3):275-82.

Nishigaki M, Kobayashi K, Abe Y, Seki N,
Yokomura

T,

Yokoyama

M,

KazumaK.

17. Koyama Y, Miyashita M, Irie S, Yamamoto M,
Karita T, Moro T, Takatori Y, Kazuma K. A study

Preventive behavior in adult offspring of type2

ofdiabetes patients and its relationship withosteoarthritis

parental advice. Diabet Med. 2008; 25: 1343-48.

treatment. J Orthop Nurs. 2008; 12(2): 75-83.

10. Kusakabe T, Irie S, Ito N, Kazuma K. Feelings ofdiseasemanagement
patients

activities
under

of

hip

conservative

18. Yamagishi A, Morita T, Miyashita M, Akizuki N,

277

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 Med.
2008; 25: 412-8.
19. Furukawa F, Kazuma K, Kojima M, Kusukawa R.
Effects of an Off-site Walking Program on
Fibrinogen and Exercise Energy Expenditure in
Women. Asian Nursing Research. 2008; 2(1):35-45.
20. Shiozaki M, Hirai K, Dohke R, Morita T,
Miyashita M, Sato K, Tsuneto S, Shima Y,
Uchitomi Y. Measuring of the regret of bereaved
family members regarding the decision to admit
cancerpatients

topalliative

careunits.

Psychooncology. 2008; 17(9): 926-31.
21. Taru C, Tsutou A, Nakawatase Y, Usami M,
Miyawaki I. Gender differences of dietaryself-management

behavior

affectingcontrol

indices in type II diabetes. Kobe J Med Sci.
2008; 54: E82-96.

278

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, Ph.D., 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
Health was established in 2002.
Currently, it has 4 faculty members introduced
above and 10 part-time lecturers, 7 graduate students(4 in 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(2 credits, lectures)
2) Advanced Midwifery and Women’s Health 2(2 credits, 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)
4. Master’s thesis
The followings were research themes in 2008;
1) The relationship between functions of transverses
abdomens/pelvic floor muscles and stress urinary
incontinence in postpartum women.
2) The relationship between the maternal plasma
total homocysteine levels and the birth weight.
3) The prospective study of relationships between
breastfeeding and postpartum depressive symptom
from 1 month to 5 months postpartum.

279

5. Doctoral thesis
The following was a research theme in 2008;
1) Longitudinal changes in the relationship between
oxidative stress and lifestyle factors throughout
pregnancy.
2) Appropriate Gestational Weight Gain by Body
Mass Index for Lowering Perinatal Risks: a
Population-based Study in Nha Trang City, Khanh
Hoa Province, Vietnam.

Research activities
Our research activities focus on maternal-child healthcare as well as promoting the health and quality of lifeof women at each stage of the life cycle.
Current research projects are as follows.
1. Basic research for the efficacy of perinatal care.
1) Nutrition and weight management during
pregnancy and postpartum.
To evaluate the supervision of pregnant womenin outpatient care and to investigate methods forcontrolling the mother's body weight, nutritional
intake, physical activity, and weight change during
pregnancy in order to optimize the management
system.
2) Lifestyle and oxidative stress during pregnancy.
To identify the biochemical parameters such asoxidative stress markers for the assessment of ahealthy lifestyle during pregnancy.
3) Maternal body composition during pregnancy andinfant birth weight
To identify the optimal weight control method
and lifestyle during pregnancy for the preventionof low birth weight via the measurement of weight,
body composition, lipid metabolic biomarkers,
daily lifestyle, and nutritional intake.
4) Determination of the appropriate gestational
weight gain by body mass index for lowering
perinatal risks.
To study the association between pregnancy
weight gain among Vietnamese women withvarying prepregnancy body mass indices and therisk factors for adverse perinatal outcome.
5) Physical activity during pregnancy.
To assess the reliability and validity of theJapanese and Vietnamese versions of thepregnancy physical activity questionnaire (PPAQ).
6) Sleeping posture and sleep problems of pregnant
women.
To study the relationship between sleeping
posture and the quality of sleep, the state ofrespiration and the circulatory system.
7) Changes in the prostaglandin levels in saliva
during pregnancy, labor and the postpartum
period.
To examine the changes in the prostaglandin
levels in saliva during pregnancy, labor and the
postpartum period.
8) Promotion of women's health care after delivery.
To study the relationship between maternal
body weight or body composition and life-stylefactors among postpartum women.
2. Perinatal care program development andevaluation.
1) Determine the effectiveness of an exercise
program for promoting mental health in postnatal
women: a randomized controlled trial.
To evaluate the effectiveness of the postpartum
exercise program on mental health.
2) Change in the skeletal and muscular system during
pregnancy and postpartum.
To describe the function of the skeletal andmuscular system during pregnancy and postpartum,and to develop a perinatal physical self-care
program for the prevention of minor troubles.

References
1. Masayo Matsuzaki, Megumi Haruna, Erika Ota,
Satoshi Sasaki, Yasushi Nagai, Sachiyo
Murashima. 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. 2008; 34 (6):971-979.
2. Erika Ota, Megumi Haruna, Hideki Yanai, Motoi
Suzuki, Dang Duc Anh, Masayo Matsuzaki, Le
Huu Tho, Koya Ariyoshi, SeonAe Yeo, Sachiyo
Murashima. Reliability and validity of theVietnamese version of the Pregnancy Physical
Activity Questionnaire (PPAQ).Southeast Asian
Journal of Tropical Medicine and Public Health.

280

3.

4.

5.

6.

7.

8.

9.

2008; 39 (3):562-70.
Erika Ota, Megumi Haruna, Masayo Matsuzaki,
Yuka Honda, Satoshi Sasaki, SeonAe Yeo,
Sachiyo Murashima. Comparison of body fat
mass changes during the third trimester and at one
month postpartum between lactating andnonlactating Japanese women. BioScience Trends.
2008; 2 (5):200-205.
Kae Nakayama, Megumi Haruna, Masayo
Matsuzaki, Kyouichi Sekine, Sachiyo Murashima.
Changes in 13, 14-dihydro-15-keto-prostaglandin
F2α (PGFM) levels in saliva during pregnancy,
labor and the postpartum period. The Journal of
Obstetrics and Gynaecology Research. (in press)
Ryoko Murayama ， Kazuo Aoki. A Change ofSleep Posture with Pregnant Progress andInfluence to Respiration and Circulatory System.
Stress Science Research. In press. (in Japanese)
Mie Shiraishi, Megumi Haruna, Masayo
Matsuzaki, Erika Ota, Etsuko Watanabe, Satoshi
Sasaki, Sachiyo Murashima. The effect onnutrient intake of skipping breakfast during
pregnancy and factors related to skipping
breakfast. Japan Society of Maternal Health. In
press. (in Japanese)
Erika Ota, Megumi Haruna, Hideki Yanai, Motoi
Suzuki, Dang Duc Anh, Masayo Matsuzaki, Le
Huu Tho, Koya Ariyoshi, SeonAe Yeo, Sachiyo
Murashima. Reliability and validity of theVietnamese version of the Pregnancy Physical
Activity Questionnaire (PPAQ). The 40th
APACPH Annual Conference, Kuala Lumpur,
Malaysia, November 7-9, 2008.
Hiroyuki Moriuchi , Masako Moriuchi, Masako
Naganuma, Erika Ota, Motoi Suzuki, Lay-Myint
Yoshida, Nguyen thi Hien Anh, Le Huu Tho,
Hideki Yanai, Koya Ariyoshi, Dang Duc Ahn.
Impacts of Congenital Infections on Children in
Khanh Hoa Province: A Pilot Study. The Forum of
the Network of Research Centers on Infectious
DiseasesConference, Hall, National Institute ofHygiene and Epidemiology (NIHE) Hanoi,
Vietnam, October 6, 2008.
Erika Ota, Megumi Haruna, Hideki Yanai, Motoi
Suzuki, Dang Duc Anh, Le Huu Tho, Mitsuhiro
Isozaki, Yuka Honda, Koya Ariyoshi, Hiroyuki
Moriuchi, Sachiyo Murashima. Appropriate Body

Fat Mass toward Perinatal Period Prevents
Delivery of Infants Small or Large for Gestational
Age: a Population-based Study in Nha Trang City,
Vietnam. 12th East Asian Forum on Nursing
Science Annual Conference, Tokyo, Japan, March
13-14, 2009.
10. Erika Ota, Hideki Yanai, Megumi Haruna, Motoi
Suzuki, Dang Duc Anh, Vu Dinh Thiem, Le Huu
Tho, Koya Ariyoshi, Hiroyuki Moriuchi, Sachiyo
Murashima. Indoor passive smoking of pregnant
women increases the risk of preterm delivery but
not of delivery low birth weight infants in
Vietnam. Japan association for international
health conference, Tokyo, Japan, October 25-26,
2008.
11. Masayo Matsuzaki, Megumi Haruna, Erika Ota,
Satoshi Sasaki, Yasushi Nagai, Sachiyo
Murashima. Dietary folate intake, use of folate
supplements, lifestyle factors, and serum folate
levels among pregnant women in Tokyo, Japan.
12th East Asian Forum on Nursing Science
Annual Conference. Tokyo, Japan. March 13-14,
2009.
12. Masayo Matsuzaki, Mikiko Shimizu, Yukako
Yajima, Kiyomi Sakata, Mayumi Ikeda, Mieko
Hirade, Megumi Haruna. Midwives’ activities andwomen’s voice at one maternity house in Japan.
28th Congress of the International Confederationof Midwives; 2008 Jun 1-5; Glasgow, United
Kingdom, June 1-5, 2008.

281

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, 4 doctoral course students, 3 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

282with 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.

2.

3.

4.

5.

6.

7.

Kobayashi Y, Kaneyoshi A, Yokota A, Kawakami N.
Effects of a worker participatory program for
improving work environments on job stressors andmental health among workers: a controlled trial. J
Occup Health. 2008; 50: 455-70.
Ishizaki M, Nakagawa H, Morikawa Y, Honda R,
Yamada Y, Kawakami N; Japan Work Stress and
Health Cohort Study Group. Influence of job strain
on changes in body mass index and waist
circumference--6-year longitudinal study. Scand J
Work Environ Health. 2008; 34: 288-96.
Tsutsumi A, Nagami M, Morimoto K, Kawakami N.
Motivation, overcommitment and psychologicalhealth at work: a path analytic approach. J UOEH.
2008; 30: 279-92.
Suzuki E., Tsuchiya M., Hirokawa K., TaniguchiT., Mitsuhashi T. and Kawakami, N. :Evaluationof an Internet-Based Self-Help Program for
Better Quality of Sleep among Japanese Workers:
A Randomized Controlled Trial. Journal of
Occupational Health. 2008; 50: 387-99.
Hayashi A, Kayama M, Ando K, Ono M,
Suzukamo Y, Michimata A, Akiyama M,
Fukuhara S, Izumi S. :Analysis of Subjective
Evaluations of the Functions of Tele-Coaching
Intervention in Patients with Spinocerebellar
Degeneration. NeuroRehabilitation. 2008; 23:
159-169.
Fukuoka E., Hirokawa K., Kawakami N.,
Tsuchiya M., Haratani T., Kobayashi F., Araki S.
and Doi H.: Job strain and smoking cessation
among Japanese male employees: A two-year
follow-up study. Acta Medica Okayama 2008; 62:
83-91.
Ono Y, Kawakami N, Nakane Y, Nakamura Y,

Tachimori H, Iwata N, Uda H, Nakane H,
Watanabe M, Naganuma Y, Furukawa TA, Hata Y,
Kobayashi M, Miyake Y, Tajima M, Takeshima
T, Kikkawa T. Prevalence of and risk factors for
suicide-related outcomes in the World HealthOrganization World Mental Health Surveys Japan.
Psychiatry Clin Neurosci. 2008; 62: 442-9.
8. Takasaki Y, Kawakami N, Tsuchiya M, Ono Y,
Nakane Y, Nakamura Y, Tachimori H, Iwata N,
Uda H, Nakane H, Watanabe M, Naganuma Y,
Furukawa T, Hata Y, Kobayashi M, Miyake Y,
Takeshima T, Kikkawa T. Heart disease, othercirculatory diseases, and onset of major
depression among community residents in Japan:
results of the World Mental Health Survey Japan
2002-2004. Acta Med Okayama. 2008; 62: 241-9.
9. Ormel J, Petukhova M, Chatterji S, AguilarGaxiola S, Alonso J, Angermeyer MC, Bromet
EJ, Burger H, Demyttenaere K, de Girolamo G,
Haro JM, Hwang I, Karam E, Kawakami N,
Lepine JP, Medina-Mora ME, Posada-Villa J,
Sampson N, Scott K, Ustun TB, Von Korff M,
Williams DR, Zhang M, Kessler RC. Disability
and treatment of specific mental and physicaldisorders across the world. Br J Psychiatry. 2008;
192: 368-75.
10. Furukawa T, 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, Takeshima T,
Kikkawa T. The performance of the Japaneseversion of the K6 and K10 in the World Mental
Health Survey Japan. Int J Methods Psychiatr Res.
2008; 17: 152-8.
11. Choi B, Kawakami N, Chang S, Koh S, Bjorner J,
Punnett L, Karasek R. A cross- national study
on the multidimensional characteristics of the
five-item psychological demands scale of the Job
Content Questionnaire. Int J Behav Med. 2008;
15: 120-32.
12. Tsutsumi A, Iwata N, Wakita T, Kumagai R,
Noguchi H, Kawakami N. Improving themeasurement accuracy of the effort-reward
imbalance scales. Int J Behav Med. 2008; 15:
109-19.

283

Department ofGerontological Nursing /Wound Care Management
Professor
Hiromi Sanada, R.N., P.H.N., W.O.C.N., Ph.D.

Project Lecturer
Takashi Nagase, M.D., Ph.D.

Research Associate
Miho Oba, R.N., M.S.N.
Takeo Minematsu, Ph.D.

Homepage http://www.rounenkango.m.u-tokyo.ac.jp/english/index-e.html
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 1 professor and assisted by 1
project lecturer and 2 research associates, and 2
part-time lecturers for undergraduate course and 5 forgraduate course. The student body consists of 4
doctoral course students, 12 master course students,and 3 research students. The goal of our department isto achieve “Evidence-based practice and developmentof gerontological nursing and wound caremanagement”, where we are striving to develop newtechniques, instruments, and assessment skills inaccordance of nursing science and engineering andclinical nursing.

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 2008 curriculum were as follows;a) Practical simulation for gerontological nursingb) Physical, psychological & social characteristics ofthe elderlyc) Social, health and medical policies for a healthy
life of the elderlyd) Health and nursing of the elderly (gait disorder)e) Health and nursing of the elderly (pressure ulcer)f) Health and nursing of the elderly (dementia)g) Health and nursing of the elderly (critical care,rehabilitation, and end-of-life care and its ethicalissues)
The aim of the 4th year course is to promote
understanding of the ailments and conditions required
to provide proper care to the elderly. The main themesin the 2008 curriculum were as follows;a) Feeding and swallowing difficulty of the elderlyb) Aging and dementiac) Age-related changes in the physiologic systemd) Aging and osteoporosise) Aging and cardiovascular disorders

284f) Aging and respiratory disordersg) Aging and renal function, hypertension, andstrokeh) Pharmacologic management of the elderlyi) Nutritional management 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 discuss the ideal
situation of gerontological nursing through practicing
in the long-term care facility. This program was
supported by the long-term care facility owned by
Medical Corporation Tatsuoka.
3) Bachelor’s thesis
N/A for this year.
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 Nursing I offers review and criticalanalysis of latest world-wide researches aroundgerontological nursing. The main theme in 2008 wasto discuss the ideal situation in the geriatric medicine
by comparing insurance systems around the world
through journal club. Related lectures were also
provided, 1. Nutritional management of the elderly,and 2. Geriatric medicine in community setting.
Gerontological Nursing II provides lectures anddiscussion regarding the recent topics aroundgerontological nursing, in which the main themes in2008 were as follows;a) Influence of social activities and leisure time ofcare giver on the perceived care burden.
b) Strategies for improving quality of nursing
regarding visiting nurse, physical restraint, andnursing certification systemc) Elderly needs during a natural disasterd) Nursing care for the younger demented people
and their familye) Regeneration system of the hair follicle stem cellf) New style of home care for the highly impaired
elderly3) 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 latest world-wide researches
involving wound care management. The main theme
in 2008 was the topics on management oflymphoedema. Lymphoedema decrease QOL in the
post-surgery patients, thus adequate management isrequired. The representative text for lymphoedema
management was used to learn the basics and its
management of lymphoedema.
Wound Care Management II provides lectures anddiscussion regarding the recent topics involving
wound care management in critically ill patients, andthe main themes in 2008 were as follows;a) Mechanisms of physical response to the severe
invasionb) Respiration management of critically ill patientsc) Management of stoma and fistulad) Wound management in the emergency unite) ICU nursingf) Pressure ulcer management in acute spinal cord
injured patients and pressure ulcers
5) Master’s thesis
The followings were research themes in 2008;‘ Do nutritional markers in wound fluid reflectpressure ulcer status?’‘Inoculation of Pseudomonas aeruginosa to the fullthickness wound surface induces delayed woundhealing without inflammatory signs and symptoms
in rats -Possibility as an animal model for criticalcolonization-’‘ Evaluation of pressure redistribution in new
dynamic cushion for elderly’‘Development of the Research Awareness Scale for
Nurses’285‘Hypoxia is involved in deep tissue injury formation
in a rat model’
6) Doctoral thesis
The following was a research theme in 2008;‘Investigation of the role of the quorum sensing
system on the establishment of pressure-induced
ischemic wound infection by Pseudomonas
aeruginosa’

Research activities
1. Activity policy
Our main activity involves the “Evidence-based
Practice for Gerontological Nursing and Wound CareManagement” where we are striving to develop new
nursing techniques and instruments to fulfill the needsof 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
・ 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
・ Infection control of pressure ulcers
・ 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

References(1) Sanada H, Miyachi Y, Ohura T, Moriguchi T,
Tokunaga K, Shido K, Nakagami G. The JapanesePressure
Ulcer
SurveillanceStudy:
A
retrospective cohort study to determine theprevalence of pressure ulcers in Japanesehospitals. WOUNDS. 2008;20(6):176-182.
(2) Konishi C, Sugama J, Sanada H, Okuwa M,
Konya C, Nishizawa T. A prospective study of
blanchable erythema among university hospitalpatients, Int Wound J. 2008;5(3):470-475.
(3) Iizaka S, Nakagami G, Urasaki M, Sanada H.
Influence of the "hammock effect" in wheelchaircushion cover on mechanical loading over theischial tuberosity in an artificial buttocks model. J
Tissue V iability. 2008. doi:10.1016/j.jtv.2008.08.
001.
(4) Harding K., Sanada H, et al. Internationalguidelines. Pressure ulcer prevention: prevalence
and incidence in context. A consensus document.
London: MEP Ltd, 2009
(5) Futamura M, Sugama J, Okuwa M, Sanada H,
Tabata K. Evaluation of comfort in bedridden
older adults using an air-cell mattress with anautomated turning function: Measurement ofparasympathetic activity during night sleep. J
Gerontol Nurs. 2008;34(12):20-26.
(6) Sari Y, Nakagami G, Kinoshita A, Huang L, Ueda
K, Iizaka S, Sanada H, Sugama J. Changes inserum and exudate creatine phosphokinase286

concentrations as an indicator of deep tissue
injury: a pilot study. Int W ound J. 2008;5(5):674-680.
(7) Shigeta Y, Nakagami G, Sanada H, Oba M,
Fujikawa J, Konya C, Sugama J. Exploring therelationship between skin property and absorbent
pad environment. J Clin Nurs. 2009. doi:10.1111/j.
1365-2702.2008.02606.x(8) Sakai K, Sanada H, Matsui N, Nakagami G,
Sugama J, Komiyama C, Yahagi N. Continuous
monitoring of interface pressure distribution in
intensive care patients for pressure ulcer
prevention. J Adv Nurs. 2009. doi:10.1111/j.13652648.2008.04935.x(9) Baharestani MM, Black JM, Carville K, Clark M,
Cuddigan JE., Dealey C, Defloor T, Harding KG,
Lahmann NA, Lubbers MJ, Lyder CH, Ohura T,
Orsted HL, Reger, SI, Romanelli M, Sanada H.
Dilemmas in measuring and using pressure ulcer
prevalence and incidence: an international
consensus. Int Wound J. 2009;6(2):97-104.
(10) Yabunaka K, Iizaka S, Nakagami G, Aoi N,
Kadono T, Koyanagi H, Uno M, Ohue M, Sanada
S, Sanada H. Can ultrasonographic evaluation of
subcutaneous fat predict pressure ulceration? J
Wound Care. 2009;18(5):192-198.

International Health
1. International Social Medicine

288

Department of
Global Health Policy
Professor
Kenji Shibuya, MD, DrPH

Research Associate
Ali Moazzam, MD, PhD, Yoshihisa Shirayama, PhD

Homepage

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

Introduction and Organization

Education

Our mission is to improve population health byenhancing accountability and improving evidencebase of global health programmes through theprovision of best possible information and rigorous
monitoring and evaluation. The department's members
generate knowledge and ideas through their research,strengthen technical and leadership skills througheducational programs, and enhance national capacities
through collaborative projects, especially in thedeveloping world.

Master's program
The
Master's
programisademanding,interdisciplinary program emphasizing studentdirected learning, problem-solving, and theacquisition of fundamental public health skills
required for global health practices (health policy,
statistics, epidemiology, and social sciences). Students
are required to complete a minimum of 30 course
credits and a master thesis. Beyond the program andconcentration requirements, students are encouraged
to consult with faculty advisers to choose elective
courses best suited to their needs.

The priority areas of research are:
- Health outcome research (mortality, morbidity anddisability, health services, cost-effectiveness ofinterventions, disease modeling, resource flows,
and impact evaluation, including tracking the
progress towards the Millennium Development
Goals and contribution to the Global Burden of
Disease study);- Health system performance assessment, including
the analysis of health system inputs (financing,human resources), outputs (service delivery, effective coverage), and impact (health status);- Health and foreign policy (e.g. global healtharchitecture and governance, G8 and global
health, donor commitments).
Finally, the fundamental role of the department is to
produce the next generations of leaders in global
health.

PhD program
The PhD program is designed to train the next
generation of leaders in global health. PhD students
are required to complete a minimum of 24 course
credits and a doctoral thesis with which needs to be
published in a peer-reviewed journal. PhD students
without MPH degree should take the lectures toacquire fundamental public health skills such as healthpolicy, biostatistics and epidemiology.
Global Health Policy I and IIThis course introduces the principles and theories ofglobal health problems, as well as practicalapplications of quantitative methods (demography,
statistics, epidemiology and econometrics) to analyze
and interpret issues and challenges for policy.

289

The followings are the topics covered in the academic
year 2008;
1. Global health policy: overview
2. MDG4
3. MDG5
4. MDG 6 (HIV/AIDS, Tuberculosis, Malaria)
5. Acute disease surveillance
6. Non-communicable diseases
7. Global health policy: 30 years since Alma Ata
8. Burden of disease and risk factor assessment
9. Human resources for health
10. Priority setting
11. Health financing
12. Global health challenges

earthquake survivors in Pakistan,
Research Grant Program (Two-Year Project),
The Toyota Foundation

Publications
1.

2.

GHP Monday seminar
3.
Every Monday, 13:30-15:00 pm
1) Journal clubStudents present a brief summary of research articles
from the major medical, social science, economics
journals, which are relevant for global health policy.
The major objective is to share knowledge, evoke
debates and facilitate discussions.

4.

5.
2) Research seminar
A guest speaker or a master or doctoral student
presents his/her research. There is a 15-minutepresentation-followed by a 30-minute discussion.

6.

ResearchStrengthening health systems to achieve MDG 4 and 5
Research on Global Health Issues,
Health and Labour Sciences Research Grants
Epidemiology of HIV/AIDS: A cohort study andmeta-analysis
Research on HIV/AIDS,
Health and Labour Sciences Research Grants
Genetic analysis of tuberculosis epidemiology
Scientific Research (B)Grants-in-Aid for Scientific Research
Assessment of post-traumatic stress disorder among

7.

8.

9.

Masuno K, Phengsavanh A, Xaysomphoo D,
Douangmala S, Kuroiwa C. Scaling up
interventions to eliminate neonatal tetanus :Factors associated with the coverage of tetanus
toxoid and clean deliveries among women in
Vientiane, Lao PDR. Vaccine. 2009 (in press)
Sasaki Y, Ali M, Kakimoto K, Saroeun O, Kanal
K, Kuroiwa C. Predictors of exclusive
breastfeeding in early infancy: A survey reportfrom Phnom Penh, Cambodia. Journal of
Pediatric Nursing. 2009 (in press)
Vandan N, Ali M, Prasad R, Kuroiwa C.
Physician's knowledge assessment in tuberculosis
management in Lucknow, India: A public-private
sector comparison. Public Health. 2009 (in press)
Mori R, Dougherty M, and Whittle M.
Commentary on critical appraisal of the paper by
Gyte et al. British Journal of Obstetrics andGynecology. 2009 (in press)
Aiga H, Matsuoka S, Kuroiwa C, Yamamoto S.
Malnutrition among children in rural Malawianfish-farming households. Trans R Soc Trop Med
Hyg. 2009 (in press)
Gai R, Xu L, Li H, Zhou C, He J, Shirayama Y,
Tang W, Kuroiwa C. Investigation of health carewaste management in Binzhou District, China"
Waste Management. (in press)
Ali M, Kuroiwa C. The status and challenges of
hospital solid waste management: Case studies
from Thailand, Pakistan, and Mongolia. Journalof Material Cycles and Waste Management. (inpress)
Putthakeo P, Ali M, Vilayhong P, Ito C, Kuroiwa
C. Factors influencing breastfeeding in children
below 2 years of age in Lao PDR. Journal of
Pediatrics and Child Health. (in press)
Ikeda N, Murray CJ, Salomon JA. Tracking
population health based on self-reported
impairments: Trends in the prevalence of hearing
loss in US adults, 1976-2006. Am J Epidemiol.
2009;170(1):80-7.

290

10. Aiga H, Alvarez HR, Zúniga C, Serpas MV,
Acevedo FJ, Arenas EC. Donor agency
commitment to combating Chagas disease.
Lancet. 2009;373(9680):2024-2025
11. Masuno K, Shibuya K. Measles elimination: lackof progress in the Western Pacific Region.
Lancet. 2009;373(9668):1008.
12. Qazi MS, Ali M. Pakistan's Health Management
Information
System:HealthManagers'
Perspectives. Journal of Pakistan Medical
Association. 2009;59(1): 10-14.
13. Boschi-Pinto C, Velebit L, Shibuya K. Estimating
child mortality due to diarrhoea in developing
countries. Bull World Health Organ. 2008;86(9):710-7.
14. Shibuya K. Conditional cash transfer: a magicbullet for health? Lancet. 2008;371(9615):789-91.
15. Chandramohan D, Shibuya K, Setel P, CairncrossS, Lopez AD, Murray CJ, Zaba B, Snow RW,
Binka F. Should data from demographic
surveillance systems be made more widely
available to researchers? PLoS Med. 2008;5(2):e57.
16. Ali M, Ahmed KM, Kuroiwa C. Emergency
obstetric care in Punjab, Pakistan: Improvement
needed. The European Journal of Contraception
and Reproductive Health Care. 2008;13(2):201207.
17. Shirayama Y, Phompida S, Kuroiwa C.
Monitoring malaria control in Khammouane
province, Laos: an active case detection survey ofPlasmodium falciparum malaria using theParacheck rapid diagnostic test. Trans R Soc Trop
Med Hyg. 2008;102:743-750.
18. Vandan N, Ali M, Prasad R, Kuroiwa C.
Physician’s knowledge on prescribed regimen ofanti-tuberculosis medicine: a cross-sectional
survey from Lucknow, India. South East Asian
Journal of Public Health. 2008;39(6):1072-1075.
19. Ikeda N, Gakidou E, Hasegawa T, Murray
CJ.Understanding the decline of mean systolicblood pressure in Japan: an analysis of pooleddata from the National Nutrition Survey,
1986-2002.Bull World Health Organ. 2008;86(12):978-88.
20. Aiga H. How many people are really hungry?

21.

22.

23.

24.

Lancet. 2008;372(9647):1367-9.
Tullus K, Lakhanpaul M, and Mori R. A different
view on imaging of UTI. Acta Paediatrica.
2008;97(8):1016-1018.
Mori R, Shiraishi J, Negishi H, and Masanori F.
Predictive value of Apgar score in infants withvery low birth weight. Acta Paediatrica. 2008;
97(6):720-723.
Mori R, Dougherty M, and Whittle M. An
estimation of intrapartum-related perinatal
mortality rates for booked home births in
England and Wales between 1994 and 2003.
British Journal of Obstetrics and Gynecology.
2008;115(5):554-559.
Furuta M and Mori R. Factors affecting women’s
health-related behaviours and safe motherhood: A
qualitative study from a refugee camp in Eastern
Sudan. Health Care for Women International.
2008;29(8):884-905.

291

Department of Community andGlobal HealthProfessor
Masamine Jimba, MD, PhD, MPH

Assistant Professor
Krishna C. Poudel, PhD, MHSc
Junko Yasuoka, DSc, MPH
Kayako Sakisaka, PhD

Homepage: http://www.sih.m.u-tokyo.ac.jp/comm.html
Introduction and Organization
The department of community and global health(formerly department of international community
health) has been headed by four professors since
1993; Professors Gen Ohi (1993-1996), Som-Arch
Wongkhomthong (1996-1999), Susumu Wakai (19992005), and Masamine Jimba (2006-present).
The mission of the department is to seek equity
and social justice in health within and across thenations. By bring together clinical, public health andsocial science research, we aim at:
1. Investigating how to improve health status of themost vulnerable people, in particular, indeveloping countries,
2. Undertaking research on the influence of
globalization on health and social development,
3. Investigating mechanisms to reduce inequalities
between and within nations on health anddevelopment.
The name of the department has been changed
from “Department of International Community
Health” to “Department of Community and Global
Health” in April 2009. Our research will place moreemphasis on how to activate community-based
activities and how bottom-up approach can be linked
to national or international policy. Our department

consists of: Professor (1), Assistant Professors (3),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. We have worked
for Toyako G8 Summit as a member of Takemi
Working Group from the end of 2007 to 2008 andattended a series of meetings as follows:- Trilateral Commission Plenary Meeting Presentation of Working Group draft paper"Global Health as a Human Security Challenge"(April 26, 2008)- Brookings Institution Roundtable - "Challenges in
Global Health and Japan's Contributions:Preparation for the G8 Summit" (April 28, 2008)- Council on Foreign Relations Seminar - "Global
Health and the G8" (April 29, 2008)- International Conference on Global Action for
Health System Strengthening (November 3-4,
2008)
- G8 Hokkaido T
oyako Summit Follow-Up
Dissemination Seminar in Asia - Global Action for
Health System Strengthening (January 27, 2009)

292

In addition, we are working as an advisor for
Filariasis control program of the WHO South-East
Asia Regional Office. We also provide technicalsupport to projects run by the JICA and NGOs in Lao
PDR, Thailand, Vietnam, and Brazil, and conducted
research in collaboration with the Cambodian
government.

Teaching Activities
The objectives of our teaching activities are
summarized as follows:
1. Train those who are willing to work forinternational cooperation in future,
2. Train those who are willing to contribute to carryout research in international health,
3. Teach general students who are interested ininternational health.
The major topics for teaching is as follows: 1)
Global health, 2) Health promotion 3) School healthin developing countries, 4) Community-based healthinterventions 5) Social Capital, 6) Research ethics, 7)
Medical Anthropology, 8) 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, malaria,
leprosy, etc, in South and South East Asia.

References
1. Takanashi K, Chonan Y, Quyen DT, Khan NC,
Poudel KC, Jimba M. Survey of food hygiene
practices at home and childhood diarrhoea in
Hanoi, Vietnam. J Health Pop Nutr. (2009, inpress).
2. Castro MC, Tsuruta A, Kanamori S, Kannady K,
Mkude S. Community-based environmental
management for malaria control: evidence from asmall-scale intervention in Dar es Salaam,
Tanzania. Malar J. 2009;8:57.
3. Jimba M, Ready MK. Opportunities forovercoming health workforce crisis. In Reich MR,
Takemi K.G8 and strengthening of healthsystems: follow-up to the Toyako summit. Lancet.
2009;373:508-15.
4. Yoshimura N, Jimba M, Poudel KC,
Chanthavisouk C, Iwamoto A, Phommasack B,
Saklokham K. Health promoting schools in urban,
semi-urban and rural Lao PDR. Health Promot Int.
2009 24:166-76.
5. Yi S, Poudel KC, Yasuoka J, Ichikawa M, Tan V,
Jimba M. Influencing factors for seeking HIV
voluntary counseling and testing among
tuberculosis patients in Cambodia. AIDS Care.
2009;21:529-34.
6. Jayatilleke AU, Nakahara S, Dharmaratne SD,
Jayatilleke AC, Poudel KC, Jimba M. Working
conditions of bus drivers in the private sector andbus crashes in Kandy district, Sri Lanka: acase-control study. Inj Prev. 2009;15:80-6.
7. Tokuda Y, Fujii S, Jimba M, Inoguchi T. The
relationship between trust in mass media and thehealthcare system and individual health: evidence
from the AsiaBarometer Survey. BMC Med.
2009;22:7:4.
8. Jimba M, Yasuoka J, Sakisaka K, Poudel KC.
Primary health care must go beyond WHO.
Lancet.
2008;372:887.
PubMedPMID:
18790301.
9. Poudel KC, Nakahara S, Poudel-Tandukar K,
Yasuoka J, Jimba M. Unsafe Sexual Behaviors
among HIV-positive Men in Kathmandu Valley,
Nepal. AIDS Behav. 2008 Sep 4.
10. Otsuka K, Dennis CL, Tatsuoka H, Jimba M. The
relationship between breastfeeding self-efficacy

293

and perceived insufficient milk among Japanesemothers. J Obstet Gynecol Neonatal Nurs. 2008;
37:546-55.
11. Jimba M. Poudel-Tandukar K, Poudel KC. School
and community health project: Part 1: acommunity development and health project in
Nepal. Japan Medical Association Journal 2008;
51:225-234.
12. Takemi K, Jimba M, Ishii S, Katsuma Y,
Nakamura Y. Working Group on Challenges in
Global Health and Japan's Contribution. Human
security approach for global health. Lancet.
2008;5;372:13-4.
13. Aikawa R, Jimba M, Nguen KC, Binns CW.
Prenatal iron supplementation in rural Vietnam.
Eur J Clin Nutr. 2008;62:946-52. Epub 2007 May
23.
14. Takemi K, Jimba M, Ishii S, Katsuma Y,
Nakamura Y; Working Group on Challenges in
Global Health and Japan's Contribution. Human
security approach for global health. Lancet. 2008;
5;372:13-4.
15. Sakisaka K, Jimba M. International nutrition
training for local action. Lancet. 2008;24;371:
1752.
16. Poudel-Tandukar K, Poudel KC, Yasuoka J, Eto T,
Jimba M. Domestic violence against women in
Nepal. Lancet. 2008;17;371:1664.
17. Nonaka D, Kobayashi J, Jimba M, Vilaysouk B,
Tsukamoto
K,
Kano
S,
Phommasack
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.
18. Tokuda Y, Jimba M, Yanai H, Fujii S, Inoguchi T.
Interpersonal trust and quality-of-life: across-sectional study in Japan. PLoS ONE. 2008;
3:e3985.

International Health
2. International Biomedical Sciences

295

Department of Human Genetics
Professor
Katsushi Tokunaga, Ph.D.

Associate Professor
Akihiko Mabuchi, M.D., Ph.D.

Research Associate
Hiroko Miyadera, Ph.D.,

Taku Miyagawa, Ph.D.(August 2008-)

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, 12 graduate students, 2 research fellows,
and 7 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 thegenetics of complex diseases, including thedevelopment of statistical approaches forsusceptibility gene mapping in complex diseases,
genomic studies for the understanding of genetic
background and pathogenesis of autoimmune
diseases, sleep disorders, hypertension, diabetes,
as well 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
focuses on the elucidation of genetic susceptibility
to those, based on four cohorts established inJapan.

296

References

pathways for hypertension: a millennium genome
project for hypertension. Hypertens. Res. 31(2):1.

Hoa B.K., Hang N.T.L., Kashiwase K, Ohashi J,
Lien L.T., Horie J, Shojima J, Hijikata M, Satake2.

203-212, 2008
7.

Osawa H, Furuta H, Hirota Y, Yamagata K,

HLA-A, B, C, DRB1 and DQB1 alleles andHinokio Y, Oka Y, Iwasaki N, Iwamoto Y,

haplotaypes in the Kinh population in Vietnam.

Yamada Y, Seino Y, Maegawa H, Kashiwagi A,

Tissue Antigens 71: 127-134, 2008.

Yamamoto K, Tokunaga K, Takeda J, Makino H,

Shi Li, Ogata S, Yu JK, Ohashi J, Yu L, Shi L,

Nanjo

Sun H, Lin K, Huang XQ, Matushita M, Horai S,

Association of TCF7L2 polymorphisms with

Muramatsu M, Chu JY, and Tokunaga K:

susceptibility to type 2 diabetes in 4,087 JapaneseDistribution of HLA alleles and haplotypes insubjects. J. Hum. Genet. 53(2): 174-180, 2008.

Jinuo and Wa populations in Southwest China.

8.

Hum. Immunol. 69(1): 58-65, 2008.
3.

5.

6.

K,

KadowakiT,andKasugaM:

Kawasaki A, Kyogoku C, Ohashi J, Miyashita R,
Hikami K, Kusaoi M, Tokunaga K, Takahashi Y,

Yabe T, Matsuo K, Hirayasu K, Kashiwase K,

Hashimoto H, Behrens TW, and Tsuchiya N:

Kawamura-Ishii

A,

Association of interferon regulatory factor 5

Takanashi M, Satake M, Nakajima K, Tokunaga(IRF5) polymorphisms with systemic lupus

K, Inoko H, Saji H, Ogawa S, Juji T, Sasazuki T,

erytematosus in Japanese: Support for a crucial

Kodera Y, and Morishima Y: Donor killer

role of intron 1 polymorphisms. Arth. Rheum.

immunoglobulin-like receptor (KIR) genotype-58(3): 826-834, 2008.

S,

TanakaH,

Ogawa

patient cognate KIR ligand combination and4.

Miyake K, Horikawa Y, Hara K, Yasuda K,

M, Tokunaga K, Sasazuki N, and Keicho K:

9.

Fujimoto A, Kimura R, Ohashi J, Omi K,

anti-thymocyte globulin pre-administration are

Yuliwulandari R, Batubara L, Mustofa MS,

critical factors in outcome of HLA-C-KIR ligand

Samakkarn U, Settheetham-Ishida W, Ishida T,

mismatched T cell-replete unrelated bone marrow

Morishita Y, Furusawa T, Nakazawa M, Ohtsuka

transplantation. Bio. Blood Marrow Transplant.

R, and Tokunaga K: A scan for genetic

14(1): 75-87, 2008.

determinants of human hair morphology: EDAR

Amano K, Yamada K, Iwayama Y, Detera-is associataed with Asian hair thickness. Hum.

Wadleigh SD, Hattori E, Toyota T, Tokunaga K,

Mol. Genet. 17(6): 835-843, 2008.

Yoshikawa T, and Yamakawa K: Association

10. Yuliwulandari R, Sachrowardi Q, Nishida N,

study between the Down syndrome cell adhesion

Takasu M, Batubara L, Susmiarsih TP, Rochabi JT,

molecule (DSCAM) gene and bipolar disorder.

Wikaningrum R, Miyashita R, Miyagawa T, Sofro

Psychiat. Genet. 18(1): 1-10, 2008.

ASM, and Tokunaga K: Polymorphisms of

Omi K, Hachiya NS, Tanaka M, Tokunaga K, andpromoter and coding regions of the arylamine

Kaneko K: 14-3-3 zeta is indispensable for the

N-acetyltransferase

aggregate

polyglutamine-Indonesian population: Proposal for a new

expanded huntingtin protein. Neurosci. Lett.

nomenclature. J. Hum. Genet. 53(3): 201-209,

431(1): 45-50, 2008.

2008.

formation

with2(NAT2)

gene

in

the

Kohara K, Tabara Y, Nakura J, Imai Y, Ohkubo T,

11. Ueta M, Tokunaga K, Sotozono C, Inatomi T,

Hata A, Soma M, Nakayama T, Umemura S,

Yabe T, Matsushita M, Mitsuishi Y, and Kinoshita

Hirawa N, Ueshima H, Kita Y, Ogihara T,

S: HLA class I and II gene polymorphisms in

Katsuya T, Takahashi N, Tokunaga K, and Miki T:

Stevens-Johnson

Systemic multiple candidate gene approach forcomplications in Japanese. Mol. Vis. 14: 550-555,

identification of susceptible genes and susceptible

2008

syndromewithocular297

12. Mashimo Y, Suzuki Y, Hatori K, Tabara Y, Miki T,

18. Ohnishi Y, Tamura Y, Yoshida M, Tokunaga K,

Tokunaga K, Katsuya T, Ogihara T, Yamada M,

andTakahashi N, Makita Y, Nakayama T, Soma M,

discrimination by introduction of nucleotide

Hirawa N, Umemura S, Ohkubo T, Imai Y, andmismatches into siRNA in allele-specific geneHatasilencing by RNAi. PLoS ONE. 3(5): e2248,

A:

Assocaitionof

TNFRSF4

gene

polymorphisms with essential hypertension. J.
Hypertens. 26(5): 902-913, 2008.
I,

Tokunaga

Krudsood

Enhancementofallele2008.

and natural selection in Oceania: Inference fromK, and Patarapotikul J: Significant

genome-wide SNP typing. Mol. Biol. Evol. 25(8):between

Looareesuwan

Inaoka T, Phtsuka R, and Tokunaga K: Gene flowS,

association

S,

H:

19. Kimura R, Ohashi J, Matsumura Y, Nakazawa M,

13. Nuchnoi P, Ohashi J, Kimura R, Hananantachai H,
Naka

HohjohTIM1

promoter

1750-1761, 2008.

polymorphisms and protection against cerebral

20. Nuchnoi P, Ohashi J, Naka I, Nacapunchai D,

malaria in Thailand. Ann. Hum. Genet. 72(Pt 3):

Tokunaga K, Nishida N, and Patarapotikul J:

327-336, 2008.

Linkage disequilibrium structure of the 5q31-33

14. Ueno T, Soma M, Tabara Y, Tokunaga K, TahiraK, Fukuda N, Matsumoto K, Nakayama T,

region in Thai.

J. Hum. Genet. 53(9): 850-856,

2008.

Katsuya T, Ogihara T, Makita Y, Hata A, Yamada

21. Nakatsuji N, Nakjima F, and Tokunaga K:

M, Takahashi N, Hirawa N, Uemura S, and Miki

HLA-haplotype banking and iPS cells. Nat.

T: Association between fatty acid binding protein

Biotech. 26(7): 739-740, 2008.

3 gene variants and essential hypertension in

22. Hikami K, Ehara Y, Hasegawa M, Fujimoto M,

humans. Am. J. Hypertens. 21(6): 691-695, 2008.

Matsushita M, Oka T, Takehara K, Sato S,

15. Mamegano K, Kuroki K, Miyasguta R, Kusaoi M,

Tokunaga K, and Tsuchiya N: Association of

Kobayashi S, Matsuta K, Maenaka K, Colonna N,

lL-10 Receptor 2 (lL10RB) with systemic

Ozaki S, Hshimoto H, Takasaki Y, Tokunaga K,

sclerosis. Biochem. Biophys. Res. Commun. 373:

and Tsuchiya N: Association of LILRA2 (ILT1,

403-407, 2008.

lIR7) splice site polymorphism with systemic

23. Miyagawa T, Nishida N, Kimura R, Fujimoto A,

lupus erytematosus and microscopic polyangiitis.

Kawashima M, Sasaki T, Tanii H, Otowa T,

Genes Immun. 9(7): 214-223, 2008.

Momose Y, Nakahara Y, Okazaki Y, Tsuji S, and

16. Hirayasu K, Ohashi J, Tanaka H, Kashiwase K,

Tokunaga K: Appropriate data cleaning method

Ogawa A, Takanashi M, Satake M, Jia GJ,

for genome-wide association study. J. Hum.

Chimge N-O, Sideltseva E, Tokunaga K, andGenet. 53(10): 886-893, 2008.

Yabe T: Evidence for natural selection onleukocyte

immunoglobulin-likereceptors

24. Shiota S, Tochigi M, Ohashi J, Kasai K, Kato N,

forTokunaga K, and Sasaki T: Association and

HLA class l in Northeast Asians. Am. J. Hum.

interaction analyses of NRH1 and FRBB4 genes

Genet. 82(5): 1075-1083, 2008.

with schizophrenia in a Japanese population. J.

17. Horikawa Y, Miyake K, Yasuda K, Enya M,

Hum. Genet. 53(10): 929-935, 2008.

Hirota Y, Yamagata K, Hinokio Y, Oka Y, Iwasaki

25. Fujimoto A, Ohashi J, Nishida N, Miyagawa T,

N, Iwamoto Y, Yamada Y, Seino Y, Maegawa H,

Morishita Y, Tsunoda T, Kimura R, and Tokunaga

Kashiwagi A, Yamamoto K, Tokunaga K, Takeda

K: A replication study confirmed the EDAR geneJ, and Kasuga M: Replication of genome-widetoassociationdifferentiation regarding head hair thickness instudies

of

type

2

diabetessusceptibility in Japan. J. Clin. Endocrinol. Metab.
93(8): 3136-3141, 2008.

be

a

major

contributor

topopulation

Asia. Hum. Genet. 124(2): 179-185, 2008
26. Yasuda K, Miyake K, Horikawa Y, Hara K,

298

Osawa H, Furuta H, Hirota Y, Mori H, Jonsson A,
Sato Y, Yamagata K, Hinokio Y, Wang HY,
Tanahashi T, Nakamura N, Oka Y, Iwasaki N,
Iwamoto Y, Yamada Y, Seino Y, Maegawa H,
Kashiwagi A, Takeda J, Maeda E, Shin HD, Cho
YM, Park KS, Lee HK, Ng MCY, Ma RCW, So
WY,Chan JCN, Lyssenko V, Tuomi T, Nilsson P,
Groop L, Kamatani N, Sekine A, Nakamura Y,
Yamamoto K, Yoshida T, Tokunaga K, Itakura M,
Makino H, Nanjo K, Kadowaki T, and Kasuga M:
Variants

insusceptibility

KCNQ1

are

to

2

type

associateddiabetes

withmellitus.

Nat.Genet. 40(9): 1092-1097, 2008.
27. Naka I, Ohashi J, Nuchnoi P, Hananantachai H,
Looareesuwan S, Tokunaga K, and Patarapotikul
J: Lack of association of the HbE variant withprotection from cerebral malaria in Thailand.
Biochem. Genet. 46(11-12): 708-711, 2008.
28. Yoshikawa A, Shimada H, Numazawa K, Sasaki T,
Ikeda M, Kawashima M, Kato N, Tokunaga K,
and Ebisawa T:
lines

showingbioluminescence.

Establishment of human cell
circadianrhythmsof

Neuroscience

Letters

446:

40-44, 2008.
29. Nishida N, Koike A, Tajima A, Ogasawara Y,
Ishibashi Y, Uehara Y, Inoue I, and Tokunaga K:
Evaluating the performance of Affymetrix SNP
Array 6.0 platform with 400 Japanese individuals.
BMC Genomics 9: e431, 2008.
30. Miyagawa T, Kawashima M, Nishida N, Ohashi J,
Kimura R, Fujimoto A, Shimada M, Morishita S,
Shigeta T, Lin L, Hong SC, Faraco J, Shin YK,
Jeong JH, Okazaki Y, Tsuji S, Honda M, Honda Y,
Mignot E, and Tokunaga K: Variant between
CPT1B and CHKB associated with susceptibility
to narcolepsy. Nat. Genet. 40(11): 1324-1328,
2008.
31. Teeranaipong P, Ohashi J, Patarapotikul J, Kimura
R, Nuchonoi P, Hananantachai H, Naka I,
Putaporntip C, Jongwutiwes S, and Tokunaga K:
A functional SNP in the CR1 promoter region
contributes to protection against cerebral Malaria.
J. Infect Dis. 198(12): 1880-1891, 2008.

299

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 1966 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 entered a new era, putting moreemphasis than ever on the research on developmental
disorders of the human nervous system.
At present, our department consists of one professor,
one associate professor, two associates, one assistantclerk, one technical assistant, fifteen visiting lecturers,
sixteen visiting researchers, sixteen graduate students(including seven 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,300

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.

References
1.

Research activities(1) Studies on developmental brain disorders caused
by abnormal intracellular signal transduction,such as tuberous sclerosis, Noonan syndrome andCostello syndrome.
(2) Clinical, genetic and pathologic studies of acuteencephalopathies:
Acutenecrotizing
encephalopathy and acute encephalopathy withfebrile convulsive status epilepticus.
(3) Molecular genetic and cell biologic studies
combined with post-genomic approaches onmolecules regulating neuronal migration, such as
Doublecortin and Cdk5.
(4) Molecular pathologic studies on childhood
intractable epilepsy and developmental disorders,such as West syndrome and Rett syndrome, using
genetically engineered animals.
(5) Molecular genetics and biochemistry of inheritedmetabolic disorders, such as peroxisomal
disorders, and of neurodegenerative diseases,
such as spinal muscular atrophy.
(6) Pharmacological studies on the pathogenesis andtreatment of developmental disorders, such asattention deficit/ hyperactivity disorder., using
genetically engineered animals.
(7) Molecular epidemiology of pediatric infectious
diseases, in particular viral diarrheal diseases(rotavirus, norovirus, adenovirus, sapovirus andastrovirus) and HIV infection.
(8) Epidemiological studies on nutrition and child
growth.
(9) Studies on the epigenetics of the fetal origin of
adult diseases.
(10) Effects of high-rise living on physical and mental
development of children.
(11) Epidemiological tudies on the mental health ofschoolchildren, and of mothers and children
living abroad

2.

3.

4.

5.

6.

7.

8.

9.

Chan-It W, Khamrin P, Saekhow P, Pantip C,
Thongprachum A, Peerakome S, Ushijima H,
Maneekarn N. Multiple combinations of P[13]like genotype with G3, G4, and G5 in porcine
rotaviruses. J Clin Microbiol. 2008; 46(4): 11691173.
Dey SK, Islam A, Mizuguchi M, Okitsu S,
Ushijima H. Epidemiological and molecularanalysis of astrovirus gastroenteritis in Dhaka
City, Bangladesh. J Trop Pediatr. 2008; 54(6):423-425.
Khamrin P, Nguyen TA, Phan TG, Satou K,
Masuoka Y, Okitsu S, Maneekarn N, Nishio O,
Ushijima
H.
Evaluationofimmunochromatography
andcommercial
enzyme-linked immunosorbent assay for rapid
detection of norovirus antigen in stool samples. J
Virol Methods. 2008; 147(2): 360-363.
Khamrin P, Okitsu S, Ushijima H, Maneekarn N.
Novel nonstructural protein 4 genetic group inrotavirus of porcine origin. Emerg Infect Dis.
2008 ; 14(4): 686-688.
Khamrin P, Peerakome S, Malasao R, Mizuguchi
M, Okitsu S, Ushijima H, Maneekarn N. Genetic
characterization of group C rotavirus isolated
from a child hospitalized with acutegastroenteritis in Chiang Mai, Thailand. Virus
Genes. 2008; 37(3): 314-321.
Khamrin P, Maneekarn N, Peerakome S, Okitsu S,
Mizuguchi M, Ushijima H. Bovine kobuviruses
from cattle with diarrhea. Emerg Infect Dis.
2008; 14(6): 985-986.
Nguyen TA, Hoang L, Pham le D, Hoang KT,
Mizuguchi M, Okitsu S, Ushijima H.
Identification of human astrovirus infections
among children with acute gastroenteritis in theSouthern Part of Vietnam during 2005-2006. J
Med Virol. 2008; 80(2): 298-305.
Nguyen TA, Hoang LP, Pham LD, Hoang KT,
Okitsu S, Mizuguchi M, Ushijima H. Use of
sequence analysis of the VP4 gene to classify
recent Vietnamese rotavirus isolates. Clin
Microbiol Infect. 2008; 14(3): 235-241.
Nguyen TA, Hoang LP, Pham LD, Hoang KT,
Okitsu S, Mizuguchi M, Ushijima H. Norovirus
and sapovirus infections among children withacute gastroenteritis in Ho Chi Minh city during
2005-2006. J Trop Pediatr. 2008; 54(2): 102-113.

301

10. Ozeki N. Transcultural stress factors of Japanesemothers living in the United Kingdom. J
Transcult Nursing. 2008; 19(1): 47-54.
11. Pham NT, Trinh QD, Khamrin P, Nguyen TA,
Dey SK, Phan TG, Hoang le P, Maneekarn N,
Okitsu S, Mizuguchi M, Ushijima H. Sequence
analysis of the capsid gene of Aichi viruses
detected from Japan, Bangladesh, Thailand, andVietnam. J Med Virol. 2008; 80(7): 1222-1227.
12. Saijo M, Ami Y, Suzaki Y, Nagata N, Iwata N,
Hasegawa H, Ogata M, Fukushi S, Mizutani T,
Iizuka I, Sakai K, Sata T, Kurata T, Kurane I,
Morikawa S. Diagnosis and assessment ofmonkeypox virus (MPXV) infection by
quantitative PCR assay: differentiation of Congo
Basin and West African MPXV strains. Jpn J
Infect Dis. 2008; 61(2): 140-142.
13. Saitoh M, Yamashita S, Shimozawa N,
Mizuguchi M, Iwamori M. Changes in theamounts of myelin lipids and molecular speciesof plasmalogen PE in the brain of an autopsy casewith D-bifunctional protein deficiency. Neurosci
Letters. 2008; 442(1): 4-9.
14. Takanashi S, Okame M, Shiota T, Takagi M,
Yagyu F, Tung PG, Nishimura S, Katsumata N,
Igarashi T, Okitsu S, Ushijima H. Developmentof a rapid immunochromatographic test fornoroviruses genogroups I and II. J Virol Methods.
2008; 148(1-2): 1-8.
15. Yamada M, Murakami K, Sasaki S, Takahashi Y,
Okubo H. Soft drink intake is associated with
diet quality even among young Japanese womenwith low soft drink intake. J Am Diet Assoc.
2008; 108(12): 1997-2004.
16. Yan H, Koyano S, Inami Y, Yamamoto Y,
Suzutani T, Mizuguchi M, Ushijima H, Kurane I,
Inoue N. Genetic variations in the gB, UL144
and UL149 genes of human cytomegalovirus
strains collected from congenitally- andpostnatally-infected Japanese children.
Arch
Virol. 2008; 153(4): 667-674. 12(3): 506-508.

302

Department of Human Ecology
Professor
Chiho WATANABE, D. Hlth Sc.

Associate Professor
Masahiro UMEZAKI, Ph.D.

Research Associate
Hana SHIMIZU, Ph.D.
Shoko KONISHI, 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 FY2008.
Apart from the faculty staffs, two secretaries, four
doctoral candidates (three foreign students), six
master course students (including two foreign
students), and three research fellows are working in
the department. There are nine extra-university
lecturers delivering lectures in either graduate orundergraduate course. Prof. Watanabe holds the
additional post in the Transdisciplinary Initiative for
Global Sustainability (TIGS).

Teaching activities
The department is one of the six departments of the
School of International Health. Human Ecolog ySpecial 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”.
Attheundergraduate 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 have

303

been conducted, emphasizing the factors that modify
the effects. What follows is a list of major projects
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 delayed effectsof perinatal exposures. The effects of cadmium on thecultured neurons were examined using proteomics;
non- monotonous dose-effect relationships were foundand 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, surveys in each of the targeted countries
was completed, and the analyses of the collected
samples has been done, while some of the chemical
analyses are still going on. Many unexpectedchemicals were found in the biological samples,
demonstrating the “invasion” of industrial potentiallyhazardous chemicals to rural communities ofdeveloping countries. In addition, substantial
between-community difference in the chemical
exposures was revealed. Final report of the project
was submitted to the Ministry of Environment, Japan.
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 the304effect of nutritional status on the arsenic toxicity wereobserved and reported.

Emergence of methylmercury toxicity long after

Referenceswild-type C57BL mice strains. Environmental
Health Perspectives, 116: 746-751.

(1) Fukuyama, S., Watanabe, C., Umezaki, M. and
Ohtsuka, R. (2009) Twenty years' demographic
change in sedentes and migrants of an internationalmigrant-sending community in Tonga. Journal of
Biosocial Science, 41(1): 77-87.
(2) Hirano, M., Kitamura, K., Kato, I., Yanaihara, C.,
Iwamoto,K.,

perinatal exposure in metallothionein-null and

Sekiyama,

M.,

Watanabe,C.,

Nakamoto, T., Miyamoto, N., Onishi, Y. and Arizono,
K. (2008) Development of enzyme immunoassay for
detection of DDT. Journal of Environmental Scienceand Health, Part A, (2008) 43: 44-49.
(3) Ikegaya, H., Zhong, S., Shimizu, H., Sekiyama, M.,
Soemantri, AG., Ishida, T., Nakazawa, M., Ohtsuka,R., Takasaka, T., Shibuya, A., Kitamura, T., andYogo, Y. (2008) The pacific lineage (2E) of JC
polyomavirus is prevalent in Sumba island, Eastern
Indonesia. Anthropological Science, 116(2): 183186.
(4) Kondo, K., Lee, JS., Kawakubo, K., Kataoka, Y.,
Asami, Y., Mori, K. and Umezaki, M. (2009)
Association between daily physical activity andneighborhood environments. Environmental Healthand Preventive Medicine (in press)(5) Otani-Kaneko, R., Tazawa, H., Yokosuka, M.,
Yoshia, M., Satoh, M. and Watanabe, C. (2008)
Suppressive effects of cadmium on neurons andaffected proteins in cultured developing cortical cells.
Toxicology, 253: 110-116.
(6) Parajuli, R.P., Umezaki, M. and Watanabe, C. (2008)
Behavioral and Nutritional Factors and Geohelminth
infection among Two Ethnic Groups in the Terai
Region, Nepal. American Journal of Human Biology,
21: 98-104.
(7) Yokosuka, M., Ohtani-Kaneko, R., Yamashita, K.,
Muraoka, D., Kuroda, Y. and Watanabe, C. (2008)
Estrogen and environmental estrogenic chemicals
exert developmental effects on rat hypothalamic
neurons and glias. Toxicology in Vitro, 22: 1-9.
(8) Yoshida, M., Shimizu, N., Suzuki, M., Watanabe, C.,
Satoh, M., Mori, K. and Yasutake A. (2008)

305

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.biomedchem.m.u-tokyo.ac.jp/

Introduction and Organization
Aim of our department is to contribute to global
health and welfare from basic research. Our department,
formerly named Biochemistry and Nutrition was
renamed on April 1st, 1996 to The Department of
Biomedical Chemistry as newly affiliating with
Biomedical Science Division of International Health,Graduate School of Medicine, The University of Tokyo.
Prof. Kita has moved from The Institute of Medical
Science, The University of Tokyo 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 toprovide basic concepts and newer vistas forunderstanding nutrition with special reference tobiochemistry and molecular biology. These include thestructure 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, Medical Chemistry,
Practice on Medical Chemistry, Parasitology.

Research activities
Energy metabolism is essential for the survival,continued growth and reproduction of living organisms.
From the standpoint of biological adaptation, we havebeen studying on the molecular mechanism of energy
transducing systems such as mitochondrial andbacterial respiratory chain. In addition, we areinterested in the basic biological reactions such asprotein synthesis. Our research have been 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 expression of
mitochondrial proteins)2) mitochondrial fumarate reductase (structure
function relationship, enzyme evolution)3) C. ele gans as a model system of parasitic
nematode (expression of foreign genes or cDNAs,

306

gene knockout)
III. Parasitic protozoa (Plasmodium fal ciparum ,Trypanosoma bruc ei, T rypanosoma cruz i,
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.

2.

3.

4.

5.

Anaerobic NADH-Fumarate Reductase System Is
Predominant in the Respiratory Chain of
Echinococcus m ultilocularis, 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
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
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
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.
180, 6877-6884
Compelling EPR evidence that the alternativeoxidase is a diiron carboxylate protein. Moore, A.
L., Carré, J. E. , Affourtit, C., Albury, M. S.
Crichton, P. G., Kita, K. and Heathcote, P. (2008)
Biochim Biophys. Acta (Bioenergetics) 1777,

327-330
6. 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 25, 1167-1179
7. 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. 18, 607-613
8. 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. 582, 2299-2302
9. Structures of Trypanosoma cr uzi 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) Biochemistry47, 10881-10891
10. Screening of detergents for solubilization,
purification and crystallization of membraneproteins: a case study on succinate:ubiquinone
oxidoreductase from Escherichia coli . Shimizu,
H., Nihei, C., Inaoka, D. K., Mogi, T., Kita, K. andHarada, S. (2008) Acta Crystallographica F64,
858-862

School of Public Health
1. Epidemiology and Health Sciences

308

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

309

public health activities and tasks based on theory of
epidemiology.
We have also several lectures for students in otherschools.

Ohya Y, Sasaki S, Tanaka K, Oda H, Ishiko O,

Research activities

baseline data from the Osaka Maternal and Child

Hirota Y; The Osaka Maternal and Child HealthStudy Group. Ambient formaldehyde levels andallergic disorders among Japanese pregnant women:
Health Study. Ann Epidemiol 2008; 18: 78-84.

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.

5. 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. J
Obstet Gynaecol Res 2008; 34(6): 971-9.
6. Miyake Y, Arakawa M, Tanaka K, Sasaki S, Ohya Y.
Tuberculin reactivity and allergic disorders inschoolchildren, Okinawa, Japan. Clin Exp Allergy
2008; 38: 486-92.
7. Miyake Y, Sasaki S, Arakawa M, Tanaka K,
Murakami K, Ohya Y. Fatty acid intake and asthma
symptoms in Japanese children: The Ryukyus Child
Health Study. Clin Exp Allergy 2008; 38(10):1644-50.
8. Miyake Y, Sasaki S, Tanaka K, Ohya Y, Matsunaga I,

References

Yoshida T, Hirota Y, Oda H. Relationship between
dietary fat and fish intake and the prevalence of

1. Daimon M, Sato H, Sasaki S, Toriyama S, Emi M,

atopic eczema in pregnant Japanese females:

Muramatsu M, Hunt SC, Hopkins PN, Karasawa S,

baseline data from the Osaka Maternal and Child

Wada K, Jimbu Y, Kameda W, Susa S, Oizumi T,

Health Study. Asia Pac J Clin Nutr 2008; 17(4):Fukao A, Kubota I, Kawata S, Kato T. Salt

612-9.

consumption-dependent association of the GNB3

9. Morikawa Y, Miura K, Sasaki S, Yoshita K,

gene polymorphism with type 2 DM. Biochem

Yoneyama S, Sakurai M, Ishizaki M, Kido T, Naruse

Biophys Res Commun 2008; 374(3): 576-80.

Y, Suwazono Y, Higashiyama M, Nakagawa H.
S,

Evaluation of the effects of shift work on nutrient

Rafamantanantsoa HH, Okazaki H, Okubo H,

intake: a cross-sectional study. J Occup Health 2008;

Tanaka S, Yamamoto S, Shirota T, Uchida K,

50: 270-8.

2. Ishikawa-Takata

K,

TabataI,

Sasaki

Murata M. Physical activity level in healthy

10. Morita A, Ohmori Y, Suzuki N, Ide N, Morioka M,

free-living Japanese estimated by doubly labelled

Aiba N, Sasaki S, Miyachi M, Noda M, Watanabe S,

water method and International Physical Activity

for SCOP. Anthropometric and Clinical Findings in

Questionnaire. Eur J Clin Nutr 2008; 62: 885-91.

Obese Japanese:The Saku Control Obesity Program

3. Kim YO, Lee SA, Yoon YM, Kim MK, Sasaki S. A

(SCOP) Anti-Aging Med 2008; 5(1): 13-6.

study testing the usefulness of a dish-based food

11. Murakami K, Miyake Y, Sasaki S, Tanaka K,

frequency questionnaire (DFFQ) developed for

Yokoyama T, Ohya Y, Fukushima W, Kiyohara C,

epidemiological studies in Korea. Br J Nutr 2008;

Hirota Y, the Osaka Maternal and Child Health101(8): 1218-27.

Study Group. Dietary glycemic index and load and

4. Matsunaga I, Miyake Y, Yoshida T, Miyamoto S,

the risk of postpartum depression in Japan: the310

Osaka Maternal and Child Health Study. J Affectincomplete 24-h urine collection. Nutrition 2008;

Disord 2008; 110: 174-9.

24: 16-22.

12. Murakami K, Mizoue T, Sasaki S, Ohta M, Sato M,

19. Murakami K, Sasaki S, Takahashi Y, Uenishi K,

Matsushita Y, Mishima N. Dietary intake of folate,

Watanabe T, Kohri T, Yamasaki M, Watanabe R,

other B vitamins, and ω-3 polyunsaturated fatty

Baba K, Shibata K, Takahashi T, Hayabuchi H, Ohkiacids in relation to depressive symptoms in JapaneseK, Suzuki J. Dietary glycemic index is associatedadults. Nutrition 2008; 24: 140-7.

with decreased premenstrual symptoms in young

13. Murakami K, Sasaki S, Takahashi Y, Okubo H,
Hirota

N,

Notsu

A,

Fukui

M,

Date

Japanese women. Nutrition 2008; 24: 554-61.

C.

20. Murakami K, Sasaki S, Takahashi Y, Uenishi K,

Reproducibility and relative validity of dietary

Yamasaki M, Hayabuchi H, Goda T, Oka J, Baba K,

glycaemic index and load assessed with a self-

Ohki K, Kohri T, Watanabe R, Sugiyama Y.

administered diet-history questionnaire in Japanese

Misreporting of dietary energy, protein, potassium

adults. Br J Nutr 2008; 99: 639-48.

and sodium in relation to body mass index in young

14. Murakami K, Sasaki S, Takahashi Y, Okubo H,

Japanese women. Eur J Clin Nutr 2008; 62: 111-8.

Hirota N, Notsu A, Fukui M, Date C. Comparability

21. Murakami K, Sasaki S, Takahashi Y, Uenishi K,

of weighed dietary records and a self-administered

Yamasaki M, Hayabuchi H, Goda T, Oka J, Baba K,

diet history questionnaire for estimating monetary

Ohki K, Muramatsu K, Sugiyama Y. Total n-3

cost of dietary energy. Environmental Healthpolyunsaturated fatty acid intake is inversely

Insights 2008; 1: 35-43.

associated with serum C-reactive protein in young

15. Murakami K, Sasaki S, Takahashi Y, Uenishi K, theJapanese women. Nutr Res 2008; 28: 309-14.

Japan Dietetic Students' Study for Nutrition and22. Ohsawa M, Itai K, Onoda T, Tanno K, Sasaki S,

Biomarkers Group. Association between dietary

Nakamura M, Ogawa A, Sakata K, Kawamura K,

acid-base load and cardiometabolic risk factors in

Kuribayashi T, Yoshida Y, Okayama A. Dietary

young Japanese women. Br J Nutr 2008; 100:

intake of n-3 polyunsaturated fatty acids is inversely

642-51.

associated with CRP levels, especially among male

16. Murakami K, Sasaki S, Takahashi Y, Uenishi K, thesmokers. Atherosclerosis 2008; 201: 184-91.

Japan Dietetic Students' Study for Nutrition and23. Okubo H, Sasaki S, Murakami K, Kim MK,

Biomarkers Group. Intake of water from foods but

Takahashi Y, Hosoi Y, Itabashi M, the Freshmen in

not beverages, is related to lower body mass index

Dietetic Courses Study II Group. Three major

and waist circumference in humans. Nutrition 2008;

dietary patterns are all independently related to the

24: 925-32.

risk of obesity among 3760 Japanese women aged

17. Murakami K, Sasaki S, Takahashi Y, Uenishi K,

18-20 y. Int J Obes 2008; 32: 541-9.

Watanabe T, Kohri T, Yamasaki M, Watanabe R,

24. Okubo H, Sasaki S, Rafamantanantsoa HH,

Baba K, Shibata K, Takahashi T, Hayabuchi H, Ohki

Ishikawa-Takata K, Okazaki K, Tabata I. Validation

K, Suzuki J. Lower estimates of δ-5 desaturase andof self-reported energy intake by a self-administeredelongase activity are related to adverse profiles fordiet history questionnaire using the doubly labeledseveral metabolic risk factors in young Japanesewater method in 140 Japanese adults Eur J Clin Nutr

women. Nutr Res 2008; 28: 816-24.

2008; 62: 1343-50.

18. Murakami K, Sasaki S, Takahashi Y, Uenishi K,

25. Ota E, Haruna M, Matsuzaki M, Honda Y, Sasaki S,

Watanabe T, Kohri T, Yamasaki M, Watanabe R,

Yeo S, Murashima S. Comparison of body fat mass

Baba K, Shibata K, Takahashi T, Hayabuchi H, Ohkichanges during the third trimester and at one month

K, Suzuki J. Sensitivity and specificity of published

postpartum between lactating and nonlactating

strategies using urinary creatinine to identify

Japanese women. BioScience Trends 2008; 2（5）:311

200-5.
26. Sasaki S. Dietary Reference Intakes (DRIs) in Japan.
Asia Pac J Clin Nutr 2008; 17(S2): 420-44.
27. Sasazuki S, Hayashi T, Nakachi K, Sasaki S,
Tsubono Y, Okubo S, Hayashi M, Tsugane S.
Protective effect of vitamin C on oxidative stress: arandomized controlled trial. Int J Vitam Nutr Res
2008; 78(3): 121-8.
28. Takahashi Y, Murakami K, Morita A, Aiba N, Sasaki
S, for SCOP. Baseline dietary intake in the Saku
Control Obesity Program (SCOP) Anti-Aging Med
2008; 5(1): 6-12.
29. Tanaka K, Sasaki S, Murakami K, Okubo H,
Takahashi Y, Miyake Y. Relationship between soy
and isoflavone intake and peridontal disease: theFreshmen in Dietetic Courses Study II. BMC Public
Health 2008; 8(1): 39.
30. Tanaka K,Miyake Y,Sasaki S,Ohta Y,Matsunaga
I,Yoshida T,Hirota Y,Oda H,the Osaka Maternal andChild Health Study Group. Bevarage consumption
and the prevalence of tooth loss in pregnant
Japanese women : The Osaka Maternal and Child
Health Study. Fukuoka Acta Medica 2008; 99(4):80-9.
31. Yamada M, Murakami K, Sasaki S, Takahashi Y,
Okubo H. Soft drink intake is associated with dietquality even among young Japanese women withlow soft drink intake. J Am Diet Assoc 2008; 108:
1997-2004.

312

Department of Health Economics
and Epidemiology Research
Professor
Hideki Hashimoto, M.D.,D.PH.

Associate Professor
Takashi Fukuda, Ph.D.

Homepage

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

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313

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
















Kuwabara K, Matsuda S, Imanaka Y, Fushimi K,
Hashimoto H, Ishikawa K. The effect of age andprocedure on resource use for patients withcerebrovascular disease. J Health Serv Res Policy.
2008 Jan;13(1):26-32.
Tsunoda A, Yasuda N, Nakao K, Yokoyama N,
Marumori T, Hashimoto H, Kusano M, West K.
Validation of the Japanese version of EORTCQLQ-CR38. Qual Life Res. 2008 Mar;17(2):317-22.
Kuwabara K, Imanaka Y, Matsuda S, Fushimi K,
Hashimoto H, Ishikawa KB, Horiguchi H,
Hayashida K, Fujimori K. Impact of age andprocedure on resource use for patients withischemic heart disease. Health Policy. 2008 Feb;
85(2):196-206.
Kitada S, Akutsu K, Tamori Y, Yoshimuta T,
Hashimoto H, Takeshita S. Usefulness offibrinogen/fibrin degradation product to predict
poor one-year outcome of medically treatedpatients with acute type B aortic dissection. Am J
Cardiol. 2008 May 1;101(9):1341-4.
Ito S, Akutsu K, Tamori Y, Sakamoto S,
Yoshimuta T, Hashimoto H, Takeshita S.
Differences in atherosclerotic profiles between
patients with thoracic and abdominal aortic
aneurysms. Am J Cardiol. 2008 Mar 1;101(5):696-9.
Tomiyama H, Okazaki R, Inoue D, Ochiai H,
Shiina K, Takata Y, Hashimoto H, Yamashina A.
Link between obstructive sleep apnea andincreased bone resorption in men. Osteoporos Int.
2008 Jan 26. [Epub ahead of print]
Fujimoto H, Taguchi J, Imai Y, Ayabe S,
Hashimoto H, Kobayashi H, Ogasawara K,Aizawa
T, Yamakado M, Nagai R, Ohno M. Manganesesuperoxide dismutase polymorphism affects theoxidized
low-density
lipoprotein-induced
apoptosis of macrophages and coronary arterydisease. Eur Heart J. 2008 May;29(10):1267-74.
Shimizu F, Fujino K, Ito YM, Fukuda T, Kawachi
Y, Minowada S, Fujime M, Ohashi Y. Factors
Associated with Variation in Utility Scores among

314





Patients with Prostate Cancer. Value Health 2008;
11(7): 1190-1193.
Kinoshita H, Kobayashi Y, Fukuda T.
Duplicative medications in patients who visit
multiple medical institutions among the insured ofa corporate health insurance society in Japan.
Health Policy 2008; 85(1):114-23.
Shiroiwa T, Fukuda T, Shimozuma K, Ohashi Y,
Tsutani K. The model-based cost-effectivenessanalysis of 1-year adjuvant trastuzumab treatment:
based on 2-year follow-up HERA trial data. Breast
Cancer Research and Treatment 2008; 109:559-566.

315

Department of HealthCommunication
Professor
Takahiro Kiuchi, M.D., Ph.D.

Instructor
Hiroshi Nishiuchi, M.S.

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 andassociate professors.
Whereas health communication is a major disciplinein the USA and there are many such graduate
programs, our department offers one of only two
health communication programs in Japan. However,
the importance of the health communication disciplineis gradually 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 healthprofessionals as well as researchers. We strive to
make the most of our professional activities andexperience at UMIN Center. We provide lectures andpractical 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.”

316

Research Activities
The two main characteristics of research studies
conducted through the Department of HealthCommunication, which distinguish them from studies
at other medical informatics programs, are thefollowing:(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, nothealthcare 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 focused on information systems for medical
science, such as medical literature databases, dataregistries for clinical studies, 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
an important role in healthcare, its comprehensive
usefulness, including cost-effectiveness, has beenrarely evaluated. We conducted a literature review in2003 and concluded that there were few costeffectiveness analyses for telemedicine programs eventhough many telemedicine programs have been
implemented throughout many developed countries,
including the USA and Japan. Based on the review, wehave done a cost-effectiveness analysis for
information technologies.
(3) Edutainment Research
To disseminate clinical knowledge and information tolaypersons, it is important to consider standards suchas “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 anddecisions in order to achieve optimal outcomes, a
process which is termed “management.” However,scientific research and evaluations related to patient
safety, quality improvement and medical management
have not been well established in Japan. We focus on
the Theory of Constraint (TOC) as a tool for medical
management from a perspective of information
utilization, and conducted research on medical error
prevention and quality improvement.
(5) Research Related to UMIN Activities
Most systems developed at the UMIN Center havebeen subjects for research. In particular, we publishedand reported systems utilizing advanced technologies
and having 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,such as the Clinical Data Interchange Standards

317

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
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, Uda K, Ohta S, Kiuchi T, Fukui T. Impactof miscommunication in medical dispute cases inJapan. International Journal

School of Public Health
2. Behavioral Health Sciences

319

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, 31 visiting researchers and 10 graduate
students (including two international students from
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

320

to conduct social surveys using questionnaire/interview method. The students are divided into
several groups, and each group is given asurvey area. They will go through all theprocesses of a health sociological survey, fromplanning the survey to writing a report based on
the survey. They have the opportunity to reportand discuss their surveys with each other.
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 a largescale cohort of the residents in Nagano Prefectureand examine variables influencing the life
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. Yoshino MA, Takahashi M, Kai I:
Trick of probabilities ―Pregnant women'sinterpretation of maternal serum screening results inJapan
Nurs. Health Sci. 10(1):23-30, 2008
2. Watanabe Y, Takahashi M, Kai I:
Japanese cancer patient participation in andsatisfaction with treatment-related decision-making―A qualitative study
BMC Public Health 8:77 (10 pages), 2008
3. Chalise HN, Saito T, Kai I:
Functional disability in activities of daily living andinstrumental activities of daily living among
Nepalese Newal elderly

321

Public Health 122:394-396, 2008
4. Aita K, Miyata H, Takahashi M, et al.:Japanese physicians' practice of withholding andwithdrawing mechanical ventilation and artificial
nutrition and hydration from older adults with very
severe strokeArch. Gerontol. Geriatr. 46(3):263-272, 2008
5. Akabayashi A, Slingsby BT, Nagao N, et al.:A five-year follow-up national study of ethics
committees in medical organizations in JapanHEC Forum 20(1):49-60, 2008
6. Okubo S, Takahashi M, Kai I:
How Japanese parents of deaf children arrive atdecisions regarding pediatric cochlear implantation
surgery ―A qualitative study
Soc. Sci. & Med. 66(12):2436-2447, 2008
7. Yokokawa Y, Hongo M, Urayama H, et al.:Effects of low-intensity resistance exercise with
vascular occlusion on physical function in healthyelderly people
BioScience Trends 2(3):117-123, 2008
8. Lee S, Saito T, Takahashi M, et al.:Volunteer participation among older adults in Japan―An analysis of the determinants of participation
and reasons for non-participation
Arch. Gerontol. Geriatr. 47(2):173-187, 2008
9. Takahashi M, Ohno S, Inoue H, et al.:
Impact of breast cancer diagnosis and treatment on
women's sexuality ―A survey of Japanese patients
Psycho-Oncology 17(9):901-907, 2008
10. Yoshie S, Saito T, Takahashi M, et al.:Effects of work environment on care managers' roleambiguity ―An exploratory study in Japan
Care Management J. 9(3):113-121, 2008
11. Akizuki Y, Kai I:
Infertile Japanese women’s perception of positive
and negative social interactions within their social
network
Hum. Reprod. 23(12):2737-2743, 2008
12. Gautam R, Saito T, Kai I:
Correlates of life satisfaction among older Nepalese
adults living with a son
BioScience Trends 2(5):187-192, 2008

School of Public Health
3. Health Services Sciences

323

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Homepage:

http://home.cie.m.u-tokyo.ac.jp/

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.

324

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, computer science,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. Katsumura Y, Yasunaga H, Imamura T, Ohe K,
Oyama H. Relationship between risk information
on total colonoscopy and patient preferences forcolorectal cancer screening options: Analysis
using the Analytic Hierarchy Process. BMC
Health Serv Res. 2008 May 21;8(1):106.

Endowed Department

326

Department ofPharmacoepidemiology
Professor
Kiyoshi Kubota M.D.,Ph.D.

Associate
Hiroshi Nishimura, M.D. Ph.D., Tsugumichi Sato, Ph.D.

Homepage

http://square.umin.ac.jp/pe/

Introduction and Organization
The Department of Pharmacoepidemiology was set up
in 1993 as a temporary department endowed by apharmaceutical company (Rhone-Poulenc Rorer) witha time limit of 3-year period. The department has beenfurther renewed five times in 1996, 1999, 2002, 2005
and 2008 as a department endowed by 15-20
pharmaceutical companies located in Japan. Currently,
the Department of Pharmacoepidemiology has 1
professor, 2 associates and some assistants. The
department also has a dozen of part-time workers.

Teaching activities
As in other endowment departments in the university,
the department has no formal course of lectures towhich it is responsible. However, the staff in thedepartment has often made the lectures on
pharmacoepidemiology and relevant issues. Suchspecial lectures in the University of Tokyo include:(1)those in a lecture course of “pharmacology” formedical undergraduates and (2)those in a lecture
course of “pharmacology and toxicology”
From 2006, the department has played the major
roles
inorganizing
andoperating“pharmacoepidemiology seminars” sponsored by theUnion of Japanese Scientists and Engineers (JUSE)(http://www.juse.or.jp/e/education_training/02_conventions.html). In the seminar, participants who comefrom drug companies, academia and regulatory bodylearn various aspects of pharmacoepidemiology
including the basic concepts of pharmacovigilance,
signal generation, study design, analysis of data andrelated topics including pharmacoeconomics. The
course consists of 2 days per month for 6-months..

Research activities
To conduct epidemiological researches, thedepartment has close association with the nonprofitable organization (NPO) Drug Safety Research
Unit Japan (DSRU Japan) which was established in
2001. The NPO is important to provide various
functions needed to conduct large scale studies.
This NPO had a key function in many studies
which the department conducted. For example, theNPO worked as the study office of pilot studies of
Prescription-Event Monitoring in Japan (J-PEM) inlate 1990s and also played the role of the study officeof case-control study for the association between
Non-steroidal inflammatory drugs and uppergastrointestinal bleeding of which the results were
published in Eur J Clin Pharmacol in 2006.
One of the current main projects done by thedepartment with the co-operation of the above NPO isJapan Statin Study (JSS) sponsored by the Public
Health Research Foundation and directly conductedby Japanese Society for Pharmacoepidemiology(JSPE) and Sicentific committee of Japanese Societyof Hospital Pharmacies (JSHP). In JSS, currently
more than 60 hospitals participate and identify the327

study subjects using electronic prescription records inthe hospital. In JSS, the design of case-cohort study
is used and adverse muscle events (increase in CPK
and rhabdomyolysis), hepatic events (increase in AST
and ALT) and renal events (hematuria, proteinuria andincrease in serum creatinine) are compared between
the users of 6 kinds of statins currently available inJapan(pravastatin,
simvastatin,
fluvastatin,
atorvastatin, pitavastatin and rosuvastatin).
The
design of case-cohort study is cost-effective suitable
when studying multiple events and this study could be
one of the prototypes for the future post-marketingcomparative observational studies sponsored by drug
companies. The above NPO plays the role as thestudy office of JSS as well.
Another study is on “Incidence of interstitial lungdisease,myelotoxicity
associatedwithchemotherapeutic agents and factors related tosurvival in patients with malignant mesothelioma: aretrospective cohort study in west part of Japan”. In
this study, more than 300 patients of malignant
mesothelioma were identified and the incidence ofinterstitial lung disease, one of the major adverse
events associated with anti-neoplastic treatments inJapanese population, incidence of other major adverse
events including those due to myelotoxicity as well as
survival of patients with mesothelioma are studied.
The study will provide the baseline incidence of ILD
in patients with mesothelioma, which will give an
important information in evaluating the adverse events
associated with the future study of patients withmalignant mesothelioma.
The data-mining methodology for spontaneous
reports has been adopted and routinely used in various
administrative agencies in the Western countries andWorld
HealthOrganization.
Japaneseadministrative agency is also currently trying to
introduce this new methodology. Currently, in thedepartment an efficient new methodology is being
studied where the data of Drug Use Investigations(DUIs) are used. The DUIs are cohort studies of
thousands of patients using the new product without acomparator group conducted for about 30 years by alarge number of drug companies as a legal duty for
years.
In the Western countries as well as in Korea andTaiwan, pharmacoepidemiology studies are normallyconducted using large databases including claims
database. In Japan the construction and use of
database of monthly claims (called as “Rezepts”) aretaking place. To give an efficient way of the use ofsuch claims database, a similar but smaller claims
database currently available and provided by Japan
Medical Data Center (JMDC) are analyzed. The
JMDC data are used to estimate the relationshipbetween anti-hypertensive drugs and the incidence ofdiabetes mellitus.
In the recent years, as the field associated withpharmacoepidemiology,the“therapeuticrisk
management” including risk minimization actionplans (often abbreviated as RiskMAP) has beenrecognized as an important issue. A typical drugclass requiring RiskMAP is teratogenic drugs.
Thalidomide has been imported by individual doctors
in Japan for the treatment of multiple myeloma sincearound 2000. Thalidomide is one such teratogenic
drug requiring RiskMAP.
The department hasdeveloped“safety
management
systemforunapproved drugs” abbreviated as SMUD as the study
supported by the Ministry of Health, Labour andWelfare between 2005 to 2008 with the support from
UMIN center located in the Tokyo University Hospital.
The SMUD will be operated sometime in 2009 by the
MHLW which will assign some body to conduct
SMUD under the service contract with the MHLW.
The NPO DSRU Japan will be one of the candidatesof such bodies. W

References
1. Kamijima Y, Ooba N, Yagame M, Samizo K,
Shimodozono Y, Kageyama S, Horiguchi S, Nagai
R, Kusunoki T, Kubota K : Hypertension
management in diabetic patients: prescribing
trends from 1999 to 2005 in three Japanese
university hospitals. Pharmacoepidemiol Drug Saf
2008 ; 17 : 904-911.
2. Hayashi T. Kawashima S. Itoh H. Yamada N.
Sone H. Watanabe H. Hattori Y. Ohrui T.
Yoshizumi M. Yokote K. Kubota K. Nomura H.
Umegaki H. Iguchi A. Japan CDM group. :Importance of lipid levels in elderly diabetic
individuals: baseline characteristics and 1-year
survey of cardiovascular events. Circulation

328

Journal. 2008 ; 72 : 218-25.
3. Akira Wakana, Kiyoshi Kubota :AConsideration on Sample Size Determination for
Stratified
Case-Cohort
Studies.
Pharmacoepidemiol Drug Saf 2008 ; 17: S108.
4. Shuko Nojiri, Tsugumichi Sato, Takuhiro
Yamaguchi, Kennichi Gemba, Keisuke Aoe,
Katsuya Kato, Takumi Kishimoto, Kiyoshi
Kubota : Chemotherapeutic Agents Used in
Patients with Malignant Mesothelioma and Their
Myelotoxicity: A Retrospective Survey in theWest Part of Japan. Pharmacoepidemiol DrugSaf 2008 ; 17: S154.
5. Hikaru Watanabe, Yukari Kamijima, Tsugumichi
Sato, David W Kaufman, Kiyoshi Kubota :Ex-Drinking May Add the Risk of Upper
Gastrointestinal Bleeding (UGIB) in Patients
Prescribed
NonSteroidal
Anti-Inflammatory
Drugs (NSAIDs) Pharmacoepidemiol Drug Saf
2008 ; 17: S219

329

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.
Itrequired 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.

330

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 as a phytoandrogen.

Endocrinological activities of anti-aging herbs areinvestigated using various molecular cell biologicalapproaches including biochemistry, immunochemistry,
molecular biology, molecular genetics such as genetargeting and transgenic mouse approaches, molecularbiophysics.
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 on androgen receptors.
Our studies arefocused on endocrinological activities of anti-aging
herbs which are through their genomic or nongenomic actions of steroid hormones..
The spinocerebellar ataxias (SCAs) are clinically andgeneticallyaheterogeneous
groupofneurodegenerative disorders. At present, we have noeffective therapeutic tools. 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.
It has been reported that some herbal medicines may
be effective for acute episodes of chronic nonspecific
low back pain. Spondylolisthesis is one of thecauses of low back or neck pain. Although surgicaltreatment is often performed for symptomatic
spondylolisthesis, we have succeeded in herbal
therapy for degenerative spondylolisthesis.
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 been

331

obtained in both disorders. Extensive studies are under
way to elucidate the mechanisms by which systems
therapy exerts the therapeutic activities.

References
1.

2.

3.

4.

5.

6.

7.

8.

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 involvementof androgen receptor. Biochem Biophys Res
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
resistant asthma. International Medical Journal(IMJ).2007; 14: 211-4.
Tsuji K., Koizumi H., and Okabe T. Successfultreatment of spondylolisthesis with medicinal
herbs. Geriatr. Gerontol. Int.8:126-129, 2008.
Yu, J., Eto. M., Kozaki K., Akishita M., Okabe,T.,and Ouchi Y. Raloxifene analogue LY 117018
suppresses oxidative stress - induced endothelial
cell apoptosis through activating ERK1/2
signaling pathway. Eur. J. Pharmacol. 589:32-36,
2008.
Yu , J., Eto, M., Akishita , M., Okabe,T. andOuchi, Y. A selective estrogen receptor modulator
inhibits TNF-α-induced apoptosis by activating
ERK1/2 signaling pathway in vascularendothelial cells. Vascular Pharmacol. 51:21-28,
2009.

332

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

333

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334

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.

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. Hishikawa D, Shindou H, Kobayashi S,
Nakanishi H, Taguchi R, Shimizu T., Discovery
of a lysophospholipid acyltransferase family
essential for membrane asymmetry and diversity.
Proc Natl Acad Sci USA.; 105(8):2830-5,2008
2. Ogiso H, Suzuki T, Taguchi R., Development of areverse-phase liquid chromatography electrosprayionization mass spectrometry method forlipidomics, improving detection. Anal Biochem. ;375(1):124-31. 2008
3. Okuno T, Iizuka Y, Okazaki H, Yokomizo T,
TaguchiR,
ShimizuT.
12(S)-Hydroxyheptadeca-5Z, 8E, 10E-trienoic
acid is a natural ligand for leukotriene B4
receptor 2. J. Exp. Med. 205(4):759-66. 2008

4. Ogiso H, Taguchi R. Reverse-Phase LC/MS
Method for Polyphosphoinositide Analyses:
Changes in Molecular Species Levels during
Epidermal Growth Factor-Activation in A431
Cells. Anal. Chem.;80(23):9226-32. 2008
5. Nakanishi H, Iida Y, Shimizu T, Taguchi R.
Analysis of oxidized phosphatidylcholines asmarkers for oxidative stress, using multiple
reaction monitoring with theoretically expanded
data
sets
with
reversed-phaseliquidchromatography/tandem mass spectrometry. J.
Chromatog. B, 877(13):1366-74. 2008
6. Sato H, Kato R, Isogai Y, Saka GI, Ohtsuki M,
Taketomi Y, Yamamoto K, Tsutsumi K, Yamada J,
Masuda S, Ishikawa Y, Ishii T, Kobayashi T,
Ikeda K, Taguchi R, Hatakeyama S, Hara S, Kudo
I, Itabe H, Murakami M. Analyses of group III
secreted phospholipase A2 transgenic mice
reveals potential participation of this enzyme inplasma lipoprotein modification, macrophage
foam cell formation, and atherosclerosis. J Biol
Chem. 283(48):33483-97 2008
7. Ikeda K, Shimizu T, Taguchi R Targeted analysis
of ganglioside and sulfatide molecular species by
LC/ESI-MS/MS with theoretically expanded
multiple reaction monitoring. J Li pid Re s.
49(12):2678-89.2008
8. Hayasaka T, Goto-Inoue N, Sugiura Y, Zaima N,
Nakanishi H, Ohishi K, Nakanishi S, Naito T,
Taguchi R, Setou M.
Matrix-assisted laser
desorption/ionization quadrupole ion trap
time-of-flight (MALDI-QIT-TOF)-based imaging
mass spectrometry reveals a layered distributionof phospholipid molecular species in the mouse
retina..Rapid Commun MassSpectrom.
22(21):3415-26. 2008
9. Oka T, Itoi T, Terada N, Nakanishi H, Taguchi R,
Hamaoka K. Change in the membranous lipid
composition accelerates lipid peroxidation inyoung rat hearts subjected to 2 weeks of hypoxia
followed by hyperoxia. Ci rc J. 72(8):1359-66.
2008
10. Tanaka K, Fukuda R, Ono Y, Eguchi H,
Nagasawa S, Nakatani Y, Watanabe H, Nakanishi
H, Taguchi R, Ohta A.Incorporation andremodeling of extracellular phosphatidylcholine
with short acyl residues in Saccharomyces335

cerevisiae. Biochim Biophys Acta. 1781(8):391-9.
2008
11. Tsumoto H, Ra M, Samejima K, Taguchi R,
Kohda K. Chemical derivatization of peptides
containing phosphorylated serine/threonine for
efficient ionization and quantification in
matrix-assisted laser desorption/ionization timeof-flight mass spectrometry. Rapid Commun
Mass Spectrom. 22(7):965-72.2008

336

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 114 participants at the clinicalauditorium on every Tuesdays (6 series) from
September 2 to October 14 in 2008, 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.

337

In addition, the public lectures for the trend andfuture of computerization in clinical trials was held at
the Nogizaka school in the international university ofhealth and welfare on Novenber 27, 2008.

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 was implemented in March, 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.

2.

3.

4.

5.

6.

7.

Fujita M, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R
TheJCAD Study
Investigators Pleiotropic effects of statins on
cardiovascular events in the Japanese Coronary
Artery Disease study International Journal of
Cardiology 2008, 129; 294-296
Nagai R, Izumi T, Kurabayashi M, Daida H, Tojo
T, Hasegawa A, Miyauchi K, Hayashi D, Kohro T,
Okada Y, Yamazaki T on behalf of the JCADII
Investigators. Rationale and Design of a Study to
Examine Lower Targets for Low-Density
Lipoprotein-Cholesterol and Blood Pressure inCoronary Artery Disease Patients -The JapaneseCoronary Artery Disease Study II (JCADII)- Circ
J 2008: 72(4); 515-520
Wang G, Watanabe M, Imai Y, Hara K, Manabe I,
Maemura K, Horikoshi M, Kohro T, Amiya E,
Sugiyama T, Fujita T, Kadowaki T, Yamazaki T,
Nagai R Genetic variations of Mrf-2/Arid5b
confer risk of coronary atherosclerosis in theJapanese population International Heart J 2008:
49(3); 313-327
Inoue Y, Usui M, Ohashi Y, Shiota H, Yamazaki
T Preoperative disinfection of the conjunctival
Sac with antibiotics and iodine compounds: A
prospective randomized multicenter study Jpn J
Opthalmol 2008: 52; 151-161
Monzen K, Ito Y, Naito A, Kasai H, Hiroi Y,
Hayashi D, Shiojima I, Yamazaki T, Miyazono K,
Asashima M, Nagai R, Komuro I A crucial roleof a high mobility group protein HMGA2 in
cardiogenesis
Nature Cell Biol 2008: 10;
567-574
Kohro T, Hayashi D, Okada Y, Yamazaki T,
Nagai R
Demographics and changes inmedical/interventional treatment of coronary
artery disease patients over a 3.5-year period inJapan –The Japanese Coronary Artery Disease
Study: Trend ExaminationCirculation J
2008: 72; 1397-1402
Kurabayashi M, Yamazaki T and the SUBARU
Study Group Superior benefit of aggressive

338

8.

lipid-lowering therapy for high risk patientsusing statins: the SUBARU StudyJAtherosclerosis and Thrombosis 2008; 15: 314323
George Ochieng Otieno, Toyama Hinako,
Asonuma Motohiro, Koide Daisuke, Naitoh
Keiko: Measuring effectiveness of electronic
medical records systems: Towards building acomposite index for benchmarking hospitals.
International Journal of Medical Informatics
2008; 77: 657-69

339

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

340

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. Suzuki T, Distante A, Zizza A, Trimarchi S, Villani
M, Salerno Uriarte JA, de Luca Tupputi Schinosa L,
Renzulli A, Sabino F, Nowak R, Birkhahn R,
Hollander JE, Counselman F, Bossone E, Eagle K;
International Registry of Acute Aortic Dissection
Substudy on Biomarkers (IRAD-Bio) Investigators.
Preliminary experience with the smooth muscle
troponin-like protein, calponin, as a novel biomarker
for diagnosing acute aortic dissection. Eur Heart J
29:1439-1445, 2008
2. Suzuki T, Nagai R. Molecular markers for
cardiovascular disease: cardiovascular biomarkers toproteomic discovery. Nat Clin Pract Cardiovasc
Med 5:295, 2008
3. Kada N, Suzuki T, Aizawa K, Munemasa Y,
Matsumura T, Sawaki D, Nagai R. Acyclic retinoid
inhibits functional interaction of transcription factors
Krüppel-like factor 5 and retinoic acidreceptor-alpha. FEBS Lett 582:1755-1760, 2008
4. Munemasa Y, Suzuki T, Aizawa K, Miyamoto S,
Imai Y, Matsumura T, Horikoshi M, Nagai R.
Promoter region-specific histone incorporation by
the novel histone chaperone ANP32B andDNA-binding factor KLF5. Mol Cell Biol
28:1171-1181, 2008
Academic Papers in Japanese
1. Sawaki D, Suzuki T. Aortic dissection and aneurysm.
Naika 102(6):1143-1150, 2008
2. Sawaki D, Suzuki T. Etiology of aortic diseases,
up-to-date. Heart View 12(11):25-29, 2008
3. Aizawa K, Suzuki T. Ptoteomics analysis of the
cardiovascular pathologies. Junkanki Senmoni.
16(1):43-49, 2008
4. Aizawa K, Suzuki T. New methods for oxidized low
density lipoprotein. Igaku no ayumi. 224(5):399-402,
2008
Books
1. Aizawa K, Suzuki T. DNA damage and repair.
Annual Review 2008 Junkanki (editorial
supervisors, Yamaguchi T, Takamoto S, Nakazawa
M, Komuro I), Chugai-Igakusha, pp23-27, 2008
Reviews
1.
Suzuki T. Hot issue on hypertension treatment~
Evaluation of ON-TARGET from the aspect of341

cardiovascular events~. Proceedings of Niihama
Aichi medical association. 614 ： 11940-11942,
2008
International Conferences
1. Suzuki T, Aizawa K, Munemasa Y, Matsumura T,
Sawaki D, Kada N, Nagai R: Epigenetic control ofgene transcription at the chromatin level with afocus on Krüppel-like factors. 15th International
Vascular Biology Meeting (June 1-5, 2008, Sydney,
Australia)
2. Aizawa K, Suzuki T, Zhan H, Kada N, Sawaki D,
Matsumura T, Nagai R: Proteome analysis of anovel Pathogenic pathway of DNA damage response
as mediated by KLF5 and its transcriptional
complexes
inthecardiovasculature.
15th
International Vascular Biology Meeting (June 1-5,
2008, Sydney, Australia)
3. Sawaki D, Suzuki T, Aizawa K, Matsumura T, Kada
N, Munemasa Y, Nagai R: Krüppel-like Factor 5
Promotes Vascular Remodeling by Stage-specificContribution: Inhibition of Smooth Muscle Cell
Apoptosis and Stimulation of Cell Growth. 15th
International Vascular Biology Meeting (June 1-5,
2008, Sydney, Australia)
4. Shiran H, Nienaber C, Isselbacher E, Tsai T,
Meinhardt G, Cooper JV, Grzybowski M, Pyeritz R,
Braverman A, Suzuki T, Eagle K, Froehlich JB:
Effect of low suspicion presentation of type A acuteaortic dissection on care and outcomes: Data fromthe international registry of acute aortic dissection(IRAD). The American College of Cardiology 57th
Annual Scientific Session (March 29-April 1, 2008,
Chicago USA)
National Conferences
1. Munemasa Y, Suzuki T, Aizawa K, Matsumura T,
Sawaki S, MizunoY, Kada N, Nagai R: Promoter
region- specific histone incorporation by histone
chaperone p32, TAF-I and DNA-binding factor
KLF5. 31st Annual Meeting of the Molecular
Biology Society of Japan and the 81st Annual
Meeting of the Japanese Biochemical Society(December 9-12, 2008, Kobe)
2. Tabuse Y, Miyazaki K, Teramoto R, Fujita M,
Hattori W, Kawaura H, Munemasa Y, Matsumura T,
Aizawa K, Nagai R, Suzuki T: Detection of posttranslationally modified proteins by electrofocusing
pattern chip. 6th annual meeting of HUPO (July29-30, 2008, Osaka)
3. Miyazaki K, Tabuse Y, Teramoto R, Fujita M,
Hattori W, Kawaura H, Munemasa Y, Matsumura T,
Aizawa K, Nagai R, Suzuki T: Rapid profiling of
immunoprecipitated products. 6th annual meeting of
HUPO (July 29-30, 2008, Osaka)
4. Aizawa K, Suzuki T, Hong A, Kada N, Sawaki D,
Matsumura T, Nagai R: A novel pathogenic pathwayof DNA damage response as mediated by KLF5 anditstranscriptional
complexesinthecardiovasculature. The 72nd Annual Scientific
Meeting of the Japanese Circulation Society(March 28-30, 2008, Fukuoka)
5. Kada N, Suzuki T, Aizawa K, Matsumura T,
Takeda N, Sawaki D, Nagai R: Acyclic Retinoid
Inhibits Vascular Remodeling by Regulating
KLF5. The 72nd Annual Scientific Meeting of theJapanese Circulation Society (March 28-30, 2008,
Fukuoka)
6. Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Kada N, Munemasa Y, Friedman SL, Nagai R:
Krüppel-like Factor 6 is a Key Transcription
Factor that Controls Cardiac Fibrosis. The 72nd
Annual Scientific Meeting of the Japanese
Circulation Society (March 28-30, 2008, Fukuoka)
Lectures
1. Suzuki T: Novel biomarkers in cardiovasculardiseases-Focused on oxidized LDL-. Luncheon
seminar of the 55th National Congress ofJapanese Society of Laboratory Medicine(November 29, 2008, Nagoya)
2. Suzuki T: Reconsideration of RAS inhibitors on
cardio-renal diseases. Luncheon seminar of the
38th Eastern Regional Meeting of the JapaneseSociety of Nephrology (October 11, 2008, Tokyo)
3. Suzuki T: Molecular markers for cardiovascularbiomarkers to proteomic discovery. Meet The
Specialist 2008 (August 22, 2008, The Universityof Tokyo Hospital, Tokyo)
4. Suzuki T: Proteomic analysis of cardiovascularpathologies-From chromatin remodeling tobiomarkers-. A research conference of thedepartment of nephrology, the University ofTokyo Hospital. (July 15, 2008, The University ofTokyo Hospital, Tokyo)

342

Department of Advanced Skin Care(Miss Paris)
Visiting Professor
Junko Sugama, R.N., Ph.D.

Project Research Associate
Tomoko Akase, R.N., RPh., Ph.D.

Homepage http:// www.advskincare.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Advanced Skin Care (Miss Paris)is the newest department of the Graduate School of
Medicine, established in April 2008. Current member
includes 1 visiting professor and 1 project research
associate. The supportive department is the
Department of Gerontological Nursing/Wound CareManagement.
With a rapid extension of the average life
expectancy in Japan, many health related problems
have occurred. As a consequence of aging, the skinundergoes a number of pathological changes, which
lowers the protective mechanism of skin against theadverse effects of mechanical stresses. Eventually,
these lead to pressure ulcers, diabetic ulcers or otherchronic wounds. Therefore, our goal is to establish“advanced skin care” based on the wellness promotion
sciences.
On 29th June, 2008, kick-off meeting of thedepartment of advanced skin care was held.
Moreover, the special lecture entitled “Regeneration
system of the hair follicle stem cell” presented by
Hideo Oshima, MD, PhD, director of plastic surgery,
National Hospital Organization Kumamoto Medical
Center, was held on 14 November.

Teaching activities
We cooperated in the research relevant to theadvanced skin care, which was conducted by thegraduate students of the Department of GerontologicalNursing/Wound Care Management.

Research activities
We focus on the changes of the skin with the aging
and its related factors. Based on the information ofboth healthy people and patients with skin injuries, we
try to develop the objective evaluation method of thedegree of skin health status. Our study method isranged from cell biological approaches to clinicalepidemiologic approaches. We also make an effort toestablish the new translational research in nursing
science.
In 2008, the two research projects were started;
1) Prevention and management of the metabolic
syndrome disease2) Evaluation for the elderly skin and the peristomal
skin.

References
1. Shimada T, Kudo T, Akase T, Aburada M.
Preventive effects of Bofutsushosan on obesityand various metabolic disorders. Biol Pharm Bull.
2008;31(7):1362-1367.
2. Konishi C, Sugama J, Sanada H, Okuwa M,
Konya C, Nishizawa T. A prospective study of
blanchable erythema among university hospitalpatients. Int Wound J. 2008;5(3):470-475.
3. Nishizawa T, Sugama J, Sanada H. Changes in343

nurses'competency
forpressure
ulcer
management after the introduction of a pressure
ulcer management program. J So Nurs Pr act.
2008;20(1):24-33.
4. Futamura M, Sugama J, Okuwa M, Sanada H,
Tabata K. Evalution of comfort in bedridden older
adults using an air-cell mattress with anautomated turning function measurement of parasympathetic activity during night sleep. J
Gerontol Nurs. 2008;34(12):20-26.
5. Sari Y, Nakagami G, Kinoshita A, Huang L, Ueda
K, Iizaka S, Sanada H, Sugama J. Changes inserum and exudate creatine phosphokinase
concentrations as an indicator of deep tissue
injury: a pilot study. Int Wound J. 2008;5(5):674680.

344

Department of Chronic Kidney
Disease (CKD)
Associate Professor
Miki Nagase, M.D., Ph.D.

Associate
Shigetaka Yoshida, M.D., Ph.D.

Homepage
Introduction and Organization

Research activities

The Department of Chronic Kidney Disease (CKD)
was established in January 2009 by a donation fromJapan Boehringer Ingelheim Co., Ltd., in cooperation
with the Department of Nephrology and
Endocrinology (Prof. Toshiro Fujita) and Department
of Urology (Prof. Yukio Homma).
Chronic kidney disease (CKD) is a disease entity
advocated by National Kidney Foundation in 2002.
CKD is regarded as one of the highest priority medical
issues at present. CKD patients, if untreated, willdevelop end-stage renal disease requiring artificial
dialysis. They are also high risk group of
cardiovascular disease (CVD).
The main research objects of this department are to
elucidate the molecular mechanisms by whichmetabolic syndrome increases the risk of CKD or bywhich CKD promotes CVD, to identify novel
therapeutic target molecules, and to develop new
diagnostic and treatment strategies, and to constructexperimental evidence that can be applied to the CKD
treatment.
We cooperate with Department of Nephrology and
Endocrinology, Department of Urology, and otherresearch groups having abundant clinical resources
and analytical strategies, and perform basic research
as well as translational and clinical researches. We
hope that our department will become the center of
excellence for CKD research.

In our department, we investigate the roles ofaldosterone/mineralocorticoid receptor (MR) system,
salt, adipokines, oxidative stress, inflammation caused
by immune cells in the processes linking metabolic
syndrome to CKD, especially focusing on glomerular
podocyte injury, a major cause of proteinuria.
Aldosterone has recently been recognized as animportant mediator of target organ damage, in
addition to its role in salt and blood pressure
homeostasis. Recent epidemic of obesity and high salt
diet in our modern society are postulated to cause
inappropriate activation of the aldosterone/mineralocorticoid receptor (MR) system, leading tocardiovascular and renal disease. We demonstrated
that metabolic syndrome rat is susceptible to renal
injury, especially when fed a high salt diet, due toinappropriate aldosterone/MR activation. Adipocytederived aldosterone-releasing factors (ARF) may
account for aldosterone excess in this model. We
further identified small GTPase Rac1 as a novel
activator of MR, and reported that the ligandindependent MR activation by Rac1 contributes to thenephropathy of several CKD models.
We have several ongoing projects, such as basic
research focusing on “cross-talk between Rac1 andMR”, and translational research to verify the clinicalsignificance of Rac1/MR activation and to develop
epoch-making diagnostic and therapeutic strategies.

345(1) Analysis of Rac1-MR interaction and target organ
injury, using experimental models of metabolic
syndrome (KKAy, SHR/cp, diet- induced obesity,etc.). Search for stimuli causing Rac1 activation.
(2) Generationofcelltype-specific(ex.
podocyte-specific) Rac1 Tg / KO mice.
(3) Identification of ARF, based on the comparative
analysis of fat cell conditioned media from obese
SHR and non-obese SHR.
(4) Elucidation of other mechanisms of MR
activation.
(5) Development of drugs (reagents to inhibit Rac1,
ARF, and newly-identified target molecules),diagnostic tools (indicators of MR activation in thetarget organ), specification of clinical conditions
in which Rac1-MR overactivation is involved.

Teaching activities
The education of post-graduate students is also an
important task of our department. Our staffs help thestudents to plan and perform basic experiments and/or
clinical studies, to make oral or poster presentation at
Japanese or international society, and to publish
scientific article. We have educational programs
including journal club in order to polish theiracademic skills.

References
1. Shibata S, Nagase M, Yoshida S, Kawarazaki W,
Kurihara H, Tanaka H, Miyoshi J, Takai Y, Fujita
T. Modification of mineralocorticoid receptor
function by Rac1 GTPase: implication inproteinuric kidney disease. Nat Med. 2008 Dec;
14(12):1370-6.
2. Matsui H, Ando K, Kawarazaki H, Nagae A,
Fujita M, Shimosawa T, Nagase M, Fujita T. Salt
excesscausesleft
ventricular
diastolicdysfunction in rats with metabolic disorder.
Hypertension. 2008 Aug;52(2):287-94.
3. Yoshida S, Nagase M, Shibata S, Fujita T.
Podocyte injury induced by albumin overload invivo and in vitro: involvement of TGF-beta andp38 MAPK. Nephron Exp Nephrol. 2008;108(3):e57-68.
4. Nagase M, Fujita T. Aldosterone and glomerular

podocyte injury. Clin Exp Nephrol. 2008 Aug;12(4):233-42.
5. Nagase T, Nagase M, Machida M, Fujita T.
Hedgehog signalling in vascular development.
Angiogenesis. 2008;11(1):71-7.

346

Department of
Immunotherapeutics (Medinet)
Project Associate Professor
Kazuhiro Kakimi, M.D., Ph.D.

Project Research Associate
Yukihiro Yoshida, M.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 v itro 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

347back 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 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 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 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  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 T 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348

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. Sawanobori Y, Ueha S, Kurachi M, Shimaoka T,
Talmadge JE, Abe J, Shono Y, Kitabatake M, Kakimi
K, Mukaida N, Matsushima K.Chemokine-mediatedrapid turnover of myeloid-derived suppressor cells intumor-bearing mice.Blood. 2008

June 15; 111(12):5457-5466.
2. Kimura K, Nagaki M, Kakimi K, Saio M, Saeki T,
Okuda Y, Kuwata K, Moriwaki H.Critical role ofCD44 in hepatotoxin-mediated liver injury.J Hepatol.
2008 Jun;48(6):952-61.
3. Hosoi A, Takeda Y, Furuichi Y, Kurachi M, Kimura K,
Maekawa R, Takatsu K, Kakimi K. Memory Th1
Cells Augment Tumor-Specific CTL following Transcutaneous Peptide Immunization.

Cancer Res.

2008 May 15;68(10):3941-9.
4. Hosoi A, Takeda Y, Sakuta K, Ueha S, Kurachi M,
Kimura K, Maekawa R, Kakimi K. Dendritic cell
vaccine with mRNA targeted to the proteasome bypolyubiquitination. Biochem Biophys Res Commun.
2008 Jun 27;371(2):242-6
5. Saito A, Motomura N, Kakimi K, Narui K, Noguchi

N, Sasatsu M, Kubo K, Koezuka Y, Takai D, Ueha S,
Takamoto S. Vascular allografts are resistant to methicillin-resistant Staphylococcus aureus through indoleamine 2,3-dioxygenase in a murine model. J
Thorac Cardiovasc Surg. 2008 Jul;136(1):159-67.
6. Kimura K, Nagaki M, Matsuura T, Moriwaki H, Kakimi K. Pathological role of CD44 on NKT cells incarbon tetrachloride-mediated liver injury.Hepatol
Res. 2008 Aug 19.
7. Kondo M, Sakuta K, Noguchi A, Ariyoshi N, Sato K,
Sato S, Sato K, Hosoi A, Nakajima J, Yoshida Y,
Shiraishi K, Nakagawa K, Kakimi K. Zoledronate
facilitates large-scale ex vivo expansion of functional
gammadelta T cells from cancer patients for use in
adoptive immunotherapy.
18:1-15

Cytotherapy. 2008 Nov

349

Department of Integrated
Molecular Science on Metabolic
Diseases
Project Associate Professor
Toshimasa Yamauchi, M.D.,Ph.D.

Project Research Associate
Yukiko Okazaki, 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350

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. Kadowaki T, Yamauchi T, Kubota N: The
physiological and pathophysiological role ofadiponectin and adiponectin receptors in the
peripheral tissues and CNS. FEBS Lett.2008:582:
74-80.
2. Fujisawa T, Endo H, Tomimoto A, Sugiyama M,
Takahashi H, Saito S, Inamori M, Nakajima N,
Watanabe M, Kubota N, Yamauchi T, Kadowaki
T, Wada K, Nakagama H, Nakajima A:
Adiponectin suppresses colorectal carcinogenesis

under the high-fat diet condition. Gut.2008:57:
1531-1538.
3. Uchida-Kitajima S, Yamauchi T, Takashina Y,
Okada-Iwabu M, Iwabu M, Ueki K, Kadowaki T:
5-Hydroxytryptamine 2A receptor signalingcascade modulates adiponectin and plasminogenactivator inhibitor 1 expression in adipose tissue.
FEBS Lett.2008:582: 3037-3044.
4. Hashimoto H, Eto T, Kamisako T, Hoya N,
Hatakeyama T, Arai T, Yokosuka M, Ohnishi Y,
Ito M, Hioki K, Suzuki R, Ohsugi M, Saito M,
Ueyama Y, Yamauchi T, Kubota N, Tobe K,
Kadowaki T, Tamaoki N, Nomura T, Kosaka K:
An Efficient reproductive method for Irs2-/- micewith C57BL/6JJcl genetic background. Exp
Anim.2008:57: 407-411.
5. Arai T, Hashimoto H, Kawai K, Mori A, Ohnishi
Y, Hioki K, Ito M, Saito M, Ueyama Y, Ohsugi M,
Suzuki R, Kubota N, Yamauchi T, Tobe K,
Kadowaki T, Kosaka K: Fulminant type 1
diabetes mellitus observed in insulin receptor
substrate 2 deficient mice. Clin Exp Med.2008:8:
93-99.

351

Department of Advanced Clinical
Science and Therapeutics
Project Associate Professor
Jun-ichi Suzuki, M.D., Ph.D.

Project Assistant Professor
Nobutaka Koibuchi, Ph.D.

Homepage

http://square.umin.ac.jp/sentan/

Introduction and Organization
The Department of Advanced Clinical Science andTherapeutics, established at the University of Tokyoin 2004, aims to develop new clinical strategies andtherapy in cardiovascular medicine and otherareas. This department hopes to develop not only
basic research, but also applications to devise newclinical strategies.

Research activities
Followings are our recent basic and clinical research
activities.
Basic Research New strategies to regulate acute rejection andgraft arterial diseases in cardiac transplantation.
 New
strategies to regulate acute/chronic
myocarditis.
 New strategies to regulate acute myocardial
infarction and ischemia/reperfusion injury.
 New strategies to regulate restenosis after
coronary angioplasty.
 New strategies to regulate atherosclerosis andaneurism.
 New strategies to regulate systolic/diastolic heart
failure.
 New strategies to regulate sleep apnea syndromeand circadian rhythm abnormality.
 New
strategies to regulate cardio-kidney
syndrome.

New strategies to regulate oral-pathogen induced
cardiovascular diseases.
 Development of gene therapies (anti-inflammationetc.).
 Development of new growth factor treatments(hepatocyte growth factor, etc.).
 Development of new anti-adhesion molecule
treatments (anti-inflammation, etc.).
 Development of new anti-extracellular treatments(anti-inflammation, anti-oxidation, etc.).
 Development of new chemical compounds(anti-inflammation, anti-coagulation, etc.).
 Expanding the use of foods and natural extracts.
 Expanding the application of existing drugs anddevices.
 Analysisof angiogenesis using in situ
hybridization.
Clinical Research Gene therapies to prevent restenosis andthrombosis after coronary intervention.
 Pathophysiology
oforal
disorderandcardiovascular diseases.
 Pathophysiology of sleep apnea syndrome andcardiovascular diseases.
 Pathophysiologyof renal dysfunction andcardiovascular diseases.
References
1.

Suzuki J, Ogawa M, Muto S, Itai A, Isobe M. A
specific inhibitor of plasminogen activator

352

2.

3.

4.

5.

6.

7.

8.

9.

inhibitor-1
suppresses
ratautoimmune
myocarditis. Expert Opin Ther Targets. 2008
Nov;12(11):1313-20.
Suzuki J, Ogawa M, Muto S, Yamaguchi Y, Itai A,
Isobe M. The effects of pharmacological PAI-1
inhibition on thrombus formation and neointima
formation after arterial injury. Expert Opin
Ther Targets. 2008 Jul;12(7):783-94.
Ogawa M, Suzuki J, Hishikari K, Takayama K,
Tanaka H, Isobe M. Clarithromycin attenuates
acute and chronic rejection via MMP suppression
in murine cardiac transplantation. J Am Coll
Cardiol. 2008 May 20;51(20):1977-85.
Egashira K, Suzuki J, Ito H, Aoki M, Isobe M,
Morishita R for INDOR Study Group. Long-term
follow up of initial clinical cases with NF-kB
decoy oligodeoxynucleotide transfection at thesite of the coronary stenting. J Gene Med. 2008
Jul;10(7):805-9.
Wakatsuki S, Suzuki J, Ogawa M, Masumura M,
Muto S, Shimizu T, Takayama K, Itai A, Isobe M.
A novel IKK inhibitor suppresses heart failureand chronic remodeling after myocardialischemia via MMP alteration. Expert Opin Ther
Targets. 2008 Dec;12(12):1469-76.
Saiki H, Suzuki J, Kosuge H, Haraguchi G, Haga
T, Maejima Y, Isobe M. Blockade of the 4-1BB
pathway attenuates graft arterial disease in
cardiac allografts. Int Heart J. Jan;49(1):105-18.
Haraguchi G, Kosuge H, Maejima Y, Suzuki J,
Imai T, Yoshida M, Isobe M. Pioglirazone
reduces systematic inflammation and improvesmortality in apolipoprotein E knockout mice withsepsis. Intens Care Med. 2008 Jul;34(7):1304-12.
Nakamura K, Koibuchi N, Nishimatsu H,
Higashikuni Y, Hirata Y, Kugiyama K, Nagai R,
Sata M. Candesartan ameliorates cardiac
dysfunction observed in ACE2-deficient mice.
Hypertens Res. 2008 Oct;31(10):1953-61.
Wakayama K, Shimamura M, Sata M, Koibuchi
N, Sato N, Ogihara T, Morishita R. A model of
cerebrovasucular injury in rats. J Neurosci
Methods. 2008 Nov 15;175(2):187-95

353

Department of Ischemic
Circulatory Physiology,
KAATSU training
Associate Professor
Toshiaki Nakajima, M.D., Ph.D.

Research Associate
Toshihiro Morita, M.D., Ph.D.

Research Associate
Hiroyuki Imuta

Home page

http://kaatsu.umin.jp/

Introduction of this chair
We investigate the clinical usefulness and basic
mechanisms of KAATSU training for rehabilitation inpatients with various diseases. Especially, the
KAATSU training is applied for muscle training inpatients with cardiovascular and respiratory (COPD)
diseases. In addition, we have examined the clinicalbenefits of KAATSU training on cardiac rehabilitation.
The KAATSU training also may be able to be applied
to various kinds of fields such as the muscle training
for astronauts, and severe patients with marked
muscle atrophy in long-term bed rest.

Contents of our study
The KAATSU training is a unique technique of
performing low-load exercises such as resistance
exercises and treadmill with restricted muscle bloodflow that results in an increase of muscle mass andmuscular strength comparable to high-intensity
training. Additionally, the KAATSU trainings canpromote endocrine activities such as growth hormone(GH) secretion. Therefore, KAATSU training may be
an epoch-making rehabilitation training for patientswith various kinds of diseases and old-aged patients.

Also, since KAATSU femoral blood flow restriction
induces the retention of blood flow in lower
extremities, it reduces venous return, and induces
subsequent hemodynamic changes like lower body
negative pressure (LBNP). Thus, KAATSU may partly
provide an orthostatic stimulus, and an effective
countermeasure for cardiovascular deconditioning inweightlessness like LBNP. In our laboratory, we havebeen studying the clinical usefulness of the KAATSU
training and comparing it with the ordinary
rehabilitation. The main targets of our study are as
follows: (1) Clinical usefulness of the KAATSU
training in cardiac rehabilitation. There are many
severe patients with muscle atrophy, especially inintensive care units (ICU) and high-intensive care unit
(HCU), and in our cardiovascular ward. We haveexamined the possibility of KAATSU training formuscle training and early ambulation of these patients.
(2) Clinical usefulness of this training in patients withrespiratory diseases (COPD). There are several
mechanisms involving the effects of KAATSU
training including hypoxic effects of skeletal muscles,
GH responses, and shear stress to cardiovascularhemodynamics. Therefore, we have also examined thebasic experimental studies using a variety of methods
using electrophysiology and molecular physiology

354

techniques. Also, we have investigated the effects ofthis rehabilitation on endothelial function by using
PWV, ABI, and body pletysmography, andmeasurements of blood biomarkers such as endothelial
progenitor cell and high sensitive CRP. We havestarted the cardiac rehabilitation program using
KAATSU resistance training in outpatients withcardiovascular diseases. Finally, the KATTSU training
may be applied to other clinical fields such as
orthopedics and patients with endocrine diseases suchas metabolic syndrome and diabetes mellitus. We hopethat the KAATSU training can be accepted as amethod of new advanced medical technology.

Further studies
We investigate the usefulness and basic
mechanisms of KAATSU training in patients withvarious kinds of diseases. And, we believe thatKAATSU training can provide a clinical benefit to avariety fields for muscle training or muscle strength,
and contributes to improve quality of life in patients
including old persons.

List of papers
Nakajima T, Jo T, Meguro K, Oonuma H, Ma J,
Kubota N, Imuta H, Takano H, Iida H, Nagase T,
Nagata T. 2008. Effect of dexamethasone on
voltage-gated Na+ channel in cultured humanbronchial smooth muscle cells. Life Sci. 82:.
Kubota N, Takano H, Tsutsumi T, Kurano M, Iida H,
Yasuda T, Meguro K, Morita T, Sato Y, Kawashima S,
Yamazaki Y, Ohshima H, Tachibana S, Ishii N, Abe T,
Nakajima T.。2008. Resistance exercise combined withKAATSU during simulated weightlessness Int J
KAATSU Training Res 4:9-15.
Nakajima T, Iida H, Kurano M, Takano H, Morita T,
Meguro K, Sato Y, Yamazaki Y, Kawashima S,
Ohshima H, Tachibana S, Ishii N, Abe T. 2008.
Hemodynamic responses to simulated weightlessnessof 24-h head-down bed rest and KAATSU blood flow
restriction. Eur J Appl Physiol. 104: 727-737.
Meguro K, Iida H, Takano H, Morita T, Sata M, Nagai

R, Nakajima T. 2009. Function and Role ofVoltage-Gated Sodium Channel (NaV1.7) Expressedin Aortic Smooth Muscle Cells. Am J Physiol Heart
Circ Physiol 296:H211-H219.
Nakajima T, Kubota N, Tsutsumi T, Oguri A, Imuta H,
Jo T, Oonuma H, Soma M, Meguro K, Takano H,
Nagase T, Nagata T. 2009. Eicosapentaenoic acidinhibits voltage-gated sodium channels andinvasiveness in prostate cancer cells. Br J Pharmacol
56:420-431.
Ogawa S, Yamashita T, Yamazaki T, Aizawa Y,
Atarashi H, Inoue H, Ohe T, Ohtsu H, Okumura K,
Katoh T, Kamakura S, Kumagai K, Kurachi Y,
Kodama I, Koretsune Y, Saikawa T, Sakurai M, Sugi
K, Tabuchi T, Nakaya H, Nakayama T, Hirai M,
Fukatani M, Mitamura H; J-RHYTHM Investigators.
2009. Optimal treatment strategy for patients withparoxysmal atrial fibrillation: J-RHYTHM Study.Circ
J. 73: 242-248.
Matsuyama N, Tsutsumi T, Kubota N, Nakajima T,
Suzuki H, Takeyama Y. 2009. Direct action of anangiotensin II receptor blocker on angiotensin
II-induced left atrial conduction delay inspontaneously hypertensive rats. Hypertens Res.
[Epub ahead of print]

355

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
and lifestyle
4. Analysis on the current state of the medical system
5. Spread of accurate medical information to society

356

utilizing the information technology

Research Grants
A Grant from the Ministry of Health, Labour andWelfare (2008-2010)(to Morita H and Kohro T)
Research Award of Tokyo Medical Association(toMorita H)
Research Grant of the Cell Science Research
Foundation(to Morita H)
Research Grant of Takeda Science Foundation(toMorita H)
Research Fund of Mitsukoshi Health and Welfare
Foundation(to Morita H)
Young Investigator Imura Award of Japan Vascular
Disease Research Foundation(to Morita H)

References
1.

2.

3.

4.

5.

Kohro T, Hayashi D, Okada Y, Yamazaki T,
Nagai R; JCAD Investigators. Demographics andchanges in medical/interventional treatment ofcoronary artery disease patients over a 3.5-year
period in Japan: the Japanese Coronary Artery
Disease Study: trend examination. Circ J. 2008;
72:1397-1402.
Morita H, Rehm HL, Menesses A, McDonough B,
Roberts AE, Kucherlapati R, Towbin JA,
Seidman JG, Seidman CE. Shared genetic causesof cardiac hypertrophy in children and adults.
New England Journal of Medicine 2008;358:
1899-1908.
Wang G, Watanabe M, Imai Y, Hara K, Manabe I,
Maemura K, Horikoshi M, Kohro T, Amiya E,
Sugiyama T, Fujita T, Kadowaki T, Yamazaki T,
Nagai R. Genetic variations of Mrf-2/ARID5B
confer risk of coronary atherosclerosis in theJapanese population. Int Heart J. 2008;49:313327.
Kohro T, Furui Y, Mitsutake N, Fujii R, Morita H,
Oku S, Ohe K, Nagai R. The Japanese national
health screening and intervention program aimed
at preventing worsening of the metabolic
syndrome. Int Heart J. 2008;49:193-203.
Morita H, Hayashi D, Nagai R. CTGF
polymorphism associated with systemic sclerosis.
New England Journal of Medicine 2008;358:308.

357

Department of Joint Disease
Research
Project Associate Professor
Noriko Yoshimura, M.D., Ph.D.

Project Research Associate
Hiroyuki Oka, M.D.

Homepage

http://www.h.u-tokyo.ac.jp/center22/index.html

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. 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
2. 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
3. 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 of

358

4.

5.

6.

7.

8.

9.

gastric cancer in asymptomatic, middle-aged
Japanese subjects based on serum pepsinogen andHelicobacter pylori antibody levels. Int J Cancer
123, 917-926, 2008
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 Cartilage 16: 13001306, 2008
Yoshimura N, Muraki S, Oka H, Kinoshita H,
Yoshida M, Mabuchi A, Kawaguchi H, Nakamura
K, Akune T: Epidemiology of lumbar osteoporosis
and osteoarthritis and their causal relationship - Is
osteoarthritis a predictor for osteoporosis, or
vice-versa?: The Miyama Study, Osteoporos Int
20, 999-1008, 2009 DOI:10.1007/s00198-0080771-3
Muraki S, Akune T, Oka H, Mabuchi A, Akune T,
En-yo Y, Yoshida M, Saika A, Nakamura K,
Kawaguchi H, Yoshimura N: Association ofoccupational activity with radiographic knee
osteoarthritis and lumbar spondylosis in theelderly of population-based cohorts: the ROAD
study. Arthritis Care & Research (Arthritis
Rheum) 61:779-786, 2009
Muraki S, Oka H, Mabuchi A, Akune T, En-yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Prevalence ofradiographic lumbar spondylosis and its
association with low back pain in the elderly of
population-based cohorts: the ROAD study. Ann
Rheum Dis, in press, 2009 [Epub ahead of print
2008, Aug 21]
Yoshimura N, Muraki S, Oka H, Mabuchi A,
En-yo Y, Yoshida M, Saika A, Suzuki T, Yoshida
H, Kawaguchi H, Nakamura K, Akune T:
Prevalence of knee osteoarthritis, lumbar
spondylosis and osteoporosis in Japanese men andwomen: The Research on Osteoarthritis/
osteoporosis Against Disability (ROAD). J Bone
Miner Metab, in press, 2009
Muraki S, Oka H, Mabuchi A, Akune T, En-yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Prevalence ofradiographic knee osteoarthritis and its
association with knee pain in the elderly ofJapanese population-based cohorts: the ROAD
(research on osteoarthritis against disability) study.
Osteoarthritis Cartilage, in press, 2009
10. Yanaoka K, Oka M, Yoshimura N, Deguchi H,
Mukoubayashi C, Enomoto S, Iguchi M, Magari
H, Utsunomiya H, Tamai H, Ohata H, Fujishiro M,
Takeshita T, Mohara O, Ichinose M: EradicationofHelicobacter
pyloriprevents
cancerdevelopment in subjects with mild gastric atrophy
identified by serum pepsinogen levels. Int J
Cancer, in press, 2009

359

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) wasestablished in May 2005. It is under the supervision of
the Department of Radiology, and receives funding
from Himedic Co. Ltd. and GE Yokogawa Medical
Systems, Ltd.
The aim of our research project is as follows: (1) tocreate a large database of health screening clinicaldata including medical images, (2) to develop methods
to analyze large volumes of medical images and to
search for algorithms to detect subtle abnormal
findings in these images, and (3) to evaluate theclinical usefulness of such image processing methods
and to apply the system in clinical settings.
The department comprises two project associate
professors and three project research associates, alongwith a medical staff of approximately 40 employees in
the health-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 (3T-MRI) systems,
ultrasoundimagingsystems,
anddigitalmammography.

Teaching Activities
At present, CDRPM does not accept students.
However, CDRPM participates in the education of
students and residents in the Department of Radiology.
CDRPM endeavors to help students whose research
themesincludeimage
analysissuchascomputer-assisted detection, or 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 health screening data. This information systemis still under constant revision. The medical images
acquired in the health screenings are stored in the

360

hospital picture archiving and communication system(PACS) for clinical use. Medical images used solely
for research purposes are stored in an independent
PACS installed inside the CDRPM department.

this work.) Obese adipose tissue remodeling,malfunctioning, and chronic inflammation visualized
by in vivo molecular imaging. Inflammation andRegeneration 2009; 29(2): 126-130.

2) Image processing software development

Nishimura S, Manabe I, Nagasaki M, Eto K,
Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K,
Sugiura S, Yoshimura K, Kadowaki T, Nagai R. CD8+
effector T cells contribute to macrophage recruitment
and adipose tissue inflammation in obesity. Nature
Medicine, in publication, 2009.

We have structured an integrated software developing
system to facilitate the production of image processing
software. 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 software development, and clinical application of
the developed software. The research part consists ofan interface to obtain images of the representative
cases to develop the software, and an interface to test
the developed software with the accumulated cases.

3) Clinical evaluation, application
software, and epidemiological studies

Nishimura S, Seo K, Nagasaki M, Hosoya Y,
Yamashita H, Fujita H, Nagai R, Sugiura S. Responsesof single ventricular myocytes to dynamic axial
stretching. Progress in Biophysics and Molecular
Biology, 2008; 97: 282-297.

ofResearches based on the health-screening database arecarried out in collaboration with other researchers ofvarious specialties. Images are analyzed using thedeveloped software.

References
Goto M, Suzuki Y, Abe O, Hayashi N, Aoki S, Mori H,
Masumoto T, Watanabe Y, Satake Y, Ino K, Yano K,
Iida K, Mima K, Ohtomo K. Customization of normal
data base specific for 3-tesla MRI is mandatory in
VSRAD analysis. Radiological Physics andTechnology, 2008; 1: 196–200.
Ito H, Yoshikawa T, Hayashi N, Ohtomo K. MDCT
demonstration of intraarticular gas in the
glenohumeral joint and sternoclavicular joint withreference to arm position. Radiat Med, 2008; 26(7):422-426.

Nishimura S, Manabe I, Nagasaki M, Seo K,
Yamashita H, Hosoya Y, Ohsugi M, Tobe K,
Kadowaki T, Nagai R, Sugiura S. In vivo imaging inmice reveals local cell dynamics and inflammation inobese adipose tissue. J Clin Invest, 2008; 118(2): 710721.
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.
A
comparison
withangiotension-converting enzyme inhibitors. Int Heart J,
2008; 49(1): 95-103.
Sonoda M, Takenaka K, Uno K, Ebihara A, Nagai R.
A larger aortic annulus causes aortic regurgitation anda smaller aortic annulus causes aortic stenosis inbicuspid aortic valve. Echocardiography. 2008; 25(3):242-248.

Maeda E, Akahane M, Kiryu S, Kato N, Yoshikawa T,
Hayashi N, Aoki S, Minami M, Uozaki H, Fukayama
M, Ohtomo K. Spectrum of Epstein-Barr virus-relateddiseases: a pictorial review. Japanese Journal ofRadiology 2009; 27(1): 4-19.

Uno K, Takenaka K, Ebihara A, Nawata K, Hayashi N,
Nagasaki M, Sonoda M, Takayuki O, Ono M, Kyo S,
Nagai R, Takamoto S. Value of live 3D
transoesophageal echocardiography in the diagnosis of
mitral valve lesions. Eur J Echocardiogr, 2009; 10(2):350-351.

Nagasaki M*, Nishimura S*, Manabe I, Kadowaki T,
Nagai R. (* These two authors contributed equally to

Yoshikawa T, Aoki S, Abe O, Hayashi N, Masutani Y,
Masumoto T, Mori H, Satake Y, Ohtomo K. Diffusion

361

tensor imaging of the brain: effects of distortion
correction with correspondence to numbers of
encoding directions. Radiat Med, 2008; 26(8):481487.

362

Department of Hospital
Environment
Project Associate Professor
Yushi Uetera, Ph.D.

Project Research Associate
Yuhei Saito M.Sc.

Introduction and Organization
Department of Hospital Environment was founded on
July 1, 2005, when the surgical center of Tokyo
University Hospital celebrated its 50th year
anniversary. Its aim is to improve the hospitalmanagement and environment on the basis of the perioperative medicine and management of operatingrooms (OR’s).
This department is considered one of the few
laboratories, in which these researches are performed
integrally in Japan.

medical students February to March when they start
their study in the clinical wards. Surgical scrubbing is
also taught to the new residents of our hospital at theend of March and in the beginning of April.

Research activities
Current research topics are focused on the inactivationof prions, application of chlorine dioxide and ozone in
the disposal of hospital sewage, and application ofstereolithography to manufacture the reduced-scalemodels of OR’s.

Clinical activities

References

Prevention of health care associated infection is
mandatory so that the high quality of healthcare
service is provided to all patients. Moreover, it is
known that healthcare associated infection is one of
the main causes to increase the expenditures ofhealthcare services. For instance, it is required toprevent
healthcare
associatedinfections
perioperatively in the infection control. For thesereasons, the department of hospital environment isconcerned with the management of operating theatres
integrally.

1.

Teaching activities
Handwashing is one of the most important proceduresin the prevention of health-care associated infection.
Surgical scrubbing is taught to the second grade

2.

Reduced water supply to the water ring vacuum
pump. Y.Uetera, Y.Saito,K. Ide, H.Yasuhara,
N.Kumada,
R.Saio,O.Takahashi.
Zentralsterilisation. Vol.16. pp182-185, 2008.
Investigation of “prion” chemical indicators in a
prevacuum autoclave using a wireless logger
system. Y.Uetera, Y.Saito, K. Ide, H.Yasuhara,
N.Kumada, R.Saio. Zentralsterilisation. Vol.16.
pp372-376, 2008.

363

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:// www.h.u-tokyo.ac.jp/center22/index.html

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.

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.

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

2.

3.

4.

Oka H, Muraki S, Akune T, Mabuchi A, Suzuki T,
Yoshida H, Yamamoto S, Nakamura K,
Yoshimura N, Kawaguchi H: Fully automaticquantification of knee osteoarthritis severity on
standard radiographs. Osteoarthritis Cartilage 16:
1300-1306, 2008.
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
19:21-8, 2008.
Yoshimura N, Muraki S, Oka H, Mabuchi A,
En-yo Y, Yoshida M, Saika A, Yoshida H, Suzuki
T, Kawaguchi H, Nakamura K, Akune T:
Prevalence of knee osteoarthritis, lumbar
spondylosis and osteoporosis in Japanese men
and women: The Research on Osteoarthritis/
osteoporosis Against Disability (ROAD). J Bone
Miner Metab (in press).
Muraki S, Oka H, Mabuchi A, Akune T, En-yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Prevalence of

364

5.

6.

radiographic lumbar spondylosis and its
association with low back pain in the elderly of
population-based cohorts: the ROAD study. Ann
Rheum Dis (in press).
Muraki S, Akune T, Oka H, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Nakamura K, Kawaguchi H,
Yoshimura N: Association of occupational
activity with radiographic knee osteoarthritis andlumbar spondylosis in the elderly of populationbased cohorts: The ROAD Study. Arthritis
Rheum (in press).
Yoshimura N, Muraki S, Oka G, Kinoshita H,
Yoshida M, Mabuchi A, Kawaguchi H, Nakamura
K, Akune T: Epidemiology of lumbar
osteoporosis and osteoarthritis and their causal
relationship - Is osteoarthritis a predictor for
osteoporosis, or vice-versa?: The Miyama Study.
Osteoporos Int (in press).

365

Department of Medical Safety
Management
Project Professor
Yasushi Kodama, M.D., LL.M., Ph.D.

Project Associate Professor
Shoichi Maeda, Ph.D.

Project Researcher
Shiho Andoh, D.D.S., M.P.H., Tomoko Takahashi, M.H.Sc.

Homepage http://www.h.u-tokyo.ac.jp/center22/iryou_anzen.html
http://square.umin.ac.jp/MSMCM/
Introduction and Organization
The Department of Medical Safety Management wasestablished in the 22nd century medical center of the
University of Tokyo Hospital by the contribution of
Tokio Marine & Nichido Fire Insurance Co., Ltd. in
December, 2005.
The public concern to the malpractice and the medical
affairs dispute has risen in developed countries withseveral events such as the public inquiry into
children’s heart surgery at the Bristol Royal Infirmary
and the accidental chemotherapy overdoses occurredin the Dana-Farber Cancer Institute at the end of the20th century. Reports of media in our country
concerning the malpractice and the medical affairs
dispute increase suddenly on the boundary of 1999.
Fears rise to making the criminal case through theMedical Law Article 21 mandatory reporting to thepolice. Some events become targets of investigations
while several verdicts are put out as acquittals. Thereexist various discussions and confusions over theintervention of the police authority procedures to theprocess of medical treatment.
On the other hand, in the medical affairs dispute overthe civil affairs compensation for damages, a lot ofcases have been done through various channels suchas the correspondence procedures of the explanationand the reconciliation before they become lawsuits. In
spite of such an effort, the civil affairs medical
treatment lawsuit number has kept increasing
according to about twice the ratio for every ten years
from about 1970. Though the civil affairs medical
treatment lawsuit number shows a plain decreasing
tendency in the comparison of years 2004, 2005, and2006, it is not clear whether this tendency continues.
In our department, while looking straight at the realityof the malpractice and the medical affairs dispute fromeach aspect of the patient, the medical treatment
person, and the society, it aims at a healthy rebuildingof the medical care and the confidence recovery to the
medical treatment, by thinking about the ideal way of
a better legal system in cooperation with the clinicalsite. With the best use of the experience in thestate-of-the-art university hospital, we are establishing
an approach that promotes mutual understanding by
the conversation between the patient and the medical
treatment person.

Research activities
Malpractice events during recent years have beenfrequently reported, and medical treatment disputes
have become social problems. In this situation, basic
researches concerning both the prevention of

366

malpractice and the truthful resolution of medical
accidents by preventing disputes and lawsuits areurgent issues. Such research activities are vigorously
carried out in our department to return the result
widely to the society by the development ofeducational activities.

Teaching activities
We promote education based on the research results
described above for the purpose of training
researchers and graduate students in the university.
Furthermore, as an educational extension, we also
target medical staff for the purpose of training
high-level professionals. In order to advance theseeducational extension activities, the development ofvarious types of educational programs and teachingmaterials is also being carried out.
* Patient Safety Support Center Comprehensive
Support Project
Training and related activities are carried our targetingthe personnel of the “Patient Safety Support Centers”
established in each prefecture of Japan pursuant to theprovisions of the Medical Care Law (a Ministry of
Health, Labor and Welfare commissioned project).
* Model Project for Investigation and Analysis ofMedical Practice Associated Deaths
As part of this project, our training targets theconcerned model project personnel, hospital patient
safety managers, and related staff.

Clinical activities
Based on the research results described above, thisdepartment supports the operation of the “Patient
Consultation - Clinical Ethics Center” newly
established at the University of Tokyo Hospital.
Together with on-site supporting measures, we
promote research related to topics transmitted fromthe site and education for staff of the site.

References
Research Articles
1. Yasushi Kodama. Study on Medical Accidents,from the viewpoint of a lawyer. Journal of Japan
Surgical Society. 2008:109:28-29 (in Japanese)
2. Miyaji Kyakuno, Takayuki Fujii, Masahiro
Nakagawa, Shoichi Maeda. Consideration on
medical lawsuits in urology for the past ten years.
Clinical Urology 2008:62(1): 35 ‐ 40 (inJapanese)Books
3. Yasushi Kodama. Border of Life and Deathassociated with Health Care and Law. Death andLife Studies volume 5:81-96 ， University ofTokyo Press, Tokyo, 2008 (in Japanese)
4. Shoichi Maeda. Initial Management of Medical
Accidents. Igaku Shoin, Tokyo, 2008
(inJapanese)
Conference Presentations
International Meeting
5. The 7th International Symposium ADVANCES INLEGAL MEDICINE．International Association of
Forensic Sciences ． Kazumasa Ehara, Eiji
Kohmura, Shoichi Maeda ． Analysis ofcivil-lawsuit cases regarding to neurosurgery inJapan．2008.9.2
Domestic Meetings
Invited Presentation
6. Yasushi Kodama. Exceeding ten years of the
medical affairs dispute, from the experience of theModel Project for Investigation and Analysis ofMedical Practice Associated Deaths. Japan
Surgical Society 108th Regular Scientific Meeting.
May 16, 2008
Symposium
7. Yasushi Kodama. Ideal way of malpracticeinvestigation as a self-regulation in medical
institutions. Third Scientific Meeting of JapaneseSociety for Quality and Safety in Healthcare.
November 22, 2008
Lectures8. Yasushi Kodama. Practices of Dental hygienists.
Medical treatment safety management committee
and odontology department medical treatment
safety task force combination conference. May 28,

367

2008
9. Yasushi Kodama. Looking back on ten years ofthe medical affairs dispute. Japan Red Cross
medical treatment safety promotion department
general manager conference. May 30, 2008
10. Yasushi Kodama. Looking back on ten years ofthe medical affairs dispute. Independentadministrative
agencyNational
Hospitals
mechanism director training association. June 26,
2008
11. Yasushi Kodama. Case report of therapy cost andcompensation money claim event (medical
treatment ADR event). Tokyo 3 meeting
arbitration business society. July 15, 2008
12. Yasushi Kodama. Current state of medical affairs
dispute, Law and Economics of the compensation
amends in view. Medical treatment security policy
research conference. September 17, 2008
13. Yasushi
Kodama.
Currentstate
andcorrespondence of medical affairs dispute.
Japanese hospital association medical treatment
safety manager training course. September 19,
2008
14. Yasushi Kodama. Individual information andmedical treatment. XI next bioethics of the second
times of Japan Medical Association informalsocial gathering. November 21, 2008
15. Yasushi Kodama. Risk management outline.
Nationwide social welfare facilities manager
conference beginner's class risk manager training
course. November 25, 2008
16. Yasushi Kodama. Early correspondence toemergency. Nationwide social welfare facilities
manager conference senior risk manager training
course. December 16, 2008
Researches supported by public advertisement science
research expense subsidy
17. Yasushi Kodama. Public welfare labor science
research expense subsidy-medical treatmentgeneral -002 "Research on modern problem of
ethics and method over protection of developmentof medical treatment and patient" (Futoshi Iwata,
Principal Investigator), allotment researcher
18. Yasushi Kodama. Public welfare labor science
research expense subsidy-medical treatmentgeneral -008 "Research on ideal way ofinvestigation for cause of one's death associatedwith medical practice" (Satoshi Kimura, Principal
Investigator), research cooperator
19. Shoichi Maeda. Global COE "Educational
research base creation for the next generation lifeand medical ethics" (Akira Akabayashi, research
representative), Person in charge of businesspromotion
The Ministry of Health, Labour and Welfare trust
business
20. Patient Safety Support Center Comprehensive
Support ProjectLecture meeting and research meeting sponsored by
the department
21. Personnel development training seminar for the
Model Project of the Investigation of Death
Associated with Medical Practice. The Universityof Tokyo Hospital. March 14-15, 2008

368

Division of Molecular
Cardiovascular Metabolism(Daiichi-Sankyo Company,
Limited)Associate Professor
Katsuyuki Ando, M.D., Ph.D.

Research Associate
Hiromitsu Matsui, M.D., Ph.D., Megumi Fujita, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/~kid-endo/a-3-13.html

Introduction and Organization
In order to investigate common diseases such as
hypertension
and
their
reno-cardiovascularcomplication, which is induced by deflective lifestyle(salt excess, obesity, and so on), the Division of
Molecular Cardiovascular Metabolism was started
with donation of Daiichi-Sankyo Company Limited
and supported by the Department of Nephrology and
Endocrinology, in 2006. This division consists of theabove-mentioned three staffs and a few part-time staff
and graduate fellows. Our academic activity ismajorly basic research using animals. However, we
also participate in clinical research. In 2007, ourown achievements have begun to be published.

Teaching activities
In March of 2007 and 2008, total two graduate fellows
required for the medical degree. And now a few
graduate fellows works in our laboratory.

Research activities
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. For example, we
demonstrated that sympathoexcitation by oxidative
stress in the brain mediated blood pressure (BP)elevation in salt-sensitive hypertension, and that similar
mechanism existed in obese hypertension (1).
Recently, our data suggest that the similar central
mechanism contributes to increase in BP andprogression of renal damage in chronic kidney disease.
This finding suggests that sympathoexcitation by ROS
in the brain is a common and important mechanism for
pahtophysiology of many type of hypertensive disease.
Also, dietary potassium supplementation revealedvascular protection in cuff-induced injury of femoral
artery via its antioxidant effect in salt-sensitive
hypertension (2), which was the similar to protective
action of dietary potassium in cardiac damage insalt-sensitive hypertension. This paper (2) received
particular attention, so that a figure of the paper
appeared on the cover of the journal “Hypertension”.
Moreover, we demonstrated that ROS played an
important role of the progress of renal and cardiac
injury in obese spontaneously hypertensive rats,
kown as SHR/NDmcr-cps, a model of metabolic

369

syndrome (3). These results also suggest that
aldosterone contributed to reno—cardiovasculardamage via ROS overproduction.
In addition, we demonstrated that pepubertal
administration of mineralocorticoid receptor blocker
suppressed the development of renal injury andhypertension even after its discontinuation insalt-sensitive hypertension model animals and are
examining the contribution of its antioxidant effect.
This investigation may clarify the pathophsiology ofdeflective lifestyle-induced hypertension and renal
damage in pepubertal age.
Clinical investigation: The results of the clinicalstudy were published: L-/N-type calcium channel
blocker (CCB) exerted superior antiproteinuric action
than L-type CCB, probably due to its sympatholytic
effect. The results of the paper had not beenpresented in Japan before publication. However,after publication, it was featured in the Late Breaking
Clinical Trial session of the 51st annula meeting ofJapanese Society of Nephrology and the reports about
it was published as the topic in “Annual Review
Nephrology 2009”. We will contribute to anotherclinical study in future. Now, we are participating in a
few clinical studies.
We are investigation a common disease such as
hypertension and metabolic syndrome, and can
indicate meaningful results.

References
1. Nagae A, Fujita M, Kawarazaki H, Matsui H,
Ando K, Fujita T: Sympathoexcitation byoxidative stress in the brain mediates arterialpressure elevation in obesity-induced hypertension.
Circulation. 2009; 119(7): 978-986.
2. Kido M, Ando K, Onozato ML, Tojo A,
Yoshikawa M, Ogita T, Fujita T: Protective effectof dietary potassium against the vascular injury insalt-sensitive hypertension. Hypertension 2008;
51(2); 225-231.
3. Matsui H, Ando K, Kawarazaki H, Nagae A,
Fujita M, Shimosawa T, Nagase M, Fujita T: Salt
excess causes left ventricular diastolic dysfunction
in rats with metabolic disorder. Hypertension
2008; 52(2): 287-294.
4. Ando K, Fujita T: Metabolic Syndrome and

5.

6.

7.

8.

Oxidative Stress. Free Radic Biol Med. in press.
Ando K, Matsui H, Fujita M, Fujita T: Protective
Effectof
Dietary
Potassium
againstCardiovascularDamagein
Salt-sensitive
Hypertension: Possible Role of its Antioxidant
Action. Curr Vasc Pharmacol. in press
Nagae A, Fujita M, Kawarazaki H, Matsui H,
Ando K, Fujita T: Effect of High Fat Loading in
Dahl Salt-Sensitive Rats. Clin Exp Hypertens. inpress.
Ando K, Isshiki M, Takahashi K: Effect of
combination therapy with telmisartan andlow-dose hydrochlorothiazide switching from
amlodipine. Hypertens Res in press
Matsui H, Ando K, Tsukamoto K, Osuga J, Asano
T, Fujita T: Angiotensin receptor blocker improves
leftventricular
diastolicdysfunction
inasymptomaticpatients
withdiabetic
microalbuminuria. Clin Exp Hypertens. in press.

370

Department of Anti-Aging
Medicine
Professor
Satoshi Inoue, M.D., Ph.D.

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

Homepage

http://www.h.u-tokyo.ac.jp/center22/koukarei.html

Introduction and Organization
The Department of Anti-Aging Medicine wasestablished at the 22nd Century Medical and ResearchCenter of University of Tokyo Hospital in 2006,
supported by the funds from Coca-Cola Tokyo
Research & Development Co. This department has aclose relationship with the Department of GeriatricMedicine at the Graduate School of Medicine,
University of Tokyo. The goal of this research
program is to understand the genetic andenvironmental factors that contribute to thepathogenesis of age-related disorders, including
obesity, diabetes, metabolic disorders, osteoporosis,
osteoarthritis, sarcopenia, atherosclerosis, dementia,
age-related macular degeneration, prostate cancer,
mammary carcinoma, and immunocompromised
conditions. In particular, the program aims to clarify
the roles of sex hormones estrogen and androgen in
normal, aging and disease processes. Through basic
biomedical research, our department will reveal agedependent changes at cellular, tissue, and whole-bodylevels, and will contribute to the development ofmolecule-targeted
treatment
andalternative
prevention of age-related processes and diseases.

Research activities
Aging causes degeneration and dysfunction of cells invarious organs, leading to the development of multiple
disorders in elderly people, as exemplified by obesity,

glucose intolerance, dyslipidemia. Osteoporosis andosteoarthritis are also common bone and cartilage
disorders among elderly people. In addition, aging is
an important risk factor for the prognosis of
hormone-dependent tumors, prostate cancer andmammary carcinoma. Since aging and age-relateddisorders affect the quality of daily living and lifespanof elderly people, we will identify the genetic andenvironmental factors that control aging processes
using recent technology of human genetics andmolecular biology.
Our recent findings contribute to the progress in threefollowing research fields.
1. We originally identified estrogen-responsive finger
protein (Efp/TRIM25) as an estrogen target genethrough genome binding-site cloning technique. Efp
has a structure of the TRIM/RBCC protein, with
RING finger, B-box, and coiled-coil domains, and it
has been shown as a critical molecule that promotes
the progression of mammary carcinoma. In addition
we recently discovered that Efp has another importantrole in antiviral defenses. Extending our findings on
TRIM25, we also study the functions of other TRIM
proteins in normal states and in cancer and immune
response, including TRIM5, TRIM17 (Terf), andTRIM44.
2. Using chromatin immunoprecipitation microarray
analysis and systems biology approach, we discovered

371

novel androgen responsive genes including UGT1A1,
CDH2, APP, and FOXP1. The tumor-promoting effectof APP has been shown in in vi vo models of prostatecancer.
3. As a genetic approach, we perform single
nucleotide polymorphisms (SNP) analysis to identify
disease-related factors for osteoporosis, osteoarthritis,
and age-related macular degeneration. Throughgenome-wide associated study and candidate geneapproach, we identify several interesting diseaserelated genes and focus on the functional studies forthese genes. We also combine mouse genetics to solve
the functions of disease-related genes in physiologicalstates as well as in pathophysiological states.
Our intensive studies will provide novel molecularevidences for aging processes, which will be usefulfor the establishment of anti-aging medicine and thedevelopment of novel therapeutic modalities forage-related disorders.

References
1.

2.

3.

4.

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 insulin-like growth factor-1 receptor genewith spinal disc degeneration in postmenopausal
Japanese women. Spine 33, 1256-1261, 2008.
Takayama K, Horie-Inoue K, Ikeda K, Urano T,
Murakami K, Hayashizaki Y, Ouchi Y, Inoue S:
FOXP1 is an androgen-responsive transcription
factor that negatively regulates androgen
receptor signaling in prostate cancer cells.
Biochem Biophys Res Commun 374, 388-393,
2008.
Shiraki M, Urano T, Kuroda T, Saito M, Tanaka
S, Miyao-Koshizuka M, Inoue S: The synergistic
effectofbonemineraldensityandmethylenetetrahydrofolate reductase (MTHFR)
polymorphism (C677T) on fractures. J Bone
Miner Metab 26, 595-602, 2008.
Kumagai J, Urano T, Ogushi T, Takahashi S,
Horie-Inoue K, Fujimura T, Azuma K,
Muramatsu M, Ouchi Y, Kitamura T, Inoue S:
EBAG9 is a tumor-promoting and prognostic

factor for bladder cancer. Int J Cancer 124,
799-805, 2009.
5. Takayama K, Tsutsumi T, Suzuki T, Horie-Inoue
K, Ikeda K, Kaneshiro K, Fujimura T, Kumagai J,
Urano T, Sakaki Y, Shirahige K, Sasano H,
Takahashi S, Kitamura T, Ouchi Y, Aburatani H,
Inoue S: Amyloid precursor protein is a primary
androgen target gene that promotes prostatecancer growth. Cancer Res 69, 137-142, 2009.
6. Kubo M, Ijichi N, Ikeda K, Horie-Inoue K,
Takeda S, Inoue S: Modulation of adipogenesisrelated gene expression by estrogen-related
receptor  during adipocytic differentiation.
Biochim Biophys Acta - Gene Regulatory
Mechanisms 1789, 71-77, 2009.
7. Takeo C, Ikeda K, Horie-Inoue K, Inoue S:
Identification of Igf2, Igfbp2 and Enpp2 as
estrogen-responsive genes in rat hippocampus.
Endocrine J 56, 113-120, 2009.
8. Fujimura T, Takahashi S, Urano T, Liu X, Ogushi
T, Muramatsu M, Ouchi Y, Kitamura T, Homma
Y, Inoue S: EBAG9 expression and its clinicalsignificance in human testicular cancer. Int J
Urol 16, 329-332, 2009.
9. Azuma K, Urano T, Horie-Inoue K, Hayashi S,
Sakai R, Ouchi Y, Inoue S: Association of
estrogen receptor  and histone deacetylase 6
causes rapid decetylation of tubulin in breast
cancer cell. Cancer Res 69, 2935-2940, 2009.
10. Furuya T, Urano T, Ikari K, Kotake S, Inoue S,
Hara M, Momohara S, Kamatani N, Yamanaka
H: A1330V polymorphism of low-density
lipoprotein receptor-related protein 5 gene andself-reported incident fractures in Japanese
female patients with rheumatoid arthritis. Mod
Rheumatol 19, 140-146, 2009.

372

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 include
 Design of clinical trials
 CDM
 Protocol development
 Regulatory science Ethics
 IT
 Safety information and PMS
 Translational research methodology
 …
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 Systems
 Consultation works on medical statistics andresearch methodology
 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373

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.
Finally, we started the Eplerenone Combination
Versus Conventional Agents to Lower Blood Pressure
on Urinary Antialbuminuric Treatment Effect Trial(EVALUATE) in collaboration with the Department ofNephrology and Endcrinology, Department ofPharmacoepidemiology, University of Tokyo ClinicalResearch Center and UMIN. The responsibility of theData Center is the data management including
operation of the internet system of the patient registry
and informing data and of handling the individual casesafety reports for the serious adverse events.

References
1. 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; 28(4): 552-558.
2. 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; 112:2579-82.
3. 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;
44(12): 1657-62.
4. 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). European Journal ofCancer. 2008; 44(12): 1657-62.
5. Nito T, Ushio M, Kimura M, Yamaguchi T,
Tayama N. Analyses of risk factors for
postoperative airway compromise following
arytenoid adduction. Acta Otolaryngol. 2008;
21:1-6.
6. Homma Y, Yamaguchi T, Yamaguchi O. A
randomized, double-blind, placebo-controlled
phase II dose-finding study of the novelanti-muscarinic agent imidafenacin in Japanesepatients with overactive bladder. Int J Urol 2008;
15(9): 809-15.
7. Morita T, Murata H, Kishi E, Miyashita M,
Yamaguchi T, Uchitomi Y; on behalf of theJapanese
Spiritual
Care
Task
Force.
Meaninglessness in Terminally Ill Cancer
Patients: A Randomized Controlled Study. Journalof Pain Symptom Management 2008; 37(4):649-58.
8. Ueta T, Yanagi Y, Tamaki Y, Yamaguchi T.
Cerebrovascular accidents in ranibizumab.
Ophthalmology. 2009; 116(2): 362.
9. Arita R, Itoh K, Inoue K, Kuchiba A, Yamaguchi
T, Amano S. Contact lens wear is associated withdecrease of meibomian glands. Ophthalmology.
2009; 116: 379-384.
10. Ogawa S, Yamashita T, Yamazaki T, Aizawa Y,
Atarashi H, Inoue H, Ohe T, Ohtsu H, Okumura K,
Katoh T, Kamakura S, Kumagai K, Kurachi Y,
Kodama I, Koretsune Y,Saikawa T, Sakurai M,
Sugi K, Tabuchi T, Nakaya H, Nakayama T, Hirai
M, Fukatani M, Mitamura H; for the J-RHYTHM
Investigators. Optimal Treatment Strategy for
Patients With Paroxysmal Atrial Fibrillation. Circ
J. 2008

374

11. Karasaki T, Nakajima J, Murakawa T, Fukami T,
Yoshida Y, Kusakabe M, Ohtsu H, Takamoto S.
Video-assisted thoracic surgery lobectomy
preserves more latissimus dorsi muscle thanconventional surgery. Interact Cardiovasc Thorac
Surg. 2008
12. Kunimatsu N, Aoki S, Kunimatsu A, Yoshida M,
Abe O, Yamada H, Masutani Y, Kasai K, Yamasue
H, Ohtsu H, Ohtomo K. Tract-specific analysis of
the superior occipitofrontal fasciculus in
schizophrenia. Psychiatry Res. 2008
13. Imamura M, Okunishi K, Ohtsu H, Nakagome K,
Harada H, Tanaka R, Yamamoto K,Dohi M.
Pravastatin
attenuatesallergic
airwayinflammation by suppressing antigen sensitisation,interleukin 17 production and antigen presentationin the lung. Thorax. 2009 Jan
14. Nakajima J, Murakawa T, Fukami T, Sano A,
Takamoto S, Ohtsu H. Postthymectomy
myasthenia gravis: relationship with thymoma andantiacetylcholine receptor antibody. Ann Thorac
Surg. 2008 Sep

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

377

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 maintenanceof laboratory system and blood and urine sampling.
In 2008, 232,150 outpatient blood sampling were
performed in this section.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2008, over 4,198,907

serum enzyme tests (such as AST and ALT), and458,071 immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology
and DM-related tests, gene analysis tests andurinalysis. In 2008, 978,253 samples were examinedfor complete blood cell counts, cell surface marker
analysis, prothrombin time, fibrinogen, glucose, andHbA1C tests, and 214,281 urine samples were
examined.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2008, 43,640 ECG, 21,277
pulmonary function tests, 19,532 echocardiography
tests, 11,721 abdominal echography tests, and 9,823
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378

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.

2.

3.

4.

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.

5.

6.

References
7.
1.

Asano-Mori, Y., Kanda, Y., Oshima, K., Kako, S.,
Shinohara, A., Nakasone, H., Kaneko, M., Sato,
H., Watanabe, T., Hosoya, N., Izutsu, K., Asai, T.,
Hangaishi, A., Motokura, T., Chiba, S., andKurokawa, M. False-positive Aspergillus

8.

galactomannan
antigenaemia
afterhaematopoietic stem cell transplantation. J.
Antimicrob. Chemother. 61: 411-416, 2008.
Hosogaya, S., Yatomi, Y., Nakamura, K., Ohkawa,R., Okubo, S., Yokota, H., Ohta, M., Yamazaki,
H., Koike, T., and Ozaki, Y. Measurement ofplasma lysophosphatidic acid concentration in
healthy subjects: strong correlation withlysophospholipase D activity. Ann. Clin.
Biochem. 45: 364-368, 2008.
Kage, H., Kohyama, T., Kitagawa, H., Takai, D.,
Kanda, Y., Ohishi, N., and Nagase, T. Noninfectious bronchiolitis as an early pulmonary
complication of hematopoietic stem celltransplantation. Intern. Med. 47: 61-64, 2008.
Kimura, A., Ohmori, T., Kashiwakura, Y.,
Ohkawa, R., Madoiwa, S., Mimuro, J.,
Shimazaki, K., Hoshino, Y., Yatomi, Y., andSakata, Y. Antagonism of sphingosine
1-phosphate receptor-2 enhances migration ofneural progenitor cells toward an area of brain.
Stroke 39: 3411-3417, 2008.
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.,
and Kurihara, H. Multiple renal cysts, urinary
concentration
defects,andpulmonaryemphysematous changes in mice lacking TAZ.
Am. J. Physiol. Renal Physiol. 294: F542-553,
2008.
Masuda, A., Nakamura, K., Izutsu, K., Igarashi,K., Ohkawa, R., Jona, M., Higashi, K., Yokota,
H., Okudaira, S., Kishimoto, T., Watanabe, T.,
Koike, Y., Ikeda, H., Kozai, Y., Kurokawa, M.,
Aoki, J., and Yatomi, Y. Serum autotaxin
measurement in haematological malignancies: apromising marker for follicular lymphoma. Br. J.
Haematol. 143: 60-70, 2008.
Masuzaki, R., Tateishi, R., Yoshida, H., Goto, E.,
Sato, T., Ohki, T., Goto, T., Yoshida, H., Kanai, F.,
Sugioka, Y., Ikeda, H., Shiina, S., Kawabe, T.,
and Omata, M. Comparison of liver biopsy andtransient elastography based on clinical relevance.
Can. J. Gastroenterol. 22: 753-757, 2008.
Masuzaki R., Tateishi R., Yoshida H., Yoshida H.,

379

9.

10.

11.

12.

13.

14.

15.

Sato S., Kato N., Kanai F., Sugioka Y., Ikeda H.,
Shiina S., Kawabe K., and Omata M. Risk
assessment of hepatocellular carcinoma inchronic hepatitis C patients by transient
elastography. J. Clin. Gastroenterol. 42: 839-843,
2008.
Matsubayashi, J., Kawakubo, Y., Suga, M., Takei,
Y., Kumano, S., Fukuda, M., Itoh, K., Yumoto,M., and Kasai, K. The influence of gender andpersonality traits on individual difference inauditory mismatch: a magnetoencephalographic(MMNm) study. Brain Res. 1236: 159-165,
2008.
Matsui, H., Ando, K., Kawarazaki, H., Nagae, A.,
Fujita, M., Shimosawa, T., Nagase, M., andFujita, T. Salt excess causes left ventricular
diastolic dysfunction in rats with metabolic
disorder. Hypertension 52: 287-294, 2008.
Nakamura, K., Igarashi, K., Ide, K., Ohkawa, R.,
Okubo, S., Yokota, H., Masuda, A., Oshima, N.,
Takeuchi, T., Nangaku, M., Okudaira, S., Arai, H.,
Ikeda, H., Aoki, J., and Yatomi, Y. Validation of
an autotaxin enzyme immunoassay in humanserum samples and its application tohypoalbuminemia differentiation. Clin. Chim.
Acta 388: 51-58, 2008.
Nakamura, K., Nangaku, M., Ohkawa, R., Okubo,
S., Yokota, H., Ikeda, H., Aoki, J., and Yatomi, Y.
Analysis of serum and urinary lysophospholipase
D/autotaxin in nephrotic syndrome. Clin. Chem.
Lab. Med. 46: 150-151, 2008.
Nannya, Y., Yokota, H., Sato, Y., Yamamoto, G.,
Asai, T., Ichikawa, M., Watanabe, T., Kumano,
K., Hangaishi, A., Takahashi, T., Chiba, S.,
Yatomi, Y., and Kurokawa, M. Molecular andcytogenetic response of chronic myelogenous
leukemia treated with imatinib mesylate: one
institutional experience in Japan. Int. J. Hematol.
88: 159-164, 2008.
Ohkawa, R., Nakamura, K., Okubo, S., Hosogaya,
S., Ozaki, Y., Tozuka, M., Osima, N., Yokota, H.,
Ikeda,
H.,
andYatomi,Y.
Plasmasphingosine-1-phosphate measurement in healthy
subjects: close correlation with red blood cellparameters. Ann. Clin. Biochem. 45: 356-363,
2008.
Okazaki, M., Kaneko, Y., Yumoto, M., and Arima,

16.

17.

18.

19.

K. Perceptual change in response to a bistablepicture increases neuromagnetic beta-band
activities. Neurosci. Res. 61: 319-328, 2008.
Saito, A., Motomura, N., Kakimi, K., Narui, K.,
Noguchi, N., Sasatsu, M., Kubo, K., Koezuka, Y.,
Takai, D., Ueha, S., and Takamoto, S. Vascularallografts are resistant to methicillin-resistant
Staphylococcus aureus through indoleamine
2,3-dioxygenase in a murine model. J. Thorac.
Cardiovasc. Surg. 136: 159-167, 2008.
Sonoda, M., Aoyagi, T., Takenaka, K., Uno, K.,
and Nagai, R. A one-year study of theantiatherosclerotic effect of the angiotensin-II
receptor blocker losartan in hypertensive patients.
A comparison with angiotension-converting
enzyme inhibitors. Int. Heart J. 49: 95-103,
2008.
Sonoda, M., Takenaka, K., Uno, K., Ebihara, A.,
and Nagai, R. A larger aortic annulus causes
aortic regurgitation and a smaller aortic annulus
causes aortic stenosis in bicuspid aortic valve.
Echocardiography 25: 242-248, 2008.
Wang, H., Shimosawa, T., Matsui, H., Kaneko, T.,
Ogura, S., Uetake, Y., Takenaka, K., Yatomi, Y.,
and Fujita, T. Paradoxical mineralocorticoid
receptor activation and left ventricular diastolic
dysfunction under high oxidative stressconditions. J. Hypertens. 26: 1453-1462, 2008.

380

Surgical Center
Director (Professor)
Hiroshi Yasuhara M.D., Ph.D.

Associate Professor
Yoshikazu Mimura, M.D., Ph.D.
Kazuhiro Fukatsu. 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 thesurgical center had 14 operating rooms, including one
bio-clean room. The administration staffs consisted of
4 doctors, 75 nurses, 6 technical officials, 5 part-time
employees. The surgical center became to afford
services to 18 clinical departments after the newsurgical center started.
The total number of operations did not apparently
increase between 1999 and 2000, partly because of thelimited 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 elective operations
remarkably increased and became over 7500. Efficacy
became a key to improve the availability of theoperating rooms. Two new operating rooms weretentatively used to overcome the tremendous increasein the number of elective operations. The one was 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 rooms began to be used
for elective operations. In the year 2007, the newest
central building, which had 11 operating rooms, wasopen to solve the relative shortage of operating rooms.
As a result, the total number of operating rooms
became 23, and then the number of operations has
been dramatically increased. The number ofoperations increased thereafter.
A total of 8,322 and 9,374 operations, which counts
for 1.5 times comparing to those in 2001, were
performed in 2006 and 2007, respectively. Morerecently, the number of operations was 9,868 (1,268

381

emergency cases) in 2008.
There has been much concern about the apparent
increase in the patients who are positive for the
microbiological tests such as tuberculosis, MRSA,
pseudomonas aeruginosa, HBV, HCV and HIV. Thosepatients have been increasing by 5-18% per year overthe last 4 years. Administrative efforts might beneeded more in the near future to protect the staffs aswell as the patients against the new infectious agent
such as prion.

Activities of Surgical Center
Our works range 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 theinformation on the operation. In May 1999, on-line
computer system was introduced for ordering systemof the elective and emergency operations. Then, theoperations have become ordered through the computer
terminal of the clinical departments since May l999.
The doctors and nurses became to be able to see
postoperative information through the computer
system since March 2000.
For the efficacy of the operation, the information on
the status of the procedures has been displayed on thecomputer monitor screen since May 1997. This
monitor also tells the hospital staffs whether there are
any operating rooms available on the next day.
Furthermore, since November 2000, the hospital staffs
have become to be able to see how the clinicaldepartments plan the operations through the hospitalcomputer network.
As for digitalized visual information, thephotographs of operative fields, resected organs andreal-time visual images have been distributed to eachclinical department through hospital computer
network since February 1997.
In the new ward building, the 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
organtransplantation
microvascularsurgery,
cardiovascular surgery, minimally invasive surgery
and orthopedic surgery have 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, organtransplantation and intraoperative three-dimensional
echo-guided surgery are performed in the surgicalcenter.
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 informed 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 ismandatory to meet the increase in the perioperative
healthcare services for those patients.

Teaching Activities
The following lectures are given to theundergraduates and postgraduates: aseptic techniques,
sterilization
methods,
disinfection
methods,
prevention of perioperative infections, humoral andcellular responses to trauma and shock, training ofscrubbing and gown techniques, Curriculum is
updated every year. For example, introductory course
for disinfection, sterilization and preservation ofsurgical instruments and medical devices was added in
the training courses in 1998, which gained interest andpopularity among students.

382

In the surgical center, the innovative surgicalinstruments and medical devices are recently
introduced to perform highly advanced operations
such as in the navigation surgery, transplantation
surgery, cardiovascular surgery and so forth.
Consequently, education has become one of the mostimportant activities in the surgical center. The lecturesof advanced technologies are in the curriculum for thesurgeons, nursing staffs and medical electronics
engineers so that they can understand how to use themproperly.
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 acirculating 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 theoperating room. An advanced course is also preparedto the 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 ofintroduction on the medical electronic instruments anddevices, precautions of accidental troubles in handlingsurgical
instruments
andmedicaldevices,development of new surgical instruments and medical
devices, cardiopulmonary bypass techniques andillumination techniques in the operating fields. The
contents of this course are summarized in the manual
for the nursing staffs and contribute to decrease thenumber 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
in the surgical center. They are lectured on aseptic
techniques, sterilization methods, disinfection
methods, prevention of perioperative infections andhow to check the faults in the reusable surgicalinstruments such as forceps, scissors and clamps.
These contents are summarized in the manual.

Lectures are also given to senior technical officers andtemporary employees to upgrade their technicalknowledge 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 theoperating theaters
6) Perioperative infection control of patients
undergoing operations and prevention ofoccupational infection of medical staffs working
in the surgical center
7) Development of new sterilization methods8) Improvement of cost-effectiveness in sterilizationand preservation of medical instruments andintroduction of international standardization ofsterilization methods8) Cost-effectiveness analysis of disposable andreusable 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（2006-2008）
1. Fukatsu K, Sakamoto S, Hara E, Ueno C,
Maeshima Y, Matsumoto I, Mochizuki H, Hiraide
H. Gut ischemia-reperfusion affects gut mucosal
immunity: A possible mechanism for infectious
complications after severe surgical insults. Crit

383

2.

3.

4.

5.

6.

7.

8.

Care Med. 2006 Jan;34(1):182-7.
Ikezawa F, Fukatsu K, Moriya T, Maeshima Y,
Okamoto K, Hara E, Hiraide H: Albumin infusion
after reperfusion prevents gut ischemia
reperfusion-induced gut associated lymphoidtissue atrophy. JPEN J Parenter Enteral Nutr.
2006;30(5):380-6
Yaguchi Y, Fukatsu K, Moriya T, Maeshima Y,
Ikezawa F, Omata J, Ueno C, Okamoto K, Hara E,
Ichikura T, Hiraide H, Mochizuki H: Influence oflong term antibiotic administration on Peyer’s
patch lymphocytes and mucosal IgA levels. JPENJ Parenter Enteral Nutr. 2006;30(5):395-8
Fukatsu K, Moriya T, Ikezawa F, Maeshima Y,
Omata J, Yaguchi Y, Okamoto K, Mochizuki H,
Hiraide H: Interleukin-7 dose dependently
restoresparenteralnutrition-inducedgut
associated lymphoid tissue cell loss. JPEN J
Parenter Enteral Nutr. 2006;30(5):388-93
Ueno C, Fukatsu K, Kang W, Maeshima Y,
Nagayoshi H, Omata J, Saito H, Hiraide H,
Mochizuki H: Lack of enteral nutrition delays
nuclear factor kappa B activation in peritoneal
exudative cells in a murine glycogen-induced
peritonitis model. JPEN J Parenter Enteral Nutr.
2006;30(3):179-85.
Konishi T, Watanabe T, Morikane K, Fukatsu K,
Kitayama J, Umetani N, Kishimoto J, Nagawa H:
Prospective surveillance effectively reduced rates
of surgical site infection associated with elective
colorectal surgery at a university hospital in Japan.
Infect Control Hosp Epidemiol. 2006 May;27(5):526-8.
Einama T, Kagata Y, Tsuda H, Morita D, Ogata S,
Ueda S, Takigawa T, Kawarabayashi N, Fukatsu
K, Sugiura Y, Matsubara O, Hatsuse K: Highlevel Skp2 expression in pancreatic ductal
adenocarcinoma: correlation with the extent oflymph node metastasis, higher histological grade,and poorer patient outcome. Pancreas. 2006 May;32(4):376-81.
Ueda S, Hatsuse K, Tsuda H, Ogata S,
Kawarabayashi N, Takigawa T, Einama T, Morita
D, Fukatsu K, Sugiura Y, Matsubara O,
Mochizuki H: Potential crosstalk between insulinlike growth factor receptor type 1 and epidermal
growth factor receptor in progression andmetastasis of pancreatic cancer. Mod Pathol. 2006
Jun;19(6):788-96.
9. Maeshima Y, Fukatsu K, Moriya T, Ikezawa F,
Ueno C, Saitoh D, Mochizuki H. Influence ofadding fish oil to parenteral nutrition on gutassociated lymphoid tissue. JPEN J Parenter
Enteral Nutr. 2007 Sep-Oct;31(5):416-22.
10. Moriya T, Fukatsu K, Maeshima Y, Ikezawa F,
Ueno C, Kang WD, Takakayama E, D Saito, H
Mochizuki, Miyazaki M. Nutritional route affects
ERK phosphorylation and cytokine production in
hepatic mononuclear cells. Ann Surg2007 Apr;
245(4):642-50
11. Omata J, Fukatsu K, Ueno C, Hara E, Maeshima Y,
Nagayoshi H, Yaguchi Y, Hiraide H, Mochizuki H.
Intraluminal glutamine administration during
ischemia worsens survival after gut ischemia
reperfusion. J Surg Res 2007, 143(2):260-4
12. Ikezawa F, Fukatsu K, Moriya T, Ueno C,
Maeshima Y, Okamoto K, Hara E, Saitoh D.
Reversal of parenteral nutrition-induced gut
mucosal immunity impairment with small
amounts of a complex enteral diet. J Trauma 2008
Aug;65(2):360-5
13. Maeshima Y, Fukatsu K, Kang W, Ueno C,
Moriya T, Saitoh D, Mochizuki H. Lack of enteralnutrition blunts extracellular regulated kinase
phosphorylation in gut-associated lymphoid tissue.
Shock. 2007;27(3):320-325.
14. Yasuhara H, Ohara N, Hattori T, Shigeta O.
Importance of combination of persistentunderlying factors in deep vein thrombosis. Int
Angiol 26(suppl) 79, 2007.
15. Sotome K, Onishi T, Hirano A, Nakamaru M,
Furukawa A, Miyazaki H, Morozumi K, Tanaka Y,
Iri H, Mimura Y. A rare case of anaplastictransformation within the metastatic site of theretroperitoneal 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
16. 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.

384

Results of a phase I clinical study using dendritic
cell vaccinations for thyroid cancer. Thyroid 17:
53-58, 2007
17. 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: 17541756, 2007
18. 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
19. Ueda S, Tsuda H, Asakawa H, Omata J, Fukatsu
K, Kondo N, Kondo T, Hama Y, Tamura K,
Ishida J, Abe Y, Mochizuki H. Utility of
18F-fluoro-deoxyglucose emission tomography/
computed tomography fusion imaging (18F-FDG
PET/CT) in combination with ultrasonography foraxillary staging in primary breast cancer. BMC
Cancer. 9;8:165, 2008.
20. Ueda S, Kondoh N, Tsuda H, Yamamoto S,
Asakawa H, Fukatsu K, Kobayashi T, Yamamoto
J, Tamura K, Ishida J, Abe Y, Yamamoto M,
Mochizuki H. Expression of centromere protein F(CENP-F) associated with higher FDG uptake on
PET/CT, detected by cDNA microarray, predicts
high-risk patients with primary breast cancer.
BMC Cancer. 2008 Dec 22;8:384.
21. Ueda S, Tsuda H, Asakawa H, Shigekawa T,
Fukatsu K, Kondo N, Yamamoto M, Hama Y,
Tamura K, Ishida J, Abe Y, Mochizuki H.
Clinicopathological and prognostic relevance of
uptake level using 18F-fluorodeoxyglucose
positronemission
tomography/computed
tomography fusion imaging (18F-FDG PET/CT)
in primary breast cancer. Jpn J Clin Oncol.38(4):250-8, 2008.
22. Fukatsu K, Ueno C, Maeshima Y, Mochizuki H,
Saitoh D. Detrimental effects of early nutrition
administration after severe gut ischemiareperfusion. J Surg Res. 149(1):31-8, 2008
23. Fukatsu K, Nagayoshi H, Maeshima Y, Ueno C,
Saitoh D, Mochizuki H. Fish oil infusion reverses
5-fluorouracil-induced impairments in mucosal
immunity in mice. Clin Nutr. 27(2):269-75, 2008

24. Furuya Y, Yasuhara H, Naka S, Yamazaki K,
Yanagie H, Wakahara T, Akimoto H. Intestinal
evisceration through the anus caused by fragile
rectal wall. Int J Coplorectal Dis 2008; 23:721-22
25. Uetera Y, Saito Y, Ide K, Yasuhara H, Kumada N,
Saito R, Takahashi O. Reduced water supply to
the water ring vacuum pump. Central Sevice 16:
182-185, 2008.
26. Yasuhara H, Hattori T, Shigeta O. Significance ofPhlebosclerosis in Non-healing Ischemic Foot
Ulcers of End-stage Renal Disease. Eur J Vasc
Endovasc Surg 36:346-352, 2008.

385

Department of Clinical Radiology
Professor (department manager)
Kuni Ohtomo, M.D.,Ph.D.

Associate Professor (vice manager)
Masaaki Akahane, M.D.,Ph.D.

Assistant Professor
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 andintervention), Radiation Oncology (radiotherapy),
Nuclear Medicine and the Radiation Safety Control
System are provided 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 technicalofficial of the radiation control. The staff members of
the Department of Radiology (teachers, the graduate
school students, medical staffs, and the clinicaltrainees) join this. In addition, the doctors and thenurses of other clinical departments cooperate and arealso engaged in the clinical radiology activities. The
educational training and registration of the radiation
engaging persons are controlled according to the
University of Tokyo 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(the MR rooms, the operation rooms, and theemergency department) and some other clinicaldepartments. The services provided are X-ray imaging,fluoroscopic imaging, computed tomography (CT),magnetic resonance imaging (MRI) and angiography.
Radiation Oncology Section is operated at thirdbasement floor of the Central Clinic Building 2. The
outpatient clinic is also located here and not in the
Outpatient Clinic building. The methods of therapy
providedarelinearaccelerator(LINAC),
gamma-knife, Remote After Loading System (RALS)
and Brachytherapy (Radioactive Seed Implantation
Therapy). Nuclear Medicine Section is operated at thebasement 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 is located at the third floor of
the old Central Clinic Building.
Department of Clinical Radiology is actively
participating in the following projects. 1) PACS: We
have recently developed a radiology information
system (RIS) networking with hospital information
system (HIS) and PACS (picture archiving andcommunicating system). The PACS of the whole
hospital (the film-less imaging system) wasestablished in 2003. The new reporting system wasinstalled in 2002. 2) Radiation Safety Control:
Stimulated by the need for evaluating the individualaccumulated exposure dose by medical radiation, we
have started a working group to solve this problem.
We aim to provide the accumulated exposure dose386

data on RIS. 3) Image Computing & Analysis
Laboratory: The clinical section of this project islocated at the reading room in the Diagnostic
Radiology Section. The main services are processingof volume image data into clinical 3D-images andanalysis of imaging data. 4) Researches on new
radiology
techniques:
Ongoingcollaborative
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, andangiography and vascular interventional procedures
except for cardiac and peripheral arterial studies. Allof these examinations are performed under therequests of clinicians. Over one hundred and fifty CT
examinations are performed using five MDCT
scanners each day. Interventional procedure such as
percutaneous biopsy and abscess drainage are alsodone by CT guidance. About fifty MR examinations
are done using 1.5-Tesla and 3-Tesla scanners everyday. About six angiographies, most of which areinterventional
procedures
includingarterial
embolization, arterial infusion therapy, arterial
infusion port placement, and angioplasty, 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 offunctional 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 planningsystems 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 havedeveloped a new linear accelerator with C-arm andmultileaf 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 withcone-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 andcardiologists. 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.
Whole body FDG-PET is one of the most promisingstudies for exploring metastatic lesions of cancer
patients. Combination display of SPECT/PET with
XCT/MRI would be a routine job and anatomofunctional images would play an important role in theclinical management of the patients.

387

In conclusion, the department of clinical radiology
is a service section to all clinical departments. Main
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 ofclinical radiology.

References
See the corresponding part of the department ofRadiology.

388

Delivery Unit
Professor
Shiro Kozuma

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 lecturer,
and about 10 fellows. All the staff members are taking
part in research activities of reproductive
endocrinology, gynecologic oncology, or perinatal
medicine, as well as being engaged with in-patient andout-patient care for pregnant women including theactivities in the delivery units.

Activities
Total number of delivery cases was 891 in 2008,
797 in 2007.
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
are on duty every night. Our service is an importantpart of Tokyo Metropolitan Service System for
Maternal Welfare and Perinatal Medicine.

References in 2008
[See Department of Perinatal Medicine.]

389

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 theCentral Diagnostic and Therapeutic Service
Department. The Central Rehabilitation Service
became an independent unit in 1970. After the
reorganization of the University of Tokyo Hospital
according to major organic classification in 1998,
outpatient clinic as rehabilitation medicine wasinstalled. 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 theorthopedic surgery department and the physicalmedicine 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 inteaching activities for medical students. Fourteen
physical therapists and five acupuncture therapists areworking in the physical therapy section. In theoccupational therapy section, three occupational
therapists work for the general rehabilitation service
and the other two therapists work for the psychiatricrehabilitation. In the Day-care Unit, a clinicalpsychologist and a nurse also work. In 2006, speechtherapists and orthoptists who belong to otherdepartments in the University of Tokyo Hospital aregoing 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 Rehabilitation Center,the University of Tokyo Hospital. Both departments
are united and engage in clinical practice. We have atpresent no charged ward, and treat about 1,000 newreferrals annually from almost all the departments of
the university hospital. We always take charge ofabout 150 patients corresponding about 15% of thewhole number of inpatients. We also see 15 people per
day at the outpatient rehabilitation setting. The
numerical ratio of outpatient is being reduced in orderto give priority to the clinical service corresponding toneeds 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 ascerebrovascular disturbances, spinal cord injuries andspina bifida, neuromuscular diseases, bone and joint

390

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 a longterm clerkship from several PT/OT training schools.
Eleven graduate school students entered by 2006
and six of them acquired a degree of Ph.D. andgraduated.

Research activities
Our research activities are growing up. In 2006, theRehabilitation Center moved to the new building and a
research laboratory was provided for the first time. As
the motion analysis system was partially renewed, weare planning our researches mainly in the field ofmusculoskeletal disabilities. In addition, we areplanning collaborating researches with otherdepartments in our hospital, other faculties in our
university, and institutions outside the University ofTokyo. The ongoing and scheduled projects are as
follows.
going and scheduled projects are as follows.
1) Motion analysis of patients with joint disorders in
the lower extremities
2) Motion analysis of motor development in children
3) Early detection, diagnosis, and progression
prevention of musculoskeletal disorders
4) Analysis of motion and energy expenditure in theactivities of daily living in the physically disabled
5) Non-invasive evaluation of lower limb motor
function in spina bifida6) Evaluation of higher brain function in patientswith spina bifida7) Disabilities and handicaps in patients with skeletal
dysplasias

8) Influence of physical therapy to skeletal muscles

References
1. Chiba Y, Nishihara K, Yamaguchi A, Haga N:
Midpoint
fixationtask:
Quantitative
assessment of visual neglect. J Clin Neurosci
15: 647-649, 2008.
2. Chiba Y, Haga N: Analyzing non-motor bias inunilateral neglect with a new variant of the line
bisection task. Brain Injury 22: 952-959, 2008.
3. Fukuda T, Kanomata K, Nojima J, Kokabu S,
Akita M, Ikebuchi K, Jimi E, Komori T, Maruki
Y, Matsuoka M, Miyazono K, Nakayama K,
Nanba A, Tomoda H, Okazaki Y, Ohtake A, Oda
H, Owan I, Yoda T, Haga N, Furuya, H, Katagiri
T: A unique mutation of ALK2, G356D, found ina patient with fibrodysplasia ossificans
progressiva is a moderately activated BMP type
I receptor. Biochem Biophys Res Commun 377:
905-909, 2008.
4. Jigjid E, Kawashima N, Ogata H, Nakazawa K,
Akai M, Eto F, Haga N: Effects of passive leg
movement on the oxygenation level of lower
limb muscle in chronic stroke patients.
Neurorehabil Neural Repair 22(1): 40-49, 2008.
5. Takikawa K, Haga N, Tanaka H, Okada K:
Characteristic factors of ankle valgus withmultiple cartilaginous exostoses. J Pediatr
Orthop 28: 761-765, 2008.
6. Yu E, Abe M, Masani K, Kawashima N, Eto F,
Haga N, Nakazawa K: Evaluation of posturalcontrol in quiet standing using the center ofmass acceleration: comparison among the young,the elderly, and people with stroke. Arch Phys
Med Rehabil 89: 1133-1139, 2008.

391

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

392

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

393

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.

394

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.

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.

Sugisaki K, Usui T, Nishiyama N, Jang WD,
Yanagi Y, Yamagami S, Amano S, Kataoka K.
Photodynamic
therapyforcornealneovascularization using polymeric micelles
encapsulating dendrimer porphyrins. Invest
Ophthalmol Vis Sci 49:894-899, 2008
2. Osakabe Y, Amano S, Fukuoka S, Yamagami S.
Histologic evaluation of a cornea in a patientwith apolipoprotein A-I deficiency. Cornea 27:
372-373, 2008
3. Mochimaru H, Usui T, Yaguchi T, Nagahama Y,
Hasegawa G, Usui Y, Shimmura S, Tsubota K,
Amano S, Kawakami Y, Ishida S. Suppression ofalkali burn-induced corneal neovascularization
by dendritic cell vaccination targeting VEGF
receptor 2. Invest Ophthalmol Vis Sci 49:21722177, 2008
4. Arita R, Itoh K, Inoue K, Amano S. Non-contact
infrared meibography to document age-relatedchanges of the meibomian glands in a normal
population. Ophthalmology 115:911-915, 2008
5. Hitani K, Yokoo S, Honda N, Usui T, Yamagami
S, Amano S. Transplantation of a sheet of humancorneal endothelial cell in a rabbit model. Mol
Vis 14:1-9, 2008
6. Mimura T, Amano S, Yokoo S, Uchida S, Usui T,
Yamagami S. Isolation and distribution of rabbit
keratocyte precursors. Mol Vis 14:197-203, 2008
7. Amano S, Shimomura N, Yokoo S, Yamagami S,
Araki-Sasaki K. Decellularizing corneal stroma
using N2 gas. Mol Vis 14:878-882, 2008
8. Miyai T, Maruyama Y, Osakabe Y, Nejima R,
Miyata K, Amano S. Karyotype changes incultured human corneal endothelial cells. Mol
Vis 14:942-950, 2008
9. Yokoo S, Yamagami S, Usui T, Amano S, Araie
M. Human corneal epithelial equivalents forocular surface reconstruction in complete serum
free culture system without unknown factors.
Invest Ophthalmol Vis Sci 49:2438-2443, 2008
10. Hayashi T, Yamagami S, Tanaka K, Yokoo S,
Usui T, Amano S, Mizuki N. A mouse model ofallogeneic corneal endothelial cell transplantation.
Cornea 27:699-705, 2008
11. Yokoo S, Yamagami S, Shimada T, Sato T, Usui T,

395

12.

13.

14.

15.

16.

Amano S, Araie M, Hamuro J. A novel isolation
technique of progenitor cells in human corneal
epithelium using uncoated dishes. Stem Cells
26:1743-1748, 2008
Miyai T, Miyata K, Nejima R, Honbo M,
Minami K, Amano S. Comparison of laser in situ
ketatomileusis and photorefractive keratectomy
in long-term follow-up. J Cataract Ref Surg
34:1527-1531, 2008
Amano S, Nakai Y, Ko A, Inoue K, Wakakura M.
A case with keratoconus progression during theuse of topical latanoprost. Jpn J Ophthalmol
52:334-336, 2008
Mimura T, Yamagami S, Usui T, Honda N, Araki
F, Amano S. In vivo confocal microscopy ofhuman cornea covered with human amniotic
membrane. Jpn J Ophthalmol 52:493-496, 2008
Mimura T, Amano S, Fukuoka S, Honda N, Arita
R, Ochiai M, Yanagisawa M, Usui T, Ono K,
Araki F, Yamagami S, Araie M, Awaya Y. In vivo
confocal microscopy of hereditary sensory andautonomic neuropathy. Cur Eye Res 33:940-945,
2008
Mimura T, Amano S, Yokoo S, Uchida S,
Yamagami S, Usui T, Kimura Y, Tabata Y.
Tissue engineering of corneal stroma with rabbit
fibroblast precursors and gelatin hydrogels. Mol
Vis 4:1819-28, 2008

396

Department of Cell Therapy andTransplantation Medicine
Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Junko Takita, M.D., Ph.D. (Pediatrics/Hematology-Oncology)

Special Lecturer (Hospital)
Keiki Kumano, M.D., Ph.D. (Hematology-Oncology)

Associate
Koji Kandabashi, M.D. (Hematology-Oncology)

Homepage

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

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 four medical doctors listed above. Clinicalfacilities include 8 single-patient rooms with highefficiency 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 andinfused 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 at-196°C in cooperation with Department ofTransfusion Medicine. Recently, transplantation after
pre-conditioning of reduced intensity (RIST for
reduced-intensity stem cell transplantation or NST for
non-myeloabrative stem cell transplantation) is
commonly performed for the elderly patients andpatients with organ damages, etc. The development of
this strategy is expanding the eligibility of transplant
recipients. Allogeneic hematopoietic stem celltransplantations for the elderly are performed under
the admission of ethical committee of the Faculty of
Medicine.
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 used in
the allogeneic stem cell harvest are performed forleukapheresis and preservation of autologous stem
cell.
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 ofDepartment of Transfusion Medicine routinely
participate and discuss on the patients receiving
hematopoietic stem cell transplantation.

397

Teaching activities
Together with the members of Department of
Hematology/Oncology and Hematology/Oncology
group in 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 thesecond grade medical students. Courses for bedsidelearning 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 clerkship courses are given to the fourth
grade medical students, who join the patient careteams consisting of junior and 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.

(3)

(4)

Research activities(5)
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, leukemogenesis
and regenerative medicine using hematopoietic cells.
In the area of pediatric oncology, we continue thestudies on molecular mechanisms of pediatricmalignancies,
suchasneuroblastoma,
rhabdomyosarcoma,
andinfantleukemia.
Representative publications from our department
published in the past year are listed in the references.

(6)

(7)

References(1) Kako S, Kanda Y, Oshima K, Nishimoto N, Sato
H, Watanabe T, Hosoya N, Motokura T,
Miyakoshi S, Taniguchi S, Kamijo A, Takahashi
K, Chiba S, and Kurokawa M. Late onset of
autoimmune hemolytic anemia and pure red cellaplasia after allogeneic hematopoietic stem celltransplantation using in vivo alemtuzumab.
American Journal of Hematology 83: 247-249,
2008.
(2) Oshima K, Kanda Y, Nakasone H, Arai S,
Nishimoto N, Sato H, Watanabe T, Hosoya N,(8)

Izutsu K, Asai T, Hangaishi A, Motokura T,
Chiba S, and Kurokawa M. Decreased incidenceof acute graft-versus-host disease by continuous
infusion of cyclosporine with a higher target
blood level. American Journal of Hematology 83:
226-232, 2008.
Asano-Mori Y, Kanda Y, Oshima K, Kako S,
Shinohara A, Nakasone H, Kaneko M, Sato H,
Watanabe T, Hosoya N, Izutsu K, Asai T,
Hangaishi A, Motokura T, Chiba S, andKurokawa
M.
False-positive
Aspergillus
galactomannan antigenemia after hematopoietic
stem cell transplantation. The Journal of
Antimicrobial Chemotherapy 61: 411-416, 2008.
Kumano K, Masuda S, Sata M, Saito T, Lee SY,
Yanagimoto-Sakata M, Tomita T, Iwatsubo T,
Natsugari H, Kurokawa M, Ogawa S, and Chiba
S. Both Notch1 and Notch2 contribute to theregulation of melanocyte stem cells. Pigment
Cell Melanoma Research 21: 70-78, 2008.
Ichikawa M, Goyama S, Asai T, Kawazu M,
Nakagawa M, Takeshita M, Chiba S, Ogawa S,
and Kurokawa M. AML1/Runx1 negatively
regulates quiescent hematopoietic stem cells in
adult hematopoiesis. The Journal of Immunology
180: 4402-4408, 2008.
Suzuki H, Asai T, Tamaki Z, Yoshimi A,
Hangaishi A, Kanda Y, Motokura T, Chiba S, andKurokawa M. Drug-induced hypersensitivity
syndromewithrapid
hematopoietic
reconstitution during treatment for acute myeloid
leukemia. Haematologica 93: 469-470, 2008.
Suzuki H, Asai T, Okada K, Kazuyama Y, Kanda
Y, Motokura T, Chiba S, and Kurokawa M.
Disseminated adenovirus disease by multiple
adenovirus serotypes following allogeneic
hematopoietic stem cell transplantation. Biologyof Blood and Marrow Transplantation 14: 353355, 2008.
Yoshimi A, Izutsu K, Takahashi M, Oshima K,
Kako S, Kanda Y, Motokura T, Chiba S, Momose
T, Ohtomo K, and Kurokawa M. Conventional
allogeneic
hematopoietic
stem
cell
transplantation for lymphoma may overcome
poor prognosis associated with positive FDGPET scan before transplantation. American
Journal of Hematology 83: 477-481, 2008.

398(9) Asano-Mori Y, Kanda Y, OshimaK, Kako S,
Shinohara A, Nakasone H, Sato H, Watanabe T,
Hosoya N, IzutsuK, Asai T, Hangaishi A,
Motokura T, Chiba S, and Kurokawa M.
Long-term ultra-low-dose acyclovir against
varicella-zoster virus reactivation after allogeneic
hematopoietic
stem
cell
transplantation.
American Journal of Hematology 83: 472-476,
2008.
(10) Asano-Mori Y, Kanda Y, Oshima K, Kako S,
Shinohara A, Nakasone H, Sato H, Watanabe T,
Hosoya N, Izutsu K, Asai T, Hangaishi A,
Motokura T, Chiba S, and Kurokawa M. Clinicalfeatures of late cytomegalovirus infection after
hematopoietic
stem
cell
transplantation.
International Journal of Hematology 87: 310-318,
2008.
(11) Suzuki T, Izutsu K, Kako S, Ohta S, Hangaishi A,
Kanda Y, Motokura T, Chiba S, and Kurokawa M.
A case of adult Langerhans cell histiocytosis
showing successfully regenerated osseous tissueof the skull after chemotherapy. Internatinal
Journal of Hematology 87: 284-288, 2008.
(12) 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, and Tsuji S. Lymphomatoid
Granulomatosis involving central nervous system
successfully treated with rituximab alone.
Archives of Neurology 65: 662-655, 2008.
(13) Nakamoto T, Seo S, Sakai R, Kato T, Kutsuna H,
Kurokawa M, Noda M, Miyasaka N, andKitagawa
S.
Expression
andtyrosine
phosphorylation of Crk associated substrate
lymphocyte type (Cas-L) protein in humanneutrophils. J Cellular Biochemistry 105: 121128, 2008.
(14) Nagai S, Asai T, Watanabe T, Oshima K,
Hangaishi A, Kanda Y, Motokura T, Chiba S,
Aoki S, Ohtomo K, and Kurokawa M.
Simultaneous appearance of central nervous
system relapse and subarachnoid hemorrhage
during or after targeted therapies for acutepromyelocytic leukemia. Annals of Hematology
87: 593-595, 2008.
(15) Takeshita M, Ichikawa M, Nitta E, Goyama S,
Asai T, Ogawa S, Chiba S, and Kurokawa M.

AML1-Evi-1
specificallytransforms
hematopoietic stem cells through fusion of theentire Evi-1 sequence to AML1. Leukemia 22:1241-1249, 2008.
(16) Kataoka K, Yamamoto G, Nannya Y, Yoshimi A,
Okada S, Asai T, Kumano K, Hangaishi A,
Takahashi T, Chiba S, and Kurokawa M.
Successful
engraftment
following
HLAmismatched cord blood transplantation forpatients with anti-HLA antibodies. Bone Marrow
Transplantation 42: 129-130, 2008.
(17) Yoshimi A, Kumano K, Motokura T, Takazawa Y,
Oota S, Chiba S, Takahashi T, Fukayama M, andKurokawa M. ESHAP therapy was very effective
for a patient with Langerhans cell sarcoma.
International Journal of Hematology 87: 532-537,
2008.
(18) Kataoka K, Izutsu K, Nagai S, Hangaishi A,
Motokura T, Takahashi T, and Kurokawa M.
Elevated serum levels in interleukin-2 receptor inchronic
eosinophilic
leukemia/
hypereosinophilic syndrome with FIP1L1PDGFRα fusion gene. International Journal of
Hematology 87: 440-441, 2008.
(19) Yoshimi A, Asai T, Hangaishi A, Takahashi T,
Chiba S, and Kurokawa M. Hemorrhagic cystitis
in a patient receiving gemtuzumab ozogamicin
for relapsed acute promyelocytic leukemia after
cord
blood
transplantation.
Annalsof
Hematology 87: 851-852, 2008.
(20) Suzuki H, Izutsu K, Nagai S, Watanabe T,
Oshima K, Kanda Y, Motokura T, Chiba S, andKurokawa M. Late onset pneumatosis cystoides
intestinalis associated with non-infectious
pulmonary complications after allogeneic
hematopoietic
stem
cell
transplantation.
International Journal of Hematology 88: 116-118,
2008.
(21) Suzuki H, Hangaishi A, Hosoya N, Watanabe T,
Kanda Y, Motokura T, Chiba S, and Kurokawa M.
Herpes simplex encephalitis and subsequentcytomegalovirus
encephalitis
after
chemoradiotherapy for central nervous system
relapse of diffuse large B-cell lymphoma: a casereport and literature review. International Journalof Hematology 42: 285-287, 2008.
(22) Sato T, Goyama S, Nitta E, Takeshita M, Yoshimi

399

M, Nakagawa M, Nakagwa M, Kawazu M,
Ichikawa M, and Kurokawa M. Evi-1 promotes
para-aortic
splanchnopleural
hematopoiesis
through up-regulation of GATA-2 and repressionof TGF-β signaling. Cancer Science 99: 14071413, 2008.
(23) Sakata-Yanagimoto M, Nakagami-Yamaguchi E,
Saito T, Kumano K, Yasutomo K, Ogawa S,
Kurokawa M, and Chiba S. Coordinatedregulation of transcription factors throughNotch2 is an important mediator of mast cell fate.
Proceedings of National Academy of Science U S
A 105: 7839-7844, 2008.
(24) Suzuki H, Suzuki T, Kamijo A, Ohta S, Sato H,
Hangaishi A, Takahashi T, Kanda Y, Motokura T,
Chiba S, and Kurokawa M. Antileukemic
immunity associated with antineutrophil antibody
production after allogeneic hematopoietic stem
celltransplantationformyeloid/NK-cell
precursor acute leukemia. Bone Marrow
Transplantation 42: 285-287, 2008.
(25) Yoshimi A, Nannya Y, Sakata-Yanagimoto M,
Oshima K, Takahashi T, Kanda Y, Motokura T,
Chiba S, and Kurokawa M. A myeloablative
conditioning regimen for patients with impaired
cardiac function undergoing allogeneic stem celltransplantation:
reducedcyclophosphamide
combined with etoposide and total body
irradiation. American Journal of Hematology 83:
635-639, 2008.
(26) Nannya Y, Yokota H, Sato Y, Yamamoto G, Asai
T, Ichikawa M, Watanabe T, Kumano K,
Hangaishi A, Takahashi T, Chiba S, andKurokawa M. Molecular and cytogenetic
response of chronic myelogenous leukemia
treated with imatinib mesylate: one institutional
experience in Japan. International Journal of
Hematology 88: 159-164, 2008.
(27) Oshima K, Kanda Y, Kako S, Asano-Mori Y,
Watanabe T, Motokura T, Chiba S, Shiraki K, andKurokawa
M. Case Report:
Persistentcytomegalovirus(CMV)
infection
after
haploidentical
hematopoietic
stem
cell
transplantation using in vivo alemtuzumab:
emergence of resistant CMV due to mutations in
the UL97 and UL54 genes. Journal of Medical
Virology 80: 1769-1775, 2008.

(28) Goyama S, Yamamoto G, Shimabe M, Sato T,
Ichikawa M, Ogawa S, Chiba S, and Kurokawa
M. Evi-1 is a critical regulator for hematopoietic
stem cells and transformed leukemic cells. Cell
Stem Cell 3: 207-220, 2008.
(29) Fukuo W, Yoshiuchi K, Takimoto Y, Sakamoto N,
Kikuchi H, Hachizuka M, Inada S, Nannya Y,
Kumano K, Takahashi T, Kurokawa M, andAkabayashi A. Comparison of temporal changesof psychological distress during hematopietic
stem cell transplantation among underlying
diseasesinJapaneseadultpatients.
BioPsychoSocial Medicine 2: 24, 2008.
(30) Masuda A, Nakamura K, Izutsu K, Igarashi K,
OhkawaR, Jona M, Higashi K, Yokota H,
Okudaira S, Kishimoto T, Watanabe T, Koike Y,
Ikeda H, Kozai Y, Kurokawa M, Aoki J, andYatomi Y. Serum autotaxin measurement inhaematological malignancies: a promisingmarker for follicular lymphoma. British Journalof Haematology, 143: 60-70, 2008.
(31) Nakagawa K, Kanda Y, Yamashita H, Nakagawa
S, Sasano N, Ohtomo K, Oshima K, Kumano K,
Ban N, Minamitani Y, Kurokawa M, and Chiba S.
Ovarian shielding allows ovarian recovery andnormal birth in female hematopoietic SCT
recipients undergoing TBI.
Bone Marrow
Transplantation, 42: 697-699, 2008.
(32) Kanda Y, Okamoto S, Tauchi T, Kizaki M,
Inokuchi K, Yabe M, Yokoyama K, Ito Y, Kimura
Y, Higashihara M, Bessho M, Ando K, Chiba S,
Kurokawa M, Oshimi K, Dan K, Ohyashiki K,
and Ikeda Y.
Multicenter prospective trial
evaluating the tolerability of imatinib forJapanese patients with chronic myelogenous
leukemia in the chronic phase: Does body weightmatter? American Journal of Hematology, 83:
835-839, 2008.

400

Department of Endoscopy andEndoscopic Surgery
Associate Professor
Mitsuhiro Fujishiro, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kogaku.html

Introduction and Organization

gastric and colorectal tumors, and polypectomy forcolonic polyps, are recently 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.

Department of Endoscopy and Endoscopic Surgery
were 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
and otorhinolaryngology participate the examinations.
The examination rooms moved to the new building in
Oct. 2006.

Teaching activities

Clinical activities

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.

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,

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

*

4384

5555

5667

5923

6346

7324

7920

7597

8265

8131

8796

9822

Colonoscopy

1398

2415

2472

2799

3212

3529

3873

3728

4084

4327

4360

4679

Bronchoscopy

190

239

282

233

194

220

207

194

212

201

201

165

**

347

562

569

470

479

583

586

476

461

438

484

402

Laparoscopy

19

7

2

0

-

-

-

-

-

-

-

-

Laryngoscopy

131

96

99

115

154

93

68

61

89

127

91

63

Colposcopy

272

213

153

149

181

103

124

139

88

58

117

256

Total

6741

9087

9244

9689

10566

11852

12778

12195

13199

13282

EGD

EUS

*Esophagogastroduodenoscopy, **Endoscopic ultarasonography14043 15387

401

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

References
1. Fujishiro M, Kodashima S, Takubo K, Kakushima
N, Omata M. Detailed comparison between
endo-cytoscopy and horizontal histology of anesophageal
intraepithelial
squamouscellcarcinoma. Dis Esophagus 2008; 21(2): 181-5
2. Fujishiro M. Endoscopic submucosal dissection
for gastric cancer. Curr Treat Options
Gastroenterol 2008 Mar; (2): 119-24.
3. Goto O, Fujishiro M, Kakushima N, Kodashima S,
Ono S, Yamaguchi H, Nomura S, Kaminishi M,
Omata M. Endoscopic submucosal dissection as astaging measure may not lead to worse prognosis
in early gastric cancer patients with additional
gastrectomy. Dig Liver Dis. 2008 Apr; 40(4):293-7.
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, Mohara 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. 2008 Apr; 17(4):838-45.
5. Ogura K, Okamoto M, Sugimoto T, Yahagi N,
Fujishiro M,
Kakushima N,
Kodashima S,
Kawabe T, Omata M. Efficacy and safety ofendoscopic submucosal dissection for gastriccancer in patients with liver cirrhosis. Endoscopy.
2008 May; 40(5): 443-5.
6. Fujishiro M, Kodashima S, Goto O, Ono S,
Muraki Y, Kakushima N, Omata M. Successful en
bloc resection of superficial esophageal cancer
treated by endoscopic submucosal dissection witha splash-needle (with video). Endoscopy. 2008;
40: E81-2
7. Goto O, Fujishiro M, Kodashima S, Kakushima N,
Ono S, Yahagi N, Omata M. Feasibility ofelectrocautery snaring as the final step ofendoscopic submucosal dissection for stomach

epithelial neoplasms. Dig Liver Dis. 2009 Jan;41(1): 26-30.
8. Kakushima N, Fujishiro M. Endoscopic
submucosal dissection for gastrointestinal
neoplasms. World J Gastroenterol 2008; 14:2362-7
9. Yanaoka K, Oka M, Yoshimura N, Mukoubayashi
C, Enomoto S, Iguchi M, Magari H, Utsunomiya
H, Tamai H, Arii K, Yamamichi N, Fujishiro M,
Takeshita T, Mohara O, Ichinose M. Risk ofgastric cancer in asymptomatic, middle-aged
Japanese subjects based on serum pepsinogen andHelicobacter pylori antibody levels. Int J Cancer.
2008 Aug 15; 123(4): 917-26.
10. Otani K, Kitayama J, Kaisaki S, Ishigami H,
Hidemura A, Fujishiro M, Omata M, Nagawa H.
Early gastric cancer shows different associations
with adipose tissue volume depending on
histological type. Gastric Cancer. 2008; 11(2):86-95.
11. Fujishiro M. Perspective on the practicalindications of endoscopic submucosal dissectionofgastrointestinal
neoplasms.
World
J
Gastroenterol. 2008; 14: 4289-95
12. Kakushima N, Fujishiro M, Gotoda T: Stomach.
In: Conio M, Siersema P, Repici A, Ponchon T(Eds): Endoscopic Mucosal Resection. WileyBlackwell, USA, 2008; pp97-111.
13. Fujishiro
M.
Current
perspectiveonendocytoscopic diagnosis in the esophagus basedon the multicenter study at the endoscopy forum
Japan. In: Niwa H, Tajiri H, Nakajima M, Yasuda
K (Eds): New challenge in gastrointestinalendoscopy. Springer-Verlag Tokyo, 2008; pp95100.
14. Fujishiro M, Kodashima S, Ono S, Goto O,
Yamamichi N, Yahagi N, Kashimura K, Matsuura
T, Iguchi M, Oka M, Ichinose M, Omata M.
Submucosal injection of normal saline may
prevent unexpected deep thermal injury of argon
plasma coagulation in an in vivo porcine stomach.
Gut and Liver. 2008; 2:95-8.
15. Ono S, Fujishiro M, Kodashima S, Goto O, Omata
M. Submerging endoscopic submucosal dissection
leads to successful en bloc resection of coloniclaterally spreading tumor with submucosal fat.
Gut and Liver. 2008; 2:209-12.

402

16. Fujishiro M, Kodashima S, Goto O, Ono S,
Muraki Y, Kakushima N, Omata M. Technicalfeasibility of endoscopic submucosal dissection
for the gastrointestinal epithelial neoplasms with asplash-needle. Surg Laparosc Endosc Percutan
Tech2008; 18:592-7.

403

Department of Hemodialysis &Apheresis
Director
Toshiro Fujita, MD, PhD, Professor

Deputy Director
Eisei Noiri, MD, PhD, Associate Professor
Noiri Hanafusa, MD, PhD, Lecturer

Homepage

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

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 acute andchronic
renal
failureincludingdiabetic
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 for ulcerative
colitis and rheumatological arthritis.

404

Research6.
1. Prognostic analysis for post-liver transplantpatients received plasma exchange therapy.
2. Development and application of a non-invasive
pulse hemoglobin meter.
3. Genome wide association study for Nephrotic
syndrome and those functional analyses.
4. Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
5. Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
6. AKI biomarkers and those clinical significance in
ICU/CCU.
7. Renal biomarker to determine clinical actionability
in CKD and type-2 DN.
8. The potentiality of urine biomarker tests fordeveloping country.

7.

8.

9.

References
1.

2.

3.

4.

5.

Noiri E, Doi K, Negishi K, Tanaka T, Hamasaki Y,
Fujita T, Portilla D, Sugaya T: Urinary fatty acidbinding protein 1: An early predictive biomarker
of kidney injury. Am J Physiol Renal Physiol
296:F669-F679, 2009
Tanaka T, Doi K, Maeda-Mamiya R, Negishi K,
Portilla D, Sugaya T, Fujita T, Noiri E: Urinary
L-type fatty acid binding protein can reflect renal
tubulointerstitial injury. Am J Pathol 174:120311, 2009
Negishi K, Noiri E, Doi K, Maeda-Mamiya R,
Sugaya T, Portilla D, Fujita T: Monitoring ofurinary L-type fatty acid-binding protein predicts
histological severity of acute kidney injury. Am J
Pathol 174:1154-9, 2009
Noiri E, Doi K, Inagi R, Nangaku M, Fujita T:
Contribution of T-lymphocytes to rat renal
ischemia/reperfusion injury. Clin Exp Nephrol
13:25-32, 2009
Nemeth K, Leelahavanichkul A, Yuen PS, Mayer
B, Parmelee A, Doi K, Rober PG,
Leelahavanichkul K, Koller BH, Brown JM, Hu
X, Jelinek I, Star RA, and Mezey E. Bonemarrow stromal cells attenuates sepsis via
prostaglandin E2-dependent reprogramming of
host macrophages to increase their interleukin-10

10.

11.

12.

13.

14.

production. Nat Med 15:42-9,2009
Doi K, Yuen PST, Eisner C, Hu X,
Leelahavanichkul A, Schnermann J, and Star RA.
Reduced creatinine production limits serum
creatinine as an indicator of acute kidney injury
in sepsis. J Am Soc Nephrol 20:1217-21,2009
Doi K, Okamoto K, Tokunaga K, Fujita T, Noiri
E: Genome study of kidney disease in the age ofpost
genome-sequencing.
EndocrMetabImmune Discord Drug Targets 8:173-83,2008
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
Leelahavanichkul A, Yasuda H, Doi K, Hu X,
Zhou H, Yuen PST, and Star RA.
Methyl-2-acetamidoacrylate, an ethyl pyruvateanalogue, decreases sepsis-induced acute kidney
injury in mice. Am J Physiol Renal Physiol
295:F1825,2008
Doi K, Leelahavanichkul A, Hu X, Sidransky KL,
Qin Y, Eisner C, Schnermann J, Yuen PST, andStar RA. Pre-existing renal disease promotes
sepsis-induced acute kidney injury and worsens
sepsis outcome via multiple pathways. Kidney
Int 74:1017-25, 2008.
Doi K, Hu X, Yuen PST, Leelahavanichkul A,
Yasuda H, Kim SM, Schnermann J, Jonassen
TEN, Frøkiær J, Nielsen S, and Star RA. Effectof α-melanocyte-stimulating hormone analogue
AP214 on sepsis-induced acute kidney injury andmortality. Kidney Int 73: 1266-1274, 2008.
Yasuda H, Leelahavanichkul A, Tsunoda S, Dear
JW, Takahashi Y, Ito S, Hu X, Zhou H, Doi K,
Childs RW, Klinman DM, Yuen PST, Star RA.
Chloroquine and inhibition of Toll-like receptor 9
protect from sepsis-induced acute kidney injury.
Am J Physiol Renal Physiol 294: F1050-1058,
2008.
Doi K, Okamoto K, Tokunaga K, Fujita T, andNoiri E. Genome study of kidney disease in theage of post genome-sequencing. Endocr Metab
Immune Disord Drug Targets 8: 173-183, 2008.
Bennett KM, Zhou H, Sumner JP, Dodd SJ,
Bouraoud N, Doi K, Star RA, and Koretsky AP.
MRI of the basement membrane using charged

405

15.

16.

17.

18.

19.

20.

21.

22.

23.

nanoparticles as contrast agents. Magn Reson
Med. 60: 564-574, 2008.
Zhou H, Cheruvanky A, Hu X, Matsumoto T,
Hiramatsu
N,
Cho
ME,
BergerA,
Leelahavanichkul A, Doi K, Chawla L, Kopp JB,
Balow JE, Austin HA, Yuen PST, and Star RA.
Urinary exosomal transcription factors, a newclass of biomarkers for renal disease. Kidney Int
74: 613-621, 2008.
Maeda R, Noiri E, Isobe H, Homma T, Tanaka T,
Negishi K, Doi K, Fujita T, and Nakamura E.
Water-soluble fullerene vesicle alleviates
angiotensin II induced oxidative stress in humanumbilical venous endothelial cells. Hypertens
Res 31: 141-151, 2008.
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
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
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
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
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
Doi K, Noiri E, Fujita T, Tokunaga K:
Non-association of VEGF genetic polymorphism
in promoter—5’ UTR with end-stage renal
disease. Nephrol Dial Transplant 21:1124, 2006
Doi K, Noiri E, Nakao A, Fujita T, Kobayashi S,

24.

25.

26.

27.

28.

29.

30.

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
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 offolic acid-induced renal inflammatory injury inplatelet-activating factor receptor-deficient mice.
Am J Pathol 168:1413, 2006
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
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 anda history of multiple early micharges. Ther
Apher Dial 10:498, 2006
Okamoto K, Kobayashi S, Noiri E: Longer
treatment time and slower ultrafiltration inhemodialysis:
associations
withreducedmortality in the Dialysis Outcomes and PracticePatterns Study. Kidney Int 70:1877, 2006
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
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
Doi K, Noiri E, Nakao A, Fujita T, Kobayashi S,
Tokunaga K: Haplotype analysis of NAD(P)H
oxidase p22 phox polymorphism in end-stage
renal disease. J Hum Genet 50:641, 2005

406

Clinical Research Center
Professor
Masao Omata, M.D., Ph.D.

Associate Professor
Yoshihiro Arakawa, Ph.D.

Research Associate
Keiji Ogura, M.D., Ph.D.

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 thecommission to support investigator-initiated clinical
trials. The staff of the center as of March, 2009, iscomprised of one professor, one associate professor,
one research associate, seven pharmacists, five nurses,
one clinical psychologist and three officials, of which
three pharmacist and three nurses were full-timeworkers with three years' tenure and two officials andone clinical psychologist were part-time workers. The
center consists of four subdivisions: Division of
consultation on protocol development (one associate
professor and one research associate), division ofpharmaceutical administration (three pharmacists),
division of clinical research coordination (eight nurses,
six pharmacists and one clinical psychologist) anddivision of clerkship (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 48 new protocols and 73
ongoing protocols for industry-initiated clinical trials
in fiscal 2008. We also dealt with 2 new protocol forinvestigator-initiated regulatory clinical trials and 57
investigator-initiated non-regulatory clinical trials,
which include the ethical use of non-approved drugs.
A protocol hearing was held every month forapplications of new industry-initiated protocols tofacilitate a review with meaningful discussion in the
IRB and to give practical advice in carrying out the
protocols properly. The meeting was held with theattendance of applicant company representatives,principal and sub investigators and the staffs of thecenter. We also dealt applications for changes in theinitial application documents (594 applications),
safety information (747 reports), and other reports infiscal 2008.
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) wasestablished in 2006 and is collaborating with eachother in continuing improvement of our clinical trial407

environments. Until the end of 2008, 37 protocols
were introduced to the alliance including 18
multi-national trials.
As for pharmaceutical administration, we tookcharge of 135 clinical trial drugs and medical devices
and filled 1538 prescriptions in fiscal 2008.
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 weretransferred to a new system as a part of the hospital
clinical information system in March 2006, allowing
the direct access to the clinical trial information fromthe 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 withinspections, assistance in the preparation of casereport forms (CRF), arrangements for monitoring andaudits, and arrangements for medical accounting.
There were a total of 5172 times of coordination of
outpatients' visits and medical treatments of inpatientsin fiscal 2008. CRCs also support the implementationof some of the investigator-initiated non-regulatory
clinical trials. In 2005, we introduced a principle that
beneficiaries should pay for part of a personnel cost of
CRCs and adopted three investigator-initiatedprotocols 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 andscientifically 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
57
new
investigator-initiated clinical trials which include theethical use of non-approved drugs in fiscal 2008.

Teaching activities
The Center accepted 38 fourth grade students fortraining in collaboration with the Pharmaceutical
Department. Arakawa is taking charge of one
half-year lecture on clinical pharmacology for thegraduate course students in the Faculty of
Pharmaceutical Sciences every year. One student
belonged to our research labs in fiscal 2008.
The Center is involved as an on-the-job training
institution in CRC training programs. In fiscal 2008,
we accepted one three-week trainees from theprogram operated by Pharmacist Training Center.

Research activities
We performed the publication of four original
papers written in English, four review papers inJapanese and the 20 presentations in academic
conferences in 2008.

References
1.

2.

3.

4.

Tomimatsu N, Arakawa Y. Protein kinase
C-mediated protection of motoneurons fromexcitotoxicity. Neurosci. Lett. 439: 143-146,
2008.
Tomimatsu N, Arakawa Y. Survival-promoting
activity of pituitary adenylate cyclase-activating
polypeptide in the presence of phosphodiesterase
inhibitors on rat motoneurons in culture:cAMP-protein kinase A-mediated survival. J
Neurochem. 107: 628-635, 2008.
Ogura K, Hirata Y, Yanai A, Shibata W, Ohmae
T, Mitsuno Y, Maeda S, Watabe H, Yamaji Y,
Okamoto M, Yoshida H, Kawabe T, Omata M.
The Effect of Helicobacter pylori Eradication on
Reducing the Incidence of Gastric Cancer. J Clin
Gastroenterol 42:279-283, 2008.
Ogura K, Okamoto M, Sugimoto T, Yahagi N,
Fujishiro M, Kakushima N, Kodashima S,

408

Kawabe T, Omata M. Efficacy and safety ofendoscopic submucosal dissection for gastriccancer in patients with liver cirrhosis. Endoscopy
40:443-445, 2008.

409

University hospital Medical
Information Network (UMIN)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Instructor
Hiroshi Nishiuchi, M.S.

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.

410

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411(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412

Organ Transplantation Service
Director and Professor
Norihiro KOKUDO

Homepage
The University of Tokyo Hospital has aggressively
performed organ transplantation. In 1966, the firstkidney transplantation in Japan was performed. In
1996, the first living donor liver transplantation was
performed. Organ Transplant Service started tofunction since 2003. Until today, more than 400 casesof living donor liver transplantation has been
performed, and 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
anddeceased
donor
liver
transplantation.

References (2008)
1.

2.

3.

4.

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 Apr;10(2):110-6.
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.
Inoue Y, Sugawara Y, Tamura S, Makuuchi M.
Intraoperative ultrasound guided portal venous
thrombectomyinlivingdonor
liver
transplantation recipient surgery. Transpl Int.
2008 May;21(5):428-33.
Kyoden Y, Tamura S, Sugawara Y, Yamashiki N,
Matsui Y, Togashi J, Kaneko J, Kokudo N,
Makuuchi M. Outcome of living donor livertransplantation for post-Kasai biliary atresia in

adults. Liver Transpl. 2008 Feb;14(2):186-92.
5. Kaneko J, Sugawara Y, Matsui Y, Makuuchi M.
Spleen size of live donors for livertransplantation. Surg Radiol Anat. 2008 Aug;30(6):515-8.
6. Hashimoto T, Miki K, Imamura H, Sano K, SatouS, Sugawara Y, Kokudo N, Makuuchi M.
Sinusoidal perfusion in the veno-occlusive regionof living liver donors evaluated by indocyanine
green and near-infrared spectroscopy. Liver
Transpl. 2008 Jun;14(6):872-80
7. Matsui Y, Sugawara Y, Yamashiki N, Kaneko J,
Tamura S, Togashi J, Makuuchi M, Kokudo N.
Living donor liver transplantation for fulminant
hepatic failure. Hepatol Res. 2008 Oct;38(10):987-96.
8. Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Makuuchi M. Bloodstream
infection after living donor liver transplantation.
Scand J Infect Dis. 2008;40(6-7):509-16.
9. Kaneko J, Sugawara Y, Tamura S, Togashi J,
Matsui Y, Makuuchi M. Heparin-induced
thrombocytopenia after liver transplantation.
Transplant Proc. 2008 Jun;40(5):1518-21.
10. Kishi Y, Sugawara Y, Matsui Y, Akamatsu N,
Makuuchi M. Late onset portal vein thrombosis
and its risk factors. Hepatogastroenterology. 2008
May-Jun;55(84):1008-9.
11. Kaneko J, Sugawara Y, Tamura S, Togashi J,
Matsui Y, Makuuchi M. Antithrombin effect on
coagulation and fibrinolytic profiles after living
donor liver transplantation: a pilot study. Int J
Lab Hematol. 2009 Feb;31(1):81-6.
12. Pan XC, Guo L, Deng YB, Naruse K, Kimura H,
Sugawara Y, Makuuchi M. Further study of antiICOS immunotherapy for rat cardiac allograft

413

13.

14.

15.

16.

17.

18.

19.

20.

rejection. Surg Today. 2008;38(9):815-25.
Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Kokudo N, Omata M,
Makuuchi M. Double-dose double-phase use of
second generation hepatitis B virus vaccine inpatients after living donor liver transplantation:
Not an effective measure in transplant recipients.
Hepatol Res. 2009 Jan;39(1):7-13.
Kyoden Y, Tamura S, Sugawara Y, Matsui Y,
Togashi J, Kaneko J, Kokudo N, Makuuchi M.
Portal vein complications after adult-to-adultliving donor liver transplantation. Transpl Int.
2008 Dec;21(12):1136-44.
Tamura S, Sugawara Y, Kaneko J, Togashi J,
Matsui Y, Yamashiki N, Kokudo N, Makuuchi M.
Recurrence of cholestatic liver disease after
living donor liver transplantation. World J
Gastroenterol. 2008 Sep 7;14(33):5105-9.
Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Kokudo N, Makuuchi M. Pseudomonas
aeruginosa infection after living-donor livertransplantation in adults. Transpl Infect Dis. 2009
Feb;11(1):11-9.
Tamura S, Sugawara Y, Kukudo N, Makuuchi M.
Systematic grading of morbidity after living
donationforlivertransplantation.
Gastroenterology. 2008 Nov;135(5):1804.
Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Moriya K, Koike K,
Makuuchi M. Acquisition of methicillin-resistant
Staphylococcus aureus after living donor livertransplantation: a retrospective cohort study.
BMC Infect Dis. 2008 Nov 11;8:155.
Takemura N, Kokudo N, Imamura H, Takazawa Y,
Sano K, Sugawara Y, Nakagawa K, Ohtomo K,
Makuuchi M.
Eleven-year survivor ofunresectable intrahepatic cholangiocarcinoma
treatedusing
long-term
UFTtherapy.
Hepatogastroenterology. 2008 Nov-Dec;55(88):1997-9.
Hirai I, Kimura W, Suto K, Fzjimoto H,
Watanabe T, Fuse A, Kobayashi K, Iijima M,
Saheki T, Nakatsuka T, Sugawara Y, Makuuchi M.
Living donor liver transplantation for type II
citrullinemia from a heterozygous donor.
Hepatogastroenterology. 2008 Nov-Dec;55(88):2211-6.

414

Center for 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.,
Motoko Seto, 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, theCenter for Epidemiology and Preventive Medicine
was established on January 1, 2007, within the Central
Clinical Facilities and the relevant regulations wererevised. On January 9, the Working Group for the
Establishment of the Center for Epidemiology andPreventive Medicine was organized; on April 1,
Steering Committee for the Establishment of theCenter for Epidemiology and Preventive Medicine
was organized; preparation for offering its services
continued until May 31; on June 4, the department
started offering its services on a trial basis (in-hospital
services) and was officially inaugurated in July,
starting to provide public services.
The principal objectives of the establishment of
the Center for Epidemiology and Preventive Medicine
are 1) to scientifically demonstrate the utility andeffectiveness of examinations and preventive
interventions, 2) to integrate a vast amount of clinicaldata and health-related information to develop more
efficient models for disease management, 3) by doing

the above 1) and 2), to promote preventive medicine
and medicine for health promotion in an effort tocontribute to the improvement 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 Center for
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 supported by
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, Oral-Maxillofacial Surgery, Dentistry andOrthodontics).
The staff of the Center for Epidemiology andPreventive Medicine is composed of five physicians(two regular physicians and three physicians from therelated departments). One of the regular physicians415

also performs upper gastrointestinal endoscopy andcolonoscopy in the Department of Endoscopy andEndoscopic Surgery. Our department also has four
regular nurses and four 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
cerebrovascularexaminations,3) colorectal
cancerscreening,4) uterine cancer screening, 5) breast cancer screening,6) lung cancer screening, 7) tumor marker diagnosis,
8) estimation of gastric cancer risk, and 9) oral/dental
examinations. While meeting the needs of examinees,
we have increased the number of the optional
examinations and provided 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) 2008 from April 1, 2007 to
March 31, 2009, the total number of examinees (whohad basic examinations and optional examinations)was 4,702, including 1,507 in basic examinations, 410
in complete cardiovascular examinations, 451 incomplete cerebrovascular examinations, 252 incolorectal cancer screening, 297 in uterine cancer
screening, 341 in breast cancer screening, 458 in lungcancer screening, 491 in tumor marker diagnosis, 357
in estimation of gastric cancer risk, and 121 inoral/dental examinations.
When examinees visit other departments in our
hospital for a work-up or treatment, we write a letterof referral by request. In the FY 2008, we issued 758
letters of referral to other departments in our hospitaland 44 to other hospitals.
We have expanded our public relations efforts andduring the FY 2008 our brochure has reached its ninth
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 Center for
Epidemiology and Preventive Medicine has attracted
much media attention and was covered by the press
including the well-known magazine, ATES.

416

References
Academic Papers in English(1) 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 International Journal of Cardiology 2008,
129; 294-296(2) Nagai R, Izumi T, Kurabayashi M, Daida H, Tojo T,
Hasegawa A, Miyauchi K, Hayashi D, Kohro T,
Okada Y, Yamazaki T on behalf of the JCADII
Investigators. Rationale and Design of a Study to
Examine Lower Targets for Low-Density
Lipoprotein-Cholesterol and Blood Pressure inCoronary Artery Disease Patients -The JapaneseCoronary Artery Disease Study II (JCADII)- Circ J
2008: 72(4); 515-520(3) Wang G, Watanabe M, Imai Y, Hara K, Manabe I,
Maemura K, Horikoshi M, Kohro T, Amiya E,
Sugiyama T, Fujita T, Kadowaki T, Yamazaki T,
Nagai R Genetic variations of Mrf-2/Arid5b
confer risk of coronary atherosclerosis in theJapanese population International Heart J 2008:
49(3); 313-327(4) Inoue Y, Usui M, Ohashi Y, Shiota H, Yamazaki T
Preoperative disinfection of the conjunctival Sac
with antibiotics and iodine compounds: A
prospective randomized multicenter study Jpn J
Opthalmol 2008: 52; 151-161(5) Monzen K, Ito Y, Naito A, Kasai H, Hiroi Y,
Hayashi D, Shiojima I, Yamazaki T, Miyazono K,
Asashima M, Nagai R, Komuro I A crucial role ofa high mobility group protein HMGA2 in
cardiogenesis Nature Cell Biol 2008: 10; 567-574(6) Kohro T, Hayashi D, Okada Y, Yamazaki T, Nagai
R
Demographics and changes in medical/
interventional treatment of coronary artery disease
patients over a 3.5-year period in Japan –TheJapanese Coronary Artery Disease Study: Trend
Examination- Circulation J 2008: 72; 1397-1402(7) Kurabayashi M, Yamazaki T and the SUBARU
Study Group
Superior benefit of aggressive
lipid-lowering therapy for high risk patients using
statins: the SUBARU Study J Atherosclerosis andThrombosis 2008; 15: 314-323(8) Suzuki T, Distante A, Zizza A, Trimarchi S, Villani

M, Salerno Uriarte JA, de Luca Tupputi Schinosa L,
Renzulli A, Sabino F, Nowak R, Birkhahn R,
Hollander JE, Counselman F, Bossone E, Eagle K;
International Registry of Acute Aortic Dissection
Substudy on Biomarkers (IRAD-Bio) Investigators.
Preliminary experience with the smooth muscle
troponin-like protein, calponin, as a novel
biomarker for diagnosing acute aortic dissection.
Eur Heart J 29:1439-1445, 2008
(9) Suzuki T, Nagai R. Molecular markers for
cardiovascular disease: cardiovascular biomarkers
to proteomic discovery. Nat Clin Pract Cardiovasc
Med 5:295, 2008(10) Kada N, Suzuki T, Aizawa K, Munemasa Y,
Matsumura T, Sawaki D, Nagai R. Acyclic retinoid
inhibits functional interaction of transcription
factors Krüppel-like factor 5 and retinoic acidreceptor-alpha. FEBS Lett 582:1755-1760, 2008(11) Munemasa Y, Suzuki T, Aizawa K, Miyamoto S,
Imai Y, Matsumura T, Horikoshi M, Nagai R.
Promoter region-specific histone incorporation by
the novel histone chaperone ANP32B andDNA-binding factor KLF5. Mol Cell Biol 28:
1171-1181, 2008(12) Akishita M, Hashimoto M, Ohike Y, Ogawa S,
Iiijima K, Eto M, Ouchi Y: Association of plasma
dehydroepiandrosterone-sulfate
levelswithendothelial function in postmenopausal womenwith coronary risk factors. Hypertens Res. 31:
69-74, 2008
Academic Papers in Japanese(1) Sawaki D, Suzuki T. Aortic dissection andaneurysm. Naika 102(6):1143-1150, 2008
(2) Sawaki D, Suzuki T. Etiology of aortic diseases,
up-to-date. Heart View 12(11):25-29, 2008
(3) Aizawa K, Suzuki T. Ptoteomics analysis of the
cardiovascular pathologies. Junkanki Senmoni.
16(1):43-49, 2008
(4) Aizawa K, Suzuki T. New methods for oxidized
low density lipoprotein. Igaku no ayumi.
224(5):399-402, 2008
Books
(1) Aizawa K, Suzuki T. DNA damage and repair.
Annual Review 2008 Junkanki (editorial
supervisors, Yamaguchi T, Takamoto S, Nakazawa
M, Komuro I), Chugai-Igakusha, pp23-27, 200(2) Ohike Y, The character, discrimination and417intervention of the elderly people in acute phase: 5.
Ill-treatnment. Masafumi K, Akishita M: Bedsidelearning in geriatric medicine: Nanzandou, Tokyo
183-9, 2008
(3) Ohike Y, The character, discrimination andintervention of the elderly people inacute phase: 8.
Chest pain. Masafumi K, Akishita M: Bedsidelearning in geriatric medicine: Nanzandou, Tokyo
203-8, 2008
Reviews(1) Suzuki T, Elucidation of the mechanisms ofvascular oxidative stress using proteomic
methods, Research Report of Takeda Medical
Research Foundation 35:91-97, 2008
International Conferences(1) Suzuki T, Aizawa K, Munemasa Y, Matsumura T,
Sawaki D, Kada N, Nagai R: Epigenetic control ofgene transcription at the chromatin level with afocus on Krüppel-like factors. 15th International
Vascular Biology Meeting (June 1-5, 2008, Sydney,
Australia)(2) Aizawa K, Suzuki T, Zhan H, Kada N, Sawaki D,
Matsumura T, Nagai R: Proteome analysis of anovel Pathogenic pathway of DNA damage
response as mediated by KLF5 and its
transcriptional complexes in thecardiovasculature.
15th International Vascular Biology Meeting (June
1-5, 2008, Sydney, Australia)(3) Sawaki D, Suzuki T, Aizawa K, Matsumura T, Kada
N, Munemasa Y, Nagai R: Krüppel-like Factor 5
Promotes Vascular Remodeling by Stage-specificContribution: Inhibition of Smooth Muscle Cell
Apoptosis and Stimulation of Cell Growth. 15th
International Vascular Biology Meeting (June 1-5,
2008, Sydney, Australia)(4) Shiran H, Nienaber C, Isselbacher E, Tsai T,
Meinhardt G, Cooper JV, Grzybowski M, Pyeritz R,
Braverman A, Suzuki T, Eagle K, Froehlich JB:
Effect of low suspicion presentation of type A acuteaortic dissection on care and outcomes: Data fromthe international registry of acute aortic dissection(IRAD). The American College of Cardiology 57th
Annual Scientific Session (March 29-April 1, 2008,
Chicago USA)
National Conferences(1) Munemasa Y, Suzuki T, Aizawa K, Matsumura T,
Sawaki S, MizunoY, Kada N, Nagai R: Promoter

(2)

(3)

(4)

(5)

(6)

(7)

(8)

region- specific histone incorporation by histone
chaperone p32, TAF-I and DNA-binding factor
KLF5. 31st Annual Meeting of the Molecular
Biology Society of Japan and the 81st Annual
Meeting of the Japanese Biochemical Society(December 9-12, 2008, Kobe)
Tabuse Y, Miyazaki K, Teramoto R, Fujita M,
Hattori W, Kawaura H, Munemasa Y, Matsumura T,
Aizawa K, Nagai R, Suzuki T: Detection of posttranslationally modified proteins by electrofocusing
pattern chip. 6th annual meeting of HUPO (July29-30, 2008, Osaka)
Miyazaki K, Tabuse Y, Teramoto R, Fujita M,
Hattori W, Kawaura H, Munemasa Y, Matsumura T,
Aizawa K, Nagai R, Suzuki T: Rapid profiling of
immunoprecipitated products. 6th annual meetingof HUPO (July 29-30, 2008, Osaka)
Aizawa K, Suzuki T, Hong A, Kada N, Sawaki D,
Matsumura T, Nagai R: A novel pathogenic
pathway of DNA damage response as mediated by
KLF5 and its transcriptional complexes in the
cardiovasculature. The 72nd Annual Scientific
Meeting of the Japanese Circulation Society (March
28-30, 2008, Fukuoka)
Kada N, Suzuki T, Aizawa K, Matsumura T, Takeda
N, Sawaki D, Nagai R: Acyclic Retinoid Inhibits
Vascular Remodeling by Regulating KLF5. The
72nd Annual Scientific Meeting of the Japanese
Circulation Society (March 28-30, 2008, Fukuoka)
Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Kada N, Munemasa Y, Friedman SL, Nagai R:
Krüppel-like Factor 6 is a Key Transcription Factor
that Controls Cardiac Fibrosis. The 72nd Annual
Scientific Meeting of the Japanese Circulation
Society (March 28-30, 2008, Fukuoka)
Seto M, Ohta M, Tada M, Mohri D, Asaoka Y,
Tanaka Y, Ijichi H, Kanai F, Kawabe T, Omata M.
Decreased Expression of RAS Protein Activator
Like 1 in Gastric Cancer. The 50th Annual Meetingof the Japanese Society of Gastroenterology(October 1-4, 2008, Tokyo)
Kojima T, Akishita M, Nakamura T, Nomura K,
Ohike Y, Ogawa S, Iijima K, Eto M, Ouchi Y.
Medication use as a risk factor for falls in theelderly people. 50th Annual meeting of the Japan
geriatric society (Jun 19-21, 2008, Makuhari,
Chiba.)

418

Lectures(1) Suzuki T: Novel biomarkers in cardiovasculardiseases-Focused on oxidized LDL-. Luncheon
seminar of the 55th National Congress of JapaneseSociety of Laboratory Medicine (November 29,
2008, Nagoya)(2) Suzuki T: Reconsideration of RAS inhibitors on
cardio-renal diseases. Luncheon seminar of the 38th
Eastern Regional Meeting of the Japanese Societyof Nephrology (October 11, 2008, Tokyo)(3) Suzuki T: Molecular markers for cardiovascularbiomarkers to proteomic discovery. Meet The
Specialist 2008 (August 22, 2008, The Universityof Tokyo Hospital, Tokyo)(4) Suzuki T: Proteomic analysis of cardiovascularpathologies-From chromatin remodeling tobiomarkers-. A research conference of thedepartment of nephrology, the University of Tokyo
Hospital. (July 15, 2008, The University of Tokyo
Hospital, Tokyo)

419

Division of Tissue Engineering
Director & Professor
Tsuyoshi Takato, M.D., Ph.D.

Vice Director & Professor
Ung-il Chung, M.D., Ph.D.

Project 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.,

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.

Makoto Komura, 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 of Clinical Renal Regeneration,
Department of Cartilage & Bone Regeneration,
Project for Regeneration Medicine of Hematopoiesis,
Corneal Tissue Regeneration Project, and Laboratory
for Pediatric Regenerative Medicine. We have invited
talented personnel of various fields from home andabroad. One project associate professor and one or
two project research associates who are assigned toeach department are conducting research with many
post graduate students. Aiming at clinical application
within a few years, the researchers continue theirstudies 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 Pharmaceutical

420

Co., Ltd.
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.
January,
2007
Laboratory
for
Pediatric
Regenerative Medicine was founded by department ofpediatric surgery.
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 by nanomicelle technology and to generate, to devise methods
to precisely control 3D shape of biomaterials, and totransplant 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421

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(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.
In the laboratory for pediatric regenerative medicine,
we are doing research to fabricate an engineered
airway by cells originated from trachea tissue. In
addition, the fundamental study of the amniotic fluid
cell is performed to create new therapy for new bornbabies.
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
Project for Regenerative Medicine of Hematopoiesis,
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, a clinical study onbone implants into non-loading parts (IRB approval
number #1310) was conducted on 10 patients
successfully and a large-scale clinical trial was started
across the nation. As stated above, we are proceedingtranslational research aiming at clinical application oftissue 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(1) Mimura T, Amano S, Yokoo S, Uchida S, Usui T,
Yamagami S. Isolation and distribution of rabbit
keratocyte precursors. Mol Vis. 2008;14:197203.
(2) Sugisaki K, Usui T, Nishiyama N, Jang WD,
Yanagi Y, Yamagami S, Amano S, Kataoka K.
Photodynamic
therapyforcornealneovascularization using polymeric micelles
encapsulating dendrimer porphyrins. Invest
Ophthalmol Vis Sci. 2008;49:894-899.
(3) Yokoo S, Yamagami S, Usui T, Amano S, Araie
M. Human corneal epithelial equivalents forocular surface reconstruction in a complete
serum-free culture system without unknown
factors. Invest Ophthalmol Vis Sci. 2008 Jun;49(6):2438-43.

422(4) Yokoo S, Yamagami S, Shimada T, Usui T, Sato
TA, Amano S, Araie M, Hamuro J.
A novel isolation technique of progenitor cells inhuman corneal epithelium using non-tissue
culture dishes. Stem Cells. 2008 Jul;26(7):1743-8.
Epub 2008 Apr 24.
(5) Miyata K, Oba M, Kano MR, Fukushima S,
Vachutinsky Y, Han M, Koyama H, Miyazono K,
Nishiyama N, Kataoka K. Polyplex micelles from
triblock copolymers composed of tandemlyaligned segments with biocompatible, endosomal
escaping, and DNA-condensing functions for
systemic gene delivery to pancreatic tumor tissue.
Pharmaceutical Research. 2008; 25(12):2924-36.
(6) Lee Y, Miyata K, Oba M, Ishii T, Fukushima S,
Han M, Koyama H, Nishiyama N, Kataoka K.
Charge-conversion ternary polyplex withendosome disruption moiety: a technique for
efficient and safe gene delivery. Angewandte
Chemie. International Ed. in English. 2008;
47(28):5163-6.
(7) Yasuda Y, Koyama H, Tabata Y, Fujihara Y, Oba
M, Uchinuma E, Takato T. Controlled delivery ofbFGF remodeled vascular network in muscle flap
and increased perfusion capacity via minor
pedicle. Journal of Surgical Research. 2008;
147(1):132-7.
(8) Takae S, Miyata K, Oba M, Ishii T, Nishiyama N,
Itaka K, Yamasaki Y, Koyama H, Kataoka K.
PEG-detachable polyplex micelles based on
disulfide-linked block catiomers as bioresponsive
nonviral gene vectors. Journal of the American
Chemical Society. 2008;130(18):6001-9.
(9) Fujihara Y, Koyama H, Ohba M, Tabata Y,
Fujihara H, Yonehara Y, Takato T.Controlled
delivery of bFGF to recipient bed enhances thevascularization and viability of an ischemic skinflap. Wound Repair & Regeneration. 2008;16(1):125-31.
(10) Oba M, Aoyagi K, Miyata K, Matsumoto Y, Itaka
K, Nishiyama N, Yamasaki Y, Koyama H,
Kataoka K. Polyplex micelles with cyclic RGD
peptide ligands and disulfide cross-links
directing to the enhanced transfection via
controlled intracellular trafficking. Molecular
Pharmaceutics. 2008;5(6):1080-92.
(11) Takase O, Marumo T, Hishikawa K, Fujita T,

Quigg RJ, Hayashi M. NF-kappaB-dependent
genes induced by proteinuria and identified using
DNA microarrays. Clin Exp Nephrol, 2008;12:
181-188.
(12) Marumo T, Hishikawa K, Yoshikawa M, Fujita
T. Epigenetic regulation of BMP7 in theregenerative response to ischemia. J Am Soc
Nephrol. 2008 ;19:1311-1320.
(13) Inowa T, Hishikawa K, Takeuchi T, Kitamura T,
Fujita T. Isolation and potential existence of side
population cells in adult human kidney. Int J Urol.
2008;15:272-274.
(14) Takase O, Minto AW, Puri TS, Cunningham PN,
Jacob A, Hayashi M, Quigg RJ. Inhibition of
NF-kappaB-dependent Bcl-xL expression byclusterin promotes albumin-induced tubular cell
apoptosis. Kidney International. 2008;73(5):56777.
(15) Sakai T, Matsunaga T, Yamamoto Y, Ito C,
Yoshida R, Sasaki N, Suzuki S, Shibayama M,
Chung U. Design and fabrication of a highstrength hydrogel with ideally homogeneous
network
structurefromtetrahedron-likemacromonomers. Macromolecules. 2008;41:
5379-84.
(16) Saijo H, Chung U, Igawa K, Mori Y, Chikazu D,
Iino M, Takato T. Clinical application of artificial
bone in the maxillofacial region. J Artif Organs.
2008;11:171-6.
(16) Hojo H, Igawa K, Ohba S, Yano F, Nakajima K,
Komiyama Y, Ikeda T, Lichtler AC, Woo J-T,
Yonezawa T, Takato T, Chung U. Development ofhigh-throughput screening system for osteogenic
drugs using a cell-based sensor. Biochem
Biophys Res Commun. 2008;376:375-379.
(17)Kawasaki Y, Kugimiya F, Chikuda H, Kamekura S,
Ikeda T, Kawamura N, Saito T, Shinoda Y,
Higashikawa A, Yano F, Ogasawara T, Ogata N,
Hoshi K, Hofmann F, Woodgett JR, Nakamura K,
Chung U, Kawaguchi H. Phosphorylation of
GSK-3β by cyclic GMP-dependent protein
kinase II promotes chondrocyte hypertrophy andskeletal growth. J Clin Invest. 2008;118: 25062515.
(18) Ohba S, Kawaguchi H, Kugimiya F, Ogasawara T,
Kawamura N, Saito T, Ikeda T, Fujii K, Miyajima
T, Kuramochi A, Miyashita T, Oda H, Nakamura

423

K,
TakatoT,
ChungU.
Patched1
haploinsufficiency increases adult bone mass andmodulates Gli3 repressor activity. Dev Cell.
2008;14:689-699.
(19) Tamiya H, Ikeda T, Jung JH, Saito T, Jung YK,
Kawaguchi H, Ohba S, Chung UI, Choi JY.
Analysis of the Runx2 promoter in osseous andnon-osseous cells and identification of HIF2A as
a potent transcriptional activator. Gene.2008;
416:53-60.
(20) Zhao J, Shinkai M, Ohba S, Chung U, Nagamune
T. Icariin induce osteoblastic differentiation invitro by a BMP and runx2 pathway. Biochem
Biophys Res Commun.2008;369:444-448.
(21) 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
Chemistry. 2008;390:825-832.
(22) Komura M, Komura H, Kanamori Y, Tanaka Y,
Suzuki K, Sugiyama M, Nakahara S, Kawashima
H, Hatanaka A, Hoshi K, Ikada Y, Tabata Y,
Iwanaka T. An animal model study fortissue-engineered trachea fabricated from abiodegradable scaffold using chondrocytes toaugment repair of tracheal stenosis. J Pediatr
Surg. 2008 Dec;43(12):2141-6.
(23) Komura M, Komura H, Tanaka Y, Kanamori Y,
Sugiyama M, Nakahara S, Kawashima H, Suzuki
K, Hoshi K, Iwanaka T.
Human tracheal
chondrocytes as a cell source for augmenting
stenotic tracheal segments: the first feasibility
study in an in vivo culture system. Pediatr Surg
Int. 2008 Oct;24(10):1117-21.
(24) Komura M, D. Eberli, J. J. Yoo, A. Atala (2008)
Phalanges and small Joints, in Atala A (eds):
Princeple of Regenerative Medicine. Burlington,
MA, Academic Press; pp1198-1205(25) Tanaka Y, Ogasawara T, Asawa Y, Yamaoka H,
Nishizawa S, Mori Y, Takato T, Hoshi K. 2008
Growth factor contents of autologous human sera
prepared by different production methods andtheir biological effects on chondrocytes. Cell
Biol Int. 2008;32(5):505-14.
(26) Walsh CS, Ogawa S, Karahashi H, Scoles DR,
Pavelka JC, Tran H, Miller CW, Kawamata N,
Ginther C, Dering J, Sanada M, Nannya Y,

Slamon DJ, Koeffler HP, Karlan BY. ERCC5 is a
novel biomarker of ovarian cancer prognosis. J
Clin Oncol. 2008;26:2952-2958.
(27) Sakata-Yanagimoto M, Nakagami-Yamaguchi E,
Saito T, Kumano K, Yasutomo K, Ogawa S,
Kurokawa M, Chiba S. Coordinated regulation oftranscription factors through Notch2 is an
important mediator of mast cell fate. Proc Natl
Acad Sci U S A. 2008;105:7839-7844.
(28) Ogawa S, Matsubara A, Onizuka M, Kashiwase
K, Sanada M, Kato M, Nannya Y, Akatsuka Y,
Satake M, Takita J, Chiba S, Saji H, Maruya E,
Inoko H, Morishima Y, Kodera Y, Takehiko S.
Exploration of the genetic basis of GVHD bygenetic association studies. Biol Blood Marrow
Transplant. 2008;15:39-41.
(29) Kawamata N, Ogawa S, Zimmermann M,
Niebuhr B, Stocking C, Sanada M, Hemminki K,
Yamatomo G, Nannya Y, Koehler R, Flohr T,
Miller CW, Harbott J, Ludwig WD, Stanulla M,
Schrappe M, Bartram CR, Koeffler HP. Cloningof genes involved in chromosomal translocationsbyhigh-resolution
singlenucleotide
polymorphism genomic microarray. Proc Natl
Acad Sci U S A. 2008;105:11921-11926.
(30) Kawamata N, Ogawa S, Yamamoto G, Lehmann
S, Levine RL, Pikman Y, Nannya Y, Sanada M,
Miller CW, Gilliland DG, Koeffler HP. Genetic
profiling of myeloproliferative disorders bysingle-nucleotide polymorphism oligonucleotide
microarray. Exp Hematol. 2008;36:1471-1479.
(31) Kawamata N, Dashti A, Lu D, Miller B, Koeffler
HP, Schreck R, Moore S, Ogawa S. Chronic
phase of ETV6-ABL1 positive CML responds toimatinib. Genes Chromosomes Cancer. 2008;47:
919-921.
(32) Ichikawa M, Goyama S, Asai T, Kawazu M,
Nakagawa M, Takeshita M, Chiba S, Ogawa S,
Kurokawa
M.
AML1/Runx1
Negatively
Regulates Quiescent Hematopoietic Stem Cells in
Adult Hematopoiesis. J Immunol. 2008;180:4402-4408.
(33) Goyama S, Yamamoto G, Shimabe M, Sato T,
Ichikawa M, Ogawa S, Chiba S, Kurokawa M.
Evi-1 Is a Critical Regulator for Hematopoietic
Stem Cells and Transformed Leukemic Cells.
Cell Stem Cell.2008;3:207-220.

424(34) Chen Y, Takita J, Choi YL, Kato M, Ohira M,
Sanada M, Wang L, Soda M, Kikuchi A, Igarashi
T, Nakagawara A, Hayashi Y, Mano H, Ogawa S.
Oncogenic mutations of ALK kinase inneuroblastoma. Nature. 2008;455:971-974.

425

Hospital Planning andManagement
Associate Professor
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
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 practicalapplication 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 wasincorporated under the National University
Corporation Law, the University of Tokyo Hospital
underwent drastic organizational restructuring. In
addition to the establishment of Hospital Executives,
there was also the launch of four organizations that
support hospital management (Hospital Planning andManagement; Personnel Administration and Human
Resources;
Performance
Monitoring,
Risk
Management, and Staff Development; and Education
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 thehospital. It has three full-time faculty members fromthe Department of Planning, Information andManagement, and boasts a team of two pharmacists,

two nurses, one engineering staff member, and 12
administrative staff.

Clinical activities
Hospital Planning and Management is responsible
for all of the organizational and strategic businessaffairs 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
andstandardized
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- andlong-term plans. Following is a list of hospitalmanagement achievements in which Hospital
Planning and Management 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 and GCU)

426

・ Reduced the average length of hospital stays,
and improved the bed occupancy rate
・ Achieved reductions in drug costs and costs for
medical materials
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 hospitalbuildings. At the same time, the division has
worked to develop an environment in which
medical care staff can provide high-quality andsafe 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
policyrecommendations aimed at improving the
medical system in Japan and at deregulating
medical care.
Furthermore, we point out issues related toJapan’s medical insurance system based onevidence, and we constantly issue messages fortheir improvement.

Teaching activities
Turning to postgraduate education, the division
accepts 1 doctoral student from the Department ofMedical 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 hospitalmanagement, 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 thecollection of data. The students present regularresearch progress reports, they are given thoroughinstruction on writing academic papers, and they also
follow a rigid schedule of academic presentations.

Research activities
The research activities of the division are notlimited 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
has on the length of hospital stays. The divisionalso conducted research related to the efficientuse of medical facilities, by studying therelationship between the running of operatingrooms and the number of hospital beds.
In an attempt to systemize healthcare management,
the division edited a standard textbook. The
division is also conducting research into thedevelopment 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 otherdeveloped countries. Empirical studies related tothe disparity 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 inparticular, conducted research into improvements
to the 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
for hepatitis 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 otherresearch institutes

427

References
1. Kanagawa Y, Matsumoto S, Koike S, Tajima B,
Fukiwake N, Shibata S, et al. Association ofclinical findings in Yusho patients with serum
concentrations of polychlorinated biphenyls,
polychlorinated quarterphenyls and 2,3,4,7,8pentachloro dibenzofuran more than 30 years
after the poisoning event. Environmental Health2008;7:47
2. Kanagawa Y, Matsumoto S, Koike S, Imamura T.
Association Analysis of Food Allergens. PediatricAllergy and Immunology 2008.
3. Ide H, Yasunaga H, Kodama T, Koike S, Taketani
Y, Imamura T. The Dynamics of Obstetricians andGynaecologists in Japan: A Retrospective Cohort
Model using the Nationwide Survey of Physicians
data. Journal of Obstetrics & Gynaecology
Research.
4. Koike S, Yasunaga H, Matsumoto S, Ide H,
Kodama T, Imamura T. A future estimate ofphysician distribution in hospitals and clinics inJapan. Health Policy. in press
5. Ide H, Mollahaliloglu S. How firms set prices
for medical materials: A multi-country study.
Health Policy. doi:10.1016/j.healthpol.2009.03.003
6. Ide H, Yasunaga Y, Koike S, Kodama T, Igarashi T,
Imamura T. Shortage of Pediatricians in Japan: aLongitudinal Analysis Using Physicians' Survey
Data. Pediatrics International. in press
7. Kuse H, Ide H, et al. Byouin-no-Logistics. (inJapanese) Tokyo: Hakutou-Shobou; 2009

428

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 wasestablished in April 2005 as the clinical counterpart to
the Clinical Education Center of Mental Development,
both of which are funded by the special grant forfaculty development. The major aim of the Clinical
Education Center is to train mental health specialists
in various fields with a fundamental grounding inchild psychiatry and neurosciences. Much of theservices provided are based on the 37 years ofexperience in intervention and treatment fordevelopmentally disabled children established in theformer child psychiatry division of Department of
Neuropsychiatry.
The
departmentusesamultidisciplinary
approachbyworkingincollaboration not only with the Department of
Neuropsychiatry, Department of Pediatrics andGraduate School of Education in the University ofTokyo but also several other educational and/or
clinical facilities on mental development ordevelopmental disorders. The Department of Child
Psychiatry complements the Clinical Education Centerby providing fieldwork for clinical training. It alsooffers clinical services to patients with various
development problems and places an emphasis on
research to provide evidence-based clinical andeducational activities.

In the year 2008, the Department of Child
Psychiatry consisted of 8 psychiatrists including 3
full-time child psychiatrists and 8 psychologists(full-time and part-time). Although patients withvarious disorders are seen, the focus of the department
is mainly on patients with developmental disorders.
We offer services to patients with a broad range ofdevelopmental
disorders
including
Pervasive
Developmental Disorders (PDD), Attention-Deficit/
Hyperactivity
Disorder(AD/HD),
Learning
Disabilities (LD), Mental Retardation (MR), tic
disorders and child Obsessive-Compulsive Disorders(OCD).
The number of new patients in the year 2008 was
more than 500, in contrast to 300 in the year of 2005.
This indicates an increase of about 70% comparedwith that of the year of 2005. Among the new patients,
about 50% were patients with disorders of
psychological development including LD, with PDD
being the most prevalent diagnosis. The second mostprevalent diagnosis was tic disorders (11%), followed
by AD/HD (11%) and stress-related disorders (9%).
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 toearly childhood group.

429

The number of follow-up patients has been
increasing consistently and become 2.3times of that in
the year of 2005. Among follow-up patients, disordersof psychological development were again the mostprevalent at about 50%, followed by tic disorders,stress-related disorders, AD/HD and mood disorders.
About half of the patients at follow-up were adultpatients, especially high in number were patients intheir twenties, constituting a total of 20%. Thishighlights the need for long-term follow-up in patientswith 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 ofpharmacotherapy, psychotherapy, psychoeducation
and also work closely with the schools andcommunity.
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 eachchild. “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 ofparents and providing information to the child’s
support network (relatives, schools). “Short-termgroup therapy” is a 10 session group therapy for asmall group of children with similar developmental
levels. These services are provided mainly bypsychologists under the supervision of childpsychiatrists.

intensive training course, which includes more clinicalexperience 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 100 trainees per year. Trainees
consisted of 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 thegroundwork for creating a multidisciplinary network
for professionals involved in issues related to mental
development. Feedback from questionnaires indicatedthat 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 a pediatrician, a psychiatrist, a speechtherapist, and a psychologist.
A seminar and symposium is held annually in orderto facilitate understanding of mental development anddevelopmental disorders among the general public. In
the year 2008, a seminar entitled “Facilitating social
participation of adolescents with developmental
disorders” and a symposium entitled “Understanding
and support for developmental disorders -from theview point of life-span development” each attracted an
audience of about 200 and 700 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 anddevelopment of effective treatment on PDD and
AD/HD, which are organized in collaboration with the
Department of Neuropsychiatry and other research,
Education
educational and clinical facilities. In addition, research
As part of the Clinical Education Center of Mental related specifically to the clinical activities in theDevelopment, two training courses (Course A and B) Department of Child Psychiatry is currently being
are offered for graduate level students and various investigated.
mental health professionals including psychiatrists
and pediatricians. Course A is a lecture course which Clinical evaluation and treatment
incorporates an interactive component with role-play
The reexamination of reliability and validity of
exercises and case conferences. Course B is an Ohta Staging (an evaluation system using symbol

430

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.
A comparison study of the effectiveness of
individual treatment and “short-term group therapy”
in a randomized 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.

Tourette syndrome. Dev Med Child Neurol (inpress).
2.

Kano Y, Ohta M, Nagai Y, Spector I, Budman C:
Rage attacks and aggressive symptoms in Japaneseadolescents with tourette syndrome. CNS Spectr.
13(4):325-332, 2008.

3.

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 of thecommonly recognized breakpoints in chromosome
15q11-q13 in Japanese autistic patients. Psychiatric
Genet. 18(3): 133-136, 2008.

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.

4.

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).

Genetic research
Research exploring susceptibility genes of PDD inchromosome 2, long arm of chromosome 7 and longarm of chromosome 15 are conducted. As we areinterested in gene-environment interaction, we are
examining influence of endocrinologic change
including thyroid hormone in PDD. In addition to themolecular genetic study, investigation of specificfamily and environment of Tourette syndrome is being
undertaken.

147B(7): 1008-1012, 2008.
5.

Matsumoto H, Hashimoto O, Nanba E, Nishida H,
Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato
N: Association of the neuronal cell adhesion
molecule (NRCAM) gene variants with autism. Int
J Neuropsychopharmaco. 30: 1-10, 2008.
6.

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 7.
non invasive and easily applicable to children anddevelopmentally disabled individuals.

References
1. Freeman RD, Zinner SH, Müller-Vahl KR, Fast DK,
Burd LA, Kano Y, Rothenberger A, Roessner V,
Kerbeshian J, Stern JS: Coprophenomena in

Marui T, Funatogawa I, Koishi S, Yamamoto K,

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. 62(3):341-344, 2008.
Yamasue H, Kuwabara H, Kawakubo Y, Kasai K.
Oxytocin, sexually dimorphic features of the social
brain, and autism. Psychiatry Clin Neurosci (inpress).

431

Department of Palliative Medicine
Homepage

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 2008.
The cumulative number of patients who consulted our
palliative care team was over 1300 (20.3 average daily
patients). The maximum monthly patients were 58 of
December (28.9 daily patients). According to site of
the cancer, 402 cancers were divided into 49 pancreas,
36 uterine, 32 lungs and so on. We visited almost all
the ward in the hospital. According to gender, a totalof 402 patients were divided into 219 males and 183
females. According to the age group, there were 140,
103, and 81 in sixties, seventies, and 50 years old,
respectively. These figures proved significantly theimportance 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 careby selecting an optional subject for one, two, four oreight months. And then they can participate in thepalliative care team and attend the daily conference of432

palliative 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.
○ pain control○ delirium control○ Introduction of the guideline and its use○ Basic drug therapy for palliative care
○ Spiritual care for Japanese
Clinical training schedule･ Conference: Monday - Friday (every day) 9:0010:30･ 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 nurseof The Tokyo University Graduate School of
Medicine and others participate in the daily
conference besides the regular member of the433

palliative 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, Nakamura N, Igaki H,
Tago M, Hosoi Y, Momose T, Ohtomo K, Muto T,
Nagawa H.: Preoperative Radiation Response
Evaluated by 18-Fluorodeoxyglucose Positron
Emission Tomography Predicts Survival in
Locally Advanced Rectal Cancer. Dis Colon
Rectum. 2008 ;51(7):1055-60
2. Yamashita H, Nakagawa K, Asari T, Murakami N,
Igaki H, Ohtomo K.: Radiotherapy for 41
patients with stages I and II MALT lymphoma: A
retrospective study. Radiother Oncol. 2008 Apr
16.
3. Hiroshi Igaki, Keisuke Maruyama, Masao Tago,
Masahiro Shin, Naoya Murakami, Tomoyuki

Koga, Keiichi Nakagawa, Nobutaka Kawahara,
Kuni Ohtomo: Cyst Formation after Stereotactic
Radiosurgery for Intracranial Meningioma
Stereotact Funct Neurosurg 2008;86:231-236
4. Igaki H, Nakagawa K, Shiraishi K, Shiina S,
Kokudo N, Terahara A, Yamashita H, Sasano N,
Omata M, Ohtomo K. Three-dimensional
conformal radiotherapy for hepatocellular
carcinoma with inferior vena cava invasion. Jpn J
Clin Oncol. 2008 Jun;38(6):438-44.
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. 2008 May 29.
6. Nakamura N, Sasano N, Yamashita H, Igaki H,
Shiraishi K, Terahara A, AsakagT, Nakao K,
Ebihara Y, Ohtomo K, Nakagawa K. Oral
pilocarpine (5mg t.i.d.) used for xerostomia
causes adverse effects in Japanese. Auris Nasus
Larynx. 2008 Jul 15.
7. Yamashita H, Nakagawa K, Hosoi Y, Kurokawa
A, Fukuda Y, Matsumoto I, Misaka T, Abe K.
Umami taste dysfunction in patients receiving
radiotherapy for head and neck cancer. Oral
Oncol. 2009 Mar;45(3):e19-23.
8. Miyashita M., Yasuda M., Baba R., Iwase S.,
Teramoto R., Nakagawa K., Kizawa Y. & Shima:
Inter-rater reliability of proxy simple symptom
assessment scale between physician and nurse: ahospital-based palliative care team setting.
European Journal of Cancer Care, in press
9. Igaki H, Nakagawa K, Yamashita H, Terahara A,
Haga A, Shiraishi K, Sasano N, Yamamoto K,
Onoe T, Yoda K, Ohtomo K. Contrast mediaassisted visualization of brain metastases bykilovoltage cone-beam CT. Acta Oncol. 2009;48(2):314-7
10. Hideomi YAMASHITA, Takafumi KADONO,
Kunihiko TAMAKI, Keiichi NAKAGAWA.
Interesting
responsetoconcurrent
chemoradiationinmetastatic
eccrineporocarcinoma. Journal of Dermatology 2008;
35: 606-607

434

11. Yoda K, Nakagawa K, Shiraishi K, Okano Y,
Ohtomo K, and Pellegrini RG, Doseverificationof intensity modulated arc therapy
using Ergo++ treatment planning system andElekta internal multi-leaf collimators for prostate
treatment. The British Journal of Radiology, inpress (2008).
12. Yamashita H, Nakagawa K, Asari T, Murakami N,
Igaki H, Okuma K, Ohtomo K. Concurrent
chemoradiation alone with curative intent forlimited-disease small-cell esophageal cancer innine Japanese patients. Dis Esophagus. 2008
13. Nakagawa K, Kanda Y, Yamashita H, Nakagawa
S, Sasano N, Ohtomo K, Oshima K, Kumano K,
Ban N, Minamitani Y, Kurokawa M, Chiba S.
Ovarian shielding allows ovarian recovery andnormal birth in female hematopoietic SCT
recipients undergoing TBI. Bone Marrow
Transplant. 2008
14. Nakagawa K, Yamashita H, Igaki H, Terahara A,
Shiraishi K, Yoda K. Contrast medium-assisted
stereotactic image-guided radiotherapy using
kilovoltage cone-beam computed tomography.
Radiat Med. 2008 Nov;26(9):570-2.
15. Murakami N, Itami J, Okuma K, Marino H,
Nakagawa K, Ban T, Nakazato M, Kanai, K,
Naoi K, Fuse M. Urethral Dose and Increment ofInternational Prostate Symptom Score (IPSS) in
Transperineal Permanent Interstitial Implant(TPI) of Prostate Cancer. Strahlenther Onkol.
2008 Oct;184(10):515-519.
16. Nakagawa K, Haga A, Shiraishi K, Yamashita H,
Igaki H, Terahara A, Ohtomo K, Saegusa S,
Shiraki T, Oritate T, Yoda K. First clinicalcone-beam CT imaging during volumetricmodulated arc therapy. Radiother Oncol. 2009
Mar;90(3):422-3.
17. Yamashita H, Murakami N, Asari T, Okuma K,
Ohtomo K, Nakagawa K. Correlation AmongSix Biologic Factors (p53, p21(WAF1), MIB-1,
EGFR, HER2, and Bcl-2) and Clinical Outcomes
After Curative Chemoradiation Therapy in
Squamous Cell Cervical Cancer. Int J Radiat
Oncol Biol Phys. 2008
18. Kan Y, Yamashita H, Le Pavoux A, Ushiku T,
Ohtomo K, Nakagawa K. Histological changes
after single high-dose irradiation for squamouscell carcinoma arising from a burn scar. Med
Oncol. 2009
19. Takemura N, Kokudo N, Imamura H, Takazawa Y,
Sano K, Sugawara Y, Nakagawa K, Ohtomo K,
Makuuchi M.
Eleven-year survivor ofunresectable intrahepatic cholangiocarcinoma
treatedusing
long-term
UFTtherapy.
Hepatogastroenterology. 2008
20. Iwase S, Kuroda Y. Guideline for Lymphedema,
Kanehara Publication, 2008
21. Kuroda Y, Iwase S. Menopausal symptom and its
affects to quality of life among breast cancer
patients. General Hospital Psychiatry, 2008
22. Kuroda Y, Iwase S. Comparative study of qualityof life among breast cancer patients. Japanese
Breast Cancer Society, 2008
23. Kuroda
Y,
Iwase
S,
Nakagawa
K.
Chemoradiotherapy. Nanzando, 2008
24. Kuroda Y, Iwase S, Nakagawa K. The practice of
medical oncology, 2008.

435

Clinical Genomics
Director & Professor
Shoji Tsuji, M.D., Ph.D.

Vice-director & Lecturer
Jun Goto, M.D., Ph.D.

Homepage
Organization
The Department of Clinical Genomics started asa 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.

the Departments of Cardiovascular Surgery,
Cardiovascular Medicine, Pediatrics, Spinal Surgery
and Ophthalmology.
In collaboration with Clinical Laboratory Center,
Pharmaceutical Services, Departments of Planning
Information and Management, and several clinicaldepartments we started pharmacogenetics tests in2006. Those include tests for proton inhibitor,
warfarin, irinotecan, and tacrolimus.

References
1.

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 withwhich the hospital and the faculty charge thedepartment.
To build suitable clinical systems including
modern genomic medicine we are cooperating withother departments. We are participating in Marfan’sSyndrome Clinic which is managed collaboratively by

2.

3.

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
Fukuda Y, Nakahara Y, Date H, Takahashi Y,
Goto J, Miyashita A, Kuwano R, Adachi H,
Nakamura E, and Tsuji S. SNP HiTLink: ahigh-throughput
linkageanalysis
systememploying dense SNP data. BMC Bioinformatics
10:121 doi:10.1186/1471-2105- 10-121, 2009
Hara K, Shiga A, Fukutake T, Nozaki H,
Miyashita A, Yokoseki A, Kawata H, Koyama A,
Arima K, Takahashi T, Ikeda M, Shiota H,
Tamura M, Shimoe Y, Hirayama M, Arisato T,
Yanagawa S, Tanaka A, Nakano I, Ikeda S,
Yoshida Y, Yamamoto T, Ikeuchi T, Kuwano R,
Nishizawa M, Tsuji S, Onodera O. Familial
Ischemic Cerebral Small-Vessel Disease,436

Alopecia, and Spondylosis Caused by Mutationsin the HTRA1 Gene. New Engl J Med 360:,
1729-1739, 2009
4. Hara K, Kokubo Y, Ishiura H, Fukuda Y,
Miyashita A, Kuwano R, Sasaki R, Goto J,
Nishizawa M, Kuzuhara S, and Tsuji S. TRPM7
is not associated with amyotrophic lateralsclerosis-parkinsonism dementia complex in theKii peninsula of Japan. Am. J. Med. Genet. (inpress)
5. Iwata A, Nagashima Y, Matsumoto L, Suzuki T,
Yamanaka T, Date H, Deoka K, Nukina N, Tsuji
S. J Biol Chem. (in press) 2009 Feb 13. [Epubahead of print]
6. Dick Krueger KA, Tsuji S, Fukuda Y, Takahashi
Y, Goto J, Mitsui J, Ishiura H, Dalton JC, Miller
MB, Day JD, Ranum LPW. SNP Haplotype
Mapping in a Small ALS Family. PLoS ONE.
4:e5687, 2009.
7. Mitsui, J, Mizuta, I, Toyoda, A, Ashida, R,
Takahashi, Y, Goto, J, Fukuda, Y, Date, H, Iwata,A, Yamamoto, M, Hattori, N, Murata, M, Toda,
Miyagawa T, Kawashima M, Nishida N, Ohashi J,
Kimura R, Fujimoto A, Shimada M, Morishita S,
Shigeta T, Lin L, Hong SC, Faraco J, Shin YK,
Jeong JH, Okazaki Y, Tsuji S, Honda M, Honda Y,
Mignot E, Tokunaga K. Variant between CPT1B
and CHKB associated with susceptibility to
narcolepsy. Nat Genet. 40:1324-8, 2008.
8. Miyagawa T, Kawashima M, Nishida N, Ohashi J,
Kimura R, Fujimoto A, Shimada M, Morishita S,
Shigeta T, Lin L, Hong SC, Faraco J, Shin YK,
Jeong JH, Okazaki Y, Tsuji S, Honda M, Honda Y,
Mignot E, Tokunaga K. Variant between CPT1B
and CHKB associated with susceptibility to
narcolepsy. Nat Genet. 40:1324-8, 2008.
9. Miyagawa T, Nishida N, Ohashi J, Kimura R,
Fujimoto A, Kawashima M, Koike A, Sasaki T,
Tanii H, Otowa T, Momose Y, Nakahara Y, Gotoh
J, Okazaki Y, Tsuji S, Tokunaga K. Appropriate
data cleaning methods for genome-wide
association study. J Hum Genet. 53:886-93, 2008
10. Sato, T, Miura, M, Yamada, M, Yoshida, T, Wood,JD, Yazawa, I, Masuda, M, Suzuki, S, Shin, R-M,
Yau,H-J, Liu, F-C, Shimohata, T, Onodera, O,
Ross, CA, Katsuki, M, Takahashi, H, Kano, M,
Aosaki, T and Tsuji, S. Severe neurological

11.

12.

13.

14.

phenotypes of Q129 DRPLA transgenic mice
serendipitously created by en masse expansion of
CAG repeats in Q76 DRPLA mice. Hum. Mol.
Genet. 18:723-736, 2009
Sidransky E, Aasly JO, Aharon-Peretz J, Annesi
G, Barbosa ER, Bar-Shira A, Berg D, Bras J,
Brice A, Chen C-M, Clark ON, Condroyer C, De
Marco EV, Dürr A, Eblan MJ, Fahn S, Farrer M,
Fung H-C, Gan-Or Z, Gasser T, Gershoni-Baruch
R, Giladi N, Griffith A, Gurevich T, Januario C,
Kropp R, Lang AE, Lee-Chen G-J, Lesage S,
Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta
I, Nalls MA, Nicoletti G, Oliveira C, Ottman R,
Orr-Urtreger A, Pereira LV, Quattrone A,
Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R,
Samii A, Samaddar T, Schulte C, Sharma M,
Singleton A, Spitz M, Tan E-K, Tayebi N, Toda T,
Troiano A, Tsuji S, Wittstock M, Wolfsberg TG,
Wu Y-R, Zabetian CP, Zhao Y, Ziegler SG.
International
multi-center
analysisofglucocerebrosidase mutations in Parkinson
disease. New Engl J. Med. (in press)
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 andTsuji, S. Development of high-throughput
microarray-based resequencing system forneurological disorders and its application tomolecular genetics of amyotrophic lateralsclerosis. Arch Neurol 65:1326-1332, 2008.
Takei N, Miyashita A, Tsukie T, Arai H, Asada T,
Imagawa M, Shoji M, Higuchi S, Urakami K,
Kimura H, Kakita A, Takahashi H, Tsuji S,
Kanazawa I, Ihara Y, Odani S, Kuwano R.
Genetic association study on in and around the
APOE in late-onset Alzheimer disease inJapanese. Genomics (in press)
Wang K, Takahashi Y, Gao Z-L, Wang GX, Chen
XW, Goto J, Lou J-N, Tsuji S*. Mitochondrial
ND3 as the Novel Causative Gene for Leber
Hereditary Optic Neuropathy and Dystonia.
Neurogenetics (in press)

437

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 ofMedicine and Engineering Research at The Universityof Tokyo Hospital to create a new research andeducation center, which cross-sectionally unites
medicine with engineering research for thedevelopment 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 was organized by representative members of
relevant clinical departments. The committee made adecision of the following basic principles; recruitment
for the participation to this unit should be, as a generalrule, an open call for a joint project of clinicaldepartment and engineering or pharmaceuticalresearch 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438

review and approve of the steering committee is
indispensable.
2002 October. An open call for participants to thisunit started. There were 18 applications and thesteering committee approved all projects after review.
A liaison conference of Cooperative Unit of Medicine
and Engineering Research was organized by arepresentative member of each project. Configurationof each project in a space of 554.4m2 that is consistedof a portion of the first floor and the basement of an
administration building came to a decision by theconference.
2003 May. The construction of Cooperative Unit ofMedicine and Engineering Research was completed.
The cost of the construction was shared by theparticipation 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 took 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 clinicaluse. To visualize peritoneum metastases (peritonitis)
and micro-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.
LaboratoryofMedicalUltrasoundwithMicrobubbles 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 indeep situ. To make a precise assessment on tumor
invasion in μm 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

439

including genome. In particular, they consist of
establishmentof
personalized
medicineastranslational research, selection of drug targets byproteomics,
interpretationoftranscriptional
regulations and drug development by targetingtranscription factors in cardiovascular diseases(arteriosclerosis, cardiac hypertrophy, cardiac failure,etc.). Other analyses and development are also quite
active, such as creation of transgenic animals,
analyses of genomic functions, clinical safety
monitoring by clinical database and assessments ofclinical 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 ofneuromuscular 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 Universityof Tokyo
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 andTechnology, 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 andTechnology, University of TokyoTo
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
ofImmunotherapeutics (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
ReserchTetsuo 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 toestablish cures of arteriosclerosis
Laboratory of Artificial Organs
Division of Artificial Organs & Transplantation:
Katsutoshi Naruse and Lei Guo

440

Institute of Industrial Science and Center for Disease
Biology and Integrative Medicine, Graduate School of
Medicine: Yasuyuki Sakai
Laboratory of Artificial Organs consists of researchers
belonging to Division of Artificial Organs &Transplantation, and Sakai Laboratory. We have beencollaborating in the research of bioartificial liver
support systems in the past 10 years. Our current
specialization is, development of artificial liver
support, clinical use of new apheresis therapy,
development of transgenic pig producing humanserum albumin, and development of implantable livertissue equivalents.
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 thedevelopment of the metabolic syndrome. To explore
the signal transduction pathways of major adipokines
including adiponectin
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
University of Tokyo
Laboratory 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
andvascularregeneration.
Regeneration of bone and cartilage tissue in vitro
promoted by physical stimulation

Molecular and cellular mechanics laboratory forthe development of multi-scale heart simulator
Department of Cardiothoracic Surgery, The Universityof 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 cellularphysiology and computational mechanics. For
collecting quantitative data for the simulator,
mechanical analysis of cardiomyocytes is performed.
Laboratory of Hard-Tissue Nanomedicine
Kataoka & Yamasaki Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Department of ″Menicon″ Cartilage & BoneRegeneration, Graduate School of Medicine, The
University of Tokyo
Department of Bone & Cartilage Regenerative
Medicine, Graduate School of Medicine, The
University of Tokyo
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo Department of Oraland Maxillofacial 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 ofTokyo 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 applicationof regenerated cartilage and bone. Development ofeasy, precise, non-invasive systems to detect
osteoblastic and chondroocytic differentiation.
Determination of a finite set of signaling factors
sufficient for induction of osteoblasts andchondrocytes. Development of a method to induce
osteogenesis and angiogenesis simultaneously .

441

Development of a cell-sheet culture system for bone
and cartilage. Screening for compounds that inducebone and cartilage regeneration
Cooperative Unit of Kataoka Laboratory andDepartment 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 aredeveloping 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 biocompatiblepoly(ethylene glycol) (PEG) palisades, and a varietyof pilot molecules can be installed on the surface ofpolymericmicelles.
This"virusmimicking"
nanoparticles might achieve efficient gene transfer tothe targeted tissues or cells because of protection of
the loaded DNA from nuclease attack, their lowered
non-specific interaction with proteins and cells andfacilitated internalization by the targeted cells throughspecific interaction of the pilot molecules. Currently,
our research has been focused on in vivo gene transfer
to artery walls and muscles using polymeric micelles
incorporated genes.

References
1.

2.

3.

Saijo H, Chung U, Igawa K, Mori Y, Chikazu D,
Iino M, Takato T. Clinical application of artificial
bone in the maxillofacial region. J Artif Organs
11:171-6, 2008.
Hojo H, Igawa K, Ohba S, Yano F, Nakajima K,
Komiyama Y, Ikeda T, Lichtler AC, Woo J-T,
Yonezawa T, Takato T, Chung U. Developmentof high-throughput screening system forosteogenic drugs using a cell-based sensor.
Biochem Biophys Res Commun 376:375-379,
2008.
Oshima Y, Akiyama T, Hikita A, Iwasawa M,
Nagase Y, Nakamura M, Wakeyama H,
Kawamura N, Ikeda T, Chung U, Hennighausen

L, Kawaguchi H, Nakamura K, Tanaka S.
Pivotal role of Bcl-2 family proteins in theregulation of chondrocyte apoptosis. J Biol
Chem 283:26499-508, 2008.
4. Shinoda Y, Ogata N, Higashikawa A, Manabe I,
Shindo T, Yamada T, Kugimiya F, Ikeda T,
Kawamura N, Kawasaki Y, Tsushima K, Takeda
N, Nagai R, Hoshi K, Nakamura K, Chung UI,
and Kawaguchi H: Kruppel-like factor 5 causes
cartilage degradation through transactivation of
matrix metalloproteinase 9. J Biol Chem 283:
24682-9, 2008.
5. Kawasaki Y, Kugimiya F, Chikuda H, Kamekura
S, Ikeda T, Kawamura N, Saito T, Shinoda Y,
Higashikawa A, Yano F, Ogasawara T, Ogata N,
Hoshi K, Hofmann F, Woodgett JR, Nakamura K,
Chung U, Kawaguchi H. Phosphorylation of
GSK-3β by cyclic GMP-dependent protein kinase
II promotes chondrocyte hypertrophy and skeletal
growth. J Clin Invest 118: 2506-2515, 2008.
6. Wu S, Nishiyama N, Kano MR, Morishita Y,
Miyazono K, Itaka K, Chung UI, Kataoka K.
EnhancementofAngiogenesis
Through
Stabilization of Hypoxia-inducible Factor-1 bySilencing Prolyl Hydroxylase Domain-2 Gene.
Mol Ther 16:1227-34, 2008.
7. Ohba S, Kawaguchi H, Kugimiya F, Ogasawara T,
Kawamura N, Saito T, Ikeda T, Fujii K, Miyajima
T, Kuramochi A, Miyashita T, Oda H, Nakamura
K,
TakatoT,
ChungU.
Patched1
haploinsufficiency increases adult bone mass andmodulates Gli3 repressor activity. Dev Cell 14:
689-699, 2008.
8. Tamiya H, Ikeda T, Jung JH, Saito T, Jung YK,
Kawaguchi H, Ohba S, Chung UI, and Choi JY:
Analysis of the Runx2 promoter in osseous andnon-osseous cells and identification of HIF2A as
a potent transcriptional activator. Gene 416:53-60,
2008.
9. Zhao J, Shinkai M, Ohba S, Chung U, Nagamune
T. Icariin induce osteoblastic differentiation invitro by a BMP and runx2 pathway. Biochem
Biophys Res Commun 369:444-448, 2008.
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

442

11.

12.

13.

14.

15.

16.

17.

18.

Chemistry 390:825-832, 2008.
Arata,J., Takahashi,H., Yasunaka,S., Onda,K.,
Tanaka,K., Sugita, N., Tanoue,K., Konishi,K.,
Ieiri,S.,Fujino,Y.,
Ueda,Y.,
Fujimoto,H.,
Mitsuishi,M. and Hashizume,M., “Impact of
network time-delay and force feedback ontele-surgery,” International Journal of Computer
Assisted Radiology and Surgery, Vol.3,
pp.371-378, 2008.
Norihiro Koizumi, Shin'ichi Warisawa, Hiroyuki
Hashizume, and Mamoru Mitsuishi, “Continuous
path controller for the remote ultrasounddiagnostic system,” IEEE/ASME Trans. on
Mechatronics, Vol.13, No.2, pp.206-218, 2008.
Norihiro Koizumi, Kohei Ota, Deukhee Lee, Shin
Yoshizawa, Akira Ito, Yukio Kaneko, Kiyoshi
Yoshinaka, Yoichiro Matsumoto, and Mamoru
Mitsuishi, “Feed-forward controller for the
integrated non-invasive ultrasound diagnosis andtreatment,”
Journalof
Robotics
andMechatronics, Vol.20, No.1, pp.89-97, 2008.
Mitsuishi,M., Sugita,N., Kono,I., Warisawa,S.,“Analysis of Laser Micromachining in Silica
Glass with an Absorbent Slurry,” Annals of theInternational
Institution
for
Production
Engineering Research (CIRP Annals.), vol.57/1,
pp.217-222, 2008.
Tanaka K, Sata M, Natoti T, Kim-Kaneyama J-R,
Nose K, Shibanuma M, Hirata Y, Nagai R:
Circulating progenitor cells contribute toneointimal formation in non-irradiated chimericmice. FASEB J 22:428-436, 2008
Nishimatsu H, Suzuki E, Takeda R, Takahashi M,
Oba S, Kimura K, Nagano T, Hirata Y: Blockadeof endogenous proinflammatory cytokines
ameliorates endothelial dysfunction in obese
zucker rats. Hypertens Res 31:737-743, 2008
Takeda R, Suzuki E, Takahashi M, Oba S,
Nishimatsu H, Kimura K, Nagano T, Nagai R,
Hirata
Y: Calcineurinis critical for
sodium-induced
neointimal
formationinnormotensive and hypertensive rats. Am J
Physiol Heart Circ Physiol 294:H2871- H2878,
2008
Takahashi M, Suzuki E, Takeda R, Oba S,
Nishimatsu H, Kimura K, Nagano T, Nagai R,
Hirata Y: Angiotensin II and tumor necrosis

19.

20.

21.

22.

23.

24.

25.

factor-α synergistically promote monocyte
chemoattractant protein-1 expression: roles of
NFκB, p38 and reactive oxygen species. Am J
Physiol Heart Circ Physiol 294:H2879- H2888,
2008
Nakamura K, Koibuchi N, Nishimatsu H,
Higashikuni Y, Hirata Y, Kugiyama K, Nagai R,
Sata M. Candesartan ameliorates cardiac
dysfunction observed in angiotensin-converting
enzyme 2-deficient mice. Hypertens Res
31:1953-1961, 2008
Kawaguchi M, Terai T, Utata R, Kato M,
Tsuganezawa K, Tanaka A, Kojima H, Okabe T,
Nagano T. Development of a novel fluorescentprobe for fluorescence correlation spectroscopic
detection of kinase inhibitors. Bioorg Med Chem
Lett 2008;18:3752-5
Fujikawa Y, Urano Y, Komatsu T, Hanaoka K,
Kojima H, Terai T, Inoue H, Nagano T. Designand synthesis of highly sensitive fluorogenic
substrates for glutathione S-transferase andapplication for activity imaging in living cells. J
Am Chem Soc 2008;130:14533-43
Yogo T, Urano Y, Mizushima A, Sunahara H,
Inoue T, Hirose K, Iino M, Kikuchi K, Nagano T.
Selective photoinactivation of protein function
through environment-sensitive switching of
singlet oxygen generation by photosensitizer.
Proc Natl Acad Sci U S A 2008;105:28-32
Hanaoka K, Kikuchi K, Terai T, Komatsu T,
Nagano T. A Gd3+-based magnetic resonanceimaging
contrast
agent
sensitive
tobeta-galactosidase
activity
utilizinga
receptor-induced magnetization enhancement(RIME)
phenomenon.
Chemistry
2008;14:987-95.
Matsumoto
T,
Urano
Y,
MakinoY,
Kikura-Hanajiri R, Kawahara N, Goda Y, Nagano
T. Evaluation of characteristic deuterium
distributionsofephedrines
andmethamphetamines by NMR spectroscopy for
drug profiling. Anal Chem 2008;80:1176-81
Fujita M, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R
TheJCAD Study
Investigators Pleiotropic effects of statins on
cardiovascular events in the Japanese Coronary
Artery Disease study International Journal of

443

26.

27.

28.

29.

30.

31.

32.

33.

Cardiology 2008, 129; 294-296
Nagai R, Izumi T, Kurabayashi M, Daida H, Tojo
T, Hasegawa A, Miyauchi K, Hayashi D, Kohro
T, Okada Y, Yamazaki T on behalf of the
JCADII Investigators. Rationale and Design of a
Study to Examine Lower Targets for
Low-Density Lipoprotein-Cholesterol and Blood
Pressure in Coronary Artery Disease Patients-The Japanese Coronary Artery Disease Study II(JCADII)- Circ J 2008: 72(4); 515-520
Wang G, Watanabe M, Imai Y, Hara K, Manabe I,
Maemura K, Horikoshi M, Kohro T, Amiya E,
Sugiyama T, Fujita T, Kadowaki T, Yamazaki T,
Nagai R Genetic variations of Mrf-2/Arid5b
confer risk of coronary atherosclerosis in theJapanese population International Heart J 2008:
49(3); 313-327
Inoue Y, Usui M, Ohashi Y, Shiota H, Yamazaki
T Preoperative disinfection of the conjunctival
Sac with antibiotics and iodine compounds: A
prospective randomized multicenter study Jpn J
Opthalmol 2008: 52; 151-161
Monzen K, Ito Y, Naito A, Kasai H, Hiroi Y,
Hayashi D, Shiojima I, Yamazaki T, Miyazono K,
Asashima M, Nagai R, Komuro I A crucial roleof a high mobility group protein HMGA2 in
cardiogenesis
Nature Cell Biol 2008:
10;567-574
Kohro T, Hayashi D, Okada Y, Yamazaki T,
Nagai R
Demographics and changes inmedical/interventional treatment of coronary
artery disease patients over a 3.5-year period inJapan ?The Japanese Coronary Artery Disease
Study:Trend ExaminationCirculation J
2008: 72; 1397-1402
Kurabayashi M, Yamazaki T and the SUBARU
Study Group Superior benefit of aggressive
lipid-lowering therapy for high risk patients using
statins: the SUBARU Study J Atherosclerosis
and Thrombosis 2008; 15: 314-323
Kazuhiro Imai, Isao Ohnishi, Seizo Yamamoto,Kozo Nakamura. In vivo Assessment of Lumbar
Vertebral Strength in Elderly Women using
CT-based Nonlinear Finite Element Model. Spine
Vol.33, No.1, pp27-32, 2008
Juntaro Matsuyama, Isao Ohnishi, Ryouichi
Sakai, Masahiko Bessho,Takuya Matsumoto,

34.

35.

36.

37.

38.

39.

40.

41.

Koichi Miyasaka, Akimitsu Harada, Satoru
Ohashi, Kozo Nakamura. A New Method for
Evaluation of Fracture Healing by Echo Tracking.
Ultrasound in Medicine and Biology Vol.34,
No. 5, pp. 775-783, 2008
A robot assisted hip fracture reduction with anavigation system. Joung S. Kamon H. Liao H.
Iwaki J. Nakazawa T. Mitsuishi M. Nakajima Y.
Koyama T. Sugano N. Maeda Y. Bessho M.
Ohashi S. Matsumoto T. Ohnishi I. Sakuma I.
Medical Image Computing & Computer-Assisted
Intervention: 11(Pt 2):501-8, 2008.
Douke T. Nakajima Y. Mori Y. Onogi S. Sugita N.
Mitsuishi M. Bessho M. Ohhashi S. Tobita K.
Ohnishi I. Sakuma I. Dohi T. Maeda Y. Koyama T.
Sugano N. Yonenobu K. Matsumoto Y. Nakamura
K. of the Control of fracture reduction robot
using force/torque measurement. Transactions of
the IEEE Engineering in Medicine & Biology
Society. 2008:3265-8, 2008.
NishimuraS, Manabe I, Nagasaki M, Hosoya Y,
Yamashita H, Ohsugi M, Tobe K, Kadowaki T,
Nagai R, Sugiura S In vivo imaging revealed local
cell dynamics in obese adipose tissue
inflammation J Clin Invest 118: 710-721 (2008)
Nishimura S, Seo K, Hosoya Y, Nagasaki M,
Yamashita H, Fujita H, Nagai N, Sugiura S
Responses of single ventricular myocytes todynamic axial stretching Prog Biophys Mol Biol
97: 282–297 (2008)
Ohnuki Y, Nishimura S, Sugiura S, Saeki Y
Phosphorylation Status of Regulatory Proteinsand Functional Characteristics in Myocardium of
Dilated Cardiomyopathy of Syrian Hamsters. J
Physiol Sci 58:15-20. (2008)
Watanabe H, Sugiura S, Hisada T The looped
heart does not save energy by maintaining the
momentum of blood flowing in the ventricle Am
J Physiol 294: H2191–H2196 (2008)
Katayama S, Umetani N, Sugiura S, Hisada T,
The sinus of Valsalva relieves abnormal stress onaortic valve leaflets by facilitating smoothclosure J Thorac Cardiovasc Surg 136:1528-1535(2008)
Sugi H, Minoda H, Inayoshi Y, Yumoto F,
Miyakawa T, Miyauchi Y, Tanokura M, Akimoto
T, Kobayashi T, Chaen S, Sugiura S Direct

444

42.

43.

44.

45.

46.

47.

48.

49.

50.

demonstration of the cross-bridge recovery strokein muscle thick filaments in aqueous solution byusing the hydration chamber Poc Natl Acad Sci
USA 105:17396–17401 (2008)
Hashimoto T, Deguchi J, Endo H, and Miyata T
Successful treatment tailored to each splanchnicarterial lesion due to segmental arterial
mediolysis (SAM): report of a case J Vasc Surg
48: 1338-1341, 2008
Takayama T, Miyata T, Shirakawa M, andNagawa H. Isolated spontaneous dissection of thesplanchnic arteries. J Vasc Surg 48: 1338-1341,
2008.
Yamamoto K, Kimura H, Murayama T, Kashima
T, Kikuchi Y, Akiyama T, Kawano H, Miyata T,
and Nagawa H. Chronic expanding hematoma in
combination with a pseudoaneurysm: a casereport. Int Angiol 27: 366-268, 2008.
Shigematsu K, Choudhury NA, Kanetaka T, Saito
T, Takazawa Y, Miyata T, Shigematsu H.
Aneurysm of gastroepiploic artery and vein withan arteriovenous fistula after partial gastrectomy
in a patient with abdominal aortic aneurysm-report of a case. Ann Vasc Disease 1: 52-55,
2008.
KS Furukawa, K Imura, T Tateishi, T Ushida,
Scaffold-free cartilage by rotational culture fortissue engineering, Journal of Biotechnology,
133:134-145 (2008)
Mizoguchi F, Mizuno A, Hayata T, Nakashima K,
Heller S, Ushida T, Sokabe M, Miyasaka N,
Suzuki M, Ezura Y, Noda M. , Transient receptor
potential vanilloid 4 deficiency suppresses
unloading-induced bone loss. J Cell Physiol. Jul;
216(1):47-53. (2008)
Toshihiro Nagai, Katsuko S. Furukawa, Masato
Sato, Takashi Ushida, and Joji Mochida,
Characteristics of a Scaffold-Free Articular
Chondrocyte Plate Grown in Rotational Culture ,Tissue Engineering Part A, 14(7): 1183-1193(2008)
Kawaguchi H: Endochondral ossification signals
in cartilage degradation during osteoarthritis
progression in experimental mouse models. Mol
Cells 25: 1-6, 2008.
Yamakawa K, Kamekura S, Kawamura N,
Saegusa M, Kamei D, Murakami M, Kudo I,

51.

52.

53.

54.

55.

56.

Uematsu S, Akira S, Chung UI, Nakamura K, andKawaguchi H: Association of microsomal
prostaglandin E synthase 1 deficiency with
impaired fracture healing, but not with bone loss
or osteoarthritis, in mouse models of skeletal
disorders. Arthritis Rheum 58: 172-183, 2008.
Kyomoto M, Moro T, Miyaji F, Konno T,
Hashimoto M, Kawaguchi H, Takatori Y,
Nakamura K, and Ishihara K: Enhanced wear
resistance of orthopaedic bearing due to thecross-linking of poly (MPC) graft chains induced
by gamma-ray irradiation. J Biomed Mater Res
B 84: 320-327, 2008.
Tamiya H, Ikeda T, Jung JH, Saito T, Jung YK,
Kawaguchi H, Ohba S, Chung UI, and Choi JY:
Analysis of the Runx2 promoter in osseous andnon-osseous cells and identification of HIF2A as
a potent transcriptional activator. Gene 416:
53-60, 2008.
Ohba S, Kawaguchi H, Kugimiya F, Ogasawara T,
Kawamura N, Saito T, Ikeda T, Fujii K, Miyajima
T, Kuramochi A, Miyashita T, Oda H, Nakamura
K, Takato T, and Chung UI: Patched1
haploinsufficiency increases adult bone mass andmodulates Gli3 repressor activity. Dev Cell 14:
689-699, 2008.
Kawasaki Y, Kugimiya F, Chikuda H, Kamekura
S, Ikeda T, Kawamura N, Saito T, Shinoda Y,
Higashikawa A, Yano F, Ogasawara T, Ogata N,
Hoshi K, Hofmann F, Woodgett JR, Nakamura K,
Chung UI, and Kawaguchi H: Phosphorylation of
GSK-3β by cGMP-dependent protein kinase IIpromotes hypertrophic differentiation of murinechondrocytes. J Clin Invest 118: 2506-2515,
2008.
Kyomoto M, Moro T, Miyaji F, Hashimoto M,
Kawaguchi H, Takatori Y, Nakamura K, andIshihara K: Effect of 2-methacryloyloxyethyl
phosphorylcholine concentration on photoinduced graft polymerization of polyethylene inreducing the wear of orthopaedic bearing surface.
J Biomed Mater Res A 86: 439-47, 2008.
Shinoda Y, Ogata N, Higashikawa A, Manabe I,
Shindo T, Yamada T, Kugimiya F, Ikeda T,
Kawamura N, Kawasaki Y, Tsushima K, Takeda
N, Nagai R, Hoshi K, Nakamura K, Chung UI,
and Kawaguchi H: Krüppel-like factor 5 causes

445

57.

58.

59.

60.

61.

62.

63.

cartilage degradation through transactivation of
matrix metalloproteinase 9. J Biol Chem 283:
24682-24689, 2008.
Oshima Y, Akiyama T, Hikita A, Iwasawa M,
Nagase Y, Nakamura M, Wakeyama H,
Kawamura N, Ikeda T, Chung UI, Hennighausen
L, Kawaguchi H, Nakamura K, and Tanaka S:
Pivotal role of Bcl-2 family proteins in theregulation of chondrocyte apoptosis. J Biol
Chem 283: 26499-26508, 2008.
Oka H, Muraki S, Akune T, Mabuchi A, Suzuki T,
Yoshida H, Yamamoto S, Nakamura K,
Yoshimura N, and Kawaguchi H: Fully automaticquantification of knee osteoarthritis severity on
plain radiographs. Osteoarthritis Cartilage 16:
1300-1306, 2008.
Nicholas Herlambang, Hongen Liao, Kiyoshi
Matsumiya, Ken Masamune, Takeyoshi Dohi,
Real-Time Autostereoscopic Visualization ofRegistration-Generated 4D MR Image of Beating
Heart, Medical Imaging and Augmented Reality
4th International Workshop Tokyo, Japan(MIAR2008, LNCS 5128), 349-358, August 2008
Herlambang N., Liao H., Matsumiya K.,
Masamune
K.,
Dohi
T.,
Interactive
Autotereoscopic Medical Image Visualization
Systemusing
GPU-accelerated
IntegralVideography
DirectVolumeRendering,International Journal of Computer Assisted
Radiology and Surgery, Barcelona, Spain, Vol.3
Suppl. 1, S110-111, June 2008
Masamune K., Mizutani M., Tsukihara H.,
Takamoto S., Matsumiya K., Dohi T., A new
blood-permeable endoscope system with plasma
flushing for off-pump cardiac surgery,
International Journal of Computer Assisted
Radiology and Surgery, Barcelona, Spain, Vol.3
Suppl. 1, S245-246, June 2008
Huy Hoang Tran, Hongen Liao, Kiyoshi
Matsumiya, Ken Masamune, Takeyoshi Dohi:
Development of interactive three-dimensional
autostereoscopic image for surgical navigation
system, 7th Asian-Pacific Conference on Medical
and Biological Engineering: APCMBE 2008,
Beijing, China, 745-749, April 2008
Oba M, Aoyagi K, Miyata K, Matsumoto Y, Itaka
K, Nishiyama N, Yamasaki Y, Koyama H,

64.

65.

66.

67.

68.

69.

70.

Kataoka K. Polyplex micelles with cyclic RGD
peptide ligands and disulfide cross-links directing
to the enhanced transfection via controlled
intracellular trafficking. Mol Pharm. 2008, 5(6):1080-92.
Miyata K, Oba M, Nakanishi M, Fukushima S,
Yamasaki Y, Koyama H, Nishiyama N, Kataoka
K. Polyplexes from poly(aspartamide) bearing
1,2-diaminoethaneside
chainsinducepH-selective,endosomal
membranedestabilization with amplified transfection andnegligible cytotoxicity. J Am Chem Soc. 2008,
130(48):16287-94.
Miyata K, Oba M, Kano MR, Fukushima S,
Vachutinsky Y, Han M, Koyama H, Miyazono K,
Nishiyama N, Kataoka K. Polyplex micelles from
triblock copolymers composed of tandemlyaligned segments with biocompatible, endosomal
escaping, and DNA-condensing functions for
systemic gene delivery to pancreatic tumor tissue.
Pharm Res. 2008. 25(12):2924-36.
Lee Y, Miyata K, Oba M, Ishii T, Fukushima S,
Han M, Koyama H, Nishiyama N, Kataoka K.
Charge-conversion ternary polyplex withendosome disruption moiety: a technique for
efficient and safe gene delivery. Angew Chem Int
Ed Engl. 2008;47(28):5163-6.
Wu S, Nishiyama N, Kano MR, Morishita Y,
Miyazono K, Itaka K, Chung UI, Kataoka K.
Enhancementofangiogenesis
throughstabilization of hypoxia-inducible factor-1 bysilencing prolyl hydroxylase domain-2 gene. Mol
Ther. 2008, 16(7):1227-34.
Takae S, Miyata K, Oba M, Ishii T, Nishiyama N,
Itaka K, Yamasaki Y, Koyama H, Kataoka K.
PEG-detachable polyplex micelles based on
disulfide-linked block catiomers as bioresponsive
nonviral gene vectors. J Am Chem Soc. 2008,
130(18):6001-9.
Sugisaki K, Usui T, Nishiyama N, Jang WD,
Yanagi Y, Yamagami S, Amano S, Kataoka K.
Photodynamic
therapyforcornealneovascularization using polymeric micelles
encapsulating dendrimer porphyrins. Invest
Ophthalmol Vis Sci. 2008, 49(3):894-9.
Wu S, Murai S, Kataoka K, Miyagishi M. Yin
Yang 1 induces transcriptional activity of p73

446

71.

72.

73.

74.

75.

76.

77.

78.

through cooperation with E2F1. Biochem
Biophys Res Commun. 2008, 365(1):75-81
Sakai T, Matsunaga T, Yamamoto Y, Ito C,
Yoshida R, Sasaki N, Suzuki S, Shibayama M,
Chung U. Design and fabrication of a highstrength hydrogel with ideally homogeneous
network
structurefromtetrahedron-likemacromonomers. Macromolecules. 2008;41:
5379-84.
Saijo H, Chung U, Igawa K, Mori Y, Chikazu D,
Iino M, Takato T. Clinical application of artificial
bone in the maxillofacial region. J Artif Organs.
2008;11:171-6.
Hojo H, Igawa K, Ohba S, Yano F, Nakajima K,
Komiyama Y, Ikeda T, Lichtler AC, Woo J-T,
Yonezawa T, Takato T, Chung U. Developmentof high-throughput screening system forosteogenic drugs using a cell-based sensor.
Biochem Biophys Res Commun.2008;376:375379.
Kawasaki Y, Kugimiya F, Chikuda H, Kamekura
S, Ikeda T, Kawamura N, Saito T, Shinoda Y,
Higashikawa A, Yano F, Ogasawara T, Ogata N,
Hoshi K, Hofmann F, Woodgett JR, Nakamura K,
Chung U, Kawaguchi H. Phosphorylation of
GSK-3β by cyclic GMP-dependent protein kinase
II promotes chondrocyte hypertrophy and skeletal
growth. J Clin Invest. 2008;118: 2506-2515.
Ohba S, Kawaguchi H, Kugimiya F, Ogasawara T,
Kawamura N, Saito T, Ikeda T, Fujii K, Miyajima
T, Kuramochi A, Miyashita T, Oda H, Nakamura
K,
TakatoT,
ChungU.
Patched1
haploinsufficiency increases adult bone mass andmodulates Gli3 repressor activity. Dev Cell.
2008;14:689-699.
Tamiya H, Ikeda T, Jung JH, Saito T, Jung YK,
Kawaguchi H, Ohba S, Chung UI, Choi JY.
Analysis of the Runx2 promoter in osseous andnon-osseous cells and identification of HIF2A as
a potent transcriptional activator. Gene.2008;
416:53-60.
Zhao J, Shinkai M, Ohba S, Chung U, Nagamune
T. Icariin induce osteoblastic differentiation invitro by a BMP and runx2 pathway. Biochem
Biophys Res Commun.2008;369:444-448.
Jang K, Sato K, Igawa K, Chung U, Kitamori T.
Development of an osteoblast cell-based 3D

79.

80.

81.

82.

83.

84.

85.

86.

continuous perfusion microfluidic system for
drug
screening.
Analytical
Bioanalytical
Chemistry. 2008;390:825-832.
Tanaka Y, Ogasawara T, Asawa Y, Yamaoka H,
Nishizawa S, Mori Y, Takato T, Hoshi K. 2008
Growth factor contents of autologous human sera
prepared by different production methods andtheir biological effects on chondrocytes. Cell Biol
Int. 2008;32(5):505-14.
Yoshinaka K, Yoshizawa S, Iida N, Kajiyama K,
Maruyama T, Takagi S, Matsumoto Y, "HIFU
Treatment
with
Varying
Microbubble
Conditions", Int J CARS(2008)3(Suppl 1),
Proceedings of the 22nd International Congress
and Exhibition, S283, 2008
Yoichiro Matsumoto,Shin Yoshizawa,Shu Takagi,"Nonlinear Phenomena of Acoustic Cloud
Cavitation",NONLINEAR
ACOUSTICSFUNDAMENTALS AND APPLICATIONS,
pp237-240, 2008
Yoji Nakamura, Kiyoshi Yoshinaka, Shu Takagi,
Yoichiro Matsumoto, "Ultrasound gene transfer
into fibroblast cells under microbubble", 8thInternational
symposiumon
Therapeutic
Ultrasound, pp433-437, 2008
Ryuhei Ohta, Kiyoshi Yoshinaka, Shu Takagi,
Yoichiro Matsumoto, "Development of HIFU
Therapy System for Lower Extremity Varicose
Veins", 8th International symposium on
Therapeutic Ultrasound, pp362-366, 2008
Yoichiro Matsumoto, Shu Takagi, Numerical
Simulations of Deformed Red Blood Cells in
Capillary
Vessels,
ASME
International
MechanicalEngineering
CongressandExposition, IMECE2008-66099, 2008
A. Mori, T. Kato, K. Mizuno, N. Yusa, R.
Okayasu, M. Uesaka"DNA damage induced bycolloidal gold or its combined effect with
X-rays"10th International Workshop on Radiation
Damage to DNA 2008/6/8
Mitsuru Uesaka, Hiroki Taguchi, Azusa Mori,
Noritaka
Yusa,Takamitsu
Kato,
RyuichiOkayasu,"Application of monochromatic keV
X-ray source to X-ray drug delivery system"ICFA
Workshop on "Compton Sources for X/gamma
rays: Physics and Applications"" ,Porto Conte,
Alghero (Sardinia) Italy, 2008/9/7-12

447

87. Miyatake A, Nishio T, Ogino T, Saijo N, Uesaka
M "Verification of positron emitter nuclei
generated in human body by proton irradiation"
50th Annual Meeting of the American Society for
Therapeutic Radiology and Oncology 2008/9
88. Hiroki Taguchi, Noritaka Yusa, Akira Sakumi,
Fumito Sakamoto, Eiko Hashimoto, Tomohiko
Yamamoto, Takuya Natsui, Yoshihiro Taniguchi,
Mitsuru Uesaka" Medical Application of Dualenergy X-ray CT using Compton Scattering
Monochromatic X-ray Source" The 5th KOREAJAPAN Joint Meeting on Mediacal Physics
2008/989. Kazue Mizuno, Azusa Mori, Noritaka Yusa,
Teruaki Konishi, Tsuyoshi Hamano, Takahiro
Ishikawa, Hiroyuki Iso, Takamitsu Kato, Ryuichi
Okayasu, Hitoshi Imaseki, Mitsuru Uesaka"
PIXE
ANALYSISOFPLATINUMCONTAINING DDS DRUGS"the 8th AsiaOceania Congress of Medical Physics (AOCMP)
and 6th Southeast Asian Congress of Medical
Physics (SEACOMP) 2008/11
90. Nakagawa K, Yamashita H, Nakamura N, Igaki H,
Tago M, Hosoi Y, Momose T, Ohtomo K, Muto T,
Nagawa H.: Preoperative Radiation Response
Evaluated by 18-Fluorodeoxyglucose Positron
Emission Tomography Predicts Survival in
Locally Advanced Rectal Cancer. Dis Colon
Rectum. 2008 ;51(7):1055-60
91. Yamashita H, Nakagawa K, Asari T, Murakami N,
Igaki H, Okuma K, Ohtomo K. Concurrent
chemoradiation alone with curative intent forlimited-disease small-cell esophageal cancer innine Japanese patients. Dis Esophagus. 2008 Oct
1.
92. Nakagawa K, Yamashita H, Igaki H, Terahara A,
Shiraishi K, Yoda K. Contrast medium-assisted
stereotactic image-guided radiotherapy using
kilovoltage cone-beam computed tomography.
Radiat Med. 2008 Nov;26(9):570-2.
93. Murakami N, Itami J, Okuma K, Marino H,
Nakagawa K, Ban T, Nakazato M, Kanai, K,
Naoi K, Fuse M. Urethral Dose and Increment ofInternational Prostate Symptom Score (IPSS) in
Transperineal Permanent Interstitial Implant(TPI) of Prostate Cancer. Strahlenther Onkol.
2008 Oct;184(10):515-519.

94. Nakagawa K, Haga A, Shiraishi K, Yamashita H,
Igaki H, Terahara A, Ohtomo K, Saegusa S,
Shiraki T, Oritate T, Yoda K. First clinicalcone-beam CT imaging during volumetricmodulated arc therapy. Radiother Oncol. 2009
Mar;90(3):422-3.

University Hospital
Pharmaceutical Service

449

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Associate Professor
Kousei Ito, Ph.D.

Research Associate
Tomonobu Uchino, Ph.D.,
Kazuo Takayama,
Takehito Yamamoto

Yuko Sekine, Ph.D.,
Masashi Honma,

Tappei Takada, Ph.D.,
Yoshitsugu Yanagihara, Ph.D.,

Homepage http://square.umin.ac.jp/todaiyak/index.html
Introduction and Organization
We have 9 faculty members, 52 pharmacy staffs, 32
pharmacy residents, and 14 graduate students and 5
undergraduate students from the faculty ofpharmaceutical sciences (as of December 1st, 2008).
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, automatic dispensing system andbar code label printer 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). In order tosupport advanced medical care, they develop andcheck formulations (characterization of theuniformity, 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
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450

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. 2,260 items), out-patient medicines,
anesthetics, muscle relaxation drugs, psychotropic
drugs, poison medicines.
5) Nacrotic section
Under the supervision of authorized manager fornarcotics (the director of the pharmacy
department), narcotics are properly managed,
recorded, reported, inspected and directed.
Nacrotics 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 Hematology andOncology.
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 2008)
Number of items on in-hospital formulary:
2,260
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
475,890 ps.
(outside :406,171 ps.)(inside :69,719 ps.)
Out-patient chemotherapy:
6,786 ps.
in-patients:
213,518 ps.
injection drugs:
189,552 ps.
IVH:
16,686 pp.
chemotherapy:
12,570 pp.
TDM consultations (annual) :15,660
Numbers of hospital pharmaceutical cares (annual):
3,730

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)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"

451(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 2008, 32 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) Basic and clinical approach to prevent and curedrug induced liver injury.
3) Intracellular trafficking and dynamic rearrangementof transporter complexes.
4) Regulation of intracellular trafficking andtranscription of signaling molecules involved inbone homeostasis

5) Polymorphism of drug metabolizing enzymes andtransporters. Quantitative prediction of clinicaleffects.
6) 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) Yoshida N, Takada T, Yamamura Y, Adachi I,
Suzuki H, Kawakami J. Inhibitory effects ofterpenoids on multidrug resistance-associatedprotein 2- and breast cancer resistance proteinmediated transport. Drug Metab Dispos 2008; 36:
1206-1211.
(2) Sekine S, Ito K, Horie T. Canalicular Mrp2
localization is reversibly regulated by the
intracellular redox status. Am J Physiol
Gastrointest Liver Physiol 2008; 295: G10351041.
(3) Ohno Y, Hisaka A, Ueno M, Suzuki H. Generalframework for the prediction of oral druginteractions caused by CYP3A4 induction fromin vivo information. Clin Pharmacokinet 2008;
47: 669-680.
(4) Narushima K, Takada T, Yamanashi Y, Suzuki H.
Niemann-pick C1-like 1 mediates alphatocopherol transport. Mol Pharmacol 2008; 74:
42-49.
(5) Kobayashi K, Ito K, Takada T, Sugiyama Y,
Suzuki H. Functional analysis of nonsynonymous
single nucleotide polymorphism type ATPbinding cassette transmembrane transporter
subfamily C member 3. Pharmacogenet
Genomics 2008; 18: 823-833.
(6) Iwayanagi Y, Takada T, Suzuki H. HNF4alpha isa Crucial Modulator of the CholesterolDependent Regulation of NPC1L1. Pharm Res
2008; 25: 1134-1141.
(7) Ito K, Hoekstra D, van Ijzendoorn SC.
Cholesterol but not association with detergent
resistant membranes is necessary for thetransport function of MRP2/ABCC2. FEBS Lett
2008; 582: 4153-4157.
(8) Ito K. ABCC2/Abcc2 transport property in452

different species and its modulation byheterogeneous
factors.
Drug
Metab
Pharmacokinet 2008; 23: 394-405.
International Meeting(1) Suzuki H, Yoshikado T, Ito K, Takada T.
Functional analysis of ABCB4 and its mutants invitro 2nd FEBS Special Meeting ABC2008;
Innsbruck, Austria: (2008, March).
(2) Hisaka A, Hibino Y, Kusama M, Hisaki H,
Suzuki H. Evaluation of Intrinsic Clearance ofVarious Drugs Using Human Liver Microsome
with CYP2D6*10 Variant. 2nd Asian Pacific
ISSX meeting; Shanghai, China: ( 2008, May).
(3) Suzuki H, Takada T. Mechanism of regulation ofbile acid transport in the small intestine. Falk
Symposium 165: XX International Bile Acid
Meeting, Amsterdam, The Netherlands: (2008,
June).
(4) Ikebuchi Y, Takada T, Ito K, Yoshikado T, Anzai
N, Kanai Y, Suzuki H. Molecular associations of
ABCB4 with RACK1 regulates its cellular
localization and function. Falk Symposium 165;
Amsterdam, Netherlands: (2008, June).

Center for Disease Biology andIntegrative Medicine

454

Laboratory of Molecular
Biomedicine for Pathogenesis
Professor
Toru Miyazaki, M.D., Ph.D.

Lecturer/Associate Professor
Satoko Arai, Ph.D.

Assistant Professor
Katsuhiko Nakashima, 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 the455

maturational 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
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 vi vo and in vit ro.
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. 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 (-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 WORKSHOPIn 2007, we had a workshop at Unzen, a great resort
place in Nagasaki prefecture. Along the policy for
DBELS, we invited 8 top-scientists from Kyoto,
Tokyo, Hokkaido, Okinawa, and Boston as lecturers,
and many young participants as audiences. Staying ina beautiful resort hotel, we all had a scientifically andculturally fruitful time. The next workshop is
scheduled to be held in Switzerland, probably in 2010
summer.
Music and ScienceAs an opening ceremony of our lab, we invited
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. Bhatia, H., Hallock, J.L., Sterner, L.S., Karkashon,S., Miyazaki, T., Dean, A., & Little, J.A. A

456

2.

3.

4.

5.

6.

7.

8.

9.

short-chain fatty acid mediated reversed globin
gene switch in primary definitive erythroid cells.
Blood 113: 6440-8 (2009)
Kurabe, N., Arai, S., Nishijima, A., Kubota, N.,
Suizu,
F.,
Mori,
M.,
Kurokawa,
J.,
Kondo-Miyazaki, M., Ide, T., Murakami, K.,
Miyake, K., Ueki, K., Koga, K., Yatomi, Y.,
Tashiro, F., Noguchi, M., Kadowaki, T., &Miyazaki,
T.
The
death
effectordomain-containing DEDD supports S6K1 activity
via preventing Cdk1-dependent inhibitory
phosphorylation. J. Biol. Chem. 284 : 5050-5055(2009)
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).
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).
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).
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).
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/Sp/Api6 in atherosclerosis development.
Cell Metab. 1: 201-213 (2005).
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).
Haks, M.C., Lefebvre, J.M., Lauritsen, J.P.H.,

Carleton, M., Rhodes, M., Miyazaki, T., Kappes,
D.J. & Wiest, D.L. Attenuation of TCR
signaling efficiently diverts thymocytes to the 
lineage. Immunity 22: 595-606 (2005).
10. 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).
11. 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).
12. 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).
13. 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).
14. 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).
15. 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).
16. 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
cysteine-rich domain superfamily. J. Exp. Med.
189:413-422 (1999).

457

17. 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).
18. 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).
19. Miyazaki, T., Müller, U. & Campbell, K.S.
Normal development but differentially alteredproliferative responses of lymphocytes in micelacking CD81. EMBO. J. 16: 4217-4225. (1997).
20. 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).
21. Miyazaki, T., Dierich, A., Benoist, C. & Mathis D.
Independentmodesofnaturalkilling
distinguished in mice lacking Lag3. Science 272:405-408 (1996).
22. 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).
23. 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).

458

Laboratory ofStructural Physiology
Professor
Haruo Kasai, M.D.,Ph.D.

Associate Professor
Masanori Matsuzaki, Ph.D.

Lecturer
Noriko Takahashi, M.D., Ph.D.

Research Associate
Jun Nogichi, Ph.D., Satoshi Watanabe, Ph.D.

Homepage

http://www.bm2.m.u-tokyo.ac.jp/

Introduction and Organization

Research activities

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 forPhysiological Sciences at that time, and officially took
office in the University of Tokyo in November, 2005.
The Kasai laboratory has moved to the first buildingof Faculty of Medicine in January, 2006. Ourlaboratory belongs to the Section of Functional
Biology in the Graduate School of Medicine. The
name of our laboratory has been changed from
Division of Biophysics to Laboratory of Structural
Physiology in the April, 2008.

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

Teaching activities
In 2008, 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 ourown laboratory.

459

biomedical applications.
1) The subspine organization of actin fibers regulates
the structure and plasticity of dendritic spines.
Synapse function and plasticity depend on thephysical structure of dendritic spines as determined by
the actin cytoskeleton. We have investigated theorganization of filamentous (F-) actin within
individual spines on CA1 pyramidal neurons in slicesofrat
hippocampus.
Using
two-photon
photoactivation of green fluorescent protein fused toβ-actin, we found that a dynamic pool of F-actin at the
tip of the spine quickly treadmilled to generate an
expansive force. The size of a stable F-actin pool at
the base of the spine depended on spine volume.
Repeated two-photon uncaging of glutamate formed athird pool of F-actin and enlarged the spine. Creationof this "enlargement pool" required calmodulin. The
spine often released the enlargement pool into thedendritic shaft, but the pool had to be physicallyconfined by a spine neck for the enlargement to belong-lasting.
Ca2+/calmodulin-dependent
proteinkinase II regulated this confinement. Thus, we haverevealed that spines have a mechanical nature that isregulated by the three pools of F-actin (Ref. 1).
2) Protein-Synthesis and Neurotrophin Dependent
Structural Plasticity of Single Dendritic Spines
Long-term potentiation (LTP) at glutamatergic synapses is considered to underlie learning and memory,and is associated with enlargement of dendritic spines.
Because consolidation of memory and LTP requires
protein synthesis, it is important to clarify how protein
synthesis affects spine enlargement.
Repetitive
pairing of postsynaptic spikes and two-photon uncaging of glutamate at single spines (spike-timing protocol) displayed both immediate and gradual phases ofspine enlargement in CA1 pyramidal neurons. The
gradual enlargement was strongly dependent on protein-synthesis and BDNF action, often associated withspine twitching, and was induced specifically at thespines which were immediately enlarged by the synaptic stimulation. Thus, spike-timing protocol is anefficient trigger for BDNF secretion, and induces protein-synthesis dependent long-term enlargement at thelevel of single spines (Ref. 2).

3) Principles of Long-Term Dynamics of Dendritic
SpinesLong-term potentiation (LTP) of synapse strength
requires enlargement of dendritic spines on cerebral
pyramidal neurons. Long-term depression (LTD) is
linked to spine shrinkage. Indeed, spines are dynamic
structures: they form, change their shapes andvolumes or can disappear in the space of hours. Do allsuch changes result from synaptic activity, or do somechanges result from intrinsic processes? How doenlargement and shrinkage of spines relate toelimination and generation of spines, and how dothese processes contribute to the stationary
distribution of spine volumes? To answer thesequestions, we recorded the volumes of many
individual spines daily for several days using
two-photon imaging of CA1 pyramidal neurons in
cultured slices of rat hippocampus between postnatal
day 17 to 23. With normal synaptic transmission,spines often changed volume or were created oreliminated, thereby showing activity-dependent
plasticity. However, we found that spines changed
volume even after we blocked synaptic activity,
reflecting a native instability of these small structures
over the long term. Such “intrinsic fluctuations”
showed unique dependence on spine volume. A
mathematical model constructed from these data andthe theory of random fluctuations explains population
behaviors of spines, such as rates of elimination andgeneration, stationary distribution of volumes and thelong-term persistence of large spines. Our study findsthat generation and elimination of spines are moreprevalent than previously believed, and spine volume
shows significant correlation with its age and life
expectancy. The population dynamics of spines also
predict key psychological features of memory(Ref. 3).
4) Three-dimensional mapping of unitary synaptic
connections by twophoton macro photolysis of caged
glutamate.
To understand the precise microarchitecture of thecortical circuitry, it is crucial to know the distributionof synaptic connections and their synaptic strengths at
the level of a single cell, rather than a group of cells.
Here, we describe a new application of two-photon
photolysis of caged glutamate that enabled us toinduce an action potential in only a small number (~5)
of pyramidal neurons by increasing the volume of

460

two-photon excitation by reducing the effective
numerical aperture of the objective. We performed
whole-cell patch-clamp recordings from layer 2/3
pyramidal neurons in the rat visual cortex andstimulated many neurons in a large three-dimensional
space (~600 x 600 x 100μm) including neurons inlayers 2/3 and 4 using this new technique. We mapped
the density and amplitude of unitary excitatory
postsynaptic currents and found that the basic
microarchitecture of excitatory synaptic connections
consists of two regions: a columnar, dense core region
with a radius of 150 μm and an outer, sparse region.
The dense core region includes the majority of strong
synaptic connections in layer 2/3. Our results reveal
the columnar organization ofsynaptic connectivity in the rat visual cortex, where
functional columns have not been clearly
demonstrated. Thus, this technique will be a uniquely
powerful tool for quantifying synaptic connectivity
and manipulating neural activity at the single-celllevel (Ref. 4).

References
1. Honkura N, Matsuzaki M, Noguchi J, Ellis-Davies
GCR & Kasai H. The subspine organization ofactin fibers regulates the structure and plasticity ofdendritic spines. Neuron 2008;57:719-729.
2. Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T,
Ellis-Davies GCR & Kasai H. Protein synthesis
and neurotrophin-dependent structural plasticity ofsingle dendritic spines, Science 2008;319:16831687.
3. Yasumatsu N, Matsuzaki M, Miyazaki T, Noguchi
J. & Kasai H. Principles of long-term dynamics ofdendritic spines. J. Ne urosci. 2008;28: 1359213608.
4. Matsuzaki M, Ellis-Davies GCR & Kasai H.
Three-dimensional mapping of unitary synaptic
connections by two-photon macro photolysis of
caged glutamate. J. Ne urophysiol. 2008;99:15351544.

461

Laboratory of Regenerative
Medical Engineering
Professor
Takashi Ushida, Ph.D.

Associate Professor
Taichi Ito, 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.
2) Cellular signal transduction induced by physical462

stimulations- Hydrostatic pressure loading to chondrocytes orarticular cartilage- Shear stress loading to endothelial cells- Stretch loading to endothelial cells, smooth muscle
cells
Biomaterials are one of important keys in medicine
and medical engineering. In the field of tissue
engineering, scaffold materials are extremely
important. In the drug delivery field, drugs areencapsulated in various materials which achieve ideal
release kinetics. The functions of these biomaterials
and phenomena inside and outside biomaterials invivo are complicated both in terms of chemistry andbiology. Ito Laboratory is trying to design and develop
novel biomaterials for tissue engineering and drugdelivery by the combination of medicine and chemicalsystem engineering. Especially we focus onbiomaterials which can be utilized in peritoneum andfuture smart biomaterials which can autonomously
respond to biological signals. We also study processengineering of the system composed of cells andbiomaterials for the progress of tissue engineering.
1) In situ crosslinked hydrogels- Development of novel in situ crosslinked hydrogels
for a medical use- Application of the hydrogels for peritoneal
adhesion and peritoneal dissemination- Application of the hydrogels for scaffolds
2) Molecular recognition smart biomaterials- Development of membranes and micelles in
response to a specific ion signal- Application of the smart biomaterials for drugdelivery3) Process design of tissue regeneration- Mathematical understanding and process design oftissue regeneration in vitro and in vivo, especially inperitoneum

References
1.

KS Furukawa, K Imura, T Tateishi, T Ushida,
Scaffold-free cartilage by rotational culture fortissue engineering, Journal of Biotechnology,
133 : 134-145 (2008)

2.

3.

4.

5.

6.

7.

8.

9.

Du D, Furukawa K, Ushida T. , Oscillatory
perfusion seeding and culturing of osteoblast-likecells on porous beta-tricalcium phosphate
scaffolds. J Biomed Mater Res A. 86A: 796-803(2008)
Mizoguchi F, Mizuno A, Hayata T, Nakashima K,
Heller S, Ushida T, Sokabe M, Miyasaka N,
Suzuki M, Ezura Y, Noda M. , Transient receptor
potential vanilloid 4 deficiency suppresses
unloading-induced bone loss. J Cell Physiol.
2008 Jul;216(1):47-53.
Toshihiro Nagai, Katsuko S. Furukawa, Masato
Sato, Takashi Ushida, and Joji Mochida,
Characteristics of a Scaffold-Free Articular
Chondrocyte Plate Grown in Rotational Culture ,Tissue Engineering Part A, 14(7): 1183-1193(2008)
Toshihiro Nagai, Masato Sato, Katsuko S.
Furukawa, Toshiharu Kutsuna, Naoshi Ohta,
Takashi Ushida, and Joji Mochida, Optimizationof Allograft Implantation Using Scaffold-Free
Chondrocyte Plates, Tissue Engineering Part A,
14(7): 1225-1235 (2008)
Reverse Response of an Ion-recognition
Polyampholyte to Specific Ion Signals at
Different pHs, Hara N, Ohashi H, Ito T,
Yamaguchi T., Macromolecules, 42: 980-986(2008)
Anti-inflammatory function of an in-situ
cross-linkable conjugate hydrogel of hyaluronic
acid and dexamethasone, Ito T, Fraser IP, Yeo Y,
Highley CB, Bellas E, Kohane DS., Biomaterials
28: 1778-86 (2007)
Ito T, Yeo Y, Highley CB, Bellas E, Benitez CA,
Kohane DS., The prevention of peritoneal
adhesions by in-situ cross-linking hydrogels of
hyaluronic acid and cellulose derivatives,
Biomaterials 28: 975-83 (2007)
Ito T, Yamaguchi T., Nonlinear self-excitedoscillation of a synthetic ion channel-inspired
membrane, Angewandte Chemie International
Edition 45: 5630-5633 (2006)

463

Laboratory of Clinical
Biotechnology
Professor
Kazunori Kataoka, Ph.D.

Research Associate Professor
Keiji Itaka, M.D., Ph.D.

Lecturer
Nobuhiro Nishiyama, 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) and Global COE (GCOE) program, whichstarted in 2004 and 2008, respectively, as a novel
medicine-engineering interdisciplinary program, andtries to contribute to the production of medical
ventures by promoting liaison with the industrial
sector and to the production of professionals who
understandbothadvanced
medicineandnanotechnology. The division consists of one
professor, one research associate professor, one
lecturer and several project staff members belonging
to the CNBI, NBEP and GCOE.

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464

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
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. Thus, polymeric micelles are expected as
useful nanocarriers of pDNA and siRNA for in vivo
use.

References
1.

2.

M. Oba, K. Aoyagi, K. Miyata, Y. Matsumoto, K.
Itaka, N. Nishiyama, Y. Yamasaki, H. Koyama, K.
Kataoka, Polyplex micelles with cyclic RGD
peptide ligands and disulfide cross-links
directing to the enhanced transfection via
controlled intracellular trafficking. Mol. Pharm.
5 (6) 1080-1092 (2008)
K. Miyata, M. Oba, M. Nakanishi, S. Fukushima,
Y. Yamasaki, H. Koyama, N. Nishiyama, K.
Kataoka, Polyplexes from poly(aspartamide)
bearing 1,2-diaminoethane side chains induce

465

pH-selective,endosomal
membranedestabilization with amplified transfection andnegligible cytotoxicity. J. Am. Chem. Soc. 130(48) 16287-16294 (2008)
3. K. Miyata, M. Oba, M. R. Kano, S. Fukushima,
Y. Vachutinsky, M. Han, H. Koyama, K.
Miyazono, N. Nishiyama, K. Kataoka, Polyplex
micelles from triblock copolymers composed oftandemly aligned segments with biocompatible,
endosomal escaping, and DNA-condensing
functions for systemic gene delivery topancreatic tumor. Pharm. Res. 25 (12) 2924-2936(2008)
4. T. Tatsumi, M. Oishi, K. Kataoka, Y. Nagasaki,
PEG-siRNA conjugate bearing 27 bp siRNA toform novel PEGylated polyplexes with improved
stability. Trans. Mater. Res. Soc. Jpn. 33 (3)807-810 (2008)
5. S. Wu, N. Nishiyama, M. R. Kano, K. Itaka, U. -I.
Chung,
K.
Kataoka,EnhancementofAngiogenesis through Stabilization of Hypoxia
Inducible Factor-1 by Silencing Prolyl
Hydroxylase Domain 2 Gene. Mol Ther. 16 (7)1227-1234 (2008)
6. Y. Lee, K. Miyata, M. Oba, T. Ishii, S.
Fukushima, M. Han, H. Koyama, N. Nishiyama,
K. Kataoka, Charge-conversion ternary polyplex
with endosome disruption moiety: A techniquefor efficient and safe gene delivery. Angew.
Chem. Int. Ed. 47 (28) 5163-5166 (2008)
7. S. Takae, K. Miyata, M. Oba, T. Ishii, N.
Nishiyama, K. Itaka, Y. Yamasaki, H. Koyama, K.
Kataoka, PEG-detachable polyplex micelles
based on disulfide-linked block catiomers asbioresponsive nonviral gene vectors. J. Am.
Chem. Soc. 130 (18) 6001-6009 (2008)
8. 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)
9. S. Wu, S. Murai, K. Kataoka, M. Miyagishi, Yin
Yang 1 induces transcriptional activity of p73
through cooperation with E2F1. Biochem. Bioph.
Res. Comm. 365 (1) 75-81 (2008)
10. A. Harada, K. Kataoka, Selection between block-and homo-polyelectrolytes through polyion
complex formation in aqueous medium. Soft
Matter 4 (1) 162-167 (2008)

466

Laboratory 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
Children’s health problems of today include suchconditions as disorders in the reproductive andimmune functions, learning deficits, mental problem
and ‘metabolic syndrome’. Our research is carried out
on the recognition that the homeostasis is disrupted byvarious environmentally hazardous chemicals, towhich expectant mothers and their newborn babies are
exposed during their highly sensitive period of life,
and that the contamination with these chemicals maylead to various disease conditions in children after
birth. Our experimental investigations are focused on
the epigenetic mechanisms that alter the susceptibility
to chemicals, effects of chemicals on the learning andemotion and the identification of molecular target ofchemicals. Our research efforts are further directed todevelop methodologies for evaluating behavioral
toxicities in vi vo and to establish in vi tro toxicity
techniques at cellular and molecular levels. In addition
to these basic approaches to the environmental
toxicology, we aim to provide data for obtaining thesafety standard in environmental factors and food, andto contribute to the development of research in lifeand clinical sciences. Among a variety of potentially
toxic substances in the environment, we focus
especially on dioxin and its related-compounds andheavy metals which react with specific receptors andproteins.
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’467

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.

2.
3.

4.

Elucidation of mechanisms involved in the
manifestation of toxicity at the molecular andcellular level due to exposure to environmental
pollutants, such as dioxin/PCBs and heavy
metals.
Clarification of epigenetic mechanisms that altersusceptibility to environmental chemicals.
Development of methodologies for evaluating thetoxicity of chemicals to the learning and emotionof rodents and of in v itro toxicity techniques at
the molecular and cellular levels.
Development and application of techniques andmethodology for evaluating risks of toxic
substances in formulating safety standard for theenvironment and food.

Teaching activities
The Laboratory of Environmental Health Sciences
has important missions to train postdoctoral fellows to
become promising scientist leaders in the field ofenvironmental toxicology in the future and to give a
toxicology and environmental health courses forgraduate and undergraduate students. This laboratoryis actively involved in these tasks. The Laboratory
will be responsible for full a credit course on‘Principles and Applications of Environmental Health
Sciences’. In addition, several lectures are given toundergraduate students at School of Medicine andSchool of Health Sciences and Nursing. From 2008
this laboratory has become a member of a Global COE

project, ‘Medical system innovation’.

Publications
1. Kurita H, Yoshioka W, Nishimura N, Kubota N,
Kadowaki T, Tohyama C. Arylhydrocarbon
receptor-mediatedeffects
of
2,3,7,8-tetrachlorodibenzop-dioxinon
glucose-stimulated insulin secretion in mice. J.
Appl. Toxicol. (in press)
2. Nohara1 K, Suzuki1 T, Ao K, Murai H,
Miyamoto Y, Inouye K, Pan X, Motohashi H,
Fujii-Kuriyama Y, Yamamoto M, Tohyama C.
Constitutively active aryl hydrocarbon receptor
expressed in T cells increases immunizationinduced IFN-g production in mice but does not
suppress Th2-cytokine production or antibody
production. International Immunology (in press)
3. Ishimura Ishimura R, Kawakami T, Ohsako S,
Tohyama C. Dioxin-induced toxicity on vascularremodeling of the placenta. Biochem. Pharamcol.,77 : 660-669, 2009.
4. Ao K, Suzuki T, Murai H, Matsumoto M, Nagai H,
Miyamoto Y, Tohyama C, Nohara K. Comparison
ofimmunotoxicity
among
tetrachloro-,pentachloro-, tetrabromo- and pentabromodibenzo-p-dioxins in mice. Toxicology. 256:25-31,
2009.
5. Nohara K, Ao K, Miyamoto Y, Suzuki T,
Imaizumi S, Tateishi Y, Omura S, Tohyama C,
Kobayashi 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. 101: 226-238,
2008.
6. Ito T, Inouye K, Nohara K, Tohyama C, Fujimaki
H.
TCDD exposure exacerbates atopic
dermatitis-related inflammation in NC/Nga
mice.Toxicol Lett. 177: 31-37, 2008.
7. Miyazaki W, Iwasaki T, Takeshita A, Tohyama C,
Koibuchi N., Identification of the functional
domain of thyroid hormone receptor responsibleforpolychlorinatedbiphenyl-mediatedsuppression of its action in vitro. Environ. Health
Perspect. 116: 1231-1236, 2008.
8. Nishimura N, Matsumura F, Vogel CFA,
Nishimura H, Yonemoto J, Yoshioka W, Tohyama

468

C. Critical role of cyclooxygenase-2 activation inpathogenesis of hydronephrosis caused bylactational exposure of mice to dioxin. Toxicol.
Appl. Pharmacol. 231: 374-383, 2008
9. Kakeyama M, Sone H, Tohyama C. Perinatal
Exposure of Female Rats to 2,3,7,8Tetrachlorodibenzo-p-dioxin Induces Central
Precocious Puberty in the Offspring. J Endocrinol.
197: 351-358, 2008.
10. 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 28:724-733, 2008.
11. Hojo R, Kakeyama M, Kurokawa Y, Aoki Y,
Yonemoto J, Tohyama C. Learning behavior in rat
offspring after in utero and lactational exposure toeither TCDD or PCB126. Environ. Health Prevent.
Med., 13:169-180, 2008
12. Hozumi I, Suzuki JS, Kanazawa H, Hara A, Saio
M, Inuzuka T, Miyairi S, Naganuma A,
Tohyama C. Metallothionein-3 is expressed in thebrain and various peripheral organs of the rat.
Neuroscience Letters 438: 54-58. 2008.

469

Laboratory of Animal Resources
Professor
Atsuo Ogura, D.V.M., Ph.D.

Lecturer
Ken-Ichi Hanaki, D.V.M., Ph.D.

Homepage

http:// www.cdbim.m.u-tokyo.ac.jp/research/01_06.html

Introduction and Organization
Laboratory of Animal Resources (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,
a veterinarian, was employed in April 1972. The
building was completed in March 1973, and the center
began to provide services for animal experimentationin April 1973. Animal Center for Biomedical Research
was at first a facility attached to the faculty. In 2003, it
was reorganized as the Section and Animal Researchbelonging to the Center for Disease Biology andIntegrative Medicine (CDBIM). In 2008, theLaboratory of Animal Resources was established as a
research laboratory, standing side by side with thesection.
The members of this laboratory (including section)are 2 teaching staffs, 2 technical support staffs, theassistant manager of CDBIM, a teaching assistant, 3assistant laboratory animal technicians, and 4
assistance clerks. In addition, about 10 contracted
employees work together with us in the building tomaintain 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 ourbuilding after the registration. The number ofregistered persons was 257 at the end of 2008

academic year. The most of them were theinvestigators 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, teaching staffs have overall
responsibility for the health and welfare of animals
used in research. The office of this section is in chargeof the secretariat of the Animal Care and the Use
Committee of Graduate School of Medicine, theUniversity of Tokyo (IACUC). We check submitted
animal experiment plans to the committee whether theplans would be carried out in consideration of animal
welfare, and then give comment and/or advice torespective principal investigators. The committee(Chair, Prof. Hiroki Kurihara) will review the latest
plans and will approve, withhold approval, or require
modifications to secure approval in accordance withlaw, regulations and University policies governing theuse of animals.

Teaching activities
Our teaching responsibility is to give lectures on
Laboratory Animal Science to the 2nd-year students(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

470

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 thehandling of laboratory animals(iii) Items related to the care and management oflaboratory 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 thissection. Followings are the research profiles.
1) Development of reproductive engineering
techniques for application to epigenetics research andconservation of research bioresources: Reproductiveengineering techniques in mammals have been
extensively used for research, clinical, and industrial
purposes. Our aim is to develop reproductiveengineering techniques that can be applied toepigenetic researches and conservation of genetic
bioresources, especially laboratory mice. Thosetechniques
includenucleartransfer,
microinsemination (ICSI), and embryo/gamete
cryopreservation and we hope that these would
unravel a mystery of germ cells and totipotency.
2) Development of new stem cell lines as
experimental models for reproductive biology andregenerative medicine: Stem cells are populations ofcells with the potential of self-renew anddifferentiation. We have been developing new stem
cell lines including mouse and rabbit ES cells andmouse thecal stem cells. They provide us withinvaluable experimental models for reproductive
biology and regenerative medicine.
3) Development of immunoassays based on nucleic
acid
amplification
technology:
Rapid
and
ultra-sensitive techniques to detect a trace amount ofpathogen in blood, feces, and water are very importantfor both human and animal healthcare. We have beendeveloping new immunoassays based on nucleic acidamplification technology (NAT). We have also beendeveloping new immunohistochemical diagnoses
based on NAT.

References
1. Yamashita M, Honda A, Ogura A, Kashiwabara SI,
Fukami K, Baba T. Reduced fertility of mouse
epididymal sperm lacking Prss21/Tesp5 is rescuedby sperm exposure to uterine microenvironment.
Genes Cells. 2008 Aug. 2008;:27.
2. Wakisaka N, Inoue K, Ogonuki N, Miki H, Sekita
Y, Hanaki K, Akatsuka A, Kaneko Ishino T, Ishino
F, Ogura A. Ultrastructure of Placental
Hyperplasia in Mice: Comparison of Placental
Phenotypes with Three Different Etiologies.
Placenta. 2008;29:753-9.
3. Tachibana M, Terada Y, Ogonuki N, Ugajin T,
Ogura A, Murakami T, Yaegashi N, Okamura K.
Functional assessment of centrosomes ofspermatozoa and spermatids microinjected into
rabbit oosytes. Mol Reprod Dev. 2008;76:270-7.
4. Sekita Y, Wagatsuma H, Nakamura K, Ono R,
Kagami M, Wakisaka N, Hino T, Suzuki
Migishima R, Kohda T, Ogura A, Ogata T,
Yokoyama M, Kaneko Ishino T, Ishino F. Role ofretrotransposon-derived imprinted gene, Rtl1, in
the feto-maternal interface of mouse placenta. Nat
Genet. 2008;40:243-8.
5. Ogonuki N, Inoue K, Hirose M, Miura I, Mochida
K, Sato T, Mise N, Mekada K, Yoshiki A, Abe K,
Kurihara H, Wakana S, Ogura A. A high-speed
congenic strategy using first-wave male germ
cells. PLoS ONE. 2009;4:e4943.
6. Nakanishi T, Ishibashi N, Kubota H, Inoue K,
Ogonuki N, Ogura A, Kashiwabara S, Baba T.
Birth of Normal Offspring from Mouse Eggs
Activated by a Phospholipase Czeta Protein
Lacking Three EF-hand Domains. J Reprod Dev.
2008;54:244-9.
7. Nakamura T, Inoue K, Ogawa S, Umehara H,
Ogonuki N, Miki H, Kimura T, Ogura A, Nakano
T. Effects of Akt signaling on nuclear
reprogramming. Genes Cells. 2008;13:1269-77.

471

8. Miki H, Wakisaka N, Inoue K, Ogonuki N, Mori
M, Kim JM, Ohta A, Ogura A. Embryonic rather
than extraembryonic tissues have more impact on
the development of placental hyperplasia incloned mice. Placenta. 2009;30:543-6.
9. Miki H, Hirose M, Ogonuki N, Inoue K, Kezuka F,
Honda A, Mekada K, Hanaki KI, Iwafune H,
Yoshiki A, Ishino F, Ogura A. Efficient productionof androgenetic embryos by round spermatid
injection. Genesis. 2009;47:155-60.
10. Lee J, Kanatsu Shinohara M, Ogonuki N, Miki H,
Inoue K, Morimoto T, Morimoto H, Ogura A,
Shinohara T. Heritable imprinting defect causedbyepigenetic
abnormalities
inmouse
spermatogonial stem cells. Biol Reprod. 2009;80:
518-27.
11. Lee J, Kanatsu Shinohara M, Ogonuki N, Miki H,
Inoue K, Morimoto T, Morimoto H, Ogura A,
Shinohara T. Heritable Imprinting Defect Caused
by Epigenetic Abnormalities in Mouse
Spermatogonial Stem Cells. Biol Reprod. 2009;
80:518–527.
12. Kazuki Y, Hoshiya H, Kai Y, Abe S, Takiguchi M,
Osaki M, Kawazoe S, Katoh M, Kanatsu
Shinohara M, Inoue K, Kajitani N, Yoshino T,
Shirayoshi Y, Ogura A, Shinohara T, Barrett JC,
Oshimura M. Correction of a genetic defect inmultipotent germline stem cells using a humanartificial chromosome. Gene Ther. 2008;15:
617-24.
13. Kanatsu Shinohara M, Lee J, Inoue K, Ogonuki N,
Miki H, Toyokuni S, Ikawa M, Nakamura T,
Ogura A, Shinohara T. Pluripotency of a Single
Spermatogonial Stem Cell in Mice. Biol Reprod.
2008;78:681-687, 2008.
14. Honda A, Hirose M, Ogura A. Basic FGF andActivin/Nodal but not LIF signaling sustain
undifferentiated status of rabbit embryonic stem
cells. Exp Cell Res. 2009 Feb. 2009; (in press)
15. Honda A, Hirose M, Inoue K, Ogonuki N, Miki H,
Shimozawa N, Hatori M, Shimizu N, Murata T,
Hirose M, Katayama K, Wakisaka N, Miyoshi H,
Yokoyama KK, Sankai T, Ogura A. Stableembryonic stem cell lines in rabbits: potential
small animal models for human research. Reprod
Biomed Online. 2008;17:706-15.
16. Honda A, Hirose M, Inoue K, Hiura H, Miki H,

Ogonuki N, Sugimoto M, Abe K, Kanatsu
Shinohara M, Kono T, Shinohara T, Ogura A.
Large-scale production of growing oocytes invitro from neonatal mouse ovaries. Int J Dev Biol.
2009;53:605-13.
17. Goto M, Honda E, Ogura A, Nomoto A, Hanaki K.
Colorimetricdetectionofloop-mediatedisothermal amplification reaction by usinghydroxy naphthol blue. Biotechniques. 2009;46:
167-72.

472

Laboratory of Molecular Radiology
Professor
Kiyoshi Miyagawa, 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
This laboratory was renamed as the Laboratory of
Molecular Radiology in 2008 to strengthen research
activities. The main duty to support the use ofradioisotope at Graduate School of Medicine has been
also continued. Historically, in 2003, the Departmentof Radiation Oncology and the Radiation ResearchInstitute were joined to form a new department.
The aim of this laboratory is to facilitatetranslational research from frontier life science toapplied radiology by introducing molecular biology
into conventional radiology.
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.

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.
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 and DNA repair
is more emphasized.
In addition, education courses for users ofradioactive materials frequently take place.

Teaching activities

Research activities

We are responsible for the education of basic radiation
medicine for the 3rd 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

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.

473

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 chromosomaltranslocations 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
cross-linking agents rather than to replication
inhibitors. Cisplatin and its analogs are widely used incurrent cancer treatment. Because these drugs induce
DNA cross-linking, we are trying to understand therole of Mus81-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.

2.

3.

4.

5.

Enomoto A, Kido N, Ito M, Morita A,
Matsumoto Y, Takamatsu N, Hosoi Y, Miyagawa
K. Negative regulation of MEKK1/2 signaling by
Serine-Threonine Kinase 38 (STK38). Oncogene.
2008;27:1930-1938.
Miyagawa K. Clinical relevance of thehomologous recombination machinery in cancer
therapy. Cancer Sci. 2008;99:187-194.
Shimura T, Torres MJ, Martin MM, Rao AV,
Pommier Y, Katsura M, Miyagawa K, Aladjem
MI. Bloom’s syndrome helicase and Mus81 arerequired to induce transient double-strand DNA
breaks in response to DNA replication stress. J
Mol Biol. 2008;375:1152-1164.
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 radiationexposed worker at the Tokai-mura criticality
accident. J Radiat Res. 2008;49:55-62.
Sarai N, Kagawa W, Fujikawa N, Saito K, Hikiba
J, Tanaka K, Miyagawa K, Kurumizaka H,
Yokoyama S. Biochemical
analysis of the

474

6.

7.

N-terminal domain of human RAD54B. Nucleic
Acids Res. 2008;36:5441-5450.
Kobayashi J, Iwabuchi K, Miyagawa K, Sonoda
E, Suzuki K, Takata M, Tauchi H. Current topics
in DNA double-strand break repair. J Radiat Res.
2008;49:93-103.
Enomoto A, Miyagawa K. How to cope with
DNA damage induced by ionizing radiation andanti-cancer drugs? Progress of Theoretical
Physics (supple) 2008;173:109-123.

475

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 2008 (April
through March).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2008, there were 154 foreign students (38 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 81 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 ofTokyo 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 65 people attended in 2008, 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 2008 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, nine University of Tokyo students have taken
research electives at the University of Pennsylvania
every year, and one student from the University of476

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, fourteen 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, four
University of Tokyo students 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, five 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 four 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, five
University of Tokyo students visited to attend research
electives at Mahidol University, and five 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 forcounselingregarding
pre-graduationor
post-graduation studies abroad are received by the
Office of 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 18 researchers were invited to Japan (683 researcher-days) and 9 Japanese researchers were sent
abroad (70 researcher-days) in 2008.
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 ofTokyo 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

477

research.
(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, eight 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. Shin Yamazaki, Shunichi Fukuhara, Joseph
Green, Osamu Takahashi, Takuro Shimbo, Hiroyoshi
Endo, Shigeaki Hinohara, and Tsuguya Fukui.
Headache, Mental Health, and Use of Medical
Resources: Health Diary Study in Japan. J Health Sci,
54(1), 30-36, 2008.

478

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.

Lecturer
Hiroshi Nishigori, M.D., M.M.E., Ph.D.

Homepage

http://www.ircme.u-tokyo.ac.jp

History and organization
The University of Tokyo has establishedInternational 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 ofInternational 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 healthcare in many 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 Facultyof Medicine, takes pride in its academic excellence
not only in Japan but also other foreign countries.
Compared with other Western distinguisheduniversities, however, activities and research ininternational 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 approachtakes longer time but will influence people indeveloping countries with sustainability andindependence.
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 implementationof 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

479

the Faculty of Medicine to raise awareness ofinternational 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 healthprofessions education area in Japan and aim at
face-to-faceandheart-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.
Currently IRCME is working for the follow-up
scheme of the above project (Jul 2008- Jun 2011).
Counterpart of the project has been Ministry ofHigher Education and Kabul Medical University.
2. 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-sponsoredlecturesandseminars, they also provide intellectual stimulation to
medical students, interns, and residents, and introduce

new information on medical education andinternational cooperation to a wider audience.
In 2008, we accepted four visiting professors:- Dr. Shirin Aqa Zarif (1 Feb-14 Mar 2008, Vice
Chancellor,
Kabul
Medical
University,
Afghanistan)- Dr. Mohammad Farid Barnayar (1 Feb-14 Mar
2008, Vice Chancellor, Kabul Medical University,
Afghanistan)- Dr. Dwi Tyastuti Kusuma (1 Mar-30 Apr 2008,
Lecturer, Family Medicine, Islamic University,
Indonesia)- Dr. Michael F. Lubin (7 July-6 November,
Professor, General Internal Medicine, Emory
University, USA)
They offered several seminars, lectures forinternational trainees, and many suggestions to
IRCME.

References1.

Hirotaka Onishi. The role of case presentation forteaching and learning activities. Kaohsiung J Med
Sci 24: 356–60, 2008