ISSN 1883-9606

2011

Vol.123

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2010 ---- March 2011

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2010-March 2011

Introduction
This is volume 123 (the edition of year 2010) of the annual report by the University of Tokyo’s
Graduate School of Medicine and Faculty of Medicine.
In it are recorded the past year’s research, educational, clinical, and other activities of the
Graduate School of Medicine and Faculty of Medicine, the International Research Center for
Medical Education, and the Tokyo Society of Medical Sciences.
It reports our accomplishments, and each year we make such a document freely available bypublishing it on compact disk and on the Internet, expecting it to be used for internal and external
evaluations.
The University of Tokyo’s Faculty of Medicine was founded 150 years ago. Since then we haveconsistently driven Japan’s progress in medical research, medical education, and clinical care, andin some fields we have become world leaders.
We have more than 1000 students in the Graduate School of Medicine, and with as many as 150
foreign researchers and students we are an international center for medical research and education.
Pursuing excellence in our research, educational, and clinical activities, we will continue meetingthe needs for tomorrow’s pioneers in medical sciences and clinical care.

Takao Shimizu, Dean
Graduate School of Medicine and Faculty of Medicine
The University of Tokyo
March, 2011

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 Structural Biology ···············································································

4

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

6

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

7

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

8

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

11

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

15

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

18

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

19

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

22

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

26

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

28

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

29

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

32

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

37

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

38

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

44

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

48

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

49

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

52

ii

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

54

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

55

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

59

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

60

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

67

Department of Chemical Biology and Molecular Imaging ·················································

68

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

70

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

74

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

75

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

78

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

83

2. Integrative Medical Neuroscience ·············································································

85

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

86

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

88

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

90

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

91

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

95

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

101

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

106

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

107

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

109

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

112

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

113

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

116

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

119

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

120

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

125

iii

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

130

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

138

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

139

Department of Diabetes and Metabolic Diseases ····························································

144

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

150

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

155

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

158

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

161

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

163

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.421] )Department of Transfusion Medicine ·········································································

164

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

167

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

168

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

170

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

176

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

178

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

179

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

184

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

187

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

188

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

191

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

192

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

195

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

199

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

204

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

206

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

210

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

214

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

216

iv

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

218

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

219

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

223

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

225

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

230

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

236

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

240

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

244

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

246

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

247

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

250

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

253

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

254

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

257

Department of Biostatistics / Epidemiology and Preventive Health Sciences ···························

260

Department of Social Gerontology (See Department of Social Gerontology [P.324] )Department of Biomedical Ethics & Department of Health Promotion Sciences ·······················

264

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

267

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

268

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

272

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

274

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

278

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

279

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

283

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

286

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

289

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

294

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

295

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

298

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

301

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

302

v

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

305

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

308

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

311

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

313

Department of Biostatistics (See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.260] )Department of Social and Preventive Epidemiology ························································

314

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

318

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

320

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

323

Department of Mental Health(See Department of Mental Health [P.257] )Department of Health Sociology and Health Education(See Department of Health Sociology / Health Sociology and Health Education [P.254] )Department of Social Gerontology ············································································

324

Department of Biomedical Ethics & Department of Health Promotion Sciences(See Department of Biomedical Ethics & Department of Health Promotion Sciences [P.264] )3. Health Services Sciences ·························································································

327

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.109] )Department of Healthcare Informatics (See Department of Medical Informatics and Economics [P.116] )Department of Clinical Information Engineering ····························································

328

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.113] )Endowed Department ···································································································

330

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

331

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

333

Department of Vascular Regeneration (Daiichi Sankyo Co.,Ltd.)(See Department of Oral-Maxillofacial Surgery [P.225] )Department of Bone & Cartilage Regenerative Medicine(See Department of Orthopaedic Surgery [P.230] )Department of Cartilage & Bone Regeneration (Fujisoft)(See Department of Oral- Maxillofacial Surgery [P.225] )Department of Clinical Renal Regeneration(See Department of Nephrology and Endocrinology [P.139] )Department of Metabolome ····················································································

336

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

340

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

343

vi

Science for joint reconstruction ( See Department of Orthopaedic Surgery [P.230] )Department of Molecular Research for Vascular Diseases ·················································

347

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

349

Laboratory of Molecular Physiology on Energy Metabolism ··············································

351

Department of Molecular Neuroscience on Neurodegeneration(See Department of Neurology [P.95] )Department of Chronic Kidney Disease (CKD) ·····························································

353

Department of Molecular Structure and Dynamics ··························································

355

Department of Molecular Vascular Endocrinology(See Department of Nephrology and Endocrinology [P.139] )Department of Continence Medicine ··········································································

356

Department of Medical Genomics ·············································································

359

Department of Molecular Psychiatry ··········································································

362

Endowed Department (22nd Century Medical and Research Center) ···········································

363

Department of Clinical & Molecular Epidemiology ························································

364

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

367

Division of Total Renal Care Medicine ·······································································

370

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

372

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

374

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

378

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

381

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

383

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

386

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

388

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

390

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

391

Department of Health Care Safety Management ·······························································

394

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

397

Department of Healthcare Quality Assessment ······························································

399

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

402

Department of Integrated Imaging Informatics ······························································

405

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

407

Pharmacology and Pharmacokinetics ·········································································

410

Department of Therapeutic Strategy for Heart Failure ······················································

412

Social Cooperation Program (22nd Century Medical and Research Center) ···································

415

Department of Ubiquitous Health Informatics ·······························································

416

vii

University Hospital
Clinical Divisions ····································································································
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.120] )Respiratory Medicine (See Department of Respiratory Medicine [P.125] )Gastroenterology (See Department of Gastroenterology [P.130] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.139] )Diabetes and Metabolic Diseases (See Department of Metabolic Diseases [P.144] )Hematology and Oncology (See Department of Hematology and Oncology [P.150] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.155] )Infectious Diseases (See Department of Infectious Diseases [P.158] )Neurology (See Department of Neurology [P.95] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.188] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.161] )Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.199] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.210] )Hepatobiliary Pancreatic Surgery(See Department of Hepatobiliary Pancreatic Surgery [P.204] )Vascular Surgery (See Department of Vascular Surgery [P.214] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.216] )Artificial Organ and Transplantation Surgery(See Department of Artificial Organ and Transplantation Surgery [P.204] )Cardiovascular Surgery (See Department of Cardiothoracic Surgery [P.195] )Thoracic Surgery (See Department of Thoracic Surgery [P.192] )Neurosurgery (See Department of Neurosurgery [P.101] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.247] )Urology and Andrology (See Department of Urology [P.206] )Gynecologic Surgery (See Obstetrics and Gynecology [P.167] )Dermatology and Photolaser Medicine (See Department of Dermatology [P.219] )Ophthalmology and Vision Correction (See Department of Ophthalmology [P.236] )Orthopaedic Surgery and Spinal Surgery(See Department of Orthopaedic Surgery [P.230] )Otorhinolaryngology, and Auditory and Voice Surgery(See Department of Otorhinolaryngology and Head & Neck Surgery [P.240] )Rehabilitation Medicine (See Department of Rehabilitation Medicine [P.244] )

419

viii

Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.223] )Oral-Maxillofacial Surgery Dentistry and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.225] )Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.179] )Pediatrics Surgery (See Department of Pediatrics Surgery [P.184] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.168, 170, 176] )Neuropsychiatry (See Department of Neuropsychiatry [P.91] )Radiology (See Department of Radiology [P.60] )Central Clinical Facilities ···························································································

420

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

421

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

424

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

428

Department of Emergency Services(See Department of Emergency and Critical Care Medicine [P.250] )Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.164] )Delivery Unit ·····································································································

431

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

432

Department of Intensive Care Unit
(See Department of Emergency and Critical Care Medicine [P.250] )Division of Diagnostic Pathology ··············································································

434

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

436

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

439

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

443

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

445

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

449

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.52] )Department of Planning, Information, and Management(See Department of Medical Informatics and Economics [P.116] )University Hospital Medical Information Network (UMIN) Center ······································

452

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

455

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

457

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

462

ix

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

467

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

470

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

473

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

477

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

480

Medical Specialists Training Center ···········································································

490

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

491

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

492

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

496

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

497

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

501

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

504

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

506

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

510

Laboratory of Animal Resources ···············································································

513

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

516

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

519

Museum of Health and Medicine ··················································································

522

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

524

x

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

History
1858

May

Practitioners, trained in Dutch (European) medicine in Edo (Tokyo), laid out money to establish
the Shutojo (vaccination center) in Kanda Mitamagaike.

Nov.

Shutojo was destroyed in a fire that had spread from Kanda Aioicho. Shutojo continued its
operations at other sites such as the residence of Ito Genboku.

1859

Sep.

Shutojo was reconstructed at Shitaya Izumibashi Dohri.

1860

Oct.

Shutojo became an official medical institution of the Shogunate Government.

1861

Oct.

Shutojo was renamed as Seiyo Igaku-Sho (Institute of Western Medicine) and offered courses ofWestern Medicine in the fields of Education, Autopsy, and Vaccination.

1863

Feb.

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

1868

Jul.

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

1869

1871

Feb.

The Daibyoin was renamed as Igakko-Ken-Byoin (Medical School and Hospital).

Dec.

Igakko-Ken-Byoin was renamed as Daigaku Toko (University East Building).

Jul.

The Ministry of Education was established and Daigaku-Toko was renamed as Toko (East
Building).

1872

Aug.

A School System was established. Toko was renamed as Daiichi-Daigaku-Ku- Igakko (The First
University 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, was 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 The University of Tokyo
Faculty of Medicine was renamed as the Imperial University Medical College. A Graduate
School was established.

1897

Jun.

The Imperial University was renamed as Tokyo Imperial University.

1917

Aug.

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

1919

Apr.

A faculty system was established renaming Tokyo Imperial University Medical College as theFaculty of Medicine.

1931

Feb.

The first building of the Faculty of Medicine was constructed.

1936

Jan.

The Brain Research Laboratory was built with funds donated by Mr. Hisasaburo Horikoshi.

Nov.

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

1947

Oct.

Tokyo Imperial University was renamed as The University of Tokyo.

1950

Apr.

The Institute of Nursing was renamed as The University Nursing School.

1953

Apr.

The School of Health Care and Nursing was founded.

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

Jul.

xi

The Graduate School was founded, and the Division of Medical Doctor Biological Science wasestablished. The Brain Research Laboratory became the Brain Research Institute of the Facultyof Medicine.

1956

Apr.

The Midwives School was established.

1958

Apr.

The Division of Pharmaceutical Sciences became an independent faculty.

May

The University of Tokyo Faculty of Medicine celebrated its centennial anniversary.

Mar.

The Medical Library was built in commemoration of the centenary.

Apr.

The Institute of Medical Electronics was established.

Apr.

The Research Institute of Logopedics and Pediatrics was established. The School of Health Care

1961

1965

and Nursing was reorganized as the School of Health Sciences. The Graduate School of The
University of Tokyo was reorganized and the Division of Medical Doctor Biological Science
became the Faculty of Medicine. The Health science Course was established in the Medical
Science Division.
1966

Sep.

The third building of the Faculty of Medicine was constructed.

1971

Apr.

The Laboratory of Animal Experiments was established.

1973

Mar.

The Animal Center for Biomedical Research was constructed.

1983

Jan.

An annex of the third building of the Faculty of Medicine was constructed.

1985

Sep.

The office of International Academic Affairs was established.

1987

Apr.

Specialized courses were introduced to the Graduate School of Medicine.

1992

Apr.

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

1995

Jul.

The Radiation Research Institute was established.

Apr.

As a result of the shift to the chair system of the Graduate School of Medicine, four divisions,Third Basic Medicine, Social Medicine, Third and Fourth Clinical Medicine, were replaced with
Pathology, Immunology and Microbiology, Social Medicine, Reproduction and Development,
and Aging Science and Surgery.

1996

Apr.

As a result of the shift to the chair system of the Graduate School of Medicine, three divisions,First Clinical Medicine, Health Science, and International Health, were replaced with Internal
Medicine, Health Science and Nursing, and International Health.

1997

Apr.

As a result of the shift to the chair system of the Graduate School of Medicine, three divisions,First and Second Basic Medicine, and Second Clinical Medicine, were replaced with Molecular
Cell Biology, Functional Biology, Radiology and Biomedical Engineering, and Neuroscience.
As a result of the above-mentioned reorganization, three institutes, the Institute of Brain
Research, the Institute of Medical Electronics, and the Institute of Logopedics and Phoniatrics
were made redundant.

1999

Apr.

The Master course of Medical Science was established in the Graduate School of Medicine. This
course accepts graduates of all faculties except those from Schools of Medicine, Dentistry, andVeterinary Medicine.

xii

2000

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

Apr.

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

2001

Apr.

The University Branch Hospital was united with the University Hospital.

2003

Apr.

The Center for Disease Biology and Integrative Medicine was established.

2004

Apr.

All

the

National

Universities owned

by

the

Japanese

Government

becameNational University Corporations. and the University of Corporation.
2007

Apr.

The School of Public Health was established. This school offers programs for Master of Public
Health.

2008

May.

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

2010

Apr.

The School of Health Science and Nursing became the School of Integrated Health Sciences.

2011

Jan.

The Museum of Health and Medicine was established.

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

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

Chemical Biology and Molecular Imaging
Biosystem Construction and Control
Neuropathology

Basic Neuroscience

Neurochemistry
Neurobiology
Developmental Neuroscience

Neuroscience

Integrativ Medical Neurosciences

Cognitive Neuroscience
Systems Medical Neuroscience

Graduate School of
Medicine

Child Neuropsychiatry
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. 123, October 2011

Cardiovascular Medicine
Vascular Biology
Medicine I

Respiratory Medicine
Gastroenterology
Nephrology
Endocrinology

Internal Medicine

Diabetes and Metabolic Diseases
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

xv

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011
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

Medical Science (Master’s Program)

Biostatistics
Epidemiology and Health Sciences

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

School of Public HealthBehavioral Health Sciences
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
Laboratory of Molecular Radiology
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. 123, October 2011
Office of International Academic Affairs
Institution

Medical Library
Medical Scientist Training Program
Museum of Health and Medicine
Pharmacoepidemiology
Integrated Traditional Medicine (Tsumura)
Vascular Regeneration (Daiichi Sankyo Co.,Ltd.)
Bone & Cartilage Regenerative Medicine
Cartilarge &Bone Regeneration(Fujisoft)
Clinical Renal Regeneration
Metabolome (-2011.1)
Clinical and Molecular Epidemiology (Mitsubishi Tanabe Pharma Corporation.)
Immunotherapeutics (Medinet)
Total Renal Care Medicine
Integrated Molecular Science on Metabolic Diseases
Advanced Clinical Science and Therapeutics
Ischemic Circulatory Physiology. Kaatsu Training
Translational Research for Healthcare and Clinical Science
Joint Disease Research
Health Management and Policy

Endowed Department

Computational Diagnostic Radiology and Preventive Medicine
Clinical Motor System Medicine
Health Care Safety Management(Tokio Marine & Nichido)
Molecular Cardiovascular Metabolism
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 Failure
Molecular Physiology on Energy Metabolism
Molecular Neuroscience on Neurodegeneration
Chronic Kidney Disease
Molecular Structure and Dynamics(JEOL/Zeiss)
Molecular Vascular Endocrinology
Medical Genomics

Social Cooperation Program

Molecular Psychiatry

General Affairs OfficeContinence Medicine

Personnel Office

Department of Life Support Technology (Molten)

Research Liaison

Quality Assessment and Control of
Medical Device Sterilization

Educational Affairs

Ubiquitous Health Informatics

Buget Office

Administrative office

Graduate Student Affairs

Purchasing Office

xvii

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

Faculty of Medicine
Graduate School of
Medicine

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

Administrative Office

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

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

Faculty of
Medicine

Family Nursing
Comunity Health Nursing
Fundamental Nursing
Gerontological Nursing
School of Integrated
Health Sciences

Midwifery and Women’s Health
Adult Health 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. 123, October 2011

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

Diabetes and Metabolic Medicine
Hematology and Oncology
Allergy and Rheumatology
Infectious Diseases

ClinicalDivisions

Neurology
Geriatric Medicine
Psychosomatic Medicine
General Surgery
Stomach and Esophagus Surgery

University
Hospital

Colon and Rectal Surgery
Hepatobiliary Pancreatic Surgery
Vascular Surgery
Breast and Endocrine Surgery
Surgery

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

Sensory and Motor System
Medicine

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

Pediatrics, Perinatal and
Women's Medicine

Pediatric Surgery

Neuropsychiatry

NeuropsychiatryRadiology

Obstetrics and Gynecology

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

Central Clinical Facilities

Emergency Services
Blood Transfusion
Perinatal Center
Rehabilitation Service
Medial Engineering

Office of General Administration
Office of Procurement andFacility Management
Office of Management Planning
Office of Medical Accounting

xix

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

Central Supply Service
Intensive Care Unit
Pathology
Corneal Transplantation
Department of Cell a Therapy and Transplantation Medicine
Department of Endoscopy and Endoscopic Surgery
Department of Hemodialysis and Apheresis
Department of Medical Community Network
Clinical Research Center
Infection Control and Prevention Service
Department of Planning, Information, and Management
University Hospital Medical Information Network Center
Organ Transplantation Service
Department of Nutrition
Labor Safety and Health Management Office
Department of Child Psychiatry
Tissue Bank
Epidemiology and Preventive Medicine
Cancer Resource Center
Center for Liaison and Public Relations
Database Center of the National University Hospitals
Outpatient Chemotherapy Department
Neonatal and Pediatric Intensive Care Unit
Department of Health Record Management
Critical Care Center
Division of Tissue Engineering
Department of Clinical and Genetic Informatics
Departments under the bylaws

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

Organization of ClinicalManagement Support

Personnel Administration and
Human Resource Management

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

Organization of ClinicalManagement

Outpatient Services
Administration
Central Clinical Services
Administration

Translational Research Center
22nd Century Medical and Research Center

Medical Specialists
Training Center

Pediatric Medical Center

Vascular Board

xx

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

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

Masayoshi Mishina

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

Masahide Kikkawa

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

Masanori Hatakeyama

professor

Kyoji Moriya

professor

Tadatsugu Taniguchi

Department of Radiology

professor

Kuni Otomo

Department of Biomedical Engineering

professor

Yasuteru Urano

professor

Takeshi Iwatsubo

Professor

Kenzo Hirose

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

xxi

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

Department of Integrative Medical Neuroscience
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

Kazuhiko koike

professor

Toshiro Fujita

professor

Takashi Kadowaki

professor

Mineo Kurokawa

professor

Kazuhiko Yamamoto

professor

Akira Akabayashi

professor

Yutaka Yatomi

professor

Koki Takahashi

professor

Yuji Taketani

professor

Shiro Kozuma

professor

Takashi Igarashi

professor

Tadashi Iwanaka

professor

Yasuyoshi Ouchi

professor

Minoru Ono

professor

Yasuyuki Seto

professor

Norihiro Kokudo

professor

Yukio Homma

professor

Shinichi Sato

professor

Isao Koshima

professor

Tsuyoshi Takato

Professor

Kozo Nakamura

professor

Shiro Amano

professor

Tatsuya Yamasoba

professor

Nobuhiko Haga

Social Medicine

Internal Medicine
Department of Medicine I

Department of Medicine II

Department of Clinical Laboratory Medicine and Pathology

Reproductive, Developmental and Aging Science
Department of Obstetrics and Gynecology

Department of Pediatric Science

Department of Aging Science
Surgical Sciences
Department of Surgery

Department of Sensory and Motor System Medicine

xxii

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

Department of Vital Care Medicine

Professor

Yoshitsugu Yamada

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

professor

Kenji Shibuya

professor

Masamine Jinba

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
Department of International Social Medicine

Department of International Biomedical Sciences

School of Public Health
Department of Epidemiology and Health Sciences

Department of Behavioral Health Sciences

Department of Health Services Sciences

xxiiiThe Tokyo Journal of Medical Sciences. Vol. 123, October 2011

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

Atsu Aiba

Laboratory of Molecular Radiology

professor

Kiyoshi Miyakawa

International Academic Affairs

professor

Tatsuya Yamasoba

Medical LibraryProfessor

Kazuhiko Ohe

Medical Scientist Training Program

Professor

Shigeo Okabe

Museum of Health and Medicine

Professor

Kazuhiko Ohe

Department of Pharmacoepidemiology

professor

Kiyoshi Kubota

Department of Integrated Traditional Medicine(Tsumura)

Associate professor

Tetsuro Okabe

Department of Vascular Regeneration (Daiichi Sankyo Co.,Ltd)

Associate professor

Hiroyuki Koyama

Department of Bone & Cartilage Regenerative Medicine

Associate professor

Taku Saito

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

Division of Research Resources and Support

Faculty of Medicine
Endowed Departments

Cartilage & Bone Regeneration(Fujisoft)

Clinical and Molecular Epidemiology (Mitsubishi Tanabe Pharma Corporation.)
Associate professor

Takanari Gotoda

Immunotherapeutics (Medinet)

Associate professor

Kazuhiro Kakimi

Total Renal Care Medicine

Associate professor

Akira Ishikawa

Integrated Molecular Science on Metabolic Diseases

Associate professor

Hara Kazuo

Department of Advanced Clinical Science and Therapeutics

Associate professor

Junichi Suzuki

Associate professor

Yasunobu Hirata

Ischemic Circulatory Physiology, Kaatsu Training

Associate professor

Toshiaki Nakajima

Translational Research for Healthcare and Clinical Science

Associate professor

Hiroyuki Morita

Department of Joint Disease Research

Associate professor

Noriko Yoshimura

Health Management and Policy

Associate professor

Hideo Yasunaga

Computational Diagnostic Radiology and Preventive Medicine

Associate professor

Naoto Hayashi

Associate professor

Kansei Uno

Clinical Motor System Medicine

Associate professor

Toru Akune

Medical Safety Management (Tokio Marine & Nichido)

Professor

Yasushi Kodama

Molecular Cardiovascular Metabolism

Associate professor

Katsuyuki Andoxxiv

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

The Department of Healthcare Quality Assessment

Associate professor

Hiroaki Miyata

Anti-Aging Medicine

professor

Satoshi Inoue

Integrated Imaging Informatics

Associate professor

Naoki Yoshioka

The Department of Nutriproteomics

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

Associate professor

Takashi Nishimura

Laboratory of Molecular Physiology on Energy Metabolism

Associate professor

Naoya Yahagi

Department of Molecular Neuroscience on Neurodegeneration

Associate professor

Atsushi Iwata

Department of Chronic Kidney Disease

Associate professor

Miki Nagase

Department of Molecular Structure and Dynamics (JEOL/Zeiss)

professor

Nobutaka Hirokawa

Department of Molecular Vascular Endocrinology

Associate professor

Masashi Isshiki

Department of Medical Genomics

professor

Hiroyuki Mano

Associate professor

Young Lim Choi

Department of Molecular Psychiatry

Associate Professor

Kazuya Iwamoto

Continence medicine

Professor

Yasuhiko Igawa

Department of Life Support Technology (Molten)

Associate Professor

Taketoshi Mori

Quality assessment and control of medical device sterilization

Associate Professor

Yushi Uetera

Associate Professor

Hideo Fujita

Director

Kazuhiko Yamamoto

professor

Kiyoshi Kitamura

General Medicine

Head

Syoji Tsuji

Cardiovascular Medicine

Head

Ryozo Nagai

Department of Molecular Psychiatry

Social Cooperation Program
Department of Ubiquitous Health Informatics

International Research Center for Medical Education

University Hospital
Clinical Divisions

xxv

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

Respiratory Medicine

Head

Takahide Nagase

Gastroenterology

Head

Kazuhiko Koike

Nephrology and Endocrinology

HeadToshiro Fujita

Diabetes and Metabolic Medicine

Head

Takashi Kadowaki

Hematology and Oncology

Head

Mineo Kurokawa

Allergy and Rheumatology

Head

Kazuhiko Yamamoto

Infectious Diseases

Head

Hiroshi Yotsuyanagi

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

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

HeadMinoru Ono

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

Shinichi Sato

Ophthalmology and Vision Collection

Head

Shiro Amano

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

Central Clinical Facilites

xxvi

The Tokyo Journal of Medical Sciences. Vol. 123, October 2011

Emergency Services

Head

Naoki Yahagi

Blood Transfusion

Head

Koki Takahashi

Perinatal Center

Head

Shiro Kozumai

Rehabilitation Service

Head

Nobuhiko Haga

Central Supply Service

Head

Hisayoshi Tamai

Department of Medical Engineering

Head

Kazuhiko Fukatsu

Intensive Care Unit

Head

Naoki Yahagi

Department of Pathology

Head

Masashi Fukayama

Corneal Transplantation

Head

Shiro Amano

Department of Cell Therapy and Transplantation Medicine

Head

Mineo Kurokawa

Department of Endoscopy and Endoscopic Surgery

Head

Mitsuhiro FujisiroCenter for Hemodialysis and Apheresis

Head

Toshiro Fujita

Medical Community Network

Head

Yasuyoshi Ouchi

Clinical Research Support Center

Head

Takashi Kadowaki

Infection Control and Prevention Service

Head

Kyoji Moriya

Department of Planning, Information and Management

Head

Kazuhiko Ohe

University Hospital Medical Information Network Center

Head

Takahiro Kiuchi

Organ Transplantation Service

Head

Norihiro Kokudo

Department of Child Psychiatry

Head

Yukiko Kano

Tissue Bank

Head

Noboru Motomura

Epidemiology and Preventive Medicine

Head

Tsutomu Yamazaki

Cancer Resource Center

Head

Shoichi Kaisaki

Center for Liaison and Public Relations

Head

Kazuhiko Ohe

Database Center of the National University Hospitals

Head

Hiroshi Kushiyama

Outpatient Chemotherapy Department

Head

Norihiro Kokudo

Neonatal and Pediatric Intensive Care Unit

Head

Arata Murakami

Department of Health Record Management

Head

Yasuyoshi Ouchi

Critical Care Center

Head

Susumu Nakajima

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 Nakamura

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 andAnatomyAssociate Professor
Yoshimitsu Kanai, M. D., Yosuke Takei, M. D.,

Associate
Yasushi Okada, M. D.,

Yosuke Tanaka, M. D.,

Noriko Homma, Ph. D.,

Harukata Miki, Ph. D.,

Homepage

Ryo Nitta, M. D.,

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

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

Research activities
Our research field covers the molecular cell biologyof the cytoskeleton. We focus on the molecularmechanisms of cell morphogenesis and intracellulartransports.
Our laboratory studies molecular architecture, dynamics and function of the neuronal cytoskeleton using various new molecular cell 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 targetingand 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
along the direction of impulse propagation. The neuronal cytoskeleton plays three major important roles.
1) It provides dynamic frameworks for neurite extension and maintenance.
2) It provides structural bases for organelle transports
in the cells. Namely it works as rails and motor 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 elec-

3tron microscopy of molecular resolution, biochemistry,
biophysics, molecular biology and molecular genetics
and X-ray crystallography.

References
1. Hirokawa, N., S. Niwa and Y. Tanaka. Molecularmotors in neurons: Transport mechanisms androles in brain function, development and disease.
Neuron 18; 610-638, 2010.
2. Ueno, H., X. Huang, Y. Tanaka, and N. Hirokawa.
KIF16B/Rab14 molecular motor complex is critical for early embryonic development by transporting FGF receptor. Developmental Cell 20;
60-71, 2011
3. Yin, X,. Y. Takei, M. Kido and N. Hirokawa.
Molecular motor KIF17 is fundamental for
memory and learning via differential support ofsynaptic NR2A.2B levels. Neuron 70; 310-325,
2011

4

Department of Cell Biology &Anatomy (Structural Biology)
Professor
Masahide Kikkawa, M.D.,Ph.D.

Lecturer
Toshiki Yagi, Ph.D.

Associate
Toshiyuki Oda, Ph. D.

Homepage

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

Introduction and Organization
Our laboratory is one of the laboratories in
Department of Cell Biology and Anatomy. Since thereorganization of School of Medicine in 1997, the lab
was named as “Structural Biology”. The current lab
was established in 2009 when Masahide Kikkawa was
appointed as a professor.
Currently the lab members includes: Masahide
Kikkawa (Professor), Toshiki Yagi (Lecturer),
Toshiyuki Oda (Joshu), Toshiharu Sano, Yuma Tani,and Shohei Fujita (student), and Yuka Kimura(secretary).

Teaching activities
Our lab, together with Hirokawa and Okabe’s lab, isin charge of teaching following courses:
1) Gross Anatomy for medical students.
2) Cell Biology and Histology for medical students.
3) Special training (Free Quarter) for medical students.
4) Advance cell biology course for graduate students.

about 250 nm. From the recent studies, it is becoming
clear that flagella/cilia is involved in various importantcell functions.
To study the functions of flagella/cilia, we employ
various imaging techniques, including cryo-electron
microscopy and 3D-tracking microscope incombination with genetic manipulations.
Cryo-electron microscopy
One of our strength is in the high-resolution
cryo-electron microscopy (cryo-EM). This techniqueenables preserving biological samples by quickly
freezing them and observes the frozen samples
without staining. Using electron microscopy, we areable
toobtainnano-meter
resolutionofmacromolecular complexes such as axonemes. We
have been developing new techniques, such asasymmetric helical reconstruction and Ruby-Helix
software.
By using these new techniques, we are currently
studying dynein-microtubule complex, dynein
stalk-microtubule complex to elucidate the mechanismof dynein’s motor functions.

Research activities
Model Organism
Our lab focuses on the structure and function of
eukaryotic flagella/cilia. Flagella/cilia is both“propeller” and “antenna” of cells, whose diameter is

Our lab currently uses Chlamydomonas as a modelorganism for studying flagella. To identify molecules

5that are involved in regulating dynein, we use various
genetic tools, including classical mutagenesis, siRNA.
In addition, we are also developing 3D-tracking
microscopy in collaboration with Dr. Oku in
Department of Engineering. We are trying to track
Chlamydomonas cells and simultaneously record
flagella movement to elucidate the mechanism offlagella regulation.

References

6

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

Research Associate
Hirohide Iwasaki, Ph.D., Shinji Tanaka, Ph.D.

Homepage

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

Introduction and Organization
The Department of Cellular Neurobiolgy was
initially established as Neuroanatomy department offormer 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 25 members.

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
lectures and seminars.
1. Cellular Neurobiology.
2. Cell Biology and Histology.
3. Discussion seminars and progress reports ofexperiment.
4. Joint seminar with other departments

Research activities
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.
Synapse formation during development
Synapse is one of the major elements to transduce
information from neuron to neuron. Most of thesynapses are formed during the early development andthereafter they become stable after the intensive
pruning. We are interested in how synapse is formed
and maintained. We are investing this subject in vitro
and in vivo by visualizing the synaptic molecules andneuronal morphology simultaneously by imaging
techniques.

Molecular Cell Biology
2. Biochemistry and Molecular Biology

8Department of Molecular Biology
Professor
Hiroto Okayama, M.D., Ph.D.

Associate Professor
Shigeki Jinno, Ph.D.

Associate
Hanako Yamamoto, 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

9University 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. Identification of the intra-cellular pathways
mediating signals for cellular anchorage to
extra-cellularmatrices–theTSC1/TSC2-Rheb-mTORC1 pathway
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 haveidentified that the TSC1/2-Rheb-mTORC1
pathway mediates an anchorage signal andcontrols Cdk4/Cdk6 activity.
Integrins bound to the extracellular matrix
allow GTP-bound Rho A to activate ROCK.
Activated ROCK controls assembly of the actin
filaments, thereby regulating cell shape andmotility. In addition, activated ROCK activates
mTORC1 via inactivating Tsc2 by directly

phosphorylating Thr1203. Activated mTORC1
activates Cdk4/Cdk6, which in turn inactivates Rb,
and therefore activates E2F, resulting in inductionof Emi1 as well as Cdc6 and Cyclin A. Induced
Emi1 inactivates the APC/CCDH1 ubiquitin ligase,
thereby suppressing degradation of Cdc6 andCyclin A. This finding strongly suggests that the
Tsc1/2-Rheb-mTOR cascade serves a majortransduction pathway for the anchorage signal tocontrol the G1-S transition. How does mTORC1
control Cdk4/Cdk6 activity? We still do notknow the mechanism, but it seems to involve anever anticipated mechanism independent of CKI
and cyclin availability.
2. Identification of the intra-cellular pathways
mediating signals for cellular anchorage to
extra-cellular matrices – the anchorage signal
pathway to activate Cdk2
One remaining question regarding the anchorage
signal cascade to control the G1-S transition in thecell cycle is: how does anchorage signal regulate
Cdk2 activity. When cells traverse G1 phase,
Cdk2 is inactivated mainly by p27 until S phase
onset. We solved this question. We initially foundthat when CKI-resistant Cdk6/cyclin D3 complex
is overexpressed in anchorage-deprived rat
embryonic fibroblasts, Cdk2 remains active atleast for initial 36 hr. Detailed analysis revealed
the following cascade reactions. Overexpressionof Cdk6/cyclin D3 stabilizes Pim1, an oncogene
product inactivated by proviral insertion of mouse
leukemia virus, and activates ROCK in theabsence of anchorage. Activated Pim1 and ROCK
phosphorylate the C-terminus of free orCdk2-bound p27. Cdc6 then activates the Cdk2 byutilizing ATP hydrolysis energy.
Thus, ROCK-mediated C-terminal p27
phosphorylation and subsequent activation of the
p27-bound Cdk2 by Cdc6 are the rest of theanchorage signal cascade that regulates the G1-Stransition. Consequently, overexpression of
Cdk6/cyclin D3, Cdc6 and active Rheb to activate
mTORC1 conferred on rat embryonic fibroblasts
the ability to proliferate in anchorage-free soft
agar medium as rapidly as HeLa, a fully
developed human cancer line.

10

3. New function of Cdc6
We found that Cdc6 has an additional novel
function to promote cell proliferation. When cells
are deprived of anchorage, they not only arrest in
G1 but also suffer cell death known as anoikis,
which is executed by caspase-3 activated by
FADD –activated caspase-8. But when mTORC1
is activated during anoikis, the apoptosome
participates in the activation of caspase-3 because
Apaf1 remains expressed during anchorage
deprivation while anchorage loss induces
mitochondrial permeabilization resulting inrelease cytochrome C into the cytosol. But whenCdc6 is expressed in anchorage-deprived
mTORC1-activated cells, Cdc6 forms a stablecomplex with cytochrome C-bound Apaf1,
thereby blocking caspase-9 activation. Thisfunction of Cdc6 is its ATPase-dependent but
cyclin-binding motif-independent. Thus, Cdc6 is atri-functional AAA+ ATPase all working for life.
Our finding also provides a clear solution to theparadox that genes essential for proliferation andcell death are regulated at the same time and by
the same E2F transcription factor.

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.

Publication
Arakawa-Takeuchi, S., Kobayashi, K., Park, J.-H.,
Uranbileg, B., Yamamoto, H., Jinno, S., and Okayama,
H. Mammalian Target of Rapamycin Complex 1
Signaling Opposes the Effects of Anchorage Loss,
Leading to Activation of Cdk4 and Cdc6 Stabilization.
2010. FEBS Lett. 584, 2779-2785

11

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

Associate Professor
Motonao Nakamura, Ph.D.

Research Associate
Yoshihiro Kita, Ph.D.,

Homepage

Hideo Shindou, Ph.D.,

Keisuke Yanagida, Ph.D.

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

Introduction and Organization

scientists.

In addition to the above 5 faculty members, wehave 8 graduate students (7 doctor course students and1 master course student), and 8 undergraduate medical
students (Free Quarter and others). Three postdoc
scientists and several clinical researchers are also ourmembers. We have two foreign scientists (one postdoc
from Germany and one graduate student from Taiwan).
Ms. Toshie Takahashi (Assistant belongs to the Deanof the Faculty), Ms. Fumie Hamano (Research
associate) and Mr. Shinji Ichihara (Technical staff) arein charge of maintenance and education of various
instruments for common use.
Professor Takao
Shimizu has been awarded Japan Academy Prize inJune 2009.

Research

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 2010 is over25.
For graduate course students, we havethree-month lecture series and one-week practicaltraining (Lecture on receptor and signal transduction),and an eight-week laboratory course for clinical

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 vivo 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

12

identified several lysophospholipid acyltransferases
involving in Lands’ cycle. Thus, we are able toexplain the molecular mechanism and biologicalsignificance 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 2,000–5,000 pg.
Indeed, we
successfully detected dynamic changes in a series oflipid 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 (LCMS-IT-TOF,
AXIMA, Performance [Shimadzu], Exactive, TSQ
7000, TSQ Quantum Ultra, LCQ [Thermo Fischer],
Q-TOF micro [Waters], Q-TOF micro [JASCO], and4000 Q TRAP [AB Sciex]) 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 ofthe maintenance of these machines and instruction forthe beginners.
As her own projects, she isidentifying peptide sequences of various proteins by
HPLC-MS, and identification of small-molecularweight compounds by GC-MS and HPLC-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 thishomepage, you will also find our experimental
protocol useful for the molecular and cellular biology
studies. Dr. Kita and Mr Harayama are in charge ofthe homepage.
5. Collaboration with Department of Metabolome
and Department of Lipidomics
Department of Metabolome (2003-2011) and
Department of Lipidomics (2011-present) have been
established by the donation of Shimadzu Co., Ltd, and
Ono Pharmaceutical Co. In collaboration with them,
we are searching for novel lipid mediators that bind toorphan G-protein-coupled receptors, lacking identified
cognate ligands. In this collaboration we recently
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 from
the Ministry of Education, Culture, Sports, Science,
and Technology of Japan, the Ministry of Health,Labour, and Welfare of Japan (Health and Labour
Sciences Research Grants), Nanobio Integration
Program of the University of Tokyo, and a global
COE program.

Publications
1.

2.

Hirota, N., Yasuda, D., Hashidate, T., Yamamoto,T., Yamaguchi, S., Nagamune, T., Nagase, T.,
Shimizu, T., and Nakamura, M. Amino acidresidues critical for endoplasmic reticulum export
and trafficking of platelet-activating factor receptor.
J. Biol. Chem. 2010; 285: 5931-5940
Tanaka, K., Yamamoto, Y., Uozumi, N., Kita, Y.,
Yoshida, A., Shimizu, T., Hisatome, I. The
cyclooxygenase-2-selective inhibitor, etodolac, but
not aspirin reduces neovascularization in a murine

13

3.

4.

5.

6.

7.

8.

9.

ischemic hind limb model. Eur. J. Pharmacol.
2010; 627: 223-228
Ogiso, H., Nakamura, K., Yatomi, Y., Shimizu, T.,
and Taguchi, R. Liquid chromatography/mass
spectrometry analysis revealing preferential
occurrenceof
non-arachidonate-containing
phosphatidylinositol bisphosphate species in nuclei
and changes in their levels during cell cycle. Rapid.
Commun. Mass Spectrom. 2010; 24: 436-442
Le, T. D., Shirai, Y., Okamoto, T., Tatsukawa, T.,
Nagao, S., Shimizu, T., and Ito, M. Lipid signalingincytosolicphospholipase
A2alphacyclooxygenase-2 cascade mediates cerebellar
long-term depression and motor learning Proc.
Natl. Acad. Sci. U.S.A. 2010; 107: 3198-3203
Tanimura, A., Yamazaki, M., Hashimotodani, Y.,
Uchigashima, M., Kawata, S., Abe, M., Kita, Y.,
Hashimoto, K., Shimizu, T., Watanabe, M.,
Sakimura, K., Kano, M. The endocannabinoid
2-arachidonoylglycerol produced by diacylglycerol
lipase (alpha) mediates retrograde suppression ofsynaptic transmission. Neuron, 2010; 65: 320-327
Hori, T., Sato, Y., Takahashi, N., Takio, K.,
Yokomizo, T., Nakamura, M., Shimizu, T., andMiyano, M. Expression, purification andcharacterization of leukotriene B4 receptor, BLT1
in Pichia pastoris. Protein Expr. Purif. , 2010; 72:
66-74
Kihara, Y., Yokomizo, T., Kunita, A., Morishita, Y.,
Fukayama, M., Ishii, S., and Shimizu, T. The
leukotriene B4 receptor, BLT1, is required for the
inductionofexperimental
autoimmune
encephalomyelitis. Biochem. Biophys. Res.
Commun., 2010; 394: 673-678.
Toda, A., Terawaki, K., Yamazaki, S., Saeki, K.,
Shimizu, T., and Yokomizo, T. Attenuated Th1
induction by dendritic cells from mice deficient in
the leukotriene B4 receptor 1. Biochimie, 2010;
92: 682-691
Niknami, M., Vignarajan, S., Yao, M., Hua, S.,
Witting, P.K., Kita, Y., Shimizu, T., Sved, P., Patel,
M.I., and Dong, Q. Decrease in Expression orActivity of Cytosolic Phospholipase A2 Increases
Cyclooxygenase-1 Action: A Cross-talk between
Key Enzymes in Arachidonic Acid Pathway in
Prostate Cancer Cells. Biochim. Biophys. Acta. ,2010; 1801: 731-737

10. Hashidate, T., Murakami, N., Nakagawa, M.,
Ichikawa, M., Kurokawa, M., Shimizu, T., andNakamura, M. AML1 enhances the expression ofleukotriene B4 type-1 receptor in leukocytes.
FASEB J., 2010; 24: 3500-3510
11. Nakamura, M., Yasuda, D., Hirota, N., andShimizu, T. Specific ligands as pharmacologicalchaperons: The transport of misfolded G-protein
coupled receptors to the cell surface. IUBMB Life ,2010; 62: 453-459
12. Iwabu, M., Yamauchi, T., Okada-Iwabu, M., Sato,K., Nakagawa, T., Funata, M., Yamaguchi, M.,
Namiki, S., Nakayama, R., Tabata, M., Ogata, H.,
Kubota, N., Takamoto, I., Hayashi, YK.,
Yamauchi, N., Waki, H., Fukayama, M., Nishino,I., Tokuyama, K., Ueki, K., Oike, Y., Ishii, S.,
Hirose, K., Shimizu, T., Touhara, K., andKadowaki, T. Adiponectin and AdipoR1 regulate
PGC-1alpha and mitochondria by Ca(2+) and
AMPK/SIRT1. Nature , 2010; 464: 1313-1319
13. Hori, T., Sato, Y., Takahashi, N., Takio, K.,
Yokomizo, T., Nakamura, M., Shimizu, T., andMiyano, M. Expression, purification andcharacterization of leukotriene B4 receptor, BLT1
in Pichia pastoris. Protein Expr. Purif. 2010; 72:
66-74
14. Wu, YZ., Aholhassani, M., Ollero, M., Dif, F.,
Uozumi, N., Lagranderie, M., Shimizu, T.,
Chignard, M., and Touqui, L. Cytosolic
phospholipase A2alpha mediates Pseudomonas
aeruginosa LPS-induced airway constriction of
CFTR -/- mice. Respir. Res., 2010; 11: 49
15. Hasegawa, S., Kohro, Y., Shiratori, M., Ishii, S.,
Shimizu, T., Tsuda, M., and Inoue, K. Role of PAF
receptor in proinflammatory cytokine expression in
the dorsal root ganglion and tactile allodynia in arodent model of neuropathic pain. PLoS One,2010; 5: e10467
16. Iizuka, Y., Okuno, T., Saeki, K., Uozaki, H., Okada,S., Misaka, T., Sato, T., Toh, H., Fukayama, M.,
Takeda, N., Kita, Y., Shimizu, T., Nakamura, M.,
and Yokomizo, T. Protective role of the leukotriene
B4 receptor BLT2 in murine inflammatory colitis.
FASEB J., 2010; 24: 4678-4690
17. Morimoto, R., Shindou, H., Oda, Y., and Shimizu,
T. Phosphorylation of lysophosphatidylcholine
acyltransferase 2 at Ser34 enhances platelet-14

activating factor production in endotoxinstimulated macrophages. J. Biol. Chem., 2010;
285: 29857-29862
18. Ma, J., Altomare, A., de la Monte, SM., Tong, M.,
Rieder, F., Fiocchi, C., Behar, J., Shindou, H.,
Biancani, P., Harnett, KM. HCl-induced
inflammatory mediators in esophageal mucosa
increase migration and production of H2O2 byperipheral blood leukocytes. Am. J. Physiol.
Gastrointest. Liver Physiol., 2010; 299: G791G798
19. Koeberle A., Shindou H., Harayama T., andShimizu T. Role of lysophosphatidic acidacyltransferase 3 for the supply of highly
polyunsaturated fatty acids in TM4 Sertoli cells.
FASEB J., 2010; 24: 4929-4938
20. Sumida, H., Noguchi, K., Kihara, Y., Abe, M.,
Yanagida, K., Hamano, F., Sato, S., Tamaki, K.,
Morishita, Y., Kano, MR., Iwata, C., Miyazono, K.,
Sakimura, K., Shimizu, T., and Ishii, S. LPA4
regulates blood and lymphatic vessel formation
during mouse embryogenesis. Blood, 2010; 116:
5060-5070
21. Ihara, Y., Kihara, Y., Hamano, F., Yanagida, K.,
Morishita, Y., Kunita, A., Yamori, T., Fukayama,
M., Aburatani, H., Shimizu, T., and Ishii, S. The G
protein-coupled receptor T-cell death-associatedgene 8 (TDAG8) facilitates tumor development byserving as an extracellular pH sensor. Proc. Natl.
Acad. Sci. U. S. A., 2010; 107: 17309-17314
22. Taniguchi, M., Masuda, T., Mikami, Y., Kimura,M., Yoshida, T., Mishina, M., and Shimizu, T.
Identification and characterization of a novel
zebrafish semaphorin. Neurosci. Lett., 2011; 488:
215-220
23. Jonson, F., Mancardi, DA., Kita, Y., Karasuyama,
H., Iannascoli, B., Rooijen, NV., Shimizu, T.,
Daeron, M., and Bruhns, P. Mouse and humanneutrophils induce anaphylaxis. J. Clin. Invest.,
2011; 121: 1484-1496
24. Doi,K., Hamasaki, Y., Noiri, E., Nosaka, K.,
Suzuki, T., Toda, A., Shimizu, T., Fujita, T., Nakao,
A. Role of leukotriene B4 in accelerated
hyperlipidaemic renal injury. Nephrology, 2011;
16: 304-309
25. Tanaka, K., Yamamoto, Y., Ogino, K., Tsujimoto,S., Saito, M., Uozumi, N., Shimizu, T., Hisatome, I.

Cytosolic Phospholipase A2{alpha} Contributes to
Blood Pressure Increases and Endothelial
Dysfunction Under Chronic NO Inhibition.
Arterioscler. Thromb. Vasc. Biol., 2011; 31:
1133-1138
26. Soontrapa, K., Honda, T., Sakata, D., Yao, C.,
Hirata, T., Hori, S., Matsuoka, T., Kita, Y., Shimizu,
T., Kabashima, K., Narumiya, S. Prostaglandin
E2-prostoglandin E receptor subtype 4 (EP4)signaling mediates UV irradiation-induced
systemic immunosuppression. Proc. Natl. Acad.
Sci. U. S. A., 2011; 108: 6668-6673
27. Nakamura, M., and Shimizu, T. Leukotriene
Receptors. Chem. Rev., 2011; in press

15

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

Research Activities

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.

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 andTeaching 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.

16

its role in the organogenesis of the kidney and lungas revealed by gene knockout.
(2) Preimplantation development
We characterized the role of sirtuins,
NAD+-dependent protein deacetylases, in mouse
preimplantation development under in vitro culture
conditions. Among all sirtuins (Sirt1-7), which are
expressed in eggs and early embryos, Sirt3 proved
to play a protective role against oxidative stressduringpreimplantation
development.
Sirt3
inactivation
increased
mitochondrial
ROS
production, leading to the upregulation of p53 andchanges in downstream gene expression. p53
inactivation improved developmental outcome of
Sirt3-knockdown embryos, indicating that the
ROS-p53 pathway is responsible for thedevelopmental defects. These findings may
contribute to the understanding of preimplantation
biology and give a clue to the better outcome ofassisted reproductive technologies.
(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.

(3)

(4)

(5)

(6)

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)

(2)

Kawamura Y, Uchijima Y, Horike N, Tonami
K, Nishiyama K, Amano T, Asano T, Kurihara
Y, Kurihara H. Sirt3 protects in vitro-fertilized
mouse preimplantation embryos against
oxidative
stress-induced
p53-mediateddevelopmental arrest. J. Clin. Invest. 120:2817-2828, 2010.
Asai R, Kurihara Y, Fujisawa K, Sato T,
Kawamura Y, Kokubo H, Tonami K,
Nishiyama K, Uchijima Y, Miyagawa-Tomita

(7)

(8)

S, Kurihara H. Endothelin receptor type-A
expression defines a distinct cardiac
subdomain within the heart field, with a later
implication of this signaling pathway inchamber myocardium formation. Development
137: 3823-3833, 2010.
Fujimoto C, Ozeki H, Uchijima Y, Suzukawa
K, Mitani A, Fukuhara S, Nishiyama K,
Kurihara Y, Kondo K, Aburatani H, Kaga K,
Yamasoba T, Kurihara H. Establishment ofmice expressing EGFP in the placode-derived
inner ear sensory cell lineage and FACS-array
analysis focused on the regional specificity ofthe otocyst. J. Comp. Neurol. 18: 4702-4722,
2010.
Heude E, Bouhali K, Kurihara Y, Kurihara H,
Couly G, Janvier P, Levi G. Jaw
muscularization requires Dlx expression by
cranial neural crest cells. Proc. Natl. Acad. Sci.
U. S. A. 107: 11441-11446, 2010.
Vieux-Rochas M, Mantero S, Heude E,
Barbieri O, Astigiano S, Couly G, Kurihara H,
Levi G, Merlo GR. Spatio-temporal dynamics
of gene expression of the Edn1-Dlx5/6
pathway during development of the lower jaw.
Genesis 48: 262-273, 2010.
Nakatsu Y, Sakoda H, Kushiyama A, Ono H,
Fujishiro M, Horike N, Yoneda M, Ohno H,
Kamata H, Tahara H, Isobe T, Nishimura F,
Katagiri H, Oka Y, Fukushima T, Takahashi SI,
Kurihara H, Uchida T, Asano T. Pin1
associates with and induces translocation of
CRTC2 to the cytosol, thereby suppressing
CRE transcriptional activity. J. Biol. Chem.
285: 33018-33027, 2010.
Cui X, Kushiyama A, Yoneda M, Nakatsu Y,
Guo Y, Zhang J, Ono H, Kanna M, Sakoda H,
Ono H, Kikuchi T, Fujishiro M, Shiomi M,
Kamata H, Kurihara H, Kikuchi M, Kawazu S,
Nishimura F, Asano T. Macrophage foam cell
formation is augmented in serum from patientswith diabetic angiopathy. Diabetes Res. Clin.
Pract. 87: 57-63, 2010.
Tanaka A, Itoh F, Nishiyama K, Takezawa T,
Kurihara H, Itoh S, Kato M. Inhibition ofendothelial cell activation by bHLH protein

17E2-2 and its impairment of angiogenesis.
Blood 115: 4138-4147, 2010.
(9) Tonami K, Kurihara Y, Arima S, Nishiyama K,
Uchijima Y, Asano T, Sorimachi H, Kurihara
H. Calpain 6, a microtubule-stabilizing protein,
regulates Rac1 activity and cell motility
through interaction with GEF-H1. J. Cell Sci.
124: 1214-1223, 2011.
(10) Kitazawa T, Sato T, Nishiyama K, Asai R,
Arima Y, Uchijima Y, Kurihara Y, Kurihara H.
Identification and developmental analysis ofendothelin receptor type-A expressing cells in
the mouse kidney. Gene Expr. Patterns. (inpress).
(11) Nakatsu Y, Sakoda H, Kushiyama A, Zhang J,
Ono H, Fujishiro M, Kikuchi T, Fukushima T,
Yoneda M, Ohno H, Horike N, Kanna M,
Tsuchiya Y, Kamata H, Nishimura F, Isobe T,
Ogihara T, Katagiri H, Oka Y, Takahashi S,
Kurihara H, Uchida T, Asano T. Peptidyl-prolyl
cis/trans isomerase NIMA-interacting 1
associates with insulin receptor substrate-1 andenhances insulin actions and adipogenesis. J.
Biol. Chem. 286:20812-20822, 2011.
(12) Mishima T, Ito Y, Hosono K, Tamura Y, Uchida
Y, Hirata M, Suzuki T, Amano H, Kato S,
Kurihara Y, Kurihara H, Hayashi I, Watanabe
M, Majima M. Calcitonin gene-related peptide
facilitates revascularization during hindlimb
ischemia in mice. Am. J. Physiol. Heart Circ.
Physiol. 300: H431-H439, 2011.

Functional Biology
1. Physiology

19

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, inteaching activities for undergraduate courses and thenursing school. The fields in which our laboratory
specializes span the entire spectrum of animalfunctions of physiology, including general physiology,
sensory physiology, endocrinology, neurophysiology,
higher nervous functions and cognitive neurosciences.

Teaching activities
The staff members as well as experts from otheruniversities (Drs. A. Nambu, S. Kaname, S. Sugiura
and Y. Shibagaki) take part in giving lectures andlaboratory courses to the undergraduate students of theMedical School. The lectures are aimed at providing aclear understanding of the hierarchical functionalorganizations of living systems. The curriculum is
updated every year. For example, a newelectrocardiogram experiment in humans wasintroduced to the laboratory course, in which students

learned human physiology of electrocardiogram, its
practical procedure in clinical settings and its cellularphysiological origins. This practice gained popularity
and interest among students. We accept Free-Quarter
students every year. Usually these students' activities
are not limited to one Quarter, and 4 students (M0,
M1 and M4) continued to enjoy their researches from2010 through 2011. Some of these students completed
their own projects, and gave oral presentations ininternational meetings and published original papers
in top-rank international journals. It is not rare thatstudents who enjoyed his/her Free-Quarter decided to
get into the Ph-D. course after the completion of the
2-year clinical training and started to study
neurophysiology in our laboratory. Furthermore, we
accepted a Ph-D.-M.D course student who enjoyed his
Free-Quarter and decided to get into the Ph-D.-M.D
course. Thus the Free-Quarter system has proved toprovide an excellent basis for bringing up M.D.
researchers for future Japanese basic medicine.
To facilitate communication among research groups
in our laboratory, a weekly conference is held for
discussing current research activities. We also have amonthly joint seminar with Department ofPharmacology, Department of Psychology in Facultyof Letters and Department of Biophysics in Faculty of
Science. As part of a teaching activity for the graduate
students, we have another weekly English seminar, in20

which the graduate students learn how to givepresentations and hold discussions and debates inEnglish.

Research activities
Most of our research is focused on the higher brain
function of the mammalian central nervous system :(1) higher functions of vision and memory, (2)non-invasive measurements of human brain activitiesand (3) non-invasive functional measurements ofmonkey brain activities that links above (1) and (2).
The results of such research have been published infirst-rate journals, as listed in the reference. A briefsummary of each topic follows:(1) In the primate, visual information processing in
the cerebral cortex proceeds along the neuralpathway originating from the primary visual areain the occipital lobe to the anterior part of thetemporal association cortex. Our laboratory
discovered several classes of important
memory-neurons electrophysiologically in thetemporal lobe of the monkey. In theinferotemporal cortex, which we propose to be thestorehouse of visual long-term memory, we
discovered a group of neurons which encode
object-object association. We found that the
backward signal from the medial temporal lobe to
the inferotemporal cortex mediates formation of
the mnemonic neural circuits for the association.
Recently we also found that the top-down signal
from the prefrontal cortex to the inferotemporal
cortex plays a central role in retrieval of themnemonic associative neural code stored in theinferotemporal cortex. Since association is a basic
mechanism for constructing the humanmemory-based knowledge system, our finding
provides a key to understanding the basicorganization of the primate cerebral cortex.
(2) The recent explosion of new technologies fornoninvasive measurements of human brain
activities, especially of functional magnetic
resonance imaging (fMRI), allows us to observe
parallel activation of functional brain modules inhumans engaged in various mental tasks. We
contributed to development of a new method
called “event-related fMRI”, which enables toutilize the time resolution of fMRI. We applied
this “event-related fMRI” method to the analysis
of human cognition, and identified several
functional centers in the human prefrontal cortex
in cognitive tasks such as the Wisconsin Card
Sorting Task.
(3) Recently, we successfully applied fMRI method tomacaque monkeys performing highly intelligent
cognitive tasks. These fMRI studies were done inultra-high field MRI scanner at 4.7 Tesla,
successfully providing much higher spatial
resolution than in a conventional clinical MRI
scanner. This approach provides us a new
approach that bridges a gap between the humannon-invasive studies and the various invasive
studies in animals, including intra-corticalelectricalmicrostimulation
andreversiblefunctional inactivation with GABA agonist drug
injections.

References
1

2

3

4

5

Takeuchi, D., Hirabayashi, T., Tamura, K. andMiyashita, Y. : Reversal of interlaminar signal
between sensory and memory processing inmonkey temporal cortex.
Science 331, 1443-1447, 2011.
Kamigaki, T., Fukushima, T. and Miyashita, Y. :Neuronal signal dynamics during preparation andexecution for behavioral shifting in Macaqueposterior parietal cortex. J. Cogn. Neurosci. 23,
2503-2520, 2011.
Koyano, K.W., Machino, A., Takeda, M., Matsui,T., Fujimichi, R., Ohashi, Y. and Miyashita, Y. :In vivo visualization of single-unit recording sites
using MRI-detectable elgiloy deposit marking.
J. Neurophysiol. 105, 1380-1392, 2011.
Matsui, T., Tamura, K., Koyano, K.W., Takeuchi,D., Adachi, Y., Osada, T. and Miyashita, Y. :Direct comparison of spontaneous functional
connectivity and effective connectivity measured
by intracortical microstimulation: an fMRI study
in macaque monkeys.
Cereb. Cortex 21, 2348-2356, 2011.
Watanabe, T., Hirose, S., Wada, H., Katsura, M.,
Chikazoe J., Jimura, K., Imai, Y., Machida, T.,
Shirouzu, I., Y. Miyashita and Konishi, S. :

21

6

7

8

9

10

11

12

13

14

PredictionofSubsequent
Recognition
Performance Using Brain Activity in the Medial
Temporal Lobe. NeuroImage 54, 3085-3092,
2011.
Konishi, S., Watanabe, T., Jimura, K., Chikazoe,J., Hirose, S., Kimura, H.M. and Miyashita, Y. :Role for presupplementary motor area ininhibition of cognitive set interference.
J. Cogn. Neurosci. 23, 737-745, 2011.
Ohashi, Y., Tsubota, T., Sato, A., Koyano, K.W.,
Tamura, K. and Miyashita, Y. : A bicistronic
lentiviral vector-based method for differential
transsynaptic tracing of neural circuits.
Mol. Cell. Neurosci. 46, 136-147, 2011.
Hirabayashi, T., Takeuchi, D., Tamura, T. andMiyashita, Y. : Triphasic dynamics of stimulus-dependent information flow between single
neurons in macaque inferior temporal cortex.
J. Neurosci. 30, 10407-10421, 2010.
Chikazoe, J. : Localizing Performance of
Go/No-Go Tasks to Prefrontal Cortical
Subregions.
Curr. Opin. Psychiatry 23,267-272, 2010.
Fujimichi, R., Naya, Y., Koyano, K.W., Takeda,
M., Takeuchi, D. and Miyashita, Y. : Unitized
representation of paired objects in area 35 of themacaque perirhinal cortex. Eur. J. Neurosci. 32,
659-667, 2010.
Asari, T., Konishi, S., Jimura, K., Chikazoe, J.,
Nakamura, N. and Miyashita,Y. : Amygdalar
enlargement associated with unique perception.
Cortex 46, 94-99, 2010.
Asari, T., Konishi, S., Jimura, K., Chikazoe, J.,
Nakamura, N. and Miyashita, Y. : Amygdalar
modulation of frontotemporal connectivity during
the inkblot test.
Psychiatry Research:
Neuroimaging 182, 103-110, 2010.
Jimura, K., Konishi, S., Asari, T. and Miyashita.
Y. : Temporal pole activity during understanding
other persons' mental state correlated withneuroticism trait.
Brain Research 1328,
104-112, 2010.
Konishi, S., Hirose, S., Jimura, K., Chikazoe, J.,
Watanabe, T., Kimura, H.M. and Miyashita, Y. :Medial prefrontal activity during shifting undernovel situations. Neurosci. Lett. 484, 182-186,
2010.

15 Kimura, H.M., Hirose, S., Kunimatsu, A.,
Chikazoe, J., Jimura, K., Watanabe, T., Abe, O.,
Ohtomo, K., Miyashita, Y. and Konishi, S. :Differential temporo-parietal cortical networks
that support relational and item-based recency
judgments. NeuroImage 49, 3474-3480, 2010.

22

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, 3
postdoctoral researchers, 2 visiting scientist, 8
graduate students and 1 secretary stuff.

Using multidisciplinary approaches including
electrophysiology, optical imaging, molecular andcellular biology and molecular genetics, we at the
Department of Cellular and Molecular Physiology aim
at understanding neuronal circuit mechanisms for thetranslation of olfactory sensory inputs to a variety of
behavioral and emotional outputs in the mammalianbrain. Our recent focus includes the functional andspatial organization of the odor maps in the olfactorybulb, axonal projection pattern of olfactory bulb
neurons to various areas of the olfactory cortex, andolfactory cortical mechanisms for the recognition of
objects. We study also behavioral state-dependentchange in the information processing mode in theolfactory bulb and olfactory cortex, focusing on theexperience-dependent reorganization of neuronal
circuitry in the olfactory cortex and bulb during
postprandial slow-wave sleep.

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

Granule cells in the olfactory bulb continue to begenerated in adulthood, with nearly half incorporated
and remainder eliminated into or from the neuronal
circuit of the olfactory bulb. We have been
investigating the neuronal mechanisms during
olfactory experience and those during postprandial
sleep for the sensory-experience dependent

23

incorporation and/or elimination of adult-born granulecells into or from the pre-existing neuronal circuit in
the olfactory bulb.
Currently we are focusing on the following topics.
(1) Analysis of the functional neuronal circuits in thecentral olfactory system.
Based on the knowledge of the ‘odorant
receptor maps’ and ‘functional compartmentalization in the odor map’ in the olfactory bulb, weare studying the manner of olfactory information
processing in the olfactory bulb, olfactory cortex
and higher olfactory association regions.
The glomerular layer of the mammalianolfactory bulb forms odorant receptor maps. Eachmap is structurally and functionally compartmentalized into zones (dorsal and ventral) anddomains (DI and DII). We previously reported thatglomeruli with similar molecular receptive range
properties formed molecular feature clusters atstereotypical positions in the rat olfactory bulb.
However the spatial arrangement of the molecularfeature clusters with regard to the zones anddomains has not been systematically examined.
We optically mapped the molecular featureclusters of glomeruli within the domain and zone
framework of the olfactory bulb using
domain-visible class II GFP transgenic mice. In
all mice examined, fatty acid-responsive cluster A
was located in the lateral part of domain DI,
whereas clusters B, C, and D were arranged in ananterior to posterior order within domain DII.
These results show that molecular feature clusters
correspond to specific subsets of glomeruli inselective domains of the odorant receptor map,suggesting that the molecular feature clusters
represent specific odorant receptors that have
similar molecular receptive range properties andfunctional roles.
By combining the methods of optical imaging
of intrinsic signals to identify the glomeruli that
respond to fox odor trimethylthiazoline (TMT),
the electrophysiological single-neuron recordingfrom individual TMT-responsive mitral cells or
tufted cells, and juxtacellular single cell labelingmethods, we traced the entire axons of the labeled
mitral and tufted cells in various areas of theolfactory cortex.
Rodents can localize odor sources bycomparing inputs to the right and left nostrils.
However, the neuronal circuits underlying suchodor localization are not known. We recorded
neurons in the anterior olfactory nucleus (AON)
while administering odors to the ipsilateral orcontralateral (ipsi- or contra-) nostril. Neurons in
the AON pars externa (AONpE) showed
respiration
phase-locked
excitatory
spike
responses to ipsinostril-only stimulation with acategory of odorants, and inhibitory responses tocontranostril-only stimulation with the sameodorants. Simultaneous odor stimulation of theipsi- and contranostrils elicited significantly
smaller responses than ipsinostril-only stimulation,
indicating that AONpE neurons subtract thecontranostril odor inputs from ipsinostril odor
inputs. An ipsilateral odor source induced larger
responses than a centrally located source, whereas
an odor source at the contralateral position elicited
inhibitory responses. These results indicate that
individual AONpE neurons can distinguish theright or left position of an odor source byreferencing signals from the two nostrils.
(2) Reorganization of olfactory neuronal circuits
during slow-wave sleep
The olfactory cortex is functionally isolated fromthe external odor world during slow-wave sleep.
However, the neuronal activity pattern in theolfactory cortex and its functional roles duringslow-wave sleep are not well understood. We
demonstrate in freely behaving rats that theanterior piriform cortex, a major area of theolfactory cortex, repeatedly generates sharp waves
that are accompanied by synchronized discharges
of numerous cortical neurons. Olfactory cortex
sharp waves occurred relatively independently ofhippocampal sharp waves. Current source density
analysis showed that sharp wave generation

24

involved the participation of recurrent association
fiber synapses to pyramidal cells in the olfactorycortex. During slow wave sleep, the olfactory bulb
showed sharp waves that were in synchrony witholfactory cortex sharp waves, indicating that
olfactory cortex drove synchronized top-down
inputs to the olfactory bulb. Based on these results,
we speculate that the olfactory cortex sharp waves
may play a role in the reorganization of bulbar
neuronal circuits during slow-wave sleep.
(3) Incorporation of adult-born interneurons in the
pre-existing neuronal circuit in the olfactory bulb.
The olfactory system is chosen as a model
system with which to study the recruitment of
newly-generated neurons in the adult neuronal
circuit. We are studying cellular and molecularmechanisms that segregate the fate of newneurons between successful incorporation andapoptotic elimination into/from the neuronal
circuit. Recently we noted that the eliminationof newly-generated granule cells in the olfactory
bulb is greatly enhanced during the specific time
window of postprandial sleep. Sensory
experience-dependent enhancement of granulecell elimination also occurred during postprandial
rest/sleep period. These results suggest that
extensive structural reorganization of bulbar
circuitry occurs during the postprandial period,
reflecting sensory experience during preceding
waking period.

Publications (2010~)
1. Matsumoto, H., Kobayakawa, K., Kobayakawa, R.,
Tashiro T., Mori, K., Sakano, H. and Mori, K.
Spatial arrangement of glomerular molecularfeature clusters in the odorant-receptor-classdomains of the mouse olfactory bulb

J

Neurophysiol. 103: 3490-3500 (2010)
2. Kikuta S., Sato, K., Kashiwadani H., Tsunoda, K.,
Yamasoba, T and Mori K.
Neurons in theanterior olfactory nucleus pars externa detect rightand left localization of odor sources Proc. Natl.
Acad. Sci. USA 107: 12363-12368. (2010)

3. Imayoshi, I., Sakamoto M., Yamaguchi, M., Mori,
K. and Kageyama, R.

Essential roles of Notch

signaling in maintenance of neural stem cells inthe developing and adult brains

J. Neurosci.

30(9):3489-3498. (2010)
4. Nagayama, S., Enerva A., Fletcher M.L., Masurkar
A.V., Igarashi, K., Mori, K., Chen W.R.
Differential axonal projection of mitral and tufted
cells in the mouse main olfactory system
Frontiers in Neural Circuits
4: 1-8. (2010)
5. Matsuda, I., Fukaya, M., Nakao, H., Nakao, K.,
Matsumoto, H., Mori, K., Watanabe, M. and Aiba,
A. Development of the somatosensory cortex,
the cerebellum, and the main olfactory system in
Semaphorin 3F knockout mice. Neurosci Res.
66(3):321-329. (2010)
6. Tsuboi, A., Imai, T., Kato, H.K., Matsumoto, H.,
Igarashi, K.M., Suzuki, M., Mori, K. and Sakano,
H. Two highly homologous mouse odorant
receptors encoded by tandemly-linked MOR29A
and MOR29B genes differently respond to phenyl
ethers.
European Journal of Neuroscience
33(2): 205-213 (2011)
7. Mitsui, S., Igarashi, K.M., Mori, K. and Yoshihara,
Y. Genetic visualization of the secondary olfactory
pathway in Tbx21 transgenic mice.
NeuralSystems and Circuits 1: 5 (2011)
8. Mori, K. and Sakano, H. How is the olfactory map
formed and interpreted in the mammalian brain?
Annu. Rev. Neurosci. 34: 467-499 (2011)
9. Sakamoto, M., Imayoshi, I., Ohtsuka,T.,
Yamaguchi, M, Mori, K. and Kageyama, R.
Continuous neurogenesis in the adult forebrain isrequired for innate olfactory responses Proc.
Natl. Acad. Sci. USA
108(20): 8479-8484(2011)
10. Manabe, H., Kusumoto-Yoshida, I., Ota, M. andMori, K.
Olfactory cortex generates
synchronized top-down inputs to the olfactory
bulb during slow-wave sleep.
J. Neurosci.
31(22): 8123-8133 (2011)
11. Murata, M., Imai, M., Nakanishi S., Watanabe, D.,
Pastan I., Kobayashi, K., Nihira T., Mochizuki, H.,
Yamada, S., Mori, K. and Yamaguchi, M.
Compensation of depleted neuronal subsets by
new neurons in a local area of the adult olfactory

25bulb. J. Neurosci. (in press, 2011)12. Yokoyama, T.K., Mochimaru, D., Murata, K.,
Manabe H, Kobayakawa, K., Kobayakawa, R.,
Sakano, H., Mori, K., and Yamaguchi M.
Elimination of adult-born neurons in the olfactory
bulb is promoted during the postprandial period.
Neuron (in press, 2011)

26

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

Associate Professor
Kazuo Kitamura, Ph.D.

Associate
Naofumi Uesaka, 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. The current members of this laboratory are
3 faculty members (professor, associate professor,
associate), 6 postdoctoral fellows, 7 graduate students,
1 undergraduate and 4 technicians. We teachneurophysiology for medical undergraduates and forstudents in the Master and Ph.D. courses. Our researchaims at elucidating cellular and molecular mechanisms
underlying regulation of synaptic transmission andpostnatal 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 andmatured during postnatal development. In the practicalcourses, students perform two types of classicalexperiments of neurophysiology. First, students makeintracellular recording from frog skeletal muscle
fibers and examine the end-plate potential forunderstanding
basic
properties
ofsynaptictransmission. Second, students record electromyogram(EMG) from human gastrocnemius 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 orpresents papers closely related to his/her research.
Moreover, for mutual communication between thelaboratories with similar interests in neuroscience, wehave a weekly joint seminar with Department of
Cellular Neurobiology, Division of Structural
Physiology, and Laboratory of Animal Resources.

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). We take various methodologicalapproaches including electrophysiology, pharmacology, morphology, and genetic engineering of

27mouse. We particularly focus on observing neuronal
activities in real time in intact neurons. We use
whole-cell patch clamp recording, calcium imaging,two-photon imaging and their combinations in various
preparations (cultured neurons, brain slices and intact
animals) and investigate molecular mechanisms ofsynaptic transmission and plasticity.
The main subjects of our research are as follows(1) Refinement of synaptic organization during
cerebellar development:
In early postnatal days, all Purkinje cells in the
cerebellum are innervated by multiple climbing fibers.
These surplus climbing fibers are eliminatedeventually with the progress of postnatal development,
and most Purkinje cells become innervated by single
climbing fibers by the end of the third postnatal weekin mice. We investigate the mechanisms how single
climbing fibers are selected and how the surplus
climbing fibers are eliminated.
(2) Retrograde synaptic modulation mediated byendogenous cannabinoids:
We reported in 2001 that endogenous cannabinoids
are released from postsynaptic neurons in an
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, addiction, andanxiety.
(3) Synaptic integration in intact animals:
To understand the physiological function ofsynapses in vivo, we analyze synaptic transmission
and integration in single neurons in the intact brain byusing in vivo two-photon imaging and whole-cellrecording. We also develop new methods toimplement these experiments.

(2) Yoshida, T., Uchigashima, M., Yamasaki, M.,
Katona, I., Yamazaki, M., Sakimura, K., Kano,
M., Yoshioka, M. & Watanabe, M.: Unique
inhibitory

synapsewithparticularly

rich

endocannabinoid signaling machinery on pyramidal
neurons in basal amygdaloid nucleus. Proc Natl
Acad Sci USA 108, 3059-3064, 2011.
(3) Ludányi, A., Hu, S.S., Yamazaki, M., Tanimura, A.,
Piomelli, D., Watanabe, M., Kano, M., Sakimura,K., Maglóczky, Z., Mackie, K., Freund, T.F.,
Katona, I.: Complementary synaptic distribution of
enzymes responsible for synthesis and inactivationof the endocannabinoid 2-arachidonoylglycerol in
the human hippocampus. Neuroscience. 3, 50-63,
2011.
(4) Yamada, A., Uesaka, N., Hayano, Y., Tabata, T.,Kano, M. & Yamamoto, N.: Role of pre- andpostsynaptic activity in thalamocortical axon
branching. Proc Natl Acad Sci USA 107,7562-7567, 2010.
(5) Tanimura, A., Yamazaki, M., Hashimotodani, Y.,
Uchigashima, M., Kawata, S., Abe, M., Kita, Y.,
Hashimoto, K., Shimizu, T., Watanabe, M.,
Sakimura, K. & Kano, M.: The endocannabinoid
2-arachidonoylglycerol produced by diacylglycerol
lipase α mediates retrograde suppression ofsynaptic transmission. Neuron 65, 320-327, 2010.
(6) Fujita, Y., Shimomura, T., Hosoguchi, M., Kano, M.,
Fukurotani, K. & Tabata, T.: A new multiple-drug
applicator with minimal drug cross-talk, leakage, andconsumption. Neurosci Res, 66, 412-414, 2010.
(7) Yamazaki, M., Fukaya, M., Hashimoto, K.,
Yamasaki, M., Tsujita, M., Itakura, M., Abe, M.,
Natsume, R., Takahashi, M., Kano, M., Sakimura,
K. & Watanabe, M.: TARPs γ-2 and γ-7 areessential for AMPA receptor expression in the

References

cerebellum. Eur J Neurosci, 31, 2204-2220, 2010.
(8) Tabata, T. & Kano, M.: GABAB receptor-mediated(1) Hashimotodani, Y., Ohno-Shosaku, T., Yamazaki,

modulation of metabotropic glutamate signaling

M., Sakimura, K. & Kano, M.: Neuronaland synaptic plasticity in central neurons. In:protease-activated receptor 1 drives synaptic

GABAB Receptor Pharmacology: A Tribute to

retrograde

by

the

Norman Bowery (Advances in Pharmacology (Vol.

2-arachidonoylglycerol.

J.

58) , Thomas P. Blackburn and S. J. Enna, (eds),

signalingendocannabinoid

mediated

Neurosci. 31, 3104-3109, 2011.

Academic Press, 149-173, 2010.

Functional Biology
2. Pharmacology

29

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 within the cell. This property
allows the Ca2+ signal to be an extremely versatile
cellular switch regulating diverse cell functions.
One of the most notable spatiotemporal patterns of
Ca2+ signals is the oscillatory change inintracellular Ca2+ concentration ([Ca2+]i), or Ca2+
oscillation. Many cellular functions are regulatedby the Ca2+ oscillation frequency. However,fundamental questions remain. How and why does
[Ca2+]i oscillate? We have addressed thesequestions.
First,
westudiedinositol
2+
1,4,5-trisphosphate (IP3)-induced Ca
releasemechanism, which is one of the most important
Ca2+ mobilizing mechanisms in many types of cell.
We showed that the activity of the IP3 receptor(IP3R) is dependent on the cytoplasmic Ca2+
concentration. Therefore, Ca2+ release via the IP3R
appears to be under the feedback control ofmobilized Ca2+. We identified the Ca2+ sensor
region of the IP3R and showed that the positive
feedback regulation of IP3R via the Ca2+ sensor of

30

IP3R indeed plays an essential role in regulating
the Ca2+ signal dynamics including Ca2+
oscillation.
In order to further study the mechanism
underlying Ca2+ oscillation, we visualized the Ca2+
concentrations within the intracellular organelles(both endoplasmic reticulum and mitochondria)
during Ca2+ oscillations. We found that Ca2+
shuttles between these intracellular organelles inphase with cytoplasmic Ca2+ oscillations. Our
results also indicated that the Ca2+ shuttlingdetermines the Ca2+ oscillation frequency. Thus,
we have shown that mitochondria play animportant role in the generation of Ca2+ oscillation.
These results provide a clue to the mechanism 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
demonstrated that bursting synaptic activities
cause glutamate spillover from the synaptic cleft
to activate perisynaptic metabotropic glutamate
receptors, and will provide a basis for the researchof extrasynaptic glutamate transmission that is
involved in many important 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

31with neighbouring cells generate local transient
intracellular Ca2+ signals (Ca2+ lightning). Ca2+
lightning was exclusively observed near cell-cell
contact regions and was not observed in the central
regions of cells, nor was it found in solitary cells
that are not in contact with other cells. We also
show that Ca2+ lightning is capable of 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. We are now studying the molecularmechanism that links between Ca2+ signals andN-cadherin expression. Furthermore, we recently
showed that IP3-Ca2+ signaling in cerebellar
astrocytes (Bergmann glia) regulates glutamate
transporter levels in Bergman glial cells tomaintain glutamate clearance in the mature
cerebellum.
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 analyzing the basis of
the cell-to-cell variability. We found that thebalance between Ca2+ release and uptake isenhanced by the positive feedback property of theCa2+ relase to generate the all-or-none propety of
the Ca2+ relase. Furthermore, individual cells
switched between the caffeine-sensitive andcaffeine-insensitive states with an averagetransition time of approximately 65 h, suggestiveof temporal fluctuation in endogenous protein
expression levels associated with caffeine response.
Thus, the study provides a conceptual basis of thecell-to-cell phenotypic variability in mammaliancells.

References
1. Iino, M. Spatiotemporal dynamics of Ca2+
signaling and its physiological roles. Proc. Jpn.
Acad. Ser. B-Phys. Biol. Sci. 86: 244, 2010.
2. Okubo, Y., Sekiya, H, Namiki, S, Sakamoto, H.,
Iinuma, S., Yamasaki, M., Watanabe, M., Hirose, K.
and Iino, M. Imaging extrasynaptic glutamate
dynamics in the brain. Proc. Natl. Acad. Sci.
U.S.A. 107: 6526, 2010.
3. Mashimo, M., Okubo, Y., Yamazawa, T., Yamasaki,M., Watanabe, M., Murayama, T. and Iino, M.
Inositol 1,4,5-trisphosphate signaling maintains theactivity of glutamate uptake in Bergmann glia.
Eur. J. Neurosci. 32: 1668, 2010.

32

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

LecturerTomoyuki Yoshida, Ph.D.

Research Associate
Takeshi Uemura, Ph.D.,

Misato Yasumura, Ph.D.

Takashi Hayashi, Ph.D.

Homepage

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

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

Research activities
Current research activities are focused on themolecular mechanism and regulation of learning andmemory. Brain function is based on highly complex
neural networks and their dynamics. The glutamate
receptor (GluR) plays a key role in brain dynamics.
We elucidated the diversity of the NMDA-type GluR

by molecular cloning and functional expression.
Ablation of the NMDA receptor GluRε1 (GluN2A) by
gene targeting resulted in the increase of thresholds
for both hippocampal long-term potentiation (LTP)
induction and contextual learning. Furthermore,
cerebellar Purkinje cell (PC)-specific GluRδ2 (GluD2)
mutant mice showed impairment of cerebellar
long-term depression (LTD) and motor learning.
These results suggest that GluR is a key molecule oflearning and memory. We found Delphilin as a
GluRδ2-interacting molecule, which showed selective
expression in cerebellar PCs similar to GluRδ2.
Ablation of Delphilin facilitated LTD induction atparallel fiber (PF)-PC synapses and enhanced
optokinetic response (OKR) gain-increase adaptation
without affecting any detectable histologicalabnormalities. This finding suggests that LTD
induction at PF-PC synapses is a crucial rate-limiting
step for OKR adaptation, a simple form of motor
learning. Further analyses of GluRδ2 and GluRε1mutant mice revealed that the temporal relationship ofconditioned and unconditioned stimuli determines theneural substrates of eyeblink conditioning, a simple
form of associate learning, implying a systemic
regulation of learning and memory.
To investigate the regulation of learning andmemory, we established an inducible and33

neuron-specific gene targeting system on the pure
C57BL/6 genetic background by employing
Cre-progesterone receptor fusion recombinase(CrePR) for temporal regulation of gene targeting and
Flp/frt recombination system for elimination ofmarker genes. Since brain functions are the productsof dynamic interactions between multiple genes andenvironments, 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.
Fear is one of the most potent emotional
experiences and is an adaptive component of response
to potentially threatening stimuli. On the other hand,
too much or inappropriate fear accounts for many
common psychiatric problems. Cumulative evidence
suggests that the amygdala plays a central role in theacquisition, storage and expression of fear memory.
We developed an inducible striatal neuron ablation
system in transgenic mice. The ablation of striatal
neurons hardly affected the auditory fear learning
under the standard condition in agreement withprevious studies. When conditioned with a
low-intensity unconditioned stimulus, however, theformation of long-term fear memory but not short-tem
memory was impaired in striatal neuron-ablated mice.
Consistently, the ablation of striatal neurons 24 h after
conditioning with the low-intensity unconditioned
stimulus, when the long-term fear memory wasformed, diminished the retention of the long-term
memory. Our results reveal a novel form of theauditory fear memory depending on striatal neurons at
the low-intensity unconditioned stimulus.
Synchronized discharges in the hippocampal CA3
recurrent network are supposed to underlie network
oscillations, memory formation and seizure generation.
In the hippocampal CA3 network, NMDA receptors
are abundant at the recurrent synapses but scarce at
the mossy fiber synapses. We generated mutant micein which NMDA receptors were abolished in
hippocampal CA3 pyramidal neurons by postnatal day
14. We found that mutant mice lacking NMDA
receptors selectively in CA3 pyramidal neurons
became more susceptible to kainate-induced seizures.
Consistently, mutant mice showed characteristic large
EEG spikes associated with multiple unit activities(MUA), suggesting enhanced synchronous firing of

CA3 neurons. The electrophysiological balance
between fast excitatory and inhibitory synaptictransmission was comparable between control andmutant pyramidal neurons in the hippocampal CA3
region, while the NMDA receptor-slow AHP coupling
was diminished in the mutant neurons. In the adultbrain, inducible ablation of NMDA receptors in the
hippocampal CA3 region by the viral expression
vector for Cre recombinase also induced similar large
EEG spikes. Furthermore, pharmacological blockadeof CA3 NMDA receptors enhanced the susceptibility
to kainate-induced seizures. These results raise an
intriguing possibility that hippocampal CA3 NMDA
receptors may suppress the excitability of therecurrent network as a whole in vivo by restricting
synchronous firing of CA3 neurons
Interestingly, the NMDA receptor GluRε2(GluN2B) was essential for formation of thewhisker-related neuronal barrelette structure in thebrainstem trigeminal nucleus. The number of PF-PC
synapses was decreased in GluRδ2 mutant mice andmultiple climbing fiber innervation was sustained.
These observations led to a working hypothesis thatmemory formation in the adult brain and synapse
refinement during development may share common
molecular mechanisms.
We then examined the role of GluRδ2 in the adultbrain by inducible and cerebellar PC-specific genetargeting. Concomitant with the decrease of
postsynaptic GluRδ2 proteins, presynaptic active
zones shrank progressively and postsynaptic density(PSD) expanded, resulting in mismatching between
pre- and postsynaptic specializations at PF-PC
synapses. Furthermore, GluRδ2 and PSD-93 proteins
were concentrated at the contacted portion of
mismatchedsynapses,while
α-amino-3-hydroxy-5-methyl-4-isozaxole propionicacid (AMPA) receptors distributed in both thecontacted and dissociated portions. When GluRδ2proteins were diminished, PC spines lost theirsynaptic contacts. We thus identified postsynaptic
GluRδ2 as a key regulator of the presynaptic active
zone and PSD organization at PF-PC synapses in theadult brain. Possibly, the postsynaptic GluRδ2complex makes a physical linkage between the active
zone and PSD to ensure the pre- and postsynaptic
matching. These observations support the notion that34

there is a common molecular mechanism underlying
synaptic plasticity and synapse formation.
GluRδ2 selectively expressed in cerebellar PCs
plays key roles in LTD induction at PF-PC synapses,
motor learning, the matching and connection of PF-PC
synapses in developing and adult cerebella, theelimination of multiple climbing fibers (CFs) during
development and the regulation of CF territory on PCs.
However, it remains unsolved how GluRδ2 regulates
cerebellar synaptic plasticity, PF-PC synapse
formation and CF wiring. One possible signalingmechanism through GluRδ2 is signaling byprotein-protein interactions. The carboxyl-terminal
region of GluRδ2 contains at least three domains forprotein-protein interactions. The PDZ-binding domain
at the carboxyl terminal, named as the T site, interacts
with several PSD proteins. We generated GluRδ2ΔT
mice carrying mutant GluRδ2 lacking the T site. There
were no significant differences in the amount of
receptor proteins at synapses, histological features andthe fine structures of PF-PC synapses between
wild-type and GluRδ2ΔT mice. However, LTD
induction at PF-PC synapses and improvement in theaccelerating rotarod test were impaired in GluRδ2ΔT
mice. Furthermore, CF territory expanded distally andectopic innervation of CFs occurred at distal dendrites
in GluRδ2ΔT mice, but the elimination of surplus CF
innervation at proximal dendrites appeared to proceed
normally.
These
resultssuggestthatthecarboxyl-terminal T site of GluRδ2 is essential for
LTD induction and the regulation of CF territory, but
is dispensable for PF-PC synapse formation and theelimination of surplus CFs at proximal dendrites
during development.
We propose that GluRδ2 regulates synapse
formation by making a physical linkage between theactive zone and postsynaptic density. To examine theissue, GluRδ2-transfected 293T cells were cultured
with cerebellar neurons. We found numerous punctatesignals for presynaptic markers on the surface of 293T
cells
expressing
GluRδ2.
The
presynaptic
specializations induced by GluRδ2 were capable ofexo- and endocytosis as indicated by FM1-43 dyelabeling. Replacement of the extracellular N-terminal
domain (NTD) of GluRδ2 with that of the AMPA
receptor GluRα1 abolished the inducing activity. The
NTD of GluRδ2 fused to the immunoglobulin constantregion successfully induced the accumulation ofpresynaptic specializations on the surface of beads
bearing the fusion protein. These results suggest that
GluRδ2 triggers presynaptic differentiation by directinteraction with presynaptic components through the
NTD.
To investigate the molecular mechanism of synapse
formation, we developed neuron-specific genemanipulations in transparent zebrafish embryos.
Transparent zebrafish embryos enable us to visualize
synapse formation in vivo. Synaptic vesicle
accumulation and morphological changes arecharacteristic features of axon terminal differentiation
during synaptogenesis. To investigate the regulatory
mechanism that orchestrates synaptic molecules toform mature presynaptic terminals, we visualized asingle axon terminal of zebrafish olfactory sensory
neurons in vivo and examined the effects of theneuron-specific gene manipulations on the axon
terminal differentiation. Synaptic vesicles visualizedwith vesicle-associated membrane protein 2(VAMP2)-enhanced green fluorescent protein (EGFP)
fusion protein gradually accumulated in axon
terminals, while the axon terminals visualized with
GAP43 fused with EGFP remodeled from complex
shapes with filopodia to simple shapes without
filopodia from 50 hours postfertilization (hpf) to 84
hpf.
Expression of dominant-negative protein kinase A(PKA) or cAMP response element binding protein(CREB) suppressed the VAMP2-EGFP punctum
formation in axon terminals during synaptogenesis.
Consistently, constitutively active PKA or CREB
stimulated VAMP2-EGFP puncta formation. On theother hand, cyclosporine A treatment or suppression of
nuclear factor of activated T cells (NFAT) activation
prevented the axon terminal remodeling from complex
to simple shapes during synaptogenesis. Consistently,
expression of constitutively active calcineurin
accelerated the axon terminal remodeling. These
results suggest that calcineurin-NFAT signaling
regulates axon terminal remodeling and PKA-CREB
signaling controls synaptic vesicle accumulation.
As upstream signals of presynaptic differentiation,
we focused on Ca2+ signaling since Ca2+/calmodulin isrequired for the activation of both calcineurin andsome adenylyl cyclases. We showed that application

35

of Ca2+/calmodulin inhibitor or olfactory sensory
neuron-specific expression of calmodulin inhibitory
peptide suppressed both synaptic vesicle accumulation
and axon terminal remodeling. Thus, the trigger ofpresynaptic differentiation could be Ca2+ release fromintracellular stores or Ca2+ influx. Application of aphospholipase C inhibitor or olfactory sensory
neuron-specificexpressionofinositol
1,4,5-trisphosphate (IP3) 5-phosphatase suppressed
synaptic vesicle accumulation, but not morphologicalremodeling. In contrast, application of a voltage-gated
Ca2+ channel blocker or expression of Kir2.1 inward
rectifying potassium channel prevented themorphological remodeling. We also provided evidence
that IP3 signaling acted upstream of PKA signaling.
Our results suggest that IP3-mediated Ca2+/calmodulin
signaling stimulates synaptic vesicle accumulation andsubsequentneuronal
activity-dependent2+
Ca /calmodulin signaling induces the morphologicalremodeling of axon terminals.
Mental retardation (MR), defined as a failure todevelop cognitive abilities, is the most frequent cause
of serious handicap in children and young adults.
Nonsyndromic MR is characterized by reduced
cognitive function without any other clinical features,
thus providing the most direct approach to specificallystudy the neurobiology of cognition and pathogenesisof MR. The expression of Il1rapl 1b, the zebrafish
orthologue of mammalian IL1RAPL1 responsible fora nonsyndromic form of X-linked MR, stimulated
synaptic vesicle accumulation in the axon terminal ofolfactory sensory neurons. On the other hand, theexpression of Il1rapl 1b-P455H prevented themorphological remodeling of axon terminal fromcomplex shape to simple ones. These results suggestthat Il1rapl 1b regulates synaptic vesicle accumulationand morphological remodeling through thecarboxyl-terminal domain and TIR domain,
respectively. We thus provide evidence that mental
retardation protein Il1rapl 1b plays an important rolein the axon terminal differentiation during neuronal
network formation. An intriguing possibility is that
IL1 receptor accessory protein-like 1 may mediate
upstream signals to induce axon terminal
differentiation during synapse formation.
Synapse formation is the key step in thedevelopment of neuronal networks. Precise synaptic

connections between nerve cells in the brain provide
the basis of perception, learning, memory, andcognition. Thus, elucidation of molecular mechanismsthat regulate the formation and modulation of central
synapses will be essential for the understanding ofneural wiring, brain functions and mental disorders
such as schizophrenia, autism and mental retardation.

References(1) Uemura, T., Lee, S., Yasumura, M., Takeuchi, T.,
Yoshida, T., Ra, M., Taguchi, R., Sakimura, K.
and Mishina, M. Trans-synaptic interaction of
GluRδ2 and neurexin through Cbln1 mediates
synapse formation in the cerebellum. Cell 2010;
141, 1068-1079.
(2) Mozhui, K., Karlsson, R-M., Kash, T. L., Ihne, J.,
Norcross, M., Patel, S., Farrell, M. R., Hill, E.,
Martin, K., Camp, M., Fitzgerald, P. J., Ciobanu,
D. C., Sprengel, R., Mishina, M., Wellman, C. L.,
Winder, D. G., Williams, R. W., and Holmes, A.
Strain differences in stress responsivity areassociated with divergent amygdala gene
expression and glutamate-mediated neuronal
excitability. J. Neurosci. 2010; 30, 5357-5367.
(3) Ikeda, K., Fukushima, T., Ogura, H., Tsukui, T.,
Mishina, M., Muramatsu, M. and Inoue, S.
Estrogen regulates the expression of N-methyl-aspartate (NMDA) receptor subunit epsilon 4(Grin2d), that is essential for the normal sexual
behavior in female mice. FEBS Lett. 2010; 584,
806-810.
(4) Ohno, T., Maeda, H., Murabe, N., Kamiyama, T.,
Yoshioka, N., Mishina, M. and Sakurai, M.
Specific involvement of postsynaptic GluRN2Bontaining NMDA receptors in the developmental
elimination of corticospinal synapses. Proc. Natl.
Acad. Sci. USA 2010; 107, 15252-15257.
(5) Hagino, Y., Kasai, S., Han, W., Yamamoto, H.,
Nabeshima, T., Mishina, M. and Ikeda, K.
Essential role of NMDA receptor channel ε4
subunit (GluN2D) in the effects of phencyclidine,
but not methamphetamine. PLoS ONE 2010; 5,e13722.
(6) Miyazaki, T., Yamasaki, M., Takeuchi, T.,
Sakimura, K., Mishina, M. and Watanabe, M.
Ablation of glutamate receptor GluRδ2 in adult

36

Purkinje cells causes multiple innervation ofclimbing fibers by inducing aberrant invasion toparallel fiber innervation territory. J. Neurosci.
2010; 30, 15196-15209.
(7) Mozhui, K., Karlsson, R-M., Kash, T., Ihne, J.,
Norcross, M., Patel, S., Farrell, M., Hill, E.,
Martin, K., Camp, M., Fitzgerald, P., Ciobanu, D.,
Sprengel, R., Mishina, M., Wellman, C., Winder,D., Williams, R. W., and Holmes, A. Strain
differences in stress responsivity are associatedwith divergent amygdala gene expression andglutamate-mediated neuronal excitability. J.
Neurosci. 2010; 30, 5357-5367.
(8) Hayashi, R., Nakazato, Y., Takamori, S., Ebihara,
S., Uematsu, M., Mishina, M., Miyazaki, J.,
Yokoyama, M., Konishi, S., Inoue, K., Fukuda,A., Fukumoto, M., Nakamura, K., Obata, K., andYanagawa, Y. The physiological roles ofvesicular GABA transporter during embryonicdevelopment: a study using knockout mice. Mol.
Brain 2010; 3, 40.
(9) Taniguchi, M. Masuda, T., Mikami, Y., Kimura,M., Yoshida, T., Mishina, M. and Shimizu, T.
Identification and characterization of a novel
zebrafish semaphorin. Neurosci. Lett. 2011; 488,
215-220.
(10) Larsen, R. S., Corlew, R. J., Henson, M. A.,
Roberts, A. C., Mishina, M., Watanabe, M.,
Lipton, S. A., Nakanishi, N., Pérez-Otaño, I.,
Weinberg, R. J., and Philpot, B. D.
NR3A-containing NMDA receptors promote
neurotransmitter release and spike timingependent plasticity. Nature Neurosci. 2011; 14,338-344.
(11) Yamasaki, M., Miyazaki, T., Azechi, H., Abe, M.,
Natsume, R., Hagiwara, T., Aiba, A., Mishina, M.,
Sakimura, K. and Watanabe, M. Glutamate
receptor δ2 is essential for input pathwayependent regulation of synaptic AMPAR contents
in cerebellar Purkinje cells. J. Neurosci. 2011; 31,
3362-3374.
(12) Joo, J., Lee, S., Uemura, T., Yoshida, T.,
Yasumura, M., Watanabe, M. and Mishina, M.
Differential interactions of cerebellin precursor
protein (Cbln) subtypes and neurexin variants forsynapse formation of cortical neurons. Biochem.
Biophys. Res. Commun. 2011; 406, 627-632.

(13) Kaneko, M., Yamaguchi, K., Eiraku, M., Sato, M.,
Takata, N., Kiyohara, Y., Mishina, M., Hirase, H.,
Hashikawa, T. and Kengaku, M. Remodeling ofmonoplanar Purkinje cell dendrites during
cerebellar circuit formation. PLoS ONE 2011; 6,e20108.
(14) Biase, L. D., Kang, S., Potter, E., Fukaya, F.,
Pucak, M., Mishina, M., Calabresi, P. and Bergles,
D. NMDA receptor signaling in oligodendrocyte
progenitorsisnotrequiredforoligodendrogenesis and myelination. J. Neurosci.
2011.
(15) Chen, X., Yoshida, T., Sagara, H., Mikami, Y. andMishina, M. Protein tyrosine phosphatase regulates the synapse number of zebrafish
olfactory sensory neurons. j. Neurochem. 2011;
E-pub (29 August).
(16) Yoshida, T., Yasumura, M., Uemura, T., Lee, S.,
Ra, M., Taguchi, R., Iwakura, Y. and Mishina, M.
IL1RAPL1 associated with mental retardation
and autism mediates synapse formation bytrans-synaptic interaction with PTPδ. J. Neurosci.
2011; 31, 13485-13499.

Pathology, Immunology andMicrobiology
1. Pathology

38

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

Associate Professor
Hiroshi Uozaki, M.D., Ph.D., Shumpei Ishikawa, M.D., Ph.D.

Lecturer
Satoshi Ota, M.D., Ph.D. (Chiba University, Associate Professor)
Yutaka Takazawa, M.D., Ph.D.*
Junji Shibahara, M.D., Ph.D.

Associate
Akiteru Goto, M.D., Ph.D. (Institute of Medical Science, Lecturer),
Rumi Hino, M.D., Ph.D., Aya Shinozaki, M.D., Ph.D., Yukako Shintani, M.D., Ph.D.,
Tetsuo Ushiku, M.D., Ph.D.*, Masako Ikemura, M.D., Ph.D.*, Daichi Maeda, M.D., Ph.D.*,
Teppei Morikawa, M.D., Ph.D. * (visiting researcher, USA)
Naoko Yamauchi, M.D., Ph.D. (Global COE Program)
Takeo Nakaya, M.D., Ph.D. (Cancer Genomics Project)

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”.
Dr. Ota moved to Department of Pathology,
Chiba University Hospital, as an Associate Professor
on September, and Dr. Goto to Department of
Pathology, Institute of Medical Science on December,2010. Dr. Shibahara was promoted to a Lecturer on
December, and Dr. Shintani was adopted to be an
Associate on March, 2011.
In the new fiscal year, 2011, three new students
will enter the postgraduate course, and there will be 15
postgraduates (including two foreign students).
We are responsible for the pathology practice of
the University Hospital, and carrying forward themorphology-based research targeting human diseases.
As for the education of Pathology, we take charge ofthe following courses for the medical students;
General Pathology course for the 1st grade students incollaboration with Department of Molecular Pathology,

39

Systemic Pathology for the 2nd grade, ClinicalClerkship for the 3rd grade, and Bedside-learning(BSL) for the 4th grade students, respectively.
Programs for postgraduates and junior residents arealso included in our education activities.

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, liver, pancreato-biliary tract,urology, gynecology, breast, and orthopedics, as wellas biopsy cases of liver, kidney and skin are discussed.
Clinico-pathological conferences (CPCs) for two
autopsy cases are held every month in the hospital.
Together with weekly autopsy conferences, they areuseful for the education of clinical residents.
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 of the project in corporation
with Department of Legal Medicine. We have finishedthe two-year research project, “Feasibility of post
mortem imaging as a method assisting the autopsy
inspection of DRMT” (Grants-in-Aid from Ministry of
Health, Labor and Welfare). The report 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 andexercises are 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).
Clinical clerkship for the 3rd grade, and BSL for
the 4th grade are carried out. In BSL, following
courses are included; autopsy pathologic practices
with a case presentation for paired students, surgicalpathologic practices using various tumor sections, anda tour of the pathology laboratory. The past
examinations for graduation and Systemic Pathology
for the second grade students are referred to thewebsite.
We also have charge of the lecture series of tumor
pathology for the Cancer Profession Training Programin postgraduate school.

Research activities
The first major theme is “chronic inflammation andneoplasms”, especially Epstein-Barr virus (EBV)
associated gastric carcinoma (GC) (Drs. Uozaki, Hino,
Sakatani, Morikawa and Nakaya).
We
arefocusing on mechanisms of abnormalties in CpG
island methylation and microRNA molecules in thedevelopment and progression of EBV-associated GC(Shinozaki A et al. ref.34)
The second major theme is ‘traslational researchpathology’. We are engaged in search of target
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. In
addition, we take part in a global COE program,“Comprehensive Center of Education and research
for Chemical Biology of the Diseases”, in which weare investigating the morphological analysis of gene
expression abnormalities of the key molecules forseveral diseases (Dr. Yamauchi), aiming thedevelopment of new morphological methods andfuture application to diagnosis and therapy.
Dr. Ishikawa developed a new method foranalyzing the precise copy number of genes ingenome-wide scale (EG-method) in corporation with
Prof. Aburatani (RCAST). EG-method enables
high-precision measurement of gene expressions ineach allele of individual person in genome-wide level.
His group is applying the method to pathology
research.
The third theme is to re-evaluate the disease40

entities and tumor entities from the standpoint ofclassical histopathology. We clarified the entity of fetal
type of gastric carcinoma (Ushiku T et al., ref.39), andthe importance of fallopian tube epithelia for thedevelopment of ovarian cancers of serous subtype(Maeda D, et al., ref.17).

Nakagawa T, Funata M, Yamaguchi M, Namiki S,

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Endocr J. 2010;57(6):485-492.

Kan Y, Yamashita H, Le Pavoux A, Ushiku T,
Ohtomo K, Nakagawa K. Histological changes

Hori M, Makita N, Andoh T, Takiyama H, Yajima
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Kaji Y, Oshika T, Takazawa Y, Fukayama M,

Kanamori Y, Iwanaka T, Sugiyama M, Nakahara
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by a ureteral polyp.

Pediatr Int. 2010 Feb;

52(1):e11-3.
10. Kaneko J, Sugawara Y, Togashi J, Tamura S,
Motoi R, Fukayama M, Kokudo N. Sarcomatouschange of hepatocellular carcinoma in a patientundergoing living donor liver transplantation.
Biosci Trends. 2010 Oct;4(5):279-82.
11. Kataoka K, Seo S, Ota S, Takahashi T, Kurokawa
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Bone Marrow

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Fukayama M, Niki T. Molecular predictors ofGenet. 2010 Mar 1;19(5):761-73.
14. Kihara Y, Yokomizo T, Kunita A, Morishita Y,

sensitivity to the MET inhibitor PHA665752 in

Fukayama M, Ishii S, Shimizu T.

lung carcinoma cells. J Thorac Oncol. 2010

The

leukotriene B4 receptor, BLT1, is required for the
inductionofexperimental

encephalomyelitis.

Biochem

autoimmune
BiophysRes

Sep;5(9):1317-24.
22. Matsubara D, Ishikawa S, Sachiko O, Aburatani
H, Fukayama M, Niki T. Co-activation of
epidermal growth factor receptor and c-MET

Commun. 2010 Apr 9;394(3):673-8.
15. Kusakabe M, Kutomi T, Watanabe K, Emoto N,
Aki N, Kage H, Hamano E, Kitagawa H, Nagase

defines a distinct subset of lung adenocarcinomas.
Am J Pathol. 2010 Nov;177(5):2191-204.

T, Sano A, Yoshida Y, Fukami T, Murakawa T,

23. Matsusaka

K,Kinoshita

Nakajima J, Takamoto S, Ota S, Fukayama M,

Fukayama

M,

Ohashi

Yatomi Y, Ohishi N, Takai D. Identification ofcarcinoma

arising

G0S2 as a gene frequently methylated inbronchopulmonary-foregut malformation. Humsquamous lung cancer by combination of in silico

Pathol. 2010 Nov;41(11):1650-4.

and experimental approaches. Int J Cancer. 2010
Apr 15;126(8):1895-902.
T,

Taketani

ClinicopathologicalUdagawaH,

K.

Squamouscellacommunicating

24. Mitsui J, Takahashi Y, Goto J, Tomiyama H,
Ishikawa S, Yoshino H, Minami N, Smith DI,

16. Maeda D, Mao TL, Fukayama M, Nakagawa S,
Yano

in

Y,

Y,

Shih,

significance

of

IeM.
loss

of

Lesage S, Aburatani H, Nishino I, Brice A,
Hattori N, Tsuji S. Mechanisms of genomic
instabilities

underlying

two

commonARID1A immunoreactivity in ovarian clear cellfragile-site-associated loci, PARK2 and DMD, in

carcinoma Int J Mol Sci. 2010, Dec; 11, 5120-8.

germ cell and cancer cell lines. Am J Hum Genet.

17. Maeda D, Ota S, Takazawa Y, Ohashi K, Mori M,
Imamura T, Nakagawa S, Yano T, Taketani Y,

2010 Jul 9;87(1):75-89.
25. Morikawa T, Goto A, Nishimatsu H, Fukayama

theM. Metastatic Small Intestinal Cancer of the

fallopian tube coexists with ovarian cancer ofUrinary Bladder. Case Rep Oncol. 2010 Sep

serous subtype only: a study of Japanese cases.

14;3(3):334-338.

Fukayama

M.

Mucosalcarcinomaof

Virchows Arch. 2010 Nov;457(5):597-608.

26. Morikawa T, Hino R, Uozaki H, Maeda D,

18. Maeda D, Takazawa Y, Oda K, Nakagawa S,

Ushiku T, Shinozaki A, Sakatani T, Fukayama M.

Fukayama M. Glomus tumor of the ovary: a case

Expression of ribonucleotide reductase M2

report. Int J Surg Pathol. 2010 Dec;18(6):557-60.

subunit in gastric cancer and effects of RRM2

19. Maeda D, Takazawa Y, Ota S, Takeuchi Y, Seta A,

inhibition in vitro. Hum Pathol. 2010 Dec;

Nakagawa S, Yano T, Taketani Y, Fukayama M.

41(12):1742-1748.

Bilateral microscopic adenocarcinoma of the

27. Morikawa T, Maeda D, Kume H, Homma Y,

fallopian tubes detected by an endometrial

Fukayama M. Ribonucleotide Reductase M2

cytologic smear. Int J Gynecol Pathol. 2010

Subunit is a Novel Diagnostic Marker and aMay;29(3):273-7.

Potential Therapeutic Target in Bladder Cancer

20. Maeshima AM, Tochigi N, Yoshida A, Asamura
H, Tsuta K, Tsuda H.

Histopathology. 2010 Dec;57(6):885-92.

Clinicopathologic

28. Murayama-Hosokawa S, Oda K, Nakagawa S,

analysis of multiple (five or more) atypical

Ishikawa S, Yamamoto S, Shoji K, Ikeda Y,

adenomatous hyperplasias (AAHs) of the lung:

Uehara Y, Fukayama M, McCormick F, Yano T,

42

TaketaniY,

Aburatani

single-nucleotide
endometrial

H.

Genome-wide

Nakashima H, Makita N, Kurokawa M. Erdheim-

polymorphism

arraysin

Chester disease: multisystem involvement andextensive

management with interferon-alpha. Leuk Res.

carcinomas

associate

chromosomal instability with poor prognosis andunveilfrequent

chromosomal

2010 Jan;34(1)imbalances

36. Tajima T, Takao H, Akai H, Kiryu S, Imamura H,

involved in the PI3-kinase pathway. Oncogene.

Watanabe Y, Shibahara J, Kokudo N, Akahane M,2010 Apr 1;29(13):1897-908.

Ohtomo K. Relationship between liver function

29. Ohmatsu H, Sugaya M, Fujita H, Miyagaki T,

and liver signal intensity in hepatobiliary phase

Kadono T, Maeda D, Takazawa Y, Fukayama M,

of gadolinium ethoxybenzyl diethylenetriamine

Tamaki K, Sato S. Primary cutaneous CD8+pentaacetic acid-enhanced magnetic resonanceaggressive

imaging.

epidermotropic

cytotoxic

T-celllymphoma in a human T-cell leukaemia virus
type-1 carrier. Acta Derm Venereol. 2010

J

ComputAssistTomogr.

2010

May-Jun;34(3):362-6.
37. Tanaka

M,

Fukayama

M,

Fukushima

N.Undifferentiated Carcinoma of the Pancreas

May;90(3):324-5.
30. Okada S, Nannya Y, Ota S, Takazawa Y,
Yamamoto G, Kumano K, Izutsu K, Takahashi T,
Chiba S, Kurokawa M.

With/Without

Osteoclast-like

Giant

Cells

Pathology Case Reviews 2010; 15(6): 210-214

Cutaneous T-cell

38. Ueda K, Watadani T, Maeda E, Ota S, Kataoka K,

lymphoma (mycosis fungoides) relapsed withSeo S, Kumano K, Hangaishi A, Takahashi T,

different immunological phenotype after bone

Imai Y, Ohtomo K, Fukayama M, Nannya Y,

marrow transplant. Br J Dermatol. 2010;162(1):Kurokawa M. Outcome and treatment of late-229-30

onset noninfectious pulmonary complications

31. Ohtomo N, Tomiya T, Tanoue Y, Inoue Y,

after allogeneic haematopoietic SCT.

Bone

Nishikawa T, Ikeda H, Seyama Y, Kokudo N,

Marrow Transplant. 2010 Dec;45(12):1719-27.

Shibahara J, Fukayama M, Koike K, Shirataki H,

39. Ushiku T, Shinozaki A, Shibahara J, Iwasaki Y,

Fujiwara

K.

Expressionof

α-taxilin

inTateishi Y, Funata N, Fukayama M. SALL4

hepatocellular carcinoma correlates with growth

represents fetal gut differentiation of gastricactivity and malignant potential of the tumor. Int

cancer,J Oncol. 2010 Dec;37(6):1417-23.

distinguishing hepatoid gastric carcinoma from

32. Sasaki T, Xu A, Ito K, Ishimoto SI, Yamasoba T,
Kaga

K,

YamauchiN.

Histopathological

and

is

diagnosticallyusefulinhepatocellular carcinoma. Am J Surg Pathol.
2010;34(4):533-40

differences in bony destruction of malleus and40. Ushiku T, Shinozaki A, Uozaki H, Iwasaki Y,

incus following mastoidectomy. J Laryngol Otol.

Tateishi Y, Funata N, Seto Y, Fukayama M.

2010 Nov;124(11):1162-6.

Gastric carcinoma with osteoclast-like giant cells.

33. Shinozaki A, Ushiku T, Fukayama M. Prominent

Lymphoepithelioma-like carcinoma with Epstein-

Mott cell proliferation in Epstein-Barr virus-

Barr virus infection is the predominant type.

associated gastric carcinoma. Hum Pathol. 2010

Pathol Int. 2010;60(8):551-8.

Jan;41(1):134-8.

41. Yamamoto S, Midorikawa Y, Morikawa T,

34. Shinozaki A, Sakatani T, Ushiku T, Hino R,

Nishimura Y, Sakamoto H, Ishikawa S, Akagi K,

Isogai M, Ishikawa S, Uozaki H, Takada K,

Aburatani H. Identification of chromosomal

Fukayama M. Downregulation of microRNA-200

aberrations of metastatic potential in colorectal

in EBV-associated gastric carcinoma. Cancer Res.

carcinoma. Genes Chromosomes Cancer. 20102010 Jun 1;70(11):4719-4127.

May;49(5):487-96.

35. Suzuki HI, Hosoya N, Miyagawa K, Ota S,

42. Yoshida A, Oda R, Shibahara J, Fukayama M,

43

Tsuda H. Soft-tissue hemangioblastoma of theretroperitoneum: a case study and review of theliterature. Appl Immunohistochem Mol Morphol.
2010 Oct;18(5):479-82.
43. Yoshida A, Ushiku T, Motoi T, Shibata T, Beppu
Y, Fukayama M, Tsuda H. Immunohistochemical
Analysis of MDM2 and CDK4 Distinguishes
Low-Grade Osteosarcoma from Benign Mimics.
Mod Pathol. 2010;23:1279-1288.
44. Yoshida A, Ushiku T, Motoi T, Shibata T,
Fukayama M, Tsuda H.

Well-DifferentiatedLiposarcoma with Low-Grade Osteosarcomatous
Component: An Underrecognized Variant. Am J
Surg Pathol. 2010;34:1361-1366.

44

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

Associate Professor
Tetsuro Watabe, Ph.D.

Lecturers
Mitsunobu R. Kano, M.D., Ph.D., Daizo Koinuma, M.D., Ph.D.

Assistant Professors
Shogo Ehata, M.D., Ph.D., Caname Iwata, 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, two lecturers, two assistantprofessors, one project assistant professor, technicalassistants, and some research fellows, including 15
graduate students, 2 master course students, and 3
post-doctoral fellows.

Teaching activities
Our department takes responsibility for lectures on“General Pathology” for the undergraduate students of
the Faculty of Medicine in collaboration with the staffof the Department of Human Pathology. Teaching
responsibilities include lectures on General Pathology
related to the mechanisms of diseases. Since webelieve it very important for medical students to study
Basic Oncology, we teach a basic tumor biology
course in our lectures of General Pathology. In

addition, we offer several laboratory courses forstudents from molecular pathological points of view.
We also supervise research activities of thegraduate students of the Department. Our laboratory is
located at the 11th floor at the Research Building ofGraduate School of Medicine. The laboratory is very
convenient for doing research, since most of theexperiments can be done at this floor. We have
“Progress Meeting” twice a month and “Monday
Seminar” once a month.
We have been doing collaboration with the Ludwig
Institute for Cancer Research, Uppsala, Sweden for
more than 10 years, and our collaboration between
Sweden, the Netherlands, and Japan is supported by
the Core-to-Core Program “Cooperative International
Framework in TGF-beta Family Signaling” of Japan
Society for the Promotion of Science (JSPS)(http://c2ctgfb. umin.jp/). We have annual TGF-β
meeting in Sweden or in the Netherlands every
autumn, and some graduate students participate in themeeting and orally present their results.
We are currently supported by the Global Centerof Excellence (GCOE) Program for "Integrative Life
Science Based on the Study of Biosignaling

45

Mechanisms" (from the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) of
Japan. This program stimulates interaction withstudents and scientists in the program as well as those
from
other
laboratories(http://www.coe.s.utokyo.ac.jp/integr-life/index.html).
Graduate students also present data at various
meetings, including Annual Meetings of the JapaneseCancer Association, and Annual Meeting of the
Molecular Biology Society of Japan. At the corridor of
our laboratory, posters of our graduate students
reported at these meetings are presented.

Research activities
Our major research interest is to elucidate how
members of the TGF (transforming growth
factor)-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.
Smads can be classified into there subclasses.
Inhibitory Smads (I-Smads), i.e. Smad6 and Smad7 in
mammals, are negative regulators of TGF-beta family
signaling. I-Smads inhibit TGF-beta family signaling
through multiple mechanisms, among which physicalinteraction of I-Smads with type I receptors andcompetition with receptor-regulated Smads (R-Smads)
is the principal mechanism of their action. Smad7
inhibits all TGF-beta family signaling, while Smad6
inhibits BMP signaling mediated by BMP type I
receptors ALK-3 and ALK-6. We reported that Smad7
has two modes of interaction with type I receptors.
One is through the three-finger-like structure and theL3 loop in the C-terminal MH2 domain, while theother is through the basic groove in the MH2 domain.
In contrast, Smad6 mainly uses the basic groove in theMH2 domain for interaction with type I receptors. Ourfindings revealed that Smad7 has an additional modeof interaction with type I receptors which is not sharedwith Smad6, and suggest that the mode of interaction
with type I receptors may play unique roles inmediating the inhibitory effects of Smad7 (Kamiya etal. J. Biol. Chem. 2010).
Diffuse-type gastric carcinoma is characterized by

rapid progression and poor prognosis. High expressionof TGF-beta and thick stromal fibrosis are observed indiffuse-type gastric carcinoma. We had previously
shown that disruption of TGF-beta signaling by adominant negative form of TGF-beta type II receptor(dnTbRII) in diffuse-type gastric cancer cell lines
caused enhanced tumor growth through induction oftumor angiogenesis in vivo. We had also reported that
repression of the expression of thrombospondin-1(TSP1), a potent angiogenic inhibitor, is involved in
the tumor angiogenesis regulated by TGF-beta
signaling in diffuse-type gastric carcinoma. We now
show that TGF-beta induces tissue inhibitor of
metalloproteinase 2 (TIMP2) expression in the
OCUM-2MLN cell line, and that expression of TIMP2
is decreased by dnTbRII. Enhanced tumor growth of
the OCUM-2MLN cells by dnbβRII in vivo wasabolished by overexpression of TIMP2. Interestingly,
the degree of hypoxia in tumor tissues was increased
and pericytes covering tumor vasculatures weredecreased by TIMP2 in OCUM-2MLN cells. Thesefindings suggest that the function of tumor
vasculatures was repressed by TIMP2. Thus, thepossible mechanisms of the increased angiogenesis indiffuse-type gastric carcinoma by dnTbRII is thedown-regulation of TSP1 and that of TIMP2(Johansson et al. Cancer Sci, 2010).
Arkadia is a positive regulator of TGF-beta
signaling that induces ubiquitin-dependent degradationof some inhibitory molecules of TGF-beta signaling,including Smad7, c-Ski, and SnoN. We have foundthat Arkadia induces degradation of some otherproteins and regulates signaling pathways other than
TGF-beta signaling pathway. By yeast-two-hybrid
screening for Arkadia-binding proteins, we found thatthe mu2 subunit of clathrin-adaptor 2 (AP2) complex
interacts with Arkadia. The C-terminal YXXΦ-binding
domain of the mu2 subunit interacted with the
N-terminal YALL motif of Arkadia. We have shownthat by interaction with the AP2 complex, Arkadia
regulates EGF signaling by modulating theendocytosis of EGF receptor through interaction with
AP2 complex (Mizutani et al., J. Biochem. 2010).
Epithelial-mesenchymal transition (EMT) is a
crucial event in wound healing, tissue repair, andcancer progression in adult tissues, and TGF-beta is
well known to induce EMT in normal and transformed

46

epithelial cells. We demonstrated that during the EMT
process, TGF-beta induced isoform switching ofvarious proteins, including fibroblast growth factor(FGF) receptors, causing the cells to become sensitive
to FGF-2 (basic FGF). TGF-beta induced theexpression of alpha-smooth muscle actin (alpha-SMA)in NMuMG epithelial cells. When FGF-2 was added
together with TGF-beta, the cells no more expressedalpha-SMA, and showed a phenotype of activatedfibroblasts through the MEK-Erk pathway activatedby FGF-2. Consequently, normal epithelial cells thathave undergone EMT by TGF-beta and FGF-2
promoted the invasion of breast cancer cells in vitro.
These findings suggest that TGF-beta and FGF-2
cooperate with each other and regulate EMT in cancer
microenvironment
duringcancerprogression(Shirakihara et al. EMBO J., 2011).
We have organized the 59th Fujihara International
Seminar “TGF-beta signaling and cancer” on July
14-17,
2010
inTomakomai,Japan(http://fis59.umin.jp/; supported by the Fujihara
Foundation of Science and the Core-to-Core Programof JSPS). More than 80 scientists and students
participated in the Seminar, and exchanged their mostrecent data.

5. Oba M, Vachutinsky Y, Miyata K, Kano MR,
Ikeda S, Nishiyama N, Itaka K, Miyazono K,
Koyama H, Kataoka K. (2010) Antiangiogenic
gene therapy of solid tumor by systemic injectionof polyplex micelles loading plasmid DNA
encoding soluble flt-1. Mol Pharm. 7 (2): 501-9.
6. Saito RA, Micke P, Paulsson J, Augsten M, Peña
C, Jönsson P, Botling J, Edlund K, Johansson L,
Carlsson P, Jirström K, Miyazono K, Ostman A.
(2010) Forkhead box F1 regulates tumor-romoting
properties of cancer- associated fibroblasts in lungcancer. Cancer Res. 70 (7): 2644-54.
7. Suzuki Y, Ohga N, Morishita Y, Hida K,
Miyazono K, Watabe T. (2010) BMP-9 induces
proliferation of multiple types of endothelial cells
in vitro and in vivo. J Cell Sci. 123 (10): 1684-92.
8. Suzuki HI, Kiyono K, Miyazono K. (2010)
Regulation of autophagy by transforming growth
factor-beta (TGFbeta) signaling. Autophagy. 6 (5):645-7.
9. Ikushima H, Miyazono K. (2010) TGFbeta
signalling: a complex web in cancer progression.

References

Nat Rev Cancer. 10 (6): 415-24.
1. Miyazono K, Kamiya Y, Morikawa M. (2010)

10. Suzuki HI, Miyazono K. (2010) Dynamics ofBone morphogenetic protein receptors and signal

microRNA biogenesis: crosstalk between p53transduction. J Biochem. 147 (1): 35-51.

network and microRNA processing pathway. J

2. Flister MJ, Wilber A, Hall KL, Iwata C, Miyazono

Mol Med (Berl). 88 (11): 1085-94.

K, Nisato RE, Pepper MS, Zawieja DC, Ran S.

11. Nagata M, Nagata S, Yuki K, Isogaya K, Saitoh M,(2010) Inflammation induces lymphangiogenesis

Miyazono K, Miyazawa K. (2010) Identification

through up-regulation of VEGFR-3 mediated byof a phosphorylation site in c-Ski as serine 515. J

NF-kappaB and Prox1. Blood. 115 (2): 418-29.

Biochem. 148 (4): 423-7.

3. Nagano Y, Koinuma D, Miyazawa K, Miyazono K.

12. Kamiya Y, Miyazono K, Miyazawa K. (2010)(2010) Context-dependent regulation of theSmad7 inhibits transforming growth factor-beta

expression of c-Ski protein by Arkadia in humanfamily type I receptors through two distinct modes

cancer cells. J Biochem. 147 (4): 545-54.

of interaction. J Biol Chem. 285 (40): 30804-13.

4. Ikushima H, Miyazono K. (2010) Cellular
context-dependent"colors"oftransforming

growth factor-beta signaling. Cancer Sci. 101 (2):306-12.

47

13. Sumida H, Noguchi K, Kihara Y, Abe M,
Yanagida K, Hamano F, Sato S, Tamaki K,
Morishita Y, Kano MR, Iwata C, Miyazono K,
Sakimura K, Shimizu T, Ishii S. (2010) LPA4
regulates blood and lymphatic vessel formation
during mouse embryogenesis. Blood. 116 (23):5060-70.
14. Johansson E, Komuro A, Iwata C, Hagiwara A,
Fuse Y, Watanabe A, Morishita Y, Aburatani H,
Funa K, Kano MR, Miyazono K. (2010)
Exogenous introduction of tissue inhibitor of
metalloproteinase 2 reduces accelerated growth of
TGF-beta-disrupted

diffuse-type

gastric

carcinoma. Cancer Sci. 101 (11): 2398-403.
15. Mizutani A, Saitoh M, Imamura T, Miyazawa K,
Miyazono K. (2010) Arkadia complexes withclathrin adaptor AP2 and regulates EGF signalling.
J Biochem. 148 (6): 733-41.

Pathology, Immunology andMicrobiology
2. Microbiology

49

Department of Microbiology
Professor
Masanori Hatakeyama, M.D.,Ph.D.

Associate
Naoko Kamiya, Ph.D., Ryohei Tsutsumi, Ph.D.

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

Introduction and Organization
Professor emeritus Akio Nomoto who had been thechief of the Department retired in 2008 and moved to
Microbial Chemistry Research Foundation as the
Chairman of Board. From 2009, new Department ofMicrobiology started with Professor Masanori
Hatakeyama as the new chief. The present Department
consists of 20 members; 1 professor (Dr. Hatakeyama),
2 associates (Drs. Kamiya and Tsutsumi), 1 Post-doc(Dr. Seidi), 5 technical staffs (Ms. Yano, Morohashi,
Yoshihashi, Goto, Azami), 11 Graduate School
students (Ms. and Mrs. Takahashi, Fujii, Saito,
Yamahashi, Hayashi, Safari 、 Suzuki, Kashiba,
Yanagiya, Kikuchi, Nagase).

Teaching activities
In a series of lectures (totally 64 hr) and laboratory
courses (36 hr), the following subjects are covered.
1) Molecular biology of bacteria, phages, and animalviruses2) Mechanisms of microbial diseases
3) Laboratory diagnosis of pathogenic microbes
4) Infection control and biosafety
5) Application of
microbial organisms
forbiotechnology
6) Socioeconomic impact of microbial diseases

Research activities
Gastric cancer is the second leading cause (10.4%) ofcancer death worldwide. It has now been wellestablished that infection with Helicobacter pylori (H.
pylori) is associated with the development of gastriccancer. Especially, infection of H. pylori strains
carrying a gene called cagA plays an essential role ingastric carcinogenesis. The cagA-positive H. pylori
delivers the cagA gene product, the CagA protein, into
the host gastric epithelial cells via the type IV
secretion system. Through a series of studies, we haveuncovered the molecular mechanisms by which
delivered CagA causes transformation of gastricepithelial cells.
East Asian countries such as Japan, Korea and Chin,are known to show the highest incidence of gastriccancer in the world. In Japan, for instance, 50,000
peoples are killed by gastric cancer each year. Thus,
establishment of new strategies for prevention andtreatment for gastric cancer is urgently required. H. In
our Department, we are conducting cutting-edge
researches, ranging from molecular structural biology
to mouse genetics, to elucidate oncogenic mechanismsof the bacterial CagA protein. These researches will
provide an opportunity to develop molecular-targeting
methods that effectively prevent the development ofgastric cancer.
1. elivery mechanism of H. pylori CagA into gastricepithelial cells.
The lipid bilayer of the cell membrane is composedof the outer and inner leaflets, which comprisedifferent phospholipid species. The outer leaflet isprimarily made of phosphatidylcholine, whereas the50

inner leaflet is characterized by the specificenrichment of amino phospholipids such as
phosphatidylserine (PS), phosphatidyl ethanolamine(PE), and phosphatidylinositol (PI). We found that PS
is rapidly and transiently turned over from the innerleaflet to the outer leaflet of the plasma membrane
upon direct attachment of H. pylori. Although PS
externalization is known to be an early sign ofapoptosis, cells infected with H. pylori do not induce
apoptosis. The transient PS externalization requires alive H. pylori and is induced by both cagA-positiveand cagA-negative strains. Masking of surface
externalized PS by Annexin V or anti-PS antibodies
significantly inhibits delivery of CagA into gastricepithelial cells. The result indicates that the membrane
exposed PS is involved in the translocalization of H.
pylori CagA.
Electron microscopic analysis revealed that CagA,
which is secreted via the type IV secretion system, isfixed on top of the type IV syringe. The bacterial
surface-exposed CagA protein then directly binds to
PS that has been externalized on the host membrane.
The CagA-PS interaction requires Arg-X-Arg (RxR)
motif that is present at the middle portion of CagA. In
order to examine if the CagA-PS interaction is criticalfor CagA delivery into host cells, we generated an H.
pylori strain that produces a CagA mutant in which thePS-binding RxR motif was destroyed. Infection ofgastric epithelial cells with H. pylori revealed that, incontrast to the wild-type CagA, the mutant CagA is
not delivered into the host cells. The observation
indicated that the CagA-PS interaction plays a criticalrole in the delivery of H. pylori CagA into host gastricepithelial cells.
An important question as to the translocation of
CagA from the bacterial side to the host cell cytoplasm
is whether host cell machineries, especially thosemediating endocytosis, are involved in this process ornot. Depletion of ATP in the host cells abolishes CagA
translocation, indicating active role of hostmachineries in CagA delivery. However, inhibition ofclathrin, dynamin, CDC42 or ARF6 did not influencetranslocalization of CagA from the bacterium to thehost cell. Likewise, inhibition of macropinocytosis byamiloride fails to inhibit CagA delivery. Hence,delivery of CagA via the type IV secretion system
involves ATP-dependent host cell machineries, but do

not utilize endocytic processes known to date.
Upon delivery into gastric epithelial cells, CagA is
localized to the inner side of the plasma membrane.
This membrane tethering is also mediated at least
partly by the interaction of CagA with PS, which is
specifically distributed to the inner leaflet .
2. H. pylori CagA-mediated loss of epithelial polarity
in the development of gastric carcinoma.
A series of studies with CagA-transgenic mice
revealed that CagA has an oncogenic potential in vivo.
In contrast, when expressed in non-polarized epithelial
cells cultured in vitro, CagA potently inhibits cellproliferation. The CagA-mediated inhibition of cell
growth is due to accumulation of p21
cyclin-dependent kinase inhibitor in response to Erk
MAP kinase signaling, which is aberrantly activatedby CagA. Cells growth-arrested by CagA-induced p21
become flat and express cell-senescence markers,
indicating that CagA-expressing cells undergo
senescence program. It is well known that
non-transformed cells cease proliferation after acertain rounds of cell division. This phenomenon iscalled “replicative senescence”. In contrast, when cells
received non-physiological stresses, they emergently
turn on the senescence program and thereby stop
proliferation. The cellular response is called“premature senescence”. One of non-physiologicalstresses that induce premature cell senescence is theactivation of oncogene such as ras or myc. Indeed,aberrant activation of oncogenes in non-transformed
cells efficiently induces premature cell senescence,
which is currently thought to act as a cell-autonomous
tumor suppression system that prevents malignant
transformation. Our results therefore indicate that theH. pylori oncoprotein CagA also induces prematuresenescence by triggering oncogenic stress.
In the stomach, H. pylori delivers CagA into
polarized epithelial monolayer that consists gastricmucosa, but not non-polarized epithelial cells.
Accordingly, we expressed CagA in polarized
epithelial cells and found that, under polarized
condition, CagA expression induces abnormal cellproliferation through Erk activation without p21
accumulation.
Thefinding
indicates
that
CagA-deregulated Erk signaling can induce an
opposite response in cell proliferation, premature

51

senescence or aberrant proliferation, in apolarity-context dependent manner.
Upon inhibition of RhoA small GTPase activity inpolarized epithelial cells, CagA expression causes
accumulation of p21 as is the case of non-polarizedcells. Hence, the status of RhoA activation plays a keyrole in determining cellular response, either
growth-arrest or proliferation, in response to CagA.
RhoA activity is positively regulated by GDP/GTP
exchanger (GEF) and negatively regulated by GTPase
activating protein (GAP). Among various RhoA GEFs,
GEF-H1 is known for its altered subcellular
distribution that is dependent on epithelial polarity
status. In non-polarized epithelial cells, GEF-H1 islocalized to the cytoplasm, where the GEF activity is
inhibited through binding with microtubules. In
polarized epithelial cells, however, GEF-H1 istranslocalized from the cytoplasm to the plasma
membrane, where it is concentrated to the tightjunctions. At the tight junction, GEF-H1 is associatedwith its inhibitor cingulin and thereby functionallyinactivated. This in turn indicates that release of
cingulin from the GEF-H1-cingulin complex activates
RhoA GEF activity of GEF-H1. When CagA isdelivered into polarized epithelial cells, the bacterial
protein is localized to the plasma membrane, where it
is associated with SHP2 and PAR1. Now, we foundthat CagA-associated PAR1 also interacts with the
GEF-H1/cingulin complex in polarized epithelial cells.
Formation of the CagA/PAR1/GEF-H1 heterotrimericcomplex causes a release of cingulin from GEF-H1
and thereby activates RhoA GEF activity in polarized
epithelial cells. As long as a substantial amount of
CagA is continuously delivered into epithelial cells,
the CagA/PAR1/GEF-H1 complex is kept at theplasmamembrane,preventing
cytoplasmic
redistribution of GEF-H1 even after cells become
non-polarized. In contrast to the polarized cells,
expression of CagA in non-polarized epithelial cells
fails to generate the CagA/PAR1/GEF-H1 complex
because GEF-H1 is present in the cytoplasm, making
it difficult for CagA to activate RhoA.
RhoA activated by CagA in polarized epithelial
cells then stimulates Rho kinase (ROCK), which inturn potentiates transcriptional activity of c-Myc
through phosphorylation. The ROCK-activated c-Myc
specifically induces microRNAs, miR-17 and miR-20a,

which target p21 mRNA and thereby prevent p21
accumulation.
This work uncovered a here-to-fore unidentified
signaling pathway (GEF-H1/RhoA/ROCK/-Myc/
iRNA/21) coordinating cell polarity and cell cycle.
The work also reveals that H. pylori CagA is a uniqueoncoprotein that specifically triggers aberrant
mitogenesis by deregulating the GEF-H1/RhoA/OCK/-Myc/miRNA/p21 signaling pathway upon delivery
into polarized epithelial cells.

References
1.

2.

3.

4.

5.

Saito Y, Murata-Kamiya N, Hirayama T, Ohba,Y,Hatakeyama M. Conversion of Helicobacter pylori
CagA from senescence inducer to oncogenic driverthrough polarity-dependent regulation of p21. J
Exp Med 2010:207:2157-2174.
Murata-Kamiya N, Kikuchi K, Hayashi T, Higashi
H, Hatakeyama M. Helicobacter pylori exploits
host membrane phosphatidylserine for delivery,
localization and pathophysiological action of the
CagA oncoprotein. Cell Host Microbe 2010:7:
99-411.
Ding S-Z, Goldberg JB, Hatakeyama M.
Helicobacter pylori infection, oncogenic pathways
andepigenetic
mechanisms
ingastric
carcinogenesis. Future Oncol 2010:6:851-862.
Tanaka H, Yoshida M, Nishiumi S, Ohnishi N,
Kobayashi K, Yamamoto K, Fujita T, Kutsumi H,
Hatakeyama M, Azuma T. The CagA protein of
Helicobacter pylori suppresses the functions of
DCs in mice. Arch Biochem Biophys
2010:498:35-42.
Ding S-Z, Fischer W, Kaparakis-Liaskos M,
Lietchi G, Merrell S, Grant P, Ferrero R, Crowe S,
Haas R, Hatakeyama M, Goldberg J. Helicobacter
pylori-induced histone modification, associatedgene expression in gastric epithelial cells, and its
implication in pathogenesis. Plos One 2010:5:
e9875.

52

Department of Infection Control
and Prevention
Professor
Kyoji Moriya, M.D., Ph.D.

Research Associate
Shu Okugawa,M.D.,Ph.D.
Youko Nukui, M.D., Ph.D.
Keita Tatsuno, M.D., Ph.D.
Masashi Suzuki,M.D.,Ph.D.

Homepage http://www.cc.h.u-tokyo.ac.jp/mulins/kansen/index.html(inside the hospital 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, five guest lecturers, four
research associates, 11 laboratory technicians, and two
office assistants. For isolation and identification of
microorganisms from clinical specimens, we
amalgamated the microbiology unit from the
Department of Clinical Laboratory in 2001.

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

3) Microbiological investigation of wards andenvironment (at request or need).
4) Detection, investigation, intervention and controlof the hospital infection outbreak.
5) Offering of information and advice on
HIV-infected patients’ 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
4th grade students). These lectures and exercises
contain subjects not only on the hospital infection but
also on clinical microbiology. We are also engaged in
the education of graduate students as well as hospital
staff.
For postgraduate education, we have been committed
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.

53

Research activities
We have been mainly studying on following subjects:
Several studies are now going with the members of
department of parmacy and of surgery.
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 in microorganism infection
9) New detection method and pathogenesis ofopportunistic cytomegaloviral infection10) Mechanism of multi-drug resistant microorganisms

References(1) Lipid metabolism and liver disease in hepatitis C
viral infection.Koike K, Tsutsumi T, Yotsuyanagi
H, Moriya K.Oncology. 2010 Jul;78 Suppl
1:24-30. Epub 2010 Jul 8.
(2) Hepatitis C virus core protein compromises
iron-induced activation of antioxidants in miceand HepG2 cells.Moriya K, Miyoshi H,
Shinzawa S, Tsutsumi T, Fujie H, Goto K,
Shintani Y, Yotsuyanagi H, Koike K.J Med Virol.
2010 May;82(5):776-92.
(3) Animal models for hepatitis C and related liverdisease.Koike K, Moriya K, Matsuura Y. Hepatol
Res. 2010 Jan;40(1):69-82.
(4) Inflammasome
sensor
Nlrp1b-dependent
resistance to anthrax is mediated by caspase-1,
IL-1 signaling and neutrophil recruitment.
Moayeri M, Crown D, Newman ZL, Okugawa S,
Eckhaus M, Cataisson C, Liu S, Sastalla I,
Leppla SH.PLoS Pathog. 2010 Dec 9;6(12):e1001222.

(5) Anthrax toxin targeting of myeloid cells throughthe CMG2 receptor is essential for establishment
of Bacillus anthracis infections in mice.Liu S,
Miller-Randolph S, Crown D, Moayeri M,
Sastalla I, Okugawa S, Leppla SH.Cell Host
Microbe. 2010 Nov 18;8(5):455-62.
(6) MyD88-dependent signaling protects against
anthrax lethal toxin-induced impairment ofintestinal barrier function.Okugawa S, Moayeri
M, Eckhaus MA, Crown D, Miller-Randolph S,
Liu S, Akira S, Leppla SH.Infect Immun. 2011
Jan;79(1):118-24. Epub 2010 Oct 25.
(7) Cryptococcus gattii genotype VGIIa infection inman, Japan, 2007.Okamoto K, Hatakeyama S,
Itoyama S, Nukui Y, Yoshino Y, Kitazawa T,
Yotsuyanagi H, Ikeda R, Sugita T, Koike
KEmerg Infect Dis. 2010 Jul;16(7):1155-7.
(8) Cryptococcal pleuritis containing a high level ofadenosine deaminase in a patient with AIDS: acase report.Yoshino Y, Kitazawa T, Tatsuno K,
Ota Y, Koike K.Respiration. 2010;79(2):153-6.
Epub 2009 Apr 29.
(9) Defective membrane expression of the
Na(+)-HCO(3)(-) cotransporter NBCe1 is
associated with familial migraine.Suzuki M, Van
Paesschen W, Stalmans I, Horita S, Yamada H,
Bergmans BA, Legius E, Riant F, De Jonghe P,
Li Y, Sekine T, Igarashi T, Fujimoto I, Mikoshiba
K, Shimadzu M, Shiohara M, Braverman N,
Al-Gazali L, Fujita T, Seki G.Proc Natl Acad Sci
U S A. 2010 Sep 7;107(36):15963-8. Epub 2010
Aug

Pathology, Immunology andMicrobiology
3. Immunology

55

Department of Immunology
Professor
Tadatsugu Taniguchi, Ph.D.

Associate Professor
Kenya Honda, M.D., Ph.D.

Assistant Professor
Hideyuki Yanai, Ph.D.; Hideo Negishi, Ph.D.; Kouji Atarashi, Ph.D.; Junko Nishio, M.D.,
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 the rate Dr. Tomio Tada took his position in1977 as professor and chair of the department.
Through his innovative research and great
contributions to the international community of
immunologists, Dr. Tada raised the stature of thedepartment to a world-renowned status. After hisretirement in 1994, Taniguchi had tried to follow andimprove the high standards of the department by
providing a first-rate education to students as well as
performing cutting-edge, internationally recognizedresearch in the field of immunology.
In the late 1970s and early 1980s, Taniguchi’s
research was the first to identify and subsequentcharacterize two cytokine genes, interferon (IFN)-beta
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. In addition,a new area of research was initiated on intestinal
immunity.

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

56

Rockefeller University) and Shimon Sakaguchi(Professor of Osaka University).

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. Recently, we
have established DAI-deficient mice and plan toinvestigate the physiological role of DAI. Central toprotective and pathological immunities is theactivation of innate immune responses by nucleic
acids, which is mediated by the transmembrane
Toll-like receptors (TLRs) and cytosolic receptors.
In mammals, the transmembrane pattern recognition
receptors TLR3, TLR7 and TLR9 respectively
recognize double-stranded RNA, single-stranded RNA
and hypomethylated DNA; while the RIG-I-likereceptors (RLRs), namely, RIG-I and MDA5 are

known as cytosolic RNA-sensing receptors.
In
addition, cytosolic DNA-sensing receptors which
include DAI, RIG-I/MDA5 and AIM2 also trigger
innate immune responses. For all except AIM2, thehallmark of the innate immune responses activated bythese receptors is the induction of type I IFNs,
proinflammatory cytokines and chemokines. Our
recent study revealed a hierarchy in the nucleic
acid-mediated activation of innate immune responses,
wherein the selective activation of the nucleic
acid-sensing receptors is contingent on thepromiscuous sensing by high-mobility group box
proteins (HMGBs).
From the above new finding, we reasoned that
nonimmunogenic nucleotides with high-affinity
HMGB binding may function as suppressing agentsfor HMGB-mediated diseases, particularly thoseinitiated and/or exacerbated by nucleic acids. We
characterized
an
array
of
HMGB-binding,nonimmunogenic oligodeoxynucleotides (ni-ODNs).
Interestingly, we fund that binding affinity is for themost part independent of nucleotide sequence, but isinstead dependent on length and the secondary
structure of the deoxyribose backbone. We further
showed that these ni-ODNs can strongly suppress theactivation of innate immune responses induced byboth classes of nucleic acid-sensing receptors. We
also provided evidence for the suppressive effect of an
ni-ODN, termed ISM ODN, on the induction ofadaptive immune responses and in mouse models of
sepsis and autoimmunity. Thus, our study suggests
the possible use of these ni-ODNs in therapeuticinterventions.
We also conducted applied research projects, inwhich we discovered several unique compounds thatinterfere with innate immune receptor signaling. Oneof these compounds turned out to be quite unique inthat it activated stress-induced MAK kinases, JNK and
p38 while inhibiting the activation of NF-κB
transcription factor. We have promising results,
indicating the usefulness of this compound for thetreatment of inflammatory autoimmune diseases andcancers. We aim at improving the efficacy of thiscompound by modifying its structure for clinicalpurposes and, at the same time, try to elucidate its
mechanism of action.
Finally, we have also been conducting a new57

research project focusing on the intestinal immune
system and their relationship with the intestinal
microbiota. The intestinal mucosa has a unique andcomplicated immune system composed of a variety ofadaptive immune cell populations. In particular,
CD4+ T cells in the intestinal mucosa comprisesignificant numbers of interleukin (IL)-17-producing
cells (‘Th17 cells’) and IL-10-producing regulatory T
cells (‘Treg cells’). These cells are particularly
abundant at the intestine and are present even at thesteady state. Employing gnotobiotic techniques, wehave demonstrated that components of the intestinalcommensal microbiota, particularly segmented
filamentous bacteria (SFB), strongly induce small
intestinal Th17 cells, whereas the accumulation of
Foxp3+ Treg cells in the colon of mice is promoted by
the presence of the spore-forming component ofindigenous intestinal microbiota—particularly thegenus Clostridium belonging to clusters XIVa and IV.
By extending our results, we are currently trying todevelop new therapeutic strategies by intervention of
the microbiota for various diseases including Crohn’sdisease and ulcerative colitis.

Curr. Opin. Immunol., 1, 17-22(6) Suzuki, S., Nakasato, M., Shibue, T., Koshima, I.
and Taniguchi, T.; Therapeutic potential ofproapoptotic molecule Noxa in the selective
elimination of tumor cells. (2009) Cancer Sci., 100,759-769(7) 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.
(8) Takaoka, A., Tamura T., and Taniguchi, T.; IRF
family transcription factors and regulation of
oncogenesis. (2008) Cancer Sci. 99, 467-478.
(9) 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.
(10) Negishi, H., Osawa, T., Ogami, K., Ouyang, X.,
Sakaguchi, S., Koshiba, R., Yanai, H., Seko, Y.,

References

Shitara, H., Bishop, K., Yonekawa, H., Tamura, T.,
Kaisho, T., Taya, C., Taniguchi, T. and Honda, K.; A(1) Wang, Z., Choi, M.K., Ban, T., Yanai, H., Negishi,

critical link between Toll-like receptor 3 and type II

H., Lu, Y., Tamura, T., Takaoka, A., Nishikura, K.,interferon signaling pathways in antiviral innate

and Taniguchi, T.; Regulation of immune responses

immunity. (2008) Proc. Natl. Acad. Sci. USA., 105,

by DAI (DLM-1/ZBP1) and other DNA-sensing

20446-20451

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

(11) 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
(12) Chen, H.M., Tanaka, N., Mitani, Y., Oda, E.,
Nozawa, H., Chen, J.Z., Yanai, H., Negishi, H.,(3) Tamura, T., Yanai, H., Savitsky, D., and Taniguchi,Choi, M.K., Iwasaki, T., Yamamoto, H., Taniguchi,T.; The IRF Family Transcription Factors in

T. and Takaoka, A.; Critical role for constitutive

Immunity and Oncogenesis. (2008) Annu. Rev.

type I interferon signaling in the prevention of

Immunol. 26, 535-584.

cellular transformation. (2009) Cancer Sci., 100,

(4) Taniguchi, T.; Aimez-vous Brahms? A story

449-456

capriccioso from the discovery of a cytokine family(13) Yanai, H., Savitsky, D., Tamura, T. and Taniguchi,

and its regulators. (2009) Nat. Immunol., 10,

T.; Regulation of the cytosolic DNA-sensing

447-449

system in innate immunity: a current view. (2009)(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(14) Taniguchi, T.; Aimez-vous Brahms? A story

58

capriccioso from the discovery of a cytokine family

Induction of colonic regulatory T cells by

and its regulators. (2009) Nat. Immunol., 10,

indigenous Clostridium species. Science 331,

447-449337-341(2011).

(15) Nakajima A, Nishimura K, Nakaima Y, Oh T,
NoguchiS,

Taniguchi

T,

TamuraT. Cell

type-dependent proapoptotic role of Bcl2L12
revealed by a mutation concomitant with thedisruption of the juxtaposed Irf3 gene. Proc. Natl.
Acad. Sci. USA 106, 12448-12452 (2009).
(16) Choi MK, Wang Z, Ban T, Yanai H, Lu Y, Koshiba
R, Nakaima Y, Hangai S, Savitsky D, Nakasato M,
Negishi H, Takeuchi O, Honda K, Akira S, Tamura
T, and Taniguchi T. A selective contribution of the
RIG-I-like receptor pathway to type I interferon
responses activated by cytosolic DNA. Proc. Natl.
Acad. Sci. USA 106, 17870-17875 (2009).
(17) Yanai H, Ban T, Wang Z, Choi MK, Kawamura T,
Negishi H, Nakasato M, Lu Y, Hangai S, Koshiba
R, Savitsky D, Ronfani R, Akira S, Bianchi ME,
Honda K, Tamura T, Kodama T, and Taniguchi
T. HMGB proteins function as universal sentinels
fornucleic

acid-mediatedinnateimmuneresponses. Nature 462, 99-103 (2009).
(18) Savitsky D, Tamura T, Yanai H, and Taniguchi
T. Regulation of immunity and oncogenesis by the
IRF transcription factor family. Cancer Immunol.
Immunother. 59, 489-510 (2010).
(19) Savitsky D, Yanai H, Tamura T, Taniguchi T and
Honda K. Contribution of IRF5 in B cells to thedevelopment of murine SLE-like disease through its
transcriptional control of the IgG2a locus. Proc.
Natl. Acad. Sci. USA 107, 10154-10159 (2010).
(20) Yanai, H., Chiba, S., Ban, T., Nakaima, Y., Onoe,
T., Honda, K., Ohdan, H. and Taniguchi, T.
Suppressionofimmuneresponses

bynonimmunogenic oligodeoxynucleotides with highaffinity for high-mobility group box proteins(HMGBs). Proc. Batl. Acad. Sci. USA. Published
online (2011)(21) Atarashi K, Tanoue T, Shima T, Imaoka A,
Kuwahara T, Momose Y, Cheng G, Yamasaki S,
Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S,
Ivanov II, Umesaki Y, Itoh K and Honda K.

Radiology and Biomedical
Engineering
1. Radiology

60

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

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

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

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

Lecturer
Yoshitaka Masutani, Ph.D.,

Hiroshi Igaki, M.D.,Ph.D.,

Harushi Mori, M.D.

Assistant Professor
Syuhei Komatsu, M.D.,

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

Tsuyoshi Nojo, M.D., Ph.D.,

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

Jiro Sato, M.D.,

Hiroki Sasaki, M.D., Ph.D.,

Takeyuki Watadani, M.D., Ph.D.,

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

Homepage

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

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

Clinical activities
Clinical services on Diagnostic Radiology, Nuclear
Medicine, and Radiation Oncology are provided in thecentralized Clinical Radiology Service Department incooperation with radiology technologists and nurses.

In the section of Diagnostic Radiology, all CT and
MRI examinations are monitored and reported bydiagnostic radiologists. Diagnostic radiologists,
gastroenterologists and cardiologists mainly perform
interventional procedures.
In the section of Nuclear Medicine, there are two
SPECT rooms and three PET rooms. These nuclear
imaging procedures are chiefly performed andreported by radiologists and cardiologists.
Each year, over 700 new patients receive radiation
therapy in the Radiation Oncology section. Highly
accurate 3D radiation therapy is the most outstanding
feature. Stereotactic radiation therapy for small lungor liver tumors has been carried out.
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61radionuclide (RN) therapy in the same floor. In
addition, four beds are allotted to terminal care ward
located in the 14th floor.

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

Research activities
Research activities in our department include
clinicalresearch,
animalexperiments
anddevelopment of instruments as well as computer-based
new technology. Diagnostic Radiology group in thedepartment promotes research activities aiming at
efficacy improvement of diagnostic imaging andexpansion of its application. Multi-row detector
helical computed tomography (MDCT) enables us totake tomographic images in a three-dimensional (3D)fashion. Using the data acquired by MDCT, various
kinds of diseases in almost all parts of the body, from
cerebral diseases to musculoskeletal diseases, can bedisplayed in 3D images. New 3D software developedin our departments is now widely used in the field of
the gastrointestinal tract, lung, and central nervous
system. In addition, we have opened a new laboratory
section named Image Computing and Analysis
Laboratory with invitation of a new staff from theFaculty of Engineering, the University of Tokyo. Thissection will contribute to development of novelsoftware to abstract clinically useful information fromthe 3D imaging data more sophisticatedly. In the fieldof magnetic resonance (MR) imaging, MR digital
subtraction angiography, perfusion imaging, anddiffusion tensor imaging are the foci of research.
These techniques are aggressively applied to theinvestigation of vascular and neoplastic diseases ofthe brain.
Radiation oncology group promotes research
projects in two major fields, one is physicalengineering aspect of radiotherapy and the other isreduction of injuries due to radiation exposure. With
the purpose of achieving precise external irradiation, a
new linear accelerator with C-arm and multileaf
collimator systems was developed and installed,which is utilized mainly for non-coplanar radiation
therapy in many patients especially with brain tumor
or head and neck tumor. Dynamic conical conformal
radiotherapy (Dyconic therapy) for metastatic brain
tumors using the accelerator is under evaluation. In
addition to gamma knife radiosurgery, this new
accelerator based stereotactic radiotherapy for brain
diseases has been undergone, and stereotactic
radiotherapy for body tumors, such as lung and liver
tumors, has been investigated. A new technology to
track mobile tumors, represented by lung tumors isunder investigation in collaboration with accelerator
makers. Novel approach to terminal care of patientswith various cancers has been investigated andimplemented as the palliative care team in cooperation
with expert nurses. The relationship between terminal
condition and cytokines, and newly developed scoring
system of quality of life are being evaluated. The
gustatory injury due to radiotherapy has been
investigated through animal experiments incombination with the laboratory of biological function,
Graduate School of Agricultural and Life Sciences,
University of Tokyo, and through taste tests in clinicalsetting. Radiation injuries in many tissues in thecritically accident in Tokai-mura were also
investigated.
Nuclear Medicine group promote clinical researchon images of function by the application ofradioisotope-labeled tracer technology. In particular,emission tomography (PET and SPECT) is applied for62the evaluation of cerebral blood flow and metabolism
inpatients
withdementia,
epilepsy,andcerebrovascular diseases. Cerebral blood flow, glucose
metabolism and neural synaptic functions aremeasured for the understanding of normal andpathophysiological states of CNS disorders, using avariety of positron-emitter radiotracer, such as [O-15]
H2O, CO2, O2, CO, [F-18] FDG, [C-11] methionine,[F-18]Dopa, [C-11]NMSP, NMPB and [C-11]
raclopride. The study of dementia using SPECT andthe standard brain atlas has made it possible tocategorize the type of dementia. Evaluation of
dopaminergic function by PET is very important in the
differential diagnosis of Parkinsonism. Cardiac PET
and SPECT are also active fields. Myocardial viability,
vascular reserve and sympathetic nerve denervation in
the ischemic heart disease are evaluated with [F-18]
FDG, [N-13] NH3, Tl-201 and [I-123] MIBG. Higher
brain functions such as reading, speech and thinking
have been studied with PET by comparing blood flow
and receptor binding potential (BP) under various
tasks and at rest. For the precise localization ofactivated brain function, computer processing andreconstruction of composite images of function andanatomy is an essential subject for investigation. At
present, whole body FDG-PET is one of the mosteffective tool for exploring metastatic lesions ofcancer patients. Combination display of SPECT/PET
with XCT/MRI would be a routine job andanatomo-functional images would play an importantrole in the clinical management of the patients.

3.

4.

5.

6.

7.

References
1.

2.

Abe O, Takao H, Gonoi W, Sasaki H, Murakami
M, Kabasawa H, Kawaguchi H, Goto M, Yamada
H, Yamasue H, Kasai K, Aoki S, Ohtomo K.
Voxel-based analysis of the diffusion tensor.
Neuroradiology 52(8): 699-710, 2010
Akai H, Kiryu S, Matsuda I, Satou J, Takao H,
Tajima T, Watanabe Y, Imamura H, Kokudo N,
Akahane M, Ohtomo K.
Detection of hepatocellular carcinoma by
Gd-EOB-DTPA-enhanced
liver
MRI:
Comparison with triple phase 64 detector row
helical CT.
Eur J Radiol: Epub ahead of print, 20108.

9.

Baba T, Sato-Matsushita M, Kanamoto A, Itoh A,
Oyaizu N, Inoue Y, Kawakami Y, Tahara H.
Phase I clinical trial of the vaccination for thepatients with metastatic melanoma using
gp100-derived epitope peptide restricted to
HLA-A*2402.
J Transl Med 8: 84, 2010
Bedayat A, Rybicki FJ, Kumamaru KK, Powers
SL, Signorelli J, Steigner ML, Steveson C, Soga
S, Adams K, Mitsouras D, Clouse ME, Mather
RT.
Reduced exposure using asymmetric cone beamprocessing for wide area detector cardiac CT.
Int J Cardiovasc Imaging: Epub ahead of print,
2011
Furukawa R, Akahane M, Yamada H, Kiryu S,
Sato J, Komatsu S, Inoh S, Yoshioka N, Maeda E,
Takazawa Y, Ohtomo K.
Endometrial stromal sarcoma located in the
myometrium with a low-intensity rim on
T2-weighted images: report of three cases andliterature review.
J Magn Reson Imaging 31(4):975-9, 2010
Gonoi W, Abe O, Yamasue H, Yamada H,
Masutani Y, Takao H, Kasai K, Aoki S, OhtomoK.
Age-related changes in regional brain volume
evaluated by atlas-based method.
Neuroradiology 52(10): 865-73, 2010
Gonoi W, Akai H, Hagiwara K, Akahane M,
Hayashi N, Maeda E, Yoshikawa T, Tada M, Uno
K, Ohtsu H, Koike K, Ohtomo K.
Pancreas divisum as a predisposing factor forchronic and recurrent idiopathic pancreatitis:
initial in vivo survey.
Gut: Epub ahead of print, 2011
Gonoi W, Akanhane M, Akai H, Hagiwara K,
Kiryu S, Hayashi N, Ohtomo K.
Retroportal
main pancreatic ductwithcircumportal pancreas: radiographic visualization.
Clin Imaging: in press, 2011
Goto M, Abe O, Miyati T, Yoshikawa T, Hayashi
N, Takao H, Inano S, Kabasawa H, Mori H,
Kunimatsu A, Aoki S, Ino K, Iida K, Yano K,
Ohtomo K.
Entorhinal cortex volume measured with 3T MRI
is positively correlated with the Wechsler

63

10.

11.

12.

13.

14.

15.

16.

17.

Memory Scale-Revised logical/verbal memory
score for healthy subjects.
Neuroradiology: Epub ahead of print, 2011
Hachizuka M, Yoshiuchi K, Yamamoto Y, Iwase
S, Nakagawa K, Kawagoe K, Akabayashi A.
Development of a personal digital assistant(PDA) system to collect symptom informationfrom home hospice patients.
J Palliat Med 13(6): 647-51, 2010
Hori M, Mori H, Aoki S, Abe O, Masumoto T,
Kunimatsu S, Ohtomo K, Kabasawa H, Shiraga
N, Araki T.
Three-dimensional
susceptibility-weighted
imaging at 3 T using various image analysis
methods in the estimation of grading intracranial
gliomas.
Magn Reson Imaging 28(4): 594-8, 2010
Inano S, Itoh D, Takao H, Hayashi N, Mori H,
Kunimatsu A, Abe O, Aoki S, Ohtomo K.
High signal intensity in the dural sinuses on
3D-TOF MR angiography at 3.0 T.
Clin Imaging 34(5): 332-6, 2010
Inano S, Takao H, Hayashi N, Abe O, Ohtomo K.
Effects of age and gender on white matter
integrity.
AJNR Am J Neuroradiol: in press, 2011
Inoue Y, Masutani Y, Kiryu S, Haishi T,
Watanabe M, Tojo A, Ohtomo K.
Integrated imaging approach to tumor model
mice using bioluminescence imaging andmagnetic resonance imaging.
Mol Imaging 9(3): 163-72, 2010
Inoue Y, Kiryu S, Watanabe M, Tojo A, Ohtomo
K.
Timing of imaging after d-luciferin injection
affects the longitudinal assessment of tumor
growth using in vivo bioluminescence imaging.
Int J Biomed Imaging 2010: 471408, 2010
Ishida M, Kojima K, Ohtomo K.
Renal cell carcionma with double synchronous
contralateral adrenal metastases.
Korean J Urol 51(12): 879-81, 2010
Katsura M, Morita A, Horiuchi H, Ohtomo K,
Machida T.
IgG4-related inflammatory pseudotumor of thetrigeminal nerve: another component of
IgG4-related sclerosing disease?

18.

19.

20.

21.

22.

23.

24.

AJNR Am J Neuroradiol: Epub ahead of print,
2010
Kin T, Shin M, Oyama H, Kamada K, Kunimatsu
A, Momose T, Saito N.
Impact of multiorgan fusion imaging andinteractive three-dimensional visualization for
intraventricular neuroendoscopic surgery.
Neurosurgery: Epub ahead of print, 2011
Koga T, Maruyama K, Kamada K, Ota T, Shin M,
Itoh D, Kunii N, Ino K, Terahara A, Aoki S,
Masutani Y, Saito N.
Outcomes of diffusion tensor tractographyintegrated stereotactic radiosurgery.
Int J Radiat Oncol Biol Phys: Epub ahead of print,
2011
Kumamaru KK, Hoppel BE, Mather RT, Rybicki
FJ.
CT angiography: current technology and clinicaluse.
Radiol Clin North Am 48(2): 213-35, 2010
Kumamaru KK, Steigner ML, Soga S, Signorelli
J, Bedayat A, Adams K, Mitsouras D, andRybicki FJ.
Coronaryenhancementforprospective
ECG-gated single R-R axial 320-detector row
coronary computed tomography angiography:
comparison of 60 and 80 ml Iopamidol-370
contrast medium injection.
AJR Am J Roentgenol: in press, 2011
Kunishima K, Shin M, Kunimatsu A, Aoki S,
Sasaki H, Koga T, Itoh D, Mori H, Abe O,
Ohtomo K, Saito N.
Contrast-enhanced
magnetic
resonance
characteristics of arteriovenous malformations
after gamma knife radiosurgery: predictors of
post-angiographic obliteration hemorrhage.
Neurosurgery 67(1): 100-9, discussion 109, 2010
Matsuda I, Hanaoka S, Akahane M, Sato J,
Komatsu S, Inoh S, Kiryu S, Yoshioka N, Ino K,
Ohtomo K.
Adaptive statistical iterative reconstruction forvolume-rendered
computed
tomography
portovenography: improvement of image quality.
Jpn J Radiol 28(9): 700-6, 2010
Mori H, Kunimatsu A, Abe O, Sasaki H, Takao H,
Nojo T, Kawai K, Saito N, Ohtomo K.
Diagnostic ability of fluid-attenuated inversion

64

25.

26.

27.

28.

29.

30.

31.

recovery MR imaging for detectiong remnant orrecurrent meningiomas after resection.
The Neuroradiology J: in press, 2010
Murakami M, Mori H, Kunimatsu A, Abe O,
Chikuda H, Ono T, Kabasawa H, Uchiumi K,
Sato J, Amemiya S, Komatsu S, Ohtomo K.
Postsurgical spinal magnetic resonance imaging
with iterative deconposition of water and fat withecho asymmetry and least-squares estimation.
J Comput Assist Tomogr 35(1): 16-20, 2011
Murakami M, Takao H, Abe O, Yamasue H,
Sasaki H, Gonoi W, Takano Y, Takei K, Kasai K,
Ohtomo K.
Cortical thickness, gray matter volume, and whitematter anisotropy and diffusivity in schizophrenia.
Neuroradiology: Epub ahead of print, 2011
Nagayama H, Matsumoto K, Isoo N, Ohno H,
Takahashi N, Nakaoka T, Shinozaki M, Watanabe
M, Inoue Y, Nagamura F, Oyaizu N, Yamashita N.
Gastrointestinal bleeding during the antiangiogenic peptide vaccination in combination
with gemcitabine for advanced pancreatic cancer.
Clin J Gastroenterol 3(6): 307-17, 2010
Nakagawa K, Kida S, Haga A, Masutani Y,
Yamashita H, Imae T, Tanaka K, Ohtomo K, Iwai
Y, Yoda K.
Cone beam computed tomography dataacquisition during VMAT delivery withsubsequent respiratory phase sorting based on
projection image cross-correlation.
J Radiat Res 52(1): 112-3, 2011
Nakamura K, Igarashi K, Ohkawa R, Saiki N,
Nagasaki M, Uno K, Hayashi N, Sawada T,
Syukuya K, Yokota H, Arai H, Ikeda H, Aoki J,
Yatomi Y.
A novel enzyme immunoassay for thedetermination of phosphatidylserine-specificphospholipase A(1) in human serum samples.
Clin Chim Acta 411(15-16): 1090-4, 2010
Nakamura N, Shikama N, Takahashi O, Ito M,
Hashimoto M, Uematsu M, Hama Y, Sekiguchi K,
Nakagawa K.
Variability in bladder volumes of full bladders in
definitive radiotherapy for cases of localized
prostate cancer.
Strahlenther Onkol 186(11): 637-42, 2010
Nakata Y, Aoki S, Sato N, Yasmin H, Masutani Y,

32.

33.

34.

35.

36.

37.

38.

Ohtomo K.
Tract-specific analysis for investigation of
Alzheimer disease: a brief review.
Jpn J Radiol 28(7): 494-501, 2010
Nakata Y, Sato N, Masumoto T, Mori H, Akai H,
Nobusawa H, Adachi Y, Oba H, Ohtomo K.
Parasellar T2-dark sign on MRI in patients withlymphocytic hypophysitis.
AJNR Am J Neuroradiol 31(10): 1944-50, 2010
Nomura Y, Hayashi N, Masutani Y, Yoshikawa T,
Nemoto M, Hanaoka S, Miki S, Maeda E,
Ohtomo K.
CIRCUS: an MDA platform for clinical image
analysis in hospitals.
Transactions on Mass-Data Analysis of Images
and Signals 2(1): 112-27, 2010
Ota T, Kamada K, Kawai K, Yumoto M, Aoki S,
Saito N.
Refined analysis of complex language
representations by non-invasive neuroimaging
techniques.
Br J Neurosurg 25(2): 197-202, 2011
Sasano N, Enomoto A, Hosoi Y, Katsumura Y,
Matsumoto Y, Morita A, Shiraishi K, Miyagawa
K, Igaki H, Nakagawa K.
Edaravone, a known free radical scavenger,
enhances X-ray-induced apoptosis at low
concentrations.
Cancer Lett 293(1): 52-7, 2010
Sato K, Aoki S, Iwata NK, Masutani Y, Watadani
T, Nakata Y, Yoshida M, Terao Y, Abe O, Ohtomo
K, Tsuji S.
Diffusion tensor tract-specific analysis of theuncinate fasciculus in patients with amyotrophic
lateral sclerosis.
Neuroradiology 52(8): 729-33, 2010
Sheng F, Inoue Y, Kiryu S, Watanabe M, Ohtomo
K.
Interstitial MR lymphography in mice withgadopentetate dimeglumine and gadoxetate
disodium.
J Magn Reson Imaging 33(2): 490-7, 2011
Sheng F, Inoue Y, Kiryu S, Watanabe M, Ohtomo
K.
Lymph drainage from the mammary glands inmice a magnetic resonance lymphographic study
with gadofluorine m.

65

39.

40.

41.

42.

43.

44.

45.

46.

Acad Radiol 18(4): 512-7, 2011
Shibata K, Arai M, Matsuura M, Uno K, Yoshida
T, Momose T, Ohtomo K.
Relationship of detection rate of PET cancer
screening examinees and risk factors: analysis ofbackground of examinees.
Ann Nucl Med 25(4): 261-7, 2011
Shiraishi K, Nakagawa K, Niibe Y, Ishiwata Y,
Yokochi S, Ohtomo K, Matsushima K.
Abscopal Effect of Radiation Therapy and Signal
Transduction.
Curr Signal Transduct Ther 5(3): 212-22, 2010
Soga S, Pomahac B, Mitsouras D, Kumamaru K,
Sara LP, Prior RF, Signorelli J, Bueno EM,
Steigner ML, Rybicki FJ.
Preoperative vascular mapping for facial
allotransplantation: four-dimensional computer
tomographic angiography versus
magnetic
resonance angiography.
Plast Reconstr Surg: in press, 2011
Tajima T, Takao H, Akai H, Kiryu S, Imamura H,
Watanabe Y, Shibahara J, Kokudo N, Akahane M,
Ohtomo K.
Relationship between liver function and liver
signal intensity in hepatobiliary phase ofgadolinium ethoxybenzyl diethylenetriamine
pentaacetic acid-enhanced magnetic resonanceimaging.
J Comput Assist Tomogr 34(3): 362-6, 2010
Takao H, Nojo T, Ohtomo K.
True pancreaticoduodenal artery aneurysms: adecision analysis.
Eur J Radiol 75(1): 110-3, 2010
Takao H, Abe O, Hayashi N, Kabasawa H,
Ohtomo K.
Effects of gradient non-linearity correction andintensity
non-uniformity
correction
inlongitudinal studies using structural image
evaluation using normalization of atrophy(SIENA).
J Magn Reson Imaging 32(2): 489-92, 2010
Takao H, Abe O, Ohtomo K.
Computational analysis of cerebral cortex.
Neuroradiology 52(8): 691-8, 2010
Takao H, Doi I, Watanabe T, Yoshioka N,
Ohtomo K.
Natural history of true pancreaticoduodenal

47.

48.

49.

50.

51.

52.

53.

54.

55.

artery aneurysms.
Br J Radiol 83(993): 744-6, 2010
Takao H, Abe O, Yamasue H, Aoki S, Sasaki H,
Kasai K, Yoshioka N, Ohtomo K.
Gray and white matter asymmetries in healthy
individuals aged 21-29 years: A voxel-based
morphometry and diffusion tensor imaging study.
Hum Brain Mapp: Epub ahead of print, 2010
Takao H, Hayashi N, Ohtomo K.
Effect of scanner in asymmetry studies using
diffusion tensor imaging.
Neuroimage 54(2): 1053-62, 2011
Takao H, Akai H, Tajima T, Kiryu S, Watanabe Y,
Imamura H, Akahane M, Yoshioka N, Kokudo N,
Ohtomo K.
MR imaging of the biliary tract with
Gd-EOB-DTPA: effect of liver function on signal
intensity.
Eur J Radiol 77(2): 325-9, 2011
Takao H, Hayashi N, Kabasawa H, Ohtomo K.
Effect of scanner in longitudinal diffusion tensor
imaging studies.
Hum Brain Mapp: Epub ahead of print, 2011
Takao H, Hayashi N, Inano S, Ohtomo K.
Effect of head size on diffusion tensor imaging.
Neuroimage: Epub ahead of print, 2011
Takao H, Hayashi N, Ohtomo K.
Effect of scanner in longitudinal studies of brain
volume changes.
J Magn Reson Imaging: in press, 2011
Tomizawa N, Komatsu S, Akahane M, Torigoe R,
Kiryu S, Ohtomo K.
Relationship between beat to beat coronary artery
motion and image quality in prospectively
ECG-gated two heart beat 320-detector row
coronary CT angiography.
Int J Cardiovasc Imaging: Epub ahead of print,
2010
Ueda K, Ichikawa M, Takahashi M, Momose T,
Ohtomo K, Kurokawa M.
FDG-PET is effective in the detection of
granulocytic sarcoma in patients with myeloid
malignancy.
Leuk Res 34(9): 1239-41, 2010
Watanabe T, Hirose S, Wada H, Katsura M,
Chikazoe J, Jimura K, Imai Y, Machida T,
Shirouzu I, Miyashita Y, Konishi S.

66

56.

57.

58.

59.

60.

61.

Predictionofsubsequent
recognition
performance using brain activity in the medial
temporal lobe.
Neuroimage 54(4): 3085-92, 2011
Yamamoto D, Iwase S, Yoshida H, Kuroda Y,
Yamamoto C, Kitamura K, Odagiri H, Nagumo Y.
Efficacy of S-1 in patients with capecitabineresistant breast cancer-Japan Breast Cancer
Research Network (JBCRN) 04-1 trial.
Anticancer Res 30(9): 3827-31, 2010
Yamashita H, Haga A, Hayakawa Y, Okuma K,
Yoda K, Okano Y, Tanaka K, Imae T, Ohtomo K,
Nakagawa K.
Patient setup error and day-to-day esophageal
motion error analyzed by cone-beam computed
tomography in radiation therapy.
Acta Oncol 49(4): 485-90, 2010
Yamashita H, Kobayashi-Shibata S, Terahara A,
Okuma K, Haga A, Wakui R, Ohtomo K,
Nakagawa K.
Prescreening based on the presence of CT-scanabnormalities and biomarkers (KL-6 and SP-D)
may reduce severe radiation pneumonitis after
stereotactic radiotherapy.
Radiat Oncol 5: 32, 2010
Yamashita H, Okuma K, Kawana K, Nakagawa S,
Oda K, Yano T, Kobayashi S, Wakui R, Ohtomo
K, Nakagawa K.
Comparison Between Conventional Surgery Plus
Postoperative Adjuvant Radiotherapy andConcurrent Chemoradiation for FIGO Stage IIB
Cervical Carcinoma: A Retrospective Study.
Am J Clin Oncol 33(6): 583-6, 2010
Yamashita
H,
Okuma
K,
Wakui
R,
Kobayashi-Shibata S, Ohtomo K, Nakagawa K.
Details of recurrence sites after elective nodal
irradiation
(ENI)
using
3D-conformal
radiotherapy(3D-CRT)
combinedwithchemotherapy for thoracic esophageal squamouscell carcinoma - A retrospective analysis.
Radiother Oncol 98(2): 255-60, 2011
Yamashita H, Kida S, Sakumi A, Haga A, Ito S,
Onoe T, Okuma K, Ino K, Akahane M, Ohtomo K,
Nakagawa K.
Four-dimensional
measurementofthedisplacement of internal fiducial markers during
320-multislice computed tomography scanning ofthoracic esophageal cancer.
Int J Radiat Oncol Biol Phys 79(2): 588-95, 2011

Radiology and Biomedical
Engineering
2. Biomedical Engineering

68

Department of Chemical Biology
and Molecular Imaging
Professor
Yasuteru Urano, Ph.D.

Assistant Professor
Mako Kamiya, Ph.D.

Homepage

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

Introduction and Organization

Research activities

The Department of Chemical Biology and Molecular
Imaging is one of the laboratories in the department ofRadiology and Biomedical Engineering. Ourlaboratory is located in the annex of the medicalbuilding 3. Former professor of our laboratory is Prof.
Shogo Ueno, who extensively did the research of
bio-magnetic imaging and magnetoencephalographyof brain functions. After his retirement in 2006, Dr.
Yasuteru Urano took up the post, and the newlaboratory was launched since January of 2010. Dr.
Mako Kamiya joined in May 2010 as an assistantprofessor, and one postdoc and one technician has
joined by the end of March 2011.

1. Development of novel fluorescence probes
By the end of March 2011, various instruments forchemical syntheses, purification, and characterization
were settled in our department, i.e., four chemical
hoods, four evaporators, two instruments for the
purification of compounds based on different
chromatographical mechanisms, two HPLC systems,
400 MHz NMR, ESI-TOF mass, and so on. UV-Vis
spectrometers and fluorometers were also settled in
our laboratory. So now, molecular design, chemical
syntheses, purification, characterization of novel
probes can be done in our department.
By using above instruments, we are now conducting
various projects of establishing novel bioimaging
techniques based on the development of new
fluorescence probes. So far, we have succeeded inestablishing rational design strategies of fluorescenceprobes based on photoinduced electron transfer
mechanism. Further in 2010, we newly succeeded toestablish another versatile design strategy by utilizing
the concept of intramolecular spirocyclization.

Teaching activities
As for under-graduate education, our department takes
a part in medical engineering lectures for the 3rd year
medical students. As for PhD course education, ourdepartment delivers the lecture of fluorescenceimaging for both master and doctor course students.
Our laboratory is also accepting Free Quarter students
every year, and this year we had two 3rd year students
for one month and two 2nd year students for two weeks,
respectively. They were trained to synthesize chemicalprobes and observe live cells with fluorescent
microscopes.

2. Live imaging of cellular functions and in vivo
tumors by precisely designed fluorescence probes
Various instruments for live imaging of cells andanimals were already settled in our laboratory, i.e.,
confocal fluorescence microscope equipped with awhite-light laser, wide field fluorescence microscope,
FACS, in vivo fluorescent imager, in vivo

69

bioluminescent imager, fluorescent endoscope, etc.
Also, instruments for cell culture and DNA work werealso settled in our laboratory.
By using these instruments, we are doing live imaging
of cancer cells and model mice extensively, forelucidating characteristic features of live cancer cells.
Based on the acquired data, we are developing novel
fluorescence probes for detecting tiny tumor sites invivo. In 2010, hydrolase activities in cancer andnormal cells were extensively examined by utilizing
novel probes, and we found that some glycosidase andpeptidase activities are truly upregulated in cancer
cells.
Further, we also succeeded to detect tiny
tumor sites in cancer bearing model mice by applying
appropriate fluorescence probes. Now, we start toapply these probes to real human resected tumor
samples, and examine the efficiency of our probes.

References
1. Koide Y, Urano Y, Hanaoka K, Terai T, Nagano
T: Development of an Si-rhodamine-based far-red
to near-infrared fluorescence probe selective for
hypochlorous acid and applications for biologicalimaging. J. Am. Chem. Soc. 133(15): 5680-5682,
Mar, 2011.
2. Sasaki H, Hanaoka K, Urano Y, Terai T, Nagano
T: Design and synthesis of a novel fluorescenceprobe for Zn2+ based on the spirolactam
ring-opening process of rhodamine derivatives.
Bioorg. Med. Chem. 19(3): 1072-1078, Feb, 2011.
3. Takakura H, Sasakura K, Ueno T, Urano Y, Terai
T, Hanaoka K, Tsuboi T, Nagano T: Developmentof luciferin analogues bearing an amino group andtheir application as BRET donors. Chem. Asian J.
5(9): 2053-2061, Sep, 2010.
4. Yogo T, Urano Y, Kamiya M, Sano K, Nagano T:
Development of enzyme-activated photosensitizer
based on intramolecular electron transfer. Bioorg.
Med. Chem. Lett., 20(15): 4320-4323, Aug, 2010.
5. Kobayashi H, Ogawa M, Alford R, Choyke PL,
Urano Y: New strategies for fluorescent probe
design in medical diagnostic imaging. Chem. Rev.
110(5): 2620-2640, May, 2010.
6. Hanaoka K, Muramatsu Y, Urano Y, Terai T,
Nagano T: Design and synthesis of a highly
sensitive off-on fluorescent chemosensor for zincion utilizing internal charge transfer. Chem. Eur. J.
16(2): 568-572, May, 2010.
7. Togashi M, Urano Y, Kojima H, Terai T,
Hanaoka K, Igarashi K, Hirata Y, Nagano T:
Sensitive detection of acrolein in serum using
time-resolved luminescence. Org. Lett. 12(8):1704-1707, Apr, 2010

70

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

Teaching activities

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 therapeutic medical
engineering technologies for clinical medicine. To
date, medical engineering has grown up not only to avery important academic discipline but also to a very
important means for clinical medicine. With thestructural reformation of the Faculty of Medicine,
Institute of Medical Electronics has been shifted to the
Graduate School of Medicine, and the name of thedepartment has been changed as shown above sinceApril 1, 1997.
The current members include 1 associate professor, 1lecturer, 6 graduate students, 1 professor emeritus, 2
research fellows, 17 visiting researchers, 1 technicalstaff, and 1 secretary.
Our research covers wide area of interdisciplinary andcomprehensive research fields based on the advanced
medical and engineering technologies. We arecooperating with various laboratories. Our doctor
course students have the opportunity to performresearch works under the guidance of Prof. Mabuchi
at Department of Information Physics and Computing,
Graduate School of Information Science andTechnology.

We take a part in systematic lectures for the 3rd year
medical students, and provide practice in the “freequarter” course for the 3rd and 4th year medical
students. In systematic lectures, we teach basic
knowledge of the advanced diagnostic and therapeutic
medical engineering technologies. The lectures of
introduction for artificial organ technologies areincluded.
For post-graduate education, we provide lectures forthe master course students, and we take a part in seriesof lectures for the doctor course students. In thelectures for the master course students, we teachartificial organ technologies. In the lectures for the
doctor course students, we teach philosophy,
methodology and basic and special knowledge ofadvanced medical engineering technologies for basic
and clinical medicine.
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, andother important information are acquired through thedevelopment and the animal experiment of theartificial hearts. In the practice, we give the mastercourse students several assignments from the field of
the artificial organs as a subject of their research. The
doctor course students have to find the subject of theirresearch by themselves. The research subject of the

71

doctor course students is not limited to the field of theartificial organs but is found from the wide area ofadvanced medical engineering technologies.
Students must attend to the weekly meeting. They canlearn how to perform the research work and how toreport it through the meeting.
The education to train the leaders of medical
engineers and clinical engineers is another importantrole of our department.

Research activities
Our research field covers advanced diagnostic andtherapeutic medical engineering technologies forclinical medicine. The main subjects are artificialorgans (artificial hearts, assist circulations, artificial
lungs, artificial valves, tissue engineered artificialorgans, regenerative artificial organs, etc). Especially,
the artificial heart is our world famous research
project having a long history since 1959. Almost all
the researches and developments for driving
mechanisms, energy converters, blood pumps,
artificial valves, biomaterials, power transmissions,
measurement techniques, control methods, anatomicalcompatibility, hemocompatibility, tissue compatibility,
computer fluid dynamics, physiology, pathology, andso on, have been studied. All the stuffs and students
are in part participating in the artificial heart project.
In 1995, we succeeded to survive a goat for 532 days
with the paracorporeal total artificial heart (TAH) withno anticoagulant, which is still the longest surviving
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, for the implantable TAH. 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 a pulsatile flow bychanging motor speed periodically. Recently, the newmodel of a UPTAH was developed for the purpose of
studying physiology with a nonpulsatile TAH. This
UPTAH can switch a pulsatile flow to a nonpulsatile
flow with a single device easily. We succeeded tosurvive a goat for 153 days with the UPTAH.

How to control the output of a TAH is another big
interest. We have developed our original control
method, named 1/R control. The 1/R control is aphysiological flow control method of TAH developedwith a conductance (1/R: reciprocal of a resistance)
parallel circuit model. At the present time, the 1/R
control is the only reported method to achieve
physiological control of a TAH. With the 1/R control,
the particular problems of a TAH such as venous
hypertension, slight anemia, low thyroid hormone
level, and so on, were not observed and the output waschanged in accordance with a metabolic demand of
the animal.
The 1/R control was installed in the UPTAH and thepathophysiological study was performed with a
nonpulsatile TAH. The result showed that the 1/R
control could be possible not only with a pulsatile
TAH, but also with a nonpulsatile TAH. The generalconditions and organ functions were not changed by
the application of the nonpulsatile mode. The cardiac
output and the arterial pressure changed with thecondition of the goat in the pulsatile mode and also in
the nonpulsatile modes, which seemed almost
identical. However, the sucking effect of atria wasmore significant in the nonpulsatile mode than thepulsatile mode. Therefore, the nonpulsatile TAH withthe 1/R control was considered to be inadequate,
unless some pulsatility would be introduced to avoid
the sucking effect for ensuring sufficient inflow
condition.
A new blood pump, named the helical flow pump
(HFP), for the TAH is under the development. The
HFP is a novel blood pump having a hydrodynamic
levitating impeller. We are expecting to develop an
ideal TAH that surpass the outcome of the hearttransplantation with the technologies of the UPTAH,
HFP, 1/R control, and hybrid materials described later.
A project of the emergency life support system(ELSS) that is a compact and transportablepercutaneous cardiopulmonary support (PCPS) device
for emergency use has been started in 2004. The
device consists of a blood pump, an oxygenator, adrive and control unit, and a battery unit. A new
membrane oxygenator and a new blood pump were
designed and integrated into one piece. An
experimental model exhibited good performance. The
improved model of the ELSS is under the72

development to realize one-month support. The wholesystem components will be packed in a case having
180 mm in diameter and 390 mm in length. The whole
weight will be 20 kg.
Concerning the biomaterials, we have beendeveloping a new method to develop hybrid materials.
In general, it is not easy to develop mechanical partsof implantable artificial organs from the componentsof living tissue because these components haveinsufficient strength and durability. To overcome these
problems, an insert molding method, which iscommonly used for the molding of resin in theindustrial field, was introduced. In this method, themold, in which an artificial material was inserted, was
implanted in the animal, and the tissue grew into themold to make a hybrid material. The method was first
applied to the Jellyfish valve that was originally apolymer valve for the artificial hearts. The hybrid
Jellyfish valve demonstrated a good possibility. This
year, with this insert molding technique, we started todevelop the tip of the inflow conduit for theventricular assist device. The tip of the conduit isinserted into the apex of the left ventricle where thethrombus often formed. In this method, the mold inwhich the core of the tip was inserted was implanted
under the skin of a goat. The experiments are going on.
This hybrid technique will be important technology
for developing the next generation artificial organs.
Concerning the measuring technique, an implantablevideo camera for observation of angiogenesis has beendeveloped using a CMOS chip. This device is an
evolved version of our implantable video camera forobservation of microcirculation using a CCD image
sensor. In the new devices, a scaffold was attached tothe camera and was implanted in the animal. The
camera having a polyglycolic acid fabric sheet as a
scaffold was implanted in goats and succeeded toobserve the real-time growth of tissue and micro
blood vessels in the scaffold. The influence of cellseeding in the scaffold was studied. The subcutaneous
tissue of a goat was cultured to obtain the seeding
cells. These cells were seeded in the scaffold attachedto the camera. The camera was implanted under theskin of the same goat. Another camera without cellseeding was also implanted in the same goat as acontrol study. The results showed that the growth
speed of tissue and micro blood vessels in the scaffold

was faster in the cell-seeding scaffold thannon-seeding one. The technique of the observation of
microcirculation and angiogenesis will give important
information for the studies of tissue engineering andregenerative medicine as well as the implantableartificial organs.
Our research of the IT (information technology)
medicine is focused to the home medical care. The
research and development of the IT infrastructures formonitoring the condition of the patients living at homeis being performed. The miniaturized wireless ECG(electro cardiogram) unit is attached on the patient’s
chest at home. The ECG data is transmitted to thelaptop computer set in the patient’s home. The data isthen transmitted to the data server set at our laboratory
through the mobile Internet communication. The
client computers in the clinic or doctor’s mobile
computer receive the real-time data through theInternet lines from the data server. This system has
been tested experimentally in a clinic and theoperating records revealed that the system was very
useful for the remote real-time monitoring of thepatients at home. The system is being improved forgeneral use in Japan.
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 at Prof.
Mabuchi’s laboratory, Department of Information
Physics and Computing, Graduate School ofInformation Science and Technology.

References
1. Kishi A, Isoyama T, Saito I, Miura H, Nakagawa
H, Kouno A, Ono T, Inoue Y, Yamaguchi S, Wei S,
Abe Y, Imachi K, and Noshiro M. Use of in vivo
insert molding to form a jellyfish valve leaflet.
Artificial Organs. 2010;34:1125-1131.
2. Shintaku H, Yonemura T, Tsuru K, Isoyama T,
Yambe T, and Kwano S. Oxygenation to bovine
blood in artificial heart and lung using vibrating
flow pump: experiment and numerical analysis
based on non-newtonian model. Journal of fluid
science and technology. 2010;5:292-304.
3. Koshiba Y, Nakamura Y, Ito D, Yokoyama T,

73

Okazaki S, Nakagawa H, Arai T. Development ofa durable fiber-optic oxygen sensor for harsh
undergroundenvironments. Talanta.

2010;82:1495-1499.
4. Saito I, Ishii K, Isoyama T, Ono T, Nakagawa H,
Shi W, Inoue Y, Abe Y. Preliminary study ofphysiological control for the undulation pumpventricular assist device. Conf Proc IEEE Eng
Med Biol Soc. 2010;2010:5218-5221.

Neuroscience
1. Basic Neuroscience75

Department of Neuropathology
Professor
Takeshi Iwatsubo, M.D.

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

Homepage

http://web.f.u-tokyo.ac.jp/~neuropsc/entranceja2.html

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

serves as the PI of Japanese ADNI.
1. Research on β-amyloid and presenilins
Using
C-terminal
specific
monoclonal
antibodies that discriminate amyloid β peptides (Aβ)
ending at 40th or 42nd residues (Aβ40 and Aβ42,
respectively), Dr. Iwatsubo has performed asystematic immunohistochemical studies on autopsied
brain tissues from patients with AD, Down syndrome
and familial AD, and demonstrated that Aβ42, thatmost readily form amyloid fibrils in vitro, is theinitially and predominantly deposited species inhuman cerebral β-amyloidosis (Iwatsubo et al. Neuron
1994, Ann Neurol 1995). Dr. Iwatsubo’s group thenestablished celllar models expressing mutant forms ofpresenilin (PS) genes linked to familial AD (FAD),
and using their original highly-sensitive ELISA
quantitation system, his group has clearly shown thatan increase in the production of Aβ42 is thepathogenic mechanism leading to FAD (Tomita et al.
Proc Natl Acad Sci USA, 1997). These findings haveprovided a firm basis for the currently prevailing
β-amyloid hypothesis. They then focused on themechanisms of γ-secretase complex that cleaves the C
terminus of Aβ, and set out to cell biological studies
using RNA interference on the formation and function

76of the γ-secretase complex harboring PS as thecatalytic center, associated with three 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 showedthat PS, APH-1, nicastrin and PEN-2 are the essential
set of proteins that comprise the γ-secretase complex(Takasugi et al. Nature, 2003). This study ishighlighted as a milestone work that elucidated themechanistic roles of protein cofactors in the formationand function of γ-secretase (see reviews; Iwatsubo
Mol Psychiatr, 2004; Curr Opin Neurobiol, 2004). His
group has also shown by establishing in vitro
γ-secretase assays that sulindac sulfide, a major
non-steroidal anti-inflammatory drugs, directly acts on
γ-secretase and selectively reduce Aβ42-generating
activities (Takahashi et al., J Biol Chem, 2003),
providing important implications to the therapeuticstrategies of AD by γ-secretase modulation. Recently,
he has established a novel method for an efficient invitro reconstituion of γ-secretase complex, paving theway towards the structural analysis of active
γ-secretase (Hayashi et al. J Biol Chem, 2004), andusing thus highly purified γ-secretase particles, they
have partially unveiled the submolecular structure ofthis complex by single-particle EM analysis (Ogura etal. BBRC, 2006). Very recently, his group has
established an elegant strategy to analyze thestructure-function relationship within the catalytic
structure of γ-secretase complex by cystein chemistry,and demonstrated that γ-secretase harbors awater-permeable catalytic pore (Sato et al. J Neurosci,
2006), and that substrate proteins enter the catalytic
pore through the lateral gate located at the C terminalside of PS (Sato et al. J Neurosci, 2008). Thus, Dr.
Iwatsubo’s group started from an elegant
immunohistochemical analysis of Aβ deposits in AD
brains and extended it to a contemporary
molecular/cellular biology of PS, that proved to play a
key role in the important biological reaction termed“intramembrane proteolysis”.
2. Identification and characterization of α-synuclein
as a major component of Lewy bodies.
Using cortical Lewy bodies purified frompostmortem brains of patients with dementia with

Lewy bodies (DLB) by his original method (Iwatsubo
et al. Am J Pathol 1996) as immunogens, Dr.
Iwatsubo’s group, in collaboration with Drs. Virginia
Lee and John Trojanowski at Univ. Penn, performed
an extensive immunochemical search for componentsof Lewy bodies. They have demonstrated by raising a
specific monoclonal antibody that α-synuclein, thatproved to be a product of pathogenic gene for familial
form of Parkinson’s disease, is one of the major
constituent of Lewy bodies in sporadic Parkinson’s
disease and DLB (Baba et al. Am J Pathol 1998). His
group then purified aggregated α-synuclein from DLB
cortices using fine biochemical techniques, purified it
to near homogeneity, and 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 arange of studies focusing on the role of synuclein
phosphorylation in neurodegeneration. Also, thephospho-specific α-synuclein antibody is widely usedas the most sensitive marker for α-synucleinopathy
lesions, and they have characterized a wide spectrumof 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 ofmolecular masses of 50/100 kDa. Dr. Iwatsubo’sgroup raised a monoclonal antibody against amyloid
fraction that recognizes this protein, and using thisantibody as a probe, they conducted a thoroughbiochemical purification of these antigens and finallycloned a cDNA coding for the precursor of this protein.
This protein turned out to be a novel class ofmembrane-bound collagen, which was named CLAC
(collagen-like Alzheimer amyloid plaque component)
and its precursor CLAC-P (Hashimoto et al. EMBO J
2002). This finding had an immense impact both on
fields of AD research as well as on general biology as
a first discovery of neuron-specific collagen harboring

77

a unique membrane-spanning structure. CLAC has
been highlighted as a protein that may affectfibrillization of Aβ and contribute to amyloid plaqueformation. Indeed, he has recently shown that
CLAC-positive senile plaques constitute a uniquesubset of plaques distinct from the classical,
β-sheet-rich amyloid deposits, underscoring thepathobiological role of CLAC in amyloid formation(Kowa et al. Am J Pathol, 2004), and that CLAC
inhibits fibrillization of Aβ in vitro (Osada et al. J Biol
Chem, 2005). Transgenic mice studies are confirming
the role of CLAC in the morphogenesis of senile
plaques in vivo.
4. Japanese ADNI: clinical studies for theidentification 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 theprincipal investigator on 2006, recruiting 35 clinicalsites nationwide, and preparing all the infrastructures
required for the large-scale clinical study. The J-ADNI
group is starting to recruit participants on June 2008
(total, 600 cases for 5 years), and the instruments andframework of J-ADNI are being adopted in multiple
global clinical trials in Japan.

References
1) Cheung KH, Mei L, Mak DOD, Hayashi I, Iwatsubo
T, Kang DE, Foskett JK: Gain of function
Alzheimer’s disease presenilin regulation of InsP3
receptor modal gating in patient cells and AD mouseneurons. Science Signaling 3:ra22, 2010
2) Watanabe N, Takagi S, Tomita T, Iwatsubo T:
Functional analysis of the transmembrane domainsof presenilin 1: participation of transmembrane
domains 2 and 6 in the formation of initial substratebinding site of γ-secretase. J Biol Chem
285:19738-19746, 2010

3) Fukumoto H, Takahashi H, Tarui N, Matsui J, Tomita
T, Hirode M, Sagayama M, Maeda R, Kawamoto M,
Hirai K, Terauchi J, Sakura Y, Kakihana M, Kato K,
Iwatsubo T, Miyamoto M: A non-competitive
BACE1 inhibitor TAK-070 ameliorates Aβ
pathology and behavioral deficits in a mouse modelof Alzheimer’s disease. J Neurosci 30:11157-11166,
20104) Kurosumi M, Nishio Y, Osawa S, Kobayashi H,
Iwatsubo T, Tomita T, Miyachi H: Novel
Notch-sparing γ-secretase inhibitors derived from aperoxisome proliferator- activated receptor agonist
library. Bioorg Med Chem Lett 20:5282-5285, 20105) Nonaka T, Watanabe ST, Iwatsubo T, Hasegawa M:
Seeded aggregation and toxicity of α-synuclein andtau: cellular models of neurodegenerative diseases. J
Biol Chem 285:34885-34898, 2010
6) Asai M, Iwata N, Tomita T, Iwatsubo T, Ishiura S,
Saido TC, Maruyama K: Efficient four-drug cocktail
therapy targeting amyloid-β peptide for Alzheimer’s
disease. J Neurosci Res 88:3588-3597, 2010
7) Takagi S, Tominaga A, Sato C, Tomita T, Iwatsubo T:
Participation of transmembrane domain 1 ofpresenilin 1 in the catalytic pore structure of theγ-secretase. J Neurosci 30: 15943-15950, 2010

78

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

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

Homepage

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

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

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

79

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

Teaching activities
The Department’s teaching activities include:
1) Introductory Neuroscience coursework provided to
pre-medical students in the Komaba campus (onehour);
2) Neurochemistry lectures to medical students as partof 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 lecturesfrom outstanding neuroscientists from all overJapan).
Additionally, Neurochemistry Seminars are
frequently and regularly organized under the auspicesof the Global Center of Excellence Program Grant“Global Center of Education and Research for
Chemical Biology of the Diseases”. This enables
direct exposure of Ph.D. graduate students andpostdocs to both young promising researchers andestablished investigators from all over the world.

Research activities
The Department of Neurochemistry currently
focuses its resources into two core projects:
1) Molecular investigation (including identification,
characterization and real-time visualization) of
signaling molecules involved in calcium-dependent
synaptic modification, especially during signalingfrom synapse-to-nucleus, and back from nucleus-tosynapses.
Changes in efficacy of synaptic transmission
have been 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 activated atand 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 consolidation ofsuch 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 ofa
CaMKK/CaMKIV
cascadeintriggering
synaptically-stimulated nuclear CREB phosphorylation in hippocampal neurons. The extreme
biochemical efficacy and the relative poor frequencydependence of this signaling cascade, in combination
with the robust 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 and indeed pCREB immunofluorescence is now considered as a universal marker
for integrated synaptic activity that is more sensitive
than that of c-Fos (Nonaka, J. Neurosci. 2009). The
critical function of CaMKK/CaMKIV/pCREB cascade80in the expression of long-term synaptic plasticity was
also validated in long-term potentiation in the
hippocampus (Redondo et al., J Neurosci. 2010).
Furthermore,
CaMKIV-KO,
CaMKK-KO
and
CaMKIV-dominant negative transgenic studies bymany laboratories have confirmed the critical role for
CaMKIV as synaptic activity-triggered CREB kinase.
We subsequently also showed that CaMKIV inthe cerebellar granule cells played a critical role intuning the pCREB response necessary for
depolarization-mediated neuronal survival, and that infact CaMKIV stability was actively maintained bydepolarization. Loss of depolarizing signal led to a
caspase-mediated proteolytic degradation of CaMKIV.
This in turn severely impaired CREB phosphorylation,
facilitating apoptosis, and conversely rescuing pCREB
by overexpressing 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).
To elucidate the significance of the genes
regulated downstream of CREB during learning andmemory, we set out to uncover the most elementary
regulatory element required and sufficient to trigger
robust activity-dependent gene induction of theimmediate early gene Arc, whose expression in many
brain areas have been invariably associated with key
cognitive activities mediated by these areas. We
discovered a fundamentally novel synaptic activityresponsive element (SARE) which was present as a
distal regulatory promoter element and was conserved
across most mammalian species (Kawashima et al.
PNAS 2009; Kim et al. Nature 2010; Inoue et al.
Commun. Integr. Biol. 2010). Surprisingly, SARE
contained juxtaposed binding elements for all three
activity-regulated transcription factors, CREB, MEF2

and SRF. Currently, experiments are ongoing tocapitalize on this knowledge in order to build reporter
virus and mouse lines that are expected to be useful to
map the extent of neuronal circuit activation during
various kinds of cognitive activities.
One parallel branch of CaMK signaling that has
not been widely studied is the CaMKK/CaMKI
pathway. During the search for potential CaMKIV-like
CREB regulatory kinases (CLICKs) (Ohmae et al., J.
Biol. Chem. 2006), we identified a novel CaMKI
isoform that contained a C-terminal CAAX lipid
modification motif (Takemoto-Kimura, Ageta-Ishihara
et al., J. Biol. Chem., 2003; Takemoto-Kimura et al.
Neuron 2007). This novel membrane-bound CaMK
(CLICK-III/CaMKIγ) is most expressed in the central
nucleus of the amygdala and in the ventral medial
hypothalamus, while also being present at a much
weaker amount in most central neurons. Ongoingbiochemical and cell biological studies indicate acritical role for lipidification of this kinase to beproperly sorted into specific lipid-restricted membrane
microdomains. The function played by this lipidified,membrane-inserted CaMK in circuitry formation andmaturation was scrutinized using RNA interference.
Along with the identification of the criticallipid-modifying enzyme that controls lipid-anchoringof this kinase, we discovered a novel activityregulated mechanism whererby CLICK-III/CaMKIγ isactively sorted into dendritic lipid rafts, where it
specifically regulates Rac-mediated actin remodelingthat is required for BDNF-stimulated dendritogenesis(Takemoto- Kimura et al., Neuron, 2007; TakemotoKimura et al. Eur. J. Neurosci. 2010). Similar studies
in axonal growth also suggest the active contributionof CaMKK cascade in this process (Ageta-Ishihara etal., J. Neurosci. 2009; Takemoto-Kimura et al. Eur. J.
Neurosci. 2010).
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 of

81

these newly synthesized gene products affect synaptic
protein complexes (Okuno and Bito, AfCS/Nature
Mol. Pages, 2006).
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sidesof the synapses, in the dendritic spines and in axon
terminals.
Both synaptic maturation and synaptic plasticity
have been shown to include a morphologicalcomponent that is directed by the dynamics of actin
cytoskeleton, a major cytoskeletal component both in
the dendritic spines and at the very proximity ofboutons in the axon terminals. Few studies in the past,
however, had directly addressed what moleculardeterminants regulate actin dynamics in living central
neurons undergoing synaptic activity. This was in part
because actin filament assembly and disassembly wereclassically studied mostly at the moving edges oflamellipodia of large growth cones in large-size
neurons from either mollusc or peripheral nerve cells.
Such visualization turned out to be much moredifficult in seemingly far less mobile spine structures
tightly apposed to presynaptic active zones.
We (and others) used GFP-actin imaging to try tounderstand how neuronal actin cytoskeleton in
hippocampal neurons was organized and reorganizedby exposure to synaptic activity. In our dissociatedculture 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-1α released from thepia mater was likely to be a predominant Rho
activator via stimulation of a cognate and specific
GPCR CXCR4 (Arakawa et al., J. Cell Biol., 2003).
While a true gradient in SDF-1α still remains to be
demonstrated in vivo, it is intriguing to note that mostactive axonal process formation and elongation
actually occur in the inner zone of EGL that is
opposite and most distant from the interface with the
pia mater (Bito, J. Biochem., 2003). Most strikingly,
we demonstrated that axon elongation could actively
occur in an intermediate Rho activity range thatenables ROCK to be weakened enough while allowing
another Rho effector mDia1 to actively mediate its
effect on actin nucleation and polymerization(Arakawa et al., J. Cell Biol., 2003).
Whether similar or distinct mechanisms also
operate during spinogenesis and spine maturation
remains to be determined, though a role for Rho and82

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

Publications by lab members(January 2010- December 2010)
1. InoueM,

Yagishita-Kyo

N,

NonakaM,

Kawashima T, Okuno H, Bito H. Synaptic
Activity-Responsive Element (SARE): A uniquegenomic structure with an unusual sensitivity toneuronal activity. Commun. Integr. Biol., 3:443-446, 2010.
2. Takemoto-Kimura S, Suzuki K, Kamijo S,
Ageta-Ishihara N, Fujii H, Okuno H, Bito H.
Differentical roles for CaM kinases in mediating

excitation-morphogenesis

coupling

duringformation and maturation of neuronal circuits.
Eur. J. Neurosci., 32: 224–230, 2010.
3. Bito H. The chemical biology of synapses andneuronal circuits. Nature Chem. Biol., 6: 560-563,
2010.
4. Kim TK, Hemberg M, Gray JM, Costa AM, Bear
DM, Wu J, Harmin DA, Laptewicz M, BarbaraHaley K, Kuersten S, Markenscoff-Papadimitriou
E, Kuhl D, Bito H, Worley PF, Kreiman G,
Greenberg ME. Widespread transcription atneuronal activity-regulated enhancers. Nature,
465: 182-187, 2010.
5. Redondo RL, Okuno H, Spooner PA, Frenguelli
BG, Bito H, Morris RGM. Synaptic tagging andcapture: differential role of distinct calcium/
calmodulin kinases in protein synthesis-dependent
long-term potentiation. J. Neurosci., 30: 49814989, 2010.

83

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

84function as molecular switches in many signalingcascades. These indicators revealed spatial-temporal
dynamics of Rho family proteins activation in
randomly migrating HT1080 cells. In contrast to
previous studies, Rho and Cdc42 were activated inbroad areas of the plasma membrane in motile cells.
Therefore, our probes can be used for more effective
and quantitative study for cell movement. Furthermore,in a central nervous system, Rho family is known as amolecules regulation cell motility of neuronal cells
and synaptic function. We applied our fluorescentprobes to experiments for analysis of these cellfunctions.
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.

Using

EPRIL

technology and imaging techniques, we explore
physiologically functional molecules by a highthroughput screening system.

References
1.

2.

Tsuji T, Ohta Y, Kanno Y, Hirose K, Ohashi K,
Mizuno K. Involvement of p114-RhoGEF and
Lfc in Wnt-3a- and dishevelled-induced RhoA
activation and neurite retraction in N1E-115
mouse neuroblastoma cells. Mol Biol Cell.
213590-600 (2010)
Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K,
Nakagawa T, Funata M, Yamaguchi M, Namiki S,
Nakayama R, Tabata M, Ogata H, Kubota N,
Takamoto I, Hayashi YK, Yamauchi N, Waki H,
Fukayama M, Nishino I, Tokuyama K, Ueki K,

3.

Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K,
Kadowaki T.Adiponectin and AdipoR1 regulate
PGC-1alpha and mitochondria by Ca2+ and
AMPK/SIRT1. Nature. 464, 1313-9 (2010)
Okubo Y, Sekiya H, Namiki S, Sakamoto H,
Iinuma S, Yamasaki M, Watanabe M, Hirose K,
Iino M. Imaging extrasynaptic glutamate
dynamics in the brain. Proc Natl Acad Sci U S A.
107, 6526-31 (2010)

Neuroscience
2. Integrative Medical Neuroscience86

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

Associate
Kazumasa Umeda, Ph.D., Kenji Morita, Ph.D.

Homepage

http://square.umin.ac.jp/dcntky/English/Etop.html

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

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

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

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

87

This decoding technique can be used to demonstratethat the brain is the cause of our cognition.
To answer these questions we are using various
behavioral paradigms such as selective attention, task
switching, perceptual decision making, masked
priming and so on. We are interested in themechanistic explanation of brain function. Students
and younger researchers are free to choose any kind of
behavioral paradigms if we agree that the paradigm isthe best one to answer the questions about the brain.

References
1. Morishima Y, Okuda J, Sakai K. Reactive
mechanism of cognitive control system. Cerebral
Cortex. 20: 2675-2683, 2010.
2. Akaishi R, Morishima Y, Rajeswaren VP, Aoki S,
Sakai K. Stimulation of the frontal eye fieldreveals persistent effective connectivity after
controlled behavior. Journal of Neuroscience 30:
4295-4305, 2010.

88

Department of Child
Neuropsychiatry
Associate Professor
Yukiko Kano, M.D.,Ph.D.

Assistant professor
Hitoshi Kuwabara, M.D., Ph.D., Yuki Kawakubo, Ph.D.

Homepage

http: //childpsy.umin.jp/

Introduction and Organization
Recently, mental problems of child and adolescent or
problems of mental development are continuously
increasing, and serious deficiency of specialists suchas child psychiatrists and necessity of theirdevelopment are emphasized. Especially, as Japan
falls far behind other nations in research andeducation system of child psychiatry, development ofspecialists who can promote research by themselves
and improve quality of diagnosis and treatment basedon their own research are strongly demanded. In
response to these needs, Department of Child
Neuropsychiatry, Graduate School of Medicine wasestablished in April 2010. This is believed to be thefirst Japanese department which works as an actual
department of child psychiatry managed by childpsychiatrist. Based on experience of clinical-based
research as well as medical care and training ofclinicians for decades in child psychiatry division of
Department of Neuropsychiatry and Department ofChild Psychiatry since April 2005, we are developing
new activities. Three professors are administrating
Department of Child Psychiatry, the University
Hospital also, and trying to utilize its clinical activities
for research more effectively.

Teaching activities
As the year of 2010 was the first year of thisdepartment, we had no graduate students. However,we were involved to supervision of research projects
about autism spectrum disorder (ASD) andattention-deficit/hyperactivity disorder (ADHD) by
three graduate students from Department of
Neuropsychiatry.

Research activities
Main subjects of our research are ASD including
autism and Asperger syndrome, ADHD, Tourette
syndrome which is a severe and chronic tic disorder,and child & adolescent obsessive-compulsive disorder(OCD). We are trying to combine scientific analysis ofobjective mental and behavioral indicators withneuropsychological, brain-imaging, and genetic
studies into comprehensive and multidimensional
approach to problems in development of brain andmind. We are applying this comprehensive approach
to intervention studies including pharmacotherapy.
Major research projects with full or preliminary
performance in 2010 are as follows:
・Behavior phenotype, neuropsychological and genetic
study of Tourette syndrome and child & adolescent
OCD
・Brain-imaging study of ASD, ADHD and Tourette
syndrome by structural-MRI, functional-MRI andnear-infrared spectroscopy (NIRS)
・Genomic and epigenomic analysis of ASD
・Development of predictor of pharmacotherapy andparent training for ADHD
・Effectiveness study of early intervention for autistic

Neuroscience
3. Clinical Neuroscience89

preschoolers and group cognitive behavior therapy for
adults with high-functioning ASD(Details can be found in the report of Department ofChild Psychiatry.)

References
1. Kano Y, Kono T, Shishikura K, Konno C,
Kuwabara H, Ohta M, do Rosario MC: Obsessive
compulsive symptom dimensions in Japanese
Tourette syndrome subjects. CNS Spectr, 15(5):296-303, 2010.
2. Liu X, Kawamura Y, Shimada T, Otowa T, Koishi
S, Sugiyama T, Nishida H, Hashimoto O,
Nakagami R, Tochigi M, Umekage T, Kano Y,
Miyagawa T, Kato N, Tokunaga K,Sasaki T:
Association of the oxytocin receptor (OXTR)
gene polymorphisms with autism spectrum
disorder (ASD) in the Japanese population. J Hum
Genet, 55(3):137-141, 2010.
3. Marui T, Funatogawa I, Koishi S, Yamamoto K,
Matsumoto H, Hashimoto O, Jinde S, Nishida H,
Sugiyama T, Kasai K, Watanabe K, Kano Y, Kato
N: The NADH-ubiquinone oxidoreductase 1 alphasubcomplex 5 (NDUFA5) gene variants areassociated with autism. Acta Psychiatr Scand,2010 Sep 5.[Epub ahead of print]
4. Takei Y, Kumano S, Maki Y, Hattori S, Kawakubo
Y, Kasai K, Fukuda M, Mikuni M: Preattentive
dysfunction in bipolar disorder: a MEG study
using auditory mismatch negativity. Prog
Neuropsychopharmacol Biol Psychiatry 34(6):903-912, 2010.
5. Yamasaki S, Yamasue H, Abe O, Suga M, Yamada
H, Inoue H, Kuwabara H, Kawakubo Y, Yahata N,
Aoki S, Kano Y, Kato N, Kasai K: Reduced graymatter volume of pars opercularis is associatedwith impaired social communication in
high-functioning autism spectrum disorders. Biol
Psychiatry 68(12): 1141-1147, 2010.
6. Kano Y, Ohta M, Nagai Y, Scahill L: Association
between Tourette syndrome and comorbidities inJapan. Brain Dev, 32(3): 201-207, 2010.

91

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

Associate Professor
Hidenori Yamasue, M.D., Ph.D.

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

Lecturer
Seiichiro Jinde, M.D., Ph.D.,

Mamoru Tochigi, M.D., Ph.D.

Research Associate
Motomu Suga, M.D., Ph.D.,

Junichi Terai, M.D.

Ryu Takizawa, M.D., Ph.D.,

Takuji Nishida, M.D.,

Tatsuya Nagai, M.D.

Wataru Kanata, M.D.,

Takafumi Makino, M.D.

Youhei Kabaya, M.D.,

Shinya Fujikawa, M.D.

Homepage

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

Introduction and Organization
The Department of Neuropsychiatry is the oldest
department of psychiatry in Japan which wasestablished in 1886. "Anti-Psychiatry" movement in
the last 3 decades had brought highly negative impacts
on the progress of all aspects of our activities.
However, in 1994, our department has beennormalized and restarted to play a leading role inpsychiatry in Japan. Since 2005, we have begun tofocus on basic and clinical neuroscience in pervasive
developmental disorders (PDDs). From 2006, we havebeen working in the new closed ward (30 beds) and in
the open ward (29 beds). Dr. Kiyoto Kasai has been
serving as a professor since 2008. Now the
Department of NeuroPsychiatry is dedicated to highquality clinical services, excellent training, education
for students and innovative research.

Clinical activities
For outpatient services, we have more than 20 staff

psychiatrists, 4 clinical psychologists and 1
psychiatric social worker. Approximately 1100 new
patients visited yearly (2010), and the total visits per
day was about 160.
The secluded ward has 29 beds including 3
seclusion rooms. We also have 31 beds for the open
general ward. Approximately 550 patients withvarious psychiatric disorders were admitted in a year
(2010). Recently, the number of patients who werereferred from the emergency unit is increasing. The
age of patients is variable from teenager to senior. The
majority of the patients are schizophrenia, mooddisorder and psychosis based on the somatic disease.
Mean hospitalization is 30 day long, and modified
electro-convulsive therapy was performed for over
400 patients.
We established day care unit for outpatients withschizophrenia in 1974, and the patients are engaged inrehabilitation and re-work programs. We also haveJapan's first child psychiatry day care unit in national
university hospitals since 1967, and mainly patientswith pervasive developmental disorders are engaged

92

in clinical and educational activities.
From the last year, new diagnostic program usingnear infrared spectroscopy (NIRS) has started as anadvanced medical treatment.

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.
This year, Mental Health research course has started
as one of 10 programs for the education in clinicalresearch field.

Research activities
Our mission in research is to clarify thepathophysiology of the mental illness to develop
better treatment approach.
1) Neuroimaging
Our research plays a leading role in psychiatricneuroimaging in Japan and aims at multi-modality
neuroimaging (structural and functional MRI, MR
spectroscopy, EEG, MEG, near-infrared spectroscopy[NIRS], PET) in schizophrenia, mood disorders,pervasive developmental disorders, and posttraumaticstress disorder (PTSD).
2) Molecular/cellular neuroscience
The goal of the molecular cellular neuroscience groupis to build causal bridges among the molecular,
cellular, neural systems, and behavior on the rodent
model of neuropsychiatric disorders. We employ
integrated multidisciplinary techniques including
genetics, cell biology, biochemistry, histology,
electrophysiology, imaging and behavioral analysis
for elucidating molecular pathophysiology of rodent
models of neuropsychiatric disorder. We have been

focusedonschizophrenia.

Epilepsy,

PTSD,

autismand3) Genetic and Epidemiology research
The Genetic Research Group of the department isinvestigating genetic as well as environmental
mechanism of psychiatric disorders. A major focus of
the studies is exploration of susceptibility genes of thedisorders including schizophrenia, autism, theirspectrum disorders and anxiety disorder (mainly panic
disorder). A number of candidates of the susceptible
genes are studied using case-control and TDT(transmission disequilibrium test) designs.

References(1) Abe O, Takao H, Gonoi W, Sasaki H, Murakami M,
Kabasawa H, Kawaguchi H, Goto M, Yamada H,
Yamasue H, Kasai K,
Aoki S, Ohtomo K.
Voxel-based analysis of the diffusion tensor.
Neuroradiology 52: 699-710, 2010.
(2) Abe O, Yamasue H, Yamada H, Aoki S, Kasai K,
Inoue H, Takei K, Suga M, Matsuo K, Kato T.
Voxel-based analyses of gray/white matter volume
and deffusion tensor data in major depression.
Psychiatry Res 181: 64-70, 2010.
(3) Abe O, Yamasue H, Yamada H, Masutani Y,
Kabasawa H, Sasaki H, Takei K, Suga M, Kasai K,
Aoki S, Ohtomo K. Sex dimorphism in gray/whitematter volume and diffusion tensor during normal
aging. NMR Biomed 23: 446-458, 2010.
(4) Brigman J, Wright T, Talani G, Prasad-Mulcare S,
Jinde S, Seabold G, Mathur P, Davis M, Bock R,
Gustin R, Colbran R, Alvarez V, Nakazawa K,
Delpire E, Lovinger DM, Holmes A. Loss of
GluN2B-containing NMDA receptors in CA1
hippocampus and cortex impairs long-term
depression, reduces dendritic spine density anddisrupts learning. J Neurosci 30: 4590-4600, 2010.
(5) Gonoi W, Abe O, Yamasue H, Yamada H, Masutani
Y, Takao H, Kasai K, Aoki S, Ohtomo K.
Age-related changes in regional brain volume
evaluated by atlas-based method. Neuroradiology
52: 865-73. 2010.
(6) Ikeda Y, Yahata N, Takahashi H, Koeda M, Asai H,
Okubo Y, Suzuki H. Auditory load-dependent
cerebral activation during the diotic listening task:

93

an fMRI study. Neurosci Res 67: 65-71, 2010.
(7) Inoue H, Yamasue H, Tochigi M, Abe O, Liu X,
Kawamura Y, Takei K, Suga M, Yamada H, Rogers
MA, Aoki S, Sasaki T, Kasai K. Association
between the oxytocin receptor gene (OXTR) andamygdalar volume in healthy adults. Biol
Psychiatry(8) Inoue H, Yamasue H, Tochigi M, Suga M, Iwayama
Y, Abe O, Yamada H, Rogers MA, Aoki S, Kato T,
Sasaki T, Yoshikawa T, Kasai K. Functional (GT)npolymorphismsin promoter region of N-methyl-Daspartate receptor 2A subunit (GRIN2A) gene affecthippocampal and amygdala volumes. Genes Brain
Behav 9: 269-75, 2010.
(9) Inoue H, Yamasue H, Tochigi M, Takei K, Suga M,
Abe O, Yamada H, Rogers MA, Aoki S, Sasaki T,
Kasai K. Effect of tryptophan hydroxylase-2 genevariants on amygdalar and hippocampal volumes.
Brain Res 1331: 51-57, 2010.
(10) Kano Y, Kono T, Shishikura K, Konno C, Kuwabara
H, Ohta M, do Rosario MC. Obsessive Compulsive
Symptom Dimensions in Japanese TouretteSyndrome subjects. CNS Spectr 15: 296-303, 2010.
(11) Kano Y, Ohta M, Nagai Y, Scahill L. Association
between Tourette syndrome and comorbidities inJapan. Brain Dev 32: 201-207, 2010.
(12) Kawamura Y, Akiyama T, Shimada T, Minato T,
Umekage T, Noda Y, Ukawa K, Hashidume C,
Sakai Y, Otowa T, Sasaki T, Akiskal HS. Six-year
stability of affective temperaments as measured by
TEMPS-A. Psychopathology 43: 240-247, 2010(13) Kawamura Y, Liu X, Akiyama T, Shimada T, Otowa
T, Sasaki T, Kakiuchi C, Umekage T, Sasaki T,
Akiskal HS. Association between oxytocin receptor
gene (OXTR) polymorphisms and affective
temperaments as measured by TEMPS-A. J Affect
Disord in press.
(14) Kubota M, Kasahara T, Iwamoto K, Komori A,
Miyauchi T, Ishiwata M, Kato T. Therapeutic
implications of down-regulation of cyclophilin D in
bipolar disorder. Int J Neuropsychopharmacol 13:
1355-1368, 2010.
(15) Liu X, Kawamura Y, Shimada T, Otowa T, Koishi S,
Sugiyama T, Nishida H, Hashimoto O, Nakagami R,
Tochigi M, Umekage T, Kano Y, Miyagawa T, Kato
N, Tokunaga K, Sasaki T. Association of theoxytocin receptor (OXTR) gene polymorphism with

autism spectrum disorder (ASD) in the Japanese
population. J Hum Genet 55, 137-141, 2010.
(16) Nakamura K, Enomoto H, Hnajima R, Shimizu E,
Kawamura Y, Sasaki T, Hamada M, Matsuzawa D,
Sutoh C, Shirota S, Terao Y, Ugawa Y. Quadri-pulse
stimulation (QPS) induced LTP/LTD was notaffected by Val66Met polymorphism in thebrain-derived neurotrophic factor (BDNF) gene.
Neurosci Res 2011.
(17) Nishimura Y, Takizawa R, Muroi M, Marumo K,
Kinou M, Kasai K. Prefrontal cortex activity during
response inhibition associated with excitement
symptoms in schizophrenia. Brain Res 2011(18) Munesue T, Yokoyama S, Nakamura K, Anitha A,
Yamada K, Hayashi K, Asaka T, Liu HX, Jin D,
Koizumi K, Islam MS, Huang JJ, Ma WJ, Kim UH,
Kim SJ, Park K, Kim D, Kikuchi M, Ono Y,
Nakatani H, Suda S, Miyachi T, Hirai H, Salmina A,
Pichugina YA, Soumarokov AA, Takei N, Mori N,
Tsujii M, Sugiyama T, Yagi K, Yamagishi M,
Sasaki T, Yamasue H, Kato N, Hashimoto R,
Taniike M, Hayashi Y, Hamada J, Suzuki S, Ooi A,
Noda M, Kamiyama Y, Kido MA, Lopatina O,
Hashii M, Amina S, Malavasi F, Huang EJ, Zhang J,
Shimizu N, Yoshikawa T, Matsushima A, Minabe Y,
Higashida H. Two genetic variants of CD38 insubjects with autism spectrum disorder and controls.
Neurosci Res 67: 181-191, 2010.
(19) Okamoto N, Ogawa M, Murata Y, Sakamoto K,
Nagai T, Yamada M, Higuchi T. Major depressive
disorder complicated with spinocerebellar ataxia:
report of 2 cases. Case Rep Neurol 2: 52-56, 2010(20) Otowa T, Minato T, Sugaya N, Yasuda S, Inoue K,
Shimada T, Kawamura Y, Tochigi M, Umekage T,
Tanii H, Miyagawa T, Nishida N, Tokunaga K,
Okazaki Y, Kaiya H Sasaki T. Replication of agenome-wide association study of panic disorder ina Japanese population. J Hum Genet 55: 91-96,
2010.
(21) Sasayama D, Hayashida A, Yamasue H, Harada Y,
Kaneko T, Kasai K, Washizuka S, Amano N.
Neuroanatomical correlates of attention deficit
hyperactivity disorder accounting for comorbid
oppositional defiant disorder and conduct disorder.
Psychiatry Clin Neurosci 64: 394-402, 2010.
(22) Suga M, Yamasue H, Abe O, Yamasaki S, Yamada
H, Inoue H, Takei K, Aoki S, Kasai K. Reduced

94

gray matter volume of Brodmann’s Area 45 is
associated with severe psychotic symptoms inpatients with schizophrenia. Eur Arch Psychiatry
Clin Neurosci 260: 465-73, 2010.
(23) Sugaya Y, Jinde S, Kato N, Maru E. Levetiracetam
inhibits kindling-induced synaptic potentiation in
the dentate gyrus of freely moving rats. Neurosci
Res 66: 228-231, 2010.
(24) Takahashi H, Kato M, Sassa T, Shibuya T, Koeda M,
Yahata N, Matsuura M, Asai K, Suhara T, Okubo Y.
Functional deficits in the extrastriate body area
during observation of sports-related actions in
schizophrenia. Schizophr Bull 36: 642-647, 2010.
(25) Takao H, Abe O, Yamasue H, Aoki S, Kasai K,
Ohtomo K. Cerebral asymmetry in patients withschizophrenia: a voxel-based morphometry (VBM)
and diffusion tensor imaging (DTI) study. Magn
Reson Imaging 31: 221-226, 2010.
(26) Takao H, Abe O, Yamasue H, Aoki S, Sasaki H,
Kasai K, Yoshioka N, Ohtomo K. Gray and whitematter asymmetries in healthy individuals aged
21-29 years: a voxel-based morphometry anddiffusion tensor imaging study. Human Brain Mapp
in press.
(27) Takayanagi Y, Takahashi T, Orikabe L, Masuda N,
Mozue Y, Nakamura K, Kawasaki Y, Itokawa M,
Sato Y, Yamasue H, Kasai K, Okazaki Y, Suzuki M.
Volume reduction and altered sulco-gyral pattern oftheorbitofrontal
cortexinfirst-episodeschizophrenia. Schizophr Res 121: 55-65, 2010.
(28) Yamasaki S, Yamasue H, Abe O, Suga M, Yamada
H, Inoue H, Kuwabara H, Kawakubo Y, Yahata N,
Aoki S, Kano Y, Kato N, Kasai K. Reduced graymatter volume of pars opercularis is associated with
impaired social communication in high-functioning
autism spectrum disorders. Biol Psychiatry 68(12):1141-7 2010

95

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96

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. This finding was
further confirmed by international collaboration. A
high throughput pipeline for linkage analysis wasestablished, which was applied for linkage analysis ofmany neurodegenerative diseases. Large-scale genome

analysis employing next generation sequencers were
initiated to identify causative genes for familial
neurologic
diseases.
We
haveinitiated
multicenter-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., Ishiura, H., Ihara, R.,
Hahimoto, A)
Development of pathomechanism-based therapy
for amyotrophic lateral sclerosis (ALS) is a mission ofneurologists. In motor neurons of sporadic ALS
patients, naturally occurring RNA editing of glutamate
receptor subunit GluR2 is inefficient in a neuronalclass-selective and disease-specific manner. Because
RNA editing at the GluR2 Q/R site is specificallycatalyzed by ADAR2, we developed mice in which theADAR2 gene was conditionally targeted. By
analyzing these mice, we demonstrate that failure toedit the GluR2 Q/R site is the primary cause of deathof motor neurons. Based on these findings, we are
currently involved in the development of specifictherapy for ALS. (Kwak, S., Hideyama, T., Yamashita,T., Teramoto, S., Hachiga K., Kaneko, S., Chai, H.)
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 EOG. 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 started a project to treat patientswith movement disorders, intractable pain, epilepsy
and so on using that new treatment. (Terao, Y.,
Hanajima, R., Okabe, S., Matsumoto, H., Furubayashi,

97T., Higashihara, M., Shirota, Y, Ohminami, S.,
Tsutumi, R.)
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,
cancer 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., Tokimura, N., Nishizawa, M.).
Department of Molecular Neuroscience on
Neurodegenerationisfundedby
JanssenPharmaceuticals. Several projects are ongoing/ We
found new ubiquitin ligase UHRF-2 and new
ubiquitin-like modulator FAT10 related to thepathogenesis of polyglutamine diseases. Studies on
epigenetics of Parkinson’s disease revealed abnormal
epigenetic changes in the disease. We also reported anovel mutation of aceruloplasminemia (Iwata, A.,
Hyashi, H.).

Publication
1. Aizawa H, Sawada J, Hideyama T, Yamashita T,
Katayama T, Hasebe N, KimuraT, Yahara O,
Kwak S: TDP-43 pathology in sporadic ALS
occurs in motor neurons lacking RNA editing
enzyme ADAR2. Acta Neuropathol. 120：75-84，
2010.
2. 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. Gene.
153B:310-313, 2010.
3. Hida A, Kowa H, Iwata A, Tanaka M, Shimizu J,

Kwak S and Tsuji S. Aceruloplasminemia in a
Japanese woman with a novel mutation of CP
gene: Clinical presentations and analysis ofgenetic and molecular pathogenesis. J. Neurol.
Sci. 298: 136-139, 2010.
4. Hideyama T, Yamashita T, Suzuki T, Tsuji S,
Higuchi M, Seeburg PH, Takahashi R, Misawa H,
Kwak S: Induced loss of ADAR2 engenders slow
death of motor neurons from Q/R site-unedited
GluR2. J. Neurosci. 30:11917-11925, 2010.
5. Hideyama T, Yamashita Y, Nishimoto Y, Suzuki T,
Kwak S: Novel etiologic and therapeuticstrategies for neurodiseases: RNA editing enzyme
abnormality in sporadic amyotrophic lateralsclerosis. J. Pharmacol. Sci. 113：9-13,2010.
6. Higashihara M, Sonoo M, Imafuku I, Ugawa Y,
Tsuji S. Origin of ulnar Compound muscle action
potential investigated in patients with ulnar
neuropathy at the wrist. Muscle Nerve 41:704-706,
2010.
7. Higashihara M, Sonoo M, Tsuji S, and Ugawa Y.
Two-step technique to optimize the medial
antebrachial cutaneous nerve response. Clinical
Neurophysiol. 121: 712-713, 2010.
8. Katsuno M, Banno H, Suzuki K, Takeuchi Y,
Kawashima M, Yabe I, Sasaki H, Aoki M, Morita
M, Nakano I, Kanai K, Ito S, Ishikawa K,
Mizusawa H, Yamamoto T, Tsuji S, Hasegawa K,
Shimohata T, Nishizawa M, Miyajima H, Kanda F,
Watanabe Y, Nakashima K, Tsujino A, Yamashita
T, Uchino M, Fujimoto Y, Tanaka F, and Sobue G.
Effi cacy and safety of leuprorelin in patients withspinal and bulbar muscular atrophy (JASMITT
study): a multicentre, randomised, double-blind,placebo-controlled trial. Lancet Neurol. 9:875-984, 2010.
9. Koike A, Nishida N, Inoue I, Tsuji S, andTokunaga K. Replication of a genome-wide
association study of panic disorder in a Japanese
population. J. Hum. Genet. 55: 91-96, 2010.
10. Matsumoto H, Hanajima R, Terao Y, Hamada M,
Yugeta A, Shirota Y, Yuasa K, Sato F, Matsukawa
T, Takahashi Y, Goto J, Tsuji S, and Ugawa Y.
Efferent and afferent evoked potentials in patientswith adrenomyeloneuropathy. Clin. Neurol.
Neurosurg. 112: 131-136, 2010.
11. Matsumoto H, Hanajima R, Terao Y, Yugeta A,

98

Hamada M, Shirota Y, Ohminami S,
Nakatani-Enomoto S, Tsuji S, and Ugawa Y.
Prominent cauda equina involvement in patientswith chronic inflammatory demyelinating
polyradiculoneuropathy. J. Neurol. Sci. 290:112-114, 2010.
12. Matsumoto L, Hanajima R, Matsumoto H ,Ohminami S, Terao Y, Tsuji S, and Ugawa Y.
Supramaximal responses can be elicited in handmuscles by magnetic stimulation of the cervicalmotor roots. Brain Stimulation 3: 153-160, 2010.
13. Matsumoto L, Takuma H, Tamaoka A, Kurisaki H,
Date H, Tsuji S, and Iwata A. CpG Demethylation
Enhances Alpha-Synuclein Expression and
Affects the Pathogenesis of Parkinson's Disease.
PLOS One 5:e15522, 2010.
14. Mitsui J, Fukuda Y, Azuma K, Tozaki H, Ishiura H,
Takahashi Y, Goto J, and Tsuji S. Multiplexed
resequencing analysis to identify rare variants inpooled DNA with barcode indexing employing
next-generation
sequencer
Running
Title:
Multiplexed resequencing analysis of pooled
DNA. J. Hum. Genet. 55: 448-455, 2010.
15. Mitsui J, Takahashi Y, Goto J, Tomiyama H,
Ishikawa S, Yoshino H, Minami N, Smith DI,
Lesage S, Aburatani H, Nishino I, Brice I, Hattori
N, and Tsuji S. Mechanisms of genomic
instabilities underlying two common fragile
site-associated loci, PARK2 and DMD, in germ
cell and cancer cell lines. Am. J. Hum. Genet. 87:
75-89, 2010.
16. Nagashima Y, Suzuki T, Terada S, Tsuji T, andMisawa K. Improved signal extraction method forsingle-pulse heterodyne CARS spectroscopy.
SPIE Proceedings 7376: doi:10.1117/12.871162,
2010.
17. Sato K, Yabe I, Fukuda Y, Soma H, Nakahara Y,
Tsuji S, and Sasaki H. Mapping of autosomal
dominant cerebellar ataxia without the pathogenic
PPP2R2B
mutation
to
the
locus
for
spinocerebellar ataxia 12. Arch Neurol 67:
1257-1262, 2010.
18. Sato K, Aoki S, Iwata NK, Masutani Y, Watadani
T, Nakata Y, Yoshida M, Terao Y, Abe O, Ohtomo
K and Tsuji S. Diffusion tensor tract-specificanalysis 5 of the uncinate fasciculus in patientswith amyotrophic 6 lateral sclerosis. Neuroradiol.

52: 729-733, 2010.
19. Shimizu J, Hatanaka Y, Hasegawa M, Iwata A,
Sugimoto I, Date H, Goto J, Shimizu T, Takatsu
M, Sakurai Y, Nakase H, Uesaka Y, Hashida H,
Hashimoto K, Komiya T, and Tsuji S. IFN β-1b
May Severely Exacerbate Japanese Optico-Spinal
MS in Neuromyelitis Optica Spectrum. Neurol.
75:1423-1427, 2010.
20. Shirota Y, Iwata A, Ishiura H, Hashimoto M, Goto
J, Shimizu J, Hanajima R, Nakajima J, Takazawa
Y, and Tsuji S. A case of atypical amyloid
polyneuropathy with predominant upper-limb
involvement with the diagnosis unexpectedly
made by lung operation. Int. Med. 49:1627-1631,
2010.
21. Shirota Y, Hamada M, Hanajima R, Terao Y,
Matsumoto H, Ominami S, Tsuji S, and Ugawa Y.
Cerebellar
dysfunction
inprogressive
supranuclear palsy: a transcranial magnetic
stimulation study. Mov. Disord. 25: 2413-2419,
2010.
22. Tamaoka A., Arai M., Itokawa M., Arai T.,
Hasegawa M., Tsuchiya K., Takuma H., Tsuji H.,
Ishii A., Watanabe M., Takahashi Y., Goto J., Tsuji
S., Akiyama H. TDP-43 M337V mutation infamilial amyotrophic lateral sclerosis in Japan. Int.
Med. 49:331-334, 2010.
23. Tsuji S. Genetics of neurodegenerative diseases:
insights from high-throughput resequencing. Hum.
Mol. Genet. 19: R65-70, 2010. (doi:
10.1093/hmg/ddq162, 2010)
24. Yamada K, Miura K, Hara K, Suzuki M,
Nakanishi K, Kumagai T, Ishihara N, Yamada Y,
Kuwano R, Tsuji S and Wakamatsu N. A wide
spectrum of clinical and brain MRI findings inpatients with SLC19A3 mutations. BMC Med.
Genet.
11:171,2010.
(doi:
10.1186/1471-2350-11-171.)
25. Yoshida M, Takahashi Y, Koike A, Fukuda Y,
Goto J, and Tsuji S. A variation database foramyotrophic lateral sclerosis. Human Mutation
31:875-884, 2010.
26. Bomprezzi R, Powers JM, Shimizu J, Tsuji S,
Weinshenker BG, Wingerchuk DM. IFNβ-1b may
severely exacerbate Japanese opticspinal MS inneuromyelitis optica spectrum: Japanese opticspinal MS: Is it MS or neuromyelitis optica and99

does the answer dictate treatment? Neurol.
77:195-6, 2011.
27. Hanajima R, Terao Y, Nakatani-Enomoto S,
Okabe S, Shirota Y, Oominami S, Matsumoto H,
Tsuji S, and Ugawa Y. Triad stimulation frequency
for cortical facilitation in cortical myoclonus. Mov.
Disord. 26: 685-90, 2011.
28. Hanajima R, Terao Y, Nakatani-Enomoto S,
Okabe S, Furubayashi T, Shirota Y, Oominami S,
Matsumoto H, Tsuji S, and Ugawa Y. Intrinsic
rhythm of the primary motor cortex in cortical
myoclonus. Mov. Disord. (in press)
29. Higashihara M, Sonoo M, Yamamoto T,
Nagashima Y, Uesugi H, Terao Y, Ugawa Y,Stålberg E, Tsuji S. Evaluation of spinal andbulbar muscular atrophy by the Clustering Index
method. Muscle Nerve (in press)
30. Iida A, Takahashi A, Kubo M, Saito S, Hosono N,
Ohnishi Y, Kiyotani K, Mushiroda T, Nakajima M,
Ozaki K, Tanaka T, Tsunoda T, Oshima S, Sano M,
Kamei T, Tokuda T, Aoki M, Hasegawa K,
Mizoguchi K, Morita M, Takahashi Y, Katsuno M,
Atsuta N, Watanabe H, Tanaka F, Kaji R, Nakano
I, Kamatani N, Tsuji S, Sobue G, Nakamura Y,
Ikegawa S. A functional variant in ZNF512B is
associated with susceptibility to amyotrophic
lateral sclerosis in Japanese. Hum. Mol. Genet.
(in press)
31. Ishiura H, Fukuda Y, Mitsui J, Nakahara Y, Ahsan
B, Takahashi Y, Ichikawa Y, Goto J, Sakai T, Tsuji
S. Posterior column ataxia with retinitis
pigmentosa in a Japanese family with a novel
mutation in FLVCR1. Neurogenet. 12:117-21,
2011.
32. Kagoya R, Iwasaki S, Chihara Y, Ushio M,
Murofushi T, Tsuji S, and Yamasoba T. Cephalictetanus presenting as acute vertigo with bilateral
vestibulopathy. Acta Oto-Laryngologica 131:334-336, 2011.
33. Matsukawa T, Asheuer M, Takahashi Y, Goto J,
Suzuki Y, Shimozawa N, Takano H, Onodera O,
Nishizawa M, Aubourg P and Tsuji S.
Identification of novel SNPs of ABCD1, ABCD2,
ABCD3 and ABCD4 genes in patients with
X-linked adrenoleukodystrophy (ALD) based oncomprehensive resequencing and association
studies with ALD phenotypes. Neurogenet. 12:

41-50, 2011.
34. Matsukawa T, Wang X, Liu R, Onuki Y, Kubota A,
Hida A, Kowa H, Fukuda Y, Ishiura H, Mitsui J,
Takahashi Y, Aoki S, Takizawa T, Shimizu J, Goto
J, Proud CG and Tsuji S. Adult-onset
leukoencephalopathies with vanishing whitematter with novel missense mutations in EIF2B2,
EIF2B3, and EIF2B5. Neurogenet. (in press)
35. Nagashima Y, Suzuki T, Terada S, Tsuji S and
Misawa K. In-vivo molecular labeling of
halogenated volatile anesthetics via intrinsic
molecular vibrations using nonlinear Raman
spectroscopy. J. Chem. Physics 134: 024525,
2011.
36. Nagashima Y, Kowa H, Tsuji S, Iwata A. FAT10
binds to polyglutamine proteins and modulates
their solubility. J. Biol. Chem. (in press)
37. Pan W, Kwak S, Lu Y, Fang Z, Zhu X, Yamamoto
Y: Traditional Chinese medicine improvesnocturnal activity with nighttime in Parkinson's
disease. Sleep Med. 12:307-308，2011.
38. Saigoh K, Izumikawa T, Koike T, Shimizu J,
Kitagawa H, Kusunoki S. Chondroitin beta-1,
4-N-acetylgalactosaminyltransferase-1 missense
mutations are associated with neuropathies. J.
Hum. Genet. 56:143-6, 2011.
39. Seki N, Takahashi Y, Tomiyama H, Rogaeva E,
Murayama S, Mizuno Y, Hattori N, Marras C,
Lang AE, St George-Hyslop P, Goto J and STsuji
S. Comprehensive mutational analysis of LRRK2
reveals variants supporting association with
autosomal dominant Parkinson's disease. J. Hum.
Genet. (in press)
40. Shirota Y, Hanajima R, Hamada M, Terao Y,
Matsumoto H, Tsutsumi R, Ohminami S,
Furubayashi T, Ugawa Y. Inter-individual
variation in the efficient stimulation site formagnetic
brainstem
stimulation.
Clin
Neurophysiol. (in press)
41. Soga T, Sugimoto M, Honma M, Mori M, Igarashi
K, Kashikura K, Ikeda S, Hirayama A, Yamamoto
T, Yoshida H, Otsuka M, Tsuji S, Yatomi Y,
Sakuragawa T, Watanabe H, Nihei K, Saito T,
Kawata S, Suzuki H, Tomita M, and Suematsu M.
Serum Metabolomics Reveals-Glutamyl
Dipeptides as Biomarkers for Discrimination
among Different Forms of Liver Disease. J.

100

Hepatol. (in press)
42. Terao Y, Fukuda H, Yugeta A, Hikosaka O,
Nomura Y, Segawa M, Hanajima R, Tsuji S,
Ugawa Y. Initiation and inhibitory control ofsaccades with the progression of Parkinson's
disease - changes in three major drives converging
on the superior colliculus. Neuropsychologia.
49:1794-806, 2011.
43. Yokoseki A, Ishihara T, Koyama A, Shiga A,
Yamada M, Suzuki C, Sekijima Y, Maruta K,
Tsuchiya M, Date H, Sato T, Tada M, Ikeuchi T,
Tsuji S, Nishizawa M and Onodera O.
Genotype-phenotype correlations in early onset
ataxia with ocular motor apraxia andhypoalbuminaemia. Brain 134:1387-99, 2011.
44. Yoshikado T, Takada T, Yamamoto T, Yamaji H,
Ito K, Santa T, Yokota H, Yatomi Y, Yoshida H,
Goto
J,
Tsuji
S
and
SuzukiH.
Itraconazole-induced cholestasis: involvement of
the inhibition of bile canalicular phospholipid
translocator MDR3/ABCB4. Mol. Pharmacol. 79:
241-250, 2011.

101

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

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

Lecturer
Hirofumi Nakatomi, M.D., Ph.D.,

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

Hideaki Imai, M.D., Ph.D.,

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

Associate
Kazuhiko Ishii, M.D.,

Masaaki Shojima, M.D., Ph.D.,

Akihiro Ito, M.D., Ph.D.,

Kuniaki Saito, M.D.,

Tomoyuki Koga, M.D.,

Taichi Kin, M.D., Ph.D.,

Hajime 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 13 staff neurosurgeons,
who participate in the three major academic activities:
patient care, research and education. The staffs
include a professor/chairman, an associate professor,
four lecturers and seven 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, endovascularintervention, epilepsy, and gamma knife treatment.
From April 2010 to March 2011, 15,572 patients weretreated at the outpatient clinics.
The Neurosurgery Ward has about 40 beds on theseventh floor of the new hospital building opened in
Sept. 2001. In 2009 and 2010, 771 and 874 patientswere admitted to the Neurosurgical Ward, respectively.
Three hundred and ninety one and 426 surgicalprocedures were performed with 134 and 150 gamma
knife precedures in each year. Our practice covers awide variety of neurosurgical diseases including
malignant and benign brain tumors, hemorrhagic andocclusive cerebrovascular diseases, spinal disorders,
epilepsy, pain and movement disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional
mapping in epilepsy surgery are frequently used to102preserve brain function as much as possible.
State-of-the-art techniques including intraoperative
computer-aided
navigation
andintravascular
procedures help our continuous effort to increase thesafety of surgical treatment.
Our department is affiliated with 27 neurosurgicalinstitutions in and around the city of Tokyo including
5 university medical centers, where our residents andstudents are exposed to various clinical experiences.
Surgical case volume in all hospitals exceeds
9100cases.

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

Teaching activities

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.

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 2010 as a neurosurgicalresidency program. These residents are trained in theuniversity hospital and affiliated hospitals toexperience every aspects of neurosurgical practice forfive years in average. Our residency training is
finalized after the sixth year, when the finishingresidents serve as senior resident 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 meeting of Japan Neurosurgical Society.
After the residents finish their training, or during
training, they can choose to be admitted into the Ph.D.
course at the graduate school of Medicine, Universityof Tokyo, to be involved in advanced basic research
activities for 4 year. After complete training, our
graduates stay in the department to be an associate in
our or other university hospitals or become clinicalstaff in our affiliated hospitals.

Research activities

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 are currently
conducting a clinical trial on patients with progressive
glioblastoma. We are also conducting clinical research
for immunotherapy with human umbilical vein
endothelial cell (HUVEC) as a vaccine.To develop
novel strategy for the treatment of malignant gliomas,
we have isolated brain tumor initiating cells (BTICs),
which are supposed to be responsible for resistance toconventional therapy, from surgical specimens, andwe are studying specific targeting therapy against
BTICs.
We also practice optimized therapy based on the103

results of genetic analyses routinely performed ontumor specimens obtained from glioma patients.
3) Development and evaluation of functionpreserving and less invasive treatment of
intractable epilepsy
We have been promoting the research on
development, evaluation and standardization of thenovel treatment for intractable epilepsy. Since ourfacility was the first in Japan to provide vagus nerve
stimulation therapy, we evaluated its efficacy andsafety in epilepsy treatment. We are now establishinga new intraoperative monitoring method ofvagus-nerve evoked potential. Efficacy evaluation anddevelopment of surgical instruments were promoted
for novel function-preserving techniques, multiple
subpial transection and multiple hippocampal
transection. Basic and clinical research on gamma
knife treatment of epilepsy has been performed as well.
For the purpose of more precise localization of
epileptic foci and elucidation of epileptogenesis, weare now developing novel types of intracranial
eletrodes.
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 electrocorticography (ECoG) obtainedby intracranial electrodes implanted in epilepsy
patients. The latter is our markedly advantageous
feature that enables us to extract brain information
with much higher spatial resolution and SN ratio. We
aim to understand brain mechanisms as complicatednetwork systems and to improve the reliability of
non-invasive techniques. Since ECoG is a strong
candidate for a decoding source of brain-computerinterface (BCI), we are planning to expand theresearch on this field to clinical implementation of
BCI for communication and motor control incooperation with other brain research laboratories andengineering laboratories.

as one of treatment options for various intracranial
disorders such as brain tumors, vascular disorders andfunctional disorders. The first gamma knife in Japanwas introduced at our department and diverse clinicalresults have been published. Recently, less invasive
treatment has taking on an added significance in thefield of neurosurgery as well. Therefore, appropriate
combination of radical surgery and radiosurgery isnecessary to manage difficult-to-treat lesions such as
skull base tumors and deeply seated cerebral
arteriovenous malformations, and thus gamma knife
radiosurgery would play a more important role inneurosurgery. Further, technological progress has
refined treatment as an example of integration ofdiffusion tensor tractography which was firstly
attempted at our department. Such technologicalprogresses might contribute to better outcomes ofgamma knife radiosurgery in the future.
6) Clinical applications of the functional brain
imaging and operative simulation using threedimensional computer graphics for neurosurgery
Our department intensively utilizes various kinds offunctional and metabolic imaging modalities including
magnetoencephalography, functional MRI, anddiffusion 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. We could develop
virtual reality operative simulation using multi-modal
fusion three-dimensional computer graphics. Then, it
was possible to precisely examine surgical strategy.

References
1.

Fukuhara H, Homma Y, Todo T: Oncolytic virus
therapy for prostate cancer. Int J Urol 17: 20-30,
20105) Gamma knife radiosurgery
Gamma knife is a kind of devices for stereotactic
radiosurgery in which high doses of radiation aredelivered at one session and has been widely accepted2.

Inda MM, Bonavia R, Mukasa A, Narita Y, Sah DW,
Vandenberg S, Brennan C, Johns TG, Bachoo R,
Hadwiger P, Tan P, Depinho RA, Cavenee W,

104

3.

Furnari F: Tumor heterogeneity is an active process

Proc Natl Acad Sci USA 107: 2616-2621, 2010

maintained by a mutant EGFR-induced cytokine

11. Okuma Y, Hosomi Y, Takagi Y, Miyamoto S,

circuit in glioblastoma. Genes Dev 24: 1731-1745,

Shimokawa T, Iguchi M, Okamura T, Saito K,

2010

Shibuya M: K. Long-term survival following

Ino Y, Todo T: Clinical development of ametachronous intratumoral hemorrhage in an

third-generation oncolytic HSV-1 (G47∆) for

HIV-infected patient with lung cancer. Int J Clin

malignant glioma. Gene Therapy and Regulation 5:

Oncol 15: 515-518, 2010

101-111, 2010
4.

12. Ota T, Kamada K, Saito N: Repair of Cerebrospinal

Koga T, Shin M, Maruyama K, Terahara A, Saito

Fluid Leak via Petrous Bone Using Multilayer

N:Technique with Hydroxyapatite Paste. World

Long-term

Outcomesof

Stereotactic

Radiosurgery for Arteriovenous Malformations in
the Thalamus. Neurosurgery 67: 398-403, 20105.

13. Ota T, Kawai K, Kamada K, Kin T, Saito N:

Koga T, Shin M, Saito N: Role of gamma knife

Intraoperative monitoring of cortically recorded

radiosurgery in neurosurgery: past and future

visual response for posterior visual pathway. J

perspectives. Neurol Med Chir (Tokyo) 50: 737-748,

Neurosurg 112： 285-294, 2010

2010
6.

14. Sato I, Higuchi A, Yanagisawa T, Mukasa A, Ida K,

Koga T, Shin M, Saito N: Treatment with highSawamura Y, Sugiyama K, Saito N, Kumabe T,

marginal dose is mandatory to achieve long-term

Terasaki M, Nishikawa R, Ishida Y, Kamibeppu K:

controlandDevelopment of the Japanese version of thestereotactic

Pediatric Quality of Life InventoryTM Brain Tumor

of

skull

chondrosarcomas

base

by

chordomas

means

of

radiosurgery. J Neurooncol. 98: 233-238, 2010
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8.

Module. Health Qual Life Outcomes 8: 38, 2010

Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y,

15. Shin M, Faria Penholate M, Lefaucheur JP,

Imai H, Takeuchi T: Constitutive reactive oxygen

Gurruchaga JM, Brugieres P, Nguyen JP: Assessing

species generation from autophagosome/lysosome

accuracy of the MRI-CT fusion images to evaluate

in neuronal oxidative toxicity. J Biol Chem 285:

the electrode positions in subthalamic nucleus after

667-674, 2010

deep

Kunishima K, Shin M, Kunimatsu A, Aoki S,

1193-1202, 2010

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Neurosurgery

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Sasaki H, Koga T, Itoh D, Mori H, Abe O, Ohtomo

16. Shinoura N, Suzuki Y, Yamada R, Tabei Y,

K, Saito N: Contrast-enhanced magnetic resonanceTakahashi M, Yagi K: Combined movement ofcharacteristics of arteriovenous malformations after

multi-joint muscles activates a smaller area

gamma

of

compared to the sum of areas activated byhemorrhage.

respective single-joint muscles after restoration of

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post-angiographic

radiosurgery:obliteration

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Morita A, Kimura T, Shojima M, Sameshima T,

17. Shinoura N, Yoshida M, Yamada R, Tabei Y, Saito

Nishihara T: Unruptured intracranial aneurysms:

K, Suzuki Y, Yagi K: Combined damage to the rightcurrent perspectives on the origin and natural

hemispheric hand area in the primary motor andcourse, and quest for standards in the management

sensory area plays a critical role in motor

strategy, Neurol Med Chir (Tokyo) 50: 777-787,

hemineglect. Eur Neurol 63:17-23, 2010.

2010

18. Shinoura N, Suzuki Y, Tsukada M, Yoshida M,

10. Mukasa A, Wykosky J, Ligon KL, Chin L, Cavenee

Yamada R, Tabei Y, Saito K, Koizumi T, Yagi K:

WK, Furnari F: Mutant EGFR is required for

Deficits in the left inferior longitudinal fasciculus

maintenance of glioma growth in vivo, and its

results in impairments in object naming. Neurocase

ablation leads to escape from receptor dependence.

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19. Shinoura N, Suzuki Y, Yamada R, Tabei Y, Saito K,
Yagi K: Relationships between brain tumor andoptic tract or calcarine fissure are involved in visual
field deficits after surgery for brain tumor. Acta
Neurochir (Wien) 152: 637-42, 2010
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N,

KirinoT:

Symptomatic

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vertebral

hemangioma in a pregnant woman treated by one
stage combination surgery; posterior stabilization
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Neurol Med Chir (Tokyo) 50: 674-677, 2010
21. Shojima M, Nemoto S, Morita A, Oshima M,
Watanabe E, Saito N: Role of Shear Stress in the
BlisterFormationof

Cerebral

Aneurysms,

Neurosurgery 67: 1268-1275, 2010
22. Shojima M, Nemoto S, Morita A, Miyata T, Namba
K, Tanaka Y, Watanabe E: Protected endovascularrevascularization of subacute and chronic total
occlusion of the internal carotid artery, AJNR Am J
Neuroradiol 31: 481-486, 2010
23. Takai K, Taniguchi M, Takahashi H, Usui M, Saito
N:

Comparative

analysisofspinalhemangioblastomas in sporadic disease and vonHippel-Lindau

syndrome.

NeurolMed

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Hydrocephalus Associated with

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25. Usami K, Kamada K, Kunii N, Tsujihara H,
Yamada Y, Saito N: Transient asystole during
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26. Wykosky J, Mukasa A, Furnari F, Cavenee WK:
Escape from targeted inhibition: the dark side ofkinase inhibitor therapy. Cell Cycle 9: 1661-1662,
2010Social Medicine
1. Occupational, Environmental
and Preventive Medicine

107

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

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

Shinichi Hashimoto, Ph.D.

Research Associate
Satoshi Ueha, Ph. D.,

Jun Abe, Ph. D.,

Makoto Kurachi, 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 inour department, including research fellows, graduate
and undergraduate students, and guest researchers.

Teaching activities
The field of our department covers the wide area of
preventive medicine. The main scope of our 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.

108

References

K. Matsushima. A conceptual molecular network forchemotactic behaviors characterized by feedback of(1) Hodo, Y., S. Hashimoto, M. Honda, T. Yamashita, Y.

molecules cycling between the membrane and theSuzuki, S. Sugano, S. Kaneko, and K. Matsushima.

cytosol. Science signaling. 2010; 3(152): ra89.

Comprehensive gene expression analysis of 5'-end(8) Shono, Y., S. Ueha, Y. Wang, J. Abe, M. Kurachi, Y.

of mRNA identified novel intronic transcripts

Matsuno, T. Sugiyama, T. Nagasawa, M. Imamura,associated with hepatocellular carcinoma. Genomics.

and K. Matsushima. Bone marrow graft-versus-host

2010; 95(4): 217-23.

disease: early destruction of hematopoietic niche(2) Hoshino, A., T. Iimura, S. Ueha, S. Hanada, Y.

after MHC-mismatched hematopoietic stem cellMaruoka, M. Mayahara, K. Suzuki, T. Imai, M. Ito,transplantation. Blood. 2010; 115(26): 5401-11.

Y. Manome, M. Yasuhara, T. Kirino, A. Yamaguchi,(9) Toda, M., L. Wang, S. Ogura, M. Torii, M. Kurachi,

K. Matsushima, and K. Yamamoto. Deficiency of

K. Kakimi, H. Nishikawa, K. Matsushima, H. Shiku,

chemokine receptor CCR1 causes osteopenia due toK. Kuribayashi, and T. Kato. UV irradiation of

impaired functions of osteoclasts and osteoblasts.

immunized mice induces type 1 regulatory T cells

The Journal of biological chemistry. 2010; 285(37):that suppress tumor antigen specific cytotoxic T

28826-37.

lymphocyte responses. International journal of(3) Ikeuchi, N., J. Futami, A. Hosoi, S. Noji, M. Kurachi,
S. Ueha, S. Fujii, H. Yamada, K. Matsushima, F.
Moriyasu,

andK.

Kakimi.

cancer. 2010; Nov 15.
(10) Yamamoto, K., A. Utsunomiya, K. Tobinai, K.

EfficientTsukasaki, N. Uike, K. Uozumi, K. Yamaguchi, Y.

cross-presentation of soluble exogenous antigens

Yamada, S. Hanada, K. Tamura, S. Nakamura, H.

introduced into dendritic cells using a weak-based

Inagaki, K. Ohshima, H. Kiyoi, T. Ishida, K.

amphiphilic peptide. Biochemical and biophysicalMatsushima, S. Akinaga, M. Ogura, M. Tomonaga,

research communications. 2010; 392(2): 217-22.

and R. Ueda. Phase I study of KW-0761, a(4) Iwata, Y., K. Furuichi, K. Kitagawa, A. Hara, T.

defucosylated humanized anti-CCR4 antibody, inOkumura, S. Kokubo, K. Shimizu, N. Sakai, A.

relapsed patients with adult T-cell leukemia-

Sagara, Y. Kurokawa, S. Ueha, K. Matsushima, S.

lymphoma and peripheral T-cell lymphoma. Journal

Kaneko, and T. Wada. Involvement of CD11b+of clinical oncology : official journal of theGR-1 low cells in autoimmune disorder in MRL-Fas

American Society of Clinical Oncology. 2010;

lpr mouse. Clinical and experimental nephrology.

28(9): 1591-8.

2010; 14(5): 411-7.

(11) Yoshiura, C., Y. Kofuku, T. Ueda, Y. Mase, M.

(5) Komura, T., Y. Sakai, M. Honda, T. Takamura, K.

Yokogawa, M. Osawa, Y. Terashima, K. Matsushima,

Matsushima, and S. Kaneko. CD14+ monocytes are

and I. Shimada. NMR analyses of the interaction

vulnerable

under

between CCR5 and its ligand using functional

endoplasmic reticulum stress in patients with type 2

reconstitution of CCR5 in lipid bilayers. Journal of

diabetes. Diabetes. 2010; 59(3): 634-43.

the American Chemical Society. 2010; 132(19):andfunctionally

impaired(6) Mizukoshi, E., Y. Nakamoto, K. Arai, T. Yamashita,
N. Mukaida, K. Matsushima, O. Matsui, and S.
Kaneko. Enhancement of tumor-specific T-cell
responses by transcatheter arterial embolization withdendritic cell infusion for hepatocellular carcinoma.
International journal of cancer. Journal international
du cancer. 2010; 126(9): 2164-74.
(7) Otsuji, M., Y. Terashima, S. Ishihara, S. Kuroda, and

6768-77.

109

Department of Public Health/
Department of Health Policy
Professor
Yasuki Kobayashi, M.D., Ph.D.

Associate Professor
Takahiro Higashi, 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 variety
for public health issues, including health policy andeconomics,
occupational
medicine,clinicalepidemiology, health services research, and so on. In
addition, the staff members of the Department haveoffered public and occupational health services to thegovernments, industries, and local communities.
Currently, the Department consists of four faculty
members above listed, three supporting staffs, 11
graduate students (nine in PhD program and two in
MPH program), one research students, 15 part-time
lecturers, and 12 visiting fellows.

Teaching activities
1) Undergraduate Program (Medical School)
In the winter term of the fourth grade in the School

110

of Medicine (M2), students are provided with thefollowing lectures; current issues of public health,preventive services, epidemiology, health economics,
community health and medicine, occupational andenvironmental health, infection and tuberculosis
control, mental health, human ecology, international
health, current health policy and administration in
Japan, quality of care, 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 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 Integrated Health Sciences,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) 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 healthservices research, such as quality of care. Thesestudies have been published in international policy
journals.
We have continued a collaborative study on asystem of HIV/AIDS care with the introduction ofhighly active anti-retroviral therapy (HAART) in
Thailand, since such a system involves medical,
behavioral, social, and economic factors, and would
inevitably become an important health policy issue.
2) Occupational health
We have carried on a longitudinal study onlife-style, occupational stress, and health status ofworkers in various occupational settings for the
purpose of preventing occupational and life-stylediseases.
3) Collaboration with overseas institutions
We have done a couple of studies in collaboration
with overseas institutions, such as the study of factors
associated with diagnosis delays of tuberculosis in theeastern region of Afghanistan, and the study of
preventive behaviors among people living with HIV in
Khon Kane, Thailand.
4) Academic meeting
We held the Fifth Annual Conference of Japan
Health Economics Association at Tetsumon Memorial
Hall and seminar rooms, Graduate School of Medicine,

111

the University of Tokyo, on July 10, 2010.

9.

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Tomio J, Toyokawa S, Tanihara S, Inoue K,
Kobayashi Y: Quality of care for diabetes patientsusing National Health Insurance claims data inJapan. Journal of Evaluation in Clinical Practice
16 (6): 1164-1169, 2010.
Tomio J, Sato H, Mizumura H: Interruption of
medication among outpatients with chronic
conditions after a flood. Prehospital and Disaster
Medicine 25 (1): 42-50, 2010.
Yamamoto Y, Hayashino Y, Higashi T, Matsui M,
Yamazaki S, Takegami M, Miyachi Y, Fukuhara
S: Keeping vulnerable elderly patients free frompressure ulcer is associated with high caregiverburden in informal caregivers. Journal of
Evaluation in Clinical Practice 16 (3): 589-589,
2010.
Higashi T, Nakayama T, Fukuhara S, Yamanaka
H, Mimori T, Ryu J, Yonenobu K, Murata N,
Matsuno H, Ishikawa H, Ochi T: Opinions ofJapanese rheumatology physicians regarding
clinical practice guidelines. International Journal
for Quality in Health Care 22 (2): 78-85, 2010.
Inoue M, Toyokawa S, Inoue K, Suyama Y,
Miyano Y, Suzuki T, Miyoshi Y, Kobayashi Y:
Lifestyle, weight perception and change in bodymass index of Japanese workers: MY Health Up
Study. Public Health 124 (9): 530-537, 2010.
Kachi Y, Inoue K, Toyokawa S: Associations
between contractual status, part-time work, andintent to leave among professional caregivers forolder people: Results of a national cross-sectional
survey in Japan. International Journal of Nursing
Studies 47 (8): 1028-1036, 2010.
Nishi A, Tamiya N, Kashiwagi M, Takahashi H,
SatoM,
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Matsumoto M, Inoue K, Bowman R, Noguchi S,
Toyokawa S, Kajii E: Geographical distributionsof physicians in Japan and US: Impact ofhealthcare system on physician dispersal pattern.
Health Policy 96 (3): 255-261, 2010.
Matsumoto M, Inoue K, Bowman R, Noguchi S,
Kajii E: Physician scarcity is a predictor offurther scarcity in US, and a predictor ofconcentration in Japan. Health Policy 95 (2-3):
129-136, 2010.
Kachi Y: Latent structure of dieting amongfemale high-school students in Japan. Personality
and Individual Differences 48(1): 11-15, 2010.
Matsumoto M, Inoue K, Farmer J, Inada H, Kajii
E: Geographic distribution of primary care
physicians in Japan and Britain. Health & Place
16(1): 164-166, 2010.
Gunji T, Matsuhashi N, Sato H, Iijima K,
Fujibayashi K, Okumura M, Sasabe N, Urabe A:
Risk factors for serum alanine aminotransferase
elevation: a cross-sectional study of healthy adultmales in Tokyo, Japan. Digestive and Liver
Disease 42 (12): 882-887, 2010.
Miyaji K, Miyamoto T, Kohira S, Itatani K,
Tomoyasu T, Sato H, Ohara K: The effectivenessof prestorage leukocyte-reduced red blood celltransfusion on perioperative inflammatory
response with a miniaturized biocompatible
bypass system. Journal of Thoracic andCardiovascular Surgery 139 (6): 1561-1567,
2010.
Ohya TR, Endo H, Kawagoe K, Yanagawa T,
Hanawa K, Ohata K, Asayama M, Hisatomi K,
Teratani T, Gunji T, Sato H, Matsuhashi N: A
prospective randomized trial of lafutidine vsrabeprazole on post-ESD gastric ulcers. World
Journal of Gastrointestinal Endoscopy 2 (1):36-40, 2010.

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

113

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

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

Assistant Professor
Hisashi Nagai, M.D.

Homepage

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

Introduction and Organization
Associate Professor Kuniyoshi Katayama lectured“judicial medicine” in University of Tokyo since 1882
before our department was founded as the firstdepartment of forensic medicine in Japan in 1888. He
renamed “judicial medicine” to “forensic medicine” in1891 since the department should cover legislation as
well as general forensic practices. Dr. Katayama
became the first professor of forensic medicine inJapan.
The 2nd Professor Sadanori Mita also founded theserological department (Department of Immunology atpresent). He studied the antigen-antibody reaction anddiscovered complement fixation reaction.
The 3rd Professor Tanemoto Furuhata was very
famous for ABO blood group genetics, and also
contributed to the development of criminology. He
autopsied several cases of historical crimes.
The 4th Professor Shokichi Ueno discovered acomplex componet. 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
the mechanism of ischemic heart disease and sudden
cardiac death related to emotional stress, with respect
to gap junction, intracellular signaling, andproteolysis.
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.

Forensic autopsy
The determination of precise cause of death is themost important mission of our department. We
autopsy about 120 criminal cases in eastern part ofTokyo every year. We have already autopsied more

114

than 11,000 cases since 1897. Some of these cases arevery 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 1897. 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.
The 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.

Education
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.

Research
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.
1. Molecular mechanism of myocardial lesions andcell death in ischemia-reperfusion
We autopsy many cases suddenly died inassociation with accidents, violence, restraint, or
medical practices. Particularly, cardiac lesion andarrhythmias related to a brief ischemia andemotional stress respectivly are important inforensic practices. The diagnosis and demonstrationof scientific evidence are very difficult in thesecases. Contraction bans, often found in sudden
cardiac cases, are reproduced during reperfusion
following brief ischemia. We have found that
contraction bands propagates through Gap Junction(GJ), and derangement of sarcoplasmic (SR)calcium handling. Additionally, we found that
calpain (calcium-dependent protease) contributes tothe myocardial injury, contractile dysfunction anddevelopment of infarction in reperfusion. We study
the mechanism of these phenomena in the modelsof coronary occlusion, isolated perfused heart, or
cultured cardiomyocytes through circulatory
physiology, biochemistry,
histology, and molecular biology. The results will
warrantabetterunderstandingoftheaforementioned diseases, and potentially usefuldiagnostic methods for sudden death cases.
2. Research on arrhythmic death related to emotional
stress, diseases, or drugs.
GJ functions are disturbed in myocardial infarction
and heart failure. Restraint of these persons oftencauses sudden death. With pharmacological GJ
inhibition, restraint induces lethal ventriculartachycardia/fibrillation in rats. The restrain of the rat
is well-known model to investigate cardiovascularresponse to emotional stress. We also study themechanism of arrhythmogenesis in the model ofheart diseases and amphetamine treated animals.
3. Research on cardiovascular risk and sudden deathin sleep apnea syndrome（SAS）
This is the most challenging theme in the field ofcardiovascular research, but the production of agood animal model has been difficult. We have

115

successfully developed an apparatus for the rat
model of SAS, and have undertaken theinvestigation on the molecular mechanism of
cardiac hypertrophy, hypertension, and arrhythmias.
We have organized multi-facility research groups topromote the project, after the Ministry of Education,
Culture and Sport has accepted our proposal as theclass A grant.
4. Lesion propagation in rat model of brain contusion.
We study the mechanism underlying the
propagation of neural death through the corticallayer VI through GJ, activation of calpain andastrocyte.
5. Development of a kit for ethnic affiliation.
We are developing a novel practical method for
determination of the ethnic affiliation using single
nucleotide polymorphisms (SNPs).
6. Investigation on the law and social system related
to death investigation, medical safety, and lawsuit.
We found that the disclosure of the information andbereavement service related to medicolegal autopsy
are limited. Additionally, the information related to
medicolegal autopsy cannot be used for accident
prevention. Moreover, ethical problems are to beaddressed for the research or educational purpose.
The Department of Health, Welfare, Labor, andSports has promoted the model project on theinvestigation of medical practice-associated deaths(MPADs), and been trying to establish the newinvestigative system for MPADs. We havecontributed to the review of the model project, andsubmitted reports on review and recommendations.
With corroboration with the society of emergency
medicine, we have conducted a questionnaire study
on the usefulness of feedback of autopsy
information to the frontline of medical practices.
7. Development of new methods for forensic
examinations
Through the experience in forensic practices, wehave adopted or developed new methodology fortoxicological analyses. Additionally, we developed
new methods for forensic practices such as the
production of distribution map of planktons indifferent river and sea areas.
8. Case studies and forensic pathology.
We have reported rare cases related to clinicalmedicine or potentially therapeutic deaths, for the

training or education of graduate students or young
pathologists. Recently, we reported three cases as
the first autopsy case or new disease modality.

Publications
1.

2.

3.

4.

5.

6.

7.

8.

Shintani-Ishida K, Harada K, Nakajima M,
Yoshida K. Usefulness of blood vessels as a DNA
source for PCR-based genotyping based on twocases of corpse dismemberment. Leg Med. 2010;
12(1):8-12.
Ito T, Nobutomo K, Fujimiya T, Yoshida K.
Importance of explanation before and after
forensic autopsy to the bereaved family: lessons
from a questionnaire study. Journal of Medical
Ethics. 2010;36(2):103-5.
Unuma K, Shintani-Ishida K, Yahagi N,
Tsushima K, Shimosawa T, Ueyama T, Yoshida K.
Restraintstressinducesconnexin-43
translocation via α-adrenoceptors in rat heart.
Circ J. 2010;74(12):2693-701.
Unuma K, Harada K, Nakajima M, Ito T, Okutsu
K, Yoshida K. Unexpected death of a patient withrheumatoid arthritis complicated by a cervicaldeformity. Leg Med. 2010;12(5):242-5.
Unuma K, Harada K, Nakajima M, Eguchi H,
Tsushima K, Ito T, Shintani-Ishida K, Kojima H,
Yoshida K. Autopsy report on central pontine
myelinolysis triggered by vomiting associatedwith digoxin intoxication. Forensic Sci Int.
2010;194(1-3):e5-8.
Unuma K, Shintani-Ishida K, Tsushima K,
Shimosawa T, Ueyama T, Kuwahara M, Yoshida
K. Connexin-43 redistribution and gap junction
activation during forced restraint protects against
sudden arrhythmic death in rats. Circ J.
2010;74(6):1087-95.
Tojo A, Unuma K, Harada K, Yoshida K, Fujita T.
Localization and mechanism of nephrocalcinosis
in pseudo-Bartter's syndrome. Kidney Int. 2010;
77(9):831.
Kondo-Nakamura M, Shintani-Ishida K, Uemura
K, Yoshida K. Brief exposure to carbon
monoxide preconditions cardiomyogenic cells
against apoptosis in ischemia-reperfusion.
Biochem Biophys Res Commun. 2010;393(3):449-54.

116

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 dedicated 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, Assoc.
Prof. H. Yasunaga from the Department of HealthManagement and Policy, Assoc. Prof. H. Fujita fromthe Department of Ubiquitous Health Informatics,
Assoc. Prof. R. Yamamoto from Interfaculty Initiativein 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
was established in present division of social medicine

117

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 activities1). 4-year Ph.D. Course in the Department ofMedical Informatics and Economics at the Division ofSocial Medicine: The Department of Medical
Informatics and Economics at the Division of Social
Medicine offers the Medical Sciences doctoral course(4-year program) and admission is open to those who
graduate from a 6-year program at the Faculty of
Medicine (the School of Medicine), and those whocomplete the master course either in the University ofTokyo or any other institutions (not necessary to be adoctor). Students will acquire Doctoral Degree (Ph.D.)of Medical Science with completion of required units
and passing a doctoral thesis.
2). 3-year Ph.D. Course and 2-year M.H.S course in
the Department of Health Informatics at the Divisionof Health Sciences and Nursing: The Department ofMedical Informatics and Economics is a collaborating
department with the Division of Health Sciences andNursing at the Graduate School of Medicine, and it iscalled the Department of Health Medical Informatics.
At the Department of Health Medical Informatics
within the Division of Health Sciences and Nursing,the department offers the Master course in Health
Science and Nursing (2-year program) and the Health
Sciences and Nursing doctoral course (3-year
program). In the master course, students will acquire
Master of Health Sciences with completion ofrequired units and passing a master’s thesis. In the

doctoral course, students will acquire Doctor of
Health Sciences(Ph.D.) with completion of required
units and passing a doctoral thesis.
3). 2-year M.P.H and 1-year M.P.H in the
Department of Health Informatics in the Shool of
Public Health: We offer 2-year Master of Publics
Health (M.P.H) course and the 1-year M.P.H programin the School of Publics Health. See the homepage of
the Shool of Publics Health.
4). 2-year M.M.S in the Department of Health
Medical Informatics in the Medical Science Graduate
Program: Graduate School of Medicine, theUniversity of Tokyo, offers the master course in
Medical Sciences. The course was established forstudents who graduate from faculties other than a
6-year program at Faculty of Medicine and eventuallywish to advance to the Medical Sciences doctoral
course of the University of Tokyo. It enables students
to enroll in the department they plan to carry out theirresearch for Doctor of Medical Science. (the entrance
examination required for enrollment in Medical
Sciences doctoral course) In this Master’s course, allstudents entering the course spend the first fourmonths taking formal coursework for students of alldivisions, and then will decide which department theywish to affiliate with. At the department students are
expected to conduct their research for the Master andcomplete a master’s thesis in the last one and an halfyear. They will acquire the Master’s degree (inMedical Sciences) with completion of required units
and passing a master’s thesis. Our department also
accepts students in this course.
The enrolled students in FY2010 are one in doctor’scourse for Medical Informatics and Economics, one inmaster’s course for Health Informatics.
The students’ researches cover various topics;
development of self medication management systemusing smart-phone devices, medical ontology, etc.

Research activities
The research domains are 1) application studies ondevelopments 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

118

of medical economics indicators by using databases of
hospital information system and electronic healthrecords system, 4) structured representations andstandardization of medical terms and concepts, 5) , 6)
privacy protection and security in healthcare
information systems, 6) information analysis on foodsafety, 7) analysis of various issues on DPC.
In these domains, major research topics are as listed
below.
1) A study on development methods for large scale
ontology databases of medical terms andconcepts :This research develops the methods to build thelarge scale medical ontology, which is a databasefor hundreds of thousand of clinical terms andconcepts and their relationships. It focuses on thedevelopment of basic methods for making andaccessing databases and will be applied for the
research.
2) Development of standardized IT infrastructure forclinical researches (Funding Program forWorld-Leading Innovative R&D on Science andTechnology: the FIRST program, 2010.3-2014.3)
This research develops autonomic, distributed,
real–time clinical support system. This project is apart of the FIRST program; ”Development ofMedical Technology for Treating Intractable
Cancers and Cardiovascular Diseases” supervised
by Professor Ryozo Nagai in the Department of
Cardiovascular Medicine.
3) A study on Natural Language Processing ofClinicalDocument(Industry-academia
collaboration project with Fuji Xerox Limited,
2007-2011). This research is on extracting
medical knowledge such as time-oriented clinicalevents and adverse drug reaction of patients fromelectrinic medical records.

References
1. Aramaki E, Miura Y, Tonoike M, Ohkuma T,
Masuichi H, Waki K, Ohe K. Extraction of adverse
drug effects from clinical records. Stud HealthTechnol Inform 2010;160(Pt 1):739-43.
2. Imai T, Kajino M, Sato M, Ohe K. Developmentof structured ICD-10 and its application tocomputer-assisted ICD coding. Stud HealthTechnol Inform 2010;160(Pt 2):1080-4.
3. Yamada E, Aramaki E, Imai T, Ohe K. Internal
structure of a disease name and its application for
ICD coding. Stud Health Technol Inform
2010;160(Pt 2):1010-4.
4. Soichi Koike, Hiroo Ide, Hideo Yasunaga, Tomoko
Kodama, Shinya Matsumoto, Tomoaki Imamura.
Postgraduate training and career choices: An
analysis of the Physicians Survey in Japan.
Medical Education2010 ;44:289-297
5. Soichi Koike, Tomoko Kodama, Shinya
Matsumoto, Hiroo Ide, Hideo Yasunaga andTomoaki . Retention rate of physicians in publichealth administration and their career path inJapan. BMC Health Service Research 2010,
10:101
6. Soichi Koike, Tomoko Kodama, Shinya
Matsumoto, Hiroo Ide, Hideo Yasunaga, Tomoaki
Imamura. Residency Hospital Type and Career
Paths in Japan: An Analysis of Physician
Registration Cohorts. Medical Teacher 2010；32:
e239-247
7. Soichi Koike, Shinya Matsumoto, Tomoko
Kodama, Hiroo Ide, Hideo Yasunaga, Tomoaki
Imamura. Specialty choice and physicians’ career
paths in Japan: An analysis of National Physician
Survey data from 1996 to 2006. Health Policy
2010; 98(2-3):236-244
8. Ide H, Koike S, Yasunaga H, Kodama T, Ohe K,
Imamura T. Long-term Career Transition in the
Surgical Workforce of Japan: A Retrospective
Cohort Study Using the Nationwide Survey ofPhysicians Data from 1972 to 2006. World Journalof Surgery 2010;34:1748-55.
9. Shinya Matsumoto, Yoshiyuki Kanagawa, Soichi
Koike, Manabu Akahane, Hiroshi Uchi, Satoko
Shibata, Masutaka Furue and Tomoaki Imamura:
Twenty-year changes of penta-chlorodibenzofuran(PeCDF) level and symptoms in Yusho patients,using association analysis: BMC Research Notes
2010, 3:129
10. Yasunaga H, Shi Y, Takeuchi M, Horiguchi H,
Hashimoto H, Matsuda S, Ohe K. Measles-related
hospitalizations and complications in Japan, 20072008. Intern Med 2010;49(18):1965-70. Epub2010 Sep 15.

Internal Medicine
1. Medicine Ⅰ

120

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.

Koichiro Kinugawa, M.D., Ph.D.

Hospital Lecturer
Atsushi Yao, M.D., Ph.D.

Homepage

Yukio Hiroi, M.D., Ph.D.

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

Introduction and Organization

Outline of department

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

Staff: one professor (Ryozo Nagai), 1 associate
professor (Yasunobu Hirata), 2 assistant professors(hospital ward Hiroshi Yamashita and outpatient clinic
Koichiro Kinugawa), 15 research associates, 5 staff
members, 38 graduate school students, and 2 members
studying abroad.

Clinical activities
In 2010, 1,611 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 2,144 patients, of which 635 cases wereinterventional procedures. CT coronary angiography
was examined in 360 patients and cardiovascular MRI
in 67. For arrhythmias, there were 94 cases of
implantation of a pacemaker, 73 cases of catheter
ablation, and other specialized pacemaker devices
such as 12 cases of implantation of a cardioverterdefibrillator, and 14 cases of implantation of a cardiac
resynchronization device.
As we are an authorized facility for heart121

transplantation, left ventricular assist device (LVAD)
use for severe heart failure cases has been increasing.
In 2006, the first case of heart failure from ourdepartment underwent a heart transplant procedure atthe Department of Cardiovascular Surgery. The hearts
were transplanted to 6 cases also in 2010 (total 15
cases). Duration of hospitalization is on average 12.6
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 and heart failure and arrhythmia
in addition to hypertension and peripheral arterydisease. Out-patient clinics are open both mornings
andafternoonsfrom
Mondayto
Friday.
Approximately 220 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, grand rounds
and clinical conferences.

5.
6.
7.
8.

Nitric oxide and endothelial function
Mechanisms for cardiorenal association
Regeneration therapy for cardiovascular disease
Genetic polymorphisms and risk factors in
cardiovascular disease
9. Optimization of individual treatment using theComputer Heart Simulator
10. Development of new integrated databases forclinical information and research
11. Investigation of disease pathophysiology anddevelopment of novel therapies (severe heart
failure, cardiac transplantation, congenital heartdisease)12. Anti-arrhythmia therapy using catheter ablation
13. Diagnosis and treatment of Marfan syndrome
14. New treatment for pulmonary hypertension
15. Ischemic heart disease in patients with diabetic
retinopathy
16. Aerobic threshold and cardiac rehabilitation
17. Imaging techniques (echocardiography, MRI, CT,
RI) in cardiovascular diseases

References
1)

2)

Research activities
Areas of interest are as follows:
1. Interplay between organs, cells, and molecules inchronic inflammation
2. Cardiac hypertrophy and heart failure: analyses ofpathogenic mechanisms and development of novel
therapies (gene therapy, etc.)
3. Transcriptional regulation of various genes
involved in cardiovascular development andpathogenesis
4. Differentiationofsmoothmusclecells(atherosclerosis and restenosis after vascularinterventions)

3)

4)

Fujita M, Sasayama S, Terasaki F, Mitani, S,
Morimoto T, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R. Treatment effects ofrenin-angiotensin system inhibitor and calcium
channel blocker in patients with coronary artery
narrowing (from the Japanese Coronary Artery
Disease Study). Heart Vessels: 2010;25:453-9.
Fukuda D, Enomoto S, Hirata Y, Nagai R, Sata
M. The angiotensin receptor blocker, telmisartan,
reduces and stabilizes atherosclerosis in ApoE
and AT1aR double deficient mice. Biomed
Pharmacother. 2010;64:712-7.
Fukuda T, Maegawa T, tsumoto A, omatsu
Y,Nakajima T, Nagai R, Kawahara T. Effects ofacute hypoxia at moderate altitude on strokevolume and cardiac output during exercise. Int
Heart J. 2010;51:170-5.
Hatano M, Yao A, Shiga T, Kinugawa K, Hirata Y,
Nagai R. Imatinib mesylate has the potential toexert its efficacy by down-regulating the plasma
concentration of platelet-derived growth factor inpatients with pulmonary arterial hypertension. Int
Heart J. 2010 ;51:272-6.

122

5)

Higashikuni Y, Sainz J, Nakamura K, Takaoka M,
Enomoto S, Iwata H, Sahara M, Tanaka K,
Koibuchi N, Ito S, Kusuhara H, Sugiyama Y,
Hirata Y, Nagai R, Sata, M. The ATP-binding
cassette transporter BCRP1/ABCG2 plays apivotal role in cardiac repair after myocardial
infarction via modulation of microvascularendothelial cell
survival
andfunction.
Arterioscler Thromb Vasc Biol. 2010;30:
2128-35.
6) Hirata Y, Nagata D, Suzuki E, Nishimatsu H,
Suzuki J, Nagai R. Diagnosis and treatment ofendothelial dysfunction in cardiovascular disease.
Int Heart J. 2010;51:1-6.
7) Hirata Y: Significance of B-type natriuretic
peptide measurement in patients with chronic
kidney disease. Circ J. 2010; 74: 632-3.
8) Horinaka S, Yabe A, Yagi H, Ishimitsu T,
Yamazaki T, Suzuki S, Kohro T, Nagai R.
Effects of Nicorandil on Cardiovascular Eventsin Patients With Coronary Artery Disease in The
Japanese Coronary Artery Disease (JCAD) Study.
Circ J. 2010;74:503-9.
9) Ishizaka N, Hongo M, Matsuzaki G, Furuta K,
Saito K, Sakurai R,Sakamoto A, Koike K, Nagai
R. Effects of the AT(1) receptor blocker losartan
and the calcium channel blocker benidipine on
the accumulation of lipids in the kidney of a rat
model of metabolic syndrome. Hypertens Res.
2010;33:263-8.
10) Ishizaka N, Ishizaka Y, Toda A, Tani M, Koike
K, Yamakado M, Nagai R. Changes in waist
circumference and body mass index in relation tochanges in serum uric acid in Japaneseindividuals. J Rheumatol. 2010;37:410-6.
11) Ishizaka N, Ishizaka Y, Toda A, Yamakado M,
Koike K, Nagai R. Association between
gamma-glutamyltransferase levels and insulin
resistance according to alcohol consumption andnumber of cigarettes smoked. J Atheroscler
Thromb. 2010;17:476-85.
12) Ishizaka N, Sakamoto A, Saito K, Nagai R. The
observation that risk increases according to thenumber of components does not necessarily
indicate that each component is a risk factor. J
Atheroscler Thromb. 2010;17:889-90.
13) Iwata H, Manabe I, Fujiu K, Yamamoto T,

Takeda N, Eguchi K, Furuya A, Kuro-o M, Sata
M, Nagai R. Bone marrow-derived cells
contribute to vascular inflammation but do notdifferentiate into smooth muscle cell lineages.
Circulation. 2010;122: 2048 -57.
14) Iwata H, Sata M, Ando J, Fujita H, Morita T,
Sawaki D, Takahashi M, Hirata Y, Takanashi S,
Tabata M, Hirata Y, Nagai R. Impact of primitive
cells in intracoronary thrombi on lesion
prognosis: temporal analysis of cellularconstituents of thrombotic material obtained frompatients with acute coronary syndrome. Heart.
2010;96: 748-55.
15) Kiyosue A, Hirata Y, Ando J, Fujita H, Morita T,
Takahashi M, Nagata D, Kohro T, Imai Y, Nagai
R. Relationship between renal dysfunction andseverity of coronary artery disease in Japanesepatients. Circ J. 2010 ;74:786-91.
16) Kiyosue A, Hirata Y, Ando J, Fujita H, Morita T,
Takahashi M, Nagata D, Kohro T, Imai Y, Nagai
R. Plasma cystatin C concentration reflects theseverity of coronary artery disease in patients
without chronic kidney disease. Circ J. 2010;74:
2441-7.
17) Kiyosue A, Hirata Y. Reply to the comments on“Relationship between renal dysfunction andseverity of coronary artery disease in japanesepatients”. Circ J. 2010;74:1764-5.
18) Kohro T, Fujita M, Sasayama S, Mitani S,
Yamazaki T, Hayashi D, Okada Y, Nagai R.
Prognostic effects of combined treatment withcalcium channel blockers and statins in patientswith coronary narrowing: from the JapaneseCoronary Artery Disease study. Int Heart J.
2010;51:299-302.
19) Kohro T, Hayashi D, Yamazaki T, Nagai R, The
JCAD Investigators. Beta-Bloker Prescription
Among Japanese Cardiologists and Its Effects on
Various Outcomes. Circ J. 2010; 74:962-9.
20) Morita H, Nagai R. MMP12, lung function, and
COPD in high-risk populations. N Engl J Med.
2010;362:1241.
21) Morita H, Nagai R, Seidman JG, Seidman CE.
Sarcomere gene mutations in hypertrophy andheart failure. J Cardiovasc Transl Res. 2010;3:
297-303.
22) Morita H, Nagai R. Retinopathy progression in

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type 2 diabetes. Retinopathy progression in type2 diabetes. N Engl J Med. 2010; 363: 2171;
author reply 2173-4.
23) Nagata D, Hirata Y: The role of AMP-activatedprotein kinase in the cardiovascular system.
Hypertens Res 2010;33:22-28.
24) Nakajima T, Kurano M, Hasegawa T, Takano H,
Iida H, Yasuda T, Fukuda T, Madarame H, Uno K,
Meguro K, Shiga T, Sagara M, Nagata T,
Maemura K, Hirata Y, Yamasoba T, Nagai R.
Pentraxin3 and hsCRP are independent
inflammatory markers released during highintensity exercise. Eur J Appl Physiol 2010;110:905-13.
25) Nishimura S, Nagasaki M. Adipose tissue
remodeling and chronic inflammation in obesity
visualized by in vivo molecular imaging method
Journal of Biorheology, 2010;24: 11-5.
26) Nishimura S, Takizawa H, Takayama N, Oda A,
Nishikii H, Morita Y, Kakinuma S, Yamazaki S,
Okamura S, Tamura N, Goto S, Sawaguchi A,
Manabe I, Takatsu K, Nakauchi H, Takaki S, Eto
K. Lnk/Sh2b3 regulates integrin alpha-IIb-beta3
outside-in signaling in platelets leading tostabilization of developing thrombus in vivo . J
Clin Invest., 2010;120:179-90.
27) Ogawa M, Suzuki J, Yamaguchi Y, Muto S, Itai A,
Hirata Y, Isobe M, Nagai R. The effects ofpharmacologicalplasminogenactivator
inhibitor-1 inhibition in acute and chronic
rejectioninmurinecardiacallografts.
Transplantation. 2010;91:21-26.
28) Oguri A, Tanaka T, Iida H, Meguro K, Takano H,
Oonuma H, Nishimura S, Morita T, Yamasoba T,
Nagai R, Nakajima T. Involvement of CaV3.1
T-type calcium channels on cell proliferation inmouse preadipocytes. Am J Physiol Cell Physiol
2010;298:C1414-23.
29) Ohno T, Kinoshita O, Fujita H, Kato S, Hirose A,
Sigeeda T, Otomo K, Ando J, Kadowaki T, Araie
M, Nagai R, Takamoto S. Detecting occult
coronary artery disease followed by earlycoronary artery bypass surgery in patients withdiabetic retinopathy: report from a diabetic
retinocoronary clinic. J Thorac Cardiovasc Surg.
2010; 139: 92-7.
30) Oishi Y, Manabe I, Imai Y, Hara K, HorikoshiM, Fujiu K, Tanaka T, Aizawa T, Kadowaki T,
Nagai R. Regulatory polymorphism intranscription factor KLF5 at the MEF2 element
alters the response to angiotensin II and isassociated with human hypertension. FASEB J.
2010;24:1780-8.
31) Sahara M, Sata M, Morita T, Nakajima T, Hirata
Y, Nagai R.A phosphodiesterase-5 inhibitor
vardenafil enhances angiogenesis through aprotein kinase G-dependent hypoxia-inducible
factor-1/vascular endothelial growth factor
pathway. Arterioscler Thromb Vasc Biol. 2010;
30:1315-24.
32) Sakamoto A, Ishizaka Y, Toda E, Nagai R, Koike
K, Yamakado M, Ishizaka N. Impact of changes
in obesity parameters on glucose metabolism andinsulin resistance over a one-year period. J
Atheroscler Thromb. 2010;17:1246-55.
33) Seki S, Kato N, Ito N, Kinugawa K, Ono M,
Motomura N, Yao A, Watanabe M, Imai Y,
Takeda N, Inoue M, Hatano M, Kazuma K.
Valitidy and reliability of Seattle Angina
Questionnaire Japanese version in patients withcoronary artery disease. Asian Nur Res. 2010;4:57-63.
34) Seo K, Inagaki M, Nishimura S, Hidaka I,
Sugimachi M, Hisada T, Sugiura S. Structural
heterogeneity in the ventricular wall plays asignificant role in the initiation of stretch-induced
arrhythmias in perfused rabbit right ventricular
tissues and whole heart preparations. Circ Res,
2010;106:176-84.
35) Shiga T, Kinugawa K, Hatano M, Yao A,
Nishimura T, Endo M, Kato N, Hirata Y, Kyo S,
Ono M, Nagai R. Age and preoperative total
bilirubin level can stratify prognosis after
extracorporeal pulsatile left ventricular assist
device implantation. Circ J. 2010;75:121-8.
36) Shimizu T, Ohno T, Ando J, Fujita H, Nagai R,
Motomura N, Ono M, Kyo S, Takamoto S.
Mid-term results and costs of coronary artery
bypass vs drug-eluting stents for unprotected left
main coronary artery disease. Circ J. 2010;74:
449-55.
37) Suzuki J, Isobe M, Morishita R, Nagai R.
Characteristics of chronic rejection in hearttransplantation:
importantelementsof

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pathogenesis and future treatments. Circ J. 2010;
74: 233-9.
38) Suzuki J, Ogawa M, Takayama K, Taniyama
Y,Morishita R, Hirata Y, Nagai R, Isobe M.
Ultrasound-microbubble- mediated intercellularadhesion molecule-1 small interfering ribonucleic
acid transfection attenuates neointimal formation
after arterial injury in mice. J Am Coll Cardiol.
2010;55:904-13.
39) Suzuki J, Aoyama N, Ogawa M, Hirata Y, Izumi
Y, Nagai R, Isobe M. Periodontitis andcardiovascular diseases. Expert Opin Ther Tar.
2010;14:1023-7.
40) Suzuki T, Distante A, Zizza A, Trimarchi S,
Villani M, Antonio J, Salerno Uriarte JA, deLuca Tupputi Schinosa L, Renzulli A, Sabino F,
Nowak R, Birkhahn R, Hollander J, Counselman
F, Vijayendran R, Bossone E, Eagle K. Response
to letter regarding article, “Diagnosis of acuteaortic dissection by D-dimer; the IRAD-Bioexperience”. Circulation. 2010;121: e24.
41) Suzuki T, Distante A, Eagle KA. Biomarkerassisted diagnosis of acute aortic dissection; how
far we have come and what to expect. Curr Opin
Cardiol. 2010;25:541-5.
42) Takahashi M, Suzuki E, Oba S, Nishimatsu H,
Kimura K, Nagano T, Nagai R, Hirata Y.
Adipose tissue-derived stem cells inhibit
neointimal formation in a paracrine fashion in rat
femoral artery. Am J Physiol Heart Circ Physiol.
2010; 298: H415-23.
43) Takaoka M, Suzuki H, Shioda S, Sekikawa K,
Saito Y, Nagai R, Sata M. Endovascular injury
induces rapid phenotypic changes in perivascularadipose tissue. Arterioscler Thromb Vasc Biol.
2010;30:1576-82.
44) Takeda N, Manabe I, Uchino Y, Eguchi K,
Matsumoto S, Nishimura S, Shindo T, Sano M,
Otsu K, Snider P, Conway SJ, Nagai R. Cardiac
fibroblasts are essential for the adaptive responseof the murine heart to pressure overload. J Clin
Invest. 2010;120:254-65.
45) Uchino Y, Watanabe M, Hirata Y, Shigematsu K,
Miyata T, Nagai R. Efficacy of renal
revascularization in a patient with fibromuscularrenal artery stenosis and heart failure. Int Heart J.
2010; 51: 432-5.

46) Yasuda T, Abe T, Brechue WF, Iida H, Takano H,
Meguro K, Kurano M, Fujita S, Nakajima T.
Venous blood gas and metabolite response to
low-intensity muscle contractions with externallimb compression. Metabolism. 2010;59:1510-9.
47) Zhan H, Suzuki T, Aizawa K, Miyagawa K,
Nagai R. Ataxia telangiectasia mutated(ATM)-mediated DNA damage response inoxidative stress-induced vascular endothelial cellsenescence. J Biol Chem. 2010; 285: 29662-70.

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

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

Associate
Masashi Desaki, M.D.,Ph.D., Shin Kawasaki, M.D.,Ph.D., Hitoshi Oonuma, M.D.,Ph.D.,
Yasuhiro Yamauchi, M.D.,Ph.D., Goh Tanaka M.D.,Ph.D., Taisuke Jo M.D.,Ph.D.,
Reiko Okudaira M.D.,Ph.D., Hidenori Kage, M.D.,Ph.D.

Homepage

http://kokyuki.umin.jp/

Introduction and Organization

Clinical Activities

The staff of the Department of Respiratory Medicine,
Graduate School of Medicine, University of Tokyo,
consists of 1 professor, 2 lecturers, and 8 associates. In
the University of Tokyo, affiliated hospitals andforeign institutions, approximately 50 members
belong to the Department. In the University of Tokyo
Hospital, about 20 respiratory physicians are doingclinical works.
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.

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
pneumonia, 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 severe
pneumonia and ARDS, we conduct ventilatory supportof such patients in collaboration with ICU staff. A
specialized clinical conference for respiratory diseasehas been held once a week since late 1990s, where
staff of our department, department of thoracic
surgery and department of radiology join and discuss
together to make best diagnostic and therapeutic
approach to individual patients. This conference isappreciated as prototype of Cancer Board of the
University of Tokyo Hospital, which launched four

126

years ago, and is now the most frequently held Cancer
Board in our hospital. 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.
Respiratory infections are now the 4th leading cause of
all death and COPD will be the 5th leading cause of alldeath in the near future. In respiratory diseases, there
are several disorders to which no effective therapeuticmodalities are currently available. For example, ARDS
is an acute lung injury and the mortality rate for ARDS
is extremely high despite of intensive care using
currently available tools.
Idiopathic pulmonary
fibrosis is a progressive and fatal inflammatory andfibrotic disorder of the lung parenchyma, while only a
few medications are currently available to treat thedisease. We would like to make every effort to develop
a novel and potential therapeutic approach to these
diseases.
Number of in-patients in 2010
1. Primary lung cancer
2. Respiratory infection
3. Interstitial pneumonia
4. COPD
5. Asthma

497
86
47
26
14

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. In this conference, radiologicaldiagnosis, indication of CT-guided biopsy andthoracoscopic biopsy, and treatment strategies not
only about thoracic malignancies but also about broad
spectrum of respiratory diseases are discussed, making
it possible to give best care to individual patients.

Teaching Activities
As for under-graduate education, our department takes
part in systematic lectures and specific learning for

diagnosis and treatment of respiratory diseases for the
4th year medical students, bedside 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 systematic 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 andpneumothorax, and try to discuss with the students
several important points for planning the diagnostic
evaluation and treatment in collaboration with theFaculty of the Department of Thoracic Surgery. Recent
major advance in the relevant fields are also reviewed.
During the period of bedside 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. The
respiratory specialists provide lecture on fundamental
chest radiology as one of essential elements in bedsidelearning and this lecture is highly appreciated by thestudents.
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 diseases such as medical treatment of lungcancer are also provided. Each student is expected tolearn and acquire the professionalism required for a
medical doctor during this period.
As for post-graduate education, respiratory physicians(one senior resident and one associate) assemble ateam with one junior resident, and provide medical
cares for patients with various respiratory diseases.
Under these processes, residents are able to acquire
the knowledge and skills required for diagnosis andtreatment of respiratory diseases. Seminars on
important themes such as medical treatment of lung

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cancer, chest imaging, pneumonia, COPD and so on
are held at regular interval.

References
1.

Research Activities
Our department is conducting basic and clinicalresearches for many respiratory disorders including
lung cancer, COPD, asthma, interstitial pneumonia,
respiratory infections and others. Epidemiological,
clinical, cellular and molecular biological techniques
are utilized for the elucidation of pathogenetic
mechanisms and for the development of novel
diagnostic and therapeutic modalities in respiratory
medicine. Postgraduate students as well as the Faculty
members make considerable studies about genetic
alterations in lung cancer in collaboration with theFaculty of the Department of Thoracic Surgery, cellbiological analysis using airway epithelial cells,
fibroblast and smooth muscle cells, analysis ofgenetically-engineered mice as disease-models and soon. These results have been presented and/or
published in the Scientific Meeting and/or peer-review
Journals. Our main research projects are as follows.

2.

3.

4.

5.
Molecular analysis of ion channels expressed on
airway smooth muscle cells and lung cancer cells.
Exploration of diseases-susceptibility genes in
respiratory diseases.
Analysis of disease-models using geneticallyengineered mice.
Analysis of DNA methylation and miRNA in lungcancer and its clinical application.
Elucidation of molecular mechanisms of diseases
using conditional vectors for siRNA knockdowns.
Analysis of functional alterations of airway epithelial
cells and fibloblasts in relation to tissue repair andremodeling in asthma and COPD.
Studies on pathogenesis of tobacco-smoke induced
respiratory diseases using mouse model of long-term
tobacco exposure.
Search for predictive factors for responses tochemotherapy in maligancy including lung cancer.
Takahide Nagase is GOLD National Leader; APSR,
Chair of Central Congress Committee; andProgram Officer, Research Center for Science
Systems, JSPS.

6.

7.

8.

9.

Goto Y, Hojo M, Takeda Y, Kobayashi N, Kudo
K. Gefitinib-induced interstitial lung diseaseaddition of intravenous cyclophosphamide tocorticosteroids is a valuable treatment option: A
case report. Med Oncol 2010;27:753-5.
Hassan M, Jo T, Risse PA, Tolloczko B, Lemière
C, Olivenstein R, Hamid Q, Martin JG. Airway
smooth muscle remodeling is a dynamic process
in severe long-standing asthma. J Allergy Clin
Immunol 2010;125:1037-1045.
Hirota N, Yasuda D, Hashidate T, Yamamoto T,
Yamaguchi S, Nagamune T, Nagase T, Shimizu T,
Nakamura M. Amino acid residues critical for
endoplasmic reticulum export and trafficking ofplatelet-activating factor receptor. J Biol Chem
2010;285:5931-5940.
Horie M, Noguchi S, Tanaka W, Yoshihara H,
Kawakami M, Suzuki M, Sakamoto Y, Oka T.
Primary malignant pericardial mesothelioma
mimickingpericardial
metastasis
fromadenocarcinoma. J Thorac Oncol 2010;5:2012-4.
Kage H, Sugimoto K, Sano A, Kitagawa H,
Nagase T, Ohishi N, Takai D. Suppression ofTgfβ1 in lung alveolar epithelium-derived cells
using adeno-associated virus type 2/5 vectors tocarry short hairpin RNA. Exp Lung Res 2011;37:175-85.
Kamio K, Liu XD, Sugiura H, Togo S, Kawasaki S,
Wang X, Ahn Y, Hogaboam C, Rennard SI. Statins
inhibit matrix metalloproteinase release fromhuman lung fibroblasts. Eur Respir J 2010;35:
637-46.
Kamitani S, Yamauchi Y, Kawasaki S, Takami K,
Takizawa H, Nagase T, Kohyama T.
Simultaneous Stimulation with TGF-β1 andTNF-α
Induces
Epithelial
Mesenchymal
Transition in Bronchial Epithelial Cells. Int Arch
Allergy Immunol 2010;155:119-128.
Kitagawa H, Watanabe K, Kage H, Inoh S, GotoA, Fukayama M, Ohishi N, Nagase T, Takai D.
Pulmonary venous invasion, determined by chest
CT scan, as a potential early indicator of
Zygomycosis infection: a case series. J Thorac
Imaging in press
Kohyama T, Yamauchi Y, Takizawa H, Kamitani S,

128

10.

11.

12.

13.

14.

15.

16.

Kawasaki S, Nagase T. Histamine stimulates humanlung fibroblast migration. Mol Cell Biochem
2010;33:77-81.
Kusakabe M, Kutomi T, Watanabe K, Emoto N,
Aki N, Kage H, Hamano E, Kitagawa H, Nagase
T, Sano A, Yoshida Y, Fukami T, Murakawa T,
Nakajima J, Takamoto S, Ota S, Fukayama M,
Yatomi Y, Ohishi N, Takai D. Identification of
G0S2 as a gene frequently methylated insquamous lung cancer by combination of in silico
and experimental approaches. Int J Cancer
2010;126:1895-902.
Li YJ, Takizawa H, Azuma A, Kohyama T,
Yamauchi Y, Takahashi S, Yamamoto M, Kawada
T, Kudoh S, Sugawara I. Nrf2 is closely related toallergic airway inflammatory responses induced
by low-dose diesel exhaust particles in mice. Clin
Immunol 2010;137:234-241.
Oguri A, Tanaka T, Iida H, Meguro K, Takano H,
Oonuma H, Nishimura S, Morita T, Yamasoba T,
Nagai R, Nakajima T. Involvement of CaV3.1
T-type calcium channels in cell proliferation inmouse preadipocytes. Am J Physiol Cell Physiol.
2010;298:C1414-23.
Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG,
Osterreicher CH, Takahashi H, Karin M. Dietaryand genetic obesity promote liver inflammation andtumorigenesis by enhancing IL-6 and TNF
expression. Cell 2010;140:197-208.
Risse PA, Jo T, Suarez F, Hirota N, Tolloczko B,
Ferraro P, Grutter P, Martin JG. Interleukin-13
inhibits proliferation and enhances contractilityof human airway smooth muscle cells withoutchange in contractile phenotype. Am J Physiol
Lung Cell Mol Physiol 2011;300:L958-66.
Shiraishi K, Kohno T, Tanai C, Goto Y, Kuchiba
A, Yamamoto S, Tsuta K, Nokihara H, Yamamoto
N, Sekine I, Ohe Y, Tamura T, Yokota J, Kunitoh
H. Association of DNA repair gene
polymorphisms with response to platinum-based
doublet chemotherapy in patients with non-smallcell lung cancer. J Clin Oncol 2010;28:4945-52.
Siddiqui S, Jo T, Tamaoka M, Shalaby KH,
Ghezzo H, Bernabeu M, Martin JG. Sites ofallergic airway smooth muscle remodeling andhyperresponsiveness are not associated in the rat.
J Appl Physiol. 2010;109:1170-8.

17. Simet SM, Sisson JH, Pavlik JA, Devasure JM,
Boyer C, Liu X, Kawasaki S, Sharp JG, Rennard SI,
Wyatt TA. Long-term Cigarette Smoke Exposure ina Mouse Model of Ciliated Epithelial Cell Function.
Am J Respir Cell Mol Biol. 2010;43:635–640.
18. Sunohara M, Kawakami M, Kage H, Watanabe K,
Emoto N, Nagase T, Ohishi N, Takai D.
Polymerase reaction without primers throughout
for the reconstruction of full-length cDNA fromproducts of rapid amplification of cDNA ends
(RACE). Biotechnol Lett in press
19. Takahashi H, Ogata H, Nishigaki R, Broide H,
Karin M. Tobacco smoke promotes lungtumorigenesis by triggering IKKbeta- andJNK1-dependent inflammation. Cancer Cell
2010;17:89-97.
20. Tanioka M, Nokihara Y, Yamamoto N, Yamada Y,
Yamada M, Goto Y, Fujimoto T, Sekiguchi R,
Uenaka K, Callies S, Tamura T. Phase I studyof LY2181308, an antisense oligonucleotide
against survivin, in patients with advanced solid
tumors. Cancer Chemother Pharmacol. 2010 Nov
16 (Epub ahead of print).
21. Togo S, Sugiura H, Nelson A, Kobayashi T,
Wang X, Kamio K, Kawasaki S, Bitterman P,
Rennard SI, Liu X. Hepatic growth factor(HGF) inhibits cigarette smoke extract induced
apoptosis in human bronchial epithelial cells. Exp
Cell Res 2010;316:3501-11.
22. Tsuchiya K, Jo T, Takeda N, Al Heialy S,
Siddiqui S, Shalaby KH, Risse PA, Maghni K,
Martin JG. EGF receptor activation during
allergic sensitization affects IL-6-induced T-cell
influx to airways in a rat model of asthma. Eur J
Immunol 2010;40:1590-602.
23. Watanabe K, Emoto N, Sunohara M, Kawakami
M, Kage H, Nagase T, Ohishi N, Takai
D.Treatment of PCR products with exonuclease I
and heat-labile alkaline phosphatase improves thevisibility of combined bisulfite restriction
analysis. Biochem Biophys Res Commun 2010;
399:422-4.
24. Watanabe K, Emoto N, Hamano E, Sunohara M,
Kawakami M,Kage H, Kitano K, Nakajima J,
Goto A, Fukayama M, Nagase T, Yatomi Y,
Ohishi N, Takai D. Genome structure-based
screening identified epigenetically silenced

129

microRNA associated with invasiveness in
non-small-cell lung cancer. Int J Cancer in press
25. Yamauchi Y, Kohyama T, Takizawa H, Kamitani S,
Desaki M, Takami K, Kawasaki S, Kato J, Nagase
T. Tumor necrosis factor-alpha enhances bothepithelial-mesenchymaltransition
andcellcontraction induced in A549 human alveolar
epithelial cells by transforming growth factor-beta1.
Exp Lung Res 2010;36:12-24.

130Department of Gastroenterology
Professor
Kazuhiko Koike, 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.

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

Yoshizumi Shintani, M.D., Ph.D.

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

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

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

Tadashi Goto, 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.

Hirotsugu Watabe, M.D., Ph.D.

Nobutake Yamamichi, M.D., Ph.D.

Natsuyo Yamamoto, M.D., Ph.D.

Yoshinari Asaoka , M.D., Ph.D.

Yuji Kondo, M.D., Ph.D.

Kazuyuki Hanajiri , M.D., Ph.D.

Shinya Kodashima, M.D., Ph.D.

Homepage

http://gastro.m.u-tokyo.ac.jp/med/home.html

Introduction and Organization
The Department of Gastroenterology wasestablished through a re-organization of the Graduate
School of Medicine and that of the Division ofInternal Medicine of The University of Tokyo
Hospital in 1998. The department is responsible forclinical services, education and research activities in
the field of liver, pancreato-biliary and digestive canal.
It is comprised of a professor, 3 lecturers, 20
associates, 15 fellows, 62 graduates and 5 othervisiting researchers including students from abroad(March, 2011). A number of others are under atemporary transfer in- and outside the country. The
North and South wings on the 11th floor of Ward A
have provided core hospital rooms for the department.

At present, forth, fifth and sixth floors of Ward B also
take important part for providing rooms for inpatients.
Laboratories of the department are scattered in eachfloor, mainly of Clinical Research Center and First
Research Building as in the other departments.

Clinical Activities
The Department of Gastroenterology is in chargeof about 96 inpatients on average, which are about
2,800 in total per year. We receive about 110 new
patients in and out of the hospital each week, with anaverage hospital stay of 12.3 days. Resident, juniorand senior staff members bear the responsibility for a
medical management of each inpatient, in
collaboration with subspecialty groups concerned. The

131

staff members examine about 5,700 outpatients withvarious 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(1063 cases in 2010). 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 (129 casesin 2010). In addition, we are making efforts to develop
an innovation for daily clinical activities. For example,
fibrosis progression in chronic liver disease isconventionally assessed by liver biopsy. Recently we
can evaluate the stage of liver fibrosis by Fibroscan®,newly developed equipment that measures liver
stiffness by ultrasound.
In the pancreato-biliary field, ERCP is performed
for more than 900 cases each year. The number ofpatients treated for choledocholithiasis withendoscopic papillary balloon dilation method exceeds
1,000, which is possibly the largest in the world.
Endoscpic metallic stenting is an effective palliative
care for malignant obstructive jaundice (60 patients ayear). Covered metallic stent placement has been
performed in a total of 700 cases, which may be theworld’s largest number. Pancreatic interventions suchas pancreatic stenting, cystic drainage, endoscopic
stone extraction and lithotripsy using ESWL
(extracorporeal shock-wave lithotripsy) are performed
for many challenging cases. Also we have applied the
EUS-guided techniques to various clinical treatments.
In the gastrointestinal field, ESD (endoscopic
submucosal dissection) is performed as a curativeendoscopic treatment for neoplasms in esophagus,
stomach or colon (200 patients a year). Endoscopic
variceal ligations for esophageal varices (80 patients ayear) are also frequently done. As a big breakthroughin this field, double-balloon endoscopy and capsuleendoscopy have been introduced recently, whichenabled the examination of whole small intestines. All
those interventions are performed by the members ofthe department, specially trained for each technique.

In addition, for the management strategy against
inoperative malignancies, we effectively combine theinterventional treatments with various chemotherapy
regimens using new molecular-targeting drugs.
On outpatient basis, ultrasonography is
performed on 15,000 patients, gastroduodenalendoscopy on 8,200, and colonoscopy on 3,800
patients each year, leading the detection of about 170
cases of gastric cancer and 210 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 bedside learning 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 in the style of oral examination. Students arealso required to summarize and outline articles fromworld’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 in a basic or clinical research area.
Currently, the department has 74 students who were
graduated from more than 30 medical schools inJapan.

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Research Activities
Both basic and clinical researchers are equallyencouraged, on condition that the results may
eventuallycontribute
to
the
cure
of
gastroenterological disorders. The themes of ourrecent basic researches include molecular elucidationof carcinogenesis in gastroenterological neoplasms,
metabolic aspects of viral hepatitis, mechanisms ofreplication of hepatitis viruses, mechanisms of liver
regeneration
andfibrosis,
pathogenesisofHelicobacter pylori infection, role of miRNA in
hepatocarcinogenesis, etc.
Various clinical activities are recorded indatabase and analyzed. Studies oriented forevidence-based medicine are highly appreciated.
Recent studies include radiofrequency ablation forliver metastasis of colorectal cancer, impact of
metabolic factors in hepatocarcinogenesis. We havealso designed clinical trials of molecular target drugs
for advanced hepatocellular carcinoma, erythropoietin
for anemia introduced by interferon with ribavirin
therapy, TS-1 alone or combined with gemcitabine,for pancreatic and bile duct cancers, gemcitabine
alone or combined with cisplatin, additional
mosapride in therapy of gastro-esophageal reflux
disease, and investigation and treatment trial of thesmall intestinal lesions in NSAID users by capsuleendoscopy.
The department is dedicated to pursuing bettermedical services from all facets of the subspecialty ofgastroenterology, which is brought about by bothbasic and clinical researches.

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Tomiya T. Sex difference in non-alcoholic fatty
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Y, Yagioka H, Kogure H, Sasaki T, Arizumi T,
Togawa O, Matsubara S, Nakai Y, Sasahira N,
Hirano K, Tada M, Kawabe T, Omata M, Koike
K. Endoscopic papillary balloon dilation for bile
duct stone removal in patients 60 years old or
younger. J Gastroenterol 2010;45:1072-9.
Tsukada K, Sugawara Y, Kaneko J, Tamura S,
Tachikawa N, Morisawa Y, Okugawa S, Kikuchi
Y, Oka S, Kimura S, Yatomi Y, Makuuchi M,
Kokudo N, Koike K. Living donor livertransplantations in HIV- and hepatitis C
virus-coinfected hemophiliacs: Experience in aSingle Center. Transplantation 2011;91(11):12611264.
Wakita T, Suzuki T, Evans MJ, Shimotohno K,
Chayama K, Matsuura Y, Hijikata M, Moriishi K,

137

71.

72.

73.

74.

Seya T, Enomoto N, Koike K, Kato N, Kanto T,
Hotta H. Will There Be an HCV Meeting in
2020? Summary of the 17th International
Meeting on Hepatitis C Virus and Related Viruses.
Gastroenterology 2011 Jul;141(1):e1-5.
Watanabe S, Enomoto N, Koike K, Izumi N,
Takikawa H, Hashimoto E, Moriyasu F, Kumada
H, Imawari M. Prolonged treatment with
pegylated interferon alpha 2b plus ribavirin
improves sustained virological response inchronic hepatitis C genotype 1 patients with late
response in a clinical real-life setting in Japan.
Hepatol Res 2010;40:135-44.
Yagioka H, Hirano K, Isayama H, Tsujino T,
Sasahira N, Nagano R, Hamada T, Miyabayashi
K, Ito Y, Mohri D, Kawakubo K, Kogure H,
Sasaki T, Tada M, Koike K. Clinical significanceof bile cytology via an endoscopic nasobiliary
drainage tube for pathological diagnosis ofmalignant biliary strictures. J Hepatobiliary
Pancreat Sci 2011 Mar;18(2):211-5. Epub 2010.
Yamashiki N, Sugawara Y, Tamura S, Tateishi R,
Yoshida H, Kaneko J, Matsui Y, Togashi J,
Akahane M, Makuuchi M, Omata M, Kokudo N.
Postoperative surveillance with monthly serum
tumor markers after living-donor livertransplantation for hepatocellular carcinoma.
Hepatol Res 2010;40:278-86.
Yashima Y, Tsujino T, Masuzaki R, Nakai Y,
Hirano K, Tateishi R, Sasahira N, Isayama H,
Tada M, Yoshida H, Kawabe T, Omata M.
Increased liver elasticity in patients with biliary
obstruction. J Gastroenterol 2011;46:86-91.

Internal Medicine
2. Medicine Ⅱ139

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.,

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

Masashi Isshiki, 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.,

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

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

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

Hideomi Yamada, M.D., Ph.D.,

Takehiko Wada, M.D., Ph.D.,

Manabu Taguchi, M.D., Ph.D.,

Takamoto Ohse, M.D., Ph.D.

Visiting Associate, Project Associate
Kent Doi, M.D., Ph.D.,

Takeshi Marumo, M.D., Ph.D.,

Osamu Takase, 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

140

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.

141

Department of Clinical &Molecular Epidemiology

Department of Molecular
Vascular Endocrinology

Homepage
http://www.h.u-tokyo.ac.jp/research/center22/contribute/rinsyo_bunshi.
html

Homepage
http://plaza.umin.ac.jp/~kid-endo/0
7-lab/17-issikilab/issikilabtop.html

Introduction and Organization
The Department of Clinical & Molecular
Epidemiology was established in June 2004 as anendowed department (Mitsubishi Tanabe Pharma Co.,
Ltd.) of the Graduate School of Medicine, theUniversity of Tokyo. Our department also belongs to
the 22nd Century Medical Research 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
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 diagnostic 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.

Introduction and Organization
Department of Molecular Vascular Endocrinology was
founded in June 2009 as an endowed department(Novartis Pharmaceutical Co., Ltd.) of the Graduate
School of Medicine, the University of Tokyo. The
main object of this department is to investigate
molecular mechanisms and pathophysiology ofvascular dysfunction caused by risk factors such as
hypertension or atherosclerosis. Final goal of ourresearch is to contribute to the prevention and therapyof cardiovascular disease.

Research activities
Our current research interests are as follows: Imaging and discovery of a novel regulatory
system of endothelial function in view of
intracellular signaling molecules such as Ca2+ orcAMP.
 Investigation of novel and known substances suchas H2S that can affect vascular function andanalysis of the mechanisms.
 Exploration of novel diagnostic markers andtherapeutic tools for endothelial and cardiovascular
dysfunction.

Publications(1) Tanaka M, Seki G, Ishizawa K, Hirahashi J,
Miura K, Sekine T, Someya T, Hataya H, Nagata
M, Fujita T. Resolution of Henoch-Schönlein
purpura nephritis after acquired IgA deficiency.
Pediatr Nephrol 2010;25:2355-2358.
(2) Suzuki M, Paesschen WV, Stalmans I, Horita S,
Yamada H, Bergmans BA, Legius E, Riant F,
Jonghe PD, Li Y, Sekine T, Igarashi T, Fujimoto I,
Mikoshiba M, Shimadzu M, Shiohara M,
Braverman N, Al-Gazali L, Fujita Y, Seki G.
Defective membrane expression of the

142

Na+-HCO3− cotransporter NBCe1 is associatedwith familial migraine. Proc Natl Acad Sci USA
2010;107:15963-15968.
(3) Jutabha P, Anzai N, Kitamura K, Taniguchi A,
Kaneko S, Yan K, Yamada H, Shimada H,
Kimura T, Katada T, Fukutomi T, Tomita K,
Urano W, Yamanaka H, Seki G, Fujita T,
Moriyama Y, Yamada A, Uchida S, Michael F.
Wempe MF, Endou H, Sakurai H. Human
sodium-phosphate transporter 4 (hNPT4/SLC17A3)
as a common renal secretory pathway for drugs
and urate. J Biol Chem 2010;285:35123-35132.
(4) Hanafusa N, Aozasa N, Fujita T. A patient whose
factor XIII level was decreased by double filtrateplasmapheresis and successfully recovered byinfusion of factor XIII concentrate. Ther Apher
Dial 2010;14:432-433.
(5) Hanafusa N, Satonaka H, Doi K, Noiri E, Fujita
T. Virus removal and eradication by modified
double filtration plasmapheresis decreases factor
XIII levels. Ther Apher Dial 2010;14:287-291.
(6) Hanafusa N, Satonaka H, Doi K, Yatomi Y, Noiri
E, Fujita T. Platelet-derived microparticles are
removed by a membrane plasma separator.
ASAIO J 2010;56:323-325.
(7) Tojo A, Unuma K, Harada K, Yoshida K, Fujita T.
Localization and mechanism of nephrocalcinosis
in pseudo-Bartter’s syndrome. Kidney Int 2010;
77:831.
(8) Tojo A. Optical coherence tomography in thekidney: A step toward echo microscopy. J Urol
2010;183:1669-1670.
(9) Kinugasa S, Tojo A, Sakai T, Fujita T.
Silver-enhanced immunogold scanning electron
microscopy using vibratome sections of rat
kidney: detection of albumin filtration andreabsorption. Med Mol Morphol 2010;43:
218-225.
(10) Oba S, Kumano S, Suzuki E, Nishimatsu H,
Takahashi M, Takamori H, Kasuya M, Ogawa Y,
Sato K, Kimura K, Homma Y, Hirata Y, Fujita T.
miR-200b precursor can ameliorate renal
tubulointerstitial fibrosis. PLoS One 2010;5:e13614.
(11) Ando K, Matsui H, Fujita M, Fujita T. Protective
effect of dietary potassium against cardiovasculardamage in salt-sensitive hypertension: Possible

role of its antioxidant action. Curr Vasc
Pharmacol 2010;8:59-63.
(12) Ando K, Ohtsu H, Arakawa Y, Kubota K,
Yamaguchi T, Nagase M, Yamada A, Fujita T.
Rationale and design of the Eplerenone
combination Versus conventional Agents to
Lower
blood
pressureon
Urinary
Antialbuminuric Treatment Effect (EVALUATE)
trial: A double-blinded randomized placebocontrolled trial to evaluate the antialbuminuric
effects of an aldosterone blocker in hypertensive
patients with albuminuria. Hyperterns Res 2010;
33:616-621.
(13) Kawarazaki H, Ando K, Nagae A, Fujita M,
Matsui H, Fujita T. Mineralocorticoid receptor
activation
contributes
tosalt-induced
hypertension and renal injury in prepubertal Dahl
salt-sensitive rats. Nephrol Dial Transplant
2010;25:2879-2889.
(14) Marumo T, Hishikawa K, Yoshikawa M,
Hirahashi J, Kawachi S, Fujita T. Histone
deacetylase modulates the proinflammatory and-fibrotic changes in tubulointerstitial injury. Am J
Physiol Renal Physiol 2010;298:133-141.
(15) Yoshikawa M, Hishikawa K, Idei M, Fujita T.
Trichostatin
A prevents
TGF-b1-induced
apoptosis by inhibiting ERK activation in humanrenal tubular epithelial cells. Eur J Pharmacol
2010;642:28-36.
(16) Inowa T, Hishikawa K, Matsuzaki Y, Isagawa T,
Takeuchi T, Aburatani H, Kitamura T, Fujita T.
GADD45β determines chemoresistance andinvasive growth of side population cells ofhuman embryonic carcinoma. Stem Cells Int
2010:782967.
(17) Igarashi M, Osuga J, Isshiki M, Sekiya M,
Okazaki H, Takase S, Takanashi M, Ohta K,
Kumagai M, Nishi M, Fujita T, Nagai R,
Kadowaki T, Ishibashi S. Targeting of neutralcholesterol ester hydrolase to the endoplasmic
reticulum via its N-terminal sequence. J Lipid
Res 2010;51:274-285.
(18) Shimizu H, Hori Y, Kaname S, Yamada K,
Nishiyama N, Matsumoto S, Miyata K, Oba M,
Yamada A, Kataoka K, Fujita T. siRNA-based
therapy ameliorates glomerulonephritis. J Am
Soc Nephrol 2010;21:622-633.

143(19)Danno H, Ishii KA, Nakagawa Y, Mikami M,
Yamamoto T, Yabe S, Furusawa M, Kumadaki S,
Watanabe K, Shimizu H, Matsuzaka T, Kobayashi
K, Takahashi A, Yatoh S, Suzuki H, Yamada N,
Shimano H. The liver-enriched transcription
factor CREBH is nutritionally regulated andactivated by fatty acids and PPARalpha. Biochem
Biophys Res Commun 2010;391:1222-1227.
(20)Yamamoto T, Watanabe K, Inoue N, Nakagawa Y,
Ishigaki N, Matsuzaka T, Takeuchi Y, Kobayashi
K, Yatoh S, Takahashi A, Suzuki H, Yahagi N,
Gotoda T, Yamada N, Shimano H. Protein
kinase Cbeta mediates hepatic induction ofsterol-regulatory element binding protein-1c byinsulin. J Lipid Res 2010;51:1859-1870.
(21)Takeuchi Y, Yahagi N, Izumida Y, Nishi M,
Kubota M, Teraoka Y, Yamamoto T, Matsuzaka
T, Nakagawa Y, Sekiya M, Iizuka Y, Ohashi K,
Osuga J, Gotoda T, Ishibashi S, Itaka K, Kataoka
K, Nagai R, Yamada N, Kadowaki T, Shimano H.
Polyunsaturated fatty acids selectively suppress
sterol regulatory element-binding protein-1
through proteolytic processing and autoloop
regulatory circuit. J Biol Chem 2010;285:
11681-11691.
(22)Hirashio S, Izumi K, Ueno T, Arakawa T, Naito T,
Taguchi T, Yorioka N. Point mutation (C to T) of
the LCAT gene resulting in A140C substitution. J
Atheroscler Thromb 2010;17:1297-1301.
(23)Bakhtiar Y, Hirano H, Arita K, Yunoue S, Fujio S,
Tominaga A, Sakoguchi T, Sugiyama K, Kurisu K,
Yasufuku-Takano Y and Takano K. Relationshipbetween cytokeratin staining patterns andclinico-pathological features in somatotropinomae.
Eur J Endocrinol 2010;163:531-539.
(24)Ito T, Sasano H, Tanaka M, Osamura RY, Sasaki I,
Kimura W, Takano K, Obara T, Ishibashi M,
Nakao K, Doi R, Shimatsu A, Nishida T, Komoto
I, Hirata Y, Nakamura K, Igarashi H, Jensen RT,
Wiedenmann B, Imamura M, Kawabe K,
Nakamura K. Epidemiological study ofgastroenteropancreatic neuroendocrine tumors inJapan. J Gastroenterol 2010;45:234-243.
(25)Hasegawa H, Nagano N, Urakawa I, Yamazaki Y,
Iijima K, Fujita T, Yamashita T, Fukumoto S,
Shimada T. Direct evidence for a causative role of
FGF23 in the abnormal renal phosphate handlingand vitamin D metabolism in rats with early-stage
chronic kidney disease. Kidney Int 2010;78:
975-980.
(26)Hori M, Makita N, Andoh T, Takiyama H, Yajima
Y, Sakatani T, Fukumoto S, Iiri T, Fujita T.
Long-term clinical course of IgG4-related
systemic disease accompanied by hypophysitis.
Endocr J 2010;57:485-492.
(27)Inose H, Ochi H, Kimura A, Fujita K, Xu R, SatoS, Iwasaki M, Sunamura S, Takeuchi Y,
Fukumoto S, Saito K, Nakamura T, Siomi H, Ito
H, Arai Y, Shinomiya KI, Takeda S. A microRNA
regulatory mechanism of osteoblast differentiation.
Proc Natl Acad Sci U S A 2010;106:2079420799.
(28)Ito N, Shimizu Y, Suzuki H, Saito T, Okamoto T,
Hori M, Akahane M, Fukumoto S, Fujita T.
Clinical utility of systemic venous sampling of
FGF23 for identifying tumours responsible fortumour-induced osteomalacia. J Intern Med
2010;268:390-394.
(29)Kimura A, Inose H, Yano F, Fujita K, Ikeda T,
Sato S, Iwasaki M, Jinno T, Ae K, Fukumoto S,
Takeuchi Y, Itoh H, Imamura T, Kawaguchi H,
Chung UI, Martin JF, Iseki S, Shinomiya KI,
Takeda S. Runx1 and Runx2 cooperate during
sternal morphogenesis. Development 2010;137:
1159-1167.
(30)Mori Y, Ogasawara T, Motoi T, Shimizu Y,
Chikazu D, Tamura K, Fukumoto S, Takato T.
Tumor-induced osteomalacia associated with amaxillofacial tumor producing fibroblast growth
factor 23: report of a case and review of theliterature. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2010;109:e57-e63.

144

Department of Diabetes andMetabolic Diseases
Professor
Takashi Kadowaki, M.D., Ph.D.

Associate Professor
Kohjiro Ueki, M.D., Ph.D.

Lecturer
Kazuhisa Tsukamoto, M.D., Ph.D. (-2010.11)
Toshimasa Yamauchi, M.D., Ph.D. (2010.12-)

Assistant Professor
Ken Ohashi, M.D., Ph.D., Hideyuki Sakoda, M.D., PhD.,
Midori Fujishiro, M.D., Ph.D., Mitsuru Ohsugi, M.D.,
Nobuhiro Shojima, M.D., Ph.D., Yukiko Okazaki, M.D., Ph.D.,
Yoko Iizuka, M.D., Ph.D., Yusuke Hada, M.D., Ph.D.,
Motoharu Awazawa, M.D., Ph.D., Yoshihiko Izumida, M.D., Ph.D.

Homepage http://dm.umin.jp/
Introduction and Organization
In 1998 the Department of Internal Medicine at the
University of Tokyo was reorganized to the morefunctional units based on clinical specialties. 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.
Masato Iwabu), 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 and Assistant Professors, Drs. Iseki
Takamoto and Ryo Suzuki), 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

145(Lecturer, Dr. Noriko Takahashi), 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
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 6500 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

146secretion 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
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.

2.

3.

4.

5.

6.

References
1.

Baur, J.A., Chen, D., Chini, E.N., Chua, K.,
Cohen, H.Y., de Cabo, R., Deng, C., Dimmeler,
S., Gius, D., Guarente, L.P., Helfand, S.L., Imai,
S., Itoh, H., Kadowaki, T., Koya, D.,
Leeuwenburgh, C., McBurney, M., Nabeshima,Y., Neri, C., Oberdoerffer, P., Pestell, R.G.,

7.

8.

Rogina, B., Sadoshima, J., Sartorelli, V., Serrano,M., Sinclair, D.A., Steegborn, C., Tatar, M.,
Tissenbaum, H.A., Tong, Q., Tsubota, K.,
Vaquero, A., and Verdin, E. Dietary restriction:
standing up for sirtuins. Science 329, 1012-1013,
2010.
Hada, Y., Yamauchi, T., and Kadowaki, T.
[Incretin related drugs]. Nippon Rinsho 68,
1900-1905, 2010.
Igarashi, M., Osuga, J., Isshiki, M., Sekiya, M.,
Okazaki, H., Takase, S., Takanashi, M., Ohta, K.,
Kumagai, M., Nishi, M., Fujita, T., Nagai, R.,
Kadowaki, T., and Ishibashi, S. Targeting of
neutral cholesterol ester hydrolase to theendoplasmic reticulum via its N-terminal
sequence. J Lipid Res 51, 274-285, 2010.
Igarashi, M., Osuga, J., Uozaki, H., Sekiya, M.,
Nagashima, S., Takahashi, M., Takase, S.,
Takanashi, M., Li, Y., Ohta, K., Kumagai, M.,
Nishi, M., Hosokawa, M., Fledelius, C., Jacobsen,P., Yagyu, H., Fukayama, M., Nagai, R.,
Kadowaki, T., Ohashi, K., and Ishibashi, S. The
critical role of neutral cholesterol ester hydrolase
1 in cholesterol removal from humanmacrophages. Circ Res 107, 1387-1395, 2010.
Iwabu, M., Yamauchi, T., Okada-Iwabu, M., Sato,K., Nakagawa, T., Funata, M., Yamaguchi, M.,
Namiki, S., Nakayama, R., Tabata, M., Ogata, H.,
Kubota, N., Takamoto, I., Hayashi, Y.K.,
Yamauchi, N., Waki, H., Fukayama, M., Nishino,I., Tokuyama, K., Ueki, K., Oike, Y., Ishii, S.,
Hirose, K., Shimizu, T., Touhara, K., andKadowaki, T. Adiponectin and AdipoR1 regulate
PGC-1alpha and mitochondria by Ca(2+) and
AMPK/SIRT1. Nature 464, 1313-1319, 2010.
Iwamoto, Y., Tajima, N., Kadowaki, T., Nonaka,K., Taniguchi, T., Nishii, M., Arjona Ferreira,J.C., and Amatruda, J.M. Efficacy and safety ofsitagliptin monotherapy compared with voglibose
in Japanese patients with type 2 diabetes: arandomized, double-blind trial. Diabetes Obes
Metab 12, 613-622, 2010.
Kadowaki, T. [Diabetic treatment strategies tocontrol the onset and development of diabetic
macrovascular disease]. Nippon Rinsho 68,
788-795, 2010.
Kaneko, K., Ueki, K., Takahashi, N., Hashimoto,

147

S., Okamoto, M., Awazawa, M., Okazaki, Y.,
Ohsugi, M., Inabe, K., Umehara, T., Yoshida, M.,
Kakei, M., Kitamura, T., Luo, J., Kulkarni, R.N.,
Kahn, C.R., Kasai, H., Cantley, L.C., andKadowaki, T. Class IA phosphatidylinositol
3-kinase in pancreatic beta cells controls insulin
secretion by multiple mechanisms. Cell Metab 12,
619-632, 2010.
9. Kawashima, D., Ohno, T., Kinoshita, O.,
Motomura, N., Kiyosue, A., Fujita, H., Ando, J.,
Ohtomo, K., Shigeeda, T., Kato, S., Kadowaki, T.,
Nagai, R., Takamoto, S., and Ono, M. Prevalenceof vitreous hemorrhage following coronary
revascularization in patients with diabetic
retinopathy. Circ J 75, 329-335, 2011.
10. Kondo, K., and Kadowaki, T. Colestilan
monotherapy significantly improves glycaemic
control and LDL cholesterol levels in patientswith type 2 diabetes: a randomized double-blind
placebo-controlled study. Diabetes Obes Metab12, 246-251, 2010.
11. Kumagai, K., Kubota, N., Saito, T.I., Sasako, T.,
Takizawa, R., Sudo, K., Kurokawa, M., andKadowaki, T. Generation of transgenic mice on
an
NOD/SCID
background
using
the
conventional microinjection technique. Biol
Reprod 84, 682-688, 2011.
12. Kurokawa, J., Arai, S., Nakashima, K., Nagano,
H., Nishijima, A., Miyata, K., Ose, R., Mori, M.,
Kubota, N., Kadowaki, T., Oike, Y., Koga, H.,
Febbraio, M., Iwanaga, T., and Miyazaki, T.
Macrophage-derived AIM is endocytosed into
adipocytes and decreases lipid droplets via
inhibition of fatty acid synthase activity. Cell
Metab 11, 479-492, 2010.
13. Misu, H., Takamura, T., Takayama, H., Hayashi,
H., Matsuzawa-Nagata, N., Kurita, S., Ishikura,K., Ando, H., Takeshita, Y., Ota, T., Sakurai, M.,
Yamashita, T., Mizukoshi, E., Honda, M.,
Miyamoto, K., Kubota, T., Kubota, N., Kadowaki,T., Kim, H.J., Lee, I.K., Minokoshi, Y., Saito, Y.,
Takahashi, K., Yamada, Y., Takakura, N., andKaneko, S. A liver-derived secretory protein,selenoprotein P, causes insulin resistance. Cell
Metab 12, 483-495, 2010.
14. Muraoka, T., Aoki, K., Iwasaki, T., Shinoda, K.,
Nakamura, A., Aburatani, H., Mori, S.,

Tokuyama, K., Kubota, N., Kadowaki, T., andTerauchi, Y. Ezetimibe decreases SREBP-1c
expression in liver and reverses hepatic insulin
resistance in mice fed a high-fat diet. Metabolism
60, 617-628, 2011.
15. Nakata, K., Choo, J., Hopson, M.J., Ueshima, H.,
Curb, J.D., Shin, C., Evans, R.W., Kadowaki, T.,
Otake, T., Kadota, A., Kadowaki, S., Miura, K.,
El-Saed, A., Edmundowicz, D., Sutton-Tyrrell, K.,
Kuller, L.H., and Sekikawa, A. Stronger
associations of sagittal abdominal diameter withatherogenic lipoprotein subfractions than waist
circumference in middle-aged US white andJapanese men. Metabolism 59, 1742-1751, 2010.
16. Noda, M., Kato, M., Takahashi, Y., Matsushita, Y.,
Mizoue, T., Inoue, M., Tsugane, S., andKadowaki, T. Fasting plasma glucose and 5-year
incidence of diabetes in the JPHC diabetes study- suggestion for the threshold for impaired fasting
glucose among Japanese. Endocr J 57, 629-637,
2010.
17. Ohno, T., Kinoshita, O., Fujita, H., Kato, S.,
Hirose, A., Sigeeda, T., Otomo, K., Ando, J.,
Kadowaki, T., Araie, M., Nagai, R., andTakamoto, S. Detecting occult coronary arterydisease followed by early coronary artery bypass
surgery in patients with diabetic retinopathy:
report from a diabetic retinocoronary clinic. J
Thorac Cardiovasc Surg 139, 92-97, 2010.
18. Ohta, K., Sekiya, M., Uozaki, H., Igarashi, M.,
Takase, S., Kumagai, M., Takanashi, M.,
Takeuchi, Y., Izumida, Y., Kubota, M., Nishi, M.,
Okazaki, H., Iizuka, Y., Yahagi, N., Yagyu, H.,
Fukayama, M., Kadowaki, T., Ohashi, K.,
Ishibashi, S., and Osuga, J. Abrogation of neutralcholesterol ester hydrolytic activity causes
adrenal enlargement. Biochem Biophys Res
Commun 404, 254-260, 2011.
19. Oishi, Y., Manabe, I., Imai, Y., Hara, K.,
Horikoshi, M., Fujiu, K., Tanaka, T., Aizawa, T.,
Kadowaki, T., and Nagai, R. Regulatory
polymorphism in transcription factor KLF5 at the
MEF2 element alters the response to angiotensin
II and is associated with human hypertension.
FASEB J 24, 1780-1788, 2010.
20. Okamoto, K., Iwasaki, N., Nishimura, C., Doi, K.,
Noiri, E., Nakamura, S., Takizawa, M., Ogata, M.,148

Fujimaki, R., Grarup, N., Pisinger, C.,
Borch-Johnsen, K., Lauritzen, T., Sandbaek, A.,
Hansen, T., Yasuda, K., Osawa, H., Nanjo, K.,
Kadowaki, T., Kasuga, M., Pedersen, O., Fujita,T., Kamatani, N., Iwamoto, Y., and Tokunaga, K.
Identification of KCNJ15 as a susceptibility genein Asian patients with type 2 diabetes mellitus.
Am J Hum Genet 86, 54-64, 2010.
21. Okazaki, Y., Eto, K., Yamashita, T., Okamoto, M.,
Ohsugi, M., Noda, M., Terauchi, Y., Ueki, K.,
and Kadowaki, T. Decreased insulin secretion
and accumulation of triglyceride in beta cells
overexpressing a dominant-negative form of
AMP-activated protein kinase. Endocr J 57,
141-152, 2010.
22. Okazaki, Y., and Ueki, K. [Japan Diabetes
Outcome Intervention Trial 3]. Nippon Rinsho
68 Suppl 9, 87-90, 2010.
23. Okazaki, Y., Ueki, K., and Kadowaki, T. [Japan
Diabetes Outcome Intervention Trial 3 (Japan
Diabetes Optimal Integrated Treatment Study for
3 major risk factors of cardiovascular diseases:
J-DOIT3)]. Nippon Rinsho 68, 861-864, 2010.
24. Otani, K., Kitayama, J., Kamei, T., Soma, D.,
Miyato, H., Yamauchi, T., Kadowaki, T., andNagawa, H. Adiponectin receptors are
downregulated in human gastric cancer. J
Gastroenterol 45, 918-927, 2010.
25. Otani, K., Kitayama, J., Yasuda, K., Nio, Y.,
Iwabu, M., Okudaira, S., Aoki, J., Yamauchi, T.,
Kadowaki, T., and Nagawa, H. Adiponectin
suppresses tumorigenesis in Apc(Min)(/+) mice.
Cancer Lett 288, 177-182, 2010.
26. Park, K.W., Waki, H., Choi, S.P., Park, K.M., andTontonoz, P. The small molecule phenamil is a
modulator of adipocyte differentiation and
PPARgamma expression. J Lipid Res 51,
2775-2784, 2010.
27. Park, S.W., Zhou, Y., Lee, J., Lu, A., Sun, C.,
Chung, J., Ueki, K., and Ozcan, U. The
regulatory subunits of PI3K, p85alpha andp85beta, interact with XBP-1 and increase its
nuclear translocation. Nat Med 16, 429-437,
2010.
28. Sakoda, H., Ito, S., Kanda, H., Fujishiro, M.,
Osuga, J., Tsukamoto, K., Ueki, K., andKadowaki, T. Association between type 1

diabetes mellitus and remitting seronegative
symmetrical synovitis with pitting edema: a casereport. Diabetes Res Clin Pract 91, e43-44, 2011.
29. Sopasakis, V.R., Liu, P., Suzuki, R., Kondo, T.,
Winnay, J., Tran, T.T., Asano, T., Smyth, G.,
Sajan, M.P., Farese, R.V., Kahn, C.R., and Zhao,
J.J. Specific roles of the p110alpha isoform ofphosphatidylinsositol 3-kinase in hepatic insulin
signaling and metabolic regulation. Cell Metab11, 220-230, 2010.
30. Suzuki, R., Lee, K., Jing, E., Biddinger, S.B.,
McDonald, J.G., Montine, T.J., Craft, S., andKahn, C.R. Diabetes and insulin in regulation ofbrain cholesterol metabolism. Cell Metab 12,567-579, 2010.
31. Takahashi, I., Yamada, Y., Kadowaki, H.,
Horikoshi, M., Kadowaki, T., Narita, T., Tsuchida,S., Noguchi, A., Koizumi, A., and Takahashi, T.
Phenotypical variety of insulin resistance in a
family with a novel mutation of the insulin
receptor gene. Endocr J 57, 509-516, 2010.
32. Takamoto, I., and Kadowaki, T. [New diagnostic
criteria of diabetes mellitus in Japan, 2010].
Nippon Rinsho 68 Suppl 9, 26-31, 2010.
33. Takeuchi, Y., Yahagi, N., Izumida, Y., Nishi, M.,
Kubota, M., Teraoka, Y., Yamamoto, T.,
Matsuzaka, T., Nakagawa, Y., Sekiya, M., Iizuka,
Y., Ohashi, K., Osuga, J., Gotoda, T., Ishibashi,
S., Itaka, K., Kataoka, K., Nagai, R., Yamada, N.,
Kadowaki, T., and Shimano, H. Polyunsaturated
fatty acids selectively suppress sterol regulatory
element-binding protein-1 through proteolytic
processing and autoloop regulatory circuit. J Biol
Chem 285, 11681-11691, 2010.
34. Waki, H., Yamauchi, T., and Kadowaki, T.
[PPARgamma antagonist as a potential drug forthe treatment of obesity and diabetes]. Nippon
Rinsho 68, 350-355, 2010.
35. Waki, H., Yamauchi, T., and Kadowaki, T.
[Regulation of differentiation and hypertrophy of
adipocytes
andadipokine
networkby
PPARgamma]. Nippon Rinsho 68, 210-216,
2010.
36. Waki, H., Yamauchi, T., and Kadowaki, T.
[Recent advances in PPARgamma research].
Nippon Rinsho 68, 181-188, 2010.
37. Waki, K., Hayashi, A., Ikeda, S., Nagatsuka, K.,

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Honma, Y., Kadowaki, T., and Yoshinoya, S.
Measuring platelet aggregation in dialysis
patients with a whole blood aggregometer by thescreen filtration pressure method. Ther Apher
Dial 15, 203-206, 2011.
38. Waki, K., Sugawara, Y., Tamura, S., Yamashiki,N., Fujita, H., Kadowaki, T., and Kokudo, N.
Simultaneous pancreas-kidney transplantation in
the United States: an analysis of the UNOS
registry. Clin Transpl, 35-44, 2010.
39. Waki, K., Terasaki, P.I., and Kadowaki, T.
Long-term pancreas allograft survival insimultaneous pancreas-kidney transplantation byera: UNOS registry analysis. Diabetes Care 33,
1789-1791, 2010.
40. Winnay, J.N., Boucher, J., Mori, M.A., Ueki, K.,
and Kahn, C.R. A regulatory subunit ofphosphoinositide 3-kinase increases the nuclear
accumulation of X-box-binding protein-1 tomodulate the unfolded protein response. Nat Med
16, 438-445, 2010.
41. Yamamoto, T., Watanabe, K., Inoue, N.,
Nakagawa, Y., Ishigaki, N., Matsuzaka, T.,
Takeuchi, Y., Kobayashi, K., Yatoh, S., Takahashi,A., Suzuki, H., Yahagi, N., Gotoda, T., Yamada,N., and Shimano, H. Protein kinase Cbeta
mediates hepatic induction of sterol-regulatory
element binding protein-1c by insulin. J Lipid
Res 51, 1859-1870, 2010.
42. Yamauchi, T., Hara, K., Maeda, S., Yasuda, K.,
Takahashi, A., Horikoshi, M., Nakamura, M.,
Fujita, H., Grarup, N., Cauchi, S., Ng, D.P., Ma,
R.C., Tsunoda, T., Kubo, M., Watada, H.,
Maegawa, H., Okada-Iwabu, M., Iwabu, M.,
Shojima, N., Shin, H.D., Andersen, G., Witte,
D.R., Jorgensen, T., Lauritzen, T., Sandbaek, A.,
Hansen, T., Ohshige, T., Omori, S., Saito, I.,
Kaku, K., Hirose, H., So, W.Y., Beury, D., Chan,
J.C., Park, K.S., Tai, E.S., Ito, C., Tanaka, Y.,
Kashiwagi, A., Kawamori, R., Kasuga, M.,
Froguel, P., Pedersen, O., Kamatani, N.,
Nakamura, Y., and Kadowaki, T. A genome-wide
association study in the Japanese population
identifies susceptibility loci for type 2 diabetes at
UBE2E2 and C2CD4A-C2CD4B. Nat Genet 42,
864-868, 2010.
43. Zhou, Y., Koizumi, N., Kubota, N., Asano, T.,

Yuhashi, K., Mochizuki, T., Kadowaki, T.,
Sakuma, I., and Liao, H. Fast and accurate
ultrasonography for visceral fat measurement.
Med Image Comput Comput Assist Interv 13,
50-58, 2010.

150

Department of
Hematology and Oncology
Professor
Mineo Kurokawa, M.D., Ph.D.

Lecturer
Keiki Kumano, M.D., Ph.D.

Motoshi Ichikawa, M.D., Ph.D.

Special Lecturer (Hospital)
Yasuhito Nannya, M.D., Ph.D.

Associate
Sachiko Seo, M.D., Ph.D.,

Go Yamamoto, M.D., Ph.D.,

Fumihiko Nakamura, M.D., Ph.D.,

Masahiro Nakagawa, M.D., Ph.D.,

Akihito Shinohara, M.D., Ph. D.,

Nahoko Nishimoto, 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. Mineo Kurokawa, M.D., Ph.D. wasinstalled as Professor of Department of Hematology
and Oncology in 2005. The staff of Department of
Hematology and Oncology consists of about twenty
members including one professor, 2 lecturers, one
special lecturer (hospital), and 6 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 of thought-provoking
cases are also discussed twice per month in theclinical conferences, each focusing on hematologicaldiseases, lymphomas, or hematopoietic stem celltransplantation.
Approximately 40 patients with acute leukemia,
150 with malignant lymphoma, 40 with chronic

151

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 1200 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.
3. We also started the clinical study of maintenancetherapy after autologus stem cell transplantation ofmultiple myeloma patients under the admission of
ethical committee of the Faculty of Medicine.

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 hematologists
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)reprogramming of leukemic cells into iPS cells.
Translational research to develop novel methods fordiagnosis 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

152

published in the past year are listed in the reference.

References(1) Asano H, Imai Y, Ota S, Yamamoto G, Takahashi
T, Fukayama M, Kurokawa M. CD30-positive
anaplastic variant diffuse large B cell lymphoma:a rare case presented with cutaneous involvement.
Int J Hematol. 2010 Oct;92(3):550-2.
(2) Asano H, Yamamoto G, Hosoi M, Takahashi T,
Hangaishi A, Kurokawa M. Complete molecularremission in refractory acute myeloid leukemiawith MLL/AF9 treated with gemtuzumab
ozogamicin. Leuk Res. 2010 Jul;34(7):e152-3.
(3) Goyama S, Kurokawa M. Evi-1 as a criticalregulator of leukemic cells. Int J Hematol. 2010
Jun;91(5):753-7.
(4) Goyama S, Nitta E, Yoshino T, Kako S,
Watanabe-Okochi N, Shimabe M, Imai Y,
Takahashi K, Kurokawa M. EVI-1 interacts withhistone methyltransferases SUV39H1 and G9a
for transcriptional repression and bone marrowimmortalization. Leukemia. 2010 Jan;24(1):81-8.
(5) Hangaishi A, Kurokawa M. Blimp-1 is a tumor
suppressor gene in lymphoid malignancies. Int J
Hematol. 2010 Jan;91(1):46-53.
(6) Hangaishi A, Takahashi T, Masuda A, Okada S,
Kandabashi K, Kurokawa M. Rituximab therapy
for refractory immune thrombocytopenic purpura
in elder patients. Int J Hematol. 2010 Mar;91(2):336-7.
(7) Hosoi M, Ichikawa M, Imai Y, Kurokawa M. A
case of anaplastic large cell lymphoma, ALK
positive, primary presented in the skin andrelapsed with systemic involvement andleukocytosis after years of follow-up period. Int J
Hematol. 2010 Nov;92(4):667-8.
(8) Hosoi M, Nannya Y, Sasaki T, Suzuki HI, Ueda K,
Tsujino T, Isayama H, Takahashi T, Koike K,
Kurokawa M. Biliary cast syndrome and benign
biliary stricture as complications of allogeneic
hematopoietic stem cell transplantation. Ann
Hematol. 2010 Dec;89(12):1287-9.
(9) Hosoi M, Yamamoto G, Imai Y, Kurokawa M.
Reversible
posteriorleukoencephalopathy
syndrome following R-CHOP therapy for diffuse
large B-cell lymphoma. Ann Hematol. 2010

Feb;89(2):207-8.
(10) Ichikawa M, Hangaishi A, Nannya Y, Kurokawa
M. Postremission gemtuzumab ozogamicin for
elderly patients with acute myelogenous
leukemia with favorable characteristics andcomorbid conditions. Int J Hematol. 2010
Nov;92(4):673-4.
(11) Imai Y, Shimaoka M, Kurokawa M. Essential
roles of VLA-4 in the hematopoietic system. Int J
Hematol. 2010 May;91(4):569-75.
(12) Kagoya Y, Hangaishi A, Takahashi T, Imai Y,
Kurokawa M. High-dose dexamethasone therapy
for severe thrombocytopenia and neutropenia
induced by EBV infectious mononucleosis. Int J
Hematol. 2010 Mar;91(2):326-7.
(13) Kataoka K, Nannya Y, Iwata H, Seo S, Kumano
K, Takahashi T, Nagai R, Kurokawa M. Plasma
brain natriuretic peptide is associated with
hepatic veno-occlusive disease and earlymortality after allogeneic hematopoietic stem celltransplantation. Bone Marrow Transplant. 2010
Nov;45(11):1631-7.
(14) Kataoka K, Nannya Y, Ueda K, Kumano K,
Takahashi T, Kurokawa M. Differential
prognostic impact of pretransplant comorbidity
on transplant outcomes by disease status and timefrom transplant: a single Japanese transplant
centre study. Bone Marrow Transplant. 2010
Mar;45(3):513-20.
(15) Kataoka K, Seo S, Ota S, Takahashi T, Kurokawa
M. Positron emission tomography in the
diagnosis and therapeutic monitoring of
post-transplant lymphoproliferative disorder after
cord blood transplantation. Bone Marrow
Transplant. 2010 Mar;45(3):610-2.
(16) Kataoka K, Seo S, Sugawara Y, Ota S, Imai Y,
Takahashi T, Fukayama M, Kokudo N, Kurokawa
M. Post-transplant lymphoproliferative disorder
after adult-to-adult living donor liver transplant:
case series and review of literature. Leuk
Lymphoma. 2010 Aug;51(8):1494-501.
(17) Kataoka K, Takahashi T, Iwata H, Hangaishi A,
Kumano K, Kurokawa M. Fulminant myocarditis
after allogeneic bone marrow transplantation:
successful
cytomegalovirus
therapyandmechanical circulatory support for bridge torecovery. Biol Blood Marrow Transplant. 2010

153

Jan;16(1):129-30.
(18) Kobayashi H, Ichikawa M, Hangaishi A, Imai Y,
Kurokawa M. Concurrent development of"Burkitt-like" lymphoma and BCL-2-rearranged
low-grade B cell lymphoma sharing the same
germinal center origin. Int J Hematol. 2010
Jan;93(1):112-7.
(19) Koike Y, Miyazaki K, Higashihara M, Kimura E,
Jona M, Uchihashi K, Masuda A, Kandabashi K,
Kurokawa M, Yatomi Y. Clinical significance ofdetection of immature platelets: comparison
between percentage of reticulated platelets as
detected by flow cytometry and immature platelet
fraction as detected by automated measurement.
Eur J Haematol. 2010 Feb;84(2):183-4.
(20) Kumano K, Kurokawa M. The role ofRunx1/AML1 and Evi-1 in the regulation ofhematopoietic stem cells. J Cell Physiol. 2010
Feb;222(2):282-5.
(21) Nagai S, Nannya Y, Arai S, Yoshiki Y, Takahashi
T, Kurokawa M. Molecular or cytogenetic
monitoring and preemptive therapy for central
nervous system relapse of acute promyelocytic
leukemia. Haematologica. 2010 Jan;95(1):16971.
(22) Nagai S, Nannya Y, Takahashi T, Kurokawa M.
Jumping translocation involving 1q21 duringlong-term complete remission of acute myeloid
leukemia. Ann Hematol. 2010 Jul;89(7):741-2.
(23) Nagai S, Takahashi T, Kurokawa M. How should
we prevent hematologic relapse of acutepromyelocytic leukemia? J Clin Oncol. 2010
Feb;28(4):e62; author reply e3-4.
(24) Nagai S, Takahashi T, Kurokawa M.
Risk-adapted maintenance therapy for acutepromyelocytic leukemia. J Clin Oncol. 2010
Jan;28(2):e21; author reply e2-3.
(25) Nagai S, Takahashi T, Kurokawa M. The impact
of molecularly targeted therapies upon theunderstanding of leukemogenesis and the role ofhematopoietic stem cell transplantation in acutepromyelocytic leukemia. Curr Stem Cell Res
Ther. 2010 Dec;5(4):372-8.
(26) Nakahara F, Sakata-Yanagimoto M, Komeno Y,
Kato N, Uchida T, Haraguchi K, Kumano K,
Harada Y, Harada H, Kitaura J, Ogawa S,
Kurokawa M, Kitamura T, Chiba S. Hes1

immortalizes committed progenitors and plays arole in blast crisis transition in chronic
myelogenous leukemia. Blood. 2010 Apr;115(14):2872-81.
(27) Nakazaki K, Hangaishi A, Nakamura F, Hosoi M,
Imai Y, Takahashi T, Nannya Y, Kurokawa M.
IgG-associated immune thrombocytopenia in
Waldenstrom macroglobulinemia. Int J Hematol.
2010 Sep;92(2):360-3.
(28) Nishimoto N, Imai Y, Ueda K, Nakagawa M,
Shinohara A, Ichikawa M, Nannya Y, Kurokawa
M. T cell acute lymphoblastic leukemia arisingfrom familial platelet disorder. Int J Hematol.
2010 Jul;92(1):194-7.
(29) Okada S, Nannya Y, Ota S, Takazawa Y,
Yamamoto G, Kumano K, Izutsu K, Takahashi T,
Chiba S, Kurokawa M. Cutaneous T-cell
lymphoma (mycosis fungoides) relapsed withdifferent immunological phenotype after bonemarrow transplant. Br J Dermatol. 2010
Jan;162(1):229-30.
(30) Oshima K, Takahashi T, Mori T, Matsuyama T,
Usuki K, Asano-Mori Y, Nakahara F, Okamoto S,
Kurokawa M, Kanda Y. One-year low-dose
valacyclovir as prophylaxis for varicella zoster
virus disease after allogeneic hematopoietic stem
cell transplantation. A prospective study of theJapan Hematology and Oncology Clinical Study
Group. Transpl Infect Dis. 2010 Oct;12(5):421-7.
(31) Shinohara A, Ichikawa M, Ueda K, Takahashi T,
Hangaishi A, Kurokawa M. A novel
MLL-AF1p/Eps15 fusion variant in therapyrelated acute lymphoblastic leukemia, lacking theEH-domains. Leuk Res. 2010 Feb;34(2):e62-3.
(32) Takahashi T, Hangaishi A, Yamamoto G,
Ichikawa M, Imai Y, Kurokawa M. HIV-negative,
HHV-8-unrelated primary effusion lymphomalike lymphoma: report of two cases. Am J
Hematol. 2010 Jan;85(1):85-7.
(33) Ueda K, Ichikawa M, Takahashi M, Momose T,
Ohtomo K, Kurokawa M. FDG-PET is effectivein the detection of granulocytic sarcoma inpatients with myeloid malignancy. Leuk Res.
2010 Sep;34(9):1239-41.
(34) Ueda K, Nagai S, Miyashita SI, Kaise T,
Ichikawa M, Kumano K, Hangaishi A, Nannya Y,
Kurokawa M. Arsenic-induced pericardial and154

pleural effusion without acute promyelocytic
leukemia differentiation syndrome. Leuk Res.
2010 Jan;34(1):e25-6.
(35) Ueda K, Nannya Y, Asai T, Yamamoto G,
Hangaishi A, Takahashi T, Imai T, Kurokawa M.
Efficacy and safety of modified rituximabESHAP therapy for relapsed/refractory B-cell
lymphoma. J Chemother. 2010 Feb;22(1):54-7.
(36) Ueda K, Watadani T, Maeda E, Ota S, Kataoka K,
Seo S, Kumano K, Hangaishi A, Takahashi T,
Imai Y, Ohtomo K, Fukayama M, Nannya Y,
Kurokawa M. Outcome and treatment of lateonset noninfectious pulmonary complications
after allogeneic haematopoietic SCT. Bone
Marrow Transplant. 2010 Dec;45(12):1719-27.

155

Department of Allergy andRheumatology
Professor
Kazuhiko Yamamoto, M.D. (Rheumatology, Allergology)

Lecturer
Fujio Takeuchi, M.D. (Rheumatology)
Makoto Dohi, M.D. (Allergology)
Zen-ichiro Honda, M.D. (Rheumatology)

Lecturer (Hospital)
Kimito Kawahata, M.D. (Rheumatology)

Research Associate
Hiroko Kanda, M.D. (Rheumatology)
Keishi Fujio, M.D. (Rheumatology)
Noboru Hagino, M.D. (Rheumatology)
Kanae Kubo, M.D. (Rheumatology)
Akiko Okamoto (Rheumatology)

Project Research Associate
Tomohisa Okamura

The Department of Allergy and Rheumatology
presently consists of 10 staff mentioned above, who
preside over 6 medical staff, 9 graduate students for"Doctor of Medical Science" and 1 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.
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

156

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 are rounded and on
Tuesday afternoon the professor makes his rounds. To
achieve the highest quality of medical care, clinicalconferences are held. Majority of patients in the ward
are suffered from connective tissue diseases andusually exhibit multiple organ involvements.
Therefore, a careful, well-rounded approach to eachpatient as a whole is required rather than a limited
special approach to a single organ system.

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

2010
1. Yukinori Okada, Tomomitsu Hirota,
Yoichiro Kamatani, Atsushi Takahashi,
Koichi Matsuda, Tatsuhiko Tsunoda,
Toshihiro Tanaka, Michiaki Kubo, Yusuke
Nakamura, Mayumi Tamari, Kazuhiko
Yamamoto,
Naoyuki
Kamatani.
Identification of nine novel loci associatedwith white blood cell subtypes in a
Japanese population. PLos Genetics. 2011.
in press
2. Kochi Y, Thabet MM, Suzuki A, Okada Y,
Daha NA, Toes REM, Huizinga TWJ,
Myouzen K, Kubo M, Yamada R,
Nakamura Y, Yamamoto K. PADI4
polymorphism predisposes male smokers
to rheumatoid arthritis. Ann Rheum Dis,
70:512-5, 2011.
3. Fujio K, Okamura T, Yamamoto K. The
family of IL-10 secreting CD4+ T cells.
Advances in Immunology. 105:99-130,
2010.
4. Shimane K, Kochi Y, Horita T, Ikari K,
Amano H, Hirakata M, Okamoto A,
Yamada R, Myouzen K, Suzuki A, Kubo M,
Atsumi T, Koike T, Takasaki Y, Momohara
S, Yamanaka H, Nakamura Y, Yamamoto
K. The association of a nonsynonymous
single-nucleotide
polymorphismin
TNFAIP3
withsystemic
lupus
erythematosus and rheumatoid arthritis in
the Japanese population. Arthritis Rheum.
62:574-579, 2010.
5. Kochi Y, Suzuki A, Yamada R, Yamamoto K.
Ethnogenetic heterogeneity of rheumatoid
arthritis-implications for pathogenesis.
Nat Rev Rheumatol. 6:290-5, 2010.
6. Kochi Y, Okada Y, Suzuki A, Ikari K, Terao
C, Takahashi A, Yamazaki K, Hosono N,
Myouzen K, Tsunoda T, Kamatani N,
Furuichi T, Ikegawa S, Ohmura K, Mimori
T, Matsuda F, Iwamoto T, Momohara S,
Yamanaka H, Yamada R, Kubo M,
Nakamura Y, Yamamoto K. A regulatory
variant in CCR6 is associated withrheumatoid arthritis susceptibility. Nat

157

7.

8.

9.

Genet. 42:515-9, 2010.
Myouzen K, Kochi Y, Shimane K, Fujio K,
Okamura T, Okada Y, Suzuki A, Atsumi T,
Ito S, Takada K, Mimori A, Ikegawa S,
Yamada R, Nakamura Y, Yamamoto K.
Regulatory polymorphisms in EGR2 areassociated with susceptibility to systemic
lupus erythematosus. Hum Mol Genet.
19:2313-20, 2010.
Okada Y, Suzuki A, Yamada R, Kochi Y,
Shimane K, Myouzen K, Kubo M,
Nakamura Y, Yamamoto K. HLA-DRB1*0901 lowers anti-cyclic citrullinatedpeptide antibody levels in Japanesepatients with rheumatoid arthritis.Ann
Rheum Dis. 69:1569-70, 2010.
Okada Y, Kamatani Y, Takahashi A,
Matsuda K, Hosono N, Ohmiya H, Daigo Y,
Yamamoto K, Kubo M, Nakamura Y,
Kamatani N. Common variations in
PSMD3-CSF3 and PLCB4 are associatedwith neutrophil count. Hum Mol Genet.
19:2079-2085, 2010.

158

Department of Infectious
Diseases (Internal Medicine)
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. An associate professor, 6 guest
lecturers, an associate, 2 graduate students and full-time
staff members are all performing their own duties inclinical, 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 learning 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
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

159

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
Hiroshi Yotsuyanagi, Takeya Tsutsumi, Shuji
Hatakeyama, Shu Okugawa, Shintaro Yanagimoto,
Yohko Nukui, Atsuhito Fukishima, Keita Tatsuno,
Sohei Harada, Koji Goto, Mahoko Ikeda, Koh Okamoto,
Yoshitaka Wakabayashi, Tetsuro Kobayashi, Haruka
Nakamura, Makoto Saito, Hideki Hashimoto, Kohei
Harada.

References
1) Kumada H, Okanoue T, Onji M, Moriwaki H, Izumi
N, Tanaka E, Chayama K, Sakisaka S, Takehara T,
Oketani M, Suzuki F, Toyota J, Nomura H, Yoshioka
K, Seike M, Yotsuyanagi H, Ueno Y; The Study
Group for the Standardization of Treatment of Viral
Hepatitis Including Cirrhosis, Ministry of Health,
Labor and Welfare of Japan. Guidelines for thetreatment of chronic hepatitis and cirrhosis due tohepatitis B virus infection for the fiscal year 2008 in
Japan. Hepatol Res. 2010;40:1-7.
2) Kumada H, Okanoue T, Onji M, Moriwaki H, Izumi
N, Tanaka E, Chayama K, Sakisaka S, Takehara T,
Oketani M, Suzuki F, Toyota J, Nomura H, Yoshioka
K, Seike M, Yotsuyanagi H, Ueno Y; The Study
Group for the Standardization of Treatment of Viral
Hepatitis Including Cirrhosis, Ministry of Health,Labour and Welfare of Japan. Guidelines for thetreatment of chronic hepatitis and cirrhosis due tohepatitis C virus infection for the fiscal year 2008 in
Japan. Hepatol Res. 2010;40:8-13.
3) Nakahara K, Takahashi H, Okuse C, Shigefuku R,
Yamada N, Murao M, Matsunaga K, Koike J,
Yotsuyanagi H, Suzuki M, Kimura K, Itoh F.
Membranous nephropathy associated with chronic
hepatitis B occurring in a short period after acutehepatitis

B

virus

infection.

InternMed.

160

2010;49:383-8.

12) Miyoshi H, Moriya K, Tsutsumi T, Shinzawa S, Fujie

4) Moriya K, Miyoshi H, Shinzawa S, Tsutsumi T, Fujie

H, Shintani Y, Fujinaga H, Goto K, Todoroki T,

H, Goto K, Shintani Y, Yotsuyanagi H, Koike K.

Suzuki T, Miyamura T, Matsuura Y, Yotsuyanagi H,

Hepatitis

compromises

Koike K. Pathogenesis of lipid metabolism disorder iniron-induced activation of antioxidants in mice andhepatitis C: polyunsaturated fatty acids counteract

HepG2 cells. J Med Virol. 2010;82:776-92.

lipid alterations induced by the core protein. J Hepatol.

C

virus

core

protein5) Okuse C, Yotsuyanagi H, Yamada N, Okamoto M,

2011;54:432-8.

Ikeda H, Kobayashi M, Fukuda Y, Takahashi H,13) Chayama K, Hayes CN, Yoshioka K, Moriwaki H,

Nagase Y, Suzuki Y, Matsunaga K, Ishii T, Matsumoto

Okanoue T, Sakisaka S, Takehara T, Oketani M,

N, Koike K, Suzuki M, Itoh F. Effect of nucleoside

Toyota J, Izumi N, Hiasa Y, Matsumoto A, Nomura H,

analog-interferon sequential therapy on patients with

Seike M, Ueno Y, Yotsuyanagi H, Kumada H. Factors

acute exacerbation of chronic hepatitis B. Hepatol Res.

predictive of sustained virological response following

2010;40:461-9.

72 weeks of combination therapy for genotype 1b6) Yanagimoto S, Tatsuno K, Okugawa S, Kitazawa T,

hepatitis C. J Gastroenterol. 2011;46:545-55.

Tsukada K, Koike K, Kodama T, Kimura S, Shibasaki

14) Yoshino Y, Kitazawa T, Ikeda M, Tatsuno K,

Y, Ota Y. A single amino acid of toll-like receptor 4

Yanagimoto S, Okugawa S, Ota Y, Yotsuyanagi H.

that is pivotal for its signal transduction andClinical features of Bacteroides bacteremia and theirsubcellular localization. J Biol Chem. 2009;284:

association with colorectal carcinoma. Infection. 20113513-20.

Jul 20. [Epub ahead of print]7) Yoshino Y, Kitazawa T, Tatsuno K, Ota Y, Koike K.
Cryptococcal pleuritis containing a high level ofadenosine deaminase in a patient with AIDS: a casereport. Respiration. 2010;79:153-6.
8) Okamoto K, Hatakeyama S, Itoyama S, Nukui Y,
Yoshino Y, Kitazawa T, Yotsuyanagi H, Ikeda R,
Sugita T, Koike K. Cryptococcus gattii genotype
VGIIa infection in man, Japan, 2007. Emerg InfectDis. 2010;16:1155-7.
9) Koike K, Tsutsumi T, Yotsuyanagi H, Moriya K. Lipid
metabolism and liver disease in hepatitis C viral
infection. Oncology. 2010;78:24-30.
10) Yoshino Y, Kitazawa T, Kamimura M, Tatsuno K, Ota
Y, Yotsuyanagi H. Pseudomonas putida bacteremia in
adult patients: five case reports and a review of theliterature. J Infect Chemother. 2011;17:278-82.
11) Chayama K, Hayes CN, Yoshioka K, Moriwaki H,
Okanoue T, Sakisaka S, Takehara T, Oketani M,
Toyota J, Izumi N, Hiasa Y, Matsumoto A, Nomura H,
Seike M, Ueno Y, Yotsuyanagi H, Kumada H.
Accumulation of refractory factors for pegylated
interferon plus ribavirin therapy in older female
patients with chronic hepatitis C. Hepatol Res.
2010;40:1155-1167.

161

Department of Stress Science andPsychosomatic Medicine
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Kazuhiro Yoshiuchi, M.D., Ph.D.

Associate
Yoshiyuki Takimoto, M.D., Ph.D.,

Homepage

Yuichiro Tomita, M.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 3 seniorresidents, 6 graduate students, and 3 researchers.

Clinical activities
Our department is responsible for both outpatient
clinic and inpatient ward. The ward is managed as apart of the Division of General Internal Medicine, andsenior residents, an associate, and the associate
professor attend it every day and provide closeside-by-side instruction to junior residents. The
weekly professor’s round is scheduled on Thursday
morning. During 2010 January to 2010 December, 58
patients were admitted to the ward, many of whomwere eating disorder patients. Outpatient clinic is
attended on every morning and afternoon in three
consultation rooms by approximately fifteen

physicians. During 2010 January to 2010 December,the numbers of the new outpatients and of the overall
outpatients in our department were 123 and 3131,
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 clinical lectures on
psychosomatic diseases in cardiology for fifth gradestudents and on eating disorders for sixth gradestudents. We are trying to teach them not only basic
knowledge of specific diseases, ways of physicalexamination, or interpretation of laboratory data, butalso relevant ways of clinical interview, doctor-patient
relationship building, 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.

162

Research activities

2.

Mizukoshi A, Kumagai K, Yamamoto N, Noguchi
M, Yoshiuchi K, Kumano H, Yanagisawa Y. A

Targeting stress-related diseases such as not only
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.

novel methodology to evaluate health impacts
caused by VOC exposures using real-time VOC
and Holter monitors. International Journal ofEnvironmental Research and Public Health, inpress.
3.

Yoshiuchi K, Inada S, Kikuchi H. Food diaries: useof new technology versus the written record. CAB
Reviews: Perspectives in Agriculture, Veterinary
Science, Nutrition and Natural Resources 2010;
5:048.

4.

Aoyagi Y, Park H, Park S, Yoshiuchi K, Kikuchi H,
Kawakami H, Morita Y, Ono A, Shephard RJ.
Interactive

effects

of

milk

basic

proteinsupplements and habitual physical activity on bonehealth in older women: a 1-year randomized
controlled trial. Int Dairy J 2010;20:724-730.
5.

Yoshiuchi K, Inada S, Nakahara R, Akabyashi A,
Park H, Park S, Shephard RJ, Aoyagi Y. Stressful
life events and habitual physical activity in older
adults: 1-year accelerometer data from the
Nakanojo Study. Ment Health Phys Act 2010;3:
23-25.

6.

Hachizuka M, Yoshiuchi K, Yamamoto Y, Iwase S,
Nakagawa K, Kawagoe K, Akabayashi A.
Development of a personal digital assistant (PDA)
system to collect symptom information in home

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.

hospice patients. J Palliat Med 2010;13:647-651.
7.

Aoyagi Y, Park H, Kakiyama T, Park S, Yoshiuchi
K, Shephard RJ. Yearlong physical activity andregional stiffness of arteries in older adults: theNakanojo Study. Eur J Appl Physiol 2010;109:455-464.

8.

Yoshiuchi K, Takimoto Y, Moriya J, Inada S,
Akabayashi

ReferencesA.

Thrombopoietin

andthrombocytopenia in anorexia nervosa with severe
liver dysfunction. Int J Eat Disord 2010;43:

1.

Fukui S, Yoshiuchi K, Fujita J, Sawai M, Watanabe
M. Japanese people’s preference for place of
end-of-life care and death: a population-based
nationwide survey. J Pain Symptom Manage, inpresss.

675-677.

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

164

Department of Transfusion
Medicine
Professor
Koki Takahashi, M.D., Ph.D.

Lecturer
Nelson H. Tsuno, M.D., Ph.D.,

Associate
Minoru Tanaka, M.D., Ph.D.,
Naoko Okochi, 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.

165

I.

Control and preservation of blood products andits derivatives;;
II. Laboratory tests
1) Blood typing and histocompatibility testing;2) Detection of anti-erythrocyte, anti-leukocyte andanti-platelet antibodies;3) Detection of HBV antigens and antibodies, HCV,
HAB, ATLA and HIV antibodies;
4) HLA typing for bone marrow and 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 to the post-transfusional complications, their etiology, prevention and treatment.
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. Clinical application of refrigerated and frozenstored blood for autologous transfusion in surgicalpatients.
4. Study on the mechanisms of transfusionassociated GVHD and its prevention.
5. Development of a new methodology for plateletcross-match.
6. Detection and characterization of anti-endothelial
cell antibodies, and study on their role in thepathogenesis of inflammatory and autoimmune
diseases, as well as in organ transplantation.

166

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: Ishizawa T, Hasegawa K, Tsuno NH, Tanaka M,
Mise Y, Aoki T, Imamura H, Beck Y, Sugawara Y,
Makuuchi M, Takahashi K, Kokudo N. Predeposit
autologous plasma donation in liver resection forhepatocellular carcinoma: toward allogenic
blood-free operations. J Am Coll Surg. 2009;
209(2):206-14.
2: Matsuhashi M, Tsuno NH, Kawabata M,
Yokoyama T, Tazaki Y, Takashima T, Oda H,
Kuroda Y, Nagayoshi Y, Morita S, Shibata Y,
Santoso S, Takahashi K. The first case of
alloantibody against HPA-15b in Japan:Possible
alloimmunization by a hydatidiform mole.
Transfusion 2009 (in Press)
3: Nishikawa T, Watanabe T, Sunami E, Tsuno NH,
Kitayama J, Nagawa H. Prognostic value of
peritoneal cytology and the combination of
peritoneal cytology and peritoneal disseminationin colorectal cancer. Dis Colon Rectum. 2009;52(12):2016-21.
4: Yoshikawa N, Yamada J, Tsuno NH, Okaji Y,
Kawai K, Tsuchiya T, Yoneyama S, Tanaka J,
Shuno Y, Nishikawa T, Nagawa H, Oshima N,
Takahashi K. Plaunotol and Geranylgeraniol
Induce Caspase-Mediated Apoptosis in Colon
Cancer. J Surg Res. 2009; 153(2):246-53
5: 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 by
Inhibition of Endothelial Progenitor Cell
Differentiation. J Surg Res. 2009;151(1):115-20.
6: Yoshikawa N, Yamada J, Tsuno NH, Okaji Y,

Kawai K, Tsuchiya T, Yoneyama S, Tanaka J,
Shuno Y, Nishikawa T, Nagawa H, Oshima N,
Takahashi K. Plaunotol and geranylgeraniol
induce caspase-mediated apoptosis in coloncancer. J Surg Res. 2009; 153(2):246-53

Reproductive, Developmental andAging Sciences
1. Obstetrics and Gynecology

168

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 vitro 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,
laparoscopic
hysterectomyorlaparoscopically assisted vaginal hysterectomy,
laparoscopicorlaparoscopicallyassisted
myomectomy, diagnostic laparoscopy for infertility ,laparoscopic surgery for ectopic pregnancy,
hysteroscopic surgery and so on, which make a totalof about 400 cases per year.

169

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.

102(6):1061-7,2010(9) Kodama A, et al. Progesterone decreases bonemorphogenetic protein (BMP) 7 expression and
BMP7 inhibits decidualization and proliferation in
endometrial stromal cells. Hum Reprod. 25(3):751-6,2010(10) Koyama S, et al. Repression of estrogen receptor
beta function by putative tumor suppressor DBC1.
Biochem Biophys Res Commun. 392(3):357-62,
2010(10) Koizumi M, et al. Inhibition of proteases involvedin embryo implantation by cholesterol sulfate. Hum
Reprod. 25(1):192-7, 2010(11) Koga K, et al. Autoamputated adnexa presents as aperitoneal loose body. Fertil Steril. 93(3):967-8,

References published in 20102010(12) Ouyang Z, et al. Interleukin-4 induces expression of(1) Harada M, et al. Dienogest, a new conservative
strategy for extragenital endometriosis: a pilot study.
Gynecol Endocrinol. 2010

eotaxin in endometriotic stromal cells. Fertil Steril.
94(1):58-62, 2010(13) Koga K, et al. Elevated serum soluble fms-like(2) Hirata T, et al. Recruitment of CCR6-expressing

tyrosine kinase 1 (sFlt1) level in women with

Th17 cells by CCL 20 secreted from IL-1 beta-,

hydatidiform mole. Fertil Steril. 94(1):305-8, 2010

TNF-alpha-, and IL-17A-stimulated endometriotic(14) Koizumi M, et al. Expression and regulation ofstromal cells. Endocrinology. 151(11):5468-76,

cholesterol sulfotransferase (SULT2B1b) in human2010

endometrium. Fertil Steril. 93(5):1538-44, 2010

(3) Yoshino O, et al. Decreased pregnancy rate islinked to abnormal uterine peristalsis caused byintramural fibroids. Hum Reprod. 25(10):2475-9,
2010(4) Isono W, et al. Uterine artery pseudoaneurysm after
cesarean section: case report and literature review. J
minim Invasive Gynecol. 17(6):687-91, 2010(5) Harada M, et al. Case of chronic ectopic pregnancy
diagnosed in which the complete shape of the fetus
was visible by ultrasonography. Circ J. 74(7):1494-6, 2010(6) Hasegawa A, et al. Hyaluronic acid reagent
suppressed endometriotic lesion formation in amouse model. Fertil Steril. 93(8):2757-9, 2010(7) Nakae H, et al. Inhibition of cell invasion andprotease activity by cholesterol sulfate. Fertil Steril.
94(6):2455-7, 2010(8) Hiraike H, et al. Identification of DBC1 as atranscriptional repressor for BRCA1. Br J Cancer.

170

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

171

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 designed a placebocontrolled trial in healthy adults to evaluate the safety
and immunogenicity of a synthetic peptide consistingof the aa 108-120 of HPV16 L2 (L2-108/120) region,
because this region contains a cross-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 or placebo (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 of ubiquitinmediated degradation by human papillomavirus E6
and the E6AP ubiquitin-protein ligase. In the present
study, we re-vealed that hScrib localised to thebasolateral regions of the epithelial cell line MDCKand human uterine cervical epithelial tissues byimmunofluorescence. 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 the progression of
disease from normal uterine cervical tissues toinvasive cervical cancers through the precursor lesions.
In contrast, the expression of hScrib was retained in
the throughout epithelial layer of the HPV-negative
cervical high-grade squamous intraepithelial lesions(H-SIL). Although quantitative RT-PCR revealed nosignificant downregu-lation of hScrib mRNA
expression in the H-SIL, it revealed a clear
downregulation in the invasive cancers. These results

172suggest the possibility that degradation by HPV E6 is
one of the causal roles for the progressive decrease of
hScrib expression during the disease progression fromlow-grade squamous intraepithelial lesions to H-SIL,
and a cooperative role of downregulation of hScribmRNA expression and ubiquitin-mediated degradationof hScrib by E6 and E6AP led to the complete
decrease of hScrib expression during the process ofcarcinogenesis from H-SIL to invasive cancer. These
data underscore the importance of hScrib in theconstruction of tissue architecture and prevention ofcancer development.
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173human 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, p53, ER

174

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 nonpolyposis 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,

175

and 63 (41%) in stage IIB. The conventional surgery
group included 115 patients (76%) who underwent
hysterectomy with pelvic lymph node dissection. Of
these, 72 (63%) received postoperative radiotherapy.
Thirty-seven patients (24%) were assigned to the RT
group. Of these, 14 (38%) received 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 2010
(1) Nagasaka K, et al. The mechanism and implicationsof hScrib regulation of ERK. Small Gtpases.
1(2):108-112, 2010(2) Miura S, et al. CD1d, a sentinel molecule bridging
innate and adaptive immunity, is downregulated by
the human papillomavirus (HPV) E5 protein: apossible mechanism for immune evasion by HPV. J
Virol. 84(22):11614-23, 2010
(3) Nagasaka K, et al. The cell polarity regulator hScrib
controls

ERK

activation

throughsite-dependenta

KIM

interaction.

Oncogene.29(38):5311-21, 2010(4) Shoji K, et al. Aromatase inhibitor anastrozole as asecond-line hormonal treatment to a recurrent
low-grade endometrial stromal sarcoma: a casereport. Med Oncol. 2010
(5) Adachi K, et al. Oral immunization with a
Lactobacillus casei vaccine expressing humanpapillomavirus (HPV) type 16 E7 is an effective
strategy to induce mucosal cytotoxic lymphocytes
against HPV16 E7. Vaccine. 28(16):2810-7, 2010(6) Murayama-Hosokawa S, et al. Genome-wide
single-nucleotide

polymorphism

arraysinendometrial

carcinomas

associate

extensive

chromosomal instability with poor prognosis andunveil frequent chromosomal imbalances involvedin the PI3-kinase pathway. Oncogene. 29(13):1897-908, 2010

176

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%.

177

References published in 2010(1) Imada S et al. Hypothermia-induced increase ofoligodendrocyte

precursor

cells:

Possible

involvement of plasmalemmal voltage-dependentanion channel 1. J Neurosci Res. 88(16):3457-66,
2010Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

179

Department ofPediatrics, Department ofDevelopmental Pediatrics
Professor
Takashi Igarashi, M.D.,Ph.D.

Associate Professor
Sachiko Kitanaka, M.D., Ph.D.
Kohmei Ida, M.D., Ph.D

Lecturer
Tatsuo Katori, M.D., Ph.D.
Junko Takita, M.D., Ph.D. (Department of Cell Therapy andTransplantation Medicine)

Associate
Hiroshi Ono, M.D., Keiji Goishi, M.D., Nobutaka Shimizu, M.D., Ph.D., Mitsuteru Hiwatari,M.D., Masato Takeuchi, M.D., Kan Takahashi, M.D., Hiroyuki Iwasaki, M.D., Ken-ichirou
Miura, M.D., Tsuyoshi Isojima, M.D., Ryo Inuzuka, M.D., Koujirou Yasui, M.D., Taiyu
Hayashi, M.D., Ai Motomura, M.D., Kouhei Kashima, M.D., Yuki Kimura, M.D., Nagahisa
Takahashi, M.D., Kiyoko Morita, M.D., Shunpei Uchimo, M.D.,(As of March 31, 2011)

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, 2 lecturers, 18 associate professors, 17senior residents, 2 research fellow, and 19 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.

Clinical activities
We have specialized outpatient clinics covering allpediatric fields in addition to general pediatrics. In
July, 2008, the capacity of the pediatric and pediatricsurgery ward was increased to 100 beds, including 9
beds in the neonatal intensive care unit (NICU), 15
beds in the growing care unit (GCU) and 6 beds in the180pediatric 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 4,000g 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
April, 2006.
(As of March 31, 2009)

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: We discovered
another mechanism of aberrant ALK activation
observed in a neuroblastoma-derived cell line,
NB-1, in which a short formal ALK protein having
a truncated extra-cellular domain. Several novel
mutations of IDH1/2 were detected in pediatricsolid tumors including neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma. Functional
impact of these mutations was currently analyzed
by a high-throughput metabolome study.
② Nephrology group: We analyzed clinical featuresand pathophysiological findings of nine EPSFTNS patients with MYH9 mutations, and foundthe novel role of NMMHC-IIA in the developmentof FSGS.
③ Cardiology group: A novel intervention catheter
technique in PDA was applied in several
congenital heart disease patients.
④ Immunology group: Research area of interest
includes refractory Kawasaki disease andepidemiology of childhood infectious disease.
⑤ Neonatology group: We conducted a research on
the establishment of the methods of newborn

181

screening system about the patients of congenital
cytomegalovirus infection. Also a trial of making
new artificial milk contains less protein equivalentof human milk.
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, in particular periventricular leukomalacia,
is also performed.
⑦ Endocrinology and Metabolism group: Molecularanalyses of genes involved in hereditary rickets
and a novel insight in their functional
consequences are studied. Genetic factors forvitamin D deficiency are analyzed.

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184

Department of Pediatric Surgery
Professor
Tadashi Iwanaka, M.D., Ph.D.

Associate Professor
Yutaka Kanamori, M.D., Ph.D.
Lecturer
Makoto Komura, M.D., Ph.D.

Research Associate
Masahiko Sugiyama, M.D., Kan Terawaki, M.D., Ph.D.
Teturou kodaka, M.D., Ph.D. Kan Suzuki., 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 staffs are the chief professor,
one associate professor, one lecturer, four research
associates, two senior residents, and three graduate
students. More than 20 members of our department
shoulder the clinical work as pediatric surgeons.

Clinical activities
Staffs higher than research associate level take chargeof the out-patient clinic from Monday through Friday.
The pediatric surgical outpatient clinic takes place in185

the same location as the pediatric outpatient clinic andwe closely cooperate with pediatricians to diagnose
and treat patients. We also have specialized outpatient
clinics, liver and biliary tract clinics and a tumor clinic.
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. This group creates multiple
functional forceps 3 mm in a diameter for robotic
surgery system at first. And they are developing
radical operation for long gap esophageal atresia byusing the latest technique of NOTES (Natural OrificeTransluminal Endoscopic Surgery).
The intestinal tract immunity study group was thefirst to start infant digestive organ function activation
medical treatment using a probiotic, Shinbiotic, withgood clinical effects. Further more inspection is
performed in order to do randomized control study inclinical course.
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.
The tumor study group analyzes the genes related totumor development and suppression. Further more,
new tumor marker is studying by using tumor tissues
and blood samples.

186

References(1) Tatekawa Y, Komuro H. A technical surgery forrefractory gastroparesis in a patient with amitochondrial disorder. Pediatr Surg Int.
2010;26:655-658.
(2) Iwanaka T, Kanamori Y, Sugiyama M, Komura M,
Tanaka Y, Kodaka T, Ishimaru T. Laparoscopic
fundoplication for gastroesophageal reflux
disease in infants and children. Surg Today. 2010;
40:393-397.
(3) Ishimaru T, Kitano Y, Uchida H, Kawashima H,
Gotoh C, Satoh K, Yoshida M, Kishimoto H,
Iwanaka T. Histopathologic improvement inbiliary cirrhosis after definitive surgery forcholedochal cyst. J Pediatr Surg. 2010;45:e11-14.
(4) Tatekawa Y, Kawazoe N, Chen G, Shirasaki Y,
Komuro H, Kaneko M. Tracheal defect repair
using a PLGA-collagen hybrid scaffold
reinforced by a copolymer stent with bFGFimpregnated gelatin hydrogel. Pediatr Surg Int.
2010;26:575-580.
(5) Uchida H, Goto C, Kishimoto H, Kawashima H,
Sato K, Yoshida M, Takazawa S. Laparoscopic
spleen-preserving distal pancreatectomy for solid
pseudopapillary tumor with conservation of
splenic vessels in a child. J Pediatr Surg.
2010;45:1525-1529.
(6) Ogura M, Kikuchi E, Kaito H, Kamei K,
Matsuoka K, Tanaka H, Kuroda T, Sekine T, Ito S.
ABO-incompatible renal transplantation in
Epstein syndrome. Clin Transplant. 2010; Suppl
22:31-34.
(7) Tanaka Y, Masuda S, Abe T, Hayashi S, Kitano Y,
Nagao Y, Hanazono Y.Intravascular route is notsuperior to an intraperitoneal route for in uterotransplantation of human hematopoietic stem
cells and engraftment in sheep.Transplantation.
2010;90:462-463.
(8) Tanaka H, Fukuda A, Shigeta T, Kuroda T,
Kimura T, Sakamoto S, Kasahara M. Biliary
reconstruction in pediatric live donor livertransplantation: duct-to-duct or Roux-en-Y
hepaticojejunostomy. J Pediatr Surg. 2010;45:
1668-1675.
(9) Komuro H, Kudou S, Matsubara M, Hoshino N.
Thoracoscopic treatment of chylothorax after

patch repair of congenital diaphragmatic hernia. J
Pediatr Surg. 2010;45:1748-1750.
(10) Komura M, Kanamori Y, Sugiyama M,
Fukushima N, Iwanaka T. A pediatric case oflife-threatening airway obstruction caused by acervicomediastinal thymic cyst. Pediatr Radiol.
2010;40:1569-1571.
(11) Komuro H, Hoshino N, Urita Y, Fujishiro J,
Sakamoto N, Ono K, Kaneko M.Pathogenic
implications of remnant vitelline structures ingastroschisis. J Pediatr Surg. 2010;45:2025-2029.
(12) Komura M, Komura H, Kanamori Y, Tanaka Y,
Ohatani Y, Ishimaru T, Sugiyama M, Hoshi K,
Iwanaka T. Study of mechanical properties ofengineered cartilage in an in vivo culture fordesign of a biodegradable scaffold. Int J Artif
Organs. 2010;33:775-781.
(13) Uchida H, Kawashima H, Goto C, Sato K,
Yoshida M, Takazawa S, Iwanaka T. Inguinal
hernia repair in children using single-incision
laparoscopic-assisted
percutaneous
extraperitoneal closure. J Pediatr Surg. 2010;45:
2386-2389.
(14) Takayasu H, Kitano Y, Kuroda T, Morikawa N,
Tanaka H, Fujino A, Muto M, Nosaka S,
Tsutsumi S, Hayashi S, Sago H. Successful
management of a large fetal mediastinal teratoma
complicated by hydrops fetalis. J Pediatr Surg.
2010;45:e21-24.
(15) Usui N, Kitano Y, Okuyama H, Saito M,
Morikawa N, Takayasu H, Nakamura T, Hayashi
S, Kawataki M, Ishikawa H, Nose K, Inamura N,
Masumoto K, Sago H. Reliability of the lung tothorax transverse area ratio as a predictive
parameterin
fetuseswithcongenital
diaphragmatic hernia. Pediatr Surg Int. 2011;27:
39-45(16) Sato K, Gotoh C, Uchida H, Kawashima H,
Yoshida M, Kitano Y, Kishimoto H. Sialolipomaof the submandibular gland in a child. J Pediatr
Surg. 2011;46:408-410.
(17) Sakamoto S, Shigeta T, Hamano I, Fukuda A,
Kakiuchi T, Matsuno N, Tanaka H, Nakagawa A,
Kasahara M. Graft outflow venoplasty on
reduced left lateral segments in living donor livertransplantation for small babies. Transplantation.
2011;91:e38-40.

Reproductive, Developmental andAging Sciences
3. Aging Sciences

188

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

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

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

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

Yasuhiro Yamaguchi, M.D., Ph.D.,

Research Associate
Hiroshi Yamamoto, M.D., Ph.D.

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

Hidetaka Ota, 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 of the patients as awhole from multiple points of view. In addition, in theelderly patients, symptoms, signs and responses to thetreatment are sometimes quite different from theyoung. We have to have a broad knowledge on thephysiological and metabolic changes with aging when
we treat the elderly patients. Quality of life of thepatients is another point of view which should beemphasized.
Our sub-specialty includes respirology, cardiology,
neurology, hematology, endocrinology, and bonemetabolism, besides the general geriatric internal
medicine.
We are trying to elucidate the pathophysiology of
aging process and understand elderly patients fromviewpoints of basic aging science using molecularbiology technique and clinical aspects using the recent
advancement of technology and geriatric assessment.

In the clinical ward, there are around 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 ajunior resident, give instructions as to the assessmentof the patient's problem, making of future plans, andhelp the resident with various procedures. Very
important issues are discussed and decisions are madein weekly professor's round.
Specialized services are provided to out-patients ona daily basis in all areas of internal medicine. 354 newand a total of 19,250 patients visited 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189

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
1) Research on the molecular mechanism of vascular
calcificationi) Molecular biology of vascular calcification invitroii) Animal model of vascular calcificationiii) Clinical factors associated with vascular
calcification
2) Regulation of vascular function by sex hormone
3) Molecular biology for the control of aging.
Cellular senescence and Sirt1 in vascular cells4) Clinical association of androgen with functional
decline in the elderly5) Multicenter-investigation of the optimal treatment
strategy for hypertension or lipid disorder in theelderly6) Clinical study on metabolic syndrome in theelderly7) Diagnosis and treatment of the demented patients
8) Expression and regulation of nuclear receptors inosteoblast and osteoclast9) Molecular mechanism under the treatment of
osteoporosis10) Genetic analysis of osteoporosis and osteoarthritis
11) Identification and functional analysis of the target
gene networks associated with hormone
responsiveness in prostate and breast cancers12) Role of nuclear receptors in senescence andcarcinogenesis13) Diagnosis and prevention of aspiration pneumonia
14) Novel roles of antimicrobial peptide, defensin
15) Adrenomedullin and airway hyperresponsiveness16) Klotho protein and vitamin D in lung17) Clinical investigation of sleep-related breathing
disorderPublications
1.

Akishita M, Fukai S, Hashimoto M, Kameyama
Y, Nomura K, Nakamura T, Ogawa S, Iijima K,
Eto M, Ouchi Y. Association of low testosterone

with metabolic syndrome and its components in
middle-aged Japanese men. Hypertens Res.
2010; 33: 587-591.
2. Akishita M, Hashimoto M, Ohike Y, Ogawa S,
Iijima K, Eto M, Ouchi Y. Low testosterone levelas a predictor of cardiovascular events inJapanese men with coronary risk factors.
Atherosclerosis. 2010; 210: 232-236.
3. Azuma K, Casey SC, Ito M, Urano T, Horie K,
Ouchi Y, Kirchner S, Blumberg B, Inoue S.
Pregnane X receptor knockout mice display
osteopenia with reduced bone formation andenhanced bone resorption. J Endocrinol. 2010;
207: 257-263.
4. Fujita M, Sugama S, Sekiyama K, Sekigawa S,
Tsukui T, Nakai M, Waragai M, Takenouchi T,
Takamatsu Y, Wei J, Rockenstein E, LaSpada AR,
Masliah E, Inoue S, Hashimoto M. Αβ-synuclein mutation linked to dementia
produces neurodegeneration when expressed inmouse brain. Nat Commun. 2010; 1: 110.
5. Fukai S, Akishita M, Miyao M, Ishida K, Toba K,
Ouchi Y. Age-related changes in plasma
androgen levels and their association withcardiovascular risk factors in male Japanese
office workers. Geriatr Gerontol Int. 2010; 10:32-39.
6. Fukai S, Akishita M, Yamada S, Ogawa S,
Yamaguchi K, Kozaki K, Toba K, Ouchi Y.
Plasma sex hormone levels and mortality indisabled older men and women. Geriatr
Gerontol Int. 2010; 11: 196-203.
7. Fukai S, Akishita M, Yamada S, Toba K, Ouchi Y.
Effects of testosterone in older men with mild tomoderate cognitive impairment. J Am Geriatr
Soc. 2010; 58: 1419-1421.
8. Iijima K, Hashimoto H, Hashimoto M, Son BK,Ota H, Ogawa S, Eto M, Akishita M, Ouchi Y.
Aortic arch calcification detectable on chest
X-ray is a strong independent predictor of
cardiovascular events beyond traditional risk
factors. Atherosclerosis. 2010; 210: 137-144.
9. Iwaoka Y, Hashimoto R, Koizumi H, Yu J, Okabe
T. Selective stimulation by cinnamaldehyde ofprogesterone secretion in human adrenal cells.
Life Sci. 2010; 86: 894-898.
10. Koizumi H, Yu J, Hashimoto R, Ouchi Y, Okabe

190

11.

12.

13.

14.

15.

16.

17.

18.

T. Involvement of androgen receptor in nitricoxide production induced by icariin in humanumbilical vein endothelial cells. FEBS Lett.
2010; 584: 2440-2444.
Kurosawa T, Hiroi H, Momoeda M, Inoue S,
Taketani Y. Clomiphene citrate elicits estrogenagonistic/antagonistic effects differentially via
estrogen receptors α and β. Endocr J. 2010; 57:
517-521.
Murata T, Takayama K, Katayama S, Urano T,
Horie-Inoue K, Ikeda K, Takahashi S, Kawazu C,
Hasegawa A, Ouchi Y, Homma Y, Hayashizaki Y,
Inoue S. miR-148a is an androgen-responsive
microRNA that promotes LNCaP prostate cell
growth by repressing its target CAND1
expression. Prostate Cancer Prostatic Dis. 2010;
13: 356-361.
Nomura K, Eto M, Kojima T, Ogawa S, Iijima K,
Nakamura T, Araki A, Akishita M, Ouchi Y.
Visceral fat accumulation and metabolic risk
factor clustering in older adults. J Am Geriatr
Soc. 2010; 58: 1658-1663.
Onodera Y, Miki Y, Suzuki T, Takagi K, Akahira
JI, Sakyu T, Watanabe M, Inoue S, Ishida T,
Ohuchi N, Sasano H. Runx2 in human breast
carcinoma: its potential roles in cancer
progression. Cancer Sci. 2010; 101: 2670-2675.
Ota H, Eto M, Kano MR, Kahyo T, Setou M,
Ogawa S, Iijima K, Akishita M, Ouchi Y.
Induction of Endothelial Nitric Oxide Synthase,
SIRT1, and Catalase by Statins Inhibits
Endothelial Senescence Through the Akt
Pathway. Arterioscler Thromb Vasc Biol. 2010;
30: 2205-2211.
Oyama M, Nagashima T, Suzuki T, Kozuka-Hata
H, Yumoto N, Shiraishi Y, Ikeda K, Kuroki Y,
Gotoh N, Ishida T, Inoue S, Kitano H,
Okada-Hatakeyama M. Integrated Quantitative
Analysis of the Phosphoproteome andTranscriptome in Tamoxifen-Resistant Breast
Cancer. J Biol Chem. 2011; 286: 818-829.
Shigemoto K, Kubo S, Mori S,Yamada S,
Akiyoshi T, Miyazaki T. Muscle weakness andneuromuscular junctions in aging and disease.
Geriatr Gerontol Int. 2010; 10: S137-147.
Son BK, Akishita M, Iijima K, Ogawa S,
Maemura K, Yu J, Takeyama K, Kato S, Eto M,

19.

20.

21.

22.

23.

24.

Ouchi
Y.
Androgen
Receptor-dependent
Transactivation of Growth Arrest-specific Gene
6 Mediates Inhibitory Effects of Testosterone on
Vascular Calcification. J Biol Chem. 2010; 285:7537-7544.
Takayama K, Tsutsumi S, Katayama S, Okayama
T, Horie-Inoue K, Ikeda K, Urano T, Kawazu C,
Hasegawa A, Ikeo K, Gojyobori T, Ouchi Y,
Hayashizaki Y, Aburatani H, Inoue S. Integrationof cap analysis of gene expression and chromatin
immunoprecipitation analysis on array reveals
genome-wide androgen receptor signaling inprostate cancer cells. Oncogene. 2011; 30:
619-630.
Urano T, Shiraki M, Usui T, Sasaki N, Ouchi Y,
Inoue S. Identification of non- synonymous
polymorphisms in the WDSOF1 gene as novel
susceptibility markers for low bone mineraldensity in Japanese postmenopausal women.
Bone. 2010; 47: 636-642.
Urano T, Narusawa K, Sasaki N, Shiraki M,
Hosoi T, Ouchi Y, Nakamura T, Inoue S. A
single-nucleotide
polymorphism
inthehyaluronan and proteoglycan link protein 1(HAPLN1) gene is associated with spinal
osteophyte formation and disc degeneration in
Japanese women. Eur Spine J. 2011; 20:572-577.
Urata Y, Goto S, Kawakatsu M, Yodoi J, Eto M,
Akishita M, Kondo T. DHEA attenuates
PDGF-induced phenotypic proliferation ofvascular smooth muscle A7r5 cells throughredox regulation. Biochem Biophys Res
Commun. 2010; 396: 489-494.
Yamada S, Akishita M, Fukai S, Ogawa S,
Yamaguchi K, Matsuyama J, Kozaki K, Toba K,
Ouchi Y. Effects of dehydroepiandrosterone
supplementation on cognitive function and ADL
in older women with mild to moderate cognitive
impairment. Geriatr Gerontol Int. 2010; 10:280-287.
Yu J, Akishita M, Eto M, Ogawa S, Son BK,
Kato S, Ouchi Y, Okabe T. Androgen
receptor-dependent activation of endothelial
nitric oxide synthase in vascular endothelial
cells: role of phosphatidylinositol 3-kinase/akt
pathway. Endocrinology. 2010; 151: 1822-1828.

Surgical Sciences
1. Surgery

192

Department of Thoracic Surgery
Professor
Nakajima, Jun

Assistant Professor
Murakawa, Tomohiro

StaffsSano, Atsushi and Nagayama, Kazuhiro

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 Tsuduki, Masao adopted
the modified Coryllos’s thoracoplasty for thetreatment of the pulmonary tuberculosis in 1934. They
initiated thoracoscopy for the treatment of the
tuberculosis in our country. After the successful
application of the antituberculous drugs, surgicaltreatment of the thoracic malignant neoplasms was the
major concern of 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 ~ 2009.3.31).
The Department of Cardiothoracic Surgery has been
divided into two departments, Department of
Cardiovascular Surgery and Department of Thoracic
Surgery in 1997.
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 Sano A),
who are certificated as members of the Japanese
Board of General Thoracic Surgery, are in charge of
the Department of Thoracic Surgery, University ofTokyo Hospital. They specialize in surgical treatmentof the diseases of the respiratory and the mediastinalorgans and the chest wall, except for diseases of theesophagus and mammary glands. Approximately 330
surgeries are performed in the department in 2010.
Primary lung cancer has been the leading cause ofdeath among the malignant neoplasms in our country.
Basic and clinical investigations for the treatment oflung cancer are very important, because number of thepatients who died of the lung cancer has been
increasing. In our department, the staffs are engaging
the clinical works, studies and educations ofdiagnostics and therapeutics of the lung cancer andother 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

193

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 thoracic
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.
We are now preparing clinical lung transplantation
program in this hospital with the usage of lungs frombrain-dead donors.
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) Global analysis of oncogenes and suppressor
genes associated with lung cancer.
(4) Clinical trial and basic research on adoptive
anticancer
immunityoftheautologous
gamma-delta-T-cell for the treatment of therecurrent primary lung cancer or pulmonary
metastasis from colorectal cancer.
(5) Clinical trial of vaccine immunotherapy for therecurrent non-small cell lung cancer.
(6) Analysis on mechanisms of acute or chronic
rejection of the allogeneic lung and trachea.

Selected publications(1) Nakajima J, Murakawa T, Fukami T, Goto S,
Kaneko T, Yoshida Y, Takamoto S, Kazuhiro K. A
phase I study of adoptive immunotherapy forrecurrent non-small cell lung cancer patients withautologous gammadelta T cells. Eur J CardioThorac Surg 2010, 37:1191-7(2) Kusakabe M, Kutomi T, Watanabe K, Emoto N,
Aki N, Kage H, Hamano E, Kitagawa H, Nagase T,
Sano A, Yoshida Y, Fukami T, Murakawa T,
Nakajima J, Takamoto S, Ota S, Fukayama M,
Yatomi Y, Ohishi N, Takai D. Identification of
G0S2 as a gene frequently methylated in squamouslung cancer by combination of in silico andexperimental approaches. Int J Cancer. 2010; 126:895-902(3) Murakawa T, Yoshida Y, Fukami T, Nakajima J.
Life-threatening tracheal perforation secondary todescending

necrotizing

mediastinitis.

Interact

Cardiovasc Thorac Surg. 2010; 10: 454-6(4) Takahashi T, Murakawa T, Fukami T, Nakajima J.
Pneumothorax

after

left

pneumonectomy:

194

accentuated negative pressure at azygoesophageal
recess by a mediastinal shift and rotation. Eur J
Cardiothorac Surg. 2010, 37:1222(5) Sakamoto M, Murakawa T, Kitano K, Murayama T,
Tsuchiya T, Nakajima J. Resection of solitary
pulmonary lesion is beneficial to patients with ahistory of malignancy. Ann Thorac Surg. 2010,
90:1766-71.
(6) Murakawa T, Ito N, Fukami T, Nakajima J,
Takamoto S. Application of lobe-selective bronchialblockade against airway bleeding. Asian Cardiovasc
Thorac Ann. 2010, 18:483-5.
(7) Nakajima J. Pulmonary metastasis: rationale for
local treatments and techniques. Gen Thorac
Cardiovasc Surg. 2010, 58:445-51(8) Shirota Y, Iwata A, Ishiura H, Hashimoto M, Goto J,
Shimizu J, Hanajima R, Nakajima J, Takazawa Y,
Tsuji S. A case of atypical amyloid polyneuropathy
with predominant upper-limb involvement with thediagnosis unexpectedly found at lung operation.
Intern Med. 2010, 49:1627-31(9) Nakajima J. Surgery for secondary spontaneous
pneumothorax. Curr Opin Pulm Med. 2010, 16:
376-80(10) Mise Y, Imamura H, Hashimoto T, Seyama Y, Aoki
T, Hasegawa K, Beck Y, Sugawara Y, Makuuchi M,
Nakajima J, Kokudo N. Cohort study of thesurvival benefit of resection for recurrent hepatic
and/orpulmonarymetastases

afterprimary

hepatectomy for colorectal metastases. Ann Surg.
2010, 251: 902-9.

195

Department of
Cardiac Surgery
Professor
Minoru Ono, M.D.

Associate Professor
Arata Murakami, M.D.

Lecturer
Noboru Motomura, M.D.,

Tetsuro Morota, M.D.,

Associate
Tetsuhiro Takaoka, M.D.,

Tsuyoshi Taketani, M.D.,

Kazuo Kitahori, M.D.,

Tadashi Kitamura, M.D.,

Aya Saito, M.D.,

Kan Nawata, M.D.,

Osamu Kinoshita, M.D.

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. Dr. Minoru Ono
was elected as the sixth Professor in November 2009.
Present staffs are one Chief Professor, one Associate
Professor and two Lecturer and six Associates.

196

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.
Adult patients are hospitalized in the South Wing of
5th floor, and pediatric patients in the South Wing of
2nd floor. Clinics are open Monday through Friday forthe follow-up visit as well as for patient referral.
Case volume in recent years has been about 350,
which is one of the highest in Japan. We are leading inJapan by showing excellent surgical results. There areeight Board-certified surgeons, each of whom has his
own subspecialty among adult cardiac, thoracic aortic
or congenital heart disease. We are famous for aortic
valve sparing root replacement, arch replacement
using retrograde cerebral perfusion, treatment ofextended thoracic aortic aneurysm, ventricular assist
device implantation, off- pump coronary artery bypass
surgery, mitral valve plasty and repair of complex
congenital heart diseases, such as Jatene, Fontan and
Norwood operations.
The University of Tokyo Tissue Bank was founded
in 1997, based on the Department of Cardiovascular
Surgery. The Bank has been actively promoting
procurement, preservation and shipping of humanvalve and blood vessel allograft in Japan. We take thelead in surgical treatment using allograft for severe
active endocarditis or infection of aortic aneurysm or
vascular prosthesis. Surgical treatment using allograft
was approved as advanced medical technology by theGovernment in 2006. As of March 2011, 15 cases ofheart transplantation and 71 cases of ventricular assist
device implantation 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 once a month 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) establishment of recovery and weaning
protocols of left ventricular assist device, 2)
etiological approach to diabetic retinopathy andischemic heart disease, 3) basic and clinical researchon cryopreserved allograft, 4) new effective brain andspinal cord protection strategy, 5) a new technique ofaortic valve sparing root replacement and its
hemodynamic evaluation, 6) mechanism analysis ofright heart failure and development of effective

197

pharmacologicaltherapy,
7)
applicationofregenerative medicine to end-stage heart failure, 8)
development of new heart preserving solution .

Takamoto S: Stomach pierced by apical cuff lateafter removal of Toyobo assist device. Asian
Cardiovasc Thorac Ann 2010, 18; 74-76(2) Shimizu T, Ohno T; Ando J, Fujita H, Nagai R,
Motomura N, Ono M, Kyo S, Takamoto S:
Mid-Term Results and Costs of Coronary Artery
Bypass vs Drug-Eluting Stents for Unprotected
Left Main Coronary Artery Disease. Circ J 2010,
74: 449 – 455(3) Ono M, Shimizu T, Nawata K, Saito A,
Motomura N, Murakami A, Kyo S: Routine useof bilateral papillary muscle elevation for
surgical treatment of functional mitral valve
regurgitation in dilated cardio- myopathy. Circ J
2010, 74 Suppl 1, 46(4) Kawashima D, Ohno T, Fujita H, Kato A,
Kadowaki T, Araie M, Nagai R, Ono M,
MurakamiA,

Takamoto

S:

Prevalence of vitreous hemorrhage following
coronary revascularization among patients withdiabetic retinopathy. Circ J 2010, 74 Suppl 1, 721(5) Kinoshita O, Nishimura T, Kawata M, Ando M,
Kyo S, Ono M: Vacuum assisted closure with
Safetac technology for mediastinitis in patientswith ventricular assist device. J Artif Organ 2010,
13, 126-128(6) Kashiwa K, Nishimura T, Kubo H, Tamai H,
Baba A, Ono M, Takamoto S, Kyo S: Study ofDevice Malfunctions in Patients with Implantable
Ventricular Assist Devices Living at Home. J
Artif Organ 2010, 13, 134-138(7) Seki S, Kato N, Ito N, Kinugawa K, Ono M,
Motomura N, Yao A, Watanabe M, Imai Y,
Takeda N, Inoue M, Hatano M, Kazuma K:
Validity

andNishimura E, Okumura T, Ishii M, Hisagi M,
A novel external counter- pulsation system for(1) Nawata K, Kyo, S, Ono, M, Motomura N,

N,(8) Shimizu T, Kyo S, Imanaka K, Nakaoka K,
Nishimura T, Motomura N, Ono M, Takamoto S:

References

Motomura

2010, 4, 57-63

reliabilityof

SeattleAnginaQuestionnaire Japanese version in patients withcoronary artery disease. Asian Nursing Researchcoronary artery disease and heart failure: pilot
studies and initial clinical experiences. J Artif
Organ 2010, 13, 161-169(9) Hisagi M, Nishimura T, Ono M, Gojo S, Nawata
K, Kyo S: New pre-clotting method for fibrin
glue in a non-sealed graft used in an LVAD: theKYO method. J Artif Organ 2010, 13, 174-177(10) Ono M, Kyo S, Nishimura T, Hisagi M, Nawata
K, Kinoshita O: How do we construct an ideal
infrastructureforincreasing

demandofimplantable ventricular assist device. J Cardiac
Fail 2010, 16; S144
(11) Kitahori K, Murakami A, Takaoka T, Takamoto S,
Ono M: Precise evaluation of bilateral pulmonary
artery banding for initial palliation in high-risk
hypoplastic

left

heart

syndrome.

J

ThoracCardiovasc Surg 2010, 140, 1084-91(12) Nawata K, Nishimura T, Kyo S, Hisagi M,
Kinoshita O, Saito A, Motomura N, Takamoto S,
Ono M: Thrombotic occlusion of the ascending
aorta after Toyobo LVAD implantation withdescending aortic perfusion in a post-Bentall
patient. J Artif Organ 2010, 13, 228-231(13) Nawata K, Nishimura T, Kyo S, Hisagi M,
Kinoshita O, Saito A, Motomura N, Takamoto S,
Ono M: Outcomes of midterm circulatory support
by left ventricular assist device implantation withdescending aortic anastomosis. J Artif Org 2010,
13, 197-201(14) Shimada S, Motomura N, Kinoshita O, Saito A,
Kasuga J, Matsusaka Y, Kawabata J, Kuwabara C,
Fujikawa S, Ono M

Successful

introductionof novel supercoolant, Kaempferol 7-O-beta-Dglucopyranoside(KF7G),

tosub-zeronon-freezing rat heart preservation. Low Temp Med
2010; 36, 20-24(15) Motomura N, Miyata H, Tsukihara H, Takamoto
S,

Japan

Cardiovascular

Surgery

Database

198

Organization: Risk model of valve surgery inJapan using the Japan Adult Cardiovascular
Surgery Database. J Heart Valve Dis. 2010; 19:684-91(16) Nishimura T, Kyo S: Triple-site pacing: a new
supported

therapy

approachforbridgetorecovery with a left ventricular assist system in apatient with idiopathic dilated cardiomyopathy. J
Artif Organs. 2010 ; 13: 54-7
(17) Nishimura T, Kyo S: High-dose carvedilol
therapy for mechanical circulatory assisted
patients. J Artif Organs. 2010; 13: 88-91(18) Itatani K, Miyaji K, Nakahata Y, Ohara K,Takamoto S, Ishii M: The lower limit of thepulmonary artery index for the extra- cardiac
Fontan circulation. J Thorac Cardiovasc Surg.
2011; 142: 127-35(19) Itatani K, Miyaji K, Miyamoto T, Inoue N,
Tomoyasu T, Kohira S, Sato H, Ohara K:
Miniaturized biocompatible cardiopul- monary
bypass for the Fontan procedure. Surg Today.
2010; 40: 1040-5(20) Itatani K, Miyaji K, Inoue N, Ohara K:

Ebsteinanomaly associated with double- orifice tricuspid
valve. J Thorac Cardiovasc Surg. 2010; 139:e131-3

199

Department of
Gastrointestinal Surgery
Professor
Yasuyuki

Seto MD. PhD.

Associate Professor
Sachiyo Nomura MD. PhD.

Nobuyuki Shimizu MD. PhD.

Lectuler
Ikuo Wada MD. PhD.

Associates
Fumihiko Hatao MD. PhD

Masashi Abe MD.

Tetsuya Ueda MD.PhD.

Takashi Fukuda MD.

Kazuhiko Mori MD. PhD.

Keiji Kato 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.

200

Educational Activities:
We educate chief residents and junior residents inrotation．Our educational systems for residents andstudents reflect our aforementioned principles.
Medical students are encouraged to be members ofclinical staffs rather than mere students during their
bedsideLearning. They learn generic patient care which
encompasses not only perioperative management ofdiseases but also non-surgical management of
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

201- Mechanism of pepermint oil solution of digestivetract- Role of cytokine and COX-2 in gastrointestinal
motility- Manipulation of the intestine and postoperative
motility

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

References
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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?
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 molecularsignature of gastric metaplasia arising in
response to acute parietal 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,
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Hiki N, Fukunaga T, Yamaguchi T, Nunobe S,
Tokunaga M, Ohyama S, Seto Y, Yoshiba H,
Nohara K, Inoue H, Muto T. The benefits ofstandardizing 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 between definitive chemoradiotherapy and radical surgery in 82 Japanesepatients with resectable esophageal squamouscell 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 with

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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
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.
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resistance. Antioxid Redox Signal 9:319-329,
2007
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M, Nomura S, Kakushima N, Muraki Y, Goto O,
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
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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,
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Tetsuya T, Tanaka H, Tatematsu M, Nomura S,
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204

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

Associate Professor
Yasuhiko Sugawara, MD., Kiyoshi Hasegawa, MD.

Lecturers
Yoshifumi Beck, MD., Taku Aoki, MD.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/hbps_md/index.html

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 (2010)
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Song P, Tang W, Tamura S, Hasegawa K,
Sugawara Y, Dong J, Kokudo N. The
management of hepatocellular carcinoma in Asia:a guideline combining quantitative andqualitative evaluation. Biosci Trends 2010;
4:283-7.
Kaneko J, Sugawara Y, Togashi J, Tamura S,
Motoi R, Fukayama M, Kokudo N. Sarcomatouschange of hepatocellular carcinoma in a patient

205

undergoing living donor liver transplantation.
Biosci Trends 2010; 4:279-82.
3. Hasegawa K, Kokudo N, Shiina S, Tateishi R,
Makuuchi M. Surgery versus radiofrequency
ablation for small hepatocellular carcinoma: Startof a randomized controlled trial (SURF trial).
Hepatol Res 2010; 40:851-2.
4. Ishizawa T, Bandai Y, Ijichi M, Kaneko J,
Hasegawa
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Fluorescentcholangiography illuminating the biliary tree
during laparoscopic cholecystectomy. Br J Surg
2010; 97:1369-77.
5. Harada N, Ishizawa T, Muraoka A, Ijichi M,
Kusaka K, Shibasaki M, Yamamoto K, Hasegawa
K, Bandai Y, Kokudo N. Fluorescence navigation
hepatectomy by visualization of localizedcholestasis from bile duct tumor infiltration. J
Am Coll Surg 2010; 210:e2-6.
6. Shindoh J, Imamura H, Kokudo N. Isolated sling
suspension during resection of the Spiegel lobeof the liver: a safe alternative technique fordifficult cases. J Hepatobiliary Pancreat Sci
2010; 17:359-64.
7. Inagaki Y, Tang W, Zhang L, Du G, Xu W,
Kokudo N. Novel aminopeptidase N (APN/
CD13) inhibitor 24F can suppress invasion ofhepatocellular carcinoma cells as well as
angiogenesis. Biosci Trends 2010; 4:56-60.
8. Takamoto T, Hashimoto T, Sano K, Maruyama Y,
Inoue K, Ogata S, Takemura T, Kokudo N,
Makuuchi M. Recovery of liver function after the
cessation of preoperative chemotherapy forcolorectal liver metastasis. Ann Surg Oncol 2010;17:2747-55.
9. Kokudo N, Arita J. Staging for intrahepaticcholangiocarcinoma. Liver Int 2010; 30:931-3.
10. Mise Y, Imamura H, Hashimoto T, Seyama Y,
Aoki T, Hasegawa K, Beck Y, Sugawara Y,
Makuuchi M, Nakajima J, Kokudo N. Cohort
study of the survival benefit of resection forrecurrent hepatic and/or pulmonary metastases
after primary hepatectomy for colorectal
metastases. Ann Surg 2010; 251:902-9.
11. Shindoh J, Mise Y, Satou S, Sugawara Y, Kokudo
N. The intersegmental plane of the liver is notalways flat--tricks for anatomical liver resection.
Ann Surg 2010; 251:917-22.

12. Inoue Y, Takahashi M, Arita J, Aoki T, Hasegawa
K, Beck Y, Makuuchi M, Kokudo N. Intraoperative freehand real-time elastography forsmall focal liver lesions: "visual palpation" fornon-palpable tumors. Surgery 2010; 148:100011.
13. Yamashiki N, Sugawara Y, Tamura S, Tateishi R,
Yoshida H, Kaneko J, Matsui Y, Togashi J,
Akahane M, Makuuchi M, Omata M, Kokudo N.
Postoperative surveillance with monthly serum
tumor markers after living-donor livertransplantation for hepatocellular carcinoma.
Hepatol Res 2010; 40:278-86.
14. Tamura S, Sugawara Y, Yamashiki N, Kaneko J,
Kokudo N, Makuuchi M. Pre-emptive antiviraltherapy in living donor liver transplantation forhepatitis C: observation based on a single-center
experience. Transpl Int 2010; 23:580-8.
15. Ishizawa T, Mise Y, Aoki T, Hasegawa K, Beck Y,
Sugawara Y, Kokudo N. Surgical technique: newadvances for expanding indications andincreasing safety in liver resection for HCC: theEastern perspective. J Hepatobiliary Pancreat Sci
2010; 17:389-93.
16. Hasegawa K, Kokudo N, Sano K, Makuuchi M.
Single HCC between 2 and 5 cm: the grey zon:
surgeon’s perspective. J Hepatobiliary Pancreat
Sci 2010; 17:430-3.
17. Kishi Y, Imamura H, Sugawara Y, Sano K,
Kaneko J, Kokudo N, Makuuchi M. Evaluationof donor vasculobiliary anatomic variations inliver graft procurements. Surgery 2010; 147:
30-9.
18. Kyoden Y, Tamura S, Sugawara Y, Matsui Y,
Togashi J, Kaneko J, Kokudo N, Makuuchi M.
Incidenceandmanagementofbiliary
complications after adult-to-adult living donorliver transplantation. Clin Transplant 2010; 24:
535-42.

206

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

Associate Professor
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.

Motofumi Suzuki, M.D., Ph.D.

Research Associate
Chihiro Hosoda, M.D., Ph.D.

Daisuke Yamada, M.D., Ph.D.

Masayoshi Nagata, M.D., Ph.D.

Yaro Murata, M.D., Ph.D.

Akira Nomiya, M.D.

Aya Niimi, M.D.

Shinichiro Murayama, M.D.

Satoru Taguchi, M.D.

Mami Hattori, 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 robotic surgery forprostatectomy 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 1,800 fromJanuary 2010 to December 2010.

207

Elective operations are performed on Tuesday andThursday. A total of 1,446 operations were performed
in 2010. The numbers of main operations are
adrenalectomy 31, radical nephrectomy 32, partial
nephrectomy 25, radical cystectomy 19, radical
prostatectomy 73, transurethral resection of the
bladder tumor (TUR-Bt) 206, transurethral resectionof the prostate (TUR-P) 28, and laparoscopic surgery
55.
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, pediatricurology and female urology receive sophisticated careon the particular day of the week.
The total number of out-patients was 29,472
patient-days from January 2010 to December 2010.

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

References1)2)

Teaching activities
Systematic urological lectures are provided forsecond year medical students. Both clinical lecturesand bed side teaching are scheduled for third andfourth year medical students. Thirteen times ofsystematic lectures are performed by professor,
associate professors and instructors concerning their
specialties.
Bed side teaching is concentrated on practical careof the patients. Teachers give lectures mainly
regarding pre- and post-operative management,
indication of operation, surgical anatomy and surgical
techniques.

3)

4)

Research activities
There are 9 research themes for research as below.
The basic principles for research are program insurgical techniques and therapy for incurable diseases,
which include advanced cancer, renal insufficiency,
sexual dysfunction, and interstitial cystitis. We havepublished approximately 30 English papers every

5)

Fukuhara H, Kume H, Suzuki M, Fujimura T,
Enomoto Y, Nishimatsu H, Ishikawa A, Homma
Y
Maximum tumor diameter: a simple independent
predictor for biochemical recurrence after radical
prostatectomy.
Prostate Cancer Prostatic Dis, 13, 244-7, 2010
Kitamura T, Suzuki M, Nishimatsu H, Kurosaki T,
Enomoto Y, Fukuhara H, Kume H, Takeuchi T,
Miao L, Jiangang H, Xiaoqiang L
Final report on low-dose estramustine phosphate(EMP) monotherapy and very low-dose EMP
therapy combined with LH-RH agonist forpreviously untreated advanced prostate cancer.
Aktuelle Urol, 41, 534-40, 2010
Fujimura T, Takahashi S, Urano T, Ijichi N, Ikeda
K, Kumagai J, Murata T, Takayama K,
Horie-Inoue K, Ouchi Y, Muramatsu M, Homma
Y, Inoue S
Differential expression of estrogen-related
receptors beta and gamma (ERRbeta and
ERRgamma) and their clinical significance inhuman prostate cancer.
Cancer Sci, 101, 646-51, 2010
Kume H, Suzuki M, Fujimura T, Fukuhara H,
Enomoto Y, Nishimatsu H, Homma Y
Distant metastasis of renal cell carcinoma with adiameter of 3 cm or less-which is aggressive
cancer?
J Urol, 184, 64-8, 2010
Sato K, Suzuki M, Nagata M, Nishimatsu H,
Ishikawa A, Igawa Y, Kume H, Homma Y
Condom-assisted transurethral resection: a newsurgical technique for urethral tumor.

208

Surgical Science, 1, 46-48, 2010
6) Kaneko T, Matsushima H, Morimoto H, Tsuzaka
Y, Homma Y.
Efficacy of low dose tamsulosin in medical
expulsive therapy for ureteral stones in Japanesemale patients: a randomized controlled study.
Int J Urol, 17, 462-5, 2010
7) Yamanishi Y, Kitaura J, Izawa K, Kaitani A,
Komeno Y, Nakamura M, Yamazaki S,
EnomotoY, Oki T, Akiba H, Abe T, Komori T,
Morikawa Y, Kiyonari H, Takai T, Okumuraa K,
Kitamura T.
TIM1 is an endogenous ligand for LMIR5/
CD300b: LMIR5 deficiency ameliorates mouse
kidney ischemia/reperfusion injury.
J. Exp. Med, 207, 1501-11, 20108) Hiraike H, Wada-Hiraike O, Nakagawa S,
Koyama S, Miyamoto Y, Sone K, Tanikawa M,
Tsuruga T, Nagasaka K, Matsumoto Y, Oda K,
Shoji K, Fukuhara H, Saji S, Nakagawa K, Kato
S, Yano T, Taketani Y
Identification of DBC1 as a transcriptional
repressor for BRCA1.
Br J Cancer, 102, 1061-4, 20109) Koyama S, Wada-Hiraike O, Nakagawa S,
Tanikawa M, Hiraike H, Miyamoto Y, Sone K,
Oda K, Fukuhara H, Nakagawa K, Kato S, Yano
T, Taketani Y
Repression of estrogen receptor beta function by
putative tumor suppressor DBC1.
Biochem Biophys Res Commun, 392, 357-62,
201010) Oikawa R, Hosoda C, Nasa Y, Daicho T, TanoueA, Tsujimoto G, Takagi N, Tanonaka K, Takeo S.
Decreasedsusceptibility
tosalt-induced
hypertension in subtotally nephrectomized micelacking the vasopressin V1a receptor.
Cardiovasc Res, 87, 187-94, 201011) Tanaka M, Niimi A, Tomita K, Homma Y
Convesion to Silodosin in Men on Conventional
α1-blockers for Symptomatic Benign Prostatic
Hyperplasia
LUTS, 2, 11-5, 201012) Sugihara T, Fujimura T, Kume H, Homma Y
Successful treatment of metastatic malignant
fibrous histiocytoma of the kidney.
Urologia Internationalis, 85, 118-20, 201013) Koga H, Ozono S, Tsushima T, Tomita K,
Horiguchi Y, Usami M, Hirao Y, Akaza H, Naito
S
BCG Tokyo Strain Study Group.
Maintenance intravesical bacillus CalmetteGuérin instillation for Ta, T1 cancer andcarcinoma in situ of the bladder: randomized
controlled trial by the BCG Tokyo Strain Study
Group.
Int J Urol, 17, 759-66, 201014) Hashimoto K, Fujimoto H, Kouno T, Koseki M,
Yonemori K, Hirata T, Yunokawa M, Shimizu C,
Katsumata N, Tamura K, Ando M, Takeuchi M,
Nakanishi H, Komiyama M, Nakagawa T,
Fujiwara Y.
The incidence and management of metachronous
testicular germ cell tumors in patients withextragonadal germ cell tumors.
Urol Oncol, in press, 201015) Minagawa T, Imamura T, Igawa Y, Aizawa N,
Ishizuka O, Nishizawa O.
Differentiation of smooth muscle cells fromhuman amniotic mesenchymal cells implanted in
the freeze-injured mouse urinary bladder.
Eur Urol, 58, 299-306, 201016) Ogawa T, Homma T, Igawa Y, Seki S, Ishizuka O,
Imamura T, Akahane S, Homma Y, Nishizawa O.
CXCR3 binding chemokine and TNFSF14 overexpression in bladder urothelium of patients withulcerative interstitial cystitis.
J Urol, 183, 1206-12, 201017) Kinebuchi Y, Aizawa N, Imamura T, Ishizuka O,
Igawa Y, Nishizawa O.
Autologous bone-marrow-derived mesenchymal
stem cell transplantation into injured rat urethral
sphincter
Int J Urol, 17, 359-68, 201018) Kosho T, Miyake N, Hatamochi A, Takahashi J,
Kato H, Miyahara T, Igawa Y, Yasui H, Ishida T,
Ono K, Kosuda T, Inoue A, Kohyama M, Hattori
T, Ohashi H, Nishimura G, Kawamura R, Wakui
K, Fukushima Y, Matsumoto N.
A new Ehlers-Danlos syndrome with craniofacialcharacteristics, multiple congenital contractures,progressive joint and skin laxity, and multisystemfragility-related manifestations.
Am J Med Genet A, 152, 1333-46, 2010

20919) Aizawa N, Igawa Y, Andersson KE, Iijima K,
Nishizawa O, Wyndaele JJ.
Effects of intravesical instillation of ATP on rat
bladder primary afferent activity and its
relationship with capsaicin-sensitivity.
Neurourol Urodyn, 30, 163-8, 201020) Aizawa N, Iijima K, Rosenbaum JS, Downs TR,
Igawa Y, Andersson KE, Wyndaele JJ. .
Comparison of the effects of oestrogen
deficiency and old age on primary bladderafferent activity and voiding behaviour in theageing female rat
BJU Int, 108, 10-6, 201021) Kurizaki Y, Ishizuka O, Imamura T, Ichino M,
Ogawa T, Igawa Y, Nishizawa O, Andersson KE.
Relation
betweenexpressionofα(1)-adrenoceptor mRNAs in bladder mucosa
and urodynamic findings in men with lower
urinary tract symptoms.
Scand J Urol Nephrol, 45, 15-9, 201022) Takeda M, Homma Y, Araki I, Kakizaki H,
Yamanishi T, Yokota T, Gotoh M, Igawa Y, Seki
N, Takei M, Yoshida M, Sugaya K, Nishizawa O
The Japanese Naftopidil Neurogenic Lower
Urinary Tract Dysfunction Study Group
Predictive factors for the effect of the α1-D/A
adrenoceptor antagonist naftopidil on subjective
and objective criteria in patients with neurogenic
lower urinary tract dysfunction.
BJU Int, 108, 100-7, 201023) Aizawa N, Igawa Y, Nishizawa O, Wyndaele JJ
Effects of Nitric Oxide on thePrimary Bladder
Afferent Activities of the Rat With and Without
Intravesical Acrolein Treatment.
Eur Urol, 59, 264-71, 201024) Murata T, Takayama K, Katayama S, Urano T,
Horie-Inoue S, Ikeda K, Takahashi S, Kawazu C,
Hasegawa A, Ouchi Y, Homma Y, Hayashizaki Y,
Inoue S.
miR-148a is an androgen-responsive microRNA
that promotes LNCaP prostate cell growth byrepressing its target CAND1 expression.
Prostate Cancer Prostatic Dis, 13, 356-61, 201025) Seo J, Koizumi N, Yoshinaka K, Nomiya A,
Homma Y, Matsumoto Y, Mitsuisi M
Three-dimensional computer-controlled acousticpressure scanning and quantification of focusedultrasound.
IEEE Trans Ultrason Ferroelectr Freq Control, 57,
883-91, 201026) Muraoka K, Ishibashi Y, Yamaguchi J,
Kawarasaki H, Kume H, Fujita T
Early Partial Reimplantation of Tenckhoff
Catheters to Treat Intractable Exit-Site/Tunnel
Infection
Peritoneal Dialysis Internatio, 31, 350-3, 201027) Ijichi N, Shigekawa T, Ikeda K, Horie-Inoue K,
Fujimura T, Tsuda H, Osaki A, Saeki T, Inoue S.
Estrogen-related receptor γ modulates cellproliferation and estrogen signaling in breast
cancer.
J Steroid Biochem Mol Biol, 123, 1-7, 201028) Suzuki M, Kitamura T, Homma Y
Hormonal therapy for prostate cancer: Current
topics and future perspectives; Personalized
medication of estramustine phosphate byindividual
single-nucleotide
polymorphism
analysis.
Int J Urol, 17, 302-13, 201029) Homma Y
IJU this issue
Int J Urol, 17, 3, 201030) Fukuhara H, Homma Y, Todo T
Oncolytic virus therapy for prostate cancer.
Int J Urol, 17, 20-30, 2010

210

Department of Surgical Oncology
Associate professor
Joji Kitayama, M.D., Ph.D.

Lecturer
Eiji Sunami, M.D., Ph.D.,

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

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

Takamitsu Kanazawa, M.D.,

Hironori Yamaguchi, M.D., Ph.D.

Kazushige Kawai, M.D., Ph.D.

Kentaro Yazawa M.D., Ph.D.

Ken Mori M.D., Ph.D.

Tomomitsu Kiyomatsu M.D., Ph.D.

Hiroharau Yamashita 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 Associate Professor, one lecturer andnine Assistants. 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.

211

Teaching activities
The Department of Surgical Oncology also offers afellowship in surgical oncology for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in surgicaloncology. The Department of Surgical Oncology has a
Surgical Oncology Training Program and provides
broad reaching experience in technical aspects ofdiagnosis, treatment and management for adultpatients with both surgical and oncologic problems,development of surgical judgment, and increasing
knowledge about routine and complex conditions. In
addition, the dedicated staff allows multiple
opportunities for academic development both along
clinical and basic scientific lines.
In the undergraduate education program, ourdepartment plays a role in the systemic and clinicallectures and the bedside learning program for 3rd year
medical students, in cooperation with otherdepartments of surgery. In the systemic lectures onsurgery for the fiscal year of 2009, various fields werecovered such as surgical oncology and immunology,
injury, somatic reaction to surgery, infectious diseases,
shock, pre- and post-surgical management andnutrition. In the clinical lectures, we presented many
diseases such as colon cancer, colonic polyp, colonicpolyposis and ulcerative colitis. In the postgraduate
education program, new residents are trained to
become qualified surgeons. In addition to pre- andpost-surgery clinical conferences, the residents are
expected to attend research conferences and seminars,
which are held periodically. They are also asked topresent cases at clinical meetings, which are held
locally such as the local meeting of the JapaneseSociety of Gastroenterology.

Research activities
At present, our department has three major research
units divided according to the members’ special fields.
The clinical and academic interests of our department
are the upper and lower gastrointestinal tract, and thebreast. We also apply the techniques used in molecularand cellular biology to our research. The following are
the major themes under research.
1) Preoperative radiotherapy in lower rectal cancer

2)
3)
4)
5)
6)

Cancer surveillance in ulcerative colitis
Carcinogenesis in ulcerative colitis
Laparoscopically assisted colon surgery
Local immunity in colorectal cancer
Genetic analysis of colorectal cancer andadenoma
7) Prognostic factor of early colorectal cancer8) Surveillance program following colectomy forcolorectal cancer
9) The mechanism of liver metastasis of colorectal
cancer10) Dendritic cell Immunotherapy for advanced
cancer11) Cancer Immunotherapy targeting to the tumor
vessels12) Role of LPA S1P and productive enzymes intumor metastasis
13) Lipid metabolism in carcinogenesis and tumor
progression14) Role of peripheral nerve on the growth og
gastrointestinal cancer15) Genetic
analysisonsensitivity
tochemotherapeutic agents16) Hemostasis and fibrinolysis in Oncology17) Adiponectin and adiponectin receptors in
Oncology18) Intraabdominal chemotherapy for peritoneal
metastasis of gastric cancer
19) Pharmacokinetics in intraperitoneal chemotherapy20) Fibloblast Growth Factor (FGF) in inflammatory
bowel disease21) Genetic analysis of undifferentiated colorectal
cancer22) High Frequency Ultrasonography (HIFU) for
solid cancer23) Quantitative analysis of intraperitoneal cancer
cells in peritonitis carcinomatosis24) Immunomodulation in chemoradiotherapy for
locally advanced rectal cancer25) Autophagy in Oncology

References(1) Konishi T, Watanabe T, Nagawa H, Oya M, Ueno
M, Kuroyanagi H, Fujimoto Y, Akiyoshi T,
Yamaguchi T, Muto T
Preoperative
chemoradiation
andextended
pelvic

212

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

lymphadenectomy for rectal cancer: Two distinct
principles. World J Gastrointest Surg. 2010 Apr
27;2(4):95-100.
Watanabe T, Kobunai T, Ikeuchi H, Yamamoto Y,
Matsuda K, Ishihara S, Nozawa K, Iinuma H,
Kanazawa T, Tanaka T, Yokoyama T, Konishi T,
Eshima K, Ajioka Y, Hibi T, Watanabe M, Muto
T, Nagawa H. RUNX3 copy number predicts thedevelopment of UC-associated colorectal cancer.
Int J Oncol. 2011 Jan;38(1):201-7.
Emoto S, Kitayama J, Yamaguchi H, Ishigami H,
Kaisaki S, Nagawa H. Analysis of pO(2) in
Malignant Ascites of Patients with Peritoneal
Dissemination of Gastric Cancer. Case Rep
Oncol. 2010 Oct 1;3(3):344-348.
Miyato H, Kitayama J, Hidemura A, Ishigami H,
Kaisaki S, Nagawa H. Vagus Nerve Preservation
Selectively Restores Visceral Fat Volume inPatients with Early Gastric Cancer who
Underwent Gastrectomy. J Surg Res. 2010 Sep
22
Kamei T, Kitayama J, Yamaguchi H, Soma D,
Emoto S, Konno T, Ishihara K, Ishigami H,
Kaisaki S, Nagawa H. Spatial distribution of
intraperitoneallyadministrated
paclitaxel
nanoparticles
solubilized
with
poly
(2-methacryloxyethyl
phosphorylcholine-con-butyl methacrylate) in peritoneal metastatic
nodules. Cancer Sci. 2011 Jan;102(1):200-5.
Kawai K, Tsuno NH, Kitayama J, Sunami E,
Takahashi K, Nagawa H. Catechin inhibits
adhesion and migration of peripheral blood B
cells by blocking CD11b. Immunopharmacol
Immunotoxicol. 2011 Jun;33(2):391-7.
Ishihara S, Watanabe T, Kiyomatsu T, Yasuda K,
Nagawa H. Prognostic significance of response
to preoperative radiotherapy, lymph nodemetastasis, and CEA level in patients undergoing
total mesorectal excision of rectal cancer. Int J
Colorectal Dis. 2010 Dec;25(12):1417-25.
Kawai K, Kitayama J, Tsuno NH, Sunami E,
NagawaH.
Hyperfibrinogenemia
after
preoperative chemoradiotherapy predicts poor
response and poor prognosis in rectal cancer.
Int J Colorectal Dis. 2011 Jan;26(1):45-51. Epub2010 Sep 1.
Yoshikawa N, Tsuno NH, Okaji Y, Kawai K,

Shuno Y, Nagawa H, Oshima N, Takahashi K.
Isoprenoid geranylgeranylacetone inhibits humancolon cancer cells through induction of apoptosis
and cell cycle arrest. Anticancer Drugs. 2010
Oct;21(9):850-60.
(10) Nishikawa T, Tsuno NH, Okaji Y, Sunami E,
Shuno Y, Sasaki K, Hongo K, Kaneko M,
Hiyoshi M, Kawai K, Kitayama J, Takahashi K,
Nagawa H. The inhibition of autophagy
potentiates
anti-angiogenic
effectsofsulforaphanebyinducing
apoptosis.
Angiogenesis. 2010 Sep;13(3):227-38.
(11) Sasaki K, Tsuno NH, Sunami E, Tsurita G, Kawai
K, Okaji Y, Nishikawa T, Shuno Y, Hongo K,
Hiyoshi M, Kaneko M, Kitayama J, Takahashi K,
Nagawa H.
Chloroquine potentiates theanti-cancer effect of 5-fluorouracil on coloncancer cells. BMC Cancer. 2010 Jul 15;10:370.
(12) Kazama S, Kitayama J, Aoki J, Mori K, Nagawa
H. Immunohistochemical Detection of Autotaxin(ATX)/Lysophospholipase D (lysoPLD) in
Submucosal Invasive Colorectal Cancer.
J
Gastrointest Cancer. 2010(13) Yamashita H, Hata K, Yamaguchi H, Tsurita G,
Wake K, Watanabe S, Taki M, Ueno S, Nagawa
H. Short-term exposure to a 1439-MHz TDMA
signal exerts no estrogenic effect in rats.
(14) Watanabe T, Kobunai T, Yamamoto Y, Kanazawa
T, Konishi T, Tanaka T, Matsuda K, Ishihara S,
Nozawa K, Eshima K, Muto T, Nagawa H.
Prediction of liver metastasis after colorectal
cancer using reverse transcription-polymerase
chain reaction analysis of 10 genes. Eur J
Cancer. 2010 Jul;46(11):2119-26.
(15) Kitayama J, Yasuda K, Kawai K, Sunami E,
Nagawa H. Circulating lymphocyte number has apositive association with tumor response inneoadjuvant chemoradiotherapy for advanced
rectal cancer. Radiat Oncol. 2010 Jun 3;5:47.
(16) Kato M, Kitayama J, Yamaguchi H, Sanuki J,
Kaisaki S, Nagawa H. [Three cases of metastatic
breast cancer effectively treated with S-1
therapy].
Gan To Kagaku Ryoho. 2010
May;37(5):903-6. Japanese.
(17) Otani K, Kitayama J, Kamei T, Soma D, Miyato
H, Yamauchi T, Kadowaki T, Nagawa H.
Adiponectin receptors are downregulated in

213human gastric cancer. J Gastroenterol. 2010
Sep;45(9):918-27.
(18) Kitayama J, Ishigami H, Kaisaki S, Hidemura A,
Kato M, Otani K, Kamei T, Soma D, Miyato H,
Yamashita H, Nagawa H. Weekly intravenous
and intraperitoneal paclitaxel combined with S-1
for malignant ascites due to advanced gastriccancer. Oncology. 2010;78(1):40-6.
(19) Kawasaki H, Kitayama J, Ishigami H, Hidemura
A, Kaisaki S, Nagawa H. Solitary splenic
metastasis from early gastric cancer: report of acase. Surg Today. 2010;40(1):60-3

214

Department of Vascular Surgery
Associate Professor
Tetsuro Miyata, M.D., Ph.D.

Lecturer
Kunihiro Shigematsu, M.D., Ph.D.

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

Katsuyuki Hoshina, M.D., Ph.D.,

Akihiro Hosaka, 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 Associate Professor, one lecturer, andthree Associates. The outpatient office is located on
the third floor of the Outpatient Building. The ward issituated on the eighth floor of the Ward Building. The
administrative office and research laboratories arelocated in the Administration and Research Building.
Current activities of the Department of Vascular
Surgery in clinical practice, education, and research
are summarized as follows.

Clinical activities
The Department of Vascular Surgery has anextensive clinical program in both primary and tertiarycare for vascular problems, and manages patients with
peripheral arterial occlusion, abdominal and thoracoabdominal aortic aneurysms, peripheral aneurysm,
visceral arterial occlusion, carotid artery disease andcommon disorders of the venous circulation such asvaricose veins and venous leg ulcers. State-of-the-art
techniques of percutaneous transluminal angioplasty,
angioscopy and intraoperative ultrasonography areavailable for the treatment of peripheral arterial
disease. And endovascular aneurysm repair was alsoavailable for the treatment of abdominal aortic
aneurysm. The outpatient clinic is open from Monday
through Friday, and twenty-four-hour consultation isavailable for urgent or emergency problems.
Included in the department is the non-invasive
Clinical Vascular Laboratory, which sees over 500
patients per year, with broad reaching expertise inperipheral vascular diagnostic modalities. Also thedepartment has an active angiography program, which
encompasses all aspects of diagnostic and therapeuticintervention in over 500 patients per year and a fullrange of other support and collaborative services.
On Monday, Wednesday and Friday mornings, preand post-surgery conferences are held. Operating days
are Monday, Tuesday and Thursday. The vascularclinical conference is held every Tuesday evening.

Teaching activities
The Department of Vascular Surgery also offers afellowship in vascular surgery for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in vascularsurgery. The Department of Vascular Surgery has a
Vascular Surgery Training Program and provides
broad reaching experience in technical aspects ofvascular surgery, development of surgical judgment,

215

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.

9) Mechanism of arteriogenesis in ischemic limb.
10) Development of a new drug delivery system fortherapeutic angiogenesis11) Introduction of gene into vascular wall cells byelectroporation
12) Application of nano technology for in-vivo genetransfer to vascular wall cells
13) Basic research for arterialization of artificial
organ
14) Development of a new method for evaluation oflimb ischemia
15) Development of a new machine for autoevaluation of in-vivo endothelial function16) Creating strategy for diagnosis of acute aortic
syndrome.

Research activities
References
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) Navigation system for less invasive vascularsurgery2) Pathophysiology of the development of theaneurysm
3) Pathophysiology of stent restenosis
4) Analyzing the intercellular transmission of thegrowth signal in the vascular smooth muscle cells5) Tissue oxygen dynamics assessed by near infrared
spectroscopy6) Development of a minimally invasive treatment
modality for varicous veins of lower extremity
using high frequency ultrasound.
7) Genome
wide-association
studiesforarteriosclerosis.
8) Pharmacological analysis of microcirculation in
in-vivo model(1) Deguchi J, Nagayoshi M, Miyahara T, Nishikage
S, Kimura H, Shigematsu K, Miyata T. Do
inferior vena cava filters reduce the risk of acutepulmonary embolism in preoperative patientswith venous thromboembolism?

Surgery Today

2010;40(6):533-537(2) Hoshina K, Kato M, Miyahara T, Mikuriya A,
Ohkubo N, Miyata T. A retrospective study of
intravascular ultrasound use in patients
undergoing endovascular aneurysm repair: its
usefulness and description of the procedure. Eur J
Vasc Endovasc Surg 2010;40(5):559-563(3) Isaji T, Takayama T, Endo A, Akai A, Kudo M,
Kagaya H, Suzuki J, Hashimoto T, Hoshina K,
Kimura H, Okamoto H, Shigematsu K, Miyata T.
Current status of the medical expenses for thetreatment of arteriosclerosis obliterans in Japan.
Int Angio 2010;29(suppl2):61-68(4) Kimura H, Sato O, Deguchi JO, Miyata T.
Surgical treatment and long-term outcome ofrenovascular hypertension in children andadlescentsr. Eur J Vasc Endovasc Surg
2010;39(6):731-737

216

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

Associate Professor
Toshihisa Ogawa MD. PhD.

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
endocrine internal medicine and have about 240
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 microbreast lesions under ultrasonographic guides; 3)preoperative diagnosis for thyroid neoplasmas andbreast tumors based on telomerase activity using
Q-Fish.

217

Research Acitivities
Our section has been studying about the mostfundamental issues to surgery, i.e., “surgical stress”
which means postoperative physiological andendocrine internal reaction and “nutritional support”
for the postoperative patients. These are subjects to
reduce the intra- and post-operative stresses thatwould be risky for the patients. Our section is like apioneer for this area in Japan and we establishedJapanese Society for Surgical Metabolism andNutrition 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
Hatao F, Hiki N, Mimura Y, Ogawa T, Kojima J,
Mafune K, Hawkins LD, Muroi M, Tanamoto K,
Kaminishi M. The induction of super-resistanceusing synthetic lipolysaccahride recepotor agonist
rescues fatal emdotoxemia in rats without excessive
immunosuppression. Shock 23:365-370,2005
Kurabayashi R, Takubo K, Aida J, HonmaN, Poon
SSS,Kammori M, Izumiyama-Shimomura N,
Nakamura KI, Tsuji FI, Matsuura M, Ogawa T,
Kaminishi M. Luminal and cancer cells in the breast
show more rapid telomere shortening thanmyoepithelial cells and fibroblasts. Human Pathol
39:1647-1655,2008.
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
Hatao F, Yamamoto M, Muroi M, Kaminishi, M,
Tanamoto K. MyD88-induced downregulation of
IRAK-4 and its structural requirements. Immunol
Med Microbiol 53:260-264, 2008.

Surgical Sciences
2. Sensory and Motor System Medicine

219

Department of Dermatology
Professor
Shinichi Sato, M.D., Ph.D.
Associate Professor
Takafumi Kadono, M.D., Ph.D.

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

Yayoi Tada, M.D.,Ph.D

Hiroshi Mitsui, M.D., Ph.D.

Yoshihide Asano, M.D.,Ph.D

Associate
Shinji Kagami, M.D. Ph.D.

Zenshiro Tamaki , M.D. Ph.D

Mizuho Yamamoto, M.D.

Tomomitsu Miyagaki, M.D., Ph.D.

Manabu Tomita, M.D., Ph.D.

Akie Miyamoto, M.D.

Takashi Taniguchi, M.D.

Takehiro Takahashi, M.D.

Sho Masuda, M.D.

Home page

http://www.h.u-tokyo.ac.jp/der/Introduction and Organization

Clinical Activities

The Department of dermatology celebrated its
100th anniversary in 1990. Originally it was foundedas the Department of dermatology and Urology, which
also encompassed venereology. In 1946 theDepartment of dermatology was separated from thatof Urology. Regarding venereology, sexuallytransmitted diseases only related to skinmanifestations are now dealt in our department.
The professor, one associate professor, fivelecturers and nine assistants 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.

Education
We have ten dermatologists and are studying in the220postgraduate course under the guidance of staff
members of our department.
In addition to series of lectures, clinical education isprovided for fifth- and six grade medical students,
which aims at giving a general introduction for how
make dermatological 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.

6.

7.

References Activities
8.
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.

9.

10.
1.

2.

3.

4.

5.

Asano Y, Stawski L, Hant F, Highland K, Silver
R, Szalai G, Watson DK, Trojanowska M:
Endothelial Fli1 deficiency impairs vascularhomeostasis - a role in scleroderma vasculopathy.
Am J Pathol. 176:1983-1998, 2010.
Asano Y, Kaji K, Idezuki T, Igarashi A: Primary
idiopathic cutaneous pustular vasculitis. Acta
Derm Venereol. 90:420-421, 2010.
Asano Y, Bujor AM, Trojanowska M: The impact
of Fli1 deficiency on the pathogenesis ofsystemic sclerosis. J Dermatol Sci. 59(3):153162, 2010.
Ashida R, Asano Y, Tamaki Z, Tomita M,
Kawashima T, Aakamata K, Sato S: Close
associationofanti-U1
ribonucleoprotein
antibody with drug allergy in patients withconnective tissue diseases. J Dermatol Sci.
60:56-57, 2010.
Bu S, Asano Y, Kapanadze B, Bujor A, Highland
K, Hant F, Trojanowska M: Dihydrosphingosine1 phosphate has a potent anti-fibrotic effect in

11.

12.

13.

14.

Scleroderma fibroblasts via modulation of PTEN
levels. Arthritis Rheum. 62:2117-2126, 2010.
Yoshizaki A, Yanaba K, Yoshizaki A, Iwata Y,
Komura K, Ogawa F, Takenaka M, Shimizu K,
Asano Y, Hasegawa M, Fujimoto M, Sato S:
Treatment with rapamycin prevents fibrosis intight-skin and bleomycin-induced mouse models
of systemic sclerosis. Arthritis Rheum. 62:24762487, 2010.
Kagami S, Rizzo HL, Lee JJ, Koguchi Y,
Blauvelt A: Circulating Th17, Th22, and Th1
cells are increased in psoriasis. J Invest
Dermatol. 130:1373-1383, 2010.
Kagami S, Rizzo HL, Kurtz SE, Miller LS,
Blauvelt A: IL-23 and IL-17A, but not IL-12 andIL-22, are required for optimal skin host defense
against Candida albicans. J Immunol. 185:54535462, 2010.
Kanda N, Ishikawa T, Kamata M, Tada Y,
Watanabe S: Increased serum leucine, leucine-37
levels in psoriasis: positive and negative
feedback loops of leucine, leucine-37 and pro- or
anti- inflammatory cytokines. Hum Immunol.
71(12):1161-71, 2010.
Karakawa M, Komine M, Tamaki K, Ohtsuki M:
Roxithromycin downregulates production of
CTACK/CCL27 and MIP-3α/CCL20 fromepidermal keratinocytes. Arch Dermatol Res.
302(10):763-7, 2010.
Kawashima T, Tada Y, Asano Y, Yazawa N,
Tomita M, Tamaki Z, Kubo M, Ihn H, Sugaya M,
Kadono T, Tamaki K, Sato S: Serum TARC/
CCL17 levels are increased in dermatomyositis
associated with interstitial lung disease. J
Dermatol Sci. 60:52-54, 2010.
Kuwano Y, Spelten O, Zhang H, Ley K, Zarbock
A: Rolling on E- or P-selectin induces theextended, but not high affinity conformation of
LFA-1 in neutrophils. Blood. 116:617-624, 2010.
Miyagaki T, Sugaya M, Shibata S, Ohmatsu H,
Fujita H, Tamaki K: Serum interleukin-27 levels
in patients with cutaneous T-cell lymphoma. ClinExp Dermatol. 35:e143-144, 2010.
Miyagaki T, Sugaya M, Fujita H, Ohmatsu H,
Kakinuma T, Kadono T, Tamaki K, Sato S:
Eotaxins and CCR3 Interaction Regulates theTh2 Environment of Cutaneous T-Cell

221

15.

16.

17.

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20.

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Lymphoma. J Invest Dermatol. 130:2304-2311,
2010.
Asahina A, Hasegawa K, Ishiyama M, Miyagaki
T, Tada Y, Suzuki Y, Kanabe T, Saito I: Bullous
amyloidosis mimicking bullous pemphigoid:
usefulness of electron microscopic examination.
Acta Derm Venereol. 90:427-428, 2010.
Noda S, Asano Y, Tamaki Z, Takekoshi T, Sugaya
M, Sato S: A case of dermatomyositis with "liverdisease associated with rheumatoid diseases"
positive for anti-liver-kidney microsome-1
antibody. Clin Rheumatol. 29:941-943, 2010.
Ohmatsu H, Sugaya M, Fujita H, Miyagaki T,
Kadono T, Maeda D, Takazawa Y, Fukayama M,
Tamaki K, Sato S: Primary cutaneous CD8+
aggressive epidermotropic cytotoxic T-cell
lymphoma in a human T-cell leukaemia virus
type-1 carrier. Acta Derm Venereol. 90:324-325,
2010.
Ohmatsu H, Kadono T, Sugaya M, Tomita M,
Kai H, Miyagaki T, Saeki H, Tamaki K, Steeber
DA, Tedder TF, and Sato S: α4β7 integrin isessential for contact hypersensitivity by
regulating migration of T cells to skin. J Allergy
Clin Immun. 126:1267-76, 2010.
Asahina A, Ohshima N, Nakayama H, Shirai A,
Juji T, Matsui T: Henoch-Schönlein purpura in apatient with rheumatoid arthritis receiving
etanercept. Eur J Dermatol. 20:521-2, 2010.
Shibata S, Tada Y, Kanda N, Nashiro K, Kamata
M, Karakawa M, Miyagaki T, Kai H, Saeki H,
Shirakata Y, Watanabe S, Tamaki K, Sato S:
Possible roles of IL-27 in the pathogenesis ofpsoriasis. J Invest Dermatol. 130:1034-9, 2010.
Sugaya M: Chemokines and cutaneous
lymphoma. J Dermatol Sci. 59:81-89, 2010.
Sumida H, Noguchi K, Kihara Y, Abe M,
Yanagida K, Hamano F, Sato S, Tamaki K,
Morishita Y, Kano MR, Iwata C, Miyazono K,
Sakimura K, Shimizu T, Ishii S: LPA4 regulates
blood and lymphatic vessel formation during
mouse embryogenesis. Blood. 116:5060-5070,
2010.
Kronenberg K, Brosch S, Butsch F, Tada Y,
Shibagaki N, Udey MC, von Stebut E:
Vaccination with TAT-Antigen Fusion Protein
Induces Protective, CD8 (+) T Cell-Mediated

24.

25.

26.

27.

28.

29.

30.

31.

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Immunity Against Leishmania Major. J Invest
Dermatol. 130:2602-2610, 2010.
Takekoshi T, Tada Y, Watanabe T, Sugaya M,
Hoashi T, Komine M, Kawashima T, Shimizu T,
Hau CS, Asahina A, Yokomizo T, Sato S, Tamaki
K: Identification of a novel marker for dendritic
cell maturation, mouse transmembrane protein
123. J Biol Chem. 285:31876-31884, 2010.
Watanabe R, Ishiura N, Nakashima H, Kuwano Y,
Okochi H, Tamaki K, Sato S, Tedder TF,
Fujimoto M: Regulatory B cells (B10 cells) havea suppressive role in murine lupus: CD19 andB10 cell deficiency exacerbates systemic
autoimmunity. J Immunol. 184:4801-4809, 2010.
Haas KM, Watanabe R, Matsushita T, Nakashima
H, Ishiura N, Okochi H, Fujimoto M, Tedder TF:
Protective and pathogenic roles for B cells duringsystemic autoimmunity in NZB/W F1 mice. J
Immunol. 184:4789-4800, 2010.
Campbell JJ, Clark RA, Watanabe R, Kupper TS:
Sezary syndrome and MF arise from distinct T
cell subsets: a biologic rationale for their distinct
clinical behaviors. Blood. 116:767-771, 2010.
Hara T, Shimizu K, Ogawa F, Yanaba K, Iwata Y,
Muroi E, Takenaka M, Komura K, Hasegawa M,
Fujimoto M, Sato S: Platelets control leukocyte
recruitment in a murine model of cutaneous
arthus reaction. Am J Pathol. 176(1):259-269,
2010.
Bae SJ, Shimizu K, Yozaki M, Yamaoka T,
Akiyama Y, Yoshizaki A, Muroi E, Hara T,
Ogawa F, Sato S: Involvement of L-selectin incontact hypersensitivity responses augmented byauditory stress. Am J Pathol. 176(1):187-197,
2010.
Yanaba K, Yoshizaki A, Muroi E, Hara T, Ogawa
F, Shimizu K, Sato S: The proteasome inhibitor
bortezomib
inhibitsTcell-dependent
inflammatory responses. J Leukoc Biol. 88(1):117-122, 2010.
Yanaba K, Yoshizaki A, Muroi E, Hara T, Ogawa
F, Shimizu K, Hasegawa M, Fujimoto
M,Takehara K, Sato S: CCL13 is a promising
diagnostic marker for systemic sclerosis. Br J
Dermatol. 162(2):332-336, 2010.
Odaka M, Hasegawa M, Hamaguchi Y, Ishiura N,
Kumada S, Matsushita T, Komura K, Sato S,

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Takehara K, Fujimoto M: Autoantibody-mediatedregulation of B cell responses by functional antiCD22 autoantibodies in patients with systemicsclerosis. Clin Exp Immunol. 159(2):176-184,
2010.
Ito I, Kawaguchi Y, Kawasaki A, Hasegawa M,
Ohashi J, Kawamoto M, Fujimoto M, Takehara K,
Sato S, Hara M, Tsuchiya N: Association of the
FAM167A-BLK region with systemic sclerosis.
Arthritis Rheum. 62(3):890-895, 2010.
Hamaguchi Y, Hasegawa M, Tanaka C, Kumada
S, Sato S, Takehara K, Fujimoto M: Elevatedserum placenta growth factor (PlGF) levels inpatients with systemic sclerosis: a possible rolein the development of skin but not lung fibrosis.
J Dermatol Sci. 58(3):229-231, 2010.
Yoshizaki A, Yanaba K, Iwata Y, Komura K,
Ogawa A, Akiyama Y, Muroi E, Hara T, Ogawa F,
Takenaka M, Shimizu K, Hasegawa M, Fujimoto
M, Tedder TF, Sato S: Cell adhesion molecules
regulate fibrotic process via Th1/Th2/Th17 cellbalance in a bleomycin-induced scleroderma
model. J Immunol. 185(4):2502-2515, 2010.
Hoashi T, Sato S, Yamaguchi Y, Passeron T,
TamakiK,
Hearing
VJ:
Glycoprotein
nonmetastatic melanoma protein b, a melanocytic
cell marker, is a melanosome-specific andproteolytically released protein. FASEB J.
24(5):1616-1629, 2010.
Tanaka C, Fujimoto M, Hamaguchi Y, Sato S,
Takehara K, Hasegawa M: Inducible costimulator
ligand regulates bleomycin-induced lung andskin fibrosis in a mouse model independently of
the inducible costimulator/inducible costimulator
ligand pathway. Arthritis Rheum. 62(6):17231732, 2010.
Ogawa A, Yoshizaki A, Yanaba K, Ogawa F,
Hara T, Muroi E, Takenaka M, Shimizu K,
Fujimoto M, Tedder TF, Sato S: The differential
role of L-selectin and ICAM-1 in Th1-type andTh2-type contact hypersensitivity. J Invest
Dermatol. 130(6):1558-1570, 2010.
Yoshizaki A, Yanaba K, Yoshizaki A, Iwata Y,
Komura K, Ogawa F, Takenaka M, Shimizu K,
Asano Y, Hasegawa M, Fujimoto M, Sato S:
Treatment with rapamycin prevents fibrosis intight-skin and bleomycin-induced mouse models

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62(8):2476-2487, 2010.
Koike Y, Muroi E, Yoshizaki A, Ogawa F, Yanaba
K, Takenaka M, Shimizu K, Sato S:
Autoantibody against survivin in patients withsystemic sclerosis. J Rheumatol. 37(9):1864-70,
2010.
Hasegawa M, Fujimoto M, Matsushita T,
Hamaguchi Y, Takehara K, Sato S: Serumchemokine and cytokine levels as indicators of
disease activity in patients with systemicsclerosis. Clin Rheumatol. 30(2):231-237, 2010.
Yanaba K, Yoshizaki A, Muroi E, Ogawa F,
Asano Y, Kadono T, Sato S: Serum CCL23 levels
are increased in patients with systemic sclerosis.
Arch Dermatol Res. 303(1):29-34, 2010.
Yoshizaki A, Yanaba K, Iwata Y, Komura K,
Ogawa A, Muroi E, Ogawa F, Takenaka M,
Shimizu K, Hasegawa M, Fujimoto M, Sato S:
Elevated serum interleukin-27 levels in patientswith systemic sclerosis: association with T cell,
B cell and fibroblast activation. Ann Rheum Dis.
70(1):194-200, 2010.
Nakashima H, Hamaguchi Y, Watanabe R,
Ishiura N, Kuwano Y, Okochi H, Takahashi Y,
Tamaki K, Sato S, Tedder TF, Fujimoto M: CD22
expression mediates the regulatory functions ofperitoneal B-1a cells during the remission phaseof contact hypersensitivity reactions. J Immunol.
184(9):4637-4645, 2010.
Ishiura N, Nakashima H, Watanabe R, Kuwano Y,
Adachi T, Takahashi Y, Tsubata T,Okochi H,
Tamaki K, Tedder TF, Fujimoto M: Differential
phosphorylation of functional tyrosines in CD19
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223

Department of Plastic andReconstructive Surgery
Professor
Isao Koshima, M.D., Ph.D.

Lecturer
Kotaro Yoshimura, M.D., Ph.D.

Associate
Gentaro Uchida, M.D.,D.D.S., Ph.D.

Takuya Iida, M.D., Ph.D.

Mitsunaga Narushima, M.D.

Makoto Mihara, M.D.

Takeshi Todokoro, M.D.

Homepage

http://www.h.u-tokyo.ac.jp/plastic/english/index.html

Organization
The present faculty of the Department of Plastic
and Reconstructive Surgery consists of 1 professor, 1
associate professor, 1 lecturer, 5 associates, 7
physicians, and 3 residents. There are about 100
doctors in the department, including 8 graduate school
students, but most are serving in rotation at affiliatedhospitals.
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
1,356 new patients and the total number of revisiting
patients are about 9,703 in a year. In the operating
theater over 410 operations are achieved under generalanesthesia, while in the outpatient clinic about 150
operations are achieved under local anesthesia in ayear. Each week, the professor goes the round of
inpatients on Wednesday morning. Preoperative andpostoperative conferences and seminar that all
members of the department should attend are held on
Wednesday evening. Research conferences are held on
every Friday evening.

Teaching Activities
In regard to pregraduate education, the department
has the duty of lecturing to 2nd and 4th year medical
students, and also of instructing 4th medical students
in bed side practice. The subjects taken up in thelectures include general concepts of plastic surgery,wound healing, congenital malformations, skin grafts
and flaps, microsurgery, head and neck reconstruction,
hand surgery, craniomaxillofacial surgery, burn and224

trauma, 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.

Research Activities

15) Studies on mechanism of biological effects ofretinoids on epidermis and dermis.
16) Studies on regeneration of peripheral nerves.

References (2010)
1:

Yamamoto

T,KoshimaI,

Yoshimatsu

H,

Narushima M, Mihara M, Iida T. Simultaneous
multi-site

lymphaticovenular

anastomosesforprimary lower extremity and genital lymphoedema
complicated with severe lymphorrhea.. J Plast
Reconstr Aesthet Surg. 2011 Jun; 64(6): 812-5.
2:

Koshima I, Yamamoto T, Narushima M, Mihara M,
Iida T. Perforator flaps and Supermicrosurgery. Clin

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 on molecular mechanisms of vasculogenesis and angiogenesis in the mouse embryo.
11) Studies on molecular pathogenesis of holoprosencephaly 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.

Plast Surg, 2010 Oct; 37(4): 683-9, vii-iii.
3:

Koshima I, Narushima M, Mihara M, Yamamoto Y,
Iida T, Uchida G. Prophylactic cross-face nerve flap
for muscle protection prior to facial palsy. J Plast
Reconstr Aesthet Surg. 2011 Feb; 64(2): 185-8.
Epub 2010 Jun 26..

4:

Narushima M, Mihara M, Yamamoto Y, Iida T,
Koshima I, Mundinger GS. The intravascular
stenting method for treatment of extremity
lymphedema with multiconfiguration lymphaticovenous anastomoses. Plast, Reconstr Surg. 2010
Mar; 125(3): 935-43.

5:Koshima I, Narushima M, Mihara M, Uchida G,
Nakagawa M. Cross-face nerve transfer forestablished trigeminal branch II palsy. Ann Plast
Surg. 2009 Dec; 63(6): 621-3.

6:

Narushima M, Mihara M, Koshima I, Gonda K,
Iida T, Kato H, Araki J, Yamamoto Y, Otaki Y,
Todokoro T, Ishikawa S, Uehara E, Mundinger GS.
Digital artery perforator (DAP) flaps: modifications
for fingertip and finger stump reconstruction. J
Plast Reconstr Aesthet Surg. 2010 Aug; 63(8):1312-7.

7:

Koshima I, Narushima M, Mihara M, Uchida G,
Nakagawa M. Fascicular turnover flap for nerve
gaps. J Plast Reconstr Aesthet Surg. 2010 Jun;
63(6): 1008-14.

8:

Koshima I, Narushima M, Mihara M, Iida T, Gonda
K, Uchida G, Nakagawa M. J Plast Reconstr
Aesthet Surg. 2010 Jan; 63(1): 140-5.

225

Department ofOral-Maxillofacial Surgery
Professor
Tsuyoshi Takato, M.D.,Ph.D.

Associate Professor
Takafumi Susami, D.D.S., Ph.D.

Yoshiyuki Mori, D.D.S., Ph.D.

Lecturer
Toru Ogasawara, D.D.S., Ph.D.

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

Ichiro Seto, D.D.S., Ph.D.

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

Associate
Gen-ichiro Takagi, D.D.S.

Takahiro Abe, 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.

Yuki Kanno, D.D.S.

Madoka Sugiyama, D.D.S.

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.

226

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 that 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. Dental caries 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 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

2272) Multidisciplinary treatment of dentomaxillofacial
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 technique3) 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) Aoki A, Kawamoto T, Aoki K, Inokuchi T, Kudoh
A, Nagahama K, Baba Y,Suzuki S, Ohya K,
Moriyama K.

A mount of bone lengthening

affects blood flow recovery and bone mineralization
after distraction osteogenesis in a canine cleft palate
model. Cleft Palate Craniofac J. 2010 May;
47(3):303-13.
(2) Broggini N, Hofstetter W, Hunziker E, Bosshardt
DD, Bornstein MM, Seto I, Weibrich G, Buser D:
The Influence of PRP on Early Bone Formation in
Membrane Protected Defects. A Histological andHistomorphometric Study in theRabbit Calvaria.
Clin Implant Dent Relat Res.2010 13(1): 1-12
(3) Fujihara H, Chikazu D, Saijo H, Suenaga H, Mori Y,

Basic and experimental research:
1) Contribution of periosteum to bone regeneration
2) Chondrogenic potential of the perichondrium3) Bone regeneration using growth plate chondrocyte4) Role of cell cycle factors in regulation of osteochondrocyte 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

Iino M, Hamada Y, Takato T.Metastasis ofhepatocellular carcinoma into the mandible withradiographic findings mimicking a radicular cyst: acase report. J Endod. 2010 Sep;36(9):1593-6. Epub2010 Jul 8. PubMed PMID: 20728734.
(4) Fujihara Y, Takato T, Hoshi K. Immunologicalresponse to tissue-engineered cartilage derived fromauricular chondrocytes and a PLLA scaffold intransgenic mice. Biomaterials. 2010 Feb;31(6):1227-34. Epub 2009 Nov 12. PubMed PMID:
19913296.
(5) Fukai A, Kawamura N, Saito T, Oshima Y, Ikeda T,
Kugimiya F, Higashikawa A, Yano F, Ogata N,

Tissue engineering:
Clinical section
1) Clinical application of artificial bone that displace
into bone2) Implant type artificial bone generated from tissue
engineered human chondrocyte

Nakamura K, Chung UI, Kawaguchi H. Akt1 inmurine chondrocytes controls cartilage calcification
during endochondral ossification under physiologic
and pathologic conditions. Arthritis Rheum. 2010
Mar;62(3):826-36.PMID: 20187155

228(6) Gutwald R, Haberstroh J, Stricker A, Rüther E, Otto

Maxillofac Surg 39; 916-921,2010

F, Xavier SP, Oshima T, Marukawa E, Seto I,(13) Nakajima K, Komiyama Y, Hojo H, Ohba S, Yano F,

Enomoto S, Hoogendijk CF, Schmelzeisen R,

Nishikawa N, Ihara S, Aburatani H, Takato T,

Sauerbier S: Influence of rhBMP-2 on bone

Chung UI. Enhancement of bone formation ex vivo

formation and osseointegration in different implantand in vivo by a helioxanthin-derivative. Biochem

systems after sinus-floor elevation. An in vivo study

Biophys Res Commun. 2010 May 14;395(4):502-8.

on sheep. J Craniomaxillofac Surg. 2010 Dec;

Epub 2010 Apr 9. Erratum in: Biochem Biophys

38(8):571-9.

Res Commun. 2010 Jul 2;397(3):631. Ihara, Sigeo(7) Hojo H, Yano F, Ohba S, Igawa K, Nakajima K,[added]. PubMed PMID: 20382113.

Komiyama Y, Kan A, Ikeda T, Yonezawa T, Woo JT,(14) Nakashima Y, Haga N, Kito H, Kamizono J,

Takato T, Nakamura K, Kawaguchi H, Chung UI.

Tozawa K, Katagiri T, Susami T, Fukushi J,

Identification of oxytetracycline as a chondrogenic

Iwamoto Y. Deformity of the great toe incompound using a cell-based screening system. J

fibrodysplasia ossificans progressiva. J Orthop Sci.

Bone Miner Metab. 2010 Nov;28(6):627-33. Epub

15: 804-9, 2010.

2010 Apr 8.PMID: 20376510(15) Saijo H, Mori Y, Fujihara H, Kanno Y, Chikazu D,(8) Inokuchi T, Kawamoto T, Aoki K, Aoki A,

Ohkubo K, Hikiji H, Iino M, Yonehara Y, Takato

Nagahama K, Baba Y, Suzuki S, Shibayama M,

T：Evaluation and analysis of bone formation at

Mano Y, Ohya K, Moriyama K. The effects ofpalate of cleft lip and palate patients after

hyperbaric oxygen on tooth movement into thepalatoplasty based on computed tomographic

regenerated area after distraction osteogenesis. Cleft

scanning and three dimensional data.：Scand J Plast

Palate Craniofac J. 2010 Jul; 47(4):382-92.

Reconstr Surg Hand SURG 2010 Feb;44(1):21-25.

(9) Iwata K, Asawa Y, Fujihara Y, Tanaka Y, Nishizawa(16) Saijo H, Kanno Y, Mori Y, Chikazu D, Iino M,

S, Nakagawa T, Nagata S, Takato T, Hoshi K. The

Takato T.; A bone harvesting method involving aeffects of rapid- or intermediate-acting insulin on

surgicalthe proliferation and differentiation of cultured

dimensional model．Asian. J. Oral.Maxillofac. Surg

chondrocytes. Curr Aging Sci. 20102010; 22: 20-22

Feb;3(1):26-33. PubMed PMID: 20298167.
EisenhaberF,

Maurer-Strohpreparedusingathree-(17) Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F, Ohba

(10) Kawase-Koga Y, Low R, Otaegi G, Pollock A, DengH,

templateS,Sun

S, Nishida N, Akune T, Yoshimura N, Nakagawa T,

T.

Nakamura K, Tokunaga K, Chung UI, Kawaguchi

RNAase-III enzyme Dicer maintains signaling

H. Transcriptional regulation of endochondral

pathways for differentiation and survival in mouseossification by HIF-2alpha during skeletal growthcortical neural stem cells. J Cell Sci. 2010;123(Ptand osteoarthritis development. Nat Med. 20104):586-94.

Jun;16(6):678-86. Epub 2010 May 23.PMID:(11) Kimura A, Inose H, Yano F, Fujita K, Ikeda T, Sato

20495570

S, Iwasaki M, Jinno T, Ae K, Fukumoto S, Takeuchi(18) Tanaka Y, Yamaoka H, Nishizawa S, Nagata S,

Y, Itoh H, Imamura T, Kawaguchi H, Chung UI,

Ogasawara T, Asawa Y, Fujihara Y, Takato T, Hoshi

Martin JF, Iseki S, Shinomiya K, Takeda S. Runx1

K. The optimization of porous polymeric scaffolds

and Runx2 cooperate during sternal morphogenesis.

forDevelopment. 2010 Apr;137(7):1159-67. Epubengineered cartilage. Biomaterials. 2010Jun;31(16):2010 Feb 24.PMID: 20181744

4506-16. Epub 2010 Mar 4. PubMed PMID:(12) Mori Y, Yano F, Shimohata N, Suzuki S, Chung UI,Takato T: Trehalose inhibits oral dryness byprotecting the cell membrane.

Int J Oral

chondrocyte/atelocollagenbasedtissue-20206380.
(19) Yamaoka H, Tanaka Y, Nishizawa S, Asawa Y,
Takato T, Hoshi K. The application of atelocollagen229

gel in combination with porous scaffolds for
cartilage tissue engineering and its suitableconditions. J Biomed Mater Res A. 2010Apr;93(1):123-32. PubMed PMID: 19536835.
(20) Yonenaga K, Nishizawa S, Akizawa M, Asawa Y,
Fujihara

Y,

TakatoT,

Hoshi

K.Utilityof

NucleoCounter for the chondrocyte count in thecollagenase digest of human native cartilage.
Cytotechnology. 2010 Dec;62(6):539-45. Epub2010 Sep 16. PubMed PMID: 20845070; PubMed
Central PMCID: PMC2995145.
(21) Yonenaga K, Nishizawa S, Fujihara Y, Asawa Y,
Sanshiro K, Nagata S, Takato T, Hoshi K. The
optimal conditions of chondrocyte isolation and its
seeding in the preparation for cartilage tissue
engineering. Tissue Eng Part C Methods. 2010
Dec;16(6):1461-9. Epub 2010 Nov 2. PubMed
PMID: 20412008.
(22) Thoren H, Seto I, Iizuka T: Patterns of frontobasal
and frontal sinus fractures in children and theirrelationship to the developmental stage of the facialskeleton. Arch Otolaryngol Head and Neck Surg 13(No.5) (in press)(23) Uchiyama T, Yamashita Y, Susami T, Kochi S,
Suzuki S, Takagi R, Tachimura T, Nakano Y, Shibui
T, Michi K, Nishio J, Hata Y: Primary treatment forcleft lip and /or palate in children in Japan. Cleft
Palate-Craniofac J (in press).

230

Department ofOrthopaedic Surgery
Associate Professors
Hiroshi Kawaguchi, M.D., Ph.D.,

Sakae Tanaka, M.D., Ph.D.

Lecturers
Katsushi Takeshita, M.D., Ph.D.,

Hirotaka Kawano, M.D., Ph.D.,

Takumi Nakagawa, M.D., Ph.D.,

Toshiki Miura, M.D., Ph.D.,

Associates
Hideya Itoh, M.D.,

Hirotaka Chikuda, M.D., Ph.D.,

Nobuhiro Hara, M.D.,

Yusuke Shinoda, M.D., Ph.D.,

Satoru Ohashi, M.D., Ph.D.,

Yasushi Ohshima, M.D., Ph.D.,

Tetsuro Yasui, M.D., Ph.D.,

Hiroshi Inui, M.D.,

Shuji Taketomi, M.D.,

Tetsuo Yamamoto, M.D.,

Takeyuki Tanaka, M.D.,

Satoshi Baba, M.D.,

Koichi Ogura, M.D.

Homepage

http://www.u-tokyo-ortho.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 Germany 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% of 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
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231

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 two
associate professors, four lecturers, 13 associates,
eight medical staff members, a visiting fellow, six
senior residents, and 11 part-time teachers.

Teaching activities
As for undergraduate education, our department
provides a comprehensive series of lectures, physicalassessment classes and problem-based learning (PBL)
program to 4th year medical students, bedsidelearning and clinical clerkship programs to 5th year
students and clinical lectures to 6th year medical
students.
A comprehensive series of lectures provides basic
knowledge of the physiology, pathology, diagnosis
and treatment of various musculoskeletal disorders.
Twelve consecutive lectures in total cover a whole
field of orthopaedics: basic science, pediatricdisorders, rheumatic diseases, metabolic bone diseases,
musculoskeletal neoplasm, 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 1-8 months. In total 30
doctors-in-training (21 first-year doctors and 9second-year doctors) completed our program during
this fiscal year. Since the training period is short,they are encouraged to experience emergency cases asoften 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 in 2010.
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 include ward rounds by the professor
on Tuesday. Post- and preoperative case conferences
are held on Monday evening, Tuesday morning andThursday evening.
941 operations were performed in 2010. These
include 101 cervical and thoracic spine surgeries(including 27 computer-assisted surgeries (CAS)), 85
lumbar spine surgeries, 27 scoliosis surgeries(including 26 CAS), 67 surgeries for rheumatoid
arthritis patients, 107 hip surgeries, 202 knee surgeries(including 37 computer-assisted ACL reconstruction,
51 computer-assisted TKA), 6 shoulder surgeries, 130
hand surgeries, 8 limb lengthening and reconstruction
surgeries using external fixators, 101 surgeries forbone and soft tissue tumor and 114 trauma surgeries.
The main disorders of cervical spine surgery weremyelopathy due to spondylosis or OPLL. We
successfully adopted double-door open laminoplasty
by splitting the spinal processes for most of thesecases. This procedure was invented and developed inour department and is now used nationwide. Difficult

232

operations such as subluxation of the cervical spine
due to rheumatoid arthritis, Down’s syndrome or
cerebral palsy were treated using a navigation systemthat has been officially approved as a high-leveladvanced 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 conducted 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 background of osteoarthritis using amouse genomics approach2) Signaling of differentiation and apoptosis ofosteoclasts
3) Etiology of OPLL
4) Molecular background underlying the joint
destruction by rheumatoid arthritis
5) Non-invasive evaluation of bone strength using afinite element method
6) In vivo bone formation by cytokines and its
clinical application
7) Molecular mechanism of age-related bone andcartilage disorders
8) Molecular mechanism of glial cell differentiation
9) Ultrasonic evaluation of articular cartilage
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. In the collaboration of the departments, theROAD (research on osteoarthritis against disability)
study has been established as the biggest osteoarthritis
project that covers from basic to clinical researches ofthe disease. The fourth is founded in the Graduate
School of Medicine and the researchers aredeveloping durable artificial joints in cooperation with
the Ishihara, Sakata & Takai Laboratory of the
Graduate School of Engineering. Furthermore, we
collaborate with the Center for Disease Biology andIntegrative Medicine (CDBIM), and are developing
nonviral gene delivery vectors (polyion complex
micelles).

233

We also take part in National Database of
Rheumatic Diseases by iR-net in Japan (NinJa), a
nationwide observational cohort database of rheumatic
disease.
8.

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Kawaguchi H, Takatori Y, Nakamura K, andIshihara K: Lubricity and stability ofpoly(2-methacryloyloxyethyl phosphorylcholine)
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Nakamura K, Ishihara K. Self-initiated surface
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and Hu K: tPA activates LDL receptor-related
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236

Department of Ophthalmology
Professor
Shiro Amano, 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.,

Shinsuke Konno, M.D., Ph.D.

Takashi Shigeeda, M.D.,

Chihiro Mayama., M.D., Ph.D., Tatsuro Tanabe, M.D.,

Takashi Miyai, M.D., Ph.D.,

Tatsuya Inoue, M.D., Ph.D.,

Tomoyasu Shiraya, M.D.,

Hiromasa Sawamura, M.D., Ph.D.,

Rei Sakata, M.D.,

Hitomi Saito M.D.

Homepage

Kenji Sugisaki, M.D.,

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 3000 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 2100
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237

corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged inpractical training for medical students on
ophthalmological examinations at the outpatient clinic.
As a postgraduate course, we give lectures on topics
concerning corneal transplantation, corneal diseases
and new medical therapies.

Research activities
Research topics in our department cover a variety offields in ophthalmology; e.g. ocular pharmacology,
regenerative medicine in the cornea and retina,
aqueous humour dynamics, immunology andmolecular biology. Special laboratories for physiology,
pharmacology and genetic engineering have been
established. Specific fields of research in our
department are as follows.
1. Analysis with laser-speckle method of vascularflow in retina and iris
2. Clinical investigation of normal tension glaucoma
3. Drug effect on glaucoma
4. Screening method of glaucoma
5. Tissue engineering of the cornea
6. Clinical investigation of corneal shape
7. Novel culture system of corneal limbal epitheliumand oral mucosal epithelium for ocular surface
reconstruction
8. Analysis of Meibomian gland with Mibography
9. Clinical and basic research of excimer laser
refractive surgery
10. Molecular analysis of retinal degenerative
diseases
11. Color blindness and visual function
12. Electrophysiological analysis of the effect ofdrugs on the retina
13. Pathophysiologyofage-related
maculardegeneration
14. Molecular analysis of retinal neovascularization
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: Clinical appraisal of tafluprost in the
reduction of elevated intraocular pressure (IOP)
in open-angle glaucoma and ocular hypertension.
Clin Ophthalmol 4:163-170, 2010
2. Amano S, Kaji Y, Mimura T: Biology of corneal
endothelial cells in vivo and in vitro. Jpn J
Ophthalmol 54:211-214, 2010
3. Amano S, Kaji Y, Mimura T: Biology of corneal
endothelial cells in vivo and in vitro. Jpn J
Ophthalmol 54:211-214, 2010
4. Araie M, Shirato S, Yamazaki Y, Kitazawa Y,
Ohashi Y. Nipradilol-Timolol Study Group:
Visual field loss in patients with normal-tension
glaucoma under topical nipradilol or timolol:
subgroup and subfield analyses of the nipradiloltimolol study. Jpn J Ophthalmol 54:278-285,
2010
5. Arita R, Itoh K, Maeda S, Maeda K, Furuta A,
Tomidokoro A, Amano S: Meibomian gland duct
distortion in patients with perennial allergic
conjunctivitis. Cornea 29:858-860, 2010
6. Arita R, Itoh K, Maeda S, Maeda K, Furuta
A,Tomidokoro A, Amano S: Proposed diagnostic
criteria for seborrheic meibomian gland
dysfunction. Cornea 29:980-984, 2010
7. Arita R, Itoh K, Maeda S, Maeda K, Tomidokoro
A, Amano S: Efficacy of diagnostic criteria forthe differential diagnosis between obstructive
meibomian gland dysfunction and aqueous
deficiency dry eye. Jpn J Ophthalmol 54:387-391,
2010
8. Azar DT, Casanova FH, Mimura T, Jain S, Zhou
Z, Han KY, Chang JH: Corneal Epithelial
MT1-MMP Inhibits Vascular Endothelial Cell
Proliferation and Migration. Cornea 29:321-330,
2010
9. Dimitrova G, Kato S: Color doppler imaging of
retinal diseases. Survey of Ophthalmology
55:193-214, 2010
10. Endo N, Kato S, Haruyama K, Shoji M, Kitano S:
Efficacy of Bromfenac sodium ophthalmic
solution in preventing cystoid macular edema
after cataract surgery in diabetic patients. Acta
Ophtalmologica 88:896-900, 2010

238

11. Fukuoka S, Honda N, Ono K, Mimura T, Usui T,
Amano S: Extended long-term results ofpenetrating keratoplasty for keratoconus. Cornea
29:528-530, 2010
12. Hayashi K, Tomidokoro A, Konnno S, Mayama C,
Aihara M, Araie M: Evaluation of optic nerve
head configurations of superior segmental optic
hypoplasia by spectral-domain optical coherence
tomography. Br J Ophthalmol 94:768-772, 2010
13. Hayashi K, Tomidokoro A, Konno S, Mayama C,
Aihara M, Araie M: Evaluation of optic nerve
head configurations of superior segmental optic
hypoplasia by spectral-domain optical coherence
tomography. Br J Ophthalmol 94:768-772, 2010
14. Henzan MI, Tomidokoro A, Uejo C, Sakai H,
Sawaguchi S, Iwase A, Araie M: Ultrasoundbiomiccroscopic configurations of the anterior
ocular segment in a population-based study: The
Kumejima Study. Ophthalmology 117:1720-1728,
2010
15. Higa A, Sakai H, Sawaguchi S, Iwase A,
Tomidokoro A, Amano S, Araie M: Corneal
endothelial cell density and associated factors ina population-based study in Japan: The
Kumejima study. Am J Ophthalmol 149:794-799,
2010
16. Hirasawa H, Tomidokoro A, Araie M, Konno S,
Saito H, Iwase A, Shirakashi M, Abe H, Ohkubo
S, Sugiyama K, Ootani T, Kishi S, Matsushita K,
Maeda N, Hangai M, Yoshimura N: Peripapillary
retinal nerve fiber layer thickness determined byspectral-domain optical coherence tomography inophthalmologicallynormaleyes.
ArchOphthalmol 128:1420-1426, 2010
17. Honda N, Miyai T, Nejima R, Miyata K, Mimura
T, Usui T, Aihara M, Araie M, Amano S: Effectof latanoprost on the expression of matrix
metalloproteinases and tissue inhibitor of
metalloproteinase-1 on the ocular surface. Arch
Ophthalmol 128:466-471, 2010
18. Ito Y, Nakamura S, Tanaka H, Tsuruma K,
Shimazawa M, Araie M, Hara H: Lomerizine, aCa2+-channel blocker, protects against neuronaldegeneration within the visual cortex of the brain
after retinal damage in mice. CNS Neurosci Ther
16:103-114, 2010
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Yoshida A, Numaga J, Fujino Y, Kawashima H:
Best-corrected visual acuity and frequency ofocular attacks during the initial 10 years inpatients with Behçet's disease. Graefes Arch
Clin Exp Ophthalmol 248:709–714, 2010
Kaburaki T, Takamoto M, Araki F, Fujino Y,
Nagahara M, Kawashima H, Numaga J:
Endogenous Candida albicans infection causing
subretinal abscess. Int Ophthalmol 30:203-206,
2010
Kaburaki T, Takamoto M, Numaga J, Kawashima
H, Araie M, Ohnogi Y, Harihara S, Kuwata S,
Takeuchi F: Genetic association of HLA-A*2601
with ocular Behçet's disease in Japanese Patients.
Clin Exp Rheumatol28:S39-S44, 2010
Kawashima H, Fujishiro T, Obata R, Mayama C,
Ishii K, Kojima T: Statistical analyses of ocularinflammatory diseases at Saitama Red Cross
Hospital (2003-2007). Jpn J Ophthalmol 54:
96-97, 2010
Lee KY, Nakayama M, Aihara M, Chen YN,
Araie M: Brimonidine is neuroprotective against
glutamate-induced neurotoxicity, oxidative stress,and hypoxia in purified rat retinal ganglion cells.
Mol Vis 16:246-251, 2010
Lee KY, Tomidokoro A, Sakata R, Konno S,
Mayama C, Hayashi K, Iwase A, Araie M:
Cross-sectional anatomic configurations ofperipapillary atrophy evaluated with spectral
domain-optical coherence tomography. Invest
Ophthalmol Vis Sci 51:666-671, 2010
Mayama C, Ishii K, Saeki T, Ota T, Tomidokoro
A, Araie M: Effects of topical phenhylephrine
and tafluprost on optic nerve head circulation inmonkeys with unilateral experimental glaucoma.
Invest Ophthalmol Vis Sci 51:4117-4124, 2010
Mimura T, Usui T, Mori M, Aixinjueluo W,
Funatsu
H,
Noma
H,
Amano
S:
Immunochromatographic assay for measurementof total IgE in tears, nasal mucus, and saliva of
patients with allergic rhinoconjunctivitis. J
Asthma 47 1153-1160, 2010
Mimura T, Usui T, Mori M, Funatsu H, Noma H,
Aixinjueluo W, Yamamoto H, Amano S: Rapid
immunochromatography
of
total
tear
immunoglobulin E in allergic conjunctivitis with
Allerwatch. J Investig Allergol Clin Immunol

239

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20:627-628, 2010
Mimura T, Usui T, Mori M, Yamamoto H, Obata
H, Yamagami S, Funatsu H, Noma H, Honda N,
Amano S: Pinguecula and contact lenses. Eye
24:1685-1691, 2010
Mimura T, Usui T, Yamagami S, Funatsu H,
Noma H, Honda N, Amano S: Recent causes ofsubconjunctival hemorrhage. Ophthalmologica
224:133-137, 2010
Mimura T, Yamagami S, Mori M, Funatsu H,
Usui T, Noma H, Amano S: Contact lens-induced
subconjucntival hemorrhage. Am J Ophthalmol
150:656-665, 2010
Mimura T, Yamagami S, Uchida S, Yokoo S, Ono
K, Usui T, Amano S: Isolation of adult progenitor
cells with neuronal potential from rabbit corneal
epithelial cells in serum- and feeder layer-free
culture conditions. Mol Vis 16:1712-1719, 2010
Mimura T, Yamagami S, Usui T, Funatsu H,
Noma H, Honda N, Fukuoka S, Hotta H, Amano
S: Location and extent of subconjunctival
hemorrhage. Ophthalmologica 224:90-95, 2010
Mimura T, Yamagami S, Yokoo S, Usui T, Amano
S: Selective isolation of young cells from humancorneal endothelium by the sphere-forming assay.
Tissue Eng Part C Methods 16:803-812, 2010
Nomura Y, Tamaki Y, Yanagi Y: Vitreopapillarytraction diagnosed by spectral domain opticalcoherence tomography. Ophthalmic Surg Lasers
Imaging 41:S74-76, 2010
Ooto S, Hangai M, Sakamoto A, Tomidokoro A,
Araie M, Otani T,Kishi S, Matsushta K, Maeda N,
Shirakashi M, Abe H, Takeda H, Sugiyama K,
Saito
H,
Iwase
A,
YoshimuraN:
Three-dimensional profile of macular retinal
thickness in normal Japanese eyes. Invest
Ophthalmol Vis Sci 51:465-473, 2010
Saito H, Tsutsumi T, Iwase A, Tomidokoro A,
Araie M: Correlation of disc morphology
quantified on stereophotographs to results by
HRT II, GDx VCC and visual field tests.
Ophthalmology 117:282-289, 2010
Sugiyama T, Araie M, Riva CE, Schmetterer L,
Orgul S: Use of laser speckle flowgraphy inocular blood flow research. Acta Ophthalmol
88:723-729, 2010
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Nomura N, 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, HigashideT, Sugiyama K, Kanamoto T, Kiuchi Y, Iwase A,
Ohno S, Inoko H, Mizuki N: Genotyping
HLA-DRB1 and HLA-DQB1 alleles in Japanesepatients with normal tension glaucoma. Mol Vis
15:1874-1879, 2010
Writing Committee fot the Normal Tension
Glaucoma Genetic Study of Japan Glaucoma
Society (Aihara M, et al): Genome-wide
association study of normal tension glaucoma:
Common variants in SRBD1 and ELOVL5
contributetodiseasesusceptibility.
Ophthalmology 117:1331-1338, 2010
Tomoyose E, Higa A, Sakai H, Sawaguchi S,
Iwase A, Tomidokoro A, Amano S, Araie M:
Intraocular pressure and relating systemic andocular biometric factors in a population-based
study in Japan. The Kumejima Study. Am J
Ophthalmol 150:279-286, 2010
Tsuji H, Kanda H, Kashiwagi H, Mimura T:
Primary epithelioid haemangioendothelioma of
the eyelid. Br J Ophthalmol 94:261-262, 2010
Tsuji H, Tamura M, Yokoyama M, Takeuchi K,
Mimura T: Ocular involvement by EBV-positive
diffuse large B-cell lymphoma of the elderly, a
new disease entity in the WHO classification.
Arch Ophthalmol 128:258-259, 2010
Ueta T, Nakano T, Ida Y, Sugita N, Mitsuishi M,
Tamaki Y: Comparison of robot-assisted andmanual retinal vessel microcannulation in an
animal model. Br J Ophthalmol 95:731-734,
2011.
Usui T, Nakagawa S, Yokoo S, Mimura T,
Yamagami S, Amano S: Bilateral limbal stem cell
deficiency with chromosomal translocation of 3p
and 9p. Jpn J Ophthalmol 54:357-358, 2010
Yuda K, Inoue Y, Tomidokoro A, Tamaki Y,
Yanagi Y: Nerve fiber layer thickness in
exudative age-related macular degeneration in
Japanese patients. Graefe's Arch Clin Exp
Ophthalmol 248:353-359, 2010

240

Department ofOtorhinolaryngology andHead & Neck Surgery
Professor
Tatsuya Yamasoba, M.D, Ph.D.

Associate Professor
Takahiro Asakage, M.D.,Ph.D

Shin-ichi Iwasaki, MD.PhD

Lecturer
Kenji Kondo, M.D, Ph.D

Akinobu Kakigi, M.D., Ph.D,

Takaharu Nito, M.D., Ph.D.

Takashi Sakamoto, M.D. PhD.

Research Associate
Shotaro Karino, M.D, Ph.D,

Yasuhiro Ebihara, M.D,

Munetaka Ushio, M.D., Ph.D,

Takuya Yasui, M.D., Ph.D.

Naoya Egami, M.D.

Mizuki Ando, M.D.

Keigo Suzukawa, M.D.,

Shontaro Baba, MD.,

Masahiro Yoshida, M.D,

Akinori Kashio, M.D,

Kaori Kanaya, 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.

241

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 800 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 and neck surgery, bronchoesophagology and rhinology and is related to caseresersch, clinical statistics and clinical electrophysiology. 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

242

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.

8.

9.
Various clinical and basic research are conducted bystaffs, residents, postgraduate doctors and seniordoctors at affiliated hospitals.

10.

References
1.

2.

3.

4.

5.

6.

7.

Adachi N, Ito K, Sakata H. Risk Factors for
Hearing Loss After Pediatric Meningitis in Japan.
Ann Otol. Rhinol Laryngol 119:294-296,2010
Adachi N, Ito K, Sakata H, Yamasoba T. Etiology
and one-year follow-up results of hearing loss
identified by screening of newborn hearing inJapan.Otolaryngol Head Neck Surg.143:97-100,
2010
Ando M, Asai M, Ono T, Nakanishi Y, Asakage T,
Yamasoba T.Metastases to the lingual nodes intongue cancer: a pitfall in a conventional neckdissection.Auris Nasus Larynx.37:386-389,2010
Egami N, Ushio M, Yamasoba T, Murofushi T,
Iwasaki S. Indication of the side of delayed
endolymphatic hydrops by vestibular evoked
myogenic potential and caloric test. ORL J
Otorhinolaryngol Relat Spec. 72:242-6 2010
Fujimoto C, Murofushi T, Chihara Y, Ushio M,
Yamaguchi T, Yamasoba T, Iwasaki S. Effects of
unilateral dysfunction of the inferior vestibular
nerve system on postural stability. Clin
Neurophysiol 121:1279-1284,2010
Fujimoto C, Ozeki H, Uchijima Y, Suzukawa K,
Mitani A, Fukuhara S, Nishiyama K, Kurihara Y,
Kondo K, Aburatani H, Kaga K, Yamasoba T,
Kurihara H.Establishment of mice expressing
EGFP in the placode-derived inner ear sensory
cell lineage and FACS-array analysis focused on
the regional specificity of the otocyst.J Comp
Neurol.518:4702-4722,2010
Hayashi S, Hirose H, Tayama N, Imagawa H,
Nakayama M, Seino Y, Okamoto M, Kimura M,

11.

12.

13.

14.

15.

16.

17.

Nito T.High-speed digital imaging laryngoscopyof the neoglottis following supracricoid
laryngectomy with cricohyoidoepiglottopexy J
Laryngol Otol.124:1234-8,2010
Inokuchi G, Okuno T, Hata.Y, Baba M, Sugiyama
D. Congenital Cholesteatoma: Posterior Lesions
and the staging system Ann Otol.119:490-494,
2010
Inoue A, Egami N, Kitahara N, Yagi M.
Differential diagnosis of proptosis: Report of 2
cases. Auris Nasus Larynx 37:526- 29,2010
Ito K, Chihara Y, Iwasaki S, Komuta Y, Sugasawa
S, Sahara Y.Functional ligand-gated purinergic
receptors (P2X) in rat vestibular ganglion
neurons.Hear Res.267:89-95,2010
Ito K, Dulon D. Purinergic signaling incochleovestibular hair cells and afferent neurons.
Purinergic Signal.6:201-209,2010
Iwasaki S, Murofushi T, Chihara Y, Ushio M,
Suzuki M, Curthoys IS, Yamasoba T. Ocularvestibular evoked myogenic potentials tobone-conductedvibrationinvestibular
schwannomas. Otol Neurotol. 31:147-52, 2010
Kagoya R, Ito K, Kashio A, Karino S, Yamasoba
T.Dislocation of stapes with footplate fracturecaused by indirect trauma.Ann Otol Rhinol
Laryngol. 119:628-630,2010
Kagoya R, Monobe H, Tojima H.Utility ofelastography for differential diagnosis of benign
and malignant thyroid nodules Otolaryngol Head
Neck Surg.143:230- 234.2010
Kakigi A, Okada T, Takeda T, Takeda S, Taguchi
D, Nishimura M, Yamasoba T. Endocytosis of
MPO in marginal cells is regulated by PKC,
protein phosphatase, ERK and PI3-K signalingcascades, but not by PKA and MEK signalingcascades. ORL J Otorhinolaryngol Relat Spec.
72:188-95, 2010
Kawamura S,Sakamoto T,Kasio A,Kakigi A,Ito
K,Suzuki M,Yamasoba T.Cochlear implantation
in a patient with atypical Cogan's syndrome
complicatedwithhypertrophic
cranialpachymeningitis Auris Nasus Larynx. 37:737-41,
2010
Kikuta S,Sato K, Kashiwadani H,Tsunoda
K,Yamasoba T, Mori K.From the Cover: Neurons
in the anterior olfactory nucleus pars externa

243

18.

19.

20.

21.

22.

23.

24.

detect rightanterior olfactory nucleus pars externa
detect rightor left localization of odor sources.
Proc Natl Acad .Sci U S A.107(27):12363-8,
2010.6
Kimura M, Imagawa H, Nito T, Sakakibara K,
Chan RW, Tayama N. Arytenoid adduction forcorrecting vocal fold asymmetry: High-speed
imaging.
Ann Otol Rhinol Laryngol. 119:439-446,2010
Kimura M, Nito T, Imagawa H, Sakakibara K,
Chan RW, Tayama N. Collagen injection forcorrecting vocal fold asymmetry: high-speed
imaging. Ann Otol Rhinol Laryngol. 119:359-368,
2010
Kondo K, Suzukawa K, Sakamoto T, Watanabe K,
Kanaya K, Ushio M, Yamaguchi T, Nibu K, KagaK, Yamasoba T. Age-related changes in cell
dynamics of the postnatal mouse olfactory
neuroepithelium
cell proliferation, neuronaldifferentiation and cell death. J Comp Neurol.
518:1962-1975,2010
Matsumoto, Y., Nomoto, T., Cabral, H.,
Matsumoto, Y., Watanabe, S., Christie, R.J.,
Miyata, K., Oba, M., Ogura, T., Yamasaki, Y.,
Nishiyama, N., Yamasoba, T., Kataoka, K.
Direct and Instantaneous Observation of
Intravenously
Injected
Substances
Using
Intravital Confocal Micro-Videograp hy Biomed.
Opt.Express.1(4): 1209- 1216,2010
Nakajima T, Kurano M, Hasegawa T, Takano H,
Iida H, Yasuda T, Fukuda T, Madarame H, Uno K,
Meguro K, Shiga T, Sagara M, Nagata T,
Maemura K, Hirata Y, Yamasoba T, Nagai R.
Pentraxin3 and high-sensitive C-reactive protein
are independent inflammatory markers released
during high-intensity exercise. Eur J Appl
Physiol. 110:905-13, 2010
Nakajima T, Kurano M, Sakagami F, Iida H,
Fukumura K, Fukuda T, Takano H, Madarame H,
Yasuda T, Nagata T, Sato Y, Yamasoba T, Morita
T. Effects of low- intensity KAATSU resistancetraining on skeletal muscle size/ strength andendurance capacity in patients with ischemic
heart disease. Int. J. KAATSU Training Res.
6:1-7,2010
Oguri A, Tanaka T, Iida H, Meguro K, Takano H,
Oonuma H, Nishimura S, Morita T, Yamasoba T,

Nagai R, Nakajima T. Involvement of CaV3.1
T-type calcium channels in cell proliferation inmouse preadipocytes. Am J Physiol Cell Physiol.
298(6):C1414-23, 2010
25. Omura G, Watanabe K, Fujishiro Y, Ebihara Y,
Nakao K, Asakage T. Organized hematoma in theparanasal sinus and nasal cavity-Imaging
diagnosis and pathological findings. Auris Nasus
Larynx. 37:173-77,2010
26. Saito K, Kimura M, Imagawa H, Nito T, Tayama
N, Shiotani A High-speed digital imaging of theneoglottis after supracricoid laryngectomy withcricohyoidepiglottopexy. Otolaryngol Head Neck
Surg.142:598-60, 2010
27. Sakamoto T, Iwamura H, Kashio A, Ito K, Kaga
K, Suzuki M, Yamasoba T. Comparison ofhearing improvement and complications afterstapes surgery with and without potassium titanyl
phosphate laser for manipulation of the foot plate.
ORL J Otorhinolaryngol Relat Spec. 72:16-21,
2010
28. Sasaki T, Tsunoda K. How I do it: chopsticks
technique for hemostasis in tonsillectomy. Eur
Arch Otorhinolaryngol. [Epub ahead of print]
2010
29. Sasaki T, Xu A, Ito K, Ishimoto SI, Yamasoba T,
Kaga K, Yamauchi N. Histopathologicaldifferences in bony destruction of malleus andincus following mastoidectomy. J Laryngol Otol.
124: 1162-6, 2010
30. Someya S, Tanokura M, Weindruch R, Prolla TA,
Yamasoba T. Effects of caloric restriction on
age-related hearing loss in rodents and rhesus
monkeys. Curr Aging Sci. 3:20-5, 2010
31. Suzuki M, Kashio A, Sakamoto T, Yamasoba T.
Effect of Burow's solution on the guinea pig
inner ear. Ann Otol Rhinol Laryngol. 119:495-500 2010
32. Takano S, Kimura M, Nito T, Imagawa H,
Sakakibara K, Tayama N. Clinical analysis ofpresbylarynx - Vocal fold atrophy in elderly
indivisuals. Auris Nasus Larynx 37: 461-464,
2010

244

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 2009, and eight ofthem were granted Ph.D.

Clinical activities
There is not enough doctors arranged for the
department of rehabilitation medicine, and we cannot
run own beds for rehabilitation patients at present. The
professor serves as a director of 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 250 patients corresponding about 25% 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245

rehabilitation medicine for 4th, 5th, and 6th year
medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such ascerebrovascular disturbances, spinal cord injuries andspina bifida, neuromuscular diseases, bone and joint
diseases, and cerebral palsy as well as on outline ofrehabilitation, welfare system, and prostheses /orthoses . We have provided a clinical practice insmall group, so-called bedside learning for 5th year
students from Wednesday to Friday every other week.
They experience a few patients and learn how to takea patients’ history, physical findings, functional
evaluation, and how to plan rehabilitation programs.
We have introduced a few of elective students forclinical clerkship to our collaborating hospitals withspecialized rehabilitation ward.
In addition, we have provided the training of comedical students including physical therapy andoccupational therapy. Twenty students or more comeand stay at the university hospital annually as 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 in theelderly4) Analysis of motion and energy expenditure in theactivities of daily living in the physically disabled

5) Rehabilitation approaches for patients with spina
bifida6) Treatment and rehabilitation for patients withcongenital limb deficiencies
7) Disabilities and handicaps in patients with skeletal
dysplasias
8) Analysis of musculo-skeletal involvement incongenital insensitivity to pain
9) Rehabilitation of patients with hematogenic
malignancies around the stem cell transplantation

References
1. Chiba Y, Haga N: Evaluating visual bias andeffect of proprioceptive feedback in unilateralneglect. J Clin Neurosci, 17: 1148-1152, 2010
2. Iijima M, Haga N: Evaluation of nonnociceptive
sensation in patients with congenital insensitivity
to pain with anhidrosis. Childs Nerv Syst 26:
1085-1089, 2010
3. Nakashima Y, Haga N, Kitoh H, Kamizono J,
Tozawa K, Katagiri T, Susami T, Fukushi J,
Iwamoto Y: Deformity of the great toe infibrodysplasia ossificans progressiva. J Orthop Sci
15: 804-809, 2010
4. Takedani H, Fujii T, Kobayashi Y, Haga N,
Tatsunami S, Fujii T: Inter–observer reliability of
three different radiographic scores for adulthaemophilia. Haemophilia 17(1): 134-138, 2010

Surgical Sciences
3. Vital Care Medicine

247

Department of Anesthesiology
Professor
Yoshitsugu Yamada, M.D., Ph.D.

Lecturer
Ryo Orii, M.D., Ph.D.

Kyung-Ho Chang, M.D., Ph.D.

Nobuko Ito, M.D., Ph.D. Toshiya Tomioka, M.D., Ph.D.

Instructor
Hiroshi Sekiyama, M.D., Makoto Ogawa, M.D.,

Yuichiro Saito, M.D.,

Kanji Uchida, M.D., Ph.D Nobuhide Kin, M.D.,

Takayuki Kitamura, M.D.,

Makoto Nakamura, M.D., Kanako Sato, M.D.,

Jun Ninagawa, M.D.,

Gaku Kawamura, M.D.,

Junko Takarada, M.D.,

Kenichi Kishida, M.D.,

Yoshiteru Mori, M.D.,

Masahiko Sumitani,M.D.,PhD., Miho Asahara, M.D.,

Hiroko Tsujihara, M.D.,

Yoshie Suzuki, M.D.,

Kenji Azuma, M.D.,

Masaaki Asamoto, M.D.

Rui Sato, M.D.,

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/aprc_md/index.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 heart / liver transplant,
spinal/epidural anesthesia and monitored anestheticcare for electro-convulsion therapy. Recently, thenumber of high risk or geriatric patents is increasing.
In addition, more than 20% of the surgery among
8000 cases per year spends more than eight hours. A
new operating theater opened in January 2007 and thedemand for sufficient number of competentanesthesiologists is increasing.
Pain clinic services are provided for out-patients(including patients in the ward of the otherdepartment) on a daily basis in all areas of diseases
accompanied with pain. We also provide preoperative
anesthetic consult service for patients who havevarious medical complications. From April 2010 toApril 2011, the number of ambulatory patients was
about ten thousand; six hundred of those were
newcomer patients. Currently we have three beds inthe ward. Annually, we provide inpatient service forsixty patients in our ward as well as for seven hundred
and twenty patients in other wards. Preoperative
anesthetic consults were done for about twelve
hundred patients last year.

248

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, the mechanisms ofanesthesia, inhalational anesthesia, intravenous
anesthesia, anesthesia and respiratory/circulatory
system, the balance of body fluid, acid-base balance,
muscle relaxants, management of the patient during
anesthesia, monitoring, resuscitation, pain clinic andthe physiology and the management of pain.
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
how to evaluate patients in the peri-operative period.
Through the practice of pain management, we teachstudents 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 submit a report of a case who underwent generalanesthesia and the summary of anesthetics andcardiovascular drugs in peri-operative use. We discuss
the contents of the reports and summaries withstudents at the end of bedside learning, for theirfurther understandings.

Research activities
We have seven research groups and their fields
include respiration, circulation, pain, immune systemand shock.
These are recent major subjects of our research.
1) A role of cytokine signaling in acute lung injury2) Evaluation of optimal ventilatory strategy for

respiratory failure3) Modulation of immune system by anesthetics
4) Signal transduction pathway related to apoptosis
activated by sepsis or ischemia-reperfusion5) Pathophysiology of shock6) A role of lipid mediators in organ damage
mediated by ischemia-reperfusion injury7) 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 pain
10) 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
warming17) Effect of anesthetics on glucose metabolism invivo18) Role of new plasma substitutes on hemorrhagic
shock

References(1) Sumitani M, Yozu A, Tomioka T, Yamada Y,
Miyauchi S. Using the intact hand for objective
assessment of phantom hand perception. European
Journal of Pain 2010;14:261-5(2) Sumitani M, Miyauchi S, Yozu A, Otake Y, Saitoh Y,
Yamada Y. Phantom limb pain in the primary motor
cortex. Journal of Anesthesia 2010;24:337-41(3) Kishima H, Saitoh Y, Oshino S, Hosomi K,
Mohamed A, Hirata M, Goto T, Maruo T,
Yanagisawa T, Sumitani M, Osaki Y, Hatazawa J,
Yoshimine T. Modulation of neuronal activity after
spinal cord stimulation for neuropathic pain:
H2O15 PET study. NeuroImage 2010;49:2564-9

249(4) Sumitani M, Shibata M, Sakaue G, Mashimo T,
Japanese CRPS Research Group. Development ofcomprehensive diagnostic criteria of complex
regional pain syndrome in the Japanese population.
Pain 2010;150:243-9(5) Sakagami T, Beck D, Uchida K, Suzuki T, Carey
BC, Nakata K, Keller G, Wood RE, Wert SE,
Ikegami M, Whitsett JA, Luisetti M, Davies S,
Krischer JP, Brody A, Ryckman F, Trapnell BC.
Patient-derived

GM-CSF

Autoantibodies

Reproduce Pulmonary Alveolar Proteinosis in
Non-human Primates. Am J Respir Crit Care Med
2010;182(1):49-61(6) Uchida K, Carey B, Suzuki T, Nakata K, Trapnell
BC. Response: Granulocyte/macrophage colonystimulating factor autoantibodies and myeloid cell
immune functions in healthy persons. Blood 2010;
115(2):431-3(7) Watanabe M, Uchida K, Nakagaki K, Trapnell BC,
Nakata K. High avidity cytokine autoantibodies inhealth and disease: pathogenesis and mechanisms.
Cytokine Growth Factor Rev 2010;21(4):263-73(8) Bougaki M, Searles RJ, Kida K, De Yu J, Buys ES,
Ichinose F. NOS3 protects against systemic
inflammation and myocardial dysfunction in murine
polymicrobial sepsis. Shock 2010;34(3):281-90

250

Department of Emergency andCritical Care Medicine
Professor
Naoki Yahagi, M.D.

Associate Professor
Susumu Nakajima, M.D.

Lecturer
Yukio Tanaka, M.D., Ph.D.

Associate
Takeshi Ishii, M.D.,
Jiro Ando, M.D.,

Masataka Gunshin, M.D.,
Yumiko Hosoya, M.D.,

Takahiro Hiruma, M.D.,

Takehiro Matsubara, M.D.,

Juntaro Matsuyama, M. D.,

Hidenobu Fujita, M.D.,

Rei Ito, M.D.,

Yasuyuki Jujo, M.D.,

Kanae Nagatomo, M.D.,

Staff
Ryota Inokuchi, M.D., Shiho Oide, M.D.,

Homepage

http://square.umin.ac.jp/todaiqq/

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. The
university of Tokyo hospital was officially designated251

as emergency medical care center in December 2010.

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 2006,
we had about 6,000 ambulance patients out of total
20,300 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 and gynecology, 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 2,700 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.

252

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 andSupport) program, triage training, and risk
communication techniques using wireless network.
In addition, we produce the seminar for nurses suchas medical support in the big earthquake.

4.

5.

6.

Research activities
7.
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.

Miura T, Nishigaki M, Matsubara T, Sakamoto M,
Kikuchi Y, Nakajima S, Tanaka Y. Nurse-led
educational session for non-medical staff
improved the appropriateness of rapid response
team activation. Jpn J Trauma Emerg Med 2010:
1; 9-15.
Sorimachi M, Nakada Y, Izumi A, Matsubara T.
Cardiac function before operation affects
operative results in patients with hip fractures.
Jpn J Trauma Emerg Med 2010:1; 1-8.
Matsuse S, Hara Y, Ohkura T. Arterial
sevoflurane concentration during one-lungventilation (OLV). Possible influence ofpulmonary arterio-venous shunt and hypoxic
pulmonary vasoconstriction. Anesth Analg 2010
Nov 16. [Epub ahead of print]

Doi K, Noiri E, Maeda-Mamiya R, Ishii T,
Negishi K, Hamasaki Y, Fujita T, Yahagi N,
Koide H, Sugaya T, Nakamura T. Urinary L-type
fatty acid-binding protein as a new biomarker ofsepsis complicated with acute kidney injury. Crit
Care Med 2010 Jul 22. [Epub ahead of print]
Furumoto N, Yamaoka T, Matsubara T, Gunshin
M, Ishii T, Nakajima S, Tanaka Y, Yahagi N. On
issues with medical responses observed in majordisasters in Japan and the countermeasures (Aninterview study with officials aiming better
readiness). Jap J Disaster Med 2010; 15: 53-62.
Unuma K, Shintani-Ishida K, Yahagi N,
Tsushima K, Shimosawa T, Ueyama T, Yoshida K.
Restraint
StressInduces
Connexin-43
Translocation via α-Adrenoceptors in Rat Heart.
Circ J 2010; 74: 2693-701.
Inamori S, Fujii Y, Oshita T, Kobayashi Y,
Minamiyama M, Sasaki S, Murakami T, Sakuma
I, Suematsu Y, Gunshin T, Yahagi N.
Development of a pulsatile flow-generating
circulation assist device for cardiac management.
J Artif Organs 13: 67-70. 2010

Health Sciences and Nursing
1. Health Sciences

254

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/※For this department, this year’s text is the same as that published last year.

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), 25 graduate
students (8 master course students and 17 doctor
course students) including 2 international students and
11 students qualified with nurse, and 5 research
students. More than thirty 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 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 2009, 5 MC students
submitted Master Thesis and gained Master’s Degree.
One DC student and one Ronpaku researcher
submitted Doctoral Dissertation and got Doctor’sDegree.

255

In Undergraduate Courses, School of Health
Sciences and Nursing, our department is in charge ofthe following subjects as: Health Sociology (with alecturer, 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.

4.

5.

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, especially

6.

7.

among the middle-aged, in Japan. Anotherpurpose of this project is to consider possible
explanations for these differences and theimplications for policy.
Studieson
Changing
Professional-Patient
Relationship and Patient Autonomy
The aim of this project is to examine the current
situation of professional-patient relationship andpatient autonomy in Japan, and to derive newtheories. Both empirical and theoretical studies
have been conducted from various perspectives.
Studies on “Way of Working and Living” andFatigue/Stress of Working People
Recently Japanese industrial society has been
subjected to the never-experienced structuralchanges. The aims of this project are to explore
the effects of these changes on “ways of working
andliving”,
work-familybalanceandfatigue/stress of working people, and to clarify themechanism of the effects.
Studies on Characteristics of the Physical andPsychological Distresses in Human Service Work
Human service work is spread over the many
fields including medicine, nursing and caring. The
aims of this project is to examine thecharacteristics of the psychological and physicaldistress of human service workers and theirrelated factors.
Studies on the Onset of Pneumoconiosis among
Tunnel Construction Workers
In Japan, many tunnel construction workers
suffered from the onset of severe pneumoconiosis
in 1970’s. It is still continuing in 1990’s. The
purpose of this research project is to reveal theprocess and the related factors on the onset ofpneumoconiosis in recent years.

References
1.

2.

Yuko Hirano, Yoshihiko Yamazaki: Ethical issues
ininvasivemechanicalventilationforamyotrophic lateral sclero, Nursing Ethics,
2010.1. 17(1), 51-63.
Yoshihiko Yamazaki: Concept and Definition ofSense of Coherence (SOC) as Power for
Successful Stress Coping, Jpn. Nursing Research
2009.12. 42(7):479-490 (in Japanese)

256

3.

Taisuke Togari, Yoshihiko Yamazaki: How to Use
Sense of Coherence Scales: Versions, Items,
Precautions and Future Issues, Jpn. Nursing
Research 2009.12. 42(7):505-516 (in Japanese)
4. Tomoko Takeuchi, Taisuke Togari, Yoshihiko
Yamazaki: Nurses’ Sense of Coherence andWorkplace: The Workplace Characteristics forLively Nurses, Jpn. Nursing Research 2009.12.
42(7):517-526 (in Japanese)
5. Asami Fujishima, Taisuke Togari, Yoshihiko
Yamazaki: The Experience of Living with
Untreated Illness: Trial of a Qualitative Analysis
Using Sense of Coherence Theory, Jpn. Nursing
Research 2009.12. 42(7):527-538 (in Japanese)
6. Ryoko Taguchi, Yoshihiko Yamazaki, Taisuke
Togari､Development of a family relationships
scale based on the Family Relationships
Index(FRI) Japanese version､Jpn J Public Health2009.6 56(7): 468-477, (in Japanese)
7. Hirono Ishikawa, Eiji Yano, Shin Fujimori,
Makoto Kinoshita, Toshikazu Yamanouchi,
Mayuko Yoshikawa, Yoshihiko Yamazaki, Tamio
Teramoto:
Patient
healthliteracy
andpatient-physician information exchange during avisit, Family Practice, 2009. 26; 517-523,
8. Michiko Kato, Yoshihiko Yamazaki. An
examination of factors related to work-to-family
conflict among employed men and women in
Japan. Journal of Occupational Health, 2009.7.
51(4),303-313,
9. Taisuke Togari, Yoshihiko Yamazaki, The
socioeconomic gradient of sense of coherencefrom representative sample survey of 4,800
Japanese people aged 20 to 40. Bulletin ofSocial Medicine 2009.6 26(2): 45-52, (inJapanese)
10. Taisuke Togari, Reika Otemori, Yoshihiko
Yamazaki, Miho Sato,Yuki Yonekura, Naoko
Kumada, Keiko Seki Sakakibara, Sense of
Coherence (SOC) and its related factors among
Japanese urban high school students -The
relationship between retrospective evaluations ofschool lives in elementary school and Junior andsenior high schools, and the changing pattern of
SOC during a 10 month period. Jpn J Health
Education and Promotion. 2009.5.29.17(2):71-86,(in Japanese)

11. Yuko Hirano, Yoshihiko Yamazaki: Illness
experiences of invasive mechanical ventilatordependent amyotrophic lateral sclerosis patientsin Japan: A study of trajectories and correlatesof psychological well-being, Jpn J Human
Ecology 2009.75(3):79-89,

257

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, 6 doctoral course
students, 3 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 courses on mental
health I and II, featuring research methodology of
epidemiology in mental health and occupational
mental health, respectively, in the fiscal year of 2010.
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,

258

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.

21.
5.

2002-2006 Survey Group: Epidemiological aspects
of intermittent explosive disorder in Japan;
prevalence and psychosocial comorbidity: findings
from the World Mental Health Japan Survey
2002-2006. Psychiat Res. Epub 2010 Aug 14.
6.

Petukhova

M,

M, Posada- Villa J, Sagar R, Carmen Viana M,
Williams D, Kessler RC. Associations of serious
mental illness with earnings in the WHO World
Mental Health surveys. Br J Psychaitry. 2010 Aug;
197(2):114-21.
M,

TanakaK,

Kawakami

N.

Development and validity of the Japanese versionof the organizational justice scale. Ind Health. 2010;

Japanese have healthier profiles than Americans.
Brain Behav Immun. 2010 Nov 26. [Epub ahead of

Shibaoka M, Takada M, Watanabe M, Kojima R,
Kakinuma

Population differences in proinflammatory biology:

48(1):66-73.
8.

print]

Shikata K, Haneda M, Koya D, Suzuki Y, Tomino Y,
Yamada K, Maeda S, Kawakami N, Uzu T,

Shimada K, Shimazu A, Bakker AB, Demerouti E,
KawakamiN.

Work-family

spilloverNishimura M, Sato C, Ogawa D, Makino H;

among

DNETT-Japan Study Group. Diabetic Nephropathy

Japanese dual-earner couples: A large community-

Remission and Regression Team Trial in Japan

based study. J Occup Health 2010;52:335-343(DNETT-Japan): Rationale and study design.

Kessler RC, McLaughlin KA, Green JG, Gruber MJ,
Sampson NA, Zaslavsky AM, Aguilar-Gaxiola S,
Alhamzawi AO, Alonso J, Angermeyer M, Benjet C,
E,

ChatterjiS,deGirolamoG,

Demyttenaere K, Fayyad J, Florescu S, Gal G,
Gureje O, Haro JM, Hu CY, Karam EG, Kawakami
N, Lee S, Lepine JP, Ormel J, Posada-Villa J, Sagar
R, Tsang A, Ustun TB, Vassilev S, Viana MC,
Williams DR. Childhood adversities and adultpsychopathology in the WHO World Mental Health
Surveys. Br J Psychiatry. 2010; 197: 378-85.
4.

M,N, Lee S, Lepine JP, Oakley Browne M, Okoliyski

Coe CL, Love GD, Karasawa M, Kawakami N,

BrometLakomaGureje O, Haro JM, Hu C, Karam AN, Kawakami

Kitayama S, Markus HR, Tracy RP, Ryff CD.

3.

D,

Borges G, Bruffaerts R, de Girolamo G, de Graaf R,

7.

2.

Levinson

Schoenbaum M, Zaslavsky AM, Angermeyer M,

References (Jan.-Dec., 2010)1.

Yoshimasu K, Kawakami N, and the WMH-J

Fujiwara T, Kawakami N, World Mental HealthJapan Survey Group. Association of childhood
adversities with the first onset of mental disorders
in Japan: Results from the World Mental HealthJapan, 2002-2004 J Psychiat Res. Epub 2010 Aug

Diabetes Res Clin Pract. 2010 Feb;87(2):228-32.
9.

Koyama A, Miyake Y, Kawakami N, Tsuchiya M,
Tachimori H, Takeshima T; World Mental HealthJapan

Surveyprevalence,Group,
psychiatric2002-2006.

Lifetimecomorbidity

anddemographic correlates of "hikikomori" in acommunity population in Japan. Psychiatry Res.
2010 Mar 30; 176(1): 69-74.
10. Ogawa M, Miyamoto Y, Kawakami N. Factors
associated with glycemic control and diabetes selfcare among outpatients with schizophrenia and type2 diabetes. Arch Psychiat Nurs. Epub 2010 Aug 4.
11. Tsuno K, Kawakami N, Inoue A, Abe K. Measuring
Workplace Bullying: Reliability and Validity of theJapanese

Versionof

the

Negative

Acts

259

Questionnaire. J Occup Health. 2010;52(4):216-26.

Kuroda M. Organizational justice, psychological

Epub 2010 Jun 21.

distress, and work engagement in Japanese workers.

12. Inoue A, Kawakami N, Tsuchiya M, Sakurai K,
HashimotoH.

Associationof

Int Arch Occ Env Hea 2010; 83: 29-38.

occupation,

20. de Jonge J, van Vegchel N, Shimazu A, Schaufeli

employment contract, and company size with

WB, Dormann C. A longitudinal test of themental health in a national representative sample ofdemand-control model using specific job demands

employees in Japan. J Occup Health 2010; 52:

and specific job control. Int J Behav Med 2010; 17:227-240.

125-133.

13. Chiba R, Kawakami N, Miyamoto Y, Andresen R.

21. Shimazu A, Schaufeli WB, Taris TW. How does

Reliability and validity of the Japanese version of

workaholism

the Self-Identified Stage of Recovery for people

performance? The mediating role of coping. Int J

with long term mental illness. Int J Ment Health Nu,

Behav Med 2010; 17: 154-160.

2010; 19(3):195-202.

affectworkerwell-being

22. Shimazu A, Bakker AB, Demerouti E,

andPeeters

14. Inoue A, Kawakami N, The Japan Work Stress and

MCW. Work-family conflict in Japan: How job and

Health Cohort Study Group. Interpersonal conflict

home demands affect psychological distress. Ind

and depression among Japanese workers with highHealth 2010; 48: 766-773.

or low socioeconomic status: findings from theJapan Work Stress and Health Cohort Study. Soc
Sci Med 2010; 71: 173-180.
15. Inoue A, Kawakami N, Haratani T, Kobayashi F,Ishizaki M, Hayashi T, Fujita O, Aizawa Y,
Miyazaki S, Hiro H, Masumoto T, Hashimoto S,
Araki S. Job stressors and long-term sick leave due
to depressive disorders among Japanese male
employees: findings from the Japan Work Stressand Health Cohort Study. J Epidemiol Commun H
2010; 64: 229-235.
16. Sakurai K, Kawakami N, Yamaoka K, Ishikawa H,
Hashimoto H. The impact of subjective andobjective social status on psychological distressamong men and women in Japan. Soc Sci Med.
2010 Feb 12. [Epub ahead of print]
17. Kubota K, Shimazu A, Kawakami N, Takahashi M,
Nakata A, Schaufeli, W. B. Association between
Workaholism and Sleep Problems among Hospital
Nurses. Ind Health. 2010;48(6):864-71.
18. Chiba R, Miyamoto Y, Kawakami N. Reliability
and validity of the Japanese version of the
Recovery Assessment Scale (RAS) for people withchronic mental illness: scale development. Int J
Nurs Stud, 2010; 47(3): 314-322.
19. Inoue A, Kawakami N, Ishizaki M, Shimazu A,
Tsuchiya M, Tabata M, Akiyama M, Kitazume A,

260

Department of Biostatistics/
Epidemiology andPreventive Health Sciences
Professor
Yasuo Ohashi, Ph.D.

Associate Professor
Yutaka Matsuyama, Ph.D.

Research Associate
Ayano Takeuchi, MS

Project Research Associate
Satoshi Iimuro, Ph.D.
Yukari Uemura, Ph.D

Homepage

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

Introduction and Organization
The Department of Epidemiology and Biostatistics
changed the name from “Epidemiology” in 1992 andhas responsibility for providing educational courses
on epidemiology and biostatistics to undergraduate
students as well as graduate ones. As compared to thesituation in the United States, the education ofbiostatistics
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)2615) 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
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’

3.

4.

5.

6.

7.

8.

References
1.

2.

Tsuda H, Kozu T, Ohashi Y, et al: Cancer
prevention by bovine lactoferrin: from animalstudies to human trial. Biometals 2010;23:
399-409.
The GASTRIC Group(Paoletti X. Oba K, Ohashi
Y, et al): Benefit of adjuvant chemotherapy forresectable gastric cancer. A meta-analysis.
Journal of American Medical Association 2010;
303(17):1729-1737.

9.

Aihara T, Takatsuka Y, Ohashi Y, et al. PhaseⅢ
randomized adjuvant study of tamoxifen alone
versus sequential tamoxifen and anastrozole inJapanese postmenopausal women with hormoneresponsive breast cancer: N-SAS BC03 Study
Breast Cancer Research Treatment 2010;121:379-387.
Inoue K, Nakagami K, Ohashi Y, et al.
Randomized phase Ⅲ trial of trastuzumab
monotherapy followed by trastuzumab plus
docetaxel versus trastuzumab plus docetaxel as
first-line therapy in patients with HER2-positive
metastatic breast cancer: the JO17360 Trial
Group Breast Cancer Research Treatment 2010;
119:127-136.
Sone H, Tanaka S, Ohashi Y, et al. Long-termlifestyle intervention lowers the incidence ofstroke in Japanese patients with type 2 diabetes: anationwide multicentrer randomized controlled
trial (the Japan Diabetes Complications Study)
Diabetologia 2010;07 January
Sakurai T, Iimuro S, Ohashi Y, et al. Ageassociated increase in abdominal obesity andinsulin resistance, and usefulness of AHA/NHLBI definition of metabolic syndrome forpredicting cardiovascular disease in Japaneseelderly with type 2 diabetes mellitus.
Gerontology 2010;56:141-149.
Matsuyama Y. A comparison of the results ofintent-to-treat, per-protocol, and g-estimation in
the presence of non-random treatment changes ina time-to-event non-inferiority trial. Statistics in
Medicine 2010 in press(http://www3.interscience.wiley.com/journal/965
15927/issue).
Shimizu F, Taguri M, Harada Y, Matsuyama Y,
Sase K, Fujime M. Impact of dry ejaculation
caused by highly selective alpha1A-blocker:
Randomized, double-blind, placebo-controlled
crossover pilot study in healthy volunteer men.
Journal of Sexual Medicine 2010; 7(3): 12771283.
Takayasu K, Arii S, Ikai I, Kudo M, Matsuyama
Y, Kojiro M, and Makuuchi M for the Liver
Cancer Study Group of Japan. Overall survival
after transarterial lipiodol infusion chemotherapy
with or without embolization for unresectable

262

10.

11.

12.

13.

14.

15.

hepatocellular carcinoma: Propensity scoreanalysis. American Journal of Roentgenology
2010; 194: 830-837.
Takeuchi A, Matsuyama Y, Ohashi Y, andUeshima H. Monte Carlo sensitivity analysis foradjusting multiple-bias in the longitudinalcardiovascular study. Japanese Journal of
Biometrics 2010; 31: 63-76.
Matsumura N, Nakamura Y, Kohjimoto Y,
Inagaki T, Nanpo Y, Yasuoka H, Ohashi Y, Hara I.
The prognostic significance of humanequilibrative nucleoside transporter 1 expression
in patients with metastatic bladder cancer treatedwith gemcitabine-cisplatin-based combination
chemotherapy. Britishi Journal of Urology
International 2010;108:110-116.
Yatsuya H, Toyoshima H, Yamagishi K,
Tamakoshi K, Taguri M, Harada A, Ohashi Y,
Kita Y, Naito Y, Yamada M, Tanabe N, Iso H,
Ueshima H; Japan Arteriosclerosis Longitudinal
Study (JALS) group. Body mass index and riskof stroke and myocardial infarction in a relatively
lean population: meta-analysis of 16 Japanesecohorts using individual data. CardiovascularQuality and Outcomes 2010;3:298-505.
Teramoto T, Nakaya N, Yokoyama S, Ohashi Y,
Mizuno K, Nakamura H; MEGA Study Group.
Association between lowering low-density
lipoprotein cholesterol with pravastatin andprimary prevention of cardiovascular disease in
mild to moderate hypercholesterolemic Japanese.
Journal of Atherosclerosis and Thrombosis
2010:17;879-87.
Taguri M, Matsuyama Y, Ohashi Y, Sone H,
Yoshimura Y, and Yamada N. A hierarchicalregression model for dietary data adjusting forcovariates measurement error by regression
calibration: An application to a large prospective
study for diabetic complications. Japanese
Journal of Biometrics 2010; 31: 49-62.
Tanabe N, Iso H, Okada K, Nakamura Y, HaradaA, Ohashi Y, Ando T, Ueshima H; Japan
Arteriosclerosis Longitudinal Study Group.
Serum total and non-high-density lipoproteincholesterol and the risk prediction ofcardiovascular events - the JALS-ECC -.
Circulation Journal 2010:74;1346-1356.

16. Saito M, Iwata N, Kawakami N, Matsuyama Y,
Ono Y, Nakane Y, Nakamura Y, Tachimori H,
Uda H, Nakane H, Watanabe M, Naganuma Y,
Furukawa TA, Hata Y, Kobayashi M, Miyake Y,
Takeshima T, Kikkawa T; World Mental HealthJapan 2002?2003 Collaborators. Evaluation of
the DSM-IV and ICD-10 criteria for depressive
disorders in a community population in Japan
using item response theory. International Journalof Methods in Psychiatric Research 2010; 19:
211-222.
17. Ikai I, Kudo M, Arii S, Omata M, Kojiro M,
Sakamoto M, Takayasu K, Hayashi N, Makuuchi
M, Matsuyama Y and Monden M. Report of the
18th follow-up survey of primary liver cancer inJapan. Hepatology Research 2010 40; 10431059.
18. Yamamoto K, Imamura H, Matsuyama Y, Kume
Y, Ikeda H, Norman GL, Shums Z, Aoki T,
Hasegawa K, Beck Y, Sugawara Y, Kokudo N.
AFP, AFP-L3, DCP, and GP73 as markers formonitoring treatment response and recurrence
and as surrogate markers of clinicopathologicalvariables of HCC. Journal of Gastroenterology
2010; 45: 1272-1282.
19. Matsuyama Y. A comparison of the results ofintent-to-treat, per-protocol, and g-estimation in
the presence of non-random treatment changes ina time-to-event non-inferiority trial. Statistics in
Medicine 2010; 29: 2107-2116.
20. Takao T, Idea T, Yanagisawa H, Kikuchi M,
Kawazu S, Matsuyama Y. The effect of fasting
plasma glucose variability on the risk ofretinopathy in type 2 diabetic patients:
retrospective long-term follow-up. Diabetes
Research and Clinical Practice 2010; 89:296-302.
21. Shimizu F, Taguri M, Harada Y, Matsuyama Y,
Sase K, Fujime M. Impact of dry ejaculation
caused by highly selective alpha1A-blocker:
Randomized, double-blind, placebo-controlled
crossover pilot study in healthy volunteer men.
Journal of Sexual Medicine 2010; 7(3):1277-1283.
22. Takayasu K, Arii S, Ikai I, Kudo M, Matsuyama
Y, Kojiro M, and Makuuchi M for the Liver
Cancer Study Group of Japan. Overall survival

263

after transarterial lipiodol infusion chemotherapy
with or without embolization for unresectable
hepatocellular carcinoma: Propensity scoreanalysis. American Journal of Roentgenology
2010; 194: 830-837.

264

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.
Jung Su Lee became the associate professor and tookcharge 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,
six undergraduate lecturers and eight graduate

265

lecturers from other organizations, and ten visiting
researchers contribute to department teaching andresearch 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. Eight bachelor theses, twelve master theses,
and six doctoral dissertations were completed between
April 2004 and March 2011. 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 ofproviding international leadership in the future(http://www.cbel.jp/).
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

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Department of Health Promotion Sciences
The main research activity of the Department of
Health Promotion Sciences is making health policy
proposals concerning health promotion in thecommunity and work place through experimental 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.

Doshi P, Akabayashi A. Japanese childhood
vaccination policy. Camb Q Healthc Ethics.
2010; 19(3):283-9.
Fujita M, Matsui K, Monden M, Akabayashi A.
Attitudes of medical professionals andtransplantation facilities toward living-donorliver transplantation in Japan. Transplant Proc.
2010; 42(5):1453-9.
Matsuzaki M, Haruna M, Hasumi Y, Sekine K,
Tanizaki T, Watanabe E, Murashima S.
Ubiquinol-10 and ubiquinone-10 levels inumbilical cord blood of healthy fetuses and thevenous blood of their mothers. Free Radical
Research 2010; 44(11):1338-1344.
4. Oba M, Lee JS, Kawakubo K, Haruna Y. Effectsof 20 days of bed rest and concomitant resistancetraining on basal energy expenditure and bodycomposition. Jpn J Health & Human Ecology
2010; 76 (3):120-130.
5. Tashiro S. Research, practice, and innovative
therapy: on the theoretical models of Robert J.
Levine. Asian Bioethics Review 2010; 2(3):229-239.
6. Tashiro S. Unintended consequences of “soft”
regulations: the social control of biomedical
research in Japan. International Journal ofJapanese Sociology 2010; 19:4-17.
7. Akabayashi, A., Kodama, S., Slingsby, B.T.
Biomedical Ethics In Asia: A Casebook forMulticultural Learners. McGraw-Hill (Asia),
Singapore, 2010.
8. Kodama S, Akabayashi A. “Neither a “person”
nor a “thing”: The Controversy concerning theMoral and Legal Status of Human Embryos inJapan.” In Contested Cells: Global Perspectives
on the Stem Cell Debate (Benjamin J Capps andAlastair V Campbell eds.) London: Imperial
College Press, 2010; 421-439.
9. Ibuki T. Ethical issues of conducting neuroenhancement as medicine. UTCP Booklet 15:
Neuroethics 2010; 111-136 (in Japanese).
10. Nakata A, Fujita M, Kodama S, et al. A
questionnaire survey on the ethics education in
medical representatives’ continuing education in
Japan. Japanese Journal of Drug Information
2010; 12(2): 61-68 (in Japanese).
11. Hayashi Y. Researcher’s obligations to handle
incidental findings and their implications. Journalof Japan Association for Bioethics 2010; 4: 29-43(in Japanese).
12. Lee JS, Kawakubo K. Supportive social-physicalenvironments for residents’ health promotion incommunities in Japan. Journal of Japan Health
Medicine Association 2010; 19(2): 50-63 (inJapanese).

Health Sciences and Nursing
2. Preventive and Administrative Nursing

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Department of
Nursing Administration /Advanced Clinical Nursing
Professor
Katsuya Kanda, Ph.D., R.N.

Assistant Professor
Mami Onishi, M.S.N., R.N., Ayako Nagata, M.A., R.N., Satoko Nagai, M.S.N., 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 theirprofessional carriers in various settings, we areconstantly exploring new issues to make students beable to take wide and long viewpoints.

and structures in organization, decision/policy making
process, and application of management theory andnursing process to nursing administration. Theory andpractice in nursing education is also explored.
Nursing Administration 2 (2 credits, Lectures)Prof. Kanda and Affiliates

Studies on application of management theory to nursing administration. Focuses are on; 1) issues in nursing management such as budgetary management,
nursing informatics, patient classification systems,
staffing, and quality improvement, and 2) issues instaff management such as staff development and continuing education. Students will learn concepts andskills essential to solving economic issues in healthcare and nursing to meet professional demands in thecomplexity of health care systems.
Advanced Clinical Nursing 1 (2 credits, Lectures)Prof. Kanda and Affiliates

Teaching activities
Graduate courses
Nursing Administration 1 (2 credits, Lectures)Prof. Kanda and Affiliates

Exploration of political and administrative functionalrole in nursing. The course offers critical analysis oftheories in nursing administration related to quality
assurance/ improvement and cost- effective/efficient
care delivery systems. Discussions include concepts

An overview on models, theories and research innursing. Focuses are on; 1) conceptual frameworks ofclients' potential and actual physiological andpsychosocial responses to health problems, 2) healthassessment skills in nursing practice, 3) measurementof clients' health and nursing intervention outcome.
Students will establish their own theoreticalknowledge and practical skills essential to advanced
clinical nursing.

269

Advanced Clinical Nursing 2(2 credits, Lectures and practicum)

Clinical Practicum in Fundamental Nursing(2 credits, practicum)

Prof. Kanda and Affiliates

Prof. Kanda, Staffs and Affiliates

This course explores issues related to advanced
clinical practice, research, and education with anemphasis on specific theoretical perspectives,
methodologies, practice and economic implications.

Under instructors' supervision, students haveopportunity to apply their fundamental knowledge andskills of nursing in a variety of settings. Students willassess clients' health and needs through application ofnursing process.
Nursing Administration (1 credit, Lectures)

Undergraduate Courses

Prof. Kanda and Affiliates

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) firstaid to the victim with bleeding, intoxication, or burn,3) how to carry an injured person, and 4) CPR(cardiopulmonary resuscitation).

This
coursepreparesstudentsfor
nurse
administrators/managers of all types of health caresettings such as institutions, organizations, communityand politics. Students will learn fundamental theory
and practice in nursing administration/ management
through analyzing current issues in health care andnursing.
Nursing Administration Practicum(1 credit, practicum)

Fundamental Nursing 1 (2 credits, Lectures)Prof. Kanda and Affiliates

This course offers fundamental knowledge of nursing,such as history and theory in nursing, concepts ofprofessional nursing practice, nursing service and caredelivery systems, nursing administration, and nursing
education.
Discussions
includecontemporary
challenging issues and future strategies in nursing.
Fundamental Nursing 2 (2 credits, Lectures)Prof. Kanda and Staffs

Students have administrative/ management practicumin units or divisions in hospitals. Students will learncare delivery systems such as staffing and patientclassification systems, nursing informatics, andbudgetary issues including cost effectiveness andquality improvement.

Research activities

Prof. Kanda and Affiliates

This course offers fundamentals in understanding
interpersonal relationships and assessing clients'
health. Students will learn; 1) theory and practice incommunication, 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 ethicalissues in nursing and health.

Nursing research starts with an approach to address avariety 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.

Fundamental Nursing 3(4 credits, Lectures and laboratory practicum)

Issues of Nursing Administration
Critical analysis and international comparative studyof administrative, socioeconomic and political issues
in contemporary nursing. Focuses are on; 1) patientclassification systems and nursing care delivery
systems, 2) cost- effectiveness of nursing services, 3)
nursing case management, and 4) nursing policy andstrategies to meet the professional demands.

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 and maintenance.

270

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) occupationalsafety and health of health care workers, and 5)
infection control.
Physiological and Psychological Human Responses
to Stimulus
This area of study aims at exploring the nature, or
determining various effects of physiological andpsychological stimulus to participants' physiologicalbio-information and psychological measurements.
Research scenarios include; 1) patient' daily activities,2) caregivers' workload and sleep deprivations, or 3)
nurses focus of attention, eye movement, and electroencephalography 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 of structureof nursing theories and models in nursing, 2)
development of clinical and scholarly knowledge forthe identification of health problems and assessmentof 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 the advanced
practice nurses in Japan is also explored.

References
1. Ozawa M, Sasaki M, Kanda K. Effect ofprocedure light on the physiological response of
preterm infants. Jpn J Nurs Sci. 2010; 7: 76-83.
2. Okuyama A, Sasaki M, Kanda K. The relationshipbetween incident reporting by nurses and safety
management in hospitals. Qual Manag Health Care.
2010; 19: 164-172.
3. Onishi M, Kanda K. Expected roles andutilization of specialist nurses in Japan: the nurse

administrators' perspective. J Nurs Manag. 2010;
18: 311-318.
4. Kodama S, Kanda K. Nurse risk managers' criteria
for dealing with near-miss events. Biosci Trends.
2010; 4: 231-238.
5. Zhao H, Lu T, Zhang C, Deng F, Zheng J, Onishi
M, Nagata A, Kobayashi H, Kanda K. Testing for
reliability and validity of the Chinese version of
the nurse’s career identity scale. Chinese Nursing
Management 2010; 10(11): 49-51. (in Chinese)
6. Ozawa M, Kanda K, Hirata M, Kusakawa I,
Suzuki C．Utility of a Japanese version of thePremature Infant Pain Profile．Journal of Japan
Academy of Neonatal Nursing 2010; 16: 28-33.
(in Japanese)
7. Nagata A, Hamai T, Kanda K. Risk of ad hocinterpreters on the medical care services for
Brazilian residents in Japan. Journal ofInternational Health 2010; 25: 161-169. (inJapanese)
8. Komi K, Onishi M, Kanda K. Measuring thephysician-nurse collaboration: Reliability andvalidity of the Japanese version of Collaborative
Practice Scales. J Jpn Acad Nurs Admin Policies.
2010; 14(2): 15-21. (in Japanese)
9. Kanda K. Research on evaluation in nursing.
Japanese Journal of Nursing Administration 2010;
20: 742-745. (in Japanese)
10. Ozawa M, Hirata M, Kusakawa I, Suzuki C,
Kanda K. Influence of repeated painfulprocedures on frontal cortical pain response andpain expression in newborns. The 12th World
Congress of the World Association for Infant
Mental Health, Poster P322; 2010 Jun 29-Jul 3;
Leipzig, Germany.
11. Onishi M, Komi K, Kanda K. The need forinterprofessional education to promote physiciannurse collaborative relationship. 8th European
Conference of Nurse Educators, Oral 110; 2010
Oct 6-9; Lisbon, Portugal.
12. Takeuchi T, Onishi M, Kanda K. Research activity
and utilization in Japanese hospitals: A nationwide
survey. 8th European Conference of Nurse
Educators, Oral 121; 2010 Oct 6-9; Lisbon,
Portugal.
13. Ozawa M, Kanda K, Hirata M, Kusakawa I,
Suzuki C. Effect of gender and hand laterality on

271

pain processing in human neonates. Early Hum
Dev. (in press)
14. Ozawa M, Kanda K, Hirata M, Kusakawa I,
Suzuki C. Influence of repeated painfulprocedures on prefrontal cortical pain responses innewborns. Acta Paediatr. (in press)
15. Komi K, Onishi M, Kanda K. Development ofJapanese version of the Jefferson Scale ofAttitudes toward Physician- Nurse Collaborationand measuring physicians’ and nurses’ attitudes
toward collaboration in Japan. Medical Education.
(in Japanese) (in press)
16. Kataoka J, Sasaki M, Kanda K. Effects of mental
workload on nurses' visual behaviors duringinfusion pump operation. Jpn J Nurs Sci. (inpress)
17. Sasaki M, Kanda K. Development of the Japaneseversion of the Nursing Work Empowerment Scale.
J Jpn Acad Nurs Sci. (in Japanese) (in press)
18. Kobayashi H, Takemura Y, Kanda K. Patient
perception of nursing service quality; an applied
model of Donabedian's structure- processoutcome approach theory. Scand J Caring Sci. (inpress)

272

Department of Family Nursing
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
Kafumi Sugishita, R.N., R.M., M.H.S.
Shiho Murayama, 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 four faculty members: an associate professor, alecturer, and two research associates. Also it has 11
doctoral students, 10 master’s course students, and 17
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
Practice in Translational Research Nursing
Advanced Nursing Consultation
2. Undergraduate Courses, School of Integrated
Health Sciences
Family Nursing
Pathophysiologic Immunology
3. Undergraduate Courses of Nursing, School ofIntegrated Health Sciences
Pediatric Nursing
Clinical Practicum in Pediatric Nursing
4. Undergraduate Courses of Midwifery, School ofIntegrated Health Sciences
Midwifery III
Clinical Practicum in Midwifery

Research
The topics of our current research projects are as
follows:
1. Postnatal depression and difficulties inchildrearing.
2. Prevention of child abuse and neglect.
3. Development of Pediatric QOL Inventory forchild with chronic illness and their parents.
4. Late effect of treatment and posttraumatic stressdisorder in children with cancer.
5. The roles and expertise of the nursing staffs indaycare centers.
6. Primary caregivers’ burden of the severely
disabled children and the utilization of the respitecare.
7. Care for dying patients and their families (QOL,
family function).
8. Development of Japanese version of Families’
Importance in Nursing Care – Nurses’ Attitudes.

Publications(1) Kamibeppu K, Sato I, Honda M, Ozono S,
Sakamoto N, Iwai T, et al. Mental health among
young adult survivors of childhood cancer andtheir siblings including posttraumatic growth.
Journal of Cancer Survivorship: Research and273

Practice. 2010;4:303-312.
(2) Ishida Y, Honda M, Ozono S, Okamura J, Asami
K, Maeda N, Sakamoto N, Inada H, Iwai T,
Kamibeppu K, et al. Late effects and quality oflife of childhood cancer survivors: Part 1. Impact
of stem cell transplantation. International Journalof Hematology. 2010;91:865-876.
(3) Ishida Y, Sakamoto N, Kamibeppu K, Kakee N,
Iwai T, Ozono S, et al. Late effects and quality oflife of childhood cancer survivors: Part 2. Impact
of radiotherapy. International Journal of
Hematology. 2010;92:95-104.
(4) Yamazaki A. Living with their stillborn babies asfamily members: Japanese women who
experienced intrauterine fetal death after 28
weeks gestation. Health Care for WomenInternational. 2010;31:921-937.
(5) Kobayashi K, Kamibeppu K. Measuring qualityof life in Japanese children: Development of theJapanese version of PedsQLTM. Pediatrics
International. 2010; 52(1):80-88.
(6) Sato I, Higuchi A, Yanagisawa T, Mukasa A, Ida
K, Sawamura Y, Sugiyama K, Saito N, Kumabe
T, Terasaki M, Nishikawa R, Ishida Y,
Kamibeppu K. Development of the Japaneseversion of the Pediatric Quality of Life
InventoryTM Brain Tumor Module. Health andQuality of Life Outcomes. 2010;8:38. [Openaccess].
(7) Ueno R, Kamibeppu K. Relationship between
positive self-recognition of maternal role andpsychosocial factors in Japanese mothers withsevere mental illness. Community Mental Health
Journal. 2010. [Epub ahead of print].
(8) Chen J, Murayama S, Kamibeppu K. Factors
related to well-being among the elderly in urban
China focusing on multiple roles. BioScience
Trends. 2010;4(2):61-71.
(9) Kamibeppu K, Sugishita K, Kurihara K,
Murayama S, Yamazaki A. Development ofchildrearing support system for perinatal mental
health and child abuse prevention (No.1): The
perspective of community maternal and childhealth. Japanese Society for Prevention of Child
Abuse and Neglect. 2010; 12 (1): 61-68. (inJapanese)(10) Ishida Y, Honda M, Kamibeppu K, Ozono S,

Iwai, T, Kakee N, et al. Cross-sectional survey
on the late effects and QOL of childhood cancer
survivors Part 1: Research methods and subjects.
Journal of the Japan Pediatric Society. 2010;
114(4): 665-675. (in Japanese)(11) Ishida Y, Ozono S, Honda M, Asami K, Maeda N,
Okamura J, Inada H, Kamibeppu K, et al.
Cross-sectional survey on the late effects and
QOL of childhood cancer survivors Part 2:
Anthropometorical features and late effects.
Journal of the Japan Pediatric Society. 2010;
114(4): 676-686. (in Japanese)(12) Kurihara K, Sugishita K, Ikeda M, Yamazaki A,
Furuta M, Yamamoto H, Otsuka H, Kamibeppu
K. Development of childrearing support systemfor perinatal mental health and child abuse
prevention (No.2): The perspective of hospitals.
The Japanese Society for Prevention of Child
Abuse and Neglect. 2010; 12(1):69-77. (inJapanese)(13) Nishigaki K, Kuroki H, Egawa F, Fujioka H,
Kamibeppu K. Relevant factors in use andprovision of respite care for children with severe
disabilities living at home. The Journal of
Ambulatory
andGeneralPediatrics.
2010;13(2):98-108. (in Japanese)(14) Tsumura A, Yamazaki A, Kamibeppu K. Nursing
strategies to help malignant glioma patients andtheir families make end-of-life decisions. Journalof Japanese Academy of Nursing Science. 2010;30(4):27-35. (in Japanese)(15) Aiba S, Kamibeppu K. Examination ofdepression and the factors involved in students ofa private high school: With focus on the impactof parental support. Japanese Journal of Childand Adolescent Psychiatry. 2010;51(1):21-30. (inJapanese)274

Department ofCommunity Health Nursing /Public Health Nursing
Professor
Sachiyo Murashima, Ph.D., R.N., P.H.N.

Lecturer
Satoko Nagata, Ph.D., R.N., P.H.N.

Research Associate
Atsuko Taguchi, M.H.S., R.N., P.H.N.
Azusa Arimoto, Ph.D., R.N., P.H.N.

Homepage http://park.itc.u-tokyo.ac.jp/chn/
Introduction and Organization
Department of Community Health Nursing wasestablished in June 1992. Department of Public HealthNursing was established related to opening of mastercourse for public health nurses in 2006. At present,
there are four faculty members introduced above and
24 graduate course students (14 in master course, 10in doctoral course) in the department. Also, we accept
many visiting researchers from other colleges andinstitutions.

Teaching activities
1. Undergraduate program, in the School ofIntegrated Health Sciences
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 andactivities of community health nurses.
2) Home Health Nursing (2 credits, lectures)
The aim of this class is to have a deep
understanding of the social context around thehome care patients and the medical, health andwelfare system. Students learn the basics of caremanagement, home health care service, and healthcare system.
3) Health Guidance (2 credits, lectures)This class is to study the methodology andpractice of health guidance, which is the
supporting technique to promote health of thepeople living in the community.
4) Community Health Nursing Practice (2 credits,
practice)This program is intended to understand the systemof health promotion and prevention by attending
the actual community health nursing activities athealth center. Students are expected to realize theprinciple and the common technique ofcommunity health nursing activities by observing
the activities of public health nurses.
5) Home Health Nursing Practice (1 credits, practice)This program offers opportunities to learn the

275basis 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.
6) Health Assistance Practice I・II (2 credits, practice)In this program, students will comprehend
multilaterally how characteristics of the residents,
health resources and environment of thecommunity effects health and discuss on the healthmatters of the overall community. In addition,
students will visit various working sites for nurses
to deepen their knowledge of multiple healthrelated resources, and learn the actual skills of
health guidance towards individuals/ families/
groups through experience.
2. Graduate program, in the Graduate School of
Health Sciences and Nursing
1) Advanced Community Health Nursing I (2 credits,
lectures)This program is to study the health at thecommunity-level and theory and application of thecommunity organization.
2)Advanced Community Health Nursing II (2 credits,
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 theoretical concept ofcommunity health nursing, assessment of thecommunity, problem finding, prioritization
procedure, and planning, operation and evaluationof countermeasures needed in advanced
community health nursing practice using the
textbook for master course students in westerncountries.
4) Advanced Public Health Nursing II (2 credits)
This program is to understand policymaking of
national and local government, method 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 healthnursing management are given.
In addition to these programs, we have department
meeting (journal reading and research introduction) on
every Tuesday and monthly seminar on every 3rd
Friday.

Research activities
Our research focuses on the development andevaluation of health care programs, establishment ofcommunity health care systems, and standardizationof skills of public health nurses, in response to thehealth care needs of individuals, families, aggregates
and the communities. We are conducting researches
on Grant-in-Aid for Scientific Research of Ministry of
Education, Culture, Sports, Science and Technology,
Health Science research Grants of Ministry of Health,Labour and Welfare, and grants from somefoundations.
Research projects which are undergoing in our
department are listed below.
1. Developing community health nursing activity
model of public health nurse
In collaboration with community health organizations,
we intend to develop the evaluation method ofcommunity health nursing activities according to thenatural characteristics of each community by publichealth nurses, and develop methodology to provide
subsequent nursing efficiently. Pioneering community
health nursing or health activities by public healthnurses are chosen, their degree of performance andcurrent situation are evaluated in several small areas,
and the way to develop the activity according to eachareal feature is discussed.
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 interviews by experienced PHNs and extract their

276

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 byliterature review and field study.
3. Establishment and evaluation of community
health care 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 areconducting the research to promote community
organization and interorganizational network.
Especially about the around-the-clock in-homecare system, through the model project at visiting
nurse services stations, we clarify the effects of theservices and the methods to establish the system. Also
we are developing method of measuring effect ofhome-visit nursing with accompany of care staff andefficiency of visiting nurse service stations.

characteristics. Also, the network for childrearing wasinvestigated to prevent 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 2009 are 1) Condition,
reason of admission and succession of residents at
geriatric medical care facility for the elderly, 2)
Psychological experience of the mother who delivered
to Down syndrome child, 3) Acceptance to diseases
and experiences in hospitalization for tuberculosis
patients, 4) The characteristics of patients withdelayed hospital visit for tuberculosis diagnosis and 5)
The factors relating to the time of PEG among patientswith ALS.

References
1. Nagata S, Taguchi A, Naruse T, Kuwahara Y,
Murashima S. Actual situation and characteristics ofthe clients who are judged to need home-visiting

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, todevelop the outcome indicator of discharge planning,
and to produce the educational program of dischargeplanning for ward nurse. We are conducting research
about discharge planning system, developing theguidelines for multisectoral and interagency
cooperation among nurses and the method forevaluation of the capacity of discharge planning
nurses 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 of mothers 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 raising families, mothers’ difficulty ofchild-rearing and their children’s behavioral

nurse services by certified care managers and thecomparison of users and non-users of home-visiting
nurse services among them. Japan Journal of Public
Health，57(12)，1084-1093，2010．
2. Tomura H, Yamamoto-Mitani N, Nagata S,
Murashima S, Suzuki S. Creating an Agreed
Discharge: Discharge Planning for Clients with High
Care Needs. Journal of Clinical Nursing, 20(3), 444453, 2011
3. Naruse T, Nagata S, Taguchi A, Murashima S.
Classification tree model identifies home-based
service needs of Japanese long-term care insurance
consumers.Public Health Nursing, inpress.
4. Shimamura T, Taguchi A, Kobayashi S, Nagata S,
Kushihara Y, Nagata Y, Kobayashi N, Murashima S.
The Perceptions and Feelings of Multi-drug
Resistant Tuberculosis Patients in Their Prolonged
Hospital-life. Journal of Japan Academy of Nursing
Science, 30(2)，3-10，2010
5. Kuwahara Y, Nagata S, Taguchi A, Murashima S.
An investigation of the work a visiting nurse did forpre and post discharge. Journal of the Japan Society

277

for Healthcare Administration，47(2)，93-101，2010

Suzuki Y, Arakida M, Oli S, Okamoto R, Okuyama

6. Murayama H, Taguchi A, Murashima S. The

N, Kaihara I, Sudo H, Nagae H, Miyazaki M,

Relationships Between Feelings of Satisfaction andMurashima S. A framework for assessing essential

Burden With Respect to Activity and Social Support

public health nursing skills and achievement levels

Among Health Promotion Volunteers in Japan.

required for students graduating from schools that

Health Education & Behavior, 37, 275-287, 2010provide education for obtaining a license as a public

7. Murayama H, Taguchi A,

Ryu S, Nagata S,

Murashima S. Is Sekentei Associated with the
Attitude toward Care? Multilevel Analysis in Japan.
Geriatrics & Gerontology International 2010 (inpress)
8. Murayama H, Taguchi A, Murashima S. Exploring
Strategies

toEncourage

Community

HealthOutreach by Health Promotion Volunteers in Japan.
Journal of Ambulatory Care Management (in press)
9. Shimazu T, Kageyama M, Hoshida Y, Taguchi A,
Asahara K. Goals and Skills of Public Health Nurses
Working in Rural Districts in Post-War Japan before
Its Rapid Economic Growth (circa 1945-1970):
Working to Change Traditional Practices in Order to
Save Lives. Japan Academy of Community HealthNursing, 12(2)，22-28，2010
10. Murayama H, Tomaru M, Narabu H, Kojima T,
Murashima S. Development of a Checklist for
Network

Building

betweenaCommunity

Comprehensive Support Center and an Informal
Community

Organization.

JournalofJapan

Academy of Community Health Nursing,13(1),91-99, 2010
11. Murayama H, Narabu H, Kojima T, Tomaru M,
Tachibana R, Yamaguchi T, Murashima S. Program
Development to promote network building between
disciplinary agencies and informal community
organizations. Japan Journal of Public Health,57(10), 900-908, 2010
12. Murayama H, Narabu H, Kojima T, Tomaru M,
TachibanaR,

YamaguchiT,

MurashimaS.

Evaluation of a program to promote networkbuilding between disciplinary agencies and informal
community organizations: Trial in a community
comprehensive support center. Japan Journal of
Public Health, 57(10), 909-920, 2010
13. Asahara K, Omori J, Kobayashi M, Hirano Y,

health nurse in Japan. Japan Journal of Public Health,57(3), 184-194, 2010

Health Sciences and Nursing
3. Clinical Nursing

279

Department of Adult Nursing /Palliative Care Nursing
Professor
Keiko Kazuma, R.N., Dr.Hlth.Sci.

Research Associate
Makoto Tanaka, R.N., Dr.Hlth.Sci.
Masakazu Nishigaki, R.N., Dr.Hlth.Sci.

Project Research Associate
Ryota Ochiai, R.N., Dr.Hlth.Sci.
Tomoko Sakai, R.N., Dr.Hlth.Sci.
Yuki Shirai, R.N., Dr.Hlth.Sci.

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 thecenter; therefore, such nursing comprises an extremely
wide range of periods of practice. We have been

280

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 possible effectiveness and feasibility.
We take this approach into public health setting;controlled
trial ofcomputer-based lifestyleintervention combined with genetic counseling has
been started at medical checkup institution.
Inflammatory bowel disease (IBD)：To study theissues associated with providing information to
Japanese IBD patients, we conducted two studies. The
aim of the first study was to describe the contents ofbrochures given to patients with IBD in Japanesehospitals. These brochures were compared to thoseused in Western countries. The existing situation forproviding information in Japanese hospitals was
unsatisfactory. Furthermore, we revealed thecharacteristics of information provided in Japanesehospitals. As a result of these characteristics, second
study was conducted to investigate medication
adherence and difficulties in taking their medicine. We
suggest that it is important to provide reasonable andspecific information to improve their adherence.
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.
Generally, self-management behavior such as
maintenance of immunosuppressive medication
adherence is essential for patients after transplantationto achieve long-term graft survival. We haveinvestigatedtheimplementation
statusofrecommended self-management behaviors forkidney-transplant recipients and its association with
their post kidney-transplantation period.
We have also contributed to establish donor
coordination system in the hematopoietic stem celltransplantation (HSCT) thorough the project whichdevelops adult 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 the281

elderly 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 had performed nation-wide surveys
which aim to clarify the effectiveness of nurse
specialist assignment, and conducted educational
activities regarding the promotion of nursing activity
in outpatient care.
4) Genetic Counseling
Genetic counseling for patient and their family who
have concerns about hereditary disease is an importantand unique research field for our department. Current
researches mainly focused on public health genomics,
disease management in patients with familial cancer,
and establishment of medical system about genetictest.
5) Home Care for cancer patients
A 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.
Visiting-home nursing has an important role inpalliative care at home. So we tried to facilitate thevisiting-home nursing practice by identifying barriers
for providing that in clinical setting. We also
developed screening tool for the needs tovisiting-home nursing.

Publications
1. Hori M, Tanaka M, Suzuki Y, Fukao M, Shimizu H,
Mikoshiba N, Tateishi R. Peri-procedural pain ofradiofrequency
ablationforhepatocellular
carcinoma. Gastroenterol Nurs. 2011; 34(2):129-134.
2. Ito N, Ishiguro M, Tanaka M, Tokunaga K, Sugihara
K, Kazuma K. Response shift in quality of life
assessment in patients undergoing curative surgery
with permanent colostomy: Preliminary study.
Gastroenterol Nurs. 2010; 33(6): 408-12.
3. Kusakabe T, Irie S, Ito N, Kazuma K. Feelings ofliving donors about adult-to-adult living donor livertransplantation. Gastroenterology Nursing.
4. Miura T, Nishigaki M, Matsubara T, Sakamoto M,

Kikuchi Y, Nakajima S, Tanaka Y. Nurse-led
educational session for non-medical staff improved
the appropriateness of rapid response team
activation. Jpn J of Trauma & Emerg Med. 2010;
1(1): 9-15.
5. Nishigaki M, Ota A, Kusakabe T, Matsuzaki C,
Taguchi S, Kazuma K. Feasibility and efficiency of
indirect lifestyle interventions in offspring of type 2
diabetic patients. Public Health Genomics 2011;
14:85-93.
6. Nishigaki M, Sato E, Ochiai R, Shibayama T,
Kazuma K. Impact of a booklet about diabetes
genetic susceptibility and its prevention on attitudes
towards prevention and perceived behavioral change
in patient with type 2 diabetes and their offspring.
Adv Preven Med.2011; (E-pub online DOI:10.4061/
2011/365132)
7. Nishigaki M, Sugino Y, Seo J, Shimada M, Ikeda K,
Kazuma K. Influence of allocating HIV specilized
nurses on clinical outcomes in Japan. Asian Nurs
Res. 2011; 5(1): 1-8.
8. Ochiai R, Murakami A, Toyoda T, Kazuma K, Niwa
K. Opinions of physicians regarding problems andtasks involved in the medical care system forpatients with adult congenital heart disease in Japan.
Congenital Heart Disease. (in press)
9. Sasahara T, Miyashita M, Umeda M, Higuchi H,
Shinoda J, Kawa M, Kazuma K. Multiple evaluationof a hospital-based palliative care consultation teamin a university hospital: Activities, patient outcome,and referring staff’s view. Palliat Support Care.
2010; 8: 49-57.
10. Seki S, Kato N, Ito N, Kinugawa K, Ono M,
Motomura N, Yao A, Watanabe M, Imai Y, Takeda N,
Inoue M, Hatano M, Kazuma K. Translation andvalidation study of the Japanese versions of theCoronary Revascularisation Outcome Questionnaire(CROQ-J). Eur J Cardiovasc Nurs (in press).
11. Seki S, Kato N, Ito N, Kinugawa K, Ono M,
Motomura N, Yao A, Watanabe M, Imai Y, Takeda N,
Inoue M, Hatano M, Kazuma K. Valitidy andreliability of Seattle Angina Questionnaire Japaneseversion in patients with coronary artery disease.
Asian Nursing Research (in press).
12. Shibayama T, Sato E, Nishigaki M, Ochiai R,
Kazuma K. Influence of Dietary Therapy Appraisal
on Future Perceived Control of Type 2 Diabetes.

282

Journal of Health Psychology (in press)
13. Shirai Y, Fujimori M, Ogawa A, Yamada Y,
Nishiwaki Y, Ohtsu A, Uchitomi Y. Patients’
perception of the usefulness of a question prompt
sheet for advanced cancer patients when deciding
the initial treatment: A randomized, controlled trial.
Psycho-Oncology. in press.
14. Tanaka M, Kawakami A, Iwao Y. Descriptive
information about Crohn's disease: content analysisof brochures for patient education. Gastroenterol
Nurs. 2010; 33(6): 432-9.
15. Tanaka M, Murakami Y, Fukushima T, Kazuma K.
Hypoglycemia-like symptoms after restorative
proctocolectomy for ulcerative colitis: A preliminary
study. Gastroenterology Nursing. (in press)
16. Yuri Tokunaga-Nakawatase, Chiemi Taru, Ikuko
Miyawaki. Development of an evaluation scale forself-management behavior related to physicalactivity of patients with coronary heart disease. Eur J
Cardiovasc Nurs (in press).

283

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
Masayo Matsuzaki, Ph.D., R.N.M., P.H.N.
Homepage http://park.itc.u-tokyo.ac.jp/midwifery/index.html

Introduction and Organization
The Department of Midwifery and Women’s Healthwas established in 2002.
Currently, it has 4 faculty members introduced above
and 10 part-time lecturers, 4 graduate students (1 inmaster course, 3 in doctoral course) and 2 visiting
researchers.

Teaching activities
We have graduate and undergraduate courses for
midwifery and maternal care, and women's health.

(2 credits, practice)
3. Undergraduate Advanced Courses for Midwifery,
School of Health Sciences and Nursing1) Midwifery 1 (1 credit, lectures)
2) Midwifery 2 (1 credit, lectures)
3) Midwifery 4 (3 credits, lectures)
4) Administration for Midwifery(1 credit, lectures)
5) Clinical Practice of Midwifery 1(1 credit, practice)6) Clinical Practice of Midwifery 2(7 credits, practice)

Research activities
1. Graduate Courses, School of Health Sciences andNursing1) Advanced Midwifery and Women’s Health 1 (2credits, lectures)
2) Advanced Midwifery and Women’s Health 2 (2credits, lectures)
2. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
1) Maternity Care and Nursing(2 credits, lectures)
2) Maternity Care and Nursing Practice

Our research activities are focus on maternal and childhealth with emphasis on the promotion of women’s
health and their quality of life at every stage
throughout the life span.
We conduct the following research projects:
1. Collecting evidence for health guidance during
pregnancy.
1) Adequate maternal nutrition and weight
management.

284

Maternal body composition, lipid metabolic
biomarkers and nutritional intake are examined to
optimize weight control and a healthy lifestyleduring pregnancy to prevent a low birth weight.
Based on our investigations on the optimal
maternal nutritional status and gestational weight
gain, we propose health guidance which can help
pregnant women to lower their risk of pregnancy
complications and their babies' risk of adverse
birth outcomes.
2) Lifestyle factors and oxidative stress during
pregnancy.
The study aims to assess the potential
relationships between lifestyle factors and someoxidative stress markers during pregnancy and toestablish optimal oxidative stress markers forpredicting healthy lifestyle for pregnant women.
3) Plasma total homocysteine (tHcy) during
pregnancy and the infant’s birth weight.
There are conflicting evidences that shows
elevated tHcy contribute as a risk factor for
intrauterine growth retardation.
This study aims to determine whether tHcy is arisk factor for the fetal growth.
4) Evaluation of a dietary assessment tool for
Japanese pregnant women.
Validity, reproducibility and factors related to theunder- or over-reporting of a self-administered
diet history questionnaire (DHQ/BDHQ) among
Japanese pregnant women are studied.

abdominal muscles and urinary incontinenceamong women across lifespan.
2) Development of the preventive and restorative
program of pelvic floor muscle hypergasia.
The use of ultrasonographic method as abiofeedback tool for body management isevaluated.
3) Anal sphincter defects after delivery.
Prevalence and risk factors of anal sphincter
defects among postpartum women are determinedbyusing
three-dimensionaltransperineal
ultrasound.
4) Promotion of women's health care after delivery.
The relationship between maternal bodycomposition and lifestyle factors including breast
feeding among postpartum women are studied.

References
1.

2.

3.
2. Development of accurate predictors of postpartum
hemorrhage.
Possible associations of multiple biomarkers withuterine smooth muscle contraction or relaxation (13,14-dihydro-keto- prostaglandin F2α and Nitricoxide metabolites) and postpartum hemorrhage arestudied.
3. Development of self body management support
system after delivery
1) Postpartum stress urinary incontinence and thetransverses abdominis /pelvic floor muscles.
We conduct functional evaluation of postpartum
local muscles using ultrasonographic method.
These techniques are developed to establish therelationship between the pelvic floor or

4.

5.

Megumi Haruna, Masayo Matsuzaki, Erika Ota,
Yuka Honda, Takashi Tanizaki, Kyoichi Sekine,
Nobuyuki Tabata, SeonAe Yeo, Sachiyo
Murashima. Positive correlation between
maternal serum coenzyme Q10 levels and infantbirth weight. BioFactors. 2010; 36(4): 312-8.
Masayo Matsuzaki, Megumi Haruna, Erika Ota,
Ryoko Murayama, Murashima Sachiyo. Factors
related to the continuation of employment during
pregnancy among Japanese women. Japan
Journal of Nursing Science. 2010. (Accepted)
Masayo Matsuzaki, Megumi Haruna, Yoko
Hasumi, Kyoichi Sekine, Takashi Tanizaki,
EtsukoWatanabe,
SachiyoMurashima.
Ubiquinol-10 and ubiquinone-10 levels inumbilical cord blood of healthy fetuses and thevenous blood of their mothers. Free Radical
Research. 2010; 44(11): 1338-44.
Masayo Matsuzaki, Megumi Haruna, Erika Ota,
SeonAe Yeo, Ryoko Murayama, Sachiyo
Murashima. Translation and cross-cultural
adaptation of the Pregnancy Physical Activity
Questionnaire (PPAQ) to Japanese.BioScience
Trends. 2010; 4(4): 170-7.
Elisabeth Severinsson, Megumi Haruna, Febe
FribergMidwives group supervision and theinfluence of the continuity of care model －apilot study. Journal of Nursing Management

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6.

7.

8.

2010; 18(4):400-8.
Mie Shiraishi, Megumi Haruna, Masayo
Matsuzaki, Erika Ota, Ryoko Murayama, Sachiyo
Murashima. Association between the serum
folate levels and tea consumption during
pregnancy. BioScience Trends. 2010; 4(5):225-30.
Mie Shiraishi, Megumi Haruna, Masayo
Matsuzaki, Erika Ota, Ryoko Murayama, Satoshi
Sasaki, Sachiyo Murashima. Relationshipbetween the plasma total homocysteine levels
and skipping breakfast during pregnancy. Journalof Japan Academy of Midwifery. 2010; 24(2):252-60.
Mikako Okamoto, Ryoko Murayama, Megumi
Haruna, Masayo Matsuzaki, Shiro Kozuma Maki
Nakata, Sachiyo Murashima. Evaluation of pelvic
floor function by transabdominal ultrasound in
postpartum women. Journal of Medical
Ultrasonics. 2010; 37: 187-193.

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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, 6 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 a variety of study clubs. We havepsychiatric nursing study club, study group for multilevel analysis, qualitative research study group, and soon.
The following is a master’s thesis theme from ourdepartment in 2010.
 “Reliability and validity of the Japanese versionof the Drug and Drug Problems Perception
Questionnaire for nurses.”

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The following are PhD thesis themes from ourdepartment in 2010.
 “Study of parental difficulties in families with
Hikikomori
syndrome
children(Socialwithdrawal).” “Analysis of home nursing care for people whohave schizophrenia.”
 “Relationship between manager communication
behaviors and mental health among hospitalnurses in Japan.”

Research
Our research field covers mental health andpsychiatric nursing. Our department has many
research projects across diverse fields as follows:
study of self-management in mental health; recovery
for people with mental health difficulties; community
support system for the people with mental healthneeds; peer support; stigma; social inclusion; issues ofcaregiver burden in family caregivers; behavioral andpsychological symptoms of dementia; patientsatisfaction with psychiatric services; and practice andevaluation of home visiting psychiatric nursing. We
are conducting studies in collaboration withresearchers in other institutions and universities.

Publications
1.

2.

3.

4.

Coe CL, Love GD, Karasawa M, Kawakami N,
Kitayama S, Markus HR, Tracy RP, Ryff CD.
Population differences in proinflammatory biology:
Japanese have healthier profiles than Americans.
Brain Behav Immun. 2010 Nov 26. [Epub ahead ofprint]
Shimada K, Shimazu A, Bakker AB, Demerouti E,
Kawakami N. Work-family Spillover among
Japanese Dual-earner Couples: A Large
Community-based Study. J Occup Health 2010;52:335-343
Ito J, Oshima I, Nishio M, Sono T, Suzuki Y,
Horiuchi K, Niekawa N, Ogawa M, Setoya Y,
Hisanaga F, Kouda M, Tsukada K. The effect ofAssertive Community Treatment in Japan. Acta
Psychiatrica Scandinavica. 2010 Nov 10. [Epubahead of print]
Kessler RC, McLaughlin KA, Green JG, Gruber MJ,

Sampson NA, Zaslavsky AM, Aguilar-Gaxiola S,
Alhamzawi AO, Alonso J, Angermeyer M, Benjet C,
Bromet E, Chatterji S, de Girolamo G,
Demyttenaere K, Fayyad J, Florescu S, Gal G,
Gureje O, Haro JM, Hu CY, Karam EG, Kawakami
N, Lee S, Lepine JP, Ormel J, Posada-Villa J, Sagar
R, Tsang A, Ustun TB, Vassilev S, Viana MC,
Williams DR. Childhood adversities and adultpsychopathology in the WHO World Mental Health
Surveys. Br J Psychiatry. 2010; 197: 378-85.
5. Fujiwara T, Kawakami N, World Mental HealthJapan Survey Group. Association of childhood
adversities with the first onset of mental disorders
in Japan: Results from the World Mental HealthJapan, 2002-2004 Journal of Psychiatric Research.
Epub 2010 Aug 21.
6. Yoshimasu K, Kawakami N, and the WMH-J
2002-2006 Survey Group: Epidemiological aspects
of intermittent explosive disorder in Japan;
prevalence and psychosocial comorbidity: findings
from the World Mental Health Japan Survey 20022006 Psychiatry Research. Epub 2010 Aug 14.
7. Levinson D, Lakoma M, Petukhova M,
Schoenbaum M, Zaslavsky AM, Angermeyer M,
Borges G, Bruffaerts R, de Girolamo G, de Graaf R,
Gureje O, Haro JM, Hu C, Karam AN, Kawakami
N, Lee S, Lepine JP, Oakley Browne M, Okoliyski
M, Posada- Villa J, Sagar R, Carmen Viana M,
Williams D, Kessler RC. Associations of serious
mental illness with earnings in the WHO World
Mental Health surveys. Br J Psychaitry. 2010 Aug;
197(2):114-21.
8. Shibaoka M, Takada M, Watanabe M, Kojima R,
Kakinuma M, Tanaka K, Kawakami N.
Development and validity of the Japanese versionof the organizational justice scale. Ind Health.
2010;48(1):66-73.
9. Shikata K, Haneda M, Koya D, Suzuki Y, Tomino Y,
Yamada K, Maeda S, Kawakami N, Uzu T,
Nishimura M, Sato C, Ogawa D, Makino H;
DNETT-Japan Study Group. Diabetic Nephropathy
Remission and Regression Team Trial in Japan(DNETT-Japan): Rationale and study design.
Diabetes Res Clin Pract. 2010 Feb;87(2):228-32.
10. Koyama A, Miyake Y, Kawakami N, Tsuchiya M,
Tachimori H, Takeshima T; World Mental HealthJapan Survey Group, 2002-2006. Lifetime

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11.

12.

13.

14.

15.

16.

17.

18.

prevalence,
psychiatriccomorbidity
anddemographic correlates of "hikikomori" in acommunity population in Japan. Psychiatry Res.
2010 Mar 30; 176(1): 69-74.
Ogawa M, Miyamoto Y, Kawakami N. Factors
associated with glycemic control and diabetes
self-care among outpatients with schizophrenia andtype 2 diabetes. Archives of Psychiatric Nursing.
Epub 2010 Aug 4.
Tsuno K, Kawakami N, Inoue A, Abe K. Measuring
Workplace Bullying: Reliability and Validity of theJapanese Version of the Negative Acts
Questionnaire. Journal of Occupational Health.
2010;52(4):216-26. Epub 2010 Jun 21.
Chiba R, Miyamoto Y, Funakoshi A. Characteristics
of benefit-finding in people with mental illness. [inJapanese] J. Jpn, Acad. Nurs, Sci. 2010; 30(3):32-40.
Inoue A, Kawakami N, Tsuchiya M, Sakurai K,
Hashimoto H. Association of occupation,
employment contract, and company size withmental health in a national representative sample ofemployees in Japan. Journal of Occupational Health2010; 52: 227-240.
Chiba R, Kawakami N, Miyamoto Y, Andresen R.
Reliability and validity of the Japanese version of
the Self-Identified Stage of Recovery for people
with long term mental illness. International Journalof Mental Health Nursing, 2010; 19(3):195-202.
Inoue A, Kawakami N, The Japan Work Stress and
Health Cohort Study Group. Interpersonal conflictand depression among Japanese workers with highor low socioeconomic status: findings from theJapan Work Stress and Health Cohort Study. Social
Science & Medicine 2010; 71: 173-180.
Inoue A, Kawakami N, Haratani T, Kobayashi F,Ishizaki M, Hayashi T, Fujita O, Aizawa Y,
Miyazaki S, Hiro H, Masumoto T, Hashimoto S,
Araki S. Job stressors and long-term sick leave due
to depressive disorders among Japanese male
employees: findings from the Japan Work Stressand Health Cohort Study. Journal of Epidemiology
and Community Health 2010; 64: 229-235.
Sakurai K, Kawakami N, Yamaoka K, Ishikawa H,
Hashimoto H. The impact of subjective andobjective social status on psychological distressamong men and women in Japan. Soc Sci Med.

19.

20.

21.

22.

2010 Feb 12. [Epub ahead of print]
Kubota K, Shimazu A, Kawakami N, Takahashi M,
Nakata A, Schaufeli, W. B. Association between
Workaholism and Sleep Problems among Hospital
Nurses.Ind Health. 2010;48(6):864-71.
Miyamoto Y, Tachimori H, Ito H. Formal caregiverburden in dementia: impact of behavioral andpsychological symptoms of dementia and activities
of daily living.Geriatric Nursing, 2010 Jul-Aug;
31(4):246-53. Epub 2010 Mar 6.
Chiba R, Miyamoto Y, Kawakami N. Reliability
and validity of the Japanese version of the Recovery
Assessment Scale (RAS) for people with chronic
mental illness: scale development. International
Journal of Nursing Studies, 2010; 47(3): 314-322.
Inoue A, Kawakami N, Ishizaki M, Shimazu A,
Tsuchiya M, Tabata M, Akiyama M, Kitazume A,
Kuroda M. Organizational justice, psychologicaldistress, and work engagement in Japanese workers.
International Archives of Occupational andEnvironmental Health 2010; 83: 29-38.

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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.

Lecturer
Gojiro Nakagami, R.N., Ph.D.

Research Associate
Tomoko Akase, R.N., R.Ph., Ph.D.

Project Research Associate
Makoto Oe, R.N., 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, 1 lecturer, 1 research associate, 1
project research associate, and 7 part-time lecturers
for undergraduate course (2) and for graduate course(5). The student body consists of 10 doctoral course
students, 11 master course students and 1
undergraduate student. The goal of our department isto achieve “Evidence-based practice and developmentof gerontological nursing and wound caremanagement”.

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, and to learn
fundamental theories of gerontological nursing. The
main themes in the 2010 contents were as follows;a) Practical simulation for gerontological nursingb) Physical, psychological and social characteristicsof the elderly from a nursing standpointc) Gerontological nursing and its theoriesd) Social, health and medical policies for a healthy
life of the elderlye) Drug induced geriatric syndromef) Geriatric syndrome and nursing (gait disorder,
malnutrition, infection, dementia and pressure
ulcer)
g) Future perspectives of gerontological nursing

Teaching activities
1.Undergraduate course

The aim of the 4th year course is to promote
understanding of the ailments and conditions required

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to provide proper care to the elderly. The main themesin the 2010 contents were as follows;a) Age-related changes in the physiologic system,
Aging and dementiab) Aging and osteoporosis, Aging and renal function,
hypertension, and strokec) Aging and respiratory disorders, Aging andcardiovascular disordersd) Pharmacological management of the elderlye) Feeding and swallowing difficulty of the elderlyf) Nutritional management of the elderlyg) Relationship and communication skills with theelderly
The above lectures were developed under thecooperation by the Department of Geriatric Medicine
at The University of Tokyo Hospital.
2) Clinical Practice in Gerontological Nursing(4th yr/ 3 credits)
The aim of this practicum is to learn present situationof gerontological nursing through practicing in thelong-term care facility. This program in 2010 was
supported by the long-term care facility owned by
Medical Corporation Tatsuoka.
3) Bachelor’s thesis
The following was the research theme in 2010;“Impaired AQP3 expression in epithelialization ofskin wound healing in diabetes”
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 recent research
trends and problems related to the elderly.
The main theme of Gerontological Nursing I in 2010
was geriatric syndrome. The students were instructedto learn the research trends of geriatric syndrome
through critical reading of recent papers. Future
perspectives of gerontological nursing were also
discussed. Geriatric syndromes such as fall, delirium,
depression, dysphagia, malnutrition, urination
disorders, pressure ulcers and dementia were includedin this program.
Gerontological Nursing II provided lectures regarding

the recent topics around gerontological medicine andnursing from the broad viewpoints including
biological, individual and social aspects by thepart-time lecturers, specialists of each research field.
The aim of this course was to obtain scientific ways ofthinking for gerontological considerations of the
future Japanese community. The main themes in 2010
were as follows;a) Biochemical fundamentals required for nutritional
managementb) Physical and mental approach of terminal carebased on nutrition and metabolismc) Relationship between psycho-social factors andhealth outcomes in the community based elderlyd) The present status and problems in the nursing
education and preventive training against natural
disasters in the center hospital of disastermedicinee) Support for younger dementia patients and theirfamiliesf) Development and evaluation of the high-risk
preventive care approach program for the elderlywith mild cognitive impairment (MCI)g) Quality evaluation of gerontological nursing
3) Wound Care Management I(Summer course/ 2 credits)4) Wound Care Management II(Winter course/ 2 credits)
The main theme of Wound Care Management I in2010 was the critical reading and related discussion of
the textbook “Bioengineering Research of Chronic
Wounds” (Amit Gefen et al. eds. Springer, 2009). This
textbook is a multi-disciplinary omnibus of recent
researches in this field including a chapter from ourlaboratory, offering the newest information ofprediction, prevention, diagnosis and treatment ofchronic wounds from the standpoint of bio-cellular
engineering.
Wound Care Management II in 2010 was a series oflectures entitled “Cutting Edge of Woundmanagement: from basic researches to clinicalapplications.”The
lecturers
withadvanced
experiences in this field were invited from various
institutions to give lectures as follows.
a) Inflammaging: a new perspective of the aging
and its evolution.

291

b)
c)
d)

e)
f)

Intestinal stoma and its complication
Application of regenerative medicine to wound
management
Cell biology in dermatology (the special lecture
held jointly with Department of Advanced Skin
Care)
Aging and senescence of the skin
Breast cancer and the fungating wounds

5) Master’s thesis
The followings were research themes in 2010;“Novel biomarkers for the detection of wound
infection by wound fluid RT-PCR in rats”“Oxidative stress mediates skin fragility in obese
diabetic mice”“Health-related quality of life and associated factors
in patients with primary lymphoedema ““Development and evaluation of new product for maleurinary incontinence care using pouch”“A qualitative study of morphological characteristics
and wound healing process in venous leg ulcers”

Research activities
1. Activity policy
Our gerontological nursing researches are focusing onelderly suffering with geriatric syndrome such aspressure ulcers, incontinence, malnutrition, pain,
dysphagia, osteoporosis and dementia. Our woundcare management researches are focusing on pressure
ulcers, diabetic foot ulcers, ulcers with peripheral
vascular diseases and malignant fungating ulcers.
Majority of our clinical researches are conducted at
the University of Tokyo Hospital as a main field. We
are participating in pressure ulcer ward rounds as
members of the Pressure Ulcer Team of the hospital.
We also attend the Foot Care Outpatient Clinic held
by Department of Metabolic Diseases, and the Stoma
Outpatient Clinic held by Department of Urology andDepartment of Colorectal Surgery. We also actively
perform epidemiological and clinical researches in therelated institutes other than the University hospital, sothat our research is always based on clinical practice.
Our special research missions in 2010 were twofold:(1) We aimed to develop our research system within
our department as a sequential flow of “translational
research,” from the basic biology, through engineeringby industry-academia cooperation, and to theestablishment of clinical evidences returning theachievement of our research to the society. Some ofthe studies described below were performed in thisdirection.
(2) Development of new nursing devices requires
involvement of engineering specialists. We haveinvented a number of nursing products andequipments
based
on
our
researchbyacademia-industrial cooperation. In October, the newendowed department, the Department of Life Support
Technology (Molten), was established under intimate
collaboration with our department, where Dr.
Taketoshi Mori, a specialist of bioengineering, wasinvited as the Project Associate Professor. We havestarted to develop life support technologies based on
new engineering concept, together with this new
department.
We held the 6th University of Tokyo Open Seminar of
Advanced Wound Care on November 2010 at YasudaHall, entitled “Expectation for the new nursing
position in the field of wound, ostomy and continence
nursing: Development of an advanced wound nursing
education.” We had a fruitful discussion regarding thesignificance of the novel nursing position and thefuture nursing in Japan 20 years later, through theevidence based on our research and the practice in theother country.
Our international research activities include aleadership of Japanese Society of International
Lymphoedema Framework (ILF), a internationalgroup for lymphoedema management. We conductedepidemiological research of the primary andsecondary lymphoedema, under the collaboration with
Prof. Christine Moffatt (Glasgow University, UK), thehead of ILF. Especially, international research ofeffect of lymphoedema and its treatment on the healthrelated quality of life has been executed with British
and French researchers. Further mission regarding
lymphoedema was an invitation of Dr. Hans Pritschow(the head of the center of manual lymph drainage,
Germany), an internationally well-known therapist of
the manual lymph drainage (MLD) and combined
decongestive therapy (CDT). We held an internationalsession including a lecture and a therapy
demonstration to lymphoedema patients by Dr.
Pritschow.

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2. Research fields and themes in 2010
1) Basic experimental studies
・ Development of a novel method for controllingwound infection focusing on gene expression ofbacteria and hosts
・ Evaluation of wound condition using exudates
・ Establishment of the animal model of pressure
ulcer of deep tissue injury type and elucidationof its pathophysiological mechanisms
・ Skin vulnerability and aging in the metabolic
syndrome model mice・ Cutaneous wound healing and diabetes mellitus
・ New animal model of wound infection
・ Mechanisms of skin maceration
2) Nursing engineering
・ Development of a new air-mattress equippedwith interface pressure sensing system andautomatic pressure control
・ Non-invasive detection of tissue injury andpre-injury status using ultrasonography andthermography
・ Development of a handy type kit for diagnosis
of wound infection3) Clinical studies
・ Cross-sectional study of diabetic foot (callus,
fissures, onychomycosis etc.) and its risk factors
・ Evaluation of wound nutritional status in elderlywith pressure ulcers
・ Risk factors of venous leg ulcers and fungatingbreast cancer
・ Survey and international comparison oflymphoedema (collaboration with International
Lymphoedema Framework)・ Clinical outcomes and cost-effectiveness of
WOC nurse practice with advanced educationand discretion
・ Evaluation of a new concept diaper for elderly
people for incontinence associated dermatitis
management
・ New assessment technology of the aged skin byengineering analysis.
・ Thermographic assessment of the footcirculation based on the concept of angiosome
・ Establishment of a novel diagnosis method oflatent dysphagia

Several awards were given to our research as follows.
“Mechanisms of regulation of MMP expression by
quorum sensing signals of P.aeruginosa.” Dr. Gojiro
Nakagami (Lecturer) won the research prize of the40th Annual Meeting of the Japan Society for Wound
Healing.
“Skin bacterial contamination around the coccyx andthe urethra under the circumstance of pad use.” Dr.
Gojiro Nakagami (Lecturer) won the congress prize ofthe 25th Annual Meeting of Japanese Society ofGeriatric Urology.
“A preliminary study of estimation of exudate volume
from the full-thickness pressure ulcers: Versatility of
DESIGN-R.” A doctor course student Shinji Iizaka(The DC2 Research Fellow of Japan Society for the
Promotion of Science) won the best paper prize of the
19th Annual Meeting of Japanese Society of Wound,
Ostomy and Continence Management.

References
1.

2.

3.

4.

5.

6.

Takehara K, Oe M, Tsunemi Y, Nagase T, Ohashi Y,
Iizaka S, Ueki K, Tsukamoto K, Kadowaki T,
Sanada H. Factors associated with presence andseverity of toenail onychomycosis in patients withdiabetes: A cross-sectional study. Int J Nurs Stud.
2011 Feb 28. [Epub ahead of print]
Yabunaka K, Sanada H, Sanada S, Konishi H,
Hashimoto T, Yatake H, Yamamoto K, Katsuda T,
Ohue M. Sonographic assessment of hyoid bone
movement during swallowing: a study of normal
adults with advancing age. Radiol Phys Technol.
2011;4(1):73-7.
Nakagami G, Morohoshi T, Ikeda T, Ohta Y, Sagara
H, Huang L, Nagase T, Sugama J, Sanada H.
Contribution of quorum sensing to the virulence ofPseudomonas aeruginosa in pressure ulcer infection
in rats. Wound Repair Regen. 2011;19(2):214-22
Akase T, Shimada T, Terabayashi S, Ikeya Y,
Sanada H, Aburada M. Antiobesity effects of
Kaempferia parviflora in spontaneously obese type
II diabetic mice. J Nat Med. 2011;65(1):73-80.
Urasaki M, Nakagami G, Sanada H, Kitagawa A,
Tadaka E, Sugama J. Interface pressure distributionof elderly Japanese people in the sitting position.
Disabil Rehabil Assist Technol. 2011;6(1):38-46.
Shigeta Y, Nakagami G, Ssanada H, Konya C,

293

7.

8.

9.

10.

11.

12.

13.

14.

15.

Sugama J. Factors influencing intact skin in womenwith incontinence using absorbent products: resultsof a cross-sectional, comparative study. Ostomy
Wound Manage. 2010;56(12):26-33.
Nakagami G, Sanada H, Iizaka S, Kadono T,
Higashino T, Koyanagi H, Haga N. Predicting
delayed pressure ulcer healing using thermography:
a prospective cohort study. J Wound Care. 2010;19(11):465-72.
Fujii K, Sugama J, Okuwa M, Sanada H, Mizokami
Y. Incidence and risk factors of pressure ulcers inseven neonatal intensive care units in Japan: amultisite prospective cohort study. Int Wound J.
2010;7(5):323-8.
Huang L, Nakagami G, Minematsu T, Kinoshita A,
Sugama J, Nakatani T, Sagara H, Sanada H.
Ulceration and delayed healing following pressureloading in hyperglycemic rats with an immaturedermal collagen fiber network. WOUNDS. 2010;22(9):237-44.
Ueda K, Akase T, Nakagami G, Nagase T,
Minematsu T, Huang L, Sagara H, Ohta Y, Sanada
H. A possible animal model for critical colonisation.
Journal of Wound Care. 2010;19(7):295-300.
Arashi M, Sugama J, Sanada H, Konya C, Okuwa
M, Nakagami G. Inoue A, Tabata K. Vibration
therapy accelerates healing of stage I pressure
ulcers in older adult patients. Adv Skin Wound Care.
2010;23(7):321-7.
Tsuda K, Nakatani T, Sugama J, Okuwa M, Sanada
H. Infuluence of the timing of switching a proteinfree to a protein-containing diet on the woundhealing process in a rat all-layer skin defect. Int
Wound J. 2010;7(3):135-46.
Konya C, Sanada H, Sugama J, Okuwa M,
Kamatani Y, Nakagami G, Sakaki K. Skin injuriescaused by medical adhesive tape in older people
and associated factors. J Clin Nurs. 2010;19(9-10):
1236-42.
Minematsu T, Nakagami G, Sari Y, Akase T,
Sugama J, Nagase T, Sanada H. Candidate
biomarkers for deep tissue damage from molecularbiological and biochemical aspects. J Tissue
Viability. 2010;19(2):77-83.
Nakagami G, Sari Y, Nagase T, Iizaka S, Ohta Y,
Sanada H. Evaluation of the usefulness of skinblood flow measurements by laser speckle

16.

17.

18.

19.

flowgraphy in pressure-induced ischemic wounds
in rats. Ann Plast Surg. 2010;64(3):351-4.
Oe M, Okuwa M, Sanada H, Sugama J, Inagaki M,
Kasahara Y, Tabata K, Nakagami G, Nishizawa T.
Difference of foot manifestations between young,
adult, and bedridden elderly with diabetes: a crosssectional observational study. J So Nurs Pract.
2010;22(1):19-27.
Sari Y, Nagase T, Minematsu T, Akase T, Nakagami
G, Sanada H, Sugama J. Hypoxia is involved indeep tissue injury formation in a rat model.
WOUNDS. 2010;22(2):45-51.
Kaitani T, Tokunaga K, Matsui N, Sanada H. Risk
factors related to the development of pressure ulcers
in the critical care setting. J Clin Nurs. 2010;19(3-4):414-21.
Iizaka S, Sanada H, Minematsu T, Oba M,
Nakagami G, Koyanagi H, Nagase T, Konya C,
Sugama J. Do nutritional markers in wound fluidreflect pressure ulcer status? Wound Repair Regen.
2010;18(1):31-7.

International Health
1. International Social Medicine

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Department of
Global Health Policy
Professor
Kenji Shibuya, MD, DrPH

Faculty members
Rintaro Mori, MD, PhD, MSc, FRCPCH
Nayu Ikeda, MA
Ai Koyanagi, MD, MSc, PhD

Homepage

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

Introduction and Organization
Our mission is to improve population health byenhancing accountability and improving evidencebase of global health programs through the provisionof best possible information and rigorous monitoringand evaluation. The department's members generateknowledge and ideas through their research,strengthen technical and leadership skills througheducational programs, and enhance national capacities
through collaborative projects, especially in thedeveloping world.
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,
effec¬tive 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.

Education
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.
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.

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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.
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

country, Health and Labour Sciences Research Grant

GHP Monday seminar

Development and application of statistical techniquefor correction of systematic measurement error margin
in health statistics. Grant-in-Aid for Young Scientists(B).

Every Monday, 13:00-15:00 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.
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.

ResearchStrengthening health systems to achieve MDG 4 and 5.
Research on Global Health Issues, Health and Labour
Sciences Research Grant
Epidemiology of HIV/AIDS: A cohort study andmeta-analysis. Research on HIV/AIDS, Health andLabour Sciences Research Grant
Inclusive proof research on health medical care of ourGenetic analysis of tuberculosis epidemiology.
Scientific Research (B), Grants-in-Aid for Scientific
Research.
The WHO Multi-country Survey on Maternal andNewborn Health. World Health Organization
Multicenter study concerning the improvement of theoutcome for newborn baby's serious illness. Healthand Labour Sciences Research Grant
Research on role and possibility of diagnosis andtreatment guideline for EBM spread promotion in the
future. Health and Labour Sciences Research Grant.
Grand design of child health and development
research. Child Health and Development Research
Grant.

Publications(1) Shibuya K, Chen LC, Takemi K, Summerskill W.
Japan―a call for research papers. Lancet 2010;
376:1207.
(2) Togoobaatar G, Ikeda N, Ali M, Sonomjamts M,
Dashdemberel S, Mori R, Shibuya K. Survey of
non-prescribed use of antibiotics for children in
an urban community in Mongolia. Bulletin of theWorld Health Organization 2010;88:930–936.
(3) Kislitsyna O, Stickley A, Gilmore A, McKee M.
The social determinants of adolescent smoking in
Russia in 2004. International Journal of Public
Health 2010;55:619-626.
(4) Stickley A, Pridemore WA. The effects of binge
drinking and social capital on violent
victimisation: findings from Moscow. Journal of
Epidemiology and Community Health 2010;64:
902-907.
(5) Matsuzaki M, Haruna M, Ota E, Yeo SA,
Murayama R, Murashima S: Translation and297cross-cultural adaptation of the Pregnancy
Physical Activity Questionnaire (PPAQ) to
Japanese. BioScience Trends. 2010 Aug;4(4):170-7.
(6) Lee AH, Liang W, Hirayama F, Binns CW.
Association between green tea consumption andlung cancer risk. Journal of Preventive Medicine
and Public Health 2010 Jul;43(4):366-7.
(7) Koyanagi A, Ruff AJ, Moulton LH, Ntozini R,
Mutasa K, Iliff P, Humphrey JH; ZVITAMBO
Study Group. Postpartum plasma CD4 change in
HIV-positive women: implications for timing of
HAART initiation. AIDS Research and Human
Retroviruses 2010;26(5):547-52.
(8) Koyanagi A, Shibuya K. What do we really know
about adult mortality worldwide? Lancet 2010;
375(9727):1668-70.
(9) King G, Lu Y, Shibuya K. Designing Verbal
Autopsy Studies Population Health Metrics 2010.
April 6, 2010.
(10) Guo Y, Shibuya K, Cheng G, Rao K, Tang S.
Tracking China's health reform. Lancet 2010;
375:1056-1058.
(11) Stevens GA, King G, Shibuya K. Deaths fromheart failure: Using coarsened exact matching tocorrect cause of death statistics. Population
Health Metrics 2010. April 13, 2010.
(12) Stickley A, Carlson P. Factors associated with
non-lethal violent victimisation in Sweden in
2004-2007. Scandinavian Journal of Public
Health 2010;38:404-410.
(13) 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 2010;30(2):246-250.
(14) Lumbiganon P, Laopaiboon M, Gülmezoglu AM,
Souza JP, Taneepanichskul S, Ruyan P, Attygalle
DE, Shrestha N, Mori R, Hinh ND, Bang HT,
Rathavy T, Chuyun K, Cheang K, Festin M,
Udomprasertgul V, Germar MJV, Yanqui G, Roy
M, Carroli G, Ba-Thike K, Filatova E, Villar J.
Method of delivery and pregnancy outcomes in
Asia: The WHO Global Survey on Maternal andPerinatal Health 2007-08. Lancet 2010;375(9713):490-9.
(15) Mori R, Yonemoto N, Fitzgerald A, Tullus K,
Verrier-Jones K, and Lakhanpaul M. Diagnostic

performance of urine dipstick testing in children
with suspected UTI: A systematic review ofrelationship with age and comparison withmicroscopy. Acta Paediatrica 2010;99(4):581-4.
(16) Nagai S, Andrianarimanana D, Rabesandratana N,
Yonemoto N, Nakayama T, and Mori R. Earlier
versus Later Continuous Kangaroo Mother Carefor stable Low-birth-weight Infants: A
Randomized Controlled Trial. Acta Paediatrica
2010;99(6):826-35.
(17) Mori R, Khanna R, Pledge D, Nakayama T. A
meta-analysis of physiological effects byskin-to-skin contact for newborns and mothers.
Pediatrics International 2010;52(2):161-70.
(18) Matsuoka S, Aiga H, Rasmey LC, Rathavy T,
Okitsu A. Perceived barriers to utilization ofmaternal health services in rural Cambodia.
Health Policy 2010 May;95(2-3):255-63

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Department of Community andGlobal HealthProfessor, Academic Leader
Masamine Jimba, MD, PhD, MPH

Assistant Professors
Krishna C. Poudel, PhD, MHSc
Junko Yasuoka, DSc, MPH
Keiko Otsuka, MD

Homepage http://www.ich.m.u-tokyo.ac.jp/en/index.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 (19931996), Som-Arch Wongkhomthong (1996-1999),
Susumu Wakai (1999-2005), and Masamine Jimba(2006-present).
The mission of the department is to seek equity
and social justice in health within and across nations.
To achieve this, we aim toward:
1. Investigating how to improve the health status of
the most 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.
Our research focuses on how to activate
community-based activities and how a to linkbottom-up approach to national and international
policy. The department currently consists of: our
Department Chair and Professor, 3 AssistantProfessors, 10 Visiting Lecturers, 20 PhD course

students, 27 Master’s course students, 4 research
students, and 17 visiting researchers. About 40% of
the students are international students.

International Cooperation
Activities
Among our international cooperation activities at
the global level was a human security project
conducted in collaboration with the Japan Center forInternational Exchange (JCIE). Designed to promote
Japan’s contribution to global health, the Working
Group on Challenges in Global Health and Japan’sContribution (September 2007 - July 2009) was
ultimately reformed/strengthened into the Global
Health and Human Security program. Within thisframework, we have conducted activities to facilitate
policy discussions among national/international
global health personnel and to strengthen concrete
policy implementation.
In concrete, we attended the JCIE/UN Seminaron Health and Human Security held in New York in
May 2010. Furthermore, we will play a leading rolein the “health and human security” project, which has
been initiated in Africa, Central/South America, andAsia.
We also contributed to planning the Second
Global Forum on Human Resources for Health

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organized in Bangkok in January 2011, in which theJapan International Cooperation Agency (JICA) was
also involved. Our efforts were also made to develop
a position paper related to health workforce for the
first Global Symposium on Health Systems Researchheld in Montreux, Switzerland in October 2010.
We also provided technical support to projects
run by the JICA and NGOs in Lao PDR (medical
education), Thailand (HIV/AIDS education for labor
unions), and Vietnam (safe water and better nutrition),and have conducted research in collaboration with theCambodian government.

Teaching Activities
The main objective of our teaching activities is totrain compassionate global health leaders. In concreteterms, we aim:
1. To train future leaders in the field of global
health targeting careers with the United Nations,
the Global Fund, JICA, and civil societies;
2. To train academics with the potential to become
leaders in global health in universities or
research institutes.
Major areas covered by our educational
curriculum include: 1) Global health, 2) healthpromotion, 3) school health in developing countries,4) community-based health interventions, 5) social
capital, 6) medical anthropology, and 7) reproductive
health.
Our department has accepted students of various
backgrounds and disciplines: medical doctors, nurses,
co-medical workers, social scientists and others. The
academic year for the Master’s course (MA, 2 years)
as well as the Doctor’s course (PhD, 3 years) starts in
April and ends in March every year. All lectures andseminars are conducted in English.
Even outside school, we were also involved in
education for JICA trainees from abroad and madeseveral lectures at other universities during theacademic year 2010. In addition, we made a lecture
on “safe water” in a public lecture (for the generalpublic) held by our university. In addition, by therequest from the Japanese government, we lectured on“safe water in developing countries” for high school
students, participating in the Asian Youth Exchanging
Program.

Research activities
The Department aims to contribute to policy
making and promoting actions for better health bymaking the best use of community-based research.
We carry out research by working in tandem withdifferent international organizations, NGOs, anduniversities in developing countries. The major
directions of current research have encompassed
primary health care, health promotion, school health,health and human rights (including migrants’ health),
human security, conflict and health, injury prevention,
HIV/AIDS, tuberculosis, malaria, neglected tropicaldiseases, and nutrition among others. Our researchhas been conducted in various countries, including
Nepal, India, Myanmar, Thailand, Bangladesh, Viet
Nam, Lao PDR, Cambodia, Mongolia, Ghana,Tanzania, Kenya, Zambia, and Peru.

References
1.

2.

3.

4.

5.

6.

Poudel KC, Poudel-Tandukar, Nakahara S, Jimba
M. Knowing the consequences of unprotected
sex with seroconcordant partner is associatedwith increased safer sex intentions among
HIV-positive men in Kathmandu, Nepal. J Health
Popul Nutr. (In press)
Yi S, Poudel KC, Yasuoka J, Palmer PH, Yi S,
Jimba M. Risk vs. protective factors for
substance use among adolescents in Cambodia. J
Subst Use. (In press)
Poudel KC, Fujita M, Green K, Poudel-Tandukar
K, Jimba M. Non-communicable diseases insoutheast Asia. Lancet. 2011 Jun 11;377(9782):
2004-5
Nomoto M, Nonaka D, Mizoue T, Kobayashi J,
Jimba M. Content analysis of school textbooks
on health topics: A systematic review. Biosci
Trends. 2011 Apr;5(2):61-8.
Takahashi K, Thuy NTM, Poudel KC, Sakisaka
K, Jimba M, Yasuoka J. Social capital and life
satisfaction: a cross-sectional study on persons
with musculoskeletal impairments in Hanoi,
Vietnam. BMC Public Health. 2011 Apr 1;11(1):206.
Yamaguchi N, Poudel KC, Poudel-Tandukar K,
Shakya D, Ravens-Sieberer U, Jimba M.

300

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

Reliability and validity of a Nepalese version of
the Kiddo-KINDL in adolescents. Biosci Trends.
2010 Aug;4(4):178-85.
Okawa S, Yasuoka J, Ishikawa N, Poudel KC,
Ragi A, Jimba M. Perceived social support andthe psychological well-being of AIDS orphans inurban Kenya. AIDS Care. 2011 Apr14:1-9.
Nonaka D, Laimanivong S, Kobayashi J,
Chindavonsa K, Kano S, Vanisaveth V, Yasuoka J,
Phompida S, Jimba M. Is staying overnight in a
farming hut a risk factor for malaria infection in asetting with insecticide-treated bed nets in rural
Laos? Malar J. 2010 Dec 23;9:372.
Yamaguchi N, Poudel KC, Poudel-Tandukar K,
Shakya D, Ravens-Sieberer U, Jimba M.
Reliability and validity of a Nepalese version of
the Kiddo-KINDL in adolescents. Biosci Trends.
2010 Aug;4(4):178-85.
Yi S, Poudel KC, Yasuoka J, Palmer PH, Yi S,
Jimba M. Role of risk and protective factors inrisky sexual behavior among high school
students in Cambodia. BMC Public Health 2010
Aug 12;10(1):477.
Jayatilleke AC, Poudel KC, Yasuoka J,
Jayatilleke AU, Jimba M. Intimate partner
violence in Sri Lanka. Biosci Trends. 2010 Jun;
4(3):90-5.
Yanagisawa S, Poudel KC, Jimba M. Sibling
caregiving among children orphaned by AIDS:
Synthesis of recent studies for policy
implications. Health Policy. 2010 Jun 28.
Oshiro A, Poudyal AK, Poudel KC, Jimba M,
Hokama T. Intimate Partner Violence Among
General and Urban Poor Populations in
Kathmandu, Nepal. J Interpers Violence. 2010
Jun 28.
Jayatilleke AU, Poudel KC, Nakahara S,
Dharmaratne SD, Jayatilleke AC, Jimba M.
Traffic rule violations of private bus drivers andbus crashes in Sri Lanka: a case-control study.
Traffic Inj Prev. 2010 Jun;11(3):263-9.
Sakisaka K, Jimba M, Hanada K. Changing poor
mothers' care-seeking behaviors in response tochildhood illness: findings from a cross-sectional
study in Granada, Nicaragua. BMC Int Health
Hum Rights. 2010 Jun 1;10:10.
Jayatilleke A, Poudel KC, Sakisaka K, Yasuoka J,

17.

18.

19.

20.

Jayatilleke AU, Jimba M. Wives' Attitudes
Toward Gender Roles and Their Experience ofIntimate Partner Violence by Husbands inCentral Province, Sri Lanka. J Interpers Violence.
2010 May 6.
Poudel KC, Poudel-Tandukar K, Yasuoka J, Joshi
AB, Jimba M. Correlates of sharing injection
equipment among male injecting drug users in
Kathmandu, Nepal. Int J Drug Policy. 2010 Apr
20.
Yasuoka J, Poudel KC, Poudel-Tandukar K,
Nguon C, Ly P, Socheat D, Jimba M. Assessing
the quality of service of village malaria workers
to strengthen community-based malaria control
in Cambodia. Malar J. 2010 Apr 23;9:109.
Ayi I, Nonaka D, Adjovu JK, Hanafusa S, Jimba
M, Bosompem KM, Mizoue T, Takeuchi T,
Boakye DA, Kobayashi J. School-based
participatory health education for malaria control
in Ghana: engaging children as healthmessengers. Malar J. 2010 Apr 18;9:98.
Sugiura Y, Ju YS, Yasuoka J, Jimba M. Rapid
increase in Japanese life expectancy after WorldWar II. Biosci Trends. 2010 Feb;4(1):9-16.

International Health
2. International Biomedical Sciences

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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.

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, 13 graduate students, 3 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) Analyses on the molecular mechanisms of
HLA-associated autoimmune and infectious
disorders, by protein functional studies.
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.

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References
1.

2.

3.

4.

5.

6.

7.

Miyagawa T, Honda M, Kawashima M,Shimada
M, Tanaka S, Honda Y , and Tokunaga K:
Polymorphism located in TCRA locus confers
susceptibility to essential hypersomnia with
HLA-DRB1*1501-DQB1*0602 haplotype. J.
Hum. Genet. 55(1): 63-65, 2010.
Okamoto K, Iwasaki N, Nishimura C, Doi K,
Noiri E, Nakamura S, Takizawa M, Ogata M,
Fujimaki R, Grarup N, Pisinger C, BorchJohnsen K, Lauritzen T, Sandbaek A, Hansen T,
Yasuda K, Osawa H, Nanjo K, Kadowaki T,
Kasuga M, Pedersen O, Fujita T, Kamatani N,
Iwamoto Y, and Tokunaga K: Identification of
KCNJ15 as a susceptibility gene in Asian patientswith type 2 diabetes mellitus. Am. J. Hum. Genet.
86(1): 54-64, 2010.
Ebisawa T, Numazawa K, Shimada H, Izutsu H,
Sasaki T, Kato N, Tokunaga K, Mori A, Honma
K, Honma S, and Shibata S: Self-sustained
circadian rhythm in cultured human mononuclear
cells isolated from peripheral blood. Neurosci.
Res. 66(2): 223-227, 2010.
Shi L, Yao Y, Shi L, Matsushita M, Yu L, Lin K,
Tao Y, Oka T, Chu J, and Tokunaga K: HLAalleles and haplotypes distribution in Dai
population in Yunnan Province, southwest of
China. Tissue Antigens 75(2): 159-165, 2010.
Otowa T, Tanii H, Sugaya N, Yoshida E, Inoue K,
Yasuda S, Shimada T, Kawamura Y, Tochigi M,
Minato T, Umekage T, Miyagawa T, Nishida N,
Tokunaga K, Okazaki Y, Kaiya H, and Sasaki T:
Replication of a genome-wide association studyof panic disorder in a Japanese population. J.
Hum. Genet. 55(2): 91-96, 2010.
Honda M, Sakai A, Yamashita T, Nakamoto Y,
Mizukoshi E, Sakai Y,
Yamashita T,
Nakamura M, Shirasaki T, Horimoto K, Tanaka Y,
Tokunaga K, Mizokami M, Kaneko S, Hokuriku
Liver Study Group: Hepatic ISG expression isassociated with genetic variation in IL28B andthe outcome of IFN therapy for chronic hepatitis
C. Gastroenterology 139(2): 499-509, 2010.
Liu X, Kawamura Y, Shimada T, Otowa T, Koishi
S, Sugiyama T, Nishida H, Hashimoto O,
Nakagami R, Tochigi M, Umekage T, Kano Y,

8.

9.

10.

11.

12.

13.

Miyagawa T, Kato N, Tokunaga K, and Sasaki T:
Association of the oxytocin receptor (OXTR)
gene polymorphisms autism spectrum disorder(ASD) in Japanese population. J. Hum. Genet.
55(3): 137-141, 2010.
Xu S, Kangwanpong D, Seielstad M,
Srikummool M, Kampuansai J, Jin L, HUGO
Pan-Asian SNP Consortium: Genetic evidence
supports linguistic affinity of Mlabri—a huntergatherer group in Thailand. BMC Genet. 11: e18,
2010 Mar.
Yao Y, Shi L, Shi L, Kulski JK, Chen J, Liu S, Yu
L, Lin K, Huang X, Tao Y, Tokunaga K, and Chu
J. The association and differentiation of MHC
class I polymorphic Alu insertions and HLAB/Cw alleles in seven Chinese populations.
Tissue Antigens 76(3): 194-207, 2010.
Shimada M, Miyagawa T, Kawashima M, Tanaka
S, Honda Y, Honda M, and Tokunaga K: An
approach based on a genome-wide association
study reveals candidate loci for narcolepsy. Hum.
Genet. 128(4): 433-441, 2010.
Tanaka Y, Nishida N, Sugiyama M, Tokunaga K,
and Mizokami M: λ- interferons and the single
nucleotide polymorphisms: A mikestone totailor-made therapy for chronic hepatitis C.
Hepatol. Res. 40(5): 449-460, 2010.
Ridruechai C, Mahasirimongkol S, Phromjai J,
Yanai H, Nishida N, Matsushita I, Ohashi J,
Yamada N, Moolphate S, Summanapan S,
Chuchottaworn C, Manosuthi W, Kantipong P,
Kanitvittaya S, Sawanpanyalert P, Keicho N,
Khusmith S, and Tokunaga K: Association
analysis of susceptibility candidate region on
chromosome 5q31 for tuberculosis. Genes
Immun. 11(5): 416-22, 2010.
Tabara Y, Kohara K, Kita Y, Hirawa N, Katsuya
T, OhkuboT, Hiura Y, Tajima A, Morisaki T,
Miyata T, Nakayama T, Takashima N, Jun
Nakura J, Kawamoto R, Takahashi N, Hata A,
Soma M, Imai Y, Kokubo Y, Okamura T,
Tomoike H, Iwai N, Ogihara T, Inoue I,
Tokunaga K, Johnson T, Caulfield M, Munroe P
on behalf of the Global BPgen consortium,
Umemura S, Ueshima H, and Miki T. Common
variants in the ATP2B1 gene are associated withsusceptibility to hypertension: The Japanese

304

14.

15.

16.

17.

18.

19.

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Millennium Genome Project. Hypertension
56(5): 973-980, 2010.
Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F,
Ohba S, Nishida N, Akune T, Yoshimura N,
Nakagawa T, Nakamura K, Tokunaga K, Chung
UI, and Kawaguchi H:
Transcriptional
regulation of endochondral ossification by HIF2alpha during skeletal growth and osteoarthritis
development. Nat. Med. 16(6): 678-686, 2010.
Shi L, Shi L, Yao YF, Matsushita M, Yu L, Huang
XQ, Yi W, Oka T, Tokunaga K, and Chu JY:
Genetic link among Hani, Bulang and other
Southeast Asian populations: evidence from HLA-A, -B, -C, -DRB1 genes and haplotypes
distribution. Int. J. Immunogenet. 37(6): 467-75,
2010.
Yuliwulandari R, Sachrowardi Q, Nakajima F,
Kashiwase K, Hirayasu K, Mabuchi A, Salam A
M, and Tokunaga K: Association of HLA-A, -B,
and -DRB1 with pulmonary tuberculosis inwestern Javanese Indonesia. Hum. Imunol. 71(7):697-701, 2010.
Toyoda H, Tanaka S, Miyagawa T, Honda Y,
Tokunaga K, and Honda M: Anti-tribbles
homolog 2 autoantibodies in Japanese patientswith narcolepsy. Sleep 33(7): 875-878, 2010.
Ohnishi Y, Totoki Y, Toyoda A, Watanabe T,
Yamamoto Y. Tokunaga K, Sakaki Y, Sasaki H,
and Hohjoh H: Small RNA class transition fromsiRNA/piRNA to miRNA during pre-implantaion
mouse development. Nucleic Acids Res. 38(15):5141-5151, 2010
Sakamoto N, Tanaka Y, Nakagawa M, Yatsuhashi
H, Nishiguchi S,
Enomoto N, Azuma S,
Nishimura-Sakurai Y, Kakinuma S, Nishida N,
Tokunaga K, Honda M, Ito K, Mizokami M, and
Watanabe M: ITPA gene variant protects against
anemia induced by pegylated interferon-αandribavirin therapy for Japanese patients withchronic hepatitis C. Hepatol. Res. 40(11):10631071, 2010.
Adachi S, Tajima A, Quan J, Haino K, Yoshihara
K, Masuzaki H, Katabuchi H, Ikuma K,
Suginami H, Nishida N, Kuwano R, Okazaki Y,
Kawamura Y, Sasaki T, Tokunaga K, Inoue I, andTanaka K: Meta-analysis of genome-wide
association scans for genetic susceptibility to

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22.

23.

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endometriosis in Japanese population. J. Hum.
Genet. 55(12): 816-21, 2010.
Hijikata M, Matsushita I, Tanaka G, Tsushiya T,
Ito H, Tokunaga K, Ohashi J, Honma S, Kobashi
Y, Taguchi Y, Azuma A, Kudoh S, and Keicho N:
Molecular cloning of two novel mucin-like genes
in the disease-susceptibility locus for diffuse
panbronchiolitis. Hum. Genet. 129(2): 117-128,
2011.Epub 2010 Oct 28.
Kurosaki M, Tanaka Y, Nishida N, Sakamoto N,
Enomoto N, Honda M, Sugiyama M, Matsuura K,
Sugauchi F, Asahina Y, Nakagawa M, Watanabe
M, Sakamoto M, Maekawa S, Sakai A, Kaneko S,
Ito K, Masaki N, Tokunaga K, Izumi N,
Mizokami M: Pre-treatment prediction of
response to pegylated-interferon plus ribavirin forchronic hepatitis C using genetic polymorphism in
IL28B and viral factors. J. Hepatol. 54(3):439-448, 2011. Epub 2010 Sep 19.
Kornum BR, Kawashima M, Faraco J, Lin L, Rico
TJ, Hesselson S, Axtell RC, Kuipers H, Weiner K,
Hamacher A, Kassack MU, Han F, Knudsen S,Li J,
Dong X, Winkelmann J, Plazzi G, Nevsimalova S,
Hong SC, Honda Y, Honda M, Högl B, Ton TG,
Montplaisir J, Bourgin P, Kemlink D, Huang]
YS, Warby S, Einen M, Eshragh JL, Miyagawa T,
Desautels A, Ruppert E, Hesla PE, Poli F, Pizza F,
Frauscher B, Jeong JH, Lee SP, Strohl KP,
Longstreth WT Jr, Kvale M, Dobrovolna M,
Ohayon MM, Nepom GT, Wichmann HE, Rouleau
GA, Gieger C, Levinson DF, Gejman PV,
Meitinger T, Peppard P, Young T, Jennum P,
Steinman L, Tokunaga K, Kwok PY, Risch N,
Hallmayer J, and Mignot E: Common variants in
P2RY11 are associated with narcolepsy. Nat.
Genet. 43(1): 66-71, 2011. Epub 2010 Dec19.
Otowa T, Kawamura Y, Sugaya N, Yoshida E,
Shimada T, Liu X, Tochigi M, Umekage T,
Miyagawa T, Nishida N, Kaiya H, Okazaki Y,
Tokunaga K, and Sasaki T: Association study of
PDE4B with panic disorder in the Japanese
population. Prog. Neuropsychopharmacol. Biol.
Psychiatry 35(2): 545-549, 2011. Epub 2010
Dec22.

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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,
thirteen visiting researchers, and fifteen graduate
students, including seven overseas students.
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,
School of International Health Sciences

306

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) Clinical, genetic and pathologic studies of acuteencephalopathy:
Acutenecrotizing
encephalopathy and acute encephalopathy withfebrile convulsive status epilepticus.
(2) Studies on developmental brain disorders caused
by abnormal intracellular signal transduction,such as tuberous sclerosis, Noonan syndrome andCostello syndrome.
(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 studies on the mental health ofschoolchildren, and of mothers and children
living abroad

2.

3.

4.

5.

6.

7.

8.

9.

Chan-it W, Thongprachum A, Okitsu S,
Mizuguchi M, Ushijima H. Epidemiological andmolecular characterization of sapovirus andastrovirus in Japan. Jpn J Infect Dis 2010, 63(4):302-303.
Dey SK, Phan GT, Nishimura S, Mizuguchi M,
Okitsu S, Ushijima H. Molecular andepidemiological trend of sapovirus, andastrovirus infection in Japan. J Trop Pediatr
2010; 56(3): 205-207.
Dey SK, Phathammavong O, Okitsu S,
Mizuguchi M, Ohta Y, Ushijima H. Seasonalpattern and genotype distribution of norovirus
infection in Japan. Pediatr Infect Dis J 2010;29(5): e32-34.
Dey SK, Ushijima H, Phathammavong O, Chanit
W, Okitsu S, Mizuguchi M, Ota Y. Seasonal
trend and serotype distribution of rotavirus
infection in Japan, 1981-2008. Pediatr Infect Dis
J 2010; 29(2): 166-167
Hayakawa Y, Zhou Y, Mizuguchi M, Frey TK,
Ushijima H. Quantitative and qualitative assay
of rubella IgA antibody in breast milk. J Med
Virol 2010; 82(8): 1475-1479.
Kanda S, Saito M, Hayashi M, Atsumi S,
Komine S, Tanuma N. Hypoglossal hypoplasia
and hyperplasia of the area postrema following
perinatal hypoxic brain damage. Brain Dev
2010; 32(4): 285-288
Khamrin P, Dey SK, Chan-it W, Thongprachum
A, Satou K, Okitsu S, Maneekarn N, Ushijima H.
Evaluation of a rapid immunochromatography
strip test for detection of astrovirus in stool
specimens. J Trop Pediatr 2010; 56(2): 129-131.
Khamrin P, Maneekarn N, Thongprachum A,
Chaimongkol N, Okitsu S, Ushijima H.
Emergence of new norovirus variants andgenetic heterogeneity of noroviruses andsapoviruses in children admitted to hospital withdiarrhea in Thailand. J Med Virol 2010; 82(2):289-296.
Khamrin P, Okame M, Thongprachum A,
Nantachit N, Nishimura S, Okitsu S, Maneekarn
N, Ushijima H. A single-tube multiplex PCR for
rapid detection in feces of 10 viruses causing

307

10.

11.

12.

13.

14.

15.

16.

17.

diarrhea. J Virol Methods 2011; 173(2): 390393.
Kim Pham NT, Trinh QD, Takanashi S,
Abeysekera C, Abeygunawardene A, Shimizu H,
Khamrin P, Okitsu S, Mizuguchi M, Ushijima H.
Novel human parechovirus, Sri Lanka. Emerg
Infect Dis 2010; 16(1): 130-132.
Kohno S, Kida H, Mizuguchi M, Shimada J; for
the S-021812 Clinical Study Group. Efficacy
and safety of intravenous peramivir for thetreatment of seasonal influenza. Antimicrob
Agents Chemother 2010; 54(11): 4568-4574.
Okitsu S, Khamrin P, Thongprachum A,
Maneekarn N, Mizuguchi M, Ushijima H.
Predominance of porcine P[23] genotype
rotaviruses in piglets with diarrhea in northern
Thailand. J Clini Virol 2010; 49(1): 442-445.
Pham NT, Takanashi S, Tran DN, Abeysekera C,
Abeygunawardene A, Khamrin P, Okitsu S,
Shimizu H, Mizuguchi M, Ushijima H. Humanparechovirus infection in children hospitalizedwith acute gastroenteritis in Sri Lanka. J Clin
Virol 2010; 49(1): 364-366.
Pham NT, Trinh QD, Chan-It W, Khamrin P,
Shimizu H, Okitsu S, Mizuguchi M, Ushijima H.
A novel RT-multiplex PCR for detection of Aichi
virus, human parechovirus, enteroviruses, andhuman bocavirus among infants and children
with acute gastroenteritis. J Virol Methods 2010;
169(1): 193-197.
Pham NT, Trinh QD, Khamrin P, Maneekarn N,
Shimizu H, Okitsu S, Mizuguchi M, Ushijima H.
Diversity of human parechoviruses isolated instool samples collected from Thai children withacute gastroenteritis. J Clin Microbiol 2010;
48(1): 115-119.
Thongprachum A, Chaimongkol N, Khamrin P,
Pantip C, Mizuguchi M, Ushijima H, Maneekarn
N. A Novel Multiplex RT-PCR for Identificationof VP6 Subgroups of Human and Porcine
Rotaviruses. J Virol Methods 2010; 168(1/2):
191-196.
Thongprachum A, Khamrin P, Chaimongkol N,
Malasao R, Okitsu S, Mizuguchi M, Maneekarn
N,
Ushijima
H.
Evaluationofanimmunochromatography method for rapid
detection of noroviruses in clinical specimens in

18.

19.

Thailand. J Med Virol 2010; 82(12): 2106-2109.
Trinh QD, Pham NT, Nguyen TA, Phan TG, Yan
H, Hoang le P, Khamrin P, Maneekarn N, Li Y,
Okitsu S, Mizuguchi M, Ushijima H. Sequence
analysis of the VP7 gene of human rotaviruses
G2 and G4 isolated in Japan, China, Thailand,
and Vietnam during 2001-2003. J Med Virol
2010; 82(5): 878-885.
Tumurkhuu M, Saitoh M, Sato A, Takahashi K,
Mimaki M, Takita J, Takeshita K, Hama T, Oka
A, Mizuguchi M. Comprehensive genetic
analysis of overlapping syndromes of RAS/RAF/
MEK/ERK pathway. Pediatr Int 2010; 52(4):557-562.

308

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.

Homepage http://www.humeco.m.u-tokyo.ac.jp/index-e.html
Introduction and Organization
We had four research/teaching faculties in FY2010.
Apart from the faculty staffs, two secretaries, four
doctoral candidates (two foreign students), sevenmaster course students (including four foreign
students), one post-doctoral fellow and three research
fellows are working in the department. There are ten
extra-university lecturers delivering lectures in either
graduate or undergraduate course. Prof. Watanabeholds 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 Ecology
Special Lecture I focused on the basic components of
Human Ecology such as demography, nutrition, andenvironment. In “Human Ecology Special Lecture II”,emphases were on recent topics and ongoing
researches in the field of Human Ecology and relatedareas. With these classes for the Graduate Students,
we tried to describe Human Ecology as a basic
component of International Health, and gave examplesof the recent issues that have been dealt with andapproaches used in this field. The lectures for the
Graduate Course were given in English.
In the undergraduate course, the department is incharge of a part of the School of Health Sciences andNursing, providing the lectures on “Human Ecology”,“Environmental
Health”,“Demography”,“International Health”. We were also responsible fororganizing“Pharmacology
andToxicology”,“Physiology”, “Anatomy”, as well as “Environmental
Engineering/
Human
Engineering”.
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.
As a part of the Global30 program, staff made a site
visit to Australia National University, where they arerunning a Human Ecology program with a highproportion of foreign students and exchanged
information regarding the operation of such a
program.

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, and309

environment and sustainability. Experimental studies
focusing on the effects of perinatal exposures to heavy
metals have been conducted, emphasizing the factorsthat modify the effects. What follows is a list of major
activities conducted in the past two years.
1. Evaluation and Alleviation of Environmental
Burden due to Subsistence Transition in AsiaPacific –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. The
analyses of the collected samples have been
progressed, and the data analyses are still going on.
Part of the results had been presented in someinternational conference such as ICHE in UK and ESA
in USA, 2009 and 2010.
2. Development and subsistence activity, subsistencetransition and adaptation:
In many Asian and Oceanian 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.
3. Human
Ecologyrelatedwithregional
sustainability issues in Asian urban and ruralcommunities:
We have participated in a water-reuse project
conducted in a suburb area close to Bangkok,
Thailand, in which we are in charge of developing anappropriate method/protocol for health risk
assessment. We have carried out a survey on the site
selected last year, regarding the pattern of water use as
well as attitude towards the potential use of reclaimed
water. The results showed heterogeneity in both water
consumption and attitude towards reclaimed water
within relatively small geographical area, which might
be related with the proximity to the industrial area.
In West Java, Indonesia, we did a survey regarding
the system for health information gathering andregarding activities associated with environmental
health. Discussions and information exchange wereconducted with local stakeholders to extract the urgent
health issues in the locality in relation to regionalsustainability.
In a suburb of Dhaca, capitol of Bangladesh,
exposure to lead (Pb) among the school children was
evaluated, and the relationship between a genetic
polymorphism and the effect of Pb on blood ALA (atoxicity biomarker of Pb) was evaluated. Genderassociated difference in Pb exposure and in genetic
susceptibility were identified among this children’s
population.
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. We
have been focusing on modifiers of arsenic toxicity,
including sex or nutritional status. We are focusing on
the effects of oral contraceptives as well as some
genetic polymorphisms in As-metabolism pathway.

310

5. Neurodevelopmental effects of perinatal exposure
to environmental chemicals:
The fetus/newborn is said to be relatively sensitive
to many of the environmental chemicals. We focusedon the exposure to chemicals during perinatal period.
Using cultured neurons, effect of bisphenol A, atypical endocrine disrupting chemical, has been
examined. In addition, the basic action mechanism ofsuch estrogenic chemicals have been examined andreported.
6. Role of selenium in a population highly exposed
to methylmercury through fish consumption:
Relatively high concentration of methylmercury(MeHg) can be found in some predator fish species
through food chain, and health risks associated withexcessive consumption of such seafood items havebeen debated long time. On the other hand, fish isvery important source of some nutrients including
protein, polyunsaturated fatty acids, and minerals, andsome of these nutrients might interfere with MeHg
toxicity. We have collaborated with other institutes
like National Institute for Minamata Diseases who
conducted a survey in a fish-eating population in
Japan, and examined the nutritional status of selenium,
a micronutrient for which fish provide substantial
amount.
7. Prediction and adaptation measures for healthrisks due to climate change and/or air pollution:
Concerns are growing over the potential healtheffects of climate change, especially global warming,
as well as of air pollution, especially long-range
pollution that could occur beyond national borders.
In collaboration with the Atomosphere and Ocean
Research Institute as well as National Institute ofEnvironmental Studies, we are trying to develop ahealth risk map in a small-scale range like Kanto
plane, taking advantage of the climate prediction
models using assimilation technique. During this year,
basic information about the relationship between
temperature, air pollutants and various health effects
has been collected, which will be fed into this climate
model.

References
1.

2.

3.

4.

5.

6.

7.

Eriguti, T., Takahashi, M., Ji, H., Umezaki, M.,
Watanabe, C., Koga, M., and Arizono, K. (2010)
Analysis of DDT and its metabolites in human
cord blood in Nepal. Oraganohalogen
Compounds 72: 822-825.
Iwakura, T., Iwafuchi, M., Muraoka, D.,
Yokosuka, M., Shiga, T., Watanabe, C., andOhtani-Kaneko, R. (2010) In vitro effects ofbisphenol A on developing hypothalamic neurons.
Toxicology 272: 52-58.
Tadokoro, K. (2010) An analysis of theorganization of groups for fish poisoning among
the Tewada of Papua New Guinea. People andCulture in Oceania 26: 1-22.
Takahashi, M., Eriguti, T., Ji, H., Umezaki, M.,
Watanabe, C., Koga, M., and Arizono, K. (2010)
2,4-Dichloroaniline in human urine relevant to
the lifestyle in four cities in Nepal.
Oraganohalogen Compounds 72: 902-905.
Uda, S. (2010) The Behavior of Fishers after
Implementation of the Project to Exterminate
Nonindigenous Fish in Lake Biwa, Japan. Human
Ecology 38(2): 237-249.
Umezaki, M. (2010) Adaptive Strategies of Huli
Migrant Settlers. Goddard M. (ed.) Villagers in
the City: Melanesian Experiences of Port
Moresby, Papua New Guinea.
Sean Kingston
Press, pp. 75-92.
Onishi, M., Tida, S., Ono, R., Tadokoro, K.,
Negishi, Y., and Furusawa, T. (2009) Book
Review: Papuan Pasts: Cultural, Linguistic, andBiological Histories of Papuan-speaking People.
Andrew Pawley, Robert Attenborough, Jack
Golson, and Robin Hide (eds.) Pacific
Linguistics, Canberra, 2005, 817pp. People andCulture in Oceania 24: 81-87.

311

Department of
Biomedical Chemistry
Professor
Kiyoshi Kita, Ph.D.

Associate Professor
Yoh-ichi Watanabe, Ph.D.

Associate
Kimitoshi Sakamoto, Ph.D.,

Homepage

Tomoo Shiba, 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. elegans as a model system of parasitic
nematode (expression of foreign genes or cDNAs,
gene knockout)

312

Nara, T., Aoki, T., Honma, T., Tanaka, A., Inoue,M., Matsuoka, S., Michels, P. AM,. Harada, S. andKita, K. (2010) Acta Crystallographica, F66,
304-308
7. Purification and kinetic characterization ofrecombinant alternative oxidase from Trypanosoma
brucei brucei. Kido,Y., Sakamoto, K., Nakamura, K.,
Harada, M., Suzuki, T., Yabu, Y., Saimoto, H.,
Yamakura, F., Ohmori, D., Moore, A., Harada, S.
IV. Protein synthesis
and Kita, K. (2010) Biochim Biophys. Acta
1) Mitochondrial protein synthesis(Bioenergetics), 1797, 443-450
2) Biogenesis of cytoplasmic ribosomes
8. A bacterial elongation factor G homolog exclusivelyfunctions in ribosome recycling in the spirochaete
References
Borrelia burgdorferi. Suematsu, T., Yokobori, S.,
Morita, H., Yoshinari, S., Ueda, T., Kita, K.,
1. IL-10 plays a crucial role for the protection of
Takeuchi, N. and Watanabe, Y. (2010) Mol.
experimental cerebral malaria by coinfection with
Microbiol. 75, 1445-1454
nonlethal malaria parasites. Niikura, M., Kamiya, S.,
9. Extensive frameshift at all AGG and CCC codons in
Nakane, A., Kita, K. and Kobayashi, F. (2010) Int. J.
the mitochondrial cytochrome c oxidase subunit 1
Parasitol. 40, 101-108
geneofPerkinsus
marinus(Alveolata;
2. Contribution of the FAD and quinone binding sites
Dinoflagellata). Masuda, I., Matsuzaki, M. and Kita,
to the production of reactive oxygen species (ROS)
K. (2010) Nucleic Acids Research. 38, 6186-6194
from Ascaris suum mitochondrial complex II.
Paranagama, M. P., Sakamoto, K., Amino, H., 10. Trypanosome alternative oxidase, a potential
therapeutic target for sleeping sickness, is conserved
Awano, M., Miyoshi, H. and Kita, K. (2010)
among Trypanosoma brucei subspecies. Nakamura,
Mitochondrion, 10, 158-165
K., Fujioka, S., Fukumoto, S., Inoue, N., Sakamoto,
3. Crystallization and preliminary crystallographic
Hirata, H., Kido, Y., Yabu, Y., Suzuki, T., Watanabe,
analysis of cyanide-insensitive alternative oxidase
Y., Saimoto, H., Akiyama, H. and Kita, K. (2010)
from Trypanosoma brucei brucei. Kido, Y., Shiba, T.,
Parasitol. Int. 59, 560-564
Inaoka, D. K. Sakamoto, K., Nara, K., Aoki, T.,
Honma, T., Tanaka, A., Inoue, M., Matsuoka, S.,
Moore, A., Harada, S. and Kita, K. (2010) Acta
Crystallographica, F66, 275-278
4. A broad distribution of mitochondrial alternativeoxidase in microsporidian parasites. Williams, B. A.
P., Elliot, C., Burri, L., Kido, Y., Kita, K., Moore, A.
L. and Keeling, P. J. (2010) PLoS Pathogens, 6,e1000761
5. Divergence of mitochondrial genome structure in theapicomplexan parasites, Babesia and Theileria.
Hikosaka, K., Watanabe, Y., Tsuji, N., Kita, K.,
Kishine, H., Arisue, N., Palacpac, N. M. Q., Kawazu,
S., Sawai, H., Horii, T., Igarashi, I. and Tanabe, K.
(2010) Mol. Biol. Evolution, 27, 1107-1116
6. Overproduction, purification, crystallization andpreliminary X-ray
diffraction analysis of
Trypanosoma brucei gambiense glycerol kinase.
Balogun, O. E., Inaoka, D. K., Kido, Y., Shiba, T.,
III. Parasitic protozoa (Plasmodium falciparum ,Trypanosoma
brucei,
Trypanosoma
cruzi,
Cryptosporidium)1) characterization of mitochondria as a target forthe chemotherapy2) molecular biology of mitochondrial DNA3) structure based drug design (SBDD)

School of Public Health
1. Epidemiology and Health Sciences

314

Department of Social andPreventive Epidemiology
Professor
Satoshi Sasaki, M.D., Ph.D.

Associate
Kentaro Murakami, Ph.D.

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
public health activities and tasks based on theory of
epidemiology.
We have also several lectures for students in otherschools.

Research activities
Our main topic is basic research for development andapplication of research methodology in the field of
nutritional epidemiology. Based on this basic research,
we also conduct a wide range of epidemiologic
research for investigating the relationship of nutrition

315

with health and disease. As a characteristic of thisresearch field, we conduct many multi-center studies
with various kinds of disease.
Another characteristic is collection of researchfindings(scientificpapers)derivedfromepidemiologic research all over the world on theassociation of nutrition with health and disease, which
is applied for health control through nutrition
improvement and disease control.

References
1.

2.

3.

4.

5.

6.

Murakami K, Sasaki S, Takahashi Y, Uenishi K,
the Japan Dietetic Students' Study for Nutrition
and Biomarkers Group. No meaningful
association of neighborhood food store
availability with dietary intake, body mass index,
or waist circumference in young Japanese women.
Nutr Res 2010; 30(8): 565-73.
Murakami K, Miyake Y, Sasaki S, Tanaka K,
Arakawa M. Dietary folate, riboflavin, vitamin
B-6, and vitamin B-12 and depressive symptoms
in early adolescence: the Ryukyus Child HealthStudy. Psychosom Med 2010; 72: 763-8.
Murakami K, Miyake Y, Sasaki S, Tanaka K,
Arakawa M. Fish and n-3 PUFA intake anddepressive symptoms: Ryukyus Child HealthStudy. Pediatrics 2010; 126: e623-30.
Murakami K, Sasaki S, Takahashi Y, Uenishi K,
the Japan Dietetic Students' Study for Nutrition
and Biomarkers Group. Neighbourhood foodstore availability in relation to 24 h urinary
sodium and potassium excretion in young
Japanese women. Br J Nutr 2010; 104: 1043-50.
Murakami K, Miyake Y, Sasaki S, Tanaka K,
Fukushima W, Kiyohara C, Tsuboi Y, Yamada T,
Oeda T, Miki T, Kawamura N, Sakae N,
Fukuyama H, Hirota Y, Nagai M, the Fukuoka
Kinki Parkinson's Disease Study Group. Dietaryintake of folate, vitamin B6, vitamin B12 andriboflavin and risk of Parkinson's disease: acase-control study in Japan. Br J Nutr 2010; 104:757-64.
Murakami K, Sasaki S, Takahashi Y, Uenishi K,
Watanabe T, Kohri T, Yamasaki M, Muramatsu K,
Baba K, Shibata K, Takahashi T, Hayabuchi H,
Ohki K, Suzuki J. Neighborhood socioeconomic

7.

8.

9.

10.

11.

12.

13.

status and premenstrual symptoms: a crosssectional study of young Japanese women.
Clinical Medicine: Women's Health 2010; 2: 1-9.
Murakami K, Sasaki S, Takahashi Y, Uenishi K,
the Japan Dietetic Students' Study for Nutrition
andBiomarkers
Group.
Neighborhoodsocioeconomic status in relation to dietary intake
and insulin resistance syndrome in female
Japanese dietetic students. Nutrition 2010; 26:508-14.
Murakami K, Sasaki S. Dietary intake anddepressive symptoms: a systematic reivew ofobservational studies. Mol Nutr Food Res 2010;
54: 471-88.
Murakami K, Miyake Y, Sasaki S, Tanaka K,
Fukushima W, Kiyohara C, Tsuboi Y, Yamada T,
Oeda T, Miki T, Kawamura N, Sakae N,
Fukuyama H, Hirota Y, Nagai M, the Fukuoka
Kinki Parkinson's Disease Study Group. Dietary
glycemic index is inversely associated with therisk of Parkinson's disease: a case-control study
in Japan. Nutrition 2010; 26: 515-21.
Okubo H, Sasaki S, Murakami K, Takahashi Y,
the Freshmen in Dietetic Course Study II Group.
Nutritional adequacy of four dietary patterns
defined by cluster analysis in 3756 Japanesewomen aged 18-20 years Asia Pac J Clin Nutr
2010; 19(4): 555-63.
Okubo H, Murakami K, Sasaki S, Kim MK,
Hirota N, Notsu A, Fukui M, Date C. Relative
validity of dietary patterns derived from aself-administered diet history questionnaire using
factor analysis among Japanese adults. Public
Health Nutr 2010; 13(7): 1080-9.
Yamada M, Sasaki S, Murakami K, Takahashi Y,
Okubo H, Hirota N, Notsu A, Todoriki H, Miura
A, Fukui M, Date C. Estimation of caffeine
intake in Japanese adults using 16-d weighed dietrecords based on a food composition database
newly developed for Japanese populations.
Public Health Nutr 2010; 13(5): 663-72.
Yamada M, Sasaki S, Murakami K, Takahashi Y,
Okubo H, Hirota N, Notsu A, Todoriki H, Miura
A, Fukui M, Date C. Estimation of trans fatty
acid intake in Japanese adults using 16-day dietrecords based on a food composition database
newly developed for Japanese population. J

316

14.

15.

16.

17.

18.

19.

20.

Epidemiol 2010; 20(2): 119-27.
Fukushima W,Miyake Y,Tanaka K,Sasaki
S,Kiyohara C,Tsuboi Y, Yamada T,Oeda T,Miki
T,Kawamura N,Sakae N,Fukuyama H,Hirota
Y,Nagai M,the Fukuoka Kinki Parkinson's
Disease Study Group. Alcohol drinking and riskof Parkinson's disease: a case-control study inJapan. BMC Neurology 2010; 10: 111.
Tanaka K, Miyake Y, Fukushima W, Sasaki S,
Kiyohara C, Tsuboi Y, Yamada T, Oeda T, Miki T,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M; the Fukuoka Kinki Parkinson’s disease
Study Group. Active and passive smoking andrisk of Parkinson's disease. Acta Neurol Scand
2010; 122(6): 377-382.
Oya J, Nakagami T, Sasaki S, Jimba S, Murakami
K, Kasahara T, Wasada T, Sekiguchi H,
Hasegawa M, Endo Y, Iwamoto Y. Intake of n-3
polyunsaturated fatty acids and non-alcoholic
fatty liver disease: a cross-sectional study inJapanese men and women. Eur J Clin Nutr. 2010;
64(10): 1179-85.
Nakashima M, Sakurai M, Nakamura K, Miura K,
Yoshita K, Morikawa Y, Ishizaki M, Murakami K,
Kido T, Naruse Y, Sasaki S, Nakagawa H.
Dietary glycemic index, glycemic load and blood
lipid levels in middle-aged Japanese men andwomen. J Atheroscler Thromb 2010; 17(10):1082-95.
Nanri A, Kimura Y, Matsushita Y, Ohta M, Sato
M, Mishima N, Sasaki S, Mizoue T. Dietary
patterns and depressive symptoms among
Japanese men and women. Eur J Clin Nutr 2010;
64: 832-9.
Miyake Y,Tsuboi Y, Koyanagi M,Fujimoto
T,Shirasawa S,Kiyohara C, Tanaka K,Fukushima
W,Sasaki S,Yamada T,Oeda T,Miki T,Kawamura
N, Sakae N,Fukuyama H,Hirota Y,Nagai
M,Fukuoka Kinki Parkinson's Disease Study
Group1. LRRK2 Gly2385Arg polymorphism,
cigarette smoking, and risk of sporadic
Parkinson's disease: a case-control study in Japan.
Journal of the Neurological Sciences 2010;
297(1-2): 15-8.
Nakagi Y, Ito T, Hirooka K, Sugioka Y, Endo H,
Saijo Y, Imai H, Takeda H, Kayama F, Sasaki S,
Yoshida T. Association between lifestyle habits

21.

22.

23.

24.

25.

26.

27.

28.

29.

and bone mineral density in Japanese juveniles.
Environ Health Prev Med 2010; 15: 222-8.
Miyake Y, Sasaki S, Tanaka K, Hirota Y.
Consumption ofvegetables,
fruit,
andantioxidants during pregnancy and wheeze andeczema in infants. Allergy 2010; 65(6): 758-65.
Karasawa S, Daimon M, Sasaki S, Toriyama S,
Oizumi T, Susa S, Kameda W, Wada K,
Muramatsu M, Fukao A, Kubota I, Kawata S,
Kayama T, Kato T. Association of the common
fat mass and obesity associated (FTO) gene
polymorphism with obesity in a Japanese
population. Endocr J 2010; 57(4): 293-301.
Tanaka K, Miyake Y, Arakawa M, Sasaki S,
Ohya Y. Household smoking and dental caries inschoolchildren:the Ryukyus Child Health Study.
BMC Public Health 2010; 10: 335.
Tsuji T, Fukuwatari T, Sasaki S, Shibata K.
Twenty-four-hour urinary water-soluble vitaminlevels correlate with their intakes in free-living
Japanese university students. Eur J Clin Nutr
2010; 64(8): 800-7.
Tsuji T, Fukuwatari T, Sasaki S, Shibata K.
Urinary excretion of vitamin B1, B2, B6, niacin,
pantothenic acid, folate, and vitamin C correlateswith dietary intakes of free-living elderly, female
Japanese. Nutr Res 2010; 30(3): 171-8.
Okuda M, Bando N, Terao J, Sasaki S, Sugiyama
S, Kunitsugu I, Hobara T. Association of serum
carotenoids and tocopherols with atopic diseases
in Japanese children and adolescents. Pediatr
Allergy Imminol 2010; 21: e705-10.
Miyake Y, Tanaka K, Fukushima W, Sasaki S,
Kiyohara C, Tsuboi Y, Yamada T, Oeda T, Miki T,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M; Fukuoka Kinki Parkinson's Disease
Study Group. Case-control study of risk of
Parkinson's disease in relation to hypertension,
hypercholesterolemia, and diabetes in Japan. J
Neurol Sci 2010; 293: 82-6.
Tanaka K, Miyake Y, Sasaki S. Intake of dairy
products and the prevalence of dental caries inyoung children. J Dent 2010; 38: 579-83.
Kiyohara C,Miyake Y,Koyanagi M,Fujimoto
T,Shirasawa S,Tanaka K,Fukushima W,Sasaki S,
Tsuboi Y,Yamada T, Oeda T,Miki T, Kawamura
N,Sakae N,Fukuyama H,Hirota Y,Nagai M,the

317

30.

31.

32.

33.

34.

35.

Fukuoka Kinki Parkinson's Disease Study Group.
GST polymorphisms, interaction with smoking
and pesticide use, and risk for Parkinson's disease
in a Japanese population. Parkinsonism andRelated Disorders 2010; 16: 447-52.
Horiguchi H, Aoshima K, Oguma E, Sasaki S,
Miyamoto K, Hosoi Y, Katoh T, Kayama F.
Latest atatus of cadmium accumulation and its
effects on kidneys,bone,and erythropoiesis ininhabitants of the formerly cadmium-polluted
Jinzu River Basin in Toyama,Japan,after
restoration of rice paddies. Int Arch Occup
Environ Health 2010; 83(8): 953-70.
Nanri A, Mizoue T, Matsushita Y, Sasaki S, Ohta
M, Sato M, Mishima N. Serum folate andhomocysteine and depressive symptoms among
Japanese men and women. Eur J Clin Nutr 2010;
64(3): 289-96.
Miyake Y, Sasaki S, Tanaka K, Fukushima W,
Kiyohara C, Tsuboi Y, Yamada T, Oeda T, Miki T,
Kawamura N, Sakae N, Fukuyama H, Hirota Y,
Nagai M for the Fukuoka Kinki Parkinson's
Disease Study Group. Dietary fat intake and riskof Parkinson's disease: a case-control study inJapan. J Neurol Sci 2010; 288: 117-22.
Miyake Y, Sasaki S, Tanaka K, Hirota Y. Dairy
food, calcium, and vitamin D intake in pregnancy
and wheeze and eczema in infants. Eur Respir J
2010; 35(6): 1228-34.
Miyake Y, Tanaka K, Fujiwara H, Mitani Y,
Ikemi H, Sasaki S, Ohya Y, Hirota Y. Residential
proximity to main roads during pregnancy andthe risk of allergic disorders in Japanese infants:
The Osaka Maternal and Child Health Study.
Pediatr Allergy Imminol 2010; 21: 22-8.
Saito K, Yokoyama T, Miyake Y, Sasaki S,
Tanaka K, Ohya Y, Hirota Y. Maternal meat andfat consumption during pregnancy and suspected
atopic eczema in Japanese infants aged 3-4
months: The Osaka Maternal and Child HealthStudy. Pediatr Allergy Imminol 2010; 21: 38-46.

318

Department of Health Economics
and Epidemiology Research
Professor
Hideki Hashimoto, M.D.,DPH.

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 skills for evidencebased practice, and to empirically evaluate the healthcare system/policy for further improvement of thequality of health care in this country. For this purpose,
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.
A new course starting in 2009 takes up hot topics inhealth policy such as physician deficiency, andencourages students to debate strictly based on
available empirical evidences.
The Department accepted 4 doctoral student and 2
master students for the fiscal years of 2010.

Research activities
Teaching activities
Under the MPH program, the Department is
responsible for 5 courses, two on clinicalepidemiology and the other three 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. In thecollaboration with the Department of HealthManagement and Policy in 22nd Medical Research319Center in the University of Tokyo Hospital, theDepartment has also contributed to the development
and refinement of Japanese original patientclassification
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 Department has contributed to an
ongoing panel survey on socioeconomic status andhealth among elderly (Japanese Study of Ageing andRetirement; J-STAR) since 2007 and the young adults(Japanese Study of Stratification, Income, andNeighborhood; J-SHINE) since 2010, in thecollaboration with other established research
institutes.
Since health care services should be delivered
efficiently under the publicly funded health caresystem, economic evaluation of new health caretechnologies is one of the research topics in the
Department. Molecular target therapies of cancer,
which are effective but costly, attract the great concern.
Based on the modeling of therapies and efficacy data
in clinical trials, cost effectiveness of the therapies
have been evaluated. Preventive services such as
smoking cessation therapies are also important field
for economic evaluation. We also contribute for the
piggy bag style data collection for economic
evaluation in the clinical trials and epidemiologicalprospective studies. Standardized methods of datacollection for both costs and outcomes in economic
evaluations should be established through these
activities. If the result of economic evaluation would
be used as the reference for coverage decision of newtechnologies under publicly funded health care system,
acceptable thresholds of payment must be discussed.
International comparative survey was conducted to see
people’s willingness to pay for additional year of life
in perfect condition.

References
1.

2.

3.

4.

5.

6.

7.

8.

Sakamoto S, Yokoyama N, Tamori Y, Akutsu K,
Hashimoto H, Takeshita S. Patients with
peripheral artery disease who complete 12-weeksupervised exercise training program show
reduced cardiovascular mortality and morbidity.
Circ J. 2009 Jan;73(1):167-73.
Ohwaki K, Hashimoto H, Sato M, Tamiya N,
Yano E. Predictors of continuity in home care forthe elderly under public long-term care insurancein Japan. Aging Clin Exp Res. 2009 AugOct;21(4-5):323-8.
Hayashida K, Imanaka Y, Otsubo T, Kuwabara K,
Ishikawa KB, Fushimi K, Hashimoto H,
Yasunaga H, Horiguchi H, Anan M, Fujimori K,
Ikeda S, Matsuda S. Development and analysis ofa nationwide cost database of acute-care hospitals
in Japan. J Eval Clin Pract. 2009 Aug;15(4):626-33.
Nishiura C, Narai R, Ohguri T, Funahashi A,
Yarita K, Hashimoto H. The effect of smoking
prevalence at worksites on individual cessation
behavior. J Occup Health. 2009;51(1):48-56.
Igarashi A, Takuma H, Fukuda T, Tsutani K.
Cost-utility analysis of varenicline, an oral
smoking-cessation
drug,inJapan.
Pharmacoeconomics 2009; 27(3): 247-61.
Shiroiwa T, Fukuda T, Tsutani K. Costeffectiveness analysis of XELOX for metastatic
colorectal cancer based on the NO16966 andNO16967 trials. Br J Cancer 2009; 101: 12-18.
Shiroiwa T, Fukuda T, Shimozuma K, Ohashi Y,
Tsutani K. Cost-effectiveness analysis of
capecitabine compared with bolus 5-fluorouracil/l-leucovorin for the adjuvant treatment of coloncancer in Japan. Pharmacoeconomics 2009;27(7): 597-608.
Shiroiwa T, Fukuda T, Tsutani K. Health utility
scores of colorectal cancer based on societal
preference in Japan. Qual Life Res 2009; 18(8):1095-1103.

320

Department of HealthCommunication
Professor
Takahiro Kiuchi, M.D., Ph.D.

Associate Professor
Hirono Ishikawa, Ph.D.

Homepage

http://www.umin.ac.jp/hc/

Introduction and Organization
The Department of Health Communication wasestablished as a 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 members: a professor and an
associate professor.
Whereas health communication is a major disciplinein the USA and there are many such graduate
programs, our department offers one of the only two
health communication programs in Japan. However,
the importance of the health communication discipline
has gradually been recognized among the academic
society as well as among general public.

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. Introduction to Health Communication
2. Theories in Health Communication
3. Science Communication
4. Communication during Emergency and Disaster
5. Patient-provider
Communication:
Patient
Perspective
6. Communication Skills for Health Care Providers
7. Mass Media and Communication: Television
8. Internet Communication
9. Mass Media and Communication: News Paper
10. Social Marketing
11. Methodology of Health Communication Research
12. Health Communication Campaign
13. Patient-provider
Communication:
ProviderPerspective[Health Communication Practice]
1. Coaching
2. Manners in Interpersonal Relationship
3. Internet: Research, Analysis and Evaluation of
Websites
4. Internet: Website Development
5. Practice of Media Publicity
6. Evaluation of News
7. MBTI (Myers-Briggs Type Indicator)
8. Image / Film Development
We also provide lectures and practical instruction in321

medical informatics / economics as part of the PhD
program of the Faculty of Medicine.
In theundergraduate program, Professor Kiuchi presents a
lecture entitled “Medical Literature Informatics.”

Research Activities
The followings are two distinguishing characteristicsof the research conducted in our Department of HealthCommunication, as compared to the research at othermedical informatics programs in Japan:(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 the research at most medical
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 on 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) Research on Patient-Professional Relationship andCommunication

Communication between patients and health care
professionals is the foundation of effective health care.
Based on the analysis of the communication in actual
as well as simulated medical encounters, weinvestigate the relationship of patient and provider
characteristics with their communication behaviors,
and impacts of the communication on patient
outcomes. In addition, we have a seminar to introduce
the Roter Interaction Analysis System (RIAS), one of
the most widely used tools of the analysis of medical
communication,(3) Research on Health Literacy
The increase in media reports and the rapid expansionof the Internet have rendered various sources of healthinformation more available to the general public. Thus,
skills in understanding and applying information
about health issues may have a substantial impact on
health behaviors and health outcomes. These skills
have recently been conceptualized as health literacy.
We have developed a measure of health literacy
considering the social and cultural context of Japan,
and investigated its relationship with patient andprovider communication, and patient health behaviors
and outcomes.
(4) 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.
(5) 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
Consortium (CDISC). We utilized the achievements
attained by the medical research data center at the
UMIN.
(6) Research Regarding the Security of an Information

322

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.

References
1.

2.

3.

Zenitani S, Nishiuchi N, Kiuchi T.
Smartcard-based Automatic Meal Record System
Intervention Tool for Analysis Using Data Mining
Approach. Nutrition Research 30(4):261-270, 2010
Ishikawa H., Kiuchi T. Health literacy and healthcommunication. BioPsychoSocial Medicine 2010;
4:18.
Ishikawa H., Hashimoto H., Kinoshita M., Yano E.
Can nonverbal communication skills be taught?
Medical Teacher 2010; 32(19): 860-863.

School of Public Health
2. Behavioral Health Sciences

324

Department ofSocial Gerontology
Professor
Ichiro Kai, M.D., M.P.H.

Lecturer
Hajime Iwasa, Ph.D.

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, 25 visiting researchers and 7 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

325

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. Aita K, Kai I:
Physicians’ psychological barriers to different
modes of withdrawal of life support in critical care
―A qualitative study in Japan
Soc. Sci. & Med. 70(4):616-622, 2010
2. Ohta M, Kai I:
Factors affecting attitudes toward care of theelderly mothers ―Urban versus agricultural areas
Arch. Gerontol. Geriatr. 51(3):241-244, 2010
3. Chalise HN, Kai I, Saito T:
Social support and its correlation with loneliness―A cross-cultural study in Nepalese older adults
Int. J. Aging Hum. Dev. 71(2):115-138, 2010
4. Fukahori H, Yamamoto-Mitani N, Sugiyama T, et

326

al.:
Psychometric properties of the Caregiving Burden
Scale for Family Caregivers with Relatives in
Nursing Homes ―Scale development
Jpn. J. Nurs. Sci. 7(2):136-147, 2010
5. Sasaki Y, Ali M, Kakimoto K, et al.:Predictors of exclusive breast-feeding in early
infancy ―A survey report from Phnom Penh,
Cambodia
J. Pediatr. Nurs. 25(6):463-469, 2010
6. Sasaki Y, Ali M, Sathiarany V, et al.:Prevalence and barriers to HIV testing among
mothers at a tertiary care hospital in Phnom Penh,
Cambodia
BMC Public Health 10:494 (7 pages), 2010
7. Kim H, Traphagan JW:
Irony and the sociocultural construction of old age
in South Korea ―Perspectives from government,
the medical profession, and the aged
Care Manag. J. 11(3): 183-191, 2010
8. Gautam R, Saito T, Houde SC, et al.:Social interactions and depressive symptoms
among community dwelling older adults in Nepal―A synergic effect model
Arch. Gerontol. Geriatr. 53:24-30, 2011 (available
online)9. Ledesma D, Takahashi M, Kai I:
Interest in a group psychotherapy program among
Philippine breast cancer patients and its associatedfactors
Psycho-Oncology DOI:10.1002/pon.1804 (available
online)10. Sasaki Y, Arifin A, Ali M, et al.:Willingness to undergo HIV testing among factory
workers in Surabaya, Indonesia
AIDS Care (available online)
11. Aita K:
New organ transplant policies in Japan, including
the family-oriented priority donation clauseTransplantation 91:489-491, 2011
12. Takahashi M:
Health promotion for cancer survivors ―New
paradigm beyond prevention and treatment
in Muto T, Nakahara T and Eun WN (Eds.):“Asian Perspectives and Evidence on Health
Promotion and Education”, Springer, 2010
(pp.78-86)

School of Public Health
3. Health Services Sciences

328

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Homepage:

http://home.cie.m.u-tokyo.ac.jp:8080/Plone

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.

329

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.
At present, we are studying
differences in the computerization of publichealth in the US and Japan.

References
1. Taichi Kin, Hiroshi Oyama, Nobuhito Saito.
Operative simulation on neurosurgery by 3D
computer graphics using multi-layer fusion image.
Proc. of The 8th China-Japan Friendship
Neurosurgical Symposium. 6/18-19/2010 China
2. Kin T, Shin M, Oyama H, Kamada K, Kunimatsu
A, Momose T, Saito N. Impact of multiorgan
fusion imaging and interactive three-dimensional
visualization for intraventricular neuroendoscopic
surgery. Neurosurgery. 2011 Feb 16.

Endowed Department

331

Department ofPharmacoepidemiology
Professor
Kiyoshi Kubota, M.D., Ph.D.

Associate
Hiroshi Nishimura, M.D., Tsugumichi Sato, Ph.D.

Homepage

http://square.umin.ac.jp/pe/

Introduction and Organization
As of April 2010, the Department of Pharmacoepidemiology consists of a professor (Kiyoshi
Kubota), two associates (Takafumi Nishimura andTsugumichi Sato), 3 teaching assistants, 2 clericalassistants.
The department was established as a donateddepartment in April 1993 for a limited time of 3 years
till March 1996. The department has been extended
5 times for 3-year period in each extension and thedepartment is now in the 3rd year of the 6th period(March 2008-April 2010).
Pharmacoepidemiology is a new scientific fieldstarting in 1980s. In Japan, Japanese Society for
Pharmacoepidemiology was established led byProfessor Tadashi Kusunoki who was the firstJapanese professor of pharmacoepidemiology in thedepartment between April 1993 to March 1996.
In the second period from April 1996 to March
1999, two pilot studies of Prescription-Event
Monitoring in Japan were conducted. In the third
period from April 1999 to March 2002, the department
exerted a leadership to establish a non-profitableorganization (NPO) Drug Safety Research Unit Japan(DSRU Japan). This Unit worked as the study officefor two pilot studies on Prescription-Event Monitoring
and also for a case-control study on the association
between non-steroidal anti-inflammatory drugs andupper gastrointestinal bleeding. It also worked as thestudy office of other studies including clinical trials

led by researchers or those sponsored by a drug
company or Ministry of Health and Welfare.

Teaching activities
The department is involved in the teachingactivities inside University of Tokyo including
Graduate School of Medicine and Faculty of Medicine
and School of Public Health. The department also
played a leading role to organize a 6-month course of“pharmacoepidemiology seminar” held by Union ofJapanese Scientists and Engineers. This seminar is
to educate those in drug companies, school ofpharmacies of colleges and universities and those
involved in administration in Pharmaceuticals Medical
Devices Agency (PMDA). The first seminar washeld in 2006. In 2010, the 5th seminar is being
conducted.
Furthermore, the department has been a driving
force to make a textbook of pharmacoepidemilogy inJapanese published in 2010. The department is also
contributing to translate a textbook by Dr PatricWaller, a former regulator in the regulatory body in
the UK entitled an “An Introduction to Pharmacovigilance” which will be published sometime in2011.

Research activities
Like other epidemiological studies, pharmacoepidemiology studies are those on people and the332

study requires an organization which supports thestudy. NPO Drug Safety Research Unit establishedin 2001 has been working to support various studies
including pilot studies of Prescription-Event
Monitoring in Japan, a case-control study on theassociation between non-steroidal anti-inflammatory
drugs and upper gastrointestinal bleeding, andhandling of information on serious adverse event
experienced in the investigator-led clinical trials.
The department and NPO Drug Safety Research
Unit also studied the baseline incidence of Interstitial
Lung Diseases (ILDs) in 328 patients with malignant
mesothelioma by collaborating with doctors in 26
hospitals in the west part of Japan.
Since April 2010, the department has beenrecognized as a department to manage ‘Safety
Information Division’ of Clinical Research Support
Center of the University of Tokyo Hospital. The
Center will be developed as the center for
multi-institutional clinical trials.
The department developed a web-based systemcalled as Safety Management system for Unapproved
Drugs (SMUD) between 2005 and 2007 by the
co-operation with the University hospital Medical
Information Network (UMIN) to monitor the safety ofthalidomide imported by individual doctors under the
support of Ministry of Health, Labour and Welfare(MHLW). From 2009, the NPO worked as thebureau for the operation of SMUD which is needed
even after the approval of thalidomide for multiple
myeloma in 2008, as thalidomide is still imported byindividual doctors because of the need to use
thalidomide in treatments of diseases other thanmultiple myeloma and other reasons.
The department has been a driving force ofanother study called as “Japan Statin Study (JSS)”, a
joint
researchbyJapanese
SocietyofPharmacoepidemiology and Japanese Society of
Hospital Pharmacisgts, using a design of a case-cohort
study and NPO Drug Safety Research Unit works as
the study office.
Another research activity in the department is theresearch of the application of data-mining
methodology to the analysis of spontaneous reports.
The
use
of
data-mining
methodology
inpharmacovigilance began in 1990 in WHO Uppsala
Monitoring Centre, Food and Drug Administration in

the US and other regulatory bodies in the Westerncountries. Recently, Japanese Ministry of Health
Labour and Welfare also decided to introduce themethod into the regulation in Japan. The research in
the department is to develop a new method to utilize
the large data of Drug Use Investigation in theevaluation of spontaneous reports using the method ofreporting odds ratio.
One of other research activities is on the use ofelectronic claims database. It is now clear thatnational claims database (NDB) in Japan is provided
for the secondary purposes including researches from
April 2011. Some relatively small data sources ofclaims data are already commercially available andthe department started to search for the effective useof Japanese claims database. The department will
start studies using NDB based on this experience.

References
1.

2.

3.

4.

Nojiri S, Gemba K, Aoe K, Kato K, Yamaguchi T,
Sato T, Kubota K, Kishimoto T. Survival andprognostic factors in malignant pleural
mesothelioma: a retrospective study of 314
patients in the west part of Japan. Jpn J Clin
Oncol 2010; doi: 10, 1093/jjco/hyq159
Ooba N, Kubota K. Selected control events andreporting odds ratio in signal detection
methodology.
Pharmacoepidemiol Drug Saf
2010; 19: 1159-1165..
Ando K, Ohtsu H, Arakawa Y, Kubota K,
Yamaguchi T, Nagase M, Yamada A, Fujita T.
Rationale and design of the Eplerenone
combination Versus conventional Agents to Lower
blood pressure on Urinary Antialbuminuric
Treatment Effect (EVALUATE) trial: a doubleblinded randomized placebo-controlled trial toevaluate the antialbuminuric effects of analdosterone blocker in hypertensive patients with
albuminuria. Hypertension Res 2010; 33: 616-621.
Ooba N, Sato T, Watanabe H, Kubota K:
Resolving a Double Standard for Risk
Management of Thalidomide: An Evaluation of
Two Different Risk Management Programmes inJapan. Drug Saf 2010 ; 33(1):35-4

333

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 joined
us as an another affiliated Department. 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.

334

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
and icariin exert the biological activity through its
non-genomic action on androgen receptors. Recently,
we have demonstrated that cinnamaldehyde, a major
constituent of cinnamon selectively stimulates
progesterone secretion in human adrenal cells. Ourstudies are focused on endocrinological actions ofanti-aging herbs which are exerted through theirgenomic or non-genomic 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 also demonstrated
that some herbs are effective against multiple sclerosis
and neuromyelitis optica in our laboratory.
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 the335characteristic systems biology. According to theguideline of the traditional herbal medicine, we haveexamined the clinical effect by systems therapy withmedicinal herbs in patients with bronchial asthma andessential hypertension. Long- term remission has beenobtained in both disorders. Extensive studies are under
way to elucidate the mechanisms by which systems
therapy exerts the therapeutic activities.

References
1. Yu, J., Akishita, M., Eto, M., Ogawa, S., Son,
Bo-Kyung, Kato, S., Ouchi, Y., Okabe, T.
Androgen receptor-dependent activation ofendothelial nitric oxide synthase in vascularendothelial cells: Role of phophatidylinositol
3-kinase/Akt pathway. Endocrinology 151:
1822-1828, 2010.
2. Koizumi, H., Yu, J., Hshimoto, R., Ouchi. Y.,
Okabe, T. Involvement of androgen receptor in
nitric oxide production by icariin in humanumbilical vein endothelial cells. Febs Lett.
584(2020):2440-2444,2010.
3. Iwaoka, Y., Hashimoto, R., Koizumi, H., Yu, J.,
Okabe, T. Selective stimulation by cinnamaldehyde of progesterone secretion in human adrenal
cells. Life Sci. 86：894-898, 2010.

336

Department of Metabolome
Professor
Ryo Taguchi, Ph.D.

Associate Professor
Yaoshiya Oda, Ph.D.

Homepage

http://metabo.umin.ac.jp /※For this department, this year’s text is the same as that published last year.

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. Adding
to them, 5 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

337

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 applied in selecting the detection methods
including choice of HP LC system with most effective
columns and that of the most suitable MS system andcollision 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 insightcan 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 canbe used as a flow system, and is easily combined withon-line separation systems such as HPLC or capillaryelectrophoresis (CE). Sensitivity of detection by ESI
essentially depends on the concentration of moleculesin the sample solution. Thus, for obtaining a highest
sensitivity, it is very important to use low elution ratewith small size of column.
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338

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) Ogiso H, Nakamura K, Yatomi Y, Shimizu T,
Taguchi R.
Liquid chromatography/mass
spectrometry analysis revealing preferential
occurrenceof
non-arachidonate-containing
phosphatidylinositol bisphosphate species innuclei and changes in their levels during cell
cycle. Rapid Commun Mass Spectrom. 2010
Feb;24(4):436-42.
(2) Seki H, Fukunaga K, Arita M, Arai H, Nakanishi
H, Taguchi R, Miyasho T, Takamiya R, Asano K,Ishizaka A, Takeda J, Levy BD.
The
anti-inflammatory and proresolving mediator
resolvin E1 protects mice from bacterial
pneumonia and acute lung injury. J Immunol.
2010 Jan 15;184(2):836-43(3) Nakanishi H, Iida Y, Shimizu T, Taguchi R.
Separation and quantification of sn-1 and sn-2
fatty acid positional isomers in phosphatidylcholine by RPLC-ESIMS/MS. J Biochem. 2010
Feb;147(2):245-56.
(4) Fujita M, Maeda Y, Ra M, Yamaguchi Y, Taguchi
R, Kinoshita T. GPI glycan remodeling by
PGAP5 regulates transport of GPI-anchoredproteins from the ER to the Golgi. Cell. 2009
Oct 16;139(2):352-65.
(5) Endo J, Sano M, Katayama T, Hishiki T,
Shinmura K, Morizane S, Matsuhashi T,
Katsumata Y, Zhang Y, Ito H, Nagahata Y,
Marchitti S, Nishimaki K, Wolf AM, Nakanishi H,
Hattori F, Vasiliou V, Adachi T, Ohsawa I,
Taguchi R, Hirabayashi Y, Ohta S, Suematsu M,
Ogawa S, Fukuda K. Metabolic remodeling
induced by mitochondrial aldehyde stressstimulates tolerance to oxidative stress in theheart. Circ Res. 2009 Nov 20;105(11):1118-27.
(6) Kanzawa N, Maeda Y, Ogiso H, Murakami Y,
Taguchi R, Kinoshita T. Peroxisome dependency of alkyl-containing GPI-anchor biosynthesisin the endoplasmic reticulum. Proc Natl Acad
Sci U S A. 2009 Oct 20;106(42):17711-6.
(7) Ishiyama J, Taguchi R, Yamamoto A, Murakami
K. Palmitic acid enhances lectin-like oxidized
LDL receptor (LOX-1) expression and promotes
uptake of oxidized LDL in macrophage cells.
Atherosclerosis. 2010 Mar;209(1):118-24.
(8) Nakanishi H, Ogiso H, Taguchi R. Qualitativeand quantitative analyses of phospholipids by
LC-MS for lipidomics. Methods Mol Biol.
2009;579:287-313(9) Iwashita M, Makide K, Nonomura T, Misumi Y,
Otani Y, Ishida M, Taguchi R, Tsujimoto M, Aoki
J, Arai H, Ohwada T. Synthesis and evaluationof lysophosphatidylserine analogues as inducers
of mast cell degranulation. Potent activities oflysophosphatidylthreonine and its 2-deoxy
derivative. J Med Chem. 2009 Oct 8;52(19):5837-63.
(10) Ogiso H, Taguchi R. Reversed-phase LC/MS
method for polyphosphoinositide analyses:changes in molecular species levels during
epidermal growth factor activation in A431 cells.
Anal Chem. 2008 Dec 1;80(23):9226-32.

339(11) Chisada S, Yoshimura Y, Sakaguchi K, Uemura S,
Go S, Ikeda K, Uchima H, Matsunaga N, Ogura
K, Tai T, Okino N, Taguchi R, Inokuchi J, Ito
M.
Zebrafishandmousealpha2,3sialyltransferases responsible for synthesizing
GM4 ganglioside. J Biol Chem. 2009 Oct 30;
284(44):30534-46.
(12) Yamazaki D, Komazaki S, Nakanishi H, Mishima
A, Nishi M, Yazawa M, Yamazaki T, Taguchi R,
Takeshima H. Essential role of the TRIC-B
channel in Ca2+ handling of alveolar epithelial
cells and in perinatal lung maturation.
Development. 2009 Jul;136(14):2355-61.
(13) Ikeda K, Oike Y, Shimizu T, Taguchi R. Global
analysis of triacylglycerols including oxidized
molecular species by reverse-phase highresolution
LC/ESI-QTOF
MS/MS.
J
Chromatogr B Analyt Technol Biomed Life Sci.
2009 Sep 1;877(25):2639-47.
(14) Tokudome S, Sano M, Shinmura K, Matsuhashi T,
Morizane S, Moriyama H, Tamaki K, Hayashida
K, Nakanishi H, Yoshikawa N, Shimizu N, Endo
J, Katayama T, Murata M, Yuasa S, Kaneda R,
Tomita K, Eguchi N, Urade Y, Asano K,
Utsunomiya Y, Suzuki T, Taguchi R, Tanaka H,
Fukuda K.
Glucocorticoid protects rodent
hearts from ischemia/reperfusion injury byactivating lipocalin-type prostaglandin D
synthase-derived PGD2 biosynthesis. J Clin
Invest. 2009 Jun;119(6):1477-88.
(15) Hirano T, Kishi M, Sugimoto H, Taguchi R,
Obinata H, Ohshima N, Tatei K, Izumi T.
Thioesterase activity and subcellular localizationof acylprotein thioesterase 1/lysophospholipase 1.
Biochim Biophys Acta. 2009 Aug;1791(8):797-805.
(16) Sugiura Y, Konishi Y, Zaima N, Kajihara S,
Nakanishi
H,
TaguchiR,
Setou
M.
Visualization of the cell-selective distribution of
PUFA-containing phosphatidylcholines in mousebrain by imaging mass spectrometry. J Lipid
Res. 2009 Sep;50(9):1776-88.
(17) Endo T, Kano K, Motoki R, Hama K, Okudaira S,
Ishida M, Ogiso H, Tanaka M, Matsuki N,
Taguchi R, Kanai M, Shibasaki M, Arai H, Aoki J.
Lysophosphatidylmethanol
isapanlysophosphatidic acid receptor agonist and is

produced by autotaxin in blood. J Biochem.
2009 Aug;146(2):283-93.
(18) Yanagida K, Masago K, Nakanishi H, Kihara Y,
Hamano F, Tajima Y, Taguchi R, Shimizu T, Ishii
S. Identification and characterization of a novel
lysophosphatidic acid receptor, p2y5/LPA6.
J Biol Chem. 2009 Jun 26;284(26):17731-41.
(19) 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 Chromatogr B Analyt Technol Biomed Life Sci.
2009 May 1;877(13):1366-74.

340

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 (currently MSD K.K). Our
department took over and enhanced the function andinfrastructures of the Clinical Epidemiology Divisionin Clinical Bio-Informatics Research Unit (CBI)
which had been lead by Professor Ryozo Nagai at the
Department of Cardiovascular Medicine, because theunit had been terminated its five-year programsupported by the Japan Science and Technology
Agency in 2007 as scheduled.
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
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
Department of Planning, Information and Management, the University Hospital Medical Information
Network (UMIN) Center, the Departments of
Epidemiology and Biostatistics, and the Departmentof Pharmacoepidemiology.
Also, professor Yamazaki is a member of ethics
committee in graduate school of medicine and facultyof medicine, the University of Tokyo, and associate
professor Koide is an assistant manager of personal
information that makes any data of studies regarding
human genome or gene anonymous. In the fiscal yearof 2010, we received 50 requests and made 2810
samples anonymous.
In addition, our department has been incollaboration with many institutions within andoutside the university, since the times of the CBI.

Teaching activities
As“IntroductionofClinicalMedicine”

by

341

Department of Clinical and Genetic Informatics andrelated departments, professor Yamazaki and associate
professor Koide gave lectures at the Large Conference
Hall of our Inpatients' Ward A on April 9, and on 23 in2010 respectively.
Also, the basic lectures of Medical Writing took
place at the auditorium in Pharmaceutical Sciences
Research Building as an intensive course on
September 2-3 in 2010, hosted by the non-profit
organization of Japan Medical and Scientific
Communicators Association, and supported by thethree departments of Clinical Epidemiology and
Systems, Clinical Trial Data Management, andUbiquitous Preventive Medicine.
In addition, a lecture for “Current States and Issuesof Large Clinical Trials” was held at Yokohama City
University Graduate School of Medicine on January
26 in 2010. Also, a special lecture for “ClinicalPharmacology and Bioinformatics” was given to thefourth-grade students at Hamamatsu Medical
University on February 2 in 2010.

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 our own
computer servers and Japan Clinical Research Assist
Center (JCRAC).
In particular, our department was in charge of thesecretariat for Japanese Coronary Artery Disease(JCAD) study which was comparison ofcardiovascular events between enhanced and normal
therapy for hypertension/hyperlipemia patients withcoronary narrowing, then improved the quality oftrials without any difficulties. Furthermore, we takes
the role of data management including training CRC
in EMPATHY study and J-ART study, and both ofthem are randomized controlled trials
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 member of the quality improvement andassessment committee and chairs of the clinicalpathway committee and the committee for quality careat our university hospital, associate professor Koide
contributes to develop clinical pathways for clinicalprofessionals and patients and hold a large conferenceof clinical pathway, and to assess our quality care byourselves, etc..
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. Suzuki S, Yamashita T, Otsuka T, Sagara K,
Uejima T, Oikawa Y, Yajima J, Koike A,
Nagashima K, Kirigaya H, Ogasawara K, Sawada
H, Yamazaki T, Aizawa T. Body Size and Atrial
Fibrillation in Japanese Outpatients. Circ J.
2010: 74(1); 66-70
2. Aizawa Y, Kohsaka S, Suzuki S, Atarashi H,
Kamakura S, Sakurai M, Nakaya H, Fukatani M,
Mitamura H, Yamazaki T, Yamashita T, Ogawa S,
J-RHYTHM Investigators. Comparison of
Antiarrhythmics Used in Patients with Paroxysmal
Atrial Fibrillation: Sub-analysis of J-RHYTHM
study. Circ J. 2010: 74(1); 71-76
3. Teramoto T, Shimada K, Uchiyama S, Sugawara
M, Goto Y, Yamada N, Oikawa S, Ando K,
Ishizuka N, Yamazaki T, Yokoyama K, Murata
M,and Ikeda Y. Rationale,design,and baseline dataof the Japanese Primary Prevention Project(JPPP)-A randomized, open-label, controlled trialof aspirin versus no aspirin in patients with

342

4.

5.

6.

7.

8.

9.

multiple risk factors for vascular events. American
Heart J. 2010: 159(3); 361-369
Kohro T, Hayashi D, Yamazaki T, Nagai R, The
JCAD Investigators. Beta-Bloker Prescription
Among Japanese Cardiologists and Its Effects on
Various Outcomes. Circ J. 2010: 74(5); 962-969
Horinaka S, Yabe A, Yagi H, Ishimitsu T,
Yamazaki T, Suzuki S, Kohro T, Nagai R, for the
JCAD Study Investigators. Effect of Nicorandil on
Cardiovascular Events in Patients With Coronary
Artery Disease in The Japanese Coronary Artery
Disease (JCAD) Study. Circ J. 2010: 74(5);503-509
Kohro T, Fujita M, Sasayama S, Mitani S,
Yamazaki T, Hayashi D, Okada Y, Nagai R, for the
JCAD Study Investigators. Prognostic Effects ofCombined Treatment With Calcium Channel
Blockers and Statins in Patients With Coronary
Narrowing From the Japanese Coronary Artery
Disease Study. International Heart Journal. 2010:
51(5): 299-302
Yamashita T, Inoue H, Okumura K, Kodama I,
Aizawa Y, Atarashi H, Ohe T, Ohtsu H, Kato T,
Kamakura S, Kumagai K, Kurachi Y, Koretsune Y,
Saikawa T, Sakurai M, Sato T, Sugi K, Nakaya H,
Hirai M, Hirayama A, Fukatani M, Mitamura H,
Yamazaki T, Watanabe E, and Ogawa S, on behalfofthe
J-RHYTHMⅡ
Investigators.
Randomaized trial of angiotensin Ⅱ -receptor
blocker vs. dihydropiridine calcium channel
bloker in the treatment of paroxysmal atrial
fibrillation with hypertension (J-RHYTHM Ⅱ
Study). Europace Advance Access publishedDec.10,2010.
Fujita M, Sasayama S, Terasaki F, Mitani S,
Morimoto T, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R, The JCAD Study Investigators.
Treatment effects of rennin-angiotensin system
inhibitor and calcium channel blocker in patientswith coronary artery narrowing (from the JapaneseCoronary Artery Disease Study). Heart and Vessels.
2010: 25(6); 453-59
Yamamoto K, Ozaki H, Takayasu K, Akehi N,
Fukui S, Sakai A, Kodama M, Shimonagata T,
Kobayashi K, Ota M, Horiguchi Y, Ebisuno S,
Yamazaki T, Ohtsu H, Hori M, The Effect ofLasartan and Amlodipine on left Ventricular

Diastolic Functionand Atherosclerosis in JapanesePatients With Mild-to-Moderate Hypertension
J-ELAN study. Hypertension Research. 2010:34(3); 325-330.

343

Department of Ubiquitous
Preventive Medicine
Associate Professor
Toru Suzuki, M.D., Ph.D.

Research 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. In August, 2010 (Heisei 22), our new missionof 5 years has started under the contribution ofShionogi & Co., Ltd.
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

344

the development of diagnostic biomarkers anddiagnostic/therapeutic systems. A typical example ismetabolic 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) from 2007 to 2009 under the
Ministry of Economy, Trade and Industry (METI) and
Academic-Industrial 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.

students and post-doctoral fellows in the affiliate
Department of Cardiovascular Medicine.

References
Academic Papers in English
1.

2.

3.

4.

5.

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

6.

Trimarchi S, Sangiorgi G, Sang X, Rampoldi V,
Suzuki T, Eagle KA, Elefteriades JA. In search ofblood tests for thoracic aortic diseases. Ann
Thorac Surg. 2010; 90(5): 1735-1742.
Suzuki T, Distante A, Eagle KA. Biomarkerassisted diagnosis of acute aortic dissection; how
far we have come and what to expect. Curr Opin
Cardiol. 2010; 25(6): 541-545.
Trimarchi S, Eagle KA, Nienaber CA, Pyeritz RE,
Jonker FH, Suzuki T, O'Gara PT, Hutchinson SJ,
Rampoldi V, Grassi V, Bossone E, Muhs BE,
Evangelista A, Tsai TT, Froehlich JB, Cooper JV,
Montgomery D, Meinhardt G, Myrmel T,
Upchurch GR, Sundt TM, Isselbacher EM; onbehalf of the International Registry of Acute
Aortic
Dissection(IRAD)
Investigators.
Importance of refractory pain and hypertension inacute type B aortic dissection: insights from theinternational registry of acute aortic dissection(IRAD). Circulation. 2010; 122(13): 1283-1289.
Zhan H, Suzuki T, Aizawa K, Miyagawa K,
Nagai R. Ataxia telangiectasia mutated (ATM)mediated DNA damage response in oxidative
stress-induced
vascularendothelial
cellsenescence. J Biol Chem. 2010; 285(38): 2966229670.
Tochio N, Umehara T, Munemasa Y, Suzuki T,
Sato S, Tsuda K, Koshiba S, Kigawa T, Nagai R,
Yokoyama S. Solution structure of histone
chaperone ANP32B: Interaction with core
histones H3-H4 through its acidic concave
domain. J Mol Biol. 2010; 401(1): 97-114.
Suzuki T, Distante A, Zizza A, Trimarchi S,
Villani M, Antonio J, Salerno Uriarte JA, de Luca
Tupputi Schinosa L, Renzulli A, Sabino F,
Nowak R, Birkhahn R, Hollander J, Counselman
F, Vijayendran R, Bossone E, Eagle K. Response
to letter regarding article, “Diagnosis of acuteaortic dissection by D-dimer; the IRAD-Bioexperience”. Circulation. 2010; 121(4): e24.

345

Academic Papers in Japanese
1.

2.

3.

4.

Suzuki T, Nagai R: Biomarker. The Japanise
Journal of Clinical and Experimental Medicine
2010; 87(11): 1556-1559.
Matsumura T, Suzuki T, Aizawa K, Sawaki D,
Munemasa Y, Ishida J, Nagai R: Proteomic
identification of a new mechanism of TGF-beta.
Proceedings of the Cell Science Research
Foundation 2010; 21: 11-22.
Sawaki D, Suzuki T: TGF-beta as a biomarker.
Journal of Clinical and Experimental Medicine
2010; 234(10): 993-998.
Suzuki T, Sawaki D, Nagai R: Progress of thediagnosis; Biomarker. The Journal of theJapanese Society of Internal Medicine 2010;
99(2): 269-274.

International Conferences
1.

2.

3.

4.

5.

Ishida J, Suzuki T, Aizawa K, Sawaki D,
Matsumura T, Friedman SL, Nagai R: Krüppel
-like factor 6 (KLF6) is involved in adiposity.
2010 FASEB Summer Research Conferences(August 8-13, 2010, Steamboat Springs, CO,USA)
Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Munemasa Y, Ishida J, Friedman SL, Nagai R:
Krüppel -like Factor 6 modulates initiation ofcardiac fibrosis. 2010 FASEB Summer Research
Conferences (August 8-13, 2010, Steamboat
Springs, CO, USA)
Aizawa K, Suzuki T, Matsumura T, Sawaki D,
Ishida J, Nagai R: Identification of a new
regulatory pathway of pathologic vascular injury
as mediated by KLF5 by proteome analysis. 2010
FASEB Summer Research Conferences (August
8-13, 2010, Steamboat Springs, CO, USA)
Suzuki T: Epigenetic regulation of chromatintranscription – KLFs as a model system. 2010
FASEB Summer Research Conferences (August
8-13, 2010, Steamboat Springs, CO, USA)
Aizawa K, Suzuki T, Zhan H, Matsumura T,
Sawaki D, Ishida J, Miyagawa K, Nagai R:
Ataxia telangiectasia mutated mediates oxidative
stress-induced premature cell senescence invascular endothelial cells. 16th International
vascular Biology Meeting (June 20-24, 2010, Los

6.

7.

Angeles, CA, USA)
Suzuki T: Proteomic analysis of the vasculature.
16th International vascular Biology Meeting(June 20-24, 2010, Los Angeles, CA, USA)
Fattori R, Isselbacher EM, Nienaber CA,
Froehlich JB, Evangelista A, Januzzi JL, Strauss
C, Jondeau G, Cooper JV, Montgomery DG,
Woznicki EM, Bartnes K, Suzuki T, Braverman
AC, Eagle KA, on behalf of the International
Registry of Acute Aortic Dissection (IRAD)
investigators: Characteristics of aortic dissection
in patients with bicuspid aortic valve: insightsfrom the International Registry of Acute Aortic
Dissection (IRAD). The American College of
Cardiology 59th Annual Scientific Session(March 14-16, 2010, Atlanta, GA, USA)

National Conferences
1.

2.

3.

4.

5.

Suzuki T: Epigenetic regulation of disease
biology – focus on the role of ATM and the
DNA-damage response in the cardiovasculature.
The 33nd Annual Meeting of Molecular Biology
Society of Japan The 83rd Annual Meeting of theJapanese Biochemical Society. Interface between
nuclear dynamics and diseases (December 7-10,
2010, Kobe, Japan)
Aizawa K, Suzuki T, Nagai R, Yamazaki T:
Association between masked hypertension
detected through automatic home blood pressure
measurement and metabolic syndrome. The 58th
Annual Scientific Session of the JapaneseCollege of Cardiology (September 17-19, 2010,
Tokyo, Japan)
Aizawa K, Suzuki T, Nagai R: Proteomic
identification of a novel signaling pathway in the
cardiovascular pathologies The 58th Annual
Scientific Session of the Japanese College of
Cardiology (September 17-19, 2010, Tokyo,
Japan)
Fujimoto H, Suzuki T, Aizawa K, Sawaki D,
Matsumura T, Ishida J, Nagai R: Alternate formsof B-type natriuretic peptide is a new biomarker
of ischemic heart disease. The 35th Annual
Meeting of the Japanese Society for Biomedical
Mass Spectrometry (September 9-10,2010,
Nagoya, Japan)
Aizawa K, Suzuki T, Kohro T, Ohike Y, Seto M,

346

6.

7.

Suzuki K, Nagai R, Yamazaki T: Association ofmasked hypertension and metabolic syndrome
detected through automatic home blood pressure
measurement: form evidence-based healthscreening. The 74th Annual Scientific Meeting of
the Japanese Circulation Society (March 5-7,
2010, Kyoto, Japan)
Aizawa K, Suzuki T, Zhan H, Matsumura T,
Sawaki D, Ishida J, Miyagawa K, Nagai R:
Oxidative
stress-inducedprematurecellsenescence is mediated by ataxia telangiectasia
mutated in vascular endothelial cells. The 74th
Annual Scientific Meeting of the Japanese
Circulation Society (March 5-7, 2010, Kyoto,
Japan)
Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Munemasa Y, Ishida J, Friedman SL, Nagai R:
Krüppel-like factor 6 mediates angiotensin II and
TGF-beta signaling in cardiovascular pathologies.
The 74th Annual Scientific Meeting of theJapanese Circulation Society (March 5-7, 2010,
Kyoto, Japan)

347

Department of Molecular Research
for Vascular Diseases
Associate Professor
Daisuke Nagata, M.D, Ph.D.

Associate
Kimie Tanaka, M.D, Ph.D.
※For this department, this year’s text is the same as that published last year.

Introduction and Organization

Research activities

In late years, westernization of the life style and agingof the population advance in our country, and increaseof the cardiovascular disease due to arteriosclerotic
vascular change which is evoked by metabolic
syndrome. Because its onset has been younger and isaccompanied with the aggravation, the medical cost of
cardiovascular disease traces the course of increase.
It is the time point when the prescription for effective
health resource redistribution is needed. The early
detection and development of appropriate treatment
for cardiovascular diseases are very urgent issues.
This department was established in April 2008 forinvestigating the pathogenetic mechanism of vasculardiseases associated with the metabolic diseases,
supported by the division of cardiovascular medicine.
Our main objective is to develop the fundamentals forfinding the best method to protect vascular diseases.

Our research field covers the molecular biology andphysiology of the vascular system. We focus on themolecular mechanisms of the onset of atherosclerosis,
especially endothelial dysfunction and inflammation
due to metabolic disorders.
In order that blood vessels exposed to physical stresssuch as blood pressure or shear stress and various
bioactive substances can maintain homeostasis, it isnecessary to reduce the stresses, and in such a case thevascular endothelium needs to act against arterialsclerosis. In addition, it is known that control ofgrowth and apoptosis in the neointima of the vascularsmooth muscles is important for the development ofan arterial sclerosis lesion.
On the other hand, the recent progress of adiposcience
concerning the metabolic syndrome revealed the
cardiovascular protective function of so-called‘beneficial’ adipocytokine. A part of action
mechanisms of adiponectin, representative of
adipocytokines, is recognized to be caused by
AMP-activated protein kinase (AMPK) and a part ofits molecular mechanisms has been clarified. It wasalso reported that some diabetes remedies such as
metformin or thiazolidine derivate have action toactivate AMPK, suggesting a possibility that AMPK
becomes the therapeutic target of a metabolic
abnormality.
It is certain that AMPK is a kinase highly conserved
from yeast to human, and performs an important
action for organism when the stress is applied.

Teaching activities
As for under-graduate education, our department takes
a part in systemic lectures for bed-side learning for the
5th year medical students, and clinical lectures for the
6th year medical students.
Each student can learn how to make a medical
interview, check physical findings and make the actual
plans for the diagnosis and treatment.
As for the post-graduate education, we have
responsibility for some lectures concerning tohypertension and atherosclerosis.

348

Hereafter, it is necessary to clarify the tissue-specificand stress-specific activation mechanism. Currently
there are many unclarified facts, for example, why theaction is different in cell-specific manner, as shown in
the fact that AMPK acts for activation of PI3K-Akt inthe vascular endothelial cells, whereas in other cells,
the actions of AMPK and Akt are antagonistic to eachother in many cases.

References
1. Takaoka M, Nagata D, Kihara S, Shimomura I,
Kimura Y, Tabata Y, Saito Y, Nagai R, Sata M.
Periadventitial adipose tissue plays a critical rolein vascular remodeling. Circulation research.
2009;105:906-911.
2. Nagata D, Kiyosue A, Takahashi M, Satonaka H,
Tanaka K, Sata M, Nagano T, Nagai R, Hirata Y. A
new constitutively active mutant of AMP-activatedprotein kinase inhibits anoxia-induced apoptosis ofvascular endothelial cell. Hypertens Res. 2009;
32:133-139.
3. Kimura T, Usui T, Inamoto S, Minamiguchi S,
Okuno H, Sasano H, Hagiwara H, Nagata D,
Tagami T, Naruse M, Shimatsu A. Image inendocrinology.
Pheochromocytoma
withsubclinical Cushing's syndrome caused bycorticomedullary mixed tumor of the adrenal gland.
The Journal of clinical endocrinology andmetabolism. 2009;94:746-747.
4. Kaifu K, Kiyomoto H, Hitomi H, Matsubara K,
Hara T, Moriwaki K, Ihara G, Fujita Y, Sugasawa
N, Nagata D, Nishiyama A, Kohno M. Insulin
attenuates apoptosis induced by high glucose via
the PI3-kinase/Akt pathway in rat peritoneal
mesothelial cells. Nephrol Dial Transplant. 2009;24:809-815.
5. Tanaka K, Sata M. Role of vascular progenitor
cells in cardiovascular disease. Current
pharmaceutical design. 2009;15:2760-2768.

349

Department of Advanced Skin Care(Miss Paris)
Visiting Professor
Junko Sugama, R.N., Ph.D.

Project Research Associate
Takeo Minematsu, Ph.D.

Homepage

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

Introduction and Organization
The Department of Advanced Skin Care (Miss Paris)
was established in Graduate School of Medicine in
April 2008. Current members include 1 visiting
professor and 1 project research associate. The
supportive departments are the Department ofGerontological Nursing/Wound Care Management andthe Department of Life Support Technology (Molten).
Skin is a largest organ in the body with which theentire surface of the body is covered. Since skinfunctions as the front of body defense, a healthy skinis a base of the healthy life. Additionally, appearanceof skin influences patients’ mental health through theirself images. With a rapid extension of the average life
expectancy and an increase of lifestyle diseases(diabetes mellitus, obesity, metabolic syndrome etc.),
many health related problems have occurred in Japan.
Especially at the skin, which is always exposed to theexternal stimulations, the interaction of the external
and inner factors has expanded a variety ofdermatopathy. On such a skin, it is thought that thedisruption of skin function has potentially occurredprior to manifestation of the pathological state. We aretrying to establish “Advanced Skin Care” to detectand to recover the subclinical disruption of thesefunctions promptly in order to achieve the healthierskin as a wellness promoting science.
One of our target is to investigate moderation roleof skin. The barrier function and viscoelasticity areespecially important for skin health. The former

prevents the moisture and electrolytes leaking frominside of the body, and obstructs the penetration of theforeign irritants into the body. The latter absorbs themechanical force such as pressure, shock, and friction
in defense of the muscle and bone. The viscoelasticity
of skin is also important for smooth motion of joints.
Therefore, these skin functions are the important
target of intervention as the advanced skin care, andalso are candidates of parameter to indicate the degreeof skin health.
Practical methodology of care is our another main
objective. Recently, several noninvasive technologies,
such as thermography and ultrasonography, have been
improved to be used handily at bed side. In addition tothese technologies, we also focused on the skin color
as a candidate indicator for skin health and systemic
status.
On 17th January, 2011, the special lecture
presented by Professor Masatoshi Abe, MD, Ph.D,
Department of Dermatology, Gunma University
Graduate School of Medicine, was held. More than
150 people including graduate students, nurses,
dietitians, and estheticians, attended this special
lecture.
Professor Sugama reported the progress of ourresearch and spread the novel concept, Advanced Skin
Care, in the educational lecture at 7th Conference ofSoin Esthetic Association and in Presidential Lecture
at 20th Annual Congress of Japan Sciety of Wound,
Ostomy and Continence Management.

350

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
With the object of establishing “advanced skin care”,
we are conducting the translational research ranged
from molecular and cellular biological approaches toclinical epidemiologic approaches. Our strategy is asfollows;
1) Clarification of factors and mechanisms related tothe degree of skin health,2) Development of assessment tools and parameters
to estimate the degree of skin health,3) Development of skills and devices of “advanced
skin care” to achieve the healthier skin.
We are focusing on the changes of the skin withthe aging and lifestyle diseases, and have been making
intense studies on the following four projects since
2009.
1) Morphological and functional analysis of skin inelder patients,
2) Structural and functional alteration of themacerated skin,3) Characteristics of skin in lifestyle diseases(diabetes mellitus, obesity, metabolic syndromeetc.).
4) Development of novel technology for noninvasive
skin assessment.

References(1) Minematsu T, Huang L, Ibuki A, Nakagami G,
Akase T, Sugama J, Nagase T, Yoshimura K,
Sanada H. Altered Expression of Matrix
Metalloproteinases and Their Tissue Inhibitors inMatured Rat Adipocytes in Vitro. In press.
(2) Nakagami G, Minematsu T, Asada M, Nagase T,
Akase T, Huang L, Morohoshi T, Ikeda T, Ohta Y,
Sanada H. The Pseudomonas aeruginosa
quorum-sensing
signalN-(3-oxododecanoyl)homoserine lactone can accelerate wound healing

through myofibroblast differentiation in rats. FEMS
Immunol Med Microbiol. In press.
(3) Minematsu T, Yamamoto Y, Nagase T, Naito A,
Takehara K, Iizaka S, Komagata K, Huang L,
Nakagami G, Akase T, Oe M, Yoshimura K,
Ishizuka T, Sugama J, Sanada H. Aging enhances
maceration-induced ultrastructural alteration of theepidermis and impairment of skin barrier function.
J Dermatol Sci. Epub 2011 Mar 23.
(4) Akase T, Nagase T, Huang L, Ibuki A, Minematsu
T, Nakagami G, Ohta Y, Shimada T, Aburada M,
Sugama J, Sanada H. Aging-Like Skin Changes
Induced by Ultraviolet Irradiation in an Animal
Model of Metabolic Syndrome. Biol Res Nurs.
Epub 2011 Mar 28.
(5) Shigeta Y, Nakagami G, Sanada H, Konya C,
Sugama J. Factors influencing intact skin in womenwith incontinence using absorbent products: resultsof a cross-sectional, comparative study. Ostomy
Wound Manage. 2010 Dec;56(12):26-8, 30-3.
(6) Huang L, Nakagami G, Minematsu T, Kinoshita A,
Sugama J, Nakatani T, Sagara H, Sanada H.
Ulceration and Delayed Healing Following
Pressure Loading in Hyperglycemic Rats With an
Immature Dermal Collagen Fiber Network.
WOUNDS. 2010; 19(7):295-300.
(7) Ueda K, Akase T, Nakagami G, Nagase T,
Minematsu T, Huang L, Sagara H, Ohta Y, Sanada
H. A possible animal model for critical colonization.
J Wound Care. 2010 Jul;19(7):295-300.
(8) Tsuda K, Nakatani T, Sugama J, Okuwa M, Sanada
H. Influence of the timing of switching aprotein-free to a protein-containing diet on thewound healing process in a rat all-layer skin defect.
Int Wound J. 2010 Jun;7(3):135-46.
(9) Konya C, Sanada H, Sugama J, Okuwa M,
Kamatani Y, Nakagami G, Sakaki K. Skin injuriescaused by medical adhesive tape in older people
and associated factors. J Clin Nurs. 2010
May;19(9-10):1236-42.
(10) Minematsu T, Nakagami G, Sari Y, Akase T,
Sugama J, Nagase T, Sanada H. Candidate
biomarkers for deep tissue damage from molecularbiological and biochemical aspects. J Tissue
Viability. 2010 May;19(2):77-83.

351

Laboratory of Molecular
Physiology on Energy
Metabolism
Project Associate Professor
Naoya Yahagi, M.D., Ph.D.

Project Research Associate
Hironori Waki, M.D., Ph.D.

Visiting Researcher
Yoshinori Takeuchi, Ph.D.

Homepage

http://metab.umin.ne.jp/

Introduction and Organization
The Laboratory of Molecular Physiology on Energy
Metabolism was established in 2008, supported by thefunds from Sunny Health Holdings and Sunny HealthCo., Ltd., and is in close collaboration with the
Department of Metabolic Diseases. The goal of thisresearch
programistounderstandthepathophysiology of overnutrition-related diseases
including metabolic syndrome and diabetes, the basisof which is considered to be insulin resistance closely
associated with the imbalance of energy metabolism.

Teaching activities
Our department takes a part in systemic lectures forthe master students in the Medical Science Graduate
Program. In the lectures, comprehensive presentation
for the understanding of basic knowledge about
pathogenesis, pathology, diagnosis and treatment ofdiabetes and metabolic diseases is performed.

Research activities
We focus on the molecular mechanisms of insulin
resistance, especially from the standpoint of lipid

metabolism.
For the better understanding of the basic
pathogenesis of overnutrition and insulin resistance,
we are proposing a new concept of “adipose
capacity”; insulin resistance can be considered as aphysiological response against the overload ofnutrients beyond the “adipose capacity”. To clarify themolecular basis of this concept is one of our major
goals.
The specific themes we are currently studying are
as follows:
1) The elucidation of mechanisms of negative
feedback regulation to understand the molecularbasis of “adipose capacity”, especially from theviewpoint of the involvement of tumor suppressors
such as p53.
2) The establishment of in vivo Ad-luc promoter
analyses utilizing in vivo imaging system (IVIS).
3) The development of TFEL (transcription factor
expression library) to entirely elucidate thetranscriptional regulatory network of nutrient
metabolism.
4) cis-to-trans (C2T) analyses of the transcriptional
network based on TFEL.
5) The importance of the quality of fat besides the352quantity.
6) The new approach from chemical biology to themolecular physiology on energy metabolism.
7) The involvement of epigenetic regulation in thecontrol of differentiation and energy metabolism of
adipocytes by using Formaldehyde-Assisted
Isolation of Regulatory Elements coupled with highthroughput sequencing (FAIRE-seq) that detects
regulatory elements in the genome.
8) The role of autonomic nerve system in theregulatory mechanisms of adipo-hepatic balancing.

References
1.

2.

3.

4.

Takeuchi Y, Yahagi N, Izumida Y, Nishi M,
Kubota M, Teraoka Y, Yamamoto T, Matsuzaka T,
Nakagawa Y, Sekiya M, Iizuka Y, Ohashi K,
Osuga JI, Gotoda T, Ishibashi S, Itaka K, Kataoka
K, Nagai R, Yamada N, Kadowaki T, Shimano H.
Polyunsaturated fatty acids selectively suppress
sterol regulatory element-binding protein-1
through proteolytic processing and autoloop
regulatory circuit. J Biol Chem 2010;
285:11681-11691.
Park, K. W., Waki, H., Choi, S. P., Park, K. M.
and Tontonoz, P. The small molecule phenamil isa modulator of adipocyte differentiation and
PPARgamma expression. J Lipid Res 2010; 51:
2775-2784.
Iwabu, M., Yamauchi, T., Okada-Iwabu, M., Sato,K., Nakagawa, T., Funata, M., Yamaguchi, M.,
Namiki, S., Nakayama, R., Tabata, M., Ogata, H.,
Kubota, N., Takamoto, I., Hayashi, Y. K.,
Yamauchi, N., Waki, H., Fukayama, M., Nishino,I., Tokuyama, K., Ueki, K., Oike, Y., Ishii, S.,
Hirose, K., Shimizu, T., Touhara, K. andKadowaki, T. Adiponectin and AdipoR1 regulate
PGC-1alpha and mitochondria by Ca(2+) and
AMPK/SIRT1. Nature 2010; 464: 1313-1319.
Ohta K, Sekiya M, Uozaki H, Igarashi M, Takase
S, Kumagai M, Takanashi M, Takeuchi Y,
Izumida Y, Kubota M, Nishi M, Okazaki H,
Iizuka Y, Yahagi N, Yagyu H, Fukayama M,
Kadowaki T, Ohashi K, Ishibashi S, Osuga J.
Abrogation of neutral cholesterol ester hydrolytic
activity causes adrenal enlargement. Biochem
Biophys Res Commun 2011; 404:254-60.

353

Department of Chronic Kidney
Disease (CKD)
Associate Professor
Miki Nagase, M.D., Ph.D.

Associate
Shigetaka Yoshida, M.D., Ph.D.

Homepage

http://plaza.umin.ac.jp/~kid-endo/07-lab/18-nagaselab/nagaselabtop.html

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.

354(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) Generation of cell type-specific (ex. podocytespecific) 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. Nagase

M.

Activation

of

the

aldosterone/mineralocorticoid receptor system in chronic kidneydisease and metabolic syndrome. Clin Exp Nephrol.
2010 Aug;14(4):303-14.
2. Ando K, Ohtsu H, Arakawa Y, Kubota K,
Yamaguchi T, Nagase M, Yamada A, Fujita T;
Eplerenone combination Versus conventional Agentsto Lower blood pressure on Urinary Antialbuminuric
Treatment Effect Study Investigators. Rationale anddesign of the Eplerenone combination Versus
conventional Agents to Lower blood pressure on
Urinary

Antialbuminuric

Treatment

Effect(EVALUATE) trial: a double-blinded randomized
placebo-controlled

trial

to

evaluatetheantialbuminuric effects of an aldosterone blocker inhypertensive patients with albuminuria. Hypertens

Res. 2010 Jun;33(6):616-21.

355

Department of Molecular Structure
and Dynamics
Project Professor
Nobutaka Hirokawa, M. D.

Project Associate
Tadayuki Ogawa, Ph. D.

Homepage

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

Teaching activities
We are involved in teaching medical students andMaster course and Ph.D course students in thefollowing lectures and laboratory courses together
with the Department of Cell Biology and Anatomy.
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.
Especially we devote ourselves for the teaching of the
cutting edge approaches of new light microscopy suchas the Photoactivated Localization Microscopy(PALM), cryo-electron microscopy and X-ray
crystallography.

Research activities
Our laboratory studies molecular motors and rail

microtubules and the mechanisms of intracellulartransport. To study these molecular mechanisms we
use new molecular cell biological approaches
including cutting edge light microscopies, cryoelectron microscopy of molecular resolution, X-ray
crystallography, biophysics, molecular biology andmolecular genetics. We aim to study the structure anddynamics of the molecular motors in vitro and in vivo
at the highest special and temporal resolution and onthese bases try to elucidate functions of molecularmotors in vivo combining molecular genetics.

References
1.

2.

3.

Hirokawa, N., S. Niwa and Y. Tanaka. Molecularmotors in neurons: Transport mechanisms androles in brain function, development and disease.
Neuron 18; 610-638, 2010.
Ueno, H., X. Huang, Y. Tanaka, and N. Hirokawa.
KIF16B/Rab14 molecular motor complex is
critical for early embryonic development bytransporting FGF receptor. Developmental Cell
20; 60-71, 2011
Yin, X,. Y. Takei, M. Kido and N. Hirokawa.
Molecular motor KIF17 is fundamental for
memory and learning via differential support ofsynaptic NR2A.2B levels. Neuron 70; 310-325,
2011

356

Department of Continence
Medicine
Professor
Yasuhiko Igawa, M.D.,Ph.D.

Research Associate
Naoki Aizawa, Ph.D.

Homepage

http://cont-med.umin.jp/

Introduction and Organization

Teaching activities

Our department has been established as anendowment department supported by Astellas Pharma
Inc. in close collaboration with the Department ofUrology since July 1st 2010 to facilitate researches
specially focusing on continence medicine. The aim ofour department is to contribute to the advancement ofcontinence medicine through basic and clinicalresearches on regulation mechanisms of lower urinary
tract (LUT) function and pathphysiology of LUT
dysfunction, as well as function/dysfunction of lower
bowel and pelvic floor.
We believe that a multi-disciplinary professionalteam consisted of physicians, surgeons, nurses,
physiotherapists, bio-engineers, social workers andscientists is necessary to achieve greater advancementof continence medicine and care. We hope many
researchers with different specialties are interested inour research themes and collaborate with us for the
purpose of supporting patients with continence
problems by providing them better treatment andmanagement strategies.

We take part in providing systematic urologicallectures for second year medical students, and bed
side teaching for third and fourth year medical
students.

Clinical activities
Professor Igawa offers clinical services specialized
for patients with intractable lower urinary tract
dysfunction as well as for children with urogenital
disorders in conjunction with the Department ofUrology.

Research activities
We are currently investigating regulation
mechanisms of lower urinary tract (LUT) function,and pathophysiological mechanisms of various LUT
dysfunction, including overactive bladder (OAB),
bladder outlet obstruction (BOO), interstitial cystitis/
bladder pain syndrome(IC/BPS), and underactive
bladder dysfunction, especially focusing on:
1. To elucidate bladder sensory transduction
mechanisms
2. To disclose pathophysiology of development of
detrusor overactivity/OAB
3. To find useful biomarkers for IC/BPS
4. To evaluate the effects of metabolic syndrome on
LUT function
5. To develop novel pharmacological treatment forrefractory LUT dysfunction
6. To establish continence-care system consisted ofmulti-disciplinary professionals to contribute to
the advancement of continence medicine

357

References
1.

2.

3.

4.

5.

6.

7.

8.

Aizawa N, Igawa Y, Nishizawa O, Wyndaele JJ.
Effects of nitric oxide on the primary bladderafferent activities of the rat with and without
intravesical acrolein-treatment. Eur Urol. 2011
Feb;59(2):264-71.Epub 2010 Oct 26.
Kurizaki Y, Ishizuka O, Imamura T, Ichino M,
Ogawa T, Igawa Y, Nishizawa O, Andersson KE.
Relation
betweenexpressionof
α(1)adrenoceptor mRNAs in bladder mucosa andurodynamic findings in men with lower urinary
tract symptoms. Scand J Urol Nephrol. 2011
Feb;45(1):15-9.Epub 2010 Oct 21.
Aizawa N, Igawa Y, Andersson KE, Iijima K,
Nishizawa O, Wyndaele JJ. Effects of
intravesical instillation of ATP on rat bladderprimary afferent activity and its relationship withcapsaicin-sensitivity. Neurourol Urodyn. 2011
Jan;30(1):163-8. doi:10. 1002/nau. 20940. Epub2010 Jul 21.
Igawa Y, Aizawa N, Homma Y. Beta3adrenoceptor agonists: possible role in thetreatment of overactive bladder. Korean J Urol.
2010 Dec;51(12):811-8. Epub 2010 Dec 21.
Narumi Y, Kosho T, Tsuruta G, Shiohara M,
Shimazaki E, Mori T, Shimizu A, Igawa Y,
Nishizawa S, Takagi K, Kawamura R, Wakui K,
Fukushima Y. Genital abnormalities in Pallister-Hall syndrome: Report of two patients andreview of the literature. Am J Med Genet A. 2010
Dec; 152A (12):3143-3147.
Takeda M, Homma Y, Araki I, Kakizaki H,
Yamanishi T, Yokota T, Gotoh M, Igawa Y, Seki
N, Takei M, Yoshida M, Sugaya K, Nishizawa O.
The Japanese Naftopidil Neurogenic Lower
Urinary Tract Dysfunction Study Group. BJU Int.
2011 Jul;108(1):100-107. doi: 10.1111/j.1464410X.2010.09682.x. Epub 2010 Nov 9.
Aizawa N, Iijima K, Rosenbaum JS, Downs TR,
Igawa Y, Andersson KE, Wyndaele JJ.
Comparison of the effects of oestrogen
deficiency and old age on primary bladderafferent activity and voiding behavior in theageing female rat. BJU int. 2010 in press, DOI:
10.1111/j.1464-410X.2010.09689.x.
Kosho T, Miyake N, Hatamochi A, Takahashi J,

9.

10.

11.

12.

13.

14.

15.

Kato H, Miyahara T, Igawa Y, Yasui H, Ishida T,
Ono K, Kosuda T, Inoue A, Kohyama M, Hattori
T, Ohashi H, Nishimura G, Kawamura R, Wakui
K, Fukushima Y, Matsumoto N. A new
Ehlers-Danlos syndrome with craniofacialcharacteristics, multiple congenital contractures,progressive joint and skin laxity, and multisystemfragility-related manifestations. Am J Med Genet
A. 2010 Jun :152A (6): 1333 - 46.
Aizawa N, Wyndaele JJ. Effects ofphenazopyridine on rat bladder primary afferent
activity, and comparison with lidocaine andacetaminophen. Neurourol Urodyn. 2010;29(8):1445-50.
Mimura Y, Imamura T, Kinebuchi Y, Aizawa N,
Ishizuka O, Nishizawa O. Rat Bladders
Augmented with a Novel Bovine Pericardium-Derived Biomaterial Reconstruct Functional
Tissue Structures. LUTS 2010;2:76-82
Minagawa T, Imamura T, Igawa Y, Aizawa N,
Ishizuka O, Nishizawa O. Differentiation of
Smooth Muscle Cells from Human Amniotic
Mesenchymal Cells Implanted in the Freeze-Injured Mouse Urinary Bladder. Eur Urol.
2010;58(2):299-306.
Aizawa N, Igawa Y, Nishizawa O, Wyndaele JJ.
Effects of CL316,243, a beta(3)-adrenoceptor
agonist, and intravesical prostaglandin E(2) on
the primary bladder afferent activity of the rat.
Neurourol Urodyn. 2010;29(5):771-6.
Kinebuchi Y, Aizawa N, Imamura T, Ishizuka O,
Igawa Y, Nishizawa O. Autologous Bone
Marrow-derived Mesenchymal Stem Cell
Transplantation into Injured Rat Urethral
Sphincter. Int J Urol. 2010;17(4):359-68.
Ogawa T, Homma T, Igawa Y, Seki S, Ishizuka
O, Imamura T, Akahane S, Homma Y, Nishizawa
O. CXCR3 binding chemokine and TNFSF14
over expression in bladderurothelium of patientswith ulcerative interstitial cystitis. J Urol. 2010
Mar; 183 (3):1206-12. Epub 2010 Jan 22.
Wyndaele JJ, Kovindha A, Igawa Y,
Madersbacher H, Radziszewski P, Ruffion A,
Schurch B, Castro D, Sakakibara R, Wein A; ICI
2009
Committee
10.Neurologic
fecal
incontinence. Neurourol Urodyn. 2010; 29 (1):207-12.

358

16. Wyndaele JJ, Kovindha A, Madersbacher H,
Radziszewski P, Ruffion A, Schurch B, Castro D,
Igawa Y, Sakakibara R, Wein A; Committe 10 on
Neurogenic Bladder and Bowel of theInternational Consultation on Incontinence
2008-2009. Neurologic urinary incontinence.
Neurourol Urodyn. 2010;29(1):159-64.
17. Chen Z, Ishizuka O, Imamura T, Aizawa N,
Kurizaki Y, Igawa Y, Nishizawa O, Andersson
KE. Stimulation of skin menthol receptors
stimulates detrusor activity in conscious rats.
Neurourol Urodyn. 2010;29(3):506-11.

359

Department of Medical Genomics
Professor
Hiroyuki Mano, M.D., Ph.D.

Associate Professor
Young Lim Choi, M.D., Ph.D.

Lecturer
Masahito Kawazu M.D., Ph.D.

Introduction and Organization
Cancer is the leading cause of adult deaths indeveloped countries. While the incidence of brainstroke– and heart attack–related deaths is rapidly
decreasing, that of cancer-related ones is still linearly
increasing today. More than eight millions of people
die of cancer every year worldwide, and, even only inJapan, >30,000 of people die of cancer. It is, therefore,
likely that therapeutic efficacy with current cytotoxic
drugs is coming to their limit. To overcome such
limitation, it should be desirable to develop effective
targeted therapies against causative oncogenic
molecules in each cancer.
Recently, Professor Mano and Associate
Professor Choi has developed an efficient method toconstruct retroviral cDNA expression libraries evenfrom a very small amount of clinical specimens.
Application of such technology to a lung cancer
specimen led to the discovery of a novel, fusion-type
tyrosine kinase EML4-ALK. This discovery became
the driving force to rapidly develop selective andefficient inhibitors against the catalytic activity of
ALK and to conduct clinical trials for lung cancer
patients with the inhibitors. This EML4-ALK story isclearly a “proof-of-principle” for the above hypothesis
that, to obtain a major breakthrough in cancer
treatments, we have to identify and develop drugs
against essential growth drivers in cancer.
On the other hand, rapidly emerging new

generations of nucleotide sequencing-technologies
have enabled to determine tens of gigabases ofnucleotides in a single experiment. With the advent ofsuch technologies we can now sequence an entire
human genome in a relatively short period of time.
Application of this approach to cancer specimens
makes it possible to “resequence” cancer genomes andto identify mutated genes only in cancer genomes,
which are the candidates for cancer-causing genes.
Under such circumstances, the Department ofMedical Genomics was established in September,2009 with the aim to identify essential growth drivers
in every cancer, by taking advantage of our functional
screening system coupled with the next generation
sequencing technologies. The Department of Medical
Genomics has been settled by the tight support fromthe Department of Molecular Pathology (Professor
Kohei Miyazono) and by the donation from Astellas
Pharma Inc. and Illumina, Inc. From April, 2010,
Masahito Kawazu, M.D., Ph.D. newly joined ourdepartment as a Lecturer.
The Department of Medical Genomics enjoys awide range of research collaboration with many
academic institutes within Japan and also from abroad.
Especially, the Department of Medical Genomics isunder an intimate collaboration with Division of
Functional Genomics, Institute of Molecular Medicine,
Jichi Medical University, which is chaired byProfessor Mano.

360

Teaching activities
We jointly take the responsibility for the lectures of“General Pathology” for the undergraduate students of
the School of Medicine. Additionally, Professor Mano
has conducted a number of seminars worldwide topropose the significant importance in cancer
genomics.

Research activities
The Department of Medical Genomics tries to fulfill
our goals mainly through the two approaches.
(1) Functional screening with the use of retroviral
cDNA expression libraries.
The “focus formation assay” had been widelyused in 1980s and 1990s to identify oncogenes fromhuman cancer. However, since this technology directly
uses cancer genome to transfer oncogenes into
recipient cells, expression of each gene is regulated byits own promoter/enhancer fragments. Therefore, suchtechnology is theoretically unable to capture
oncogenes whose promoter/enhancer is silent inrecipient cells. To make every gene expressedsufficiently in recipient cells, we here developed ahighly efficient retrovirus–mediated cDNA expression
library system. Our system enables to make a librarywith high complexity (containing millions of
independent cDNA clones) even from < 104 of cells.
Application of this technology to a lung cancer
specimen led to the discovery of a novel fusion-type
oncogene EML4-ALK (Nature 448:561). A tiny
chromosomal inversion, inv(2)(p21p23), within lungcancer cells fuses EML4 (Echinoderm microtubule
associated protein like 4) to ALK (anaplastic
lymphoma kinase), resulting in the production of aconstitutively active tyrosine kinase EML4-ALK.
Expression of EML4-ALK in lung epithelial cells
generated hundreds of adenocarcinoma nodules inboth lungs of transgenic mice, and treatment of suchmice with a selective inhibitor against the catalytic
activity of ALK led to a rapid disappearance of such
nodules from the mice (PNAS 105:19893). These
results reinforce the essential role of EML4-ALK in the
carcinogenesis of lung cancer patients positive for thefusion gene, also prove that selective inhibitors against
ALK should become effective therapies for lungcancer.
Indeed, most pharmaceutical companies are
currently developing ALK inhibitors, and more than
five of different inhibitors are under clinical trials totreat EML4-ALK-positive lung cancer, and theefficacy of one of such compound, crizotinib, has been
published already. Surprisingly treatment withcrizotinib resulted in ~90% of response rate plus thepresence of patients under complete remission.
Currently, we are trying to apply our retroviralscreening technologies to other cancer subtypes, andto discover novel oncogenes that could be efficiently
targeted.
(2) Cancer genome resequencing
In addition to the functional screening shown
above, we also tried to search for somatically mutatedgenes in human cancers. As an initial trial for thispurpose, we developed an extra-large nucleotide
sequencing array (Sequencing Wafer) with Perlegen,Inc. (Mountain View, CA, USA), which can determine~nine millions of bases.
With such wafer, we analyzed the coding
sequences of ~5600 protein–coding genes among thepurified blasts of acute myeloid leukemia as well as
paired normal T-cells (Oncogene, Epub ahead of print.
DOI: 10.1038/onc.2010.117). Through such screening,
we could identify a novel activating mutation in the
JAK3 tyrosine kinase. Further screening of JAK3
mutations in another cohort of leukemia led to thediscovery of various JAK3 mutations with a frequencyof 3.14%. It is, therefore, likely that anomaly in JAK3
kinase is responsible for the transformation of a subset
of acute myeloid leukemia.
In addition, the screening with the wafers also
revealed a non-synonymous somatic mutation in
DNMT3A that encodes one of the responsible
methyltransferases for the de novo methylation in our
genome. The mutated DNMT3A carries only <50% of
its enzymatic activity compared to its normal
counterpart, and was found in ~4% of our leukemia
cohort. This was the first discovery of somatic
mutations in DNMT genes in humans.
We have recently succeeded in developing a361

resequencing technology with a high accuracy with
the next generation sequencing system, “Genome
Analyzer” from Illumina, Inc. Through thistechnology we are currently pursuing to discover othersomatically mutated genes in human cancer
specimens.

References
1.

2.

3.

4.

5.

6.

Zhang MJ, Franklin S, Li Y, Wang S, Ru X,
Mitchell-Jordan SA, Mano H, Stefani E, Ping P,
Vondriska TM. Stress signaling by Tec tyrosine
kinase in the ischemic myocardium. Am J Physiol
Heart Circ Physiol. 2010;299:H713-722.
Yamashita Y, Yuan J, Suetake I, Suzuki H,
Ishikawa Y, Choi YL, Ueno T, Soda M, Hamada
T, Haruta H, Takada S, Miyazaki Y, Kiyoi H, Ito
E, Naoe T, Tomonaga M, Toyota M, Tajima S,
Iwama A, Mano H. Array-based genomic
resequencing of human leukemia. Oncogene.
2010;29:3723-3731.
Susaki K, Kitanaka A, Dobashi H, Kubota Y,
Kittaka K, Kameda T, Yamaoka G, Mano H,
Mihara K, Ishida T. Tec protein tyrosine kinase
inhibits CD25 expression in human T-lymphocyte.
Immunol Lett. 2010;127:135-142.
Sakairi Y, Nakajima T, Yasufuku K, Ikebe D,
Kageyama H, Soda M, Takeuchi K, Itami M,
Iizasa T, Yoshino I, Mano H, Kimura H.
EML4-ALK Fusion Gene Assessment Using
Metastatic Lymph Node Samples Obtained byEndobronchial Ultrasound-Guided Transbronchial
Needle Aspiration. Clin Cancer Res. 2010;16:4938-4945.
Osoegawa A, Nosaki K, Miyamoto H, Kometani
T, Hirai F, Ondo K, Seto T, Sugio K, Choi YL,
Soda M, Mano H, Ichinose Y. Incidentally provenpulmonary "ALKoma". Intern Med. 2010;49:
603-606.
Nakajima T, Kimura H, Takeuchi K, Soda M,
Mano H, Yasufuku K, Iizasa T. Treatment ofLung Cancer with an ALK Inhibitor After
EML4-ALK Fusion Gene Detection Using
Endobronchial Ultrasound-Guided Transbronchial
Needle Aspiration. J Thorac Oncol. 2010;5:

2041-2043.
7. Mano H, Takeuchi K. EML4-ALK fusion in lung.
Am J Pathol. 2010;176:1552-1553.
8. Hatanaka H, Tsukui M, Takada S, Kurashina K,
Choi YL, Soda M, Yamashita Y, Haruta H,
Hamada T, Ueno T, Tamada K, Hosoya Y, Sata N,
Yasuda Y, Nagai H, Sugano K, Mano H.
Identification of transforming activity of freefatty acid receptor 2 by retroviral expression
screening. Cancer Sci. 2010;101:54-59.
9. Hatanaka H, Takada S, Tsukui M, Choi YL,
Kurashina K, Soda M, Yamashita Y, Haruta H,
Hamada T, Tamada K, Hosoya Y, Sata N, Nagai
H, Yasuda Y, Sugano K, Mano H. Identificationof the transforming activity of Indian hedgehog
by retroviral expression screening. Cancer Sci.
2010;101:60-64.
10. Choi YL, Soda M, Yamashita Y, Ueno T,
Takashima J, Nakajima T, Yatabe Y, Takeuchi K,
Hamada T, Haruta H, Ishikawa Y, Kimura H,
Mitsudomi T, Tanio Y, Mano H. EML4-ALK
mutations in lung cancer that confer resistance to
ALK inhibitors. N Engl J Med. 2010;363:
1734-1739.

362

Department of MolecularPsychiatry
Associate Professor
Kazuya Iwamoto,Ph.D.

Assistant Professor
Miki Bundo, Ph.D.

Homepage

http://www.molpsy.com

Introduction and Organization
Major mental disorders such as schizophrenia,
affective disorders, and developmental disorders aresevere disorders showing high prevalence rate in every
population. They not only bring long-lasting suffering
to patients and their families, but also cause
tremendous loss from an economical view.
Surprisingly, cause of illness and pathophyshiology ofmental disorders remain largely unclear. The
Department of Molecular Psychiatry has been
established at the Graduate School of Medicine,
University of Tokyo since February 1st 2010, by the
donation from three pharmaceutical companies ―Astellas Pharma, Dainippon Sumitomo Pharma, andYoshitomi Yakuhin. The aim of this department is tocontribute the understanding of cause of illness andpathophysiology of major mental disorders at themolecular level, through the close collaboration with
Department of Neuropsychiatry at the University ofTokyo.

Research activities
Specimen derived from mental disorders as well asanimal models are examined by comprehensive
approaches from genetic, molecular biological,
cellular and behavioral point of views. Especially, we
will focus on the study of blood samples provided

from Department of Neuropsychiatry at the Universityof Tokyo and postmortem brains provided from brainbanks.
1. Kubota M, Kasahara T, Iwamoto K, Komori A,
Miyauchi T, Ishiwata M, Kato T. Therapeutic
implications of down-regulation of cyclophilin D
in bipolar disorder. Int. J. Neuropsychopharm.
2010;13:1355-1368.

Endowed Department(22nd Century Medical and Research Center)364

Department of Clinical &Molecular Epidemiology
Project Associate Professor
Takanari Gotoda, M.D., Ph.D.

Project Associate
Takashi Yamamoto, Ph.D.

Homepage http://www.h.u-tokyo.ac.jp/research/center22/contribute/rinsyo_bunshi.html

Introduction and Organization
The Department of Clinical & Molecular
Epidemiology was established in June 2004 as anendowed department (Mitsubishi Tanabe Pharma Co.,
Ltd.) of the Graduate School of Medicine, theUniversity of Tokyo, under supervision of the
Department of Nephrology and Endocrinology (Prof.
Toshiro Fujita) of the University of Tokyo Hospital.
At present, our department is also supported by the
Pharmaceutical Department (Prof. Hiroshi Suzuki)
and belongs to the 22nd Century Medical andResearch Center, which partly represents thetranslational research activities of the University
Hospital. At present, our research laboratory facilities
are located at the 8th floor of the Central Clinical
Service Bldg.2 and at the 10th floor of the Inpatients’
Ward B of the University Hospital. Dr. Gotoda isentirely responsible for the management of thedepartment, keeping close contact and cooperation
with the other departments of the 22nd Century
Medical and Research Center and with laboratories of
the Department of Nephrology and Endocrinology and
the Pharmaceutical Department, and focusing mainly
on research activities.
Our department is established with the main aim of
performing the clinical and epidemiological analysis
on the metabolic syndrome in the Japanese population,of isolating susceptibility gene(s) to metabolic
syndrome through molecular and genetic analysis on

human and rodent animal models, and of contributing
to the development of novel diagnostic method andtherapeutic agents for the prevention and treatment of
the cardiovascular diseases. Above all, recently, we
are focusing on the genetic susceptibility to visceralfat accumulation, a hallmark of the metabolic
syndrome, and also on the genetic susceptibility tohypertension. Furthermore, we are also trying toelucidate the novel mechanistic action of the available
pharmaceutical agents for the treatment of themetabolic syndrome such as the inhibitors of therenin-angiotensin system and the statins.

Clinical activities
Some of the members of our department is closely
involved in clinical services related to both theout-patient and admission departments. We also attend
clinical conferences and contribute to clinicalactivities of the Department of Nephrology and
Endocrinology of the University Hospital, because ourdepartment is under supervision of the Nephrology
and Endocrinology Department. We are also
performing a translational research project using
clinical materials derived from patients withagreement and approval of both the patients and theethics committee of the University Hospital. Also, in
cooperation with outpatient clinics and hospitals
outside, we are collecting and analyzing the clinicaldata on metabolic syndrome from an epidemiological365

standpoint with the aim of returning the fruitful resultsof the translational research to the clinical practicedepartments.

Teaching activities
Our department belongs to the Graduate School of
Medicine and Faculty of Medicine, the University ofTokyo. We are constantly instructing several
postgraduate students and supervising them in order tosucceed in obtaining the medical doctor degrees of the
University of Tokyo. We also contribute to
examination of the applicants for the doctor degrees,and make several lectures for the students in the
Faculty of Medicine at the University of Tokyo as
well.

Research activities
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 biologicalanalysis on human and rodent animal models of
metabolic syndrome.
● Performance of clinical and epidemiologicalanalysis with regard to metabolic syndrome.
● Development of novel diagnostic method for risk
factors of cardiovascular diseases.
● Contribution to the development of preventive
and therapeutic novel agents to treat patients withmetabolic syndrome.
● Exploration of novel mechanisms of action ofavailable pharmaceutical agents to treat patientswith cardiovascular diseases.
First of all, with regard to analysis on metabolic
syndrome, we analyzed clinical and epidemiological
data in the Japanese population by means of factor
analysis focusing on metabolic syndrome. The results
indicated that, even in the Japanese population where
severe insulin resistance can hardly be seen andcommon, the presence of insulin resistance is a crucial
factor underlying the clustering of risk factors related
to metabolic syndrome.
Recently, through the genetic analysis of animalmodel of metabolic syndrome, we have successfully
isolated and identified a novel gene underlying

visceral fat accumulation, a hallmark of metabolic
syndrome. Its characterization is described below indetail.
The spontaneously hypertensive rat (SHR) is an
important genetic animal model of hypertension,
dyslipidemia, and insulin resistance closely related tometabolic syndrome. We previously reported thegenetic heterogeneity among SHR strains, mostimportantly, the fact that SHR strains could be divided
into two separate groups according to the presence orabsence of genetic null mutation at the CD36 gene.
Representatively, the SHR/NCrj strain lacks CD36
due to the mutation while the SHR/Izm strain has
normal CD36. Although these two strains are quite
different in terms of visceral fat accumulation, insulin
secretion capacity, kidney weight and proteinuria,
very interestingly, these differences could not beascribed to the CD36 gene mutation, indicating thepresence of another important genetic abnormality. By
performing the so-called QTL (quantitative trait
locus ) analysis on the F2 cross population between
the two SHR strains, we have identified a QTL linked
significantly to epididymal fat weights and bloodpressure located near D1Wox28 on rat chromosome 1.
Next, as the result of a systematic screening of genes
located within the candidate QTL region by means ofgene expression analysis with a Gene-chip microarray,
we have identified the SLC22A18 gene located at thepeak of the QTL region. Interestingly, SHR/NCrj has apoint mutation at the donor splice site of an intron of
the SLC22A18 gene, while SHR/Izm lacking themutation found in SHR/Izm has wild-type SLC22A18,
The SLC22A18 gene is most abundantly expressed inliver and kidney, and it is also expressed ubiquitously,
for example, in the adipose tissue and pancreatic islet
cells. While the physiological function of SLC22A18
remains largely unknown, it is postulated as amembranous protein that would be possibly involvedin the membranous transport. It is also predicted thatthe donor splice site mutation found in SHR/NCrj
should cause the skipping of a single exon encoding
34 amino acids that would be crucial for normal
function of SLC22A18. In fact, the kinetic analysis
using a radio-labeled chemical agent that is postulated
to be an exogenous substrate for SLC22A18 on
isolated adipocytes clearly demonstrated that the
adipocytes derived from SHR/NCrj with the366

SLC22A18 defect have significantly altered functionin terms of uptake of the substrate into adipocytes ascompared with those from SHR/Izm, establishing thefunctional significance of the mutation.
Based upon these observations, we hypothesized thatthe genetic and functional abnormality of SLC22A18
could cause visceral fat accumulation, kidney
impairment, hypertension and impaired insulin
secretion. To test this hypothesis, we have establishedcell lines that either overexpress or underexpress
SLC22A18, and also overexpressed in vivo with useof adenovirus vectors. We are also trying to establish
genetically-engineered mice such as transgenic miceoverexpressing rat SLC22A18 and knockout mice
deficient in the SLC22A18 gene. By analyzing thephenotypes of those genetically-engineered mice, weplan to explore the clue to the etiological mechanismof visceral fat accumulation. Interestingly, since thefunction of SLC22A18 can possibly be regulated bysome synthetic exogenous substrate, verification of
the above hypothesis may open a new way to develop
a novel pharmaceutical agent to treat metabolic
syndrome focusing on SLC22A18 as a new target.
As another important approach to metabolic syndrome,
we have also generated knockout mice deficient in thegene for KAT-1 (kynurenine aminotransferase-1),
which we previously identified a promising candidate
gene of hypertension in SHR. Interestingly, thosehomozygous knockout mice developed hypertension
and manifested insulin resistance, sympathetic
hyperactivity, resistance to diet-induced obesity, anddiabetic insipidus. These observations may serve todevelop a novel pharmaceutical agent to treat
metabolic syndrome focusing on KAT-1 as a newtarget as well.
Finally, we also carry out a series of researchexperiments aiming at exploration of novel
mechanisms of action of available pharmaceuticalagents to treat patients with cardiovascular diseases.

References
1.

Danno H, Ishii KA, Nakagawa Y, Mikami M,
Yamamoto T, Yabe S, Furusawa M, Kumadaki S,
Watanabe K, Shimizu H, Matsuzaka T,
Kobayashi K, Takahashi A, Yatoh S, Suzuki H,
Yamada N, Shimano H. The liver-enriched

2.

3.

4.

transcription factor CREBH is nutritionallyregulated and activated by fatty acids and
PPARalpha. Biochem Biophys Res Commun.
2010;391:1222-7.
Yamamoto T, Watanabe K, Inoue N, Nakagawa Y,
Ishigaki N, Matsuzaka T, Takeuchi Y, Kobayashi
K, Yatoh S, Takahashi A, Suzuki H, Yahagi N,
Gotoda T, Yamada N, Shimano H. Protein
kinase Cbeta mediates hepatic induction ofsterol-regulatory element binding protein-1c byinsulin. J Lipid Res. 2010;51:1859-70.
Takeuchi Y, Yahagi N, Izumida Y, Nishi M,
Kubota M, Teraoka Y, Yamamoto T, Matsuzaka T,
Nakagawa Y, Sekiya M, Iizuka Y, Ohashi K,
Osuga J, Gotoda T, Ishibashi S, Itaka K, Kataoka
K, Nagai R, Yamada N, Kadowaki T, Shimano H.
Polyunsaturated fatty acids selectively suppress
sterol regulatory element-binding protein-1
through proteolytic processing and autoloop
regulatory circuit. J Biol Chem. 2010;285:
11681-91.
Hirashio S, Izumi K, Ueno T, Arakawa T, Naito T,
Taguchi T, Yorioka N. Point mutation (C to T) of
the LCAT gene resulting in A140C substitution. J
Atheroscler Thromb. 2010;17:1297-301.

367

Department of
Immunotherapeutics (Medinet)
Project Associate Professor
Kazuhiro Kakimi, M.D., Ph.D.

Project Research Associate
Hirokazu Matsushita, M.D., Ph.D.

Homepage

http://immunoth.umin.jp/

Introduction and Organization
The aim of our Department is to execute basic andclinical research on cancer immunology andimmunotherapy and to establish its role in thetreatment of cancer. Cancer immunotherapy requires
the expansion of functional T cells and/or dendritic
cells (DC) that are responsible for the anti-tumor
immune response in vivo. The GMP-level Cell
Processing Center (CPC) was installed in the
Department. Peripheral blood mononuclear cells(PBMC) are isolated from the patients and processedin the CPC to ensure that they maintain optimalfunctionality, or for triggering new functions in vitro
prior to clinical application. Autologous cells derived
from cancer patients are processed for therapeutic use
in our CPC in accordance with all current regulations
and ethical obligations.
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 threedivisions are situated side-by-side on the same floor,
close cooperation between the members of each groupcan be more easily and better organized. As soon as
blood is drawn from the patient at the outpatient clinic,
it is directly transferred to the CPC through the
pass-box between the two. The cells processed andcultured in the CPC are scrutinized in the laboratorynext door to the clinic and CPC regarding their quality
and function. Those cultured cells which are approved
following this examination are transferred back to theclinic and administered to the patient. The patients arefollowed-up at regular intervals by the research staff
at the laboratory to monitor their immune responses toevaluate the impact of the immunotherapy.
All protocols for cancer immunotherapy
performed in our Department are submitted to theinstitutional review board (IRB). Once approved, theprotocols are registered in the UMIN clinical researchregistration system to provide open access to any
interested parties. Because the cells used for treatment
are derived from each individual patient; it is reallydifficult to guarantee consistent quality. However, we
do everything possible to provide the cultured cellswith the best conditions, by means of well-trained
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.

Clinical activities
We provide outpatient services for cancer patients. Allinterventions performed in the department are definedby the protocols of the particular clinical trial
approved by the IRB. The following clinical trials areunderway in our department:

368

1. UMIN000001260, active, recruiting, IRB number:
1935-(2). A phase I study of vaccination with
NY-ESO-1f peptide mixed with Picibanil; OK-432
and Montanide; ISA-51 in patients with cancers
expressing NY-ESO-1 antigen
2. UMIN000001857, completed, IRB number：2475.
A phase I study of cancer vaccine with NY-ESO-1
overlapping peptides in patients with advanced
cancers
expressing
NY-ESO-1
antigen.
Condition: advanced esophageal cancer, stomach
cancer, non-small cell lung cancer (NSCLC),
malignant melanoma, bladder cancer.

9. UMIN000000854, active, recruiting, IRB number:
1781-(1). Clinical study on efficacy and safety ofautologous gamma/delta T cell transfer therapy
after pulmonary metastasectomy of colorectal
cancer
10. UMIN000001419, active, recruiting, IRB number:
2120-(1). The efficacy and safety of autologous
gamma/delta T cell transfer therapy for esophageal
cancer
11. UMIN000001418, terminated, IRB number: 2176(1). The efficacy and safety of autologous gamma/delta T cell transfer therapy for extrahepatic
metastasis of hepatocellular carcinoma

Dendritic cell therapy

Adjuvant γδT cell therapy

3. C000000451, terminated. Clinical study of
intratumoral dendritic cell injection afterradiofrequency ablation therapy in hepatitis C
virus-related hepatocellular carcinoma patients
4. UMIN000000971, terminated, Clinical study of
intratumoral dendritic cells (DC) injection afterradiofrequency ablation (RFA) therapy for thetreatmentofhepatitisCvirus-related
hepatocellular carcinoma (HCC) patients
5. UMIN000002136 , active, recruiting, IRB number:
2492. Safety, efficacy and immunogenicity ofautologous tumor lysate-pulsed dendritic celltherapy in patients with advanced renal cell
carcinoma
6. UMIN000002837 , active, recruiting, IRB number:
2759. Safety, efficacy and immunogenicity ofautologous tumor lysate-pulsed dendritic celltherapy after resection of stage2A (T2N0,T3N0)
esophageal cancer

12. UMIN000000931 , active, recruiting, IRB number:
1810-(1). Clinical study to investigate safety andefficacy on combination of gemcitabine andautologous gamma/delta T cell transfer therapy
after resection of pancreatic cancer
13. UMIN000001417 , active recruiting, IRB number:
2177-(1). The efficacy and safety of autologous
gamma/delta T cell transfer therapy after resectionof intrahepatic cholangiocarcinoma
14. UMIN000002839, active, recruiting, IRB number:
2760. The efficacy and safety of autologous
gamma/delta T cell transfer therapy after resectionof stage2A (T2N0,T3N0) esophageal cancer
15. UMIN000004130, active, recruiting, IRB number:P201019-11Z. Autologous gamma/delta T cell

Cancer vaccineγδ T cell therapy for advanced cancer
7. C000000336, active, recruiting, IRB number:
1290-(4). Clinical study on safety and efficacy of
adoptive transfer of autologous gamma/delta T
lymphocytes in patients with non-small cell lungcancer.
8. UMIN000000628, terminated, IRB number: 1511(5). A study to evaluate the safety and efficacy of
ex vivo expanded autologous gamma/delta T cell
infusion following zoledronic acid sensitization inpatients who received radiotherapy for bonemetastases.

therapy for gastric cancer with ascites.

Teaching activities
Research guidance in molecular immunology isprovided to postgraduate students. Because knowledge
and techniques for evaluation of immune response areimportant for clinicians and medical researchers, we
also provide many opportunities to postgraduate
students to learn how to analyze in vivo immune
responses by means of experiments using animalmodels and by the immunological monitoring of thepatients themselves in clinical research.

Research activities
All of our research activities are directed at369

understanding the dynamics of the immune response
in vivo at the molecular, cellular and organismal levels
and to develop more effective immunotherapy against
cancer. To this end, we perform both clinicalimmunology in humans and basic preclinicalimmunology using animal models. We especially
focus on the spatiotemporal analysis of anti-tumor
immunity in both humans and experimental animals.
During the course of each trial, many samples fromthe clinic are delivered to the research laboratory tomonitor immune responses in patients. Tumor-specificimmunityisevaluatedusing
standardized
immunological assays, such as ELISA, ELISPOT andflow 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 to thebedside and from basic to clinical immunology inorder to maximize benefit to patients via the rapid
application of new knowledge to clinical practice.

List of Publications
1. Ikeuchi N, Futami J, Hosoi A, Noji S, Kurachi M,
Ueha S, et al. Efficient cross-presentation ofsoluble exogenous antigens introduced into
dendritic cells using a weak-based amphiphilic
peptide. Biochem Biophys Res Commun 2010;
392(2):217-22.
2. Nakajima J, Murakawa T, Fukami T, Goto S,
Kaneko T, Yoshida Y, et al. A phase I study of
adoptive immunotherapy for recurrent non-smallcell lung cancer patients with autologous
gammadelta T cells. Eur J Cardiothorac Surg
2010;37(5):1191-7.
3. Toda M, Wang L, Ogura S, Torii M, Kurachi M,
Kakimi K, et al. UV irradiation of immunized
mice induces type 1 regulatory T cells thatsuppress tumor antigen specific cytotoxic T
lymphocyte responses. Int J Cancer2010 Nov 15.
4. Sakamoto M, Nakajima J, Murakawa T, Fukami T,
Yoshida Y, Murayama T, et al. Adoptive

Immunotherapy
forAdvanced
Non-small
CellLung Cancer Using Zoledronate-expanded
gammadeltaTCells: APhase I Clinical Study. J
Immunother 2011;34(2):202-11.
5. Kakimi K, Isobe M, Uenaka A, Wada H, Sato E,
Doki Y, Nakajima J, Seto Y, Yamatsuji T,
Naomoto Y, Shiraishi K, Takigawa N, Kiura K,
Tsuji K, Iwatsuki K, Oka M, Pan L, Hoffman EW,
Old LJ, Nakayama E. A phase I study ofvaccination with NY-ESO-1f peptide mixed with
Picibanil OK-432 and Montanide ISA-51 inpatients with cancers expressing the NY-ESO-1
antigen. Int J Cancer. 2011 Feb 3. doi: 10.1002/
ijc.25955. [Epub ahead of print]

370

Division of Total Renal Care
Medicine
Associate Professor
Akira Ishikawa (urologist),

Assistant Professor
Yoshitaka Ishibashi (Nephrologist)

Post-doctoral Fellow
Yohei Takara

Homepage(Nephrologist)

http://www.trc.umin.jp

The Division of Total Renal Care Medicine, sponsoredby Terumo Corporation, was established in 2004. Our
goal is to provide end-stage renal disease (ESRD)
patients with a renal replacement therapy mostsuitable for their way of life. In order to achieve this,
we are making an effort to make peritoneal dialysis(PD) more available for patients, in a country where
for most patients hemodialysis is virtually the only
choice. We are presently conducting the following
projects; (1) Research on establishing optimum PD
therapy, (2) Educational courses for medical
practitioners, and (3) research on improving clinicalskills.
We are providing care for approximately 80 PD
outpatients in our hospital with the support of thedivision of Nephrology and Endocrinology. All the 3
projects mentioned above are in close association withdaily clinical practice. Our activities in 2010 were as
follows:(1) Research on establishing optimum PD therapy.
At the present state, the main cause of PD techniquefailure is deterioration of peritoneal function due tolong-term use of bio-incompatible dialysate.
Biocompatible dialysates have been available since2001, and our research is focused on peritoneal
pathology after long-term use of new biocompatible
PD fluids. We have reported the results in the

Peritoneal Dialysis International (in press). In addition,
we have started the project of developing non-invasive
methodology of diagnosing peritoneal membrane withthe collaboration between medical-engineering
institutions.
(2) Educational courses for medical practitioners.
With the help of many nephrologists and nurses in our
hospital, we have trained 27 nephrologists and 41
renal nurses from 25 facilities (either university
hospital or central hospital in their area) from 15
prefectures in Japan in 2010. To date, we have trained
156 nephrologists and 101 renal nurses from 132
facilities between 2006-2010.
(3) Research on improving clinical skills.
PD is a mode of therapy in which the patient greatly
participates in treating his own disease. Therefore, thepatient needs to face up to his own disease, and toknow how to acquire the skills needed for
self-management. Based on this standpoint, we havefelt that it is necessary to work with experts of otherdisciplines, such as the humanities. Thus, we havestarted some collaborative research with philosophers,sociologists, and cognitive behavioral therapists.

371

References
1. Kumagai T, Ishibashi Y, Kawarazaki H,
Kawarazaki W, Shimizu H, Kaname S, Fujita T.
Effects of nocturnal oxygen therapy on sleep
apnea syndrome in peritoneal dialysis patients.
Clin Nephrol 70: 332-9, 2008
2. Mori E, Ishibashi Y, Kume H, Ishikawa A, Fujita
T. Two Cases of Catheter Obstruction Caused by
Subcutaneous Catheter Kinking Perit Dial Int 28:
677-678, 2008
3. Mimura I, Ishibashi Y, Tateishi R, Kaname S,
FujitaT.
Pegylatedinterferonalpha-2amonotherapy in a peritoneal dialysis patient withchronic hepatitis C.. Nephrol Dial Transplant Plus
1: 233-235, 2008
4. Hirahara I, Ishibashi Y, Kaname S, Kusano E,
Fujita T: Methylglyoxal induces peritoneal
thickening by mesenchymal-like mesothelial cells
in rats. Nephrol Dial Transplant 24, 437-47, 2009
5. Motonishi S, Ishibashi Y, Kawarazaki H, Katagiri
D, Hirata Y, Kume H, and Fujita T: Peritoneal
catheter obstruction by sigmoid colon wall.
Kidney International 79, 1032, 2011
6. Hirohama D, Ishibashi Y, Kawarazaki H, Kume
H, Fujita: Successful treatment of Mycobacterium
gordonae exit-site and tunnel infection by partial
catheter reimplantation of the Tenckhoff catheter.
Perit Dial Int 2011 in press
7. Katagiri D, Ishibashi Y, Kawarazaki C, Kume H,
Fujita T: Peritoneal Findings from Two Patientswith Takayasu’s Arteritis on Peritoneal Dialysis.
Perit Dial Int 2011 in press
8. Muraoka K, Ishibashi Y, Yamaguchi J,
Kawarazaki H, Kume H, and Fujita T: Early Partial
Reimplantation of Tenckhoff Catheters to Treat
Intractable Exit-Site/Tunnel Infection. Perit Dial
Int, 2011 in press
9. Ayuzawa N, Ishibashi Y, Takazawa Y, Kume H,
and Fujita T: Peritoneal Morphology after Longterm Peritoneal Dialaysis with Biocompatible
fluid: Recent Clinical Practice in Japan. Perit Dial
Int 2011 in press
10. Kume H, Miyazaki H, Ishikawa A, Ishibashi Y,
Fujita T, Homma Y: Peritoneal fixation prevents
dislocation of Tenckhoff catheter. Perit Dial Int,
2011 in press

11. Ishikawa A, Kawarazaki H, Ando K, Fujita M,
Fujita T, Homma Y: Renal preservation effect ofubiquinol, the reduced form of coenzyme Q10.
Clin Exp Nephrol 15, 30-33, 2011

372

Department of Integrated
Molecular Science on Metabolic
Diseases
Project Associate Professor
Toshimasa Yamauchi, M.D.,Ph.D. (〜2010. Nov.)
Kazuo Hara, M.D., Ph.D. (2011. Mar.〜)

Project Research Associate
Masato Iwabu, M.D.,Ph.D.

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 theadvancement of health and medical care in the future.

373

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) Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K,
Nakagawa T, Funata M, Yamaguchi M, Namiki S,
Nakayama R, Tabata M, Ogata H, Kubota N,
Takamoto I, Hayashi YK, Yamauchi N, Waki H,
Fukayama M, Nishino I, Tokuyama K, Ueki K,
Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K,
Kadowaki T.: Adiponectin and AdipoR1 regulate
PGC-1alpha and mitochondria by Ca(2+) and
AMPK/SIRT1. Nature 464, 1313-9 (2010)(2) Yamauchi T, Hara K, Maeda S, Yasuda K,
Takahashi A, Horikoshi M, Nakamura M, Fujita
H, Grarup N, Cauchi S, Ng DP, Ma RC, Tsunoda
T, Kubo M, Watada H, Maegawa H,

Okada-Iwabu M, Iwabu M, Shojima N, Shin HD,
Andersen G, Witte DR, Jørgensen T, Lauritzen T,
Sandbæk A, Hansen T, Ohshige T, Omori S, Saito
I, Kaku K, Hirose H, So WY, Beury D, Chan JC,
Park KS, Tai ES, Ito C, Tanaka Y, Kashiwagi A,
Kawamori R, Kasuga M, Froguel P, Pedersen O,
Kamatani N, Nakamura Y, Kadowaki T.: A
genome-wide association study in the Japanese
population identifies susceptibility loci for type 2
diabetes at UBE2E2 and C2CD4A-C2CD4B.
Nature Genet. 42, 864-868 (2010)(3) Otani K, Kitayama J, Kamei T, Soma D, Miyato
H, Yamauchi T, Kadowaki T, Nagawa H.:
Adiponectin receptors are downregulated inhuman gastric cancer. J. Gastroenterol. 45,
918-927 (2010)(4) Kadowaki T, Yamauchi T.: Adiponectin receptor
signaling: a new layer to the current model. Cell
Meabolism 13, 123-124 (2011)(5) Grarup N, Overvad M, Sparsø T, Witte DR,
Oisinger C, Jørgensen T, Yamauchi T, Hara K,
Maeda S, Kadowaki T, Hansen T, Pedersen O.:
The diabetogenic VPS13C/C2CD4A/C2CD4B
rs7172432 variant impairs glucose-stimulated
insulin response in 5,722 non-diabetic Danish
individuals. Diabetologia 54, 789-794 (2011)

374

Department of Advanced Clinical
Science and Therapeutics
Project Associate Professor
Yasunobu Hirata, M.D., Ph.D.
Jun-ichi Suzuki, M.D., Ph.D.

Project Assistant Professor
Nobutaka Koibuchi, Ph.D.
Shuko Takeda, M.D., 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 other areas.
This department hopes to develop not only basic
research, but also applications to devise new clinicalstrategies.

Research activities
Followings are our recent basic and clinical research
activities.
Basic Research• New strategies to regulate acute rejection and graftarterial diseases in cardiac transplantation.
• New
strategies
toregulate
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.
• Analysis of angiogenesis using in situ
hybridization.
Clinical Research• Gene therapies to prevent restenosis and thrombosis
after coronary intervention.
• Pathophysiology of oral disorder and cardiovasculardiseases.
• Pathophysiology of sleep apnea syndrome andcardiovascular diseases.
• Pathophysiology of renal dysfunction andcardiovascular diseases.

375

References
1.

2.

3.

4.

5.

6.

7.

8.

Suzuki J, Ogawa M, Takayama K, Taniyama Y,
Morishita T, Hirata Y, Nagai R, Isobe M.
Ultrasound-microbubble mediated intercellularadhesion molecule-1 small interfering ribonucleic
acid transfection attenuates neointimal formation
after arterial injury in mice. J Am Coll Cardiol.
55: 904–13, 2010.
Suzuki J, Ogawa M, Tamura N, Maejima Y,
Takayama K, Maemura K, Honda K, Hirata Y,
Nagai R, Isobe M. A critical role of sympathetic
nerve regulation for the treatment of impaired
daily rhythm in hypertensive Dahl rats.
Hypertens Res. 33: 1060-5, 2010.
Ogawa M, Suzuki J, Yamaguchi Y, Muto S, Itai A,
Hirata Y, Isobe M, Nagai R. The effects ofpharmacologicalplasminogenactivator
inhibitor-1 inhibition in acute and chronic
rejectioninmurinecardiacallografts.
Transplantation. 2010 Nov 16. [Epub ahead ofprint]
Komura M, Suzuki J, Adachi S, Takahashi A,
Otomo K, Nitta J, Nishizaki M, Obayashi T,
Nogami A, Satoh Y, Okishige K, Hirao K, Isobe
M. Clinical course of arrhythmogenic rightventricular cardiomyopathy in the era of
implantablecardioverter-difibrillators
andradiofrequency catheter ablation. Int Heart J.
51: 34-40, 2010.
Hishikari K, Watanabe R, Ogawa M, Suzuki J,
Masumura M, Shimizu T, Takayama K, Hirata Y,
Nagai R, Isobe M. Early treatment withclarithromycin attenuates rat autoimmune
myocarditis via inhibition of matrix metalloproteinase activity. Heart. 96: 523-7, 2010.
Isobe K, Kuba K, Maejima Y, Suzuki J, Kubota S,
Isobe M. Inhibition of endostatin/collagen XVIII
deteriorates left ventricular remodeling and heart
failure in rat myocardial infarction model. Circ J.
74: 109-19, 2010.
Kosuge H, Ishihara T, Haraguchi G, Maejima Y,
Okada H, Saiki H, Suzuki J, Isobe M.
Treatment with telmisartan attenuates graftarteriosclerosis in murine cardiac allografts. J
Heart Lung Transpl. 29: 562-7, 2010.
Nakajima T*, Hishikari K*, Ogawa M, Watanabe

9.

10.

11.

12.

13.

14.

R, Suzuki J, Nagashima A, Masumura M,
Takayama K, Hirata Y, Nagai R, Isobe M. (*equal
contribution)
Clarithromycin
attenuates
myocardial ischemia reperfusion injury. Expert
Opin Ther Tar. 14: 881-93, 2010.
Aoyama N, Suzuki J, Wang D, Ogawa M,
Kobayashi N, Hanatani T, Takeuchi Y, Izumi Y,
Isobe M. Porphyromonas gingivalis promotes
murine abdominal aortic aneurysms via matrix
metalloproteinase-2 induction. J Periodontal
Res. 2010 Dec 10. [Epub ahead of print]
Kiyosue A, Hirata Y, Ando J, Fujita H, Morita T,
Takahashi M, Nagata D, Kohro T, Imai Y, Nagai
R. Plasma cystatin C concentration reflects theseverity of coronary artery disease in patients
without chronic kidney disease. Circ J.
74:2441-7, 2010.
Higashikuni Y, Sainz J, Nakamura K, Takaoka M,
Enomoto S, Iwata H, Sahara M, Tanaka K,
Koibuchi N, Ito S, Kusuhara H, Sugiyama Y,
Hirata Y, Nagai R, Sata M. The ATP-binding
cassette transporter BCRP1/ABCG2 plays apivotal role in cardiac repair after myocardial
infarction via modulation of microvascularendothelial cell
survival
andfunction.
Arterioscler Thromb Vasc Biol. 30: 2128-35,
2010.
Hatano M, Yao A, Shiga T, Kinugawa K, Hirata
Y, Nagai R. Imatinib mesylate has the potential
to exert its efficacy by down-regulating theplasma concentration of platelet-derived growth
factor in patients with pulmonary arterial
hypertension. Int Heart J. 51: 272-6, 2010.
Nakajima T, Kurano M, Hasegawa T, Takano H,
Iida H, Yasuda T, Fukuda T, Madarame H, Uno
K, Meguro K, Shiga T, Sagara M, Nagata T,
Maemura K, Hirata Y, Yamasoba T, Nagai R.
Pentraxin3 and high-sensitive C-reactive protein
are independent inflammatory markers released
during high-intensity exercise. Eur J Appl
Physiol. 110: 905-13, 2010.
Iwata H, Sata M, Ando J, Fujita H, Morita T,
Sawaki D, Takahashi M, Hirata Y, Takanashi S,
Tabata M, Hirata Y, Nagai R. Impact of primitive
cells in intracoronary thrombi on lesion
prognosis: temporal analysis of cellularconstituents of thrombotic material obtained from

376

15.

16.

17.

18.

19.

20.

21.

22.

23.

patients with acute coronary syndrome. Heart.
96: 748-55, 2010.
Sahara M, Sata M, Morita T, Nakajima T, Hirata
Y, Nagai R. A phosphodiesterase-5 inhibitor
vardenafil enhances angiogenesis through aprotein kinase G-dependent hypoxia-inducible
factor-1/vascular endothelial growth factor
pathway. Arterioscler Thromb Vasc Biol. 30:
1315-24, 2010.
Togashi M, Urano Y, Kojima H, Terai T,
Hanaoka K, Igarashi K, Hirata Y, Nagano T.
Sensitive detection of acrolein in serum using
time-resolved luminescence. Org Lett. 12:
1704-7, 2010.
Kiyosue A, Hirata Y, Ando J, Fujita H, Morita T,
Takahashi M, Nagata D, Kohro T, Imai Y, Nagai
R. Relationship between renal dysfunction andseverity of coronary artery disease in Japanesepatients. Circ J. 74: 786-91, 2010.
Takahashi M, Suzuki E, Oba S, Nishimatsu H,
Kimura K, Nagano T, Nagai R, Hirata Y.
Adipose tissue-derived stem cells inhibit
neointimal formation in a paracrine fashion in rat
femoral artery. Am J Physiol Heart Circ
Physiol. 298: H415-23, 2010.
Osako MK, Nakagami H, Koibuchi N, Shimizu H,
Nakagami F, Koriyama H, Shimamura M,
Miyake T, Rakugi H, Morishita R. Estrogen
inhibits vascular calcification via vascularRANKL system: Common mechanism ofosteoporosis and vascular calcification. Circ Res.
107: 466-475, 2010.
Watanabe T, Koibuchi N, Chin MT. Transcription
Factor CHF1/Hey2 Regulates Coronary Vascular
Maturation. Mech Dev. 127: 418-27, 2010.
Iekushi K, Taniyama Y, Azuma J, Sanada F,
Kusunoki H, Yokoi T, Koibuchi N, Okayama K,
Rakugi H, Morishita R. Hepatocyte growth factor
attenuates renal fibrosis through TGF-β1
suppression by apoptosis of myofibroblasts. J
Hypertens. 2010 Sep 11. [Epub ahead of print]
Takaoka M, Suzuki H, Shioda S, Sekikawa K,
Saito Y, Nagai R, Sata M. Endovascular injury
induces rapid phenotypic changes in perivascularadipose tissue. Arterioscler Thromb Vasc
Biol. 30:1576-82, 2010.
Shiga T, Kinugawa K, Hatano M, Yao A,

24.

25.

26.

27.

28.

Nishimura T, Endo M, Kato N, Hirata Y, Kyo S,
Ono M, Nagai R. Age and preoperative total
bilirubin level can stratify prognosis after
extracorporeal pulsatile left ventricular assist
device implantation. Circ J. 75:121-8, 2010.
Oba S, Kumano S, Suzuki E, Nishimatsu H,
Takahashi M, Takamori H, Kasuya M, Ogawa Y,
Sato K, Kimura K, Homma Y, Hirata Y, Fujita T.
miR-200b precursor can ameliorate renal
tubulointerstitial fibrosis. PLoS One. 2010;5:e13614.15.
Uchino Y, Watanabe M, Hirata Y, Shigematsu K,
Miyata T, Nagai R. Efficacy of renal
revascularization in a patient with fibromuscularrenal artery stenosis and heart failure. Int HeartJ 51:432-435, 2010
Kiyosue A, Hirata Y: Reply to the comments on“Relationship between renal dysfunction andseverity of coronary artery disease in japanesepatients”. Circ J 74:1764-1765, 2010
Takahashi M, Shimizu T, Inajima T, Hosoya Y,
Takeda N, Ishizaka N, Yamashita H, Hirata Y,
Nagai R. A case of localized IgG4-related
thoracic periarteritis and recurrent nerve palsy.
Am J Med Sci, 2010 Nov 23. [Epub ahead ofprint]
Kiyose K, Hanaoka K, Oushiki D, Nakamura T,
Kajimura M, Suematsu M, Nishimatsu H,
Yamane T, Terai T, Hirata Y, Nagano T:
Hypoxia-Sensitive Fluorescent Probes for in
Vivo Real-Time Fluorescence Imaging of Acute
Ischemia. J Am Chem Soc. 132:15846-8, 2010.

English Review
1. Suzuki J, Isobe M, Morishita R, Nagai R.
Characteristics of chronic rejection in hearttransplantation–Importantelementsofpathogenesis and future treatments-. Circ J. 74:
233-239, 2010.
2. Suzuki J, Aoyama N, Ogawa M, Hirata Y, Izumi
Y, Nagai R, Isobe M. Periodontitis andCardiovascular Diseases. Expert Opin Ther Tar.
14: 1023-7, 2010.
3. Hirata Y, Nagata D, Suzuki E, Nishimatsu H,
Suzuki J, Nagai R. Diagnosis and Treatment ofEndothelial Dysfunction in Cardiovascular
Disease. Int Heart J. 51: 1-6, 2010.

377

4.

5.

6.

Hirata Y: Significance of B-type natriuretic
peptide measurement in patients with chronic
kidney disease. Circ J. 74: 632-3, 2010.
Nagai R, Awai K, Hirata Y, Iesaka Y, Ishiwata S,
Kikuchi T, Mizutani H, Nishitani H, Sakurada H,
Shoda M, Soh I, Tani S, Yamaguchi I, Yamashita
H, Izumi T, Kanmatsuse K, Ohe T, Yamaguchi T.
Guidelines for radiation safety in interventional
cardiology (JCS 2006). Circ J 74: 2760-2785,
2010.
Nagata D, Hirata Y. The role of AMP-activatedprotein kinase in the cardiovascular system.
Hypertens Res. 33: 22-8, 2010.

378

Department of Ischemic
Circulatory Physiology,
KAATSU training
Associate Professor
Toshiaki Nakajima, M.D., Ph.D.

Research Associate
Tomofumi Yasuda, Ph.D., Hiroyuki Imuta

Fellow Researcher
Toshihiro Morita, M.D., Ph.D., Haruko Iida, M.D., Ph.D., Takaaki Hasegawa

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, orthostatic dysregulation(OD) and respiratory (COPD) diseases. In addition,
we have examined the clinical benefits 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

379

using electrophysiology and molecular physiology
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
1)

Abe T, Sakamaki M, Fujita S, Ozaki H, Sugaya
M, Sato Y, Nakajima T. Effects of low-intensity
walk training with restricted leg blood flow on
muscle strength and aerobic capacity in elderly
subjects. J Geriatr Phy Ther 2010; 33:34-40.
2) Madarame H, Kurano M, Takano H, Iida H, Sato
Y, Ohshima H, Abe T, Ishii N, Morita T,
Nakajima T. Effects of low-intensity resistance
exercise with blood flow restriction on
coagulation system in healthy subjects. ClinicalPhysiology and Functional Imaging 2010
May;30(3):210-3.
3) Fukuda T, Maegawa T, Matsumoto A, Komatsu Y,
Nakajima T, Nagai R, Kawahara T.. Effects ofAcute Hypoxia at Moderate Altitude on Stroke
Volume and Cardiac Output During Exercise. Int
Heart J. 2010 May;51(3):170-175
4) Yasuda T, Abe T, Brechue WF, Iida H, Takano H,
Meguro K, Kurano M, Fujita S, Nakajima T.
Venous blood gas and metabolite response to

low-intensity muscle contractions with externallimb compression. Metabolism. 2010; 59:15101519.
5) Oguri A, Tanaka T, Iida H, Meguro K, Takano H,
Oonuma H,Nishimura S, Morita T, Yamasoba T,
Nagai R, Nakajima T. Involvement of CaV3.1
T-type calcium channels on cell proliferation inmouse preadipocytes. Am J Physiol Cell Physiol
2010 Jun;298(6):C1414-423.
6) Sahara M, Sata M, Morita T, Nakajima T, Hirata
Y, Nagai R. A Phosphodiesterase-5 Inhibitor
Vardenafil Enhances Angiogenesis Through a
Protein Kinase G-Dependent Hypoxia-Inducible
Factor-1/Vascular Endothelial Growth Factor
Pathway. Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):13151324.
7) Endo A, Kohsaka S, Suzuki S, Atarashi H,
Kamakura S, Sakurai M, Nakaya H, Fukatani M,
Mitamura H, Yamazaki T, Yamashita T, Ogawa S;
J-RHYTHM Investigators. Impact of drug
alteration to maintain rhythm control in paroxysmal
atrial fibrillation. Subanalysis from J-RHYTHM
study. Circ J. 2010 Apr 23;74(5):870-875.
8) Ozaki H, Miyauchi M, Nakajima T, Abe T.
Muscle volume and strength and arterial
compliance after walk training with blood flow
restriction in elederly women. J Am Geriatr Soc.
2010 Aug;58(8):1597-1598.
9) Madarame H, Kurano M, Takano H, Iida H,
Morita T and Nakajima T. Blood Flow restrcited
exercise in a ballet dancer with Churg-Strauss
syndrome. Gazzetta Medica Italiana 2011; 170:
63-67.
10) Nakajima T, Kurano M, Hasegawa T, Takano H,
Iida H, Yasuda T, Fukuda T, Madarame H, Uno K,
Meguro K, Shiga T, Sagara M, Nagata T,
Maemura K, Hirata Y, Yamasoba T, Nagai R.
Pentraxin3 and hsCRP are independent
inflammatory markers released during highintensity exercise. Eur J Appl Physiol 2010; 110:905-913.
11) Nakajima T, Kurano M, Sakagami F, Iida H,
Fukumura K, Fukuda T, Takano H, Madarame H,
Yasuda T, Nagata T, Sato Y, Yamasoba T, Morita
T. Effects of low-intensity KAATSU resistancetraining on skeletal muscle size/strength andendurance capacity in patients with ischemic

380

heart disease. Int J KAATSU Training Res 2010;
6: 1-7.
12) Ozaki H, Miyachi M, Nakajima T, Abe T. Effectsof 10-weeks walk training with leg blood flow
reduction on carotid arterial complianceandmuscle size in the elderly adults. Angiology.
2011; 62; 81-86.
13) Ozaki H, Sakamaki M, Yasuda T, Fujita S,
Ogasawara R, Sugaya M, Nakajima T, Abe T.
Increases in Thigh Muscle Volume and Strength
by Walk Training with Leg Blood Flow
Reduction in Older Participants. J Gerontol A
Biol Sci Med Sci 2011; 66: 257-263.

381

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). From 2008 to 2010, our research
activities were supported by Theravalues Corporationand Hitachi, Ltd. In January 2011, new mission started
under the contribution of DVx Inc., WIN
INTERNATIONAL CO.,LTD. and Mitsubishi Tanabe
Pharma. The aim of our department is to improve theclinical information database to the better one and putthat into practical use in developing the clinicalresearch.
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

382

and lifestyle
4. Analysis on the current state of the medical
system
5. Spread of accurate medical information to society
utilizing the information technology

Research Grants
A Grant from the Ministry of Health, Labour andWelfare (2008-2010) (to Morita H and Kohro T)
A Grant from the Ministry of Education, Culture,
Sports, Science and Technology (2009-2011) (toMorita H)
Research Grant of the NOVARTIS Foundation (Japan)
for the Promotion of Science (to Morita H)

References
1.

2.

3.

4.

5.

6.

Morita H, Nagai R. MMP12, lung function, and
COPD in high-risk populations. New England
Journal of Medicine 2010;362:1241.
Morita H, Nagai R, Seidman JG, Seidman CE.
Sarcomere gene mutations in hypertrophy andheart failure. J Cardiovasc Transl Res. 2010;3:
297-303.
Ogawa N, Imai Y, Morita H, Nagai R.
Genome-wide association study of coronary
artery disease. Int J Hypertens. 2010, Article ID
790539 (doi:10.4061/2010/790539)
Morita H, Nagai R. Retinopathy progression in
type 2 diabetes. New England Journal of
Medicine 2010;363:2171.
Kohro T, Fujita M, Sasayama S, Mitani S,
Yamazaki T, Hayashi D, Okada Y, Nagai R.
Japanese Coronary Artery Disease Investigators.
Prognostic effects of combined treatment withcalcium channel blockers and statins in patientswith coronary narrowing: from the JapaneseCoronary Artery Disease study. Int Heart J.
2010;51:299-302.
Kohro T, Hayashi D, Yamazaki T, Nagai R.
JCAD Investigators. Beta-blocker prescription
among Japanese cardiologists and its effect onvarious outcomes. Circ J. 2010;74:962-969.

383

Department of Joint Disease
Research
Project Associate Professor
Noriko Yosihmura, 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 activities
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

(Research on Osteoarthritis Against Disability)
consisted of total 3,040 participants, of which aims at
the elucidation of an environmental and genetic
background for bone and joint diseases, represented
by OA and OP.
We have completed the baseline study and second
comprehensive clinic visit after a follow-up period of
3 years.

References
1.

2.

3.

4.

Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Cohort Profile: Research
on Osteoarthritis/osteoporosis Against Disability(ROAD) Study. Int J Epidemiol 39, 988-995,
2010
Oka H, Muraki S, Akune T, Nakamura K,
Kawaguchi H, Yoshimura N: Normal andthreshold values of radiographic parameters forknee osteoarthritis using a computer-assisted
measuring system (KOACAD): The ROAD
Study. J Orthopaedic Science 15, 781-789, 2010
Muraki S, Akune T, Oka H, En-yo Y, Yoshida M,
Saika A, Suzuki T, Yoshida H, Ishibashi H,
Tokimura F, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Impact of knee andlow back pain on health-related quality of life inJapanese women: the Research on Osteoarthritis
Against Disability (ROAD). Mod Rheumatol 20,
444-451, 2010
Muraki S, Akune T, Oka H, Mabuchi A, En-yo Y,

384

Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Tokimura F, Yamamoto S, Nakamura
K, Kawaguchi H, Yoshimura N: Association ofradiographic and symptomatic knee osteoarthritis
with health-related quality of life in a
population-based cohort study in Japan: The
ROAD Study, Osteoarthritis Cartilage 18,
1227-1234, 2010
5. Yanaoka K, Oka M, Yoshimura N, Deguchi H,
Mukoubayashi C, Enomoto S, Maekita T, Inoue I,
Ueda K, Utsunomiya H, Iguchi M, Tamai H,
Fujishiro M, Nakamura Y, Tsukamoto T, Inada K,
Takeshita T, Ichinose M: Preventive effect of
etodolac, a selective cyclooxygenase-2 inhibitor,
on cancer development in extensive metaplastic
gastritis,aHelicobacter
pylori-negative
precancerous lesion. Int J Cancer 126,
1467-1473 , 2010
6. Dawson-Hughes B, Mithal A, Boonen S, Bonjour
JP, Burckhardt P, Ghada El-Hajj Fuleihan G EH,
Josse R, Lips P, Morales-Torres J, Yoshimura N,
for the IOF CSA Nutrition Working Group.
Vitamin D Recommendations for Older Adults.
Osteoporos Int 21, 1151-1154, 2010
7. Yoh K, Takata S, Yoshimura N, Hashimoto J:
Efficacy, torelability and safety of risedronate inJapanese patients with Paget’s disease of bone. J
Bone Miner Metab 28, 468-476, 2010
8. Enomoto S, Yanaoka K, Utsunomiya H, Niwa T,
Inada K, Deguchi H, Ueda K, Mukoubayashi C,
Inoue I, Maekita T, Nakazawa K, Iguchi M, Arii
K, Tamai H, Yoshimura N, Fujishiro M, Oka M,
Ichinose M: Inhibitory Effects of Japanese
Apricot (Prunus mume Siebold et Zucc.; Ume)on Helicobacter pylori-Related Chronic Gastritis.
Eur J Clin Nutri 64, 714-719, 2010
9. Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F,
Ohba S, Nishida N, Akune T, Yoshimura N,
Nakagawa T, Nakamura K, Tokunaga K, Chung
UI, and Kawaguchi H: Transcriptional regulationof endochondral ossification by HIF2A duringskeletal growth and osteoarthritis development.
Nature Med 16, 678-686, 2010
10. Orwoll ES, Nielson CM, Labrie F, BarrettConnor E, Cauley JA, Cummings SR, Ensrud K,
Karlsson M, Lau E, Leung PC, Lunggren Ö,
Mellström D, Patrick AL, Stefanick ML,

11.

12.

13.

14.

15.

Nakamura K, Yoshimura N, Zmuda J, Vandenput
L, Ohlsson C, for the Osteoporotic Fractures in
Men (MrOS) Research Group: Evidence for
geographical and racial variation in serum sex
steroid levels in older men. J Clin Endocrinol
Metab 95: E151-160, 2010
Tanaka S, Yoshimura N, Kuroda T, Hosoi T, Saito
M, Shiraki M:The Fracture and Immobilization
Score (FRISC) fo risk assessment of osteoporotic
fracture and immobilization in postmenopausal
women―A joint analysis of the Nagano, Miyama,
and Taiji Cohorts. Bone 47, 1064-1170, 2010
Muraki S, Akune T, Oka H, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Tokimura F, Yamamoto S, Nakamura
K, Kawaguchi H, Yoshimura N: Health-related
quality of life with vertebral fracture, lumbar
spondylosis and knee osteoarthritis in Japanesemen: The ROAD Study. Archives Osteoporos 5,91-99, 2010
Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Capacity of endogenous
sex steroids to predict bone loss, osteoporosis
and osteoporotic fracture in Japanese men:Ten-year follow-up of the Taiji Cohort Study. J
Bone Miner Metab 29, 96-102, 2011
Matsudaira K, Palmer KT, Reading I, Hirai M,
Yoshimura N, Coggon D: Prevalence andcorrelates of regional pain and associateddisability in Japanese workers. Occup Environ
Med 68, 191-196, 2011
Evangelou E, Valdes AM, Kerkhof HJ,
Styrkarsdottir U, Zhu Y, Meulenbelt I, Lories RJ,
Karassa FB, Tylzanowski P, Bos SD; arcOGEN
Consortium, Akune T, Arden NK, Carr A,
Chapman K, Cupples LA, Dai J, Deloukas P,
Doherty M, Doherty S, Engstrom G, Gonzalez A,
Halldorsson BV, Hammond CL, Hart DJ,
Helgadottir H, Hofman A, Ikegawa S, Ingvarsson
T, Jiang Q, Jonsson H, Kaprio J, Kawaguchi H,
Kisand K, Kloppenburg M, Kujala UM,
Lohmander LS, Loughlin J, Luyten FP, Mabuchi
A, McCaskie A, Nakajima M, Nilsson PM,
Nishida N, Ollier WE, Panoutsopoulou K, van dePutte T, Ralston SH, Rivadeneira F, Saarela J,
Schulte-Merker S, Shi D, Slagboom PE, Sudo A,
Tamm A, Tamm A, Thorleifsson G,

385

16.

17.

18.

19.

Thorsteinsdottir U, Tsezou A, Wallis GA,
Wilkinson JM, Yoshimura N, Zeggini E, Zhai G,
Zhang F, Jonsdottir I, Uitterlinden AG, Felson DT,
van Meurs JB, Stefansson K, Ioannidis JP,
Spector TD; Translation Research in Europe
AppliedTechnologies
forOsteoarthritis(TreatOA): Meta-analysis of genome-wide
association studies confirms a susceptibility
locus for knee osteoarthritis on chromosome
7q22. Ann Rheum Dis 70, 349-355, 2011, Epub2010 Nov 10.
Kerkhof HJ, Meulenbelt I, Akune T, Arden NK,
Aromaa A, Bierma-Zeinstra SM, Carr A, Cooper
C, Dai J, Doherty M, Doherty SA, Felson D,
Gonzalez A, Gordon A, Harilainen A, Hart DJ,
Hauksson VB, Heliovaara M, Hofman A,
Ikegawa S, Ingvarsson T, Jiang Q, Jonsson H,
Jonsdottir I, Kawaguchi H, Kloppenburg M,
Kujala UM, Lane NE, Leino-Arjas P, Lohmander
LS, Luyten FP, Malizos KN, Nakajima M, Nevitt
MC, Pols HA, Rivadeneira F, Shi D, Slagboom E,
Spector TD, Stefansson K, Sudo A, Tamm A,
Tamm AE, Tsezou A, Uchida A, Uitterlinden AG,
Wilkinson JM, Yoshimura N, Valdes AM, vanMeurs JB: Recommendations for standardizationand phenotype definitions in genetic studies ofosteoarthritis: the TREAT-OA consortium,.
Osteoarthritis Cartilage 19, 254-264, 2011. Epub2010 Nov 6
Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Association of knee
osteoarthritis with the accumulation of metabolicrisk factors such as overweight, hypertension,
dyslipidaemia, and impaired glucose tolerance inJapanese men and women: The ROAD Study, J
Rheum 38, 921-930, 2011. Epub 2011 Feb 15
Cooper C, Cole ZA, Holroyd CR, Earl SC,
Harvey NC, Dennison EM, Melton LJ3,
Cummings SR, Kanis JA and the IOF CSA
Working Group onFracture Epidemiology(Adachi J, Borgström F, Dimai HP, Clark P, Lau
E, Lewiecki EM, Lips P, Lorenc R, McCloskey E,
Ortolani S, Papaioannou A, Silverman S, Wahl
DA, Yoshimura N). Secular trends in theincidence of hip and other osteoporotic fractures.
Osteoporos Int 22, 1277-1288, 2011
Muraki S, Oka H, Akune T, En-yo Y, Yoshida M,

20.

21.

22.

23.

24.

25.

Nakamura K, Kawaguchi H, Yoshimura N:
Association of occupational activity with joint
space narrowing and osteophytosis in the medialcompartment at the knee: The ROAD study.
Osteoarthritis Cartilage 19, 840-846, 2011
Muraki S, Akune T, Oka H, En-yo Y, Yoshida M,
Saika A, Suzuki T, Yoshida H, Ishibashi H,
Tokimura F, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Health-related
quality of life in subjects with low back pain andknee pain in a population-based cohort study ofJapanese men: The ROAD study, Spine (Phila Pa
1976), in press
Inoue I, Mukoubayashi C, Yoshimura N, Deguchi
H, Watanabe M, Enomoto S, Maekita T, Ueda K,
Iguchi M, Yanaoka K, Tamai H, Oka M, Fujishiro
M, Takeshita T, Iwane M, Mohara O, Ichinose M:
Elevated risk of colorectal adenoma with
Helicobacter pylori-related chronic gastritis: A
population-based case-control study. Int J Cancer,
in press
Yoshimura N, Oka H, Muraki S, Kawaguchi H,
Nakamura K, Akune T: Changes in serum levelsof biochemical markers of bone turnover over 10
years among Japanese men and women:
associated factors and birth-cohort effect; The
Taiji Study. J Bone Miner Metab, in press,
Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Biochemical markers ofbone turnover as predictors for occurrence ofosteoporosis and osteoporotic fractures in men
and women: Ten-year follow-up of the Taiji
cohort study. Mod Rheumatol, in press
Muraki S, Akune T, Oka H, En-yo Y, Yoshida M,
Nakamura K, Kawaguchi H, Yoshimura N:
Prevalence of falls and its association with knee
osteoarthritis and lumbar spondylosis as well as
knee and low back pain in Japanese men andwomen. Arthritis Care & Research, in press
Muraki S, Oka H, Akune T, En-yo Y, Yoshida M,
Suzuki T, Yoshida H, Ishibashi H, Tokimura F,
Yamamoto S, Nakamura K, Kawaguchi H,
Yoshimura N: Indipendent association of joint
space narrowing and osteophyte formation at theknee with health-related quality of life in Japan:
A population-based cohort study. Arthritis Rheum,in press

386

Department of Health Management
and Policy
Associate Professor
Hideo Yasunaga, M.D., Ph.D.

Research Associate
Hiromasa Horiguchi, Ph.D.

Homepage

http://plaza.umin.ac.jp/~hmp/cgi-bin/wiki/wiki.cgi

Introduction and Organization
The Department of Health Management and Policy isan endowed department affiliated with the “22ndCentury Medical and Research Center,” which is a
new center of industry-academia collaboration
established by the University of Tokyo Hospital. With
donations from Nissay Information Technology Co.,
Ltd., the Department launched its first courses on
April 1, 2005. The cooperative department is the
Department of Medical Informatics and Economics,
Division of Social Medicine, Graduate School of
Medicine, University of Tokyo.
The objective of the Department’s activities is topromote interdisciplinary research designed to
improve the quality and efficiency of systems related
to health, medicine and nursing care. The mission of
our research activities is as follows:
1) Conduct research on evidence-based healthmanagement and policy
2) Bring the fruits of our research to society
Our strategies for fulfilling this mission are as
follows:
1) Develop and utilize a national database of Japan’s
Diagnosis Procedure Combination (DPC)
2) Collaborate with outside researchers in eachresearch project

Research Activities(1) Research activities of the DPC Research TeamOver the past three years, the Department has
participated in the DPC Research Team at the
Ministry of Health, Labour and Welfare. In
addition to providing support for the processing
and analysis of DPC data, we have announced theresults of these efforts. Since 2007, we have been
preparing a system using the Department’s server
to manage a database accumulated by the DPC
Research Team, which contains about 3 million
discharged cases every year.
(2) Other research activities
We have also put the following research into
practice.
(a)Research into cases of large-scale health hazards,
such as drug-induced sufferings(b) Research into the existence of, and chief causes
for, regional and departmental disparities in the
supply of doctors(c) Research into the links between the volume andoutcomes of surgical operations(d) Research into government regulations and thedisparity between domestic and overseas prices
of medical equipment(e) Research into the economic evaluation ofhealthcare services(f) Research into risk communication in foodhygiene(g) Research into the policy evaluation ofoccupational health, such as measures to prevent
karoshi (death from overwork)

387(h) Research on systems that contribute to medical
safety(i) Research for the sustainable development ofregional healthcare systems(j) Researchonnationwide
public-access
defibrillators and improvement of outcomes
after out-of-hospital cardiac arrests

7.

8.

References
1.

2.

3.

4.

5.

6.

Yasunaga H, Yanaihara H, Fuji K, Horiguchi H,
Hashimoto H, Matsuda S. Impact of hospital
volume on postoperative complications andin-hospital mortality following renal surgery:data from the Japanese diagnosis procedure
combination database. Urology 2010; 76: 548–
552
Yasunaga H, Horiguchi H, Kuwabara K,
Hashimoto H, Matsuda S. Clinical features ofBowel Anisakiasis in Japan. Am J Trop Med Hyg
2010; 83: 104-105
Yasunaga H, Shi Y, Takeuchi M, Horiguchi H,
Hashimoto H, Matsuda S, Ohe K. Measlesrelated Hospitalizations and Complications inJapan, 2007-2008. Intern Med 2010; 49: 19651970.
Yasunaga H, Horiguchi H, Tanabe S, Akahane M,
Ogawa T, Koike S, Imamura T. Collaborative
effects of bystander-initiated cardiopulmonary
resuscitation and prehospital advanced cardiac
life support by physicians on survival of out-ofhospital cardiac arrest: a nationwide populationbased observational study. Crit Care 2010;14(6):R199.
Kuwabara K, Matsuda S, Imanaka Y, Fushimi K,
Hashimoto H, Ishikawa KB, Horiguchi H,
Hayashida K, Fujimori K, Ikeda S, Yasunaga H.
Injury Severity Score, resource use, and outcome
for trauma patients within a Japaneseadministrative database. The Journal of Trauma:
Injury, Infection and Critical Care 2010;68(2):463-70.
Kadono Y, Yasunaga H, Horiguchi H, Hashimoto
H, Matsuda S, Tanaka S, Nakamura K. Statistics
in orthopaedic surgery 2006-2007: Data from theJapanese Diagnosis Procedure Combination(DPC) database. J Ortho Sci 2010; 15: 162-70

9.

10.

11.

12.

13.

Horiguchi H, Yasunaga H, Hashimoto H,
Matsuda S. Impact of drug-eluting stents ontreatment option mix for coronary artery diseasein Japan. Circ J 2010;74(8):1635-1643.
Matsui H, Hashimoto H, Horiguchi H, Yasunaga
H, Matsuda S. An exploration of the association
between very early rehabilitation and outcome
for the patients with acute ischaemic stroke inJapan: a nationwide retrospective c2ohort survey.
BMC Health Services Research 2010;10:213.
Ide H, Koike S, Yasunaga H, Kodama T, Ohe K,
Imamura T. Long-term Career Transition in the
Surgical Workforce of Japan: A Retrospective
Cohort Study Using the Nationwide Survey ofPhysicians Data from 1972 to 2006. World J Surg
2010;34(8):1748-1755.
Koike S, Ide H, Yasunaga H, Kodama T,
Matsumoto S, Imamura T. Postgraduate training
and career choices: an analysis of the National
Physicians Survey in Japan. Medical Education
2010；44: 289-297
Koike S, Kodama T, Matsumoto S, Ide H,
Yasunaga H, Imamura T. Residency Hospital
Type and Career Paths in Japan: An Analysis of
Physician Registration Cohorts. Medical Teacher
2010 in press.
Koike S, Kodama T, Matsumoto S, Ide H,
Yasunaga H, Imamura T. Retention rate ofphysicians in public health administration
agencies and their career paths in Japan. BMC
Health Services Research 2010, 10:101
Koike S, Matsumoto S, Kodama T, Ide H,
Yasunaga H, Imamura T. Specialty choice andphysicians’ career paths in Japan: An analysis of
National Physician Survey data from 1996 to
2006. Health Policy 2010;98:236-244.

388

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/english/center22/en_contribute/computer.html

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.
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
themes include image analysis such as computerassisted 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 thehospital 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.

3892) Image processing software development
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 ofsoftware, and epidemiological studies
Researches based on the health-screening database arecarried out in collaboration with other researchers ofvarious specialties. Images are analyzed using thedeveloped software.

References
1.

2.

3.

4.

Hanaoka S, Nomura Y, Nemoto M, Masutani Y,
Maeda E, Yoshikawa T, Hayashi N, Yoshioka N,
Ohtomo K. Automated segmentation method forspinal column based on a dual elliptic column
model and its application for virtual spinal
straightening. J.Comput. Assist. Tomogr.; 34(1):156-162 2010.
Nomura Y, Hayashi N, Masutani Y, Yoshikawa
T, Nemoto M, Hanaoka S, Miki S, Maeda E,
Ohtomo K. CIRCUS: an MDA Platform for
Clinical
Image
Analysisin
Hospitals.
Transactions on Mass-Data. Transactions on
Mass-Data Analysis of Images and Signals;
2(1):112-127 2010.
Takao H, Abe O, Hayashi N, Kabasawa H,
Ohtomo K. Effects of gradient non-linearity
correction
andintensity
non-uniformity
correction in longitudinal studies using structural
image evaluation using normalization of atrophy(SIENA). J.Magn. Reson. Imaging; 32(2):489492 2010.
Furukawa R, Akahane M, Yamada H, Kiryu S,
Sato J, Komatsu S, Inoh S, Yoshioka N, Maeda E,
Takazawa Y, Ohtomo K. Endometrial stromal
sarcoma located in the myometrium with a
low-intensity rim on T2-weighted images: reportof three cases and literature review. J.Magn.
Reson. Imaging; 31(4):975-979 2010.
5. Inano S, Itoh D, Takao H, Hayashi N, Mori H,
Kunimatsu A, Abe O, Aoki S, Ohtomo K. Highsignal intensity in the dural sinuses on 3D-TOF
MR angiography at 3.0 T. Clin. Imaging; 34(5):332-336 2010.
6. Nishimura S, Nagasaki M. In vivo imaging
reveals chronic inflammation and abnormal local
immunity in obese adipose tissue]. Seikagaku;
82(9):832-836 2010.
7. Yasmin H, Kabasawa H, Aoki S, Abe O,
Masutani Y, Hayashi N, Ohtomo K.
Motion-robust diffusion tensor acquisition atroutine 3T magnetic resonance imaging. Jpn.
J.Radiol.; 28(1):27-33 2010.
8. Ueda K, Watadani T, Maeda E, Ota S, Kataoka K,
Seo S, Kumano K, Hangaishi A, Takahashi T,
Imai Y, Ohtomo K, Fukayama M, Nannya Y,
Kurokawa M. Outcome and treatment of lateonset noninfectious pulmonary complications
after allogeneic haematopoietic SCT. Bone
Marrow Transplant.; 45(12):1719-1727 2010.
9. Nakajima T, Kurano M, Hasegawa T, Takano H,
Iida H, Yasuda T, Fukuda T, Madarame H, Uno K,
Meguro K, Shiga T, Sagara M, Nagata T,
Maemura K, Hirata Y, Yamasoba T, Nagai R.
Pentraxin3 and high-sensitive C-reactive protein
are independent inflammatory markers released
during high-intensity exercise. Eur J Appl
Physiol. 2010 Nov; 110(5):905-13.
10. Nakamura K, Igarashi K, Ohkawa R, Saiki N,
Nagasaki M, Uno K, Hayashi N, Sawada T,
Syukuya K, Yokota H, Arai H, Ikeda H, Aoki J,
Yatomi Y. A novel enzyme immunoassay for thedetermination of phosphatidylserine-specificphospholipase A(1) in human serum samples.
Clin. Chim. Acta; 411:1090-1094 2010.

390

Department of Hospital
Environment
Project Associate Professor
Yushi Uetera, MD. Ph.D.

Project Associate
Yuhei Saito M.Sc.
※For this department, this year’s text is the same as that published last year.

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 theperi-operative 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. Evaluation of the efficacy of a low temperature
steam and formaldehyde steriliser by using
biological indicators. R. Saio, Y. Uetera, Y. Saito,
N. Okamura, K. Moriya, K. Koike. Journal of
Hospital Infection. Vol.73. No.2, pp179-180,
2009.
2. Studies on Viral Disinfection: An Evaluation ofMoist Heat Disinfection for HBV by Using A0
Concept defined in ISO 15883-WasherDisinfectors. Y. Uetera, K. Kawamura, H.
Kobayashi, Y. Saito. PDA Journal of
Pharmaceutical Science and Technology. Vol.64.
No.4, pp327-336, 2010

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391

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.

Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F,
Ohba S, Nishida N, Akune T, Yoshimura N,
Nakagawa T, Nakamura K, Tokunaga K, Chung
UI, Kawaguchi H: Transcriptional regulation of
endochondral ossification by HIF2A duringskeletal growth and osteoarthritis development.
Nat Med 16: 678-686, 2010.
Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Cohort profile: researchon osteoarthritis/osteoporosis against disability
study. Int J Epidemiol 39: 988-995, 2010.
Muraki S, Akune T, Oka H, En-yo Y, Yoshida M,
Saika A, Suzuki T, Yoshida H, Ishibashi H,
Tokimura F, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Impact of knee andlow back pain on health-related quality of life inJapanese women: The Research on Osteoarthritis
Against Disability (ROAD). Mod Rheumatol 20:
444-454, 2010.
Muraki S, Akune T, Oka H, En-yo Y, Saika A,
Suzuki T, Yoshida H, Ishibashi H, Tokimura F,
Yamamoto S, Nakamura K, Kawaguchi H,
Yoshimura N: Health-related quality of life withvertebral fracture, lumbar spondylosis and knee

392

5.

6.

7.

8.

9.

osteoarthritis in Japanese men: the ROAD study.
Arch Osteoporos 5: 91-99, 2010.
Muraki S, Akune T, Oka H, Enyo Y, Yoshida M,
Saika A, Suzuki T, Yoshida H, Ishibashi H,
Tokimura F, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Association ofradiographic and symptomatic knee osteoarthritis
with health-related quality of life in a
population-based cohort study in Japan: theROAD study Osteoarthritis Cartilage 18:
1227-1234, 2010.
Oka H, Muraki S, Akune T, Nakamura K,
Kawaguchi H, Yoshimura N: Normal andthreshold values of radiographic parameters forknee osteoarthritis using a computer-assisted
measuring system (KOACAD): the ROAD study.
J Orthop Sci 18: 1227-1234, 2010.
Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Capacity of endogenous
sex steroids to predict bone loss in Japanese men:
10-year follow-up of the Taiji Cohort study. J
Bone Miner Metab (in press).
Kerkhof HJ, Meulenbelt I, Akune T, Arden NK,
Aromaa A, Bierma-Zeinstra SM, Carr A, Cooper
C, Dai J, Doherty M, Doherty SA, Felson D,
Gonzalez A, Gordon A, Harilainen A, Hart DJ,
Hauksson VB, Heliovaara M, Hofman A,
Ikegawa S, Ingvarsson T, Jiang Q, Jonsson H,
Jonsdottir I, Kawaguchi H, Kloppenburg M,
Kujala UM, Lane NE, Leino-Arjas P, Lohmander
LS, Luyten FP, Malizos KN, Nakajima M, Nevitt
MC, Pols HA, Rivadeneira F, Shi D, Slagboom E,
Spector TD, Stefansson K, Sudo A, Tamm A,
Tamm AE, Tsezou A, Uchida A, Uitterlinden AG,
Wilkinson JM, Yoshimura N, Valdes AM, vanMeurs JB: Recommendations for standardizationand phenotype definitions in genetic studies ofosteoarthritis: the TREAT-OA consortium.
Osteoarthritis Cartilage (in press).
Evangelou E, Valdes AM, Kerkhof HJ,
Styrkarsdottir U, Zhu Y, Meulenbelt I, Lories RJ,
Karassa FB, Tylzanowski P, Bos SD; arcOGEN
Consortium, Akune T, Arden NK, Carr A,
Chapman K, Cupples LA, Dai J, Deloukas P,
Doherty M, Doherty S, Engstrom G, Gonzalez A,
Halldorsson BV, Hammond CL, Hart DJ,
Helgadottir H, Hofman A, Ikegawa S, Ingvarsson

10.

11.

12.

13.

14.

T, Jiang Q, Jonsson H, Kaprio J, Kawaguchi H,
Kisand K, Kloppenburg M, Kujala UM,
Lohmander LS, Loughlin J, Luyten FP, Mabuchi
A, McCaskie A, Nakajima M, Nilsson PM,
Nishida N, Ollier WE, Panoutsopoulou K, van dePutte T, Ralston SH, Rivadeneira F, Saarela J,
Schulte-Merker S, Shi D, Slagboom PE, Sudo A,
Tamm A, Tamm A, Thorleifsson G,
Thorsteinsdottir U, Tsezou A, Wallis GA,
Wilkinson JM, Yoshimura N, Zeggini E, Zhai G,
Zhang F, Jonsdottir I, Uitterlinden AG, Felson DT,
van Meurs JB, Stefansson K, Ioannidis JP,
Spector TD; Translation Research in Europe
AppliedTechnologies
forOsteoarthritis(TreatOA): Meta-analysis of genome-wide
association studies confirms a susceptibility locus
for knee osteoarthritis on chromosome 7q22. Ann
Rheum Dis (in press).
Akune T, Kawaguchi H: Human genetic studies
on osteoarthritis from clinicians' viewpoints.
Osteoarthritis Cartilage (in press).
Muraki S, Akune T, Oka H, Enyo Y, Yoshida M,
Saika A, Suzuki T, Yoshida H, Ishibashi H,
Tokimura F, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Health-related
quality of life in subjects with low back pain andknee pain in a population-based cohort study ofJapanese men: the ROAD study. Spine (Phila Pa
1976) (in press)
Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Association of Knee
osteoarthritis with the accumulation of metabolicrisk factors such as overweight, hypertension,
dyslipidemia, and impaired glucose tolerance inJapanese men and women: the ROAD study. J
Rheumatol (in press).
Muraki S, Oka H, Akune T, Enyo Y, Yoshida M,
Nakamura K, Kawaguchi H, Yoshimura N:
Association of occupational activity with joint
space narrowing and osteophytosis in the medialcompartment of the knee: the ROAD study.
Osteoarthritis Cartilage (in press).
Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Changes in serum levelsof biochemical markers of bone turnover over 10
years among Japanese men and women:
associated factors and birth-cohort effect; the393

Taiji study. J Bone Miner Metab (in press).
15. Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Biochemical markers ofbone turnover as predictors for occurrence ofosteoporosis and osteoporotic fractures in men
and women: Ten-year follow-up of the Taiji
cohort study. Mod Rheumatol (in press)

394

Department of Health Care Safety
Management
Project Professor
Yasushi Kodama, M.D., LL.M., Ph.D.

Project Assistant Professor
Kenji Harada, M.D., Ph.D.

Project Researcher
Tomoko Takahashi, M.H.Sc.,
Maiko Mizuki, M.P.H.

Homepage http://www.h.u-tokyo.ac.jp/center22/iryou_anzen.html
http://square.umin.ac.jp/MSMCM/
Introduction and Organization
The Department of Health Care Safety Management
was established in the 22nd century medical center of
the University of Tokyo Hospital by the contributionof 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 themandatory reporting to the police by the Medical
Practitioners Law Article 21. Some events becometargets of investigations while several verdicts are put
out as acquittals. There exist various discussions andconfusions over the intervention of the police
authority procedures to the process 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 health carelawsuit number has kept increasing from 1970s (about
100 new cases received per year) to 2004 (1110 new
cases per year), by the pace that doubled every ten
years. Though the civil affairs health care lawsuit
number shows a decreasing tendency after 2004, a lotof medical treatment disputes became lawsuits in 2009,
733 new cases received and 952 cases paid-up.
In our department, while looking straight at the realityof the malpractice and the medical affairs dispute fromeach aspect of the patient, the health care provider,and the society, it aims at a healthy rebuilding of thehealth care and the recovery of confidence 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 healthcare provider.

395

Research activities

the site and education for staff of the site.

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
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.

References

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 the 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 from

Research Article
1. Shiho Andoh, Tomoko Takahashi, Maiko Mizuki,
Kenji Harada, Yasushi Kodama. Current status of
the medical safety support center in Japan. The
Japanese Journal of Quality and Safety in
Healthcare. 2010:5(4):296-305 (in Japanese)
Review Articles
1. Yasushi Kodama. Risk management for
emergency outpatient's care. Separate volume of
ER magazine. 2010;7(2):152-162 (in Japanese)
2. Yasushi Kodama. Looking back on ten years forpatient safety and medical affairs dispute. ICU
and CCU. 2010;34(10):870-876 (in Japanese)Books
1. Beginning of healthcare safety management.
Kazue Nakajima, Yasushi Kodama, Hiroko Dan,Aoi Uema, Hiroyuki Shinkai, Ryoko Takahashi,
Kentaro Shimizu, Tomo Ikejiri, Hiroshi Takeda,
Tsunesaburo Andoh, Kenji Harada, Tetsuro
Miyata, Atsuko Abe, Shin Ushiro, Kanako
Tsushima, Robert B. Lefler.
Igaku-Shoin,
Tokyo, 2010 (in Japanese).
2. Healthcare Safety Education. Tsuyoshi Morimoto,
Kazeu Nakajima, Kunio Yanagida, TakahiroSoma, Kenichiro Tanada, Kenji Tanaka, Ryoko
Sugiyama, Tsuyoshi Hasegawa, Atsushi Asai,
Yasushi Kodama, Yasuyuki Sahara, Shin Ushiro,
Keiko Yamauchi, Atushi Hirade, Yoshitaka Wada,
Masae Ootani, Keiichi Ikegami, Mikio Doi,
Atsushi Ohkawa, Shunzo Koizumi. Shinohara
Shuppan Shinsha. Tokyo, 2010 (in Japanese).
3. Healthcare and hospital management term
cyclopedia (new edition). Japanese society for
healthcare and hospital management. Yasushi
Kodama, et al. Ichigaya Shuppansha, Tokyo.
2011 (in Japanese).
4. Patient’s right and healthcare safety: trying tosearch the ideal way of relationship between thehealthcare and the law. Hutoshi Iwata, Norio
Higuchi, Hiroko Tsuchiya, Ryoko Hatanaka,
Keiko Sato, Yukiko Oda, Kouichiro Kido,

396

5.

6.

Yuuichiro Sato, Manabu Agatsuma, Chiaki Sato,
Tomoko Koyama, Jun Izawa, Yuuka Ishikawa,
Naoko Akimoto, Ken Mizuno, Yasushi Kodama.
Minerva shobou, Tokyo. 2011 (in Japanese).
Thinking about the healthcare safety management.
Kenji Harada. Iryobunya Teikei Kyougikai,
Hyogo. 2011 (in Japanese).
Measures against safety management you should
know. Shiho Ando. Primed-sha, Osaka. 2011
(in Japanese).

Conference Presentations
International Meetings
1. Shiho Andoh. Analysis of medical complaints
and consultations at patient safety support
centers in Japan. 2010 NPSF Annual Patient
Safety Congress. 18-19 May 2010.
2. Shiho Andoh, Kenji Harada, Yasushi Kodama.
Relationship among civil litigation, negligence,complaint, adverse event and medical practiceassociated death in Japan. 8th AustralasianConference on Safety and Quality in HealthCare. 6-8 September 2010.
Domestic Meetings
1. Yasushi Kodama. Expectation for Japanese
healthcare safety investigation mechanism.
Japanese Surgical Society 110th annual scientificmeeting.
2. Yasushi Kodama. Thinking about the next ten
years for the view of healthcare safety and dispute.
Japanese Pediatric Society 113th annual scientificmeeting.
3. Yasushi Kodama. Healthcare safety and dispute.
Japanese Orthopaedic Association 83rd annual
scientific meeting.
4. Yasushi Kodama. Can a human error be judged?
Can the life be defended by the penalty? JapaneseSociety for Quality and Safety in Healthcare 5th
annual scientific meeting.
5. Yasushi Kodama. Healthcare and the law. 5th
Annual Congress of Japanese Society for Quality
and Safety in Healthcare.
6. Kenji Harada. Akira Akabayashi, Sadayuki
Takimoto, Susumu Nakajima, Yasushi Kodama.
Guideline decision of "Range where informed
consent acquisition by document is necessary"

based on congressional questionnaire survey. 5th
Annual Congress of Japanese Society for Quality
and Safety in Healthcare.
7. Shiho Andoh, Tomoko Takahashi, Maiko Mizuki,
Kenji Harada, Yasushi Kodama. Investigation
report concerning current state of management ofpatient safety support centers. 5th Annual
Congress of Japanese Society for Quality and
Safety in Healthcare.
8. Shiho Andoh, Mayumi Yoshimura, Akiko
Kuniyoshi, Nana Tanaka, Tomoko Takahashi,
Maiko Mizuki, Kenji Harada, Yasushi Kodama.
Making of consultation guidebook 2009 forpatient safety support center staff. 5th Annual
Congress of Japanese Society for Quality and
Safety in Healthcare.
9. Tomoko Takahashi, Shiho Andoh, Maiko Mizuki,
Kenji Harada, Yasushi Kodama. Execution reportof training association and delivery course
intended for patient, resident, and medical
institution by using education and theenlightenment slide 'To become a wise patient.'
5th Annual Congress of Japanese Society for
Quality and Safety in Healthcare.

397

Division of Molecular
Cardiovascular Metabolism(Daiichi-Sankyo Company, Limited)
Research Associate Professor
Katsuyuki Ando, M.D., Ph.D.

Research Associate
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 April 1, 2006. This divisionconsists of the above-mentioned two staffs and a few
part-time staff and graduate fellows. Our academic
activity is majorly basic research using animals.
However, we also participate in clinical research.

Teaching activities
In March of 2007, 2008, and 2010, total three graduate
fellows took the medical degree. And now a few
graduate fellows work 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 (RAAS) in the pathophysiology ofsalt-sensitive hypertension, metabolic syndrome, andtheir reno-cardiovascular complication.
For
example,wedemonstrated
that
sympathoexcitation by oxidative stress in the brain
mediated blood pressure (BP) elevation in salt-sensitive
hypertension and that obesity-induced hypertension.
Actually, high fat intake and salt excess synergisticallyincrease BP and progress organ damage. Recently, ourdata suggest that the similar central mechanism
contributes to increase in BP and progression of renal
damage in chronic kidney disease. This finding
suggests that sympathoexcitation by ROS in the brain is
a commonand important mechanism for
pahtophysiology of many types of hypertensive disease.
Recently, we elucidated the role of brain aldosterone in
ROS-induced central sympathoactivation in these typesof hypertension. In addition, we suggested that
sympathoactivation contribute to glomerular injury inchronic kidney disease models using glomerulusspecific delivery system of thyrosine hydroxylase
siRNA.
Also, we demonstrated that prepubertal saltloading caused more sever hypertension and renal
injury compared with high salt intake in adulthoodprobably due to mineralocorticoid receptor (MR)
activation, inflammatory and oxidant action, and rac-1
activation (6). This investigation may clarify thepathophsiology of deflective lifestyle-induced
hypertension and renal damage in prepubertal age.

398

In addition, we suggested that MR activation also
contribute to the development of inflammationinduced renal injury, such as lupus nephritis. We arefurther examining the role of MR in lupus nephritis.
Clinical investigation: Now, we are doing
coordinating and secretarial work of a few clinical
trials in the Department of Nephrology and
Endocrinology, and join as a steering committee ofclinical trial of the other institute.
We are investigation a common disease such as
hypertension and metabolic syndrome, and can
indicate meaningful results.

References
1. Teramoto T, Shimada K, Uchiyama S, Sugawara M,
Goto Y, Yamada N, Oikawa S, Ando K, Ishizuka N,
Yamazaki T, Yokoyama K, Murata M, Ikeda Y:
Rationale, design, and baseline data of the JapanesePrimary Prevention Project (JPPP)—A randomized
open-label controlled trial of aspirin versus noaspirin in patients with multiple risk factors for
vascular events. Am Heart J 2010; 159(3):361-369.e4.
2. Ando K, Ohtsu H, Arakawa Y, Kubota K,
Yamaguchi T, Nagase M, Yamada A, Fujita T:
Rationale and design of the Eplerenone Combination
Versus Conventional Agents to Lower Blood
Pressure on Urinary Antialbuminuric Treatment
Effect (EVALUATE) Trial: A double-blindedrandomized placebo-controlled trial to evaluate theantialbuminuric effects of an aldosterone blocker inhypertensive patients with albuminuria. Hyperterns
Res 2010; 33(6): 616-621.
3. Kawarazaki H, Ando K, Nagae A, Fujita M, Matsui
H, Fujita T. Mineralocorticoid receptor activation
contributes to salt-induced hypertension and renal
injury in prepubertal Dahl salt-sensitive rats.
Nephrol Dial Transplant. 2010; 25(9):2879-2889.
4. Ishikawa A, Kawarazaki H, Ando K, Fujita M,
Fujita T, Homma Y. Renal preservation effect ofubiquinol, the reduced form of coenzyme Q10.
Clin Exp Nephrol 2011; 15(1): 30-33.
5. Kobayashi-Torii M, Takahashi Y, Sunanaga J,
Fujita M, Lee E-Y, Ichimaru Y, Fujita T, Kanmura
Y, Kuwaki T. Possible participation of
extracellular calcium-sensing receptor in bloodpressure regulation in rats. Brain Res 2011; 1367:
181-817.
6. Ando K, Fujita M. Reactive oxygen species andthe central nervous system in salt-sensitive
hypertension: possible relationship to obesityinduced hypertension. Clin Exp Pharmacol
Physiol. 2011; in press.
7. Kawarazaki H, Ando K, Fujita M, Matsui H,
Nagae A, Muraoka K, Kawarasaki C, Fujita T.
Mineralocorticoid receptor activation: a major
contributor to salt-induced renal injury andhypertension in young rats. Am J Physiol Renal
Physiol. 2011; in press

399

Department of Healthcare Quality
Assessment
Associate Professor
Hiroaki Miyata, Ph.D.

Assistant Professor
Hiroyuki Tsukihara, M.D., Ph.D.
Suguru Okubo, Ph.D.

Researcher
Ai Tomotaki, R.N., M.S.

Homepage

http://hqa.umin.jp/

Introduction and Organization
The Department of Healthcare Quality Assessment(HQA) was established in 2006 and performs
researches on healthcare quality improvement incollaboration with the Department of Cardiothoracic
Surgery in University of Tokyo. HQA has collaborated
with the Department of Health Economics andEpidemiology Research from 2009 and with the
Department of Pediatric Surgery from 2010.
Health care reform should be focus on improving
health and health care value for patients. As improving
the value of health care is something only medical
teams can do, HQA has collaborated with healthcare
professional committees. HQA supports systematic
data collection, data management, practical analysis
and useful feedback. Our benchmarking projects
based on clinical database and will drive quality
improvement in each field. With such positive-sum
competition, patients will receive better care,
physicians will be rewarded for excellence, and costs
will be contained. Three principles should guide thischange: (a) the goal is value for patients, (b) medical
practice should be organized around medical
conditions and care cycles, and (c) results —risk-adjusted outcomes and costs — must be measured.

HQA already developed risk models and provide
several practical tools for medical staff through joint
research with Japan Cardiovascular Surgery Database(JCVSD). One of practical tools is JapanSCORE
which allows a user to calculate a patient’s risk ofmortality and other morbidities. JapanSCORE
incorporates JCVSD risk models that are designed toserve as statistical tools to account for the impact ofpatient risk factors on operative mortality andmorbidity. HQA also conducted policy analysis andclinical researches which might contribute tohealthcare
quality
improvement.
Value-based
competition on results provides a path for reform thatrecognizes the role of healthcare professionals at theheart of the system.

Research activities
For healthcare quality improvement, a) healthcare
quality must be identified and b) quality indicators
must be set and monitored in each healthcare region.
A well-designed database system that collects clinicaldata continuously in reliable and validated manners isneeded to identify healthcare quality, monitor quality
indicators, and improve the quality of healthcare
services. HQA has designed and managed nationwide
database systems in collaboration with the Japan

400

Surgical Society, the Japanese Society for
Cardiovascular Surgery and the Japanese Society of
Gastroenterological Surgery.
Severity-adjusted indicators must be used forinvestigating clinical outcomes and exploring thesystems providing the best practices to patients. HQA
developed risk models and conducts outcome analyses
based on systematic data collection. These analyses
enable risk assessment and prognosis prediction ofcardiovascular surgeries and benchmarking of thedatabase-participating facilities. This information isuseful for discussion in pre-surgery conference,patients’ better understanding of treatment andpromotion of healthcare quality improvement.

References
1. Hiroaki Miyata, Hideki Hashimoto, Hiromasa
Horiguchi, Kiyohide Fushimi, Shinya Matsuda.
Assessment of hospital performance with acase-mix standardized mortality model using an
existing administrative database in Japan. BMC
Health Serv Res 2010; 10: 130.
2. Noboru Motomura, Hiroaki Miyata, Hiroyuki
Tsukihara,
ShinichiTakamoto;Japan
Cardiovascular Surgery Database Organization.
Risk model of valve surgery in Japan using theJapan Adult Cardiovascular Surgery Database. J
Heart Valve Dis 2010; 19(6): 684-691.
3. Hiroyuki Suzuki, Mitsukazu Gotoh, Kenichi
Sugihara, Yuko Kitagawa, Wataru Kimura,
Satoshi Kondo, Mituso Shimada, Naohiro Tomita,
Tohru Nakagoe, Hideki Hashimoto, Hideo Baba,
Hiroaki Miyata, Noboru Motomura. Nationwide
survey and establishment of a clinical database forgastrointestinal surgery in Japan: Targeting
integration of a cancer registration system andimproving the outcome of cancer treatment.
Cancer Sci 2011; 102(1): 226-230.
4. Kazuaki Kuwabara, Shinya Matsuda, Kiyohide
Fushimi, Koichi B. Ishikawa, Hiromasa Horiguchi,
Kenji Fujimori, Hideo Yasunaga, Hiroaki Miyata.
Quantitative assessment of the advantages oflaparoscopic gastrectomy and the impact ofvolume-related hospital characteristics on
resource use and outcomes of gastrectomy

patients in Japan. Ann Surg 2011; 253(1): 64-70.

Presentation
1. Satoshi Mogi, Shun Kohsaka, Hiroaki Miyata,
Akio Kawamura, Shigetaka Noma, Masahiro
Suzuki, Takashi Koyama, Shiro Ishikawa,
Yukihiro Momiyama, Susumu Nakagawa,
Koichiro Sueyoshi, Shunsuke Takagi, Toshiyuki
Takahashi, Shinichi Takamoto, Satoshi Ogawa,Keiichi
Fukuda.
Percutaneous
coronary
intervention for acute coronary syndrome
comparison between weekend versus weekday
presentation. American College of Cardiology
11& i2 Summit 2011, New Orleans. 2011/4.
2. Ayaka Endo, Shun Kohsaka, Hiroaki Miyata, Akio
Kawamura, Shigetaka Noma, Masahiro Suzuki,
Takashi Koyama, Shiro Ishikawa, Yukihiro
Momiyama, Susumu Nakagawa, Koichiro
Sueyoshi, Shunsuke Takagi, Toshiyuki Takahashi,
Shinichi Takamoto, Satoshi Ogawa, Keiichi
Fukuda. Who will not receive optimized medical
therapy after percutaneous coronary intervention?
Analysis from Japanese prospective multicenter
registry. American College of Cardiology 11& i2
Summit 2011, New Orleans. 2011/4.
3. Aya Saito, Noboru Motomura, Hiroaki Miyata,
Shinichi Takamoto, Shunei Kyo, Minoru Ono.
Age specific risk stratification in 11948 isolated
CABG procedures. The 24th EACTS Annual
Conference, Geneva. 2010/9.
4. Mayo Suzuki, Suguru Okubo, Iori Tani, Wakaha
Ikeda, Kazuhito Yokoyama, Fumio Kitamura.
Early symptoms of mental health problems in
employees and their support needs. The 11th
International Congress of Behavioral Medicine,
Washington, DC, USA. 2010/8.
5. Hiroaki Miyata, Noboru Motomura, Arata
Murakami,
ShinichiTakamoto;Japan
Cardiovascular Surgery Database. Effects of thebenchmarking project on outcomes of CABG
surgery: challenges and prospects regarding
quality improvement initiative in JAPAN.
American Heart Association: Quality of Care andOutcome Research in Cardiovascular Disease andStroke Conference 2010, Washington D.C.
2010/5.
6. Noboru Motomura, Hiroaki Miyata, Hiroyuki

401

Tsukihara,
ShinichiTakamoto;Japan
Cardiovascular Surgery Database. Off-pumpprocedure reduced the risk adjusted mortality ofcoronary artery bypass surgery by half incomparison
withconventional
procedure.
Propensity score analysis from the Japanese
National Database (JACVSD). American Heart
Association: Quality of Care and Outcome
Research in Cardiovascular Disease and Stroke
Conference 2010, Washington D.C. 2010/5.
7. Noboru Motomura, Hiroaki Miyata, Hiroyuki
Tsukihara,
ShinichiTakamoto;Japan
Cardiovascular Surgery Database. Off-pumpprocedure reduced the risk adjusted mortality ofcoronary artery bypass surgery by half incomparison
withconventional
procedure.
Propensity score analysis from the Japanese
National Database (JACVSD). 59th ESCVS,
Izmir, Turkey. 2010/4.
8. Hiroaki Miyata, Noboru Motomura, Shinichi
Takamoto. How to handle the cardiovascularsurgery data in Asia. Asian Society ofCardiovascular Thoracic Surgery Annual Meeting,
Delhi, India. 2010/3.
9. Noboru Motomura, Hiroaki Miyata, Shinici
Takamoto. New challenge. Starting up the Asian
Cardiovascular Surgery Database. Asian Societyof Cardiovascular Thoracic Surgery Annual
Meeting, Delhi, India. 2010/3.
10. Aya Saito, Noboru Motomura, Hiroaki Miyata,
Shunei Kyo, Hiroyuki Tsukihara, Minoru Ono,
Shinichi Takamoto. The excellent performance ofoff-pump coronary artery bypass grafting foroctage-, nonage-, and centenarians–analysis ofJapanese National Database. The 18th ASCVSAnnual Meeting, New Dehli, India. 2010/2.

402

Department of Anti-Aging
Medicine
Professor
Satoshi Inoue, M.D., Ph.D.

Research Associate
Tomohiko Urano, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/research/center22/contribute/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. This
department has a close relationship with the
Department of Geriatric Medicine at the Graduate
School of Medicine, University of Tokyo. The goal ofthis 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
age-dependent changes at cellular, tissue, andwhole-body levels, and will contribute to thedevelopment of molecule-targeted treatment andalternative prevention of age-related processes anddiseases.

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 anotherimportant role in antiviral defenses. Extending our
findings on TRIM25, we also study the functions ofother TRIM proteins in normal states and in cancer
and immune response, including TRIM5α, TRIM17(Terf), TRIM44 and TRIM63.
2. Using chromatin immunoprecipitation microarray403

analysis and systems biology approach, we
discovered novel androgen responsive genes
including UGT1A1, CDH2, APP, and FOXP1. The
tumor-promoting effect of APP has been shown inin vivo models of prostate cancer.
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.
Through genome-wide associated study andcandidate gene approach, we identify several
interesting disease-related genes and focus on thefunctional studies for these genes. We also combine
mouse genetics to solve the functions ofdisease-related genes in physiological states as wellas 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. Poeck H, Bscheider M, Gross O, Finger K, Roth S,
Rebsamen M, Hannesschlager N, Schlee M,
Rothenfusser S, Barchet W, Kato H, Akira S,
Inoue S, Endres S, Peschel C, Hartmann G,
Hornung V, Ruland J: RIG-I is a dual activator of
Card9 and inflammasome signaling for IL-1β
production upon RNA virus recognition. Nat
Immunol 11, 63-69, 2010.
2. Ikeda K, FukushimaT, Ogura H, Tsukui T,
Mishina M, Muramatsu M, Inoue S: Estrogen
regulates the expressionof N-methl-D-aspartate(NMDA) receptor subunit epsilon 4 (Grin2d), thatis essential for the normal sexual behavior infemale mice. FEBS Lett 584, 806-810, 2010.
3. Urano T, Narusawa K, Kobayashi S, Shiraki M,
Horie-Inoue K, Sasaki N, Hosoi T, Ouchi Y,
Nakamura T, Inoue S: Association of HTRA1
promoter polymorphism with spinal discdegeneration in Japanese women. J Bone Miner
Metab 28, 220-226, 2010.
4. Fujimura T, Takahashi S, Urano T, Ijichi N, Ikeda

K, Kumagai J, Murata T, Takayama K,
Horie-Inoue K, Ouchi Y, Muramatsu M, Homma
Y, Inoue S: Differential expression of
estrogen-related receptors β and γ (ERRβ and
ERRγ) and their clinical significance in humanprostate cancer. Cancer Sci 101, 646-651, 2010.
5. Azuma K, Urano T, Ouchi Y, Inoue S:
Glucocorticoid-induced gene tripartite motifcontaining 63 (TRIM63) promotes differentiationof osteoblastic cells. Endocr J 57, 455-462, 2010.
6. Mori K, Horie-Inoue K, Gehlbach PL, Takita H,
Kabasawa S, Kawasaki I, Ohkubo T, Kurihara S,
Iizuka H, Miyashita Y, Katayama S, Awata T,
Yoneya S, Inoue S: Phenotype and Genotype
Characteristics
ofAge-related
MacularDegeneration in a Japanese Population.
Ophthalmol 117, 928-938, 2010.
7. Kurosawa T, Hiroi H, Momoeda M, Inoue S,
Taketani Y: Clomiphene citrate elicits estrogenagonistic/antagonistic effects differentially via
estrogen receptors α and β. Endocr J 57, 517-521,
2010
8. Urano T, Shiraki M, Usui T, Sasaki N, Ouchi Y,
Inoue S: Identification of non-synonymous
polymorphisms in the WDSOF1 gene as novel
susceptibility markers for low bone mineraldensity in Japanese postmenopausal women.
Bone 47, 636-642, 2010.
9. Ueyama K, Ikeda K, Sato W, Nakasato N,
Horie-Inoue K, Takeda S, Inoue S: Knock-downof Efp by DNA-modified small interfering RNA
inhibitsbreast cancer cell proliferation and in vivo
tumor growth. Cancer Gene Ther 17, 624-632,
2010.
10. Murata T, Takayama K, Katayama S, Urano T,
Horie-Inoue K, Ikeda K, Takahashi S, Kawazu C,
Hasegawa A, Ouchi Y, Homma Y, Hayashizaki Y,
Inoue S: miR-148a is an androgen-responsive
microRNA that promotes LNCaP prostate cell
growth by repressing its target CAND1
expression. Prostate Cancer Prostatic Dis 13,
356-361, 2010.
11. Azuma K, Casey SC, Ito M, Urano T, Horie K,
Ouchi Y, Kirchner S, Blumberg B, Inoue S:
Pregnane X receptor knockout mice display
osteopenia with reduced bone formation andenhanced bone resorption. J Endocrinol 207,

404

257-263, 2010.
12. Fujita M, Sugama S, Sekiyama K, Sekigawa S,
Tsukui T, Nakai M, Waragai M, Takenouchi T,
Takamatsu Y, Wei J, Rockenstein E, LaSpada AR,
Masliah E, Inoue S, Hashimoto M: Α β-synucleinmutation
linkedtodementia
produces
neurodegeneration when expressed in mouse brain.
Nat Commun 1, 110, 2010.
13. Onodera Y, Miki Y, Suzuki T, Takagi K, Akahira
JI, Sakyu T, Watanabe M, Inoue S, Ishida T,
Ohuchi N, Sasano H: Runx2 in human breast
carcinoma: its potential roles in cancer
progression. Cancer Sci 101, 2670-2675, 2010.

405

Department of Integrated Imaging
Informatics
Project Associate Professor
Naoki Yoshioka, M.D., Ph.D.

Project Research Associate
Hidemasa Takao, M.D.

Homepage

http://www.h.u-tokyo.ac.jp/research/center22/contribute/tougougazou.html※For this department, this year’s text is the same as that published last year.

Introduction and Organization

References

The recent advent of various medical imaging
modalities including high-field magnetic resonanceimaging, multi-detector row computed tomography,
computed
radiography,
ultrasonography,
andendoscopy enables us to obtain data with high spatial
and temporal resolution. However, the interpretationof large amounts of volumetric data places a burden
on radiologists.
We operate a dedicated image server tosystematically develop the methods of extraction,
analysis, storage, and integration of clinically valuable
information contained within medical image data,
introducing a state-of-the-art engineering technology
and recent evidence obtained by cognitive science. We
aim to apply our results to public health service,teleradiology, professional education, and highpotential expert system that can assist diagnostic
radiologists.

1. Age-relatedchangesinregional
brain
volumeevaluated by atlas-based method. Gonoi W,
Abe O, Yamasue H, Yamada H, Masutani Y, Takao
H, Kasai K, Aoki S, Ohtomo K. Neuroradiology.
2009 Dec 23. [Epub ahead of print]
2. Cerebral asymmetry in patients with schizophrenia:
a voxel-based morphometry (VBM) and diffusion
tensor imaging (DTI) study. Takao H, Abe O,
Yamasue H, Aoki S, Kasai K, Ohtomo K. J Magn
Reson Imaging. 2010;31(1):221-6.
3. Efficacy of double-arterial phase gadolinium
ethoxybenzyl diethylenetriamine pentaacetic acidenhanced liver magnetic resonance imaging
compared with double-arterial phase multi-detector
row helical computed tomography. Akai H, Kiryu S,
Takao H, Tajima T, Shibahara J, Imamura H,
Kokudo N, Akahane M, Ohtomo K. J Comput Assist
Tomogr. 2009;33(6):887-92.
4. Hepatic segments and vasculature: projecting CT
anatomy onto angiograms.Furuta T, Maeda E, Akai
H, Hanaoka S, Yoshioka N, Akahane M, Watadani T,
Ohtomo K. Radiographics. 2009;29(7):1-22.
5. MR imaging of the biliary tract with
Gd-EOB-DTPA: Effect of liver function on signal
intensity.Takao H, Akai H, Tajima T, Kiryu S,
Watanabe Y, Imamura H, Akahane M, Yoshioka N,
Kokudo N, Ohtomo K. Eur J Radiol. 2009 Aug 31.
[Epub ahead of print]
6. Safety of using iodized oil in chemoembolization for

Research Activities
Our present research includes the following:
1. Image processing to provide comprehensive
3D-display
2. Computer-aided detection and diagnosis in upper
abdomen
3. Data-mining from medical image databases

406

liver tumors in patients with previous adverse
reactions to iodinated contrast media. Kunishima K,
Takao H, Akahane M, Yoshioka N, Ohtomo K. Clin
Imaging. 2009;33(5):365-8.
7. Use of a saline chaser in abdominal computed
tomography: a systematic review. Takao H, Nojo T,
Ohtomo K. Clin Imaging. 2009;33(4):261-6.
8. Aging effects on cerebral asymmetry: a voxel-based
morphometry and diffusion tensor imaging study.
Takao H, Abe O, Yamasue H, Aoki S, Kasai K,
Sasaki H, Ohtomo K. Magn Reson Imaging.
2010;28(1):65-9.
9. Computed tomographic coronary angiography for
diagnosing stable coronary artery disease: a costutility and cost-effectiveness analysis. Amemiya S,
Takao H. Circ J. 2009;73(7):1263-70.
10. True pancreaticoduodenal artery aneurysms: A
decision analysis. Takao H, Nojo T, Ohtomo K. Eur
J Radiol. 2009 Apr 20. [Epub ahead of print]
11. Free-breathing diffusion-weighted imaging for theassessment of inflammatory activity in Crohn's
disease. Kiryu S, Dodanuki K, Takao H, Watanabe
M, Inoue Y, Takazoe M, Sahara R, Unuma K,
Ohtomo K. J Magn Reson Imaging. 2009;29(4):880-6.
12. Structural and diffusional brain abnormality related
to relatively low level alcohol consumption.Sasaki H,
Abe O, Yamasue H, Fukuda R, Yamada H, Takei K,
Suga M, Takao H, Kasai K, Aoki S, Ohtomo K.
Neuroimage. 2009;46(2):505-10.
13. Lung cancer incidence in middle-aged men
estimated by low-dose computed tomography
screening. Nojo T, Imanaka Y, Ishizaki T, Sekimoto
M, Yoshino M, Kurosawa T, Takao H, Ohtomo K.
Lung Cancer. 2009;65(1):56-61.
14. Endometrial stromal sarcoma located in the
myometrium with a low-intensity rim on T2weighted images: report of three cases and literature
review. Furukawa R, Akahane M, Yamada H, Kiryu
S, Sato J, Komatsu S, Inoh S, Yoshioka N, Maeda E,
Takazawa Y, Ohtomo K. J Magn Reson Imaging.
2010;31(4):975-9.
15. Automated segmentation method for spinal column
based on a dual elliptic column model and its
application for virtual spinal straightening. Hanaoka
S, Nomura Y, Nemoto M, Masutani Y, Maeda E,
Yoshikawa T, Hayashi N, Yoshioka N, Ohtomo K. J

Comput Assist Tomogr. 2010;34(1):156-62.

407

Department of Clinical Trial DataManagement
Visiting Associate Professor
Takuhiro Yamaguchi, Ph.D.

Project Assistant Professor
Hiroshi Ohtsu, M.S.

Homepage

http://ctdm.umin.jp/

Introduction and Organization

the world.

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 Support 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

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408

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. Also weare responsible for Biostatistics / Data management
Division of The Clinical Research Support Center in
University of Tokyo Hospital.

3)

4)

5)

6)

References
1) Fujimoto C, Murofushi T, Chihara Y, Ushio M,
Yamaguchi T, Yamasoba T, Iwasaki S. Effects of
unilateral dysfunction of the inferior vestibular
nerve system on postural stability.
Clinical
Neurophysiology 2010; 121(8): 1279-84.
2) Ando K, Ohtsu H, Arakawa Y, Kubota K,
Yamaguchi T, Nagase M, Yamada A, Fujita T;
Eplerenone combination Versus conventional
Agents to Lower blood pressure on Urinary
Antialbuminuric
Treatment
EffectStudy
Investigators.
Rationale and design of theEplerenone combination Versus conventional
Agents to Lower blood pressure on Urinary
Antialbuminuric Treatment Effect (EVALUATE)
trial: a double-blinded randomized placebocontrolled trial to evaluate the antialbuminuric
effects of an aldosterone blocker in hypertensive

7)

8)

9)

patients with albuminuria.
Hypertension
Research 2010; 33(6): 616-21.
Aihara T, Takatsuka Y, Ohsumi S, Aogi K,
Hozumi Y, Imoto S, Mukai H, Iwata H, Watanabe
T, Shimizu C, Nakagami K, Tamura M, Ito T,
Masuda N, Ogino N, Hisamatsu K, Mitsuyama S,
Abe H, Tanaka S, Yamaguchi T, Ohashi Y. Phase
III randomized adjuvant study of tamoxifen alone
versus sequential tamoxifen and anastrozole inJapanese postmenopausal women with hormoneresponsive breast cancer: N-SAS BC03 study.
Breast Cancer Research and Treatment 2010;
121(2): 379-87.
Kondo K, Suzukawa K, Sakamoto T, Watanabe K,
Kanaya K, Ushio M, Yamaguchi T, Nibu K, KagaK, Yamasoba T. Age-related changes in cell
dynamics of the postnatal mouse olfactory
neuroepithelium: cell proliferation, neuronaldifferentiation, and cell death.
Journal ofComparative Neurology 2010; 518(11): 1962-75.
Hatanaka N, Takita M, Yamaguchi T, Kami M,
Matsumoto S. Interests in beta-cell replacement
therapies among Japanese patients with type 1
diabetes.
Diabetes Research and Clinical
Practice 2010; 89(1): e5-8.
Tsubokura M, Nakada H, Matsumura T, Kodama
Y, Narimatsu H, Yamaguchi T, Kami M. The
impact of H1N1 influenza A virus pandemic on
the blood donations in Hyogo Prefecture, Japan.
Transfusion 2010 May 3. [Epub ahead of print]
Kurosawa S, Yamaguchi T, Miyawaki S, Uchida
N, Sakura T, Kanamori H, Usuki K, Yamashita T,
Okoshi Y, Shibayama H, Nakamae H, Mawatari
M, Hatanaka K, Sunami K, Shimoyama M,
Fujishima N, Maeda Y, Miura I, Takaue Y, Fukuda
T. Prognostic factors and outcomes of adultpatients with acute myeloid leukemia after first
relapse. Haematologica 2010; 95(11): 1857-64.
Ueta T, Yanagi Y, Tamaki Y, Yamaguchi T.
Ranibizumab and stroke. Ophthalmology 2010;
117(9): 1860; author reply 1860-1.
Kurosawa S, Yamaguchi T, Miyawaki S, Uchida
N, Kanamori H, Usuki K, Yamashita T, Watanabe
M, Yakushiji K, Yano S, Nawa Y, Taguchi J,
Takeuchi J, Tomiyama J, Nakamura Y, Miura I,
Kanda Y, Takaue Y, Fukuda T. A Markov
decision analysis of allogeneic hematopoietic cell

409

transplantation versus chemotherapy in patientswith acute myeloid leukemia in first remission.
Blood 2010; 117(7): 2113-20.
10) Murayama H, Narabu H, Kojima T, Tomaru M,
Tachibana R, Yamaguchi T, Murashima S.
Program development to promote networkbuilding between disciplinary agencies andinformal community organizations.
NipponKoshu Eisei Zasshi 2010; 57(10): 900-8.
(Japanese.)11) Murayama H, Kojima T, Tomaru M, Narabu H,
Tachibana R, Yamaguchi T, Murashima S.
Evaluation of a program to promote networkbuilding between disciplinary agencies andinformal community organizations: trial in acommunity comprehensive support center.
Nippon Koshu Eisei Zasshi 2010; 57(10): 909-20.
(Japanese.)410

Pharmacology andPharmacokinetics
Project Associate Professor
Akihiro Hisaka, Ph.D.

Project Research Associate
Yoshihide Yamanashi, Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/research/center22/contribute/yakuri.html

Introduction and Organization

Education and clinical activities

The research of our laboratory, Pharmacology andPharmacokinetics, targets quantitative kinetic analysis
of efficacy and safety of drugs by applying techniquesof modeling and simulation, which have beendeveloped
systematically
in
the
field
of
Pharmacokinetics (PK). It includes some topics inseveral relating fields such as quantitative pharmacology, system pharmacology, and pharmacometrics.
We will survey various issues need to be solved in thecurrent hospital pharmacotherapy and perform various
assays of biomarkers and drug concentrations inbiological specimens kindly provided from patients.
Personalized medicine is one of our important goals toimprove current pharmacotherapies by stabilizing
efficacy without accompanying unpleasant adverse
effects.
The staffs are involved not only in the researchand the education in this university, but also in theactivity of hospital pharmacy, and are evenexperienced experts of new drug development in thepharmaceutical industry.
Pharmacology andPharmacokinetics is supported by the Department ofPharmacy in the Tokyo University Hospital.
Pharmacology and Pharmacokinetics received kind
donations from seven pharmaceutical companies(Astellas Pharma Inc, Eisai Co Ltd, Shionogi & Co
Ltd, Daiichi Sanko Co Ltd, Takeda Pharma Co Ltd,
Novartis Pharma K K, and Banyu Pharma Co Ltd).

Although Pharmacology and Pharmacokinetics is notoriented to education and clinical activities in thehospital, the staffs are hospital pharmacists and are
involved in the education of graduates andunder-graduates in the faculties of medicine andpharmaceutical sciences. Please refer to the annual
report of the Department of Pharmacy.

Research activities
Selected research topics ongoing in Pharmacology andPharmacokinetics are overviewed in the following.
Systematic analysis and prediction of drug-druginteraction
In Japan, more than two thousand drugs are usedin pharmacotherapy in hospital. Among them, somecombinations would cause unpleasant adverse effects
due to pharmacokinetic drug-drug interaction (DDI).
We surveyed DDIs caused by inhibition or inductionof drug metabolizing enzyme in the literature, anddeveloped a new framework for prediction of various
pharmacokinetic DDIs (Hisaka A et al. Pharmacol.
Ther., 2010; 125: 230-48. Hisaka A et al. Clin.
Pharmacokinet., 2009: 48: 653-66).
By applying this theory, we have been annually
making a comprehensive list of drugs which are
involved in significant pharmacokinetic DDI incollaboration with Prof. Sugiyama in the faculty of411

pharmaceutical sciences. It lists more than 300 drugs
which are classified by both clearance pathway anddegree of DDI, and is published in a journal which is
distributed to all pharmacies and relating facilities inJapan for free. The list is used for inspection ofprescriptions in pharmacies, and in addition, forvarious purposes in the industry and regulation.
Evaluation and prediction of absorption andmetabolism in the gut
Oral drugs need to be absorbed from thegastrointestinal tracts in order to exerts therapeutic
effects. In reality, therapeutic potential of many
drugs are unstable or reduced due to low absorbability
and/or extensive metabolism in the gut.
Since
multiple issues are concerned in the absorption
process of a drug, its modeling and simulation havebeen met with limited success. We developed a new
and reliable evaluation method of the intestinal
metabolism. And furthermore, a new PK model wasconstructed for consideration of physiologicalintestinal absorption and metabolism.
Study on ethnic difference in pharmacokinetics
Nowadays, a new drug development is conductedinternationally in general, and hence, clinical studies
are quite often performed first in overseas and thenintroduced in Japan. Therefore, evaluation of ethnic
difference is very important for the success of new
drug development in Japan.
We surveyed and analyzed ethnic differences inPK systematically, and found that ethnic differences
observed in phase 1 study in Japanese subjects areoften unreliable since inter-study difference isapparent. On the other hand, it was revealed that a
degree of ethnic difference in PK is rather small
compared with obvious inter-individual difference.
From the results of this study, it would be needed toreconsider the role of phase 1 studies conducted inJapan.
Furthermore, it may be helpful for
consideration of strategies for new drug developmentin Asian countries in the future.

References (English only)
1. Yamanashi Y, Takada T, Yoshikado T, Shoda JI,
and Suzuki H. NPC2 Regulates Biliary

Cholesterol Secretion via Stimulation of
ABCG5/G8-Mediated Cholesterol Transport.
Gastroenterology. 2011 in press.
2. Masuo Y, Ito K, Yamamoto T, Hisaka A, Honma
M, and Suzuki H. Characterization of inhibitory
effect of carbapenem antibiotics on thede-conjugation of valproic acid glucuronide. Drug
Metab Dispos. 2010; 38: 1828-35.
3. Yamamoto T, Ito K, Hisaka A, Ohno Y, andSuzuki H. Quantitative Prediction of Drug-Drug
Interaction Caused by CYP Inhibition andInduction from in vivo Information and its
Application for the Daily Clinical Practices –Proposal for the Pharmacokinetic Interaction
Significance Classification Systems (PISCS) – in
Text book on Pharmacy Practices (Hussain A. S.
Ed.), in press.

International Meetings
1. Hisaka A. PISCS (pharmacokinetic interaction
significance classification system): toward
seamless drug-interaction alert (symposium).
Pharmaceutical sciences world congress (PSWC) .
New Orleans, USA, Nov 14-18, 2010.
2. Hisaka A, Sasaki Y, and Suzuki H. Expressions of
Hepatic Cytochrome P450 May be Regulated
Dynamically and Cooperatively. 9th International
Meeting of ISSX. Istanbul, Turkey, Sep 4-8, 2010.
3. Hisaka A, Ohno Y, Yamaguchi R, Ueno M, andSuzuki H. Prediction of Clearance Changes of
Substrate Drugs of Major Cytochrome P450s
Caused by Drug-Drug-Interaction; Relationships
with Clearances in Poor and Intermediate
Metabolizers. 18th International Symposium on
Microsomes and Drug Oxidations, Beijing, China,
May 16-20, 2010.
4. Sasaki Y, Hisaka A, Suzuki H. Development ofPopulation Model for Expression of Cytochrome
P450s and Relating Enzymes in Human LiverMicrosome. 18th International Symposium on
Microsomes and Drug Oxidations, Beijing, China,
May 16-20, 2010.

412

Department of
Therapeutic Strategy forHeart Failure
Professor
Shunei Kyo, M.D.

Associate Professor
Satoshi Gojo, M.D.
Takashi Nishimura,M.D

Project Research Assosiate
Motoyuki Hisagi,M.D

Yoko Ogawa, M.D.

Project Researcher
Tsuyoshi Shimizu, M.D., Hideyuki Nebiya, PhD.

Project Academic Support Specialist
Kumiko Kakuya

Medical Technical AssistantMasaaki Ishii

Homepage

http: http://plaza.umin.ac.jp/~heart-f/

Introduction and Organization

Clinical Activities

The Department of Therapeutic Strategy for Heart
Failure (TSHF) in the University of Tokyo Hospital
was established by the support of the Department of
Cardiac Surgery (Professor Shinichi Takamoto) andthe Department of Cardiology (Professor Ryozo
Nagai) of the University of Tokyo Hospital in May
2008. The purpose to establish the department of
TSHF is to promote surgical and medical innovative
treatment for end-stage heart failure in the Universityof Tokyo Hospital, which includes heart transplantation, ventricular assist device, and regenerative
therapy. The Department is also supported by thirteencompanies,

1. Heart Transplantation (HTx)Patients who performed heart transplantation in
our hospital (15 patients) or in abroad transferred fromour hospital (8patients) are followed up once a monthin the out-patient clinic, and undergo myocardial
biopsy once a month in the first year and once a year
afterwards. When some symptom or findings whichsuggest rejection are detected, patients will undergo
in-hospital treatment. The Organ Transplant Law wasrevised in July 2010, the number of brain death
cadaver increased dramatically from August 2010,
Between August and December 2010 6 patients were
performed heart transplantation in the University ofTokyo Hospital.

413

2. Ventricular Assist Device (VAD) Therapy
58 patients were treated with Ventricular assist
device (VAD) since November 2002 when the
University of Tokyo Hospital started hearttransplantation program. All candidates fell into
end-stage heart failure before VAD implantation, anda significant number of them were rescued with hearttransplantation or bridge to recovery. 19 patietnts
were treated with VAD, 16 were treated in Hospitalward and 3 were treated in the outpatient clinic.
VAD was implanted in 6 patients in 2010 among them
Toyobo paracorporeal VAD were implanted in 5 andHeartMate II was implanted in one patient. They wereregistered to JOTN (Japanese Organ Transplant
Network) are waiting for HTx.. We assisted VAD
implantation in seven patients in affiliate orcooperative hospital in 2010to establish VAD network
in Kanto Shinsyu and Tohoku prefectures.
3. Compact CP (external counter-pulsation)
Compact CP is a system of external counterpulsation circulatory support system, which has beendeveloped with collaboration of Nishimura Co. Ltd.
and the University of Tokyo Hospital. Compact CPtherapy was performed in collaboration with on 10
patients at ICU for postcardiotomy cardia failure andon 1 patient in out-patient clinic for unstable angina
after CABG ad PCI.

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 forheart failure, it is essential for our department of the
University to have active research programs in clinicaland basic subjects related to assisted circulations andheart transplantation. We created highly active
research programs in the every field of medical andsurgical heart failure treatment, played aninternationally leading role and contributed to its
development. A research meeting is held every
Saturday on a research project with Department of
Cardiothoracic Surgery.
Basic and/or clinical research activities are focusedon 1) development of new driving method of rotary
blood pump, 2) development of Compact CP externalcounterpulsation, 3) basic and clinical research on
regenerative therapy, 4) establishment of social
support system for patients with implantable LVAD.
We have organized 4series of clinical trial of
implantable rotary blood pump LVAD, EVAHEART,
DuraHeart, Jarvik 2000, and HeartMate II since 2007.
EVAHEART, DuraHeart approved lase December
and insurance reimbursement was obtained this April.
Other two LVAD will be approved within this year.

References
1.

Kinoshita O, Nishimura T, Kawata M, Ando M,
Kyo S, Ono M; Vacuum-assisted closure with
Safetac technology for mediastinitis in patients

414

2.

3.

4.

5.

6.

7.

8.

9.

with a ventricular assist device; Journal of
Artificial Organs; 13(2):126-8;2010
Hisagi M, Nishimura T, Ono M, Gojo S, Nawata
K, Kyo S; New pre-clotting method for fibrin
glue in a non-sealed graft used in an LVAD:theKYO method; Journal of Artificial Organs;
13:174-177;2010
Shimizu T, Kyo S, Imanaka K, Nakaoka K,
Nishimura E, Okumura T, Ishii M, Hisagi M,
Nishimura T, Motomura N, Ono M, Takamoto S;
A novelexternal counterpulsation system forcoronary artery disease and heart failure: pilot
studies and initial clinical experiences; Journal of
Artificial Organs; 13:161-169;2010
Kashiwa K, Nishimura T, Kubo H, Tamai H,
Baba A, Ono M, Takamoto S, Kyo S; Study ofdevice malfunctions in patients with implantableventricular assist devices at home; Journal of
Artificial Organs; 13:134-138;2010
Nishimura T, Kyo S; High-dose carvedilol
therapy for mechanical circulatory assisted
patients; Journal of Artificial Organs; 13:88-91;
2010
Nishimura T, Kyo S; Triple-site pacing: a new
supported therapy approach for bridge torecovery with left ventricular assist system in apatient with idiopathic dilated cardiomyopathy;
Journal of Artificial organs; 13:54-57;2010
Sawa Y, Tatsumi E, Funakubo A, Iwasaki K,
Kishida A, Masuzawa T, Matsuda K, Myoui A,
Nishimura M, Nishimura T, Tomizawa Y, Tono T,
Yamaoka T, Watanabe H; ournal of Artificial
Organs 2009: the year in review; Journal of
Artificial Organs; 13:1-9;2010
Takashi Yamane, Shunei Kyo, Hikaru Matsuda,
Yusuke Abe, Kou Imachi, Toru Masuzawa,Takeshi Nakatani, Kazuhiro Sase, Koichi
Tabayashi, Setsuo Takatani, Eisuke Tatsumi,
Mitsuo Umezu, Toshie Tsuchiya; Japanese
Guidance for Ventricular Assist Devices/ Total
Artificial Hearts; Artificial Organs; 34(9):699702;2010
Tsuyoshi S, Takayuki O, Jiro A, Hideo F, Ryozo
N, Noboru M, Minoru O, Shunei K, Shinichi T;
Mid-Term Results and Costs of Coronary Artery
Btpass vs Drug-Eluting Stents for Unprotected
Left Main Coronary Artery Disease; Ciuculation

Journal; 74(3):449-455;2010
10. Shimizu T, Ono M; Drug-Eluting Stents vsBypass Surgery for Unprotected Left Main
Disease -Reply-.;Circ J.; 74(10):2245.;2010
11. Tohru Izumi, Michiaki Hirose, Mitsuaki Isobe,
Sachio Kawai, Masatoshi Kawana, Kazuo
Kimura, Makoto Kodama, Shunei Kyo, Akira
Matsuzaki, Shinichiro Morimoto, Tsutomu Saji,
Chikao Yutani, Kyoko Imanaka-Yoshida,
Takayuki Inomata, Hatsue Ishibashi-Ueda,
Masahiro Ishii, Hiroshi Nakamura, Kazufumi
Nakamura, Tshio Nishikawa, Ryosuke Nishio,
Shinichi Nunoda, Hiroshi Okamoto, Yuji Okura
Mamoru Satoh, Tetsuo Shioi, Hiroyuki Takano,
Fumio Terasaki, Yshikazu Yazaki, Tsutomu
Yoshikawa,
Masahiko
Kurabayashi,
Ken
Okumura, Hitonobu Tomoike, Akira Yamashina,
Michihiro Yoshimura
Guidelines for Diagnosis and Treatment of
Myocarditis (JCS2009); Ciuculation Jurnal;
75(3);734-743; 2011.3

Social Cooperation Program(22nd Century Medical and Research Center)416

Department of Ubiquitous Health
Informatics
Associate Professor
Hideo Fujita, M.D.,Ph.D.

Assistant Professor
Yuji Uchimura, DDS
Waki Kayo, M.D. Ph.D.

Homepage

http://uhi.umin.jp

Introduction and Organization
Our mission is to promote research and developmentof a novel integration system where pieces of patients’
healthcare information are virtually combined together
that are stored separately in diverse medical/
healthcare facilities. Recently developed mobile
information
communication
technologies
in
conjunction with cloud computing provide sturdy
environment to build a “virtual ubiquitous healthinformation space”. We particularly focus on better
clinical outcomes, as well as efficacy, safety, andsecurity matters achieved by those innovative systems
in the various medical/healthcare fields.

1. A 12-lead ECG system based on cloud computing
for emergency care
Treatment of cardiovascular diseases inside medical
facilities have improved dramatically in recent years.
On the other hand, the outcomes of acute cardiovascular disease is not yet sufficient depending upon
the local medical environment. In order to fill up
those “gaps” between inside and outside the medical
facilities, we working on creating a novel ECG system
as a clinically valid approach to this problem. We havedeveloped a cloud computing system with wirelesslytransmission ECG units, potentially clinical usefulness
due to the cloud-based server built. Deliverables ofthis study demonstrate that the application will betested in several clinical fields FY2011.

Research activities
To date we have been working on specific topics
shown below since this lab was established in 2009.
Our products have reached a stage of clinicalvalidation, respectively. Furthermore, we arepromoting collaborative research with several
laboratories both inside and outside the campus,
seeking for frontier fields of interdisciplinary researchand practical medicine/healthcare fields. Throughdevelopment of those specific products, we further
aim to establish a systematic methodology for creating
solutions for virtual ubiquitous health information
space.

2. Dialbetics: A novel smartphone-based selfmanagement support system for type 2 diabetic
patients
It is fundamentally important for diabetic patients tomaintain appropriate balance of diet and exercise,although the clear solution for it has not yet been
established. We have developed a novel smartphonebased self-management support system for type 2
diabetic patients. This new system has an automaticfunction of stratifying daily patient's biometric
information such as blood glucose, blood pressure,and food intake retrieved by the home sensor androuter according to medical risk evaluation.

417

Stratification engine feedback the risk level and raw
data to the patients, as well as to the administrator
only if the risk level indicates extremely high so thathe/she can urge the patient to see or consult his healthprofessionals as soon as possible. It has long been
pointed out that introduction of telemedicine canproblematically increase the burden of healthcare
workers, even if its efficacy may be ascertained,suggesting the difficulties to maintain and promote thesystem. We are also struggling to develop a new
system to overcome this kind of apprehension by
developing a new algorithm to reduce the burden ofhealth care workers. At present we performed series ofpilot studies for about 10 people in accordance withthe reviewed protocol of the ethics committee. We areto conduct 100-scale clinical trial to further confirm
validation, efficacy and safety aspects of Dialbetics in
FY2011. Besides we promote the evolutionalalgorithm in collaboration with a specific researchlaboratory in Faculty of Engineering.

5. Various assistance applications on smartphone for
medical/comedical personnel in hospitals
We have launched several development projects ofmobile ICT systems to assist medical staff andmedical technicians in the hospital.

3. Integrated System on Smartphone for Medicine
Taking Support to maintain adherence tomedication
In clinical settings, adherence to medication is apotentially important issue, previously managed bymaintaining its objective methodology has not beenreliably established. We have sought a solution bymobile ICT, which deals with prescribing informationfrom the hospital as well as dispensing informationfrom a pharmacy, and centralizes the medicine-taking
information obtained through wireless sensing unit
equipped in the pill cabinet and a newly developed
integrated application. This enables us to share
information about patients’ adherence to medication
among healthcare providers and patients.

1. Kiyosue A, Hirata Y, Ando J, Fujita H, Morita T,
Takahashi M, et al. Relationship between renal
dysfunction and severity of coronary arterydisease in Japanese patients. Circ J 2010;74:
786-791.
2. Kiyosue A, Hirata Y, Ando J, Fujita H, Morita T,
Takahashi M, et al. Plasma cystatin C
concentration reflects the severity of coronary
artery disease in patients without chronic kidneydisease. Circ J 2010;74:2441-2447.
3. Iwata H, Sata M, Ando J, Fujita H, Morita T,
Sawaki D, et al. Impact of primitive cells in
intracoronary thrombi on lesion prognosis:
temporal analysis of cellular constituents ofthrombotic material obtained from patients withacute coronary syndrome. Heart 2010;96:748-755.
4. Kawashima D, Ohno T, Kinoshita O, Motomura N,
Kiyosue A, Fujita H, et al. Prevalence of vitreous
hemorrhage following coronary revascularizationin patients with diabetic retinopathy. Circ J 2011;
75:329-335.
5. Fujita H, Nagai R. Glycemic Control Is AnotherTarget of PCI in Diabetic Patients. Circ J 2011;75:
773-774.
6. Waki K, Sugawara Y, Tamura S, Yamashiki N,
Fujita H, Kadowaki T, Kokudo N

4. Advanced smartphone-based guidance system for
outpatients
In order to improve convenience and amenity ofuniversity hospital outpatient services, we havedeveloped a new guidance system on cell phones. Thissystem will provide advanced function for reception
from outside, reducing waiting time, fast-forward ofprescription data to pharmacies, and so on. It will betested in the outpatient department of the Universityof Tokyo Hospital in FY2011.

3. Future directions
We further promote development and validation ofthese five themes. In particular, themes #1 to #3 are
expected to exert clinical efficacy, which will betested in practical world. In addition to university
hospital outpatient/ward, we will examine various
models of health care, such as community health care,and home care as joint research. To pursue scientificvalue of both clinical medicine and medical
informatics for the establishment of spatial
generalization we will move onto establishing virtual
cyberspace for medical/health informatics.

References

418

Simultaneous Pancreas-Kidney Transplantation in
the United States: An Analysis of the UNOS
Registry. Clin Transpl. 2010:35-44.
7. Ohe H, Ying Li, Nafady-Hego H, Waki K,
Sakaguchi S, Wood K, Calne R, Uemoto S,
Koshiba T Minimal But Essential Doses of
Immunosuppression: A More Realistic Approachto Improve Long-Term Outcomes for Pediatric
Living-Donor
Liver
Transplantation.
Transplantation. 2011 April; 91(7):809-810.
8. Waki K, Hayashi A, Ikeda S, Ikeda S, Nagatsuka
K, Honma Y, Kadowaki T, Yoshinoya S
Measuring platelet aggregation in dialysis patientswith a whole blood aggregometer by the screen
filtration pressure method. Ther Apher Dial. 2011
Apr;15(2):203-6 Waki K, Terasaki PI, Kadowaki
T
9. Long Term Pancreas Allograft Survival in
Simultaneous Pancreas Kidney Transplantation by
Era. Diabetes Care. 2010 Aug;33(8):1789-91.
10. Aramaki E, Miura Y, Tonoike M, Ohkuma T,
Mashuichi H, Waki K, Ohe K Extraction ofAdverse Drug Effects from Clinical Records Stud
Health Technol Inform. 2010;160(Pt 1):739-43.

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

421

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
Aya Ebihara, M.D., Makoto Kaneko, M.D., Akiko Masuda, 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, 73 technicians, and 3 nurses, and isdivided into the following sections. The second generation Laboratory Automation System is in fulloperation, and ordering of laboratory tests, the flow ofsamples, operation of laboratory analyzers, quality
control of analysis, and data reporting are allcontrolled by the Laboratory Automation computer
system.
This system has greatly improved thequality, safety, and efficiency of the laboratory andcontributed to both patients and doctors by providing
rapid and high-quality laboratory testing.
The 1st Section
This section deals mainly with the maintenance oflaboratory system and blood and urine sampling. In
2010, 235,386 outpatient blood sampling were
performed in this section.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2010, over 4,334,415

serum enzyme tests (such as AST and ALT), and460,417 immunological tests were performed.
The 3rd Section
This section deals with laboratory hematology and
DM-related tests, gene analysis tests and urinalysis.
In 2010, 1,000,221 samples were examined forcomplete blood cell counts, cell surface marker
analysis, prothrombin time, fibrinogen, glucose, andHbA1C tests, and 213,693 urine samples were
examined.
The 4th Section
This section deals with physiological tests,
including circulatory, pulmonary, and neuromuscularfunction ones.
In 2010, 45,796 ECG, 21,324
pulmonary function tests, 19,743 echocardiography
tests, 15,643 abdominal echography tests, and 10,051
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422

section is going to be further expanded since there isso much demand from clinical doctors.
3.

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.

4.

5.

Research activities
The main goal of our research projects is thedevelopment of new and useful laboratory tests, andelucidation of pathophysiology of diseases throughlaboratory tests. The areas included are: i)(Patho)physiological roles of lysophospholipid
mediators and its application into laboratory medicine,ii) platelet biology, iii) the clinical significance ofreticulated platelets and immature platelet fraction, iv)
hepatic fibrosis and ischemic reperfusion injury of theliver, v) genetic testing, vi) bioactive peptides,
especially adrenomedullin, vii) oxidative stress andorgan injury, viii) analysis of cardiac functions using
ultrasound, ix) elucidation of abnormality inepigenetics in cancer and its clinical application, andx) analysis of brain function using magnetoencephalography and near-infrared spectroscopy.

6.

7.

8.

References
1.

2.

Hanafusa, N., Satonaka, H., Doi, K., Yatomi, Y.,
Noiri, E., and Fujita, T. Platelet-derived
microparticles are removed by a membrane
plasma separator. ASAIO J. 56: 323-325, 2010.
Hangaishi, A., Takahashi, T., Masuda, A., Okada,S., Kandabashi, K., Kurokawa, M. Rituximab
therapy for refractory immune thrombocytopenic

9.

purpura in elder patients. Int. J. Hematol.
91:336-7, 2010.
Ikeda, H., Ohkawa, R., Watanabe, N., Nakamura,K., Kume, Y., Nakagawa, H., Yoshida, H., Okubo,
S., Yokota, H., Tomiya, T., Inoue, Y., Nishikawa,T., Ohtomo, N., Tanoue, Y., Koike, K., andYatomi, Y. Plasma concentration of bioactive
lipid mediator sphingosine 1- phosphate is
reduced in patients with chronic hepatitis C. Clin.
Chim. Acta. 411: 765-770, 2010.
Imasawa, T., Kitamura, H., Ohkawa, R., Satoh, Y.,
Miyashita, A., and Yatomi, Y. Unbalanced
expression of sphingosine 1-phosphate receptors
in diabetic nephropathy. Exp. Toxicol. Pathol.
62: 53-60, 2010.
Imasawa, T., Koike, K., Ishii, I., Chun, J., andYatomi, Y. Blockade of sphingosine 1-phosphate
receptor 2 signaling attenuates streptozotocininduced apoptosis of pancreatic beta-cells.
Biochem. Biophys. Res. Commun. 392: 207-11,
2010.
Kato, Y., Araki, N., Ohkubo, T., Asano, Y.,
Furuya, D., Hattori, K., Simazu, T., Yamazato,
M., Nagoya, H., Ito, Y., Shimosawa, T., Fujita, T.,
Shimazu, K. Effects of adrenoemdullin on nitricoxide production during forebrain ischemia andreperfusion in mice. Cerebral Blood Flow andMetabolism. 21: 1-6, 2010.
Koike, Y., Miyazaki, K., Higashihara, M.,
Kimura, E., Jona, M., Uchihashi, K., Masuda, A.,
Kandabashi, K., Kurokawa, M., and Yatomi, Y.
Clinical significance of detection of immatureplatelets: comparison between percentage of
reticulated platelets as detected by flow
cytometry and immature platelet fraction as
detected by automated measurement. Eur. J.
Haematol. 84: 183-4, 2010.
Kusakabe, M., Kutomi, T., Watanabe, K., Emoto,N., Aki, N., Kage, H., Hamano, E., Kitagawa, H.,
Nagase, T., Sano, A., Yoshida, Y., Fukami, T.,
Murakawa, T., Nakajima, J., Takamoto, S., Ota,
S., Fukayama, M., Yatomi, Y., Ohishi, N., andTakai, D. Identification of G0S2 as a genefrequently methylated in squamous lung cancer
by combination of in silico and experimental
approaches. Int. J. Cancer 126: 1895-902, 2010.
Nakamura, K., Igarashi, K., Ohkawa, R., Saiki,

423

10.

11.

12.

13.

14.

15.

N., Nagasaki, M., Uno, K., Hayashi, N., Sawada,
T., Syukuya, K., Yokota, H., Arai, H., Ikeda, H.,
Aoki, J., and Yatomi, Y. A novel enzyme
immunoassay for the determination ofphosphatidylserine-specific phospholipase A(1)in human serum samples. Clin. Chim. Acta 411:
1090-1094, 2010.
Ogiso, H., Nakamura, K., Yatomi, Y., Shimizu, T.,
and Taguchi, R. Liquid chromatography/mass
spectrometry analysis revealing preferential
occurrenceof
non-arachidonate-containing
phosphatidylinositol bisphosphate species innuclei and changes in their levels during cell
cycle. Rapid Commun. Mass Spectrom. 24:
436-442, 2010.
Ohtomo, N., Tomiya, T., Tanoue, Y., Inoue, Y.,
Nishikawa, T., Ikeda, H., Seyama, Y., Kokudo, N.,
Shibahara, J., Fukayama, M., Koike, K.,
Shirataki, H., Fujiwara, K.Expression of α-taxilin
in hepatocellular carcinoma correlates withgrowth activity and malignant potential of thetumor. Int. J. Oncol. 37: 1417-1423, 2010.
Okano, T., Terao, Y., Furubayashi, T., Yugeta, A.,
Hanajima, R., Ugawa, Y. The effect ofelectromagnetic field emitted by a mobile phoneon the inhibitory control of saccades. Clin
Neurophysiol. 121: 603-611, 2010.
Qi, X., Okamoto, Y., Murakawa, T., Wang, F.,
Oyama, O., Ohkawa, R., Yoshioka, K., Du, W.,
Sugimoto, N., Yatomi, Y., Takuwa, N., andTakuwa, Y. Sustained delivery of sphingosine-1phosphate using poly(lactic-co-glycolic acid)based microparticles stimulates Akt/ERK- eNOS
mediated angiogenesis and vascular maturation
restoring blood flow in ischemic limbs of mice.
Eur. J. Pharmacol. 634: 121-131, 2010.
Sakamoto, K., Nakata, H., Yumoto, M., andKakigi, R. Effect of Mastication on Human Brain
Activity. Anti-Aging Med. 7: 153-160, 2010.
Suzuki-Inoue, K., Inoue, O., Ding, G., Nishimura,S., Hokamura, K., Eto, K., Kashiwagi, H.,
Tomiyama, Y., Yatomi, Y., Umemura, K., Shin, Y.,
Hirashima, M., and Ozaki, Y. Essential in vivo
roles of the C-type lectin receptor CLEC-2:
embryonic/neonatal lethality of CLEC-2-deficient
mice by blood/lymphatic misconnections andimpaired thrombus formation of CLEC-2-

deficient platelets. J. Biol. Chem. 285: 2449424507, 2010. “Paper of the Week”
16. Tejima K., Masuzaki R., Ikeda H., Yoshida H.,
Tateishi R., Sugioka Y., Kume Y, Okano T., Iwai
T., Gotoh H., Katoh S., Suzuki A., Koike Y.,
Yatomi Y., Omata M. and Koike K.
Thrombocytopenia is more severe in advanced
chronic hepatitis C than B with the same grade ofliver
stiffnessandsplenomegaly.
J.
Gastroenterol. 45: 876-884, 2010.
17. Unuma, K., Shintani-Ishida, K., Tsushima, K.,
Shimosawa, T., Ueyama, T., Kuwahara, M.,
Yoshida, K. Connexin-43 Redistribution and Gap
Junction Activation During Forced Restraint
Protects Against Sudden Arrhythmic Death inRats. Circ. J.74:1087-1095, 2010.
18. Unuma, K., Shintani-Ishida, K., Yahagi, N.,
Tsushima, K., Shimosawa,T., Ueyama, T.,
Yoshida, K. Restraint stress induces coneexin-43
translocation via α-adrenoceptors in rat herat.
Circ. J. 74: 2693-2701, 2010.
19. Wang,F., Okamoto, Y., Inoki, I., Yoshioka, K., Du,
W., Qi, X., Takuwa, N., Gonda , K., Yamamoto,Y., Ohkawa, R., Nishiuchi, T., Sugimoto, N.,
Yatomi, Y., Mitsumo ri, K., Asano, M., Kinoshita,M., and Takuwa, Y. Sphingosine-1-phosphate
recepto r-2 deficiency leads to inhibition ofmacrophage proinflammatory activities andatherosclerosis in ApoE-deficient mice. J. Clin.
Invest. 120: 3979-3995, 2010.
20. Watanabe, K., Emoto, N., Sunohara, M.,
Kawakami, M., Kage, H., Nagase, T., Ohishi, N.,
Takai, D. Treatment of PCR products withexonucleaseIandheat-labilealkaline
phosphatase improves the visibility of combined
bisulfite restriction analysis. Biochem. Biophys.
Res. Commun. 399: 422-424, 2010.
21. Yamamoto K., Imamura H., Matsuyama Y.,
Kume Y., Ikeda H., Norman G.L., Shums Z., Aoki
T., Hasegawa K., Beck Y., Sugawara Y., andKokudo N. AFP, AFP-L3,DCP, and GP73 as
markers for monitoring treatment response andrecurrenceand as surrogate markers ofclinicopathological variables of HCC. J.
Gastroenterol. 45: 1272-1282, 2010.

424

Surgical Center
Director (Professor)
Hiroshi Yasuhara M.D., Ph.D.

Associate Professor
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 8,485, 9,550, 9921 and 9,944 operations,which counts for 1.5 times comparing to those in 2001,
were performed in 2006, 2007, and 2009, respectively.
More recently, the number of operations was 10,394(1,210 emergency cases) in 2010.
There has been much concern about the apparent
increase in the patients who undergo laparoscopic/
thoracoscopic surgery. There is also an apparent

425

increase in the number of patients who are positive forthe microbiological tests such as tuberculosis, MRSA,
pseudomonas aeruginosa, HBV, HCV and HIV.

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.
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 lectures426

of 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（2008-2010）
1. 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 65:
360-5, 2008.
2. 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 for427

axillary staging in primary breast cancer. BMC
Cancer 8:165, 2008.
3. 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 8:384, 2008.
4. 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:
250-8, 2008.
5. Fukatsu K, Ueno C, Maeshima Y, Mochizuki H,
Saitoh D. Detrimental effects of early nutrition
administration after severe gut ischemiareperfusion. J Surg Res 149:31-8, 2008.
6. 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. 27:269-75, 2008.
7. 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 23:721-22, 2008.
8. Uetera Y, Saito Y, Ide K, Yasuhara H, Kumada N,
Saito R, Takahashi O. Reduced water supply to
the water ring vacuum pump. Central Service 16:
182-185, 2008.
9. Uetera Y, Saito Y, Ide K, Yasuhara H, Kumada N,
Saito R Investigation of “Prion” chemical
indicators in a prevacuum autoclave using awireless logger system. Central Service 16:372376, 2008.
10. 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.
11. Omata J, Fukatsu K, Maeshima Y, Moriya T,
Murakoshi S, Noguchi M, Okamoto K, Fukazawa
S, Saitoh D, Mochizuki H, Yamamoto J, Hase K.

Enteral nutrition rapidly reverses total parenteralnutrition-induced impairment of hepatic immunity
in a murine model. Clin Nutr 28:668-73, 2009.
12. Furuya Y, Yanagie H, Wakahara T, Mishina Y,
Akimoto H, Quang le M, Hiroshima K, Yasuhara
H. Improved survival in patients with breast
rhabdoid tumors with multi-agent adjuvant
chemotherapy combined with irradiation. Cancer
Chemother Pharmacol 64:623-7, 2009.
13. Uetera Y, Kawamura K, Kobayashi H, Saito Y,
Yasuhara H, Saito R. Studies on viral disinfection:
An evaluation of moist heat disinfection for HBV
by using A0 concept defined in ISO 15883Washer-Disinfectors. PDA Journal of Pharmaceutical Science and Technology 64:327-336,
2010.
14. Uetera Y, Saito Y, Yasuhara H, Kumada N,
Misawa Y. Sterilizing electronic instruments forneuro-navigation using the “Prion Cycle” at 134 C
for 18 min in a prevacuum autoclave. Zentralsterilisation 18:169-179, 2010.
15. Fukatsu K, Tanabe K, Maeshima Y, Omata J,
Yasuhara H, Saitoh D. Neutrophil elastase
inhibitor restores gut ischemia reperfusioninduced impairment of gut immunity with reduced
plasma interleukin-6 concentrations in mice. Surg
Infect 11:517-22, 2010.
16. Furuya Y, Wakahara T, Akimoto H, Long CM,
Yanagie H, Yasuhara H. A case of postoperative
recurrent intussusception associated with indwelling bowel tube. World J Gastrointest Surg 2:85-8,
2010.
17. Uetera Y, Kawamura K, Kobayashi H, Saito Y,
Yasuhara H, Saito R. Studies on Viral
Disinfection: An Evaluation of Moist Heat
Disinfection for HBV by Using A0 Concept
Defined in ISO 15883-Washer-Disinfectors. PDA
J Pharm Sci Technol 64:327-36, 2010.
18. Furuya Y, Wakahara T, Akimoto H, Kishimoto T,
Hiroshima K, Yanagie H, Yasuhara H. Clear celladenocarcinoma with enteroblastic differentiationof the ascending colon. J Clin Oncol 29:e647-9,
2010

428

Department of Clinical Radiology
Professor (department manager)
Kuni Ohtomo, M.D.,Ph.D.

Associate Professor (vice manager)
Masaaki Akahane, M.D.

Assistant Professor
Jiro Sato, 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429

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 six 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 three 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.
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.
In conclusion, the department of clinical radiology

430

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.

431

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 864 in 2010.
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[See Department of Perinatal Medicine.]

432

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Lecturer

Naoshi Ogata, M.D.

Associate
Yauo Nakahara, M.D.,

HomepageShun-ichi Furukawa, M.D.

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
four 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. Sixteen
physical therapists are working in the physical therapy
section. In the occupational therapy section, four
occupational therapists work for the generalrehabilitation service and the other three therapists
work for the psychiatric rehabilitation. Fouracupuncture therapists perform acupuncture andmoxbustion. In the Day-care Unit, clinicalpsychologists and nurses also work. In 2006, speechtherapists and orthoptists who had belonged to otherdepartments in the University of Tokyo Hospital were
included in our department. From 2009, a speechtherapist added to our department to perform therapy
for patients with aphasia, dysarthria, and dysphagia.

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 250 patients corresponding about 25% 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

433

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 in theelderly4) Analysis of motion and energy expenditure in theactivities of daily living in the physically disabled
5) Rehabilitation approaches for patients with spina

6)
7)
8)
9)

bifidaTreatment and rehabilitation for patients withcongenital limb deficiencies
Disabilities and handicaps in patients with skeletal
dysplasias
Analysis of musculo-skeletal involvement incongenital insensitivity to pain
Rehabilitation of patients with hematogenic
malignancies around the stem cell transplantation

References
1. Chiba Y, Haga N: Evaluating visual bias andeffect of proprioceptive feedback in unilateralneglect. J Clin Neurosci, 17: 1148-1152, 2010
2. Iijima M, Haga N: Evaluation of nonnociceptive
sensation in patients with congenital insensitivity
to pain with anhidrosis. Childs Nerv Syst 26:
1085-1089, 2010
3. Nakashima Y, Haga N, Kitoh H, Kamizono J,
Tozawa K, Katagiri T, Susami T, Fukushi J,
Iwamoto Y: Deformity of the great toe infibrodysplasia ossificans progressiva. J Orthop Sci
15: 804-809, 2010
4. Takedani H, Fujii T, Kobayashi Y, Haga N,
Tatsunami S, Fujii T: Inter–observer reliability of
three different radiographic scores for adulthaemophilia. Haemophilia 17(1): 134-138, 2010

434

Division of Diagnostic Pathology
Professor (Director)
Masashi Fukayama, M.D., Ph.D.*

Associate Professor (Deputy Director)
Hiroshi Uozaki, M.D., Ph.D. *Associate Professor
Shumpei Ishikawa, M.D., Ph.D.*

Lecturer
Yutaka Takazawa, M.D., Ph.D.,
Satoshi Ota, M.D., Ph.D. (Chiba University, Associate Professor)
Junji Shibahara, M.D., Ph.D.

Associate
Tetsuo Ushiku, M.D., Ph.D.,
Masako Ikemura, M.D., Ph.D.
Daichi Maeda, M.D., Ph.D.
Teppei Morikawa, M.D., Ph.D. (visiting researcher, USA)
Akiteru Goto, M.D., Ph.D. * (Institute of Medical Science, Lecturer),
Rumi Hino, M.D., Ph.D. *,Aya Shinozaki, M.D., Ph.D. *Yukako Shintani, M.D., Ph.D. *Takeo Nakaya, M.D., Ph.D.* (Human Genomics Project)

Clinical Fellow
Kenya Sumitomo, M.D., Ph.D.,

Yasuaki Miura, M.D.,

Hirofumi Rokutan, M.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 organized to function
as a unit.
The proper staffs in the Division of Diagnostic
Pathology include a lecturer, a hospitall lecturer, two
associates, and three clinical staffs. Dr. Shibahara waspromoted to a Lecturer, Department of Pathology on
December.

Clinical activities (diagnostic
pathology and autopsy)
The annual statistics of the pathologic practice in 2010
fiscal year consisted of 15,502 cases of histologicalexamination (20,515 specimens), 26,370 specimens ofcytology, 780 of frozen histology, 639 of
intra-operative cytology, 75 of autopsy cases (21% asautopsy rate), and 2 autopsy cases from otherhospitals.
Clinico-pathological conferences (CPCs) for the435

two autopsy cases are held every month in the hospital.
Furthermore, the following surgical pathology
conferences are regularly held with each clinicaldivision; the cases of various tumors of organs (thedoctor in charge of each), such as thorax (Drs. Ota and
Goto), liver, pancreato-biliary tract (Dr. Shibahara),
male genitourinary (Dr. Goto) and female genitaltracts (Drs. Maeda and Takazawa), breast (Dr.
Ikemura), and bone and soft tissues (Dr. Ushiku).
Biopsy conferences are also held in the cases of liver(Dr. Shibahara), kidney (Dr. Uozaki) and skin (Dr.
Takazawa).
Our aim in the pathologic practices is to provide
the correct diagnosis as soon as possible. We are
addressing‘one-daypathology’
usinganewly-developed machine of rapid-histoprocessing.
Furthermore, a virtual slide scanner has been installed,which enabled us to save the consultation specimens
as digital information.
We are setting out a future providing system ofpathologic images for clinical divisions. Dr. Uozaki ismainly in charge of this project.
We have continued to participate the autopsy
assessment for “The Model Project for Inspection andAnalysis of the Deaths Related to Medical Treatment(DRMT)” of Health, Labor and Welfare Ministry,.

Teaching activities
The lectures and exercise course of systemic
pathology are for the 2nd grade–students. Bed-side
learning (BSL) course of autopsy and surgicalpathology are for the 4th grade students. Four students
of 3rd grade took the clinical clerkship course.
We instructed all interns to submit one report of
CPC case as a requirement of their medical training.
The Division of Diagnostic Pathology received fourinterns in 2010 for the second year program of theirinternship.

Research activities
Dr. Uozaki carried out a co-operative study with Fuji
Xerox and National Institute of Advanced Industrial
Science and Technology (AIST) to develop the
ontology, expressing diagnoses and macroscopic
findings of gastric cancer and the grammar describing

its diagnoses for the pathology report of gastriccancer.
We have finished the two-year project,“Feasibility of Post-Mortem Imaging as a Method
Assisting the Autopsy Assessment of DRMT”(Grants-in-Aid from Ministry of Health, Labor andWelfare). The report is now open to public andavailable at the website of the study group(http://humanp.umin.jp/), and the study obtained ahigh score in the ex post evaluation of the Ministry
office. In the study of Tokyo University Hospital, we
are now carrying out a research investigating
usefulness of post mortem CT images for hospital
autopsy, using a CT apparatus in the autopsy assisting
CT room. Lecturer Takazawa is in charge of thisproject.
We continue the pathological studies ofneoplastic diseases on the basis of surgical pathology
conferences. We are also developing a new
antibody-based in vivo imaging and therapy incollaboration with Genome Science Division,
Research Center for Advanced Science andTechnology, the University of Tokyo. We are
evaluating the feasibility of antibody panels for
immunohistochemistry to detect the metastasis in thesentinel lymph nodes of the gastric cancer, byconstructing the tissue array of primary and metastatic
cancers.

References
See the corresponding section of Department of
Pathology and Diagnostic Pathology

436

Department of Corneal
Transplantation
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.

437

Research activities
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.
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.

References1.

Amano S, Kaji Y, Mimura T: Biology of corneal

endothelial cells in vivo and in vitro. Jpn J
Ophthalmol 54:211-214, 2010
2. Amano S, Kaji Y, Mimura T: Biology of corneal
endothelial cells in vivo and in vitro. Jpn J
Ophthalmol 54:211-214, 2010
3. Arita R, Itoh K, Maeda S, Maeda K, Furuta A,
Tomidokoro A, Amano S: Meibomian gland duct
distortion in patients with perennial allergic
conjunctivitis. Cornea 29:858-860, 2010
4. Arita R, Itoh K, Maeda S, Maeda K, Furuta
A,Tomidokoro A, Amano S: Proposed diagnostic
criteria for seborrheic meibomian gland
dysfunction. Cornea 29:980-984, 2010
5. Arita R, Itoh K, Maeda S, Maeda K, Tomidokoro
A, Amano S: Efficacy of diagnostic criteria forthe differential diagnosis between obstructive
meibomian gland dysfunction and aqueous
deficiency dry eye. Jpn J Ophthalmol 54:387-391,
2010
6. Fukuoka S, Honda N, Ono K, Mimura T, Usui T,
Amano S: Extended long-term results ofpenetrating keratoplasty for keratoconus. Cornea
29:528-530, 2010
7. Higa A, Sakai H, Sawaguchi S, Iwase A,
Tomidokoro A, Amano S, Araie M: Corneal
endothelial cell density and associated factors ina population-based study in Japan: The
Kumejima study. Am J Ophthalmol 149:794-799,
2010
8. Honda N, Miyai T, Nejima R, Miyata K, Mimura
T, Usui T, Aihara M, Araie M, Amano S: Effectof latanoprost on the expression of matrix
metalloproteinases and tissue inhibitor of
metalloproteinase-1 on the ocular surface. Arch
Ophthalmol 128:466-471, 2010
9. Mimura T, Usui T, Mori M, Aixinjueluo W,
Funatsu H, Noma H, Amano S: Immunochromatographic assay for measurement of total
IgE in tears, nasal mucus, and saliva of patientswith allergic rhinoconjunctivitis. J Asthma 47
1153-1160, 2010
10. Mimura T, Usui T, Mori M, Funatsu H, Noma H,
Aixinjueluo W, Yamamoto H, Amano S: Rapid
immunochromatography of total tear immunoglobulin E in allergic conjunctivitis with
Allerwatch. J Investig Allergol Clin Immunol
20:627-628, 2010

438

11. Mimura T, Usui T, Mori M, Yamamoto H, Obata
H, Yamagami S, Funatsu H, Noma H, Honda N,
Amano S: Pinguecula and contact lenses. Eye
24:1685-1691, 2010
12. Mimura T, Usui T, Yamagami S, Funatsu H,
Noma H, Honda N, Amano S: Recent causes ofsubconjunctival hemorrhage. Ophthalmologica
224:133-137, 2010
13. Mimura T, Yamagami S, Mori M, Funatsu H,
Usui T, Noma H, Amano S: Contact lens-induced
subconjucntival hemorrhage. Am J Ophthalmol
150:656-665, 2010
14. Mimura T, Yamagami S, Uchida S, Yokoo S, Ono
K, Usui T, Amano S: Isolation of adult progenitor
cells with neuronal potential from rabbit corneal
epithelial cells in serum- and feeder layer-free
culture conditions. Mol Vis 16:1712-1719, 2010
15. Mimura T, Yamagami S, Usui T, Funatsu H,
Noma H, Honda N, Fukuoka S, Hotta H, Amano
S: Location and extent of subconjunctival
hemorrhage. Ophthalmologica 224:90-95, 2010
16. Mimura T, Yamagami S, Yokoo S, Usui T, Amano
S: Selective isolation of young cells from humancorneal endothelium by the sphere-forming assay.
Tissue Eng Part C Methods 16:803-812, 201017. Sonoyama H, Araki-Sasaki K, Osakabe Y,
Nakamura M, Amano S, Koizumi N, Kinoshita S,
Ideta H: Detection of cytomegalovirus DNA from
CMV corneal endotheliitis after penetrating
keratoplasty. Cornea 29:683-685, 2010
18. Tomoyose E, Higa A, Sakai H, Sawaguchi S,
Iwase A, Tomidokoro A, Amano S, Araie M:
Intraocular pressure and relating systemic andocular biometric factors in a population-based
study in Japan. The Kumejima Study. Am J
Ophthalmol 150:279-286, 2010
19. Usui T, Nakagawa S, Yokoo S, Mimura T,
Yamagami S, Amano S: Bilateral limbal stem cell
deficiency with chromosomal translocation of 3p
and 9p. Jpn J Ophthalmol 54:357-358, 2010

439

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)

Associate
Yasuhiko Kamikubo, M.D., Ph.D. (Hematology-Oncology)
Akihide Yoshimi, M.D. , Ph.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.

440

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.

Research activities
The major research projects are focused on clinicalstudies such as development of improved/new
methods for hematopoietic stem cell transplantation,
immunotherapy for hematopoietic tumors, and basic
studies on hematopoietic stem cells, leukemogenesis
and regenerative medicine using hematopoietic cells.
In the area of pediatric oncology, we continue thestudies on molecular mechanisms of pediatricmalignancies, such as neuroblastoma, rhabdomyosarcoma, and infant leukemia. Representative
publications from our department published in the past
year are listed in the references.

References
1.

2.

3.

Asano H, Imai Y, Ota S, Yamamoto G, Takahashi
T, Fukayama M, Kurokawa M. CD30-positive
anaplastic variant diffuse large B cell lymphoma:a rare case presented with cutaneous involvement.
Int J Hematol. 2010 Oct;92(3):550-2.
Asano H, Yamamoto G, Hosoi M, Takahashi T,
Hangaishi A, Kurokawa M. Complete molecularremission in refractory acute myeloid leukemiawith MLL/AF9 treated with gemtuzumab
ozogamicin. Leuk Res. 2010 Jul;34(7):e152-3.
Goyama S, Kurokawa M. Evi-1 as a criticalregulator of leukemic cells. Int J Hematol. 2010
Jun;91(5):753-7.
4. Goyama S, Nitta E, Yoshino T, Kako S,
Watanabe-Okochi N, Shimabe M, Imai Y,
Takahashi K, Kurokawa M. EVI-1 interacts withhistone methyltransferases SUV39H1 and G9a
for transcriptional repression and bone marrowimmortalization. Leukemia. 2010 Jan;24(1):81-8.
5. Hangaishi A, Kurokawa M. Blimp-1 is a tumor
suppressor gene in lymphoid malignancies. Int J
Hematol. 2010 Jan;91(1):46-53.
6. Hangaishi A, Takahashi T, Masuda A, Okada S,
Kandabashi K, Kurokawa M. Rituximab therapy
for refractory immune thrombocytopenic purpura
in elder patients. Int J Hematol. 2010 Mar;91(2):336-7.
7. Hosoi M, Ichikawa M, Imai Y, Kurokawa M. A
case of anaplastic large cell lymphoma, ALK
positive, primary presented in the skin andrelapsed with systemic involvement andleukocytosis after years of follow-up period. Int J
Hematol. 2010 Nov;92(4):667-8.
8. Hosoi M, Nannya Y, Sasaki T, Suzuki HI, Ueda K,
Tsujino T, Isayama H, Takahashi T, Koike K,
Kurokawa M. Biliary cast syndrome and benign
biliary stricture as complications of allogeneic
hematopoietic stem cell transplantation. Ann
Hematol. 2010 Dec;89(12):1287-9.
9. Hosoi M, Yamamoto G, Imai Y, Kurokawa M.
Reversible
posteriorleukoencephalopathy
syndrome following R-CHOP therapy for diffuse
large B-cell lymphoma. Ann Hematol. 2010 Feb;
89(2):207-8.
10. Ichikawa M, Hangaishi A, Nannya Y, Kurokawa
M. Postremission gemtuzumab ozogamicin for
elderly patients with acute myelogenous
leukemia with favorable characteristics andcomorbid conditions. Int J Hematol. 2010 Nov;
92(4):673-4.
11. Imai Y, Shimaoka M, Kurokawa M. Essential
roles of VLA-4 in the hematopoietic system. Int J
Hematol. 2010 May;91(4):569-75.
12. Kagoya Y, Hangaishi A, Takahashi T, Imai Y,
Kurokawa M. High-dose dexamethasone therapy
for severe thrombocytopenia and neutropenia
induced by EBV infectious mononucleosis. Int J
Hematol. 2010 Mar;91(2):326-7.

441

13. Kataoka K, Nannya Y, Iwata H, Seo S, Kumano
K, Takahashi T, Nagai R, Kurokawa M. Plasma
brain natriuretic peptide is associated with
hepatic veno-occlusive disease and earlymortality after allogeneic hematopoietic stem celltransplantation. Bone Marrow Transplant. 2010
Nov;45(11):1631-7.
14. Kataoka K, Nannya Y, Ueda K, Kumano K,
Takahashi T, Kurokawa M. Differential
prognostic impact of pretransplant comorbidity
on transplant outcomes by disease status and timefrom transplant: a single Japanese transplant
centre study. Bone Marrow Transplant. 2010
Mar;45(3):513-20.
15. Kataoka K, Seo S, Ota S, Takahashi T, Kurokawa
M. Positron emission tomography in the
diagnosis and therapeutic monitoring of posttransplant lymphoproliferative disorder after cord
blood transplantation. Bone Marrow Transplant.
2010 Mar;45(3):610-2.
16. Kataoka K, Seo S, Sugawara Y, Ota S, Imai Y,
Takahashi T, Fukayama M, Kokudo N, Kurokawa
M. Post-transplant lymphoproliferative disorder
after adult-to-adult living donor liver transplant:
case series and review of literature. Leuk
Lymphoma. 2010 Aug;51(8):1494-501.
17. Kataoka K, Takahashi T, Iwata H, Hangaishi A,
Kumano K, Kurokawa M. Fulminant myocarditis
after allogeneic bone marrow transplantation:
successful
cytomegalovirus
therapyandmechanical circulatory support for bridge torecovery. Biol Blood Marrow Transplant. 2010
Jan;16(1):129-30.
18. Kobayashi H, Ichikawa M, Hangaishi A, Imai Y,
Kurokawa M. Concurrent development of"Burkitt-like" lymphoma and BCL-2-rearranged
low-grade B cell lymphoma sharing the same
germinal center origin. Int J Hematol. 2010 Jan;
93(1):112-7.
19. Koike Y, Miyazaki K, Higashihara M, Kimura E,
Jona M, Uchihashi K, Masuda A, Kandabashi K,
Kurokawa M, Yatomi Y. Clinical significance ofdetection of immature platelets: comparison
between percentage of reticulated platelets as
detected by flow cytometry and immature platelet
fraction as detected by automated measurement.
Eur J Haematol. 2010 Feb;84(2):183-4.

20. Kumano K, Kurokawa M. The role ofRunx1/AML1 and Evi-1 in the regulation ofhematopoietic stem cells. J Cell Physiol. 2010
Feb;222(2):282-5.
21. Nagai S, Nannya Y, Arai S, Yoshiki Y, Takahashi
T, Kurokawa M. Molecular or cytogenetic
monitoring and preemptive therapy for central
nervous system relapse of acute promyelocytic
leukemia. Haematologica. 2010 Jan;95(1):16971.
22. Nagai S, Nannya Y, Takahashi T, Kurokawa M.
Jumping translocation involving 1q21 duringlong-term complete remission of acute myeloid
leukemia. Ann Hematol. 2010 Jul;89(7):741-2.
23. Nagai S, Takahashi T, Kurokawa M. How should
we prevent hematologic relapse of acutepromyelocytic leukemia? J Clin Oncol. 2010 Feb;
28(4):e62; author reply e3-4.
24. Nagai S, Takahashi T, Kurokawa M.
Risk-adapted maintenance therapy for acutepromyelocytic leukemia. J Clin Oncol. 2010
Jan;28(2):e21; author reply e2-3.
25. Nagai S, Takahashi T, Kurokawa M. The impact
of molecularly targeted therapies upon theunderstanding of leukemogenesis and the role ofhematopoietic stem cell transplantation in acutepromyelocytic leukemia. Curr Stem Cell Res
Ther. 2010 Dec;5(4):372-8.
26. Nakahara F, Sakata-Yanagimoto M, Komeno Y,
Kato N, Uchida T, Haraguchi K, Kumano K,
Harada Y, Harada H, Kitaura J, Ogawa S,
Kurokawa M, Kitamura T, Chiba S. Hes1
immortalizes committed progenitors and plays arole in blast crisis transition in chronic
myelogenous leukemia. Blood. 2010 Apr;115(14):2872-81.
27. Nakazaki K, Hangaishi A, Nakamura F, Hosoi M,
Imai Y, Takahashi T, Nannya Y, Kurokawa M.
IgG-associated immune thrombocytopenia in
Waldenstrom macroglobulinemia. Int J Hematol.
2010 Sep;92(2):360-3.
28. Nishimoto N, Imai Y, Ueda K, Nakagawa M,
Shinohara A, Ichikawa M, Nannya Y, Kurokawa
M. T cell acute lymphoblastic leukemia arisingfrom familial platelet disorder. Int J Hematol.
2010 Jul;92(1):194-7.
29. Okada S, Nannya Y, Ota S, Takazawa Y,

442

30.

31.

32.

33.

34.

35.

36.

Yamamoto G, Kumano K, Izutsu K, Takahashi T,
Chiba S, Kurokawa M. Cutaneous T-cell
lymphoma (mycosis fungoides) relapsed withdifferent immunological phenotype after bonemarrow transplant. Br J Dermatol. 2010 Jan;
162(1):229-30.
Oshima K, Takahashi T, Mori T, Matsuyama T,
Usuki K, Asano-Mori Y, Nakahara F, Okamoto S,
Kurokawa M, Kanda Y. One-year low-dose
valacyclovir as prophylaxis for varicella zoster
virus disease after allogeneic hematopoietic stem
cell transplantation. A prospective study of theJapan Hematology and Oncology Clinical Study
Group. Transpl Infect Dis. 2010 Oct;12(5):421-7.
Shinohara A, Ichikawa M, Ueda K, Takahashi T,
Hangaishi A, Kurokawa M. A novel MLL-AF1p/
Eps15 fusion variant in therapy-related acutelymphoblastic leukemia, lacking the EH-domains.
Leuk Res. 2010 Feb;34(2):e62-3.
Takahashi T, Hangaishi A, Yamamoto G,
Ichikawa M, Imai Y, Kurokawa M. HIV-negative,
HHV-8-unrelated primary effusion lymphomalike lymphoma: report of two cases. Am J
Hematol. 2010 Jan;85(1):85-7.
Ueda K, Ichikawa M, Takahashi M, Momose T,
Ohtomo K, Kurokawa M. FDG-PET is effectivein the detection of granulocytic sarcoma inpatients with myeloid malignancy. Leuk Res.
2010 Sep;34(9):1239-41.
Ueda K, Nagai S, Miyashita SI, Kaise T,
Ichikawa M, Kumano K, Hangaishi A, Nannya Y,
Kurokawa M. Arsenic-induced pericardial andpleural effusion without acute promyelocytic
leukemia differentiation syndrome. Leuk Res.
2010 Jan;34(1):e25-6.
Ueda K, Nannya Y, Asai T, Yamamoto G,
Hangaishi A, Takahashi T, Imai T, Kurokawa M.
Efficacy and safety of modified rituximabESHAP therapy for relapsed/refractory B-cell
lymphoma. J Chemother. 2010 Feb;22(1):54-7.
Ueda K, Watadani T, Maeda E, Ota S, Kataoka K,
Seo S, Kumano K, Hangaishi A, Takahashi T,
Imai Y, Ohtomo K, Fukayama M, Nannya Y,
Kurokawa M. Outcome and treatment of lateonset noninfectious pulmonary complications
after allogeneic haematopoietic SCT. Bone
Marrow Transplant. 2010 Dec;45(12):1719-27.

443

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
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 from other departments including thedepartment of internal medicine, surgery, gynecology
and otorhinolaryngology, participate the endoscopic
procedures. The endoscopic rooms moved to the newbuilding in Oct. 2006.

enhanced endoscopy for detail inspection andtherapeuticendoscopy,
includingendoscopic
submucosal dissection for esophageal, gastric andcolorectal tumors, are major advanced fields. 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, radiographic procedure rooms, surgery rooms
or intensive care units. All endoscopes are collectedin our department after use and disinfected.

Clinical activities
Teaching activities
Endoscopic
procedures,
includinguppergastrointestinal endoscopy, colonoscopy, bronchoscopy, otorhinolaryngological endoscopy and gynecological endoscopy, are performed from Monday to
Friday. Emergency endoscopy is performed in thenighttime or holidays. Enteroscopy by using capsuleendoscopes and balloon-assisted endoscopes are
rapidly increasing in number. Additionally, image

We participate in under-graduate education as a part ofsystemic lectures and bed-side learning by thedepartment of gastroenterology, surgery and otherdepartments. As for post-graduate education, training
opportunities for endoscopy and endoscopic surgery
are given to resident or young doctors in a program ofeach department.

Table 1. Endoscopic examinations in the Department of Endoscopy and Endoscopic Surgery
2001

2002

2003

2004

2005

2006

2007

2008

2009

*

EGD
Colonoscopy
Bronchoscopy
EUS**Enteroscopy
Laryngoscopy
Colposcopy

6346
3212
194
479
154
181

7324
3529
220
583
93
103

7920
3873
207
586
68
124

7597
3728
194
476
61
139

8265
4084
212
461
89
88

8131
4327
201
438
127
58

8796
4360
201
484
91
117

9822
4679
165
402
133
63
256

10262
4996
226
518
181
75
307

Total

10566

11852

12778

12195

13199

13282

14043

15520

16566

*Esophagogastroduodenoscopy, **Endoscopic ultarasonography

2010
10556
5152
255
551
311
70
361
17256

444

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

References(1) Sugimoto T, Ohta M, Ikenoue T, Yamada A, Tada
M, Fujishiro M, Ogura K, Yamaji Y, Okamoto M,
Kanai F, Kawabe T, Omata M. Macroscopic
morphologic subtypes of laterally spreadingcolorectal tumors showing distinct molecularalterations. Int J Cancer. 127:1562-9, 2010
(2) Kodashima S, Fujishiro M. Novel imageenhanced endoscopy with i-scan technology.
World J Gastroenterol 16: 1043-1049, 2010
(3) Fujishiro M, Abe N, Endo M, Kawahara Y,
Shimoda R, Nagata S, Homma K, Morita Y, Uedo
N Current managements and outcomes of peptic
and artificial ulcer bleeding in Japan. Dig Endosc
22: S9–S14, 2010
(4) Fujishiro M, Abe N, Endo M, Kawahara Y,
Shimoda R, Nagata S, Homma K, Morita Y, Uedo
N. Retrospective multicenter study concerning
electrocautery forceps with soft coagulation for
nonmalignant gastroduodenal ulcer bleeding inJapan. Dig Endosc 22: S15–S18, 2010
(5) Wong VW, Teoh AY, Fujishiro M, Chiu PW, Ng
EK. Preemptive dilatation gives good outcome toearly esophageal stricture after circumferential
endoscopic
submucosal
dissection.
Surg
Laparosc Endosc Percutan Tech. 20:e25-7, 2010(6) Ono S, Fujishiro M, Kodashima S, Minatsuki C,
Hirano K, Niimi K, Goto O, Yamamichi N,
Fukuda T, Seto Y, Koike K: High-dose
dexamethasone may prevent esophageal stricture
after endoscopic submucosal dissection. Clin J
Gastroenterol 3:155-8, 2010(7) Enomoto S, Yanaoka K, Utsunomiya H, Niwa T,
Inada K, Deguchi H, Ueda K, Mukoubayashi C,
Inoue I, Maekita T, Nakazawa K, Iguchi M, Arii
K, Tamai H, Yoshimura N, Fujishiro M, Oka M,
Ichinose M. Inhibitory effects of Japanese apricot(Prunus mume Siebold et Zucc.; Ume) on
Helicobacter pylori-related chronic gastritis. Eur
J Clin Nutr. 64:714-9, 2010(8) Niimi K, Fujishiro M, Kodashima S, Goto O,

Ono S, Hirano K, Minatsuki C, Yamamichi N,
Koike K. Long-term outcomes of endoscopic
submucosal dissection for colorectal epithelial
neoplasms. Endoscopy 42:723-9, 2010(9) Shimoyama S, Fujishiro M, Takazawa Y.
Successful type-oriented endoscopic resection for
gastric carcinoid tumors: A case report. World J
Gastrointest Endosc. 2:408-12, 2010.
(10) Ono S, Fujishiro M, Kodashima S, Minatsuki C,
Hirano K, Niimi K, Goto O, Yamamichi N,
Koike K. Controversy on the management of
anticoagulants and antiplatelet agents forscheduled endoscopy. Dig Endosc 23:1-4, 2011(11) Enomoto S, Oka M, Ohata H, Mukoubayashi C,
Watanabe M, Moribata K, Muraki Y, Shingaki N,
Deguchi H, Ueda K, Inoue I, Maekita T, Iguchi
M, Yanaoka K, Tamai H, Fujishiro M, Mohara O,
Ichinose M. Assessment of gastroesophageal
reflux disease by serodiagnosis of Helicobacter
pylori-related chronic gastritis stage. World J
Gastrointest Endosc 3: 71-77, 2011(12) Inoue I, Mukoubayashi C, Yoshimura N, Niwa T,
Deguchi H, Watanabe M, Enomoto S, Maekita T,
Ueda K, Iguchi M, Yanaoka K, Tamai H, Arii K,
Oka M, Fujishiro M, Takeshita T, Iwane M,
Mohara O, Ichinose M. Elevated risk ofcolorectal adenoma with Helicobacter pylorirelated chronic gastritis: A population-based
case-control study. Int J Cancer. 2011 Jan 10.
(13) Goto O, Mitsui T, Fujishiro M, Wada I, Shimizu
N, Seto Y, Koike K. New method of endoscopic
full-thickness resection: a pilot study of
non-exposed endoscopic wall-inversion surgery
in an ex vivo porcine model. Gastric Cancer.
2011 Mar 11.
(14) Nakai Y, Ikeda H, Nakamura K, Kume Y,
Fujishiro M, Sasahira N, Hirano K, Isayama H,
Tada M, Kawabe T, Komatsu Y, Omata M, Aoki
J, Koike K, Yatomi Y. Specific increase in serum
autotaxin activity in patients with pancreaticcancer. Clin Biochem. 2011 Mar 31.

445

Department of Hemodialysis &Apheresis
Director
Toshiro Fujita, MD, PhD

Vice Director
Head, Eisei Noiri, MD, PhD
Noiri Hanafusa, MD, PhD

Introduction
Hemodialysis and related blood purification therapy
had been individually performed in their respective
departments. However, all the departments’ apparatus
and human resources were centralized to form the
Department of Hemodialysis and Center for
Hemodialysis in 2000 at the University Hospital. The
Center for Hemodialysis was further renovated andstarted operations in Fall of 2006. This new Center for
Hemodialysis is equipped with one pressure control
unit in addition to 12 hemodialysis machines under astate-of-the-art hemodialysis control system. Ourconcept of a hemodialysis controlling system is a hub
to transfer all digital and analog data from patients andto 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.

2.
3.
4.
5.

6.

Medical Care
1.
2.

3.

Education
4.
1.

A systematic review course for M2 students,
which covers clinical features, diagnosis, andevidence-based therapeutic strategies for acuteand chronic renal failure including diabetic
nephropathy.
Technical development course for medical
engineers and nurses.
Tutorial course for clinical fellows applying to
the speciality of blood purification therapy.
Exposure in hemodialysis & apheresis course to
second year residents on request.
Our state-of-the-art blood purification protocols
are summarized in Japanese handbook in 2010
[Apheresis Pocket Manual] and 2011 [CRRTPocket Manual].
Our department takes main part in Critical Care
Nephrology Course for educating young clinicalresearchers and fellows in collaboration with
Department of Critical Care Medicine.

Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does
not accept holiday dialysis.
Emergency hemodialysis and hemodiafiltration
for ICU patients.
Plasma exchange for neurodegenerative diseases,
SLE, TTP, TMA, and pre/post-liver transplantpatients.

446

5.
6.
7.

DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
LDL apheresis for nephrotic syndrome and ASO
patients.
White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.

Research
1.
2.
3.
4.
5.
6.
7.
8.

Prognostic analysis for post-liver transplantpatients received plasma exchange therapy.
Development and application of a non-invasive
pulse hemoglobin meter.
Genome wide association study for Nephrotic
syndrome and those functional analyses.
Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
AKI biomarkers and those clinical significance in
ICU/CCU.
Renal biomarker
to determine clinicalactionability in CKD and type-2 DN.
The potentiality of urine biomarker tests fordeveloping country [JICA-JST: Science andTechnology Research Partnership for Sustainable
Development].

References
1.

2.

3.

4.

Okamoto K, Tokunaga K, Doi K, Fujita T, Suzuki
H, Katoh T, Watanabe T, Nishida N, Mabuchi A,
Takahashi A, Kubo M, Maeda S, Nakamura E,
Noiri E: Common variation in GPC5 is
associated with acquired nephrotic syndrome.
Nat Genet 43:459-63, 2011
Doi K, Negishi K, Ishizu T, Katagiri D, Fujita T,
Matsubara T, Yahagi N, Sugaya T, Noiri E:
Evaluation of new acute kidney injury
biomarkers in mixed ICU. Crit Care Med 39,
2011 in press
Kurano M, Iso-O N, Hara M, Noiri E, Koike K,
Kadowaki T, Tsukamoto K: Plant sterols
increased IL-6 and TNF-a secretion frommacrophage, but a lesser extent than cholesterol.
J Atheroscler Thromb 2011 Jan 22 [epub]
Doi K, Hamasaki Y, Noiri E, Nosaka K, Suzuki T,

Toda A, Shimizu T, Fujita T, Nakao A: Role ofleukotriene B4 in accelerated hyperlipidaemic
renal injury. Nephrology 16:304-9, 2011
5. Maeda-Mamiya R, Noiri E, Isobe H, Nakanishi
W, Okamoto K, Doi K, Sugaya T, Izumi T,
Homma T, Nakamura E: In vivo gene delivery bycationic tetraamino fullerene. Proc Natl Acad Sci
U S A 23;107:5339-5344, 2010
6. Okamoto K, Iwasaki N, Nishimura C, Doi K,
Noiri E, Nakamura S, Takizawa M, Ogata M,
Fujimaki R, Grarup N, Pisinger C, BorchJohnsen K, Lauritzen T, Sandbaek A, Hansen T,
Yasuda K, Osawa H, Nanjo K, Kadowaki T,
Kasuga M, Pedersen O, Fujita T, Kamatani N,
Iwamoto Y, Tokunaga K: Identification of
KCNJ15 as a susceptibility gene in Asian patientswith type 2 diabetes mellitus. Am J Hum Genet
86:54-64, 2010
7. Watanabe N, Ikeda H, Kume Y, Satoh Y, Kaneko
M, Takai D, Tejima K, Nagamine M, Mashima H,
Tomiya T, Noiri E, Omata M, Matsumoto M,
Fujimura Y, Yatomi Y: Increased production of
ADAMTS13 in hepatic stellate cells contributes
to enhanced plasma ADAMTS13 activity in rat
models of cholestasis and steatohepatitis.
Thromb Haemost 102:389-396, 2010
8. Doi K, Noiri E, Fujita T: Role of vascularendothelial growth factor in kidney disease. Curr
Vasc Pharmacol 8:122-128, 2010
9. Ishii T, Doi K, Okamoto K, Imamura M, Dohi M,
Yamamoto K, Fujita T, Noiri E: Neutrophil
elastase contributes to acute lung injury inducedby bilateral nephrectomy. Am J Pathol 177:
1665-73, 2010
10. Doi K, Noiri E, Maeda-Mamiya R, Ishii T,
Negishi K, Hamasaki Y, Fujita T, Yahagi N,
Koide H, Sugaya T, Nakamura T: Urinary L-type
fatty acid-binding protein as a new biomarker ofsepsis complicated with acute kidney injury. Crit
Care Med 38: 2037-42, 2010
11. Ishii T, Ohtake T, Okamoto K, Mochida Y,
Ishioka K, Oka M, Maesato K, Ikee R, Moriya H,
Hidaka S, Doi K, Noiri E, Fujita T, Kobayashi S:
Serum biological antioxidant potential predicts
the prognosis of hemodialysis patients. Nephron
117: c230-6, 2010
12. Doi K, Leelahavanichkul A, Yuen PS, Star RA:447

Animal models of sepsis and sepsis-induced
kidney injury. J Clin Invest 119:2868-2878, 2009
13. 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
14. 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.
AmJ
Pathol174:1203-11, 2009
15. 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
16. 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
17. 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 ofhostmacrophages
toincrease
theirinterleukin-10 production. Nat Med 15:42-9,
2009
18. 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 acutekidney injury in sepsis. J Am Soc Nephrol
20:1217-21,2009
19. Nakai S, Masakane I, Shigematsu T, Hamano T,
Yamagata K, Watanabe Y, Itami N, Ogata S,
Kimata N, Shinoda T, Syouji T, Suzuki K,
Taniguchi M, Tsuchida K, Nakamoto H, Nishi S,
Nishi H, Hashimoto S, Hasegawa T, Hanafusa N,
Fujii N, Marubayashi S, Morita O, Wakai K,
Wada A, Iseki K, Tsubakihara Y: An overview ofregular dialysis treatment in Japan (as of 31
December 2007). Ther Apher Dial 13:457-504,
2009
20. Yamazaki O, Hanafusa N, Yamada A, Noiri E,

21.

22.

23.

24.

25.

26.

27.

Fujita T: Recurrent intestinal bleeding treated bydouble-balloon endoscopy in haemodialysis
patients. NDT Plus 2: 469-472, 2009
Takagi H, Itoh M, Islam MZ, Razzaque A, Ekram
AR, Hashighuchi Y, Noiri E, Kimura E: Sensitive,
specific, and rapid detection of Leishmania
donovani DNA by loop-mediated isothermal
amplification. Am J Trop Med Hyg 81:578-82,
2009
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
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.
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
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

448

28. 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
29. 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

449

Clinical Research Support Center
Professor
Takashi Kadowaki, M.D., Ph.D.

Associate Professor
Yoshihiro Arakawa, Ph.D.

Research Associate
Koji Nozaki, M.D., Ph.D.
Hiroshi Satonaka, M.D., Ph.D.
Yuzaburo Uetake, M.D., Ph.D.

Homepage

http://www.cresc.h.u-tokyo.ac.jp/site/index.html

History and Organization
The Clinical Research Support Center was
established in 2010. It originated from Clinical Trial
Managing Center, which was established in 1998, andsubsequently the former Clinical Research Center,
which was established in 2001. It belongs to thecentral division of the hospital and supports not only
industry-sponsored, but also investigator-initiated,clinical trials.
With the increasing volume of clinical research
conducted in our hospital, demand mounted for the
structural framework to support investigator-initiated,
especially multicenter, trials.
It is an important mission of university hospitals todevelop novel therapeutics by clinical trials. Highethical and scientific standards as well as highreliability are now being required for the
implementation of clinical research, including
investigator-initiated translational research or trials forthe off-label use of approved drugs.
In response to the above demands, the former
Clinical Research Center was reorganized in April
2010 into the current Clinical Research Support
Center, enabling strengthened support and expeditious
promotion of clinical research.
The Center consists of Site Coordinating Unit,roughly equivalent to the former whole ClinicalResearch Center, and Central Coordinating Unit,
which provides coordinating functions for researchsuch as multicenter trials.
Site Coordinating Unit is comprised of theinstitutional review board (IRB) Secretariat Division,
Investigational Drug/Information Control Division
and Clinical Research Coordinator Division, eachcharged with IRB secretarial affairs, handling of drugs
for clinical trials and assistance with safety
information reporting, and clinical researchcoordinator activities.
In addition to the existing Consultation Division,
the Central Coordinating Unit has added newdivisions such as Biostatistics/Data Management
Division, Safety Information Division, Operation
Division which is responsible for the coordination
among the sites, and Monitoring Division responsiblefor quality control. Activities of these Divisions
include protocol formulation, project management,
data management, monitoring, statistical analysis andassistance with safety information reporting.
Clinical Research Support Center can now support
both trials registered or not registered for marketing
approval, and, therefore, can provide seamless support
to research in any phase of development.
As of March 2011, the Center staff includes aprofessor, an associate professor, 3 research associates,
9 pharmacists, 11 nurses, a laboratory technologist

450

and 4 clerical staff members.

Clinical Research Support
Activities
The duties of the Center range from serving as thesecretariat for the IRB to supporting theimplementation and reporting of clinical trials.
To further improve the quality of trials or clinicalresearch (which includes use of unapproved drugs on
a compassionate basis) respecting the principles of the
globally standard ICH-GCP, we have prepared and asneeded revised the guidelines or SOPs intended foruse in our hospital. These documents include thoserelating to preparation of the study protocol orinformed consent form, implementation of research,and handling of costs to trial participants.
For secure process of the applications ofindustry-sponsored clinical trials to IRB, we hold apreliminary hearing system (named as “protocolpresentation”) before IRB.
The items processed by the Center as the IRB
secretariat in fiscal 2009 included, as forindustry-sponsored trials for marketing approval, 33
new protocol applications, 73 study extension
applications, 477 protocol amendment applications,
827 SAE/safety information reports, 36 study closureor termination reports. As for investigator-initiatedclinical research, the Center processed 53 newprotocols (including 8 applications for compassionate
use of unapproved drugs), 149 applications for
protocol amendment, 47 SAE/safety information
reports, 23 study closure or termination reports.
Protocol presentations of industry-sponsored trials
prior to application to IRB totaled 17 applications.
Preliminary consultation for investigator-initiatedresearch application including cases of compassionate
totaled 108 applications.
To cope with the so-called `drug lag problem`
relating to the drugs unapproved in Japan,
participation in global trials was an urgent necessity.
For this purpose, University Hospital Clinical Trial
Alliance (UHCT Alliance) comprised of 6 national
university hospitals (Tokyo University, Niigata
University, Gunma University, Tsukuba University,
Tokyo Medical and Dental University and Chiba
University) located in the central part of Japan wasestablished in 2006 and has since been incollaboration toward improvement of clinical trial
environments. In 2006, the rotated managerial site wasTokyo University, where the Alliance Office wasbased. In Alliance an organizational structure has been
established that can cooperatively attract trials andsmoothly process them for IRB approval. A scheme toeducate the staff in preparation for global trials has
been put in place. In 2007 Shinshu University joined
the Alliance as the 7th member university.
From April 2009 on, a 5-year special research grantfrom the Ministry of Education, Culture, Sports,
Science and Technology for the promotion of UHCT
Alliance allowed to set up a full-time office (made upof 2 staffers) and further expand the activities.
Operational subsidies that Tokyo University received
were distributed to each university based on a joint
project agreement, which was an unprecedented
attempt for our university. Each university and the
Office was given its own task to cooperatively
promote the mission of the whole Alliance.
Until the end of March 2011, 49 protocols wereintroduced to the Alliance including 25 multinational
trials. The Alliance helped to assess feasibility in 8
trials and to select the participating sites in 33.
Cooperative protocol presentation (hearing) sessions
were held for 36 protocols. Industry sponsors applied
for regulatory drug approval from Ministry of Health,Labour and Welfare based on data of 11 trials and 4
drugs have been so far approved.
Clinical Research Support Center managed
drug/device inventory for 86 clinical trials forregulatory approval, 2 postmarketing trials, 4 trials ofdevices, 47 investigator-initiated clinical trials, onecase of compassionate use in fiscal 2010. The numberof prescriptions processed was 797 for trials forapproval and postmarketing trials combined, 652 forinvestigator-initiated clinical trials. We are currently
managing trial drugs centrally for 2 multicenter
double-blind trials. We are also in charge of the
primary review of clinical trial safety information andof maintaining the database on clinical trials ingeneral.
Clinical research coordinators (CRC) of the Center
have been supporting as a principle all clinical trials
for approval and postmarketing trials since 2002. We
started partially supporting investigator-initiated trials

451

in 2004 and have already supported 5 trials. In 2005
westartedproviding
CRC
supporttoinvestigator-initiated trials on a beneficiary-pays basisand have already supported 6 trials. CRCs exclusively
involved in investigator-initiated trials have been
employed as needed. The number of trial participantsthat CRCs interacted with was 3777 in fiscal 2006,
4853 in 2007, 5172 in 2008, 4761 in 2009 and 3776 in
2010. We started receiving monitoring visits for every
trial participant’s data in 2002. The number ofmonitoring visits increased to 569 in 2007, 952 in
2008, 840 in 2009 and 672 in 2010.
As part of patient awareness campaign activity, we
continued updating the Center homepage, preparedleaflets and distributed them at outpatient receptions.
The leaflets contain information about trials currently
recruiting participants.
Our outpatient clinic for trial participants was
moved to the second central clinic building, which
was newly opened in November 2006. The new clinic
has reception desks for consultation and own waiting
space.
At Central Coordinating Unit, which was newly
established, 5 projects were adopted for full support
by the Center including project management, data
management etc.

Teaching Activities
Two resident physicians got training for a month in
the Center as part of the M.D. residency training
program. Ten students in the Graduate School of
Medicine also got one-day training. Three trainees
from outside the University got CRC training for 3
weeks. One trainee got similar CRC training for a
week.
Annual CRC training course for national, public
and private university hospitals in 2010 was held
under the auspices of Tokyo University Hospital for 5days, in which 82 trainees from university hospitals all
across the country participated.
Dr Arakawa also gave lectures in a lecture series onclinical science for graduate course students of theFaculty of Pharmaceutical Sciences
An international symposium for clinical research
was held on March 11, 2011 as a 10th memorial
seminar. Although we met a big earthquake, thesymposium itself could be continued to the last
speaker with the change of venue.

Research Activities
An endowed course on clinical trial data
management was opened in April 2007 with thecooperation from the Center and the Biostatistics
Department, Graduate School of Medicine,
conducting research and education on data
management and biostatistics focused on practicalapplication to trials.
The Center was involved in 4 scientific meeting
presentations, 20 invited lectures in fiscal 2010 and 12
published papers in 2010. There was one news media
article that reported on the Center.

References(1) Ando K, Ohtsu H, Arakawa Y, Kubota K,
Yamaguchi T, Nagase M, Yamada A, Fujita T, on
behalf of the EVALUATE Study Investigators:
Rationale and Design of the Eplerenone
Combination Versus Conventional Agents to
Lower
Blood
Pressureon
Urinary
Antialbuminuric Treatment Effect (EVALUATE)
Trial: A Double-Blinded Randomized PlaceboControlled Trial to Evaluate the Antialbuminuric
Effects of an Aldosterone Blocker inHypertensive Patients with Albuminuria.
Hypertension Research, 33, 616-621, 2010.

452

University hospital Medical
Information Network (UMIN)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Instructor
Hirono Ishikawa, Ph.D.

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.

453

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454(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455

Organ Transplantation Service
Director and Professor
Norihiro KOKUDO

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/1512ishokugeka/index.html

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 (2009)
1.

2.

3.

4.

Song P, Tang W, Tamura S, Hasegawa K,
Sugawara Y, Dong J, Kokudo N. The
management of hepatocellular carcinoma in Asia:a guideline combining quantitative andqualitative evaluation. Biosci Trends 2010;
4:283-7.
Kaneko J, Sugawara Y, Togashi J, Tamura S,
Motoi R, Fukayama M, Kokudo N. Sarcomatouschange of hepatocellular carcinoma in a patientundergoing living donor liver transplantation.
Biosci Trends 2010; 4:279-82.
Hasegawa K, Kokudo N, Shiina S, Tateishi R,
Makuuchi M. Surgery versus radiofrequency
ablation for small hepatocellular carcinoma: Startof a randomized controlled trial (SURF trial).
Hepatol Res 2010; 40:851-2.
Ishizawa T, Bandai Y, Ijichi M, Kaneko J,
Hasegawa
K,
KokudoN.
Fluorescentcholangiography illuminating the biliary tree
during laparoscopic cholecystectomy. Br J Surg

2010; 97:1369-77.
5. Harada N, Ishizawa T, Muraoka A, Ijichi M,
Kusaka K, Shibasaki M, Yamamoto K, Hasegawa
K, Bandai Y, Kokudo N. Fluorescence navigation
hepatectomy by visualization of localizedcholestasis from bile duct tumor infiltration. J
Am Coll Surg 2010; 210:e2-6.
6. Shindoh J, Imamura H, Kokudo N. Isolated sling
suspension during resection of the Spiegel lobe of
the liver: a safe alternative technique for difficult
cases. J Hepatobiliary Pancreat Sci 2010; 17:359-64.
7. Inagaki Y, Tang W, Zhang L, Du G, Xu W,
Kokudo N. Novel aminopeptidase N (APN/
CD13) inhibitor 24F can suppress invasion ofhepatocellular carcinoma cells as well as
angiogenesis. Biosci Trends 2010; 4:56-60.
8. Takamoto T, Hashimoto T, Sano K, Maruyama Y,
Inoue K, Ogata S, Takemura T, Kokudo N,
Makuuchi M. Recovery of liver function after the
cessation of preoperative chemotherapy forcolorectal liver metastasis. Ann Surg Oncol 2010;17:2747-55.
9. Kokudo N, Arita J. Staging for intrahepaticcholangiocarcinoma. Liver Int 2010; 30:931-3.
10. Mise Y, Imamura H, Hashimoto T, Seyama Y,
Aoki T, Hasegawa K, Beck Y, Sugawara Y,
Makuuchi M, Nakajima J, Kokudo N. Cohort
study of the survival benefit of resection forrecurrent hepatic and/or pulmonary metastases
after primary hepatectomy for colorectal
metastases. Ann Surg 2010; 251:902-9.
11. Shindoh J, Mise Y, Satou S, Sugawara Y, Kokudo
N. The intersegmental plane of the liver is notalways flat--tricks for anatomical liver resection.
Ann Surg 2010; 251:917-22.

456

12. Inoue Y, Takahashi M, Arita J, Aoki T, Hasegawa
K, Beck Y, Makuuchi M, Kokudo N. Intraoperative freehand real-time elastography forsmall focal liver lesions: "visual palpation" fornon-palpable tumors. Surgery 2010; 148:100011.
13. Yamashiki N, Sugawara Y, Tamura S, Tateishi R,
Yoshida H, Kaneko J, Matsui Y, Togashi J,
Akahane M, Makuuchi M, Omata M, Kokudo N.
Postoperative surveillance with monthly serum
tumor markers after living-donor livertransplantation for hepatocellular carcinoma.
Hepatol Res 2010; 40:278-86.
14. Tamura S, Sugawara Y, Yamashiki N, Kaneko J,
Kokudo N, Makuuchi M. Pre-emptive antiviraltherapy in living donor liver transplantation forhepatitis C: observation based on a single-center
experience. Transpl Int 2010; 23:580-8.
15. Ishizawa T, Mise Y, Aoki T, Hasegawa K, Beck Y,
Sugawara Y, Kokudo N. Surgical technique: newadvances for expanding indications andincreasing safety in liver resection for HCC: theEastern perspective. J Hepatobiliary Pancreat Sci
2010; 17:389-93.
16. Hasegawa K, Kokudo N, Sano K, Makuuchi M.
Single HCC between 2 and 5 cm: the grey zon:
surgeon’s perspective. J Hepatobiliary Pancreat
Sci 2010; 17:430-3.
17. Kishi Y, Imamura H, Sugawara Y, Sano K,
Kaneko J, Kokudo N, Makuuchi M. Evaluationof donor vasculobiliary anatomic variations inliver graft procurements. Surgery 2010; 147:30-9.
18. Kyoden Y, Tamura S, Sugawara Y, Matsui Y,
Togashi J, Kaneko J, Kokudo N, Makuuchi M.
Incidenceandmanagementofbiliary
complications after adult-to-adult living donorliver transplantation. Clin Transplant 2010; 24:
535-42.

457

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.,

Shinya Kodashima, M.D., Ph.D.

Kazushi Suzuki, M.D., Ph.D.,

Tomoko Nakao, M.D., Ph.D.

Kenichi Aizawa, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)
Yoshiko Mizuno,M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Homepage:

http://www.h.u-tokyo.ac.jp/patient/depts/kenshin/index.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 five Clinical
Divisions(Breastand
Endocrine
Surgery,
Gynecologic Surgery, Ophthalmology and VisionCollection, Oral-Maxillofacial Surgery, Dentistry andOrthodontics, and Neurology).
The staff of the Center for Epidemiology andPreventive Medicine is composed of eight physicians

458(four regular physicians and four physicians from therelated departments). One of the regular physiciansalso performs upper gastrointestinal endoscopy andcolonoscopy in the Department of Endoscopy andEndoscopic Surgery. Our department also has fiveregular nurses and five regular secretaries. When our
department was established, the number of staff wasincreased in other divisions. Among our staff, one
nurse (full-time), three radiological technologists(full-time) and three medical technologists (fulltime) are assigned respectively to the Department ofEndoscopy and Endoscopic Surgery, the RadiologicalCenter and the Clinical Laboratory Center.

Clinical activities
In addition to basic examinations which are open
to the public, our department provides these elevenoptions: 1) comprehensive cardiovascular examinations, 2) home blood pressure screening, 3)
comprehensive cerebrovascular examinations, 4)check up dementia, 5) colorectal cancer screening, 6)
uterine cancer screening, 7) breast cancer screening,8) lung cancer screening, 9) tumor marker diagnosis,10) estimation of gastric cancer risk, and 11) oral/
dental examinations. While meeting the needs of
examinees, we have increased the number of theoptional 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) 2010 from April 1, to March 31,
2011, the total number of examinees (who had basic
examinations and optional examinations) was 5,851,
including 1,987 in basic examinations, 434 incomplete cardiovascular examinations, 24 in home
blood pressure screening, 459 in complete cerebrovascular examinations, 67 in check up dementia, 331
in colorectal cancer screening, 367 in uterine cancer
screening, 428 in breast cancer screening, 552 in lungcancer screening, 653 in tumor marker diagnosis, 466
in estimation of gastric cancer risk, and 75 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 2010, we issued 881
letters of referral to other departments in our hospitaland 98 to other hospitals.
We have expanded our public relations efforts andduring the FY 2010 our brochure has reached its
second edition and 25,000 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.

459

References
Academic Papers in English(1) Yamamoto K, Ozaki H, Takayasu K, Akehi N,
Fukui S, Sakai A, Kodama M, Shimonagata T,
Kobayashi K, Ota M, Horiguchi Y, Ebisuno S,
Yamazaki T, Ohtsu H, Hori M. The Effect ofLosartan and Amlodipine on Left Ventricular
Diastolic Functionand
Atherosclerosis
inJapanese Patients With Mild-to-Moderate
Hypertension J-ELAN study. Hypertension
Research, 34(3): 325-330, 2010
(2) Kohro T, Fujita M, Sasayama S, Mitani S,
Yamazaki T, Hayashi D, Okada Y, Nagai R, for
the JCAD Study Investigators. Prognostic Effectsof Combined Treatment With Calcium Channel
Blokers and Statins in Patients With Coronary
Narrowing From the Japanese Coronary Artery
Disease Study. International Heart Journal 51(5):299-302, 2010
(3) Yamashita T, Inoue H, Okumura K, Kodama I,
Aizawa Y, Atarashi H, Ohe T, Ohtsu H, Kato T,
Kamakura S, Kumagai K, Kurachi Y, Koretsune
Y, Saikawa T, Sakurai M, Sato T, Sugi K, Nakaya
H, Hirai M, Hirayama A, Fukatani M, Mitamura
H, Yamazaki T, Watanabe E, and Ogawa S , onbehalf of the J-RHYTHM Ⅱ Investigators.
Randmaized trial of angiotensin Ⅱ -receptor
bloker vs. dihydropiridine calcium channel
bloker in the treatment of paroxysmal atrial
fibrillation with hypertension (J-RHYTHM Ⅱ
Study). Europace Advance Access publishedDec.10,2010(4) Fujita M, Sasayama S, Terasaki F, Mitani S,
Morimoto T, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R, The JCAD Study Investigators.
Treatment effects of rennin-angiotensin system
inhibitors and calcium channel bloker in patientswith coronary artery narrowing (from theJapanese Coronary Artery Disease Study). Heartand Vessels. 25(6): 453-459, 2010(5) Suzuki S, Yamashita T, Otsuka T, Sagara K,
Uejima T, Oikawa Y, Yajima J, Koike A,
Nagashima K, Kirigaya H, Ogasawara K, Sawada
H, Yamazaki T, Aizawa T. Body Size and Atrial
Fibrillation in Japanese Outpatients. Circ J

74(1): 66-70, 2010
(6) Aizawa Y, Kohsaka S, Suzuki S, Atarashi H,
Kamakura S, Sakurai M, Nakaya H, Fukatani M,
Mitamura H, Yamazaki T, Yamashita T, Ogawa S.
J-RHYTHM Investigators
Comparison of
Antiarrhythmics Used in Patients with
Paroxysmal Atrial Fibrillation: Sub-analysis of
J-RHYTHM study Circ J 74(1): 71-6, 2010
(7) Teramoto T, Shimada K, Uchiyama S, Sugawara
M, Goto Y, Yamada N, Oikawa S, Ando K,
Ishizuka N, Yamazaki T, Yokoyama K, Murata M,
and Ikeda Y. Rationale, design, and baseline
data of the Japanese Primary Prevention Project(JPPP)-A randomized, open-label, controlled trialof aspirin versus no aspirin in patients withmultiple risk factors for vascular events
American Heart J 159(3); 361-369, 2010(8) Kohro T, Hayashi D, Yamazaki T, Nagai R, The
JCAD Investigators. Beta-Bloker Prescription
Among Japanese Cardiologists and Its Effects on
Various Outcomes. Circ J 74(5): 962-9, 2010(9) Horinaka S, Yabe A, Yagi H, Ishimitsu T,
Yamazaki T, Suzuki S, Kohro T, Nagai R, for the
JCAD Study Investigators. Effect of Nicorandil
on Cardiovascular Events in Patients With
Coronary Artery Disease in The JapaneseCoronary Artery Disease (JCAD) Study Circ J
74(5): 503-509, 2010(10) Suzuki T, Trimarchi S, Sawaki D, Grassi V, Costa
E, Rampoldi V, Nagai R, Eagle K. Circulating
TGFbeta levels in acute aortic dissection. J Am
Coll Cardiol, 2010, in press(11) Trimarchi S, Sangiorgi G, Sang X, Rampoldi V,
Suzuki T, Eagle KA, Elefteriades JA. In search ofblood tests for thoracic aortic diseases. Ann
Thorac Surg 90(5): 1735-1742, 2010(12) Suzuki T, Distante A, Eagle KA. Biomarkerassisted diagnosis of acute aortic dissection; how
far we have come and what to expect. Current
Opinion in Cardiology. 25(6): 541-545, 2010(13) Trimarchi S, Eagle KA, Nienaber CA, Pyeritz RE,
Jonker FH, Suzuki T, O'Gara PT, Hutchinson SJ,
Rampoldi V, Grassi V, Bossone E, Muhs BE,
Evangelista A, Tsai TT, Froehlich JB, Cooper JV,
Montgomery D, Meinhardt G, Myrmel T,
Upchurch GR, Sundt TM, Isselbacher EM; onbehalf of the International Registry of Acute

460

Aortic
Dissection(IRAD)
Investigators.
Importance of refractory pain and hypertension inacute type B aortic dissection: insights from theinternational registry of acute aortic dissection(IRAD). Circulation 122(13): 1283-1289, 2010(14) Zhan H, Suzuki T, Aizawa K, Miyagawa K, andNagai R. Ataxia telangiectasia mutated (ATM)mediated DNA damage response in oxidative
stress-induced
vascularendothelial
cellsenescence. J Biol Chem 285(38): 29662-29670,
2010(15) Tochio N, Umehara T, Munemasa Y, Suzuki T,
Sato S, Tsuda K, Koshiba S, Kigawa T, Nagai R,
and Yokoyama S. Solution Structure of Histone
Chaperone ANP32B: Interaction with Core
Histones H3-H4 through Its Acidic Concave
Domain. J Mol Biol 401(1): 97-114, 2010,(16) 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 J, Counselman F,
Vijayendran R, Bossone E, Eagle K. Response to
Letter Regarding Article, "Diagnosis of Acute
Aortic Dissection by D-Dimer: The International
Registry of Acute Aortic Dissection Substudy on
Biomarkers (IRAD-Bio) Experience". Circulation
121: e24, 2010(17) Seto M, Ohta M, Ikenoue T, Sugimoto T, Asaoka
Y, Tada M, Mohri D, Kudo Y, Ijichi H, Tateishi K,
Otsuka M, Hirata Y, Maeda S, Koike K, Omata M.
Reduced expression of RAS protein activator like
1 in gastric cancer. International Journal ofCancer, 2010, in press(18) Mizuno Y, Jacob RF, Mason RP. Advances inpharmacologic modulation of nitric oxide in
hypertension. Curr Cardiol Rep. 12(6):472-80,
2010(19) Kodashima S, Fujishiro M. Novel imageenhanced endoscopy with i-scan technology.
World J Gastroenterol 16(9): 1043-1049, 2010(20) Asaoka Y, Kanai F, Ichimura T, Tateishi K,
Tanaka Y, Ohta M, Seto M, Tada M, Ijichi H,
Ikenoue T, Kawabe T, Isobe T, Yaffe MB, Omata
M. Identification of a suppressive mechanism
for Hedgehog signaling through a novel
interaction of Gli with 14-3-3.J Biol Chem.
285(6): 4185-94, 2010

International Conferences(1) Suzuki K, Kowa H, Ooike Y, Seto M, Aizawa K,
Suzuki T, Yamazaki T, Tsuji S, Iwata A. The early
detection of cognitive deterioration in normal
populations attending medical checkups of thebrain.
The 10th Alzheimer's Association
International Conference on Alzheimer's Disease2010 (ICAD) (July 10-15, Honolulu, HI, USA)
(2) Suzuki T. Epigenetic regulation of chromatintranscription – KLFs as a model system. 2010
FASEB Summer Research Conferences（August
8-13, 2010, Steamboat Springs, CO, USA）
(3) Ishida J, Suzuki T, Aizawa K, Sawaki D,
Matsumura T, Friedman SL, Nagai R. Krüppel
-like factor 6 (KLF6) is involved in adiposity.
2010 FASEB Summer Research Conferences(August 8-13, 2010, Steamboat Springs, CO,USA)(4) Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Munemasa Y, Ishida J, Friedman SL, Nagai R.
Krüppel -like Factor 6 modulates initiation ofcardiac fibrosis. 2010 FASEB Summer Research
Conferences (August 8-13, 2010, Steamboat
Springs, CO, USA)
(5) Aizawa K, Suzuki T, Matsumura T, Sawaki D,
Ishida J, Nagai R. Identification of a new
regulatory pathway of pathologic vascular injury
as mediated by KLF5 by proteome analysis. 2010
FASEB Summer Research Conferences (August
8-13, 2010, Steamboat Springs, CO, USA)
(6) Suzuki T. Proteomic analysis of the vasculature.
16th International vascular Biology Meeting(June 20-24, 2010, Los Angeles, CA, USA)
(7) Aizawa K, Suzuki T, Zhan H, Matsumura T,
Sawaki D, Ishida J, Miyagawa K, Nagai R.
AtaxiaTelangiectasia
MutatedMediates
Oxidative
Stress-induced
Premature
Cell
Senescence in Vascular Endothelial Cells. 15th
International Vascular Biology Meeting (June20-24, 2010, Los Angeles, CA, USA)
(8) Fattori R, Isselbacher EM, Nienaber CA,
Froehlich JB, Evangelista A, Januzzi JL, Strauss
C, Jondeau G, Cooper JV, Montgomery DG,
Woznicki EM, Bartnes K, Suzuki T, Braverman
AC, Eagle KA, on behalf of the International
Registry of Acute Aortic Dissection (IRAD)
investigators. Characteristics of aortic dissection

461

in patients with bicuspid aortic valve: insightsfrom the International Registry of Acute Aortic
Dissection (IRAD). The American College of
Cardiology 59th Annual Scientific Session(March 14-16, 2010, Atlanta, GA, USA)

462

Division of Tissue Engineering
Director & Professor
Tsuyoshi Takato, M.D., Ph.D.

Vice Director
Kazuto Hoshi, M.D., Ph.D.

Project Associate Professors
Seishi Ogawa, M.D., Ph.D.,

Hiroyuki Koyama, M.D., Ph.D.,

Taku Saito, M.D., Ph.D.,

Keiichi Hishikawa, M.D., Ph.D.,

Kazuto Hoshi, M.D., Ph.D.

Research Associates
Makoto Komura, M.D., Ph.D.,

Yuko Fujihara, D.D.S., Ph.D.,

Takeshi Marumo, M.D., Ph.D.,

Yutaka Miura, Ph.D.,

Yutaka Morizaki, M.D., Ph.D.,

Seiichi Yokoo, Ph.D.

Homepage

http://square.umin.ac.jp/t-e/

Introduction and Organization
Division of Tissue Engineering was established as a
special medical office in The University of Tokyo
Hospital, in October 2001 and has a fully equipped
800 m2 laboratory on the 8th floor of the Inpatient
Word B. Division of Tissue Engineering consists of
Department of Bone & Cartilage Regenerative
Medicine, Department of Vascular Regeneration,
Department 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 industryuniversity-government cooperation is essential to thesuccess, it seems that state-level efforts are necessary.
It is expected that broad progress in tissue engineering
technologies and regenerative medicine contributes totreatment and drug discovery of all medical fields
regardless of specialties.
October, 2001 Division of Tissue Engineeringfounded as special medical office in the University ofTokyo 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

463

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464

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. On Mar 18th 2011, our clinicalstudy “Development of implant-type tissueengineered cartilage for patients with nasal deformity
in cleft lip and palate” was authorized to conduct after
being discussed based on “Guideline for Human Stem
Cell Therapy Clinical Research”.
In the laboratory for pediatric regenerative
medicine, we are doing research to fabricate anengineered airway by cells originated from trachea
tissue. In addition, the fundamental study of theamniotic fluid cell is performed to create new therapy
for new born babies.
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. In project for cartilage regeneration,
the clinical study “Development of implant-type
tissue-engineered cartilage for patients with nasal
deformity in cleft lip and palate” was authorized to
conduct on Mar 18th 2011, and is supposed to startsoon. As stated above, we are proceeding translational
research aiming at clinical application of tissue
engineering and regenerative medicine.
Contribution to the Hospital
Division of Tissue Engineering, as a cooperative
research facility in the Hospital, opens expensive
special machines that each laboratory cannot afford toequip with, such as a confocal laser scanningmicroscope, a cell analyzer and a cell sorter to the
Hospital staff, letting them use with cost sharing.
Department of Plastic Surgery is conducting researchusing this facility.

References
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Yamaguchi M, Ebihara N, Shima N, Kimoto M,
Funaki T, Yokoo S, Murakami A, Yamagami S.
Adhesion, migration, and proliferation ofcultured human corneal endothelial cells bylaminin-5. Invest Ophthalmol in press.

465

2.

Mimura T, Yamagami S, Uchida S, Yokoo S, Ono
K, Usui T, Amano S. Isolation of adult progenitor
cells with neuronal potential from rabbit corneal
epithelial cells in serum- and feeder layer-free
culture conditions. Mol Vis. 2010; 16:1712-9.
3. Usui T, Nakagawa S, Yokoo S, Mimura T,
Yamagami S, Amano S. Bilateral limbal stem cell
deficiency with chromosomal translocation of 3p
and 9p. Jpn J Ophthalmol. 2010; 54:357-8.
4. Mimura T, Yamagami S, Yokoo S, Usui T, Amano
S. Selective isolation of young cells from humancorneal endothelium by the sphere-forming assay.
Tissue Eng Part C Methods. 2010; 16:803-12.
5. Yokoo S. Regenerative medicine and stem cellsof corneal epithelium. Nippon Ganka Gakkai
Zasshi. 2010;114:968-75.
6. Ogata N, Shinoda Y, Wettschureck N,
Offermanns S, Takeda S, Nakamura K, Segre GV,
Chung UI, Kawaguchi H. G{alpha}q Signal in
Osteoblasts Is Inhibitory to the Osteoanabolic
Action of Parathyroid Hormone. J Biol Chem.
2010; 286:13733-40.
7. Ishiyama N, Moro T, Ohe T, Miura T, Ishihara K,
Konno T, Ohyama T, Yoshikawa M, Kyomoto M,
Saito T, Nakamura K, Kawaguchi H. Reductionof peritendinous adhesions by hydrogel
containing biocompatible phospholipid polymer
MPC for tendon repair. J Bone Joint Surg Am.
2010; 93:142-9.
8. Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F,
Ohba S, Nishida N, Akune T, Yoshimura N,
Nakagawa T, Nakamura K, Tokunaga K, Chung
UI, Kawaguchi H. Transcriptional regulation of
endochondral ossification by HIF-2alpha duringskeletal growth and osteoarthritis development.
Nat Med. 2010; 16:678-86
9. Kato M, Takaishi H, Yoda M, Tohmonda T,
Takito J, Fujita N, Hosogane N, Horiuchi K,
Kimura T, Okada Y, Saito T, Kawaguchi H,
Kikuchi T, Matsumoto M, Toyama Y, Chiba K.
GRIP1 enhances estrogen receptor alphadependent extracellular matrix gene expression inchondrogenic cells. Osteoarthritis Cartilage.
2010; 18:934-41.
10. Fukai A, Kawamura N, Saito T, Oshima Y, Ikeda
T, Kugimiya F, Higashikawa A, Yano F, Ogata N,
Nakamura K, Chung UI, Kawaguchi H. Akt1 in

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murinechondrocytes
controls
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calcification during endochondral ossification
under physiologic and pathologic conditions.
Arthritis Rheum. 2010; 62:826-36.
Nagase Y, Iwasawa M, Akiyama T, Ogata N,
Kadono Y, Nakamura M, Oshima Y, Yasui T,
Matsumoto T, Masuda H, Bouillet P, Nakamura K,
Tanaka S. Antiapoptotic molecule Bcl-2 isessential for the anabolic activity of parathyroid
hormone in bone. Ann N Y Acad Sci. 2010;
1192:330-7.
Shinoda Y, Kawaguchi H, Higashikawa A, Hirata
M, Miura T, Saito T, Nakamura K, Chung UI,Ogata N. Mechanisms underlying catabolic andanabolic functions of parathyroid hormone onbone by combination of culture systems of mouse
cells. J Cell Biochem. 2010; 109:755-63.
Morizaki Y, Zhao C, An KN, Amadio PC. The
Effects of Platelet-Rich Plasma on Bone Marrow
Stromal Cell Transplants for Tendon Healing In
Vitro. J Hand Surg Am. 2010; 35:1833-41.
Ogata N. Cytokines in bone diseases. Genetic
defects of PTH/PTHrP receptor in chondrodysplasia. Clin Calcium. 20:1481-8, 2010.
Yoshikawa M, Hishikawa K, Idei M, Fujita T.
Trichostatin a prevents TGF-beta1-induced
apoptosis by inhibiting ERK activation in humanrenal tubular epithelial cells. Eur J Pharmacol.
2010; 642(1-3):28-36.
Inowa T, Hishikawa K, Matsuzaki Y, Isagawa T,
Takeuchi T, Aburatani H, Kitamura T, Fujita T.
GADD45β Determines Chemoresistance andInvasive Growth of Side Population Cells of
Human Embryonic Carcinoma. Stem Cells Int.
2010; 782967.
Marumo, T., Hishikawa, K., Yoshikawa, M.,
Hirahashi, J., Kawachi, S., and Fujita, T. Histone
deacetylase modulates the proinflammatory and-fibrotic changes in tubulointerstitial injury. Am J
Physiol Renal Physiol 2010; 298:F133-141.
Fujihara Y, Takato T, Hoshi K Immunologicalresponse to tissue-engineered cartilage derived
from auricular chondrocytes and a PLLA scaffold
in transgenic mice. Biomaterials 2010; 31:
1227-34.
Iwata K, Asawa Y, Fujihara Y, Tanaka Y,
Nishizawa S, Nakagawa T, Nagata S, Takato T,

466

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Hoshi K. The effects of rapid- or intermediateacting insulin on the proliferation anddifferentiation of the cultured chondrocytes. Curr
Aging Sci 2010; 3:26-33.
Ko E, Fujihara Y, Ogasawara T, Asawa Y,
Nishizawa S, Nagata S, Takato T, Hoshi K.
Administration of the insulin into the scaffold
atelocollagen for tissue engineered cartilage. J
Biomed Mater Res A in press.
Tanaka Y, Yamaoka H, Nishizawa S, Nagata S,
Ogasawara T, Asawa Y, Fujihara Y, Takato T,
Hoshi K. The optimization of porous polymericscaffolds for chondrocyte-atelocollagen based
tissue-engineered cartilage. Biomaterials 2010;
31:4506-16.
Yamaoka H, Nishizawa S, Asawa Y, Fujihara, Y,
Ogasawara T, Yamaoka K, Nagata S, Takato T,
Hoshi K. Involvement of Fibroblast Growth
Factor 18 in Dedifferentiation of Cultured Human
Chondrocytes. Cell Prolif 2010; 43:67-76.
Yamaoka H, Tanaka Y, Nishizawa S, Asawa Y,
Takato T, Hoshi K. The application of
atelocollagen gel in combination with porous
scaffolds for cartilage tissue engineering and its
suitable conditions. J Biomed Mater Res A
2010; 93: 123-132.
Yonenaga K, Nishizawa S, Fujihara Y, Asawa Y,
Sanshiro K, Nagata S, Takato T, Hoshi K. The
optimal conditions of chondrocyte isolation andits seeding in the preparation for cartilage tissue
engineering. Tissue Eng Part C Methods. 2010;
16:1461-9.
Yonenaga K, Nishzawa S, Akisawa M, Asawa Y,
Fujihara Y, Takato T, Hoshi K. Utility of Nucleo
Counter for the chondrocyte count in thecollagenase digest of human native cartilage.
Cytotechnology 2010; 62:539-45.

467

Hospital Planning andManagement
Associate Professor
Soichi Koike M.D., M.P.H., M.B.A., Ph.D.

Assistant Professor
Hiroo Ide, M.A., Hidenao Atarashi, C.E., M.P.H., Kent Doi, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kikakukeiei/index.html

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 two 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.
・ “22nd Century Medical Center” launched・ new central hospital building launched
・ Enhanced functions in the inpatient ward
(expansion of ICU/CCU, increase in number ofbeds in the Psychiatry Department, GCU and468

MFICU, expansion of GCU)
・ To reduce the average length of hospital stays,
and improve the bed occupancy rate・ To achieve reduce drug costs and costs for
medical materials
・ Critical Care Center launched
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 policy recommendations aimed at improving the medical system inJapan 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.
(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

469

References(1) Koike S, Ide H, Yasunaga H, Kodama T,
Matsumoto S, Imamura T. Postgraduate training
and career choices: An analysis of the Physicians
Survey in Japan. Medical Education 2010;44:289-297.
(2) Koike S, Kodama T, Matsumoto S, Ide H,
Yasunaga H, Imamura T. Retention rate ofphysicians in public health administration andtheir career path in Japan. BMC Health Service
Research 2010;10:101.
(3) Koike S, Kodama T, Matsumoto S, Ide H,
Yasunaga H, Imamura T. Residency Hospital
Type and Career Paths in Japan: An Analysis of
Physician Registration Cohorts. Medical Teacher
2010;32:e239-247.
(4) Koike S, Matsumoto S, Kodama T, Ide H, Yasunaga
H, Imamura T. Specialty choice and physicians’
career paths in Japan: An analysis of National
Physician Survey data from 1996 to 2006. Health
Policy 2010;98(2-3):236-244.
(5) Ide H, Koike S, Yasunaga H, Kodama T, Ohe K,
Imamura T. Long-term Career Transition in the
Surgical Workforce of Japan: A Retrospective
Cohort Study Using the Nationwide Survey ofPhysicians Data from 1972 to 2006. World Journalof Surgery 2010;34:1748-55.
(6) Matsumoto S, Kanagawa Y, Koike S, Akahane M,
Uchi H, Shibata S, Furue M, Imamura T.
Twenty-year changes of penta-chlorodibenzofuran(PeCDF) level and symptoms in Yusho patients,using association analysis. BMC Research Notes
2010;3:129.

470

Department of Child Psychiatry
Associate Professor
Yukiko Kano, M.D.,Ph.D.

Assistant professor
Hitoshi Kuwabara, M.D., Ph.D., Yuki Kawakubo, Ph.D.

Homepage

http://kokoro.umin.jp/

Introduction and Organization
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 for faculty development. The major
aim of the Clinical Education Center is to train
mental health specialists in various fields with afundamental grounding in child psychiatry andneurosciences. Much of the services provided are
based on the 37 years of experience in intervention
and treatment for developmentally disabled children
established in the former child psychiatry divisionof Department of Neuropsychiatry. Our department
uses a multidisciplinary approach by working incollaboration 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 complemented the Clinical Education
Center by providing fieldwork for clinical training
and offered clinical services to patients with various
development problems also.
The Clinical Education Center of Mental
Development was closed in March 2010 because oftime limit of the fund, and Department of Child
Neuropsychiatry, Graduate School of Medicine wasestablished in April 2010. The Department of Child
Psychiatry, as the clinical counterpart to thedepartment in graduate school, focuses on clinicalactivity related to research as well as quality
practice of child psychiatry and education ofleading child psychiatrists and allied professionals.
In addition to 3 professors of the graduate school, 2
psychiatrists and 3 psychologists are officiallyassigned to the Department of Child Psychiatry.

Clinical activities
In the year 2010, the Department of Child
Psychiatry consisted of 8 psychiatrists and 7
psychologists (full-time and part-time). Althoughpatients with various disorders are seen, the focusof the department is mainly on patients with
developmental disorders. We offer services topatients with a broad range of developmental
disorders including Autism Spectrum Disorder(ASD), Attention-Deficit/Hyperactivity Disorder(ADHD), Learning Disabilities (LD), Mental
Retardation (MR), tic disorders and child &adolescentObsessive-Compulsive
Disorders(OCD).
With reconstruction of clinical activity, thenumber of new patients was limited to less than 200
in the year 2010. A large part of the new patients
consisted of patients with ASD, tic disorder or
ADHD. Although establishment of Tic/OCD clinic
might make a slight change, general trend of thepatients were similar to that of the previous year.
The follow-up clinic consisted of general clinicand special clinics (high-functioning ASD clinic
and Tic/OCD clinic). At the general clinic, arigorous diagnosis based on detailed assessment

471

and decision about treatment course are provided
for children and adolescents with any kinds ofmental problems. After fine adjustment of treatment
course within a given period, the patients arereferred to community hospitals/clinics orintervention/education facilities with a detailed
report. The special clinics meet a need for highlevel services and work with research for special
diseases.
Clinical activities are largely divided into twoareas of general child psychiatry outpatient services
andinterventionsforindividuals
withdevelopmental disabilities.
Services for the general child psychiatry
outpatients are provided by psychiatrists in theareasofpharmacotherapy,
psychotherapy,
psychoeducation and also work closely with theschools and community.
Interventions for developmentally disabledindividuals consist of “developmental psychology
outpatient services” and “short-term group therapy”.
Patients involved in interventions are individuals
with developmental disabilities, and individualized
treatment based on cognitive developmental therapy
is planned for each. “Developmental psychology
outpatient clinic” provides services in the following
areas: (1) evaluation of cognitive and behavioral
development, (2) individualized treatment of thedisabled individual (3) counseling of parents andproviding information to the disabled individual’s
support network (relatives, schools). One of“short-term group therapy” is a 10 session grouptherapy for a small group of preschool children with
ASD. Another is a 10 session group therapy for
adults with high-functioning ASD, and started in2010. These services are provided mainly bypsychologists under the supervision of childpsychiatrists.
In addition to these outpatient services, trial of“inpatient assessment on developmental disorders”
service started in 2010. This service is provided in
the inpatient ward of neuropsychiatry foradolescents or adults who have mental problems
such as depression and wish a detailed examination
about possibility of hidden developmental disorders
including ASD and ADHD.
We also focus on psychiatric liaison activity withother departments in the University hospital,
especially pediatrics.

Education
Undergraduates of the University of Tokyo haveopportunities to participate in an assessment anddiagnosis session at the general first visit outpatient
clinic and “short-term group therapy” for preschool
children. Graduate students in clinical psychology
course from several universities participate in“short-term group therapy” for preschoolers also.
One month training course is offered to juniorresidents in pediatric specialty course and seniorresidents of neuropsychiatry. This course includes
intake interview of first visit patients, observationof assessment and treatment for follow-up patientsand “short-term group therapy” for preschoolers,and visit to community hospital and intervention/
guidance facilities for child and adolescent mental
health.

Research
We participate in investigation of etiology anddevelopment of effective treatment on ASD and
ADHD, which are organized in collaboration with
the Department of Neuropsychiatry and otherresearch, educational and clinical facilities. In
addition, research related specifically to the clinicalactivities in the Department of Child Psychiatry iscurrently being investigated.
Clinical evaluation and treatment
The reexamination of reliability and validity of
Ohta Staging (an evaluation system using symbol
development for cognitive developmental therapy
developed in the former child division of the
Department of Neuropsychiatry) and investigationof the effectiveness of present interventions forchildren with ASD 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472(chronic tic disorder with multiple motor tics andone or more vocal tics) and child & adolescent
OCD are being evaluated.
Neuropsychological research
Neuropsychological data on ASD, ADHD andTourette syndrome are being collected. Analysis of
the relations among neuropsychological findings
and the clinical evaluation as well as comparisons
between patients and their healthy siblings arebeing conducted.
Genetic research
Research exploring susceptibility genes of ASD
in chromosome 2, long arm of chromosome 7 andlong arm of chromosome 15 are conducted. As weare interested in gene-environment interaction, weare examining influence of age of parents andassisted reproduction technologies on emergence of
ASD. Investigation of specific family andenvironment of Tourette syndrome is being
undertaken also.
Neuroimaging
Studies include structural MRI, MEG, NearInfrared Spectroscopy (NIRS) and functional MRI
with exploring the pathogenesis of developmental
disorders such as ASD. One of the intensive study
is the examination of prefrontal blood flow in ASD,
ADHD and Tourette syndrome by NIRS which is
non invasive and easily applicable to children anddevelopmentally disabled individuals. Possibility of
NIRS as a predictor of efficacy of methylphenidate
for children with ADHD is intensively examined
also. Functional MRI study of adults with ADHD
by delayed reward task is in process.

References
1.

2.

Kano Y, Kono T, Shishikura K, Konno C,
Kuwabara H, Ohta M, do Rosario MC:
Obsessive compulsive symptom dimensions inJapanese Tourette syndrome subjects. CNS
Spectr, 15(5): 296-303, 2010.
Liu X, Kawamura Y, Shimada T, Otowa T,
Koishi S, Sugiyama T, Nishida H, Hashimoto
O, Nakagami R, Tochigi M, Umekage T, Kano

3.

4.

5.

6.

Y, Miyagawa T, Kato N, Tokunaga K,Sasaki T:
Association of the oxytocin receptor (OXTR)
gene polymorphisms with autism spectrum
disorder (ASD) in the Japanese population. J
Hum Genet, 55(3):137-141, 2010.
Marui T, Funatogawa I, Koishi S, Yamamoto
K, Matsumoto H, Hashimoto O, Jinde S,
Nishida H, Sugiyama T, Kasai K, Watanabe K,
Kano Y, Kato N: The NADH-ubiquinone
oxidoreductase 1 alpha subcomplex 5(NDUFA5) gene variants are associated with
autism. Acta Psychiatr Scand, 2010 Sep
5.[Epub ahead of print]
Takei Y, Kumano S, Maki Y, Hattori S,
Kawakubo Y, Kasai K, Fukuda M, Mikuni M:
Preattentive dysfunction in bipolar disorder: a
MEG study using auditory mismatch negativity.
Prog Neuropsychopharmacol Biol Psychiatry34(6): 903-912, 2010.
Yamasaki S, Yamasue H, Abe O, Suga M,
Yamada H, Inoue H, Kuwabara H, Kawakubo
Y, Yahata N, Aoki S, Kano Y, Kato N, Kasai K.
Reduced gray matter volume of pars
opercularis is associated with impaired social
communication in high-functioning autism
spectrum disorders. Biol Psychiatry 68(12):1141-1147, 2010.
Kano Y, Ohta M, Nagai Y, Scahill L:
Association between Tourette syndrome andcomorbidities in Japan. Brain Dev, 32(3):201-207, 2010.

473

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 with patients’attending doctors and ward staff and rehabilitation
staff, etc.
Hereafter, we concretely show the consultation
situation in fiscal year 2010.
The cumulative number of patients who consulted our
palliative care team was over 2000 (20.3 average daily
patients). The maximum monthly patients were 47 ofJanuary (28.9 daily patients). According to site of thecancer, 415 cancers were divided into 62 lungs, 42
stomach, 38 pancreas, 28 ovaries, 27 uterine, 21
esophagus, 19 breasts and so on. We visited almost all
the ward in the hospital. These figures proved
significantly the importance of the palliative care.

Education
In the training at the Department of Palliative
Medicine, medical students of the first and second
year can learn the basic knowledge of palliative 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 ofpalliative care on weekdays.

4741) 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 25 consultation patients a day):
They acquire the outline of control of physical andpsychiatric symptoms of the patients with common
disease in Japan such as digestive cancers in thegeneral ward. They also acquire the outline of
spiritual and family care.
･ Cancer registry: In The University of Tokyo
Hospital, it is not unusual that the patient whom thepalliative care team treats is often in an end stage,and his or her condition changes physically andmentally day by day. Residents should input theconcise and plain content of the offered palliative
care for such a patient to the data base. Theyacquire the outline of data management of thepalliative care connected directly to a clinicalresearch.
･ The communications skills: The clinician shouldtell "Bad news" time after time by all the processesof examining the patient. It is very difficult for theclinician to explain the accurate information ofdiagnosis, progression and prognosis of cancer tothe patient. This is a lot of work of the stress to theclinician. The clinician should deal with patient's
disappointment or failure feeling when treatment
does not go well while should do the balance of"Bad news" and "The patient's hope andexpectation". We introduce Protocol (SPIKES) of
the communications skills that psychiatricallysupport the patient in Department of Palliative
Medicine of The University of Tokyo Hospital.
Resident can make the palliative care execution
program based on this Protocol, and intend toobtain the communications skills in the course offour or eight months.
Event concerning education･ Concerning the intensive course to the first stage
resident physicians, following lectures are done by
the staff.
O pain control
O delirium control
O Introduction of the guideline and its use
O Basic drug therapy for palliative care
O Spiritual care for Japanese
Clinical training schedule･ Conference: Monday - Friday (every day)9:00-10:30･ Ward consultation: Monday - Friday (every day);up to the end of request patient's consultation after
conference.
･ The cancer registry: They input data in the ward
round with the HIS (Hospital information system)
terminal on each floor.
System of guidance･ The ward consultation: Resident participate in the
consultation team (or palliative care team) thatconsists of two guidance medical doctors (oneassistant or lecturer, one designated hospice carenurse, and one resident physician). A palliative careteam examines about 20 – 30 in-patients a day.
･ The conference: Psychiatrist, morphine special
pharmacist, and nurse of The Tokyo University
Graduate School of Medicine and others participate
in the daily conference besides the regular memberof the palliative care team in the ward round. They
discuss the multidisciplinary palliative careprogram that the palliative care team offers. They

475

also guide the resident's palliative care programfrom 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.

2.

3.

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. 2010 Mar;27(1):86-90. Epub 2009 Feb
13.
Takaoka H, Takano H, Nakagawa K, Kobayashi Y,
Hiroshima K, Komuro I. Buerger's disease-likevasculitis associated with Kimura's disease. Int J
Cardiol. 2010 Apr 15;140(2):e23-6. Epub 2009
Jan 7.
Nakamura N, Shikama N, Takahashi O, Ito M,
Hashimoto M, Uematsu M, Hama Y, Sekiguchi K,
Nakagawa K. Variability in bladder volumes offull bladders in definitive radiotherapy for casesof localized prostate cancer. Strahlenther Onkol.
2010 Nov;186(11):637-42. Epub 2010 Nov 8

4.

Otomo S, Maekawa K, Baba T, Yoshitake A,
Nakagawa K, Kojo Y. [A case of Vibrio
vulnificus infection presenting with invagination].
Masui. 2010 Aug;59(8):1007-9. Japanese.
5. Yamashita H, Kida S, Sakumi A, Haga A, Ito S,
Onoe T, Okuma K, Ino K, Akahane M, Ohtomo K,
Nakagawa K. Four-dimensional measurement of
the displacement of internal fiducial markers
during 320-multislice computed tomographyscanning of thoracic esophageal cancer. Int J
Radiat Oncol Biol Phys. 2011 Feb 1;79(2):588-95.
Epub 2010 Aug 1.
6. Okuma K, Yamashita H, Kawana K, Nakagawa S,
Oda K, Nakagawa K. Advanced age is asignificant determinant of poor prognosis inpatients treated with surgery plus postoperative
radiotherapy for endometrial cancer. J Obstet
Gynaecol Res. 2010 Aug;36(4):757-63.
7. Yamashita H, Kobayashi-Shibata S, Terahara A,
Okuma K, Haga A, Wakui R, Ohtomo K,
Nakagawa K. Prescreening based on the presenceof CT-scan abnormalities and biomarkers (KL-6
and SP-D) may reduce severe radiation
pneumonitis after stereotactic radiotherapy.
Radiat Oncol. 2010 May 9;5:32.
8. Yamashita H, Haga A, Hayakawa Y, Okuma K,
Yoda K, Okano Y, Tanaka K, Imae T, Ohtomo K,
Nakagawa K. Patient setup error and day-to-day
esophageal motion error analyzed by cone-beamcomputed tomography in radiation therapy. Acta
Oncol. 2010 May;49(4):485-90.
9. Hama Y, Nakagawa K. Early distant relapse inearly stage triple-negative breast cancer:
usefulness of FDG-PET for diagnosis of distantmetastases. Breast Cancer. 2010 Jan 16. [Epubahead of print]
10. Koyama S, Wada-Hiraike O, Nakagawa S,
Tanikawa M, Hiraike H, Miyamoto Y, Sone K,
Oda K, Fukuhara H, Nakagawa K, Kato S, Yano
T, Taketani Y. Repression of estrogen receptor
beta function by putative tumor suppressor DBC1.
Biochem Biophys Res Commun. 2010 Feb 12;392(3):357-62. Epub 2010 Jan 13.
11. Yamashita H, Okuma K, Kawana K, Nakagawa S,
Oda K, Yano T, Kobayashi S, Wakui R, Ohtomo
K, Nakagawa K. Comparison between
conventional surgery plus postoperative adjuvant

476

12.

13.

14.

15.

16.

17.

radiotherapy and concurrent chemoradiation for
FIGO stage IIB cervical carcinoma: aretrospective study. Am J Clin Oncol. 2010
Dec;33(6):583-6.
Nishio T, Miyatake A, Ogino T, Nakagawa K,
Saijo N, Esumi H. The development and clinicaluse of a beam ON-LINE PET system mounted ona rotating gantry port in proton therapy. Int J
Radiat Oncol Biol Phys. 2010 Jan 1;76(1):277-86.
Nakagawa K, Shiraishi K, Kida S, Haga A,
Yamamoto K, Saegusa S, Terahara A, Itoh S,
Ohtomo K, Yoda K. First report on prostate
displacements immediately before and after
treatment relative to the position during VMAT
delivery. Acta Oncol. 2009;48(8):1206-8.
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. Epub 2008 Dec 4. No abstract
available.
Nishio T, Miyatake A, Ogino T, Nakagawa K,
Saijo N, Esumi H. The development and clinicaluse of a beam ON-LINE PET system mounted ona rotating gantry port in proton therapy. Int J
Radiat Oncol Biol Phys. 2010 Jan 1;76(1):277-86.
PubMedYamamoto D, Iwase S, Yoshida H, Kuroda Y,
Yamamoto C, Kitamura K, Odagiri H, Nagumo Y.
Efficacy of S-1 in patients with capecitabineresistant breast cancer-Japan Breast Cancer
Research Network (JBCRN) 04-1 trial.
Anticancer Res. 2010 Sep;30(9):3827-31.
Hachizuka M, Yoshiuchi K, Yamamoto Y, Iwase
S, Nakagawa K, Kawagoe K, Akabayashi A.
Development of a personal digital assistant(PDA) system to collect symptom informationfrom home hospice patients.. J Palliat Med. 2010
Jun;13(6):647-51.

477

Clinical Genomics
Director & Professor
Shoji Tsuji, M.D., Ph.D.

Vice-director & Lecturer
Jun Goto, M.D., Ph.D.

Organization
The Department of Clinical Genomics started as a
special unit conducting genomic medicine or clinicalhuman genetics services in 2003. Our department
functions as the core unit to accomplish an appropriate
and efficient application of results of recently
advanced human genetics and genomics to clinicalpractice in the hospital and as the unit of training andeducating specialists of human genetics practice. It
consists of one professor and many different
specialties participate in the department. They include
pediatricians, obstetricians, internist (cardiologists,diabetologists, and neurologists), dermatologists, andstaffs of the Departments of Clinical Laboratory
Medicine, Human Genetics and Nursing Science.

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.
We provided the lectures entitled as “Seminar for
Clinical Genetic Medicine”.

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
Wednesday every month.
Counseling of participants in researches including
genome or gene analysis is a duty with which thehospital and the faculty charge the department.
To build suitable clinical systems including
modern genomic medicine we are cooperating withother departments. We are participating in Marfan’sSyndrome Clinic which is managed collaboratively by
the Departments of Cardiovascular Surgery,
Cardiovascular Medicine, Pediatrics, Spinal Surgery
and Ophthalmology.

2.

3.

Seki N, Takahashi Y, Tomiyama H, Rogaeva E,
Murayama S, Mizuno Y, Hattori N, Marras C,
Lang AE, George-Hyslop PS, Goto J, Tsuji S.
Comprehensive mutational analysis of LRRK2
reveals variants supporting association with
autosomal dominant Parkinson's disease. J Hum
Genet. 2011 Jul 28. doi: 10.1038/jhg.2011.79.
[Epub ahead of print] PubMed PMID: 21796139.
Nagashima Y, Kowa H, Tsuji S, Iwata A. FAT10
binds to polyglutamine proteins and modulates
their solubility. J Biol Chem. 2011 Jul 8. [Epubahead of print] PubMed PMID: 21757738.
Iida A, Takahashi A, Kubo M, Saito S, Hosono N,
Ohnishi Y, Kiyotani K, Mushiroda T, Nakajima
M, Ozaki K, Tanaka T, Tsunoda T, Oshima S,
Sano M, Kamei T, Tokuda T, Aoki M, Hasegawa
K, Mizoguchi K, Morita M, Takahashi Y,
Katsuno M, Atsuta N, Watanabe H, Tanaka F,
Kaji R, Nakano I, Kamatani N, Tsuji S, Sobue G,
Nakamura Y, Ikegawa S. A functional variant in
ZNF512B is associated with susceptibility toamyotrophic lateral sclerosis in Japanese. Hum
Mol Genet. 2011 Jun 23. [Epub ahead of print]
PubMed PMID: 21665992.

478

4.

Yokoseki A, Ishihara T, Koyama A, Shiga A,
Yamada M, Suzuki C, Sekijima Y, Maruta K,
Tsuchiya M, Date H, Sato T, Tada M, Ikeuchi T,
Tsuji S, Nishizawa M, Onodera O. Genotypephenotype correlations in early onset ataxia withocular motor apraxia and hypoalbuminaemia.
Brain. 2011 May;134(Pt 5):1387-99. Epub 2011
Apr 12. PubMed PMID: 21486904.
5. Matsukawa T, Wang X, Liu R, Wortham NC,
Onuki Y, Kubota A, Hida A, Kowa H, Fukuda Y,
Ishiura H, Mitsui J, Takahashi Y, Aoki S,
Takizawa S, Shimizu J, Goto J, Proud CG, Tsuji S.
Adult-onset
leukoencephalopathies
withvanishing white matter with novel missense
mutations in EIF2B2, EIF2B3, and EIF2B5.
Neurogenetics. 2011 Apr 12. [Epub ahead ofprint] PubMed PMID: 21484434.
6. Ishiura H, Fukuda Y, Mitsui J, Nakahara Y, Ahsan
B, Takahashi Y, Ichikawa Y, Goto J, Sakai T,
Tsuji S. Posterior column ataxia with retinitis
pigmentosa in a Japanese family with a novel
mutation in FLVCR1. Neurogenetics. 2011
May;12(2):117-21. Epub 2011 Jan 26. PubMed
PMID: 21267618.
7. Yamada K, Miura K, Hara K, Suzuki M,
Nakanishi K, Kumagai T, Ishihara N, Yamada Y,
Kuwano R, Tsuji S, Wakamatsu N. A wide
spectrum of clinical and brain MRI findings inpatients with SLC19A3 mutations. BMC Med
Genet. 2010 Dec 22;11:171. PubMed PMID:
21176162;
PubMedCentralPMCID:
PMC3022826.
8. Sato K, Yabe I, Fukuda Y, Soma H, Nakahara Y,
Tsuji S, Sasaki H. Mapping of autosomal
dominant cerebellar ataxia without thepathogenic PPP2R2B mutation to the locus forspinocerebellar ataxia 12. Arch Neurol. 2010
Oct;67(10):1257-62. PubMed PMID: 20937954.
9. Hida A, Kowa H, Iwata A, Tanaka M, Kwak S,
Tsuji S. Aceruloplasminemia in a Japanese
woman with a novel mutation of CP gene:clinical presentations and analysis of genetic andmolecular pathogenesis. J Neurol Sci. 2010 Nov
15;298(1-2):136-9. Epub 2010 Sep 15. PubMed
PMID: 20828764.
10. Hideyama T, Yamashita T, Suzuki T, Tsuji S,
Higuchi M, Seeburg PH, Takahashi R, Misawa H,

11.

12.

13.

14.

15.

Kwak S. Induced loss of ADAR2 engenders slow
death of motor neurons from Q/R site-unedited
GluR2. J Neurosci. 2010 Sep 8;30(36):11917-25.
PubMed PMID: 20826656.
Akahori M, Tsunoda K, Miyake Y, Fukuda Y,
Ishiura H, Tsuji S, Usui T, Hatase T, Nakamura M,
Ohde H, Itabashi T, Okamoto H, Takada Y, Iwata
T. Dominant mutations in RP1L1 are responsible
for occult macular dystrophy. Am J Hum Genet.
2010 Sep 10;87(3):424-9. PubMed PMID:
20826268;
PubMedCentralPMCID:
PMC2933341.
Katsuno M, Banno H, Suzuki K, Takeuchi Y,
Kawashima M, Yabe I, Sasaki H, Aoki M, Morita
M, Nakano I, Kanai K, Ito S, Ishikawa K,
Mizusawa H, Yamamoto T, Tsuji S, Hasegawa K,
Shimohata T, Nishizawa M, Miyajima H, Kanda
F, Watanabe Y, Nakashima K, Tsujino A,
Yamashita T, Uchino M, Fujimoto Y, Tanaka F,
Sobue G; Japan SBMA Interventional Trial for
TAP-144-SR (JASMITT) study group. Efficacy
and safety of leuprorelin in patients with spinal
and bulbar muscular atrophy (JASMITT study): a
multicentre, randomised, double-blind, placebocontrolled trial. Lancet Neurol. 2010 Sep;9(9):875-84. Epub 2010 Aug 4. PubMed PMID:
20691641.
Shirota Y, Iwata A, Ishiura H, Hashimoto M,
Goto J, Shimizu J, Hanajima R, Nakajima J,
Takazawa Y, Tsuji S. A case of atypical amyloid
polyneuropathy with predominant upper-limb
involvement with the diagnosis unexpectedly
found at lung operation. Intern Med. 2010;
49(15):1627-31. Epub 2010 Aug 2. Review.
PubMed PMID: 20686303.
Matsukawa T, Asheuer M, Takahashi Y, Goto J,
Suzuki Y, Shimozawa N, Takano H, Onodera O,
Nishizawa M, Aubourg P, Tsuji S. Identificationof novel SNPs of ABCD1, ABCD2, ABCD3, and
ABCD4 genes in patients with X-linked
adrenoleukodystrophy
(ALD)
based
on
comprehensive resequencing and association
studies with ALD phenotypes. Neurogenetics.
2011 Feb;12(1):41-50. Epub 2010 Jul 27.
PubMed PMID: 20661612; PubMed Central
PMCID: PMC3029816.
Mitsui J, Takahashi Y, Goto J, Tomiyama H,

479

16.

17.

18.

19.

20.

Ishikawa S, Yoshino H, Minami N, Smith DI,
Lesage S, Aburatani H, Nishino I, Brice A,
Hattori N, Tsuji S. Mechanisms of genomic
instabilities underlying two common fragile-siteassociated loci, PARK2 and DMD, in germ celland cancer cell lines. Am J Hum Genet. 2010 Jul
9;87(1):75-89. PubMed PMID: 20598272;
PubMed Central PMCID: PMC2896763.
Yoshida M, Takahashi Y, Koike A, Fukuda Y,
Goto J, Tsuji S. A mutation database foramyotrophic lateral sclerosis. Hum Mutat. 2010
Sep;31(9):1003-10. PubMed PMID: 20556799.
Mitsui J, Fukuda Y, Azuma K, Tozaki H, Ishiura
H, Takahashi Y, Goto J, Tsuji S. Multiplexed
resequencing analysis to identify rare variants inpooled DNA with barcode indexing using
next-generation sequencer. J Hum Genet. 2010
Jul;55(7):448-55. Epub 2010 May 20. PubMed
PMID: 20485446.
Tsuji S. Genetics of neurodegenerative diseases:
insights from high-throughput resequencing.
Hum Mol Genet. 2010 Apr 15;19(R1):R65-70.
Epub 2010 Apr 22. Review. PubMed PMID:
20413655;
PubMedCentralPMCID:
PMC2875051.
Kobayashi N, Ueki K, Okazaki Y, Iwane A,
Kubota N, Ohsugi M, Awazawa M, Kobayashi M,
Sasako T, Kaneko K, Suzuki M, Nishikawa Y,
Hara K, Yoshimura K, Koshima I, Goyama S,
Murakami K, Sasaki J, Nagai R, Kurokawa M,
Sasaki T, Kadowaki T. Blockade of class IB
phosphoinositide-3 kinase ameliorates obesityinduced inflammation and insulin resistance.
Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5753-8. Epub 2011 Mar 21. PubMed PMID:
21436039;
PubMedCentralPMCID:
PMC3078379.
Yamauchi T, Hara K, Maeda S, Yasuda K,
Takahashi A, Horikoshi M, Nakamura M, Fujita
H, Grarup N, Cauchi S, Ng DP, Ma RC, Tsunoda
T, Kubo M, Watada H, Maegawa H,
Okada-Iwabu M, Iwabu M, Shojima N, Shin HD,
Andersen G, Witte DR, Jørgensen T, Lauritzen T,
Sandbæk A, Hansen T, Ohshige T, Omori S, Saito
I, Kaku K, Hirose H, So WY, Beury D, Chan JC,
Park KS, Tai ES, Ito C, Tanaka Y, Kashiwagi A,
Kawamori R, Kasuga M, Froguel P, Pedersen O,

21.

22.

23.

24.

Kamatani N, Nakamura Y, Kadowaki T. A
genome-wide association study in the Japanese
population identifies susceptibility loci for type 2
diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat
Genet. 2010 Oct;42(10):864-8. Epub 2010 Sep 5.
PubMed PMID: 20818381.
Oishi Y, Manabe I, Imai Y, Hara K, Horikoshi M,
Fujiu K, Tanaka T, Aizawa T, Kadowaki T, Nagai
R. Regulatory polymorphism in transcription
factor KLF5 at the MEF2 element alters the
response to angiotensin II and is associated withhuman hypertension. FASEB J. 2010 Jun;24(6):1780-8. Epub 2010 Jan 19. PubMed PMID:
20086047.
Tanaka Y, Nishida N, Sugiyama M, Tokunaga K,
and Mizokami M: λ-interferons and the single
nucleotide polymorphisms: A mikestone totailor-made therapy for chronic hepatitis C.
Hepatol. Res. 40(5): 449-460, 2010.
Sakamoto N, Tanaka Y, Nakagawa M, Yatsuhashi
H, Nishiguchi S, Enomoto N, Azuma S,
Nishimura-Sakurai Y, Kakinuma S, Nishida N,
Tokunaga K, Honda M, Ito K, Mizokami M, and
Watanabe M: ITPA gene variant protects against
anemia induced by pegylated interferon-αandribavirin therapy for Japanese patients withchronic hepatitis C. Hepatol. Res. 40(11): 10631071, 2010.
Kurosaki M, Tanaka Y, Nishida N, Sakamoto N,
Enomoto N, Honda M, Sugiyama M, Matsuura K,
Sugauchi F, Asahina Y, Nakagawa M, Watanabe
M, Sakamoto M, Maekawa S, Sakai A, Kaneko S,
Ito K, Masaki N, Tokunaga K, Izumi N,
Mizokami M: Pre-treatment prediction of
response to pegylated-interferon plus ribavirin
for chronic hepatitis C using genetic
polymorphism in IL28B and viral factors. J.
Hepatol. 54(3): 439-448, 2011. Epub 2010 Sep
19.

480

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, areview 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. Configuration

481

of 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.
2009 December 3. The sixth research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.
2011 February 2. The seventh research meeting of
Cooperative Unit of Medicine and Engineering
Research took place.

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

Research activities
Development of Advanced Sterotactic Rediation
Cancer Therapy 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

Laboratory of Cavitation & Lithotripsy
Department of Urology, Faculty of Medicine
Department of Mechanical Engineering, School ofEngineering
Development of a new method of lithotripsy using
high intensity focused ultrasound induced cavitation.
Development of Support Systems for Risk
Reduction in the Clinical Process
Department of Pharmacoepidemiology
Chemical System Engineering
Department of Clinical Epidemiology & Systems
Our specific targets are research and education on the
integration of biological and clinical information
including genome. In particular, they consist of
establishmentof
personalized
medicineas482

translational 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 of articular cartilage.
To develop a device for assisting in fracture reduction
and fixation.

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 Tokyo
To develop: real-time three-dimensional echocardiography, suture device with liner probe, integral
videography, and minimal invasive cardiac surgery
monitored by real-time three-dimensional echocardiography without cardiopulmonary bypass
Division of Neutron Capture Therapy &Immunotherapy for Cancer
Department of Cardiothoratic Surgery, Graduate /School of Medicine
Department of Radiology, University of Tokyo
Hospital
Department of Nuclear Engineering and Management,
School of Engineering
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 visualize arteriosclerotic andischemic lesions by using fluorescent probes and MRI
contrast media.
Development of a novel device for bioartificial
pancreas and development of adhesion barriermaterials using a new animal model ofliver-peritoneal adhesion
Artificial Organ and Transplantation Division,

483

Department of Surgery, Graduate School of Medicine,
University of Tokyo
Hepato-Biliary-Pancreatic
Surgery
Division,
Department of Surgery, Graduate School of Medicine,
University of Tokyo
Organs and Biosystems Engineering Laboratory,
Institute of Industrial Science, The University of Tokyo
Laboratory of Regenerative Medical Engineering,
Center for Disease Biology and Integrative Medicine,
Graduate School of Medicine, The University of Tokyo
Department of Chemical System Engineering,
Graduate School of Engineering, The University ofTokyo
Department of Bioengineering, Graduate School ofEngineering, The University of Tokyo
Islet transplantation has potential to become the mostphysiologically advantageous and minimally invasive
procedure for the treatment of type 1 diabetes mellitus.
The most serious problem is that long term insulin
independence of five years has been substantialy stillquite low. Our concern is to improve poor long term
insulin independence, of which the one cause isconsidered to be transplant site.
Adhesions between liver and other organs are an
important issue in the cases of second surgeries suchas hepatic resection. Adhesions extend operative
duration; in addition, they increase the risk ofsurgeries. Thus, it is important to avoid adhesions at afirst surgery. However, no one report both the animalmodel and adhesion barrier materials of liver adhesion.
We try to develop a new adhesion model by hepatic
resection, instead of a usual peritoneal abrasion model.
Also, we develop new materials for preventing theadhesions.

development of the metabolic syndrome. To explore
the signal transduction pathways of major adipokines
including adiponectin

Laboratory of Applied Metabolic Biotechnology
Department of Cardiovascular Medicine, Graduate
School of Medicine
Department of Metabolic Diseases, Graduate Schoolof Medicine
Department of Chemistry and Biotechnology, Schoolof Engineering
To establish the system and methods for engineering
the novel model mice of life style-related diseases
using RNAi technology and biotechnology. To
elucidate the mechanisms by which adipose tissue
derived factors, adipokines, contribute to the

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 Oral

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.

484

and 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.
Development of a cell-sheet culture system for bone
and cartilage. Screening for compounds that inducebone and cartilage regeneration

facilitated 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.

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 nanoscaled 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 and3.

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Radiat Oncol Biol Phys. 2010 Jan 1;76(1):277-86.
PubMed PMID: 20005459.
Yamashita H, Haga A, Hayakawa Y, Okuma K,
Yoda K, Okano Y, Tanaka K, Imae T, Ohtomo K,
Nakagawa K. Patient setup error and day-to-day
esophageal motion error analyzed by cone-beamcomputed tomography in radiation therapy. Acta
Oncol. 2010 May;49(4):485-90. PubMed PMID:
20230211.
Yamashita H, Kida S, Sakumi A, Haga A, Ito S,
Onoe T, Okuma K, Ino K, Akahane, M, Ohtomo
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49. Nakamura N, Shikama N, Takahashi O, Ito M,
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2010 Nov;186(11):637-42. Epub 2010 Nov 8.
PubMed PMID: 21069269.
50. Yamashita H, Okuma K, Wakui R, KobayashiShibata S, Ohtomo K, Nakagawa K. Details ofrecurrence sites after elective nodal irradiation(ENI) using 3D-conformal radiotherapy (3DCRT) combined with chemotherapy for thoracic
esophageal squamous cell carcinoma - A
retrospective analysis. Radiother Oncol. 2010
Nov 11. [Epub ahead of print] PubMed PMID:
21074880.
51. Yamashita H, Kida S, Sakumi A, Haga A, Ito S,
Onoe T, Okuma K, Ino K, Akahane M, Ohtomo
K, Nakagawa K. Four-dimensional measurementof the displacement of internal fiducial markers
during 320-multislice computed tomographyscanning of thoracic esophageal cancer. Int J
Radiat Oncol Biol Phys. 2011 Feb 1;79(2):588-95.
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52. K. Mizuno 、 Y. Ito 、 S. Matsuyama 、 H.
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Kawashima, and T Ogino ”Apparen t absence ofa proton beam dose rate effect and possible
differences in RBE between Bragg peak andplateau” Med Phys. 2010 Oct;37(10):5376-81.
54. Takuya Natsui, Azusa Mori, Hirotoshi Masuda,
Mitsuru Uesaka, Fumito Sakamoto ”BeamMeasurement of 11.424 GHz X-Band Linac for

55.

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Compton Scattering X-ray Source” The American
Institue of Physics Conference Proceedings
Series Volume1299 538-543 2010
K. Mizuno, Y. Ito, S. Matsuyama, H. Yamazaki,
K. Ishii and M. Uesaka “Evaluation of the Uptakeof CDDP-containing Polymeric micelles inSingle Pan creatic Cancer Cells” International
Journal of PIXE,vol.20,Nos1-2,pp37-43(2010)
Katsuji Aizawa, Motoyuki Iemitsu, Seiji Maeda,
Takeshi Otsuki, Koji Sato, Takashi Ushida,
Noboru Mesaki, Takayuki Akimoto, Acuteexercise activates local bioactive androgenmetabolism in skeletal muscle, Steroids 75, 219223 (2010)
Spatio-temporal PLC activation in parallel withintracellular Ca2+ wave propagation inmechanically stimulated single MDCK cells,
Akira Tsukamoto, Yasunori Hayashida, Katsuko
S. Furukawa, Takashi Ushida, Cell Calcium 47,
253–263 (2010)
Katsuko S. Furukawa, Keigo Nakamura, Yuji
Onimura, Masaki Uchida, Atsuo Ito, Takashi
Yamane, Tamotsu Tamaki, Takashi Ushida and
Tetsuya Tateishi, Quantitative Analysis of Human
Platelet Adhesions Under a Small-Scale Flow
Device, Artificial Organs, 34(4) : 295–300 (2010)
H Yanagie, H Kumada, T Nakamura, S Higashi, I
Ikushima, Y Morishita, A Shinohara, M Fujiwara,
M Suzuki, H Sugiyama, T Kajiyama, R
Nishimura, K Ono, M Eriguchi, H Takahashi :Dosimetric Evaluation for Neutron Capture
Therapy to Hepatocellular Carcinoma using
Intra-Arterial Administration of Boron-Entrapped
Water-in-Oil-in-Water Emulsion. Proceedings of
IASTED Bioengineering 2010 (Innsbruck,
AUSTRIA 2010) pp126-130, 2010
Furuya Y, Wakahara T, Akimoto H, Long CM,
Yanagie H, Yasuhara H. : A case of postoperative
recurrent intussusception associated withindwelling bowel tube. World J Gastrointest Surg.
2010 Mar 27;2(3):85-8.
Hironobu Yanagie, Hiroaki Kumada, Takemi
Nakamura, Syushi Higashi, Ichiro Ikushima,
Yasuyuki Morishita, Atsuko Shinohara, Fijiwara
Mitsuteru, Minoru Suzuki, Hirotaka Sugiyama,
Tetsuya Kajiyama, Ryohei Nishimura, Koji Ono,
Masazumi Eriguchi, and Hiroyuki Takahashi:

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Feasible Evaluation of Neutron Capture Therapy
for Hepatocellular Carcinoma using Selective
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Neutron Capture Therapy, pp 157-160, 2010

490

Medical Specialists Training Center
Associate Professor
Nobuyuki Shimizu, M.D., Ph.D.

Homepage
Introduction and Organization
The Region-based Advanced Medical Specialists
Training Promotion Center was established in April
2009 under the Personnel Affairs Department with theaim of addressing the shortage of doctors and thedecreased number of doctors on loan from university
hospitals, which are serious social issues nowadays.
Efforts are focused on establishing a circulating careerdevelopment system for medical professionals in close
cooperation between the University of Tokyo Hospitaland regional medical institutions.
Outlines
1) Serving as the contact point of the University ofTokyo Hospital (the University Hospital) for otherhospitals with which the University Hospital has
personnel exchange programs (hereinafter as the“partner hospitals”), the Center regularly gathers
information on these partner hospitals anddiscusses their needs in order to promoteinteractive personnel exchanges.
2) The Center communicates gathered information
regarding vacant positions of partner hospitals andqualifications to relevant clinical departments/
divisions of the University Hospital so as to help
fill the positions with doctors of the University
Hospital.
3) The Center also helps doctors of a partner hospital
to receive training at the University Hospital for acertain period of time, on request basis from thepartner hospital, in order to improve their medical
skills and experience.
Characteristics
The Center offers assistance not only to physicians

and dentists but also to nurses, pharmacists and othermedical professionals in their career formation.
Efforts are focused on improving training systems andenvironments at partner hospitals and establishing a
network between the University Hospital and its
partner hospitals. Thereby, it is aimed to further
improve the education and training capabilities andclinical research capabilities of the University
Hospital.
The Center will propose a model curriculum for a
career development system for medical professionals
based on interdisciplinary, interactive exchange
among medical staff from different clinicaldepartments/divisions and labora tories of the
University Hospital and its partner hospitals.

University Hospital
Pharmaceutical Service

492

Department of Pharmacy
Professor
Hiroshi Suzuki, Ph.D.

Associate Professor
Kousei Ito, Ph.D.

Research Associate
Yoshiyuki Ohno, Ph.D., Tappei Takada, Ph.D., Kazuo Takayama,
Tomoko Fujino, Masashi Honma, Yoshitsugu Yanagihara, Ph.D.,
Takehito Yamamoto

Homepage

http://square.umin.ac.jp/todaiyak/index.html

Introduction and Organization
We have 9 faculty members, 62 pharmacy staffs, 8
pharmacy residents, and 15 graduate students and 5
undergraduate students from the faculty ofpharmaceutical sciences and 4 graduate students fromthe faculty of medicine (as of December 1st, 2010).
In addition, project associate professor (Akihiro
Hisaka, Ph.D.) and project research associate(Yoshihide Yamanashi, Ph.D.) from Pharmacology
and Pharmacokinetics 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),

493

periodically reconsiders the adopted medicines,
and also manages the accountings of all the
medicines and other materials used in our
department. This section also takes statistics ofevery information of drug affairs. Drugmanagement section takes care of supplying andsafekeeping of all the in-hospital medicines(approx. 2,300 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 areproperly arranged and managed at the dispensing
section and each medical care section.
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 2010)
Number of items on in-hospital formulary: 2,303
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
468,245 ps.
(outside :379,647 ps.)(inside :88,598 ps.)out-patient chemotherapy:
7,522 ps.
in-patients:
214,467 ps.
injection drugs:
225,155 ps.
IVH:
8,834 pp.
chemotherapy:
10,870 pp.
TDM consultations (annual) :16,585
Numbers of hospital pharmaceutical cares (annual):
5,361

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 “Special Lecture Basic Pharmaceutical

494

Science IV”, “Special Lecture Clinical Science”,"Advanced Course of Medical Pharmacy" as acooperator of the Clinical Pharmacokinetics. Recent
trends of the medical pharmacy as well as the practicaldevelopments and future visions of the department ofpharmacy are presented in this lecture. In addition tothese, we accept undergraduate and graduate students
from the faculty of pharmaceutical sciences andfaculty of medicine. They are doing various research
activities.
Six year course education system has been launchedin the field of pharmaceutical sciences since 2006.
In this system, the clinical training by the pharmacists
at the hospital is one of the most importantcurriculums. In 2010, we accepted total 42 clinicaltraining students from The University of Tokyo,
Tokyo University of Pharmacy and Life Sciences,
Showa Pharmaceutical University, Hoshi University,and Musashino University and educated them for 2.5
months. On the other hand, we have had an original
one-year post-graduate training course for pharmacists
since long time before starting the 6-year course
education system. They learned various practicalknowledge and techniques necessary for hospital
pharmacists. Such education style is still continued
by shortening the period to half a year. In 2010, 8
pharmacists finished this course.
In addition, we are promoting life-long education ofpharmacists in the local area by holding regular
technical workshops and seminars.

this idea to “system pharmacology”, we will be able toidentify a molecular target which is related to thepharmacological/toxicological output in clinicalsituation or even at early drug development stage.
Based on such concept, following projects are now
ongoing:
1. Elucidation of the molecular mechanism which
controls in vivo disposition of lipids / bile acids /the uric acid, and establishment of new therapy forlife-style related diseases based on those
integrated understanding.
2. Elucidation of the dynamic regulatory mechanismof bone resorption / bone formation, andestablishment of new therapy for bone metabolic
disease based on those integrated understanding.
3. Establishment of the way to quantitative
understanding and prediction of pharmacologicaleffect and side-effect of drugs directed against
particular molecular target. Finally, these outputs
would be feed backed to early drug development
stages.
4. Elucidation of the molecular mechanism related tothe side effect of drugs using large-scale“-omics“ analysis.
Finally, the quantitative
information would be applied to develop strategies
to prevent / treat the side effect.
5. Absolute quantification of factors determining thepharmacokinetic profiles of drugs and its
application to clinical pharmacokinetics andpharmacology field.

Research activities
References
It is evident that the molecular function ofparticular element cannot always be assigned to only
one function at whole body level, because one to one
simple correspondence is not common in our body.
It is also true that the understanding of the relationshipbetween drug and its ultimate target is not sufficient topredict the pharmacological/toxicological effect. We
need to understand not only the detailed molecularmachinery of drug target, but also its environment
surrounding the target (ex. other associating proteins,
signaling molecules etc.), where and when it works,
and finally how it behaves as functional unit in our
body. This is a basic idea trying to understand“living body” as “system”. By further promoting(1) Aoki S, Honma M, Kariya Y, Nakamichi Y,
Ninomiya T, Takahashi N, Udagawa N and
Suzuki H (2010) Function of OPG as a traffic
regulator for RANKL is crucial for controlled
osteoclastogenesis. J Bone Miner Res 25(9):1907-1921.
(2) Hisaka A, Ohno Y, Yamamoto T and Suzuki H(2010) Prediction of pharmacokinetic drug-druginteraction caused by changes in cytochrome
P450 activity using in vivo information.
Pharmacol Ther 125:230-248.
(3) Hisaka A, Ohno Y, Yamamoto T and Suzuki H(2010) Theoretical considerations on quantitative

495

(4)

(5)

(6)

(7)

(8)

prediction of drug-drug Interactions. Drug Metab
Pharmacokinet 25 48-61.
Honma M, Kozawa M and Suzuki H (2010)
Methods for the quantitative evaluation andprediction of CYP enzyme induction using
human in vitro systems. Expert Opinion on Drug
Discovery 5(5):491-511.
Ikebuchi Y, Ito K, Takada T, Anzai N, Kanai Y
and Suzuki H (2010) Receptor for activated
C-kinase 1 regulates the cell surface expression
and function of ATP binding cassette G2. Drug
Metab Dispos 38(12):2320-2328.
Masuo Y, Ito K, Yamamoto T, Hisaka A, Honma
M and Suzuki H (2010) Characterization of
inhibitory effect of carbapenem antibiotics on thedeconjugation of valproic acid glucuronide. Drug
Metab Dispos 38(10):1828-1835.
Saito-Yabe M, Kasuya Y, Yoshigae Y, Yamamura
N, Suzuki Y, Fukuda N, Honma M, Yano K,
Mochizuki S, Okada F, Okada A, Nagayama Y,
Tsuda E, Fischer T, Hopner U, Zaja S, Mueller J,
Okada J, Kurihara A, Ikeda T and Okazaki O(2010)PEGylationofosteoprotegerin/
osteoclastogenesis inhibitory factor (OPG/OCIF)
results in decreased uptake into rats and humanliver. J Pharm Pharmacol 62(8):985-994.
Takada T and Suzuki H (2010) Molecularmechanisms of membrane transport of vitamin E.
Mol Nutr Food Res 54(5):616-622.

Center for Disease Biology andIntegrative Medicine

497

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.

Homepage

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

Research
Our laboratory will focus on clarification of thepathogenesis of various diseases and the related
physiological machineries in cellular and molecular
aspects. Based on our technical advantage in genemanipulation via gene knockout and transgenesis, wewill give high priorities to in vivo analyses. This willdefinitively contribute to the direct therapeutic
application of our findings. Since our rationale is tochallenge to uncharacterized disease mechanisms andphysiologies, we will not restrict our interest, strategy
or technique employed, in certain specific field.
Rather, we will expand our research area by
establishing different collaborations with a broad
spectrum of investigators. We believe this fits to thepolicy of the CDBIM, which aims the development of
a comprehensive science including the fundamental
and clinical medicines, and the biotechnology. Overall,
we will attempt to discover novel biological insights
rather than to study details of previously characterized
physiologies, by targeting molecules newly identified
by ourselves. The major specific aims during the next
five years are as follows:

1. Role of Apoptosis Inhibitor expressed byMacrophages(AIM)inatherosclerosis
development.
AIM, which we initially identified as a soluble
apoptosis inhibitory factor, is largely produced bytissue macrophages. Recently, we found that AIM
expression induction is highly correlated to
hyperlipidemia; and that expression of AIM is criticalin progression of atherosclerosis as assessed in AIM
knockout mice. We will isolate the putative receptor
for AIM, and elucidate the entire signaling pathway of
how AIM inhibits apoptosis. In addition, bygenerating functional antibodies against human AIM,we will develop a potential treatment of
atherosclerosis by suppressing AIM activity in thebody.
2. Epigenetical regulation of Genome-Stability via
Polycomb and its relevance to oncogenesis.
Recently, we discovered a novel Polycomb groupprotein MBT-1, which specifically dictates thematurational transition of immature myeloid
progenitor cells. We will clarify the definitive
molecular mechanism of how MBT-1 regulates the
myelopoiesis, which may open avenues for the further
understanding of the mechanisms responsible forleukemogenesis. In addition, we will perform a large
scale screening of leukemia patients for the mutation

498

and/or the translocation of the MBT-1 gene (locus).
3. Regulation of mitosis progression by DEDD and
its influence on cell & body sizing andoncogenesis.
It has been suggested that the regulation of
apoptosis is crucially involved in tumor development.
Our recent analysis of knockout mice of the deatheffector domain (DED) containing element DEDD-1
has implied an important role of DEDD-1 in tumor
progression. We will further determine theinvolvement of DEDD-1 in tumorgenesis in thecontext of apoptosis as well as of other potentialmachineries. We will also study the function of asimilar molecule DEDD-2 both in vivo and in vitro.
These studies will not only provide a novel insight
into the influence of apoptosis in tumorgenesis, butalso suggest a potentiality of tumor manipulation bymodulating expression of DEDD molecules.
4. Towards the development of a definitive
therapy for Propionic Acidemia.
Propionic acidemia (PA) is the most frequent inborn
error of organic acid metabolism in humans. It iscaused by a deficiency of propionyl-CoA carboxylase(PCC), which results in accumulation of toxic
propionic acid, leading to furious acceleration of
ketoacidosis. We generated a mouse model for thesevere-type PA by disrupting the PCCA (α-subunit of
PCC) gene, and successfully rescued the mice bycomplementation of a partial PCC-activity restrictedly
in the liver or in the skin via a transgene. Having thisresult, we will establish a novel therapy for PA that isbased on an idea of developing “chimeric” organs via
transplantation of hepatic stem cells or fibroblast cells
into newborns or early infants.

Lab Activities
DBELS（Disease Biology Excellent Lecture Series）
We present a lecture series by top scientists in avariety of research fields related to disease biology. Sofar, eleven lecturers have been invited from many
places including Kyoto Univ., Hokkaido Univ., Riken
Institute, Tokyo Univ. of Science, Washington Univ.
(USA), Univ. of Basel (Switzerland), and Weill
Medical College of Cornell University (USA).

DBELS-EXTRAAs a daughter series of DBELS, we started atechnical lecture series for young scientists. We invite
various scientists from not only universities but also
research institutes or industries.
DBELS 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. Kurokawa, J., Arai, S., Nakashima, K., Nagano, H.,
Nishijima, A., Miyata, K., Ose, R., Mori, M.m
Kubota, N., Kadowaki, T., Oike, Y., Koga, H.,
Febbraio, M., Iwanaga, T., Miyazaki, T.
Macrophage-derived AIM is endocytosed into
adipocytes and decreases lipid droplets via inhibitionof fatty acid synthase activity. Cell Metab 11: 479492 (2010)
2. Kurabe, H., Mori, M., Kurokawa, J.,Tniguchi, K.,
Aoyama, H., Atsuda, K., Nishijima, A., Odawara, N.,
Harada, S., Nakashima, k., Arai, S., Miyazaki T. The
death effector domain-containing DEDD forms acomplex with Akt and Hsp90, and supports their499

stability.Biochem. Biophy. Res.Commun. 391:
1708-1713 (2010)
3. Bhatia, H., Hallock, J.L., Sterner, L.S., Karkashon,S., Miyazaki, T., Dean, A., & Little, J.A. A shortchain fatty acid mediated reversed globin geneswitch in primary definitive erythroid cells. Blood
113: 6440-8 (2009)
4. Kurabe, N., Arai, S., Nishijima, A., Kubota, N.,
Suizu, F., Mori, M., Kurokawa, J., KondoMiyazaki, M., Ide, T., Murakami, K., Miyake, K.,
Ueki, K., Koga, K., Yatomi, Y., Tashiro, F.,
Noguchi, M., Kadowaki, T., & Miyazaki, T. The
death effector domain-containing DEDD supports
S6K1 activity via preventing Cdk1-dependent
inhibitory phosphorylation. J. Biol. Chem. 284 :
5050-5055 (2009)
5. 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).
6. 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).
7. 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).
8. Koltsova, E.K, Ciofani, M., Benezra, R.,
Miyazaki, T., Clipstone, N., Zuniga-Pflucker, J.C.,
Wiest, D.L. Early Growth Response 1 and NFATc1 Act in Concert to Promote Thymocyte
Development
beyondthebeta-Selection
Checkpoint.
J. Immunol. 179: 4694-4703(2007).
9. Arai, S., Shelton, J.M., Chen, M., Bradley, M.N.,
Castrillo, A, Bookout, A.L., Mak, P.A., Edwards.
P.A., Mangelsdorf, D.J., Tontonoz, P. & Miyazaki,
T. A role of the apoptosis inhibitory factor
AIM/Spα/Api6 in atherosclerosis development.
Cell Metab. 1: 201-213 (2005).
10. 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).
11. Haks, M.C., Lefebvre, J.M., Lauritsen, J.P.H.,
Carleton, M., Rhodes, M., Miyazaki, T., Kappes,
D.J. & Wiest, D.L. Attenuation of γδTCRsignaling efficiently diverts thymocytes to the αβlineage. Immunity 22: 595-606 (2005).
12. 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).
13. 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).
14. 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).
15. 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).
16. 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).
17. 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).
18. Miyazaki, T., Hirokami, Y., Matsuhashi, N.,
Takatsuka, H. & Naito, M. Increased
susceptibility of thymocytes to apoptosis in mice500

lacking AIM, a novel murine macrophage-derived
soluble factor belonging to the scavenger receptor
cysteine-rich domain superfamily. J. Exp. Med.
189:413-422 (1999).
19. Miyazaki, T. & Lemonnier, F.A. Modulation ofthymic selection by expression of an immediateearly gene, early growth response 1 (Egr-1). J.
Exp. Med. 188:715-723 (1998).
20. 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).
21. Miyazaki, T., Müller, U. & Campbell, K.S.
Normal development but differentially alteredproliferative responses of lymphocytes in micelacking CD81. EMBO. J. 16: 4217-4225. (1997).
22. 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 peptideloading pathway. Cell 84: 531-541 (1996).
23. Miyazaki, T., Dierich, A., Benoist, C. & Mathis D.
Independentmodesofnaturalkilling
distinguished in mice lacking Lag3. Science 272:405-408 (1996).
24. 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).
25. 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).

501

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
Satoshi Watanabe, Ph.D., Akiko Hayashi, M.D.,Ph.D., Jun Noguchi, 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, and officially took office inthe University of Tokyo in November, 2005. The
Kasai laboratory has moved to the first building ofFaculty of Medicine in January, 2006. It belongs to theSection of Functional Biology in the Graduate Schoolof Medicine. Its name 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
We have 6 doctor and 2 master course students in2010. We were also involved in undergraduate
education of Physiology. In particular, we were
responsible for the lectures and student experiments of
endocrine physiology.

502

biomedical applications. We will explain three
representative works of this year in some detail.
1) Two-color, two-photon uncaging of glutamate and
GABA.
Two-photon microscopy has recently revolutionized
the biological sciences. In particular, two features areproving to be very useful when compared with normal
excitation modalities, namely imaging fluorescentsignals from deep within living tissue and localized
photochemical release of caged compounds. The
non-linear nature of two-photon excitation provides
both of these benefits. Effective two-photon uncaging
is predicated upon several chemical properties of thephotosensitive probe. Nitroindolinyl-caged glutamateshave been used by many laboratories for two-photon
uncaging experiments, implying such cages can beused with non-toxic photon fluxes. These probes arephotolyzed in the 710-730 nm range such that the
response at a spine head to the uncaged glutamate
appears like single vesicle secretion.
We have here developed a method for bimodal
control of neuronal membrane potential with
subcellular resolution using optically independent
two-photon uncaging of glutamate at 720 nm and
GABA at 830 nm. Two-color, two-photon uncaging
allowed action potentials from rat hippocampal CA1
neurons to be fired and blocked with the two
wavelengths of light. Two-color, two-photon uncaging
may enable optically independent control of manyother symbiotic chemical messenger pairs (Ref. 1).
2) Simultaneous
two-photon
activationofpresynaptic cells and calcium imaging inpostsynaptic dendritic spines.
Dendritic spines of pyramidal neurons are distributed
along the complicated structure of the dendritic
branches and possess a variety of morphologies associated with synaptic strength. The location and structure of dendritic spines determine the extent of synaptic input integration in the postsynaptic neuron. However, how spine location or size relates to the positionof innervating presynaptic cells is not yet known. This
report describes a new method that represents a firststep toward addressing this issue. The technique combines two-photon uncaging of glutamate over a broad
area (~500 × 250 × 100 μm) with two-photon calcium

imaging in a narrow region (~50 × 10 × 1 μm). The
former was used for systematic activation of layer 2/3
pyramidal cells in the rat motor cortex, while the latter
was used to detect the dendritic spines of layer 5 pyramidal cells that were innervated by some of thephotoactivated cells. This technique allowed identification of various sizes of innervated spine located<140 μm laterally from the postsynaptic soma. Spines
distal to their parent soma were preferentially innervated by cells on the ipsilateral side. No cluster ofneurons innervating the same dendritic branch was
detected. This new method will be a powerful tool forclarifying the microarchitecture of synaptic connections (Ref. 6).
3) SNARE conformational changes that prepare
vesicles for exocytosis.
When cells release hormones and neurotransmittersthrough exocytosis, cytosolic Ca2+ triggers the fusionof secretory vesicles with the plasma membrane. It is
well known that this fusion requires assembly of a
SNARE protein complex. However, the timing of
SNARE assembly relative to vesicle fusion—essential
for understanding exocytosis—has not been
demonstrated. To investigate this timing, weconstructed a probe that detects the assembly of two
plasma-membrane
SNAREs,SNAP25andsyntaxin-1A, through fluorescence resonance energy
transfer (FRET). With two-photon imaging, we
simultaneously measured FRET signals and insulin
exocytosis in beta cells from the pancreatic islet of
Langerhans. In some regions of the cell we found that
the SNARE complex was preassembled, whichenabled rapid exocytosis. In other regions, SNARE
assembly followed Ca2+ influx, and exocytosis was
slower. Thus, SNARE proteins exist in multiple,
stable preparatory configurations, from which Ca2+
may trigger exocytosis through distinct mechanisms
and with distinct kinetics. (Ref. 4).

References1.

2.

Kantevari, S., Matsuzaki, M., Kanemoto, Y.,
Kasai, H.* & Ellis-Davies, G.C.R.* (2010).
Two-color, two-photon uncaging of glutamate
and GABA. Nature Methods 7, 123-125.
Obi, N., Momotake, A., Kanemoto, Y.,

503

3.

4.

5.

6.

Matsuzaki, M, Kasai, H. & Arai, T. (2010).
1-Acyl-5-methoxy-8-nitro-1,2-dihydroquinoline:
A biologically useful photolabile precursor ofcarboxylic acids. Tetrahedron letters 51,
1642-1657.
Kasai, H., Hayama, T., Ishikawa, M., Watanabe,
S. & Yagishita, S. (2010). Learning rules andpersistence of dendritic spines. Eur. J. Neurosci.
32, 241-249.
Takahashi, N., Hatakeyama, H., Okado, H.,
Noguchi, J. Ohno, M. & Kasai, H. (2010).
SNARE conformational changes that prepare
vesicles for exocytosis. Cell Metabolism 12,
19-29.
Kaneko, K., Ueki, K., Takahashi, N., Hashimoto,S.,Okamoto, M., Awazawa, M., Okazaki,
Y.,Ohsugi, M., Inabe, K., Umehara T., YoshidaM., Kakei M., Kitamura, T., Luo, J., Kulkarni,
R.N., Kahn, C.R., Kasai, H., Cantley, L.C. &Kadowaki, T. (2010). Class IA phosphoinositide
3-kinase in pancreatic β cells controls insulin
secretion by multiple mechanisms. Cell
Metabolism 12, 619-632.
Matsuzaki, M., Ellis-Davies, G.C.R., Kanemoto,Y., & Kasai, H. (2011). Simultaneous two-photon
activation of presynaptic cells and calcium
imaging in postsynaptic dendritic spines. Neural
Systems and Circuits 1:2.

504

Laboratory of Regenerative
Medical Engineering
Professor
Takashi Ushida, Ph.D.

Associate Professor
Taichi Ito, Ph.D.

Lecturer
Takayuki Akimoto, 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. Ito 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. Ito 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.

505- 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 physicalstimulations- 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.

especially using the hybrid model of cell automaton
and partial differential equations.

References
1.

2.

3.

4.

5.
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- Development of a new synthesis way of glycol
nucleic acid via a ring opening polymerization- Application of the smart biomaterials for drugdelivery3) Process design of tissue regeneration- Mathematical understanding and process design oftissue regeneration in materials in vitro and in vivo,

Katsuji Aizawa, Motoyuki Iemitsu, Seiji Maeda,
Takeshi Otsuki, Koji Sato, Takashi Ushida,
Noboru Mesaki, Takayuki Akimoto, Acuteexercise activates local bioactive androgenmetabolism in skeletal muscle, Steroids 75, 219223 (2010)
Spatio-temporal PLC activation in parallel withintracellular Ca2+ wave propagation inmechanically stimulated single MDCK cells,
Akira Tsukamoto, Yasunori Hayashida, Katsuko
S. Furukawa, Takashi Ushida, Cell Calcium 47,
253–263 (2010)
Katsuko S. Furukawa, Keigo Nakamura, Yuji
Onimura, Masaki Uchida, Atsuo Ito, Takashi
Yamane, Tamotsu Tamaki, Takashi Ushida and
Tetsuya Tateishi, Quantitative Analysis of Human
Platelet Adhesions Under a Small-Scale Flow
Device, Artificial Organs, 34 (4) : 295–300(2010)
Kazuki Akamatsu, Wei Chen, Yukimitsu Suzuki,
Taichi Ito, Aiko Nakao, Takashi Sugawara, Ryuji
Kikuchi, Shin-ichi Nakao, Preparation ofmonodisperse chitosan microcapsules with hollow
structures using the SPG membrane emulsification
technique, Langmuir 2010(26)14854-14860
Hidenori Ohashi, Taichi Ito, Takeo Yamaguchi,
Prediction of Self-Diffusivity in Multicomponent
Polymeric Systems Using Shell-Like Free Volume,
Industrial & Engineering Chemistry Research 2010(49)11676-11681

506

Laboratory of Clinical
Biotechnology
Professor
Kazunori Kataoka, Ph.D.

Associate Professor
Nobuhiro Nishiyama, Ph.D.

Research Associate Professor
Keiji Itaka, M.D., Ph.D.

Assistant Professor
Kanjiro Miyata, 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 tocontribute to the realization of nanomedicine. 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 Global COE (GCOE) program, whichstarted in 2008, as a novel medicine-engineeringinterdisciplinary program, and tries to contribute to
the production of medical ventures by promoting
liaison with the industrial sector and to the productionof professionals who understand both advanced
medicine and nanotechnology. The division consistsof one professor, one research associate professor, one
research associate professor, one assistant professor
and several project staff members.
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 the atomic/
molecular level to produce units with sophisticatedfunctions. Nanodevices produced by nanotechnology
integrate materials and systems on a nanometer scale,and hold the key to realizing the futuristic medical
system that can serve the needed function at the righttime and the right place with minimal invasiveness.
Furthermore, nanodevices are expected to become an
important interface between basic biomedical scienceand clinical medicine by facilitating the translation ofbasic achievements into clinical applications. Our
division wishes to produce revolutionary medical
nanodevices based on nanotechnology and thereby tospread the idea of "Nanomedicine" intranationally andinternationally.

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

507

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-circulation 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 escape fromthose 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), cisplatin (CDDP) and oxaliplatinby polymeric micelles, and observed enhanced
antitumor activity with reduced side effects. These
micellar formulations are currently being tested inclinical 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 andpositively charged block copolymers. The polymeric
micelles protected the loaded DNA from degradation
by nuclease attack and showed efficient gene transfer
to a variety of cells. Also, various smart functions
such as the targeting ability and environmental
sensitivity can be integrated with polymeric micelles,
offering the opportunities to develop effective
synthetic vectors resembling viral functions. Thus,
polymeric micelles are expected as useful nanocarriersof pDNA and siRNA for in vivo use.

References
1.

2.

3.

S. Herlambang, M. Kumagai, S. Horie, S.
Fukushima, M. Oba, T. Nomoto, K. Miyazaki, Y.
Morimoto, N. Nishiyama, K. Kataoka, Disulfide
crosslinked
polyioncomplexmicellesencapsulating dendrimer phthalocyanine directed
to improved efficiency of photodynamic therapy.
J. Control. Release in press
H. Cabral, N. Nishiyama, K. Kataoka,
Supramolecular nanodevices: From design
validation to theranostic nanomedicine. Acc.
Chem. Res., in press
H. -L. Lu, W. -J. Syu, N. Nishiyama, K. Kataoka,

508

4.

5.

6.

7.

8.

9.

P.-S.
Lai,
Dendrimer
phthalocyanineencapsulated
polymericmicelle-mediatedphotochemical internalization extends theefficacy of photodynamic therapy and overcome
the drug-resistance in vivo. J. Control. Release inpress
S. Uchida, K. Itaka, Q. Chen, K. Osada, K.
Miyata, T. Ishii, M. Harada-Shiba, K. Kataoka,
Combination of chondroitin sulfate and polyplex
micelles of poly(ethylene glycol)- poly{N'-[N-(2aminoethyl)-2-aminoethyl]aspartamide}: A block
copolymer for prolonged in vivo genetransfection with reduced toxicity. J. Control.
Release in press
T. C. Lai, K. Kataoka, G. S. Kwon, Pluronicbased cationic block copolymer for forming
pDNA polyplexes with enhanced cellular uptake
and
improvedtransfection
efficiency.
Biomaterials 47 (21) 6054-6056 (2011)
Y. Anraku, A. Kishimura, A. Kobayashi, M. Oba,
K. Kataoka, Size-controlled long-circulating
PICsome as ruler to measure critical cut-off
disposition size into normal and tumor tissues.
Chem. Commun. 47 (21) 6054-6056 (2011)
T. Nomoto, Y. Matsumoto, K. Miyata, M. Oba, S.
Fukushima, N. Nishiyama, T. Yamasoba, K.
Kataoka, In situ quantitative monitoring ofpolyplexes and polyplex micelles in the blood
circulation using intravital real-time confocal
laser scanning microscopy. J. Control. Release151 (2) 104-109 (2011)
F. Pittella, M. Zhang, Y. Lee, H. -J. Kim, T.
Tockary, K. Osada, T. Ishii, K. Miyata, N.
Nishiyama, K. Kataoka, Enhanced endosomal
escapeofsiRNA-incorporating
hybridnanoparticles from calcium phosphate andPEG-block charge-conversional polymer for
efficient gene knockdown with negligible
cytotoxicity. Biomaterials 32 (11) 3106-3114(2011)
R. Plummer, R. H. Wilson, H. Calvert, A. V.
Boddy, M. Griffin, J. Sludden, M. J. Tilby, M.
Eatock, D. G. Pearson, C. J. Ottley, Y. Matsumura,
K. Kataoka, T. Nishiya, A Phase I clinical studyof cisplatin-incorporated polymeric micelles(NC-6004) in patients with solid tumours. Br. J.
Cancer 104 (4) 593-598 (2011)

10. Y. Vachutinsky, M. Oba, K. Miyata, S. Hiki, M. R.
Kano, N. Nishiyama, H. Koyama, K. Miyazono,
K. Kataoka, Antiangiogenic gene therapy ofexperimental pancreatic tumor by sFlt-1 plasmid
DNA carried by RGD-modified crosslinked
polyplex micelles. J. Control. Release 149 (1)51-57 (2011)
11. M. Murakami, H. Cabral, Y. Matsumoto, S. Wu,
M. R. Kano, T. Yamori, N. Nishiyama, K.
Kataoka, Improving drug potency and efficacy bynanocarrier-mediated subcellular targeting. Sci.
Transl. Med. 3 (64) 64ra2 (2011)
12. M. Oba, K. Miyata, K. Osada, R. J. Christie, M.
Sanjoh, W. Li, S. Fukushima, T. Ishii, M. R.
Kano, N. Nishiyama, H. Koyama, K. Kataoka,
Polyplex micelles prepared from ω-cholesteryl
PEG-polycation block copolymers for systemic
gene delivery. Biomaterials 32 (2) 652-663(2011)
13. K. Osada, H. Oshima, D. Kobayashi, M. Doi, M.
Enoki, Y. Yamasaki, K. Kataoka, Quantizedfolding of plasmid DNA condensed with block
catiomer into characteristic rod structures
promoting transgene efficacy. J. Am. Chem. Soc.
132 (35) 12343-12348 (2010)
14. T. -C. Lai, Y. Bae, T. Yoshida, K. Kataoka, G. -S.
Kwon, pH-Sensitive multi-PEGylated block
copolymer as a bioresponsive pDNA delivery
vector. Pharm. Res. 27 (11) 2260-2273 (2010)
15. Y. Matsumoto, T. Nomoto, H. Cabral, Y.
Matsumoto, S. Watanabe, R. J. Christie, K.
Miyata, M. Oba, T. Ogura, Y. Yamasaki, N.
Nishiyama, T. Yamasoba, K. Kataoka, Direct andinstantaneous observation of intravenously
injected substances using intravital confocal
micro-videography. Biomed. Opt. Express 1 (4)1209-1216 (2010)
16. S. Kaida, H. Cabral, M. Kumagai, A. Kishimura,
Y. Terada, M. Sekino, I. Aoki, N. Nishiyama, T.
Tani, K. Kataoka, Visible-drug delivery bysupra-molecular nanocarriers directing tosingle-platformed diagnosis and therapy of
pancreatic tumor model. Cancer Res. 70 (18)7031-7041 (2010)
17. M. Kumagai, T. K. Sarma, H. Cabral, S. Kaida,
M. Sekino, N. Herlambang, K. Osada, M. R.
Kano, N. Nishiyama, K. Kataoka, Enhanced in

509

18.

19.

20.

21.

22.

23.

24.

25.

vivo magnetic resonance imaging of tumors by
PEGylatedironoxide-goldcore-shell
nanoparticles with prolonged blood circulation
properties. Macromol. Rapid Commun. 31 (17)1521-1528 (2010)
H. Takemoto, A. Ishii, K. Miyata, M. Nakanishi,
M. Oba, T. Ishii, Y. Yamasaki, N. Nishiyama, K.
Kataoka, Polyion complex stability and genesilencing efficiency with a siRNA-graftedpolymer delivery system. Biomaterials 31 (31)8097-8105 (2010)
Matsumoto, H. Cabral, N. Sato, K. Kataoka, Y.
Miyahara, Assessment of tumor metastasis via
direct determination of cell membrane sialic acidexpression. Angew. Chem. Int. Ed. 49 (32)5494-5497 (2010)
M. Sanjoh, S. Hiki, Y. Lee, M. Oba, K. Miyata, T.
Ishii,
K.
Kataoka,
pDNA/poly(L-lysine)
polyplexes functionalized with a pH-Sensitive
charge-conversional poly(aspartamide) derivative
for controlled gene delivery to human umbilicalvein endothelial cells. Macromol. Rapid
Commun. 31 (13) 1181-1186 (2010)
H. -J. Kim, A. Ishii, K. Miyata, Y. Lee, S. Wu, M.
Oba, N. Nishiyama, K. Kataoka, Introduction ofstearoyl moieties into a biocompatible cationicpolyaspartamide derivative, PAsp(DET), withendosomal escaping function for enhanced
siRNA-mediated gene knockdown. J. Control.
Release 145 (2) 141-148 (2010)
K. Miyata, N. Gouda, H. Takemoto, M. Oba, Y.
Lee, H. Koyama, Y. Yamasaki, K. Itaka, N.
Nishiyama, K. Kataoka, Enhanced transfection
with silica-coated polyplexes loading plasmidDNA. Biomaterials 31 (17) 4764-4770 (2010)
K. Itaka, T. Ishii, Y. Hasegawa, K. Kataoka,
Biodegradable polyamino acid-based polycations
as safe and effective gene carrier minimizing
cumulative toxicity. Biomaterials 31 (13)3707-3714 (2010)
Matsumoto, K. Yamamoto, R. Yoshida, K.
Kataoka, T. Aoyagi, Y. Miyahara, A totally
synthetic glucose responsive gel operating inphysiological aqueous conditions. Chem.
Commun. 46 (13) 2203-2205 (2010)
M. Oba, Y. Vachutinsky, K. Miyata, M. R. Kano,
S. Ikeda, N. Nishiyama, K. Itaka, K. Miyazono,

26.

27.

28.

29.

30.

H. Koyama, K. Kataoka, Antiangiogenic genetherapy of solid tumor by systemic injection ofpolyplex micelles loading plasmid DNA
encoding soluble Flt-1 . Mol. Pharm. 7 (2)501-509 (2010)
K. Itaka, K. Osada, K. Morii, P. Kim, S. -H. Yun,
K. Kataoka, Polyplex nanomicelle promotes
hydrodynamic gene introduction to skeletal
muscle. J. Control. Release 143 (1) 112-119(2010)
H. Shimizu, Y. Hori, S. Kaname, K. Yamada, N.
Nishiyama, S. Matsumoto, K. Miyata, M. Oba, A.
Yamada, K. Kataoka, T. Fujita, siRNA-based
therapy ameliorates glomerulonephritis. J. Am.
Soc. Nephrol. 21 (4) 622-633 (2010)
Y. Lee, T. Ishii, H. -J. Kim, N. Nishiyama, Y.
Hayakawa, K. Itaka, K. Kataoka, Efficientdelivery of bioactive antibodies into thecytoplasm of living cells by charge-conversional
polyion complex micelles. Angew. Chem. Int. Ed.
49 (14) 2552-2555 (2010)
S. Hiki, K. Kataoka, Versatile and selective
synthesis of "Click Chemistry" compatible
heterobifunctionalpoly(ethylene
glycol)s
possessing azide and alkyne functionalities.
Bioconjugate. Chem. 21 (2) 248-254 (2010)
Y. Anraku, A. Kishimura, M. Oba, Y. Yamasaki,
K. Kataoka, Spontaneous formation of nanosizedunilamellar polyion complex vesicles withtunable size and properties. J. Am. Chem. Soc.
132 (5) 1631-1636 (2010)

510

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 in 2005.
Since then the of the laboratory was markedly
expanded to comprise of as many as 30 members,
including postdoctoral fellows, graduate andundergraduate students. Dr. Chiharu Tohyama wasgiven Achievement Award from the Japanese Societyof Hygiene in May 2010 for the accomplishment of
his research in toxicology and environmental health. .

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 vivo and to establish in vitro 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’
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

511

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.

Publications

Laboratory’s Research Themes

3.

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 vitro 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.

1.

2.

4.

5.

6.

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’.

7.

8.

9.

Tse D, Takeuchi T, Kakeyama M, Kajii Y, Okuno
H, Tohyama C, Bito H, Morris RG.
Schema-Dependent Gene Activation and Memory
Encoding in Neocortex. Science.2011 (in press)
Yoshioka W, Higashiyama W, Tohyama C.
Involvement of microRNAs in dioxin-induced
liver damage in the mouse. Toxicol Sci. 2011 (inpress)
Yoshioka W, Peterson RE, Tohyama C.Moleculartargets that link dioxin exposure to toxicity
phenotypes. J Steroid Biochem Mol Biol. 2011(in press)
Tohyama C, Uchiyama I, Hoshi S, Hijiya M,
Miyata H, Nagai M, Nakai S, Yauchi M, Ohkubo
S. Polychlorinated dioxins, furans and biphenyls
in the blood of children and adults living in adioxin-contaminated area in Tokyo. Environ
Health Prev Med. 16:6-15, 2011
Endo T, Maekawa F, Voikar V, Haijima A,
Uemura Y, Zhang Y, Miyazaki W, Suyama S,
Shimazaki K, Wolfer DP, Yada T, Tohyama C,
Lipp HP, Kakeyama M. Automated test of
behavioral flexibility in mice using a behavioral
sequencing task in IntelliCage. Behav Brain Res.
221:172-181, 2011
Haijima A, Endo T, Zhang Y, Miyazaki W,
Kakeyama M, Tohyama C. In utero andlactational exposure to low doses of chlorinatedand brominated dioxins induces deficits in thefear memory of male mice. Neurotoxicology.
31:385-90, 2010.
Dong B, Nishimura N, Vogel CF, Tohyama C,
Matsumura F. TCDD-induced cyclooxygenase-2
expression is mediated by the nongenomic
pathway in mouse MMDD1 macula densa cells
and kidneys. Biochem Pharmacol. 79:487-97,
2010.
Alam MS., Ohsako S., Tay TW., Tsunekawa N.,
Kanai N., and Kurohmaru M. Di(n-butyl)
phthalate induces vimentin filaments disruption
in rat Sertoli cells: A possible relation with
spermatogenic
cell
apoptosis.
Anatomia
Histologia Embryologia. 39:186-93, 2010
Ohsako S., Fukuzawa N., Ishimura R., KawakamiT., Wu Q., Nagano R., Zaha H., Sone H.,

512

Yonemoto J., and Tohyama C. Comparative
contribution of the aryl hydrocarbon receptor
gene to perinatal stage development anddioxin-induced toxicity between the urogenitalcomplex and testis in the mouse. Biol Reprod.
82:636-43, 2010
10. Alam MS, Ohsako S, Matsuwaki T, Zhu XB,
Tsunekawa N, Kanai Y, Sone H, Tohyama C, andKurohmaru M. Induction of spermatogenic cell
apoptosis in prepubertal rat testes irrespective of
testicular steroidogenesis: A possible estrogenic
effect of di(n-butyl) phthalate. Reproduction.
139: 427-437, 2010.
11. Sone H, Okura M, Zaha H, Fujibuchi W,
Taniguchi T, Akanuma H, Nagano R, Ohsako S,
and Yonemoto J. pCEC: a toxicogenomics
database with a toxicoinformatics system for risk
evaluation
andtoxicity
predictionofenvironmental chemicals. J Toxcol Sci. 35: 115123, 2010.
12. Ishihara K, Ohsako S, Tasaka K, Harayama H,
Miyake M, Warita K,Tanida T, Mitsuhashi T,
Nanmori T, Tabuchi Y, Yokoyama T, Kitagawa H,
and Hoshi N. When does the sex ratio of offspringof the paternal 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) exposure decrease: In the spermatozoa
stage or at fertilization? Reprod Toxicol. 29:
68-73, 2010.

513

Laboratory of Animal Resources
Professor
Atsu Aiba, Ph.D.

Associate Professor
Kazuki Nakao, Ph.D.

Assistant Professor
Hidetoshi Kassai, Ph.D., Takeshi Harada, Ph.D.

Homepage

http://lar.cdbim.m.u-tokyo.ac.jp/index.html

Introduction and Organization
Our laboratory was established as the Division ofAnimal Research affiliated with the Faculty of
Medicine in April 1971. The building for animal
experimentation
wascompletedandtheaccommodation and experimentation of laboratory
animals started in 1973. In 2003, the laboratory was
reorganized as the Section of Animal Research of theCenter for Disease Biology and Integrative Medicine(CDBIM). In 2008, the Laboratory of Animal
Resources was established to strengthen research
activities in addition to the Section of Animal
Resources.
The members of our laboratory and section are 4
teaching staffs, 3 technical support staffs, an assistantmanager of CDBIM, an administrative staff, ateaching assistant, 8 assistant laboratory animal
technicians, and 4 assistant clerks. In addition, about
10 contracted employees are involved in animal
breeding and maintenance of the animal facility.
The laboratory animals in our facility include
macaque monkeys, dogs, swine, rabbits, rats, and mice.
The number of registered users of our facility was 378
at the end of academic year 2010.
We provide quality care for all animals in ourfacility and assist animal experimentation carried out
by the researchers. The office of our section is incharge of the secretariat of the Animal Care and the
Use Committee of Graduate School of Medicine, theUniversity of Tokyo (IACUC). The committee (Chair,Prof. Hiroki Kurihara) reviews the plans of animal
experimentation and help researchers carry out
animal experiments in accordance with law,regulations and University policies governing the useof animals.

Teaching activities
We are responsible for the education of laboratory
animal science to the 2nd-year students (M0) of the
School of Medicine. The lecture includes animal
welfare, refinement of animal experiments, animal
breeding, infectious diseases of laboratory animals
and zoonoses. We also give a lecture on mouse
molecular genetics and molecular embryology.
We are also involved in lectures by IACUC for the
researchers at the Graduate School of Medicine.

Research activities
Our laboratory focuses on understanding themolecular mechanisms which underlie the synaptic
plasticity, activity dependent formation of neuronal
circuitry, and learning and memory. We also study cell
metabolism. We generate knockout mice andtransgenic mice of signal transduction molecules
including the glutamate receptors and mammaliantarget of rapamycin (mTOR). We applied proteomics
analysis to these mice. We also try to generate murine

514

models for human genetic diseases.
1. Generation of hyperactive mTOR transgenic micemTOR is a highly conserved serine/threonine
kinase that regulates a broad range of cellularfunctions in cell growth. mTOR forms twofunctionally distinct complexes, mTOR complex 1(mTORC1) and mTORC2. mTORC1 contains raptor
and mLst8, whereas mTORC2 contains rictor, mSin1,
and mLst8. The hyperactive mTOR mutant showsenhanced kinase activity and activates the mTORC1
pathway strongly and chronically in cultured cells. We
generated transgenic mice which express a
hyperactive mTOR mutant in forebrain and cerebellar
Purkinje cells. We observed the some of the neurons
in mTOR transgenic mice were enlarged presumably
due to activation of mTOR1 pathway. We are currently
investigating molecular mechanisms underlying thephenotypes of mTOR transgenic mice.
2. Genetic approaches to cerebellar function using
metabotropic
glutamate
receptor
subtype-1(mGluR1) transgenic mice
We previously demonstrated that mGluR1 knockout
showed ataxic gait, deficient long-term depression andimpaired synapse elimination. These phenotypes were
rescued by expression of an mGluR1 transgene with
Purkinje cell-specific promoter (mGluR1-rescue mice).
However, the role of mGluR1 in the adult miceremains elusive, mainly due to lack of conventionaland reproducible method to block mGluR1 expression
at a certain developmental stage. We established an
mGluR1 conditional knockout (cKO) mice by using
the tetracycline-controlled gene expression system tounderstand roles of mGluR1 in adult brain. The
mGluR1 cKO mice express mGluR1 only in Purkinjecells and its expression can be controlled with oral
administration of a tetracycline analog, doxycycline.
We found that suppression of the mGluR1 expression
in the adult mGluR1 cKO mice led to ataxic gait andimpaired motor coordination, suggesting that mGluR1
is essential for cerebellar function in mice not only
during postnatal development but also in adulthood.
3. Role of mGluR1 in classical eyeblink conditioning
Classical eyeblink conditioning is common tohumans and other mammals such as rabbits and mice,and has been a valuable paradigm for the study of
associative motor learning as well as humanneurological disorders. Eyeblink conditioning
procedure consists of a conditioned stimulus (CS) anda blink-eliciting unconditioned stimulus (US). Naive
animals initially exhibit unconditioned response (UR)
following US onset. After repeated trials ofconditioning with a pair of CS-US, they come toassociate CS and US and to exhibit conditioned
response (CR) before the US onset. Our previous
studies using mGluR1 knockout mice showed thatmGluR1 in cerebellar Purkinje cell is required fordelay paradigm of eyeblink conditioning. We trained
the mGluR1 cKO mice in eyeblink conditioning
before or after doxycycline administration todetermine which learning process requires mGluR1
function.
4. Study of obese mice
We generated mutant mice in which a histone
H2B-KikGR fusion gene is introduced into the
ROSA26 locus by homologous recombination using
ES cells. Homozygous knock-in (R26-H2B-Kik-GR/
H2B-Kik-GR) mice died around 4 weeks after birth.
Heterozygous (R26-H2B-Kik-GR/+) mice are notlethal and develop obesity. Body weights of
R26-H2B-Kik-GR/+ mice remarkably increased incomparison with control mice at the age of 6 weeks.
LeptinandinsulinlevelsinserumofR26-H2B-Kik-GR/+ mice were significantly higher
than those of control mice, while glucose level in
R26-H2B-Kik-GR/+ mice was not significantly
changed. We also found that vacuolation of hepatocyte
in liver, hypertrophy of brown adipocytes and white
adipocytes, hypertrophy of acinar cells and islet cells
in pancreas, hyperplasia of lymphocytes in thymus.
These results suggest the possibility that
R26-H2B-Kik-GR/+ mice are new model animals forobesity.

References
1. Matsuda I, Fukaya M, Nakao H, Nakao K,
Matsumoto H, Mori K, Watanabe M, and Aiba A.
Development of the somatosensory cortex, thecerebellum, and the main olfactory system in
Semaphorin 3F knockout mice. Neurosci Res, 66,

515

2.

3.

4.

5.

321-329, 2010
Ojima K, Kawabata Y, Nakao H, Nakao K, Doi N,
Kitamura F, Ono Y, Hata S, Suzuki H, Kawahara
H, Bogomolovas J, Witt C, Ottenheijm C, Labeit
S, Granzier H, Toyama-Sorimachi N, Sorimachi
M, Suzuki K, Maeda T, Abe K, Aiba A, andSorimachi H. Dynamic distribution of musclespecific calpain in mice has a key role in physicalstress adaptation and is impaired in muscular
dystrophy. J Clin Invest, 120, 2672-2683, 2010
Takeuchi H, Inokuchi K, Aoki M, Suto F, Tsuboi
A, Matsuda I, Suzuki M, Aiba A, Serizawa S,
Yoshihara Y, Fujisawa H, and Sakano H.
Sequential arrival and graded secretion of Sema3F
by olfactory neuron axons specify map
topography at the bulb. Cell, 141, 1056-1067,2010
Ueda S, Kitazawa S, Ishida K, Nishikawa Y,
Matsui M, Matsumoto H, Aoki T, Nozaki S,
Takeda T, Tamori Y, Aiba A, Kahn CR, Kataoka
T, and Satoh T. Crucial role of the small GTPase
Rac1 in insulin-stimulated translocation of
glucose transporter 4 to the mouse skeletal muscle
sarcolemma. FASEB J, 24, 2254-2261, 2010
Nakao K, and Inoue K. Cryopreservation forbroader production of transgenic mice by DNA
injection into zygotes. Exp Anim, 46, 231-234,
2010

516

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.,

Yasuhiko Kamikubo, 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.

517

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.
Rad51C, a central component of two protein
complexes formed by the members of the Rad51
paralog family, activates DNA repair pathways by
responding DNA damage signals through its directinteraction with Rad18. We confirmed that
Rad51-dependent homologous recombination is
impaired in Rad51C-deficient human cells.
Additionally, aberrations of the centrosome, which isessential for correct chromosome segregation, andaneuploidy were found to be increased in the mutant
cells. ATR and Chk1, which transmit DNA damage
signals, were shown to be responsible for theaberrations, suggesting that the DNA damage
signaling pathway plays a causal role in the generationof centrosome aberrations and aneuploidy. Thus, weare studying on Rad51 paralogs from the viewpoint of
the maintenance of chromosomal integrity by DNA
repair.
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.

Morita A, Yamamoto S, Wang B, Tanaka K,
Suzuki N, Aoki S, Ito A, Nanao T, Ohya S,
Yoshino M, Zhu J, Enomoto A, Matsumoto Y,
Funatsu O, Hosoi Y, Ikekita M: Sodium
orthovanadate inhibits p53-mediated apoptosis.
Cancer Res. 2010; 70:257-265.
Kamikubo Y, Zhao L, Wunderlich M, Corpora T,
Hyde RK, Paul TA, Kundu M, Garrett L,
Compton S, Huang G, Wolff L, Ito Y, Bushweller
J, Mulloy JC, Liu PP: Accelerated leukemogenesis by truncated CBFβ-SMMHC defective inhigh-affinity binding with RUNX1. Cancer Cell.
2010; 17:455-468.
Hyde RI, Kamikubo Y, Anderson S, Kirby M,

518

4.

5.

6.

7.

Alemu L, Zhao L, Liu PP: Cbfb/Runx1
repression-independent
blockageofdifferentiation and accumulation of Csf2rb-e
xpressing cells by Cbfb-MYH11. Blood. 2010;
115:1433-1443.
Sasano N, Enomoto A, Hosoi Y, Katsumura Y,
Matsumoto Y, Morita A, Shiraishi K, Miyagawa
K, Igaki H, Nakagawa K: Edaravone, a known
free radical scavenger, enhances X-ray-induced
apoptosis at low concentrations. Cancer Lett.
2010; 293:52-57.
Zhan H, Suzuki T, Aizawa K, Miyagawa K,
Nagai R: Ataxia telangiectasia mutated (ATM)mediated DNA damage response in oxidative
stress-induced
vascularendothelial
cellsenescence. J Biol Chem. 2010; 285:2966229670.
Takaku M, Takahashi D, Machida S, Ueno H,
Hosoya N, Ikawa S, Miyagawa K, Shibata T,
Kurumizaka H: Single-stranded DNA catenation
mediated by human EVL and a type I
topoisomerase. Nucleic Acids Res. 2010; 38:7579-7586.
Suzuki HI, Hosoya N, Miyagawa K, Ota S,
Nakashima H, Makita N, Kurokawa M:
Erdheim-Chester
disease:multisystem
involvement and management with interferonalpha. Leukemia Res. 2010; 34:e21-24.

519

Office ofInternational Academic Affairs
HeadYasuyuki Seto

Assistant Professor
Joseph Green
Toshiyuki Maruyama
Christopher Holmes

Homepage

http://koryu.m.u-tokyo.ac.jp/homepage10.html

Status and functions
The Office of International Academic Affairs isunder the direct authority of the Dean of the Facultyof Medicine. Its three most important roles, as definedby the Committee on International Academic Affairs,
are i) international educational exchange, ii)
international contacts in research and scientific fields,
and iii) international cooperation in health care andmedicine.

Activities
This document reports on the office's activities inthese areas over the academic year 2010 (April
through March).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2010, there were 153 foreign students (39countries) officially registered in the Graduate Schoolof Medicine. Many inquiries were received during thisperiod from prospective applicants for foreign student
and trainee status: responses were sent to 76 suchinquiries.
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 thisoffice 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 80 people attended in 2010, 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 2010
Contest foreign students gave oral presentations basedon their research papers to interested fellow students
and faculty, and the five best speakers were given
awards.
A formal agreement for academic exchange
between the University of Pennsylvania and the520

University of Tokyo was renewed in May 2004. Since
that time, ten University of Tokyo students have taken
research electives at the University of Pennsylvania
every year, and two students from the University ofPennsylvania 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 Johns Hopkins University inDecember 2002. Since the start of the program in
2002, sixteen University of Tokyo students visited toattend clinical electives at Johns Hopkins University,and four students 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, seven University of Tokyo students
have attended clinical electives at the University ofMichigan Medical School, and three 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,
six University of Tokyo students visited to attend
research electives at Munich University, and three
students from Munich University have taken clinicalelectives 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, six University of Tokyo students
have attended clinical electives at the University ofWashington Medical School, and one student from the
University of Washington Medical School has 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 Taipei Medical University inNovember 2005. Since the start of the program in
2005, two University of Tokyo students visited toattend clinical electives at Taipei Medical University
and six 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 toattend research electives at Mahidol University, andseven 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 35 requests from students forcounseling regarding pre-graduation or postgraduation studies abroad are received by the Officeof International Academic Affairs. The office responds
to these requests by providing information, advice,and letters of recommendation.
2. 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 theirresearch groups.
The details of the plans for the young researchers at
the partner institution in USA are as follows.
(1) They should carry out highly advanced medical
research.
(2) They should observe and experience participatory,
student-centered forms of education (tutorials,etc.) used with medical students.
(3) They should observe and experience themanagement of research laboratories, particularly
with regard to the importance of the activities ofgraduate students and postdoctoral fellows.
(4) They should observe how teaching assistants
contribute in education and research, and how
teaching assistants are trained to become leadersand mentors.
In 2008, six young researchers from the Graduate
School of Medicine at the University of Tokyo began
studying at the partner institutions in the USA.

521

3. Education and research
3.1 Education
In 2009, Dr. Green taught a course open to allstudents 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 2009, 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. Suzukamo Y, Fukuhara S, Green J, Kosinski M,
Gandek B, Ware JE.
Validation testing of a three-component model of
Short Form-36 scores.
J Clin Epidemiol. 2011 Mar;64(3):301-8.

522Museum of Health and Medicine
Director
Kazuhiko Ohe

Specially-appointed technical expert
Atsushi Kitade

Homepage

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

History and overview
The origins of the School of Medicine and the
University of Tokyo Hospital can be traced back to theestablishment of the Kanda Otamaga-Ike Vaccination
Center in 1858. In 2008, it celebrated its 150th
anniversary. The Museum of Health and Medicine wasplanned as part of commemorative projects tocelebrate the 150th anniversary of the founding of the
School and the Hospital, and was opened on January
20, 2011.
One of the themes for the commemorative projects
marking the 150th anniversary was the “developmentof communication between health science and careand society,” and the Museum of Health and Medicine
forms one of the pillars of this.
In establishing the Museum of Health andMedicine, we renovated the School of Medicine’s
Central Building (Medical Library), which hadoriginally been instituted as part of thecommemorative projects celebrating the 100th
anniversary of the founding of the School and the
Hospital. The Museum has about 400m2 areas,
including about 70m2 of a permanent gallery and230m2 of special exhibition rooms.
The aims of the Museum are to: (1) provide healthand medical information to the public, (2) educate
medical students and students, (3) research the historyof medicine and health care through archives,
instruments and technology, and (4) preserve andinvestigate valuable medical archives and instruments,
etc.
In addition to the permanent gallery exhibiting

accomplishments related to the School and the
Hospital and its contributions made to modern andcontemporary development in Japan, a feature of theexhibitions is that a large space has also been set aside
for special exhibitions to promote understanding
among the public regarding the latest advances inmedicine and health care. Planning and supervision of
the permanent exhibition and special exhibition isdone with the cooperation of the various research
units within the School and the Hospital, otherdepartments within the University, industry, andmuseums. Special exhibitions will be changed several
times a year.
The first permanent exhibition since the openingof the Museum was a display of medical texts andinstruments from the early Meiji era, an Ishihara’s
Color Blind Test Chart and a gastroscope developed at
the University. The first special exhibition is related tothe beginnings of the School and the Hospital, Entitled“the Challenge to Infectious Diseases”. It introduced
the history of vaccinations against smallpox, research
into infectious diseases conducted in the University
and its graduates since the Meiji era (1868-1912), andthe latest information about infectious diseases.
Furthermore, the exhibition explained current efforts
in oral vaccine, virotherapy and the diagnosis andtreatment of neglected tropical diseases.
Since the opening of the Museum, more than
8,000 people had visited the first special exhibition up
until June 30, 2011. The Museum will continue to planand organize according to the aforementioned
purposes of the Museum.

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Overview of operations
The opening hours are 10:00-17:00. The Museum
is closed every Monday and during the New Yearholidays (however, it will open if Monday is a public
holiday). Admission is free.

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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

Tokyo Hospital is also our fundamental role.

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. In 2010 IRCME cerebrated the10th anniversary.
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 ofInternational Cooperative Study in Medical
Education
The University of Tokyo, especially the Faculty of
Medicine, takes pride in its academic excellenceinternationally.
Compared with other Western
distinguished universities, however, activities andresearch in medical education have been weak for along time.
To fulfill the mission, faculty and staff in IRCME
conduct research on a wide range of topics inundergraduate, postgraduate and continuing medical
education. One of our objectives is to establish acenter for medical education research in Asian PacificArea to collaborate with variety of medical education
researchers.
IRCME also makes important contributions toundergraduate and postgraduate medical curricula of
the Faculty of Medicine, the University of Tokyo
directly. As medical education experts, we are giving
appropriate information to all the faculty members
about teaching and learning in medicine.

525Planning & Cooperation for International
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.

2.

3.

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. Counterpart of the
project has been Ministry of Higher Education
and Kabul Medical University. In April 2009
Onishi visited Afghanistan to hold the National
Conference for Medical Education in Kabul. In
July and November 2009 IRCME accepted 27
faculty members from 7 medical schools in
Afghanistan to provide medical education
training.
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).
Kitamura, Nishigori and Onishi visited thehospital to provide trainings and advices to help
them establish the national standard of clinicaleducation.
IRCME established Collaborating ResearchCenter for Medical Education, University ofTokyo in University of Health Sciences, Lao
PDR to promote research in medical education.

Visiting Professors
IRCME invites specialists from abroad withexpertise in medical education and international
cooperation to be visiting professors. They advise andinstruct IRCME on planning and on educational
activities, and collaborate with IRCME faculty andstaff on educational research.
Through IRCME-sponsored lectures and seminars,
they also provide intellectual stimulation to medical
students, interns, and residents, and introduce new
information on medical education and international
cooperation to a wider audience.
In 2010, we welcomed two visiting professors:- Dr. Graham McMahon (21 Sep – 16 Dec, 2010),
Assistant Professor of Medicine, Harvard
University, USA- Dr. Gominda Ponnamperuma (7 Feb – 18 March,2011), Senior Lecturer, Department of Medical
Education, Colombo University, Sri Lanka.
They offered several seminars, lectures forinternational trainees, and many suggestions to
IRCME.