ISSN 1883-9606

2010

Vol.121

ANNUAL REPORT OF
THE GRADUATE SCHOOL OF MEDICINEAND
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2009 ---- March 2010

ANNUAL REPORT OF THE GRADUATE SCHOOL OF
MEDICINE
THE FACULTY OF MEDICINETHE UNIVERSITY OF TOKYOREPORTS FOR THE PERIOD April 2009-March 2010

Introduction
This is volume 121 (the edition of year 2009) 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, and insome 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 meeting theneeds 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, 2010

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COTETS
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 ·········································································

8

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

9

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

12

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

16

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

19

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

20

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

23

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

26

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

29

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

30

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

33

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

38

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

39

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

44

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

48

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

49

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

51

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

53

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

54

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

58

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

59

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

65

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

66

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

69

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

72

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

73

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

77

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

82

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

84

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

85

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

87

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

88

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

94

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

100

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

104

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

105

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

107

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

111

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

112

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

115

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

118

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

119

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

124

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

128

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

136

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

137

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

142

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

148

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

152

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

155

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

158

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

161

Department of Clinical Laboratory Medicine (See Department of Clinical Laboratory [P.410] )Department of Transfusion Medicine ·········································································

162

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

165

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

166

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

168

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

174

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

176

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

177

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

182

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

185

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

186

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

190

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

191

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

194

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

197

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

202

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

206

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

210

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

213

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

215

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

217

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

218

iv

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

222

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 ·······································································

245

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

247

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

248

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

251

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

254

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

255

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

258

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

261

Department of Social Gerontology (See Department of Social Gerontology [P.326] )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

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

306

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

310

v

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

313

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

316

Department of Biostatistics (See Department of Biostatistics / Epidemiology and Preventive Health Sciences [P.261] )Department of Social and Preventive Epidemiology ························································

317

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

320

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

322

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

325

Department of Mental Health(See Department of Mental Health [P.258] )Department of Health Sociology and Health Education(See Department of Health Sociology / Health Sociology and Health Education [P.255] )Department of Social Gerontology ············································································

326

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 ·························································································

329

Department of Health Policy (See Department of Public Health / Department of Health Policy [P.105] )Department of Healthcare Informatics (See Department of Medical Informatics and Economics [P.115] )Department of Clinical Information Engineering ····························································

330

Department of Forensic Medicine and Medical Law (See Department of Forensic Medicine [P.112] )Endowed Department ···································································································

332

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

333

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

336

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.137] )Department of Metabolome ····················································································

339

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

343

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

346

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

349

vi

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

351

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

354

Department of Molecular Neuroscience on Neurodegeneration(See Department of Neurology [P.94] )Department of Chronic Kidney Disease (CKD) ·····························································

356

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

358

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

360

Department of Molecular Vascular Endocrinology(See Department of Nephrology and Endocrinology [P.137] )Department of Medical Genomics ·············································································

361

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

364

Department of Clinical and Molecular Epidemiology(Mitsubishi Tanabe Pharma Corporation)(See Department of Nephrology and Endocrinology [P.137] )Department of Immunotherapeutics (Medinet) ······························································

365

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

369

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

371

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

373

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

376

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

379

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

381

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

384

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

386

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

388

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

389

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

391

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

394

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

396

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

399

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

402

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

404

Pharmacology and Pharmacokinetics(See Department of Pharmacy [P.484] )Department of Therapeutic Strategy for Heart Failure ······················································

406

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University Hospital
Clinical Divisions ······································································································································ 408
Cardiovascular Medicine (See Department of Cardiovascular Medicine [P.119] )Respiratory Medicine (See Department of Respiratory Medicine [P.124] )Gastroenterology (See Department of Gastroenterology [P.128] )Nephrology and Endocrinology(See Department of Nephrology and Endocrinology [P.137] )Diabetes and Metabolic Diseases (See Department of Metabolic Diseases [P.142] )Hematology and Oncology (See Department of Hematology and Oncology [P.148] )Allergy and Rheumatology (See Department of Allergy and Rheumatology [P.152] )Infectious Diseases (See Department of Infectious Diseases [P.155] )Neurology (See Department of Neurology [P.94] )Geriatric Medicine(See Department of Geriatric Medicine, Department of Aging Research [P.186] )Psychosomatic Medicine(See Department of Stress Science and Psychosomatic Medicine [P.158] )Stomach and Esophageal Surgery (See Department of Gastrointestinal Surgery [P.197] )Colon and Rectal Surgery (See Department of Surgical Oncology [P.210] )Hepatobiliary Pancreatic Surgery(See Department of Hepatobiliary Pancreatic Surgery [P.202] )Vascular Surgery (See Department of Vascular Surgery [P.213] )Breast and Endocrine Surgery(See Department of Metabolic Care and Endocrine Surgery [P.215] )Artificial Organ and Transplantation Surgery(See Department of Artificial Organ and Transplantation Surgery [P.202] )Cardiovascular Surgery (See Department of Cardiothoracic Surgery [P.194] )Thoracic Surgery (See Department of Thoracic Surgery [P.191] )Neurosurgery (See Department of Neurosurgery [P.100] )Anesthesiology and Pain Relief Center (See Department of Anesthesiology [P.248] )Urology and Andrology (See Department of Urology [P.206] )Gynecologic Surgery (See Obstetrics and Gynecology [P.165] )Dermatology and Photolaser Medicine (See Department of Dermatology [P.218] )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.245] )viii

Plastic, Reconstructive and Aesthetic Surgery(See Department of Plastic and Reconstructive Surgery [P.222] )Oral-Maxillofacial Surgery Dentistry and Orhtodontics(See Department of Oral-Maxillofacial Surgery [P.225] )Pediatrics(See Department of Pediatrics, Department of Developmental Pediatrics [P.177] )Pediatrics Surgery (See Department of Pediatrics Surgery [P.182] )Obstetrics and Gynecology(See Department of Reproductive Endocrinology / Department of Gynecologic Oncology / Departmentof Perinatal Medicine [P.166, 168, 174] )Neuropsychiatry (See Department of Neuropsychiatry [P.88] )Radiology (See Department of Radiology [P.59] )Central Clinical Facilities ···························································································

409

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

410

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

413

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

418

Department of Emergency Services(See Department of Emergency and Critical Care Medicine [P.251] )Department of Transfusion Medicine and Immunohematology(See Department of Transfusion Medicine [P.162] )Delivery Unit ·····································································································

421

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

422

Department of Intensive Care Unit
(See Department of Emergency and Critical Care Medicine [P.251] )Division of Diagnostic Pathology ··············································································

424

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

426

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

429

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

432

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

435

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

438

Department of Infection Control and Prevention(See Department of Infection Control and Prevention [P.51] )Department of Planning, Information, and Management(See Department of Medical Informatics and Economics [P.115] )University Hospital Medical Information Network (UMIN) Center ······································

441

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

444

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

446

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

451

ix

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

457

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

460

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

464

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

468

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

471

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

482

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

483

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

484

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

488

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

489

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

493

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

495

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

497

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

501

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

504

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

507

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

510

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

513

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010x

History1858

May.

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

Nov.

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

1859

Sep.

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

1860

Oct.

TheShutojyo became an official medical institution of the Shogunate Government.

1861

Oct.

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

1863

Feb.

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

1868

Jul.

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

1869
1871

Feb.

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

Dec.

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

Jul.

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

1872

Aug.

SchoolSystemwasestablished,renaming

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

May.

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

1876

Nov.

Tokyo-Igakko was moved to Hongo.

1877

Apr.

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

1886

Mar.

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

1897

Jun.

The Imperial University was renamed as Tokyo Imperial University.

1917

Aug.

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

1919

Apr.

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

1931

Feb.

The first building of the Faculty of Medicine was constructed.

1936

Jan.

Brain research office donated by Mr. Horikoshi Hisasaburo.

Nov.

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

1947

Oct.

Tokyo Imperial University renamed as The University of Tokyo.

1950

Apr.

Institute of Nursing renamed as University Nursing School.

1953

Apr.

School of Health Care and Nursing founded.

Jul.

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

1956

Apr.

Midwives School established.

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

1958
1961
1965

Apr.

Division of Pharmaceutical Sciences became independent Faculty.

May.

Celebrated centennial of The University of Tokyo Faculty of Medicine.

Mar.

Medical Library was built in memorial of the centenary.

Apr.

Institute of Medical Electronics established.

Apr.

Research Institute of Logopedics and Poniatrics was established.

xi

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

Sep.

The third building of Faculty of Medicine was constructed.

1971

Apr.

Laboratory for Animal Experiments was established.

1973

Mar.

Animal Center for Biomedical Research was constructed.

1983

Jan.

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

1985

Sep.

Medical and International Academic Affairs established.

1987

Apr.

Graduate School specialized course was changed to major.

1992

Apr.

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

1995

Jul.

Radiation Research Institute was established.

Apr.

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

1996

Apr.

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

1997

Apr.

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

1999

Apr.

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

2000

Apr.

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

2001

Apr.

University Branch Hospital was united to University Hospital.

2003

Apr.

The Center for Disease Biology and Integrative Medicine was established.

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

xii

2004

Apr.

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

2007

Apr.

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

2008

May.

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

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

xiii

Organization Chart
Cell Biology
Cell Biology and Anatomy

Structural Biology
Structural Cell Biology

Molecular Cell Biology

Cellular Neurobiology
Molecular Biology
Biochemistry and Molecular Biology

Cellular Signaling
Physiological Chemistry andMetabolism
Integrative Physiology

Physiology
Functional Biology

Cellular and Molecular Physiology
Neurophysiology

Pharmacology

Cellular and Molecular Pharmacology
Molecular Neurobiology
Human Pathology and Diagnostic Pathology

Pathology

Molecular Pathology
Surgical Pathology

Pathology, Immunology
and Microbiology

Microbiology

Microbiology
Infection Control and Prevention

Immunology

Molecular Immunology
Clinical Immunology
Diagnoatic Radiology

Radiology

Radiotherapy
Nuclear Medicine

Radiology and Biomedical
Engineering

System Physiology
Biomedical Engineering

Bioimaging and Biomagnetics
Biosystem Construction and Control
Neuropathology

Basic Neuroscience

Neurochemistry
Neurobiology
Speech Science

Neuroscience

Speech and Cognitive Neurosciences

Cognitive Neuroscience
Speech Physiology

Graduate School of
Medicine

Neuropsychiatry
Clinical Neuroscience

Neurology
Neurosurgery
Molecular Preventive Medicine

Occupational, Environmental andPreventive Medicine

Public HealthRadiological HealthSocial Medicine

Forensic Medicine, and Medical
Informatics and Economics

Forensic Medicine
Medical Informatics and Economics

xiv

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

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

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

xv

Health Sociology
Mental Health
Epidemiology and Preventive Health
Sciences
Health Sciences

Social Gerontology
Health Promotion Sciences
Biostatistics
Biomedical Ethics

Health Sciences andNursing

Advanced Clinical Nursing
Preventive and Administrative
NursingNursing Administration
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 HealthInternational Biomedical
Sciences

Human Genetics
Developmental Medical Sciences
Human Ecology
Biomedical Chemistry
Biostatistics

Epidemiology and Health Sciences

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

School of Public HealthBehavioral Health Sciences

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

Health Services Sciences

Healthcare Informatics
Clinical Information Engineering
Forensic Medicine and Medical Law

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

Laboratory of Clinical Biotechnology
Laboratory of Environmental Health Sciences
Laboratory of Animal Resources
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. 121, October 2010
Office of International Academic Affairs
Institution

Medical Library
Medical Scientist Training Program
Pharmacoepidemiology
Integrated Traditional Medicine (Tsumura)
Vascular Regeneration (Daiichi Sankyo Co.,Ltd.)
Bone & Cartilage Regenerative Medicine
Cartilarge &Bone Regeneration(Fujisoft)
Clinical Renal Regeneration
Metabolome
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
Ischemic Circulatory Physiology
Translational Research for Healthcare and Clinical Science
Joint Disease Research

Endowed Department

Health Management and Policy
Computational Diagnostic Radiology and Preventive Medicine
Hospital Environment
Clinical Motor System Medicine
Medical Safety Management(Tokio Marine & Nichido)
Molecular Cardiovascular Metabolism (Daiichi-Sankyo Company, Limited)
Healthcare Quality Assessment
Anti-Aging Medicine
Integrated Imaging Informatics
Nutriproteomics
Clinical Epidemiology and Systems
Clinical Trial Data Management
Pharmacology and Pharmacokinetics
Ubiquitous Preventive Medicine
Science for Joint Reconstruction
Molecular Research for Vascular Deseases
Advanced Skin Care(Miss Paris)
Therapeutic Strategy for Heart Failure
Molecular Physiology on Energy Metabolism
Molecular Neuroscience on Neurodegeneration
Chronic Kidney Disease

Social Cooperation Program

General Affairs Office

Molecular Structure and Dynamics(JEOL/Zeiss)

Personnel Office

Molecular Vascular Endocrinology

Research Liaison

Medical Genomics

Educational Affairs

Molecular Psychiatry

Graduate Student Affairs

Ubiquitous Health Informatics

Buget Office

Administrative office

Purchasing Office

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

Faculty of Medicine
Graduate School of
Medicine

xvii

Finance Office
Administrative Division

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

Administrative Office

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

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

Faculty of
Medicine

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

Mental Health and Nursing
Health Sociology
Health Administration
Epidemiology and Biostatistics
Human Ecology
Biochemistry and Nutrition
Maternal and Child HealthxviiiThe Tokyo Journal of Medical Sciences. Vol. 121, October 2010

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

Administrative Department
Management Department
Management Strategy Department
Medical Affairs Department

Radiological Center
Central Clinical Facilities

Emergency Services
Transfusion Medicine
Maternal,Fetal and Neonatal Medicine
Rehabilitation Service
Medial Engineering

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

xix

Central Supply Service
Intensive Care Unit
Pathology
Corneal Transplantation Section
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
Department of Planning Information and Management
University Hospital Medical Information Network Center
Organ Transplantation Service
Department of Nutrition
Office of Labor Safety and Health Management
Department of Child Psychiatry
Tissue Bank
Center for Preventive Medicine
Cancer Patient Support Center
The Center for Liaison and Public Relations
Database Center of the National University Hospitals
Department of Outpatient Chemotherapy
Neonatal and Pediatric Intensive Care Unit
Department of Health Record Management
Division of Tissue Engineering
Department of Clinical and Genetic Informatics
Departments under the bylaws

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

Organization of 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

Translational Research Center

Outpatient Services
Administration
Central Clinical Services
Administration

22nd Century Medical and Research Center

Medical Specialists
Training Center

Pediatric Medical Center

Vascular Board

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010ix

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

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010x

Department of Speech and Cognitive Sciences
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 honma

professor

Hirokazu Nagawa

professor

Shinichi Sato

professor

Isao Koshima

professor

Tsuyoshi Takato

Professor

Kozo Nakamura

professor

Makoto Araie

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

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

Department of Vital Care Medicine

xi

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

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

xii

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

professor

Toru Miyazaki

Laboratory of Structural Physiology

professor

Haruo Kasai

Laboratory of Regenerative Medical Engineering

professor

Takashi Ushida

Laboratory of Clinical Biotechnology

professor

Kazunori Kataoka

Laboratory of Environmental Health Sciences

professor

Chiharu Tohyama

Laboratory of Animal Resources

professor

Atsu Aiba

Laboratory of Molecular Radiology

professor

Kiyoshi Miyakawa

professor

Kazuhiko Yamamoto

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

Naoshi Ogat

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
International Academic Affairs
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

Division of Total Renal Care Medicine

Associate professor

Akira Ishikawa

Integrated Molecular Science on Metabolic Diseases

Associate professor

Toshimasa Yamauchi

Department of Advanced Clinical Science and Therapeutics

Associate professor

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

Hospital Environment

Associate professor

Yushi Uetera

Clinical Motor System Medicine

Associate professor

Toru Akune

Medical Safety Management (Tokio Marine & Nichido)

Professor

Yasushi Kodama

Molecular Cardiovascular Metabolism

Associate professor

Katsuyuki AndoThe Department of Healthcare Quality Assessment

Associate professor

Hiroaki Miyata

Anti-Aging Medicine

professor

Satoshi Inoue

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

xiii

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

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 Vascular Endocrinology

Associate professor

Masashi Isshiki

Department of Medical Genomics

professor

Hiroyuki Mano

Associate professor

Young Lim Choi

Director

Kazuhiko Yamamoto

professor

Kiyoshi Kitamura

General Medicine

Head

Syoji Tsuji

Cardiovascular Medicine

Head

Ryozo Nagai

Respiratory Medicine

Head

Takahide Nagase

Gastroenterology

Head

Kazuhiko Koike

Nephrology and Endocrinology

HeadToshiro Fujita

Metabolic Diseases

Head

Takashi Kadowaki

Hematology and Oncology

Head

Mineo Kurokawa

Allergy and Rheumatology

Head

Kazuhiko Yamamoto

Infectious Diseases

Head

Kazuhiko Koike

Neurology

Head

Shoji Tsuji

Department of Molecular Structure and Dynamics (JEOL/Zeiss)

Department of Molecular Psychiatry

International Research Center for Medical Education
University Hospital
Clinical Divisions

xiv

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

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

HeadShinichi Takamoto

Thoracic Surgery

Head

Jun Nakajima

Neurosurgery

Head

Nobuhito Saito

Anesthesiology and Pain Relief Center

Head

Yoshitsugu Yamada

Urology and Andrology

Head

Yukio Honma

Gynecologic Surgery

Head

Tetsu Yano

Dermatology and Photolaser Medicine

Head

Kunihiko Tamaki

Ophthalmology and Vision Collection

Head

Makoto Araie

Orthopaedic Surgery and Spinal Surgery

Head

Kouzo Nakamura

Otorhinolaryngology and Auditory and Voice Surgery

Head

Tatuya Yamasoba

Rehabilitation Medicine

Head

Nobuhiko Haga

Plastic, Reconstructive and Aesthetic Surgery

Head

Isao Koshima

Oral-Maxillofacial Surgery Dentistry and Orthodontics

Head

Tsuyoshi Takato

Pediatrics

Head

Takashi Igarashi

Pediatric Surgery

Head

Tadashi Iwanaka

Obstetrics and Gynecology

Head

Shiro Kozuma

Neuropsychiatry

Head

Kiyoto Kasai

Radiology

Head

Kuni Ohtomo

Department of Clinical Laboratory

Head

Yutaka Yatomi

Surgical Center

Head

Hiroshi YasuharaRadiological Center

Head

Kuni Ohtomo

Emergency Services

Head

Naoki Yahagi

Transfusion Medicine and Immunohematology

HeadKoki Takahashi

Department of Maternal, Fetal, and Neonatal Medicine

Head

Shiro Kozumai

Rehabilitation Service

Head

Nobuhiko Haga

Department of Medical Engineering

Head

Hisayoshi Tamai

Central Supply Service

Head

Yoshikazu Mimura

Intensive Care Unit

Head

Naoki Yahagi

Intensive Pathology

Head

Masashi Fukayama

Central Clinical Facilites

The Tokyo Journal of Medical Sciences. Vol. 121, October 2010

xv

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

Department of Medical Social Service and Welfare

Head

Yasuyoshi Ouchi

Clinical Research Center(tentative name)Head

Takashi Kadowaki

Infection Control and Prevention

Head

Kyoji Moriya

Department of Planning, Information and Management

Head

Kazuhiko Ohe

University Hospital Medical Information Network Center

Head

Takahiro Kiuchi

Department of Organ Transplantation Service

Head

Norihiro Kokudo

Department of Child Psychiatry

Head

Takashi Igarashi

Tissue Bank

Head

Shinichi Takamoto

Center for Epidemiology and Preventive Medicine

Head

Tsutomu Yamazaki

Cancer Resource Center

Head

Shoichi Kaisaki

Center for Liaison and Public Relations

Head

Kazuhiko Ohe

The Database Center of the National University Hospitals

Head

Hiroshi Kushiyama

Division of Tissue Engineering

Head

Tsuyoshi Takato

Department of Clinical and Genetic Informatics

Head

Ryozo Nagai

Department of Palliative Medicine

Head

Keiichi Nakagawa

Department of Clinical Genomics

Head

Shoji Tsuji

Cooperative Unit of Medicine and Engineering Research

Head

Tetsuro Miyata

Translational Research Center

Head

Ryozo Nagai

22nd Century Medical and Research Center

Head

Kozo Nalamura

Pharmaceutical Department

Head

Hiroshi Suzuki

The University of Tokyo,
Graduate School of Medicine

Molecular Cell Biology
1. Cell Biology and Anatomy

2

Department of Cell Biology andAnatomyAssociate Professor
Yoshimitsu Kanai, M. D., Yosuke Takei, M. D.,

Lecturer
Yasuko Noda, 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 biologicalapproaches including new electron microscopy suchas the quick freeze deep etch electron microscopy,
cryoelectron microscopy at atomic resolution, andcryoultramicrotomy,
biochemistry,
immunocytochemistry, molecular biology, molecular genetics suchas gene targeting and transgenic mouse approaches,molecular biophysics and structure biology including
X ray crystallography and cryoelectron microscopy.
In this way we can study structure, dynamics andfunctions of cytoskeleton from gene to cell, tissue andwhole body.
Nerve cells as units of complicated neuronal
networks in the brain develop very polarizedmorphology composed of dendrites, cell body and along axon along the direction of impulse propagation.
The neuronal cytoskeleton plays three major
important roles.
1) It provides dynamic frameworks for neurite
extension and maintenance.
2) It provides structural bases for organelle transports
in the cells. Namely it works as rails and motor
molecules to transport materials from cell center toperiphery and from periphery to cell center.
3) It very importantly regulates release processes oftransmitters and also contributes to anchor receptors at

3

the postsynaptic sites.
Our laboratory studies molecular architecture,dynamics and function of the cytoskeleton focusing onthese three major roles.
To study these molecular mechanisms we use newmolecular cell biological approaches including
electron microscopy of molecular resolution,
biochemistry, biophysics, molecular biology andmolecular genetics and X-ray crystallography.

References(1) Hirokawa, N., Y. Okada and Y. Tanaka. Fluid
dynamic mechanism responsible for breaking theleft-right symmetry of the human body: The nodal
flow. Annual Review of Fluid Mechanics. 41:
53-72, 2009.
(2) Hirokawa, N., Y. Noda, Y. Tanaka, and S. Niwa.
Kinesin superfamily motor proteins andintracellular transport. Nature Reviews Molecular
Cell Biology. 10: 682-696, 2009.
(3) Hirokawa, N., Y. Tanaka and Y. Okada.
Left-Rightdetermination:
Involvementofmolecular motor KIF3, cilia, and nodal flow.
Cold Spring Harber Perspectives in Biology. July
2009; 1:a000802.
(4) Zhou R., S. Niwa, N. Homma, Y. Takei, and
N. Hirokawa. KIF26A is an unconventional
kinesin and regulates GDNF-Ret signaling inenteric neuronal development. Cell 139: 802-813,
2009.
(5) Hirokawa, N., R. Nitta and Y. Okada. The
mechanisms of kinesin motor motility: lessons
from the monomeric motor KIF1A.
Nature
Reviews Molecular Cell Biology 10: 877-884,
2009.
(6) Okada, Y. and N. Hirokawa. Observation of
Nodal Cilia Movement and Measurement of Nodal
Flow. Methods in Cell Biology ed. by S. M. Kingand G. J. Pazour, Academic Press. Elsevier Inc.
91: 265-285, 2009.
(7) Terada, S., M. Kinjo, M. Aihara, Y. Takei and
N. Hirokawa.
Kinesin-1/Hsc70-dependent
mechanism of slow axonal transport and its relation
to fast axonal transport. EMBO J 29: 843-854,
2010

4

Department of 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), Takashi Yamano (post-doc),
Toshiharu Sano (student), and Yuka Kimura(secretary).

Teaching activities
Our lab, together with Hirokawa and Okabe’s lab, is incharge 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.

“propeller” and “antenna” of cells, whose diameter isabout 250 nm. From the recent studies, it is becoming
clear that flagella/cilia is involved in various
important cell 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
Our lab focuses on the structure and function of
eukaryotic flagella/cilia. Flagella/cilia is bothModel Organism
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(1) Bodey AJ, Kikkawa M, Moores CA.
9-Angström structure of a microtubule-boundmitotic motor. J Mol Biol. 388:218-24, 2009

6

Department of Cellulareurobiology
Professor
Shigeo Okabe, M.D., Ph.D.

Lecturer
Satoru Kondo, Ph.D.

Research Associate
Shinji Tanaka, Ph.D.

Homepage

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

Introduction and Organization

Research activities

The Department of Cellular Neurobiolgy was initiallyestablished as Neuroanatomy department of former
Brain Institute of Medical School of Imperial
University of Tokyo in 1936. Since the structural
reconstruction of School of Medicine in 1997 thisdepartment became one of the departments of Cell
Biology and Anatomy of Graduate School of Medicine.
This department is currently organized by Professor
Shigeo Okabe since September in 2007. The
department is constituted of other 20 members.

Brain functions, which are dependent on mutualcommunication of a tremendous number of neuronalcells, regulate the behavior of animals and humans.
The main structure specifically differentiated for
information exchange between neurons is called"synapse". Long-term maintenance of synaptic
properties underlies stability and reproducibility of
behavior in responses to external stimuli. In turn,
alterations of synaptic properties are thought to be thebasis of behavioral change in the course of animal
development and also after learning. Therefore,
synapses should be stabilized for a long term to realize
fidelity of various animal behaviors, but also shouldbe altered rapidly when animals adapt to a newenvironment. Molecular basis of this dichotomy,
which is unique to synapses, is the main interest of ourlaboratory.
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

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

7

techniques.

References
1. Tanaka, S., Kunii, M., Harada, A., Okabe, S.
Generation of cortactin floxed mice and cellular
analysis of motility in fibroblasts. Genesis, 47, 638-646,
2009
2. Yamagata, Y., Kobayashi, S., Umeda, T., Inoue, A.,
Sakagami, H., Fukaya, M., Watanabe, M.,
Hatanaka, N., Totsuka, M., Yagi, T., Obata, K.,
Imoto, K., Yanagawa, Y., Manabe, T. and S.
Okabe
Kinase-dead knock-in mouse reveals an essentialroleof
kinaseactivityof2+
Ca /calmodulin-dependent protein kinase II alphain dendritic spine enlargement, LTP and learning
Journal of Neuroscience 29, 7607-7618, 2009
3. Numano F, Inoue A, Enomoto M, Shinomiya K,
Okawa A, Okabe S. Critical involvement of Rho
GTPase activity in the efficient transplantation ofneural stem cells into the injured spinal cord. Mol
Brain. 2:37. 2009

Molecular Cell Biology
2. Biochemistry and Molecular Biology

9Department 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

10

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

Research Activities
Our current study focuses on the understanding of themolecular mechanism enabling the anchorageindependent S phase onset, which is the universal
property of cancer cells. All the members of ourlaboratory are participating in this study.
1. Identification of the pathways mediating
signals for cellular anchorage to extra-cellularmatrices
A key to understand the molecular basis formalignant transformation is elucidation of signal
pathways that mediate anchorage signals andcontrol expression and activity of cell cycle startfactors including Cdc6 and cyclin A. We haverecently identified that the TSC1/2-Rheb-mTOR
pathway appears to mediate an anchorage signal
and controls at least the activity of Cdh1-APC anubiquitin ligase that acts in G1 and degrades both
Cdc6 and cyclin A. Active mTOR is required forinactivation of Rb together with activated cyclin
D-dependent kinases. Inactivation of Rb activates
E2F, resulting in induction of Emi1 as well as
Cdc6 and Cyclin A. Induced Emi1 inactivates
Cdh1-APC, thereby suppressing degradation of
Cdc6 and Cyclin A. This finding strongly suggeststhat the Tsc1/2-Rheb-mTOR cascade serves amajor transduction pathway for the anchorage
signal to control the G1-S transition. How does
mTOR control Cdk4/Cdk6 activities? Unlike
generally believed scenarios, mTOR seems tocontrol these activities via unknown mechanisms
other than control of the binding of D-type cyclins
or p27 to these kinases.
2. Identification of the factor that connects ananchorage signal to the Tsc1/2-Rheb-mTOR
cascadeGiven the above findings, the next question iswhat molecule mediates the anchorage signal to
the Tsc1/2-Rheb-mTOR pathway? We haveidentified Rho-associated kinases as a strong
candidate for the molecule that connects theanchorage signal to Tec2, as suggested as follows.
1) Treatment of cells with a Rho-associated kinase
inhibitor induces destabilization of Cdc6 andcyclin A, just like by anchorage deprivation. 2)
Overexpression of an active Rock1 suppresses all
the anchorage loss effects on the G1 cell cycle
factors. 3) Tsc2 contain a Rock target consensus
site that is phosphorylated in a Rock-dependent
manner in vivo.
3. ew function of Cdc6
Cdc6 is known as the assembler of pre-replicativecomplexes that is the initial step of chromosomal
replication. We found that this factor has anadditional function: the ability to activate
p21WAF1-inhibited Cdk2 in an ATP-dependent
manner, the function never anticipated for Cdc6
and never anticipated for the regulation of acyclin-dependent kinase. This unbelievablefunction of Cdc6 is confirmed by the essentialityof the “Cy” motif and the ATPase domain for this
newly identified activity. Furthermore, we showthat Cdc6 determines utilization of the
p53-p21-dependent DNA damage checkpoint atleast in S phase cells. Whenever Cdc6 is notdestabilized, inactivation of Cdk2 by p21 isblocked in S phase. This discovery highlights theimportance of Cdc6 as a focal point of the control
of S phase onset and progression.
Our current studies indicate that Cdc6 might11

have two additional functions promoting S phase
onset and progression. Meanwhile we have foundthat Cdc6 targets neither Cdk4/6 nor Cdk1.
4. Inductionofanchorage-independent
proliferation of RK cells by manipulation offour cell cycle and related factors
One approach to understand the mechanism of
oncogenetic transformation is to find a way to
induce anchorage-independent proliferation ofcells by manipulating cell cycle factors. This
could be done with NRK cells and overexpressionof three factors: Cdc6, Cdk6 and cyclin D3, thelatter two of which can evade inhibition by
inhibitor proteins and activate E2F under growth
suppressive conditions like in anchorageloss-induced G1 arrest. Last year we succeeded in
inducing anchorage-independent proliferation ofmouse embryonic fibroblasts by overexpression of
Cdk6, cyclin D3 and Cdc6. But theanchorage-independent proliferation was transientand lasted only one week. This year we have
found
the
way
to
obtaincontinued
anchorage-independent proliferation of embryonic
fibroblasts. It can be achieved by additional
expression of constitutively active mutant Rheb,
which is a positive regulator of mTOR complex 1.
Studies on the mechanistic basis for this inductionof anchorage-independent proliferation are
currently underway.

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.

12

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 9 graduate students (8 doctor course students and1 master course student), and 5 undergraduate medical
students (Free Quarter). Three postdoc scientists andseveral clinical researchers are also our members. 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 2009 is over20.
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
for lipid mediators. Recently, we have successfully

13

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.

4. Internet Web site
To see our research activities in more detail, pleaserefer to our web site (http://biochem2.umin.jp/
index_j.html). In this homepage, you will also find
our experimental protocol useful for the molecular andcellular biology studies. Dr. Kita and Mr Harayama
are in charge of the homepage.
5. Collaboration with Department of Metabolome
In 2003, Department of Metabolome wasestablished by the donation of Shimadzu Co., Ltd, and
Ono Pharmaceutical Co. Professor Ryo Taguchi and
Associate Professor Yoshiya Oda are worldwide
leading researchers on proteomics and metabolomics.
In collaboration with them, we are searching for novel
lipid mediators that bind to orphan G-protein-coupled
receptors, lacking identified cognate ligands. In thiscollaboration 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,
Nanobio Integration Program of the University ofTokyo, and a global COE program.

Publications
1.

3. Various instrumental analyses.
The Faculty of Medicine has various analytical andpreparative instruments for the common use, which
include mass spectrometers (JEOL HX 110, Hitachi
M-80 and Finnigan MAT TSQ 7000 [ThermoQuest])
equipped with gas chromatographs or HPLC,
PerkinElmer peptide sequencers, FUJI BAS 2000
image analyzer, BD FACScan, and Beckman capillaryelectrophoresis system (P/ACE 2000).
Ms.
Takahashi is in charge of the maintenance of thesemachines and instruction for the beginners. As her
own projects, she is identifying peptide sequences ofvarious proteins by HPLC-MS, and identification ofsmall-molecular weight compounds by GC-MS andHPLC-MS.

2.

3.

Shindou H. and Shimizu T. Acyl-CoA:lysophospholipid acyltransferases. J. Biol. Chem.
2009; 284: 1-5.
Welch, E. J., Naikawadi, R. P., Li, Z., Lin, P.,
Ishii, S., Shimizu, T., Tiruppathi, C., Du, X.,
Subbaiah, P. V., and Ye, R. D. Opposing Effectsof Platelet-activating Factor and Lyso-Plateletactivating Factor on Neutrophil and Platelet
Activation. Mol. Pharmacol. 2009; 75: 227-234.
Mogi, C., Tobo, M., Tomura, H., Murata, N., He,
X.-d., Sato, K., Kimura, T., Ishizuka, T., Sasaki,T., Sato, T., Kihara, Y., Ishii, S., Harada, A., andOkajima, F. Involvement of proton-sensing
TDAG8 in extracellular acidification-induced
inhibitionof
pro-inflammatory
cytokineproduction in peritoneal macrophages. J.
Immunol. 2009; 182: 3243-3251.

14

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

Yasuda, D., Okuno, T., Yokomizo, T., Hori, T.,
Hirota, N., Hashidate, T., Miyano, M., Shimizu,T., and Nakamura, M. Helix 8 of leukotriene B4
type-2 receptor is required for the folding to passthe ER quality control. FASEB J., 2009; 23:1470-1481.
Yuki, K., Shindou, H., Hishikawa, D., andShimizu, T. Characterization of mouse
lysophosphatidic acid acyltransferase 3: An
enzyme with dual functions in the testis. J. Lipid
Res. 2009; 50: 860-869.
Shimizu, T. Lipid mediators in health anddiseases. Ann. Rev. Pharmacol. Toxicol. 2009;49: 123-150.
Shindou, H., Eto, M., Morimoto, R., and Shimizu,
T. Identification of membrane O-acyltransferase
family motifs. Biochem. Biophys. Res. Commun.,2009; 383: 320-325
Shindou, H., Hishikawa, D., Harayama, T., Yuki,
K., and Shimizu, T. Recent progress on AcylCoA:lysophospholipid acyltransferase research. J.
Lipid Res. 2009; 50: S46-S51.
Harayama, T., Shindou, H., and Shimizu, T.
Biosynthesis of phosphatidylcholine by humanlysophosphatidylcholine
acyltransferase
1.
J .Lipid Res. 2009; 50: 1824-1831
Yanagida, K., Masago, K., Nakanishi, H., Kihara,Y., Hamano, F., Tajima, Y., Taguchi, R.,
Shimizu T., and Ishii, S. Identification andcharacterization of a novel lysophosphatidic acidreceptor, p2y5/LPA6. J. Biol. Chem. 2009; 284:
17731-17741
Ishii,S., Noguchi,K., and Yanagida,K. Non-Edg
family lysophosphatidic acid (LPA) receptors.
Prostaglandins Other Lipid Mediat.. 2009; 89:
57-65
Ikeda, K., Oike, Y., Shimizu, T., and 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; 877: 2639-2647
Nakanishi, H., Iida, Y., Shimizu, T., and Taguchi,
R. Separation and quantification of sn-1 and sn-2
fatty
acid
positional
isomersinphosphatidylcholine by RPLC-ESIMS/MS. J.
Biochem. 2009; 147: 245-256

14. Murakami, N., Hashidate, T., Harayama, T.,
Yokomizo, T., Shimizu, T., and Nakamura, M.
Transcriptional regulation of human G2A inmonocytes/macrophages : involvement of c/EBPs,
Runx and Pu.1. Genes Cells, 2009; 14: 14411455
15. Matsumoto, T., Inoue, H., Sato, Y., Kita, Y.,
Nakano, T., Noda, N., Eguchi-Tsuda, M.,
Moriwaki, A., Kan-O, K., Matsumoto, K.,
Shimizu, T., Nagasawa, H., Sakuda, S., andNakanishi, Y. Demethylallosamidin, a chitinase
inhibitor, suppresses airway inflammation andhyperresponsiveness. Biochem. Biophys. Res.
Commun., 2009; 390: 103-108
16. Hikiji, H., Ishii, S., Yokomizo, T., Takato, T.,
and Shimizu, T. A distinctive role of theleukotriene B4 receptor BLT1 in osteoclastic
activity during bone loss. Proc. Natl. Acad. Sci.
U.S.A., 2009; 106: 21294-21299
17. Kihara, Y., Matsushita, T., Kita, Y., Uematsu, S.,
Akira, S., Kira, J.-i., Ishii, S., and Shimizu, T.
Targeted lipidomics reveals mPGES-1-PGE2 as atherapeutic target for multiple sclerosis. Proc.
Natl. Acad. Sci. U.S.A., 2009; 106: 21807-21812
18. Oga, T., Matsuoka, T., Yao, C., Nonomura, K.,
Kitaoka, S., Sakata, D., Kita, Y., Tanizawa, K.,
Taguchi, Y., Chin, K., Mishima ,M., Shimizu, T.,
and Narumiya, S. Prostaglandin F2alpha receptor
signalingfacilitates
bleomycin-induced
pulmonary
fibrosis
independentlyoftransforming growth factor-beta. Nature Med.
2009; 12: 1426-1430
19. 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
20. 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 amurine ischemic hind limb model. Eur. J.
Pharmacol. 2010; 627: 223-228
21. Ogiso, H., Nakamura, K., Yatomi, Y., Shimizu, T.,
and Taguchi, R. Liquid chromatography/mass
spectrometry analysis revealing preferential

15

22.

23.

24.

25.

26.

27.

28.

occurrenceof
non-arachidonate-containing
phosphatidylinositol bisphosphate species innuclei 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
signaling in cytosolic phospholipase 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
producedbydiacylglycerol lipase (alpha) mediates retrograde
suppression of synaptic 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 deficientin 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 Expressionor Activity of Cytosolic Phospholipase A2
Increases Cyclooxygenase-1 Action: A Cross-talkbetween Key Enzymes in Arachidonic Acid
Pathway in Prostate Cancer Cells. Biochim.
Biophys. Acta. , 2010 in press
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 in press
29. Nakamura, M., Yasuda, D., Hirota, N., andShimizu, T. Specific ligands as pharmacologicalchaperons: The transport of misfolded G-protein
coupled receptors to the cell surface. IUBMBLife , 2010; 62: 453-459
30. 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

16

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.

17

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.
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) Mitani A, Nagase T, Fukuchi K, Aburatani H,
Makita R, Kurihara H. Transcriptional
coactivator with PDZ-binding motif is essential
for normal alveolarization in mice. Am. J. Respir.
Crit. Care Med. 2009; 180: 326-338.
(2) Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota
M, Ralston A, Yabuta N, Hirahara S, Stephenson
RO, Ogonuki N, Makita R, Kurihara H,
Morin-Kensicki EM, Nojima H, Rossant J,
Nakao K, Niwa H, Sasaki H. The Hippo

signaling pathway components Lats and Yap
pattern Tead4 activity to distinguish mouse
trophectoderm from inner cell mass. Dev. Cell.
2009; 16: 398-410.
(3) Ogonuki N, Inoue K, Hirose M, Miura I,
Mochida K, Sato T, Mise N, Mekada K, Yoshiki
A, Abe K, Kurihara H, Wakana S, Ogura A. A
high-speed congenic strategy using first-wave
male germ cells. PLoS One. 2009; 4: e4943.
(4) Harada N, Narimatsu N, Kurihara H, Nakagata N,
Okajima K. Stimulation of sensory neurons
improves cognitive function by promoting the
hippocampal production of insulin-like growth
factor-I in mice. Transl. Res. 2009; 154: 90-102.
(5) Narimatsu N, Harada N, Kurihara H, Nakagata N,
Sobue K, Okajima K. Donepezil improvescognitive function in mice by increasing the
production of insulin-like growth factor-I in the
hippocampus. J. Pharmacol. Exp. Ther. 2009;
330: 2-12.
(6) 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 patients with diabetic
angiopathy. Diabetes Res. Clin. Pract. 2010; 87:
57-63.
(7) Tanaka A, Itoh F, Nishiyama K, Takezawa T,
Kurihara H, Itoh S, Kato M. Inhibition ofendothelial cell activation by bHLH protein E2-2
and its impairment of angiogenesis. Blood. 2010;
115: 4138-4147.
(8) Zhao J, Harada N, Kurihara H, Nakagata N,
Okajima K. Cilostazol improves cognitive
function in mice by increasing the production of
insulin-like growth factor-I in the hippocampus.
Neuropharmacology. 2010; 58: 774-783.
(9) Gitton Y, Heude E, Vieux-Rochas M, Benouaiche
L, Fontaine A, Sato T, Kurihara Y, Kurihara H,
Couly G, Levi G. Evolving maps in craniofacial
development. Semin. Cell. Dev. Biol. 2010; 21:301-308.
(10) 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

18

development of the lower jaw. Genesis. 2010; 48:
262-273.
(11) 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. 2010; 107:
11441-11446.
(12) Harada N, Zhao J, Kurihara H, Nakagata N,
Okajima K. Effects of topical application ofalpha-D-glucosylglycerol on dermal levels of
insulin-like growth factor-I in mice and on facialskin elasticity in humans. Biosci. Biotechnol.
Biochem. 2010; 74: 759-765.
(13) Harada N, Zhao J, Kurihara H, Nakagata N,
Okajima K. Stimulation of Fc RI on primarysensory neurons increases insulin-like growth
factor-I
production,
therebyreducing
reperfusion-induced renal injury in mice. J.
Immunol. 2010 (in press).
(14) Zhao J, Harada N, Kurihara H, Nakagata N,
Okajima K. Dietary isoflavone increases
insulin-like growth factor-I production, thereby
promoting hair growth in mice. J. Nutr. Biochem.
2010 (in press).
(15) 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-mediated developmental
arrest. J. Clin. Invest. 2010 (in press).
(16) 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. 2010 (in press).

Functional Biology
1. Physiology

20

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 3 students (M0 andM4) continued to enjoy their researches from 2009
through 2010. Some of these students completed theirown projects, and gave oral presentations ininternational meetings and published original papers
in top-rank international journals. It is not rare thatstudents who enjoyed his/her Free-Quarter decided to
get into the Ph-D. course after the completion of the
2-year clinical training and started to study
neurophysiology in our laboratory. Furthermore, we
accepted a Ph-D.-M.D course student who enjoyed his
Free-Quarter and decided to get into the Ph-D.-M.D
course. Thus the Free-Quarter system has proved toprovide an excellent basis for bringing up M.D.
researchers for future Japanese basic medicine.
To facilitate communication among research groups
in our laboratory, a weekly conference is held for
discussing current research activities. We also have amonthly joint seminar with Department ofPharmacology, Department of Psychology in Facultyof Letters and Department of Biophysics in Faculty of
Science. As part of a teaching activity for the graduate
students, we have another weekly English seminar, in21

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

Hirabayashi, T., Takeuchi, D., Tamura, T. andMiyashita, Y. : Triphasic dynamics of stimulus-dependent information flow between single
neurons in macaque inferior temporal cortex. J.
eurosci. in press, 2010.
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.
eurosci. in press, 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. eurosci. inpress, 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:euroimaging 182, 103-110, 2010.
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

22

6

7

8

9

10

11

12

13

14

that support relational and item-based recency
judgments. euroImage 49, 3474-3480, 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.
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.
Chikazoe, J., Jimura, K., Hirose, S., Yamashita,
K-I., Miyashita, Y. and Konishi, S. : Preparation
to inhibit a response complements response
inhibition during performance of a stop-signal
task. J. eurosci. 29, 15870-15877, 2009.
Yamashita, K., Hirose, S., Kunimatsu, A.,
Aoki, S., Chikazoe, J., Jimura, K., Masutani, Y.,
Abe, O.,
Ohtomo, K.,
Miyashita,Y. andKonishi, S. : Formation of long-term memory
representation in human temporal cortex related
to pictorial paired associates. J. eurosci. 29,10335-10340, 2009.
Chikazoe, J., Jimura. K., Asari, T., Yamashita, K.,
Morimoto, H., Hirose, S., Miyashita, Y. andKonishi, S. : Functional dissociation in rightinferior frontal cortex during performance of
go/no-go task. Cereb. Cortex 19, 146-152,
2009.
Jimura, K., Konishi, S. and Miyashita, Y. :Temporal pole activity during perception of sad
faces, but not happy faces, correlates with
Neuroticism trait. eurosci. Lett. 453, 45-48,
2009.
Jimura, K., Yamashita, K., Chikazoe, J., Hirose,S., Miyashita, Y. and Konishi, S. : A criticalcomponent that activates left inferior prefrontal
cortex during interference resolution. Eur. J.
eurosci. 29, 1915-1920, 2009.
Jimura, K., Konishi, S., Asari, T. and Miyashita,
Y. : Involvement of medial prefrontal cortex inemotionduringfeedback
Presentation.
euroReport 20, 886-890, 2009.
Hirose, S., Chikazoe, J., Jimura, K., Yamashita,K., Miyashita, Y. and Konishi, S. :Sub-centimeter scale functional organization inhuman inferior frontal gyrus. euroImage 47,442-450, 2009.
15 Kamigaki, T., Fukushima, T., and Miyashita, Y. :Cognitive set reconfiguration signaled bymacaque posterior parietal neurons. euron 61,
941-951, 2009.

23

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 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, olfactory cortical mechanisms for therecognition of food odors and for judging theiredibility. We study also the functional roles of theneuronal activity in the olfactory cortex duringslow-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.

We have been investigating also the neuronalmechanisms for the incorporation of adult-borninterneurons into the pre-existing neuronal circuit in
the olfactory bulb, and the contact-mediatedinteractions between neurons and immune cells.
Currently we are focusing on the following three
topics.
(1) Analysis of the functional neuronal circuits in thecentral olfactory system.

24

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.
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) Cellular and molecular mechanisms for thecontact-mediated interactions between neurons
and immune cells in physiological andpathological conditions.
We are currently focusing on telecncephalonspecific cell adhesion molecule, telencephalin. We
are investigating the telencephalin-mediatedsignals between neurons and immune cells
especially microglia during recovery from theneuronal damage.
(3) Incorporation of adult-born interneurons in the
pre-existing neuronal circuit in the olfactory bulb.
The olfactory system is chosen as a model
system with which to study the recruitment of
newly-generated neurons in the adult neuronal
circuit. We are studying cellular and molecularmechanisms that segregate the fate of newneurons between successful incorporation andapoptotic elimination into/from the neuronal
circuit. Recently we noted that the elimination of
newly-generated granule cells in the olfactory
bulb is greatly enhanced during the specific time
window of postprandial sleep. Current focus of
our study includes the reorganization of theolfactory bulb circuit during postprandial sleep
periods.

25

Publications (2009)
１ Matsumoto H, Kashiwadani H, Nagao H, Aiba A,
Mori K.

Odor-Induced Persistent Discharge of

Mitral Cells in the Mouse Olfactory Bulb
J europhysiol. 101: 1890-1900 (2009)2 MoriK.
Olfactory
Bulb
Mapping
Encyclopedia of euroscienceln: Squire LR (ed.), volume 7, pp.71-75.(2009)
3 Naritsuka H, Sakai K, Hashikawa T, Mori K. andYamaguchi, M. Perisomatic-targeting granulecells in the mouse olfactory bulb J Comp eurol.
515: 409-426. (2009)
4 Tsuno Y. and Mori K. (2009) Behavioral
state-dependent
processingchangesmode

Communicative

in

and

in
the

the

information

olfactoryIntegrative

systemBiology2:362-364. (2009)
5 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. eurosci.
30(9):3489-3498. (2010)
6 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
europhysiol., 103: 3490-3500. (2010)

J.

26

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

Associate Professor
Kouichi Hashimoto, Ph.D.

Associate
Kazuo Kitamura, Ph.D.

Homepage

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

Introduction and Organization
This laboratory was founded in 1953 as Departmentof Neurophysiology, Institute for Brain Research. In
1996, it was integrated into Graduate School of
Medicine. The current members of this laboratory are
3 faculty members (professor, associate professor,
associate), 6 postdoctoral fellows, 5 graduate students
and 4 technicians. We teach neurophysiology for
medical undergraduates and for students in the Masterand Ph.D. courses. Our research aims at elucidating
cellular and molecular mechanisms underlying
regulation of synaptic transmission and postnatal
development of neuronal circuits.

Teaching activities
We
teachneurophysiology
formedicalundergraduates in lectures and practical courses.
Lectures are designed for students to learn basic
mechanisms underlying the generation of electricalsignals, synaptic transmission and their regulations in
the nervous system. Students also learn how
functional neural circuits in the brain are formed 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 endplate 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 and Division of Structural
Physiology.

Research activities
The brain consists of neuronal circuits in which
neurons are connected through numerous synapses. To
understand the brain function, it is necessary to
elucidate mechanisms of synaptic transmission andthose underlying changes in synapses related todevelopment, learning and memory (synaptic
plasticity). We take various methodologicalapproaches
includingelectrophysiology,
pharmacology, morphology, and genetic engineering

27

of mouse. 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 molecularmechanisms of synaptic 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)

(3)

(4)

(5)

(6)

(7)

References(1)

Takeda, S., Sato, N., Takeuchi, D., Kurinami, H.,
Shinohara, M., Niisato, K., Kano, M., Ogihara, T.,
Rakugi, H. & Morishita, R.: Angiotensin receptor
blocker, olmesartan, improved cerebrovascular
dysfunction and prevented cognitive decline in

(8)

(9)

early-stage Alzheimer disease model mouse.
Hypertension 54, 1345-1352, 2009.
Taniguchi, S., Nakazawa, T., Tanimura, A., Kiyama,Y., Tezuka, T., Watabe, A. M., Katayama, N.,
Yokoyama, K., Inoue, T., Izumi-Nakaseko, H.,
Kakuta, S., Sudo, K., Iwakura, Y., Umemori, H.,
Inoue, T., Murphy, N. P., Hashimoto, K., Kano, M.,
Manabe, T. & Yamamoto, T.: Involvement of
NMDAR2A
tyrosine
phosphorylationindepression-related behavior. EMBO J. 28,
3717-3129, 2009.
Takeda, S., Sato, N., Niisato, K., Takeuchi, D.,
Kurinami, H., Shinohara, M., Rakugi, H., Kano, M.
& Morishita, R.: Validation of A β 1-40
administration into mouse cerebroventricles as an
animal model for Alzheimer disease. Brain Res.
1280, 137-147, 2009.
Hashimoto, K., Ichikawa, R., Kitamura, K.,
Watanabe, M. & Kano, M.: Translocation of a"winner" climbing fiber to the Purkinje cell dendriteand subsequent elimination of "losers" from thesoma in developing cerebellum. euron 63, 106118, 2009.
Tanimura, A., Kawata, S., Hashimoto, K. & Kano,
M.: Not glutamate but endocannabinoids mediate
retrograde suppression of cerebellar parallel fiber toPurkinje cell synaptic transmission in young adultrodents. europharmacology 57, 157-163, 2009.
Hildebrand, M., Isope, P., Miyazaki, T., Nakaya, T.,
Garcia, E., Feltz, A., Schneider, T., Hescheler, J.,
Kano, M., Sakimura, K., Watanabe, M., Dieudonné,
S. & Snutch, T.P.: Functional coupling between
mGluR1 and CaV3.1 T-type calcium channels
contributes to parallel fiber-induced fast calcium
signaling within Purkinje cell dendritic spines. J.
eurosci. 29, 9668-9682, 2009.
Hashimoto, K., Yoshida, T., Sakimura, K., Mishina,
M., Watanabe, M. & Kano, M.: Influence of parallel
fiber-Purkinje cell synapse formation on postnatal
development of climbing fiber-Purkinje cell
synapses. euroscience 162, 601-611, 2009.
Kano, M. & Hashimoto, K.: Synapse elimination in
the central nervous system. Curr. Opin. eurobiol.
19, 154-161, 2009.
Schultz, S. R., Kitamura, K., Post-Uiterweer, A.,
Krupic, J. & Häusser, M.: Spatial pattern coding of
sensory information by climbing-fiber evoked28

calcium signals in networks of neighboring
cerebellar Purkinje cell. J. eurosci. 29, 8005-8015,
2009.
(10) Judkewitz, B., Rizzi, M., Kitamura, K. & Häusser,
M.: Targeted in vivo single-cell electroporation. at.
Protoc. 4, 862-869, 2009.
(11) Sato, T., Miura, M., Yamada, M., Yoshida, T.,
Wood, J.D., Yazawa, I., Masuda, M., Suzuki, T.,
Shin, R.-M., Yau, H.-J., Liu, F.-C., Shimohata, T.,
Onodera, O., Ross, C.A., Katsuki, M., Takahashi, H.,
Kano, M., Aosaki, T. & Tsuji, S.: Severe
neurological phenotypes of Q129 DRPLA
transgenic mice serendipitously created by en masse
expansion of CAG repeats in Q76 DRPLA mice.
Hum. Mol. Genet. 15, 723-736, 2009.
(12) Kano, M., Ohno-Shosaku, T., Hashimotodani, Y.,
Uchigashima,
M.
&
Watanabe,
M.:
Endocannabinoid-mediated control of synaptictransmission. Physiol. Rev. 89, 309-380, 2009.

Functional Biology
2. Pharmacology

30

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

31

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 will
provide the basis for the research of extrasynaptic
glutamate transmission that is involved in many
critical brain functions.
3) Exploration of new cellular functions that are
regulated by Ca2+ signals
Although many important cell functions havebeen found to be regulated by Ca2+ signals, not all
the Ca2+-dependent cell functions have been
identified. We are now searching for new cellfunctions that are regulated by Ca2+ signals.
Cells communicate with each other to form
organized structures by cell-cell adhesion andcell-cell repulsion, but it remains to be clarified
how cell-cell contact information is converted to
intracellular signals. We found that cells in contact
with neighbouring cells generate local transient
intracellular Ca2+ signals (Ca2+ lightning). Ca2+
lightning was exclusively observed near cell-cell32

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
glutamate2+
receptor-mediated IP3-Ca 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 studying the molecularmechanism that links between Ca2+ signals andN-cadherin expression.
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. Nakamura, N., Yamazawa, T., Okubo, Y., and Iino,
M. Temporal switching and cell-to-cell variability
in Ca2+ release activity in mammalian cells. Mol.
Syst. Biol., 5:247, 2009.

33

Department of
Molecular eurobiology
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34

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35

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

36

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) Kishioka, A., Fukushima, F., Ito, T., Kataoka, H.,
Mori, H., Ikeda, T., Itohara, S., Sakimura, K. andMishina, M. A novel form of memory for auditory fear conditioning at a low-intensity unconditioned stimulus. PLoS ONE 2009; 4, e4157.
(2) Fukushima, F., Nakao, K., Shinoe, T., Fukaya, M.,
Muramatsu, S., Sakimura, K., Kataoka, H., Mori,
H., Watanabe, M., Manabe, T. and Mishina, M.
Ablation of NMDA receptors enhances the excitability of hippocampal CA3 neurons. PLoS ONE
2009; 4, e3993.
(3) Longordo, F., Kopp, C., Mishina, M., Lujan, R.
and Luthi, A. NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal plasticity to sleep loss. J. Neurosci. 2009; 29,9026-9041.
(4) Hashimoto, K., Yoshida, T., Sakimura, K., Mishina, M., Watanabe, M. and Kano, M. Influenceof parallel fiber-Purkinje cell synapse formation
on postnatal development of climbing fiber-Purkinje cell synapses: Lessons from GluRδ2knockout mice. Neuroscience 2009; 162,
601-611.
(5) Yoshida, T., Uchida, S. and Mishina, M. Regulation of synaptic vesicle accumulation and axon
terminal remodeling during synapse formation by
distinct Ca2+ signaling. J. Neurochem. 2009; 111,
160-170.
(6) Ikeda, K., Fukushima, T., Ogura, H., Tsukui, T.,
Mishina, M., Muramatsu, M. and Inoue, S. Estrogen
regulates
theexpressionof-methyl-D-aspartate (NMDA) receptor subunit

37

epsilon 4 (Grin2d), that is essential for the normal sexual behavior in female mice. FEBS Lett.
2010; 584, 806-810.
(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 associated withdivergent amygdala gene expression and glutamate-mediated neuronal excitability. J. Neurosci.
2010; 30, 5357-5367.
(8) 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.

Pathology, Immunology andMicrobiology
1. Pathology

39

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

Associate Professor
Noriyoshi Fukushima, M.D., Ph.D.(Jichi Medical University),
Hiroshi Uozaki, M.D., Ph.D., Shumpei Ishikawa, M.D., Ph.D.

Lecturer
Satoshi Ota, M.D., Ph.D.
Yutaka Takazawa, M.D., Ph.D.*

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

Associate
Akiteru Goto, M.D., Ph.D., Rumi Hino, M.D., Ph.D.
Takashi Sakatani, M.D.*, Ph.D., Tetsuo Ushiku, M.D., Ph.D.*,
Teppei Morikawa, M.D., Ph.D. *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. Fukushima moved to Jichi Medical
University, Department ofPathology as a Professor on

September, 2009. Dr. Uozaki was promoted to
Associate Professor, and Dr. Takazawa moved to theDivision of Diagnostic Pathology. Further, Dr.
Ishikawa became an Associate Professor.
Four postgraduates finished the course andreceived Ph.D. In the new fiscal year, 2010, four new
students will enter the course, and there will be 13
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.

40

On the other hand, we take charge of General
Pathology course for the 1st grade students incollaboration with Department of Molecular Pathology,
Systemic Pathology, Clinical Clerkship, andBedside-learning (BSL) for the 2nd –4th grade students.

Clinical activities (diagnostic
pathology and autopsy)
Together with Division of Diagnostic Pathology, we
are responsible for the pathologic diagnosis andautopsy in the University Hospital (see thecorresponding section of Division of Diagnostic
Pathology).
Surgical pathology conferences are regularly heldwith each clinical division, and the cases of various
tumors, including thorax, 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). The virtual
microscopy system has been introduced in thelaboratory of the students, which helps the
microscopic exercise with much moer efficiency.
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 andare referred to the website.
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 clarified
the role of latent membrane protein 2A and small RNA
molecules in the development and progression of
EBV-associated GC. Based on these studies, Prof.
Fukayama received the Japanese Pathology Award in2009.
For the research of molecular epidemiology ofhuman oncogenic viruses, we have cooperated withpathology institutes of Korea and Taiwan for thesenine years. One of the most intimate is Keimyung
University in Daegu, Korea, and Drs. Fukayama, Ota,
and Goto were invited to the Dongsan Hospital Cancer
Center International Symposium, “At the Front ofCancer Control” on June, 2009, where they presented
the results of the projects and introduced the current
status of banking system of human tumor tissues inJapan.
The second main theme is the 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 we41

are 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.
It is a new technology available for identifying thepatients susceptible to rare but serious adverse effects
with genome-level, and its practical application is
expected as an essential modality in preclinical, andclinical trials and survey after marketing (NEDO press
release on Dec. 5, 2009).

5.

Shinozaki A, Ishikawa S, Morikawa T, Nakaya T,
Sakatani T, Takada K, Fukayama M. Activationof DNA methyltransferase 1 by EBV latentmembranecarcinoma.
6.

deleted in a case with middle interhemispheric

2009

Apr

Hirano K, Fukushima N, Tada M, Isayama H,

autoimmune

pancreatitis.

J

Gastroenterol.

2009;44(7):765-73.
7.

Ishizawa T, Fukushima N, Shibahara J, Masuda

8.

pentaacetic

acid-enhanced liver magnetic resonance imaging
withdouble-arterialphasemulti-detector row helical computed tomography.
AssistTomogr.

2009

Nov-Dec;33(6):887-92.
Araki F, Mimura T, Fukuoka S, Tsuji H, Izutsu K,
Yamamoto H, Takazawa Y, Kojima T.Primary
orbital lymphomatoid granulomatosis. Br J
Ophthalmol 2009 Apr;93(4):554-6.
Deguchi J, Shigematsu K, Ota S, Kimura H,
Fukayama M, Miyata T. Surgical result of criticallimb ischemia due to tibial arterial occlusion inpatients with systemic scleroderma. J Vasc Surg.
2009 Apr;49(4):918-23.

Kokudoidentification

of

liver

N.

Real-timecancersbyusing

KashimaTG,

Nishiyama

T,

ShimazuK,

Shimazaki M, Kii I, Grigoriadis AE, Fukayama
M, Kudo A. Periostin, a novel marker of
intramembranous ossification, is expressed infibrous dysplasia and in c-Fos-overexpressing
bone

Imamura H, Kokudo N, Akahane M, Ohtomo
diethylenetriamineM,2009 Jun 1;115(11):2491-504.

Akai H, Kiryu S, Takao H, Tajima T, Shibahara J,
K.Efficacy of double-arterial phase gadolinium

Fukayama

indocyanine green fluorescent imaging. Cancer.

2009 Oct;30(10):E946-55.

4.

Res.

Diagnostic utility of biopsy specimens forboth physically and functionally. Hum Mutat.

3.

CancerTsujino T, Kawabe T, Fukayama M, Omata M.

variant of holoprosencephaly, interacts with SIX3

Computpromoter

K, Tamura S, Aoki T, Hasegawa K, Beck Y,

H, Nagao K, Yamada M, Miyashita T. EYA4,J

toSasaki T, Kogure H, Nakai Y, Sasahira N,

Ishikawa S, Aburatani H, Yokoyama S, Asahara

comparedleads

Mizuno S, Yamamoto K, Yashima Y, Yagioka H,

Abe Y, Oka A, Mizuguchi M, Igarashi T,

ethoxybenzyl

2A

1;69(7):2766-74.

(including those of Diagnostic Pathology Division)2.

proteinhypermethylation of PTEN gene in gastric

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Hum

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Kaji Y, Oshika T, Takazawa Y, Fukayama M,
Fujii N. Immunohistochemical localisation of
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acid-containing

proteins

inclimatic droplet keratopathy. Br J Ophthalmol.
2009 Jul;93(7):977-9.
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Y, Shibahara J, Louis DN, Reifenberger G, Itami

N, Ishikawa S, Igarashi H, Makuuchi M, Kokudo

J, Hara R, Saito N, Todo T. Long-term control of

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13. Lee SY, Kumano K, Nakazaki K, Sanada M,

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Matsumoto A, Yamamoto G, Nannya Y, Suzuki

T. Renal cell carcinoma in association with IgAR, Ota S, Ota Y, Izutsu K, Sakata-Yanagimoto M,

nephropathy in the elderly. Am J Med Sci. 2009

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increases of Notch2 in diffuse large B-cell

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lymphoma. Cancer Sci. 2009 May;100(5):920-6.

lymphoma and diffuse large B-cell lymphoma.

14. Maeda D, Ota S, Ikeda S, Kawano R, Hata E,

Acta Derm Venereol. 2009;89(4):421-2.

Nakajima J, Mori M, Fukayama M. Mucinous

23. Morikawa T, Toyoshima T, Fukayama M.

adenocarcinoma of the thymus: a distinct variant

Lymphoepithelioma-like carcinoma of the ureter.

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Harada K, Takahashi K, Unuma K, Yoshida K.

Nakagawa S, Yano T, Taketani Y, Kodama T,

An autopsy report on multiple system atrophy

Fukayama M. Glypican-3 expression in clear cell

diagnosed immunohistochemically despite severe

adenocarcinoma of the ovary. Mod Pathol. 2009ischaemic

Jun;22(6):824-32.

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Kawakami T, Kubo K, Higashihara M, Shimizu J,

Sagara M, Takahashi M, Ike H, Saito H,

Uozaki H, Kuramochi S, Misaki Y, Takeuchi F,

Kusakabe A, Nakajima A. Identification of

Yamamoto K. Myeloperoxidase antineutrophil

Cystatin SN as a novel tumor marker forcytoplasmic antibody-associated vasculitis withcolorectal

diffuse tubulointerstitial nephritis. J Nephrol.

Jul;35(1):33-40.

cancer.

Int

J

Oncol.

2009

35. Yoshimi A, Asai T, Maeda D, Hangaishi A,

2009 May-Jun;22(3):417-20.
29. Suzuki J, Kazama S, Kitayama J, Uozaki H,

Sakatani T, Takahashi T, Imai Y, Fukayama M,

Miyata T, Nagawa H. Signet ring cell carcinoma

Kurokawa M. Chronic myelomonocytic leukemia

ofpresenting severe uterine hemorrhage due totheappendix

manifestingascolonic

obstruction and ovarian tumors: Report of a case.

uterineSurg Today. 2009;39(3):235-40.

early-stage endometrial adenocarcinoma. Arch

30. Tanaka M, Fukushima N, Noda N, Shibahara J,
Kokudo N, Fukayama M. Intraductal oncocytic

infiltrationofleukemic

cells

and

Gynecol Obstet. 2009 Dec;280(6):1077-8.
36. Zhang S, Hayashi R, Fujii M, Hasegawa Y,

duct:

Yoshino K, Fukayama M, Ochiai A. Total

immunohistochemical

microvessel perimeter per tumor area is acharacteristics of 6 cases. Hum Pathol. 2009

predictor of radiosensitivity in early-stage glottic

Nov;40(11):1543-52.

carcinoma. Int J Radiat Oncol Biol Phys. 2009

papillaryneoplasmclinicopathologic

of

and

the

bile

31. Taoka K, Nannya Y, Yamamoto G, Sakatani T,
Ota S, Fukayama M, Takahashi T, Kurokawa M.
Progressive transition of Epstein-Barr virus
associated lymphoproliferative disease subtypes
with the development of lung cancer. Am J
Hematol. 2009 Sep;84(9):600-3.
32. Ushiku T, Uozaki H, Shinozaki A, Ota S,
MatsuzakaK,

NomuraS,

KaminishiM,

Aburatani H, Kodama T, Fukayama M. Glypican
3-expressing gastric carcinoma: distinct subgroup
unifying

hepatoid,

clear-cell,andalpha-fetoprotein -producing gastric carcinomas.
Cancer Sci. 2009 Apr;100(4): 626-32.
33. Wada Y, Nishimura G, Nagai T, Sawai H,
Yoshikata M, Miyagawa S, Hanita T, Sato S,
Hasegawa T, Ishikawa S, Ogata T. Mutation
analysis of SOX9 and single copy number variant
analysis of the upstream region in eight patientswith campomelic dysplasia and acampomeliccampomelic dysplasia. Am J Med Genet A. 2009

Mar15;73(4):1104-9.

39

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

Associate Professor
Noriyoshi Fukushima, M.D., Ph.D.(Jichi Medical University),
Hiroshi Uozaki, M.D., Ph.D., Shumpei Ishikawa, M.D., Ph.D.

Lecturer
Satoshi Ota, M.D., Ph.D.
Yutaka Takazawa, M.D., Ph.D.*

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

Associate
Akiteru Goto, M.D., Ph.D., Rumi Hino, M.D., Ph.D.
Takashi Sakatani, M.D.*, Ph.D., Tetsuo Ushiku, M.D., Ph.D.*,
Teppei Morikawa, M.D., Ph.D. *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. Fukushima moved to Jichi Medical
University, Department ofPathology as a Professor on

September, 2009. Dr. Uozaki was promoted to
Associate Professor, and Dr. Takazawa moved to theDivision of Diagnostic Pathology. Further, Dr.
Ishikawa became an Associate Professor.
Four postgraduates finished the course andreceived Ph.D. In the new fiscal year, 2010, four new
students will enter the course, and there will be 13
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.

40

On the other hand, we take charge of General
Pathology course for the 1st grade students incollaboration with Department of Molecular Pathology,
Systemic Pathology, Clinical Clerkship, andBedside-learning (BSL) for the 2nd –4th grade students.

Clinical activities (diagnostic
pathology and autopsy)
Together with Division of Diagnostic Pathology, we
are responsible for the pathologic diagnosis andautopsy in the University Hospital (see thecorresponding section of Division of Diagnostic
Pathology).
Surgical pathology conferences are regularly heldwith each clinical division, and the cases of various
tumors, including thorax, 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). The virtual
microscopy system has been introduced in thelaboratory of the students, which helps the
microscopic exercise with much moer efficiency.
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 andare referred to the website.
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 clarified
the role of latent membrane protein 2A and small RNA
molecules in the development and progression of
EBV-associated GC. Based on these studies, Prof.
Fukayama received the Japanese Pathology Award in2009.
For the research of molecular epidemiology ofhuman oncogenic viruses, we have cooperated withpathology institutes of Korea and Taiwan for thesenine years. One of the most intimate is Keimyung
University in Daegu, Korea, and Drs. Fukayama, Ota,
and Goto were invited to the Dongsan Hospital Cancer
Center International Symposium, “At the Front ofCancer Control” on June, 2009, where they presented
the results of the projects and introduced the current
status of banking system of human tumor tissues inJapan.
The second main theme is the 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 we41

are 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.
It is a new technology available for identifying thepatients susceptible to rare but serious adverse effects
with genome-level, and its practical application is
expected as an essential modality in preclinical, andclinical trials and survey after marketing (NEDO press
release on Dec. 5, 2009).

5.

Shinozaki A, Ishikawa S, Morikawa T, Nakaya T,
Sakatani T, Takada K, Fukayama M. Activationof DNA methyltransferase 1 by EBV latentmembranecarcinoma.
6.

deleted in a case with middle interhemispheric

2009

Apr

Hirano K, Fukushima N, Tada M, Isayama H,

autoimmune

pancreatitis.

J

Gastroenterol.

2009;44(7):765-73.
7.

Ishizawa T, Fukushima N, Shibahara J, Masuda

8.

pentaacetic

acid-enhanced liver magnetic resonance imaging
withdouble-arterialphasemulti-detector row helical computed tomography.
AssistTomogr.

2009

Nov-Dec;33(6):887-92.
Araki F, Mimura T, Fukuoka S, Tsuji H, Izutsu K,
Yamamoto H, Takazawa Y, Kojima T.Primary
orbital lymphomatoid granulomatosis. Br J
Ophthalmol 2009 Apr;93(4):554-6.
Deguchi J, Shigematsu K, Ota S, Kimura H,
Fukayama M, Miyata T. Surgical result of criticallimb ischemia due to tibial arterial occlusion inpatients with systemic scleroderma. J Vasc Surg.
2009 Apr;49(4):918-23.

Kokudoidentification

of

liver

N.

Real-timecancersbyusing

KashimaTG,

Nishiyama

T,

ShimazuK,

Shimazaki M, Kii I, Grigoriadis AE, Fukayama
M, Kudo A. Periostin, a novel marker of
intramembranous ossification, is expressed infibrous dysplasia and in c-Fos-overexpressing
bone

Imamura H, Kokudo N, Akahane M, Ohtomo
diethylenetriamineM,2009 Jun 1;115(11):2491-504.

Akai H, Kiryu S, Takao H, Tajima T, Shibahara J,
K.Efficacy of double-arterial phase gadolinium

Fukayama

indocyanine green fluorescent imaging. Cancer.

2009 Oct;30(10):E946-55.

4.

Res.

Diagnostic utility of biopsy specimens forboth physically and functionally. Hum Mutat.

3.

CancerTsujino T, Kawabe T, Fukayama M, Omata M.

variant of holoprosencephaly, interacts with SIX3

Computpromoter

K, Tamura S, Aoki T, Hasegawa K, Beck Y,

H, Nagao K, Yamada M, Miyashita T. EYA4,J

toSasaki T, Kogure H, Nakai Y, Sasahira N,

Ishikawa S, Aburatani H, Yokoyama S, Asahara

comparedleads

Mizuno S, Yamamoto K, Yashima Y, Yagioka H,

Abe Y, Oka A, Mizuguchi M, Igarashi T,

ethoxybenzyl

2A

1;69(7):2766-74.

(including those of Diagnostic Pathology Division)2.

proteinhypermethylation of PTEN gene in gastric

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Hum

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Kaji Y, Oshika T, Takazawa Y, Fukayama M,
Fujii N. Immunohistochemical localisation of
D-beta-aspartic

acid-containing

proteins

inclimatic droplet keratopathy. Br J Ophthalmol.
2009 Jul;93(7):977-9.
10. Kikuchi Y, Uozaki H, Itoyama S, Saijo H, Takato
T, Fukayama M.

Pagetoid spread to oral

mucosa from submandibular gland salivary duct
carcinoma: a case report. Hum Pathol. 2009
Jul;40(7):1036-9.
11. Kiryu S, Takeuchi K, Shibahara J, Uozaki H,
Fukayama M, Tanaka H, Maeda E, Akahane M,
OhtomoK.

Epstein-Barrvirus-positive

inflammatory pseudotumour and inflammatory
pseudotumour-likefolliculardendritic

cell

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tumour. Br J Radiol. 2009 Apr;82(976):e67-71.

Pathol. 2009 Jun;22(6):776-85.

12. Koga T, Morita A, Maruyama K, Tanaka M, Ino

20. Midorikawa Y, Yamamoto S, Tsuji S, Kamimura

Y, Shibahara J, Louis DN, Reifenberger G, Itami

N, Ishikawa S, Igarashi H, Makuuchi M, Kokudo

J, Hara R, Saito N, Todo T. Long-term control of

N, Sugimura H, Aburatani H. Allelic imbalances

disseminatedxanthoastrocytoma

and homozygous deletion on 8p23.2 for stepwise

with anaplastic features by means of stereotactic

progression of hepatocarcinogenesis. Hepatology.

irradiation Neuro Oncol. 2009 Aug;11(4):446-41.

2009 Feb;49(2):513-22.

pleomorphic

13. Lee SY, Kumano K, Nakazaki K, Sanada M,

21. Mimura I, Tojo A, Kinugasa S, Uozaki H, Fujita

Matsumoto A, Yamamoto G, Nannya Y, Suzuki

T. Renal cell carcinoma in association with IgAR, Ota S, Ota Y, Izutsu K, Sakata-Yanagimoto M,

nephropathy in the elderly. Am J Med Sci. 2009

Hangaishi A, Yagita H, Fukayama M, Seto M,

Nov;338(5):431-2.

Kurokawa

M,

Ogawa

S,

Chiba

S.

22. Miyagaki T, Sugaya M, Minatani Y, Fujita H,

Gain-of-function mutations and copy number

Hangaishi A, Kurokawa M, Takazawa Y, Tamaki

increases of Notch2 in diffuse large B-cell

K. Mycosis fungoides with recurrent Hodgkin's

lymphoma. Cancer Sci. 2009 May;100(5):920-6.

lymphoma and diffuse large B-cell lymphoma.

14. Maeda D, Ota S, Ikeda S, Kawano R, Hata E,

Acta Derm Venereol. 2009;89(4):421-2.

Nakajima J, Mori M, Fukayama M. Mucinous

23. Morikawa T, Toyoshima T, Fukayama M.

adenocarcinoma of the thymus: a distinct variant

Lymphoepithelioma-like carcinoma of the ureter.

of thymic carcinoma. Lung Cancer. 2009

The Internet Journal of Pathology. 2009:9(2).
24. Nakajima M, Kojima H, Takazawa Y, Yahagi N,

Apr;64(1):22-7.
15. Maeda D, Ota S, Takazawa Y, Aburatani H,

Harada K, Takahashi K, Unuma K, Yoshida K.

Nakagawa S, Yano T, Taketani Y, Kodama T,

An autopsy report on multiple system atrophy

Fukayama M. Glypican-3 expression in clear cell

diagnosed immunohistochemically despite severe

adenocarcinoma of the ovary. Mod Pathol. 2009ischaemic

Jun;22(6):824-32.

investigation of medical practice associated

16. Maeda E, Akahane M, Kiryu S, Kato N,
Yoshikawa T, Hayashi N, Aoki S, Minami M,

deathsdamage:inJapan.

anew

J

approach

Clin

Patholfor2009

Nov;62(11):1029-33.

Uozaki H, Fukayama M, Ohtomo K. Spectrum of

25. Ninomiya H, Hiramatsu M, Inamura K, Nomura

Epstein-Barr virus-related diseases: a pictorial

K, Okui M, Miyoshi T, Okumura S, Satoh Y,

review. Jpn J Radiol. 2009 Jan;27(1):4-19.

Nakagawa K, Nishio M, Horai T, Miyata S,

17. Maeda E, Akahane M, Uozaki H, Kato N,

Tsuchiya

E,

Fukayama

M,

Ishikawa

Y.

Hayashi N, Fukayama M, Ohtomo K. CT

Correlation between morphology and EGFR

appearance

virus-associatedmutations in lung adenocarcinomas SignificanceImaging.

of the micropapillary pattern and the hobnail cell

gastricof

Epstein-Barr

carcinoma.

Abdom

2009

Sep-Oct;34(5):618-25.

type. Lung Cancer. 2009 Feb;63(2):235-40

18. Maeda E, Ohta S, Watadani T, Goto A, Nakajima

26. Seike M, Goto A, Okano T, Bowman ED,

A, Ohtomo K. Imaging findings of thoracic

Schetter AJ, Horikawa I, Mathe EA, Jen J, Yang P,

low-grade fibromyxoid sarcoma: report of three

Sugimura H, Gemma A, Kudoh S, Croce CM,

cases. Jpn J Radiol. 2009 Nov;27(9):375-80.

Harris CC. MiR-21 is an EGFR-regulated

19. Matsubara D, Morikawa T, Goto A, Nakajima J,
Fukayama
myofibroblast

M,

Niki

T.

Subepithelial

in

lung

adenocarcinoma:ahistological indicator of excellent prognosis. Mod

anti-apoptotic

factorinlungcancerinnever-smokers. Proc Natl Acad Sci U S A. 2009
Jul 21;106(29):12085-90.
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43

SakataniT,

UozakiH,

FukayamaM.

Dec ;149A(12):2882-5.

Epstein-Barr virus-associated gastric carcinoma:

34. Yoneda K, Iida H, Endo H, Hosono K, Akiyama

a distinct carcinoma of gastric phenotype byT, Takahashi H, Inamori M, Abe Y, Yoneda M,

claudinFujita K, Kato S, Nozaki Y, Ichikawa Y, Uozaki

expression

profiling.

J

Histochem

H, Fukayama M, Shimamura T, Kodama T,

Cytochem. 2009 Aug;57(8):775-85.
28. Son D, Kanda H, Yamaguchi A, Kawabata K,

Aburatani H, Miyazawa C, Ishii K, Hosomi N,

Kawakami T, Kubo K, Higashihara M, Shimizu J,

Sagara M, Takahashi M, Ike H, Saito H,

Uozaki H, Kuramochi S, Misaki Y, Takeuchi F,

Kusakabe A, Nakajima A. Identification of

Yamamoto K. Myeloperoxidase antineutrophil

Cystatin SN as a novel tumor marker forcytoplasmic antibody-associated vasculitis withcolorectal

diffuse tubulointerstitial nephritis. J Nephrol.

Jul;35(1):33-40.

cancer.

Int

J

Oncol.

2009

35. Yoshimi A, Asai T, Maeda D, Hangaishi A,

2009 May-Jun;22(3):417-20.
29. Suzuki J, Kazama S, Kitayama J, Uozaki H,

Sakatani T, Takahashi T, Imai Y, Fukayama M,

Miyata T, Nagawa H. Signet ring cell carcinoma

Kurokawa M. Chronic myelomonocytic leukemia

ofpresenting severe uterine hemorrhage due totheappendix

manifestingascolonic

obstruction and ovarian tumors: Report of a case.

uterineSurg Today. 2009;39(3):235-40.

early-stage endometrial adenocarcinoma. Arch

30. Tanaka M, Fukushima N, Noda N, Shibahara J,
Kokudo N, Fukayama M. Intraductal oncocytic

infiltrationofleukemic

cells

and

Gynecol Obstet. 2009 Dec;280(6):1077-8.
36. Zhang S, Hayashi R, Fujii M, Hasegawa Y,

duct:

Yoshino K, Fukayama M, Ochiai A. Total

immunohistochemical

microvessel perimeter per tumor area is acharacteristics of 6 cases. Hum Pathol. 2009

predictor of radiosensitivity in early-stage glottic

Nov;40(11):1543-52.

carcinoma. Int J Radiat Oncol Biol Phys. 2009

papillaryneoplasmclinicopathologic

of

and

the

bile

31. Taoka K, Nannya Y, Yamamoto G, Sakatani T,
Ota S, Fukayama M, Takahashi T, Kurokawa M.
Progressive transition of Epstein-Barr virus
associated lymphoproliferative disease subtypes
with the development of lung cancer. Am J
Hematol. 2009 Sep;84(9):600-3.
32. Ushiku T, Uozaki H, Shinozaki A, Ota S,
MatsuzakaK,

NomuraS,

KaminishiM,

Aburatani H, Kodama T, Fukayama M. Glypican
3-expressing gastric carcinoma: distinct subgroup
unifying

hepatoid,

clear-cell,andalpha-fetoprotein -producing gastric carcinomas.
Cancer Sci. 2009 Apr;100(4): 626-32.
33. Wada Y, Nishimura G, Nagai T, Sawai H,
Yoshikata M, Miyagawa S, Hanita T, Sato S,
Hasegawa T, Ishikawa S, Ogata T. Mutation
analysis of SOX9 and single copy number variant
analysis of the upstream region in eight patientswith campomelic dysplasia and acampomeliccampomelic dysplasia. Am J Med Genet A. 2009

Mar15;73(4):1104-9.

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, 4 technicians, and several research fellows,
including 18 graduate students, 4 master course
students, and 1 post-doctoral fellow.

Teaching activities
Our department takes responsibility for lectures
on “General Pathology” for the undergraduate studentsof the Faculty of Medicine in collaboration with thestaff of the Department of Human Pathology. Teaching
responsibilities include lectures on General Pathology
related to the mechanisms of diseases. Since webelieve it very important for medical students to study
Basic Oncology, we teach a basic tumor biology
course in our lectures of General Pathology. In
addition, we offer several laboratory courses forstudents from molecular pathological points of view.

We also supervise research activities of thegraduate students of the Department. Our laboratory is
located at the 11th floor at the Research Building ofGraduate School of Medicine. The laboratory is very
convenient for doing research, since most of theexperiments can be done at this floor. We have
“Progress Meeting” twice a month and “Monday
Seminar” once a month.
We have been doing collaboration with the
Ludwig Institute for Cancer Research, Uppsala,Sweden for more than 10 years. We have annual
TGF-β meeting in Sweden 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 (COE) Program for "Integrative Life
Science Based on the Study of Biosignaling
Mechanisms" from the Ministry of Education, Culture,
Sports, Science and Technology of Japan. This
program stimulates interaction with students andscientists in the program as well as those from otherlaboratories.
Graduate students also present data at various
meetings, including Annual Meetings of the JapaneseCancer Association, and Annual Meeting of the45

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.
Despite recent treatment strategies, including
aggressive surgery, radiotherapy, and chemotherapy,
treatment of malignant glioma remains formidable.
Although the concept of cancer stem cells (orcancer-initiating cells) reveals a new framework ofcancer therapeutic strategies against malignant glioma,
it remains unclear how glioma-initiating cells can beeradicated. We demonstrated that autocrine TGF-beta
signaling plays an essential role in retention ofstemness of glioma-initiating cells and describe theunderlying mechanism for it. TGF-beta-induced
expression of Sox2, a transcription factor, and thisinduction was mediated by another transcription factor
Sox4, a direct TGF-beta target gene. Inhibitors of
TGF-beta signaling deprived tumorigenicity ofglioma-initiatingcells
bypromotingtheirdifferentiation, and these effects were attenuated incells transduced with Sox2 or Sox4 cDNA.
Furthermore, glioma-initiating cells treated with
TGF-beta inhibitor showed less lethal potency inintracranial transplantation assay. These findings
identify an essential pathway for glioma- initiating
cells, the TGF-beta-Sox4-Sox2 pathway, whose
disruption would be a therapeutic strategy against
gliomas (Ikushima et al., Cell Stem Cell 2009).
Members of bone morphogenetic proteins(BMPs) have been implicated in the development andmaintenance of vascular systems. Although membersof the BMP-2/4 family (including BMP-2 and 4) andthose of OP -1 groups (BMP-5, 6, 7 and 8) signal via
ALK-2, 3 and 6, BMP-9 and 10 were reported to bind
ALK-1 in endothelial cells. However, the roles of
BMP-9/ALK-1 signals in the regulation of various

endothelial cells have not yet been fully determined.
We examined the effects of BMP-9 on the
proliferation of endothelial cells using various in vitro
and in vivo assays. Vascular tube formation fromallantoic explants of E8.5 mouse embryos waspromoted by BMP-9. It also induced the proliferationof mouse embryonic endothelial cell-derived
endothelial cells (MESECs) by inducing theexpression of VEGFR2 and Tie2, a receptor for
Angiopoietin-1. Loss- and gain-of-function of ALK-1
abrogated and mimicked the effects of BMP-9 on the
proliferation of MESECs, respectively, suggesting that
BMP-9 signals via ALK-1. Furthermore, tumor
angiogenesis was promoted by BMP-9 expressed in
BxPC3 human pancreatic cancer xenograft model.
These findings strongly suggest that BMP-9 signaling
activates endothelium via ALK1 (Suzuki Y, et al. J.
Cell Sci. 2010).
During lymphatic development, Prox1 plays
central roles in the differentiation of blood vascularendothelial cells (BECs) into lymphatic endothelial
cells (LECs). We found that expression of HoxD8 wassignificantly induced by Prox1 in MESECs, a finding
confirmed in human umbilical vein endothelial cells(HUVECs) and human dermal LECs (HDLECs). In
mouse embryos, HoxD8 expression was higher in
LECs than in BECs. In a model of inflammatory
lymphangiogenesis, diameters of lymphatic vessels of
the diaphragm were increased by HoxD8. We also
found that HoxD8 induces Ang2 expression in
HDLECs and HUVECs. Moreover, we found thatHoxD8 induces Prox1 expression in HUVECs and thatknockdown of HoxD8 reduces this expression in
HDLECs, suggesting that Prox1 expression in LECs is
maintained by HoxD8. These findings indicate thattranscriptional networks of Prox1 and HoxD8 play
important roles in the maturation and maintenance oflymphatic vessels (Harada et al., J. Cell Sci. 2009).
MicroRNAs (miRNAs) have emerged as key
post-transcriptional regulators of gene expression,
involved in diverse physiological and pathologicalprocesses. Although miRNAs can function as both
tumor suppressors and oncogenes, a widespread
downregulation of miRNAs is commonly observed inhuman cancers and impairment of miRNA biogenesis
promotes cellular transformation and tumorigenesis.
This indicates an inherent significance of small RNAs

46

in tumor suppression. However, the connection
between tumor suppressor networks and miRNAbiogenesis machineries has not been fully investigated.
We showed that a central tumor suppressor, p53,
enhances the post-transcriptional maturation of several
miRNAs with growth-suppressive function, including
miR-16-1, miR-143 and miR-145, in response to DNA
damage. p53 interacts with the Drosha processing
complex through the association with DEAD-box
RNA helicase p68 and facilitates the processing ofprimary miRNAs to precursor miRNAs. We also
found that p53 mutants interfere with a functional
assembly between Drosha complex and p68, leading
to attenuation of miRNA processing activity. Thesefindings suggest that transcription-independent
modulation of miRNA biogenesis is intrinsicallyembedded in a tumor suppressive program governedby p53. Our findings reveal a novel function of p53 in
miRNA processing, which may underlie key aspects ofcancer biology (Suzuki HI, et al. Nature 2009).

References
1.

2.

3.

4.

Kano, M.R., Komuta, Y., Iwata, C., Oka, M.,
Shirai, Y., Morishita, Y., Ouchi, Y., Kataoka, K.,
and Miyazono, K. (2009) Comparison of theeffects of the kinase inhibitors imatinib, sorafenib,
and transforming growth factor-β receptor
inhibitor on extravasation of nanoparticles fromneovasculature. Cancer Sci. 100 (1): 173-180.
Koinuma, D., Tsutsumi, S., Kamimura, N.,
Taniguchi, H., Miyazawa, K., Sunamura, M.,
Imamura, T., Miyazono, K., and Aburatani, H.
(2009) Chromatin immunoprecipitation on
microarray analysis of Smad2/3 binding sites
reveals roles of ETS1 and TFAP2A intransforming growth factor β signaling. Mol. Cell.
Biol. 29 (1): 172-186.
Horiguchi, K., Shirakihara, T., Nakano, A.,
Imamura, T., Miyazono, K., and Saitoh, M.
(2009) Role of Ras signaling in the induction ofsnail by TGF-β. J Biol Chem. 284 (1): 245-253.
Takahata, M., Inoue, Y., Tsuda, H., Imoto, I.,
Koinuma, D., Hayashi, M., Ichikura, T., Yamori,T., Nagasaki, K., Yoshida, M., Matsuoka, M.,
Morishita, K., Yuki, K., Hanyu, A., Miyazawa, K.,
Inazawa, J., Miyazono, K., and Imamura, T.

(2009) SKI and MEL1 cooperate to inhibittransforming growth factor-β signal in gastriccancer cells. J. Biol. Chem. 284 (5): 3334-3344.
5. Seto, A., Ikushima, H., Suzuki, T., Sato, Y., Fukai,S., Yuki, K., Miyazawa, K., Miyazono, K.,
Ishitani, R., and Nureki, O. (2009) Crystallizationand preliminary X-ray diffraction analysis of
GCIP/HHM transcriptional regulator. Acta
Crystallogr. Sect. F Struct. Biol. Cryst. Commun.
65 (1): 21-24.
6. Yamazaki, T., Yoshimatsu, Y., Morishita, Y.,
Miyazono, K., and Watabe, T. (2009) COUP-TFII
regulates the functions of Prox1 in lymphatic
endothelial cells through direct interaction. Genes
Cells 14 (3), 425-434.
7. Saito, R.A., Watabe, T., Horiguchi, K., Kohyama,T., Saitoh, M., Nagase, T., and Miyazono, K.
(2009) Thyroid transcription factor-1 inhibitstransforming
growthfactor-β-mediatedepithelial-to-mesenchymal transition in lungadenocarcinoma cells. Cancer Res. 69 (7),2783-2791.
8. Komuro, A., Yashiro, M., Iwata, C., Morishita, Y.,
Johansson, E., Matsumoto, Y., Watanabe, A.,
Aburatani, H., Miyoshi, H., Kiyono, K., Shirai, Y.,
Suzuki, H.I., Hirakawa, K., Kano, M.R., andMiyazono, K. (2009) Diffuse-type gastriccarcinoma: Progression, angiogenesis, andtransforming growth factor-β signaling. J. atl.
Cancer Inst. 101 (8), 592-604.
9. Saitoh, M., Shirakihara, T., and Miyazono, K.
(2009) Regulation of the stability of cell surface
E-cadherin by the proteasome. Biochem. Biophys.
Res. Commun. 381 (4), 560-565.
10. Kiyono, K., Suzuki, H.I., Morishita, Y., Komuro,A., Iwata, C., Yashiro, M., Hirakawa, K., Kano,
M.R., and Miyazono, K. (2009) c-Ski
overexpression promotes tumor growth andangiogenesis through inhibition of transforming
growth factor-β signaling in diffuse-type gastriccarcinoma. Cancer Sci. 100 (10), 1809-1816.
11. Suzuki, H.I., Yamagata, K., Sugimoto, K.,
Iwamoto, T., Kato, S., and Miyazono, K. (2009)
Modulation of microRNA processing by p53.
ature 460 (7254), 529-533.
12. Koinuma, D., Tsutsumi, S., Kamimura, N.,
Imamura, T., Aburatani, H., and Miyazono K.

47(2009) Promoter-wide analysis of Smad4 bindingsites in human epithelial cells. Cancer Sci. 100(11), 2133-2142.
13. Sase, H., Watabe, T., Kawasaki, K., Miyazono, K.,
and Miyazawa, K. (2009) VEGFR2-PLCγ1 axis
is essential for endothelial specification of
VEGFR2+ vascular progenitor cells. J. Cell Sci.
122 (18), 3303-3311.
14. Harada, K., Yamazaki, T., Iwata, C., Yoshimatsu,
Y., Sase, H., Mishima, K., Morishita, Y.,
Hirashima, M., Oike, Y., Suda, T., Miura, N.,
Watabe, T., and Miyazono, K. (2009)
Identification of targets of Prox1 during in vitro
vascular differentiation from embryonic stem
cells: functional roles of HoxD8 inlymphangiogenesis. J. Cell Sci. 122 (21),3923-3930.
15. Ikushima, H., Todo, T., Ino, Y., Takahashi, M.,
Miyazawa, K., and Miyazono, K. (2009)
Autocrine
TGF-βsignaling
maintainstumorigenicity of glioma-initiating cells throughSry-related HMG-box factors. Cell Stem Cell 5(5), 504- 514.
16. Kumagai, M., Kano, M.R., Morishita, Y., Ota, M.,
Imai, Y., Nishiyama, N., Sekino, M., Ueno, S.,
Miyazono, K., and Kataoka, K. (2009) Enhanced
magnetic resonance imaging of experimental
pancreatic tumor in vivo by block copolymercoated magnetite nanoparticles with TGF-βinhibitor. J. Control. Release 140 (3), 306-311.
17. Han, M., Oba, M., Nishiyama, N., Kano, M.R.,
Kizaka-Kondoh, S., Kataoka, K. (2009)
Enhanced percolation and gene expression intumor hypoxia by PEGylated polyplex micelles.
Mol. Therapy 17(8), 1404-1410.
18. Kiyono, K., Suzuki, H.I., Matsuyama, H.,
Morishita, Y., Komuro, A., Kano, M.R.,
Sugimoto, K., and Miyazono, K. (2009)
Autophagy is activated by TGF-β and potentiates
TGF-β-mediated growth inhibition in humanhepatocellular carcinoma cells. Cancer Res. 69(23), 8844-8852.
19. Miyazono, K. (2009) Transforming growth
factor-β signaling in epithelial-mesenchymaltransition and progression of cancer. Proc. Japan
Acad. Series B, Physical and Biological Sciences
85 (8), 314-323.

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 16 members; 1 professor (Dr. Hatakeyama),
2 associates (Drs. Kamiya and Tsutsumi), 2 technicalstaffs (Ms. Yano and Gotoh) and 11 Graduate School
students (Ms. and Mr. Takahashi, Fujii, Saito,
Yamahashi, Hayashi, Safari, Suzuki, Kashiba,
Yanagiya, Kikuchi and 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) Applicationofmicrobialorganisms
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 China,
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. 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. Molecular mechanism for the type IV-mediated
CagA delivery into host cells
The H. pylori CagA protein is delivered into hostgastric epithelial cells via the bacterial syringe-likestructure called the type IV secretion system (TFSS).
We are investigating the molecular mechanism bywhich CagA is delivered through TFSS, particularly
focusing on membrane lipids.
2. Deregulation of SHP-2 oncoprotein by CagA.
After delivery into host epithelial cells, CagA istyrosine-phosphorylated by Src family kinases. We

50

identified
thattyrosine-phosphorylated
CagA
specifically associates with SHP-2 protein tyrosine
phosphatase. Upon complex formation, CagA
deregulates SHP-2, which in turn causes aberrant
activation of mitogenic MAP kinase signaling
pathway. CagA-deregulated SHP-2 also stimulates cell
motility by inhibiting FAK activity. SHP-2 has been
recently reported to be a bona-fide oncoprotein,gain-of-function mutations of which are associatedwith a variety of human malignancies. We’ve been
extensively investigating the molecular mechanisms
by which deregulated SHP-2 promotes malignant
transformation of cells.
3. Disruption of epithelial polarity by CagA
Gastric mucosa is composed of a polarized epithelialcellmonolayer
withhighlydeveloped
apical-junctional complexes. We found that CagA
specifically binds to PAR1/MARK serine/threonine
kinase, which plays a key role in the development andmaintenance of epithelial apical-basal polarity.
Through the interaction, CagA inhibits the kinase
activity of PAR1, thereby causing junctional andpolarity defects. The CagA-PAR1 interaction also
impairs the function of mitotic spindle during cell
division, causing chromosomal instability. Our present
goal is to elucidate the role for the loss of epithelial
polarity in the development of epithelial tumors(carcinogenesis).
4. In vivo oncogenic potential of CagA
To investigate oncogenic potential of H. pylori CagAin vivo, we generated transgenic mice thatsystemically express CagA. These mice developed
gastrointestinal and hematopoietic malignancies,
confirming the activity of CagA as a bacterial
oncoprotein. Now, we are investigating the process oftumor development in mice that express CagA in an
organ-specific manner.

References
1. Lamb A, Yang X-D, Nicole Tsang Y-H, Li J-D,
Higashi H, Hatakeyama M, Peek RM, Blanke SR,
Chen L-F. Helicobacter pylori CagA activates
NF-κB by targeting TAK1 for TRAF6-mediatedLys63-ubiquitination. EMBO Rep 2009:10:12421249.
2. Miura M, Ohnishi N, Tanaka S, Yanagiya K

3.

4.

5.

6.
7.

Hatakeyama M. Differential oncogenic potentialof geographically distinct Helicobacter pylori
CagA isoforms in mice. Int J Cancer 2009:125:2497-2504.
Lu H, Murata-Kamiya N, Saito Y, Hatakeyama M.
Role of Partitioning-defective 1/microtubule
affinity-regulating kinases in the morphogenetic
activity of Helicobacter pylori CagA. J Biol
Chem 2009:284:23024-23036.
Umeda M, Murata-Kamiya N, Saito Y, Ohba Y,
Takahashi M, Hatakeyama M. Helicobacter pylori
CagA causes mitotic impairment and induces
chromosomal instability. J Biol Chem 2009:284:
22166-22172.
Ishikawa S, Ohta T, Hatakeyama M. Stability of
Helicobacter pylori CagA oncoprotein in humangastric epithelial cells. FEBS Lett 2009:583:24142418.
Hatakeyama M. Helicobacter pylori and gastriccarcinogenesis. J Gastroenterol 2009:44:239- 248.
Nakayama M, Hisatsune J, Yamasaki E, Isomoto
H, Kurazono H, Hatakeyama M, Azuma T,
Yamaoka Y, Yahiro K, Moss J Hirayama T.
Helicobacter pylori VacA-induced inhibition of
GSK3 through the PI3K/Akt signaling pathway. J
Biol Chem 2009:284:1612 -1619.

51

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

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

Research Associate
Takatoshi Kitazawa, M.D., Ph.D.
Youko Nukui, M.D., Ph.D.
Keita Tatsuno, 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, two lecturers, 6 guest
lecturers, two research associates, 11 laboratory
technicians, and two office assistants. For isolationand identification of microorganisms from clinicalspecimens, we amalgamated the microbiology unit
from the Department of Clinical Laboratory in 2001.

Clinical activities
Our daily activities are as follows:
1) Surveillance and control of hospital-acquired
infection, such as infection or colonization ofmethicillin-resistant Staphylococcus 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 3rd
and 4th grade students and lectures on infectious
diseases for the 4th grade students), the course ofhealth science (lectures on microbiology), and theschool of nursing (lectures and practical exercises on
microbiology). These lectures and exercises contain
subjects not only on the hospital infection but also on
clinical microbiology. We are also engaged in the

52

education of graduate students as well as hospital
staff.
For postgraduate education, we have been committed
to the guidance for new postgraduates and residents
on the hospital and occupational infection control. We
have been also offering our information and techniqueon occasions of request.

Research activities
We have been mainly studying on following subjects:
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) Molecular characterizations of carbapenem andciprofloxacin resistance in clinical isolates of
Pseudomonas putida. Kumita W, Saito R, Sato K,
Ode T, Moriya K, Koike K, Chida T, Okamura N.J
Infect Chemother. 2009 Feb;15(1):6-12. Epub
2009 Mar 12.
(2) Chronic hepatitis C in patients co-infected withhuman immunodeficiency virus in Japan: aretrospective multicenter analysis. Yotsuyanagi H,
Kikuchi Y, Tsukada K, Nishida K, Kato M, Sakai
H, Takamatsu J, Hige S, Chayama K, Moriya K,
Koike K. Hepatol Res. 2009 Jul;39(7):657-63.
Epub 2009 Apr 7.

(3) Limitation of immunoaffinity column for theremoval of abundant proteins from plasma inquantitative plasma proteomics. Ichibangase T,
Moriya K, Koike K, Imai K.Biomed Chromatogr.
2009 May;23(5):480-7.
(4) Analysisofplasmid-mediatedmultidrug
resistance in Escherichia coli and Klebsiella
oxytoca isolates from clinical specimens in Japan.
Ode T, Saito R, Kumita W, Sato K, Okugawa S,
Moriya K, Koike K, Okamura N. Int J Antimicrob
Agents. 2009 Oct;34(4):347-50. Epub 2009 Jun
27.
(5) Proteomics analysis of mitochondrial proteins
reveals overexpression of a mitochondrial protein
chaperon, prohibitin, in cells expressing hepatitis
C virus core protein. Tsutsumi T, Matsuda M,
Aizaki H, Moriya K, Miyoshi H, Fujie H, Shintani
Y, Yotsuyanagi H, Miyamura T, Suzuki T, Koike
K. Hepatology. 2009 Aug;50(2):378-86.
(6) Tacrolimus ameliorates metabolic disturbance andoxidative stress caused by hepatitis C virus coreprotein: analysis using mouse model and cultured
cells. Moriya K, Miyoshi H, Tsutsumi T,
Shinzawa S, Fujie H, Shintani Y, Yotsuyanagi H,
Moriishi K, Matsuura Y, Suzuki T, Miyamura T,
Koike K. Am J Pathol. 2009 Oct;175(4):1515-24.
Epub 2009 Sep 3.
(7) Animal models for hepatitis C and related liverdisease. Koike K, Moriya K, Matsuura Y. Hepatol
Res. 2010 Jan;40(1):69-82.
(8) 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.

Pathology, Immunology andMicrobiology
3. Immunology

54

Department of Immunology
Professor
Tadatsugu Taniguchi, Ph.D.

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

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

Homepage

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

Introduction and Organization
The history of the Department of Immunology,
formerly the Department of Serology, dates back to1918. The department’s adopted its present namewhen Dr. Tomio Tada, now Professor Emeritus of The
University of Tokyo, took his position in 1977 as
professor and chair of the department. Through hisinnovative research and great contributions to theinternational community of immunologists, Dr. Tadaraised the stature of the department to aworld-renowned status. After his retirement in 1994,
Dr. Taniguchi had tried to follow and improve the highstandards of the department established by Dr. Tadaby providing a first-rate education to students as wellas performing cutting-edge, internationally recognizedresearch in the field of immunology.
In the late 1970s and early 1980s, Prof. Taniguchi’s
research was the first to identify and subsequentcharacterize two cytokine genes, interferon (IFN)-β
and interleukin (IL)-2. These initial studies led to theexperimental dissection of the cytokine systems in thecontext of the regulation of immunity and oncogenesis.
One of our major contributions resulting from these
efforts was the discovery and characterization of a
new family of transcription factors, termed interferon
regulatory factors (IRFs).
While the core of our current research is aimed atclarifying the functions of IRF family members in thecontext of immunity, the broad scope of our scientificinterests encompass a number of areas including thosepertaining to innate immune system activation,
autoimmunity, oncogenesis, and others. In addition,
we initiated a new area of research 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 the55

world, such as Jeffrey V. Ravetch (Professor of The
Rockefeller 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).
With respect to IRF-mediated regulation of theimmune system, we have shown that IRF-5,
previously shown by us to be important cytokine geneinduction, also regulates class switching of
immunoglobulin genes. We have shown that IRF5 is a
key transcription factor for the activation of innate
immune responses downstream of Toll-like receptor(TLR) signaling, but its contribution systemic lupus
erythematosus (SLE) was implicated, though how
IRF5 contributes to SLE was uncertain. We haveshown a requirement for IRF5 in the development ofmurine SLE via its role in B lymphocytes. In
particular, we found that production of autoantibodiesof the IgG2a and IgG2b subtypes, the most prominent
isotypes in inducing autoimmunity, requires IRF5.
By demonstrating a B cell-intrinsic role, this study
places IRF5 in a new context that may have
implications for understanding the pathogenesis ofhuman SLE.
We also conducted applied research projects, inwhich we discovered several compounds that interferewith TLR signaling. One of these compounds turned
out to be quite unique in that its augukentsstress-induced MAK kinases, JNK and p38 while
inhibiting activation of the NF-κB transcription factor.
We have promising data, indicating the usefulness of
this compound for the treatment of inflammatory
diseases and cancers. We aim at improving theefficacy of this compound my modifying its structure
for clinical purposes and, at the same time, try to
elucidate its mechanism of action.
Finally, a new research project lead by Honda
focuses on the immune regulation by intestinalcommensal bacteria reveled that Segmented

56

filamentous bacteria (SFB), a Gram-positive,
Clostridium-related bacteria, specifically induces
Th17 T cell differentiation.

References

and Taniguchi, T.; Therapeutic potential of proapoptotic molecule Noxa in the selective eliminationof tumor cells. (2009) Cancer Sci., 100, 759-769(9)Chen, H.M., Tanaka, N., Mitani, Y., Oda, E., Nozawa, H., Chen, J.Z., Yanai, H., Negishi, H., Choi,(1) Savitsky D, Yanai H, Tamura T, Taniguchi T and

M.K., Iwasaki, T., Yamamoto, H., Taniguchi, T. and

Honda K. Contribution of IRF5 in B cells to the

Takaoka, A.; Critical role for constitutive type I in-development of murine SLE-like disease throughterferon signaling in the prevention of cellular

its transcriptional control of the IgG2a locus.

transformation. (2009) Cancer Sci., 100, 449-456

Proc. atl. Acad. Sci. USA in press (2010).

(10) Yanai, H., Savitsky, D., Tamura, T. and Taniguchi,(2) Savitsky D, Tamura T, Yanai H, and Taniguchi T.

T.; Regulation of the cytosolic DNA-sensing sys-

Regulation of immunity and oncogenesis by thetem in innate immunity: a current view. (2009)

IRF transcription factor family. Cancer Immunol.

Curr. Opin. Immunol., 1, 17-22

Immunother. 59, 489-510 (2010).
(3)

(4)

(5)

(6)

(7)

(8)

(11) Negishi, H., Osawa, T., Ogami, K., Ouyang, X.,

Yanai H, Ban T, Wang Z, Choi MK, Kawamura

Sakaguchi, S., Koshiba, R., Yanai, H., Seko, Y.,

T, Negishi H, Nakasato M, Lu Y, Hangai S, Ko-

Shitara, H., Bishop, K., Yonekawa, H., Tamura, T.,

shiba R, Savitsky D, Ronfani R, Akira S, Bianchi

Kaisho, T., Taya, C., Taniguchi, T. and Honda, K.;

ME, Honda K, Tamura T, Kodama T, and Tani-

A critical link between Toll-like receptor 3 and typeguchi T. HMGB proteins function as universal

II interferon signaling pathways in antiviral innate

sentinels for nucleic acid-mediated innate im-immunity. (2008) Proc. Natl. Acad. Sci. USA., 105,mune responses. ature 462, 99-103 (2009).

20446-20451

Choi MK, Wang Z, Ban T, Yanai H, Lu Y, Ko-(12) 柳井秀元・谷口維紹, IRF ファミリー転写因子

shiba R, Nakaima Y, Hangai S, Savitsky D, Na-と生体防御シグナル，蛋白質核酸酵素 (2008)

kasato M, Negishi H, Takeuchi O, Honda K,

53, 1231-1238, 共立出版

Akira S, Tamura T, and Taniguchi T. A selective(13) Couzinet, A., Tamura, K., Chen, H., Nishimura, K.,

contribution of the RIG-I-like receptor pathway

Wang, Z., Morishita, Y., Takeda, K., Yagita, H.,

to type I interferon responses activated by cyto-

Yanai, H., Taniguchi, T., and Tamura, T.; A cellsolic DNA. Proc. atl. Acad. Sci. USA 106,

type-specific requirement for IRF5 in Fas-induced

17870-17875 (2009).

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

Nakajima A, Nishimura K, Nakaima Y, Oh T,

2556-2561.

Noguchi S, Taniguchi T, Tamura T. Cell

(14) Takaoka, A., Tamura T., and Taniguchi, T.; IRF

type-dependent proapoptotic role of Bcl2L12family transcription factors and regulation of on-

revealed by a mutation concomitant with thecogenesis. (2008) Cancer Sci. 99, 467-478.

disruption of the juxtaposed Irf3 gene. Proc. atl.

(15) Mizutani, T., Tsuji, K., Ebihara, Y., Taki, S., Ohba,

Acad. Sci. USA 106, 12448-12452 (2009).

Y., Taniguchi, T., and Honda, K.; Homeostatic

Taniguchi, T.; Aimez-vous Brahms? A story capric-

erythropoiesis by the transcription factor IRF2

cioso from the discovery of a cytokine family andthrough attenuation of type I interferon signaling.

its regulators. (2009) Nat. Immunol., 10, 447-449(2008) Exp. Hematol. 36, 255-264.

Yanai, H., Savitsky, D., Tamura, T. and Taniguchi,(16) Tamura, T., Yanai, H., Savitsky, D., and Taniguchi,T.; Regulation of the cytosolic DNA-sensing sys-T.; The IRF Family Transcription Factors in Im-

tem in innate immunity: a current view. (2009)

munity and Oncogenesis. (2008) Annu. Rev. Im-

Curr. Opin. Immunol., 1, 17-22

munol. 26, 535-584.

Suzuki, S., Nakasato, M., Shibue, T., Koshima, I.

(17) Takaoka, A., and Taniguchi, T.; Cytosolic DNA

57

recognition for triggering innate immune responses. (2008). Adv. Drug Deliv. Rev. 60,
847-57.
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molecules. (2008) Proc. Natl. Acad. Sci. USA 105,5477-5482.

Radiology and Biomedical
Engineering
1. Radiology

59

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

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

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

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

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

Yoshitaka Masutani, Ph.D.,

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

Harushi Mori, M.D.

Assisstant Professor
Syuhei Komatsu, M.D.,

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

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

Jiro Sato, M.D.,

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

Masamichi Takahashi, M.D.

Homepage

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

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

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

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

60

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 forthe evaluation of cerebral blood flow and metabolism
inpatients
withdementia,
epilepsy,and61

cerebrovascular diseases. Cerebral blood flow, glucose
metabolism and neural synaptic functions aremeasured for the understanding of normal andpathophysiological states of CNS disorders, using avariety of positron-emitter radiotracer, such as [O-15]
H2O, CO2, O2, CO, [F-18] FDG, [C-11] methionine,[F-18]Dopa, [C-11]NMSP, NMPB and [C-11]
raclopride. The study of dementia using SPECT andthe standard brain atlas has made it possible tocategorize the type of dementia. Evaluation of
dopaminergic function by PET is very important in the
differential diagnosis of Parkinsonism. Cardiac PET
and SPECT are also active fields. Myocardial viability,
vascular reserve and sympathetic nerve denervation in
the ischemic heart disease are evaluated with [F-18]
FDG, [N-13] NH3, Tl-201 and [I-123] MIBG. Higher
brain functions such as reading, speech and thinking
have been studied with PET by comparing blood flow
and receptor binding potential (BP) under various
tasks and at rest. For the precise localization ofactivated brain function, computer processing andreconstruction of composite images of function andanatomy is an essential subject for investigation. At
present, whole body FDG-PET is one of the mosteffective tool for exploring metastatic lesions ofcancer patients. Combination display of SPECT/PET
with XCT/MRI would be a routine job andanatomo-functional images would play an importantrole in the clinical management of the patients.

References
1. Akai H, Kiryu S, Takao H, Tajima T, Shibahara J,
Imamura H, Kokudo N, Akahane M, Ohtomo K.
Efficacy of double-arterial phase gadolinium
ethoxybenzyl diethylenetriamine pentaacetic
acid-enhanced liver magnetic resonance imaging
comparedwithdouble-arterialphasemulti-detector row helical computed tomography.
J Comput Assist Tomogr 33(6): 887-92, 2009
2. Amemiya S, Aoki S, Akahane M, Ohtomo K.
F-18 fluorodeoxyglucose positron emission
tomography in a transitional meningioma.
Clin Nucl Med 34(7): 462-3, 2009
3. Amemiya S, Aoki S, Ohtomo K.
Cranial nerve assessment in cavernous sinus
tumors with contrast-enhanced 3D fast-imaging

employing steady-state acquisition MR imaging.
Neuroradiology 51(7): 467-70, 2009
4. Amemiya S, Akahane M, Aoki S, Abe O, Kamada
K, Saito N, Ohtomo K.
Dynamic contrast-enhanced perfusion MR
imaging with SPIO: a pilot study.
Invest Radiol 44(9)： 503-8, 2009
5. Furuta T, Maeda E, Akai H, Hanaoka S, Yoshioka
N, Akahane M, Watadani T, Ohtomo K.
Hepatic segments and vasculature: projecting CT
anatomy onto angiograms.
Radiographics 29(7): 1-22, 2009
6. 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: Epub ahead of print, 2009
7. Haga A, Nakagawa K, Shiraishi K, Itoh S,
Terahara A, Yamashita H, Ohtomo K, Saegusa S,
Imae T, Yoda K, Pellegrini R.
Quality assurance of volumetric modulated arc
therapy using Elekta Synergy.
Acta Oncol 48(8): 1193-7, 2009
8. Hashimoto M, Tomita T, Sawada K, Fujibuchi T,
Nishio T, Nakagawa K.
Dose profile measurement using an imaging plate:
Evaluation of filters using Monte Carlo simulationof 4 MV x-rays.
Rev Sci Instrum 80(4): 045101, 2009
9. Igaki H, Nakagawa K, Yamashita H, Terahara A,
Haga A, Shiraishi K, Sasano N,Yamamoto K,
Onoe T, Yoda K, Ohtomo K.
Contrast media-assisted visualization of brain
metastases by kilovoltage cone-beam CT.
Acta Oncol 48(2): 314-7, 2009
10. Igaki H, Maruyama K, Koga T, Murakami N,
Tago M, Terahara A, Shin M, Nakagawa K,
Ohtomo K.
Stereotactic radiosurgery for skull basemeningioma.
Neurol Med Chir 49(10): 456-61, 2009
11. Inoue Y, Kiryu S, Izawa K, Watanabe M, Tojo A,
Ohtomo K.
Comparison of subcutaneous and intraperitoneal
injectionofD-luciferin
for
in
vivo
bioluminescence imaging.
Eur J Nucl Med Mol Imaging 36(5): 771-9, 200962

12. Ishida M, Kojima K, Yamahira K, Suzuki M,
Hirabayashi Y, Ohtomo K.
A case of cervical adenomyoma protruding fromvulva.
Eur J Radiol Extra 71(1): 37-9, 2009
13. Kamada K, Todo T, Ota T, Ino K, Masutani Y,
Aoki S, Takeuchi F, Kawai K, Saito N.
The motor-evoked potential threshold evaluatedby tractography and electrical stimulation.
J Neurosurg: Epub ahead of print, 2009
14. Kiryu S, Inoue Y, Watanabe M, Izawa K, ShimadaM, Tojo A, Yoshikawa K, Ohtomo K.
Evaluation of gadoxetate disodium as a contrast
agent for mouse liver imaging: comparison withgadobenate dimeglumine.
Magn Reson Imaging 27(1): 101-7, 2009
15. Kiryu S, Takeuchi K, Shibahara J, Uozaki
H,Fukayama M, Tanaka H,Maeda E, Akahane M,
Ohtomo K.
Epstein-barr
virus-positive
inflammatory
pseudotumour and inflammatory pseudotumourlike follicular dendritic cell tumour: case reportand review of the literature.
Br J Radiol 82(976): e67-71, 2009
16. Kiryu S, Dodanuki K, Takao H, Watanabe M,
Inoue Y, Takazoe M, Sahara R, Unuma K,
Ohtomo K.
Free-breathing diffusion-weighted imaging for theassessment of inflammatory activity in Crohn's
disease.
J Magn Reson Imaging 29(1): 880-6, 2009
17. Kotani Y, Ohgami Y, Kuramoto Y, Tsukamoto T,
Inoue Y, Aihara Y.
The role of the right anterior insular cortex in therighthemispherepreponderanceofstimulus-preceding negativity (SPN): an fMRI
study.
Neurosci Lett 450(2): 75-9, 2009
18. Kunishima K, Mori H, Itoh D, Aoki S, Kabasawa
H, Koga T, Maruyama K, Masumoto T, Abe O,
Ohtomo K.
Assessment of arteriovenous malformations with
3-Teslatime-resolved,
contrast-enhanced,
three-dimensional
magnetic
resonance
angiography.
J Neurosurg 110(3): 492-9, 2009
19. Kunishima K, Takao H, Akahane M, Yoshioka N,

Ohtomo K.
Safety of using iodized oil in chemoembolization
for liver tumors in patients with previous adverse
reactions to iodinated contrast media.
Clin Imaging 33(5): 365-8, 2009
20. Maeda E, Akahane M, Kiryu S, Kato N,
Yoshikawa T, Hayashi N, Aoki S, Minami M,
Uozaki H, Fukayama M, Ohtomo K.
Spectrum of Epstein-Barr virus-related diseases: apictorial review.
Japanese Journal of Radiology 27(1): 4-19, 2009
21. Maeda E, Akahane M, Uozaki H, Kato N, Hayashi
N, Fukayama M, Ohtomo K.
CT appearance of Epstein-Barr virus-associatedgastric carcinoma.
Abdom Imaging 34(5): 618-25, 2009
22. Maeda E, Ohta S, Watadani T, Goto A, Nakajima
A, Ohtomo K.
Imaging findings of thoracic low grade
fibromyxoid sarcoma: report of three cases.
Jpn J Radiol 27(9): 375-80, 2009
23. Mori K, Fukuda K, Asaoka H, Ueda T, Kunimatsu
A, Okamoto Y, Nasu K, Fukunaga K, Morishita Y,
Minami M.
Radiofrequency
ablationoftheliver:
determination of ablative margin at MR imaging
with impaired clearance of ferucarbotranfeasibility study.
Radiology: Epub ahead of print, 2009
24. Mori-Uchino M, Takeuchi T, Murakami I, Yano T,
Yasugi T, Taketani Y, Nakagawa, K, Kanda T.
Enhanced transgene expression in the mouseskeletal muscle infected by the adeno-associatedviral vector with the human elongation factor
1alpha promoter and a human chromatin insulator.
J Gene Med 11(7): 598-604, 2009
25. Nakagawa K, Haga A, Shiraishi K, Yamashita H,
Igaki H, Terahara A, Ohtomo K, Saegusa S,
Shiraki T, Oritate T, Yoda K.
First clinical cone-beam CT imaging during
volumetric modulated arc therapy.
Radiother Oncol 90(3): 422-3, 2009
26. Nakagawa K, Shiraishi K, Kida S, Haga A,
Yamamoto K, Saegusa S, Terahara A, Itoh S,
Ohtomo K, Yoda K.
First
reporton
prostate
displacements
immediately before and after treatment relative to

63

the position during VMAT delivery.
Acta Oncol 48(8): 1206-8, 2009
27. Nakamura N, Sasano N, Yamashita H, Igaki H,
Shiraishi K, Terahara A, Asakage T, Nakao K,
Ebihara Y, Ohtomo K, Nakagawa K.
Oral pilocarpine (5mg t.i.d.) used for xerostomia
causes adverse effects in Japanese.
Auris Nasus Larynx 36(3): 310-3, 2009
28. Nakata Y, Sato N, Nemoto K, Abe O, Shikakura S,
Arima K, Furuta N, Uno M, Hirai S, Masutani Y,
Ohtomo K, Barkovich AJ, Aoki S.
Diffusion abnormality in the posterior cingulum
and hippocampal volume: correlation with diseaseprogression in Alzheimer's disease.
Magn Reson Imaging 27(3):347-54, 2009
29. Nakata Y, Sato N, Nemoto K, Abe O, Shikakura S,
Arima K, Furuta N, Uno M, Hirai S, Masutani Y,
Ohtomo K, Barkovich AJ, Aoki S.
Diffusion abnormality in the posterior cingulum
and hippocampal volume: correlation with diseaseprogression in Alzheimer's disease.
Magn Reson Imaging 27(3)： 347-54, 2009
30. Nakata Y, Barkovich AJ, Wahl M, Strominger Z,
Jeremy RJ, Wakahiro M, Mukherjee P, Sherr EH.
Diffusion abnormalities and reduced volume ofthe ventral cingulum bundle in agenesis of the
corpus callosum: a 3 tesla imaging study.
AJNR Am J Neuroradiol 30(6): 1142-8, 2009
31. Nanjo S, Yoshikawa K, Harada M, Inoue Y,
Namiki A, Nakano H, Yamazaki J.
Correlation between left ventricular diastolic
function and ejection fraction in dilated
cardiomyopathy using magnetic resonanceimaging with late gadolinium enhancement.
Circ J 73(10): 1939-44, 2009
32. Nojo T, ImanakaY, Ishizaki T, Sekimoto M,
Yoshino M, Kurosawa T, Takao H, Ohtomo K.
Lung cancer incidence in middle-aged men
estimated by low ?dose computed tomography
screening.
Lung Cancer 65(1): 56-61, 2009
33. Rogers MA, Yamasue H, Abe O, Yamada H,
Ohtani T, Iwanami A, Aoki S, Kato N, Kasai K.
Smaller amygdala volume and reduced anterior
cingulate gray matter density associated withhistory of post-traumatic stress disorder．
Psychiatry Res 174(3)： 210-6, 200934. Sakai M, Inoue Y, Aoki S, Sirasaka T, Uehira T,
Takahama S, Nagai H, Yutani K, Yoshikawa K,
Nakamura H
Follow-up magnetic resonance imaging findingsinpatients
withprogressive
multifocal
leukoencephalopathy: evaluation of long-term
survivors under highly active antiretroviraltherapy.
Jpn J Radiol 27(2), 69-77, 200935. Sakai M, Aoki S, Watanabe Y, Tanabe D, Taga T,
Inoue Y, Ohtomo K, Nakamura H.
Introducer needles of peripheral intravenous
catheters: assessment of magnetic fieldinteractions with 1.5T and 3T MR systems.
Magn Reson Med Sci 8(4): 181-5, 200936. Sasaki H, Abe O, Yamasue H, Fukuda R, Yamada
H, Takei K, Suga M, Takao H, Kasai K, Aoki S,
Ohtomo K.
Structural and diffusional brain abnormality
related to relatively low level alcohol
consumption.
Neuroimage 46(2)： 505-10, 2009
37. Takahashi T, Sato N, Ota M, Nakata Y, Yamashita
F, Adachi Y, Saito Y, Sugai K, Sasaki M, Asada T.
Asymmetrical interhemispheric fiber tracts inpatients with hemimegalencephaly on diffusion
tensor magnetic resonance imaging.
J Neuroradiol 36(5): 249-54, 2009
38. Takao H, Ohtomo K.
Balloon-occluded
retrograde
transvenous
obliterationofgastric
varicesusing
three-dimensional rotational angiography.
Br J Radiol 82(975): e55-7, 2009
39. Takao H, Nojo T, Ohtomo K.
True pancreaticoduodenal artery aneurysms: A
decision analysis.
Eur J Radiol: Epub ahead of print, 2009
40. 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: Epub ahead of print, 2009
41. Takei K, Yamasue H, Abe O, Yamada H, Inoue H,
Suga M, Muroi M, Sasaki H, Aoki S, Kasai K.
Structural disruption of the dorsal cingulum

64bundle is associated with impaired Stroop
performance in patients with schizophrenia．
Schizophr Res 114(1-3)： 119-27, 2009
42. Uno K, Takenaka K, Ebihara A, Nawata K,
Hayashi N, Nagasaki M, Sonoda M, Takayuki O,
Ono M, Kyo S, Nagai R, Takamoto S.
Value of live 3D transoesophageal echocardiography in the diagnosis of mitral valve lesions.
Eur J Echocardiogr 10(2): 350-1, 2009
43. Yamashita H, Nakagawa K, Asari T, Murakami N,
Igaki H, Okuma K, Ohtomo K.
Concurrent chemoradiation alone with curative
intent for limited-disease small-cell esophageal
cancer in nine Japanese patients.
Dis Esophagus 22(2): 113-8, 2009
44. Yamashita H, Nakagawa K, Hosoi Y, Kurokawa A,
Fukuda Y, Matsumoto I, Misaka T, Abe K.
Umami taste dysfunction in patients receiving
radiotherapy for head and neck cancer.
Oral Oncol 45(3): e19-23, 2009
45. Yamashita H, Murakami N, Asari T, Okuma K,
Ohtomo K, Nakagawa K.
Correlation among six biologic factors (p53,p21(WAF1), MIB-1, EGFR, HER2, and Bcl-2)
andclinicaloutcomes
after
curativechemoradiation therapy in squamous cell cervicalcancer.
Int J Radiat Oncol Biol Phys 74(4): 1165-72, 2009
46. Yamashita H, Okuma K, Seto Y, Mori K,
Kobayashi S, Wakui R, Ohtomo K, Nakagawa K.
A retrospective comparison of clinical outcomesand quality of life measures between definitive
chemoradiation alone and radical surgery forclinical stage II-III esophageal carcinoma.
J Surg Oncol 100(6): 435-41, 2009
47. Yamashita H, Okuma K, Nakagawa K.
Iatrogenic vulvar skin metastases after interstitialradiotherapy for recurrent cervical cancer.
J Dermatol 36(12): 663-5, 2009
48. Yamashita K, Hirose S, Kunimatsu A, Aoki S,
Chikazoe J, Jimura K, Masutani Y, Abe O,
Ohtomo K, Miyashita Y, Konishi S.
Formation of long-term memory representation inhuman temporal cortex related to pictorial paired
associates.
J Neurosci 29(33)： 10335-40, 200949. Yasmin H, Aoki S, Abe O, Nakata Y, Hayashi N,

Masutani Y, Goto M, Ohtomo K.
Tract-specific analysis of white matter pathways
in healthy subjects: a pilot study using diffusion
tensor MRI．
Neuroradiology 51(12)： 831-40, 2009
50. Yoda K, Nakagawa K, Shiraishi K, Okano Y,
Ohtomo K, Pellegrini RG.
Dose verification of intensity modulated arc
therapy using ERGO++ treatment planningsystem and Elekta internal multileaf collimators
for prostate treatment.
Br J Radiol 82(976): 328-31, 2009

Radiology and Biomedical
Engineering
2. Biomedical Engineering

66

Department of System Physiology
Lecturer
Kimiko Yamamoto, M.D., Ph.D.

Homepage

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

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

Teaching activities
We provide lectures of “Early Exposure to
Medicine” for first year students, “Basic Principles ofBiomedical Engineering” for second and third year
students, “Introduction to Biomedical Engineering”
for postgraduate students, “Introduction to Medical
Science: Medical Engineering” for master’s students,
in the faculty of Medicine, and “Principles ofMedicine” for postgraduate students in the faculty ofEngineering. We offer practical training of biomedical
engineering research to third- and fourth-year studentsof undergraduate medical school. A weekly seminar isheld in our laboratory bringing together staff,
postgraduate students and research fellows to discuss
journal articles and give updates on experiments. Our
aim is to enhance the research skills of students.

Research activities
This laboratory has been pursuing the study ofbiomechanics dealing with mechanical phenomena in
the human body, especially focusing on cellularsensing and response mechanisms to mechanicalstimuli.
The main theme of our work is therelationships between shear stress or cyclic strain,mechanical forces generated by blood flow, and theirtarget cells, vascular endothelial cells. This would
be of benefit not only to understanding blood
flow-mediated regulation of vascular functions but
also to the elucidation of clinically important issues
such as angiogenesis, vascular remodeling andatherogenesis which occur in a blood flow-dependent
manner.
Original biomedical engineering methods have been
applied, in which cultured endothelial cells are
exposed to controlled levels of shear stress in a
fluid–dynamic flow apparatus and whose responses
are analyzed at the cellular and molecular levels.
Microcirculatory hemodynamics and oxygen transport
are studied by employing opto-electronics technology.
The results of these experiments are listed below.
1. Cell responses to shear stress
2. Shear stress-mediated gene regulation
3. Shear stress-induced cell differentiation
4. Shear stress signal transduction
1. Cell responses to shear stress
Our studies have demonstrated that endothelial cells
have functional responses to shear stress. When acultured endothelial cell monolayer was partiallydenuded, surrounding cells migrated to andproliferated in the denuded area, thus covering thedenuded area.
Shear stress enhanced theregenerative functions of endothelial cells (Microvasc
Res 1987, Biorheology, 1990).
Shear stressincreased the production of nitric oxide, a potent
vasodilator, in endothelial cells in a dose-dependent
manner (BBRC 1994). Shear stress also increased

67

the expression of thrombomodulin, an antithrombotic
molecule, in endothelial cells (BBRC 1994). In
contrast, it decreased the expression of vascular celladhesion, which leads to the inhibition of leukocyte
adhesion to vascular cell adhesion molecule-1(VCAM-1; BBRC 1993, Am J Physiol 1994). A
collaborative study showed that shear stress increases
the levels of adrenomedulin and C-type natriuretic
peptide mRNA which have vasodilating effects inaddition to nitric oxide (Hypertension 1997), and thatit also augments the expression of lectin like low
density lipoprotein receptor (LOX-1) at the protein
and mRNA levels (Circ Res 1998).

degradation, while turbulent shear stress increases theuPA gene expression through mRNA stabilization (AmJ Physiol 2004). We demonstrated that shear stress
up-regulates the gene expression of plasminogenactivator inhibitor-1 (PAI-1) through activation oftranscription factors Sp-1 and Ets-1 in humanhepatocytes (Am J Physiol 2006). We developed acompliant tube-type flow-loading device that allows
simultaneous application of physiological levels ofshear stress and cyclic strain to cultured cells andobserved that the response of endothelial genes toshear stress or cyclic strain depends on whether thetwo forces are applied separately or together (JBiotechnology 2008).

2. Shear stress-mediated gene regulation
We have demonstrated that shear stress regulates
endothelial gene expression transcriptionally and/or
posttranscriptionally. Shear stress downregulates
VCAM-1 gene transcription via the double AP-1
binding element (TGACTCA) in the promoter whichfunctions as a shear stress-responsive element (Am J
Physiol 1997). Shear stress has also been shown toincrease the level of granulocyte/macrophase-colony
stimulating factor (GM-CSF) via mRNA stabilization(Circ Res 1988).
Differential display analysis
showed that around 600 known and unknown
transcripts were up- or down-regulated in humanumbilical vein endothelial cells exposed to a shear
stress of 15 dynes/cm2 for 6 h (BBRC 1996). Fromthese shear stress-responsive genes, a cDNA encoding
an unknown G-protein coupled receptor was cloned(BBRC 1997). We showed that the transcription
factor SP1 is involved in the shear stress-induced
down-regulation of P2X4 (an ATP-gated cation
channel) gene expression in endothelial cells (Am J
Physiol 2001). DNA microarray analysis revealed
that approximately 3% of the all endothelial genes,
which corresponds to about 600 genes, respond toshear stress (J Athero Thromb 2003). Recently, we
revealed that endothelial genes are differentiallyregulated by laminar and turbulent shear stress.
Laminar shear stress decreases the gene expression of
urokinase plasminogen activator (uPA), which plays arole in fibrinolysis and vascular remodeling, via both
GATA6-mediateddown-regulationofgene
transcription and an acceleration of mRNA

3. Shear stress-induced cell differentiation
Recently, we revealed that endothelial progenitor
cells (EPCs) circulating in human peripheral blood
proliferate and differentiate into mature endothelial
cells in response to shear stress, thereby forming
tube-like structures in collagen gel (J Appl Physiol
2003). More recently, we revealed that shear stressincreased the gene expression of the arterial EC
marker ephrinB2 in EPCs, while it decreased the gene
expression of the venous EC marker EphB4,
suggesting that shear stress affects arterial-venous
differentiation of EPCs (J Appl Physiol 2009).
Embryonic stem (ES) cells have the potential todifferentiate into every cell type in the body, and are
attracting interest as a promising source of cells foruse in regenerative medicine. Embryonic cells are
exposed to fluid-mechanical forces, including shear
stress and the cyclic strain generated by a beatingheart during the process of embryonic development.
Recently, we found that shear stress induces thedifferentiation of murine ES cells into the vascularendothelial cell (EC) lineage in vitro (Am J Physiol
2005); cyclic strain induces the differentiation into thevascular smooth muscle cell (SMC) lineage (J Appl
Physiol 2008). Differentiation into the EC lineage
and differentiation into the SMC lineage are mediatedby ligand-independent phosphorylation of vascularendothelial growth factor (VEGF) receptor 2 and aplatelet derived growth factor receptor, respectively.
Moreover, our recent study has shown that shear stressincreases expression of ephrinB2 in murine ES cells

68

via the VEGF-Notch signaling pathways, suggestingthat shear stress can also affect the arterial-venous
differentiation of ECs (Arteioscler Throm Vasc Biol2009). Based on these findings, in a collaborative
study, a new hybrid type of artificial blood vessel, in
which ES cells were cultured on the surface ofpolymer tubes and exposed to pulsatile shear stressand cyclic strain, was developed (J Artif Organs
2005).
4. Shear stress signal transduction
We first showed that Ca2+ signaling plays animportant role in the mechanism by which endothelial
cells recognize the shear stress signal and transmit itinto the cell interior（In Vitro Cell Dev Biol 1988.
Strong shearing forces induced by dragging a balloon
across the endothelial cell surface causes an increasein cytoplasmic Ca2+ concentrations (Biorheology
1994). A relatively weak shearing force like shear
stress generated by fluid flow needs the presence of
extracellular ATP to induce a Ca2+ response, and atseveral hundred nanomolar of ATP, intracellular Ca2+
concentrations increase in a shear stress-dependent
manner (BBRC 1991, 1993). Generally, flow-induced
Ca2+ responses are initiated at a locus at the cell edge
and propagate throughout the entire cell in the form ofa Ca2+ wave. The initiation locus corresponded
precisely to caveolae rich cell edges (Proc Nat’l Acad
Sci 1998). We found that a subtype of ATP-gatedcation channel, the P2X4 receptor, is expressed inhuman vascular endothelial cells (Am J Physiol 2000)
and that P2X4 receptors play a crucial role in theshear stress-dependent Ca2+ response (Circ Res 2000).
Endogeneously released ATP by shear stress isinvolved in the P2X4-mediated Ca2+ responses (Am J
Physiol 2003). We produced P2X4-deficient miceand observed that the P2X4-deficent mice have
impaired flow-dependent control of vascular tone andremodeling, indicating that shear stress signaltransduction via P2X4 plays a critical role in theregulation of circulatory functions (Nat Med 2006).
Our recent study revealed that cell surface ATPsynthase localized in caveolae/lipid rafts is involvedin the shear-stress-induced ATP release by ECs (Am J
Physiol 2007).

References(1) Masumura T, Yamamoto K, Shimizu N, Obi S, andAndo J. Shear stress increases expression of the arterial endothelial marker ephrinB2 in murine ES
cells via the VEGF-Notch signaling pathways. Arterioscler Throm Vasc Biol. 2009;29:2125-2131.
(2) Ando J and Yamamoto K. Vascular mechanobiology: Endothelial cell responses to fluid shear stress.
Cir J. 2009; 73:1983-1992.
(3) Koga M, Sudo R, Abe Y, Yamamoto K, Ando J,
Ikeda M, and Tanishita K. Contribution of rat emdothelial progenitor cells on three-dimensional
network formation in vitro. Tissure Eng Part A.
2009;15:3727-2739.
(4) Obi S, Yamamoto K, Shimizu N. Kumagaya T,
Masumura T, Sokabe T, Asahara T, and Ando J.
Fluid shear stress induces arterial differentiation ofendothelial progenitor cells. J Appl Physiol. 2009;
106:203-211.
(5) Huang H, Zhou Y-M, Takamizawa K, Ishibashi-Ueda H, Ando J, Kanda K, Yaku H, and Nakayama Y. In vitro maturation of “Biotube” vascular grafts induced by a 2-day pulsatile flow loading.

J Biomed Mater Res B Appl Biomater.

2009;91:320-328.
(6) Shimizu N, Yamamoto K, Obi S, Kumagaya S,
Masumura T, Shimano Y, Naruse K, Yamashita
JK, Igarashi T, and Ando J. Cyclic strain induces
mouse embryonic stem cell differentiation into
vascular smooth muscle cells by activating PDGF
receptor β. J Appl Physiol. 2008;104:766-772.
(7) Tsuda T, Toyomitsu E, Komatsu T, Masuda T,
Kunifusa E, Nasu-Tada K, Koizumi S, Yamamoto
K, Ando J, and Inoue K. Fibronectin/integrin
system is involved in P2X4 receptor upregulationin the spinal cord and neuropathic pain after
nerve injury. Glia. 2008;56:579-585.
(8) Toda M, Yamamoto K, Shimizu N, Obi S,
Kumagaya S, Igarashi T, Kamiya A, and Ando J.
Differential gene responses in endothelial cells
exposed to a combination of shear stress andcyclic stretch. J Biothechnol. 2008;133:239-244.

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

Lecturer
Takashi Isoyama, Ph.D.

Homepage

http://www.bme.gr.jp/

Introduction and Organization
Institute of Medical Electronics was established in
1963 as the first research institute for medical
engineering in Japan. Department of Clinical
Medicine in the Institute of Medical Electronics wasstarted in 1964 for research and development of theadvanced diagnostic and 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 thegraduate school of Medicine, and the name of thedepartment has been changed as shown above sinceApril 1, 1997.
Our research covers wide area of interdisciplinary andcomprehensive research fields based on the advanced
medical and engineering techniques. We arecooperating with various laboratories. Our doctor
course students have the opportunity to performresearch work under the guidance of Prof. Mabuchi at
Department of Information Physics and Computing,
Graduate School of Information Science andTechnology.

Teaching activities
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 formaster course students, and we take a part in series oflectures for doctor course students. In the lectures formaster course students, we teach artificial organ
technologies. In the lectures for doctor course students,
philosophy, methodology and basic and special
knowledge of advanced medical engineering
technologies for basic and clinical medicine arepresented.
The educational practice of the post-graduate students
is performed mainly by on-the-job training method in
the daily research works. Pre-operative management,
anesthesia, surgery, post-operative management,
measurement, data processing, ethical factor, andother important information are acquired through thedevelopment and the animal experiment of artificial
hearts. In the practice, we give master course students
several assignments from the field of artificial organs
to help finding the subject of their research. Doctor
course students have to find the subject of theirresearch by themselves. The research subject of doctor
course students is not limited to the field of artificialorgans but is found from the wide area of advanced
medical engineering technology.
Students must attend to weekly meeting. They can

70learn 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 division.

Research activities
Our research field covers advanced diagnostic andtherapeutic medical engineering high-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 the world famous research project
having a long history since 1959 at the University ofTokyo. Almost all the researches and developments
for driving mechanisms, energy converters, blood
pumps, artificial valves, biomaterials, powertransmissions, measurement techniques, control
methods, anatomical compatibility, hemocompatibility,
tissue compatibility, computer fluid dynamics,
physiology, pathology, and so on, have been studied.
All the stuffs and students are participating in theartificial heart project. In 1995, we succeeded tosurvive a goat for 532 days with the paracorporeal
total artificial heart (TAH) with no anticoagulant,
which is still the longest survival record of TAH
animals in the world.
Our artificial heart research at present is to develop an
implantable
TAH.
We
inventedasmall
continuous-flow blood pump with high performance,
named undulation pump, to meet the purpose. We
are developing an undulation pump total artificial
heart (UPTAH) using undulation pumps. The UPTAH
is the most compact implantable TAH with the highest
performance in producing output in the world. ThisTAH is designed to generate pulsatile flow bychanging motor speed periodically. Recently, the newmodel of a UPTAH was developed for the purpose of
studying physiology with a nonpulsatile TAH. This
UPTAH can switch pulsatile flow to nonpulsatile flow
with a single device easily. We succeeded to survive agoat for 153 days with a UPTAH.
How to control the output of a TAH is another big
interest. We have developed our original control
method, named 1/R control, in which the cardiac

output is controlled by the cardiovascular center
through the feedback mechanism using changes intotal peripheral resistance and arterial pressure. At thepresent time, 1/R control is the only reported method
to achieve physiological control of a TAH logically.
With 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 was changed in accordance with ametabolic condition of the animal.
1/R control was installed in the UPTAH and thepathophysiological study was performed with a
nonpulsatile TAH. The result showed that 1/R control
could be possible not only with a pulsatile TAH, butalso with a nonpulsatile TAH. The general conditions
and organ functions were not changed by theapplication of the nonpulsatile mode. Cardiac output
and arterial pressure changed with the condition of thegoat in pulsatile and also in nonpulsatile modes, which
seemed almost identical. However, the sucking effectof atria was very significant in the nonpulsatile mode,
resulted in hemolysis. Therefore, nonpulsatile TAH
with 1/R control was considered to be inadequate,
unless some pulsatility would be introduced to avoid
fatal sucking effect for ensuring sufficient inflow
condition.
A project of emergency life support system (ELSS)
that is a compact and transportable percutaneous
cardio pulmonary support (PCPS) device for
emergency use has been started in 2004. The device
consists of a blood pump, an oxygenator, a drive andcontrol unit and a battery unit. A new membrane
oxygenator and a new blood pump were designed andintegrated into one piece. An experimental model
exhibited good performance. The whole systemcomponents are packed in a case having 180 mm indiameter and 390 mm in length. The whole weight
will be less than 10 kg.
Concerning the biomaterials, we developed the new
hybrid technique recently. In general, it was not easy
to develop the mechanical parts of implantableartificial organs from the components of living tissue
because these components do not have enoughstrength and durability. To overcome these problems, atissue engineered insert molding method for making
parts of artificial organs was introduced. In themethod, the mold in which the artificial material was

71

inserted was implanted in the animal, and the tissue
grew into the mold to make the hybrid parts. The
method was applied to the Jellyfish valve. The hybrid
Jellyfish valve demonstrated a possibility of themethod for practical use. This hybrid biomaterial
technique will be important technology for developing
next generation artificial organs.
An implantable video camera for observation of
microcirculation has been developed using a CMOS
chip. This device is expected to progress thephysiology of the microcirculation with a TAH. The
implantable camera can observe angiogenesis intissue-engineered material. In this method, a scaffold
was attached to the camera and implanted in the
animal. The camera succeeded to observe thereal-time growth of tissue and micro blood vessels inthe scaffold. This technique will give important
information for the studies of tissue engineering andregenerative medicine as well as implantable artificialorgans.
Our research of IT medicine is focused to the home
medical care. The research and development of IT
infrastructures for monitoring the condition of patientsliving at home is being performed. The miniaturized
RF-ECG unit attached on the patient is transmitted tothe data server through the mobile Internet
communication. The client computers in the clinic or
doctor’s mobile computer receive the real-time data
through the Internet lines from the data server. Thissystem has been tested for 2 years and the operatingrecords revealed that the system was very useful forthe remote real-time monitoring of patients at home.
The system is being improved for general use inJapan.
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. Inoue Y, Nakagawa H, Saito I, Isoyama T, Miura
H, Kouno A, Ono T, S. Yamaguchi S, Shi W, Kishi
A, Abe Y, Imachi K. Development of an

2.

3.

4.

5.

Implantable Observation System for Angiogenesis.
IFMBE Proceedings. 2009;23:1426-1429.
Abe Y, Isoyama T, Saito I, Miura H, Nakagawa H,
Shi W, Inoue Y, Yamaguchi S, Kishi A, Ono M,
Kouno A, Ono T, Chinzei T, Imachi K.
Controllability of 1/R control in non-pulsatile
total artificial heart. IFMBE Proceedings.
2009;25:523-524.
Saito I, Isoyama T, Miura H, Nakagawa H, Kouno
A, Ono T, Shi W, Inoue Y, Kishi A, Abe Y.
Developmentofthe
NaturalHeartbeat
Synchronize Control Method for the Undulation
Pump Ventricular Assist Device Using the Inflow
Pressure. IFMBE Proceedings. 2009;25:300-301.
Kato Y, Saito I, Takano H, Mabuchi K, Hoshino T.
Comparison of neuronal cell adhesiveness ofmaterials in the diX (Parylene) family.
Neuroscience Letters. 2009;464:26-28.
Matsuyama N, Okazaki S, Nakagawa H, Sone H,
Fukuda K. Response kinetics of a fiber-optic gas
sensor using Pt/WO3 thin film to hydrogen. Thin
Solid Films. 2009;517:4650-4653

euroscience
1. Basic euroscience73

Department of europathology
Professor
Takeshi Iwatsubo, M.D.

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

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

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

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harboring PS as the catalytic center, associated withthree additional membrane proteins. They demonstrated that APH-1 and Nicastrin serve as the “stabilizing” co-factor of PS, whereas PEN-2 is the component that confers proteolytic activity to this complex.
They also showed that PS, APH-1, nicastrin and
PEN-2 are the essential set of proteins that comprisethe γ-secretase complex (Takasugi et al. Nature, 2003).
This study is highlighted as a milestone work that elucidated the mechanistic roles of protein cofactors in
the formation and function of γ-secretase (see reviews;
Iwatsubo Mol Psychiatr, 2004; Curr Opin Neurobiol,2004). His group has also shown by establishing invitro γ-secretase assays that sulindac sulfide, a major
non-steroidal anti-inflammatory drugs, directly acts on
γ-secretase and selectively reduce Aβ42-generating
activities (Takahashi et al., J Biol Chem, 2003), providing important implications to the therapeutic strategies of AD by γ-secretase modulation. Recently, he
has established a novel method for an efficient in vitro
reconstituion of γ-secretase complex, paving the way
towards the structural analysis of active γ-secretase(Hayashi et al. J Biol Chem, 2004), and using thus
highly purified γ-secretase particles, they have partially unveiled the submolecular structure of thiscomplex by single-particle EM analysis (Ogura et al.
BBRC, 2006). Very recently, his group has established
an elegant strategy to analyze the structure-function
relationship within the catalytic structure ofγ-secretase complex by cystein chemistry, and demonstrated that γ-secretase harbors a water-permeable
catalytic pore (Sato et al. J Neurosci, 2006), and that
substrate proteins enter the catalytic pore through thelateral gate located at the C terminal side of PS (Satoet al. J Neurosci, 2008). Thus, Dr. Iwatsubo’s group
started from an elegant immunohistochemical analysis
of Aβ deposits in AD brains and extended it to a contemporary molecular/cellular biology of PS, thatproved to play a key role in the important biologicalreaction termed “intramembrane proteolysis”.
2. Identification and characterization of αsynuclein as a major component of Lewy bodies.
Using cortical Lewy bodies purified from postmortem brains of patients with dementia with Lewy
bodies (DLB) by his original method (Iwatsubo et al.
Am J Pathol 1996) as immunogens, Dr. Iwatsubo’sgroup, in collaboration with Drs. Virginia Lee andJohn Trojanowski at Univ. Penn, performed an extensive immunochemical search for components of Lewy
bodies. They have demonstrated by raising a specificmonoclonal antibody that α-synuclein, that proved to
be a product of pathogenic gene for familial form of
Parkinson’s disease, is one of the major constituent of
Lewy bodies in sporadic Parkinson’s disease and DLB(Baba et al. Am J Pathol 1998). His group 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 insynucleinopathy lesions is highly phosphorylated at a
specific serine residue (Fujiwara et al. Nature Cell
Biol 2002). This finding led to a range of studies focusing on the role of synuclein phosphorylation inneurodegeneration. Also, the phospho-specificα-synuclein antibody is widely used as the most sensitive marker for α-synucleinopathy lesions, and they
have characterized a wide spectrum of α-synuclein
pathologies in neurodegenerative disorders.
3. Identification of a non-Aβ Alzheimer amyloid
plaque component CLAC, and its precursor
CLAC-P
The major component of Alzheimer’s amyloid
plaques is Aβ, although there are a number of non-Aβ
components that potentially affect fibrillization anddegradation of amyloid deposits. Among these, there
has been an enigmatic “missing piece” protein of molecular masses of 50/100 kDa. Dr. Iwatsubo’s groupraised a monoclonal antibody against amyloid fractionthat recognizes this protein, and using this antibody as
a probe, they conducted a thorough biochemical purification of these antigens and finally cloned a cDNA
coding for the precursor of this protein. This protein
turned out to be a novel class of membrane-boundcollagen, which was named CLAC (collagen-like
Alzheimer amyloid plaque component) and its precursor CLAC-P (Hashimoto et al. EMBO J 2002).
This finding had an immense impact both on fields ofAD research as well as on general biology as a first
discovery of neuron-specific collagen harboring aunique membrane-spanning structure. CLAC has beenhighlighted as a protein that may affect fibrillizationof Aβ and contribute to amyloid plaque formation.

75

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

References
1) Cheng H, Vetrivel KS, Drisdel RC, Meckler X,
Gong P, Leem JY, Li T, Carter M, Chen Y, Nguyen
P, Iwatsubo T, Tomita T, Wong PC, Green WN,
Kounnas MZ, Thinakaran G: s-Palmitoylation ofγ-secretase subunits nicastrin and Aph-1. J Biol
Chem 284:1373-1384, 20092) Azeredo da Silveira S, Schneider BL, Cifuentes-Diaz C, Sage D, Abbas-Terki T, Iwatsubo T,
Unser M, Aebischer P: Phosphorylation does notprompt, nor prevent, the formation of α-synuclein
toxic species in a rat model of Parkinson’s disease.
Human Molecular Genetics 18: 872-887, 20093) Imamura Y, Watanabe N, Umezawa N, Iwatsubo T,
Kato N, Tomita T, Higuchi T: Inhibition ofγ-secretase activity by helical β-peptide foldamers.

J Am Chem Soc 131:7353-7359, 20094) Shimizu N, Watanabe H, Kubota J, Wu J, Saito R,
Yokoi T, Era T, Iwatsubo T, Watanabe T, Nishina
S, Azuma N, Katada T, Nishina H: Pax6-5a promotes neuronal differentiation of murine embryonic stem cells. Biol Pharm Bull 32:999-1003,
20095) Saha S, Guillily MD, Ferree A, Lanceta J, Chan D,
Ghosh J, Hsu CH, Segal L, Raghavan K, Matsumoto K, Hisamoto N, Kuwahara T, Iwatsubo T,
Moore L, Goldstein L, Cookson M, Wolozin B:
LRRK2 modulates vulnerability to mitochondrial
dysfunction in Caenorhabditis elegans. J Neurosci
29:9210-9218, 2009
6) Yamada K, Yabuki C, Seubert P, Schenk D, Hori Y,
Ohtsuki S, Terasaki T, Hashimoto T, Iwatsubo T:
Aβ immunotherapy: intracerebral sequestration of
Aβ by an anti-Aβ monoclonal antibody 266 withhigh affinity to soluble Aβ. J Neurosci 29:
11393-11398, 20097) Hayashi I, Takatori S, Urano Y, Iwanari H, Isoo N,
Osawa S, Fukuda MA, Kodama T, Hamakubo T,
Li T, Wong PC, Tomita T, Iwatsubo T: Single
chain variable fragment against Nicastrin inhibits
the γ-secretase activity. J Biol Chem
284:27838-27847, 2009
8) Chapuis J, Hot D, Hansmannel F, Kerdraon O,
Ferreira S, Hubans C, Maurage CA, Huot L, Bensemain F, Laumet G, Ayral AM, Fievet N, Hauw JJ,
DeKosky ST, Lemoine Y, Iwatsubo T, Wavrant-Devrièze F, Dartigues JF, Tzourio C, Buée L,
Pasquier F, Berr C, Mann D, Lendon C, Alpérovitch A, Kamboh MI, Amouyel P, Lambert JC:
Transcriptomic and genetic studies identify IL-33
as a candidate gene for Alzheimer’s disease. Mol
Psychiatr 14:1004-1016, 20099) Kamikawaji S, Ito G, Iwatsubo T: Identification of
the autophosphorylation sites of LRRK2. Biochemistry 48:10963-10975, 2009
10) Yokoshima S, Abe Y, Watanabe N, Kita Y, Kan T,
Iwatsubo T, Tomita T, Fukuyama T: Developmentof photoaffinity probes for γ-secretase equippedwith a nitrobenzenesulfonamide-type cleavable
linker. Bioorg Med Chem Lett 19:6869-6871,
200911) Masuda S, Kumano K, Suzuki T, Tomita T, Iwatsubo T, Natsugari H, Tojo A, Shibutani M, Mit-

76

sumori K, Hanazono Y, Ogawa S, Kurokawa M,
Chiba S: Dual antitumor mechanisms of Notch
signaling inhibitor in a T cell acute lymphoblastic
leukemia
xenograftmodel.
CancerSci
100:2444-2450, 2009

77

Department of eurochemistry
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, two assistant professors, three78

postdoctoral scholars, one technical staff member,four Ph.D. and three M.S.-Ph.D. graduate students,
two 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).
Furthermore,
CaMKIV-KO,
CaMKK-KOand79

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. inpress). Surprisingly, SARE contained juxtaposedbinding elements for all three activity-regulatedtranscription factors, CREB, MEF2 and SRF.
Currently, experiments are ongoing to capitalize on
this knowledge in order to build reporter virus andmouse lines that are expected to be useful to map theextent 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). Similar
studies in axonal growth also suggest the active
contribution of CaMKK cascade in this process(Ageta-Ishihara et al., J. Neurosci. 2009).
One further important topic that we have been
focusing for a number of years is the role of gene
expression in prolongation / consolidation ofsynapse-specific local changes. Neurons undergoing
various stimulus patterns have been followed up intime and the amount of newly synthesized proteins
and the local distribution of induced gene products
have been monitored. Using state-of-the-art multiwavelength fluorescence imaging techniques, we are
now quantitatively assessing how local distribution ofthese newly synthesized gene products affect synaptic
protein complexes (Okuno and Bito, AfCS/Nature
Mol. Pages, 2006).
2) Understanding molecular mechanisms controlling
cytoskeletal dynamics and remodeling on both sides

80of 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 andROCK has already been postulated in control of spinecomplexity and spine stability. However, multiple
small GTPase signaling cascades clearly seem tocontribute together, in a tightly coordinated manner, tospine regulation, since many distinct classes of GEFs
and GAPs have now been shown to be localized in the81dendritic 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 2009- December 2009)
1. Kawashima T, Okuno H, Nonaka M,
Adachi-Morishima A, Kyo N, Okamura M,
Takemoto-Kimura S, Worley PF and Bito H. A
synaptic activity-responsive element in the
Arc/Arg3.1 promoter essential for synapse-tonucleus signaling in activated neurons. Proc. atl.
Acad. Sci. USA, 106: 316-321, 2009.
2. Nonaka M. A Janus-like role of CREB protein:enhancement of synaptic property in matureneurons and suppression of synaptogenesis andreduced network synchrony in early development.
J. eurosci. 29: 6389-6391, 2009.
3. Ageta-Ishihara N, Takemoto-Kimura S, Nonaka
M, Adachi-Morishima A, Suzuki K, Kamijo S,
Fujii H, Mano T, Blaeser F, Chatila TA, Mizuno
H, Hirano T, Tagawa Y, Okuno H, Bito H.

Control of cortical axon elongation by a
GABA-driven
Ca2+/
calmodulin-dependent
protein kinase cascade. J. eurosci. 29: 1372013729, 2009.

82

Department of eurobiology
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

83

function 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
Y Isa M, Ohta Y, Namiki S, Hirose K. Artificial
control of subtype-specific platelet-derived growth
factor receptor signaling Journal of Pharmacological
Sciences, 111, 312-316 (2009)
Matsuo R, Kobayashi S, Watanabe S, Namiki S,
Iinuma S, Sakamoto H, Hirose K, Ito E. Glutamatergic
neurotransmission in the procerebrum (Olfactory
center) of a terrestrial mollusk. Journal ofeuroscience Research, 87, 3011–3023 (2009)euroscience
2. Speech and Cognitive Sciences

85

Department of Cognitiveeuroscience
Associate Professor
Katsuyuki Sakai, M.D., PhD

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

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

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

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

86

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. Morita K. Possible dendritic contribution tounimodal numerosity tuning and Weber-Fechner
law-dependent numerical cognition. Frontiers in
Computational Neuroscience 3:12, 2009.
2. Soga R, Akaishi R, Sakai K. Predictive andpostdictive mechanisms jointly contribute tovisual awareness. Consciousness and Cognition.
18:578-592, 2009.
3. Bengtsson SL, Haynes JD, Sakai K, Buckley MJ,
Passingham RE. The representation of abstract
task rules in the human prefrontal cortex. Cerebral
Cortex 19:1929-1936, 2009.
4. Morita K. Dynamical foundations of the neuralcircuit for Bayesian decision making. Journal of
Neurophysiology 102:1-6, 2009.
5. Morishima Y, Akaishi R, Yamada Y, Okuda J,
Toma K, Sakai K. Task-specific signaltransmission from prefrontal cortex in visual
selective attention. Nature Neuroscience 12:85-91,
2009.

euroscience
3. Clinical euroscience88

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

Associate Professor
Chihiro Kakiuchi, M.D., Ph.D.

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

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

Kazuya Iwamoto, Ph.D.

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

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

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

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

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

Ken Kino, M.D., Ph.D.,

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

Takuji Nishida, M.D.,

Junichi Terai, M.D.

Kazuyuki Sugishita, M.D.,

Yuko Okada M.D.

Yoshihiro Satomura, M.D.

Miki Bundo, Ph. D.

Homepage

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

Introduction and Organization

Clinical activities

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

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

89

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

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

Research activities
Stress- It is well accepted that neuropeptide Y(NPY) is involved in anxiolytic-like effects andanti-stress effects. Pharmacological and behavioral
studies have consistently indicated that these effects
are mainly mediated through an activation of NPY Y1
receptor in the brain. To further elucidate thefunctional role of Y1 receptor, we have evaluated thehistological and behavioral changes in Y1
receptor-deficient mice, after an exposure to 2h ofrestraint stress. Trimethyltin (TMT), a neurotoxic
organotin, has been shown to cause selective loss ofpyramidal neurons in the rat hippocampus, similar tostress-induced hippocampal changes. Several recent
studies in animal models of brain ischemia revealed
the neuroprotective properties of tacrolimus (FK506),
a potent immunosuppressant used in organ transplants.
Therefore, we have investigated the effect of FK-506
on the neuronal death and apoptosis in the
hippocampus after TMT intoxication, using
immunohistochemistry and TUNEL method.
Epilepsy- Systemic injection of kainic acid in rat
causes severe convulsions, increased seizure
susceptibility and seizure-induced neuronal death.
Since precise mechanisms of various anticonvulsants
are still unclear, we have investigated to elucidate
whetherthese
anticonvulsantsdemonstrateneuroprotective effects on kainic acid-induced
neuronal death in the hippocampus.
Environmental endocrine disrupter- Bisphenol-A(BPA), one of environmental endocrine disrupters, isreleased from polycarbonate plastics, and is known to
mimic oestrogens in their action. Recent studies
reported that prenatal and neonatal exposure to
low-dose bisphenol-A modulates the sexual
differentiation of behavior and the central
dopaminargic effects in vivo and in vitro. We examine
the effects of BPA on the behavior, memory and theexpression of estrogen-alpha receptor in the brain ofrats exposed to BPA during the fetal and sucklingperiods at a dosage far less than the
no-observed-adverse-effect level.
Genetic Research- The Genetic Research Group of
the department is investigating genetic as well as
environmental mechanism of psychiatric disorders. A
major focus of the studies is exploration ofsusceptibility genes of the disorders including
schizophrenia, infantile autism, their spectrum
disorders and anxiety disorder (mainly panic disorder).
A number of candidates of the susceptible genes arestudied using case-control and TDT (transmission
disequilibrium test) designs. We are at present
achieving most interesting results in the investigationsof DISC1, Neuregulin1 and other candidate genes in90schizophrenia and the chromosome 7 genes in
infantile autism. Another focus is investigation ofgenes that affect the development of personality.
euroimaging- Our group plays a leading role inpsychiatric neuroimaging in Japan. Our research aims
at multi-modality neuroimaging (structural andfunctional MRI, MR spectroscopy, EEG, MEG, nearinfrared spectroscopy (NIRS), PET) in schizophrenia,
mood disorders, pervasive developmental disorders,and posttraumatic stress disorder (PTSD).
Clinical Pharmacology- The atypical neuroleptics
have been widely prescribed in our country. They
contribute to the reduction of uncomfortable side
effects and the improvement of the patient’s QOL. But
the typical neuroleptics still have been used becauseof their sedative effects particularly in acute state of
Schizophrenia. We have been investigating a
voluntary clinical research, which contain thepractical evaluation to the treatment of atypicalneuroleptics
for
acute
psychotic
stateinSchizophrenia.
Recently the abnormal glucose tolerance induced byatypical neuroleptics had been reported and some
accidental hyperglycemia had happened in our country,
too. Though there are many reports involving to thisproblem in foreign country, few detailed investigation
was performed in Japan until now. We are preparing to
examine the glucose tolerance of inpatients that aretreated by neuroleptics in collaboration with many
hospitals and expect that the frequency of risk andsome actual factors will be revealed.
europathological study of dementias- Our interestis neuropathological background of dementia,
especially NFT-predominant form of dementia(NFTD). NFTD is a sporadic subset of dementia
pathologically characterized by abundant and almost
exclusive appearance of NFTs in the limbic areas withscarcity of senile plaques. Our study suggests that
pathogenetic background of NFTD may be different
from that of AD and cognitive decline in NFT-SC may
be affected not only by severity of NFT pathology but
also by coexisting vascular lesions and/or argyrophilic
grains.

References1

Abe O, Yamasue H, Aoki S, Suga M, Yamada H,

2

3

4

5

6

7

8

9

Kasai K, Masutani Y, Kato N, Kato N, Ohtomo K:
Aging in the CNS: comparison of gray/whitematter volume and diffusion tensor data.
Neurobiol Aging, in press.
Abe O, Yamasue H, Kasai K, Yamada H, Aoki S,
Iwanami A, Ohtani T, Masutani Y, Kato N,
Ohtomo K: Voxel-based diffusion tensor analysis
reveals aberrant anterior cingulum integrity inposttraumatic stress disorder due to terrorism.
Psychiatry Res Neuroimaging 146: 231-242, 2006
Araki T, Yamasue H, Sumiyoshi T, Kuwabara H,
Suga M, Iwanami A, Kato N, Kasai K:
Perospirone in the treatment of schizophrenia:
effect on verbal memory organization. Prog
Neuropsychopharmacol Biol Psychiatry 30:
204-208, 2006
Araki T, Kasai K, Rogers MA, Kato N, Iwanami
A: The effect of perospirone on auditory P300 in
schizophrenia: a preliminary study. Prog
Neuropsychopharmacol Biol Psychiatry 30:
1083-1090, 2006
Araki T, Kasai K, Kirihara K, Yamasue H, Kato N,
Kudo N, Nakagome K, Iwanami A: Auditory P300
latency prolongation with age in schizophrenia:
gender and subcomponent effects. Schizophr Res
88: 217-221, 2006
Ebisawa T: Circadian rhythms in the CNS andperipheral clock disorders: Human sleep disorders
and clock genes. J Pharmacol Sci, in press
Fujimura Y, Ikoma Y, Yasuno F, Suhara T, Ota M,
Matsumoto R, Nozaki S, Takano A, Kosaka J,
Zhang M.-R, Nakao R, Suzuki K, Kato N, Ito H:
Quantitative analyses of [18F]FEDAA1106
binding to peripheral benzodiazepine receptors inliving human brain. Journal of Nuclear Medicine
47: 43-50, 2006
Hibino H, Tochigi M, Otowa T, Kato N, Sasaki T:
No association of DRD2, DRD3, and tyrosinehydroxylase gene polymorphisms with personality
traits in the Japanese population. Behav Brain
Funct 2: 32, 2006
Ikoma Y, Yasuno F, Ito H, Suhara T, Ota M,
Toyama H, Fujimura Y, Takano A, Maeda J,
Zhang M.-R, Nakao R, Suzuki K: Quantitative
analysis for estimating binding potential of theperipheral
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Published online, in press
10 Kaneko N. Kudo K. Mabuchi T. Takemoto K.
Fujimaki K. Wati H. Iguchi, H. Tezuka H, Kanba
S: Suppression of cell proliferation by interferonalpha through interleukin-1 production in adult rat
dentategyrus.
Neuropsychopharmacology
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11 Kato N, Sadamatsu M, Taeko K, Noriko N,
Fukuyama Y: Paroxysmal Knesigenic Choreoathetosis: From first discovery in 1892 to genetic
linkage with benign familial infantile convulsions.
Epilepsy Research 70S: S174-S184, 2006
12 Kawakubo Y, Kasai K, Rogers MA, Nakagome K,
Iwanami A, Kamio S, Nose T, Kato N, Fukuda M:
Phonetic mismatch negativity predicts social skills
acquisition in schizophrenia. Psychiatry Res, inpress.
13 Kawakubo Y, Kasai K: Support for an association
between mismatch negativity and social
functioning in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 30: 1367-1368, 2006
14 Kawakubo Y, Rogers MA, Kasai K: Procedural
memory predicts social skills in persons withschizophrenia. J Nerv Ment Dis 194: 625-627,
2006
15 Kawakubo Y, Kasai K, Kudo N, Rogers MA,
Nakagome K, Itoh K, Kato N: Phonetic mismatch
negativity predicts verbal memory deficits inschizophrenia. Neuroreport 17: 1043-1046, 2006
16 Kawashima M, Tamiya G, Oka A, Hohjoh H, JujiT, Ebisawa T, Honda Y, Inoko H, Tokunaga K:
Genomewide association analysis of humannarcolepsy and a new resistance gene. Am J Hum
Genet 79: 252-263, 2006
17 Kazuno A, Munakata K, Nagai T, Shimozono S,
Tanaka M, Yoneda M, Kato N, Miyawaki A, Kato
T: Identification of mitochondrial DNA
polymorphisms that alter mitochondrial matrix pH
and intracellular calcium dynamics. PLoS
Genetics, in press
18 Kikuchi T, Nomura M, Tomita H, Harada N,
Kanai K, Konishi T, Yasuda A, Matsuura M, Kato
N, Yoshiura K, Niikawa N: Paroxysmal
kinesigenic choreoathetosis (PKC): Confirmationof linkage to 16p11-q21 but unsuccessful
detection of mutations among 157 genes at the
PKC-critical region in seven PKC families. J Hum

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

92

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

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

93

epigenetics and schizophrenia. J Psychiatr Res, inpress
43 Takemura N, Kato N: Adult neurogenesis andsystemic adaptation: animal experiments andclinical perspectives for PTSD. Progress in Brain
Research, in press
44 Tochigi M, Otowa T, Hibino H, Kato C, Otani T,
Umekage T, Utsumi T, Kato N, Sasaki T:
Combined analysis of association between
personality
traitsand
threefunctional
polymorphisms in the tyrosine hydroxylase,monoamine oxidase A, and catechol-Omethyltransferase genes. Neurosci Res 54:
180-185, 2006
45 Tochigi M, Hibino H, Otowa T, Kato C, Marui T,
Ohtani T, Umekage T, Kato N, Sasaki T:
Association between Dopamine D4 Receptor(DRD4) Exon III polymorphism and Neuroticism
in the Japanese Population. Neurosci Lett 398:
333-336, 2006
46 Tochigi M, Hibino H, Otowa T, Ohtani T, Ebisawa
T, Kato N, Sasaki T: No association of 5-HT2C,
5-HT6, and tryptophan hydroxylase-1 gene
polymorphisms with personality traits in theJapanese population. Neurosci Lett 403: 100-102,
2006
47 Tochigi M, Otowa T, Hibino H, Kato C, Marui T,
Ohtani T, Umekage T, Kato N, Sasaki T: No
association between the Clara cell secretory
protein (CC16) gene polymorphism andpersonality traits. Prog Neuropsychopharmacol
Biol Psychiatry 30: 1122-1124, 2006
48 Tochigi M, Kato C, Otowa T, Hibino H, Marui T,
Ohtani T, Umekage T, Kato N, Sasaki T:
Association between the Corticotropin-Releasing
HormoneReceptor
2(CRHR2)Gene
Polymorphism and Personality Traits. Psychiatry
Clin Neurosci 60: 524-526, 2006
49 Tochigi M, Zhang X, Ohashi J, Hibino H, Otowa
T, Rogers M, Kato T, Okazaki Y, Kato N,
Tokunaga K, Sasaki T: Association study of thedysbindin (DTBP1) gene in schizophrenia fromthe Japanese population. Neurosci Res 56:
154-158, 2006
50 Tochigi M, Otowa T, Suga M, Rogers M, Minato
T, Yamasue H, Kasai K, Kato N, Sasaki T: No
evidence for an association between the BDNF

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

94

Department of eurology
Professor
Shoji Tsuji, M.D., Ph.D.

Associate Professor
Shin Kwak, M.D., Ph.D.

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

Associate
Yasuo Terao, M.D.,Ph.D., Tomotaka Yamamoto, M.D.,Ph.D.,
Yaeko Ichikawa, M.D.,Ph.D., Riotsuko Hanajima, M.D., Ph.D.,
Yuji Takahashi, M.D.,PhD.

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

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 thatbased on vestibular nerve stimulation are being
conducted.

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

As for under-graduate education, our Department
takes a part in lectures of Neurology for the 4th and 5th
grade medical students, and bed-side learning for the
5th grade medical students, and clinical clerkship forthe 5th grade medical students.
In the bed-side learning we include small group
lectures covering
neurological examination,neurophysiology, neuroradiology, neuropathology,
neuropsychology, neuroimmunology, and neurogenetics.
We are also putting our effort for Free Quarters where95

we offer various opportunities for medical students to
be involved in research activities, and 2-3 medical
students are conducting their research activities in thelaboratories.
In postgraduate education we offer the integrated
program including Neurology as the part of the
program of Internal Medicine.
For training of board-certified Neurologists, weoffer the excellent program including patients’care,training in Neurophysiology and Neuropathology,
consultation for Neurology, and supervising of juniortrainees. This program is integrated with clinicalpractice at the affiliated hospitals where rich experienceis 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 have successfullycompleted the program. Following the 21st Century
COE program, we started “Global Center of Education
and Research for Chemical Biology of the Diseases” asa 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 to eventuallydevelop new therapeutic strategies. Our research
activities include molecular genetics, developmental
biology, cell biology, pharmacology, pathology, andphysiology. We aim to integrate these broad research
fields to better contribute to clinical neurology.
In the filed of molecular genetics, we have develop
a high throughput DNA-microarray-based diagnostic
system. This system provides comprehensive analysesof genes including those for Alzheimer disease,
Parkinson disease, amyotrophic lateral sclerosis, andfamilial spastic paraplegia. We have discovered that
glucocerebrosidase gene (GBA) confers a strong risk
with an odds ratio of 28.0 for susceptibility to
Parkinson disease. This finding was further confirmed
by international collaboration. A high throughput
pipeline for linkage analysis was established, which
was applied for linkage analysis of manyneurodegenerative diseases. Large-scale genome
analysis employing next generation sequencers were
initiated to identify causative genes for familial
neurologic diseases. We have initiated multicenterbased consortium for multiple system atrophy. A
large-scale genome-wide analyses are being conducted
to identify disease susceptibility genes. We haveestablishedexcellent
animalmodelsfordentatorubral-pallidoluysian atrophy, and conducting
studies for development of therapeutics. As the newprotein degradation pathway, the role of autophagy wasinvestigated. (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)
We have demonstrated that RNA editing ofglutamate receptor subunit GluR2 due to underactivityof ADAR2, an RNA editing enzyme, was significantly
reduced in motor neurons in sporadic ALS patients in aneuronal class-selective and disease specific manner.
Since this molecular change is the primary causes ofneuronal death, research work on elucidation of theunderlying molecular mechanism and development ofspecific therapy for sporadic ALS is undergoing. (Kwak,
S., Hideyama, T., Yamashita, T., Teramoto, S., Hachiga
K., Kaneko, S.)
The human neurophysiology section has been
studying normal function of the human brain andpathophysiology for neurological disorders using
several non-invasive physiological methods, such as
TMS, EEG, MEG, fMRI, NIRS and ECG. Our final
goal is to develop a new therapeutic method for
intractable disorders. One of them is deep brain
stimulation (DBS) which has been partly established.
We began a physiological approach to elucidate thetherapeutic mechanisms for DBS in the patients. We
have also recently developed a new, highly effective
TMS method to induce long-term effects on the humanbrain using repetitive, monophasic magnetic stimuli.
We have just stared a project to treat patients withmovement disorders, intractable pain, epilepsy and soon using that new treatment. (Terao, Y., Hanajima, R.,
Okabe, S., Yugeta, A., Hamada, M., Matsumoto, H.,
Furubayashi, T., Higashihara, M., Shirota, Y, Ohminami,
S.)

96

In the field of neuromuscular diseases, we provide
pathological diagnosis of biopsied materials frompatients with myopathy or neuropathy. We also provide
autoantibody testing for anti-ganglioside antibodies,muscle specific antibodies and paraneoplastic
neurological antibodies. In research field, using
biopsied muscles and collected serum samples, we havebeen studying the mechanisms of inflammatory
myopathies especially in polymyositis, cancer
associated myositis, dermatomyositis, collagen diseaseassociated myositis and myositis with autoantibodies.
We have also been studying the mechanism of muscle
fiber regeneration in various myopathies including
inclusion body myositis. We aim to increase
understanding of the etiology and pathogenesis ofneuromuscular 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 related to thepathogenesis of polyglutamine diseases. Studies on
epigenetics of Parkinson’s disease revealed abnormal
epigenetic changes in the disease (Iwata, A., Kowa, 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 inmotor neurons lacking RNA editing enzyme
ADAR2. Acta Neuropathol DOI 10.1007/s00401010-0678-x.
2. Arai N, Furubayashi T, Inomata-Terada S, Okabe S,
Kobayashi-Iwata N, Hanajima R, Terao Y, Ugawa
Y. Effects of a high-frequency, low-intensity,
biphasic conditioning train of TMS pulses on thehuman motor cortex. Neurosci Lett. 25;462:188-92,
2009.
3. Dick Krueger KA, Tsuji S, Fukuda Y, Takahashi Y,
Goto J, Mitsui J, Ishiura H, Dalton JC, Miller MB,
Day JD, Ranum LPW. SNP Haplotype Mapping in
a Small ALS Family. PLoS ONE. 4:e5687, 2009.
4. Fukuda Y, Nakahara Y, Date H, Takahashi Y, GotoJ, Miyashita A, Kuwano R, Adachi H, Nakamura E,

and Tsuji S. SNP HiTLink: a high-throughput
linkage analysis system employing dense SNP data.
BMC Bioinformatics 10:121 doi:10.1186/14712105-10-121, 2009
5. Hamada M, Hanajima R, Terao Y, Okabe S,
Nakatani-Enomoto S, Furubayashi T, Matsumoto H,
Shirota Y, Ohminami S, Ugawa Y. Primary motor
cortical metaplasticity induced by priming over the
supplementary motor area. J Physiol. 587:4845-62,
2009.
6. Hanajima R, Terao Y, Hamada M, Okabe S,
Nakatani-Enomoto S, Furubayashi T, Yugeta A,
Inomata-Terada S, Ugawa Y. Forty-hertz triplepulse stimulation induces motor cortical facilitationin humans. Brain Res. 3;1296:15-23, 2009.
7. Hanajima R, Terao Y, Nakatani-Enomoto S,
Hamada M, Yugeta A, Matsumoto H, Yamamoto T,
Tsuji S, Ugawa Y. Postural tremor in X-linked
spinal and bulbar muscular atrophy. Mov Disord.
24;2063-9, 2009
8. 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 associatedwith amyotrophic lateral sclerosis-parkinsonism
dementia complex in the Kii peninsula of Japan.
Am. J. Med. Genet. 153B:310-313, 2010.
9. Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita
A, Yokoseki A, Kawata H, Koyama A, Arima K,
Takahashi T, Ikeda M, Shiota H, Tamura M,
Shimoe Y, Hirayama M, Arisato T, Yanagawa S,
Tanaka A, Nakano I, Ikeda S, Yoshida Y,
Yamamoto T, Ikeuchi T, Kuwano R, Nishizawa M,
Tsuji S, Onodera O. Familial Ischemic Cerebral
Small-Vessel Disease, Alopecia, and Spondylosis
Caused by Mutations in the HTRA1 Gene. New
Engl J Med 360:, 1729-1739, 2009
10. Hideyama T, Yamashita Y, Nishimoto Y, Suzuki T,
Kwak S: Novel etiologic and therapeutic strategies
for neurodiseases: RNA editing enzyme
abnormality in sporadic amyotrophic lateralsclerosis. J Pharmacol Sci, doi:10.1254/jphs.
09R21FM.
11. Higashihara M, Sonoo M, Imafuku I, Ugawa Y,
Tsuji S. Origin of ulnar Compound muscle action
potential investigated in patients with ulnar

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neuropathy at the wrist. Muscle Nerve 41:704-706,
2010
12. Higashihara M, Sonoo M, Tsuji S, Ugawa Y.
Two-step technique to optimize the medial
antebrachial cutaneous nerve response. Clinical
Neurophysiology 121: 712–713, 2010
13. Iwata A, Nagashima Y, Matsumoto L, Suzuki T,
Yamanaka T, Date H, Deoka K, Nukina N, Tsuji S.
Intranuclear
degradationofpolyglutamine
aggregates by the ubiquitin-proteasome system. J
Biol Chem.284: 9796-9803, 2009
14. Koike A, Nishida N, Inoue I, Tsuji S, and Tokunaga
K. Genome-wide association database developed in
the Japanese Integrated Database Project. J. Hum.
Genet. advance online publication 24 July 2009;
doi: 10.1038/jhg.2009.68
15. Koike A, Nishida N, Inoue I, Tsuji S, Tokunaga K.
Replication of a genome-wide association study ofpanic disorder in a Japanese population. J. Hum.
Genet. 55:91-96, 2010
16. Kubota, A, Hida, A, Ichikawa, Y, Momose, Y, Goto,J, Igeta, Y, Hashida, H, Yoshida, K, Ikeda, S,
Kanazawa, I, and Tsuji, S. A novel ferritin lightchain gene mutation in a Japanese family withneuroferritinopathy: description of clinical features
andimplicationsforgenotype-phenotype
correlations. Mov. Disord. 24:441-445, 2009
17. Kwak S, Hideyama T, Yamashita T, Aizawa H:
AMPA receptor-mediated neuronal death insporadic ALS. Neuropathology 30:182-188, 2010.
doi:10.1111/j.1440-1789.2009.01090.x.
18. Matsumoto H, Hanajima R, Terao Y, Yugeta A,
Hamada M, Shirota Y, Ohminami S,
Nakatani-Enomoto S, Tsuji S, Ugawa Y. Prominentcauda equina involvement in patients with chronic
inflammatory
demyelinating
polyradiculoneuropathy. J Neurol Sci. 15;290:112-4, 2010.
19. Matsumoto H, Hanajima R, Shirota Y, Hamada M,
Terao Y, Ohminami S, Furubayashi T, NakataniEnomoto S, Ugawa Y. Cortico-conus motor
conduction time (CCCT) for leg muscles. Clin
Neurophysiol. 2010. [Epub ahead of print].
20. Matsumoto L, Hanajima R, Matsumoto H,
Ohminami S, Terao Y, Tsuji S, Ugawa Y.
Supramaximal Responses can be elicited in handmuscles by magnetic stimulation of the cervicalmotor roots. Brain Stimulation (in press)
21. Matsumoto H, Hanajima R, Terao Y, Hamada M,
Yugeta A, Shirota Y, Yuasa K, Sato F, Matsukawa T,
Takahashi Y, Goto J, Tsuji S, Ugawa Y.: Efferent
and afferent evoked potentials in patients withadrenomyeloneuropathy. Clin Neurol Neurosurg.
2009. [Epub ahead of print]
22. Mitsui, J, Mizuta, I, Toyoda, A, Ashida, R,
Takahashi, Y, Goto, J, Fukuda, Y, Date, H, Iwata, A,
Yamamoto, M, Hattori, N, Murata, M, Toda, T and
Tsuji, S. Mutations for Gaucher disease confer ahigh susceptibility to Parkinson disease. Arch
Neurol 66:571-6, 2009.
23. 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. (in press)
24. 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 siteassociated loci, PARK2 and DMD, in germ cell andcancer cell lines. Am J Hum Genet (in press)
25. Nakamura K, Igarashi K, Ohkawa R, Okubo S,
Yokota H, Kishimoto T, Ide K, Masuda A,
Yamamoto T, Saito N, Kurokawa M, Tsuji S,
Okudaira S, Ikeda H, Aoki J, Yatomi Y. Autotaxin
enzyme immunoassay in human cerebrospinal fluid
samples. Clin. Chim. Acata 405:160-162, 2009.
26. Nakatani-Enomoto S, Terao Y, Hanajima R,
Matsuda S, Ohminami S, Inomata-Terada S,
Matsumoto H, Yugeta A, Yamamoto T, Goto J,
Yumoto M, Tsuji S, Ugawa Y. Motor cortical
epilepsia partialis continua in a patient with alocalized sensory cortical lesion. Clin Neurol
Neurosurg. 111: 762-5, 2009.
27. Okano T, Terao Y, Furubayashi T, Yugeta A,
Hanajima R, Ugawa Y. The effect of electromagnetic field emitted by a mobile phone on theinhibitory control of saccades. Clin Neurophysiol.

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121:603-11, 2010.
28. Sato K, Yabe I, Fukuda Y, Soma H, Nakahara Y,
Tsuji S, Sasaki H. Autosomal dominant cerebellar
ataxia without pathogenic PPP2R2B mutation maps
to SCA12 locus. Arch Neurol (in press)
29. 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-specific analysis
5 of the uncinate fasciculus in patients withamyotrophic 6 lateral sclerosis. Neuroradiology (inpress)
30. Sato N, Amino T, Kobayashi K, Asakawa S,
Ishiguro T, Tsunemi T, Takahashi M, Matsuura T,
Flanigan KM, Iwasaki S, Ishino F, Saito Y,
Murayama S, Yoshida M, Hashizume Y, Takahashi
Y, Tsuji S, Shimizu N, Toda T, Ishikawa K,
Mizusawa H.Spinocerebellar Ataxia Type 31 Is
Associated with "Inserted" Penta-Nucleotide
Repeats Containing (TGGAA)(n). Am J Hum
Genet. 85:544-557, 200931. Sato, T, Miura, M, Yamada, M, Yoshida, T, Wood,JD, Yazawa, I, Masuda, M, Suzuki, S, Shin, R-M,
Yau,H-J, Liu, F-C, Shimohata, T, Onodera, O, Ross,
CA, Katsuki, M, Takahashi, H, Kano, M, Aosaki, T
and Tsuji, S. Severe neurological phenotypes of
Q129 DRPLA transgenic mice serendipitously
created by en masse expansion of CAG repeats in
Q76 DRPLA mice. Hum. Mol. Genet. 18:723-736,
2009
32. 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, Tsuji S. IFN β-1b May
Severely Exacerbate Japanese Optico-Spinal MS in
Neuromyelitis Optica Spectrum. Neurol. (in press)
33. 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 made by lung operation.
In.t Med. (in press)
34. Shirota Y, Hamada M, Terao Y, Matsumoto H,
Ohminami S, Furubayashi T, Nakatani-Enomoto S,
Ugawa Y, Hanajima R. Influence of short-interval
intracorticalinhibitionon
short-interval

intracortical facilitation in human primary motor
cortex. J Neurophysiol. (in press)
35. Shirota Y, Hamada M, Hanajima R, Terao Y,
Matsumoto H, Ominami S, Tsuji S, Ugawa Y.
Cerebellar dysfunction in progressive supranuclear
palsy: a transcranial magnetic stimulation study.
Movement Disordrs (in press)
36. Sidransky E, Aasly JO, Aharon-Peretz J, Annesi G,
Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A,
Chen C-M, Clark ON, Condroyer C, De Marco EV,
Dürr A, Eblan MJ, Fahn S, Farrer M, Fung H-C,
Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N,
Griffith A, Gurevich T, Januario C, Kropp R, Lang
AE, Lee-Chen G-J, Lesage S, Marder K, Mata IF,
Mirelman A, Mitsui J, Mizuta I, Nalls MA,
Nicoletti G, Oliveira C, Ottman R, Orr-Urtreger A,
Pereira LV, Quattrone A, Rogaeva E, Rolfs A,
Rosenbaum H, Rozenberg R, Samii A, Samaddar T,
Schulte C, Sharma M, Singleton A, Spitz M, Tan
E-K, Tayebi N, Toda T, Troiano A, Tsuji S,
Wittstock M, Wolfsberg TG, Wu Y-R, Zabetian CP,
Zhao Y, Ziegler SG. International multi-center
analysis of glucocerebrosidase mutations in
Parkinson disease. New Engl J. Med.
361:1651-1661, 2009
37. Takei N, Miyashita A, Tsukie T, Arai H, Asada T,
Imagawa M, Shoji M, Higuchi S, Urakami K,
Kimura H, Kakita A, Takahashi H, Tsuji S,
Kanazawa I, Ihara Y, Odani S, Kuwano R. Genetic
association study on in and around the APOE in
late-onset Alzheimer disease in Japanese.
Genomics 93:441-448, 2009
38. Tsuji S. Genetics of neurodegenerative diseases:
insights from high-throughput resequencing. Hum.
Mol. Genet. (in press)
39. Wang K, Takahashi Y, Gao Z-L, Wang GX, Chen
XW, Goto J, Lou J-N, Tsuji S*. Mitochondrial ND3
as the Novel Causative Gene for Leber Hereditary
Optic Neuropathy and Dystonia. Neurogenetics
10:337-45, 200940. Yoshida M, Takahashi Y, Koike A, Fukuda Y, GotoJ, and Tsuji S. A variation database for amyotrophic
lateral sclerosis. Human Mutation (in press)
41. Yugeta A, Terao Y, Fukuda H, Hikosaka O,
Okiyama R, Yokochi F, Taniguchi M, Takahashi H,

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Hamada I, Hanajima R, Ugawa Y. Effects of STN
stimulation on the initiation and inhibition of
saccade in Parkinson's disease. Neurology. 74:7438, 2010.

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

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

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

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

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

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

Associate
Keisuke Takai, M.D,

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

Takahiro Ohta, M.D., PhD.,

Kuniaki Saito, M.D.,

Tomoyuki Koga, M.D.,

Kenjiro Konno, PhD.

Homepage

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

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

Clinical activities
General and specialized outpatient clinics are open
three days a week (Monday, Wednesday and Friday).

New patient are accepted two days a week (Tuesday
and Thursday). Specialized outpatient clinics are open
for patient with brain tumors, pituitary disease, spinal
disease, cerebrovascular disease, epilepsy, and gamma
knife treatment. From April 2008 through March 2009,
14,447 patients were treated at the outpatient clinics.
The Neurosurgery Ward has about 40 beds on theseventh floor of the new hospital building opened in
Sept. 2001. In 2007 and 2008, 482 and 731 patientswere admitted to the Neurosurgical Ward, respectively.
Three hundred and sixty seven and 391 surgicalprocedures were performed with 135 and 134 gamma
knife precedures in each year. Our practice covers awide variety of neurosurgical diseases including
malignant and benign brain tumors, hemorrhagic andocclusive cerebrovascular diseases, spinal disorders,
epilepsy, pain and movement disorders.
Intraoperative functional monitoring in brain tumor
surgery and pre- and intra-operative functional
mapping in epilepsy surgery are frequently used topreserve brain function as much as possible.
State-of-the-art techniques including intraoperative
computer-aided
navigation
andintravascular
procedures help our continuous effort to increase thesafety of surgical treatment.

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Our department is affiliated with 42 neurosurgicalinstitutions in and around the city of Tokyo including
15 university medical centers, where our residents andstudents are exposed to various pathologies. Surgicalcase volume in all hospitals exceeds 5500cases.

Teaching activities
Medical students take lectures of clinicalneurosurgery in their second year. Clinical case studies
and bedside teaching are scheduled in the third andfourth 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 8 residents in 2009 as a new residency
program. These residents are trained in the university
hospital and affiliated hospitals to experience every
aspects of neurosurgical practice for five years inaverage. Our residency training is finalized after thesixth year, when the finishing residents serve as seniorresident at the university hospital for 6 months.
Academic training is provided through numerous
intramural clinical and research conference, journal
clubs seminars as well as quarterly regional meeting ofJapan 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 schoolof Medicine, University of Tokyo, to be involved inadvanced basic research activities for 4 year. Aftercomplete training, our graduates stay in thedepartment to be an associate in our or otheruniversity hospitals or become clinical staff in ouraffiliated hospitals.

Research activities
Clinical research in these two years have mainly
focused on treatment of acoustic neurinoma
techniques of skull base surgery, treatment ofmalignant brain tumors, radiosurgery and epilepsy
surgery. The results were presented at domestic andinternational meetings including Annual Meetings of

the Japan Neurosurgical Society and Annual Meetingsof American Association of Neurological Surgeons. .
Our department has been keeping prominent basic
research activities as well. The fields of our current
research are as follows
1) Pathogenesis of cerebral ischemia and neuronal
regeneration after ischemic brain damage
One of the major topics in recent basic science is toregenerate the brain with endogenous neuralprogenitors. Our laboratory has started basic research
to regenerate neurons in vivo following ischemic
insult. We have demonstrated that the 40% of the lost
neurons could be regenerated by administration of
growth factors. We also succeeded in regeneration of
striatal neurons. Molecular mechanisms of adultneurogenesis are currently investigated using various
models to enhance post-ischemic regeneration. By
extending the research into primate model, we are
pursuing clinical application in the future.
2) Development of New Therapeutic Modalities for
Malignant Brain Tumors
Despite advances in microsurgical techniques, thepoor prognoses of malignant glioma patients have not
improved for decades. We develop a new strategy byusing replication-competent herpes simplex viruses(HSV) that are genetically engineered to replicate in
and kill tumor cells but not normal cells. Using athird-generation oncolytic HSV, we currently prepare aclinical trial on patients with progressive glioblastoma.
Using our HSV vector construction system, we further
create and test various oncolytic HSV vectors “armed”
with immunostimulatory genes.
We also practice optimized therapy based on the
results of genetic analyses routinely performed ontumor specimens obtained from glioma patients.
Currently, using polymeric micelles, we develop a
new mode of chemotherapeutic drug delivery systemfor brain tumors.
3) Development and evaluation of function-preserving
and less invasive treatment of intractable epilepsy
We have been promoting the research on development,
evaluation and standardization of the novel treatment
for intractable epilepsy. Since our facility is presently
the only one that can provide vagus nerve stimulation
therapy in Japan, we are trying to evaluate its efficacy
and establish its significance in epilepsy treatment.
Efficacy evaluation and development of surgical102

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

References
1. Amemiya S, Akahane M, Aoki S, Abe O, Kamada
K, Saito N, Ohtomo K: Dynamic contrastenhanced perfusion MR imaging with SPIO: apilot study. Invest Radiol 44: 503-508, 2009
2. Igaki H, Maruyama K, Koga T, Murakami N,
Tago M, Terahara A, Shin M, Nakagawa K,
Ohtomo K: Stereotactic radiosurgery for skull
base meningioma. eurol Med Chir (Tokyo) 49:
456-461, 2009
3. Iijima A, Nishido H, Ishikawa O, Saito N: Three
dimensional estimation of aneurysms after coilembolization with inverted translucent images.
Interv euroradiol 15(Suppl 1): 212-213, 2009
4. Ikushima H, Todo T, Ino Y, Takahashi M,
Miyazawa K, Miyazono K: Autocrine TGF-beta
signaling maintains tumorigenicity of gliomainitiating cells through Sry-related HMG-box
factors. Cell Stem Cell 5: 504-514, 2009
5. Jarraya B, Boulet S, Ralph GS, Jan C, Bonvento G,
Azzouz M, Miskin JE, Shin M, Delzescaux T,
Drouot X, Hérard AS, Day DM, Brouillet E,
Kingsman SM, Hantraye P, Mitrophanous KA,
Mazarakis ND, Palfi S: Dopamine gene therapy
for Parkinson’s disease in a nonhuman primate
without associated dyskinesia. Sci Transl Med
1: 2-11, 2009
6. Kamada K, Todo T, Ota T, Ino K, Masutani Y,
Aoki S, Takeuchi F, Kawai K, Saito N: The
motor-evoked potential threshold evaluated bytractography and electrical stimulation. Jeurosurg 111: 785-795, 2009
7. Kawarasaki T, Uchiyama K, Hirao A, Azuma S,
Otake M, Shibata M, Tsuchiya S, Enosawa S,
Takeuchi K, Konno K, Hakamata Y, Yoshino H,
Wakai T, Ookawara S, Tanaka H, Kobayashi E,
Murakami T: “Experimental investigation of
encephalomyosynangiosis using gyrencephalicbrain of the miniature pig: histopathologicalevaluation of dynamic reconstruction of vessels
for functional anastomosis.”
Journal ofbiomedical optics 3: 408-495, 2009
8. Kimura T, Shojima M, Koizumi T, Fukaya S,
Ichikawa Y, Morita A: Surgical treatment of adural arteriovenous fistula in the superior petrosal
sinus of an elderly patient with minimal

103

suboccipital craniotomy: case report. eurol Med
Chir (Tokyo) 49: 465-467, 2009
9. Kin T, Oyama H, Kamada K, Aoki S, Ohtomo K,
Saito N: Prediction of surgical view ofneurovascular decompression using interactive
computer graphics. eurosurgery 65: 121-128,
2009
10. Koga T, Maruyama K, Igaki H, Tago M, Saito N:
The value of image coregistration during
stereotactic radiosurgery. Acta eurochir (Wien)
151: 465-471, 2009
11. Koga T, Morita A, Maruyama K, Tanaka M, Ino Y,
Shibahara J, Louis DN, Reifenberger G, Itami J,
Hara R, Saito N, Todo T: Long-term control ofdisseminated pleomorphic xanthoastrocytoma
with anaplastic features by means of stereotactic
irradiation. euro Oncol 11: 446-451, 2009
12. Kubota C, Torii S, Hou N, Saito N, Yoshimoto Y,
Imai H, Takeuchi T: Constitutive reactive oxygen
species generation from autophagosome/lysosome
in neuronal oxidative toxicity. J Biol Chem 285:667-674, 2009
13. Kunishima K, Mori H, Itoh D, Aoki S, Kabasawa
H, Koga T, Maruyama K, Masumoto T, Abe O,
Ohtomo K: Assessment of arteriovenous
malformations with 3-Tesla time-resolved,
cibtrast-enhanced, three-dimensional magnetic
resonance angiography. J eurosurg 110: 492499, 2009
14. Maruyama K, Koga T, Kamada K, Ota T, Ito D,
Ino K, Igaki H, Aoki S, Masutani Y, Shin M, Saito
N: Arcuate fasciculus tractography integrated intoGamma Knife surgery. J eurosurg 111: 520-526,
2009
15. Nakamura K, Ohkawa R, Okubo S, Yokota H,
Ikeda H, Yatomi Y, Igarashi K, Ide K, Kishimoto T,
Masuda A, Yamamoto T, Tsuji S, Saito N,
Kurokawa M, Okudaira S, Aoki J: Autotaxin
enzyme immunoassay in human cerebrospinal
fluid samples. Clin Chim Acta 405(1-2):160-162,
2009
16. Nakamura M, Imai H, Konno K, Kubota C, Seki
K, Puentes S, Faired A, Yokoo H, Hata H,
Yohimoto Y, Saito N: Experimental investigationofencephalo-myo-synangiosis
using
gyrencepharic brain of the miniature pig:
histopathologicalevaluationofdynamic

reconstruction of vessels for functional
anastomosis. J eurosurg Pediatr 3: 488-495,
2009
17. Ota T, Kamada K, Aoki S, Saito N: Visualizationof calculation centres by functional MRI for
neurosurgery. Br J eurosurg 23: 406-411, 2009
18. Ota T, Kawai K, Kamada K, Kin T, Saito N:
Intraoperative monitoring of cortically recorded
visual response for posterior visual pathway. Jeurosurg 112: 285-294, 2009
19. Oya S, Kumai J, Shigeno T: Drainage or packingof the sella ? Transsphenoidal surgery for primary
pituitary abscess: report of two cases. Case Report
Med 2009: 189304, 2009
20. Oya S, Yoshikawa G, Takai K, Tanaka JI,
Higashiyama S, Saito N, Kirino T, Kawahara N:
Attenuation of notch signaling promotes thedifferentiation of neural progenitors into neurons
in the hippocampal ca1 region after ischemic
injury. eurosci 158: 683-692, 2009
21. Shinoura N, Suzuki Y, Yamada R, Tabei Y, Saito K,
Yagi K: Damage to the right superior longitudinalfasciculus in the inferior parietal lobe plays a rolein spatial neglect. europsychologia 47: 26002603, 200922. Shinoura N, Suzuki Y, Yamada R, Tabei Y, Saito K,
Yagi K: Marked and rapid recovery of motor
strength in premotor area compared with primary
motor area in surgery for brain tumors. Br J
eurosurg 23: 309-314, 200923. Shinoura N, Suzuki Y, Yamada R, Tabei Y, Saito K,
Yagi K: Precentral knob corresponds to theprimary motor and premotor area. Can J eurol
Sci 36: 227-233, 200924. Shinoura N, Suzuki Y, Yoshida M, Yamada R,
Tabei Y, Saito K, Yagi K: Assessment of thecorona radiate sensory tract using awake surgery
and tractography. J Clin eurosci 16: 764-770,
2009
25. Shinoura N, Yoshida M, Yamada R, Tabei Y, Saito
K, Suzuki Y, Takayama Y, Yagi K: Awake surgery
with continuous motor testing for resection ofbrain tumors in the primary motor area. J Clin
eurosci 16: 188-194, 2009

Social Medicine
1. Occupational, Environmental
and Preventive Medicine

105

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

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

Research Associate
Shinichi Hashimoto, Ph.D. ( – 2009.12),

Satoshi Ueha, Ph. D.,

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

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

Homepage

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

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

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References(1) Hashimoto S, Qu W, Ahsan B, Ogoshi K, Sasaki
A, Nakatani Y, Lee Y, Ogawa M, Ametani A,
Suzuki Y, Sugano S, Lee CC, Nutter RC,
Morishita S & Matsushima K. High-resolution
analysis of the 5'-end transcriptome using a next
generation DNA sequencer. PLoS One. 4(1):e4108, 2009.
(2) Tsuchihara K, Suzuki Y, Wakaguri H, Irie T,
Tanimoto K, Hashimoto S, Matsushima K,
Mizushima-Sugano J, Yamashita R, Nakai K,
Bentley D, Esumi H & Sugano S. Massive
transcriptional start site analysis of human genes
in hypoxia cells. Nucleic Acids Res. 37(7):2249-2263, 2009.
(3) Kofuku Y, Yoshiura C, Ueda T, Terasawa H, Hirai
T, Tominaga S, Hirose M, Maeda Y, Takahashi H,
Terashima Y, Matsushima K & Shimada I.
Structural basis of the interaction between
chemokine
stromalcell-derived
factor-1/
CXCL12 and its G-protein-coupled receptor
CXCR4. J Biol Chem. 284(50): 35240-35250,
2009.
(4) Iwata Y, Furuichi K, Sakai N, Yamauchi H,
Shinozaki Y, Zhou H, Kurokawa Y, Toyama T,
Kitajima S, Okumura T, Yamada S, Maruyama I,
Matsushima K, Kaneko S & Wada T. Dendritic
cells contribute to autoimmune kidney injury in
MRL-Faslpr mice. J Rheumatol. 36(2): 306-314,
2009.
(5) Ahsan B, Saito TL, Hashimoto S, Muramatsu K,
Tsuda M, Sasaki A, Matsushima K, Aigaki T &Morishita S. MachiBase: a Drosophilamelanogaster 5'-end mRNA transcription
database. Nucleic Acids Res. 37(Database issue):D49-53, 2009.
(6) Grimstad O, Sawanobori Y, Vestergaard C,
Bilsborough J, Olsen UB, Gronhoj-Larsen C &Matsushima K. Anti-interleukin-31-antibodies
ameliorate scratching behaviour in NC/Nga mice:a model of atopic dermatitis. Exp Dermatol.
18(1): 35-43, 2009.
(7) Ishibe T, Kimura A, Ishida Y, Takayasu T,
Hayashi T, Tsuneyama K, Matsushima K, Sakata
I, Mukaida N & Kondo T. Reduced
acetaminophen-induced liver injury in mice bygenetic disruption of IL-1 receptor antagonist.
Lab Invest. 89(1): 68-79, 2009.
(8) Sasaki S, Mello CC, Shimada A, Nakatani Y,
Hashimoto S, Ogawa M, Matsushima K, Gu SG,
Kasahara M, Ahsan B, Sasaki A, Saito T, Suzuki
Y, Sugano S, Kohara Y, Takeda H, Fire A &Morishita S. Chromatin-associated periodicity ingenetic variation downstream of transcriptional
start sites. Science. 323(5912): 401-404, 2009.
(9) Toda E, Terashima Y, Sato T, Hirose K,
Kanegasaki S & Matsushima K. FROUNT is acommon regulator of CCR2 and CCR5 signaling
to control directional migration. J Immunol.
183(10): 6387-6394, 2009.
(10) Kumamoto M, Nishiwaki T, Matsuo N, Kimura H& Matsushima K. Minimally cultured bonemarrow mesenchymal stem cells ameliorate
fibrotic lung injury. Eur Respir J. 34(3): 740-748,
2009.

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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, 15
graduate students (12 in PhD program and three in
MPH program), two research students, 14 part-time
lecturers, and nine visiting fellows.

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

108

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 Health Sciences and Nursing,and the Faculty of Engineering in the University ofTokyo.
2) MPH Program
The Department offers two lectures and one fieldpractice;“HealthPolicy,”“Public
HealthPreparedness,” and “Public Health Practice.” The
Department also provides a research course forindividual students.
3) Doctoral Program (PhD Program)
The Department offers special lectures, seminars,
field practice, and laboratory work on public healthand occupational medicine to graduate students. In
these training, special emphasis has been placed on
the following points: (1) how to conduct
epidemiologicalstudies,
(2)
how
to
use

epidemiological and statistical methods, (3) how to
use economic concepts and methods in the healthfields, (4) how to establish the collaboration withhealth professionals in the various fields, and (5) how
to read and write original papers.

Research activities
1) Health policy and economics
We are interested in the topics of health care systemand economics in general. We have performed andpublished those studies related to delivery of healthservices in Japan; such as supply and distribution ofphysicians, the separation of pharmaceuticaldispensing and prescribing in medical practice, coststudies of outpatient and inpatient services, and theefficiency and equity issues of the Japan's healthinsurance system. We have also carried on 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) Special topics
We have done a couple of studies that are initiatedby foreign students, such as determinants ofout-of-pocket health expenditures in China, andfactors associated with diagnosis delays oftuberculosis in the eastern region of Afghanistan.

References
1. Kaneto C, Toyokawa S, Inoue K, Kobayashi Y:
Gender difference in physician workforce
participation in Japan. Health Policy 89 (1): 115-123,

109

2009.
2. Matsumoto M, Inoue K, Noguchi S, Toyokawa S,
Kajii E: Community characteristics that attract
physicians in Japan: a cross-sectional analysis ofcommunity demographic and economic factors.
Human
Resources
forHealth7:12,
doi:10.1186/1478-4491-7-12(online journal), 2009.
3. Inoue K, Matsumoto M, Toyokawa S, Kobayashi Y:
Transition of physician distribution(1980-2002) inJapan and factors predicting future rural practice.
Rural and Remote Health 9 (1070): 1-9 (online
journal), 2009.
4. You X, Kobayashi Y: The new cooperative medical
scheme in China. Health Policy 91 (1): 1-9, 2009.
5. Tamiya N, Chen LM, Kobayashi Y, Kaneda M, Yano
E: Gender differences in the use of transportation
services to community rehabilitaion programs. BMC
Geriatrics 9:24, doi: 10.1186/1471-2318-9-24(online journal), 2009.
6. Minami M, Kobayashi Y, Toyokawa S, Inoue K,
Takeshita Y: Risk factors for new-onset atrial
fibrillation during routine medical checkups ofJapanese male workers. International Heart Journal
50 (4): 457-464, 2009.
7. Kobayashi Y: Five decades of universal healthinsurance coverage in Japan: lessons and futurechallenges. Japan Medical Association Journal 52(4): 263-268, 2009.
8. Wenger NS, Roth CP, Shekelle PG, Young RT,
Solomon DH, Kamberg CJ, Chang JT, Louie R,
Higashi T, Maclean CH, Adams J, Min LC,
Ransohoff K, Hoffing M, Reuben DB: A
practice-based intervention to improve primary carefor falls, urinary incontinence, and dementia. Journalof American Geriatric Society 57 (3): 547-555,
2009.
9. Higashi T, Fukuhara S: Antibiotic prescriptions forupper respiratory tract infection in Japan. Internal
Medicine 48 (16): 1369-1375, 2009.

10. Campbell RG, Sato H: Examination of a global
prohibition regime: a comparative study of Japaneseand US newspapers on the issue of tobacco
regulation. The International Communication
Gazette 71 (3): 161-179, 2009.
11. Gunji T, Matsuhashi N, Sato H, Fujibayashi K,
Okumura M, Sasabe N, Urabe A: Light andmoderate alcohol consumption significantly reduces
the prevalence of fatty liver in the Japanese malepopulation. American Journal of Gastroenterology
104 (9): 2189-2195, 2009.
12. Gunji T. Matsuhashi N, Sato H, Fujibayashi K,
Okumura M, Sasabe N, Urabe A: Helicobacter
pylori infection significantly increases insulin
resistance in the asymptomatic Japanese population.
Helicobacter 14 (5): 144-150, 2009.
13. Kaneko Y, Kobayashi J, Achiwa I, Yoda H, Tsuchiya
K, Nakajima Y, Endo D, Sato H, Kawakami T:
Cardiac surgery in patients with trisomy 18.
Pediatric Cardiology 30 (6): 729-734, 2009.
14. Miyaji K, Miyamoto T, Kohira S, Nakashima K,
Inoue N, Sato H, Ohara K: The influences of red
blood cell transfusion to perioperative inflammatory
response using a miniaturized biocompatible bypass
with the asanguineous prime. International Heart
Journal 50 (5): 581-589, 2009.
15. Kitajima T, Kobayashi Y, Pagaiya N, Nasugchon K,
Sato H, Toyokawa S: Use of HAART and safer
sexual behavior among people living with HIV innortheast Thailand. Journal of International Health
24 (4): 275-280, 2009.
16. Zhang M, Higashi T: Time trends of liver cancer
incidence (1973-2002) in Asia, from cancer
incidence in five continents, Vols Ⅳ-Ⅸ. Japanese
Journal of Clinical Oncology 39 (4): 275-276, 2009.
17. Higashi T, Hirabayashi Y. Comparison of timetrends in uterine cancer incidence (1973-2002) in
Asia, from cancer incidence in five continents, Vols
IV-IX. Japanese Journal of Clinical Oncology 39(5): 337-338, 2009.

110

18. Kawakami N, Kobayashi Y, Hashimoto H (Editors):
Health and Social Disparity Japan and Beyond.
Melbourne: Trans Pacific Press, 2009.
19. Sato H (Editor): Management of Health Risks from
Environment and Food: Policy and Politics ofHealth Risk Management in Five CountriesAsbestos and BSE. Netherlands: Springer, 2009.

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

112

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

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

Assistant Professor
Takashi Kobayashi, M.D., Ph.D.

Homepage

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

Introduction and Organization
Associate Professor Kuniyoshi Katayama lectured“judicial medicine” in University of Tokyo since 1882
before our department was founded as the firstdepartment of forensic medicine in Japan in 1888. He
renamed “judicial medicine” to “forensic medicine” in1891 since the department should cover legislation as
well as general forensic practices. Dr. Katayama
became the first professor of forensic medicine inJapan.
The 2nd Professor Sadanori Mita also founded theserological department (Department of Immunology atpresent). He 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 acomplement component. He helped foundation ofnational 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 the fieldof 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 in Tokyoand identified sarin in tissue by a sophisticated method.
The present Professor Ken-ichi Yoshida has studied
the mechanism of ischemic heart disease and sudden
cardiac death related to emotional stress, with respect togap junction, intracellular signaling, and proteolysis.
The department currently has one professor, two
lecturers, one assistant professor, two special
technicians, nine postgraduate students, and one
researcher. Three doctors from this department havebecome professors since 1999. It is a nationwide
difficulty to find suitable doctors as forensic
pathologists. However, there are not a few doctors whowant to become the graduate students in our department.
Those who have experience in clinical practices, andresearchers in biochemistry, physiology, pathology, andmolecular biology are welcome. We are preparing toteach 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 100 criminal cases in eastern part of Tokyo every
year. We have already autopsied more than 11,000 cases
since 1889. Some of these cases are very famous incriminology in Japan.
In forensic autopsy, we examine the pathological,

113

alcohol, toxicological, and blood type testing of eachcase, too. Finally, forensic pathologists in our
department diagnose the cause of death. Expert
opinions expresses the cause of death and forensic
judgment for each case. We have kept them since first
autopsy case in 1889. We have serious responsibility inthe 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
have led the pilot study on the investigation andanalysis of MPAD (supported by government). We also
contribute to evolve new way of presenting expert
opinions for the jury courts that has been enacted in2009.

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

Research activities
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 molecularbiology. The results will warrant a better
understanding of the aforementioned diseases, andpotentially useful diagnostic 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 therat is well-known model to investigate
cardiovascular response to emotional stress. We
also study the mechanism of arrhythmogenesis in
the model of heart 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 havesuccessfully developed an apparatus for the rat
model of SAS, and have undertaken the

114

4.

5.

6.

7.

8.

investigation on the molecular mechanism of
cardiachypertrophy,
hypertension,andarrhythmias,.
Lesion propagation in rat model of brain
contusion.
We study whether localized brain injury propagates
through GJ and promoted by calpain activation.
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).
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.
In the new jury (Saiban-in) court system, bettermethodologies/ways for the juror’s understanding
and alleviation of emotional stress are required. We
have studied these issues.
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.
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.

References(1) Shintani-Ishida K, Unuma K, Yoshida K. Ischemia
enhances translocation of connexin43 and gap
junction intercellular communication, thereby
propagating contraction band necrosis after
reperfusion. Circ J. 2009; 73: 1661-1668.
(2) Nakajima M, Kojima H, Takazawa Y, Yahagi N,
Harada K, Takahashi K, Unuma K, Yoshida K. An
Autopsy report on multiple system atrophy
diagnosed immunnohistochemically despite severe
ischaemic damage: a new approach forinvestigation of medical practice associated deaths
in Japan. J Clin Pathol. 2009; 62: 1029-1033.
(3) Saka K, Konuma K, Asai S, Unuma K, Nakajima
M, Yoshida K. Identification of active ingredientsin dietary supplements using non-destructive mass
spectrometry and liquid chromatography-mass
spectrometry. Forensic Sci Int. 2009; 191: e5-10.
(4) Unuma K, Tojo A, Harada K, Saka K, Nakajima M,
Ishii T, Fujita T, Yoshida K. Autopsy report on
pseudo-Bartter syndrome with renal calcificationinduced by diuretics and diet pills. BMJ Case Rep
2009; doi:10.1136/bcr.12.2008.1380．
(5) Takahashi M, Nishida N, Kimura R,
Shintani-Ishida K, Osawa M, Yoshida K,
Tokunaga K. Development of multiplex SNP
typing system for presuming ethnic background offorensic samples. DNA polymorphism. 2009; 17:219-221.
(6) Nakajima N, Takeichi H, Okutsu K, Ito T, Leflar
RB, Yoshida K. Interim evaluation of the model
project for the investigation and analysis of
medical practice-associated deaths in Japan. J Med
Safety. 2009; 2: 34-39.
(7) Ueyama T, Kawabe T, Hano T, Tsuruo Y, Ueda K,
Ichinose M, Kimura H, Yoshida K. Upregulationof heme oxygenase-1 in an animal model of
Takotsubo cardiomyopathy. Circ J. 2009;73:1141-1146.
(8) Ito T, Nobutomo K, Yoshida K. Why bereaved
family sue doctors. Compensation medicine 2009;
36: 53-63 (in Japanese)(9) Ito T, Komonato Y, Kuroki H, Yoshida H. Shortageof forensic scientists in Japan. Igaku no Ayumi
2009; 228: 1183-1186 (in Japanese)

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

Homepage

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

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

established on April 1, 2003, after integration of the
Hospital Computer Center and the project team for
hospital development, which separately existed until
the end of March, 2003.
Since the professor runs the Department of Medical
Informatics and Economics with staffs of DPIM, they
are practically the same organization. Therefore,
educations and researches in the graduate course arepromoted together with DPIM activities. Only one
professor is the official faculty member of the
Department of Medical Informatics and Economics,
however, faculty outside the department participatesas teaching staffs of the graduate course: Assoc. prof.
S. Koike and Lecturer. K. Miyo from DPIM, Prof. T.
Kiuchi from UMIN center, Assoc. Prof. S. Oku fromthe Department of Healthcare Related Informatics thatis the affiliated department, Assoc. Prof. H. Yasunaga
from the Department of Health Management andPolicy, Assoc. Prof. R.Yamamoto from Interfaculty
Initiative in Information Studies, Graduate School ofInterdisciplinary Information Studies.
The origin of the Department of Medical
Informatics and Economics dates back to 1983 when
the hospital computer center was officially approved
as one of the central clinical service facilities in thehospital. At the same time, the doctor’s course for
medical informatics was established. The first
professor was Dr. Shigekoto Kaihara, who is thefounder of medical informatics in Japan, and he is
now a emeritus professor of the University of Tokyo.
In accordance with the reform to the university with
graduate school curriculum in the university of Tokyo,
the Department of Medical Informatics and economics

116

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

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

In this master’s course, all students spend the first
four months on the planned coursework, then will
decide which department they wish to be enrolled.
After assignment of each department, students
conduct their researches and complete master’s thesis
over remaining one and half year. Completing therequired units and passing the thesis, they will receive
the Master’s degree in Medical Science.
The enrolled students in FY2009 are two in doctor’scourse for Medical Informatics and Economics, one indoctor’s course for Health Informatics.
The students’ researches cover various topics. The
main ones are the analysis of medical cost for the DPC
Classification”, development of method for medical
ontology, a study on the communication model
between healthcare professionals and patients, a study
on methods for healthcare safety control, medical
support by electronic description format of chemical
therapy regimen and inference mechanism, and so on.

Research activities
In 2009 F.Y., research staffs are Prof. Kazuhiko Ohe,
Associate Prof. Soichi Koike, Assistant Prof. Kengo
Miyo, Hospital Assistant Prof. Hiroki Watanabe,
Research Associate Izumi Yamaguchi, Hiroo Ide,
Takashi Noguchi, Katsuya Tanaka, Hidenao Atarashi,
and Project Research Associate Megumi Sato, Shiro
Matsuya, and Project Research Assistant Yuichi
Yoshida, and Masayuki Kajino.
Our main research domains are 1) application
studies on developments of clinical information
systems, hospital information system and electronic
health records system, 2) studies on medical safety
infromation
systems, 3) medical knowledge
discovery and analysis of medical economics
indicators by using databases of hospital information
system and electronic health records system, 4)
structured representations and standardization of
medical terms and concepts, 5) privacy protection andsecurity in healthcare information systems, 6)
information analysis on food safety, 7) analysis ofvarious issues on DPC.
In these domains, major research topics are as listed
below.
1) A study on development methods for large scale

117

ontology databases of medical terms andconcepts :This research develops the methods to build thelarge scale medical ontology, which is a databasefor hundreds of thousand of clinical terms andconcepts and their relationships. It focuses on thedevelopment of basic methods for making andaccessing databases and will be applied for the
research.
2) A study on the development of a patient-oriented,
event-driven, and intellectual clinical support
subsystem(Industry-academia
collaboration
project with Fujitsu Limited, 2004-2009)This research develops autonomic, distributed,
real–time clinical support system. This system will
be tested by being incorporated in the information
system of the university of Tokyo Hospital.
3) A study on Natural Language Processing ofClinicalDocument(Industry-academia
collaboration project with Fuji Xerox Limited,
2007-2010). This research is on extracting
medical knowledge such as time-oriented clinicalevents and adverse drug reaction of patients fromelectrinic medical records.

References
1. Yasunaga H, Tsuchiya K, Matsuyama Y, Ohe K
High-volume surgeons in regard to reductions inoperating time, blood loss, and postoperativecomplications for total hip arthroplasty. Journal of
Orthopaedic Science 14(1):3-9, 2009.
2. Yasunaga H, Nishii O, Hirai Y, Ochiai K,
Matsuyama Y, Ohe K Impact of Surgeon and
Hospital Volumes on Short-Term Postoperative
Complications after Radical Hysterectomy for
Cervical Cancer. The Journal of Obstetrics andGynaecology Research 35(4):699-705, 2009.
3. Yasunaga H, Matsuyama Y, Ohe K, The Japan
Surgical Society. Effects of Hospital and Surgeon
Volumes on Postoperative Complications andLength of Stay after Esophagectomy in Japan.
Surgery Today 39:566-571, 2009.
4. Yasunaga H, Matsuyama Y, Ohe K, The Japan
Surgical Society. Effects of Hospital and Surgeon
Volumes on Operating Time, Postoperative
Complications and Length of Stay following

Laparoscopic
Colectomy.
Surgery
Today
39:955–961, 2009.
5. Ide H, Koike S, Kodama T, Yasunaga H, Imamura
T. The distribution and transitions of physicians inJapan: a 1974–2004 retrospective cohort study.
Human Resources for Health 7:73, 2009.
6. Ide H, Yasunaga H, Kodama T, Koike S, Taketani
Y, Imamura T. The Dynamics of Obstetricians andGynaecologists in Japan: A Retrospective Cohort
Model using the Nationwide Survey of Physicians
data. The Journal of Obstetrics and Gynaecology
Research 35(4): 761-766, 2009.
7. Ide H, Yasunaga H, Koike S, Kodama T, Igarashi
T, Imamura T. Shortage of Pediatricians in Japan:
a Longitudinal Analysis Using Physicians' Survey
Data. Pediatrics International 51(5):645-9, 2009.
8. Koike S, Yasunaga H, Matsumoto S, Ide H,
Kodama T, Imamura T. A future estimate ofphysician distribution in hospitals and clinics inJapan. Health Policy 92(2-3):244-9, 2009.
9. Eiji Aramaki, Yasuhide Miura, Masatsugu
Tonoike, Tomoko Ohkuma, Hiroshi Mashuichi,
Kazuhiko Ohe: TEXT2TABLE: Medical Text
Summarization System Based on Named Entity
Recognition
andModality
Identification,
Proceedings of the Human Language Technology
conference and the North American chapter of the
Association for Computational Linguistics(HLT-NAACL2009) Workshop on BioNLP,
pp.185-192, 2009.
10. Riichiro Mizoguchi, Hiroko Kou, Jun Zhou, Kouji
Kozaki, Ken Imai and Kazuhiko Ohe: An
Advanced Clinical Ontology, In Proc. ofInternational Conference on Biomedical Ontology(ICBO), pp.119-122, Buffalo, NY, June 24-26,
2009.

Internal Medicine
1. Medicine Ⅰ

119Department of Cardiovascular
Medicine
Professor
Ryozo Nagai, M.D., Ph.D.

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

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

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

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

Homepage

Koichiro Kinugawa

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

Introduction and Organization

Outline of department

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

Staff: one professor (Ryozo Nagai), 1 associate
professor (Yasunobu Hirata), 2 assistant professors(outpatient clinic Nobukazu Ishizaka and hospitalward Hiroshi Yamashita), 15 research associates, 9
staff members, 23 graduate school students, 3
researchers, 1 members on leave and 2 members
studying abroad.

Clinical activities
In 2009, 1,619 patients were newly admitted to our
hospital ward of approximately 50 beds. Of thesepatients, approximately 70% were due to ischemic
heart disease. Cardiovascular angiograms wereconducted in 1,806 patients, of which 541 cases wereinterventional procedures. CT coronary angiography
was examined in 322 patients and cardiovascular MRI
in 75. For arrhythmias, there were 125 cases of
implantation of a pacemaker, 91 cases of catheter
ablation, and other specialized pacemaker devices
such as 11 cases of implantation of a cardioverterdefibrillator, and 19 cases of implantation of a cardiac
resynchronization device.

120

As we are an authorized facility for hearttransplantation, left ventricular assist device (LVAD)
use for severe heart failure cases has been increasing.
In 2006, the first case of heart failure from ourdepartment underwent a heart transplant procedure atthe Department of Cardiovascular Surgery. The hearts
were transplanted to 2 cases also in 2009. Duration of
hospitalization is on average 13.0 days.
Out-patient clinics are available as part of the
Department of Medicine or as a specialized
department. The profile of diseases includes ischemic
heart disease in main in addition to hypertension andperipheral artery disease. Out-patient clinics are open
both mornings and afternoons from Monday to Friday.
Approximately 200 patients visit each day. Acutecases of coronary heart disease and aortic disease arealso a focus of the department, as emergent
catheterization is available on a 24-hours basis.

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

Teaching activities

1.

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

References2.

3.

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

4.

5.

6.

Asaba K, Tojo A, Onozato ML, Kinugasa S,
Miyazaki H, Miyashita K, Uehara Y, Hirata Y,
Kimura K, Goto A, Omata M, Fujita T.
Long-term renal prognosis of IgA nephropathy
with therapeutic trend shifts. Intern Med. 2009;
48: 883-90.
Enomoto S, Sata M, Fukuda D, Nakamura K,
Nagai R. Rosuvastatin prevents endothelial cell
death and reduces atherosclerotic lesion
formation in ApoE-deficient mice. Biomed
Pharmacother. 2009; 63: 19-26.
Fukuda D, Enomoto S, Nagai R, Sata M.
Inhibition of renin-angiotensin system attenuates
periadventitial inflammation and reduces
atherosclerotic lesion formation. Biomed
Pharmacother. 2009; 63: 754-61.
Fukuda D, Enomoto S, Shirakawa I, Nagai R,
Sata
M.
Fluvastatin
accelerates
re-endothelialization impaired by local sirolimus
treatment. Eur J Pharmacol. 2009; 612: 87-92.
Higashikuni Y, Tanabe K, Tanimoto S, Aoki J,
Yamamoto H, Nakazawa G, Chihara R, Onuma Y,
Otsuki S, Yagishita A, Yachi S, Nakajima H, Hara
K. Difference of culprit plaque composition
between patients with and without pre-infarctionangina: an intravascular ultrasound radiofrequecy
analysis. EuroIntervention. 2009; 5: 363-9.
Hongo M, Ishizaka N, Furuta K, Yahagi N, Saito

121

7.

8.

9.

10.

11.

12.

13.

14.

K, Sakurai R, Matsuzaki G, Koike K, Nagai R.
Administration of angiotensin II, but notcatecholamines, induces accumulation of lipids inthe rat heart. Eur J Pharmacol. 2009; 604: 87-92.
Ishizaka N, Ishizaka Y, Toda A, Tani M, Toda E,
Koike K, Nagai R, Yamakado R. Changes inwaist circumference and body mass index inrelation to changes in serum uric acid in Japaneseindividuals. J Rheumatol. 2009; 37: 410-6.
Ishizaka N, Ishizaka Y, Toda E, Koike K, Nagai R,
Yamakado M. Impacts of changes waist
circumference and BMI over one-year period onserum lipid data in Japanese individuals. J
Atheroscler Thromb. 2009; 16: 764-71.
Ishizaka N, Ishizaka Y, Toda E, Koike K,
Yamakado R, Nagai R. Impacts of changes inobesity parameters for the prediction of bloodpressure change in Japanese individuals. Kidney
Blood Press Res 2009; 32: 421-7.
Ishizaka N, Ishizaka Y, Yamakado R, Toda E,
Koike K, Nagai R. Association between
metabolic syndrome and carotid atherosclerosis
in individuals without diabetes based on the oral
glucose tolerance test. Atherosclerosis 2009; 204:619-23.
Iwata H, Nakamura K, Sumi M, Ninomiya M,
Sakai Y, Hirata Y, Akaike M, Igarashi T,
Takamoto S, Nagai R, Sata M. Local delivery ofsynthetic prostacycline agonist augments
collateral growth and improves cardiac function
in a swine chronic cardiac ischemia Model. Life
Sci. 2009; 85: 255-61.
Kambara H, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R. Gender differences in patientswith coronary artery disease in Japan: theJapanese Coronary Artery Disease Study (theJCAD study). Circ J. 2009; 73: 912-7.
Kato N, Kinugawa K, Ito N, Yao A, Watanabe M,
Imai Y, Takeda N, Hatano M, Kazuma K.
Adherence to self-care behavior and factors
related to this behavior among patients with heart
failure in Japan. Heart Lung. 2009; 38: 398-409.
Kato N, Kinugawa K, Yao A, Hatano M, Shiga T,
Kazuma K. Relationship of depressive symptoms
with hospitalization and death in Japanesepatients with heart failure. J Card Fail. 2009; 15:912-9.

15. Kohro T, Yamazaki T. Cardiovascular clinical
trials in Japan and controversies regarding
prospective randomized open-label blinded endpoint design Hypertens Res. 2009; 32: 109-14.
16. Kohro T, Yamazaki T. Mechanism ofstatin-induced myopathy investigated using
microarray technology. J Atheroscler Thromb.
2009; 16: 30-2.
17. Kohro T, Yamazaki T. Eicosapentaenoic acid
(EPA) in reducing secondary cardiovascular
events in hypercholesterolemic Japanese patients.
Circ J. 2009; 73: 1197-8.
18. Masuzawa A, Ohno T, Takamoto S, Motomura N,
Ono M, Fujita H, Ando J, Morita T, Hirata Y,
Nagai R, Hirose A, Shigeeda T, Kato S, Araie M.
In early-stage diabetic retinopathy, risk of cardiac
events after implantation of sirolimus-eluting
stent is higher than after coronary artery bypass
surgery. J Cardiol. 2009; 53: 86-93.
19. Matsumura T, Suzuki T, Aizawa K, Sawaki D,
Munemasa Y, Ishida J, Nagai R. Regulation oftransforming
growthfactor-beta-dependent
cyclooxygenase-2 expression in fibroblasts. J
Biol Chem. 2009; 284: 35861-71.
20. Meguro K, Iida H, Takano H, Morita T, Sata M,
Nagai R, Nakajima T. Function and role ofvoltage-gatedsodiumchannel(NaV1.7)
expressed in aortic smooth muscle cells. Am J
Physiol Heart Circ Physiol. 2009; 296: H211-19.
21. Morita H, Nagai R. Genetically elevatedC-reactive protein and vascular disease. N Engl J
Med. 2009; 360: 934.
22. Morita H, Nagai R. Smoking exposure, 17q21
variants, and early-onset asthma. N Engl J Med.
2009; 360: 1255.
23. Nagata D, Kiyosue A, Takahashi M, Satonaka H,
Tanaka H, Sata M, Nagano T, Nagai R, Hirata Y.
A newcostitutively-active
muntantof
AMP-activatedproteinkinaseinhibits
anoxia-induced apoptosis of vascular endothelialcell. Hypertens Res. 2009; 32: 133-9.
24. Nakajima T, Kubota N, Tsutsumi T, Oguri A,
Imuta H, Jo T, Oonuma H, Soma M, Meguro K,
Takano H, Nagase T, Nagata T. Eicosapentaenoic
acid inhibits voltage-gated sodium channels andinvasiveness in prostate cancer cells. Br J
Pharmacol. 2009; 156: 420-31.

122

25. Nishimura S, Manabe I, Nagai R. Adipose tissue
inflammation in obesity and metabolic syndrome.
Discovery Medicine 2009; 8: 55-60.
26. Nishimura S, Manabe I, Nagasaki M, Eto K,
Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K,
Sugiura S, Yoshimura K, Kadowaki T, Nagai R.
CD8+ effector T cells contribute to macrophage
recruitment and adipose tissue inflammation in
obesity. Nat Med. 2009; 15: 914-20.
27. Nishimura S*, Nagasaki M*, Manabe I,
Kadowaki T, Nagai R. (* These two authors
contributed equally to this work) Obese adipose
tissue remodeling, malfunctioning, and chronic
inflammation visualized by in vivo molecularimaging. Inflammation and Regeneration. 2009;
29: 126-30.
28. Nishimura S, Nagasaki M, Manabe I, Kadowaki
T, Nagai R. Obese adipose tissue remodeling,malfunctioning and chronic inflammation
visualized by in vivo molecular imaging.
Inflammation and Regeneration. 2009; 29:
118-22.
29. Ogawa M, Suzuki J, Hirata Y, Nagai R, Isobe M.
A critical role of COX-2 in the progression of
neointimal formation after wire injury in mice.
Expert Opin Ther Targets. 2009; 13: 505-11.
30. Ogawa M, Suzuki J, Kosuge H, Takayama K,
Nagai R, Isobe M. The mechanism ofanti-inflammatory effects of prostaglandin E2
receptor 4 activation in murine cardiac
transplantation. Transplantation. 2009; 87:
1645-53.
31. Ogawa S, Yamashita T, Yamazaki T, Aizawa Y,
Atarashi H, Inoue H, Ohe T, Ohtsu H, Okumura
K, Katoh T, Kamakura S, Kumagai K, Kurachi Y,
Kodama I, Koretsune Y, Saikawa T, Sakurai M,
Sugi K, Tabuchi T, Nakaya H, Nakayama T, Hirai
M, Fukatani M, Mitamura H. for the J-RHYTHM
Investigators. Optimal treatment strategy forpatients with paroxysmal atrial fibrillation. Circ J.
2009; 73: 242-8.
32. Okura T, Higaki J, Kurata M, Irita J, Miyoshi K,
Yamazaki T, Hayashi D, Kohro T, Nagai R.
Elevated serum uric acid is an independent
predictor for cardiovascular events in patientswith severe coronary artery stenosis: subanalysisof the Japanese Coronary Artery Disease (JCAD)

33.

34.

35.

36.

37.

38.

39.

40.

41.

Study. Circ J. 2009; 73: 885-91.
Seki G, Yamada H, Lia Y, Horita S, Ishizaka N,
Koike K, Fujita T. Roles of MEK/ERK pathway
in vascular and renal tubular actions ofangiotensin II. Vascular Disease Prevention.
2009; 6: 154-9.
Shimada K, Fujita M, Tanaka A, Yoshida K, Jisso
S, Tanaka H, Yoshikawa J, Kohro T, Hayashi D,
Okada Y, Yamazaki T, Nagai R. Elevated serum
C-reactive protein levels predict cardiovascular
events in the Japanese coronary artery disease(JCAD) study. Circ J. 2009; 73: 78-85.
Sugiyama H, Sahara M, Imai Y, Ono M,
Okamoto K, Kikuchi K, Nagai R. Infective
endocarditis
byBartonella
quintanamasquerading as antineutrophil cytoplasmic
antibody-associated small vessel vasculitis.
Cardiology. 2009; 114: 208-11.
Suzuki J, Isobe M, Morishita R, Nagai R. Effects
of tea catechins on inflammation-related
cardiovascular disease. Curr Immnol Review.
2009; 5: 167-74.
Suzuki T. Cardiovascular diagnostic biomarkers–The past, present and future–. Circ J. 2009; 73:
806-9.
Suzuki T, Distante A, Zizza A, Trimarchi S,
Villani M, Salerno Uriarte JA, de Luca Tupputi
Schinosa L, Renzulli A, Sabino F, Nowak R,
Birkhahn R, Hollander JE, Counselman F,
Vijayendran R, Bossone E, Eagle K; for the
IRAD-Bio Investigators. Diagnosis of acuteaortic dissection by D-Dimer. The International
Registry of Acute Aortic Dissection substudy on
biomarkers (IRAD-Bio) experience. Circulation.
2009; 119: 2702-7.
Suzuki T, Sawaki D, Aizawa K, Munemasa Y,
Matsumura T, Ishida J, Nagai R. Krüppel-likefactor 5 shows proliferation-specific roles invascular remodeling, direct stimulation of cell
growth, and inhibition of apoptosis. J Biol Chem.
2009; 284: 9549-57.
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. Circ Res. 2009; 105:906-11.
Tanaka K, Sata M. Role of vascular progenitor

123

42.

43.

44.

45.

cells in cardiovascular disease. Curr Pharm Des.
2009; 15: 2760-8.
Uno K, Takenaka K, Ebihara A, Nawata K,
Hayashi N, Nagasaki M, Sonoda M, Takayuki O,
Ono M, Kyo S, Nagai R, Takamoto S. Value oflive 3D transoesophageal echocardiography inthe diagnosis of mitral valve lesions. Eur J
Echocardiogr. 2009; 10: 350-1.
Yagi N, Manabe I, Tottori T, Ishihara A, Ogata F,
Kim JH, Nishimura S, Fujiu K, Oishi Y, Itaka K,
Kato Y, Yamauchi M, Nagai R. A nanoparticle
system specifically designed to deliver shortinterfering RNA inhibits tumor growth in vivo.
Cancer Res. 2009; 69: 6531-8.
Yamazaki T, Kurabayashi M, and the ASTRO-1
Study Group. A randomized controlled study tocompare the effects of rosuvastatin 2.5mg andpravastatin 10mg on the plasma lipid profile inJapanese patients with hypercholesterolemia(ASTRO-1). Ann Vasc Dis. 2009; 2,3:148-58.
Yamazaki T, Kurabayashi M, and the ASTRO-2
Study Group. A randomized controlled study tocompare the effects of rosuvastatin 5mg andatorvastatin 10 mg on the plasma lipid profile inJapanese patients with hypercholesterolemia(ASTRO-2). Ann Vasc Dis. 2009; 2,3:159-73.

124

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., Hitoshi Oonuma, M.D.,Ph.D., Yasuhiro Yamauchi, M.D.,
Goh Tanaka M.D.,Ph.D., Taisuke Jo M.D.,Ph.D., Reiko Okudaira M.D.,Ph.D.,
Sumiko Kamitani, 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 60 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, COPD, asthma,pneumothorax and interstitial lung diseases. There aremany emergency visits and admission due topneumonia, respiratory failure, progression of lungcancer, and so on. In cases of sever respiratory failuresuch as severe pneumonia and ARDS, we conduct
ventilatory support of such patients in collaboration
with ICU staff. A specialized clinical conference forrespiratory disease has been held once a week sinceover 10 years ago, where staff of our department,
department of thoracic surgery and department ofradiology join and discuss together to make best
diagnostic and therapeutic approach to individual
patients. This conference is appreciated as prototype
of Cancer Board of the University of Tokyo Hospital,

125

which launched three years ago, and is now the mostfrequently held Cancer Board in our hospital. Our
department contributes to the pre- and post-surgicalevaluation of respiratory functions, and also receives
consultation from other departments.
At present, there increase highlighted interests in
respiratory medicine. Primary lung cancer is now
leading cause of cancer death, and is one of the major
medical and social problem to be overcome.
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 2009
1. Primary lung cancer
3. Respiratory infection
2. COPD
4. Asthma
5. Spontaneous pneumothorax
6. Interstitial pneumonia

410
101
46
28
27
16

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 and126

treatment of respiratory diseases. Seminars on
important themes such as medical treatment of lungcancer, chest imaging, pneumonia, COPD and so on
are held at regular interval.

Research Activities
Our department is conducting basic and clinicalresearches for many respiratory disorders including
lung cancer, COPD, asthma, interstitial lung diseases,
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
analysis of lung cancer in collaboration with theFaculty of the Department of Thoracic Surgery, cellbiological analysis using airway epithelial cells,
fibroblast, smooth muscle cells, especially on themechanism of epithelial-mesenchymal transition andthe tissue-remodeling of the respiratory systems, andso on. These results have been presented and/or
published in the Scientific Meeting and/or peer-review
Journals. Our main research projects are as follows.
Molecular analysis of ion channels expressed on
airway smooth muscle cells and lung cancer cells.
Exploration of disease-susceptibility genes in
respiratory diseases.
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.
Elucidation of molecular mechanisms of tissue
remodeling, especially in relation to epithelial
mesenchymal transition and fibroblast accumulation,
in respiratory diseases.
Analysis of pathogenesis of tobacco-smoke induced
respiratory diseases using mouse model of long-term
tobacco exposure.
Roles of chemokines, cytokines and eicosanoids onfunctional regulation of airway epithelial cells,smooth muscles and fibroblasts.

Elucidation of molecular mechanisms underlying thepathogenesis of pulmonary fibrosis.
Takahide Nagase is an Associate Editor of
Respirology and an Editorial Board Member ofAmerican Journal of Physiology.

References
1.

2.

3.

4.

5.

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Kusakabe M, Watanabe K, Emoto N, Aki N,
Kage H, Nagase T, Nakajima J, Yatomi Y, Ohishi
N, Takai D. Impact of DNA demethylation of the
G0S2 gene on the transcription of G0S2 insquamous lung cancer cell lines with or without
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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
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Takahashi H, Ogata H, Nishigaki R, Broide H,
Karin M. Tobacco smoke promotes lungtumorigenesis by triggering IKKbeta- and JNK1dependent inflammation. Cancer Cell in press.
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Department 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.

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

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

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

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

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

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

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

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

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.

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

Yousuke Nakai, M.D., Ph.D.

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

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

Kazuyuki Hanajiri , 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, 11 fellows, 74 graduates and 10 othervisiting researchers including students from abroad(March, 2010). 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 91 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 12.1 days. Resident, juniorand senior staff members bear the responsibility for a
medical management of each inpatient, in
collaboration with subspecialty groups concerned. The

129

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(1154 cases in 2009). 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 (107 casesin 2008). Fibrosis progression in chronic liver disease
is conventionally assessed by liver biopsy. Recently
we can evaluate the stage of liver fibrosis by
Fibroscan®, newly developed equipment thatmeasures liver stiffness by ultrasound.
ERCP is performed more than 900 cases eachyear. The number of patients treated forcholedocholithiasis with endoscopic papillary balloon
dilation method exceeds 1,000, which is possibly thelargest in the world. Endoscpic metallic stenting is aneffective palliative care for malignant obstructive
jaundice (70 patients a year). Covered metallic stentplacement has been performed in a total of 600 cases,
which may be the world’s largest number. Pancreaticinterventions such as pancreatic stenting, cystic
drainage, endoscopic stone extraction and lithotripsy
using ESWL (extracorporeal shock-wave lithotripsy)
are also performed for many challenging cases. ESD(endoscopic submucosal dissection) is performed as a
curative endoscopic treatment for neoplasms inesophagus, stomach or colon (212 patients a year).
Endoscopic variceal ligations for esophageal
varices (50 patients a year) are also frequently done.
Double-balloon endoscopy and capsule endoscopy
have been introduced recently, which enabled theexamination of whole small intestines. All thoseinterventions are performed by the members of thedepartment, specially trained for each technique. Our
strategy for the management of malignancies isinterventional therapy and chemotherapy (180 cases
for pancreato-biliary and 60 cases for digestive tract
neoplasms).
On outpatient basis, ultrasonography is

performed on 15,000 patients, gastroduodenalendoscopy on 7,800, and colonoscopy on 3,600
patients each year, leading the detection of about 170
cases of gastric cancer and 180 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.

Research Activities
Both basic and clinical researchers are equallyencouraged, on condition that the results may

130eventuallycontribute
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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Isayama H, Kawabe T, Omata M. Are all
pancreatic lesions responsive to steroid therapy[corrected] autoimmune pancreatitis? Gut. 2009
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M, Kato N. Characteristic mutations in hepatitis
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Kume Y, Tomiya T, Inoue Y, Nishikawa T,
Ohtomo N, Tanoue Y, Iitsuka S, Fujita R, Omata
M, Chun J, Yatomi Y. Sphingosine 1-phosphate
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Sasaki T, Sasahira N, Hirano K, Tsujino T, Tada
M, Kawabe T, Omata M. Covered metallic stents
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Gon C, Ito Y, Yashima Y, Yagioka H, Kogure H,
Sasaki T, Arizumi T, Matsubara S, Yamamoto N,
Sasahira N, Hirano K, Tsujino T, Toda N, Tada M,
Kawabe T, Omata M. Measurement of radial andaxial forces of biliary self-expandable metallic
stents. Gastrointest Endosc. 2009 Jul;70(1):37-44.
(17) Isayama H, Yamamoto K, Mizuno S, Yashima Y,
Togawa O, Kogure H, Sasaki T, Sasahira N,
Nakai Y, Hirano K, Tsujino T, Tada M, Kawabe T,
Omata M. NOTES and endoscopic pancreatic
necrosectomy for the GI endoscopist. J
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(18) Iwasaki Y, Shiratori Y, Hige S, Nishiguchi S,
Takagi H, Onji M, Yoshida H, Izumi N, Kohgo Y,
Yamamoto K, Sato N, Shibuya A, Saito H, Sata
M, Suzuki K, Kaneko S, Moriyama M, Omata M.
A randomized trial of 24 versus 48 weeks ofpeginterferon alpha-2a in patients infected withchronic hepatitis C virus genotype 2 or low viralload genotype 1: a multicenter national study inJapan. Hepatol Int. 2009 May 22.
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Nishino T, Watanabe H, Kanno A, Okumura F,

Nishikawa T, Kobayashi K, Ichiya T, Takatori H,
Yamakita K, Kubota K, Hamano H, Okamura K,
Hirano K, Ito T, Ko SB, Omata M. Standard
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Gut. 2009 Nov;58(11):1504-7.
(20) Kobashi H, Fujioka S, Kawaguchi M, Kumada H,
Yokosuka O, Hayashi N, Suzuki K, Okanoue T,
Sata M, Tsubouchi H, Sato C, Kiyosawa K,
Tanikawa K, Seriu T, Ishikawa H, Takaki A,
Iwasaki Y, Osawa T, Takaki T, Sakaguchi K,
Shiratori Y, Yamamoto K, Tenney DJ, Omata M.
Two cases of development of entecavir resistanceduring entecavir treatment for nucleoside-naive
chronic hepatitis B. Hepatol Int. 2009 Jun;3(2):403-10.
(21) Kobashi H, Takaguchi K, Ikeda H, Yokosuka O,
Moriyama M, Imazeki F, Kage M, Seriu T,
Omata M, Sakaguchi K, Shiratori Y. Efficacy andsafety of entecavir in nucleoside-naive, chronic
hepatitis B patients: phase II clinical study inJapan. J Gastroenterol Hepatol. 2009 Feb;24(2):255-61.
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Gastroenterol. 2009;44 Suppl 19:82-8.
(23) Kondo Y, Yoshida H, Tomizawa Y, Tateishi R,
Shiina S, Tagawa K, Omata M. Percutaneousradiofrequency ablation of hepatocellular
carcinoma in 14 patients undergoing regularhemodialysis for end-stage renal disease. AJR
Am J Roentgenol. 2009 Oct;193(4):964-9.
(24) Li CZ, Kato N, Chang JH, Muroyama R, Shao
RX, Dharel N, Sermsathanasawadi R, Kawabe T,
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(25) Maeda S, Hikiba Y, Sakamoto K, Nakagawa H,
Hirata Y, Hayakawa Y, Yanai A, Ogura K, Karin
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H, Tateishi R, Tamura S, Kaneko J, Hasegawa K,
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Yagioka H, Yashima Y, Kawakubo K, Mizuno S,
Yamamoto K, Hirano K, Tsujino T, Ijichi H, Toda
N, Tada M, Kawabe T, Omata M. A pilot study
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C. Hepatol Int. 2009 Dec;3(4):544-50.
(44) Seto M, Ohta M, Asaoka Y, Ikenoue T, Tada M,
Miyabayashi K, Mohri D, Tanaka Y, Ijichi H,
Tateishi K, Kanai F, Kawabe T, Omata M.
Regulation of the hedgehog signaling by the
mitogen-activated protein kinase cascade in
gastric cancer. Mol Carcinog. 2009 Aug;48(8):703-12.
(45) Shiha G, Sarin SK, Ibrahim AE, Omata M,
Kumar A, Lesmana LA, Leung N, Tozun N,
Hamid S, Jafri W, Maruyama H, Bedossa P,
Pinzani M, Chawla Y, Esmat G, Doss W, Elzanaty
T, Sakhuja P, Nasr AM, Omar A, Wai CT,
Abdallah A, Salama M, Hamed A, Yousry A,
Waked I, Elsahar M, Fateen A, Mogawer S,
Hamdy H, Elwakil R. Liver fibrosis: consensus
recommendations of the Asian Pacific
Association for the Study of the Liver (APASL).
Hepatol Int. 2009 Jun;3(2):323-33.
(46) Shindo M, Chayama K, Mochida S, Toyota J,
Tomita E, Kumada H, Yokosuka O, Sata M,
Hayashi N, Suzuki K, Okanoue T, Tsubouchi H,
Ishikawa H, Seriu T, Omata M. Antiviral activity,
dose-response relationship, and safety ofentecavir following 24-week oral dosing in
nucleoside-naive Japanese adult patients withchronic hepatitis B: a randomized, double-blind,phase II clinical trial. Hepatol Int. 2009 May 23.
(47) Tada M, Omata M. Another key molecule forpathogenesis of hepatocellular carcinoma. J
Gastroenterol Hepatol. 2009 Dec;24(12):1803-4.
(48) Tateishi R, Shiina S, Ohki T, Sato T, Masuzaki R,
Imamura J, Goto E, Goto T, Yoshida H, Obi S,

Sato S, Kanai F, Omata M. Treatment strategy forhepatocellular
carcinoma:
expandingtheindications for radiofrequency ablation. J
Gastroenterol. 2009;44 Suppl 19:142-6.
(49) Kumita W, Saito R, Sato K, Ode T, Moriya K,
Koike K, Chida T, Okamura N. Molecularcharacterizationsofcarbapenem
andciprofloxacin resistance in clinical isolates of
Pseudomonas putida. J Infect Chemother2009;15:6-12.
(50) Togo M, Hashimoto Y, Iso ON, Kurano M, Hara
M, Kadowaki T, Koike K, Tsukamoto K.
Identification of a novel mutation for
phytosterolemia. Genetic analyses of 2 cases.
Clin Chim Acta. 2009 Mar;401(1-2):165-9.
(51) Tsujino T, Kawabe T, Isayama H, Yashima Y,
Yagioka H, Kogure H, Sasaki T, Arizumi T,
Togawa O, Ito Y, Matsubara S, Nakai Y,
Sasashira N, Hirano K, Tada M, Omata M.
Management of late biliary complications inpatients with gallbladder stones in situ afterendoscopic papillary balloon dilation. Eur J
Gastroenterol Hepatol. 2009 Apr;21(4):466-70.
(52) Tsujino T, Sugawara Y, Omata M. Managementof biliary strictures after living donor livertransplantation. Gastrointest Endosc. 2009
Sep;70(3):599-600; author reply -1.
(53) Tsutsumi T, Matsuda M, Aizaki H, Moriya K,
Miyoshi H, Fujie H, Shintani Y, Yotsuyanagi H,
Miyamura T, Suzuki T, Koike K. Proteomics
analysis of mitochondrial proteins reveals
overexpression of a mitochondrial protein
chaperon, prohibitin, in cells expressing hepatitis
C virus core protein. Hepatology. 2009 Aug;50(2):378-86.
(54) Watabe H, Mitsushima T, Derakhshan MH,
Yamaji Y, Okamoto M, Kawabe T, Omata M,
McColl KE. Study of association between
atrophic gastritis and body mass index: a crosssectional study in 10,197 Japanese subjects. Dig
Dis Sci. 2009 May;54(5):988-95.
(55) 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

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models of cholestasis and steatohepatitis. Thromb
Haemost. 2009 Aug;102(2):389-96.
(56) Yamaji Y, Watabe H, Yoshida H, Kawabe T,
Wada R, Mitsushima T, Omata M. High-risk
population for gastric cancer development basedon serum pepsinogen status and lifestyle factors.
Helicobacter. 2009 Apr;14(2):81-6.
(57) Yamamichi N, Inada K, Furukawa C, Sakurai K,
Tando T, Ishizaka A, Haraguchi T, Mizutani T,
Fujishiro M, Shimomura R, Oka M, Ichinose M,
Tsutsumi Y, Omata M, Iba H. Cdx2 and theBrm-type SWI/SNF complex cooperatively
regulate villin expression in gastrointestinal cells.
Exp Cell Res. 2009 Jun 10;315(10):1779-89.
(58) Yamamichi N, Shimomura R, Inada K, Sakurai K,
Haraguchi T, Ozaki Y, Fujita S, Mizutani T,
Furukawa C, Fujishiro M, Ichinose M, Shiogama
K, Tsutsumi Y, Omata M, Iba H. Locked nucleic
acid in situ hybridization analysis of miR-21
expression during colorectal cancer development.
Clin Cancer Res. 2009 Jun 15;15(12):4009-16.
(59) Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Kokudo N, Omata M,
Makuuchi M. Double-dose double-phase use of
second generation hepatitis B virus vaccine inpatients after living donor liver transplantation:
Not an effective measure in transplant recipients.
Hepatol Res. 2009 Jan;39(1):7-13.
(60) Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Ohki T, Yoshida H, Omata
M, Makuuchi M, Kokudo N. Noninvasive
estimation of hepatic steatosis in living liver
donors: usefulness of visceral fat area
measurement. Transplantation. 2009 Aug 27;88(4):575-81.
(61) Yotsuyanagi H, Kikuchi Y, Tsukada K, Nishida K,
Kato M, Sakai H, Takamatsu J, Hige S, Chayama
K, Moriya K, Koike K. Chronic hepatitis C inpatients co-infected with human immunodeficiency virus in Japan: a retrospective multicenter analysis. Hepatol Res. 2009 Jul;39(7):65763.
(62) Kumita W, Saito R, Sato K, Ode T, Moriya K,
Koike K, Chida T, Okamura N. Molecularcharacterizationsofcarbapenem
andciprofloxacin resistance in clinical isolates of
Pseudomonas putida. J Infect Chemother2009;15:6-12.
(63) Hongo M, Ishizaka N, Furuta K, Yahagi N, Saito
K, Sakurai R, Matsuzaki G, Koike K, Nagai R.
Administration of angiotensin II, but notcatecholamines, induces accumulation of lipids inthe rat heart. Eur J Pharmacol 2009;604:87-92.
(64) Yanagimoto S, Tatsuno K, Okugawa S, Kitazawa
T, Tsukada K, Koike K, Kodama T, Kimura S,
Shibasaki Y, Ota Y. A single amino acid of
toll-like receptor 4 that is pivotal for its
signaltransduction and subcellular localization. J
Biol Chem 2009;284:3513-3520.
(65) Ishizaka N, Ishizaka Y, Yamakado M, Toda E,
Koike K, Nagai R. Association between
metabolic syndrome and carotid atherosclerosis
in individuals without diabetes based on the oral
glucose tolerance test. Atherosclerosis 2009;204:
619-623.
(66) Ishizaka Y, Ishizaka N, Tani M, Toda A, Toda EI,
Koike K, Nagai R, Yamakado M. Association
between changes in obesity parameters andincidence of chronic kidney disease in Japaneseindividuals. Kidney Blood Press Res 2009;32:
141-149.
(67) Ode T, Saito R, Kumita W, Sato K, Okugawa S,
Moriya K, Koike K, Okamura N. Analysis ofplasmid-mediated multidrug resistance in
Escherichia coli and Klebsiella oxytoca isolates
from clinical specimens in Japan. Int J
Antimicrob Agents 2009;34:347-350.
(68) Ishizaka N, Ishizaka Y, Toda E, Koike K, Nagai R,
Yamakado M. Impact of changes in waist
circumference and BMI over one-year period onserum lipid data in Japanese individuals. J
Atheroscler Thromb 2009;16:764-771.
(69) Saito R, Uetera U, Saito U, Okamura N, Moriya
K, Koike K. Evaluation of the efficacy in a lowtemperature steam and formaldehyde sterilizer byusing biological indicators. J Hosp Infect2009;73:179-180.
(70) Ishizaka N, Ishizaka Y, Toda E, Koike K,
Yamakado M, Nagai R. Impacts of changes inobesity parameters for the prediction of bloodpressure change in Japanese individuals. Kidney
Blood Press Res 2009;32:421-427.
(71) Togo M, Hashimoto Y, Iso-O N, Kurano M, Hara
M, Kadowaki T, Koike K, Tsukamoto K.

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Identification of a novel mutation for
phytosterolemia. Genetic analysis of two cases.
Clin Chim Acta 2009;401:165-169.
(72) Ichibangase T, Moriya K, Koike K, Imai K.
Limitation of immunoaffinity column for theremoval of abundant proteins from plasma inquantitativeplasmaproteomics.
BiomedChromatogr 2009;23:480-487.

Internal Medicine
2. Medicine Ⅱ137

Department of ephrology 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.,

Yuichi Hori, 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
Takeshi Marumo, M.D., Ph.D.,

HomepageTakashi Yamamoto, Ph.D.

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

138

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.

139

Department of Clinical &Molecular Epidemiology

Department of Molecular
Vascular Endocrinology

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

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

Introduction and Organization

Introduction and Organization

The Department of Clinical & Molecular
Epidemiology was established in June 2004 as anendowed department (Mitsubishi Tanabe Phama Co.,
Ltd.) of the Graduate School of Medicine, theUniversity of Tokyo. Our department also belongs to
the 22nd Century Medical Center, which partly
represents the translational research activities of The
University of Tokyo Hospital. Our department isestablished with the main aim of performing theclinical and epidemiological analysis on the metabolic
syndrome in the Japanese population, of isolating
susceptibility gene(s) to metabolic syndrome throughmolecular and genetic analysis on human and rodent
animal models, and of contributing to the developmentof novel diagnostic method and therapeutic agents forthe prevention and treatment of the cardiovasculardiseases.

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 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.

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) Seki G, Yamada H, Li Y, Horita S, Ishizaka N,
Koike K, Fujita T. Roles of MEK/ERK pathway invascular and renal tubular actions of angiotensin
II. Vasc Dis Prev 2009;6:154-159.
(2) Kawakami T, Inagi R, Takano H, Sato S,
Ingelfinger JR, Fujita T, Nangaku M.
Endoplasmic reticulum stress induces autophagy
in renal proximal tubular cells. Nephrol Dial
Transplant 2009;24:2665-2672.
(3) Kumagai T, Nangaku M, Kojima I, Nagai R,
Ingelfinger JR, Miyata T, Fujita T, Inagi R.

140

Glyoxalse I overexpression ameliorates renal
ischemia-reperfusion injury in rats. Am J Physiol
Renal Physiol 2009;296:F912-F921.
(4) Eto N, Miyagishi Y, Inagi R, Fujita T, Nangaku
M. Suppression of MAP3 kinase 6 mediates
anti-angiogenic and tumor-suppressive effects via
VEGF repression. Am J Pathol 2009;174:15531563.
(5) Kojima I, Tanaka T, Inagi R, Nishi H, Aburatani
H, Kato H, Miyata T, Fujita T, Nangaku M.
Metallothionein is up-regulated by hypoxia andstabilizes HIF in the kidney. Kidney Int 2009;75:
268-277.
(6) Nangaku M, Couser WG. Mediators of renal
injury in membranous nephropathy. Arch Med Sci
2009;5:S451-S458.
(7) Nangaku M. Novel therapeutic approach targetingthe HIF-HRE system in the kidney. Adv Exp Biol
Med 2009;645: 81-86.
(8) Tanaka T, Nangaku M. Prolyl hydroxylase
inhibitors to active HIF as a novel therapeutic
approach against CKD. J Pharmacol Sci 2009;
109:24-31.
(9) Noiri E, Doi K, Inagi R, Nangaku M, Fujita T.
Contribution of T lymphocytes to rat renal
ischemia/reperfusion injury. Clin Exp Nephrol
2009;13:25-32.
(10)Asaba K, Tojo A, Onozato ML, Kinugasa S,
Miyazaki H, Miyashita K, Uehara Y, Hirata Y,
Kimura K, Goto A, Omata M, Fujita T. Long-term
renal prognosis of IgA nephropathy withtherapeutic trend shifts. Intern Med 2009;48:
883-890.
(11)Unuma K, Tojo A, Harada K, Saka K, Nakajima
M, Ishii T, Fujita T, Yoshida K. Autopsy reporton pseudo-Bartter syndrome with renal
calcification induced by diuretics and diet pills.
BMJ Case Reports (Published 25 May 2009,
e-publish only).
(12)Mimura I, Tojo A, Kinugasa S, Uozaki H, Fujita
T. Renal cell carcinoma in association with IgA
nephropathy in the elderly. Am J Med Sci
2009;338:431-432.
(13)Shimizu Y, Tada Y, Yamauchi M, Okamoto T,
Suzuki H, Ito N, Fukumoto S, Sugimoto T, Fujita
T. Hypophosphatemia induced by intravenous
administration of saccharated ferric oxide-Another form of FGF23-related hypophosphatemia. Bone 2009;45:814-816.
(14)Saito T, Nishii Y, Yasuda T, Ito N, Suzuki H,
Igarashi T, Fukumoto S, Fujita T. Familial hypophosphatemic rickets caused by a large deletion in
PHEX gene. Eur J Endocrinol 2009;161:647-651.
(15)Saito T, Fukumoto S, Ito N, Suzuki H, Igarashi T,
Fujita T. A novel mutation in GATA3 gene in a
Japanese patient with PTH-deficient hypoparathryoidism. J Bone Miner Metab 2009;27:386389.
(16)Saito T, Fukumoto S. Fibroblast growth factor 23(FGF23) and disorders of phosphate metabolism.
Int J Pediatr Endocrinol 2009;2009:496514.
(17)Iba K, Sasaki K, Takada J, Minowa T, Ito N,
Fukumoto S, Hasegawa T, Wada T, Yamashita T.
Improvement of severe bone pain and activities ofdaily living in a patient with tumor-induced
osteomalacia following the resection of a
FGF23-producing- tumor in the oral cavity. J
Orthopaedics 2009;6:e11.
(18)Fukumoto S, Martin TJ. Bone as an endocrineorgan. Trends Endocrinol Metab 2009;20:230236.
(19)Fukumoto S. The role of bone in phosphatemetabolism. Mol Cell Endocrinol 2009;310:
63-70.
(20)Aono Y, Yamazaki Y, Yasutake J, Kawata T,
Hasegawa H, Urakawa I, Fujita T, Wada M,
Yamashita T, Fukumoto S, Shimada T.
Therapeutic Effects of Anti-FGF23 Antibodies in
Hypophosphatemic Rickets/Osteomalacia. J Bone
Miner Res 2009;24:1879-1888.
(21)Takano K, Yasufuku-Takano J, Morita K, Mori S,
Takei M, Osamura RY, Teramoto A, Fujita T.
Evidence that PKA activity is constitutively
activated in human GH-secreting adenoma cells ina patient with Carney complex harbouring a
PRKAR1A mutation. Clin Endocrinol 2009;70:769–775.
(22)Nakashima M, Takano K, Matsuno A. Analyses
of factors influencing the acute effect ofoctreotide in growth hormone-secreting adenomas.
Endocr J 2009;56:295-304.
(23)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

141

I, Hirata Y, Nakamura K, Igarashi H, Jensen RT,
Wiedenmann B, Imamura M. Epidemiologicalstudy of gastroenteropancreatic neuroendocrine
tumors in Japan. J Gastroenterol 2009;45:234-43.
(24)Miyamoto N, Tanaka R, Shimosawa T, Yatomi Y,
Fujita T, Hattori N, Urabe T. PKA-dependent
suppression of ROS in transient focal ischemia in
adrenomedullin-deficient mice. J Cereb Blood
Flow Metab 2009;29:1769-1779.
(25)Hirahashi J, Hishikawa K, Kaname S, Tsuboi N,
Wang Y, Simon DI, Stavrakis G, Shimosawa T,
Xiao L, Nagahama Y, Suzuki K, Fujita T,
Mayadas TN. Mac-1 (CD11b/CD18) links
inflammation and thrombosis after glomerular
injury. Circulation. 2009;120:1255-1265.
(26)Hishikawa K, Takase O, Idei M, Fujita T.
Comparison of antioxidant activity of cilnidipine
and amlodipine. Kidney Int 2009；76：230-231.
(27)Sekiya M, Yahagi N, Tamura Y, Okazaki H,
Igarashi M, Ohta K, Takanashi M, Kumagai M,
Takase S, Nishi M, Takeuchi Y, Izumida Y,
Kubota M, Ohashi K, Iizuka Y, Yagyu H, Gotoda
T, Nagai R, Shimano H, Yamada N, Kadowaki T,
Ishibashi S, Osuga J. Hormone-sensitive lipase
deficiency suppresses insulin secretion frompancreatic islets of Lep ob/ob mice. Biochem
Biophys Res Commun. 2009;387:511-515.
(28)Nagae A, Fujita M, Kawarazaki H, Matsui H,
Ando K, Fujita T.Sympathoexcitation by oxidative
stress in the brain mediates arterial pressure
elevation in obesity-induced hypertension.
Circulation. 2009;119:978-986.
(29)Ando K, Fujita T. Metabolic syndrome andoxidative stress. Free Radic Biol Med. 2009;47:
213-218.
(30)Nagae A, Fujita M, Kawarazaki H, Matsui H,
Ando K, Fujita T: Effect of high fat loading in
Dahl salt-sensitive rats. Clin Exp Hypertens.
2009;31:451-461.
(31)Kawakami S, Matsuda A, Sunagawa T, Noda Y,
Kaneko T, Tahara S, Hiraumi Y, Adachi S, Matsui
H, Ando K, Fujita T, Maruyama N, Shirasawa T,
Shimizu T. Antioxidant, EUK-8, prevents murine
dilated cardiomyopathy. Circ J. 2009;73:21252134.
(32)Shuto E, Taketani Y, Tanaka R, Harada N, Isshiki
M, Sato M, Nashiki K, Amo K, Yamamoto H,

Higashi Y, Nakaya Y, Takeda E. Dietaryphosphorus acutely impairs endothelial function. J
Am Soc Nephrol 2009;20:1504-1512.
(33)Ando K, Isshiki M, Takahashi K, ONgoing
Evaluation of depressor effect And Safety of
combination therapy with Telmisartan andlow-dose hydrochlorothiazide (ONEAST) Study
Group. Effect of switching from amlodipine tocombination therapy with telmisartan andlow-dose hydrochlorothiazide. Hypertens Res
2009;32:748-752.
(34)Nagase M, Fujita T. Mineralocorticoid receptor
activation in obesity hypertension. Hypertens Res
2009;32:649-657.

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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.

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.

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), The Clinical Training Center(Lecturer, Dr. Kazuo Hara), Department of Patient
Safety & Risk Management (Assistant Professor, Dr.
Kenji Harada), Division of Biophysics, Center for
Disease Biology and Integrative Medicine (Lecturer,
Dr. Noriko Takahahsi), and Division for HealthService 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

143

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 4000 patients. On theinpatient ward, we not only take care of more than 30
patients in our division as mentioned above, but also
provide a sophisticated management to all patients
suffering from metabolic diseases, especially diabetes
mellitus. Diabetes mellitus, metabolic syndrome,
dyslipidemia and obesity are becoming moreprevalent in Japan, and lead to complications
including nephropathy, retinopathy, neuropathy andcardiovascular diseases. Thus, in collaboration withother departments, we optimize the treatment of eachpatient.
We provide the educational classes to the patients
every day in the inpatient ward, and also give lectures
twice a week in the outpatient unit. In addition, in
collaboration with ancillary staffs of our hospital, we
provide patients well-reasoned instructions regarding
nutritional management, excise therapy and medical
therapy.
The weekly official activities of our department
consist of the pre-round case conference and the Ward
Round by the Professor on Monday. We also hold aweekly case conference by the consultation group
staffs.

Teaching activities
As for medical student education, our department
takes a part in systemic lectures for the 4th year
medical students, bed-side learning and clinicalclerkship for the 5th year medical students, andclinical lectures for the 6th year medical students.
In systemic lectures, comprehensive presentation for

the understanding of basic knowledge about theconcept, pathogenesis, diagnosis and treatment ofcommon metabolic diseases is performed.
In clinical lectures, we present clinical cases ofimportant diseases such as diabetes mellitus, and try
to discuss with the students several points forplanning the diagnosis and treatment in collaboration
with the faculties of the Departments of Nephrology,
Cardiology, and Ophthalmology.
During the period of bed-side learning, the students
have opportunities to experience the daily clinical carewith junior and senior residents as well as with theFaculty members. Each student can learn how to dohistory taking, perform physical examinations andmake the actual plans for the diagnosis and treatment.
Lectures that lead to profound understandings of themetabolic diseases are regularly provided by the staff
physicians.
In clinical clerkship, we arrange the program so thatthe students can experience the clinical practice andlearn the disease itself more profoundly. One faculty
and one senior-resident always instruct one student.
As for the post-graduate education, attending doctor(staff) and senior resident instruct the junior residents.
We provide advanced teaching through the seminars
and grand conference.

Research activities
There are several laboratories in our departments;
collaborating with each other or with otherdepartments, we focus on the molecular mechanismsof the metabolic diseases and the establishment of the
new treatment.
1) Molecular mechanisms of type 2 diabetes
We have been attempting to elucidate the mechanisms
underlying the development of type 2 diabetes at themolecular and genetic levels. To this end, we are
exploring the signal transduction pathways andphysiological roles of insulin and adipokines invarious tissues and the mechanisms of insulin
secretion under the normal or pathological conditions,such as diabetes and obesity, using a number oftransgenic and knockout animal models.
In
particular, we are interested in the physiological andpathopysiological functions of adipokines secreted by

144

adipocytes, 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.

References
1.

2.

Aoki K, Matsui J, Kubota N, Nakajima H,
Iwamoto K, Takamoto I, Tsuji Y, Ohno A, Mori
S, Tokuyama K, Murakami K, Asano T, Aizawa
S, Tobe K, Kadowaki, T, Terauchi Y: Role of theliver in glucose homeostasis in PI3-kinasep85{alpha}-deficient mice. Am. J. Physiol.
Endocrinol. Metab. 296: E842-853, 2009
Asano T, Watanabe K, Kubota N, Gunji T,
Omata M, Kadowaki T, Ohnishi S: Adiponectinknockout mice on high fat diet develop fibrosing
steatohepatitis. J Gastroenterology Hepatol. 24:

1669-1676, 2009
3. Assmann A, Ueki K, Winnay JN, Kadowaki T,
Kulkarni RN:
Glucose effects on beta-cellgrowth and survival require activation of insulin
receptors and insulin receptor substrate 2.
Mol.Cell.Biol. 29: 3219-3228, 2009
4. Awazawa M, Ueki K, Inabe K, Yamauchi T,
Kaneko K, Okazaki Y, Bardeesy N, Ohnishi S,
Nagai R, Kadowaki T: Adiponectin suppresses
hepatic SREBP1c expression in an AdipoR1/
LKB1/AMPK dependent pathway. Biochem.
Biophys. Res. Commun. 382: 51-56, 2009
5. Chan JC, Malik V, Jia W, Kadowaki T, Yajnik
CS, Yoon KH, Hu FB: Diabetes in Asia:
epidemiology, risk factors, and pathophysiology.
JAMA 301: 2129-2140, 2009
6. Freude S, Hettich MM, Schumann C, Stohr O,
Koch L, Kohler C, Udelhoven M, Leeser U,
Muller M, Kubota N, Kadowaki T, Krone W,
Schroder H, Bruning JC, Schubert M: Neuronal
IGF-1 resistance reduces Aβ-accumulation andprotects against premature death in a model of
Alzheimer's disease. FASEB J. 23: 3315-3324,
2009
7. Fukuo W, Yoshiuchi K, Ohashi K, Togashi H,
Sekine R, Kikuchi H, Sakamoto N, Inada S, Sato
F, Kadowaki T, Akabayashi A: Development of ahand-held personal digital assistant-based fooddiary with food photographs for Japanese
subjects. J. Am. Diet. Assoc. 109: 1232-1236,
2009
8. Hara K, Kadowaki T: How controlling of
hypertension might matter - Beyond bloodpressure -. Circulation J. 73: 2208-2209, 2009
9. Hara M, Izumida Y, Sato N, Ohashi K, Osuga J,
Tobe K, Tsukamoto K, Kadowaki T: Successful
desensitization by glargine administration in apatient with insulin allergy: a case report.
Diabetes Res. Clin. Pract. 84: e48-49, 2009
10. Hashimoto H, Arai T, Mori A, Kawai K,
Hikishima K, Ohnishi Y, Eto T, Ito M, Hioki K,
Suzuki R, Ohsugi M, Saito M, Ueyama Y, Okano
H, Yamauchi T, Kubota N, Ueki K, Tobe K,
Tamaoki N, Kadowaki T, Kosaka K:
Reconsideration of insulin signals induced by
improved laboratory animal diets, Japanese andAmerican diets, in IRS-2 deficcient mice. Exp.

145

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Clin. Endocrinol. Diabetes 117(10): 577-586
Hisanaga E, Nagasawa M, Ueki K, Kulkarni RN,
Mori M, Kojima I: Regulation of calciumpermeable TRPV2 channel by insulin in
pancreatic beta-cells. Diabetes 58: 174-184, 2009
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 2009, in press
Kadowaki T, Namba M, Yamamura A, Sowa H,
Wolka AM, Brodows RG: Exenatide exhibits
dose-dependent effects on glycemic control over
12 weeks in Japanese patients with suboptimallycontrolled type 2 diabetes. Endocr. J. 56:
415-424, 2009
Kadowaki T, Yamauchi T, Kubota N, Fujisawa T,
Nakagama H, Nakajima A, Terauchi Y, Ueki K:
Role of adiponectin and its receptors in
obesity-linked insulin resistance and metabolic
syndrome. Metabolic Syndrome: Carcinogenesis
and Prevention 91-96, 2009
Kahn CR, Suzuki R: Insulin Action in the Brainand the Pathogenesis of Alzheimer’s Disease.
Diabetes, Insulin and Alzheimer's Disease Series: Research and Perspectives in Alzheimer's
Disease, Springer, in press, 2009
Kato M, Noda M, Inoue M, Kadowaki T,
Tsugane S: Psychological facors, coffee and riskof diabetes mellitus among middle-aged
Japanese: a population-based prospective study
in the JPHC Study Cohort. Endocr. J. 56:
459-468, 2009
Kawamori R, Iwamoto Y, Kadowaki T, Iwasaki
M, Kim SW, Woo JT, Baik SH, Yoon KH:
Effects of insulin glulisine as mono- or add-on
therapy in patients with type 2 diabetes mellitus.
Diabetes Obes. Metab. 11(9): 900-9, 2009
Kawamori R, Kadowaki T, Ishii H, Iwasaki M,
Iwamoto Y: Efficacy and safety of insulin
glulisine in Japanese patients with type 1 diabetes
mellitus. Diabetes Obes. Metab. 11(9): 891-9,
2009
Kurabe N, Arai S, Nishijima A, Kubota N, Suizu
F, Mori M, Kurokawa J, Miyazaki MK, Ide T,

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Murakami K, Miyake K, Ueki K, Koga H,
Yatomi Y, Tashiro F, Noguchi M, Kadowaki T,
Miyazaki T: The death effector domaincontaining DEDD supports S6K1 activity via
preventing Cdk1-dependent inhibitory phosphorylation. J. Biol. Chem. 284: 5050-5055,
2009
Kurita H, Yoshioka W, Nishimura N, Kubota N,
Kadowaki T, Tohyama C: Aryl hydrocarbon
receptor-mdeiatedeffects
of
2,3,7,8-tetrachlorodibenzo-p-dioxin on glucosestimulated insulin secretion in mice: J. Appl.
Toxicol. 29(8): 689-694, 2009
Maeda T, Honda A, Ishikawa T, Kinoshita M,
Mashimo Y, Takeoka Y, Yasuda D, Kusano J,
Tsukamoto K, Matsuzaki Y, Teramoto T: A SNP
of NPC1L1 gene affects cholesterol absorption in
Japanese. Journal of Atherosclerosis andThrombosis in press
Matsuda S, Mikami Y, Ohtani M, Fujiwara M,
Hirata Y, Minowa A, Terauchi Y, Kadowaki T,
Koyasu S: Critical role of class IA PI3K for
c-Rel expression in B lymphocytes. Blood 113:1037-1044, 2009
Miura S, Kai Y, Kamei Y, Bruce CR, Kubota N,
Febbraio MA, Kadowaki T, Ezaki O: α2-AMPK
activity is not essential for an increase in fatty
acid oxidation during low-intensity exercise. Am.
J. Physiol. Endocrinol. Metab. 296: E47-E55,
2009
Nakamura A, Terauchi Y, Ohyama S, Kubota J,
Shimazaki H, Nambu T, Takamoto I, Kubota N,
Eiki J, Yoshioka N, Kadowaki T, Koike T:
Impact of small molecule glucokinase activatoron glucose metabolism, and β cell function andmass. Endocrinology 150: 1147-1154, 2009
Miyake K, Yang W, Hara K, Yasuda K,
Horikawa Y, Osawa H, Furuta H, Ng MC, Hirota
Y, Mori H, Ido K, Yamagata K, Hinokio Y, Oka
Y, Iwasaki N, Iwamoto Y, Yamada Y, Seino Y,
Maegawa H, Kashiwagi A, Wang HY, Tanahashi
T, Nakamura N, Takeda J, Maeda E, Yamamoto
K, Tokunaga K, Ma RC, So WY, Chan JC,
Kamatani N, Makino H, Nanjo K, Kadowaki T,
Kasuga M: Construction of a prediction modelfor type 2 diabetes mellitus in the Japanese
population based on 11 genes with strong

146

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evidence of the association. J Hum Genet. 54(4):236-41, 2009
Nishide K, Nagase T, Oba M, Oe M, Ohashi Y,
Iizuka S, Nakagami G, Kadowaki T, Sanada H:
Ultrasonographic and thermographic screening
for latent inflammation in diabetic foot callus.
Diabetes Res. Clin. Pract. 85: 304-309, 2009
Nishimura S, Manabe I, Nagasaki M, Eto K,
Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki
K, Sugiura S, Yoshimura K, Kadowaki T, Nagai
R: CD8+ effector T cells contribute tomacrophage recruitment and adipose tissue
inflammation in obesity. Nature Medicine 15:
914-920, 2009
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 disesase followed by earlycoronary artery bypass surgery in patients withdiabetic retinopathy: Report from a diabetic
retinocoronary clinic. J. Thorac. Cardiovasc.
Surg. 2009 Jun 16.[Epub ahead of print]
Omori S, Tanaka Y, Horikoshi M, Takahashi A,
Hara K, Hirose H, Kashiwagi A, Kaku K,
Kawamori R, Kadowaki T, Nakamura Y, Maeda
S: Replication study for the association of new
meta-analysis-derived
risk
loci
with
susceptibility to type 2 diabetes in 6,244
Japanese individuals. Diabetologia 52: 15541560, 2009
Otani K, Kitayama J, Yasuda K, Nio Y, Iwabu M,
Okudaira S, Aoki J, Yamauchi T, Nagawa H:
Adiponectin
suppresses
tumorigenesisin
Apo(Min)(/+)mice. Cancer Lett. 2009 July 29.
[Epub ahead of print]
Park KW, H Waki, WK Kim, BS Davies, SG
Young, F Parhami, P Tontonoz: The small
molecule
phenamilinducesosteoblast
differentiation and mineralization. Mol Cell Biol,
29: 3905-3914, 2009
Sasaki-Suzuki N, Arai K, Ogata T, Kasahara K,
Sakoda H, Chida K, Asano T, Pessin JE, Hakuno
F, Takahashi S: Growth Hormone Inhibition of
Glucose Uptake in Adipocytes Occurs without
Affecting GLUT4 Translocation through an
Insulin
Receptor
Substrate-2Phosphatidylinositol
3-Kinase-dependent

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Pathway: J Biol Chem. 284(10): 6061-70. 2009
Sekiya M, Yahagi N, Tamura Y, Okazaki H,
Igarashi M, Ohata K, Takanashi M, Kumagai M,
Takase S, Nishi M, Takeuchi Y, Izumida Y,
Kubota M, Ohashi K, Iizuka Y Yagyu H, Gotoda
T, Nagai R, Shimano H, Yamada N, Kadowaki T,
Ishibashi S, Osuga J: Hormone-sensitive lipase
deficiency suppresses insulin secretion frompancreatic islets of Lep(ob/ob) mice. Biochem.
Biophys. Res. Commun. 387: 511-515, 2009
Sekiya M, Osuga J, Nagashima S, Ohshiro T,
Igarashi M, Okazaki H, Takanashi M, Tazoe F,
Wada T, Ohta K, Takanashi M, Kumagai M,
Nishi M, Takase S, Yahagi N, Yagyu H, Ohashi
K, Nagai R, Kadowaki T, Furukawa Y, Ishibashi
S: Ablation of neutral cholesterol easterhydrolase 1 accelerates atherosclerosis. Cell
Metab. 10: 219-228, 2009
Sekiya M, Yahagi N, Tamura Y, Okazaki H,
Igarashi M, Ohta K, Takanashi M, Kumagai M,
Takase S, Nishi M, Takeuchi Y, Izumida Y,
Kubota M, Ohashi K, Iizuka Y, Yagyu H, Gotoda
T, Nagai R, Shimano H, Yamada N, Kadowaki T,
Ishibashi S, Osuga J: Hormone-sensitive lipase
deficiency suppresses insulin secretion frompancreatic islets of Lep(ob)(/)(ob) mice. Biochem
Biophys Res Commun 387: 511-5, 2009
Takamoto I, Kadowaki T: Controversies about
the importance of increased waist circumference.
International Diabetes Monitor. 2009, in press
Takazawa T, Yamauchi T, Tsuchida A, Takata M,
Hada Y, Iwabu M, Okada-Iwabu M, Ueki K,
Kadowaki T: Peroxisome proliferator-activatedreceptor gamma agonist rosiglitazone increases
the expression of very low density lipoprotein
receptor gene in adipocytes. J. Biol. Chem.:
284(44): 30049-57, 2009
Togo M, Hashimoto Y, Iso-O N, Kurano M, Hara
M, Kadowaki T, Koike K,
Tsukamoto K:
Identificationofnovel
mutationsforphytosterolemia. Genetic analyses of two cases.
Clinica Chimica Acta 401: 165-169, 2009
Torii S, Saito N, Kawano A, Hou N, Ueki K,
Kulkarni RN, Takeuchi T: Gene silencing ofphogrin unveils its essential role in glucoseresponsive pancreatic beta-cell growth. Diabetes
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147

40. Wang XL, Suzuki R, Lee K, Tran T, Gunton JE,
Saha AK, Patti ME, Goldfine A, Ruderman NB,
Gonzalez FJ, Kahn CR: Ablation of
ARNT/HIF1beta in liver alters gluconeogenesis,
lipogenic gene expression, and serum ketones.
Cell Metab. 9: 428-439, 2009
41. Watanabe T, Kubota N, Ohsugi M, Kubota T,
Takamoto I, Iwabu M, Awazawa M, Katsuyama
H, Hasegawa C, Tokuyama K, Moroi M, Sugi K,
Yamauchi T, Noda T, Nagai R, Terauchi Y, Tobe
K, Ueki K, Kadowaki T: Rimonabant ameliorates
insulin resistance via both adiponectin-dependentand adiponectin-independent pathways. J. Biol.
Chem. 284: 1803-1812, 2009

148

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

Lecturer
Yoichi Imai, 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 thirty
five 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

149

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 1150 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

150

published in the past year are listed in the reference.

References(1) Kataoka K, Nannya Y, Hangaishi A, Imai Y,
Chiba S, Takahashi T, and Kurokawa M.
Influence of pretransplantation serum ferritin on
nonrelapse mortality after myeloablative andnonmyeloablative allogeneic hematopoietic stem
cell transplantation.
Biology of Blood andMarrow Transplantation, 15:195-204, 2009.
(2) Yoshimi A, Nannya Y, Asano D, Yamamoto G,
Kumano K, Hangaishi A, Matsui Y, Takahashi T,
Imai Y, Kokudo N, and Kurokawa M.
Successful
haematopoietic
stem
cell
transplantation from an HLA-identical sibling ina patient with aplastic anemia following HLAhaploidentical living-related liver transplantation
for fulminant hepatitis. Biology of Blood andMarrow Transplantation, 15:389-390, 2009.
(3) Yoshimi M, Nannya Y, Watanabe T, Asai T,
Ichikawa M, Yamamoto G, Kumano K, Hangaishi
A, Imai Y, Takahashi T, Chiba S, and Kurokawa
M.
Acute eosinophilic pneumonia is a
non-infectious lung complication after allogeneic
hematopoietic
stem
cell
transplantation.
International Journal of Hematology, 89:244-248,
2009.
(4) Yoshimi A, Takahashi T, Motokura T, Yatomi Y,
Chiba S, and Kurokawa M. Hemoperitoneum
due to spontaneous rupture of the left
gastroepiploic artery in a patient with hemophilia
A. Annals of Hematology, 88:811-812, 2009.
(5) Ueda K, Yamamoto G, Shinohara A, Hangaishi A,
and Kurokawa M.
Early onset of acutelymphoblastic leukemia with MLL rearrangement
after autologous stem cell transplantation for
multiple myeloma.
Annals of Hematology,
88:813-814, 2009.
(6) Kato T, Hangaishi A, Ichikawa M, Motokura T,
Takahashi T, and Kurokawa M.
A newthree-way variant t(15;22;17)(q22;q11.2;q21) inacute promyelocytic leukemia.
International
Journal of Hematology, 89:204-208, 2009.
(7) Lee SY, Kumano K, Nakazaki K, Sanada M,
Matsumoto A Yamamoto G, Nannya Y, Suzuki R,
Ota S, Ota Y, Izutsu K, Sakata-Yanagimoto M,

Hangaishi A, Yagita H, Fukayama M, Seto M,
Kurokawa M, Ogawa S, and Chiba S. Gainof-function mutations and copy number increasesof Notch2 in diffuse large B-cell lymphoma.
Cancer Science, 100:920-926, 2009.
(8) Izumchenko E, Plotnikova O, Singh M,
Tikhmyanova N, Little J, Seo S, Kurokawa M,
Egleston B, Klein-Szanto AJ, Pugacheva E,
Hardy R, Connolly D, Wolfson M, and Golemis
E.
NEDD9 is required for activation of
oncogenic signaling pathways in mammary
tumor development.
Cancer Research, 69:
7198-7206, 2009.
(9) Goyama S and Kurokawa M. Pathogenetic
significance of ecotropic viral integration site-1
in hematological malignancies. Cancer Science,
100:990-995, 2009.
(10) Yokoyama Y, Suzuki T, Sakata-Yanagimoto M,
Kumano K, Higashi K, Takato T, Kurokawa M,
Ogawa S, and Chiba S. Derivation of functional
mature neutrophils from human embryonic stem
cells. Blood, 113:6584-6592, 2009.
(11) Ueda K, Nannya Y, Kumano K, Hangaishi A,
Takahashi T, Imai Y, and Kurokawa M.
Monitoring trough concentration of voriconazole
is important to ensure successful antifungal
therapy and to avoid hepatic damage in patientswith hematological disorders.
International
Journal of Hematology, 89:592-599, 2009.
(12) Haraguchi K, Suzuki T, Koyama N, Kumano K,
Nakahara F, Matsumoto A, Yokoyama Y,
Sakata-Yanagimoto M, Masuda S, Takahashi T,
Kamijo A, Takahashi K, Takanashi M, Okuyama
Y, Yasutomo K, Sakano S, Yagita H, Kurokawa
M, Ogawa S, and Shigeru Chiba3.
Notch
activation induces the generation of functional
natural killer cells from human cord blood
CD34-positive cells devoid of interleukin-151.
The Journal of Immunology, 182: 6168-6178,
2009.
(13) Nagai S, Nannya Y, Hangaishi A, Takahashi T,
and Kurokawa M.
The race and dose of
chemotherapy should be considered for
optimizing maintenance therapy for acutepromyelocytic leukemia. Leukemia Research,
33:1427-1429, 2009.
(14) Yoshimi A, Asai T, Maeda D, Hangaishi A,

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Sakatani T, Takahashi T, Imai Y, Fukayama M,
and Kurokawa M. Chronic myelomonocytic
leukemia presenting as hemorrhagic shock due touterine infiltration of leukemic cells andearly-stage
endometrial
adenocarcinoma.
Archives of Gynecology and Obstetrics, 280:
1077-1078, 2009.
(15) Kataoka K, Ichikawa M, Hangaishi A, Takahashi
T, Imai Y, and Kurokawa M.
Interstitial
pneumonia associated with progression of
myelodysplastic syndrome.
International
Journal of Hematology, 89:718-719, 2009.
(16) Nakamura K, Igarashi K, Ohkawa R, Okubo S,
Yokota H, Kishimoto T, Ide K, Masuda A,
Yamamoto T, Saito N, Kurokawa M, Tsuji S,
Okudaira S, Ikeda H, Aoki J, and Yatomi Y.
Autotaxin enzyme immunoassay in humancerebrospinal fluid samples. Clinica Chimica
Acta, 405: 160-162, 2009.
(17) Taoka K, Nannya Y, Yamamoto G, Sakatani T,
Ota S, Fukayama M, Takahashi T, and Kurokawa
M. Progressive transition of Epstein-Barr virus
associated lymphoproliferative disease subtypes
with the development of lung cancer. Amarican
Journal of Hematology, 84: 600-603, 2009.
(18) Takahashi T and Kurokawa M.
Humaninvariant natural killer T cells: implication for
immunotherapy.
International Journal of
Hematology, 90: 137-142, 2009.
(19) Nagai S, Takahashi T, and Kurokawa M.
Beneficial and adverse effects of molecularly
targeted therapies for acutepromyelocytic
leukemia in central nervous system. CNS and
Neurological Disorders-Drug Targets, 8: 387-392,
2009.
(20) Miyagaki T, Sugaya M, Minatani Y, Fujita H,
Hangaishi A, Kurokawa M, Takazawa Y, andTamaki K. Mycosis fungoides with recurrent
Hodgkin’s lymphoma and diffuse large B cell
lymphoma. Acta Dermato-Venereologica, 89:
421-422, 2009.
(21) Shimabe M, Goyama S, Watanabe-Okochi N,
Yoshimi A, Ichikawa M, Imai Y, and Kurokawa
M. Pbx1 is a downstream target of Evi-1 inhematopoietic stem/progenitors and leukemic
cells. Oncogene, 28: 4364-4374, 2009.
(22) Masuda S, Kumano K, Suzuki T, Tomita T,

Iwatsubo T, Natsugari H, Tojo A, Shibutani M,
Mitsumori K, Hanazono Y, Ogawa S, Kurokawa
M, and Chiba S. Dual antitumor mechanisms of
Notch signaling inhibitor in a T cell acutelymphoblastic leukemia xenograft model. Cancer
Science, 100: 2444- 2450, 2009.

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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)

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

153

Medical Care
General and special outpatient clinics are opened from
Monday to Friday. Special outpatients clinics include
clinics for rheumatoid arthritis, connective tissue
diseases, bronchial asthma, allergy, and kidney
disorders. For inpatients, there are presently 25 to 30
beds. Every week on Monday afternoon the charts arerounded and on Tuesday afternoon the professor
makes his rounds. To achieve the highest quality of
medical care, clinical conferences are held. Majorityof patients in the ward are suffered from connective
tissue diseases and usually exhibit multiple organ
involvements. Therefore, a careful, well-rounded
approach to each patient as a whole is required rather
than a limited special approach to a single organsystem.

Research
The Department has 10 research laboratories in whichclinical and basic studies are carried out concerning
mainly rheumatology and allergology. Recently themainstream of research has employed various
techniques of molecular biology and cellularimmunology. The principal research topics are listed
below.
1) Analysis of regulatory T cells.
2) Analysis of the mechanisms of tolerance
breakdown to systemic autoantigens usingtransgenic mice.
3) Analysis of antigen specific T cell clonalities in
immunological disorders.
4) Genetic analysis of rheumatoid arthritis and otherconnective tissue diseases.
5) Development of new gene therapies for immunological diseases.
6) Analysis of the mechanisms of oral tolerance.
7) Analysis of signal transduction mechanisms in
immunological disorders.
8) Development and analysis of animal models of
bronchial asthma.
9) Study of signal transduction of IgE mediated mastcell activation.
10) Regulation of IgE antibody production.
11) Analysis of cytokines and chemokines in thepathogenesis of allergic conditions.

12) Analysis of interstitial pneumonitis associatedwith connective tissue diseases,13) Mechanism of drug allergy

References
2009
Nakagome K, Okunishi K, Imamura M, Harada H,
Matsumoto T, Tanaka R, Miyazaki J, Yamamoto K,
Dohi M. IFN-{gamma} attenuates antigen-induced
overall immune response in the airway as a Th1-type
immune regulatory cytokine. J Immunol. 1;183:209-20, 2009.
Okamura T, Fujio K, Shibuya M, Sumitomo S, Shoda
H, Sakaguchi S, Yamamoto K. CD4+CD25-LAG3+
regulatory T cells controlled by the transcription
factor Egr-2. Proc Natl Acad Sci USA.106:13974-79,
2009.
Sawada T, Hashimoto S, Kanzaki T, Suzuki A,
Yamada R, Odawara M, Yamamoto K. Citrullinatedantigens as C1q-binding and monoclonal rheumatoid
factor (mRF)-binding peptides in synovial fluids fromrheumatoid arthritis patients. Clin Exp Rheumatol.
27:989-92, 2009.
Son D, Kanda H, Yamaguchi A, Kawabata K,
Kawakami T, Kubo K, Higashihara M, Shimizu J,
Uozaki H, Kuramochi S, Misaki Y, Takeuchi F,
Yamamoto K. Myeloperoxidase antineutrophil
cytoplasmic antibody-associated vasculitis withdiffuse tubulointerstitial nephritis. J Nephrol. 22:
417-20, 2009.
Okada Y, Yamada R, Suzuki A, Kochi Y, Shimane K,Myouzen K, Kubo M, Nakamura Y, Yamamoto K.
Contribution of a haplotype in the HLA region toanti-cyclic citrullinated peptide antibody positivity inrheumatoid arthritis, independently of HLA-DRB1.
Arthritis Rheum. 60:3582-3590, 2009.
Kochi Y, Suzuki A, Yamada R, Yamamoto K. Genetics
of rheumatoid arthritis: underlying evidence of ethnic
differences. J Autoimmun. 32:158-62, 2009.
Kochi Y, Myouzen K, Yamada R, Suzuki A, Kurosaki

154T, Nakamura Y, Yamamoto K. FCRL3, an
autoimmune susceptibility gene, has inhibitory
potential on B-cell receptor-mediated signaling. J
Immunol. 183:5502-10, 2009.
Shimane K, Kochi Y, Yamada R, Okada Y, Suzuki A,
Miyatake A, Kubo M, Nakamura Y, Yamamoto K. A
single nucleotide polymorphism in the IRF5 promoter
region is associated with susceptibility to rheumatoid
arthritis in the Japanese population. Ann Rheum Dis.
68:377-83, 2009.

155

Department of Infectious
Diseases (Internal Medicine)
Professor
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, 3 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 teaching of the internal medicine forundergraduate medical students according to theeducational programs of the University of Tokyo. For
the fourth year medical students, six lectures ofinfectious diseases are given. In addition, principles of
medical diagnosis are taught at the bedside. During the

156

bed-side teaching for fifth and sixth year students, ourassociates teach them on man-to man basis the basic
way of thinking for correct diagnosis and therapy, thetechniques of interrogation and physical examination,
the way for interpretations of laboratory tests and othermedical examinations, and the basic medical
procedures on each case. The education of juniorresidents is performed as described in “Clinical
Activities”.

Research activities
Both clinical and basic researches are necessary to
improve the diagnosis and treatment. The members ofour department are doing best to obtain new findings
using highly sophisticated methodologies. A monthly
intramural research conference is held, in which two to
three members present their annual research progresses
to be discussed by all the department staff. In addition,
each laboratory holds its own conference and/or journal
club on a weekly or bi-weekly basis.
The research field covers wide areas of infectious
diseases including HIV infection, viral hepatitis andhepatocarcinogenesis, CMV infection and tuberculosis(Mycobacterium infection). Also, various emerging andre-emerging infectious diseases are covered. Following
themes are currently being investigated in thedepartment.
(1) Establishment of effective therapy for HIV
infection: we have made a great contribution in theestablishment of the guideline for treatment of HIV
infection in Japan.
(2) Elucidationofthemechanismofhepatocarcinogenesis in hepatitis viral infection:
the direct involvement of both HBV and HCV in
hepatocarcinogenesis has been demonstrated using
our transgenic mouse systems.
(3) Establishment of effective therapy for HCV and
HBV infection: we have made a great contribution
in the establishment of the guideline for treatmentof hepatitis viral infection in Japan.
(4) Establishment of effective therapy for HCV/HIV
co-infection: we have made a great contribution in
the establishment of the guideline for treatment of
HCV/HIV co-infection in Japan.
(5) Establishment of the criteria for prediction andearly diagnosis of CMV infection associated with

HIV infection.
(6) Innovation of new methods to control viral
hepatitis or prevent the development of
hepatocellular carcinoma in chronic viral hepatitis.
(7) Establishment of the effective infection control
method of MRSA and other MDRO infection.
(8) Elucidating the mechanism and signal transductionof bacterial infection through toll-like receptors.
(9) Analysis of intracellular function and signaling of
the proto-oncogene Cbl.
(10) Establishment of new methods for practical
diagnosis and treatment of respiratory infection.

Members
Kazuhiko Koike, Hiroshi Yotsuyanagi, Yoshizumi
Shintani, Takeya Tsutsumi, Shuji Hatakeyama, Satoshi
Itoyama, Takatoshi Kitazawa, Kuniko Ueda, Shu
Okugawa, Miki Kawada, Shintaro Yanagimoto, Yohko
Nukui, Katsutoshi Abe, Atsuhito Fukishima, Keita
Tatsuno, Sohei Harada, Koji Goto, Mahoko Kamimura,
Yusuke Yoshino, Takahiro Aoki, Koh Okamoto.

References
1) Tsutsumi T, Matsuda M, Aizaki H, Moriya K,
Miyoshi H, Fujie H, Shintani Y,Yotsuyanagi H,
Miyamura T, Suzuki T, Koike K. Proteomics
analysis of mitochondrial proteins reveals
overexpression of a mitochondrial protein
chaperone, prohibitin, in cells expressing hepatitis
C virus core protein. Hepatology 2009;50:378-86.
2) Moriya K, Miyoshi H, Tsutsumi T, Shinzawa S,
Fujie H, Shintani Y, Yotsuyanagi H, Moriishi K,
Matsuura Y, Suzuki T, Miyamura T, Koike K.
Tacrolimus ameliorates metabolic disturbance andoxidative stress caused by hepatitis C virus coreprotein: analysis using mouse model and cultured
cells. Am J Pathol. 2009;175:1515-24.
3) 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 Standardizationof Treatment of Viral Hepatitis Including Cirrhosis,
Ministry of Health, Labor and Welfare of Japan.
Guidelines for the treatment of chronic hepatitis

157

and cirrhosis due to hepatitis B virus infection for
the fiscal year 2008 in Japan. Hepatol Res.
2010;40:1-7.
4) 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 Standardizationof Treatment of Viral Hepatitis Including Cirrhosis,
Ministry of Health, Labour and Welfare of Japan.
Guidelines for the treatment of chronic hepatitis
and cirrhosis due to hepatitis C virus infection for
the fiscal year 2008 in Japan. Hepatol Res.
2010;40:8-13.
5) 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. Intern Med.
2010;49:383-8.
6) Moriya K, Miyoshi H, Shinzawa S, Tsutsumi T,
Fujie H, Goto K, Shintani Y, Yotsuyanagi H, Koike
K. Hepatitis C virus core protein compromises
iron-induced activation of antioxidants in mice and
HepG2 cells. J Med Virol. 2010;82:776-92.
7) Okuse C, Yotsuyanagi H, Yamada N, Okamoto M,
Ikeda H, Kobayashi M, Fukuda Y, Takahashi H,
Nagase Y, Suzuki Y, Matsunaga K, Ishii T,
Matsumoto N, Koike K, Suzuki M, Itoh F. Effectof nucleoside analog-interferon sequential therapy
on patients with acute exacerbation of chronic
hepatitis B. Hepatol Res. 2010;40:461-9.
8) Yanagimoto S, Tatsuno K, Okugawa S, Kitazawa T,
Tsukada K, Koike K, Kodama T, Kimura S,
Shibasaki Y, Ota Y. A single amino acid of
toll-like receptor 4 that is pivotal for its signaltransduction and subcellular localization. J Biol
Chem. 2009;284:3513-20.
9) 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.

158

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 2009 January to 2009 December, 49
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 2009 January to 2009 December,the numbers of the new outpatients and of the overall
outpatients in our department were 191 and 2620,
respectively.

Teaching activities
We are giving 6 methodical lectures on
psychosomatic medicine for fourth grade medical
students, ‘problem-based learning’ lasting 12 weeks(net 24 hours) for 6 or 7 fourth grade students,‘bed-side learning’ for fifth grade students lasting two
weeks, ‘clinical clerkship’ for 3 to 4 fifth gradestudents lasting 4 weeks each, and a clinical lecture on
panic disorder for sixth grade students. We are trying
to teach them not only basic knowledge of specificdiseases, ways of physical examination, orinterpretation of laboratory data, but also relevantways of clinical interview, doctor-patient relationshipbuilding, and behavior modification.
As for education for junior residents, our seniorresidents and an associate provide man-to-man
instruction. In addition, they can learn how to present
the history of newly-admitted patients at the weekly
professor’s round from our teaching staff.

159

Research activities

Neuroendocrinol. 2009;21:538-49.
2.

Targeting stress-related diseases such as not only
those covered by our department but also otherlifestyle-related disease, and cancers, we areinvestigating
theirpathophysiology
andpsychopathology
throughassessingbio-psycho-behavioral time-series data, various
questionnaire data, and autonomic nervous function.
We are also actively conducting basic as well as
clinical research on eating-related substances.
Some representative research methods are as
follows:
1) Ecological momentary assessment (EMA):
Investigation on neurobehavioral basis ofstress-related diseases such as tension-type
headache, eating disorders, insomnia, and panic
disorder using portable computers for real-timeassessmentof
subjective
symptoms
incombination with ambulatory monitors such as
electrocardiogram and actigraphy.
2) Neuroendocrinological and neuroimmunologicalstudiesinanorexia
nervosapatients:
multidisciplinary
investigationonenergymetabolism during a refeeding phase; changes invarious substances such as neuropeptides before
and after treatment; relationship between bonemetabolism and various makers; and explorationof biomarkers for evaluating treatment efficacy.

Fukuo W, Yoshiuchi K, Ohashi K, Togashi H,
Sekine R, Kikuchi H, Sakamoto N, Inada S, Sato F,
Kadowaki T, Akabayashi A. Development of ahand-held personal digital assistant-based fooddiary with food photographs for Japanese subjects.
J Am Diet Assoc. 2009;109:1232-6.

3.

Kondo K, Lee JS, Kawakubo K, Kataoka Y,
Asami Y, Mori K, Umezaki M, Yamauchi T, Takagi
H, Sunagawa H, Akabayashi A. Association
between daily physical activity and neiborhood
environments. Environ Health Prev Med 2009;14:
196-206.

4.

Nakade M, Lee JS, Kawakubo K, Kondo K, Mori
K and Akabayashi A. Changes in food intake
patterns associated with body weight loss during a
12-week health promotion program and a 9-monthfollow-up period in a Japanese population. ObesRes Clin Prac 2009;3:85-98.

5.

Komaki G, Moriguchi Y, Ando T, Yoshiuchi K,
Nakao M. Prospects of psychosomatic medicine.
Biopsychosoc Med. 2009;22;3:1.

6.

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, in press.

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.

7.

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, inpress.

8.

Hachizuka M, Yoshiuchi K, Yamamoto Y, Iwase S,
Nakagawa K, Kawagoe K, Akabayashi A.

References

Development of a personal digital assistant (PDA)
system to collect symptom information in home1.

hospice patients. J Palliat Med 2010, in press

Leibowitz SF, Akabayashi A, Alexander J,
Karatayev O, Chang GQ. Puberty onset in female

9.

Aoyagi Y, Park H, Kakiyama T, Park S, Yoshiuchi

rats: relationship with fat intake, ovarian steroids

K, Shephard RJ. Yearlong physical activity andand the peptides, galanin and enkephalin, in theregional stiffness of arteries in older adults: theparaventricular and medial preoptic nuclei. J

Nakanojo Study. Eur J Appl Physiol 2010, in press.

160

10.

Yoshiuchi K, Takimoto Y, Moriya J, Inada S,
Akabayashi A. Thrombopoietin and thrombocytopenia in anorexia nervosa with severe liver
dysfunction. Int J Eat Disord 2010, in press.

Internal Medicine
3. Clinical Laboratory Medicine
and Pathology

162

Department of Transfusion
Medicine
Professor
Koki Takahashi, M.D., Ph.D.

Associate
Nelson H. Tsuno, M.D., Ph.D.,

Minoru Tanaka, M.D., Ph.D.,

Susumu Goyama, M.D, Ph.D.(-June 30),

Naoko Okochi, M.D., Ph.D.(July 1-)

Homepage http://172.27.30.16/yuketsu/s-index.html
Introduction and Organization
The Transfusion Medicine service was established in1949, as an internal provisional measure, andofficially established in 1966. In 1984, Professor
Hiroshi Toyama assumed as the first Professor of thedepartment. Professor Toyama greatly contributed to
the field of transfusion medicine, especially by
publishing “Transfusion Medicine” (actually in its 3rd.
edition), which is the bible of transfusion medicine inJapan. Other great contributions from the department
are as follows. Dr. Kazuo Okochi, ex-lecturer of thedepartment, is the pioneer in the field oftransfusion-associated hepatitis research, ex-Professor
Takeo
Juji
clarifiedthemechanismsoftransfusion-associatedgraft-versus-hostdisease(TA-GVHD),aseriouspost-transfusional
complication, and the previous professor, Professor
Yoichi Shibata contributed enourmously to the field ofplatelet immunology. In 1997, the Department ofTransfusion Medicine was established as a chair of theDivision of Internal Medicine of the Graduate Schoolof Medical Sciences, the University of Tokyo.
Actually, the department is composed of 6 medical
doctors (4 full-time, and 2 partial-time), 10 laboratory
technicians, 1 nurse and 1 office assistant.

Clinical activities
The main activity of the department of Transfusion
Medicine is the control, preservation, and provision ofsafe blood products and their derivatives. The control
of all blood products in the hospital is centralized tothe department, which, in addition, provides
information and orientation related to bloodtransfusion. Transfusion-related laboratory tests andtests for transfusion-transmitted infectious diseases
are routine practices of the department, which also
actively takes part in the diagnosis, prevention andtreatment of adverse reactions and post-transfusion
complications. Collection, preservation and provisionof autologous blood are also important functions of
the department, where the outpatient clinic forautologous blood was established in January 2006. At
the outpatient clinic, the first established in Japan, thetransfusionist gives consultation to the patients,
prepares the adequate blood collection schedule, takes
the informed consent, and performs the bloodcollection, according to the surgeons’ needs.
Additionally, immunotherapy of cancer patients andpatients with recurrent abortion, and collection andpreservation of peripheral blood stem cells are also
performed.
I. Control and preservation of blood products andits derivatives;;
II. Laboratory tests
1) Blood typing and histocompatibility testing;1632) 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 andDNA-based methods. The HLA typing, which wasintroduced by ex-Professor Takeo Juji, one of thepioneers of this field, is an essential test for stem celland organ transplantations, and still continues as oneof the most important research fields of thedepartment. The mixed-passive hemagglutination(MPHA) method, the most popular methodology forplatelet serology in Japan, was developed by Professor
Yoichi Shibata, the previous professor, and its
applicability is now extended for granulocyte as wellas endothelial cell serology. Transplantation
immunology, including stem cell biology, anddevelopment of immunotherapeutic strategies to treat
cancer patients and patients with recurrent abortion
are also being performed. Recently, development of
new materials for medical use is being researched.
Following are the main themes.
1. Detection of platelet alloantigens and antibodies
and their role in the transfusion practice.
2. Diagnosis and prevention of post-transfusional
complications and thrombocytopenic purpura of
the newborn.
3. Clinical application of refrigerated and frozenstored blood for autologous transfusion in surgicalpatients.
4. Study on the mechanisms of transfusionassociated GVHD and its prevention.
5. Development of a new methodology for plateletcross-match.
6. Detection and characterization of anti-endothelial
cell antibodies, and study on their role in thepathogenesis of inflammatory and autoimmune
diseases, as well as in organ transplantation.
7. HLA and HPA genotyping.
8. Development of a new methodology for evaluationof platelet function.
9. Development of new strategies for the treatment of164cancer 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

166

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.

167

Primary care peri/post-menopausal women is
becoming more important. We have alreadyestablished the primary care system for womenfocusing on climacteric syndrome and osteoporosis.
Hormone replacement therapy (HRT) is employed forthe purpose.
In basic research section, a couple of projects asfollows are under way, some of which have alreadyyielded interesting findings; 1) the mechanism offolliculogenesis and follicular apoptosis in the ovary,2) the functions of gynecologic hormones such as
gonadotropins and ovarian steroids, 3) the analysis ofendometriosis, 4) effect of ovarian steroid hormoneson bone metabolism, and 6) effects of endocrine
disrupters on the reproductive system.

References published in 2009(1) Momoeda M, et al. Long-term use of dienogest
for the treatment of endometriosis. J Obstet
Gynaecol Res. 35(6):1069-76, 2009
(2) Wada-Hiraike O, et al. Aberrant implantation andgrowth of uterine leiomyoma in the abdominal
wall after laparoscopically assisted myomectomy.
Fertil Steril. 92(5):1747, 2009(3) Takamura M, et al. Post-operative oral
con-traceptive use reduces the risk of ovarian
endometrioma recurrence after laparoscopic
excision. Hum Reprod. 24(12):3042-8, 2009(4) Shi J, et al. Bone morphogenetic protein-6
stimulates gene expression of follicle-stimulating
hormone receptor, inhibin/activin beta subunits,
and anti-Müllerian hormone in human granulosa
cells. Fertil Steril. 92(5):1794-8, 2009
(5) Tsutsumi R, et al. Induction of early decidualization by cadmium, a major contaminant ofcigarette smoke. Fertil Steril. 1(4 Suppl):1614-7(6) Hasegawa A, et al. Tunicamycin enhances theapoptosis
inducedbytumor
necrosisfactor-related apoptosis-inducing ligand in
endometriotic stromal cells. Hum Reprod.
24(2):408-14, 2009(7) Hirata T, et al. Conjoined twins in a triplet
pregnancy after intracytoplasmic sperm injection
and blastocyst transfer: case report and review ofthe lite-rature. Fertil Steril. 91(3):933, 2009(8) Hirota Y, et al. Interleukin (IL)-1beta stimu-lates

migration and survival of first-trimester villous
cytotrophoblast cells through endometrial
epithelial cell-derived IL-8. Endocrinology.
150(1):350-6, 2009
(9) Fu L, et al. Expression and possible implica-tionof growth hormone-releasing hormone receptor
splice variant 1 in endometriosis. Fertil Steril.
92(1):47-53, 2009(10) Harada T, et al. Dienogest is as effective as
intranasal buserelin acetate for the relief of pain
symptoms associated with endometriosis--arandomized, double-blind, multicenter, controlled
trial. Fertil Steril. 91(3):675-81, 2009

168

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

169

presence of the NAs against HPV16 was associatedwith a higher regression rate of HPV-related CIN1
lesions. The NAs seem to have a role in deterring
HPV-related cervical lesions from progressing to
CIN2/3 by inhibiting the infection with de novo
replicated
HPV.
Then
we
designedaplacebo-controlled trial in healthy adults to evaluate
the safety and immunogenicity of a synthetic peptide
consisting of the aa 108-120 of HPV16 L2(L2-108/120) region, because this region contains across-neutralization epitope against genital HPV.. A
total of 13 volunteers were given nasal inoculations
with 0.1 (n=5) or 0.5mg (n=5) doses of the peptides orplacebo (n=3) without adjuvant at weeks 0, 4, and 12.
Sera were collected before inoculation and at 6, 16
and 36 weeks. The inoculation caused no serious local
and systemic complications. The inoculation
generated anti-L2 antibodies binding to both HPV16
and 52 L1/L2-capsids in four of the five recipients in
the 0.5mg group. Sera of the four recipients showedneutralizing activities against HPV16 and 52.
Serological responses to the peptides were not foundin the 0.1mg group and the placebo group recipients.
This study suggests the L2-108/120 peptide istolerable in humans and has the potential as abroad-spectrum prophylactic vaccine against genital
HPV.
We also investigated interacting proteins with the
HPV E6 protein. Recently, a LAP protein, scribble,
was identified in Drosophila epithelia as a basolateralprotein that controls the apical-basolateral polarity.
Loss of scribble causes disorganisation andovergrowth of the epithelia. Scribble has a humanhomologue, human scribble (hScrib), which is a
substrate of ubiquitin-mediated degradation by humanpapillomavirus E6 and the E6AP ubiquitin-protein
ligase. In the present study, we revealed that hScrib
localised to the basolateral regions of the epithelial
cell line MDCK and human uterine cervical epithelial
tissues by immunofluorescence. Human scribble
colocalised rather with the adherens junction protein
E-cadherin, but not with the tight junction protein
ZO-1. Histochemical analysis showed a dramatic
decrease in the expression of hScrib with theprogression of disease from normal uterine cervicaltissues to invasive cervical cancers through theprecursor lesions. In contrast, the expression of hScrib

was retained in the throughout epithelial layer of the
HPV-negative
cervicalhigh-grade
squamous
intraepithelial lesions (H-SIL). Although quantitative
RT-PCR revealed no significant downregulation of
hScrib mRNA expression in the H-SIL, it revealed aclear downregulation in the invasive cancers. These
results suggest the possibility that degradation by
HPV E6 is one of the causal roles for the progressive
decrease of hScrib expression during the disease
pro-gression from low-grade squamous intraepithelial
lesions to H-SIL, and a cooperative role ofdownregulation of hScrib mRNA expression andubiquitin-mediated degradation of hScrib by E6 andE6AP led to the complete decrease of hScrib
expression during the process of carcinogenesis from
H-SIL to invasive cancer. These data underscore theimportance of hScrib in the construction of tissue
architecture and prevention of cancer develop-ment.
Another basic research is focused on analysis oftumor suppressor genes in gynecological malignancies
as following.
1 Human Scribble
Recently, a LAP protein, scribble, was identified in
Drosophila epithelia as a basolateral protein that
controls the apical-basolateral polarity. Loss ofscribble causes disorganisation and overgrowth of theepithelia. Scribble has a human homologue, humanscribble (hScrib), which is a substrate ofubiquitin-mediateddegradationbyhumanpapillomavirus E6 and the E6AP ubiquitin-protein
ligase. In the present study, we re-vealed that hScrib
localised to the basolateral regions of the epithelial
cell line MDCK and human uterine cervical epithelial
tissues by immunofluorescence. Human scribble
colocalised rather with the adherens junction protein
E-cadherin, but not with the tight junction protein
ZO-1. Histochemical analysis showed a dramatic
decrease in the expression of hScrib with theprogression of disease from normal uterine cervicaltissues to invasive cervical cancers through theprecursor lesions. In contrast, the expression of hScrib
was retained in the throughout epithelial layer of the
HPV-negative
cervicalhigh-grade
squamous
intraepithelial lesions (H-SIL). Although quantitative
RT-PCR revealed no significant downregu-lation of
hScrib mRNA expression in the H-SIL, it revealed aclear downregulation in the invasive cancers. These170

results suggest the possibility that degradation by
HPV E6 is one of the causal roles for the progressive
decrease of hScrib expression during the diseaseprogression from low-grade squamous intraepithelial
lesions to H-SIL, and a cooperative role ofdownregulation of hScrib mRNA expression andubiquitin-mediated degradation of hScrib by E6 andE6AP led to the complete decrease of hScrib
expression during the process of carcinogenesis from
H-SIL to invasive cancer. These data underscore theimportance of hScrib in the construction of tissue
architecture and prevention of cancer develop-ment.
Drosophila discs large (Dlg) is one of neoplastic
tumor suppressors, which genetically links to scribble.
E6 also targets human Dlg (hDlg) for
ubiquitin-mediated degradation. Ubiquitin-protein
ligase involved in this process has not been identified
thus far. Here we investigated mechanism underlying
degradation of three target proteins of E6, hScrib,
hDlg, and p53 by using eighteen HPV 16 E6 mutants
with single amino acid substitution. In vitro
degradation ability of each E6 mutant was equivalent
for these tumor suppressors. We investigated whether
E6AP is involved in ubiquitin-mediated degradationof hDlg. In vitro binding assay revealed that hDlg
formed ternary complex with E6-E6AP complex. The
ability of E6 mutants to degrade these tumor
suppressors was correlated with their ability tointeract with E6AP. Furthermore, hDlg was targeted
for in vitro ubiquitination in the presence of both E6
and E6AP. These data revealed that E6AP isextensively involved in the ubiquitin-mediateddegradation of E6-dependent substrates as a cellular
E3 ubiquitin-protein ligase.
Human Scribble, classified as a LAP protein
containing leucine-rich repeats and PDZ domains,interacts with E6 through its PDZ domains andC-terminal PDZ do-main-binding motif of E6 protein.
Interaction between human Discs Large (hDlg), which
is a substrate of E6 for the ubiquitin-mediateddegradation, and adenomatous polyposis coli (APC)
has been shown. Here, we investigated whether hScrib
and APC interact with each other in vitro and in vivo.
Interaction between hScrib and APC is mediated by
the PDZ domains 1 and 4 of hScrib and C-terminal
PDZ domain-binding motif of APC. Human Scribble
co-localized with APC at the synaptic sites ofhippocampal neuron and at the tip of membrane
protrusion in the epithelial cell line. Interference of
the interaction between hScrib and APC caused
disruption of adherens junction. Knockdown of hScrib
expression by RNAi disrupts localization of APC at
the adherens junction. These data suggest that hScrib
may participate in the hDlg-APC complex through its
PDZ domains and regulate cell cycle and neuralfunction by associating with APC.
Drosophila tumor suppressor Scribble has been
identified as an apical-basolateral polarity determinant
in epithelia. A human homolog of Drosophila Scribble,
human Scribble (hScrib), has been identified as aprotein targeted by human papillomavirus E6 for theubiquitin-mediated degradation dependent on E6AP, acellular ubiquitin-protein ligase. Human Scribble isclassified as a LAP protein, having leucine-richrepeats (LRRs) and PDZ domains. We investigatedwhether hScrib, which is thought to have a role inpolarity determination based on the data of its
Drosophila homolog, is involved in cell-cycle
regulation and proliferation control of epithelia.
Transfection of hScrib inhibits cell-cycle progression
from G1 to S phase, and it up- and down-regulates
expression of adenomatous polyposis coli and cyclins
A and D1, respectively. Knockdown of hScrib
expression by siRNA leads to cell-cycle progression
from G1 to S phase. We explored functional domain
mapping to reveal which domains of hScrib are
critical for its cellular proliferation control andlocalization at the basolateral membrane. We foundthat LRRs and PDZ domain 1 are indispensable for
hScrib to inhibit cell growth by blocking cell-cycle
progression and to keep its proper localization. These
data indicate that basolateral membrane localization of
hScrib is closely related to its proliferation control.
Our findings suggest the possibility that hScrib isinvolved in signal transduction to negatively regulate
cell proliferation by localizing at the basolateral
membrane of epithelial cells through LRRs and PDZ
domains.
We also investigated which E3 ubiquitin-protein
ligase is involved in the ubiquitin-mediateddegradation of hDlg. Human scribble (hScrib), which
was identified as sub-strate of human papillomavirus(HPV) E6 for ubiquitin-mediated degradation
dependent on ubiquitin-protein ligase E6AP, is a

171human 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 PTE
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

172

and PgR in MPA-treated 31 cases with CAH or IaG1.
Eleven of 12 cases (92%) with CAH and 15 of 19
cases (79%) with IaG1 demonstrated an initial
complete response, while five patients underwent
hysterectomy due to no response. Four of 11
responders (36%) with CAH and five of 15 responders(33%) with IaG1 later developed relapse. Five of ninepatients (56%) with CAH and three of 11 patients(27%) with IaG1 became pregnant after infertility
treatment. Immunohistochemical analysis revealed
that phospho-Akt expression was significantly
decreased by MPA administration (p=0.002).
Furthermore, combination of two factors, weak
phosho-Akt or PTEN-null expression, was found to besignificantly associated with receiving hysterectomy(p=0.04), while each factor showed a trend without
statistical significance (p=0.07 and 0.2, respectively).
Strong expression of both ER and PgR significantly
cor-related with successful pregnancy after infertility
treat-ment following complete response to MPA(p=0.02). Our observations in vivo suggest thatanti-tumor action of MPA may be mediated bydephosphorylation
of
Akt,
and
that
immunohistochemical evaluation of phospho-Akt andPTEN may be able to predict the outcome of MPA
therapy.
3 SFRP1 gene
The SFRP1 gene on chromosome 8p11.2 en-codes a
Wnt signaling antagonist, and was recently
demonstrated to be a new tumor suppressor that isinactivated by promoter methylation in human coloncancers. Here, we analyzed promoter methylation of
the SFRP1 gene in human ovarian cancers, in whichloss of heterozygosity in 8p is frequently observed andinvolvement of the Wnt signaling pathway has beensuggested. Methylation-specific PCR (MSP) analysis
showed that four of 13 ovarian cancer cell lines andtwo of 17 primary ovarian cancers had methylated
SFRP1, while an immortalized ovarian epithelial cellline, HOSE, and seven ovarian endometrial cyst
samples did not. In the four ovarian cancer cell lines
with the methylation, SFRP1 was not expressed at all
as determined by quantitative RT-PCR analysis. These
results show that SFRP1 is inactivated by promoter
methylation in human ovarian cancers, as well ascolon cancers.
4 hMSH2

The DNA mismatch repair gene is a key regulator
in the elimination of base-base mismatches andinsertion/deletion loops (IDLs). Human MutS
homologue 2 (hMSH2), originally identified as ahuman homologue of the bacterial MutS, is a tumour
suppressor gene frequently mutated in hereditary
non-polyposis
co-lorectal
cancer.
Hereditary
non-polyposis colorectal cancer is characterised by theearly onset of colorectal cancer and the developmentof extracolonic cancers such as endometrial, ovarian,and urological cancers. Oestrogen receptor (ER) alphaand beta are members of a nu-clear receptor (NR)superfamily. Ligand-dependent transcription of ER is
regulated by the p160 steroid receptor coactivatorfamily, the thyroid hormone receptor-associatedproteins/the vitamin D receptor-interacting proteins(TRAP/DRIP) mediator complex, and the TATA
box-binding protein (TBP)-free TBP associated factor
complex (TFTC) type histone acetyltransferase
complex. We identified the interaction between ER
alpha/beta and hMSH2. Immunoprecipitation andglutathione-S-transferase pull-down assay revealed
that ER alpha and hMSH2 interacted in aligand-dependent manner, whereas ER beta andhMSH2 interacted in a ligand-independent manner.
Oestrogen receptor alpha/beta bound to hMSH2
through the hMSH3/hMSH6 interaction domain ofhMSH2. In a transient expression assay, hMSH2
potentiated the transactivation function of liganded
ER alpha, but not that of ER beta. These results
suggest that hMSH2 may play an important role as aputative coactivator in ER alpha dependent gene
expression.
(2) Clinical oncology
To compare treatment outcome results of conventional surgery vs. radiotherapy (RT) for carcinomaof the uterine cervix. A retrospective analysis was
con-ducted of 152 patients with uterine cervicalcancer radically treated with surgery or high dose-rate
intracavitary brachytherapy (HDR-ICBT) with orwithout external RT from June 1991 to May 2004. The
median follow-up time was 43.5 months (range,
1.0-130.0 months). The median age was 53 years(range, 25-81 years). There were 13 patients (9%) instage IA, 52 (34%) in stage IB, 24 (16%) in stage IIA,
and 63 (41%) in stage IIB. The conventional surgery

173

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 2009
(1) Kawana K, et al. Human papillomavirus vaccines:
current issues & future. Indian J Med Res. 130(3):341-7, 2009(2) Shoji K, et al. The oncogenic mutation in thepleckstrin

homology

domain

of

AKT1

in

endometrial carcinomas. Br J Cancer. 101(1):145-8,
2009

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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%.

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References published in 2009(1) Iwasawa Y, et al. Expression of autotaxin, an
ectoenzyme that produces lysophosphatidic acid, inhuman placenta. Am J Reprod Immunol. 62(2):90-5,
2009(2) Huang Z, et al. Effect of progesterone on HLA-E
gene expression in JEG-3 choriocarcinoma cell line.
Am J Reprod Immunol. 61(3):221-6.
(3) Iriyama T, et al. ASK1 and ASK2 differentiallyregulate the counteracting roles of apoptosis andinflammation in tumorigenesis. EMBO J. 28(7):843-53(4) Iriyama T, et al. Bax-inhibiting peptide protects
glutamate-induced cerebellar granule cell death byblocking Bax translocation. Neurosci Lett. 451(1):11-5, 2009

Reproductive, Developmental andAging Sciences
2. Pediatric Sciences

177

Department ofPediatrics, Department ofDevelopmental Pediatrics
Professor
Takashi Igarashi, M.D.,Ph.D.

Associate Professor
Akira Kikuchi, M.D., Ph.D.
Sachiko Kitanaka, M.D., Ph.D.

Lecturer
Hiroshi Watanabe, M.D., Ph.D.
Kohmei Ida, M.D., Ph.D.
Junko Takita, M.D., Ph.D. (Department of Cell Therapy andTransplantation Medicine)

Associate
Hiroshi Ono, M.D., Tatsuo Katori, M.D., Hirotsugu Kano, M.D., Ph.D.,
Keiji Goishi, M.D., Yasuo Kodachi, M.D., Naoki Ito, M.D.,
Nobutaka Shimizu, M.D.,Ph.D., Kan Takahashi, M.D., Hiroyuki Iwasaki, M.D,
Akifumi Toyoda, M.D., Ken-ichirou Miura, M.D.,
Tsuyoshi Isojima, M.D., Ayaka Furuya, M.D., Koujirou Yasui, M.D.,
Ai Motomura, M.D., Yuki Kimura, M.D.
(As of March 31, 2010)

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, 3 lecturers, 16 associate professors, 12senior residents and 15 graduate students on March 31,
2010.
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

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beds in the neonatal intensive care unit (NICU), 15
beds in the growth care unit (GCU) and 6 beds in thepediatric intensive care unit (PICU), and ourinstitution is going to fulfill the designation as
children’s hospital affiliated to the university hospital.
In NICU, we are taking care of small premature babies
weighing from 400g to 3,000g often associated withcongenital disorders requiring invasive interventions.
A variety of patients with diseases, such ashematological/oncological disorders (acute leukemia,
neuroblastoma, Ewing sarcoma, osteosarcoma, brain
tumors, etc.), cardiac disorders (congenital heartdiseases and Kawasaki disease), neuromusculardisorders, immunological/allergic disorders (common
variable immunodeficiency, chronic granulomatous
disease and bronchial asthma), renal and urinary tract
diseases(nephrotic
syndrome,
chronicglomeluronephritis, purpura nephritis and renal and/or
urinary tract anomalies), endocrinological disorders,metabolic disorders and psychosomatic diseases areadmitted in the wards. Approximately 10 patients
received hematopoietic stem cell transplantation every
year. There are patients with severe combined
immunodeficiency, aplastic anemia-myelodysplastic
syndrome, acute lymphocytic leukemia with high-riskfeatures, acute myelogenous leukemia, non-Hodgkin
lymphomas, disseminated neuroblastoma and brain
tumors.
Many patients need to stay long in the hospital. We
provide an official in-hospital school ”Kodama
Gakkyu” where patients receive education and havechances to communicate with other patients as well as
their family members. “Niko-niko Volunteer”
members, an official volunteer group in the hospital,
visit the pediatric ward every weekday to play withthe patients and help their mothers, providing
enormous comfort to both the patients and theirmothers. Various activities are scheduled for thepatients in the hospital such as the Tanabata festival, a
Christmas party and music concerts. All the residents,
fellows and nurses participate in these activities. We
have two child care specialists in the pediatric ward in
April, 2006.
(As of March 31, 2010)

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: The ALK gene, anovel protein-tyrosine kinase receptor, has been
identified as a target oncogene for neuroblastoma
harboring mutations and gene amplifications. To
elucidate the involvement of the ALK in thepathogenesis of other pediatric solid tumors, we
performed mutation analyses as well as SNP-array
analysis in total of 200 tumor samples. High
grade amplification of ALK region and novel
missense mutations in the tyrosine kinase domain
were detected in our series.
(2) Nephrology group: Genetic and clinical diversityof Dent disease was identified in more than 90
unrelated patients. In the field of podocyte biology,
novel mechanisms underlying the signaltransduction via nephrin and neph1 were
investigated.
(3) Cardiology group: A novel intervention catheter

179

technique in PDA was applied in several
congenital heart disease patients.
(4) Immunology group: A therapy using humandendritic cells for children’s cancer patients are
performed.
(5) Neonatology group: Clinical researches in theregulation of body fluid and circulation are being
conducted.
(6) Neurology Group: Our research activities arefocused mainly on the clinical, imaging andpathologic findings and genetic backgrounds ofacute encephalopathy; clinical and genetic aspectsof mitochondrial disorders and congenital
anomalies, such as holoprosencephaly, Noonan,
Costello, Arima and pseudo-TORCH syndrome;
cell biology and behavioral pharmacology oftuberous sclerosis and autism; and medical carefor severely handicapped children.

Referencess
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Kikuchi A, Kishimoto H, Minami M : Malignant
rhabdoid tumor of the liver: A case report with US
and CT manifestation. Jpn J Radiol 27: 462-465,
2009
2. Abe Y, Oka A, Mizuguchi M, Igarashi T, Ishikawa
S, Aburatani H, Yokoyama S, Asahara,H, Nagao
K, Yamada M, Miyashita T: YA4, deleted in a casewith middle interhemispheric variant ofholoprosencephaly, interacts with SIX3 both
physically and functionally. Hum Mutat 30:
E946-955, 2009
3. Akagi T, Ito T, Kato M, Jin Z, Cheng Y, Kan T,
Yamamoto G, Olaru A, Kawamata N, Boult J,
Soukiasian HJ, Miller CW, Ogawa S, Meltzer SJ,
Koeffler HP: Chromosomal abnormalities andnovel disease-related regions in progression from
Barrett's esophagus to esophageal adenocarcinoma. Int J Cancer 15: 2349-2359, 2009
4. Akagi T, Shih LY, Kato M, Kawamata N,
Yamamoto G, Sanada M, Okamoto R, Miller CW,
Liang DC, Ogawa S, Koeffler HP: Hidden
abnormalities and novel classification of t(15;17)
acute promyelocytic leukemia (APL) based on
genomic alterations. Blood 113: 1741-1748, 2009

5. Atsuta Y, Takita J (Collaborator 42), Japan Cord
Blood Bank Network: Disease-specific analysesof unrelated cord blood transplantation comparedwith unrelated bone marrow transplantation in
adult patients with acute leukemia. Blood
113:1631-1638, 2009
6. Fuji S, Kim SW, Yoshimura K, Akiyama H,
Okamoto S, Sao H, Takita J, Kobayashi N, Mori S,
Japan Marrow Donor Program: Possible
association
betweenobesityandposttransplantation complications including infectious
diseases and acute graft-versus-host disease. Biol
Blood Marrow Transplant 15: 73-82, 2009
7. Fukushi D, Watanabe N, Kasai F, Haruta M,
Kikuchi A, Kikuta A, Kato K, Nakadate H,
Tsunematsu Y, Kaneko Y: Centrosome ampli
fication is correlated with ploidy divergence, but
not with MYCN amplification, in neurob lastoma
tumors. Cancer Genet Cytogenet 188: 32-41, 2009
8. Harita Y, Kurihara H, Kosako H, Tezuka T, Sekine
T, Igarashi T, Ohsawa I, Ohta S, Hattori S:
Phosphorylation of nephrin triggers Ca2+ signaling
by recruitment and activation of phospholipase
C-γ1. J Biol Chem 284: 8951-8962, 2009
9. Hasegawa D, Manabe A, Yagasaki H, Ohtsuka Y,
Inoue M, Kikuchi A, Ohara A, Tsuchida M,
Kojima S, Nakahata T, on behalf of JapaneseChildhood MDS Study Group: Treatment ofchildren with refractory anemia: the Japanesechildhood MDS Study Group. Pediatr Blood
Cancer 53: 1011-1015, 2009
10. Ide H, Yasunaga H, Koike S, Kodama T, Igarashi
T, Imamura T: Shortage of pediatricians in Japan:
a longitudinal analysis using physician’s survey
data. Pediatr Int 51: 645-649, 2009
11. Ishiguro A, Sekine T, Kakiuchi S, Nishimura R,
Goishi K, Tsuchida S, Ohtsu H, Igarashi T: Skinand subcutaneous blood flows of very low birthweight infants during the first 3 postnatal days. J
Matern Fetal Neonatal Med 11: 1-7, 2009
12. Isojima T, Yokoya S, Ito J, Horikawa R, Tanaka T:
Inconsistent determination of overweight by twoanthrometric indices in girls with Turner
syndrome. Acta Paediatrica 98: 513-518, 2009
13. Isojima T, Yokoya S, Ito J, Horikawa R, Tanaka T:
New reference growth charts for Japanese girls
with Turner syndrome. Pediatr Inter 51: 709-714,

180

2009
14. Jo A, Tsukimoto I, Ishii E, Asou N, Mitani S,
Shimada A, Igarashi T, Hayashi Y, Ichikawa H:
Age-associated difference in gene expression of
paediatric acute myelomonocytic leukaemia (FAB
M4 and M5 subtypes) and its correlation withprognosis. Br J Haematol 144: 917-929, 2009
15. Kato M, Takita J, Takahashi K, Mimaki M, Chen
Y, Koh K, Ida K, Oka A, Mizuguchi M, Ogawa S,
Igarashi T: Hepatoblastoma in a patient with Sotos
syndrome. J Pediatr 155: 937-939, 2009
16. Kato M, Sanada M, Kato I, Sato Y, Takita J,
Tkeuchi K, Miwa A, Cehn Y, Nakazaki K,
Nomoto J, Asakura Y, Muto S, Tamura A, Iio M,
Akatsuka Y, Hayashi Y, Mori H, Igarashi T,
kurokawa M, Chiba S, Mori S, Ishikawa Y,
Okamaoto K, Tobinai K, Nakagawa H, Nakahra T,
Yoshino T, Kobayashi Y, Ogawa S: Frequent
inactivation of A20 in B-cell lymphoma. Nature
459: 712-716, 2009
17. Khamrin P, Takanashi S, Chan-It W, Kobayashi
M, Nishimura S, Katsumata N, Okitsu S,
Maneekarn N, Nishio O, Ushijima H: Immunochromatography test for rapid detection of
norovirus in fecal specimens. J Virol Methods
157: 219-222, 2009
18. Kikuchi A, Kigasawa H, Tsurusawa M, Kawa K,
Kikuta A, Tsuchida M, Nagatoshi Y, Asami K,
Horibe K, Makimoto A, Tsukimoto I: A study of
rasburicase for the management of hyperuricemia
in pediatric patients with newly
diagnosed
hematologic malignancies at high risk for tumor
lysis syndrome. Int J Hematol 90: 492-500, 2009
19. Kitamura K, Itou Y, Yanazawa M, Ohsawa M,
Suzuki-Migishima R, Umeki Y, Hohjoh H,
Yanagawa Y, Shinba T, Itoh M, Nakamura K,
Goto Y: Three human ARX mutations cause thelissencephaly-like and mental retardation withepilepsy-like pleiotropic phenotypes in mice. Hum
Mol Genet 18: 3708-3724, 2009
20. Masumura T, Yamamoto K, Shimizu N, Obi S,
Ando J: Shear stress increases expression of thearterial endothelial marker ephrinB2 in murine ES
cells via the VEGF-Notch signaling pathways.
Arterioscler Thromb Vasc Biol 29: 2125-2131,
2009
21. Miura K, Sekine T, Iida A, Takahashi K, Igarashi

T: Salt-losing nephrogenic diabetes insipidus
caused by fetal exposure to angiotensin receptor
blocker. Pediatr Nephrol 24: 1235-1238, 2009
22. Ogawa S, Matsubara A, Onizuka M, Kashiwase K,
Sanada M, Kato M, Nannya Y, Akatsuka Y, Satake
M, Takita J, Chiba S, Saji H, Maruya E, Inoko H,
Morishima Y, Kodera Y, Takehiko S: Japan
Marrow Donation Program (JMDP). Explorationof the genetic basis of GVHD by genetic
association studies. Biol Blood Marrow
Transplant 15(Suppl): 39-41, 2009
23. Oshima K, Kikuchi A, Mochizuki S, Toyama D,
Uchisaka N, Yabe M and Hanada R: Fanconi
anemia in infancy: report of hematopoietic stem
cell transplantation to a 13-month-old patient. Int
J Hematol 89: 722-723, 2009
24. Oshima K, Kikuchi A, Mochizuki S, Yamane M,
Date H and Hanada R: Living-donor
singlelobe lung transplantation for bronchiolitis
obliterans from mother to child following
previous allogeneic hematopoietic stem celltransplantation from the same donor. Int J
Hematol 90: 540-542, 200925. Saito H, Takahashi S, Nagata M, Tsuchiya T,
Mugishima H, Yan K, Kondo Y, Matsuyama T,
Sekine T, Igarashi T: Reevaluation of glomerularcharge selective protein-sieving function. Pediatr
Nephrol 24: 609-612, 2009
26. Saito T, Fukumoto S, Ito N, Suzuki H, Igarashi T,
Fujita T: A novel mutation in the GAT3
gene ofaJapanesepatient
with
PTH-deficienthypoparathyroidsm. J Bone Miner Metab 27:
386-389, 200927. Saito T, Nishii Y, Yasuda T, Ito N, Suzuki H,
Igarashi T, Fukumoto S, Fujita T: Familial
hypophosphatemic rickets caused by a large
deletion in PHEX gene. Eur J Endocrinol 161:
647-651, 200928. Sanada M, Suzuki T, Shih LY, Otsu M, Kato M,
Yamazaki S, Tamura A, Honda H, SakataYanagimoto M, Kumano K, Oda H, Yamagata T,
Takita J, Gotoh N, Nakazaki K, Kawamata N,
Onodera M, Nobuyoshi M, Hayashi Y, Harada H,
Kurokawa M, Chiba S, Mori H, Ozawa K, Omine
M, Hirai H, Nakauchi H, Koeffler HP, Ogawa S:
Gain-of-unction of mutated C-CBL tumour
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904-908, 200929. Sato A, Mizuguchi M, Mimaki M, Takahashi K,
Jimi H, Oka A, Igarashi T: Cortical gray matterlesions in acute encephalopathy with febrile
convulsive status epilepticus. Brain Dev 31:
622-624, 200930. Sekine T, Miura K, Takahashi K, Igarashi T:Children's toxicology from bench to bed-Druginduced renal injury (1): The toxic effects of
ARB/ACEI on fetal kidney development. J
Toxicol Sci 34: 245-250, 200931. Sekine T, Endou H: Children's toxicology frombench to bed-Drug-induced renal injury (3): Drugtransporters and toxic nephropathy in childhood. J
Toxicol Sci 34: 259-265, 200932. Shinozaki Y, Osawa M, Sakuma H, Komaki H,
Nakagawa E, Sugai K, Sasaki M, Goto Y:
Expansion of the first polyalanine tract of the
ARX gene in a boy presenting with generalized
dystonia in the absence of infantile spasms. Brain
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33. Takanashi S, Oishi Y, Ito N, Nanba Y, Tsukamoto
K, Nakamura T, Ito Y, Hayashi S, Sago H, Kuroda
T, Honna T: Evaluating mortality and disease
severity in congenital diaphragmatic hernia using
the McGoon and pulmonary artery indices. J
Pediatr Surg 44: 2101-2106, 2009
34. Takanashi S, Hashira S, Matsunaga T, Yoshida A,
Shiota T, Tung PG, Khamrin P, Okitsu S,
Mizuguchi M, Igarashi T, Ushijima H: Detection,
genetic characterization and quantification of
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35. Takita J, Motomura A, Koh K, Ida K, Taki T,
Hayashi Y, Igarashi T: Acute megakaryoblastic
leukemia in a child with the MLL-AF4 fusion gene.
Eur J Haematol 83: 149-153, 2009
36. Tomizawa D, Koh K, Hirayama M, Miyamura T,
Hatanaka M, Saikawa Y, Ishii E: Outcome ofrecurrent or refractory acute lymphoblastic
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37. Uchisaka N, Takahashi N, Sato M, Kikuchi A,
Mochizuki S, Imai K, Nonoyama S, Ohara O,
Watanabe F, Mizutani S, Hanada R, Morio T: Twobrothers with ataxia-telangiectasia–like disorderwith lung adenocarcinoma. J Pediatr 155: 435-438,
2009
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Finocchiaro G, Eoli M, Ruckert C, Huynh T, Liu
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Mol Cancer Res 7: 665-677, 2009
39. Yoshida N, Yagasaki H, Yoshimi A, Takahashi Y,
Xu Y, Hama A, Nishio N, Muramatsu H,
Watanabe N, Matsumoto K, Kato K, Ueyama J,
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Department of Pediatric Surgery
Professor
Tadashi Iwanaka, M.D., Ph.D.

Associate Professor
Yutaka Kanamori, M.D., Ph.D.

Research Associate
Masahiko Sugiyama, M.D.,

Makoto Komura, M.D., Ph.D.

Kan Terawaki, M.D., Ph.D.

Teturou kodaka, M.D., Ph.D.

Yujirou Tanaka, M.D., Ph.D.

Homepage

http://square.umin.ac.jp/pedsurg/index.html

History and organization
In 1951, a pediatric surgical team was established in
the Department of Second Surgery. Subsequently, in
1961, a pediatric surgical research team, which would
eventually research diaphragmatic hernia, wasestablished with a chief, Dr. Ishida, by Professor
Kimoto.
In 1971, it was authorized as the first clinicaldepartment of Pediatric Surgery in a National
University.
A pediatric intensive care unit was founded with Prof.
Ishida in 1973, and a ward which could accommodate
mainly pediatric surgical patients was completed.
Assistant Prof. Saito assumed office as the first
Director of this Pediatric Surgery clinical department.
Dr. Sumio Saito became Professor of PediatricSurgery in 1983. Professor Saito had enthusiastically
performed clinical studies such as operation
techniques and the use of biliary atresia.
Dr. Nakajo took office as a professor in 1985. Prof.
Nakajo had developed original operative procedures
such as a radical operation for umbilical hernia and ananti-reflex valve for biliary atresia. These original
operative procedures have been inherited by pediatricsurgeons as Nakajo methods.
Our department was authorized as the Department ofPediatric Surgery in 1989 after Kyusyu University by

the Ministry of Education.
Dr. Yoshiaki Tsuchida assumed the role of Professor in1990 and published many highly regarded articles,
mainly concerning neuroblastoma and Wilm’s tumor
from research and clinical work.
In 1995, the department was reorganized as the
Reproductive, Developmental and Aging Science,
Pediatric Science and Pediatric Surgery, due to the
University policy for the Graduate School.
In 1997, Dr Hashizume became Professor in the
Department of Pediatric Surgery. He started
living-related partial liver transplantation (LRPLT) for
children with Professor Makuuchi in the Department
of Second Surgery.
Dr. Tadashi Iwanaka became the sixth Professor in
August 2006. The present staff are the chief professor,
one associate professor, five research associates, threesenior residents, and three graduate students. Morethan 20 members of our department shoulder theclinical work as pediatric surgeons.

Clinical activities
Staff higher than research associate level take chargeof the out-patient clinic from Monday through Friday.
The pediatric surgical outpatient clinic takes place inthe same location as the pediatric outpatient clinic andwe closely cooperate with pediatricians to diagnose

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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
Professor Iwanka. has performed the study of theregenerative medicine positively. He founded a newlaboratory in the Department of Tissue Engineering toperform not only conventional animal experiments but
also human experiments to fabricate a trachea in theclinical course. Furthermore, The differentiation
experiment of stem cells in amniotic fluid was
performed in this laboratory by the obstetrics andgynecology department cooperation in our hospital.
The 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.

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References(1) Ishimaru T, Kitano Y, Uchida H, Kawashima H,
Gotoh C, Satoh K, Yoshida M, Sugita A, Iwanaka
T. Growth spurt-related recurrence after Nuss
procedure. J Pediatr Surg. 2009; 44: E13-6.
(2) Iwanaka T. Technical innovation, standardization,and skill qualification for pediatric minimallyinvasive surgery in Japan. J Pediatr Surg. 2009;44:36-42.
(3) Uchida H, Iwanaka T, Kitano Y, Kudou S,
Ishimaru T, Yotsumoto K, Gotoh C, Yoshida M.
Residual fistula after laparoscopically assisted
anorectoplasty: is it a rare problem? J Pediatr Surg.
2009; 44:278-281.
(4) Tanaka Y, Ikeda T, Kishi Y, Masuda S, Shibata H,
Takeuchi K, Komura M, Iwanaka T, Muramatsu S,
Kondo Y, Takahashi K, Yamanaka S, Hanazono Y.
ERas is expressed in primate embryonic stem
cells but not related to tumorigenesis. Cell
Transplant. 2009; 18: 381-389.
(5) Oue T, Fukuzawa M, Okita H, Mugishima H,
Horie H, Hata J, Saito M, Nozaki M,Chin M,
Nakadate H, Hinotsu S, Koshinaga T, Kaneko Y,
Kitano Y, Tanaka Y; Japan Wilms Tumor Study(JWiTS) Group. Outcome of pediatric renal tumor
treated using the Japan Wilms Tumor Study-1(JWiTS-1) protocol: a report from the JWiTS
group. Pediatr Surg Int. 2009; 25: 923-929.
(6) Saihara R, Komuro H, Urita Y, Hagiwara K,
Kaneko M. Myoblast transplantation to defecation
muscles in a rat model: a possible treatment
strategy for fecal incontinence after the repair ofimperforate anus. Pediatr Surg Int. 2009; 25:
981-986.
(7) Morikawa N, Kuroda T, Honna T, Kitano Y,
Tanaka H, Takayasu H, Fijino A, Kawashima N,
Tanemura H, Muto M, Matsuoka K. A novelassociation of duodenal atresia, malrotation,
segmental dilatation of the colon, and anorectal
malformation. Pediatr Surg Int. 2009; 25:10031005.
(8) Morikawa N, Kuroda T, Kitano Y, Tanaka H,
Takayasu H, Fujino A, Shibata Y, Tanemura H,
Muto M, Honna T. Repeat STEP procedure toestablish enteral nutrition in an infant with shortbowel syndrome. Pediatr Surg Int. 2009; 25:1007-1011.

(9) Ishimaru T, Uchida H, Yotsumoto K, Gotoh C,
Yoshida M, Oguma E, Kishimoto H, Iwanaka T,
Kitano Y.: Recurrence of a congenital pancreaticcyst mimicking omental cyst after laparoscopic
cyst resection. Eur J Pediatr Surg. 2009; 19:
53-54.
(10)Nagao Y, Abe T, Hasegawa H, Tanaka Y, Sasaki K,
Kitano Y, Hayashi S, Hanazono Y. Improved
efficacy and safety of in utero cell transplantationin sheep using an ultrasound-guided method.
Cloning Stem Cells. 2009; 11: 281-285.
(11)Miyasaka M, Nosaka S, Kitano Y, Ueoka K,
Tsutsumi Y, Kuroda T, Honna T. Utility of spinal
MRI in children with anorectal malformation.
Pediatr Radiol. 2009; 39:810-816.
(12)Mori Y, Kodaka T, Kato T, Kanagawa EM,
Kanagawa O. Critical role of IFN-gamma in
CFA-mediated protection of NOD mice fromdiabetes development. Int Immunol. 2009; 21:
1291-1299.
(13)Kasahara M, Nakagawa A, Sakamoto S, Tanaka H,
Shigeta T, Fukuda A, Nosaka S, Matsui A. Living
donor liver transplantation for congenital absenceof the portal vein with situs inversus. Liver
Transpl. 2009; 15: 1641-1643(14)Kasahara M, Horikawa R, Sakamoto S, Shigeta T,
Tanaka H, Fukuda A, Abe K, Yoshii K, Naiki Y,
Kosaki R, Nakagawa A. Living donor livertransplantation for glycogen storage disease type
Ib. Liver Transpl. 2009; 15: 1867-1871.

Reproductive, Developmental andAging Sciences
3. Aging Sciences

186

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

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

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

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

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

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

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

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

Homepage

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

Introduction and Organization

Clinical activities

The Department of Geriatrics was established in
1962, as the first geriatric department in Japan.
Since elderly patients usually have multiple organ
disorders, we have to take care 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. 394 newand a total of 19,498 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187

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) Role of nuclear receptors in senescence andcarcinogenesis
12) Diagnosis and prevention of aspiration pneumonia
13) Novel roles of antimicrobial peptide, defensin
14) Adrenomedullin and airway hyperresponsiveness15) Klotho protein and vitamin D in lung16) Clinical investigation of sleep-related breathing
disorderPublications
1. Azuma K, Urano T, Horie-Inoue K, Hayashi S,
Sakai R, Ouchi Y, Inoue S. Association of
estrogen receptor α and histone deacetylase 6
causes rapid decetylation of tubulin in breast
cancer cell. Cancer Res. 69; 2935-40, 2009.
2. Azuma K, Urano T, Ouchi Y, Inoue S. Vitamin K2

Suppresses Proliferation and Motility of
Hepatocellular Carcinoma Cells by Activating
Steroid and Xenobiotic Receptor. Endocr J. 56;
843-9, 2009.
3. Azuma K, Urano T, Ouchi Y, Inoue S.
Glucocorticoid-induced gene tripartite motifcontaining 63 (TRIM63) promotes differentiationof osteoblastic cells. Endocr J. 57; 457-64, 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. 10; 646-51, 2010.
5. Fujimura T, Takahashi S, Urano T, Kumagai J,
Murata T, Ogushi T, Horie-Inoue K, Ouchi Y,
Kitamura T, Muramatsu M, Homma Y, Inoue S.
Expression of cytochrome P450 3A4 and its
clinical significance in human prostate cancer.
Urology 74; 391-7, 2009.
6. Fujimura T, Takahashi S, Urano T, Liu X, Ogushi
T, Muramatsu M, Ouchi Y, Kitamura T, Homma Y,
Inoue S. EBAG9 expression and its clinicalsignificance in human testicular cancer. Int J Urol.
16; 329-32, 2009.
7. Fukai S, Akishita M, Yamada S, Hama T, Ogawa
S, Iijima K, Eto M, Kozaki K, Toba K, Ouchi Y.
Association of plasma sex hormone levels withfunctional decline in elderly men and women.
Geriatr Gerontol Int. 9, 282-9, 2009.
8. Fukai S, Akishita M, Miyao M, Ishida K, Toba K,
Ouchi Y. Age-related changes in plasma androgenlevels and their association with cardiovascularrisk factors in male Japanese office workers.
Geriatr Gerontol Int. 10; 32-9, 2010.
9. Furuya T, Urano T, Ikari K, Kotake S, Inoue S,
Hara M, Momohara S, Kamatani N, Yamanaka H.
A1330V polymorphism of low-density lipoprotein
receptor-related protein 5 gene and self-reported
incident fractures in Japanese female patients withrheumatoid arthritis. Mod Rheumatol. 19; 140-6,
2009.
10. Gack MU, Albrecht RA, Urano T, Inn KS, Huang
IC, Carnero E, Farzan M, Inoue S, Jung JU,
García-Sastre A. Influenza A virus NS1 targets theubiquitin ligase TRIM25 to evade recognition by

188

RIG-I. Cell Host Microbe 5; 439-49, 2009.
11. Hashimoto H, Iijima K, Hashimoto M, Son BK,Ota H, Ogawa S, Eto M, Akishita M, Ouchi Y.
Validity and usefulness of aortic arch calcificationin chest X-ray. J Atheroscler Thromb. 16; 256-64,
2009.
12. IIjichi N, Ikeda K, Fujita M, Usui T, Urano T,
Azuma K, Ouchi Y, Horie-Inoue K, Inoue S.
EPAS1, a dexamethasone-inducible gene inosteoblasts, inhibits osteoblastic differentiation.
Open Bone J. 1; 28-37, 2009.
13. Iwaoka Y, Hashimoto R, Koizumi H, Yu J, Okabe
T. Selective stimulation by cinnamaldehyde ofprogesterone secretion in human adrenal cells.
Life Sci. 86; 894-8, 2010.
14. Koizumi H, Yu J, Hashimoto R, Ouchi Y, Okabe T.
Involvement of androgen receptor in nitric oxide
production induced by icariin in human umbilicalvein endothelial cells. FEBS Lett. 584; 2440-4,
2010.
15. Kumagai J, Urano T, Ogushi T, Takahashi S,
Horie-Inoue K, Fujimura T, Azuma K, Muramatsu
M, Ouchi Y, Kitamura T, Inoue S. EBAG9 is atumor-promoting and prognostic factor for
bladder cancer. Int J Cancer 124; 799-805, 2009.
16. Ota H, Eto M, Ako J, Ogawa S, Iijima K, Akishita
M, Ouchi Y. Sirolimus and everolimus induce
endothelial cellular senescence via sirtuin 1
down-regulation: therapeutic implication ofcilostazol after drug-eluting stent implantation. J
Am Coll Cardiol. 53; 2298-305, 2009.
17. 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-1
production upon RNA virus recognition. atImmunol. 11; 63-9, 2010.
18. Son BK, Akishita M, Iijima K, Ogawa S,
Maemura K, Yu J, Takeyama K, Kato S, Eto M,
Ouchi
Y.
Androgen
receptor-dependenttransactivation of growth arrest-specific gene 6
mediates inhibitory effects of testosterone on
vascular calcification. J Biol Chem. 285; 7537-44,
2010.
19. Suzuki H, Forrest AR, Erik van Nimwegen, DaubCO, Balwierz PJ, Irvine KM, Lassmann T, Ravasi
R, Hasegawa Y, de Hoon MJ, Katayama S,
SchroderK,
Carninci
P,
TomaruY,
Kanamori-Katayama M, Kubosaki A, Akalin A,
Ando Y, Arner E, Asada M, Asahara H, Bailey T,
Bajic VB, Bauer D, Beckhouse AG, Bertin N,
Björkegren J, Brombacher F, Bulger E, Chalk AM,
Chiba J, Cloonan N, Dawe A, Dostie J,
Engström PG, Essack M, Faulkner GJ, Fink JL,
Fredman D, Fujimori K, Furuno M, Gojobori T,
Gough J, Grimmond SM, Gustafsson M,
Hashimoto M, Hashimoto T, Hatakeyama M,
Heinzel S, Hide W, Hofmann O, Hörnquist M,
Huminiecki L, Ikeo K, Imamoto N, Inoue S, Inoue
Y, Ishihara R, Iwayanagi T, Jacobsen A, Kaur M,
Kawaji H, Kerr MC, Kimura R, Kimura S,
Kimura Y, Kitano H, Koga H, Kojima T, Kondo S,
Konno T, Krogh A, Kruger A, Kumar A, Lenhard
B, Lennartsson A, Lindow M, Lizio M,
MacPherson C, Maeda N, Maher CA, Maqungo M,
Mar J, Matigian NA, Matsuda H, Mattick JS,
Meier S, Miyamoto S, Miyamoto-Sato E,
Nakabayashi K, Nakachi Y, Nakano M, Nygaard S,Okayama T, Okazaki Y, Okuda-Yabukami H,
Orlando V, Otomo J, Pachkov M, Petrovsky N,
Plessy C, Quackenbush J, Radovanovic A, Rehli
M, Saito R, Sandelin A, Schmeier S, Schönbach C,
Schwartz AS, Semple CA, Sera M, Severin J,
Shirahige K, Simons C, St-Laurent G, Suzuki M,
Suzuki T, Sweet MJ, Taft RJ, Takeda S, Takenaka
Y, Tan K, Taylor MS, Teasdale RD, Tegnér J,
Teichmann S, Valen E, Wahlestedt C, Waki K,
Waterhouse A, Wells CA, Winther O, Wu L,
Yamaguchi K, Yanagawa H, Yasuda J, Zavolan M,
Hume DA, Arakawa T, Fukuda S, Imamura K, Kai
C, Kaiho A, Kawashima T, Kawazu C, Kitazume
Y, Kojima M, Miura H, Murakami K, Murata M,
Ninomiya N, Nishiyori H, Noma S, Ogawa C,
Sano T, Simon C, Tagami M, Takahashi Y, Kawai
J, Hayashizaki Y. The transcriptional network that
controls growth arrest and differentiation in ahuman myeloid leukemia cell line. at Genet. 41;
553-62, 2009.
20. Takayama K, Tsutsumi T, Suzuki T, Horie-Inoue
K, Ikeda K, Kaneshiro K, Fujimura T, Kumagai J,
Urano T, Sakaki Y, Shirahige K, Sasano H,
Takahashi S, Kitamura T, Ouchi Y, Aburatani H,

189

Inoue S. Amyloid precursor protein is a primary
androgen target gene that promotes prostatecancer growth. Cancer Res. 69; 137-42, 2009.
21. Urano W, Furuya T, Inoue E, Taniguchi A, Urano
T, Kotake S, Sekita C, Inoue S, Hara M,
Momohara S, Kamatani N, Yamanaka H.
Associations between methotrexate treatment andmethylenetetrahydrofolate reductase gene polymorphisms with incident fractures in Japanese
female rheumatoid arthritis patients. J Bone
Miner Metab. 27; 574-83, 2009.
22. 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; 220-6, 2010.
23. Urano T, Shiraki M, Usui T, Sasaki N, Ouchi Y,
Inoue S. A1330V variant of the low-density
lipoprotein receptor-related protein 5 (LRP5) genedecrease Wnt signaling and affect the total bodybone mineral density in Japanese women. Endocr
J. 56; 625-31, 2009.
24. Urano T, Shiraki M, Usui T, Sasaki N, Ouchi Y,
Inoue S. Bone mass effects of a Smad6 gene
polymorphism in Japanese postmenopausal
women. J Bone Miner Metab. 27; 562-6, 2009.
25. Urano T, Shiraki M, Yamaga R, Sasaki N, Ouchi Y,
Inoue. Association of a sequence variation in thegene encoding adiponectin receptor 1 (ADIPOR1)
with body mass index in the Japanese population.
Anti-Aging Med. 6; 79-82, 2009.
26. Urano T, Usui T, Shiraki M, Ouchi Y, Inoue S.
Association of a single nucleotide polymorphismin the constitutive androstane receptor gene withbone mineral density. Geriatric Gerontol Int. 9;235-41, 2009.
27. Urano T, Usui T, Takeda S, Ikeda K, Okada A,
Ishida Y, Iwayanagi T, Otomo J, Ouchi Y, Inoue S.
TRIM44 interacts with and stabilizes terf, a TRIM
ubiquitin E3 ligase. Biochem Biophys Res
Commun. 383; 263-8, 2009.
28. Yu J, Eto M, Akishita M, Okabe T, Ouchi Y. A
selective estrogen receptor modulator inhibits
TNF-α-induced apoptosis by activating ERK1/2
signaling pathway in vascular endothelial cells.
Vascul Pharmacol. 51; 21-8, 2009.

Surgical Sciences
1. Surgery

191

Department of Thoracic Surgery
Associate Professor
Nakajima, Jun

Assistant Professor
Murakawa, Tomohiro

StaffsFukami, Takeshi, and Sano, Atsushi

Homepage http://ctstokyo.umin.ne.jp/
History
Clinical and basic researches of the thoracic surgery
have been performed since the prewar era in thisuniversity, when Professor Masao Tsuduki adopted themodified Coryllos’s thoracoplasty for the treatment of
the pulmonary tuberculosis in 1934. They initiatedthoracoscopy for the treatment of the tuberculosis in
our country. After the successful application of theantituberculous drugs, surgical treatment of thethoracic malignant neoplasms was the major concernof the thoracic surgery.
The Department of Cardiothoracic Surgery, The
University of Tokyo, was established in December 15,
1964 as the first department of this field along withthe cardiovascular surgery in the Japanese national
universities. Since then it has played an internationallyleading role and contributed to development of the
field in our country.
Professors and Chairs in the history of thedepartment are as follows: Kimoto, Seiji (1964.12.15~ 1968.3.31), Saigusa, Masahiro (1968.4.1 ~1981.3.31), Asano, Ken-ichi (1981.4.1 ~ 1986.3.31),
Furuse, Akira (1986.4.1 ~ 1997.3.31) and Takamoto,Shinichi (1997.6.1 ~ 2009.3.31).
The Department of Cardiothoracic Surgery has been
divided into two departments, Department of
Cardiovascular Surgery and Department of Thoracic
Surgery in 1998.
The mission of the Department of Thoracic Surgery
is to improve the patients with diseases of the thoracic

organs through clinical works, basic and clinicalresearches, and education of the medical students,
postgraduates, and the surgical residents in our
university.

Clinical activities
Three staffs (Nakajima J, Murakawa T, and FukamiT), certificated as members of the Japanese Board ofGeneral Thoracic Surgery, are in charge of the
Department of Thoracic Surgery, University of Tokyo
Hospital. They specialize in surgical treatment of thediseases of the respiratory and the mediastinal organs
and the chest wall, except for diseases of theesophagus and mammary glands. Approximately 280
surgeries are performed in the department in 2008.
Primary lung cancer has been the leading cause ofdeath among the malignant neoplasms in our country.
As the number of the dead patients by the lung cancer
has been increasing, the basic and the clinicalinvestigations for the treatment of the lung cancer arevery important. In our department, the staffs
participate the clinical works, studies and educationsof diagnostics and therapeutics of the lung cancer aswell as other thoracic diseases.
We have performed the modern-style thoracoscopy
for the diagnosis and treatment of the thoracic disease
with less surgical invasiveness since 1992.
Approximately a half of the surgical procedures in our
department have been safely and successfully
accomplished through thoracoscopy. Researches on

192

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.

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) Karasaki T, Nakajima J, Murakawa T, Fukami T,
Yoshida Y, Kusakabe M, Ohtsu H, Takamoto S.
Video-assisted thoracic surgery lobectomy preserves more latissimus dorsi muscle than conven-

Academic education
Medical students in the fifth grade have two-weeks’program on the clinical training of the thoracic and the
cardiovascular surgery. They are also able toparticipate the clinical clerkship of the cardiothoracic
surgery, an elective course for 4 weeks. The
Department of Thoracic Surgery also offers the 4-year
postgraduate program for qualified surgeons who arewilling to specialize in the thoracic surgery.

Current researches
Main subjects of current research at present include
basic and clinical studies on the malignant neoplasmsin the thorax, transplantation of the thoracic organs
and the cryopreserved tissues. Recently we conductedclinical studies on the immunotherapy with adopted
gamma- delta- T-cell for the treatment of the advanced

tional surgery. Interact Cardiovasc Thorac Surg.
2009: 316-9(2)Kakimi K, Nakajima J, Wada H. Active specificimmunotherapy and cell-transfer therapy for thetreatment of non-small cell lung cancer.

Lung

Cancer, 2009; 65: 1-8.
(3) Nakajima J, Takamoto S, Murakawa T, Fukami T,
Yoshida Y, Kusakabe M. Outcomes of thoracoscopic management of secondary pneumothorax inpatients with COPD and interstitial pulmonary
fibrosis. Surg Endosc. 2009; 23: 1536-40.
(4) Matsubara D, Morikawa T, Goto A, Nakajima J,
Fukayama M, Niki T. Subepithelial myofibroblast
in lung adenocarcinoma: a histological indicatorof excellent prognosis. Mod Pathol. 2009; 22:776-85(5) Murakawa T, Fukami T, Nakajima J, Takamoto S.

193

Chest wall desmoid tumor with life-threatening
intrathoracic extension. Eur J Cardiothorac Surg.
2009; 35: 538.
(6) Shiono S, Kawamura M, Sato T, Okumura S,
Nakajima J, Yoshino I, Ikeda N, Horio H,
Akiyama H, Kobayashi K; Metastatic Lung Tumor Study Group of Japan. Pulmonary metastasectomy for pulmonary metastases of head andneck squamous cell carcinomas. Ann Thorac Surg.
2009; 88: 856-60.
(7) Kusakabe M, Watanabe K, Emoto N, Aki N,
Kage H, Nagase T, Nakajima J, Yatomi Y, Ohishi
N, Takai D. Impact of DNA demethylation of the
G0S2 gene on the transcription of G0S2 insquamous lung cancer cell lines with or without
nuclear receptor agonists. Biochem Biophys Res
Commun. 2009; 390: 1283-7.
(8) 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 squamous lung cancer by combination of in silico andexperimental approaches. Int J Cancer. 2010;
126: 895-902(9) Murakawa T, Yoshida Y, Fukami T, Nakajima J.
Life-threatening tracheal perforation secondary todescending necrotizing mediastinitis. Interact
Cardiovasc Thorac Surg. 2010; 10: 454-6(10) Takahashi T, Murakawa T, Fukami T, Nakajima J.
Pneumothorax after left pneumonectomy: accentuated negative pressure at azygoesophageal recess by a mediastinal shift and rotation. Eur J
Cardiothorac Surg. 2010, 37:1222(11) Nakajima J, Murakawa T, Fukami T, Goto S,
Kaneko T, Yoshida Y, Takamoto S, Kazuhiro K. A
phase I study of adoptive immunotherapy for recurrent non-small cell lung cancer patients withautologous

gammadelta T cells. Eur J Car-

dio-Thorac Surg 2010, 37:1191-7

194

Department of
Cardiothoracic 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.,

Aya Saito, M.D.,

Mitsuhiro Kawata, M.D.,

Kan Nawata, 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. Present staffs are
one Chief Professor, one Associate Professor and two
Lecturer and six Associates. Dr. Minoru Ono waselected as the sixth Professor in November 2009.

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.

195

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 400,
which is one of the highest in Japan. We are leading inJapan by showing excellent surgical results. There areeight Board-certified surgeons, each of whom has his
own subspecialty among adult cardiac, thoracic aortic
or congenital heart disease. We are famous for aortic
valve sparing root replacement, arch replacement
using retrograde cerebral perfusion, treatment ofextended thoracic aortic aneurysm, ventricular assist
device implantation, off- pump coronary artery bypass
surgery, mitral valve plasty and repair of complex
congenital heart diseases, such as Jatene, Fontan and
Norwood operations.
The University of Tokyo Tissue Bank was founded
in 1997, based on the Department of Cardiovascular
Surgery. The Bank has been actively promoting
procurement, preservation and shipping of humanvalve and blood vessel allograft in Japan. We take thelead in surgical treatment using allograft for severe
active endocarditis or infection of aortic aneurysm or
vascular prosthesis. Surgical treatment using allograft
was approved as advanced medical technology by theGovernment in 2006. As of March 2010, nine cases ofheart transplantation were performed in The
University Hospital.

Teaching Activities
We have the chair of systematic review ofcardiovascular surgery in the spring term at the 2nd
grade of medical course. We also take charge inclinical practice on diagnosis of cardiovasculardisease in the autumn term at the 2nd grade. We expose
the students to daily clinical works as well as researchworks during the course of “Free Quarter” and“Research Lab Visit”, which are scheduled in thesummer and spring vacations at 1st and 2nd grade. Joint
lectures with the Cardiology Department arescheduled 3rd through 4th grades. Each student is
assigned one or two cardiovascular surgical cases in
the Bed Side Learning, in which he/she is required tolearn preoperative patient evaluation and management,
surgical treatment and postoperative care, based onparticipatory practice. There are also twelve small
key-lectures on cardiovascular surgery. Hands-on
practice is provided during the “Clinical clerkship”
one-month course in the last months of 3rd grade.
We take charge in core surgical curriculum in the“Super-rotation” postgraduate training. We offer a
program in which each resident can learn basic
knowledge of cardiovascular disease and surgery, andhemodynamic and respiratory evaluation as well asbasic surgical techniques and patient management.
Residents who take the course of cardiovascularsurgery are required 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 protection strategy, 5) a new technique of aortic
valve sparing root replacement and its hemodynamic
evaluation, 6) mechanism analysis of right heart
failure and development of effective pharmacologicaltherapy, 7) application of regenerative medicine to
end-stage heart failure, 8) development of new heart
preserving solution .

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References(1) Fukushima N, Ono M, Nakatani T, Minami S,
Konaka S, Ashikari J: Strategies for maximizingheart and lung trans- plantation opportunities inJapan. Transplant Proc 2009, 41, 273-276(2) Hatano M, Kinugawa K, Yao A, Shiga T,
Masukawa Y, Hirata Y, Nishimura T, Ono M, Kyo
S, Nagai R: Less frequency of aortic valve
opening and continuous flow device cause aortic
regurgitation in patients with left ventricularassist device. J Heart Fail 2009, 15; S170
(3) Hisagi M, Suematsu Y, Masuzawa A, Ono M,
Motomura N, Takamoto S: Image- guided
surgical repair of ventricular septal rupture using
self-expanding device. Interact Cardiovasc
Thorac Surg 2009, 8; 602-605(4) Itatani K, Miyaji K, Tomoyasu T, Nakahata Y,
Ohara K, Takamoto S, Ishii M: Optimal conduit
size of the extracardiac Fontan operation basedon energy loss and flow stagnation. Ann Thorac
Surg. 2009; 88:565-73(5) Kaneko Y, Takeda T, Yoda H, Kobayashi J,
Takada N, Tsuchiya K, Anderson RH. Right
ventricular plication in a neonate with anunguarded tricuspid valvar orifice. Ann Thorac
Surg 2009; 87: 305-7(6) Kaneko Y, Kobayashi J, Achiwa I, Yoda H,
Tsuchiya K, Nakajima Y, Endo D, Sato H,
Kawakami T. Cardiac Surgery in Patients with
Trisomy 18. Pediatr Cardiol. 2009; 30: 729-34(7) Kawashima D, Gojo S, Nishimura T, Ono M,
Motomura N, Murakami A, Hatada K, Kyo S:
The volume unloading effect of the Impella in
AMI model. J Heart Fail 2009, 15; S170
(8) Masuzawa A, Ohno T, Takamoto S, Motomura N,
Ono M, Fujita H, Ando J, Morita T, Hirata Y,
Nagai R, Hirose A, Shigeeda T, Kato S, Araie M:
In early diabetic retinopathy, risk of cardiac
events after implantation of sirolimus-eluting
stent is higher than after coronary artery bypass
surgery. J Cardiol 2009, 53; 86-93(9) Miyaji K, Miyamoto T, Kohira S, Inoue N, Itatani
K, Sato H, Ohara K, Takamoto S: The influencesof red blood cell transfusion on perioperative
inflammatory response. Int Heart J. 2009;50:581-9(10) Morota T, Takamoto S, Yamamoto T, Nawata K,
Kawata, M: One-stage repair of total descending
aorta for extended pathologies. AUAD
proceedings, T. Kazui et al. ed., 2009, 225-230,
Springer, Tokyo(11) Nawata K, Takamoto S, Uno K, Ebihara A,
Morota T, Ono M, Motomura N: Protective effecton preserved aortic valve cusps of reconstructedpseudosinus in the aortic root reimplantation
technique. AUAD proceedings, T. Kazui et al. ed.,2009, 241-246, Springer, Tokyo(12) Nishimura T, Kyo S, Ono M, Motomura N, Gojo
S, Murakami A: The mechanical assistance forright heart failure post left ventricular assist
device implantation. J Heart Fail 2009, 15; S177
(13) Ono M, Kyo S, Nishimura T, Ando M, Nawata K,
Motomura N, Murakami A: Present status andfuture perspective of ventricular assist device
implantation: What should we do now? J Heart
Fail 2009, 15; S147
(14) Shiga T, Kinugawa K, Hatano M, Yao, A,
Nishimura T, Ono M, Hirata Y, Kyo S, Takamoto
S, Nagai R: Preoperative clinical Profiles predict
prognosis after left ventricular assist device
implantation. J Heart Fail 2009, 15; S54(15) Takamoto S, Nawata K, Morota T, Kitahori K,
Kawata M: Intermittent pressure augmented
retrograde
cerebral
perfusion.
AUAD
proceedings, T. Kazui et al. ed., 2009, 121-122,
Springer, Tokyo(16) Tomoyasu T, Miyaji K, Miyamoto T, Inoue N:
The bilateral pulmonary artery banding forhypoplastic left heart syndrome with a diminutive
ascending aorta. Interact Cardiovasc Thorac Surg.
2009;8: 479–481(17) Yamazaki K, Saito S, Nishinaka T, Nakatani T,
Kitamura S, Matsumiya G, Sawa Y, Nishimura T,
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2009, 15; S14

197

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.

198

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

199- 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.

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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 molecular signatureof gastric metaplasia arising in response to acuteparietal cell loss. Gastroenterology 134(2):511-22, 2008
Fukuda T, Seto Y, Yamada K, Hiki N, Fukunaga
T, Oyama S, Yamaguchi T. Can immuneenhancing nutrients reduce postoperativecomplications in patients undergoing esophageal
surgery? Dis Esophagus 21(8):708-11, 2008
Hiki N, Yamamoto Y, Fukunaga T, Yamaguchi T,
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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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Raher MJ, Thibault HB, Buys ES, Kuruppu D,
Shimizu N, Brownell AL, Blake SL, Rieusset J,
Kaneki M, Derumeaux G, Picard MH, Bloch KD,
Scherrer-Crosbie M. A short duration of high-fat
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.
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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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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
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N, Yamashita S, Kanematsu T, Obara T, Mimura
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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
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T, Matsuno Y, Kodera Y, Sakamoto H,
Yamamoto N, Kaminishi M. Detection ofminimal gastric cancer cells in peritoneal
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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
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 (2009)
1:Inagaki Y, Xu H, Nakata M, Seyama Y, Hasegawa K,
Sugawara Y, Tang W, Kokudo N. Clinicopathology ofsialomucin: MUC1, particularly KL-6 mucin, in
gastrointestinal, hepatic and pancreatic cancers. Biosci
Trends. 2009 Dec;3(6):220-32. Review. PubMed
PMID: 20103851.
2:Tamura S, Sugawara Y, Yamashiki N, Kaneko J,
Kokudo N, Makuuchi M. Pre-emptive antiviral203therapy in living donor liver transplantation forhepatitis C: observation based on a single-center
experience. Transpl Int. 2009 Dec 15. [Epub aheadof print] PubMed PMID: 20028490.
3: Akai H, Kiryu S, Takao H, Tajima T, Shibahara J,
Imamura H, Kokudo N, Akahane M, Ohtomo K.
Efficacy of double-arterial phase gadolinium
ethoxybenzyl diethylenetriamine pentaacetic acidenhanced liver magnetic resonance imaging comparedwith double-arterial phase multi-detector row helicalcomputed tomography. J Comput Assist Tomogr. 2009
Nov-Dec;33(6):887-92. PubMed PMID: 19940656.
4: Kaneko J, Sugawara Y, Tamura S, Kokudo N,
Makuuchi M. Left liver with right paramedian
sector--can it be an option in living donor livertransplantation? Transplantation. 2009 Oct 15;88(7):952; author reply 953. PubMed PMID: 19935468.
5: Ishizawa T, Mise Y, Aoki T, Hasegawa K, Beck Y,
Sugawara Y, Kokudo N. Surgical technique: newadvances for expanding indications and increasing
safety in liver resection for HCC : The Eastern
perspective. J Hepatobiliary Pancreat Surg. 2009 Nov
19. [Epub ahead of print] PubMed PMID: 19924372.
6: Hasegawa K, Kokudo N, Sano K, Makuuchi M.
Single HCC between 2 and 5 cm: the grey zone :Surgeon's perspective. J Hepatobiliary Pancreat Surg.
2009 Nov 5. [Epub ahead of print] PubMed PMID:
19890599.
7: Kishi Y, Imamura H, Sugawara Y, Sano K, Kaneko
J, Kokudo N, Makuuchi M. Evaluation of donor
vasculobiliary anatomic variations in liver graft
procurements. Surgery. 2010 Jan;147(1):30-9. Epub
2009 Oct 31. PubMed PMID: 19879610.
8: Kyoden Y, Tamura S, Sugawara Y, Matsui Y,
Togashi J, Kaneko J, Kokudo N, Makuuchi M.
Incidence and management of biliary complications
after adult-to-adult living donor liver transplantation.
Clin Transplant. 2009 Oct 22. [Epub ahead of print]
PubMed PMID: 19849703.
9: Kaneko J, Sugawara Y, Matsui Y, Sakata H,

Kokudo N. Comparison of near-infrared spectroscopy
and laser Doppler flowmetry for detecting decreased
hepatic inflow in the porcine liver. J Invest Surg. 2009
Jul-Aug;22(4):268-74. Erratum in: J Invest Surg. 2010
Feb;23(1):68. PubMed PMID: 19842902.
10: Tamura S, Sugawara Y, Yamashiki N, Kaneko J,
Kokudo N. The urgent need for evaluating recurrent
primary sclerosing cholangitis in living donor livertransplantation. Liver Transpl. 2009 Oct;15(10):1383-4; author reply 1385. PubMed PMID: 19790228.
11: Hasegawa K, Kokudo N. Surgical treatment of
hepatocellular carcinoma. Surg Today. 2009;39(10):833-43. Epub 2009 Sep 27. Review. PubMed PMID:
19784720.
12: Zhang K, Tang W, Qu X, Guo Q, Inagaki Y,
Seyama Y, Abe H, Gai R, Kokudo N, Sugawara Y,
Nakata M, Makuuchi M. KL-6 mucin in metastatic
liver cancer tissues from primary colorectal carcinoma.
Hepatogastroenterology. 2009 Jul-Aug;56(93):960-3.
PubMed PMID: 19760920.
13: Kyoden Y, Imamura H, Sano K, Beck Y, Sugawara
Y, Kokudo N, Makuuchi M Value of prophylactic
abdominal drainage in 1269 consecutive cases ofelective liver resection. J Hepatobiliary Pancreat Sci.
2010 Mar;17(2):186-92. Epub 2009 Aug 29. PubMed
PMID: 19727544.
14: 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. 2009 Aug 31. [Epub ahead ofprint] PubMed PMID: 19726150.
15: Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Ohki T, Yoshida H, Omata M,
Makuuchi M, Kokudo N. Noninvasive estimation ofhepatic steatosis in living liver donors: usefulness ofvisceral fat area measurement. Transplantation. 2009
Aug 27;88(4):575-81. PubMed PMID: 19696642.
16: Yamamoto K, Imamura H, Matsuyama Y,
Hasegawa K, Beck Y, Sugawara Y, Makuuchi M,

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Kokudo N. Significance of alpha-fetoprotein anddes-gamma-carboxy prothrombin in patients with
hepatocellular carcinoma undergoing hepatectomy.
Ann Surg Oncol. 2009 Oct;16(10):2795-804. Epub
2009 Aug 11. PubMed PMID: 19669841.
17: Ikeda M, Hasegawa K, Sano K, Imamura H, Beck
Y, Sugawara Y, Kokudo N, Makuuchi M. The vessel
sealing system (LigaSure) in hepatic resection: arandomized controlled trial. Ann Surg. 2009 Aug;
250(2):199-203. PubMed PMID: 19638927.
18: 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 Aug;209(2):206-14.
Epub 2009 May 1. PubMed PMID: 19632597.
19: Xu HL, Inagaki Y, Seyama Y, Sugawara Y,
Kokudo N, Nakata M, Wang FS, Tang W. Expressionof KL-6 mucin, a human MUC1 mucin, in
intrahepatic cholangiocarcinoma and its potential
involvement in tumor cell adhesion and invasion. Life
Sci. 2009 Aug 26;85(9-10):395-400. Epub 2009 Jul 22.
PubMed PMID: 19631667.
20: Inoue Y, Sugawara Y, Tamura S, Ohtsu H, Taguri
M, Makuuchi M, Kokudo N. Validity and feasibilityof transient elastography for the transplanted liver inthe peritransplantation period. Transplantation. 2009
Jul 15;88(1):103-9. PubMed PMID: 19584688.
21: Masuzaki R, Yamashiki N, Sugawara Y, Yoshida H,
Tateishi R, Tamura S, Kaneko J, Hasegawa K,
Kokudo N, Makuuchi M, Omata M. Assessment ofliver stiffness in patients after living donor livertransplantation by transient elastography. Scand J
Gastroenterol. 2009;44(9):1115-20. PubMed PMID:
19562623.
22: Tanaka M, Fukushima N, Noda N, Shibahara J,
Kokudo N, Fukayama M. Intraductal oncocytic
papillary neoplasm of the bile duct: clinicopathologic
and immunohistochemical characteristics of 6 cases.
Hum Pathol. 2009 Nov;40(11):1543-52. Epub 2009

Jun 21. PubMed PMID: 19540556.
23: Kishi Y, Kokudo N, Tamura S, Makuuchi M.
Viable liver parenchyma in a living donor liver graft:an "egg of Columbus" or a challenge to an axiom ofliver surgery? Hepatogastroenterology. 2009 Jan-Feb;
56(89):174-5. PubMed PMID: 19453052.
24: Koga R, Yamamoto J, Saiura A, Natori T, Katori
M, Kokudo N, Makuuchi M, Yamaguchi T.
Clamp-crushing pancreas transection in pancreatoduodenectomy. Hepatogastroenterology. 2009 JanFeb;56(89):89-93. PubMed PMID: 19453035.
25: Saiura A, Yamamoto J, Kokudo N, Koga R, Seki
M, Hiki N, Yamada K, Natori T, Yamaguchi T.
Intrahepatic cholangiocarcinoma: analysis of 44
consecutive resected cases including 5 cases withrepeat resections. Am J Surg. 2009 May 8. [Epubahead of print] PubMed PMID: 19427630.
26: Ishizawa T, Bandai Y, Kokudo N. Fluorescentcholangiography using indocyanine green forlaparoscopic cholecystectomy: an initial experience.
Arch Surg. 2009 Apr;144(4):381-2. PubMed PMID:
19380655.
27: Ishizawa T, Fukushima N, Shibahara J, Masuda K,
Tamura S, Aoki T, Hasegawa K, Beck Y, Fukayama M,
Kokudo N. Real-time identification of liver cancers byusing
indocyanine green fluorescent imaging.
Cancer. 2009 Jun 1;115(11):2491-504. PubMed
PMID: 19326450.
28: Seyama Y, Kokudo N, Makuuchi M. Radical
resection of biliary tract cancers and the role ofextended lymphadenectomy. Surg Oncol Clin N Am.
2009 Apr;18(2):339-59, ix. Review. PubMed PMID:
19306816.
29: Wang SB, Cheng YN, Cui SX, Zhong JL, Ward SG,
Sun LR, Chen MH, Kokudo N, Tang W, Qu XJ.
Des-gamma-carboxy prothrombin stimulates humanvascular endothelial cell growth and migration. Clin
Exp Metastasis. 2009;26(5):469-77. Epub 2009 Mar 5.
PubMed PMID: 19263229.

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30: Ishizawa T, Tamura S, Masuda K, Aoki T,
Hasegawa K, Imamura H, Beck Y, Kokudo N.
Intraoperative fluorescent cholangiography using
indocyanine green: a biliary road map for safe surgery.
J Am Coll Surg. 2009 Jan;208(1):e1-4. Epub 2008 Oct
31. PubMed PMID: 19228492.

37: Ma M, Qu XJ, Mu GY, Chen MH, Cheng YN,
Kokudo N, Tang W, Cui SX. Vitamin K2 inhibits thegrowth of hepatocellular carcinoma via decrease ofdes-gamma-carboxy prothrombin. Chemotherapy.
2009;55(1):28-35. Epub 2008 Oct 31. PubMed PMID:
18974646.

31: Kokudo N, Makuuchi M. Evidence-based clinicalpractice guidelines for hepatocellular carcinoma inJapan: the J-HCC guidelines. J Gastroenterol. 2009;44
Suppl 19:119-21. Epub 2009 Jan 16. PubMed PMID:
19148805.

38: Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Kokudo N, Makuuchi M. Pseudomonas
aeruginosa infection after living-donor livertransplantation in adults. Transpl Infect Dis. 2009
Feb;11(1):11-9. Epub 2008 Sep 21. PubMed PMID:
18811632.

32: Seyama Y, Kokudo N. Assessment of liverfunction for safe hepatic resection. Hepatol Res. 2009
Feb;39(2):107-16. PubMed PMID: 19208031.
33: Yoshimi A, Nannya Y, Ueda K, Asano D,
Yamamoto G, Kumano K, Hangaishi A, Matsui Y,
Takahashi T, Imai Y, Sugawara Y, Kokudo N,
Kurokawa M. Successful hematopoietic stem celltransplantation from an HLA-identical sibling in apatient with aplastic anemia after HLA-haploidenticalliving-related liver transplantation for fulminant
hepatitis. Biol Blood Marrow Transplant. 2009 Mar;15(3):389-90. PubMed PMID: 19203732.
34: Ishizawa T, Hasegawa K, Kokudo N, Sano K,
Imamura H, Beck Y, Sugawara Y, Makuuchi M. Risk
factors and management of ascites after liver resection
to treat hepatocellular carcinoma. Arch Surg. 2009
Jan;144(1):46-51. PubMed PMID: 19153324.
35: Midorikawa Y, Yamamoto S, Tsuji S, Kamimura N,
Ishikawa S, Igarashi H, Makuuchi M, Kokudo N,
Sugimura H, Aburatani H. Allelic imbalances andhomozygous deletion on 8p23.2 for stepwise
progression of hepatocarcinogenesis. Hepatology.
2009 Feb;49(2):513-22. PubMed PMID: 19105209.
36: Inoue Y, Hasegawa K, Ishizawa T, Aoki T, Sano K,
Beck Y, Imamura H, Sugawara Y, Kokudo N,
Makuuchi M. Is there any difference in survival
according to the portal tumor thrombectomy methodin patients with hepatocellular carcinoma? Surgery.
2009 Jan;145(1):9-19. PubMed PMID: 19081470.

39: Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Kokudo N, Omata M, Makuuchi
M. Double-dose double-phase use of second
generation hepatitis B virus vaccine in patients after
living donor liver transplantation: Not an effective
measure in transplant recipients. Hepatol Res. 2009
Jan;39(1):7-13. Epub 2008 Aug 28. PubMed PMID:
18761679.
40: Inagaki Y, Tang W, Xu HL, Guo Q, Mafune K,
Konishi T, Nakata M, Sugawara Y, Kokudo N.
Localization of N-myc downstream-regulated gene 1
in gastric cancer tissue. Dig Liver Dis. 2009
Feb;41(2):96-103. Epub 2008 Jul 3. PubMed
PMID:18602353.

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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.

Hideyo Miyazaki, M.D., Ph.D.

Jinpei Kumagai, M.D., Ph.D.

Yuzuri Tsurumaki, M.D., Ph.D.

Akira Nomiya, M.D.

Yumiko Okuno, M.D.

Kazuhiro Sato, M.D.

Hiroshi Watanabe, M.D.

Homepage

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

Introduction and Organization
Urology is a special field of clinical medicine
covering the diseases of the adrenal gland, the kidney,
the urinary tract and the male genital system by meansof a surgical procedure as well as an approach ofinternal medicine. In addition, urology encompasses
pediatric urology, neurourology, female urology, renaltransplantation, renal vascular surgery, endocrine
surgery and geriatric urology. For this reason, urology
requires the scientific background of oncology,
nephrology, endocrinology, andrology, immunology,
pediatrics, histology, microbiology, neurology andgerontology. Now we have commenced to utilize
cellular and molecular biology to develop the researchin urology. It is expected for our department to devote
to the scientific progress in the frontier of urology.
In recent years, we have been taking international
leadership in applying the new and minimally invasive
treatment modalities. They are exemplified byendoscopic management of the diseases in the upper

urinary tract, ESWL, or laser lithotripsy for
urolithiasis, hyperthermic and laser therapies for BPH,
and minimum incision endoscopic or laparoscopic
adrenalectomy, nephrectomy, and prostatectomy
substituting open procedures.
The professor, associate professors, instructors andassociates are involved in in-patient and out-patientcares and teaching of the students as well as research
activities. Clinical visiting professors are mainly
engaged in the teaching.

Clinical activities
There are 44 beds in the ward (8th floor of thecentral-ward-building). The residents take care of all
the patients on 24-hour a day basis. Associate staff
members team up with the residents on a man-to-man
basis. The total number of inpatients was 1,500 fromJanuary 2009 to December 2009.
Elective operations are performed on Tuesday,
Wednesday, and Thursday. A total of 1,124 operations

207

were performed in 2009. The numbers of main
operations are adrenalectomy 21, radical nephrectomy
56, partial nephrectomy 26, radical cystectomy 17,
radical prostatectomy 79, transurethral resection of the
bladder tumor (TUR-Bt) 161, transurethral resectionof the prostate (TUR-P) 26, and laparoscopic surgery
49.
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 30,273
patient-days from January 2009 to December 2009.

Teaching activities
Systematic urological lectures are provided forsecond year medical students. Both clinical lecturesand bed side teaching are scheduled for third andfourth year medical students. Thirteen times ofsystematic lectures are performed by professor,
associate professors and instructors concerning their
specialties.
Bed side teaching is concentrated on practical careof the patients. Teachers give lectures mainly
regarding pre- and post-operative management,
indication of operation, surgical anatomy and surgical
techniques.

Research activities
There are 9 research themes for research as below.
The basic principles for research are program insurgical techniques and therapy for incurable diseases,
which include advanced cancer, renal insufficiency,
sexual dysfunction, and interstitial cystitis. We havepublished approximately 25 English papers every
year.

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

References(1) Ozeki T, Takeuchi M, Suzuki M, Kitamura T,
Takayanagi R, Yokoyama H, Yamada Y. Single
nucleotide
polymorphismsof
17betahydroxysteroid dehydrogenase type 7 gene:mechanism of estramustine-related adverse
reactions? Int J Urol. 2009 Oct;16(10):836-41.
(2) Zhong S, Randhawa PS, Ikegaya H, Chen Q,
Zheng HY, Suzuki M, Takeuchi T, Shibuya A,
Kitamura T, Yogo Y. Distribution patterns of BK
polyomavirus (BKV) subtypes and subgroups inAmerican, European and Asian populations
suggest co-migration of BKV and the humanrace.J Gen Virol. 2009; 90:144-152.
(3) Homma Y Should an antimuscarinic agent beused for persistent LUTS after treatment with analpha(1)-blocker? Nat Clin Pract Urol. 2009; 6:
66-67(4) Zhong S, Jeong B-H, Ikegaya H, Kim Y-S, Xu
Yawei, Zhu M, Chao Y, Suzuki M, Kitamura T,
Homma Y, Yogo Y . Comparison of the
distribution patterns of BK polyomavirus
lineages among China, Korea and Japan:
implications for human migrations in Northeast
Asia. Microbiol Immunol. 2009; 53(5): 266-76(5) Fujimura T, Takahashi S, Urano T, Liu X, Ogushi
T, Muramatsu M, Ouchi Y, Kitamura T, Homma
Y, Inoue S Estrogen receptor-binding fragmentassociated gene 9 expression and its clinicalsignificance in human testicular cancer. Int J Urol.
2009; 16: 522-525.
(6) Kurosaki T, Suzuki M, Enomoto Y, Arai T,
Sawabe M, Hosoi T, Homma Y, Kitamura T
Polymorphism of cytochrome P450 2B6 andprostate cancer risk: A significant association in a
Japanese population. Int J Urol 2009; 16:364-368.
(7) Yogo Y, Sugimoto C, Zhong, S, Homma Y

208

EvolutionoftheBK
polyomavirus:
epidemiological, anthropological and clinicalimplications. Rev Med Virol 2009; 19: 185-199(8) Tsurumaki Y, Kume H, Homma Y .Late
recurrence of uterine endometrioid carcinoma inthe upper urinary tract. Arch Gynecol Obstet
2009; 280(4): 631-2(9) Kumagai J, Urano T, Ogushi T, Takahashi S,
Horie-Inoue K, Fujimura T, Azuma K,
Muramatsu M, Ouchi Y, Kitamura T, Inoue S
EBAG9 is a tumor-promoting and prognostic
factor for bladder cancer. Int J Cancer 2009; 124:
799-805..
(10) Takayama K, Tsutsumi S, Suzuki T, Horie-Inoue
K, Ikeda K, Kaneshiro K, Fujimura T, Kumagai J,
Urano T, Sakaki Y, Shirahige K, Sasano H,
Takahashi S, Kitamura T, Ouchi Y, Aburatani H,
Inoue S Amyloid precursor protein is a primary
androgen target gene that promotes prostatecancer growth. Cancer Res. 2009; 69: 137-142(11) Fujimura T, Takahashi S, Urano T, Kumagai J,
Murata T, Takayama K, Ogushi T, Horie-Inoue K,
Ouchi Y, Kitamura T, Muramatsu M, Homma Y,
Inoue S Expression of Cytochrome P450 3A4
and Its Clinical Significance in Human Prostate
Cancer Urology 2009; 74(2): 391-7(12) Gotoh M, Homma Y, Funahashi Y, Matsukawa Y,
Kato M Psychometric validation of the Japaneseversion of the International Consultation on
Incontinence Questionnaire-Short Form Int J
Urol. 2009; 16: 303-306(13) Kume H, Teramoto S, Kitamura TMetachronous
bilateral renal cell carcinoma with an interval ofmore than 10 years. Int Urol Nephrol. 2009; 41:
843-46(14) Liu M, Kurosaki T, Suzuki M, Enomoto Y,
Nishimatsu H, Arai T, Sawabe M, Hosoi T,
Homma Y, Kitamura T Significance of Common
Variants on Human Chromosome 8q24 in
Relation to the Risk of Prostate Cancer in Native
Japanese Men. BMC Genet. 2009; 10: 37(15) Homma Y, Gotoh M Symptom severity andpatient perceptions in overactive bladder: how
are they related? BJU Int. 2009; 104: 968-72(16) Homma Y, Yamaguchi O, Imidafenacin Study
Group A randomized, double-blind, placebo- andpropiverine-controlled trial of the novel

antimuscarinic agent imidafenacin in Japanesepatients with overactive bladder. Int J Urol. 2009;
16: 499-506(17) Fukuhara H, Homma Y, Todo T. Oncolytic virus
therapy for prostate cancer
Int J Urol. 2009 Oct 13 Epub ahead of print(18) Homma Y, Araki I, Igawa Y, Ozono S, Gotoh M,
Yamanishi T, Yokoyama O, Yoshida M; JapaneseSociety of Neurogenic Bladder. Clinicalguideline for male lower urinary tract symptoms
Int J Urol. 2009 Oct;16(10):775-90.
(19) Matsumoto S, Ishikawa A, Kume H, Takeuchi T,
Homma Y. Near infrared spectroscopy study ofthe central nervous activity during artificial
changes in bladder sensation in men Int J Urol.
2009 Sep; 16(9):760-4.
(20) Homma Y, Ueda T, Tomoe H, Lin AT, Kuo HC,
Lee MH, Lee JG, Kim DY, LeeKS; Interstitial
cystitis guideline committee.Clinical guidelines
for interstitial cystitis and hypersensitive bladder
syndrome Int J Urol. 2009 Jul;16(7):597-615.
(21) Fujimura T, Takahashi S, Kume H, Takeuchi T;
Clinical Study Group of Tokyo University
Affiliated Hospitals, Kitamura T, Homma Y.
Cancer-related pain and quality of life in prostatecancer patients: assessment using the Functional
Assessment of Prostate Cancer Therapy. Int J
Urol. 2009 May;16(5):522-5.
(22) Yamaguchi O, Nishizawa O, Takeda M,
Yokoyama O, Homma Y, Kakizaki H, Obara K,
Gotoh M, Igawa Y, Seki N, Yoshida M;
Neurogenic Bladder Society.Clinical guidelines
for overactive bladder.Int J Urol. 2009 Feb;16(2):126-42.
(23) Homma Y, Ueda T, Ito T, Takei M, Tomoe H.
Japanese guideline for diagnosis and treatment ofinterstitial cystitis Int J Urol. 2009 Jan; 16(1):4-16(24) Kim MS, Kondo T, Takada I, Youn MY,
Yamamoto Y, Takahashi S, Matsumoto T,
Fujiyama S, Shirode Y, Yamaoka I, Kitagawa H,
Takeyama K, Shibuya H, Ohtake F, Kato S DNA
demethylationinhormone-induced
transcriptional derepression Nature. 2009; 461:
1007-12(25) Nakagawa T, Kanai Y, Komiyama M, Fujimoto H,
Kakizoe T. Characteristics of Prostate Cancers

209Found in Specimens Removed by Radical
Cystoprostatectomy for Bladder Cancer and
Their Relationship with Serum Prostate-Specific
Antigen Level.Cancer Sci; 2009; 100: 1880-4(26) Azuma, T., G. Zhu, H. Xu, A. C. Rietz, C. G.
Drake, E. L. Matteson, and L. Chen. Potential
role of decoy b7-h4 in the pathogenesis ofrheumatoid arthritis: a mouse model informed byclinical data. PLoS Med 2009; 6:e1000166.
(27) Zhu G, Augustine MM, Azuma T, Luo L, Yao S,
Anand S, Rietz AC, Huang J, Xu H, Flies AS,
Flies SJ, Tamada K, Colonna M, van Deursen JM,
Chen L.B7-H4-deficient mice display augmented
neutrophil-mediated innate immunity.Blood.
2009 Feb 19;113(8):1759-67.
(28) Christensen NB, Kume H, Autorino R. How towrite titles and abstracts for readers. Int J Urol.
2009 Jan;16(1):2-3.
(29) Kume H, Christensen NB. Report of theInternational Journal of Urology Editorial Board
meeting 2009 in Okayama. Int J Urol. 2009
Jul;16(7):594-5.

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

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

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

Homepage http://all-1su.umin.jp/
Introduction and Organization
In 1995, a new system for postgraduate education
was introduced. The First Department of Surgery was
reorganized to form the Department of Surgical
Oncology and the Department of Vascular Surgery.
The staff of the Department of Surgical Oncology
consists of one Professor, one Asscoiate Professor andeight 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) Ishigami H, Kitayama J, Otani K, Kamei T, Soma
D, Miyato H, Yamashita H, Hidemura A, Kaisaki
S, Nagawa H. Phase I pharmacokinetic study ofweekly intravenous and intraperitoneal paclitaxel

212

combined with S-1 for advanced gastric cancer.
Oncology. 2009;76(5):311-4.
(2) Kamei T, Kitayama J, Yamashita H, Nagawa
H.Intraoperative blood loss is a critical risk factor
for peritoneal recurrence after curative resectionof advanced gastric cancer. World J Surg. 2009
Jun;33(6):1240-6(3) Suzuki J, Kazama S, Kitayama J, Uozaki H,
Miyata T, Nagawa H. Signet ring cell carcinomaof the appendix manifesting as colonicobstruction and ovarian tumors: report of a case.
Surg Today. 2009;39(3):235-40.
(4) Yamashita H, Kitayama J, Taguri M, Nagawa H.
Effect of preoperative hyperfibrinogenemia onrecurrence of colorectal cancer without asystemic inflammatory response. World J Surg.
2009 Jun;33(6):1298-305.
(5) Soma D, Kitayama J, Ishigami H, Kaisaki S,
Nagawa H. Different tissue distribution of
paclitaxel with intravenous and intraperitoneal
administration. J Surg Res. 2009 Jul;155(1):142-6.
(6) Yamashita H, Kitayama J, Nagawa H.
Chromoendoscopy with indigo carmine dye
added to acetic acid in the diagnosis of gastricneoplasia. Gastrointest Endosc. 2009 Jun;69(7):1407-8(7) Miyato H, Kitayama J, Yamashita H, Souma D,
AsakageM,
YamadaJ,
NagawaH.
Pharmacologicalsynergismbetweencannabinoids and paclitaxel in gastric cancer celllines. J Surg Res. 2009 Jul;155(1):40-7.
(8) Nishikawa T, Tsuno NH, Shuno Y, Sasaki K,
Hongo K, Okaji Y, Sunami E, Kitayama J,
Takahashi K, Nagawa H. Antiangiogenic effect ofa selective 5-HT4 receptor agonist. J Surg Res.
2010 Apr;159(2):696-704.
(9) Soma D, Kitayama J, Konno T, Ishihara K,
Yamada J, Kamei T, Ishigami H, Kaisaki S,
Nagawa H. Intraperitoneal administration of
paclitaxel
solubilized
with
poly
(2-methacryloxyethyl
phosphorylcholine-con-butylmethacrylate)for
peritoneal
dissemination of gastric cancer. Cancer Sci. 2009
Oct;100(10):1979-85. Epub 2009(10) Ishigami H, Kitayama J, Kaisaki S, Hidemura A,
Kato M, Otani K, Kamei T, Soma D, Miyato H,

Yamashita H, Nagawa H. Phase II study ofweekly intravenous and intraperitoneal paclitaxel
combined with S-1 for advanced gastric cancer
with peritoneal metastasis. Ann Oncol. 2010
Jan;21(1):67-70. Epub 2009(11) Koketsu S, Watanabe T, Minami M, Kitayama J,
Kawamura Y, Nagawa H. Preoperative evaluationof enterovesical fistula using magnetic resonanceimaging: case report. Hepatogastroenterology.
2009 May-Jun;56(91-92):696-8.
(12) Otani K, Kitayama J, Yasuda K, Nio Y, Iwabu M,
Okudaira S, Aoki J, Yamauchi T, Kadowaki T,
NagawaH.
Adiponectin
suppresses
tumorigenesis in Apc(Min)(/+) mice. Cancer Lett.
2010 Feb 28;288(2):177-82. Epub 2009(13) 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. Epub 2009

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Department of Vascular Surgery
Professor
Hirokazu Nagawa, M.D., Ph.D.

Associate Professor
Tetsuro Miyata, M.D., Ph.D.

Associate
Kunihiro Shigematsu, M.D., Ph.D.,

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

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

Katsuyuki Hoshina, M.D., Ph.D.,

Takuya Miyahara, M.D., Ph.D.

Homepage http://all-1su.umin.jp/
Introduction and Organization
In 1995, a new system for postgraduate education
was introduced. The First Department of Surgery was
reorganized to form the Department of Vascular
Surgery and the Department of Surgical Oncology.
The staff of the Department of Vascular Surgery
consists of one Professor, one Associate Professor, one
Assintant Professor, and four Associates. The
outpatient office is located on the third floor of the
Outpatient Building. The ward is situated on theeighth floor of the Ward Building. The administrative
office and research laboratories are located in the
Administration and Research Building. Current
activities of the Department of Vascular Surgery inclinical practice, education, and research aresummarized as follows.

techniques of percutaneous transluminal angioplasty,
angioscopy and intraoperative ultrasonography areavailable for the treatment of peripheral arterial
disease. The outpatient clinic is open from Monday
through Friday, and twenty-four-hour consultation isavailable for urgent or emergency problems.
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.

Clinical activities
Teaching 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

The Department of Vascular Surgery also offers afellowship in vascular surgery for well-qualified
surgeons who have completed their training in generalsurgery and wish to further specialize in vascularsurgery. The Department of Vascular Surgery has a
Vascular Surgery Training Program and provides
broad reaching experience in technical aspects of214

vascular surgery, development of surgical judgment,
and increasing knowledge about routine and complex
conditions. In addition, the dedicated staff offers
multiple opportunities for academic development bothalong clinical and basic scientific lines.
In the undergraduate education program, theDepartment of Vascular Surgery plays a role in thesystemic and clinical lectures and the bedside learning
program for 3rd year medical students, in cooperation
with other departments of surgery. In the postgraduate
education program, new residents are trained to
become qualified surgeons in our department. In
addition to pre- and post-surgery clinical conferences,
the residents are expected to attend research
conferences and seminars, which are held periodically.

Research activities
The Department of Vascular Surgery includes major
research laboratories for academic development bothalong clinical and basic scientific lines. The clinicalvascular laboratories are approaching completely noninvasive testing for vascular disorders, analyzing
essential physiologic information about the specificproblems being addressed. The basic vascularlaboratories are actively performing research on
endothelial biology, the mechanism of intimal
hyperplasia, microcirculation, application of genetherapy to vascular surgery and vascular prosthesis
development. Vascular research meeting is held every
other Saturday morning. The following are the major
themes under research.
1) Three-dimensional visualization abdominal aorta
2) Pathophysiology of the development of theaneurysm
3) Prevention of the anastomotic intimal hyperplasia
4) Pathophysiology of stent restenosis
5) Analyzing the intercellular transmission of thegrowth signal in the vascular smooth muscle cells6) Tissue oxygen dynamics assessed by near infrared
spectroscopy7) Application of near infrared spectroscopy to bloodflow monitoring during carotid endarterectomy8) Development of a minimally invasive treatment
modality for varicous veins of lower extremity
using high frequency ultrasound.
9) Genome
wide-association
studiesforarteriosclerosis.
10) Pharmacological analysis of microcirculation in
in-vivo model11) Mechanism of arteriogenesis in ischemic limb.
12) Development of a new drug delivery system fortherapeutic angiogenesis13) Introduction of gene into vascular wall cells byelectroporation
14) Application of nano technology for in-vivo genetransfer to vascular wall cells
15) Basic research for arterialization of artificial
organ
16) Development of a new method for evaluation oflimb ischemia
17) Develolpment of a new machine for autoevaluation of in-vivo endothelial function18) Creating strategy for diagnosis of acute aortic
syndrome.

References(1) Takayama T, Taguchi T, Koyama H, Sakari M,
Kamimura W, Takato T, Miyata T, Nagawa H.
The growth of a vascular network inside acollagen-citric acid derivative hydrogel in rats.
Biomaterials 2009;30(21):3580-3587(2) Takayama T, Miyata T, Nagawa H. True
abdominal aortic aneurysm in Marfan syndrome.
J Vasc Surg 2009;49(5):1162-1165(3) Hashimoto T, Koyama H, Miyata T, Hosaka A,
Tabata Y, Takato T, Nagawa H. Selective andsustained delivery of basic fibroblast growth
factor (bFGF) for treatment of peripheral arterial
disease: results of a phase I trial. Eur J Vasc
Endovasc Surg 2009;38(1):71-75(4) Deguchi J, Shigematsu K, Ota S, Kimura H,
Fukayama M, Miyata T. Surgical result of criticallimb ischemia due to tibial arterial occlusion inpatients with systemic scleroderma. J Vasc Surg
2009;49(4):918-923

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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 60
surgical procedures annually in total.
In breast surgery, more than a half of the mammary
cancer patients undergo the breast-preserving surgery.
In addition, sentinel node navigation surgery has been
adopted, resulting in better quality of postoperative
life. Reconstruction surgery for the breast cancer islikely to provide much better QOL. In this field, we
have started collaboration with the Department of
Plastic Surgery. Chemotherapy, hormone therapy andmolecular- targeting therapy play important roles intreatment of the breast cancer. We have accumulated a
lot of experience and achievement in this field.
Our clinical themes are 1) establishment of safe
proceduresfor
endocrine
surgery
without
complications; 2) diagnosis and treatment of microbreast lesions under ultrasonographic guides; 3)preoperative diagnosis for thyroid neoplasmas andbreast tumors based on telomerase activity using
Q-Fish.

216

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 structuralrequirements.
ImmunolMed
Microbiol
53:260-264,2008.

Surgical Sciences
2. Sensory and Motor System Medicine

218

Department of Dermatology
Professor
Shinichi Sato, M.D., Ph.D.
Associate Professor
Kanako Kikuchi, M.D., Ph.D.

Lecturer
Hidehisa Saeki, M.D., Ph.D.

Takafumi Kadono,M.D., Ph.D.

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

Yayoi Tada, M.D.,Ph.D

Hiroshi Mitsui, M.D., Ph.D.

Associate
Yoshihide Asano, M.D. Ph.D.

Zenshiro Tamaki , M.D. Ph.D

Mayuko Araki, M.D.

Asako Kogure, M.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.

Home page

http://www.h.u-tokyo.ac.jp/der/Introduction and Organaization

Clinical Activities

The Department of dermatology celebrated its 100th
anniversary in 1990. Originally it was founded as the
Department of dermatology and Urology, which also
encompassed veneology. In 1946 the Department ofdermatology was separated from that of Urology.
Regarding venereology, sexually transmitted diseases
only related to skin manifestations are now dealt inour department.
The professor, one associate professor, fivelecturers and seven assistants take part in inpatientand outpatient 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.

219

Education
We have ten dermatologists and are studying in the
postgraduate 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.

5.

6.

7.

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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.
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Fujita H, Asahina A, Tamaki K: Extensive tufted
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Hasegawa M, Matsushita Y, Horikawa M,
Higashi K, Tomigahara Y, Kaneko H, Shirasaki F,
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Hasegawa M, Matsushita Y, Horikawa M,
Higashi K, Tomigahara Y, Kaneko H, Shirasaki F,
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activation suppresses tissue fibrosis in mousemodels of systemic sclerosis. Arthritis Rheum.
60: 3465-3475, 2009.
Iwata Y, Yoshizaki A, Komura K, Shimizu K,
Ogawa F, Hara T, Muroi E, Bae S, Takenaka M,
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of B lymphocytes, regulates wound healing
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production in human keratinocytes. J DermatolSci. 56: 121-127, 2009.
Jinnin M, Ihn H, Asano Y, Yamane K, Yazawa N,
Tamaki K. Retrospective study of clinical andlaboratory features in Japanese scleroderma
patients with cardiac involvement. J DermatolSci 55: 70-72, 2009.
Kawaguchi Y, Ota Y, Kawamoto M, Ito I,
Tsuchiya N, Sugiura T, Katsumata Y, Soejima M,
Sato S, Hasegawa M, Fujimoto M, Takehara K,
Kuwana M, Yamanaka H, Hara M.: Association
study of a polymorphism of the CTGF gene andsusceptibility to systemic sclerosis in theJapanese popula-tion. Ann Rheum Dis. 68: 19211924, 2009.
Komura K, Iwata Y, Ogawa F, Yoshizaki A,
Yamaoka T, Akiyama Y, Hara T, Hasegawa
M,Fujimoto M, Sato S.: .Low zone tolerance
requires ICAM-1 ex-pression to limit contact
hypersensitivity elicita-tion. J Invest Dermatol.
129: 2661-2667, 2009.
Kawaguchi Y, Ota Y, Kawamoto M, Ito I,
Tsuchiya N, Sugiura T, Katsumata Y, Soejima M,
Sato S, Hasegawa M, Fujimoto M, Takehara K,
Kuwana M, Yamanaka H, Hara M. :Association
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Kanda N, Shibata S, Tada Y, Nashiro K, Tamaki
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2009.
Kuwano Y, Kazuho I, Watanabe R, Nanko H:
Efficacy of Diagnostic Ultrasonography of
Lipomas, Epidermal Cysts, and Ganglions.
Archives of Dermatology 145: 761-764, 2009.
Miyagaki T, Sugaya M, Kagami S, Nakashima H,
Ishiura N, Watanabe R, Ohmatsu H, Fujita H,
Yazawa N, Kadono T, Fujimoto M, Saeki H,
Tamaki K: Increased CCL1 levels in the sera and

22.

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25.

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28.

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blister fluid of patients with bullous pemphigoid.
J Dermatol Sci 54: 45-47, 2009.
Miyagaki T, Sugaya M, Fujita H, Saeki H,
Tamaki K: Increased serum thymic stromal
lymphopoietin levels in patients with cutaneous T
cell lymphoma. Clin Exp Dermatol 34; 539-540,
2009.
Miyagaki T, Sugaya M, Minatani Y, Fujita H,
Hangaishi A, Kurokawa M, Takazawa Y, Tamaki
K: Mycosis fungoides with recurrent Hodgkin's
lymphoma and diffuse large B-cell lymphoma.
Acta Derm Venereol 89; 421-422, 2009.
Satoh T, Ishikawa O, Ihn H, Endo H, Kawaguchi
Y, Sasaki T, Goto D, Takahashi K, Takahashi H,
Misaki Y, Mimori T, Muro Y, Yazawa N, Sato S,
Takehara K, Kuwana M.: Clinical usefulness ofanti-RNA polymerase III antibody measurement
by enzyme-linked immunosorbent as-say.
Rheumatology (Oxford). 48: 1570-1574, 2009.
Shibata S, Saeki H, Tsunemi Y, Kato T,
Nakamura K, Kakinuma T, Kagami S, Fujita H,
Tada Y, Sugaya M, Tamaki K: IL-17F single
nucleotide polymorphism is not associated withpsoriasis vulgaris or atopic dermatitis in theJapanese population. J Dermatol Sci 53: 163-165,
2009.
Shibata S, Saeki H, Tada Y, Karakawa M,
Komine M, Tamaki K: Serum high molecularweight adiponectin levels are decreased inpsoriasis patients. J Dermatol Sci 55: 62-63,
2009.
Shibata S, Sugaya M, Minatani Y, Fujita H,
Tsunemi Y, Miyagaki T, Saeki H, Kikuchi K,
Asai T, Kurokawa M, Tamaki K: Folliculotropic
Mycosis Fungoides with Severe Hepatic Failure
due to Hepatic Involvement. Acta Derm Venereol
89: 423-424, 2009.
Shibata S, Tada Y, Karakawa M, Saeki H,
Shirakata Y, Kanda N, Watanabe S, Tamaki K:
Possible roles of IL-27 in the pathogenesis ofpsoriasis. J Invest Dermatol 130: 1034-1039,
2009.
Tsunemi Y, Saeki H, Kikuchi K, Tamaki K, Sato
S.:Extramammary
Paget'sdiseasewithintracytoplasmic lumen forma-tion. J Dermatol.
36: 649-653, 2009.
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M, Takehara K, Kawaguchi Y, KawamotoM,
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Japanese popula-tion. Ann Rheum Dis. 68: 13751376, 2009.
Tada Y, Kanda N, Haratake A, Tobiishi M,
Yabunaka K, Iizaka S, Nakagami G, Aoi N,
Kadono T, Koyanagi H, Uno M, Ohue M, Sanada
S, Sanada H: Can ultrasonographic evaluation of
subcutaneous fat predict pressure ulceration? J
Wound Care 18: 192-198, 2009.
Tada Y, Kanda N, Ohnishi T, Watanabe S:
Atypical cutaneous sarcoidosis with diffuse,indurated ery-thema. Eur J Dermatol. 19: 639,
2009.
Watanabe T, Nakashima H, Ohmatsu H, Sakurai
N, Takekoshi T, Tamaki K: Detection of humanherpesvirus-6 transcripts in carbamazepineinduced hypersensitivity syndrome by in situ
hybridization. J Dermatol Sci 54: 134-136, 2009.
Yanaba K, Yoshizaki A, Muroi E, Hara T, Ogawa
F, Usui A, Hasegawa M, Fujimoto M, Takehara K,
Sato S.: Elevated circulating TWEAK levels in
systemic sclerosis: association with lower frequency of pulmonary fibrosis. J Rheumatol. 36:
1657-1662, 2009.
Yoshizaki A, Sato S. : Olopatadine hydrochloride
inhibits scratching behavior induced by aproteinase-activated receptor 2 agonist in mice.J
Der-matol Sci. 56: 136-139, 2009.
Yanaba K, Muroi E, Yoshizaki A, Hara T, Ogawa
F, Shimizu K, Yozaki M, Hasegawa M,Fujimoto
M, Takehara K, Sato S.: Serum CXCL16
concentrations correlate with the extent of skinsclerosis in patients with systemic sclero-sis. J
Rheumatol. 36: 1917-1923, 2009.
Yanaba K, Yoshizaki A, Muroi E, Hara T, Ogawa
F, Usui A, Hasegawa M, Fujimoto M, Takehara K,
Sato S.: Elevated circulating TWEAK levels in
systemic sclerosis: association with lower
frequency of pulmonary fibrosis. J Rheumatol.
36: 1657-1662, 2009.
Yabunaka K, Iizaka S, Nakagami G, Aoi N,
Kadono T, Koyanagi H, Uno M, Ohue M, Sanada
S, Sanada H: Can ultrasonographic evaluation of
subcutaneous fat predict pressure ulceration? J
Wound Care 18: 192-198, 2009.

39. Zarbock A, Muller H, Kuwano Y, Ley K: PSGL-1
dependent myeloid leukocyte activation. J
Leukoc Biol 86: 1119-1124, 2009.

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Department of Plastic andReconstructive Surgery
Professor
Isao Koshima, M.D.

Lecturer
Kotaro Yoshimura, M.D.

Associate
Gentaro Uchida, M.D.,D.D.S.

Takuya Iida, M.D.

Takuya Higashino, M.D.

Mitsunaga Narushima, M.D.

Makoto Mihara, M.D.

Homepage

http://www.h.u-tokyo.zc.jp/plastic/

Organization
The present faculty of the Department of Plastic
and Reconstructive Surgery consists of 1 professor, 1
associate professor, 1 lecturer, 5 associates and 7
physicians. There are about 100 doctors in thedepartment, including 16 medical trainees, 7 graduate
school students, but most are serving in rotation ataffiliated hospitals.
The outpatient clinic is located on the 3rd floor of
the outpatients building, while there are wards with
about 25 available beds on the 10th floor in the New
Ward. Our faculty room is located in the Medical
Laboratory Building and laboratory rooms in the East
Laboratory Building.
The present status of the educational, research andclinical activities of the department is as follows.

Clinical Activities
The outpatient clinic is opened every morning from
Monday to Friday. There are several specialized
clinics for trauma, scars and keloids, facial paralysis,
hand, replantation, microsurgery, breasts, head andneck reconstruction, cleft lip and palate, craniofacial

malformation,congenital
anomalies,
vascularmalformations, lymphedema, and cosmetic surgery
including cosmetic dermatology. There are 1,648 newpatients and the total number of revisiting patients are
10,684 in a year. In the operating room over 670
operations are achieved under general anesthesia,
while in the outpatient clinic about 330 operations areachieved under local anesthesia in a year. Each week,
the professor goes the round of inpatients on
Wednesday morning. Preoperative and postoperative
conferences and seminar that all members of thedepartment should attend are held on Wednesday
evening. Research conferences are held on every
Monday and Friday evening.

Teaching Activities
In regard to pregraduate education, the department
has the duty of lecturing to 2nd, 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223

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
Basic and clinical researches are performed ingroups. The major research subjects are as follows:1)

Studies on less invasive reconstruction ofhumantissue using supermicrosurgical technique.
2) Studies on mechanism of hypermelanogenesis of
the skin.
3) Studies on differentiation induction of humanadult stem cells from adipose, amnion, andplacenta4) Characterization of human adult stem cells anddermal papilla cells.
5) Studies on hair regrowth using epidermal stem
cells and dermal papilla cells.
6) Clinical studies on fat regeneration using
suctioned fat tissue and adipose stromalprogenitor cells.
7) Studies on biological function of extracellularmatrix taken from human adipose tissue.
8) Studies on angiogenesis using human adult stem
cells from adipose.
9) Studies on chondrogenesis and osteogenesis using
human fibrin and adipose stromal cells.
10) Studies
onmolecular
mechanismsofvasculogenesis and angiogenesis in the mouseembryo.
11) Studies
onmolecular
pathogenesisofholoprosencephaly using a mouse model.
12) Studies on MMPs and TIMPs expressed in keloid.
13) Studies on the cultured epidermal cells and thecell adhesive function.
14) Studies on clinical application and growth factor
extraction of a fluid from continuous suction

drainage.
15) Studies on mechanism of biological effects ofretinoids on epidermis and dermis.
16) Studies on regeneration of peripheral nerves.

References (2009)
1. 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.
2. Narushima M, Mihara M, Koshima I, Gonda K,
Iida T, Kato H, Araki J, amamoto Y, Otaki Y,
Todokoro T, Ishikawa S, Uehara E, Mundinger GS.
Digitalarteryperforator(DAP)
flaps:
modifications for fingertip and finger stump
reconstruction. J Plast Reconstr Aesthet Surg.
2009 Sep 1.
3. A Aoi N, Yoshimura K, Kadono T, Nakagami G,
Iizuka S, Higashino T, Araki J, Koshima I, Sanada
H. Ultrasound assessment of deep tissue injury inpressure ulcers: possible prediction of pressure
ulcer progression. Plast Reconstr Surg. 2009
Aug;124(2):540-50.
4. 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. Epub 2009 Apr 22.
5. Yamamoto K, Igawa K, Ueno H, Yano F, Chung
UI, Koshima I. Temporal and spatial changes inelement distribution in bone and cartilage. J
Orthop Sci. 2009 Mar;14(2):198-203. Epub 2009
Apr 1.
6. Suzuki S, Nakasato M, Shibue T, Koshima I,
Taniguchi T. Cancer Sci. 2009 Apr;100(4):759-69.
Epub 2009 Mar 9.
7. Nishizawa S, Yamaoka H, Matsui M, Hirabayashi
S, Hoshi K, Koshima I, Yamaoka K. Selection andeffect of ointment bases for preparing collagenase
inhibitor ointment using high-performance liquid
chromatography and Franz cell apparatus. Ann
Plast Surg. 2009 Feb;62(2):187-93.
8. Narushima M, Mihara M, Koshima I, Gonda K,
Takuya I, Kato H, Nakanishi K, Yamamoto Y,
Araki J, Abe H, Mundinger GS, Kikuchi K,
Uehara E. Intravascular stenting (IVaS) method

224

for fingertip replantation. Ann Plast Surg. 2009
Jan;62(1):38-41.
9. Koshima I, Narushima M, Mihara M, Iida T,
Gonda K, Uchida G, Nakagawa M.
Newthoracodorsal artery perforator (TAPcp) flap withcapillary perforators for reconstruction of upper
limb. J Plast Reconstr Aesthet Surg. 2010 Jan;
63(1):140-5. Epub 2008 Nov 14.
10. Matsuo T, Ohara N, Namba Y, Koshima I, Ida K,
Kanazawa S. Ophthalmic artery embolization as
pretreatment of orbital exenteration for
conjunctival
squamouscellcarcinoma.
Cardiovasc Intervent Radiol. 2009 May;32(3):554-7. Epub 2008 Aug 14.
11. Eto H, Suga H, Matsumoto D, Inoue K, Aoi N,
Kato H, Araki J, Yoshimura K. Characterization of
structure and cellular components of aspirated andexcised adipose tissue. Plast Reconstr Surg. 2009
Oct; 124 (4):1087-97.
12. Yoshimura K, Asano Y, Aoi N, Kurita M, Oshima
Y, Sato K, Inoue K, Suga H, Eto H, Kato H, Harii
K.
Progenitor-enrichedadiposetissuetransplantation as rescue for breast implantcomplications. Breast J. 2010 Mar;16(2):169-75.
Epub 2009 Nov 12.
13. Yoshimura K, Suga H, Eto H.Adipose-derived
stem/progenitor cells: roles in adipose tissue
remodeling and potential use for soft tissue
augmentation. Regen Med. 2009 Mar;4(2):265-73.
14. Suga H, Araki J, Aoi N, Kato H, Higashino T,
Yoshimura K. Adipose tissue remodeling in
lipedema: adipocyte death and concurrent
regeneration.J Cutan Pathol. 2009 Dec;36(12):1293-8.
15. Suga H, Matsumoto D, Eto H, Inoue K, Aoi N,
Kato H, Araki J, Yoshimura K. Functional
implications of CD34 expression in humanadipose-derived stem / progenitor cells.Stem Cells
Dev. 2009 Oct; 18(8): 1201-10.
16. Inoue K, Kato H, Sato T, Osada A, Aoi N, Suga H,
Eto H, Gonda K, Yoshimura K. Evaluation ofanimal models for the hair-inducing capacity ofcultured human dermal papilla cells. Cells Tissues
Organs 2009; 190(2): 102-10. Epub 2008 Nov 26.

225

Department ofOral-Maxillofacial Surgery
Professor
Tsuyoshi Takato, M.D.,Ph.D.

Associate Professor
Takafumi Susami, D.D.S., Ph.D.

Mitsuyoshi Iino, D.D.S., Ph.D

Lecturer
Yoshiyuki Mori, D.D.S., Ph.D.

Hisako Hikiji, D.D.S., Ph.D.,

Toru Ogasawara, D.D.S., Ph.D.

Meiko Oki, D.D.S., Ph.D.

Associate
Gen-ichiro Takagi, D.D.S.

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

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

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

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

Masanobu Abe, D.D.S., Ph.D.

Hideyuki Suenaga, D.D.S., Ph.D.

Kohei Nagahama, D.D.S., Ph.D.

Yuko Fujihara, D.D.S., Ph.D.

Homepage

http://plaza.umin.ac.jp/%7Eoralsurg/

Introduction and Organization
Department of Oral and Maxillofacial Surgery,commenced by Dr. Hisashi Ishihara in 1900, is one ofthe oldest departments in Graduate School of
Medicine, the University of Tokyo. This department
consists of wide variety of specialists, such as oral
surgeons, orthodontists and prosthodontists. We
handle all diseases in the oral-maxillofacial region,such as congenital anomalies, jaw deformities, benign
and malignant tumors, trauma and inflammation.
Dental care for the patients who have systemic
disorders or under medical control is another field ofour department. Multidisciplinary treatment teamedby these specialists is characteristic and has performed
excellent results in clinical works. In research fields,
all staffs participate in the clinical and basic researchto support the treatment scientifically and to develop
new treatment protocols, and we have mainly

performed the experimental studies on theregenerative abilities of tissues such as bone,
periosteum, cartilage, perichondrium, vessels, nerve,and skin. At present, we are focusing on tissue
engineering in research works especially in bone,cartilage and vessels. Professor Takato had establishedTissue Engineering Division in the University ofTokyo Hospital and our department has two
endowment departments: Department of Cartilage andBone Regeneration (FUJI SOFT Inc.) and Departmentof Clinical Vascular Regeneration (Daiichi SankyoCo., Ltd.) in Tissue Engineering Division. Eachdepartment has 1 associate professor, 1 assistantprofessor, and several graduate students respectively.
These staffs are focusing on translational researchworks in maxillofacial regions.

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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
2) Multidisciplinary treatment of dentomaxillofacial

227

deformities, trauma and temporomandibulardiseases
3) Multidisciplinary treatment of malignant tumors
in head and neck region4) Distraction technique of orofacial osteogenesis
5) Treatment for oforofacial dysplasia with cleft lip
and palate patients
6) Speech therapy for cleft lip and palate patients
7) Advancement therapy for congenital orofacial
dysplasia
8) Evaluation of therapy for cleft lip and palatepatients
9) Surgery, chemotherapy and irradiation therapy formalignant tumors10) development of dental implant made of newmaterials
11) Advancement of orthognatic surgery for orofacial
dysplasia
12) Evaluation of treatment for temporomandibular
disorders13) Evaluation of mastication function14) Non-surgical treatment system for orofacial
trauma15) Reconstructive treatment utilizing custom-madeartificial bone from our original technique
Basic and experimental research:
1) Contribution of periosteum to bone regeneration
2) Chondrogenic potential of the perichondrium3) Bone regeneration using growth plate chondrocyte4) Role of cell cycle factors in regulation of
osteo-chondrocyte differentiation
5) Osteochondrogenic differentiation of bonemarrow derived mesenchymal stem cells by
spheroid culture6) Periodontal tissue regeneration around dental
implants
7) Reconstruction of bone and cartilage of oro-facial
region using tissue engineering technique
Tissue engineering:
Clinical section
1) Clinical application of artificial bone that displace
into bone2) Implant type artificial bone generated from tissue
engineered human chondrocyte
3) Therapy of regeneration blood vessel using

AGHM-ßFGF
Research section1) Development of intelligent type of artificial bone
invested with osteogenic differentiation factors2) Development of tetra pod type micro artificial
bone unit
3) Development of neo wound-care dressings4) Three dimensional cell culture of autologous
chondrocyte

Publications(1) Aoki A, Moriyama K, Kawamoto T, Aoki K,
Inokuchi T, Kudoh A, Nagahama K, Baba Y, Suzuki
S, Ohya K. Amount of bone lengthening affects
blood flow recovery and bone mineralization after
distraction osteogenesis in a canine cleft palate
model. Cleft Palate Craniofac J. 2009 Aug 12:1.
(2) Asawa Y, Ogasawara T, Takahashi T, Yamaoka H,
Nishizawa S, Matsudaira K, Mori Y, Takato T,
Hoshi K. Aptitude of auricular and nasoseptal
chondrocytes cultured under a monolayer orthree-dimensional condition for cartilage tissue
engineering. Tissue Eng Part A. 2009 May;15(5):1109-18.
(3) Choi SJ, Lee JI, Igawa K, Sugimori O, Suzuki S,
Mochizuki M, Nishimura R, Chung UI, Sasaki N.
Bone regeneration within a tailor-madetricalcium phosphate bone implant with bothhorizontal and vertical cylindrical holestransplanted into the skull of dogs. J Artif Organs.
2009;12(4):274-7.
(4) Ko EC, Chen MY, Hsu M, Huang E, Lai S.
Intraoral approach for arthroplasty for correction of
TMJ ankylosis. Int J Oral Maxillofac Surg. 2009
Dec;38(12):1256-62.
(5) Fujihara Y, Asawa Y, Takato T, Hoshi K. Tissue
Reactions to Engineered Cartilage Based on
Poly-L-Lactic Acid Scaffolds. TissueEng. 2009;15(7):1565-77.
(6) Saijo H, Igawa K, Kanno Y, Mori Y, Kondo K,
Shimizu K, Suzuki S, Chikazu D, Iino M, Anzai M,
Sasaki N, Chung UI, Takato T. Maxillofacialreconstruction using custom-made artificial bones
fabricated by inkjet printing technology. J Artif
Organs. 2009;12(3):200-5.
(7) Saijo H, Mori Y, Chikazu D, Iino M, Okubo K,

228

Kanno Y, Yonehara Y, Takato T. An alternative
method for correction of nasal deformity using ear
cartilage for bilateral cleft nasal correction inschool-age children. Asian J Oral Maxillofac Surg.
2009; 21:109-13.
(8) Hikiji H, Ishii S, Yokomizo T, Takato T, Shimizu T.
A distinctive role of the leukotriene B4 receptor
BLT1 in osteoclastic activity during bone loss. Proc
Natl Acad Sci U S A. 2009 Dec 15;106(50):21294-9.
(9) Hirata M, Kugimiya F, Fukai A, Ohba S,
Kawamura N, Ogasawara T, Kawasaki Y, Saito T,
Yano F, Ikeda T, Nakamura K, Chung UI,Kawaguchi H. C/EBPbeta Promotes transition fromproliferation to hypertrophic differentiation ofchondrocytes through transactivation of p57. PLoS
One. 2009;4(2):e4543. Epub 2009 Feb 20.
(10) Huang Z, Kawase-Koga Y, Zhang S, Visvader J,
Toth M, Walsh CA, SunT. Transcription factor
Lmo4 defines the shape of functional areas indeveloping cortices and regulates sensorimotor
control. Dev Biol. 2009 Mar 1;327(1):132-42.
(11) Iino M, Fukuda M, Nagai H, Hamada Y, Yamada H,
Nakaoka K, Mori Y, Chikazu D, Saijo H, Seto I,
Ohkubo K, Takato T. Evaluation of 15 mandibular
reconstructions with Dumbach Titan Mesh-Systemand particulate cancellous bone and marrow
harvested from bilateral posterior ilia. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod. 2009
Apr;107(4):e1-8.
(12) Inokuchi T, Kawamoto T, Aoki K, Aoki A,
Nagahama K, Baba Y, Suzuki S, Shibayama M,
Mano Y, Ohya K, Moriyama K. The effects ofhyperbaric oxygen on tooth movement into theregenerated area after distraction osteogenesis.
Cleft Palate Craniofac J. 2009 Oct 14:1.
(13) Kan A, Ikeda T, Saito T, Yano F, Fukai A, Hojo H,
Ogasawara T, Ogata N, Nakamura K, Chung UI,Kawaguchi H. Screening of chondrogenic factors
with a real-time fluorescence-monitoring cell line
ATDC5-C2ER: identification of sorting nexin 19 asa novel factor. Arthritis Rheum. 2009 Nov;60(11):3314-23.
(14) Kikuchi Y, Uozaki H, Itoyama S, Saijo H, Takato T,
Fukayama M. Pagetoid spread to oral mucosa fromsubmandibular gland salivary duct carcinoma: acase report. Hum Pathol. 2009 Jul;40(7):1036-9.
(15) Kawase-Koga Y, Otaegi G, Sun T. Different timingsof Dicer deletion affect neurogenesis andgliogenesis in the developing mouse central
nervous system. Dev Dyn. 2009 Nov;238(11):2800-12.
(16) Mori Y, Susami T, Chikazu D, Saijo H, Sakiyama
M, Matsuzaki M, Abe M, Wada M, Iino M, Takato
T. Unilateral expansion of a narrow mandibular
dental arch combined with bimaxillary osteotomies
in a patient with hypoglossia. Int J Oral Maxillofac
Surg. 2009 Jun;38(6):689-93.
(17) Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M,
Kelly TK, Marquez VE, Jones PA. DZNep is a
global histone methylation inhibitor that reactivates
developmental genes not silenced by DNA
methylation. Mol Cancer Ther. 2009 Jun;8(6):157988.
(18) Ogasawara T, Ohba S, Fujihara Y, Takahashi T, Liu
G, Chikazu D, Suenaga H, Chung UI, Yoda T, MoriY, Susami T, Takato T, Hoshi K. Transforming
Growth Factor–β1 in Combination with Fibroblast
Growth Factor–2 and Insulin-like Growth Factor–I
for Chondrocyte Proliferation Culture and Cartilage
Regenerative Medicine. Asian J Oral Maxillofac
Surg. 2009 ;21:18-26.
(19) Takayama T, Taguchi T, Koyama H, Sakari M,
Kamimura W, Takato T, Miyata T, Nagawa H.
The growth of a vascular network inside acollagen-citric acid derivative hydrogel in rats.
Biomaterials. 2009 Jul;30(21):3580-7.
(20) Ushita M, Saito T, Ikeda T, Yano F, Higashikawa A,
Ogata N, Chung U, Nakamura K, Kawaguchi H.
Transcriptional induction of SOX9 by NF-kappaB
family member RelA in chondrogenic cells.
Osteoarthritis Cartilage. 2009 Aug;17(8):1065-75.
(21) Yamamoto K, Igawa K, Ueno H, Yano F, Chung UI,
Koshima I. Temporal and spatial changes inelement distribution in bone and cartilage. J Orthop
Sci. 2009 Mar;14(2):198-203.
(22) Yoda T, Sato T, Abe T, Sakamoto I, Tomaru Y,
Omura K, Hatano N, Takato T, Ishii Y. Long-term
results of surgical therapy for masticatory muscle
tendon-aponeurosis hyperplasia accompanied bylimited mouth opening. Int J Oral Maxillofac Surg.
2009 Nov;38(11):1143-7.

229(23) Yokoyama Y, Suzuki T, Sakata-Yanagimoto M,
Kumano K, Higashi K, Takato T, Kurokawa M,
Ogawa S, Chiba S. Derivation of functional
mature neutrophils from human embryonic stem
cells. Blood. 2009 Jun 25;113(26):6584-92.
(24) Fujihara Y, Takato T, Hoshi K. Immunologicalresponse to tissue-engineered cartilage derived
from auricular chondrocytes and a PLLA scaffold
in transgenic mice. Biomaterials (in press)(25) Iwata K, Asawa Y, Fujihara Y, Tanaka Y, Nishizawa
S, Nakagawa T, Nagata S, Takato T, Hoshi K. The
effects of rapid- or intermediate-acting insulin on
the proliferation and differentiation of cultured
chondrocytes. Curr Aging Sci. (in press)(26) Kawase-Koga Y, Low R, Otaegi G, Pollock A,
Deng H, Eisenhaber F, Maurer-Stroh S, Sun T.
RNAase-III enzyme Dicer maintains signaling
pathways for differentiation and survival in mousecortical neural stem cells. J Cell Sci. (in press)(27) Liu G, Iwata K, Ogasawara T, Watanabe J,
Fukazawa K, Ishihara K, Asawa Y, Fujihara Y,
Chung UL, Moro T, Takatori Y, Takato T,
Nakamura K, Kawaguchi H, Hoshi K. Selection ofhighly osteogenic and chondrogenic cells frombone marrow stromal cells in biocompatible
polymer-coated plates. J Biomed Mater Res A. (inpress)(28) Mori Y, Saijo H, Fujihara H, Tanaka Y, Maeda Y,
Hayashi N, Chikazu D,

Iino M, Takato T.

Dermoid cyst with fistula formation on the dorsumof the tongue – A case report.

Asian J Oral

Maxillofac Surg. (in press)(29) 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. (in press)(30) Saijo H, Mori Y, Fujihara H, Kanno Y, Chikazu D,
Ohkubo K, Hikiji H, Iino M, Yonehara Y, Takato T.
Evaluation and analysis of bone formation at palateof cleft lip and palate patients after palatoplasty
based on computed tomographic scanning and three

dimensional data.:Scand J Plast Reconstr Surg
Hand SURG. (in press)(31) Saijo H, Kanno Y, Mori Y, Chikazu D, Iino M,
Takato T. A bone harvesting method involving asurgical template prepared using a threedimensional model.Asian J Oral.Maxillofac Surg.
(in press)(32) Yamaoka H, Nishizawa S, Asawa Y, Fujihara Y,
Ogasawara T, Yamaoka K, Nagata S, Takato T,
Hoshi K. Involvement of fibroblast growth factor
18

indedifferentiationof

culturedchondrocytes. Cell Prolif. (in press)

human

230

Department ofOrthopaedic Surgery
Professor
Kozo Nakamura, M.D., Ph.D.

Associate Professors
Hiroshi Kawaguchi, M.D., Ph.D.,

Sakae Tanaka, M.D., Ph.D.

Lecturers
Isao Ohnishi, M.D., Ph.D.,

Katsushi Takeshita, M.D., Ph.D.,

Hirotaka Kawano, M.D., Ph.D.,

Takumi Nakagawa, M.D., Ph.D.

Associates
Toshiki Miura, M.D., Ph.D.,

Hideya Itoh, M.D.,

Yuho Kadono, M.D., Ph.D.,

Hirotaka Chikuda, M.D., Ph.D.,

Nobuhiro Hara, M.D.,

Yasushi Ohshima, M.D., Ph.D.,

Tetsuro Yasui, M.D., Ph.D.,

Tomotake Okuma, M.D.,

Jinso Hirota, M.D.,

Jiro Morii, M.D.,

Toshiharu Tsunoda, M.D.,

Hideaki Miyamoto, 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 German and Austria.
Initially, the department treated patients with
infectious disorders and congenital malformations,such as poliomyelitis, tuberculosis of the spine,congenital clubfoot and hip dislocation. The numberof outpatients visiting our department in 1910 was
estimated to be no more than 3.3% that of the twosurgical departments in the University of Tokyo
Hospital.
The number and characteristics of the patients,
however, have changed dramatically in these 100

years. This is because our department addressed theacute needs of society from the beginning. Prof.
Tashiro believed that trauma should be treated byorthopedists, so he provided his pupils with thistraining. Since 1950’s, the department has
increasingly been involved in the treatment of traffic
and industrial accident victims. Prof. Tashiro and his
successor Professor Kenji Takagi devoted themselvesto the establishment of an institute for children withdisabilities. The arthroscope was developed by Prof.
Takagi, and is now considered to represent a
breakthrough in the development of minimallyinvasive surgery. We have recently been conducting
many studies related to the ossification of spinal
ligaments (OPLL), rheumatoid arthritis, biomechanics,
and the degenerative skeletal disorders such as

231

osteoporosis and osteoarthritis in response to theprogressive aging of our society.
Our department is now adept in the entire field of
medical science and medical practice related to thehuman locomotor system, the importance of which is
now clearly recognized not only in Japan, but also all
over the world. To meet the expanding needs ofsociety, we have been conducting the teaching,clinical, and research activities described below.
Faculty members of the department are the top
professor, two associate professors, four lecturers, 13
associates, six medical staff members, a visiting
fellows, eight senior residents, and 12 part-timeteachers.

Teaching activities
As for undergraduate education, our department
provides a comprehensive series of lectures, physicalassessment classes and problem-based learning (PBL)
program to 4th year medical students, bedsidelearning and clinical clerkship programs to 5th year
students and clinical lectures to 6th year medical
students.
A comprehensive series of lectures provides basic
knowledge of the physiology, pathology, diagnosis
and treatment of various musculoskeletal disorders.
Twelve consecutive lectures in total cover a whole
field of orthopaedics: basic science, pediatricdisorders, rheumatic diseases, metabolic bone diseases,
musculoskeletal 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 from April 2009 through March
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.
Eight hundred and seventy-one operations were
performed in 2009. These include 78 cervical andthoracicspine
surgeries(including
25
computer-assisted surgeries (CAS)), 81 lumbar spine
surgeries, 23 scoliosis surgeries (including 21 CAS),
71 surgeries for rheumatoid arthritis patients, 91 hip
surgeries, 167 knee surgeries (including 37
computer-assisted
ACL
reconstruction,
51
computer-assisted TKA), 6 shoulder surgeries, 110

232

hand surgeries, 12 limb lengthening andreconstruction surgeries using external fixators, 122surgeries for bone and soft tissue tumor and 90 trauma
surgeries.
The main disorders of cervical spine surgery weremyelopathy due to spondylosis or OPLL. We
successfully adopted double-door open laminoplasty
by splitting the spinal processes for most of thesecases. This procedure was invented and developed inour department and is now used nationwide. The
present professor Kozo Nakamura has also been thechief investigator of a national project to investigate
OPLL. Difficult operations such as subluxation of thecervical spine due to rheumatoid arthritis, Down’s
syndrome or cerebral palsy were treated using anavigation system that has been officially approved asa high-level advanced medical treatment.
The lumbar spine group developed a new posterior
decompression technique which preserves the spinous
processes and interspinous ligaments, and successfully
uses it for lumbar spinal canal stenosis. Randomized
clinical trials are now ongoing by this group.
Main operations performed by the rheumatoid
arthritis clinic group were total joint arthroplasty.
They are using image-free navigation system in total
knee arthroplasty operation, which is useful for theaccurate placement of the implants.
The hip surgery group treated mainly acetabular
dysplasia and osteoarthritis of the hip joint. They
performed not only total hip replacements, but also
several osteotomies including rotational acetabularosteotomy (RAO). The RAO was originated andestablished in our department. They have started aclinical trial for a new artificial hip joint using the
MPC polymer in collaboration with the Department ofMaterials Engineering in Tokyo University.
The knee clinic group developed a new anterior
cruciate ligament reconstruction technique using thenavigation
systembasedonintraoperative
three-dimensional fluoroscopic image to realize ideal
graft placement.
The peripheral nerve clinic group has developed"costal nerve transfer to the musculocutaneous nerve"
for brachial plexus injury.
The tumor group managed multidisciplinary
treatment for musculoskeletal sarcoma including
chemotherapy, limb sparing surgery and radiotherapy

in coorporation with other departments.
Limb reconstruction operations using external
fixators included non-union, leg lengthening anddeformity correction. One of the main interests of thisgroup is the development of a system to analyze themechanical properties of a skeletal system. During
this period of analysis, the mechanical properties ofthe fracture site in vivo are to be evaluated bymonitoring the motion of a dynamic pin clamp during
simulated walking.

Research activities
Our research activities cover the full range of themusculoskeletal system medicine, using the in-depthsciences of biology and technology. Especially in thefield of molecular biology of bone and cartilage
metabolism, we are regarded as being on the leadingedge in the world. Basic research is performed under
the supervision of the faculty staff members. The main
research topics we have focused on are as follows.
1) Molecular backgrounds of bone and joint diseases
using forward and reverse genetics approaches
2) Signaling of differentiation and apoptosis ofosteoclasts
3) Etiology of OPLL
4) Molecular background underlying the joint
destruction by rheumatoid arthritis
5) Molecular background of osteoarthritis using amouse genomics approach6) Non-invasive evaluation of bone strength using afinite element method
7) In vivo bone formation by cytokines and its
clinical application
8) Molecular mechanism of age-related bone andcartilage disorders
9) Molecular mechanism of glial cell differentiation
In addition, four endowment departments take anactive role in research activities in close collaboration
with our Department. Two were established in the 22th
Century Medical Center. They deal with clinicalresearch, which houses the largest clinical database of
osteoarthritis patients in the world for the pursue ofgenomic and etiological research. One department isin the Division of Tissue Engineering, which seeks todevelop epochal bone and cartilage regenerative
medicine. The fourth is founded in the Graduate

233

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).
We also take part in National Database of
Rheumatic Diseases by iR-net in Japan (NinJa), a
nationwide observational cohort database of rheumatic
disease.

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Hikita A, Tanaka N, Yamane S, Ikeda Y,
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Hirata M, Kugimiya F, Fukai A, Ohba S,
Kawamura N, Ogasawara T, Kawasaki Y, Saito T,
Yano F, Ikeda T, Nakamura K, Chung UI, andKawaguchi H: C/EBPβ promotes transition fromproliferation to hypertrophic differentiation ofchondrocytes through transactivation of p57Kip2.
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Iwasawa M, Miyazaki T, Nagase Y, Akiyama T,
Kadono Y, Nakamura M, Oshima Y, Yasui T,

Nakamura T, Kato S, Henninghausen L,
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8. Kan A, Ikeda T, Saito T, Yano F, Fukai A, Ogata
N, Nakamura K, Chung UI, and Kawaguchi H:
Screening of chondrogenic factors by a real-time
fluorescence monitoring cell line ATDC5-C2ER:
Identification of sorting nexin 19 as a novel
factor. Arthritis Rheum 2009; 60: 3314-3323.
9. Kanamori M, Fukui M, Chiba K, Kawakami M,
Miyamoto M, Nakai S, Taniguchi S, Shimamura
T, Taguchi T, Takeshita K, Tanaka Y, Tani T,
Wada E, Yonenobu K. Japanese Orthopaedic
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A validation study in lumbar disc herniation
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10. Kawakami M, Chiba K, Fukui M, Hirota Y,
Kanamori M, Kikuchi S, Konno S, Miyamoto M,
Nakai S, Seichi A, Shimamura T, Shirado O,
Taguchi T, Takahashi K, Takeshita K, Tanaka Y,
Tani T, Toyama Y, Wada E, Yonenobu K.
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using the JOACMEQ and the JOA score inpatients with myelopathy caused by cervicalspondylosis and disc herniation. J Jap Soc Spine
Surg Rel Res 2009;20:677-681.
11. Kyomoto M, Moro M, Saiga K, Miyaji F,
Kawaguchi H, Takatori Y, Nakamura K, andIshihara K: Lubricity and stability of poly
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12. Kyomoto M, Moro T, Iwasaki Y, Miyaji F,
Kawaguchi H, Takatori Y, Nakamura K, Ishihara
K. Superlubricious surface mimicking articularcartilagebygraftingpoly(2-methacryloyloxyethyl phosphorylcholine) on
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Fukazawa K, Ishihara K, Asawa Y, Fujihara Y,
Chung UI, Moro T, Takatori Y, Takato T,
Nakamura K, Kawaguchi H, and Hoshi K:
Selection of highly osteogenic and chondrogenic
cells from bone marrow stromal cells inbiocompatible polymer-coated plates. J Biomed
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Kobayashi A, Anamizu Y, Kishimoto J, Hoshi K,
Takeshita K, Nakamura K. The efficacy of
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Matsudaira K, Yamazaki T, Seichi A, Hoshi K,
Hara N, Ogiwara S, Terayama S, Chikuda H,
Takeshita K, Nakamura K. Modified fenestration
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stenosis. Technical note. J Neurosurg Spine 2009;10(6):587-94.
Miura T, Tokuyama N, Ohya J: Spontaneous
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Morioka K, Tanikawa C, Ochi K, Daigo Y,
Katagiri T, Kawano H, Kawaguchi H, Myoui A,
Yoshikawa H, Naka N, Araki N, Kudawara I,
Ieguchi M, Nakamura K, Nakamura Y, andMatsuda K: Orphan receptor tyrosine kinase
ROR2 as a potential therapeutic target forosteosarcoma. Cancer Sci 2009; 100: 1227-1233.

21. Morizaki Y, Miura T: Unusual pattern ofdislocation of the trapeziometacarpal joint withavulsion fracture of the trapezium. Hand Surg
2009; 14(2-3): 149-152.
22. Moro T, Kawaguchi H, Ishihara K, Kyomoto M,
Karita T, Ito H, Nakamura K, and Takatori Y:
Wear resistance of artificial hip joints with poly
(2-methacryloyloxyethyl
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grafted polyethylene: Comparisons with theeffect of polyethylene cross-linking and ceramic
femoral heads. Biomaterials 2009; 30: 29953001.
23. Muraki S, Akune T, Oka H, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Nakamura K, Kawaguchi H,
and Yoshimura N: Association of occupational
activity with radiographic knee osteoarthritis andlumbar spondylosis in elderly patients of
population-based
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population-based study. Arthritis Rheum 2009;
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24. Muraki S, Oka H, Akune T, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Yamamoto S, Nakamura K,
Kawaguchi H, and Yoshimura N: Prevalence ofradiographic knee osteoarthritis and its
association with knee pain in the elderly ofJapanese population-based cohorts: The ROAD
study. Osteoarthritis Cartilage 2009; 17: 11371143.
25. Muraki S, Oka H, Mabuchi A, Akune T, En-yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Yamamoto S, Nakamura K,
Kawaguchi H, and Yoshimura N: Prevalence ofradiographic lumbar spondylosis and its
association with low back pain in the elderly of
population-based cohorts: the ROAD study. Ann
Rheum Dis 2009; 68: 1401-1406.
26. Nagase Y, Iwasawa M, Akiyama T, Kadono Y,
Nakamura M, Oshima Y, Yasui T, Matsumoto T,
Hirose J, Nakamura H, Miyamoto T, Bouillet P,
Nakamura K, Tanaka S. The anti-apoptotic
molecule Bcl-2 regulates the differentiation,
activation and survival of both osteoblasts andosteoclasts. J Biol Chem. 2009; 284:36659-36669
27. Nishino J, Tanaka S, Matsui T, Mori T,
Nishimura K, Eto Y, Kaneko A, Saisho K, Yasuda
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Oka H, Akune T, Muraki S, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Sasaki S, Nakamura K,
Kawaguchi H, and Yoshimura N: Low dietary
vitamin K intake is associated with radiographic
knee osteoarthritis in the Japanese elderly:
Dietary survey in a population-based cohort of
the ROAD study. J Orthop Sci 2009; 14:687-692.
Ota N, Takaishi H, Kosaki N, Takito J, Yoda M,
Tohmonda T, Kimura T, Okada Y, Yasuda H,
Kawaguchi H, Matsumoto M, Chiba K, Ikegami
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Seichi A, Yuichi Hoshino, Takeshita K, Chikuda
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Shoda N, Seichi A, Takeshita K, Chikuda H, Ono
T, Oka H, Kawaguchi H, and Nakamura K: Sleep
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2009; 18: 905-910.
Takeshita K, Maruyama T, Chikuda H, Shoda N,
Seichi A, Ono T, Nakamura K. Diameter, Length,and Direction of Pedicle Screws for Scoliotic
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Tanaka S, Nakano H. NF-kappaB2 (p100) limits
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Ushita M, Saito T, Ikeda T, Yano F, Higashikawa
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Yoshimura N, Muraki S, Oka H, Kinoshita H,
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236

Department of Ophthalmology
Professor
Makoto Araie, M.D., Ph.D.

Associate Professor
Satoru Kato, M.D., Ph.D.,

Yasuhiko Tamaki, M.D., Ph.D.

Lecturer
Makoto Aihara, M.D., Ph.D.,

Atsushi Tomidokoro, M.D., Ph.D.,

Miyuki Nagahara, M.D., Ph.D., Toshikatsu Kaburaki, M.D., Ph.D,

Research Associate
Tomohiko Usui, M.D., Ph.D., Yasuo Yanagi, M.D., Ph.D.,
Takashi Shigeeda, M.D.,

Shinsuke Konno, M.D., Ph.D.

Chihiro Mayama., M.D., Ph.D., Tanabe Tatsuro, M.D.,

Tatsuya Mimura, M.D., Ph.D., Kohei Muranaka, M.D., Ph.D., Koichi Mishima,M.D.,Ph.D.,
Kenji Sugisaki, M.D.,

Homepage

http://plaza.umin.ac.jp/ophl

Introduction and Organization
The Department of Ophthalmology, University ofTokyo School of Medicine, was founded in 1989.
Since then, the department has contributed to Japanese
ophthalmology not only by educating a large numberof eminent ophthalmologists in Japan, but also byproducingsignificant
basic
researchinophthalmology.
The department has been active in collaboration with
ophthalmologists around the world, sponsoring
international ophthalmological meetings, educating
fellows from foreign countries and sending our staff
and fellows abroad.

Clinical activities
Altogether, approximately 4000 new outpatients areseen every year in our hospital, which has a total of 44
beds. Residents work in the ambulatory section andtake care of inpatients. Special services are provided
in units devoted to ophthalmic subspecialities such as

cornea,glaucoma,
retina,uveitis,neuroophthalmology, orthoptics, diabetic retinopathy, andgenetic and color blindness problems. The staff
members supervise the ambulatory and special
services depending on each one’s speciality.
Most of the inpatients suffer from cataract, glaucoma,
corneal diseases, retinal detachment, diabetic
retinopathy, uveitis and strabismus. Surgeries are
performed in the operating theater of the hospital
under operating microscopes. Approximately 2400
cases underwent operations in our department.
Surgeries can be monitored by TV system which ismounted on operating microscopes. Since multiple
observers can watch the same images and sharefindings, this system has a great potential in training
and promoting discussion.

Teaching activities
As an undergraduate course, we give lectures on
corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged in237

practical training for medical students on
ophthalmological examinations at the outpatient clinic.
As a postgraduate course, we give lectures on topics
concerning corneal transplantation, corneal diseases
and new medical therapies.

Research activities
Research topics in our department cover a variety offields in ophthalmology; e.g. ocular pharmacology,
regenerative medicine in the cornea and retina,
aqueous humour dynamics, immunology andmolecular biology. Special laboratories for physiology,
pharmacology and genetic engineering have been
established. Specific fields of research in our
department are as follows.
1. Analysis with laser-speckle method of vascularflow in retina and iris
2. Clinical investigation of normal tension glaucoma
3. Analysis of dynamics of aqueous flow
4. Drug effect on glaucoma
5. Screening method of glaucoma
6. Tissue engineering of the cornea
7. Clinical investigation of corneal shape
8. Gene therapy in corneal transplantation
9. Role of advanced glycation endproducts in oculardiseases
10. Clinical and basic research of excimer laser
refractive surgery
11. Molecular analysis of retinal degenerative
diseases
12. Color blindness and visual function
13. Electrophysiological analysis of the effect ofdrugs on the retina
14. Biocompatibility of intraocular lenses
15. Immuno-hereditary analysis of Harada’s disease
and Bechet’s disease
16. Immunosuppressive reagents on Bechet’s disease
17. Pathophysiology and molecular mechanisms of
diabetic retinopahty

References
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Abe H, Shirakashi M, Tsutsumi T, Araie M,
Tomidokoro A, Iwase A, Tomita G, Yamamoto T,
Tajimi Study Group. Laser scanning tomographyof optic discs of the normal Japanese population

in a population-based setting. Ophthalmology
116:223-230,2009
2. Aihara M, SaitoY, Higashide T, Okubo S, Sasaki
T, Sugiyama K Vasculature factors influencing
the filtering bleb shape after trabeculectomy withlimbal-based conjunctival flap
Jpn J
Ophthalmol. 2009 [Epub ahead of print]
3. Araki F, Mimura T, Fukuoka S, Tsuji H, Izutsu K,
Yamamoto H, Takazawa Y, Kojima T. Primary
orbital lymphomatoid granulomatosis. Br J
Ophthalmol 93:554-556, 2009
4. Dimitrova G, Kato S, Fukushima H, Yamashita
H: Circulatory parameter in the retrobulbar
central retinal artery and vein in diabetic patientswith and without systemic hypertension. Graefes
Arch Clin Exp Ophthalmol, 247:53-58,2009
5. Fukuoka S, Honda N, Usui T, Inoue K, Araie M,
Amano S. Penetrating keratoplasty for bullous
keratopathy
aftertrabeculectomy.
Eye
23:90-94,2009
6. Funatsu H, Noma H, Mimura T, Eguchi S, Hori S.
Association of vitreous inflammatory factors withdiabetic macular edema. Ophthalmology 116:
73-79, 2009
7. Hirasawa H, Tomidokoro A, Kunimatsu S,
Mishima K, Iwase A, Tomita G , Araie M.
Ultrasound biomicroscopy in narrow anteriorchamber eyes with or without peripheral anterior
synechia. J Glaucoma 2009;13 (in press)
8. Imamura K, Onoe H, Shimazawa M, Nozaki S,
Wada Y, Kato K, Nakajima H, Mizuma H, Onoe
K, Taniguchi T, Sasaoka M, Hara H, Tanaka S,
Araie M, Watanabe Y. Molecular imaging reveals
unique degenerative changes in experimental
glaucoma. NeuroReport 20:139-144,2009
9. Inokuchi Y, Imai S, Nakajima Y, Shimazawa M,
Aihara M, Araie M, Hara H. Edaravone, a free
radical scavenger, protects against retinal damage
in vitro and in vivo. J Pharmacol Exp Ther 2009;
329:687-698
10. Inokuchi Y, Nakajima Y, Shimazawa M, Kurita T,
Kubo M, Saito A, Sajiki H, Kudo T, Aihara M,
Imaizumi K, Araie M, Hara H. Inducer of BiP, an
Endoplasmic Reticulum (ER)-resident Protein,
Limits Retinal Cell Death. Invest Ophthalmol Vis
Sci. 50: 334-344, 2009
11. Inoue Y, Kadonosono K, Yamakawa T, Uchio E,

238

Watanabe Y, Yanagi Y, Tamaki Y, Araie M.
Surgically-induced inflammation with 20-, 23-,and
25-gauge
vitrectomy
systems:anexperimental study. Retina 29;477-480,2009
12. Inoue M, Iriyama A, Kadonosono K, Tamaki Y,
Yanagi Y. Effects of perfluorocarbon liquids andsilicone oil on human retinal pigment epithelial
cells and retinal ganglion cells. 29:477-480,2009.
13. Iriyama A, Inoue Y, Takahashi H, Tamaki Y, Jang
WD, Yanagi Y: A2E, a component of lipofuscin,is pro-angiogenic in vivo. J Cell Physiol 220:469475,2009.
14. Kaburaki T, Koshino T, Kawashima H, Numaga J,
Tomidokoro A, Shirato S, Araie M. Initialtrabeculectomy with mitomycin C in eyes withuveitic glaucoma with inactive uveitis. Eye
2009;23(7):1509-17.
15. Kaburaki T, Takamoto M, Araki F, Fujino Y,
Nagahara M, Kawashima H, Numaga J.:
Endogenous Candida albicans infection causing
subretinal abscess. Int Ophthalmol. 2009 Apr 10.,in press.
16. Nagayoshi H, Hiramatsu Y, Himaga M, Kato S:
Detection of fundus lesions using classifier
selection.
IEICE
TRANSACTIONSon
Information and Systems, E92-D, 1168-1176,
2009
17. Mimura T, Mimura Y, Arimoto A, Amano S,
Yamagami S, Funatsu H, Usui T, Noma H, Honda
N, Okamoto S. Relationship between refraction
and allergic conjunctivitis. Eye 23:63-66, 2009
18. Mimura T, Yamagami S, Usui T, Funatsu H,
Mimura Y, Noma H, Honda N, Amano S.
Changes of conjunctivochalasis with age in a
hospital-based study. Am J Ophthalmol 147:171177, 2009
19. Mizuno K, Koide T, Shimamura S, Mori J,
Sawanobori K, Araie M. Route of penetration of
topically instilled nipradilol into the ipsilateralposterior retina. Invest Ophthalmol Vis Sci. 2009;50:2839-2847
20. Miyanaga M, Miyai T, Nejima R, Maruyama Y,
Miyata K, Kato S: Effect of bromofenac
ophthalmic solution on ocular inflammation
following cataract surgery. Acta Ophtalmologica,
87,2009
21. Noma H, Funatsu H, Mimura T, Harino S, Hori S.

22.

23.

24.

25.

26.

27.

28.

29.

Vitreous levels of interleukin-6 and vascularendothelial growth factor in macular edema withcentral retinal vein occlusion. Ophthalmology
116:87-93, 2009
Noma H, Funatsu H, Sakata K, Harino S,
Nagaoka T, Mimura T, Sone T, Hori S. Macular
microcirculation and macular oedema in branchretinal vein occlusion. Br J Ophthalmol 93:630633, 2009
Ooto S, Hangai M, Sakamoto A, Tomidokoro A,
Araie M, Otani T, Kishi S, Matsushita K, Maeda
N, Shirakashi M, Abe H, Takeda H, Sugiyama K,
Saito H, Iwase A, Yoshimura N. Threedimensional Profile of Macular Retinal Thickness
in Normal Japanese Eyes. Invest Ophthalmol Vis
Sci 2009. in press.
Saeki T, Ota T, Aihara M, Araie M. Effects of
Prostanoid EP agonists on mouse intraocularpressure. Invest Ophthalmol Vis Sci. 50:22012208,2009
Saito H, Tsutsumi T, Araie M, Tomidokoro A,
Iwase A. Sensitivity and Specificity of the
Heidelberg Retina Tomograph II Version 3.0 in a
Population-based Study: The Tajimi Study.
Ophthalmology 2009. in press.
Saito H, Tomidokoro A, Yanagisawa M, Iwase A,
Araie M. Sensitivity and specificity with the
Glaucoma Probability Score in Heidelberg Retina
Tomograph II in Japanese Eyes. J Glaucoma.
18(3):227-232,2009
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 (in press)
Sasaki T, Watanabe W, Muranishi Y, Kanamoto T,
Aihara M, Miyazaki K, Tamura H, Saeki T, Oda
H, Souchelnytskyi N, Souchelnytskyi S, Aoyama
H, Honda ZI, Furukawa T, Mishima HK, Kiuchi
Y, Honda H. Overexpression of oculardevelopment-associated gene (ODAG) in the eye
induced elevated intraocular pressure, optic nerve
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Ophthalmol Vis Sci. 50:242-248,2009
Shiroma H, Higa A, Sawaguchi S, Iwase A,
Tomidokoro A, Amano S, Araie M. Prevalenceand Risk Factors of Pterygium in a Southwestern

239

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Ma J, Kezuka T, Hamada H, Usui T, Mochizuki
M, Yamagami S. Human corneal endothelial cells
expressing programmed death-ligand (PD-L1)
suppress PD-1+ T Helper 1 cells by acontact-dependent
mechanism.
InvestOphthalmol Vis Sci 50; 263-272, 2009
Sugiyama T, Araie M, Rive CE, Schmetterer L,
Orguel S for the Ocular Blood Flow Research
Association. Use of the laser speckle flowgraphy
in ocular blood flow research. Acta
Ophthalmologica (in press)
Takayama J, Mayama C, Mishima A, Nagahara
M, Tomidokoro A and M Araie. Topicalphenylephrine decreases blood velocity in the
optic nerve head and increases resistive index in
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Tamaki Y. Prospects for nanomedicine in treating
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complications of posterior subtenon injection oftriamcinolone acetonide in type 2 diabetes
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Tomidokoro A, Iwase A, Araie M, Yamamoto T,
Kitazawa Y. Population-based prevalence of optic
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Tsutsumi T, Tomidokoro A, Saito H, Hashizume
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Ueta T, Yanagi Y, Tamaki Y, Yamaguchi
T.Cerebrovascular accidents in ranibizumab.
Ophthalmology 116;362,2009
Usui T, Misawa Y, Honda N, Tomidokoro A,
Yamagami S, Amano S. Nontraumatic
keratomycosis caused by Alternaria in a
glaucoma patient. Int Ophthalmol 2009, in press.
Yamasaki M, Noma H, Funatsu H, Minamoto A,
Mimura T, Shimada K, Yamashita H, Kiuchi Y.
Changes in foveal thickness after vitrectomy for
macular edema with branch retinal vein occlusion
and intravitreal vascular endothelial growth

factor. Int Ophthalmol 29:161-167, 2009

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Department ofOtorhinolaryngology andHead & eck Surgery
Professor
Tatsuya Yamasoba, M.D, Ph.D.

Associate Professor
Takahiro Asakage, M.D.,Ph.D

Mistuya Musuzki、Md.Ph.D (~Aug 2009)

Shin-ichi Iwasaki, MD.PhD (Oct 2009~)

Lecturer
Kenji Kondo, M.D, Ph.D

Akinobu Kakigi, M.D., Ph.D,

Takaharu Nito, M.D., Ph.D.

Research Associate
Takashi Sakamoto, M.D. PhD.

Takuya Yasui, M.D., Ph.D.

Shotaro Karino, M.D, Ph.D,

Yasuhiro Ebihara, M.D,

Munetaka Ushio, M.D., Ph.D,

Mizuki Ando, M.D.

Yasuhiro Chirara, M.D.,

Keigo Suzukawa, M.D.,

Masahiro Yoshida, M.D,

Tsuyoshi Yoshida, M.D.

Akinori Kashio, M.D,

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

241club is held to introduce current research papers.

Clinical activities
In the out-patient clinic, general and special
services are provided to approximately 150
out-patients on a daily basis in all areas ofotorhinolaryngology and related specialties, andapproximately 300 new patients visit monthly.
In the new inpatient hospital, 44 beds are preparedfor patients under the supervision of lecturers andsenior residents from each subspecialty group
including head & neck surgery, middle ear surgery andcochlear
implant
surgery;
voice
andbronchoesophagological surgery, and paranasal
surgery and other minor surgery. Peroperative andpostoperative problems are checked and discussed byeach group, the professor’s and associate professor’s
rounds. Approximately 810 operations are performed
annually.
Cochlear implant surgery over 150 cases has been
actively performed for infants, children and adultpatients with profound hearing loss and is very
successful to provide new hearing. Head and necksurgery is performed to extirpate malignant tumor
with neighboring tissues and reconstruct upper
respiratory and swallowing functions at one stage
operation cooperating with plastic surgeons.
Reconstructive surgery of microtia and atresia toreconstruct external ear is routinely performed withplastic surgeons.
Auditory brainstem response is routinely examinedin order to diagnose peripheral and central deafness inneonates, infants and children.
Treatment of acoustic tumor using an ɤ-knife andauditory brainstem implant are performed inconsultation with neurosurgons.

Teaching activities
For the fourth year medical students’ serial lecturesand for the fifth and sixth year medical students
special lectures on current topics are provided by theprofessor and associate professor.
Clinical training is provided for the sixth year classof medical students on a one-to-one basis with staff
doctors. They are requested to write reports on aclinical case or a clinical problem. The students
participate to see surgery, special clinics and clinicalexaminations such as otoscope, fiberscope, auditory
brainstem response, and caloric test. Interview withpatient is encouraged. They are questioned many
aspects of clinical problems in seminars by professor
and associate professor. During half and a week period,
the students participate in surgery special clinics andpractice of clinic examination such otoscope,
fiberscope auditory brainstem, caloric test and so on.

Research activities
Clinical and basic research activities are highly
encouraged. Clinical research, which is supervised bysenior doctors, is very actively pursued even by young
residents. Case reports presentation and writing skills
are regarded as important experience in order todevelop young doctors’ research activity andinvestigate important findings in patients. The clinicalresearch is related to ear surgery, neurotology,
audiology,
head
&
neck
surgery,
bronchoesophagology and rhinology and is related tocase resersch, clinical statistics and clinicalelectrophysiology. Basic research is also encouraged
to solve essence of clinical problems and to elucidate
basic phenomena or anatomical and cellular structures.
Our research topics cover:1) Morphology and neurophysiology of the inner ear
focusing on sensory neural deafness: human
temporal bone pathology, electron microscopic
study in animal models, gene therapy, protein
tranasduction, and nanotechnology
2) Clinical application of otoacoustic emissions andauditory brainstem responses.
3) Histochemistry of olfactory epithelium indevelopment and aging.
4) Clinical neurophysiology of the facial nerves
focusing on degeneration and regeneration inpatients.
5) Histochemistry of head and neck cancer
pathology.
6) The central auditory cortex research using MEG.
7) Auditory brainstem response and speech andhearing after the new born hearing screening.
8) Pathology and electrophysiology of the larynx.
9) Vestibular research on the oculomotor and balance

242

systems in the brain.
10) Vestibular myogenic evoked potentials in cochlear
implant and inner ear anomaly.
11) Hair cell physiology in the vestibular end organ.
12) Newborn hearing screening and language
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.

7.

8.

Various clinical and basic research are conducted bystaffs, residents, postgraduate doctors and seniordoctors at affiliated hospitals.
9.

References
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2.

3.

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Ando M, Asai M, Asakage T, Oyama W, Saikawa
M, Yamazaki M, Miyazaki M, Ugumori T, Daiko
H, Hayashi R.Metastatic neck disease beyond thelimits of a neck dissection: attention to the“pa-ra-hyoid” area in T1/2 oral tongue cancer.
Jpn J Clin Oncol 39:231-236,2009
Boccia S, Hashibe M, Gallì P, De Feo E, Asakage
T, Hashimoto T, Hiraki A, Katoh T, Nomura T,
Yokoyama A, van Duijn CM, Ricciardi G,
Boffetta P. Aldehyde dehydrogenase 2 and headand neck cancer: a meta-analysis implementing a
Mendelianrandomization
approach.Cancer
Epidemiol Biomarkers Prev. 18;248-54,2009
Chihara Y, Iwasaki S, Fujimoto C, Ushio M,
Yamasoba T, Murofushi T. Frequency tuning
properties of ocular vestibular evoked myogenic
poten-tials. Neuroreport 20:1491-5,2009
Chihara Y, Iwasaki S, Ito K, Nakamura S,
Yama-soba T, Sahara Y. The firing properties ofvestibular ganglion cells in heterozygous BDNF
null mice. NeuroReport 20:1167-71,2009
Chihara Y, Iwasaki S, Ushio M, Fujimoto C,
Ka-shio A, Kondo K, Ito K, Asakage T,
Yamasoba T, Kaga K, Murofushi T. Ocularvestibular-evoked
myogenic
potentials(oVEMPs) require extraocular muscles but notfacial or cochlear nerve activity. Clin
Neurophysiol 120:581-587,2009
Chihara, Y., Iwasaki, S., Fujimoto, C., Ushio, M.,
Yamasoba, T., Murofushi, T. Frequency tuning

10.

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12.

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14.

properties of ocular vestibular evoked myogenic
potentials.NeuroReport 20:1491-5, 2009
Chihara, Y., Iwasaki, S., Ushio, M., Fujimoto, C.,
Kashio, A., Kondo, K., Ito, K., Asakage, T.,
Yamasoba, T., Kaga, K., Murofushi, T. Ocularvestibular-evoked
myogenic
potentials(oVEMPs) require extraocular muscles but notfacial or cochlear nerve activity.Clin Neurophsiol
120:581-587,2009
Dekio-Hotta S, Kojima T, Karino S, Yamasoba T,
Dekio I, Ito YM, Satake H, Kaga K. N1
component reflects difference of terminal chordsin three-chord sequences. Neuroreport 20:251256, 2009.
Fujimoto C, Karino S, Ito K, Murofushi T.
Existence of possible functional interaction
between the saccule and the posterior
semicircular canal in humans: an evaluation
using VEMPs. Audiol Neurootol 14:232-239,
2009
Fujimoto C, Murofushi T, Chihara Y, Suzuki M,
Yamasoba T, Iwasaki S. Novelsubtypeofidiopathic bilateral vestibulopathy: bilateralabsence of vestibular evoked myogenic potentials
in the presence of normal caloric responses. J
Neurol 256:1488-1492,2009
Fujimoto C, Murofushi T, Chihara Y, Ushio M,
Sugasawa K, Yamaguchi T, Yamasoba T, Iwasaki
S.Assessment of diagnostic accuracy of foam
posturography for peripheral vestibular disorders:
analysis of parameters related to visual andsomatosensory dependence.Clin Neurophysiol
120:1408-14,2009
Hasegawa N, Ishimoto S, Takazoe M, Tsunoda K,
Fujimaki Y, Shiraishi A, Kinoshita M, Okada K.
Recurrent Hoarseness Due to Inflammatory Vocal
Fold Lesions in a Patient With Crohn's Disease.
Ann Otol Rhinol Laryngol 118:532-535,2009
Hiromasa K, Xiong G, Hiramatsu T, Ohki M,
Nagao S. Difference of climbing fiber input
sources between the primate oculomotor-related
cerebellar vermis and hemisphere revealed by aretrograde tracing study. Neuroscience Letters462 : 10-13, 2009
Ishiki H, Miyajima C, Nakao K, Asakage T,
Sugasawa M, Motoi T. Synovial sarcoma of thehead and neck: rare case of cervical metastasis.

243

Head Neck. 31 : 131-5, 2009
15. Ishimoto S, Tsunoda K, Fujimaki Y, Okada K et
al Objective Assessment of Dry Mouth Using a
Non-Invasive Device. Acta Oto-Laryngologica
129:1527-8,2009
16. Iwasaki S, Chihara Y, Smulders YE, Burgess AM,
Halmagyi GM, Curthoys IS, Murofushi T.The
role of the superior vestibular nerve in thegeneration of ocular vestibular-evoked myogenic
potentials to bone conducted vibration. Clin
Neurophysiol 120:588-593,2009
17. Iwasaki S, Murofushi T, Chihara Y, Ushio M,
Suzuki M, Curthoys IS, Yamasoba Y. Ocular
ves-tibular evoked myogenic potentials tobone-conductedvibrationinvestibular
schwannoma. Otol Neurotol 31:147-152,2009
18. Jin Y, Shinjo Y, Akamatsu Y, Yamasoba T, Kaga
K. Vestibular evoked myogenic potentials ofchildren with inner ear malformations before andafter cochlear implantation. Acta Otolaryngol(Stockh) 2009; 129:1198-205.
19. Kashio A, Amano A, Kondo Y, Sakamoto T,
Iwamura H, Suzuki M, Ishigami A, Yamasoba T :Effect of vitamin C depletion on age-related
hearing loss in SMP30/GNL knockout mice.
Biochem Biophys Res Commun. 390: 394-820,
2009
20. Kanaya K, Ushio M, Kondo K, Hagisawa M,
Suzukawa K, Yamaguchi T, Tojima H, Suzuki M,
Yamasoba T Recovery of facial movement andfacial synkinesis in Bell's palsy patients Otol
Neurotol 30 :640-4,2009
21. Kobayashi K, Nakao K, Yoshida M, Ando M,
Ebihara Y, Asakage T, Yamasoba T. Recurrent
cancer of the parotid gland: how well does
salvage surgery work for locoregional failure?
ORL 71:239-243,2009
22. Kondo K, Watanabe K, Sakamoto T, Suzukawa K,
Nibu K, Kaga K, Yamasoba T. Distribution andseverity of spontaneous lesions in theneuroepi-thelium and Bowman’s glands in mouseolfactory mucosa: age-related progression. Cell
Tissue Res 335:489-503,2009
23. Matsumoto, Y., Itaka, K., Yamasoba, T., Kataoka,
K. Intranuclear FRET analysis ofplasmid DNA
decondensation from non-viral gene carriers J
Gene Med 11 (7):615-23,2009

24. Nakamura N, Sasano N, Yamashita H, Igaki H,
Shiraishi K, Terahara A, Asakage T, Nakao K,
Ebihara Y, Ohtomo K, Nakagawa K. Oral
pilocarpine (5mg t.i.d.) used for xerostomia
causes adverse effects in Japanese. Auris Nasus
Larynx 36:310-3,2009
25. Nakanishi W,Fujishiro Y,Nishimura S, Fukaya T.
Clinical significance of (1-->3)-beta-d-glucan ina patient with invasive sino-orbital aspergillosis.
Auris Nasus Larynx 36:224-227,2009
26. Ohki M, Kitazawa H, Hiramatsu T, Kaga K,
Ki-tamura T, Yamada J, Nagao S Role of primate
cerebellar hemisphere in voluntary eye
movement control revealed by lesion effects. J
Neurophysiol 101 : 934-947, 200927. Sekimoto S, Tsunoda K, Kaga K, Makiyama K,
Tsunoda A, Kondo K, Yamasoba T.
Commercially available high-speed system forrecording and monitoring vocal fold vibrations.
Acta Otolaryngol 1291:524-6,2009
28. Someya S, Someya S, Xu J, Kondo K, Ding D,
Salvi RJ, Yamasoba T, Rabinovitch PS,
Weindruch R, Leeuwenburgh C, Tanokura M,
Prolla TA. Age-related hearing loss in C57BL/6J
mice
ismediatedbyBak-dependent
mitochondrial apoptosis. Proc Natl Acad Sci USA
106:19432-7, 2009
29. Takanami T, Ito K, Yamasoba T, Kaga K.
Comparison of Electroaudiometry with cochlear
im-plant in children with inner ear anomaly. Int J
Pediat Otorhinolaryng 73:153-8,2009
30. Takanami T, Kondo K, Asakage T. Facial
paralysis after superselective intra-arterial
chemotherapy via the middle meningeal artery inmaxillary cancer. Auris Nasus Larynx 36: 479-81,
2009
31. Tanaka K, Ichikawa T, Yano J. Acute otitis media
due to Haemophilus influenzae with antibiotic
resistance: experience of a tertiary hospital inTokyo city. Int J Pediatr Otorhinolaryngol. 73:
817-819,2009
32. Ushio M, Iwasaki S, Chihara Y, Kawahara N,
Morita A, Saito N, Murofushi T. Is the nerve
origin of the vestibular schwannoma correlatedwith vestibular evoked myogenic potential,
caloric test and auditory brainstem response?
Acta Otola-ryngol 26:1-6,2008

244

33. Ushio M, Iwasaki S, Murofushi T, Sugasawa K,
Chihara Y, Fujimoto C, Nakamura M, Yamaguchi
T, Yamasoba T. The diagnostic value ofvestibu-lar-evoked myogenic potential in patientswith vestibular schwannoma Clin Neurophysiol
120:1149-53,2009

245

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 150 patients corresponding about 15% of thewhole number of inpatients. We also see 15 people per
day at the outpatient rehabilitation setting. The
numerical ratio of outpatient is being reduced in orderto give priority to the clinical service corresponding toneeds expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on

246

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. Haga N, Karita T, Amao R, Kanamori Y, Takatori
Y: Successful ambulation by surgical conversion
in a complex form of epigastric heteropagus. J
Pediatr Orthop Part B, Published online: 9 July2009.
2. Iijima M, Haga N: Evaluation of nonnociceptive
sensation in patients with congenital insensitivity
to pain with anhidrosis. Childs Nerv Syst,
Published online: 16 December 2009.
3. Uematsu H, Sumitani M, Yozu A, Otake Y,
Shibata M, Mashimo T, Miyauchi S: Complex
regional pain syndrome (CRPS) impairs
visuospatial perception, whereas post-herpetic
neuralgia does not: Possible implications forsupraspinal mechanism of CRPS. Ann Acad Med
Singapore 38: 931-6, 2009.

Surgical Sciences
3. Vital Care Medicine

248

Department of Anesthesiology
Professor
Yoshitsugu Yamada, M.D., Ph.D.

Lecturer
Ryo Orii, M.D., Ph.D.

Kyung-Ho Chang, M.D., Ph.D. Takami Komatsu, M.D., Ph.D.

Nobuko Ito, M.D., Ph.D.

Instructor
Hiroshi Sekiyama, M.D., Makoto Ogawa, M.D.,

Yukako Suzuki, M.D.

Yuichiro Saito, M.D.,

Nobuhide Kin, M.D.,

Takayuki Kitamura, M.D.,

Kenichi Kishida, M.D.,

Toshiya Tomioka, M.D., Ph.D., Rui Sato, M.D.

Makoto Ogawa, M.D.,

Gaku Kawamura, M.D.,

Jun Ninagawa, M.D.,

Miho Asahara, M.D.,

Yoshie Suzuki, M.D.,

Junko Takarada, M.D.,

Kanji Uchida, M.D., Ph.D
Yoshiteru Mori, M.D.

Hiroko Tsujihara, M.D.,
Kanako Sato, M.D.,

Masahiko Sumitani,M.D.,PhD.,

Homepage http://www.h.u-tokyo.ac.jp/patient/depts/aprc_md.html/
http://www.anes.umin.ne.jp/
Introduction and Organization
The Department of Anesthesiology was establishedin 1952. Our department has residents, chief residents
besides the members above. We introduce theactivities about Teaching, Research and Clinical workof our department.

Clinical activities
Our clinical activities can be divided into two areas;
surgical anesthesia in the operating theater and a pain
clinic.
Anesthesia service including pre and post-operative
care is given every day for elective and emergency
surgery. We provide general anesthesia for various
kinds of surgeries including open heart surgery (adults
and pediatrics) and liver transplant, spinal/epidural
anesthesia and monitored anesthetic care for electroconvulsion therapy. Recently, the number of high risk

or geriatric patents is increasing. In addition, morethan 20% of the surgery (about 8000 cases in total peryear) spends more than eight hours. A new operating
theater opened in January 2007 and the demand forsufficient number of competent anesthesiologists isincreasing.
Pain clinic services are provided for out-patients(including patients in the ward of the otherdepartment) on a daily basis in all areas of painful
diseases. We also provide preoperative anesthetic
consult service for patients who have various medical
diseases. From April 2009 to April 2010, the numberof ambulatory patients was about ten thousand; six
hundred of those were newcomer patients. Currently
we have three beds in the ward. Annually, we provide
inpatient service for sixty patients in our ward as well
as for seven hundred and twenty patients in otherwards. Preoperative anesthetic consults were done forabout twelve hundred patients last year.

249

Teaching activities
We give lectures for fourth year medical students
and provide clinical education for fifth and sixth year
medical students on a man-to-man basis with ourfaculty staff members. The lectures of the last year
were the history of anesthesia and the preliminary
consideration, the mechanisms of anesthesia,
inhalational anesthesia, intravenous anesthesia andcirculation, the balance of body fluid, acid-basebalance, muscle relaxants, the management of thepatient during anesthesia, monitoring, resuscitation,
pain clinic and the physiology and the management ofpain.
The curriculum of bedside learning consists of threemajor contents: learning a practice of anesthetic
management for patients undergoing surgeries,
observing a practice of pain management for
outpatients suffering from intractable pain, andinteractive lectures on specific topics. During thepractice of anesthetic management, we teach students
technique of examinations and physiological- andpharmacological-knowledge which are essential forthe management of patients in the peri-operative
period. Through the practice of pain management, weteach students causes of intractable pain as well asprocedures of nerve block. We schedule 5 lectures
entitled “introduction to anesthesiology”, “airway
management”, “central venous catheterization”,“spinal anesthesia” and “pain clinic”. These 5 lectures
cover fundamental knowledge of basic procedures
which medical students should acquire. Moreover,students can experience procedures of tracheal
intubation, central venous catheterization and spinal
anesthesia using simulators. Each student is required
to prepare a case report of anesthetic management anda paper on anesthetics and cardiovascular drugs inperi-operative use. We discuss the contents of thereports and papers with students at the end of bedsidelearning, for further comprehension.

Research activities
We have seven research groups and their fields
include respiration, circulation, pain, immune systemand shock.
These are recent major subjects of our research.

1) A role of cytokine signaling in acute lung injury2) Evaluation of optimal ventilatory strategy for
respiratory failure3) Modification of immune system by anesthetics
4) Signal transduction pathway related to apoptosis
activated by sepsis or ischemia-reperfusion insult5) investigation of pathophysiology of shock6) A role of lipid mediators in organ damage
mediated by ischemia-reperfusion injury of amouse lower limb
7) A role of lipid mediators in the formation of
hyperalgesia
8) Antihyperalgesic and antipruritic effects of alpha2-adrenergic agonists
9) A role of spinal microglial cells in thedevelopmentof
inflammation-mediatedneuropathic pain10) spinal contribution for analgesic pathway11) Mechanism of Pruritoceptive and Neurogenic Itch
12) Dose-escalation of sublingual buprenorphine inpatients with chronic pain13) Analysis of electroencephalography during
general anesthesia
14) Invention and evaluation of a new airway device15) Clinical evaluation of neurological sequelae after
cardiac surgery16) Development and assessment of the system fortreating waste anesthetic gases: against global
warming

References(1) Minamishima S, Bougaki M, Sips PY, Yu JD,
Minamishima YA, Elrod JW, Lefer DJ, Bloch KD,
Ichinose F Hydrogen sulfide improves survival
after cardiac arrest and cardiopulmonary
resuscitation via a nitric oxide synthase
3-dependent mechanism in mice Circulation 2009,
120(10) 888-96(2) Kitamura T, Ogawa M, Yamada Y Individual andcombined effects of U50,488 and flurbiprofen
axetil on visceral pain in conscious rats
Anesthesia and Analgesia 2009,108, 1964-6(3) Kitamura T, Ogawa M, Kawamura G, Sato K,
Yamada Y Effects of sevoflurane and propofol on
glucose metabolism under aerobic condition in
fed rats Anesthesia and Analgesia 2009, 109,

250

1479-85(4) Kaneki M, Shinozaki S, Chang K, Shimizu N
Could insulin sensitization be used as analternative to intensive insulin therapy to improve
the survival of intensive care unit patients withstress-induced hyperglycemia? Crit Care Med
2009,37,2856-8.
(5) Sakagami T, Uchida K, Suzuki T, Carey BC,
Wood RE, Wert SE, Whitsett JA, Trapnell BC,
Luisetti M. Human GM-CSF autoantibodies andreproduction of pulmonary alveolar proteinosis.
New England Journal of Medicine 2009,361(27),2679-81(6) Trapnell BC, Carey BC, Uchida K, Suzuki T
Pulmonary alveolar proteinosis, a primary
immunodeficiencyof
impaired
GM-CSF
stimulation of macrophages. Current Opinion in
Immunology 2009,21(5),514-21(7) Han X, Uchida K, Jurickova I, Koch D, Willson T,
Samson C, Bonkowski E, Trauernicht A, Kim
MO, Tomer G, Dubinsky M, Plevy S, KugathsanS, Trapnell BC, Denson LA Granulocytemacrophagecolony-stimulating
factorautoantibodies in murine ileitis and progressive
ileal Crohn's disease. Gastroenterology 2009,136(4),1261-71(8) Uchida K, Nakata K, Suzuki T, Luisetti M,
Watanabe M, Koch DE, Stevens CA, Beck DC,
Denson LA, Carey BC, Keicho N, Krischer JP,
YamadaY,
TrapnellBC
Granulocyte/
macrophage-colony-stimulating
factorautoantibodies and myeloid cell immune
functions in healthy subjects. Blood 2009,113(11),2547-56

251

Department of Emergency andCritical Care Medicine
Professor
Naoki Yahagi, M.D.

Lecturer
Yukio Tanaka, M.D., Ph.D.

Associate
Takeshi Ishii, M.D.,
M.D.,

Kyoko Komatsu, M.D.,

Daisuke Yamaguchi, M.D.,

Jiro Ando,

Masataka Gunshin, M.D., Yumiko Hosoya, M.D., Takehiro Matsubara, M.D.

Kouji Takamure, M.D., Kensuke Nakamura, M.D., Takahiro Hiruma, M.D., Rei Ito, M.D.,

Staff
Hidenobu Fujita, M.D., Yasuyuki Jujyo, M.D., Yuko Maekawa, 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.

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

252

emergency care on 24-hour-a-day basis. In the 2004,
we had about 6,000 ambulance patients out of total
17,000 ER outpatients.
The new ER, four times the size of the present
ER was built in November, 2006. The facility has 5
consultation rooms, 4 specialized consultation
rooms
for
dentistry,
ophthalmology,
otorhinolaryngology
andgynecology,2
resuscitation bays, 1 operating room and 4
observation beds.
2) Intensive care
Staff members specialized in internal medicine,cardiovascular medicine, orthopedic surgery,
surgery, neurosurgery or anesthesiology create “thesemi-closed ICU” model. We are responsible for theentire care of the critically ill patients (i.e. patientswith respiratory insufficiency such as ARDS, withsepsis, with MOF, with shock), post-operative
patients, and tertiary emergency patients, placing anemphasis on evidence-based medical therapy. We
had 1,000 ICU/CCU patients in the 2007. In 2007,
the number of beds in ICU/CCU increased to 16
and the facility included the 24 beds for the highcare ICU2.
3) Bed management
The objective of bed management services is toprovide a timely and appropriate bed allocation for
all the patients. In our hospital, patients areallocated to three types of wards, that is, generalward, ICU2 and ICU/CCU in accordance with theircritical condition. The ICU2 undertakes the leading
bed management in the hospital to ensure maximum
performance as an acute hospital.
4) Risk management
It is split into two categories – in-hospital andout-hospital disasters. In regard to in-hospital risk
management, including “code blue emergency”, weare responsible for patient safety on 24-hour/365day basis. And in regard to out-hospital risk
management, our hospital has been authorized by
the Tokyo Metropolitan Government as a disasterbase hospital, and also the Government hasrequested the formation of Disaster Medical
Assistant Team (DMAT) from us. We are now

proceeding with a drastic revision of in-hospitalmanual for disaster control, holding seminars on
disaster medicine, and enforcing the disastertraining. We have oxygen and medical suction
equipment on the passageways in the new ER since2006 fiscal year in case treating the large number ofdisaster patients.

Teaching activities
1) Six hours of lecture for the 2nd year medical
student, the topics include the prehospitalemergency care, the initial evaluation of emergency
patients, disaster medicine, serious infections
disease, and medical equipment. Four hours ofsimulation training of Basic Life Support.
2) One month of clinical clerkship and 1 week of
bed-side training for the 3rd year. ACLS Basiccourse (ICLS) is held for the participants in theclinical clerkship program, and successful
completion of this course will enable students to be
ICLS certified.
3) Clinical integrated lecture for the 4th year students
includes diagnosis and treatment of serious patientsusing case studies of shock, conscious disorder,
trauma, intoxication, infections disease, burns,
hypothermia, and convulsion. After learning a
ACLS course, students experience the real practiceof emergency medicine as fellow passengers in theambulance and as 2.5-day trainees in affiliatedhospitals’ emergency centers.
In conformity with the guideline by Ministry of
Health, Labour and Welfare, all residents learn andpractice emergency medicine and primary care at
every level, primary, secondary and tertiary. The
residents are trained in the ACLS Basic (ICLS)
during resident year to obtain the knowledge andskills in CPR.
Junior residents are also assigned to ICU services
to gain the knowledge of intensive care from
pathophysiological and internal medicine’s point ofview.
In the senior resident program in 2006, we willtrain the new residents to be skilled in advanced
critical care medicine including primary caretrauma, MOF, shock, and equipment support.
As medical aspects of disaster management, we253

provide the residents with lectures based on
MIMMS (Major Incident Medical Management andSupport) program, triage training, and risk
communication techniques using wireless network.
In addition, we produce the seminar for nurses suchas medical support in the big earthquake.

Research activities
The on-going researches include “the Vital Care
Network System” which manages the great number ofhigh-risk people continually, electrolyzed water,elucidation of peripheral neural regulation of heart,and brain resuscitation. In collaboration with
Department of Pharmacy, Department of ClinicalLaboratory Medicine, Department of Infectious
Diseases, we focus on several clinical research on
issues including intra-nuclear transcription of β-Dglucan in blood products .

References
1)

2)

3)

4)

5)

Sakai K, Sanada H, Matsui N, Nakagami G,
Su-gama J, Komiyama C, Yahagi N.
Continuous monitoring of interface pressure
distribution in intensive care patients for pressure
ulcer prevention. J Adv Nur 65, 809-17, 2009
Kitsuta Y, Suzuki N, Sugiyama M, Yamamoto
Changes is consciousness level and association
with hyperglycemia as tool for predicting andpreventing re-bleeding after spontaneous
subarrachnoid hemorrhage Pre-hospital anddisaster medicine, 2006; 21(3), 190-195.
Toru Sasaki, Sayaka Toriumi, Takahiro Asakage,
Kimitaka Kaga, Daisuke Yamaguchi, Naoki
YahagiThe Toothbrush; A Rare but Potentially Life
Threatening Cause of Penetrating
Pediatrics 2006(118), 1284-1286
Kobayashi K, Ikeda H, Higuchi R, Nozaki M,
Yamamoto Y, Urabe M, Shimazaki S, Sugamata
N, Aikawa N, Ninomiya N, Sakurai H, Hamabe Y,
Yahagi N, Nakazawa H.
Epidemiological and outcome characteristics ofmajor burns in Tokyo. Burns 2005; 31S: S3-11.
Hale SI, Kloner RA, Katada S, Obayashi T, Ishii
T, Nakajima S, Yahagi N.

Myocardical ischemia and infarction. In
Tisherman SA and Sterz F, editors. Therapeutic
Hypothermia. New York: Springer; 2005. pp191209.

Health Sciences and ursing
1. Health Sciences

255

Department of Health Sociology/ Health Sociology and Health
Education
Associate Professor
Yoshihiko Yamazaki, Ph.D.(Dr.Hlth.Sc.)

Homepage

http://www.hlthsoc.m.u-tokyo.ac.jp/indexj.htm/

Introduction and Organization
The Department of Health Sociology is one of thetwo departments which ex-Department of HealthSociology was devided into in 1997, when mostdepartments in the University of Tokyo werereorganized into the Graduate School of the
University of Tokyo. The department of HealthSociology is one of sixteen departments in the
Graduate School of Health Sciences and Nursing. In
2007, Master Course only in the Division of Health
Sciences was reorganized into the newly establishedschool, the Graduate School of Public Health. The
department where the master course students in the
Department of Health Sociology get affiliated isnamed as the Department of Health Sociology and
Health Education. The department consists of one
Associate Professor (Chair of Health Sociology /Health Sociology and Health Education), 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.
In Undergraduate Courses, School of Health
Sciences and Nursing, our department is in charge of

256

the 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, especiallyamong the middle-aged, in Japan. Anotherpurpose of this project is to consider possible

6.

7.

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.

3.

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)
Taisuke Togari, Yoshihiko Yamazaki: How to Use
Sense of Coherence Scales: Versions, Items,

257

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 ventilator-

dependent amyotrophic lateral sclerosis patientsin Japan: A study of trajectories and correlatesof psychological well-being, Jpn J Human
Ecology 2009.75(3):79-89,

258

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, 16 doctoral course
students, 5 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 2009.
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,

259

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.

8.

9.

10.

References (Jan.-Dec., 2009)
1.

2.

3.

4.

5.

6.

7.

Akiyama T, Tsuchiya M. Study on pathologicalmechanisms of temporal lobe epilepsy andpsychosis through kindling effect. Asian J
Psychiat. 2009;2(1):37-9.
Chen J, Tsuchiya M, Kawakami N, Furukawa TA.
Non-fearful vs. fearful panic attacks: a general
population study from the national comorbidity
survey. J Affect Disord. 2009;112(1-3):273-8.
Hirokawa K, Ochiai H, Ooi N, Kawakami N.
Relationships between serum estradiol, folliclestimulating hormone concentrations, and genderrelated identity: A study of perimenopausal
women. Pers Indiv Differ. 2009;46: 744-7.
Inoue A, Kawakami N, Ishizaki M, Tabata M,
Tsuchiya M, Akiyama M,et al. Three job stressmodels/concepts and oxidative DNA damage in asample of workers in Japan. J Psychosom Res.
2009;66:329-34.
Inoue A, Kawakami N, Tsutsumi A, Shimazu A,
Tsuchiya M, Ishizaki M, et al. Reliability andvalidity of the Japanese version of theOrganizational Justice Questionnaire. J Occup
Health. 2009;51:74-83.
Kawakami N, Kobasyashi Y, Hashimoto H,
editors. Health and social disparity in Japan:
Japan and Beyond. Melbourne: Trans Pacific
Press; 2009.
Kinoshita Y, Tsuchiya M, Kawakami N,

11.

12.

13.

14.

15.

16.

Furukawa TA, Kingdon D. Hallucinations invisually impaired individuals: an analysis of the
National Comorbidity Survey Replication. Soc
Psychiatry Psychiatr Epidemiol. 2009 Feb;44(2):104-8.
Lee S, Tsang A, Breslau J, Aguilar-Gaxiola S,
Angermeyer M, Borges G, et al. An
Epidemiological Study of Mental Disorders andTermination of Education in Developed andDeveloping Countries. Brit J Psychiat (in press).
Oishi J, Doi H, Kawakami N. Nutrition anddepressive symptoms in community-dwellingelderly persons in Japan. Acta Med Okayama.
2009; 63(1):9-17.
Saito M, Iwata N, Kawakami N, Matsuyama Y,
World Mental Health Japan 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. Int J Method Psych (in press).
Schaufeli WB, Shimazu A, Taris TW. Being
driven to work excessively hard: The evaluationof a two-factor measure of workaholism in The
Netherlands and Japan. Cross-Cult Res. 2009;43:
320-48.
Shimazu A, Bakker AB, Demerouti E. How job
demands affect the intimate partner: A test of thespillover-crossover model in Japan. J Occup
Health. 2009;51:239-48.
Shimazu A, Miyanaka D, Schaufeli WB. Work
engagement from a cultural perspective. In:
Albrecht S, editor. The handbook of employee
engagement: Models, measures and practice.
Cheltenham (UK): Edward-Elgar Publishing
House (in press).
Shimazu A, Schaufeli WB. Is workaholism goodor bad for employee well-being? The
distinctiveness of workaholism and work
engagement among Japanese employees. Ind
Health. 2009;47:495-502.
Shimazu A, Schaufeli WB. Towards a positive
occupational health psychology: The case ofwork engagement. Jpn J Stress Sci. 2009;24:
181-7.
Tominaga M, Kawakami N, Ono Y, Nakane Y,
Nakamura Y, Tachimori H, et al. Prevalence andcorrelates of illicit and non-medical use of

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17.

18.

19.

20.

21.

psychotropic drugs in Japan: Findings from theWorld Mental Health Japan Survey 2002-2004.
Soc Psych Psych Epid 2009;44:777-83.
Tsuchiya M., Kawakami N., Ono Y., Nakane Y.,
Nakamura Y., Tachimori H., et al. Lifetime
comorbidities between phobic disorders andmajor depression in Japan: Results from theWorld Mental Health Japan 2002- 2004 Survey.
Depress Anxiety. 2009;26(10):949-55.
Tsuno K, Kawakami N, Inoue A, Ishizaki M,
Tabata M, Tsuchiya M, et al. Intragroup andintergroup conflict at work, psychologicaldistress, and work engagement in a sample ofemployees in Japan. Ind Health. 2009;47:640-8.
Tsutsumi A, Nagami M, Yoshikawa T, Kogi K,
Kawakami N. Participatory intervention forworkplace improvements on mental health andjob performance among blue-collar workers: A
cluster randomized controlled trial. J Occup
Environ Med. 2009. [Epub ahead of print]
Tsutsumi A, Iwata N, Watanabe N, de Jonge J,
Pikhart H, Fernandez-Lopez JA, et al.
Application of item response theory to achievecross-cultural comparability of occupational
stress measurement. Int J Method Psych. 2009;18(1):58-67.
Umanodan R, Kobayashi Y, Nakamura M,
Kitaoka-Higashiguchi K, Kawakami N, Shimazu
A. Effects of a worksite stress management
training program with six short-hour sessions: A
controlled trial among Japanese employees. J
Occup Health. 2009;51(4):294-302.

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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)2625) 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’

References
1) Okada K, Ohashi Y, Matsuo F, Uno S, Soh M,
Nishima S. Effectiveness of an acellular pertussis
vaccine in Japanese children during a non-epidemic
period: a matched case-control study. Epidemiology
and Infection. 2009;137(1):124-30.
2) Miura K, Nakagawa H, Ohashi Y, Harada A, Taguri
M, Kushiro T, Takahashi A, Nishinaga M, Soejima H,
Ueshima H; Japan Arteriosclerosis Longitudinal Study(JALS) Group. Four blood pressure indexes and therisk of stroke and myocardial infarction in Japanese
men and women: a meta-analysis of 16 cohort studies.
Circulation. 2009;119(14):1892-8.
3) Kodama S, Saito K, Tanaka S, Maki M, Yachi Y,
Asumi M, Sugawara A, Totsuka K, Shimano H,
Ohashi Y, Yamada N, Sone H. Cardiorespiratory
fitness as a quantitative predictor of all-cause
mortality and cardiovascular events in healthy men
and women: a meta-analysis. The Journal of theAmerican Medocal Association. 2009;301(19):202435.
4) Kodama S, Saito K, Tanaka S, Maki M, Yachi Y,
Sato M, Sugawara A, Totsuka K, Shimano H, Ohashi
Y, Yamada N, Sone H. Influence of fat andcarbohydrate proportions on the metabolic profile inpatients with type 2 diabetes: a meta-analysis.
Diabetes Care. 2009;32(5):959-65.
5) Kondo-Endo K, Ohashi Y, Nakagawa H,
Katsunuma T, Ohya Y, Kamibeppu K, Masuko I.
Development and validation of a questionnairemeasuring quality of life in primary caregivers ofchildren with atopic dermatitis (QPCAD). British
Journal of Dermatology. 2009;161(3):617-25.
6) Hagino H, Nishizawa Y, Sone T, Morii H, Taketani
Y, Nakamura T, Itabashi A, Mizunuma H, Ohashi Y,
Shiraki M, Minamide T, Matsumoto T. A
double-blinded head-to-head trial of minodronate andalendronate in women with postmenopausal
osteoporosis. Bone. 2009 ;44(6):1078-84.
7) Matsumoto T, Hagino H, Shiraki M, Fukunaga M,
Nakano T, Takaoka K, Morii H, Ohashi Y, Nakamura
T. Effect of daily oral minodronate on vertebral
fractures in Japanese postmenopausal women withestablishedosteoporosis:arandomized
placebo-controlled double-blind study. Osteoporos
International. 2009 ;20(8):1429-37.
8) Ueda K, Nitta H, Ono M, Takeuchi A. Estimatingmortality effects of fine particulate matter in Japan: acomparison of time-series and case-crossover analyses.
Journal of The Air and Waste Management

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Association. 2009 ;59(10):1212-8.
9) Shimozuma K, Ohashi Y, Takeuchi A, Aranishi T,
Morita S, Kuroi K, Ohsumi S, Makino H, Mukai H,
Katsumata N, Sunada Y, Watanabe T, Hausheer FH.
Feasibility and validity of the Patient Neurotoxicity
Questionnaire during taxane chemotherapy in a phase
III randomized trial in patients with breast cancer:
N-SAS BC 02. Supportive Care in Cancer. 2009;17(12):1483-91.
12) Watanabe T, Sano M, Takashima S, Kitaya T,
Tokuda Y, Yoshimoto M, Kohno N, Nakagami K,
Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto
G, Ohashi Y. Oral uracil and tegafur compared withclassic cyclophosphamide, methotrexate, fluorouracil
as postoperative chemotherapy in patients with
node-negative, high-risk breast cancer: National
Surgical Adjuvant Study for Breast Cancer 01 Trial.
Journal of Clinical Oncology. 2009 ;27(9):1368-74.
13) Kozu T, Iinuma G, Ohashi Y, Saito Y, Akasu T,
Saito D, Alexander DB, Iigo M, Kakizoe T, Tsuda H.
Effect of orally administered bovine lactoferrin on thegrowth of adenomatous colorectal polyps in arandomized, placebo-controlled clinical trial. Cancer
Prevention Research. 2009 ;2(11):975-83.
14) Yasunaga H, Matsuyama Y, Ohe K; Japan SurgicalSociety. Effects of hospital and surgeon volumes on
operating times, postoperative complications, andlength of stay following laparoscopic colectomy.
Surgery Today 2009; 39(11): 955-961.
15) Ueno H, Kosuge T, Matsuyama Y, Yamamoto J,
Nakao A, Egawa S, Doi R,Monden M, Hatori T,
Tanaka M, Shimada M, Kanemitsu K. A randomized
phase III trial comparing gemcitabine with surgeryonly in patients with resected pancreatic cancer:
Japanese Study Group of Adjuvant Therapy for
Pancreatic Cancer. British Journal of Cancer 2009;
101: 908-915.
16)Yasunaga H, Nishii O, Hirai Y, Ochiai K,
Matsuyama Y, and Ohe K. Impact of surgeon andhospital volumes on short-term postoperativecomplications after radical hysterectomy for cervicalcancer. The Journal of Obstetrics and Gynaecology
Research 2009; 35: 699-705.
17) Yamamoto K, Imamura H, Matsuyama Y,
Hasegawa K, Beck Y, Sugawara Y, Makuuchi M and
Kokudo N. Significance of alpha-fetoprotein anddes-gamma-carboxy prothrombin in patients with
hepatocellular carcinoma undergoing hepatectomy.
Annals of Surgical Oncology 2009; 16: 2795-2804.
18) Yasunaga H, Matsuyama Y, Ohe K; Japan SurgicalSociety. Volume-outcome relationship in rectal cancer
surgery: a new perspective. Surgery Today 2009;39(8): 663-668.
19) Yasunaga H, Matsuyama Y, Ohe K; Japan SurgicalSociety. Effects of hospital and surgeon case-volumes
on postoperative complications and length of stayafter esophagectomy in Japan. Surgery Today 2009;39(7): 566-571.
20) Yasunaga H, Tsuchiya K, Matsuyama Y, Ohe K.
Analysis of factors affecting operating time,
postoperative complications, and length of stay for
total knee arthroplasty: nationwide web-based survey.
Journal of Orthopaedic Science 2009; 14(1): 10-16.
21) Kurita M, Ichioka S, Tanaka Y et al. Validity oforthopedic system for theassessment of
postoperative mortality in patients with pressure
ulcers. Wound Repair and Regeneration 2009;17:
312-7.
22) Kurahashi I., Nakagawa K., Nishio K., Ito Y. andOhashi Y. An algorithm of prediction for primary site.
Molecular Target Therapy of Cancer. 2009.7(3).14-9
23) Yasunaga H, Tsuchiya K, Matsuyama Y, Ohe K.
High-volume surgeons in regard to reductions inoperating time, blood loss, and postoperativecomplications for total hip arthroplasty. Journal of
Orthopaedic Science 2009; 14(1): 3-9.

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Department of Biomedical
Ethics & Department of
Health Promotion Sciences
Professor
Akira Akabayashi, M.D., Ph.D.

Associate Professor
Jung Su Lee, Ph.D.

Lecturer
Satoshi Kodama, Ph.D.

Research Associate
Misao Fujita, MPH, Ph.D.

Homepage

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

Introduction and Organization
The former Department of Health Administration
was established in 1967 and Dr. Tsuneo Tanaka
became its first professor in 1974. He devoted himself
to the development of the community health caresystem in Japan and published numerous papers
concerning the social theory of health administrationand data management systems for community healthcare. He also contributed to the establishment of the
School of Health Sciences. In 1985, Dr. Atsuaki Gunji
became the second professor of the department.
During Dr. Gunji’s tenure, two major research projects
were undertaken. One was “The effects of physicalactivity and inactivity on health.” From 1990, a20-day bed rest human experimental study was
conducted every year in the context of an international
cooperative research project that was supported bygovernment grants. The other project concerned healthcare systems, especially health care economics and thequality of hospital care.
In 1996, the Department of Health Administration
developed into two departments: the Department of

Health Economics and the Department of Health
Promotion Sciences. Both were established as
departments of the Graduate School of Medicine. In
1998, Dr. Yasuki Kobayashi became the professor of
the Department of Health Economics. He conducted
research into health care delivery systems in Japan. In
2001, he moved to the Department of Public Health.
From 1996 to 2002, Dr. Kiyoshi Kawakubo tookcharge of the Department of Health Promotion
Sciences as the associate professor.
In June 2002, Dr. Akira Akabayashi became
professor of the Department of Health Economics.
Professor Akabayashi’s area of research is biomedical
ethics. In April 2003, the Department of Health
Economics was restructured and named theDepartment of Biomedical Ethics. From 2007, Dr. Lee
became the associate professor and took charge of the
Department of Health Promotion Sciences.
Staff members of the two departments include a
professor, an associate professor, a lecturer, anassociate, and a technical specialist. All five members,
a total of thirteen lecturers from other organizations,and seven visiting researchers contribute to265

department teaching and research activities.
Department graduate students included four masterprogram students and two 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, eleven master theses,
and six doctoral dissertations were completed between
April 2004 and March 2010. 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
Department of Health Promotion Sciences
The main research activity of the Department of
Health Promotion Sciences is making health policy

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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.

Akabayashi A. Eyes Wide Open: Blinded Views
on Ethnic Identity. Asian Bioethics Review 2009;
1(1):65-66.

2.

Akabayashi A. Bioethics in Japan (1980-2009):
Importation, Development, and the Future. Asian
Bioethics Review 2009; 1(3):267-278.

3.

Kashihara H, Lee JS, Kawakubo K, Tamura M,
Akabayashi A. Criteria of waist circumference
according to CT-measured visceral fat area andthe clustering of cardiovascular risk factors. Cir J
2009; 73(10):1881-1886.

4.

Kondo K, Lee JS, Kawakubo K, Kataoka Y,

Asami Y, Mori K, Umezaki M, Yamauchi T,
Takagi H, Sunagawa H, Akabayashi A.
Association between daily physical activity andneighborhood environments. Environ Health Prev
Med 2009; 14(3):196-206.
5.

Nagai H, Nukaga Y, Saeki K, Akabayashi A.
Self-regulation of recombinant DNA technology
in Japan in the 1970s. Historia Scientiarum 2009;
19:1-18.

6.

Nakade M, Lee JS, Kawakubo K, Kondo K, MoriK, and Akabayashi A. Changes in food intake
patterns associated with body weight loss during
a 12 week health promotion program and a
9-month follow-up period in a Japanese
population. Obesity Research and Clinical
Practice 2009; 3:85-98.

7.

You KS, Lee HO, Fitzpatrick JJ, Kim SS, Marui
E, Lee JS. Spirituality, Depression, Live Alone,and Perceived Health among Korean Elders in
the Community. Archives of Psychiatric Nursing
2009; 23(4):309-322.

Health Sciences and ursing
2. Preventive and Administrative ursing

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Department ofursing Administration /Advanced Clinical ursing
Professor
Katsuya Kanda, Ph.D., R.N.

Assistant Professor
Mami Onishi, M.S.N., R.N., Ayako Nagata, M.A., R.N.,
Shigeko Yoshida, 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.

care delivery systems. Discussions include concepts
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.
ursing 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.

Teaching activities

Advanced Clinical ursing 1 (2 credits, Lectures)

Graduate courses

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

Prof. Kanda and Affiliatesursing 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269

clinical nursing.

integrity, and 3) health promotion and maintenance.

Advanced Clinical ursing 2(2 credits, Lectures and practicum)

Clinical Practicum in Fundamental ursing(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.
ursing 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.
ursing Administration Practicum(1 credit, practicum)

Fundamental ursing 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 ursing 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 ursing 3(4 credits, Lectures and laboratory practicum)

Issues of ursing 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 andProf. 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

270

strategies to meet the professional demands.
Quality Improvement, Safety Issues, and Risk
Management in ursing
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.
ursing 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 ursing 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. Sakaki H, Nishioka M, Kanda K, Takahashi Y. An
investigation of the risk factors for infection withmethicillin-resistant
Staphylococcus
aureusamong patients in a neonatal intensive care unit.
American Journal of Infection Control 2009;37(7): 580-586.
2. Takemura Y, Kanda K. Continuous knowing ofpatients: The Japanese nursing perspective. In:
Locsin RC, Purnell M, editors. A contemporary
nursing process: the (un) bearable weight ofknowing in nursing.
New York: Springer
Publishing; 2009. pp. 463- 479.
3. Mashimo A, Ozawa M, Inoue S, Kanda K.
Nursing administrators’ competency which
demonstrated in order to correspond to thebusiness environment change that depends on the
PFI introduction. Journal of Japan Academy of
Nursing Administration and Policies. 2009; 13(2):31-40. (in Japanese)
4. Nonaka R, Takemura Y, Sasaki M, Kanda K.
Relationship between staff nurses’ perceptions ofleadership of nurse managers and motivation forworking: Focusing on transformational leadership.
Journal of Japan Academy of Nursing
Administration and Policies. 2009; 13(2): 66-72.
(in Japanese)
5. Takeuchi T, Onishi M, Kanda K. Patients’
expectations for nurses and nursing: A review ofthe literature. Journal of Japan Academy of
Nursing Administration and Policies. 2009; 13(2):81-88. (in Japanese)
6. Ozawa M, Kanda K. A literature review on
neonate’s brain activity for sensory experience.
Journal of Japan Academy of Neonatal Nursing
2009; 15(1): 2-9. (in Japanese)
7. Kanda K. Horizon of nursing evaluation. Journalof Japan Academy of Nursing Administration and
Policies. 2009; 12(2): 5-11. (in Japanese)
8. Nishioka M, Mori N, Sakaki H, Fujita R, Numa N,
Hiramatsu T, Morikane K. Healthcare associatedinfection surveillance and hospital size in Japan:
Review. Journal of Nursing Studies National
College of Nursing, Japan. 2009; 8(1):10-19. (inJapanese)
9. Kanda K. Effectiveness of nursing to improve
quality of healthcare: Quality indicators forbenchmarking. EB NURSING 2009; 10(1): 71-73.
(in Japanese)
10. Matsumoto A, Ishii H, Tsukazaki K, Kanda K.
Implementation of the new health checkup service
and health consultation by nurses in Japan. 1st
International Congress in Nursing Research
Education and Practice, O033; 2009 Oct 15-17.
11. Onishi M, Kanda K. The organizational role

271

performance of nurse specialists in Japan. 1st
International Congress in Nursing Research
Education and Practice, O037; 2009 Oct 15-17.
12. Ozawa M, Sasaki M, Kanda K. Slowly increasingillumination of a procedural lamp by a dimmer
switch prevents hypoxia in preterm infants. The
12th East Asian Forum of Nursing Scholars,
P-2-32; 2009 Mar 13-14.

272

Department of Family ursing
Professor
Associate Professor
Kiyoko Kamibeppu, R.N., P.H.N., Ph.D.

Lecturer
Akemi Yamazaki, R.N., R.M., P.H.N., Ph.D.

Research Associate
Shiho Murayama, R.N., R.M., M.S.
Kafumi Sugishita, R.N., R.M., M.H.S.
Hiroe Yamamoto, R.N., R.M., M.S.

Homepage

http://park.itc.u-tokyo.ac.jp/fn/

Introduction and Organization
This Department was established in 1992. The
Japanese Association for Research in Family Nursing
was founded by this department in 1994. Currently, it
has five faculty members: an associate professor, alecturer two research associates and a technicalspecialist. Also it has eleven doctoral students, fivemaster’s course students, and fourteen visiting
scholars.

Education
1. Graduate Courses, School of Integrated Health
Sciences
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 Health
Sciences and Nursing
Family Nursing
Pathophysiologic Immunology
3. Undergraduate Courses of Nursing, School of

Health Sciences and Nursing
Pediatric Nursing
Clinical Practicum in Pediatric Nursing
4. Undergraduate Courses of Midwifery, School of
Health Sciences and Nursing
Midwifery III
Clinical Practicum in Midwifery

Research
Topics of our current research projects are as follows:
1. Studies of Post Traumatic Stress Disorder (PTSD)
and other late complication among persons who
experienced childhood cancer
2. Studies of perinatal mental health and childrearing
support
3. Childrearing and self care of persons with mental
disorders
4. The development of an instrument measuring thequality of life for children
5. Qualitative research to explore childbearing
family formation process
6. A study of mourning work in the family bereaved
children
7. Psychosocial factors related to symptom
management of children with cancer

273

8. Families/siblings of children with chronic illness

Publications(1) Kamibeppu K, Sato I, Honda M, Ozono S,
Sakamoto N, Iwai T,Okamura J, Asami K, Maeda
N, Inada H, Kakee N, Horibe K, Ishida Y. Mental
health among young adult survivors of childhood
cancer and their siblings including posttraumatic
growth. Journal of Cancer Survivorship:
Research and Practice. 2010; [Epub ahead ofprint].
(2) Yonemoto T, Kamibeppu K, Ishii T, Iwata S,
Hagiwara Y, Tatezaki S. Psychosocial outcomesin
long-term
survivorsofhigh-grade
Osteosarcoma:
A
Japanese
single-center
experience. Anticancer Research. 2009; 29(10):4287-4290.
(3) Kobayashi K, Kamibeppu K. Measuring qualityof life in Japanese children: Development of theJapanese version of PedsQLTM. Pediatrics
International. 2010; 52(1):80-88.
(4) 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)(5) Ishida Y, Honda M, Kamibeppu K, et al.
Cross-sectional Survey on the Late Effects and
QOL of Childhood Cancer Survivors Part 1:
Research Methods and Subjects. Journal of theJapan Pediatric Society. 2010; 114(4): 665-675.
(in Japanese)(6) 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)(7) Kurihara K, Sugishita K, Ikeda M, Yamazaki A,
Furuta M, Yamamoto H, Otsuka H, Kamibeppu
K. Development of childrearing support system
for 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)274

Department ofCommunity Health ursing /Public Health ursing
Professor
Sachiyo Murashima, D.H.S., R.N., P.H.N.

Lecturer
Satoko Nagata, D.H.S., R.N., P.H.N.

Research Associate
Atsuko Taguchi, M.H.S., R.N., P.H.N.
Azusa Arimoto, D.H.S., R.N., P.H.N.

Homepage http://park.itc.u-tokyo.ac.jp/chn/
Introduction and 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 (16 in master course, 8 indoctoral course) in the department. Also, we accept
many visiting researchers from other colleges andinstitutions.

Teaching activities
1. Undergraduate program, in the School of Health
Sciences and Nursing
1) Community Health Nursing (4 credits, lectures)
Community health nursing is a study to develop
the caring techniques and the method 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.
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 theirsupport 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 around-276

the-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.
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, making guidelines
for multisectoral and interagency cooperation amongnurses by investigation of actual situation.
5. Support for families with babies and children
We are conducting researches covering two fields,
community health and occupational health. The
former researches are aimed to prevent and reduce
anxieties 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
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) Classificationof unplanned readmission processes among the elderly
patients in internal medical wards, 2) Condition,
reason of admission and succession of residents at
geriatric medical care facility for the elderly, 3)Classificationof would-be homebound amongcommunity-dwelling elderly in urban area, 4)
Psychological experience of the mother who delivered
to Down syndrome child and 5) Acceptance todiseases and experiences in hospitalization fortuberculosis patients.

References
1. Murayama H, Taguchi A, Murashima S. The Relationships between Feelings of Satisfaction and
Burden with Respect to Activity and Social Support among Health Promotion Volunteers in Japan.
Health Education & Behavior, 37(2), 275-287,
2009
2. Haruna M, Yeo S, Watanabe E, Matsuzaki M, Ota
E, Nakayama K, Murashima S. Perceptions of
women and health-care providers in Tokyo of appropriate weight gain during pregnancy. Nursingand Health Sciences, 12(1), 21-26, 2010
3. Nakayama K, Haruna M, Matsuzaki M, Sekine K,
Murashima S. Changes in 13, 14-dihydro-15- keto-prostaglandin F2α(PGFM) levels in saliva during pregnancy, labor and the postpartum period.
The Journal of Obstetrics and Gynaecology Research, 36(1), 27-33, 2010
4. Tsuzuki C, Murashima S. Activities of publichealth nurses during routine health check-ups for
18 month children in Japan. Japanese Journal of
Public Health 56(2), 111-120, 2009.
5. Naruse T, Arimoto A, Watai I, Murashima S. Fathers’ child-rearing behavior and influencing factors. Japanese Journal of Public Health 56(6),402-410, 2009.
6. Tomura H, Nagata S, Murashima S. Analysis of
Requirements for Discharge Planning from General Hospital Wards of Older Patients Requiring
Post-discharge Care at Home: Assessment of theResults of a Follow-up Study. Journal of Japan
Academy of Community Health Nursing 12(1),50-58, 2009.
7. Suzuki Y, Omori J, Sakai M, Anzai H, Kobayashi
M, Miyazaki T, Ozaki A, Hirano Y, Arimoto A, etal. “Partnership in Community Health Activities”
in Japan: Concept Analysis. Journal of Japan
Academy of Community Health Nursing 12(1),44-49, 2009.

277

8. Yoshida M, Haruna M, Ota E, Watanabe E, Uayan
MLT, Murashima S. Child-rearing difficulties andcoping behaviors of Filipino mothers in Japan.
Japanese Journal of Maternal Health, 50(2),422-430, 2009.

Health Sciences and ursing
3. Clinical ursing

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Department of Adult ursing /Palliative Care ursing
Professor
Keiko Kazuma, R.N., Dr.Hlth.Sci.

Lecturer
Mitsunori Miyashita, R.N., Dr.Hlth.Sci. ( - 2009.9.30)

Research Associate
Makoto Tanaka, R.N., Dr.Hlth.Sci.
Masakazu Nishigaki, R.N., Dr.Hlth.Sci.

Project Research Associate
Naomi Ito, R.N., Dr.Hlth.Sci.
Yasuko Oyagi, R.N., M.N.

Homepage http://www.adng.m.u-tokyo.ac.jp/
Introduction and Organization
The Department of Adult Nursing / Palliative Care
Nursing originated as the “Department of Adult
Health” in the School of Health Sciences (1965-1992),
later becoming the “Department of Adult Health andNursing” in the School of Health Sciences & Nursing(1992-).
From 1995 to 1997, the Graduate School of
Medicine shifted to a Graduate School chair system,and our two newest departments were established. The
members of these two departments cooperate ineducational and research projects.
Our department also takes charge of the Certified
Nurse Specialist course newly established in 2008.

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
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

Our department conducts research on adult nursing
from various points of view. One such perspective
focuses on the course of a disease, in which not only
the periods of recovery and terminal treatment but
also the upstream preventive steps, before disease
onset, are assessed with the chronic phase in the280center; therefore, such nursing comprises an extremely
wide range of periods of practice. We have been
conducting studies which are expected to allow us tounderstand the state of individuals who requirenursing in those periods, and investigations on
effective and efficient nursing care for suchindividuals.
Another theme regarding nursing systems is how
care should be provided for individuals in the mostappropriate ways. We have been investigating how
nursing should be provided, and the continuity ofnursing care in various settings, such as outpatient
clinics, at home, and in palliative care facilities, by
focusing on individuals before disease onset, in thechronic phase, in the recovery period, and in theterminal period. We consider that it is essential toeliminate and/or improve the difficulties nurses inthese settings must confront, since they are associatedwith the improvement of care; therefore, such issues
have also been investigated.
Furthermore, one of our research themes is thedevelopment of evaluation measures and scales, which
are required in such studies.
Herein, we describe our current research areas. You
may refer to our homepage for more information, suchas the details of our research achievements, and theacquisition of research funds. The resources that havebeen developed in our research, such as evaluation
scales, are freely available to the public via our
homepage.
1) Nursing for Patients with Chronic Illnesses
It is necessary for individuals with chronic illnesses
to conduct self-management for symptom control intheir daily lives. Nursing has the important role ofsupporting patients to maintain their lifestyle bycontinuing self-management in their daily life.
We have developed various instruments formeasuring the difficulties that patients with chronic
illnesses experience in their daily lives, and havedescribed actual situations of difficulties using these
instruments. Furthermore, we have conducted a study
regarding support for controlling symptoms in order toreduce such difficulties.
The summaries of these studies, including sometheses in preparation for publication, are briefly
described below.

Diabetes (DM): We have developed preventive
strategies for adult offspring of diabetes patients andconfirmed its effectiveness. Now we are planning toengage this strategy more widely, especially on thehealth testing system. Meanwhile we have beendeveloping diabetes diet / physical activity-related
QOL Scale.
Cardiovascular diseases: We have developed andvalidated Japanese version of the European Heart
Failure Self-Care Behavior scale and Coronary
revascularization
outcomequestionnaire,andinvestigated the factors associated with each outcomes
which were measured by them. Furthermore, afollow-up study, evaluating the influence of theself-care on the rehospitalization has been conducted.
We are on the process of developing a disease
management program aimed to facilitate patients’ self
management. We also conducted a study about adultcongenital heart disease.
Liver / pancreas diseases: To improve Quality ofLife (QOL) of patients with pancreatic or primaryliver cancer, we are starting the development ofJapanese version of the disease-specific QOL
questionnaires of EORTC designed for use in cancer
clinical trials internationally. After the development ofJapanese version, we will explore the factors relating
to their QOL. Furthermore, we are participatinginternational EORTC project developing hepatic cell
carcinoma Module (PhaseⅣ).
HIV/AIDS: We are on the process of researchwhich investigates structure and barriers of HIV/AIDS
related self care aimed to develop self care support
tool. Another research project is carried out about
hyperlipidemia and dietary behavior in HIV/AIDS
people with anti-viral-drug- therapy.
Chronic kidney disease (CKD): For people with
CKD, it is very important to practice preventive
behavior aiming to inhibit progressing their stage in
CKD. We developed CKD self care behavior scale andknowledge scales-Japanese version.
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

281

is also important in nursing. The University of Tokyo
Hospital is a medical facility that provides one of thehighest levels of treatment in living donor livertransplantation and bone marrow transplantation in theworld. Therefore, we have conducted the following
studies on cases at the hospital:
We have described the QOL of patients who
underwent adult living donor liver transplantation, andthe experiences of donors before and after
transplantation. In addition, we initiated a study
regarding difficulties in the chronic stage followingbone marrow transplantation and support for reducing
such difficulties.
We have also contributed to establish donor
coordination system in the hematopoietic stem celltransplantation (HSCT) thorough the project whichdevelops adult donor coordination guideline about
related HSCT.
Islet transplantation in patients with type 1 Diabetes
Mellitus is yet provided now for only few patients inJapan. We surveyed recognition for Islettransplantation, information recourse and desire, andrelated factors about them in patients with type 1
Diabetes Mellitus.
3) Nursing Care System for Outpatients
Recently, the role of nursing in hospital outpatientcare and home care has changed dramatically due tothe decrease in the duration of hospitalization, theincrease of chronic diseases, and the increase of theelderly population. In the field of adult nursing, we
focus on consultation and guidance in outpatient carein order to support self-management of chronic
diseases by nurses who are specialized in each diseasecategories. We have performed nation-wide surveys
which aim to clarify the effectiveness of nurse
specialist assignment, and have been conducting
educational activities regarding the promotion ofnursing activity in outpatient care.
4) Evaluation of Specialized Palliative Care andQuality Assurance
Palliative care services in Japan are primarily
provided by palliative care teams in general wards, inpalliative care units, and at home. We have conducted
research on methods for evaluating palliative careservices by focusing on various categories, such as

symptom control and communication. We areconducting a survey on the current status of palliative
care teams, and research regarding the evaluation.
5) Continuity of the Palliative Care System
End-stage cancer patients receive care in generalwards, palliative care units, and at home. We haveconducted a study on the preparation of a system fortransition in the care setting. Actual research goals
include the identification of preference in care settings
and related factors, and the factors that facilitate asmooth transition from general wards or palliative
units to the patient’s home.
6) Palliative Care at HomeA large number of patients wish to receiveend-stage care at home; however, many difficulties are
involved in the realization of such requests. Thus, it is
one of the most important problems in palliative carein Japan.
We have conducted a study regarding the actualcare provided at home based on a survey of patientsand their families, and a study that described andevaluated the experiences of bereaved families who
attended the home death. We also take part in the
project which aims to establish regional palliative caresystem.

Publications
1. Miyashita M, Arai K, Yamada Y, Owada M,
Sasahara T, Kawa M, Mukaiyama T. Discharge
from a palliative care unit: prevalence and related
factors from a retrospective study in Japan. J
Palliat Med. 2009; 12(2): 142-9.
2. Miyashita M, Morita T, Ichikawa T, Sato K,
Shima Y, Uchitomi Y. Quality indicators of
end-of-life cancer care from the bereaved family
members' perspective in Japan. J Pain Symptom
Manage. 2009; 37(6): 1019-26.
3. Miyashita M, Narita Y, Sakamoto A, Kawada N,
Akiyama M, Kayama M, Suzukamo Y, Fukuhara
S. Care burden and depression in caregivers
caring for patients with intractable neurologicaldiseases at home in Japan. J Neurol Sci. 2009;
276: 148-52.
4. Tanaka M, Iwao Y, Okamoto S, Ogata H, Hibi T,282

Kazuma K. Coping strategy when patients withquiescent Crohn's disease recognize that theirconditions are worsening. J Gastroenterol. 2009;44(11):1109-1112.
5. Tanaka M, Murakami Y, Fukushima T, Kazuma K.
Hypoglycemia-like symptoms after restorative
proctocolectomy for ulcerative colitis: A
preliminary study. Gastroenterol Nurs. 2009;32(5):352-9.
6. Nishigaki M, Kobayashi K, Kato N, Seki N,
Yokomura T, Yokoyama M, Kazuma K.
Preventive advice given by patients with type2
diabetes to their offspring. Br J Gen Pract.
2009;59:37-42.
7. Kato N, Kinugawa K, Ito N, Yao A, Watanabe M,
Imai Y, Takeda N, Hatano M, Kazuma K.
Adherence to self-care behavior and factors
related to this behavior among heart failure
outpatients in Japan. Heart Lung. 2009; 38(5):398-409.
8. Kato N, Kinugawa K, Yao A, Hatano M, Shiga T,
Kazuma K. Relationship of depressive symptoms
with hospitalization and death in Japanese patientswith heart failure. J Card Fail. 2009; 15(10):912-919.
9. Sato K, Miyashita M, Morita T, Suzuki M.
Long-term effect of a population-based
educational intervention focusing on end-of-life
homecare, life prolongation treatment, knowledge
about palliative care. J Palliat Care. 2009; 25(3):206-12.
10. Misawa T , Miyashita M , Kawa M , Abe K, Abe
M, Nakayama Y, Given CW. Validity andreliability of the Japanese version of the Caregiver
Reaction Assessment Scale (CRA-J) for
community-dwelling cancer patients. Am J Hosp
Palliat Med. 2009;26(5):334-40.
11. Nakazawa Y, Miyashita M, Morita T, Umeda M,
Oyagi Y, Ogasawara T. The palliative careknowledge test: reliability and validity ofaninstrument to measure palliative careknowledge among healthprofessionals. Palliat
Med. 2009 Dec;23(8):754-66.
12. Sanjo M, MoritaT, Miyashita M, Shiozaki M, Sato
K, Hirai K, Shima Y, Uchitomi Y. Caregiving
Consequence Inventory: A measure for evaluating
caregiving consequence from the bereaved family

member's perspective. Psychooncology.2009;18(6):657-66
13. Yamagishi A, Morita T, Miyashita M, Kimura F.
Symptom prevalence and longitudinal follow-up
in cancer outpatients receiving chemotherapy. J
Pain Symptom Manage. 2009;37(5):823-30.
14. Yamagishi A, Morita T, Miyashita M, Kimura F.
Artificial hydration therapy for terminally illcancer patients: a nurse education intervention
trial. J Pain Symptom Manage. 2009;38(3):358-64.
15. Morita T, Miyashita M, Tsuneto S, Sato K, ShimaY. Late Referrals toPalliative Care Units in Japan:
Nationwide Follow-up Survey and Effectsof
Palliative Care Team Involvement After theCancer Control Act. J PainSymptom Manage.
2009; 38(2): 191-6.
16. Fukahori H, Miyashita M, Morita T, Ichikawa T,
Akizuki N, Akiyama M,Shirahige Y, Eguchi K.
Administrators' Perspectives on End-of-Life
Carefor Cancer. Patients in Japanese Long-TermCare Facilities. Support CareCancer. 2009;17(10): 1247-54.
17. Kusajima E, Kawa M, Miyashita M, Kazuma K,
Okabe T. Prospective evaluation of transition to
specialized home palliative care in Japan.Am J
Hosp Palliat Med. 2009. 26(3): 172-9.
18. Okishiro N, Miyashita M, Tsuneto S, Shima Y.
The Japan HOspice and Palliative care Evaluation
study (J-HOPE study): views about legalization ofdeath with dignity and euthanasia among the
bereaved whose family member died at palliative
care units. Am J osp Palliat Med. 2009; 26;
98-104.
19. Morita T, Murata H, Kishi E, Miyashita M,
Yamaguchi T, Uchitomi Y. Meaninglessness interminally ill cancer patients: a randomized
controlled study. J Pain Symptom Manage. 2009;37(4): 649-58.

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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(4 in doctoral course), 1 research students and 2
visiting researchers.

Teaching activities
We teach graduate and undergraduate courses for
midwifery and maternal care, and women's health.
1. Graduate Courses, School of Health Sciences andNursing1) Advanced Midwifery and Women’s Health 1 (2credits, lectures)
2) Advanced Midwifery and Women’s Health 2 (2credits, lectures)
2. Undergraduate Courses of Nursing, School of
Health Sciences and Nursing
1) Maternity Care and Nursing (2 credits, lectures)
2) Maternity Care and Nursing Practice(2 credits, practice)

3. Undergraduate Advanced Courses for Midwifery,
School of Health Sciences and Nursing1) Midwifery 1 (1 credit, lectures)
2) Midwifery 2 (1 credit, lectures)
3) Midwifery 4 (3 credits, lectures)
4) Administration for Midwifery(1 credit, lectures)
5) Clinical Practice of Midwifery 1(1 credit, practice)6) Clinical Practice of Midwifery 2(7 credits, practice)

Research activities
Our research activities focus on maternal-child healthcare and promote the health and quality of life forwomen at each stage of the life cycle.
We have conducted the following research projects:
1. Collecting evidence for health guidance in thefollowing areas:
1) Nutrition and weight management during
pregnancy and postpartum, to evaluate thesupervision of pregnant women in outpatient careand to investigate methods for controlling the284

mother's body weight, nutritional intake, physicalactivity, and weight changes during pregnancy tooptimize the management system.
2) Lifestyle and oxidative stress during pregnancy
to identify the biochemical parameters, such asoxidative stress markers, to assure a healthy
lifestyle during pregnancy.
3) Maternal body composition during pregnancy
and infant birth weight, to optimize weightcontrol and a healthy lifestyle during pregnancy
to prevent a low birth weight. Measurements of
the weight, body composition, lipid metabolic
biomarkers, daily lifestyle, and nutritional intake
are examined.
4) Plasma total homocysteine (tHcy) during
pregnancy and the infant’s birth weight to study
plasma tHcy levels during pregnancy to predict
the birth weight and the effects of various
lifestyle factors.
5) Validity
andreproducibilityofaself-administered diet history questionnaire(DHQ/BDHQ) for Japanese pregnant women toevaluate the validity and reproducibility of the
DHQ/BDHQ, and to examine the misreporting of
nutrient intakes and factors related to the underor over-reporting of biological markers, whichwere compared to the responses of the
DHQ/BDHQ in these subjects.
2. Development of accurate predictors of postpartum
hemorrhage.
Multiple biomarkers as predictors of postpartum
hemorrhage to examine the possible associations ofthese biomarkers with uterine smooth muscle
contraction or relaxation (13, 14-dihydro-ketoprostaglandin F2α and Nitric oxide metabolites) andpostpartum hemorrhage.
3. Development of self body management support
system during postpartum
1) Functional evaluation of postpartum innermuscles using ultrasonographic methods tomeasure the function of the transverses
abdominis /pelvic floor muscles. These
techniques were developed to establish therelationship between the inner muscles andurinary incontinence in postpartum women.

2) Preventive and restorative program of pelvic
floormusclehypergasia
todevelopultrasonographic methods as a biofeedback tool
for body management.
3) Promotion of women's health care after delivery
to study the relationship between maternal bodyweight or body composition and lifestyle factors
among postpartum women.

References
1. Uayan Maria Luisa, Sayuri Kobayashi, Masayo
Matsuzaki, Erika Ota, Megumi Haruna, Sachiyo
Murashima. Mothering and acculturation:
Experiences during pregnancy and child rearing ofFilipina mothers married to Japanese. BioScience
Trends. 3, 77-86, 2009.
2. Ryoko Murayama，Kazuo Aoki. A Change ofSleep Posture with Pregnant Progress andInfluence to Respiration and Circulatory System.
Stress Science Research. 24, 20-29, 2009. (inJapanese)
3. Mie Shiraishi, Megumi Haruna, Masayo
Matsuzaki, Erika Ota, Etsuko Watanabe, Satoshi
Sasaki, Sachiyo Murashima. The effect onnutrient intake of skipping breakfast during
pregnancy and factors related to skipping
breakfast. Japan Society of Maternal Health. 50(1),148-154, 2009. (in Japanese)
4. Manami Yoshida, Megumi Haruna, Erika Ota,
Etsuko Watanabe, Uayan Maria Luisa T，Sachiyo
Murashima. Child-rearing difficulties and coping
behaviors of Filipino mothers in Japan Japan
Society of Maternal Health.50 (2), 422-430, 2009.
(in Japanese)
5. Masayo Matsuzaki, Megumi Haruna, Erika Ota,
Satoshi Sasaki, Yasushi Nagai, Sachiyo
Murashima. Dietary folate intake, use of folate
supplements, lifestyle factors, and serum folate
levels among pregnant women in Tokyo, Japan.
12th East Asian Forum on Nursing Science
Annual Conference. Tokyo, Japan. March 13-14,
2009.
6. Erika Ota, Megumi Haruna, Hideki Yanai, Motoi
Suzuki, Dang Duc Anh, Le Huu Tho, Mitsuhiro
Isozaki, Yuka Honda, Koya Ariyoshi, Hiroyuki
Moriuchi, Sachiyo Murashima. Appropriate Body

285

Fat Mass toward Perinatal Period Prevents
Delivery of Infants Small or Large for Gestational
Age: a Population-based Study in Nha Trang City,
Vietnam. 12th East Asian Forum on Nursing
Science Annual Conference, Tokyo, Japan, March
13-14, 2009.
7. Kae Nakayama, Megumi Haruna, Masayo
Matsuzaki, Kyoichi Sekine, Sachiyo Murashima.
The relationship between 13, 14-dihydro-15-ketoprostaglandin F2α （ PGFM ） in saliva andpostpartum postpartum hemorrhage. 9th TTM
Forum. Tokyo, Japan. March 7, 2009.

286

Department of
Psychiatric ursing
Professor
Norito Kawakami, M.D., Ph.D.

Lecturer
Yuki Miyamoto, R.N., P.H.N., P.S.W., Ph.D.

Homepage

http://plaza.umin.ac.jp/heart/

Introduction and Organization
Our department was firstly established as
Department of Fourth Clinical Medical Nursing in
School of Health Care and Nursing in 1957. When the
School of Health Care and Nursing was reorganized as
the School of Health Sciences in 1965, the department
was renamed Department of Mental Health. In 1992,
as School of Health Sciences became The School of
Health Science and Nursing, Department of Mental
Health became Department of Mental Health andPsychiatric Nursing. As the result of the shift to thechair system of the Graduate School of Medicine in
1996, two departments were established, Departmentof Mental Health and Department of PsychiatricNursing. Faculty, staff, and students of two
departments have been working cooperatively eversince.
Our department currently has two faculty members
introduced above, part-time lecturers, visiting research
fellows, 5 doctoral course students, 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.

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

287

support system for the people with mental healthneeds; peer support; stigma; issues of caregiverburden 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. Tsuchiya M., Kawakami N., Ono Y., Nakane Y.,
Nakamura Y., Tachimori H., Iwata N., Uda H.,
Nakane H., Watanabe M., Naganuma Y.,
Furukawa T. A., Hata Y., Kobayashi M., Miyake
Y., Ta-keshima T., Kikkawa T. and Kessler, R. C.
Lifetime comorbidities between phobic disorders
and major depression in Japan: Results from theWorld Mental Health Japan 2002- 2004 Survey.
Depression and Anxiety. 2009;26(10):949-55.
2. Tsuno K, Kawakami N, Inoue A, Ishizaki M,
Tabata M, Tsuchiya M, Akiyama M, Kitazume A,
Kuroda M, Shimazu A. Intragroup and Intergroup
Conflict at Work, Psychological Distress, andWork En-gagement in a Sample of Employees inJapan. In-dustrial Health. 2009;47:640-648.
3. Tsutsumi A, Nagami M, Yoshikawa T, Kogi K,
Kawakami N. Participatory Intervention for
Workplace Improvements on Mental Health and
Job Performance Among Blue-Collar Workers: A
Cluster Randomized Controlled Trial. J Occup
Environ Med. 2009. [Epub ahead of print]
4. Hirokawa K, Ochiai H, Ooi N, Kawakami N.
Relationships
betweenserum
estradiol,
fol-licle-stimulating hormone concentrations, andgender-related
identity:
A
study
of
perimenopausal
women.
Personality
andIndividual Differences. 2009; 46: 744-747.
5. Oishi J, Doi H, Kawakami N. Nutrition anddepressive symptoms in community-dwellingelderly persons in Japan. Acta Med Okayama.
2009; 63(1): 9-17.
6. Tsutsumi A, Iwata N, Watanabe N, de Jonge J,
Pikhart H, Fernandez-Lopez JA, Xu L, Peter R,
Knutsson A, Niedhammer I, Kawakami N,
Siegrist J. Application of item response theory toachievecross-culturalcomparabilityofoccupational stress measurement. Int J Methods
Psychiatr Res. 2009; 18(1):58-67.
7. Lee S, Tsang A, Breslau J, Aguilar-Gaxiola S,
An-germeyer M, Borges G, Bromet E, Bruffaerts
R, de Girolamo G, Fayyad J, Gureje O, Haro JM,
Kawa-kami N, Levinson D, Oakley Browne MA,
Ormel J, Posada-Villa J, Williams DR, Kessler RC.
Mental disorders and termination of education in
high-income and low- and middle-income
countries: epidemiological study. British Journalof Psychiatry. 2009;194(5):411-7.
8. Kinoshita Y, Tsuchiya M, Kawakami N, Furukawa
TA, Kingdon D. Hallucinations in visually
impaired individuals: an analysis of the National
Comorbidity Survey Replication. Soc Psychiatry
Psychiatr Epidemiol. 2009 Feb;44(2):104-8.
9. Chen J, Tsuchiya M, Kawakami N, Furukawa TA.
Non-fearful vs. fearful panic attacks: a general
population study from the national comorbidity
survey. J Affect Disord. 2009;112(1-3):273-8.
10. Umanodan R, Kobayashi Y, Nakamura M,
Kitao-ka-Higashiguchi K, Kawakami N, Shimazu
A. Ef-fects of a Worksite Stress Management
Training Program with Six Short-hour Sessions: A
Controlled Trial among Japanese employees.
Journal of Occupational Health, 2009; 51(4):294-302.
11. Koichi R, Miyamoto Y, Akiyama M & Takamura
S. Awareness of early warning signs andhelp-seeking behaviours among patients withschizophrenia who utilize social rehabilitation
facilities in Japan. Journal of psychiatric and
Mental Health Nusing, 2009;16(8):694-702.
12. Inoue A, Kawakami N, Ishizaki M, Tabata M,
Tsu-chiya M, Akiyama M, Kitazume A, Kuroda M,
Shimazu A. Three job stress models/concepts andoxidative DNA damage in a sample of workers inJapan. Journal of Psychosomatic Research 2009;
66: 329-334.
13. Inoue A, Kawakami N, Tsutsumi A, Shimazu A,
Tsuchiya M, Ishizaki M, Tabata M, Akiyama M,
Kitazume A, Kuroda M, Kivimäki M. Reliability
and validity of the Japanese version of theOrgani-zational Justice Questionnaire. Journal of
Occupa-tional Health 2009; 51:74-83.
14. Koichi R, Miyamoto Y. Recognition of earlywarn-ing signs in patients with mental illness in288Japan. Journal of Psychiatric and Mental healthNursing, 2009;16(9):857-9.
15. Tominaga M, Kawakami N, Ono Y, Nakane Y,
Na-kamura Y, Tachimori H, Iwata N, Uda H,
Nakane H, Watanabe M, Naganuma Y, Furukawa
T. A, Hata Y, Kobayashi M, Miyake Y, Takeshima
T, Kikkawa T. Prevalence and correlates of illicit
and non-medical use of psychotropic drugs inJapan: Findings from the World Mental HealthJapan Survey 2002-2004. Social Psychiatry andPsychiatric Epidemiology 2009; 44: 777-783.

289

Department ofGerontological ursing /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.

Associate
Tomoko Akase, R.N., RPh., Ph.D.
Gojiro Nakagami, 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, 2 research associates, 1 project
research associate, and 7 part-time lecturers forundergraduate course (2) and for graduate course (5).
The student body consists of 9 doctoral course
students, 11 master course students, 2 undergraduate
students and 4 research students. The goal of ourdepartment is to achieve “Evidence-based practice anddevelopment of gerontological nursing and woundcare management”.

Teaching activities
1.Undergraduate course
1) Gerontological ursing (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 2009 contents were as follows;a) Practical simulation for gerontological nursingb) Understanding the modern status of the elderlyc) Social, health and medical policies for a healthy
life of the elderlyd) Health and nursing of the elderly (gait disorder)e) Health and nursing of the elderly (nutrition)f) Health and nursing of the elderly (pressure ulcer)g) Health and nursing of the elderly (infection)h) The cutting edge of the recent gerontological
medical researches
The aim of the 4th year course is to promote
understanding of the ailments and conditions required
to provide proper care to the elderly. The main themesin the 2009 contents were as follows;a) Aging and respiratory disorders, Age-relatedchanges in the physiologic systemb) Aging and osteoporosis, Aging and renal function,
hypertension, and strokec) Aging and dementia, Aging and cardiovasculardisordersd) Feeding and swallowing difficulty of the elderlye) Nutritional management of the elderlyf) Pharmacologic management of the elderly

290

The above lectures were developed under thecooperation by the Department of Geriatric Medicine
and The University of Tokyo Hospital.
2) Clinical Practice in Gerontological ursing(4th yr/ 3 credits)
The aim of this practicum is to learn present
situation of gerontological nursing through practicing
in the long-term care facility. This program was
supported by the long-term care facility owned by
Medical Corporation Tatsuoka.
3) Bachelor’s thesis
The followings were research themes in 2009;‘Determining the optimal inner air cell pressure of analternating air mattress’‘Algorithm for automatic distinction of body position
by body pressure’
The student of the former research won the firstprize at the reviewers’ judgment.
2. Graduate course
1) Gerontological ursing I(Summer course/ 2 credits)
2) Gerontological ursing II(Winter course/ 2 credits)
This program focuses on studying the latest
developments related to gerontological nursing.
The main theme of Gerontological Nursing I in2009 was geriatric pharmacotherapeutics. Safety andefficacy of drug therapies for the elderly werediscussed from a nursing standpoint through reading
the selected English literatures. Related lectures werealso provided, 1. Pharmacokinetics of the elderly andrelated nursing care, and 2. Wound management for
the elderly in a home care setting.
Gerontological Nursing II provides lectures anddiscussion regarding the recent topics aroundgerontological nursing, in which the main themes in2009 were as follows;a) Ethical issues in life support care in end-stageelderly patientsb) Community based nursing care for the younger
demented people and their familyc) Elderly needs during a natural disasterd) Wound healing in the elderly and state-of-the-art
therapies for pressure ulcerse) Nursing quality in visiting nursing and nursing
homesf) Nutrition control in the elderly: focusing on aging
change of metabolism and sarcopeniag) New design of home care for the highly impaired
elderly3) Wound Care Management I(Summer course/ 2 credits)4) Wound Care Management II(Winter course/ 2 credits)
The course program focuses on understanding andthe development of the practice, research, education,and perspectives in advanced wound caremanagement.
The main theme of Wound Care Management I in2009 was the critical reading and related discussion of
the textbook “Pressure Ulcer Research: Current andFuture Perspectives” (Dan Bader ed. Springer, 2005).
This textbook is a multi-disciplinary omnibus ofrecent researches in this field, offering basic
information and fundamentals of clinical practice ofpressure ulcers.
Wound Care Management II in 2009 was a series oflectures entitled “Cutting Edge of Wound Science:from basic researches to clinical applications.” Thelecturers with multiple specialties in this field wereinvited from various institutions and gave lectures asfollows.
a) Basic researches on oxidative stressb) Basic researches and clinical applications ofhyaluronanc) Skin aging and cosmetic medicine (the special
lecture held jointly with Department of Advanced
Skin Care)d) Current status and new approaches to the lower
leg ulcers with vascular disordere) Advanced engineering technology and its
application to medical practice and welfaref) Case studies of wound care in a home care setting5) Master’s thesis
The followings were research themes in 2009;‘Factors associated with characteristics of toenail
onychomycosis in diabetic patients’‘Relationship between morphological characteristics
and nursing care in the developmental process of291

specific pressure ulcers in intensive care unit
patients’‘Skin condition and nutritional status in long-termcare hospital residents: possibility of quantitative
skin evaluation as a nutritional screening tool’The student of the first theme won the first prize at
the reviewers’ judgment.
6) Doctoral thesis
The following was a research theme in 2009;‘Factors associated with deep foot fissures in diabetic
people’Research activities
1. Activity policy
Our gerontological nursing researches are focusing
on elderly suffering with geriatric syndrome such aspressure ulcers, incontinence, malnutrition, pain,
depression, dysphagia, osteoporosis and dementia.
Our wound care management researches are focusing
on pressure ulcers, diabetic foot ulcers, ulcers with
peripheral arterial disease, venous leg ulcers andmalignant 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.
Our special research missions in 2009 were
twofold: 1. Establishment of basic research systems,
including analyses at the molecular level, to elucidate
problems
andunknown
pathophysiologicalmechanisms identified in the clinical practice. 2.
Development of new technologies and equipments byreturning the achievements in the basic researches toclinical practice, such as prediction, prevention,
diagnosis and treatment of the abovementioned
diseases and pathological status. These missions canbe regarded as a translational research in the nursing
field, integrating basic and clinical researches.
We held the 7th University of Tokyo Open Seminarof Advanced Wound Care on November 2009 entitled“Practice of translational researches in biologicalnursing: new stage of wound management.” Threemembers of our group (T. Nagase and G. Nakagami
from our department, and T. Minematsu from the
Department of Advanced Skin Care) gave lectures
introducing our concept of the translational research
and a part of achievements of our missions. Our
missions may open a new avenue toward a futurenursing research, and we expect more achievements inthis direction including paper publications in the next
year and thereafter.
Another important feature of our researches isindustry-academia cooperation in development ofnovel technologies and equipments, where we needcollaborations with specialists of biotechnology andengineering. We hope through such researches to beable to increase physical activity and enhanceself-esteem of the elderly in order to maintain their
independent lifestyles.
2. Research fields and themes in 2009
1) Basic experimental studies
・ Wound infection control based on quorum
sensing signaling regulation of Pseudomonas
aeruginosa.
・ Evaluation of wound condition using exudates
・ Search for molecular markers of deep tissue
injury・ 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 maceration2) ursing 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
・ Effect of vibration on blood flow acceleration
・ Quantitative evaluation of skin texture based oncomputed image analysis
・ Development of a handy type kit for diagnosis
of wound infection

2923) Clinical studies
・ Cross-sectional study of diabetic foot (callus,
fissures, onychomycosis etc.) and its risk factors
・ Identification of ICU specific pressure ulcer andits related factors
・ Evaluation of wound nutritional status in elderlywith pressure ulcers
・ Risk factors of venous leg ulcers and fungatingbreast ulcers
・ Evaluation of new diaper for elderly people forincontinence related dermatitis management
・ 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 new diaper for elderly people forincontinence related dermatitis management

References
1. Konya C, Sanada H, Sugama J, Okuwa M,
Kamatani Y, Nakagami G, et al. Skin injuriescaused by medical adhesive tape in older people
and associated factors. J Clin Nurs. 2010 Mar 16.
(Epub ahead of print)
2. Minematsu T, Nakagami G, Sari Y, Akase T,
Sugama J, Nagase T, et al. Candidate biomarkers
for deep tissue damage from molecular biologicaland biochemical aspects. J Tissue Viability.
2010;19(2):77-83. (Epub 2010 Mar 10)
3. Nakagami G, Sari Y, Nagase T, Iizaka S, Ohta Y,
Sanada H. Evaluation of the usefulness of skinblood flow measurements by laser speckle
flowgraphy in pressure-induced ischemic wounds
in rats. Ann Plast Surg. 2010;64(3): 351-4.
4. Oe M, Okuwa M, Sanada H, Sugama J, Inagaki M,
Kasahara Y, et al. Difference of footmanifestations between young, adult, andbedridden elderly with diabetes: a cross- sectional
observational study. J So Nurs Pract. 2010;22(1):19-27.
5. Sari Y, Nagase T, Minematsu T, Akase T,
Nakagami G, Sanada H, et al.. Hypoxia is
involved in deep tissue injury formation in a rat
model. WOUNDS. 2010;22(2):45-51.

6. 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.
7. Iizaka S, Sanada H, Minematsu T, Oba M,
Nakagami G, Koyanagi H, et al. Do nutritional
markers in wound fluid reflect pressure ulcer
status? Wound Repair Regen. 2010;18(1):31-7.
8. Sanada H, Nakagami G, Mizokami Y, Minami Y,
Yamamoto A, Oe M, et al. Evaluating the effect of
the new incentive system for high-risk pressure
ulcer patients on wound healing and costeffectiveness: A cohort study. Int J Nurs Stud.
2010: 47(3):279-86.
9. Iizaka S, Okuwa M, Sugama J, Sanada H. The
impact of malnutrition and nutrition-related
factors on the development and severity ofpressure ulcers in older patients receiving homecare. Clin Nutr. 2010: 29(1):47-53.
10. Iizaka S, Sanada H, Nakagami G, Sekine R,
Koyanagi H, Konya C, et al. Estimation of protein
loss from wound fluid in older patients withsevere pressure ulcers. Nutrition. 2009 Dec 17.
(Epub ahead of print)
11. Akase T, Shimada T, Harasawa Y, Akase T, Ikeya
Y, Nagai E, et al. Preventive effects of salacia
reticulata on obesity and metabolic disorders in
TSOD mice. Evid Based Complement Alternat
Med. 2009 Jun 8. (Epub ahead of print).
12. Shimada T, Akase T, Kosugi M, Aburada
M.Preventive effect of boiogito on metabolic
disorders in the TSOD mouse, a model of
spontaneous obese Type II diabetes mellitus. Evid
Based Complement Alternat Med. 2009 Feb 10.
(Epub ahead of print)
13. Sanada H, Sugama J, Nakagami G. Innovations inpressure ulcer prevention and management: key
initiatives introduced in japan. Wounds
International. 2009;1(1).
14. Aoi N, Yoshimura K, Kadono T, Nakagami G,
Iizaka S, Higashino T, et al.. Ultrasoundassessment of deep tissue injury in pressure
ulcers: possible prediction of pressure ulcer
progression. Plast Reconstr Surg. 2009;124(2):540-50.
15. Nishide K, Nagase T, Oba M, Oe M, Ohashi Y,
Iizaka S, et al.. Ultrasonographic and thermo-

293graphic screening for latent inflammation indiabetic foot callus. Diabetes Res Clin Pract.
2009:85(3):304-9.
16. Yabunaka K, Iizaka S, Nakagami G, Aoi N,
Kadono T, Koyanagi H, et al. Can
ultrasonographic evaluation of subcutaneous fat
predict pressure ulceration? J Wound Care.
2009;18(5):192-8.
17. Sakai K, Sanada H, Matsui N, Nakagami G,
Sugama J, Komiyama C, et al. Continuous
monitoring of interface pressure distribution in
intensive care patients for pressure ulcer
prevention. J Adv Nurs. 2009; 65(4): 809-17.
18. Shigeta Y, Nakagami G, Sanada H, Oba M,
Fujikawa J, Konya C, et al. Exploring therelationship between skin property and absorbent
pad environment. J Clin Nurs. 2009;18(11):1607-16.
19. Nagase T, Sanada H, Nakagami G, Sari Y,
Minematsu T, Sugama J. Clinical and molecularperspectives of deep tissue injury: Changes inmolecular markers in a rat model. In: Gefen A,
editor. Bioengineering Research of Chronic
Wounds. Berlin: Springer; 2009. p.301-41.

International Health
1. International Social Medicine

295

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.

296

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

Scientific Research (B) , Grants-in-Aid for Scientific
Research.
The WHO Multi-country Survey on Maternal andNewborn Health. World Health Organization
Clinical guidelines development: opportunities andchallenges. Health and Labour Sciences Research
Grant.
Database development and analysis for child healthand development. Health and Labour Sciences
Research Grant
Developing effective strategy for international
cooperation in maternal and child health. International
Health Cooperation Research Grant
Grand design of child health and development
research. Child Health and Development Research
Grant.

GHP Monday seminar
Publications
Every Monday, 13:30-15:00 pm
1) Journal clubStudents present a brief summary of research articles
from the major medical, social science, economics
journals, which are relevant for global health policy.
The major objective is to share knowledge, evoke
debates and facilitate discussions.
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
Genetic analysis of tuberculosis epidemiology.

(1) Mori R, Fitzgerald A, Williams C, Tullus K,
Verrier-Jones K, Lakhanpaul M. Antibiotic
prophylaxis for children at risk of developing
urinary tract infection: a systematic review. Acta
Paediatr. 2009;98(11):1781-6.
(2) Stickley A, Pridemore WA. The effects of binge
drinking and social capital on violent
victimization: findings from Moscow. J
Epidemiol Community Health. 2009 Oct 12.
(3) Shirayama Y, Phompida S, Shibuya K.
Geographic information system (GIS) maps andmalaria
controlmonitoring:intervention
coverage and health outcome in distal villages of
Khammouane province, Laos. Malar J. 2009;8(1):217.
(4) Ikeda N, Murray CJ, Salomon JA. Tracking
population health based on self-reported
impairments: Trends in the prevalence of hearing
loss in US adults, 1976-2006. Am J Epidemiol.
2009;170(1):80-7.
(5) Aiga H, Alvarez HR, Zúniga C, Serpas MV,
Acevedo FJ, Arenas EC. Donor agency
commitment to Chagas disease. Lancet. 2009;373

297(9680):2024-25.
(6) Masuno K, Xaysomphoo D, Phengsavanh A,
Douangmala S, Kuroiwa C. Scaling up
interventions to eliminate neonatal tetanus:
factors associated with the coverage of tetanus
toxoid and clean deliveries among women in
Vientiane, Lao PDR. Vaccine. 2009;27(32):4284-8.
(7) Sasaki Y, Ali M, Kakimoto K, Saroeun O, Kanal
K, Kuroiwa C. Predictors of exclusive
breastfeeding in early infancy: A survey reportfrom Phnom Penh, Cambodia. Journal of
Pediatric Nursing. Early onlne publication,03
July 2009.
(8) Vandan N, Ali M, Prasad R, Kuroiwa C.
Assessment of doctors' knowledge regarding
tuberculosis management in Lucknow, India: apublic-private sector comparison. Public Health.
2009;123(7):484-9.
(9) Aiga H, Matsuoka S, Kuroiwa C, Yamamoto S.
Malnutrition among children in rural Malawianfish-farming households. Trans R Soc Trop Med
Hyg. 2009;103(8):827-33.
(10) Ali M, Kuroiwa C. Status and challenges of
hospital solid waste management: case studies
from Thailand, Pakistan, and Mongolia. J Mater
Cycles Waste Manag. 2009;11:251–7(11) Putthakeo P, Ali M, Ito C, Vilayhong P, Kuroiwa
C. Factors influencing breastfeeding in children
less than 2 years of age in Lao PDR. Journal of
Pediatrics and Child Health. J Paediatr Child
Health. 2009;45(9):487-92.
(12) Masuno K, Shibuya K. Measles elimination: lackof progress in the Western Pacific Region. Lancet.
2009;373(9668):1008.
(13) Qazi MS, Ali M. Pakistan's Health Management
Information
System:HealthManagers'
Perspectives. Journal of Pakistan Medical
Association. 2009;59(1):10-14.

298

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(1993-1996),
Som-Arch
Wongkhomthong(1996-1999), Susumu Wakai (1999-2005), andMasamine 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.
In April 2009, the name of the department waschanged from “Department of International
Community Health” to “Department of Communityand Global Health.” Our research will accordingly

place more emphasis on how to activate
community-based activities and how a bottom-up
approach can be linked to national and international
policy. The department currently consists of: our
Department Chair and Professor, 3 AssistantProfessors, 10 Visiting Lecturers, 22 PhD course
students, 30 Master’s course students, 5 research
students, and 19 visiting researchers (19). 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 (Sept. 2007-July 2009) was ultimately
reformed/strengthened into the Global Health andHuman Security program. Within this framework, wehave conducted activities to facilitate policy
discussions among national/international global
health personnel and to strengthen concrete policy
implementation.
In addition, the department serves as an advisor
to the Filariasis Control Program of the WHO
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South-East Asia Regional Office. In collaboration
with the JCIE, we provided technical assistance for
the WHO West Pacific Regional Office in developing“Primary Health Care (PHC) and Health System”
strategy documents. We also provided technicalsupport to projects run by the Japan International
Cooperation Agency (JICA) and NGOs in Lao PDR,
Thailand, and Vietnam, and have conducted researchin collaboration with the Cambodian government.

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, and Peru.

Teaching Activities
References
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 healthtargeting careers with the United Nations, theGlobal 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.

Research activities
The Department aims to contribute to policy
making and promoting actions for better health bymaking the best use of community-based research. To
this end, we carry out research by working in tandemwith different international organizations, NGOs, anduniversities in developing countries. The major(1) Fujiya R, Abu-Rmeileh N, Jimba M. Effect of
emergency health insurance scheme on place ofbirth in the West Bank during conflict: aretrospective analysis. Lancet (In press)(2) 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.
(In press).
(3) 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. (In Press).
(4) 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).
(5) Yanagisawa S, Poudel KC, Jimba M. Sibling
caregiving among children orphaned by AIDS:
synthesis of recent studies for policy
implications. Health Policy (In press).
(6) 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. (Inpress).
(7) Poudel KC, Poudel-Tandukar K, Yasuoka J, Joshi
AB, Jimba M. Correlates of receptive needle
sharing among male injecting drug users in
Kathmandu, Nepal. Int J Drug Policy. (In press).
(8) Nakahara S, Poudel KC, Lopchan M, Poudel OR,
Poudel-Tandukar K, Ichikawa M. Differential
effects of out-of-home day care in improving
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child nutrition and augmenting maternal income
among those with and without childcare support:
A prospective before–after comparison study in
Pokhara, Nepal. Health Policy (In press).
(9) Jayatilleke AC, Poudel KC, Sakisaka K, Yasuoka
J, 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.
(10) 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;10(1):10.
(11) Eddy C, Sase E, Schuster R. Pandemic influenza
H1N1 2009: Public health emergency response.
Georgetown Public Policy Review 2010; 15 (1):63-75.
(12) 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; 9:109.
(13) 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 18;9:98.
(14) Sakisaka K, Nakamura J. Donors' commitments
to neglected tropical diseases: not all bad. Lancet
2010 13; 375:892-3.
(15) Sugiura Y, Ju YS, Yasuoka J, Jimba M. Rapid
increase in Japanese life expectancy after WorldWar II. Biosci Trends. 2010; 4:9-16.
(16) Poudel KC, Nakahara S, Poudel-Tandukar K,
Yasuoka J, Jimba M. Unsafe Sexual Behaviors
among HIV-positive Men in Kathmandu Valley,
Nepal. AIDS Behav. 2009; 13: 1143-50(17) Jayatilleke A, Poudel KC, Jimba M. Screening
for intimate partner violence. JAMA 2009;
302(22): 2434.
(18) Yi S, Poudel KC, Yasuoka J, Ichikawa M, Tan V,
Jimba M. Influencing factors for seeking HIV
voluntary counseling and testing among
tuberculosis patients in Cambodia. AIDS Care2009; 21: 529-534.
(19) Yoshimura N, Jimba M, Poudel KC,
Chanthavisouk C, Iwamoto A, Phommasack B,
Saklokham K. Health promoting schools in urban,
semi-urban and rural Lao PDR. Health Promot
Int.2009; 24(2):166-76.
(20) Takanashi K, Chonan Y, Quyen DT, Khan NC,
Poudel KC, Jimba M. Survey of food hygiene
practices at home and childhood diarrhoea in
Hanoi, Vietnam. J Health Popul utr. 2009; 27(5):602-611.
(21) Jayatilleke AU, Nakahara S, Dharmaratne SD,
Silva AC, Poudel KC, Jimba M. Working
conditions of bus drivers in the private sector andbus crashes in Kandy district, Sri Lanka: A
case-control study. Inj Prev. 2009; 15: 80-86.
(22) Nonaka D, Vongseththa K, Kobayashi J,
Bounyadeth S, Kano S, Phompida S, Jimba M.
Public and private sector treatment of malaria in
Lao PDR. Acta Trop. 2009; 112:283-7.
(23) Tokuda Y, Fujii S, Jimba M, Inoguchi T. The
relationship between trust in mass media and thehealthcare system and individual health:evidence from the AsiaBarometer Survey. BMC
Med. 2009;7:4.
(24) Tokuda Y, Jimba M, Yanai H, Fujii S, Inoguchi T.
Interpersonal trust and quality-of-life: across-sectional study in Japan. PLoS One.
2008;3:e3985.
(25) Nakahara S, Poudel KC, Lopchan M, Ichikawa
M, Poudel OR, Poudel-Tandukar K, Yoshida K.
Hidden criteria for out-of-home day-care centre
admission in Pokhara, Nepal: a longitudinalobservational study. Early Child Dev Care. 2009;
Doi: 10.1080/03004430802525021(26) Putthakeo P, Ali M, Ito C, Vilayhong P, Kuroiwa
C. Factors influencing breastfeeding in children
less than 2 years of age in Lao PDR. J. Paediatr.
Child Health, 2009; 1440-1754.

300

International Health
2. International Biomedical Sciences

302

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.

303

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Kantipong P, Kantiwaittaya S, Sura T, Khusmith
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Vollstedt S, Yuliwulandari R, Okamoto K, LienLT, Keicho N, Rochani JT, Wikaningrum R, andTokunaga K: No evidence for association
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89(1): 71-76, 2009.
Yuliwulandari R, Kashiwase K, Nakajima H,
Uddin J, Susmirsih TP, Sofro A, and Tokunaga
K: Polymorphisms of HLA genes in Western
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Otowa T, Yoshida E, Sugaya N, Yasuda S,
Nishimura Y, Inoue K, Tochigi M, Umekage T,
Miyagawa T, Nishida N, Tokunaga K, Tanii H,
Sasaki T, Kaiya H, and Okazaki Y:
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Ichikawa N, Kotake S, Hakoda M, Higami K,
Kawasaki A, Furuya T, Nanke Y, Tsuchiya N,
Tokunaga K, and Kamatani N: Combining
effects of polymorphism of tumor necrosis factor
alpha 5'-flanking region and HLA-DRB1 on
radiological progression in patients withrheumatoid arthritis. Mod. Rheumatol. 19(2):134-139, 2009.
Miyake K, Yang W, Hara K, Yasuda K,
Horikawa Y, Osawa H, Furuta H, Ng MCY,
Hirota Y, Mori H, Ido K, Yamagata K, Hinokio Y,
Oka Y, Iwasaki N, Iwamoto Y, Yamada Y,
Seino Y, Maegawa H, Kashiwagi A, Wang H,
Tanahashi T, Nakamura N, Takeda J, Maeda E,
Yamamoto K, Tokunaga K, Ma RCW, So W,
Chan JCN, Kamatani N, Makino H, Nanjo K,
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Yao Y, Shi L, Shi L, Matsushita M, Yu L, Lin K,
Tao Y, Huang X, Yi W, Oka T, Tokunaga K, and
Chu J: Distribution of HLA-A, -B, -Cw and-DRB1 alleles and haplotypes in an isolated Han
population in Southwest China. Tissue Antigens
73(6): 561-568, 2009.
Miyagawa T, Honda M, Kawashima M, Shimada
M, Tanaka S, Honda Y, and Tokunaga K:
Polymorphism located between CPTIB and
CHKB, and HLA-DRB1*1501-DQB1*0602
haplotype confer susceptibility to CNS
hypersomnias (essential hypersomnia). PLoS
ONE 4(4): e5394, 2009.
Vu HA, Xinh PT, Kano Y, Tokunaga K, and Sato
Y: The juxtamembrane domain in ETV6/FLT3 iscritical for PIM-1 up-regulation and cellproliferation. Biochem. Biophys. Res. Commun.
383(3): 308-313, 2009.
Hallmayer J, Faraco J, Ling L, Hesselson S,
Winkelmann J, Kawashima M, Mayer G, Plazzi
G, Nevsimalova S, Bourgin P, Hong S, Honda Y,
Honda M, Hogl B, Longstreth WT, Montplaisir J,
Kemlink D, Einen M, Chen J, Musone SL,
Akana M, Miyagawa T, Duan J, Desautels A,
Erthardt C, Hesla PE, Poli F, Frauscher B, Jeong
J-H, Lee S-P, Ton TGN, Kvale M, Kolesar L,
Dobrovolna M, Nepom GT, Salomon D,
Wichmann HE, Rouleau GA, Gieger C,
Levinson DF, Gejman PV, Meitinger T, Young T,
Peppard P, Tokunaga K, Kwok P-Y, Risch N, andMignot E: Narcolepsy is strongly associatedwith the TCR alpha locus. Nat. Genet. 41(6):708-711, 2009.
Ueta M, Matsushita M, Sotozono C, Kinoshita S,
and Tokunaga K: Identification of a novel
HLA-B allele, HLA-B*5904. Tissue Antigens
73(6): 612-614, 2009.
Yoshimura N, Muraki S, Oka H, Mabuchi A,
Kinoshita H, Yosihda M, Kawaguchi H,
Nakamura K, and Akune T: Epidemiology oflumbar osteoporosis and osteoarthritis and theircausal relationship--is osteoarthritis a predictor
for osteoporosis or vice versa?: the Miyama

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Muraki S, Akune T, Oka H, Mabuchi A, En-Yo Y,
Yoshida M, Saika A, Nakamura K, Kawaguchi H,
and Yoshimura N: Association of occupational
activity with radiographic knee osteoarthritis andlumbar spondylosis in elderly patients of
population-based
cohorts:alarge-scale
population-based study. Arthritis Rheum. 61(6):779-786, 2009.
Yoshimura N, Muraki S, Oka H, Mabuchi A,
En-Yo Y, Yoshida M, Saika A, Yoshida H,
Suzuki T, Yamamoto S, Ishibashi H, Kawaguchi
H, Nakamura K, and Akune T: J. Prevalence ofknee osteoarthritis, lumbar spondylosis, andosteoporosis in Japanese men and women: theresearch on osteoarthritis/osteoporosis against
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Keicho N, Itoyama S, Kashiwase K, Phi NC,
Long HT, Ha LD, Ban VV, Hoa BK, Hang NT,
Hijikata M, Sakurada S, Satake M, Tokunaga K,
and Quy T: Association of human leukocyte
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Fujimoto A, Nishida N, Kimura R, Miyagawa T,
Yuliwulandari R, Batubara L, Mustofa MS,
Samakkarn U, Settheetham- Ishida W, Ishida T,
Morishita Y, Tsunoda T, Tokunaga K, andOhashi J: FGFR2 is associated with hairthickness in Asian populations. J. Hum. Genet.
54(8): 461-465, 2009.
Koike A, Nishida N, Inoue I, Tsuji S, andTokunaga K: Genome-wide association databasedeveloped in the Japanese Integrated Database
Project. J. Hum. Genet. 54(9): 543-546, 2009.
Muraki S, Oka H, Akune T, Mabuchi A, En-Yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Yamamoto S, Nakamura K,
Kawaguchi H, and Yoshimura N. Prevalence ofradiographic lumbar spondylosis and its
association with low back pain in elderly
subjects of population-based cohorts: the ROAD
study. Ann Rheum Dis. 68(9): 1401-1406, 2009.
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Kawaguchi H, and Yoshimura N. Prevalence ofradiographic knee osteoarthritis and its
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study. Osteoarthritis Cartilage 17(9): 1137-1143,
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Tanaka Y, Nishida N, Sugiyama M, Kurosaki M,
Matsuura K, Sakamoto N, Nakagawa M,
Korenaga M, Hino K, Hige S, Ito Y, Mita E,
Tanaka E, Mochida S, Murawaki Y, Honda M,
Sakai A, Hiasa Y, Nishiguchi S, Koike A,
Sakaida I, Imamura M, Ito K, Yano K, Masaki N,
Sugauchi F, Izumi N, Tokunaga K, andMizokami M: Genome-wide association of
IL28B with response to pegylated interferonalpha and ribavirin therapy for chronic hepatitis
C. Nat. Genet. 41(10): 1105-1109, 2009.
Hancks DC, Ewing AD, Chen JE, Tokunaga K,
and Kazazian Jr HH: Exon-trapping mediated by
the human retrotransposon SVA. Genome Res.
19(11): 1983-1991, 2009.
Naka I, Patarapotikul J, Hananantachai H,
Tokunaga K, Tsuchiya N, and Ohashi J: IFNGR1polymorphisms in Thai malaria patients. Infect.
Genet. Evol. 9(6): 1406-1409, 2009.
Naka I, Nishida N, Patarapotikul J, Nuchnoi P,
Tokunaga K, Hananantachai H, Tsuchiya N, andOhashi J: Identification of a haplotype block inthe 5q31 cytokine gene cluster associated withthe susceptibility to severe malaria. Malaria J. 8:
e232, 2009.
Naka I, Patarapotikul J, Tokunaga K,
Hananantachai H, Tsuchiya N, and Ohashi J. A
replication study of the association between the
IL 12B promoter allel CTCTAA andsusceptibility to cerebral malaria in Thai
population. Malaria J. 8: e290, 2009.
Kawabata Y, Ikegami H, Awata T, Imagawa A,
Maruyama T, Kawasaki E, Tanaka S, Shimada A,
Osawa H, Kobayashi T, Hanafusa T, Tokunaga K,
and Makino H: Differential association of HLAwith three subtypes of type 1 diabetes: fulminant,slowly-progessive and acute-onset type 1
diabetess. Diabetologia 52(12): 2513-2521.
2009.
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MA, Ahmed I, Assawamakin A, Bhak J,
Brahmachari SK, Calacal GC, Chaurasia A,
Chen CH, Chen J, Chen YT, Chu J,
Cutiongco-de la Paz EM, De Ungria MC, Delfin
FC, Edo J, Fuchareon S, Ghang H, Gojobori T,
Han J, Ho SF, Hoh BP, Huang W, Inoko H, Jha P,
Jinam TA, Jin L, Jung J, Kangwanpong D,
Kampuansai J, Kennedy GC, Khurana P, Kim
HL, Kim K, Kim S, Kim WY, Kimm K, Kimura
R, Koike T, Kulawonganunchai S, Kumar V, Lai
PS, Lee JY, Lee S, Liu ET, Majumder PP,
Mandapati KK, Marzuki S, Mitchell W, Mukerji
M, Naritomi K, Ngamphiw C, Niikawa N,
Nishida N, Oh B, Oh S, Ohashi J, Oka A, Ong R,
Padilla CD, Palittapongarnpim P, Perdigon HB,
Phipps ME, Png E, Sakaki Y, Salvador JM,
Sandraling Y, Scaria V, Seielstad M, Sidek MR,
Sinha A, Srikummool M, Sudoyo H, Sugano S,
Suryadi H, Suzuki Y, Tabbada KA, Tan A,
Tokunaga K, Tongsima S, Villamor LP, Wang E,
Wang Y, Wang H, Wu JY, Xiao H, Xu S, Yang
JO, Shugart YY, Yoo HS, Yuan W, Zhao G,
Zilfalil BA, Indian Genome Variation
Consortium: Mapping human genetic diversity
in Asia. Science 326(5959): 1541-1545, 2009.

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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

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In addition to lectures and laboratory courses by ourown staff, special lectures are given by experts both
inside and outside the University.

Research activities(1) 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

References
1. Abe Y, Oka A, Mizuguchi M, Igarashi T, Ishikawa
S, Aburatani H, Yokoyama S, Asahara H, Nagao K,
Yamada M, Miyashita T. EYA4, deleted in a casewith middle interhemispheric variant ofholoprosencephaly, interacts with SIX3 both
physically and functionally. Human Mutation
2009; 30(10): E946-955.
2. Chanit W, Thongprachum A, Khamrin P, Okitsu S,
Mizuguchi M, Ushijima H. Intergenogroup
recombinant sapovirus in Japan, 2007-2008.
Emerging Infectious Diseases 2009; 15(7):1084-1087.
3. Dey SK, Hayakawa Y, Rahman M, Islam R,
Mizuguchi M, Okitsu S, Ushijima H. G2 strain ofrotavirus among infants and children, Bangladesh.
Emerging Infectious Diseases 2009; 15(1): 91-94.
4. Dey SK, Shimizu H, Phan TG, Hayakawa Y, Islam
A, Salim AF, Khan AR, Mizuguchi M, Okitsu S,
Ushijima H. Molecular epidemiology of
adenovirus infection among infants and children
with acute gastroenteritis in Dhaka City,
Bangladesh. Infection and Genetic Evolution
2009; 9(4): 518-522.
5. Dey SK, Thongprachum A, Islam AR, Phan GT,
Rahman M, Mizuguchi M, Okitsu S, Ushijima H.
Molecular analysis of G3 rotavirus among infants
and children in Dhaka City, Bangladesh after 1993.
Infection and Genetic Evolution 2009; 9(5):983-986.
6. Dey SK, Thongprachum A, Ohta Y, Phan TG,
Nishimura S, Mizuguchi M, Okitsu S, Ushijima H.
Molecular and epidemiological trend of rotavirus
infection among infants and children in Japan.
Infection and Genetic Evolution 2009; 9(5):955-961.
7. 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. Pediatric Infectious Diseases
Journal 2010; 29(2):166-167
8. Iizuka I, Saijo M, Shiota T, Ami Y, Suzaki Y,
Nagata N, Hasegawa H, Sakai K, Fukushi S,
Mizutani T, Ogata M, Nakauchi M, Kurane I,
Mizuguchi M, Morikawa S. Loop-mediatedisothermal amplification-based diagnostic assay

308

for monkeypox virus infections. Journal of
Medical Virology 2009; 81(6): 1102-1108.
9. Kato M, Takita J, Takahashi K, Mimaki M, Chen
Y, Koh K, Ida K, Oka A, Mizuguchi M, Ogawa S,
Igarashi T. Hepatoblastoma in a patient with Sotos
syndrome. Journal of Pediatrics 2009; 155(6):937-939.
10. Khamrin P, Maneekarn N, Peerakome S, Masalao
R, Thongprachum A, Chan-it W, Mizuguchi M,
Okitsu S, Ushijima H. Molecular characterizationof VP4, VP6, VP7, NSP4, and NSP5/6 genes
identifies an unusual G3P[10] human rotavirus
strain. Journal of Medical Virology 2009; 81(1):176-182.
11. Khamrin P, Takanashi S, Chan-It W, Kobayashi
M, Nishimura S, Katsumata N, Okitsu S,
Maneekarn N, Nishio O, Ushijima H.
Immunochromatography test for rapid detectionof norovirus in fecal specimens. Journal of
Virological Methods. 2009; 157(2): 219-222.
12. Khamrin P, Thongprachum A, Chaimongkol N,
Chusri P, Okitsu S, Ushijima H, Maneekarn N.
Evolutionary consequences of G9 rotaviruses
circulating in Thailand. Infection and Genetic
Evolution 2009; 9(6): 1394-1399.
13. 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. Emerging
Infectious Diseases 2010; 16(1): 130-132.
14. Nonoda Y, Saito Y, Itoh M, Nakagawa E, Sugai K,
Takahashi A, Otsuki T, Saito Y, Arima K,
Mizuguchi M, Goto Y, Sasaki M: Activation of
microglia/macrophages expressing phosphorylated S6 ribosomal protein in a case ofhemimegalencephaly
withprogressive
calcification and atrophy. Journal of Neurological
Sciences 2009; 287(1-2): 52-59.
15. Okumura A, Abe S, Kidokoro H, Mizuguchi M.
Acute necrotizing encephalopathy: a comparison
between influenza and non-influenza cases.
Microbiology and Immunology. 2009; 53(5):277-280.
16. Okumura A, Mizuguchi M, Aiba H, Tanabe T,
Tsuji T, Ohno A. Delirious behavior in children
with acute necrotizing encephalopathy. Brain andDevelopment 2009; 31(8): 594-599.

17. Okumura A, Mizuguchi M, Kidokoro H, Tanaka
M, Abe S, Hosoya M, Aiba H, Maegaki Y,
Yamamoto H, Tanabe T, Noda E, Imataka G,
Kurahashi H: Outcome of acute necrotizing
encephalopathy in relation to treatment withcorticosteroids and gammaglobulin. Brain andDevelopment 2009; 31(3): 221-227.
18. Peng L, Wen Y, Han Y, Wei A, Shi G, Mizuguchi
M, Lee P, Hernando E, Mittal K, Wei JJ.
Expression of insulin-like growth factors (IGFs)
and IGF signaling: molecular complexity inuterine leiomyomas. Fertility and Sterility 2009;91(6): 2664-2675
19. Pham NT, Trinh QD, Nguyen TA, Dey SK, Phan
TG, Hoang LP, Khamrin P, Maneekarn N, Okitsu
S, Mizuguchi M, Ushijima H. Development ofgenotype-specific primers for differentiation of
genotypes A and B of Aichi viruses. Journal of
Virological Methods 2009; 156(1-2): 107-110.
20. Saijo M, Ami Y, Suzaki Y, Nagata N, Iwata N,
Hasegawa H, Iizuka I, Shiota T, Sakai K, Ogata M,
Fukushi S, Mizutani T, Sata T, Kurata T, Kurane I,
Morikawa S. Virulence and pathophysiology of
the Congo Basin and West African strains ofmonkeypox virus in non-human primates. Journalof General Virology 2009; 90(Pt 9): 2266-2271
21. Saitoh M, Itoh M, Takashima S, Mizuguchi M,
Iwamori M. Phosphatidyl ethanolamine withincreased polyunsaturated fatty acids incompensation for plasmalogen defect in the
Zellweger syndrome brain. Neuroscience Letters2009; 449(3): 164-167.
22. Sato A, Mizuguchi M, Mimaki M, Takahashi K,
Jimi H, Oka A, Igarashi T. Cortical gray matterlesions in acute encephalopathy with febrile
convulsive status epilepticus. Brain andDevelopment 2009; 31(8): 622-624.
23. Shinozaki Y, Osawa M, Sakuma H, Komaki H,
Nakagawa E, Sugai K, Sasaki M, Goto Y.
Expansion of the first polyalanine tract of the
ARX gene in a boy presenting with generalized
dystonia in the absence of infantile spasms. Brainand Development 2009; 31(6): 469-472.
24. Takanashi S, Hashira S, Matsunaga T, Yoshida A,
Shiota T, Tung PG, Khamrin P, Okitsu S,
Mizuguchi M, Igarashi T, Ushijima H. Detection,
genetic characterization, and quantification of

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norovirus RNA from sera of children withgastroenteritis. Journal of Clinical Virology 2009;44(2): 161-163.
25. Thongprachum A, Khamrin P, Saekhow P, Pantip
C, Peerakome S, Ushijima H, Maneekarn N.
Analysis of the VP6 gene of human and porcinegroup A rotavirus strains with unusual subgroupspecificities. Journal of Medical Virology 2009;
81(1): 183-191.
26. Trinh QD, Izumi Y, Komine-Aizawa S, Shibata T,
Shimotai Y, Kuroda K, Mizuguchi M, Ushijima H,
Mor G, Hayakawa S. H3N2 influenza A virus
replicates in immortalized human first trimester
trophoblast cell lines and induces their rapid
apoptosis. American Journal of Reproductive
Immunology 2009; 62(3): 139-146.
27. Trinh QD, Pham NT, Lam BQ, Le TP, Truong KH,
Le TQ, Vo HT, Tang TC, Ha TM, Izumi Y,
Mizuguchi M, Hayakawa S, Ushijima H.
Subtyping and env C2/V3 Sequence analysis of
HIV-1 Isolated from HIV-infected children
hospitalized in Children Hospital 1, Vietnam
during 2004-2005. Journal of Tropical Pediatrics
2009; 55(6): 399-401.
28. Usami M., Trinh QD, Phan TG, Yagyu F,
Hayakawa Y, Inaba N, Okitsu S, Ushijima H.
Throughput expression of multiple G-protein
Coupled Receptors for HIV infection inchoriocarcinoma cells, trophoblasts, and breast
milk cells. Clinical Laboratory 2009; 55(1-2):
23-30.
29. Yamada M, Sasaki S, Murakami K, Takahashi Y,
Uenishi K; Japan Dietetic Students' Study for
Nutrition and Biomarkers Group. Association oftrans fatty acid intake with metabolic risk factors
among free-living young Japanese women. Asianand Pacific Journal of Clinical Nutrition 2009;18(3): 359-371.

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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 FY2009.
Apart from the faculty staffs, two secretaries, four
doctoral candidates (three foreign students), six
master course students (including two foreign
students), one post-doctoral fellow and three research
fellows are working in the department. There are nine
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311

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
Asia-Pacific –Elucidation of Health Impact:
Most communities in Asia-Pacific undergo a very
rapid transition from traditional subsistence to casheconomy agriculture. Such transition entails
introduction and release-accumulation of chemical
substances, such as pesticides and food additives(through the purchase of processed foods), into the
local ecosystem, which in turn would affect not only
the health and survival of the inhabitants, but also thesafety of local produce. Choosing six regions that
represent diversified environments in Asia-Pacific, we(1) describe such transition and their environmental
consequences in detail, (2) investigate theinterrelationship between the transitions and thechanges of local chemical environments, and (3)examine their health impact among the individuals in
the target areas. Final goal of the study will be to
make a policy recommendation to minimize
unnecessary adverse effects of such transition. 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.
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. This year site visits were made and thetarget communities have been selected incollaboration with Thai counterpart institutions. In
West Java, Indonesia, we did a survey regarding thesystem for health information gathering and regarding
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.
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.
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.

312

References(1) Suzuki Y, Niwa M, Yoshinaga J, Watanabe C,
Mizumoto Y, Serizawa S, Shiraishi H. (2009)
Exposure assessment of phtalate esters inJapanses pregnant women by using urinary
metabolite analysis. Environmental Health andPreventive Medicine 14, 180-187(2) Ohtani-Kaneko R, Iwafuchi M, Iwakura T,
Muraoka D, Yokosuka M, Shiga T, Watanabe C.
(2009) Effects of estrogen on synapsin I
distribution in developing hypothalamic neurons.
Neurosci Res. 66(2):180-188(3) Parajuli RP, Umezaki M, and Watanabe C"Behavioral and Nutritional Factors andGeohelminth Infection among Two Ethnic
Groups in the Terai Region, Nepal" American
Journal of Human Biology 21, 98-104 (2009)(4) Yoshioka W, Akagi T, Nishimura N, Shimizu H,
Watanabe C, and Tohyama C. (2009) Severe
toxicity and cycolooxiygenase (COX)-2 mRNA
increase by lithium in the neonatal mouse kidney.
Journal of Toxicological Sciences 34, 519-525(5) Kondo, K., Lee, JS., Kawakubo, K., Kataoka, Y.,
Asami, Y., Mori, K. and Umezaki, M. (2009)
Association between daily physical activity andneighborhood environments. Environmental
Health and Preventive Medicine,14(3):196-206(6) Fukuyama, S., Watanabe, C., Umezaki, M.,
Ohtsuka, R.(2009) Twenty years' demographic
change in sedentes and migrants of aninternational migrant-sending community in
Tonga. Journal of Biosocial Science, 41(1):71-81(7) Ohtani-Kaneko R, Iwakura T, Iwafuchi M,
Muraoka D,Yokosuka M, Shiga T, Watanabe C.
(2010)In vitro effects of bisphenol A on
developing hypothalamic neurons. Toxicology (inpress)(8) Uda S (2010)The Behavior of Fishers After
Implementation of the Project to Exterminate
Nonindigenous Fish in Lake Biwa, Japan.Human
Ecology. Vol.38(2)(9) Umezaki M, and Jiang HW. (2009) Changing
adaptive strategies of two Li ethnic minority
villages in a mountainous region of Hainan Island,
China. Southeast Asian Studies 47: 348-362.
(10) 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.

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Department of
Biomedical Chemistry
Professor
Kiyoshi Kita, Ph.D.

Associate Professor
Yoh-ichi Watanabe, Ph.D.

Research Associate
Kimitoshi Sakamoto, Ph.D.,

Homepage

Shigeo Yoshinari, Ph.D.

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

Introduction and Organization
Aim of our department is to contribute to global
health and welfare from basic research. Our
department, formerly named Biochemistry andNutrition was renamed on April 1st, 1996 to The
Department of Biomedical Chemistry as newly
affiliating with Biomedical Science Division ofInternational Health, Graduate School of Medicine,
The University of Tokyo. Prof. Kita has moved fromThe Institute of Medical Science, The University ofTokyo on March 1st, 1998.

Teaching activities
Teaching activity in our department cover a broad
spectrum of biochemistry-oriented life sciences frompremise to frontiers and in either conceptual orexperimental point of view
Graduate Course: Biochemistry and Nutrition I, IIThis course is comprised of lectures and seminars
to provide basic concepts and newer vistas forunderstanding nutrition with special reference tobiochemistry and molecular biology. These include
the structure and function of biomolecules,
metabolism, its regulation, and underlying mechanism
at either molecular, cellular and systemic level.

Undergraduate Course: Biochemistry, Molecular
Biology, Laboratory Method in Health Science,
Physiological
Chemistry,
Nutrition,
MedicalChemistry, Practice on Medical Chemistry,Parasitology.

Research activities
Energy metabolism is essential for the survival,continued growth and reproduction of livingorganisms. From the standpoint of biological
adaptation, we have been studying on the molecularmechanism of energy transducing systems such as
mitochondrial and bacterial respiratory chain. In
addition, we are interested in the basic biologicalreactions such as protein synthesis. Our research havebeen focusing on
I. Human mitochondria
1) succinate-ubiquinone reductase
2) mitochondrial myopathy
II. Ascaris suum and Caenorhabditis elegans
1) molecular mechanism of adaptation to low
oxygen tension (regulation of gene expressionof mitochondrial proteins)2) mitochondrial fumarate reductase (structure
function relationship, enzyme evolution)

3143) C. elegans as a model system of parasitic
nematode (expression of foreign genes or
cDNAs, gene knockout)
III. Parasitic protozoa (Plasmodium falciparum ,Trypanosoma
brucei,
Trypanosoma
cruzi,
Cryptosporidium)1) characterization of mitochondria as a target forthe chemotherapy2) molecular biology of mitochondrial DNA3) structure based drug design (SBDD)
IV. Protein synthesis
1) Mitochondrial protein synthesis
2) Biogenesis of cytoplasmic ribosomes

References
1. Identification of New Inhibitors for Alternative
NADH Dehydrogenase (NDH-II). Mogi, T.,
Matsushita, K., Murase, Y., Kawahara, K.,
Miyoshi, H., Ui, H., Shiomi, K., Ōmura, S. andKita, K. (2009) FEMS Miclobiol. Lett. 291,
157-161
2. Mitochondrial Dehydrogenases in the Aerobic
Respiratory Chain of the Rodent Malaria Parasite
Plasmodium yoelii yoelii. Kawahara, K., Mogi,
T., Tanaka, Q. T., Hata, M., Miyoshi, H. and Kita
K. (2009) J. Biochem. 145, 229-237
3. Antibiotics LL-Z1272 identified as novel
inhibitors
discriminating
bacterialandmitochondrial quinol oxidases. Mogi, T., Ui H.,
Shiomi, K., Ōmura, S., Miyoshi, H. and Kita, K.
(2009) Biochim Biophys. Acta (Bioenergetics)
1787, 129-133
4. Fasting induced hypothermia and reduced energy
production in mice lacking Acetyl-CoA
Synthetase 2. Sakakibara, I., Fujino, T., Ishii, M.,
Tanaka, T., Shimosawa, T., Miura, S., Zhang, W.,
Tokutake, Y., Yamamoto, J., Awano, M., Iwasaki,S., Motoike, T., Okumura, M., Inagaki, T., Kita,
K., Ezaki, O., Naito, M., Kuwaki, T., Chohnan, S.,
Yamamoto, T., Hammer, R. E., Kodama, T.,
Yanagisawa, M. and Sakai, (2009) Cell

Metabolism 9, 191-202
5. Novel Mitochondrial Complex II Isolated from
Trypanosoma cruzi is Composed of Twelve
Peptides Including a Heterodimeric Ip Subunit.
Morales, J., Mogi, T., Mineki, S., Takashima, E.,
Mineki, R., Hirawake, H., Sakamoto, K., Ōmura,S. and Kita, K. (2009) J. Biol. Chem. 284,7255-7263
6. The Plasmodium HU homolog, which binds theplastid DNA sequence-independent manner, isessential for the parasite’s survival. Sasaki, N.,
Hirai, M., Maeda, K., Yui, R., Itoh, K., Namiki, S.,
Morita, T., Hata, M., Murakami-Murofushi, K.,
Matsuoka, H., Kita, K., Sato, S. (2009) FEBS
Lett. 583, 1446-1450
7. Biochemical and spectroscopic properties ofcyanide-insensitive insensitive quinol oxidasefrom Gluconobacter oxydans. Mogi T., Ano Y.,
Nakatsuka T., Toyama H., Muro A., Miyoshi H.,
Migita C. T., Ui H., Shiomi K., Ōmura S., Kita K.
and Matsushita K. (2009) J. Biochem. 146,
263-271
8. Siccanin rediscovered as a species-selective
succinate dehydrogenase inhibitor. Mogi, T.,
Kawakami, T., Arai, H., Igarashi, Y., Matsushita,K., Mori, M., Shiomi, K Ōmura, S., Harada, S.
and Kita, K. (2009) J. Biochem. 146, 383-387
9. Functional importance of Crenarchaea-specificextra-loop revealed by an X-ray structure of ahetero-tetrameric
crenarchaeal
splicing
endonuclease. Yoshinari, S., Shiba, T., Inaoka,
D., Itoh, T., Kurisu, G., Harada, S., Kita, K., and
Watanabe, Y. (2009) Nucleic Acids Research,
37, 4787-4798
10. Polymyxin B identified as an inhibitor ofaternative
NADH
dehydrogenaseandmalate:quinone
oxidoreductase
fromtheGram-positivebacterium
Mycobacterium
smegmatis. Mogi, T., Murase, Y., Mori, M.,
Shiomi, K., Ōmura, S., Paranagama, M. P. andKita, K. (2009) J. Biochem. 146, 491-499

315

11. Freezing survival of the nematode Caenorhabditis
elegans in the presence of a cryoprotectant.
Hayashi, M., Oguma, T., Amino, H., Kita, K. andMurase, N. (2009)
Cryobiology andCryotechnology, 55, 9-22
12. Regulation of succinate-ubiquinone reductase andfumarate reductase activities in human complex IIby phosphorylation of its flavoprotein subunit.
Tomitsuka, E., Kita, K. and Esumi, H. (2009) Proc.
Jap. Acad. B85, 258-265
13. Gain and loss of an intron in a protein-coding
gene in Archaea: the case of an archaeal RNA
pseudouridine synthase gene. Yokobori, S., Itoh,T., Yoshinari, S., Nomura, N., Sako, S., Yamagishi,A., Oshima, T., Kita, K. and Watanabe, Y. (2009)
BMC Evol. Biol.
http://www.biomedcentral.
com/1471-2148/9/198
14. Crystallization of mitochondrial rhodoquinolfumarate reductase from the parasitic nematode
Ascaris suum with specific inhibitor, flutolanil.
Osanai, A., Harada, S., Sakamoto, K., Shimizu, H.,
Inaoka, D. K., and Kita, K. (2009) Acta
Crystallographica, F65, 941-944
15. Identification of mitochondrial Complex II
subunits SDH3 and SDH4 and ATP synthasesubunits a and b in Plasmodium spp. Mogi, T. andKita, K. (2009) Mitochondrion, 9, 443-453
16. Crystallization and preliminary X-ray analysis of
aspartate transcarbamoylase from theparasitic
protist Trypanosoma cruzi. Matoba, K., Nara, T.,
Aoki, T., Honma, T., Tanaka, A., Inoue, M.,
Matsuoka, S., Inaoka, D.K., Kita, K. and Harada,S. (2009) Acta Crystallographica, F65, 933-936
17. Three redox states of Trypanosoma brucei
alternative oxidase identified by infrared
spectroscopy and electrochemistry. Maréchal, A.,
Kido, Y., Kita, K. Moore, A. and Rich, P. (2009) J.
Biol. Chem. 284, 31827-31833
18. Visualization of mitochondrial and apicoplast
nucleoids in the human malaria parasite

Plasmodium falciparum by SYBR Green I and
PicoGreen staining. Sano-Maeda, K., Sato, S.,
Ueda, T., Yui, R., Itoh, K., Hata, M., Nakano, A.,
Kita, K., Murakami-Murofushi, K. and Sasaki, N.
(2009) Cytologia, 74, 449-455

School of Public Health
1. Epidemiology and Health Sciences

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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

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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.

availability in relation to food intake in young
Japanese women. Nutrition 2009; 25: 640-6.
7. Murakami K, Sasaki S, Okubo H, Takahashi Y, theFreshmen in Dietetic Courses Study II Group.
Neighborhood socioeconomic status in relation todietary intake and body mass index in female
Japanese dietetic students. Nutrition 2009; 25:745-52.
8. Murakami K, Sasaki S, Takahashi Y, Uenishi K, theJapan Dietetic Students' Study for Nutrition andReferences

Biomarkers Group. Neighborhood socioeconomic
1. Ohfuji S, Miyake Y, Arakawa M, Tanaka K, Sasaki

disadvantage is associated with higher ratio of

S. Sibship size and prevalence of allergic disorders

24-hour urinary sodium to potassium in young

in Japan: The Ryukyus Child Health Study. Pediatr

Japanese women. J Am Diet Assoc 2009; 109:

Allergy Immunol. 2009; 20: 377-84.

1606-11.

2. Ohsawa M, Itai K, Tanno K, Onoda T, Ogawa A,

9. Okamoto K, Kihira T, Kobashi G, Washio M, Sasaki

Nakamura M, Kuribayashi T, Yoshida Y, Kawamura

S, Yokoyama T, Miyake Y, Sakamoto N, Inaba Y,

K, Sasaki S, Sakata K, Okayama A. CardiovascularNagai M. Fruit and vegetable intake and risk ofrisk factors in the Japanese northeastern rural

amyotrophic

population. Int J Cardiol 2009; 137(3): 226-35.

Neuroepidemiology 2009; 32: 251-6.

lateralsclerosis

inJapan.

3. Murakami K, Sasaki S, Takahashi Y, Uenishi K, the10. Murakami K, Miyake Y, Sasaki S, Tanaka K, Ohya

Japan Dietetic Students' Study for Nutrition and

Y, Hirota Y, the Osaka Maternal and Child Health

Biomarkers Group. Monetary cost of self-reported

Study Group. Education, but not occupation ordiet in relation to biomarker-based estimates ofhousehold income, is positively related to favorable

nutrient intake in young Japanese women. Publicdietary intake patterns in pregnant Japanese women:

Health Nutr 2009; 12(8): 1290-7.

the Osaka Maternal and Child Health Study. Nutr

4. Asakura K, Sasaki S, Murakami K, Takahashi Y,

Res 2009; 29: 164-72.

Uenishi K, Yamakawa M, Nishiwaki Y, Kikuchi Y,

11. Maruyama K, Iso H, Sasaki S, Fukino Y. The

Takebayashi T, the Japan Dietetic Students Study for

association between concentrations of green tea andNutrition and Biomarkers Group. Iron intake does

blood glucose levels. J Clin Biochem Nutr 2009;not significantly correlate with iron deficiency

44(1): 41-5.

among young Japanese women: a cross-sectional

12. Koitaya N, Ezaki J, Nishimuta M,Yamauchi J,

study. Public Health Nutr 2009; 12(9): 1373-83.

Hashizume E, Morishita K, Miyachi M, Sasaki S,

5. Murakami K, Sasaki S, Takahashi Y, Uenishi K, theIshimi Y. Effect of low dose vitamin K2 (MK-4)

Japan Dietetic Students' Study for Nutrition andsupplementation on bio-indices in postmenopausal

Biomarkers Group. Monetary cost of dietary energy

Japanese woman. J Nutr Sci Vitaminol (Tokyo)

is negatively associated with BMI and waist

2009; 55(1): 15-21.

circumference, but not with other metabolic risk

13. Toyoshima H, Masuoka N, Hashimoto S, Otsuka R,

factors, in young Japanese women. Public Health

Sasaki S, Tamakoshi K, Yatsuya H. Effect of the

Nutr 2009; 12(8): 1092-8.

interaction between mental stress and eating pattern

6. Murakami K, Sasaki S, Takahashi Y, Uenishi K, theJapan Dietetic Students' Study for Nutrition andBiomarkers

Group.

Neighborhood

food store

on body mass index gain in healthy Japanese maleworkers. J Epidemiol 2009; 19(2): 88-93.
14. Murakami K, Miyake Y, Sasaki S, Tanaka K, Ohya

319

Y, Hirota Y, the Osaka Maternal and Child Healthof dietary intake of sodium and potassium on blood

Study Group. Monetary diet cost is associated withpressure determination. J Hum Genet 2009; 54(8):not only favorable but also unfavorable aspects of

474-8.

diet in pregnant Japanese women: the Osaka

22. Ohta H, Kuroda T, Onoe Y, Orito S, Ohara M, Kume

Maternal and Child Health Study. Environmental

M, Harada A, Tsugawa N, Okano T, Sasaki S. The

Health Insights 2009; 2: 27-35.

impactoflifestylefactorsonserum

15. Miyake Y, Tanaka K, Sasaki S, Kiyohara C, Ohya Y,

25-hydroxyvitamin D levels: a cross-sectional study

Fukushima W, Yokoyama T, Hirota Y. Breastfeedingin Japanese women aged 19-25 years. J Bone Minerand atopic eczema in Japanese infants: The Osaka

Metab 2009; 27: 682-8.

Maternal and Child Health Study. Pediatric Allergy
and Immunology 2009; 20: 234-41.

23. Miyake Y, Sasaki S, Tanaka K, Ohfuji S, Hirota Y.
Maternal fat consumption during pregnancy and risk

16. Okamoto K, Kihira T, Kondo T, Kobashi G, Washioof wheeze and eczema in Japanese infants aged

M, Sasaki S, Yokoyama T, Miyake Y, Sakamoto N,

16-24 months: the Osaka Maternal and Child HealthInaba Y, Nagai M. Lifestyle factors and risk ofStudy. Thorax 2009; 64(9): 815-21.

amyotrophic lateral sclerosis: a case-control study inJapan. Ann Epidemiol 2009; 19: 359-64.

calcium, and vitamin D intake in pregnancy and17. Poudel-Tandukar K, Nanri A, Matsushita Y, Sasaki S,
Ohta M, Sato M, Mizoue T.

24. Miyake Y, Sasaki S, Tanaka K, Hirota Y. Dairy food,

Dietary intake ofwheeze and eczema in infants. Eur Respir J 2009;35(6): 1228-34.

alpha-linolenic acid and linoleic acid is inversely

25. Oka H, Akune T, Muraki S, En-yo Y, Yoshida M,

associated with serum C-reactive protein levels

Saika A, Sasaki S, Nakamura K, Kawaguchi H,

among Japanese men. Nutr Res 2009; 29: 363-70.

Yoshimura N. Association of low dietary vitamin K

18. Murakami K, Sasaki S, Takahashi Y, Uenishi K,

intake with radiographic knee osteoarthritis in the

Watanabe T, Kohri T, Yamasaki M, Watanabe R,

Japanese elderly population: dietary survey in a

Baba K, Shibata K, Takahashi T, Hayabuchi H, Ohki

population-based cohort of the ROAD study. J

K,

Orthop Sci 2009; 14(6): 687-92.

SuzukiJ.

Association

betweenhardness(difficulty of chewing) of the habitual diet andpremenstrual symptoms in young Japanese women.
Environmental Health Insights 2009; 3: 53-61.
19. Yamada M, Sasaki S, Murakami K, Takahashi Y,
Uenishi K; for the Japan Dietetic Students' Study for
Nutrition and Biomarkers Group. Association oftrans fatty acid intake with metabolic risk factors
among free-living young Japanese women. Asia Pac
J Clin Nutr 2009; 18: 359-71.
20. Yokoyama Y, Suzukamo Y, Hotta O, Yamazaki S,
Kawaguchi T, Hasegawa T, Chiba S, Moriya T, Abe
E, Sasaki S, Haga M, Fukuhara S. Dialysis staff
encouragement and fluid control adherence inpatients on hemodialysis. Nephrol Nurs J 2009; 36:
289-97.
21. Osada Y, Miyauchi R, Goda T, Kasezawa N, Horiike
H, Iida M, Sasaki S, Yamakawa-Kobayashi K.
Variations in the WNK1 gene modulates the effect320

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
skillsforevidence-based practice, and to empirically evaluate
the health care system/policy for further improvementof the quality of health care in this country. For thispurpose, the Department puts a unique emphasis onquantitative analytic methods and inter-disciplinary
theories across economics, epidemiology, and othersocial sciences.

cost-effective analysis, technology assessment ofsurgical treatment, and hospital management. In theapplied course, the students are required to set a
research hypothesis, design a study, and prepare an
own study protocol for fund proposal. The lecture
course on health economics provides an overview ofhealth care systems in this country and a systematic
review on basic micro-economic theories and costeffectiveness analysis. The applied course offers thestudents an opportunity for hands-on training of actual
economic evaluation of health care and technologies.
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 one doctoral student and 4
master students for the fiscal years of 2009.

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. Several
questionnaire tools for evaluating patient’s quality oflife have been developed and validated in the area of

321

orthopedic surgery. In the collaboration with the
Department of Health Management and Policy in 22nd
Medical Research Center in the University of Tokyo
Hospital, the Department also contributes to thedevelopment and refinement of Japanese original
patient classification system, Diagnosis Procedure
Combination (DPC). DPC database allows a uniqueand detailed analysis on the process of care in acutecare hospitals in this country. DPC database also
provides resource diagnosis in hospital levels as well
as regional levels, when combined with other data
sources such as the Patient Survey, and hospitalfinancial statement. Socioeconomic status affects
people’s health, which is another research focus in thisDepartment. The association between income
distribution and regional health status are widely
acknowledged across countries including this country,
yet the mechanism is still a matter of debate. The
Department has contributed to an ongoing research ofsocioeconomic status and health among elderly
population in the collaboration with the School of
Economics of the University of Tokyo and the
Research Institute of Economic, Industry, andTechnology.
Since health care services should be delivered
efficiently under the publicly funded health caresystem, economic evaluation of new health caretechnologies is one of the research topics in the
Department. Molecular target therapies of cancer,
which are effective but costly, attract the great concern.
Based on the modeling of therapies and efficacy data
in clinical trials, cost effectiveness of the therapies
have been evaluated. Preventive services such as
smoking cessation therapies are also important field
for economic evaluation. We also contribute for the
piggy bag style data collection for economic
evaluation in the clinical trials and epidemiologicalprospective studies. Standardized methods of datacollection for both costs and outcomes in economic
evaluations should be established through these
activities. If the result of economic evaluation would
be used as the reference for coverage decision of newtechnologies under publicly funded health care system,
acceptable thresholds of payment must be discussed.
International comparative survey was conducted to see
people’s willingness to pay for additional year of life
in perfect condition.

References
1) 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.
2) 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 Aug-Oct;21(4-5):323-8.
3) 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 of anationwide cost database of acute-care hospitals
in Japan. J Eval Clin Pract. 2009 Aug;15(4):626-33.
4) 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.
5) Igarashi A, Takuma H, Fukuda T, Tsutani K.
Cost-utility analysis of varenicline, an oral
smoking-cessation drug, in Japan. Pharmacoeconomics 2009; 27(3): 247-61.
6) 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.
7) 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.
8) 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.

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Department of HealthCommunication
Professor
Takahiro Kiuchi, M.D., Ph.D.

Homepage

http://www.umin.ac.jp/hc/

Introduction and Organization
The Department of Health Communication wasestablished as part of the newly developed School of
Public Health (professional graduate school) in April
2007, which was derived from the University Hospital
Medical Information Network (UMIN) Center. It
consists of two faculty groups: professors andassociate professors.
Whereas health communication is a major disciplinein the USA and there are many such graduate
programs, our department offers one of only two
health communication programs in Japan. However,
the importance of the health communication disciplineis gradually becoming recognized academically andthroughout society.

Teaching Activities
The Department of Health Communication, within the
School of Public Health, is a newly developed
professional graduate program that aims to foster thedevelopment of medical and public healthprofessionals as well as researchers. We strive to
make the most of our professional activities andexperience at UMIN Center. We provide lectures andpractical instruction in the program. The following is
the current curriculum:[Health Communication Lectures]
1. General Aspects of Health Communication

2. Social Marketing
3. Mass Media and Communication
4. Internet Communication
5. Edutainment
6. Science Communication
7. Hospital Management and Communication
8. Public Health Informatics
9. Communication During Emergency and Disaster10. Publicity in Healthcare organizations
11. Provider-patient Communication
12. Communication Among Healthcare Consumers[Health Communication Practice]
1. Research, Analysis and Evaluation of Websites
2. Website Development
3. Practice of Media Publicity
4. Evaluation of News
5. MBTI (Myers-Briggs Type Indicator)
6. Image / Film Development
We also provide lectures and practical instruction in
medical informatics / economics as part of the PhD
program of the Faculty of Medicine.
In theundergraduate program, Professor Kiuchi presents a
lecture entitled “Medical Literature Informatics.”

Research Activities
The two main characteristics of research studies
conducted through the Department of HealthCommunication, which distinguish them from studies

323

at other medical informatics programs, are thefollowing:

have done a cost-effectivenessinformation technologies.

(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.

(3) Edutainment Research
To disseminate clinical knowledge and information tolaypersons, it is important to consider standards suchas “easy to understand” and “acceptable byunknowledgeable persons.” We focus on studies
related to media, entertainment, and interface design.
For example, we have conducted the development andevaluation of edutainment tools for health education
aimed at type-1 diabetes patients, as a concrete
application.

(2) Targeting health information science, nothealthcare information practiceCurrently, main topics of research studies at mostmedical informatics programs in Japan focus on
information for healthcare practice, such as hospital
information systems, electronic medical record
systems, telemedicine, and electronic billing systems.
In contrast, the Department of Health Communication
has focused on information systems for medical
science, such as medical literature databases, dataregistries for clinical studies, and information systems
for medical education.
The following are current research topics at the
Department of Health Communication:(1) Research in Health Communication
Currently, “health communication” is becoming animportant concept in the distribution of clinical results
for the improvement of population-based clinicaloutcomes. We have conducted health communication
research focusing on knowledge and skills in“informatics” and “communication.”(2) Technological Assessment of Health Information
and Communication Technologies
Although information technology is expected to play
an important role in healthcare, its comprehensive
usefulness, including cost-effectiveness, has beenrarely evaluated. We conducted a literature review in2003 and concluded that there were few costeffectiveness analyses for telemedicine programs eventhough many telemedicine programs have been
implemented throughout many developed countries,
including the USA and Japan. Based on the review, weanalysisfor(4) Research Regarding Medical Management
It is important to make proper judgments anddecisions in order to achieve optimal outcomes, a
process which is termed “management.” However,scientific research and evaluations related to patient
safety, quality improvement and medical management
have not been well established in Japan. We focus on
the Theory of Constraint (TOC) as a tool for medical
management from a perspective of information
utilization, and conducted research on medical error
prevention and quality improvement.
(5) Research Related to UMIN Activities
Most systems developed at the UMIN Center havebeen subjects for research. In particular, we publishedand reported systems utilizing advanced technologies
and having scientifically meaningful concepts at
academic conferences.
(6) Information Systems for Clinical Epidemiologic
Studies
We have developed and applied information systems
for clinical epidemiological studies. Recently, we havefocused on research in electronic formats andstandardization that are related to clinical research,such as the Clinical Data Interchange Standards
Consortium (CDISC). We utilized the achievements
attained by the medical research data center at the
UMIN.
(7) Research Regarding the Security of an Information

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Network
The study addresses a Virtual Private Network (VPN),
and secure transactions with electronic mail(encryption), which have been also utilized for systemmanagement at the UMIN Center.
(8) Research Plan Development; A Statistical Analysisof Clinical Studies
In cooperation with clinicians, we have developed
clinical research plans and support statistical analysis.
In addition, we have done data mining research for
information extraction, knowledge discovery andprognostic modeling. Furthermore, we have conducted
research and development for decision support
systems to utilize the results in clinical practice.
(9) Patient Registry System for Quality Improvement
Many data have been accumulated in the existing
hospital information system, such as electronic record
systems; however, these data have not been utilized
significantly for quality improvement, patient safety
or medical management. We have deployed aninteractive web-based patient registry system with areal-time feedback system of quality indicators (QIs).

References
1. The Pemphigus Study Group (Kiuchi T as a memberof the Independent Data and Safety Monitoring
Committee). A ramdamized double-blind trial of
intravenous immunoglobulin for pemphigus. Journalof the American Academy of Dermatology
60(4):595-603, 2009

School of Public Health
2. Behavioral Health Sciences

326

Department ofSocial Gerontology
Professor
Ichiro Kai, M.D., M.P.H.

Lecturer
Miyako Takahashi, M.D., Dr.Hlth.Sc.

Associate
Tami Saito, M.Hlth.Sc.

Homepage

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

Introduction and Organization
It is often voiced from the general public that recent
advancement of medicinal technology would notnecessarily lead to the happiness of people: Life
prolongation technology enables even the terminally
ill to live for a considerable period. How to use thetechnology is a serious problem in clinical practice.
Also, there is evidence that the prolongation of life
expectancy for the elderly does not mean the
prolongation of health and productivity, but that ofmorbidity. Taking another example, we areexperiencing ethical dilemmas with the application of
medical technology such as genetic screenings andorgan transplantation. When we turn to the worldwide
situation regarding health, we will find poverty andunequal distribution in terms of health resources andoutcomes.
The department is studying these health-related
problems from social perspective, many of which areoften difficult to decide upon. Major topics include
elderly health, terminal care, medical ethics andinternational health among others. We are currently
conducting several research projects as described
below.
Our educational activities include lectures, practicaltraining and supervision of writing theses for students
in graduate level as well as undergraduate level. The

department consists of one professor, one lecturer, one
associate, 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

327

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: Japan approves brain death to increase
donors, but will it work?
Lancet 374: 1403-1404, 2009
2. Yamazaki H, Slingsby BT, Takahashi M, et al.:Characteristics of qualitative studies in influential
journal of general medicine: A critical review.
BioScience Trends 3(6): 202-209, 2009
3. Taira N, Sawaki M, Takahashi M, et al.:Comprehensive geriatric assessment in elderly
breast cancer patients.
Breast Cancer DOI 10.1007/s12282-009-0167-z
4. Minori K, Kataoka A, Yamaguchi H, et al.:Preoperative u-PAR gene expression in bonemarrow indicates the potential power of recurrence

328

in breast cancer cases.
Ann Surg Oncol 16(7): 2035-2041, 2009
5. Ohta M, Kai I: Factors affecting attitudes towardcare of elderly mothers: Urban versus agriculturalareas.
Arch Gerontol Geriatr
DOI 10.1016/j.archger.2009.11.007
6. Iwasa H, Yoshida Y, Kumagai S, et al.:Depression status as a reliable predictor offunctional decline among Japanese communitydwelling older adults: A 12-year population-based
prospective cohort study.
Int J Geriatr Psychiatry 24: 1192-1200, 2009
7. Iwasa H, Masui Y, Gondo Y, et al.; Personality
and participation in mass health checkups among
Japanese community-dwelling elderly.
J Psychosom Res 66: 155-159, 2009

School of Public Health
3. Health Services Sciences

330

Department of Clinical
Information Engineering
Professor
Hiroshi Oyama, M.D., Ph.D.

Homepage:

http://home.cie.m.u-tokyo.ac.jp/

Introduction and Organization
Information engineering in Japan places a great dealof weight on computer hardware, software, and dataprocessing. It is a discipline that seeks objective dataand emphasizes the conception of new methods ofdata transfer, storage, processing, and input/output. It
also targets research on developing computer devices
and systems.
Reviewing the history of the application of computersin medicine, calculating machines for supporting
scientists and technologists first appeared in the 1950s.
In the 1960s, computers were used for accounting andvarious statistics. The personal computer appeared in
the 1980s and was adopted for personal use in many
professions. The systematization of large hospitals,
such as university hospitals, pushed ahead rapidly. In
the 1990s, the computer began to be used as a tool tohelp human thinking, such as in presentations, design,and discovery. When computers became connected toeach other through the internet, the distribution of
information became very easy and rapid, not only
within organizations, but also internationally. In 2003,
a high-quality, "finished" sequence of the humangenome was completed. At the dawn of thetwenty-first century, bioinformatics appeared as a new
discipline, one that uses applied mathematics,
informatics, statistics, computer science, andbiochemistry to solve biological problems. In
medicine, advanced information technologies havebeen applied to health information infrastructures,electrical clinical guidelines, and knowledge
navigation systems.

In response to the needs of the time, the Departmentof Clinical Information Engineering (CIE) wasestablished at the School of Public Health in April
2007. Its predecessor was the clinical informationengineering division of clinical bioinformatics, using
Special Coordination Funds for Promoting Scienceand Technology from the Ministry of Education,
Culture, Sports, Science, and Technology, of Japan.

Teaching activities
The purpose of the Department of Clinical
Information Engineering is to nurture talented people
who have special knowledge and skills at aninternational level in order to apply advanced
information technologies to practical projects inclinical medicine and the health sciences. It offers
courses on information system design, development
methodology, evaluation and project management inbiomedicine, health care and public health in the
School of Public Health, and data mining and virtual
reality for clinical decision-making in social medicine.
At present, the department has only one faculty
member: Prof. Hiroshi Oyama, M.D., Ph.D. However,famous visiting lecturers and researchers from the
National Cancer Center and other universities havegiven lectures here, furthering our hope of becoming aworld leader in this field.
The education of graduate students is based on weekly
conferences at which the students present the progresson their own research projects and discuss their future
directions.

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Research activities
Our research covers the biomedical computer
applications that focus on biomedical data (collection,
analysis, and representation). It constitutes a
combination of information science, computer science,and clinical science designed to assist in the
management and processing of data, information, andknowledge to support the practice and delivery ofclinical care. Our laboratory is engaged in thefollowing research activities:(1) Medical Decision-making: We focus on how to
improve health outcomes by advancing
systematic approaches to clinical decisionmaking and policy formation in health care using
information engineering methodology (IEM),
especially electrical clinical guidelines andencoded knowledge.
(2) Data Mining & Knowledge Discovery from
Databases: It is necessary to collate
heterogeneous information, such as the clinicalindications for a drug, drug side effects,
pharmacokinetics, metabolic pathways, and drug
response
genes
forsinglenucleotide
polymorphisms (SNPs). These data are
distributed and managed in various clinicaldatabases. We are studying ways to integrate
distributed biomedical data and knowledge
mining with virtualized database technologies,
such as auto-indexing and technical term
identification algorithms.
(3) Computer Graphics & Virtual Reality (VR) for
Medical Science: Our research has three goals:(1) to improve the living conditions of in-patientswith limited physical activity by providing virtual
experiences; (2) to develop new diagnostic
methods using medical imaging; and (3) todevelop a surgical edutainment and preoperative
surgical planning support system in virtual space.
The advantages of simulating surgical procedures
using VR techniques include: (1) practicing thesurgical procedure and image-based training; (2)planning the surgical procedure for individual
patients preoperatively using VR images modeledfrom the patient's preoperative computed
tomography (CT) or magnetic resonance (MR)images, in collaboration with the Department of

Neurosurgery; (3) allowing supervisors toevaluate a procedure objectively; and (4) helping
patients and their families to better understand thesurgical procedure before and after the operation.
(4) Social Information Engineering for Public Health(Public Health Informatics): Our laboratory
researches new tools and methodologies for
applying information and computer science andtechnology to public health practice, research,and learning. This has just started. At present, weare studying differences in the computerization of
public health in the US and Japan.

References
1. Tanaka H, Watanabe K, Ma M, Hirayama M,
Kobayashi T, Oyama H, Sakaguchi Y, Kanda M,
Kodama M, Aizawa Y. The Effects of
gamma-Aminobutyric Acid, Vinegar, and Dried
Bonito on Blood Pressure in Normotensive andMildly or Moderately Hypertensive Volunteers. J
Clin Biochem Nutr. 2009 Jul;45(1):93-100. Epub
2009 Jun 30. PubMed PMID: 19590713; PubMed
Central PMCID: PMC2704332.
2. Watanabe K, Arozal W, Tanaka H, Ma M, Satoh S,
Veeraveedu PT, Kobayashi T, Oyama H, Sakaguchi
Y. Beneficial Effect of Food Substitute Containing
L-Arginine, omega-3 Poly Unsaturated Fatty Acid,and Ribonucleic Acid in Preventing or Improving
Metabolic Syndrome: A Study in 15 Overweight
Patients and a Study of Fatty Acid Metabolism in
Animals.
J
Clin
BiochemNutr.
2009
May;44(3):266-74. Epub 2009 Apr 25. PubMed
PMID: 19430616; PubMed Central PMCID:
PMC2675026.
3. Kin T, Oyama H, Kamada K, Aoki S, Ohtomo K,
Saito N. Prediction of surgical view ofneurovascular decompression using interactive
computer graphics. Neurosurgery. 2009 Jul; 65(1):121-8; discussion 128-9.

Endowed Department

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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
2009,
the
Department
ofPharmacoepidemiology consists of a professor(Kiyoshi Kubota), two associates (Takafumi
Nishimura and Tsugumichi Sato), 4 teaching assistants,
2 clerical assistants and one technical assistant.
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 2nd 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 teaching activities
inside University of Tokyo including School of
Medicine, School of Pharmacy, and School ofIntegrated Health Sciences. 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 and school ofpharmacies ofcolleges and universities in Japan who
are to design a study using pharmacoepidemiology
methodologies and/or to educate students. The
first seminar was held in 2006. In 2009, the 4th
seminar is being conducted. In addition from 2009,
the department led the activities to establish a 3-monthcourse of the “training course for experts inpharmaceutical affairs” held by Pharmaceutical andMedical Device Regulatory Science Society of Japan.
This training course is to educate those in drug
companies who are in charge of evaluating
spontaneous reports collected by the drug company.
Furthermore, the department has been a driving
force to publish a textbook in Japanese forpostgraduate students and those working in drug
companies.
The textbook will be publishedsometime in 2010.

334

Research activities
Like
other
epidemiologicalstudies,
pharmacoepidemiology studies are those on people
and the study requires an organization which supports
the study.
NPO Drug Safety Research Unitestablished in 2001 has been working to support
various studies including pilot studies of
Prescription-Event
MonitoringinJapan,
acase-control study on the association between
non-steroidal anti-inflammatory drugs and uppergastrointestinal bleeding, and handling of information
on serious adverse event experienced in theinvestigator-led 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 of anotherstudy 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 projected that claims
database will be formed by 2011 and researches may
be allowed to use the database for the research
purposes. Some relatively small data sources ofclaims data are already commercially available andthe department started to search for the effective useof Japanese claims database. The method developedin the study will promote a better use of large
nation-wide claims database which the researchers
will be allowed to use in 2011.

References
1. Watanabe H, Kamijima Y, Sato T, Kaufman DW,
Kubota K. Ex-drinking may be a surrogate forunmeasured risk factors for upper gastrointestinal
bleeding: reappraisal and an additional survey ofsubjects from a case-control study in Japan. Eur
J Epidemiol 2009; 24: 143-7.
2. Horiuchi S, Yaju Y, Koyo M, Sakyo Y, Nakayama
K. Evaluation of a web-based graduate continuing
nursing education program in Japan: A
randomized controlled trial. Nurse Educ Today;
2009; 29: 140-9.
3. Tsutani K, Yaju Y, Sato Y, Yoshida M, Yamaguchi
N. Sharp increase of the access to the Japanesetranslations of Cochrane Systematic Reviews’
abstracts after the introduction of non-login
system. 17th Cochrane Colloquium 2009; 10:
11-14.
4. Nobuhiro Ooba, Kiyoshi Kubota. Use of Selected“Control
Events”
in
SignalDetection
Methodology.
Pharmacoepidemiol Drug Saf
2009; 18: S252-S253.
5. Shuko Nojiri, Tsugumichi Sato, Takuhiro
Yamaguchi, Kenichi Gemba, Keisuke Aoe,
Katsuya Kato, Takumi Kishimoto, Kiyoshi
Kubota. Survival of Malignant Mesothelioma in
a Retrospective Survey in the West Part of Japan.
Pharmacoepidemiol Drug Saf 2009; 18: S38S39.
6. Kiyoshi Kubota, Hikaru Watanabe, Tsugumichi
Sato. Risk of Valvular Heart Disease in Patients
Treated with Dopamine Agonists in Japan: A

335

Study
Using
Spontaneous
Reports.
Pharmacoepidemiol Drug Saf 2009; 18: S218S219.
7. Kiyoshi Kubota. Two schemes for risk
management of thalidomide in Japan: double
standard to be resolved. ACPE-Taiwan 2009.
8. Kiyoshi
Kubota.
Monitoringcardiacvalvulopathy in patients using pergolide andcabergoline: some risk minimization action plan isneeded. ACPE-Taiwan 2009.
9. Tsugumichi Sato. Antihypertensive medications
and the incidence of diabetes: cohort study using
claims database in Japan. ACPE-Taiwan 2009.

336

Department of Integrated
Traditional Medicine
Project Associate Professor
Tetsuro Okabe, M.D., Ph.D.

Project Associate
Jing Yu, Ph.D

Homepage http://square.umin.ac.jp/seitai/
Introduction and Organization
In an attempt to investigate the Japanese traditional
herbal medicine, the Department of Integrated
Traditional Medicine was established in 1996 as the
Department of Bioregulatory Function affiliated with
the Department of Medicine and Physical Therapy.
In 1999, the Department of Geriatric Medicine joinedusasan
anotheraffiliatedDepartment.
Pharmacological actions by medicinal herbs have been
intensively investigated not only on allergic or
autoimmune diseases, but also the disorders associatedwith aging process. Therapeutic experiments ofherbal medicine have been carried out by using animal
disease models to clarify the mechanisms of thepharmacological actions. In additions, the biologicalactions of the herbs have been investigated at cellularlevels to clarify the intracellular signaling pathways
induced by the medicinal herbs.
In 2003, traditional medicine was introduced into corecurriculum of medical education program. Since 2004,
lecture of traditional medicine has been
started in this university as an essential study. The
lectures have been served by this department. For
postgraduate education, seminars of traditional
medicine have been held at the university.
To avoid the confusion of similar names in western
medicine, the name of this department “Department of
Bioregulatory Function” was changed to “Department

of Integrated Traditional Medicine” in 2005.
Together with the change in the department name, westarted the translational studies on the physiology andpathology of the traditional medicine to translate thetraditional medicine into scientific medicine. It
required not only the chemical or pharmacologicalstudies but also the biophysical approaches. In
addition, translation from scientific medicine into the
traditional medicine has been also required for better
understanding the integration of both medicine. For
this purpose, free seminars “traditional medicine as alife science” have been started, in which we analyze
and translate the scientific data into the traditional
medicine and also try to integrate both medicines.
Another research interest has been focused on theanti-aging medicine used in ancient traditional
medicine. Recently, hormone supplemented therapy
has been tried for disorders associated with aging inWestern medicine. Some herbs have been shown toexert their pharmacological actions through receptors
for certain hormones. The studies on this theme havebeen intensively performed at the department.
Postgraduate students have been also engaged in bothbasic and clinical sciences. The department provides awide-ranged clinical, training, and research services.
The weekly official activities of our department are ajournal club on Tuesday and research conferences on
Thursday.

337

Clinical activities
We have outpatient clinics on Tuesday, Wednesday,and Friday in the Department of General Medicine.
The diagnosis is made by the western medicine using
blood examinations and imaging studies. After thescientific diagnosis, patients are diagnosed based on
the instructions of the traditional herbal medicine, andtreated mainly with the medicinal herbs.

Teaching activities
As for under-graduate student education, ourdepartment takes a part in systemic lectures for the 4thyear medical students. In systemic lectures,comprehensive presentation for the understanding ofbasic knowledge about the concept, pathogenesis,
pathology, diagnosis and treatment is performed.
In systemic lectures, we also present clinical cases ofrepresentative cases, and try to discuss with thestudents several points for planning the diagnosis andtreatment. Demonstration of some herbs and typical
recipes is also served during the lectures.
Free seminars “traditional medicine as a life science”
are served, in which we analyze and translate thescientific data into the traditional medicine and also
try to integrate the idea from both medicines.
For international experimental educations, a special
lecture on traditional herbal medicine anddemonstration of acupuncture were given for foreign
students from over 40 countries at Harvard Project for
Asian and International Relations Tokyo Conference.
Postgraduate students are served with scientificeducation of molecular cell biology and biophysics.
As for the post-graduate clinical education, we
provide clinical lectures regularly on the use of
traditional herbal medicine.

Research activities
Our
researchfield
coversfromclinical,
pharmacological, biological, and biophysical activitiesof traditional medicinal herbs. We focus on themolecular mechanisms of cell functions andintracellular signaling pathways.

Traditional medicinal herbs such as Ginseng has long
been used as an anti-aging agent in Asian countries.
Our laboratory studies molecular mechanisms ofaction by such anti-aging herbs. Ginsenoside Rb1, amajor constituent of Ginseng
has been demonstrated to exert the biological action asa phytoandrogen. Endocrinological activities ofanti-aging herbs are investigated using various
molecular cell biological approaches including
biochemistry, immunochemistry, molecular biology,
molecular genetics such as gene targeting andtransgenic mouse approaches, molecular biophysics.
Much current interest is focused on the therapeuticpotential of hormone replacement therapy (HRT).
However, one of the major adverse reactions of HRT
is considered to promote cancer growth. It is urgent
for us to elucidate the mechanisms of action by theanti-aging herbs and to compare them with those ofhormones. Subsequently, we compare the biologicalactivities of the anti-aging herbs and their counterpart
hormones. We have demonstrated ginsenoside Rb1
exerts the biological activity through its non-genomic
action on androgen receptors.
Our studies arefocused on endocrinological activities of anti-aging
herbs which are through their genomic 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 reported that some herbal medicines may
be effective for acute episodes of chronic nonspecific
low back pain. Spondylolisthesis is one of the causesof low back or neck pain. Although surgical treatment
is often performed for symptomatic spondylolisthesis,
we have succeeded in herbal therapy for degenerative

338

spondylolisthesis.
Physiology, pathology and therapy of traditional
herbal medicine is based on the principle of thecharacteristic systems biology. According to theguideline of the traditional herbal medicine, we haveexamined the clinical effect by systems therapy withmedicinal herbs in patients with bronchial asthma andessential hypertension. Long- term remission has beenobtained in both disorders. Extensive studies are under
way to elucidate the mechanisms by which systems
therapy exerts the therapeutic activities.

References
Yu , J., Eto, M., Akishita , M., Okabe,T. andOuchi, Y. A selective estrogen receptor modulator
inhibits TNF-α-induced apoptosis by activating
ERK1/2 signaling pathway in vascularendothelial cells. Vascular Pharmacol. 51:21-28,
2009.

339

Department of Metabolome
Professor
Ryo Taguchi, Ph.D.

Associate Professor
Yaoshiya Oda, Ph.D.

Homepage

http://metabo.umin.ac.jp /Introduction and Organization

Teaching activities

Lipidomics became one of the prominent research
fields in metabolomics trough recent advances in mass
spectrometry.
Lipids are classes of molecules
thought to be very important, not only as energy
source or constituents of biological membrane, butalso as functional molecules concerning the many
regulation steps in biological process. Furthermore,
recent research has revealed the roles of lipids, such as
mediators of signal transduction and ligands ofreceptors. Thus analyses of these metabolites seem tobe extremely important to understand global and basic
biological system in the life in combination with other-omics data such as genomics, transcriptomics andproteomics.
Under such circumstances, Department ofMetabolome was settled at February 1st, 2003 by the
donation from Ono Pharmaceutical Company andShimadzu Corporation. And this laboratory has beentightly supported by the Department of cellularsignaling (Prof. Takao Shimizu). At 2008 it was
decided to be expanded for additional three years.
Adding to Prof. Taguchi, Dr. Oda, who is one of theprominent readers in the international proteomics field,
is engaged as an associate professor. Six research
associates are engaged in lipidomics research. 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

340

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 of molecules
such as lipid metabolites. This is caused by 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 the case ofproteomics, it is very difficult to detect small amountsof peptides or proteins in mammalian plasma becauseof very wide dynamic ranges of protein contents inplasma. This is exactly the same in lipid metabolites
in most of biological samples.
For detecting minor but physiologically important
lipid molecules, specified technical strategies should
be appliedin selecting the detection methods
including choice of HP LC system with most effective
columns and that of the most suitable MS systemand collision conditions.
Since electrospray ionization (ESI) is a soft ionization
method, each molecule in a mixture can be detectedwithout any fragmentation. However, in general
only the major peaks will be detected if the sample isinjected as a mixture without any LC separation. Oneof the solutions to this problem is to use specificdetecting methods, such as precursor ion scanning andneutral loss scanning; these scanning modes are often
used for measurement of particular focused
phospholipids.
Soft ionization in mass spectrometry has induced
some paradigm changes in the applications of mass
spectrometry in biological studies.
Effective
insight can be obtained by comprehensive analyses ofmetabolicmolecules
undergenetically,
environmentallyorphysiologicallydifferent

conditions. Matrix assisted laser desorption/ionization(MALDI) is essentially used as off-line methods,
while ESI can be used as a flow system, and is easily
combined with on-line separation systems such as
HPLC or capillary electrophoresis (CE). Sensitivityof detection by ESI essentially depends on theconcentration of molecules in the sample solution.
Thus, for obtaining a highest sensitivity, it is very
important to use low elution rate with small size ofcolumn. For this purpose, capillary or nana LC
system combined with ESI has been used.
Concerning metabolic molecules as target of
metabolome, individual molecular structures aremostly known and relations of each metabolite are
well studied. Thus we can easily imagine their
metabolic linkage from our former knowledge. Fromthese circumstances, we will be able to get effective
data from comprehensive analysis of metabolites bymass spectrometric analyses, for elucidating new
function of enzyme proteins including substratespecificities.
By ESIMS, selective analyses ofindividual molecules in the mixture can be effectively
obtained.
To elucidate the function of lipids, it is necessary toanalyze not only their classes but also their molecularspecies. Thus, the application of mass spectrometry(MS) has become increasingly popular in thelipidomics. As analytical methods for lipidomics, weselected several different approaches in theidentification of lipid molecular species. First one is a
shotgun LC-MS/MS analysis with data dependent
scanning for global identification of lipid molecularspecies, the second one is a structure-related focusedmethod such as precursor ion scanning or neutral loss
scanning. The third one is a sort of targeted method in
combination with theoretically constructed MS/MS
database of lipid search using multiple reaction
monitoring. We constructed this method for detecting
minor lipid metabolites such as oxidized lipids. Even,in this case structural isomers with same m/z value canbe separately detected with partially comprehensive
manner. The choice of these three different types ofmethods seems to be very important for detecting
different class of lipid metabolites. Data from both
first and second types of analyses can be subjected tooursearchengine,“LipidSearch”(http://lipidsearch.jp), and most probable molecular341

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
isomersinphosphatidylcholine 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
biosynthesis in 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

342

of mast cell degranulation. Potent activities oflysophosphatidylthreonine and its 2-deoxy
derivative. J Med Chem. 2009 Oct 8;52(19):5837-63.

Thioesterase activity and subcellular localizationof acylprotein thioesterase 1/lysophospholipase 1.
Biochim Biophys Acta. 2009 Aug;1791(8):797-805.

(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.

(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.

(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.
Zebrafishandmousealpha2,3-sialyltransferases
responsibleforsynthesizing 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.

(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.

343

Department of Clinical
Epidemiology and Systems
Professor
Tutomu Yamazaki, M.D.,Ph.D.

Associate Professor
Daisuke Koide, R.Rh., HIM, Ph.D.

Homepage

http://cbi.umin.ne.jp/dces/index_e.html

Introduction and Organization
The Department of Clinical Epidemiology and
Systems was established in 2007, supported by Banyu
pharmaceutical company. Our department took overand enhanced the function and infrastructures of theClinical Epidemiology Division in the Clinical
Bio-Informatics Research Unit (CBI) which had beenlead by Professor Ryozo Nagai at the Department of
Cardiovascular Medicine, because the unit had been
terminated its five-year program supported by theJapan Science and Technology Agency in 2007 asscheduled.
Our objectives are to develop standards for thetransfer of clinical information and improve thequality of clinical epidemiologic researches in the areaof life-style related diseases and preventive medicine,
because large and longitudinal data are necessary.
Through these activities, we evaluate such standards
and establish academic foundations of “Clinical
Epidemiology and Systems” as well as contribute toprofessional training in this field which will be more
and more required in the future.
In order to facilitate our broad activities, ourorganization is subordinate to the Department of
Cardiovascular Medicine, and works with close
collaboration with the staffs in the Center for
Epidemiology and Preventive Medicine which wasestablished in 2007 because professor Yamazaki isconcurrently the head of the both sections. The staffs
of this center overlap with faculty members in the

Department of Ubiquitous Preventive Medicine which
also took over and enhanced the function andinfrastructures of the Genomic Science Division in the
CBI. Furthermore, these departments work with the
Department of Clinical Trial Data Management in the
22nd Century Medical and Research Center, andprovide consultation on biostatistics and clinicalresearch. Since associate professor Koide has abackground of medical informatics, he develops andsystemizes the standards of information in the area ofclinical epidemiology in collaboration with the
DepartmentofPlanning,
Information
andManagement, the University Hospital Medical
Information
Network(UMIN)
Center,theDepartments of Epidemiology and Biostatistics, andthe Department of 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 2009, we received 61 requests and made 3745
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

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Department of Clinical and Genetic Informatics andrelated departments, Associate Professor Koide andProfessor Yamazaki gave lectures at the Large
Conference Hall of our Inpatients' Ward A on April 17,
and on May 29 in 2009 respectively.
Also, the basic lectures of Medical Writing took
place at the clinical auditorium as an intensive course
on September 3-4 in 2009, hosted by the non-profit
organization of Japan Medical and Scientific
Communicators Association, and under the joint
auspices of the three departments of Clinical
Epidemiology and Systems, Clinical Trial DataManagement, and Ubiquitous Preventive Medicine.
In addition, a public lecture for “Drug Safety
Information from the perspective from Academic” washeld at the Nogizaka school in International
University of Health and Welfare on November 11 in2009.

Research activities
1) Studies of Clinical Epidemiology (Clinical trials,
prospective cohort studies)
Our department facilitates large-scale clinical trials
by executing the data management with computer
servers in our department and in the Japan ClinicalResearch Assist Center. In particular, our department
was in charge of the secretariat for JCAD study which
was comparison of cardiovascular events between
combined and normal therapy for patients withcoronary narrowing.
And studies for clinical epidemiology, such as
monitoring blood pressure at home by using IT andinvestigational researches into new bio-markers forarteriosclerosis have been carried out by analyzing thedatabase in the Center for Epidemiology andPreventive Medicine.
2) Improving Quality of Health Care
As a core member of the quality improvement andassessment committee and chairs of the clinicalpathway working group (WG) and the committee for
quality care at our university hospital, our department
contributes to develop clinical indicators andcomparative studies, especially to take assessment for
renewing the accreditation by Japan Council for
Quality Health Care on December 1-3 in 2009.

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. Ogawa S, Yamashita T, Yamazaki T, Aizawa Y,
Atarashi H, Inoue H, Ohe T, Ohtsu H, Okumura K,
Katoh T, Kamakura S, Kumagai K, Kurachi Y,
Kodama I, Koretsune Y, Saikawa T, Sakurai M,
Sugi K, Tabuchi T, Nakaya H, Nakayama T, Hirai
M, Fukatani M, Mitamura H. for the J-RHYTHM
Investigators Optimal treatment strategy forpatients with paroxysmal atrial fibrillation
Circulation J 2009: 73; 242-8
2. Okura T, Higaki J, Kurata M, Irita J, Miyoshi K,
Yamazaki T, Hayashi D, Kohro T, Nagai R. and
The JCAD Study Investigators Elevated Serum
Uric Acid is an Independent Predictor for
Cardiovascular Events in Patients With SevereCoronary Artery StenosisSubanalysis of theJapanese Coronary Artery Disease (JCAD) Study
Circ J 2009: 73(5); 885-91
3. Kambara H, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R and The JCAD Study
Investigators Gender Differences in Patients With
Coronary Artery Disease in Japan The JapaneseCoronary Artery Disease Study (The JCAD Study)
Circ J 2009: 73(5); 912-7
4. Tanaka Y, Daida H, Imai Y, Miyauchi K, Sato Y,
Hiwatari M, Kitagawa A, Kishimoto J, Yamazaki
T, Kawamori R. Morning home blood pressure
may be a significant marker of nephropathy inJapanese patients with type 2 diabetes:
ADVANCED-J study 1 Hypertens R 2009: 32;
770-4

345

5. Uchiyama S, Goto S, Matsumoto M, Nagai R,
Origasa H, Yamazaki T, Shigematsu H, Shimada
K, Yamada N, Bhatt DL, Steg PG, Ikeda Y. on
behalf of the REACH Registry Investigators
Cardiovascular event rates in patients withcerebrovascular disease and atherothrombosis atother vascular locations: Results from 1-year
outcomes in the Japanese REACH Registry J
Neurol Sci 2009: 15; 287(1-2): 45-51
6. 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. Treatment strategy
and clinical outcome in Japanese patients withatrial fibrillation. Heart Vessels 2009: 24(4);287-93
7. Kaku K, Daida H, Kashiwagi A, Yamashina A,
Yamazaki T, Momomura S, Iwase T, Yamasaki Y,
Nagatsuka K, Kitagawa K, Kawamori R.
Long-term effects of pioglitazone in Japanesepatients with type 2 diabetes without a recent
history of macrovascular morbidity. Current
Medical Research & Opinion 2009: 25; 2925-32
8. Yamazaki T, Kurabayashi M, and the ASTRO-1
Study Group. A Randomized Controlled Studyto Compare the Effects of Rosuvastatin 2.5mg andPravastatin 10mg on the Plasma Lipid Profile inJapanese Patients with Hypercholesterolemia(ASTRO-1). Annals of Vascular Diseases 2009:(2,3); 148-58
9. Yamazaki T, Kurabayashi M, and the ASTRO-2
Study Group. A Randomized Controlled Studyto Compare the Effects of Rosuvastatin 5mg andAtorvastatin 10 mg on the Plasma Lipid Profile inJapanese Patients with Hypercholesterolemia(ASTRO-2). Annals of Vascular Diseases 2009:(2,3); 159-73
10. Koide D. Current Status and Future View ofElectronic
Data
Exchange
Formaton
Pharmaceutical Development. The 6th Annual
Japan DIA meeting 2009: 109-14
11. Kohro T, Yamazaki T. Cardiovascular clinical
trials in Japan and controversies regarding
prospective randomized open-label blinded
end-point design
Hypertens Res 2009: 32;
109-14
12. Kohro T, Yamazaki T.
Mechanism ofstatin-induced myopathy investigated using
microarray technology. J of Atherosclerosis andThrombosis 2009: 16; 30-2
13. Kohro T, Yamazaki T. Eicosapentaenoic acid
(EPA) in reducing secondary cardiovascular
events in hypercholesterolemic Japanese patients
Circ J 2009: 73(7); 1197-8

346

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.
The first head of the Department of Ubiquitous
Preventive Medicine is Toru Suzuki, appointed inAugust 1st, 2007, as Associate Professor. Kenichi
Aizawa serves as Research Associate.
Our objectives are to develop diagnostic biomarkers
and diagnostic/therapeutic systems for prevention andearly detection of disease.
For this purpose,advanced and highly efficient techniques of proteome
analysis are used with potential clinical application topreventive medicine. We are also committed todeveloping surrogate biomarkers for the discovery ofdrugs used in the treatment of cardiovascular diseases
as well as the optimization of their efficacy, and todevelop information infrastructure technologies foradvancing personalized medicine by clinically
applying the techniques of proteome analysis in aneffort to promote preventive medicine for healthpromotion. Our mission is to ultimately establish theacademic basis for Ubiquitous Preventive Medicine.
Our department provides diagnostic/therapeutic aswell as academic support for the Department of
Epidemiology and Preventive Medicine established in2007 within the University of Tokyo Hospital. In
collaboration with our department, the Department ofClinical Epidemiology and Systems also support the
management of the Department of Epidemiology andPreventive Medicine.

Research Activities
The principal objective of our research is to develop
diagnostic technologies for prevention and early
detection of disease by using advanced and highly
efficient techniques of proteome analysis, focusing on
the development of diagnostic biomarkers anddiagnostic/therapeutic systems. A typical example is347

metabolic syndrome which if left untreated may resultin lifestyle-related diseases including cardiovasculardiseases. While cardiovascular diseases have a very
long incubation period, protein modifications such asprocessing and denaturation play a leading role on thedevelopment of the diseases. Prevention is thereforeof utmost importance. To this end, we are in theprocess of developing methods for the measurementof protein modifications in cardiovascular diseases
and other new bio-tools for early detection oflifestyle-related diseases.
Specifically, the development of diagnostic
biomarkers and diagnostic/therapeutic systems byusing the techniques of proteome analysis is pursued
on an ongoing basis with its main research projects
being Industrial Technology Development for the New
Energy and Industrial Technology Development
Organization (NEDO) 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.

Clinical activities
The Department of Ubiquitous Preventive Medicine
is involved in the management of the Department of
Epidemiology and Preventive Medicine in the
University of Tokyo Hospital and provides diagnostic/
therapeutic as well as academic support for the
department.

Teaching activities
The Department of Ubiquitous Preventive Medicine
offers education and research supervision to graduate
students and post-doctoral fellows in the affiliate
Department of Cardiovascular Medicine.

References
Academic Papers in English
1. Matsumura T, Suzuki T, Aizawa K, Sawaki D,
Munemasa Y, Ishida J, Nagai R. Regulation oftransforming
growthfactor-β-dependent
cyclooxygenase-2 expression in fibroblasts. J Biol
Chem 284(51): 35861-35871, 2009
2. Suzuki T, Distante A, Zizza A, Trimarchi S,
Villani M, Salerno Uriarte JA, de Luca Tupputi
Schinosa L, Renzulli A, Sabino F, Nowak R,
Birkhahn R, Hollander JE, Counselman F,
Vijayendran R, Bossone E, Eagle K; for the
IRAD-Bio Investigators. Diagnosis of acute aortic
dissection by D-Dimer. The International Registryof Acute Aortic Dissection substudy on
biomarkers (IRAD-Bio) experience. Circulation
119(20): 2702-2707, 2009
3. Suzuki T. Cardiovascular diagnostic biomarkers–The past, present and future–. Circ J 73(5):806-809, 2009
4. Suzuki T, Sawaki D, Aizawa K, Munemasa Y,
Matsumura T, Ishida J, Nagai R. Krüppel-likefactor 5 shows proliferation-specific roles invascular remodeling, direct stimulation of cell
growth, and inhibition of apoptosis. J Biol Chem
284(14): 9549-9557, 2009
Academic Papers in Japanese
1. Suzuki T, Sawaki D: Review; IRAD, The results andsignificance. Cardiology 66(5): 561-566, 2009
2. Aizawa K, Suzuki T: Utility of the biomarker in adiagnosis and the treatment of the cardiovasculardisease; oxidized LDL. Mebio 26(12): 104-110,
2009
Books
1. Aizawa K, Suzuki T: New mensuration of theoxidized LDL. Supervised by Kiyohiko Seino.
“Cardiovascularmulti-biomarker
strategy”.
Ishiyaku Shuppan. pp91-94, 2009
Reviews
1.
Aizawa K, Suzuki T: The measurement of thedenaturation protein. Kokyu to Junkan 57(7):723-728, 2009
International Conferences
1. Ishida J, Suzuki T, Aizawa K, Sawaki D,
Matsumura T, Nagai R: Krüppel-like facter 6 is akeytranscription
factorinadipocyte

348

differentiation. American Heart Association 82th
Scientific Sessions (November 14-18, 2009,
Orland, FL, USA)
2. Suzuki T: The potential for development of acirculating marker for acute aortic dissection:
opportunities and challenges. Aortic Diseases
Summit (September 22-23, 2009, Baltimore, ML,USA)
3. Suzuki T: Genetics of fibrillinopathies. Advancesin Understanding Aortic Diseases (September
11-12, 2009, Hamburg, Germany)ational Conferences
1. Suzuki T: The analysis of the cardiovascularpathologies by the function control abnormality of
the nucleus. 50th Annual Meeting of the Japan
Radiation Research Society (November 11-13,
2009, Hiroshima, Japan)
2. Aizawa K, Suzuki T, Kohro T, Ohike Y, Seto M,
Suzuki K, Suzuki S, Nagai R, Yamazaki T:
Association of masked hypertension and metabolic
syndrome detected through automatic home Blood
Pressure Measurement in Health Screening. The
32nd Annual Scientific Meeting of the JapaneseHypertension Society (October 1-3, 2009, Otsu,
Japan)
3. Suzuki T: About utility of the BNP measurement in
the clinical survey. The 50th Scientific Meeting ofJapan Society of Ningen Dock/The 2nd World
Congress on Ningen Dock (September 3-4, 2009,
Tokyo, Japan)
4. Suzuki T: Aiming at the prophylactic treatment of
the cardiovascular disease by cardiovascularpreventive medicine. The 50th Scientific Meeting ofJapan Society of Ningen Dock/The 2nd World
Congress on Ningen Dock (September 3-4, 2009,
Tokyo, Japan)
5. Suzuki T: Current approaches to aortic dissection;from biomarkers to the international registry ofacute aortic dissection (IRAD). The 73rd Annual
Scientific Meeting of the Japanese Circulation
Society (March 20-22, 2009, Osaka, Japan)
6. Munemasa Y, Suzuki T, Aizawa K, Matsumura T,
Sawaki D, Nagai R: Positive regulation ofpromoter-region specific histone incorporation byhistone chaperones ANP32B and TAF-I, histone
deacetylase HDAC1 and DNA-binding factor KLF5.
The 73rd Annual Scientific Meeting of theJapanese Circulation Society (March 20-22, 2009,
Osaka, Japan)
7. Ishida J, Suzuki T, Aizawa K, Sawaki D, Matsumura
T, Nagai R: Krüppel-like factor 6 is a key
transcription factor in adipocyte differentiation. The
73rd Annual Scientific Meeting of the Japanese
Circulation Society (March 20-22, 2009, Osaka,
Japan)
8. Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Munemasa Y, Ishida J, Nagai R: Krüppel-like factor
6 modulates cardiovascular fibrosis. The 73rd
Annual Scientific Meeting of the Japanese
Circulation Society (March 20-22, 2009, Osaka,
Japan)
9. Aizawa K, Suzuki T, Zhan H, Matsumura T, Sawaki
D, Ishida J, Nagai R: A novel pathogenic pathway of
DNA damage response as mediated by KLF5 and its
transcriptional complexes in the cardiovasculature.
The 73rd Annual Scientific Meeting of theJapanese Circulation Society (March 20-22, 2009,
Osaka, Japan)
10. Fujimoto H, Suzuki T, Aizawa K, Matsumura T,
Sawaki D, Nagai R: Different molecular forms ofbrain natriuretic peptide measured using mass
spectrometry-based immunoassay are a new
biomarker of coronary artery disease. The 73rd
Annual Scientific Meeting of the Japanese
Circulation Society (March 20-22, 2009, Osaka,
Japan)

349

Department of Molecular Research
for Vascular Diseases
Associate Professor
Daisuke Nagata, M.D, Ph.D.

Associate
Kimie Tanaka, M.D, Ph.D.

Introduction and Organization
In late years, westernization of the life styleand aging of the population advance in ourcountry, and increase of the cardiovasculardisease 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 courseof increase. It is the time point when theprescription 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
for investigating the pathogenetic mechanismof vascular diseases associated with themetabolic diseases, supported by the division ofcardiovascular medicine. Our main objective isto develop the fundamentals for finding thebest method to protect vascular diseases.

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.

Research activities
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

350

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.
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
cardiovasculardisease.
Current
pharmaceutical design. 2009;15:2760-2768.

351

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 at
April 2008. Current member includes 1 visiting
professor and 1 project research associate. The
supportive department is the Department ofGerontological Nursing/Wound Care Management.
Skin is a largest organ in the body with which theentire surface of the body is covered. Therefore, ahealthy skin is a base of the healthy life. With a rapid
extension of the average life expectancy and anincrease of lifestyle diseases (diabetes mellitus,
obesity, metabolic syndrome etc.), many health related
problems have occurred in Japan. Especially at theskin, which is always exposed to the external
stimulations, the interaction of the external and innerfactors has expanded a variety of dermatopathy. On
such a skin, it is thought that the disruption of skinfunction has potentially occurred prior to actualizingof the pathological state. We are trying to establish“advanced skin care” to detect and to recover the
subclinical disruption of these functions promptly inorder to achieve the healthier skin as a wellness
promoting science.
The barrier function and viscoelasticity areespecially important for skin health. The former
prevents the moisture and electrolytes leaking frominside of body, and obstructs the penetration of theforeign body or chemicals into the body. The latter
absorbs the mechanical 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, and also candidate of parameter to indicate
the degree of skin health.
Recently, several noninvasive technologies, suchas 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 21th December, 2009, the special lecture
entitled “skin aging and cosmetic medicine” presented
by Kotaro Yoshimura, MD, PhD, Plastic andReconstructive Surgery, The University of Tokyo
Hospital, was held. More than 150 people including
graduate students, nurses, dietitians, and estheticians,
attended this special lecture.

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.

352

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.
In 2009, we focused on the changes of the skinwith the aging and lifestyle diseases, and thefollowing four projects were started;
1) Morphological and functional analysis of skin inelder patients,
2) The effect of weight reduction program on skinfunction and morphology,3) The relationship between the result of weight
reduction program and the body image ofparticipants,
4) The characteristics of skin in lifestyle diseases(diabetes mellitus, obesity, metabolic syndromeetc.).

References
1. 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 Mar 16.
[Epub ahead of print].
2. Tsuda K, Nakatani T, Sugama J, Okuwa M,
Sanada H. Infuluence of the timing of switching aprotein-free to a protein-containing diet on thewound healing process in a rat all-layer skindefect. Int Wound J. 2010; 7(3):135-146.
3. Minematsu T, Nakagami G, Sari Y, Akase T,
Sugama J, Nagase T, Sanada H. Candidate
biomarkers for deep tissue damage frommolecular biological and biochemical aspects. J
Tissue Viability. 2010; 19: 77-83.
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: across-sectional observational study. J So Nurs
Pract. 2010; 22(1): 19-27.
5. Sari Y, Nagase T, Minematsu T, Akase T,
Nakagami G, Sanada H, Sugama J. Hypoxia is
involved in deep tissue injury formation in a rat
model. WOUNDS. 2010; 22(2): 45-51.
6. 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.
7. Iizaka S, Sanada H, Nakagami G, Sekine R,
Koyanagi H, Konya C, Sugama J. Estimation ofprotein loss from wound fluid in older patientswith severe pressure ulcers. Nutrition. 2009 Dec
17. [Epub ahead of print]
8. Sanada H, Sugama J, Nakagami G. Innovations inpressure ulcer prevention and management: key
initiatives introduced in Japan. Wounds
International. 2009; 1(1).
9. Nagase T, Sanada H, Nakagami G, Sari Y,
Minematsu T, Sugama J. Clinical and molecularperspectives of deep tissue injury: Changes inmolecular markers in a rat model. (V. Biochemicalmarkers for early identification and formonitoring the healing of chronic wounds),
Bioengineering Research of Chronic Wounds,
Amit Gefen(Editor), Springer, 2009, 301-41.
10. Shimamura K, Nakatani T, Ueda A, Sugama J,
Okuwa
M.
Relationshipbetweenlymphangiogenesis and exduates during thewound-healing
process
of
mouse
skin
full-thickness wound. Wound Repair Regen 2009;17(4): 598-606.
11. Iizaka S, Okuwa M, Sugama J, Sanada H. The
impact of malnutrition and nutrition-related
factors on the development and severity ofpressure ulcers in older patients receiving homecare. Clin Nutr 2009; 29(1): 47-53.
12. Sakai K, Sanada H, Matsui N, Nakagami G,
Sugama J, Komiyama C, Yahagi N. Continuous
monitoring of interface pressure distribution in
intensive care patients for pressure ulcer
prevention. J Adv Nurs. 2009; 65(4): 809-17.
13. Shigeta Y, Nakagami G, Sanada H, Oba M,
Fujikawa J, Konya C, Sugama J. Exploring the353

relationship between skin property and absorbent
pad environment. J Clin Nurs. 2009; 18(11):1607-16.

354

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

metabolism.

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.

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.

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

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.

3555) The importance of the quality of fat besides thequantity.
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 metabolismof adipocytes.
8) The role of autonomic nerve system in theregulatory
mechanismsofadipo-hepaticbalancing.

References
1. Park KW, Waki H, Kim WK, Davies BS, Young
SG, Parhami F, Tontonoz P. The small molecule
phenamil induces osteoblast differentiation andmineralization. Mol Cell Biol 2009;29:3905-14.
2. Sekiya M, Osuga J, Nagashima S, Ohshiro T,
Igarashi M, Okazaki H, Takahashi M, Tazoe F,
Wada T, Ohta K, Takanashi M, Kumagai M, Nishi
M, Takase S, Yahagi N, Yagyu H, Ohashi K,
Nagai R, Kadowaki T, Furukawa Y, Ishibashi S.:
Ablation of neutral cholesterol ester hydrolase 1
accelerates atherosclerosis. Cell Metab 2009;10:219-228.
3. Sekiya M, Yahagi N, Tamura Y, Okazaki H,
Igarashi M, Ohta K, Takanashi M, Kumagai M,
Takase S, Nishi M, Takeuchi Y, Izumida Y,
Kubota M, Ohashi K, Iizuka Y, Yagyu H, Gotoda
T, Nagai R, Shimano H, Yamada N, Kadowaki T,
Ishibashi S, Osuga JI. Hormone-sensitive lipase
deficiency suppresses insulin secretion frompancreatic islets of Lep(ob)(/)(ob) mice. Biochem
Biophys Res Commun 2009;387:511-5.

356

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.

357(1) Analysis of Rac1-MR interaction and target organ
injury, using experimental models of metabolic
syndrome (KKAy, SHR/cp, diet- induced obesity,etc.). Search for stimuli causing Rac1 activation.
(2) Generationofcelltype-specific(ex.
podocyte-specific) Rac1 Tg / KO mice.
(3) Identification of ARF, based on the comparative
analysis of fat cell conditioned media from obese
SHR and non-obese SHR.
(4) Elucidation of other mechanisms of MR
activation.
(5) Development of drugs (reagents to inhibit Rac1,
ARF, and newly-identified target molecules),diagnostic tools (indicators of MR activation in thetarget organ), specification of clinical conditions
in which Rac1-MR overactivation is involved.

Teaching activities
The education of post-graduate students is also an
important task of our department. Our staffs help thestudents to plan and perform basic experiments and/or
clinical studies, to make oral or poster presentation at
Japanese or international society, and to publish
scientific article. We have educational programs
including journal club in order to polish theiracademic skills.

References
1. Nagase M, Fujita T. Mineralocorticoid receptor
activation in obesity hypertension. Hypertens Res.
2009 Aug;32(8):649-57.

358

Department of Molecular Structure
and Dynamics
Project

Associate Professor

Yasuko Noda, M. D.

Project

Associate

Tadayuki Ogawa, Ph. D.

Homepage

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

Teaching activities

Research 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) and Stimulated Emission Depletion
Microscopy (STED), cryo-electron microscopy and
X-ray crystallography.

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
includingcutting edge light microscopies,
cryo-electron microscopy of molecular resolution,
X-ray crystallography, biophysics, molecular biology
and molecular genetics. We aim to study the structureand dynamics of the molecular motors in vitro and invivo at the highest special and temporal resolution andon these bases try to elucidate functions of molecularmotors in vivo combining molecular genetics.

References(1) Hirokawa, N., Y. Okada and Y. Tanaka. Fluid
dynamic mechanism responsible for breaking theleft-right symmetry of the human body: The
nodal flow. Annual Review of Fluid Mechanics.
41: 53-72, 2009.
(2) Hirokawa, N., Y. Noda, Y. Tanaka, and S. Niwa.
Kinesin superfamily motor proteins andintracellulartransport.
ature
Reviews
Molecular Cell Biology. 10: 682-696, 2009.
(3) Hirokawa, N., Y. Tanaka and Y. Okada.
Left-Right determination: Involvement ofmolecular motor KIF3, cilia, and nodal flow.

359

(4)

(5)

(6)

(7)

Cold Spring Harber Perspectives in Biology.
July 2009; 1:a000802.
Zhou R., S. Niwa, N. Homma, Y. Takei, and
N. Hirokawa. KIF26A is an unconventional
kinesin and regulates GDNF-Ret signaling inenteric neuronal development. Cell 139: 802-813,
2009.
Hirokawa, N., R. Nitta and Y. Okada. The
mechanisms of kinesin motor motility: lessons
from the monomeric motor KIF1A. ature
Reviews Molecular Cell Biology 10: 877-884,
2009.
Okada, Y. and N. Hirokawa. Observation of
Nodal Cilia Movement and Measurement of
Nodal Flow. Methods in Cell Biology ed. by S.
M. King and G. J. Pazour, Academic Press.
Elsevier Inc. 91: 265-285, 2009.
Terada, S., M. Kinjo, M. Aihara, Y. Takei and
N. Hirokawa.
Kinesin-1/Hsc70-dependent
mechanism of slow axonal transport and its relation
to fast axonal transport. EMBO J 29: 843-854,
2010

360

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 europsychiatry 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 europsychiatry at the Universityof Tokyo and postmortem brains provided from brainbanks.

361

Department of Medical Genomics
Professor
Hiroyuki Mano, M.D., Ph.D.

Associate Professor
Young Lim Choi, 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.
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.

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 to362

propose thegenomics.

significant

importancein

cancerResearch 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 (ature 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 (PAS 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, a phase I clinical trial with an ALK
inhibitor is ongoing abroad, and its dramatictherapeutic efficacy (~90% of control rate, plus thepresence of patients under complete remission) has
been just reported in the 2009 annual meetings ofAmerican Society of Clinical Oncology and ofEuropean Cancer Organization.
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 inDMT3A 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
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.

363

References
1.

2.

3.

4.

5.

6.

7.

Inamura K, Takeuchi K, Togashi Y, Hatano S,
Ninomiya H, Motoi N, Mun MY, Sakao Y,
Okumura S, Nakagawa K, Soda M, Choi YL,
Mano H, Ishikawa Y. EML4-ALK lung cancers
are characterized by rare other mutations, a TTF-1
cell lineage, an acinar histology, and young onset.
Mod Pathol. 2009;22:508-515.
Kano Y, Tanaka M, Akutsu M, Mori K, Yazawa
Y, Mano H, Furukawa Y. Schedule-dependentsynergism and antagonism between pemetrexed
and docetaxel in human lung cancer cell lines invitro. Cancer Chemother Pharmacol. 2009;64:1129-1137.
Takada S, Berezikov E, Choi YL, Yamashita Y,
Mano H. Potential role of miR-29b in modulationof Dnmt3a and Dnmt3b expression in primordial
germ cells of female mouse embryos. RA.
2009;15:1507-1514.
Takeuchi K, Choi YL, Togashi Y, Soda M,
Hatano S, Inamura K, Takada S, Ueno T,
Yamashita Y, Satoh Y, Okumura S, Nakagawa K,
Ishikawa Y, Mano H. KIF5B-ALK, a novel fusion
oncokinase
identifiedbyanimmunohistochemistry-based diagnostic system
for ALK-positive lung cancer. Clin Cancer Res.
2009;15:3143-3149.
Tanaka M, Kano Y, Akutsu M, Tsunoda S, Izumi
T, Yazawa Y, Miyawaki S, Mano H, Furukawa Y.
The cytotoxic effects of gemtuzumab ozogamicin(mylotarg) in combination with conventional
antileukemic agents by isobologram analysis invitro. Anticancer Res. 2009;29:4589-4596.
Wada T, Yamashita Y, Saga Y, Takahashi K,
Koinuma K, Choi YL, Kaneda R, Fujiwara S,
Soda M, Watanabe H, Kurashina K, Hatanaka H,
Enomoto M, Takada S, Mano H, Suzuki M.
Screening for genetic abnormalities involved in
ovarian carcinogenesis using retroviral expression
libraries. Int J Oncol. 2009;35:973-976.
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 byretroviral expression screening. Cancer Sci. 2010;
101:60-64.
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 free fatty
acid receptor 2 by retroviral expression screening.
Cancer Sci. 2010;101:54-59.
9. Mano H, Takeuchi K. EML4-ALK fusion in lung.
Am J Pathol. 2010;176:1552-1553.
10. 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;49:603606.
11. 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
inhuman
T-lymphocyte. Immunol Lett. 2010;127:135-142.

Endowed Department(22nd Century Medical and Research Center)365

Department of
Immunotherapeutics (Medinet)
Project Associate Professor
Kazuhiro Kakimi, M.D., Ph.D.

Project Research Associate
Yukihiro Yoshida, M.D,

Homepage http://immunoth.umin.jp/
Introduction and Organization
The Department of Immunotherapeutics (Medinet)
was established on June 1, 2004 as one of the first of
22 departments of the 22nd Century Medical andResearch Center in the University of Tokyo Hospital.
This Center is a research complex of departments
endowed by the Business-Academia partnership. The
Department of Immunotherapeutics (Medinet) was
contributed by Medinet Co. Ltd., the leading company
in this field in Japan. The aim of our department is to
execute basic and clinical research on cancer
immunology and immunotherapy and to establish itsrole in the treatment of cancer.
Research on cancer immunotherapy is directed by
Dr. Kazuhiro Kakimi. Dr. Makoto Kurachi who
participated in the starting-up period of the department
from 2004 to March 2007 as an associate. Dr.
Kiminori Kimura joined our team in April, 2007. Our
focus remains the study of cancer immunology andpromotion of translational research for thedevelopment of improved cancer immunotherapy.
When the new building (Central Diagnosis andTreatment Building 2) of the University of Tokyo
Hospital became available in July 2006, we moved
our department to its 9th floor in September 2006. It isparticularly worth noting that the GMP-level Cell
Processing Center (CPC) was installed in thedepartment at the same time. A CPC is a criticalfacility to prepare cells for clinical applications.
Cancer immunotherapy requires the expansion offunctional T cells and/or dendritic cells (DC) that are
responsible for the anti-tumor immune response invivo. Peripheral blood mononuclear cells (PBMC) are
isolated from the patients and processed in the CPC toensure that they maintain optimal functionality, or for
triggering new functions in vitro prior to clinicalapplication. Autologous cells derived from cancer
patients are processed for therapeutic use in our CPC
in accordance with all current regulations and ethicalobligations. We began the outpatient program
specializing in cancer immunotherapy in February
2007.
To perform reliable high quality translational
research, we designed our Department’s facilities
literally from the bench to the bedside. The
Department consists of three divisions, (1) laboratory
for basic and pre-clinical research (2) Cell Processing
Center and (3) outpatient clinic. Because these 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

366

at the laboratory to monitor their immune responses toevaluate the impact of the immunotherapy.
All protocols for cancer immunotherapy performedin our department are submitted to the institutional
review board (IRB). Once approved, the protocols areregistered in the UMIN clinical research registration
system to provide open access to any interested parties.
Because the cells used for treatment are derived fromeach individual patient, it is really difficult toguarantee consistent quality. However, we doeverything possible to provide the cultured cells withthe 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 system.
In addition to cancer immunology and immunotherapy, our activities include tissue transplantationand transplantation immunology, the development ofnovel vaccination strategies and identification ofunique anti-infectious agents in collaboration with the
Department of Cardiothoracic Surgery (Professor
Shin-ichi Takamoto).

Clinical activities
We provide outpatient services for cancer patients.
All interventions performed in the department are
defined by the protocols of the particular clinical trial
approved by the IRB. The following clinical trials areunderway in our department:
Cancer vaccine
1. UMIN registration: UMIN000001260, 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 withcancers expressing NY-ESO-1 antigen
2. UMIN registration: UMIN000001857, IRB
number: 2475, A phase I study of cancer vaccinewith NY-ESO-1 overlapping peptides in patientswith advanced cancers expressing NY-ESO-1
antigenDendritic cell therapy
3. UMIN registration: C000000451 Clinical study of
intratumoral dendritic cell injection afterradiofrequency ablation therapy in hepatitis C
virus-related hepatocellular carcinoma patients
4. UMIN registration: UMIN000000971, Clinicalstudy of intratumoral dendritic cells(DC) injection
after radiofrequency ablation(RFA) therapy forthe treatment of hepatitis C virus-related
hepatocellular carcinoma(HCC) patients
5. UMIN registration: UMIN000002136 , IRB
number:2492,
Safety,efficacyandimmunogenicity of autologous tumor lysatepulsed dendritic cell therapy in patients withadvanced renal cell carcinoma
6. UMIN registration: UMIN000002837 , IRB
number:2759,
Safety,efficacyandimmunogenicity of autologous tumor lysatepulsed dendritic cell therapy after resection ofstage2A (T2N0,T3N0) esophageal cancerγ δ T cell therapy for advanced cancer
7. UMIN registration: C000000336 , 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. UMIN registration: UMIN000000628 , 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 in patients who received
radiotherapy for bone metastases.
9. UMIN registration: UMIN000000854, IRB
number: 1781-(1), Clinical study on efficacy andsafety of autologous gamma/delta T cell transfer
therapy after pulmonary metastasectomy ofcolorectal cancer
10. UMIN registration: UMIN000001419 , IRB
number: 2120-(1), The efficacy and safety ofautologous gamma/delta T cell transfer therapy
for esophageal cancer
11. UMIN registration: UMIN000001418 , IRB
number: 2176-(1), The efficacy and safety ofautologous gamma/delta T cell transfer therapy
for extrahepatic metastasis of hepatocellular
carcinoma
Adjuvant γ δ T cell therapy
12. UMIN registration: UMIN000000931 , IRB
number: 1810-(1), Clinical study to investigate
safety and efficacy on combination of gemcitabine

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and autologous gamma/delta T cell transfer
therapy after resection of pancreatic cancer
13. UMIN registration: UMIN000001417 , IRB
number: 2177-(1), The efficacy and safety ofautologous gamma/delta T cell transfer therapy
after
resectionofintrahepaticcholangiocarcinoma
14. UMIN registration: UMIN000002839 , IRB
number: 2760, The efficacy and safety ofautologous gamma/delta T cell transfer therapy
after resection of stage2A (T2N0,T3N0)
esophageal cancer

Teaching activities
Research guidance in molecular immunology isprovided to postgraduate students. Because knowledgeof and techniques for evaluation of immune response
are important 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 atunderstanding 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. Kakimi, K., J. Nakajima, and H. Wada. 2009. Active
specific immunotherapy and cell-transfer therapy forthe treatment of non-small cell lung cancer. Lung
Cancer 65:1-8.
2. Karimov, E. E., N. Motomura, K. Sakuta, K. Kakimi,
K. Narut, N. Nogucht, and S. Takamoto. 2009. Fresh
and Cryopreserved Vascular Allografts Suppress
Methicillin-Resistant
Staphylococcus
aureusProliferation Via indoleamine 2,3-Dioxigenase (IDO)
Expression. Journal of Heart and Lung
Transplantation 28:S223-S223.
3. Kimura, K., M. Nagaki, T. Matsuura, H. Moriwaki,
and K. Kakimi. 2009. Pathological role of CD44 on
NKT cells in carbon tetrachloride-mediated liver
injury. Hepatology Research 39:93-105.
4. Kimura, K., M. Nagaki, M. Saio, H. Moriwaki, and
K. Kakimi. 2009. Role of CD44 in CTL-induced
acute liver injury in hepatitis B virus transgenic mice.
Journal of Gastroenterology 44:218-227.
5. Narui, K., N. Noguchi, A. Saito, K. Kakimi, N.
Motomura, K. Kubo, S. Takamoto, and M. Sasatsu.
2009. Anti-infectious Activity of Tryptophan
Metabolites in the L-Tryptophan-L-Kynurenine
Pathway. Biological & Pharmaceutical Bulletin
32:41-44.
6. Sato, K., M. Kondo, K. Sakuta, A. Hosoi, S. Noji, M.
Sugiura, Y. Yoshida, and K. Kakimi. 2009. Impact of
culture medium on the expansion of T cells for
immunotherapy. Cytotherapy 11:936-946.
7. Ikeuchi N, Futami J, Hosoi A, Noji S, Kurachi M,
Ueha S, Fujii S, Yamada H, Matsushima K, Moriyasu
F, Kakimi K. Efficient cross-presentation of soluble
exogenous antigens introduced into dendritic cells
using a weak-based amphiphilic peptide Biochem
Biophys Res Commun. 2010、5;392(2):217-22
8. Nakajima J, Murakawa T, Fukami T, Goto S,
Kaneko T, Yoshida Y, Takamoto S, Kakimi K. A
phase I study of adoptive immunotherapy for368

recurrent non-small-cell lung cancer patients withautologous gammadelta T cells. Eur J Cardiothorac
Surg. 2010 Eepub ahead of print

369

Division of Total Renal Care
Medicine
Associate Professor
Akira Ishikawa, M.D., Ph.D.

Associate
Yoshitaka Ishibashi, M.D., Ph.D.

Homepage

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 to achievethis, 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 thefollowing projects; (1) Research on establishing
optimum PD therapy, (2) Educational courses for
medical practitioners, and (3) research on improving
clincal skills.
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 2009 were as
follows:(2) Educational courses for medical practitioners,
With the help of many nephrologists and nurses in
our hospital, we have trained 27 nephrologists and
21 renal nurses from 25 facilities (either
university hospital or central hospital in theirarea) from 18 prefectures in Japan.
(3) Research on improving clincal skills.
PD is a mode of therapy in which the patient
greatly participates in treating his own disease.
Therefore, the patient needs to face up to his own
disease, and to know how to acquire the skills
needed for self-management. Based on thisstandpoint, we have felt that it is necessary to
work with experts of other disciplines, such as thehumanities. Thus, we have started somecollaborative
researchwithphilosophers,sociologists, and cognitive behavioral therapists.

References(1) Research on establishing optimum PD therapy.
At the present state, the main cause of PD
technique failure is deterioration of peritoneal
function due to long-term use of bioincompatible
dialysate. Biocompatible dialysates have been
available since 2001, and our research is focusedon peritoneal pathology after long-term use of
new biocompatible PD fluids. We have reported
the results in the meeting of the International
Society for Peritoneal Dialysis held in Oct 2009 in
Beijing.

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,

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Fujita T. Pegylated interferon alpha-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

371

Department of Integrated
Molecular Science on Metabolic
Diseases
Project Associate Professor
Toshimasa Yamauchi, M.D.,Ph.D.

Project Research Associate
Yukiko Okazaki, M.D.,Ph.D.( ~ Dec. 2010)
Masato Iwabu, M.D.,Ph.D. (Dec. 2010 ~ )Homepage
Introduction and Organization
The Department of Integrated Molecular Science on
Metabolic Diseases (DIMSMD) is devoted toclarifying the mechanisms of onset of lifestyle-relateddiseases resulting from interactions between genetic
and environmental factors in the Japanese population
as well as to contributing to the prophylaxis, diagnosis
and treatment of these diseases, in response to thedrastic increase in the number of diabetic patients
which is becoming a major social issue of current
interest. In this regard, the DIMSMD strives toestablish an accurate method through which to predictrisk for the onset of lifestyle-related diseases bytapping into a comprehensive database for genetic andenvironmental factors for these diseases which is
being developed to integrate “Informatics on Genetic
Predisposition to Lifestyle-related Diseases” asgenerated by cutting-edge advances such as single
nucleotide polymorphism analyses with “Informatics
on Environmental Factors for Lifestyle-relatedDiseases” that draw on surveys including detailed
questionnaires on diet intake. The DIMSMD istherefore expected to make significant scientific andsocial contributions by providing effective modalities
for primary prevention of diabetes, moleculardiagnosis of onset of diabetes and its pathology, andoptimal treatment of diabetes, and to play a major role
in reducing the number of newly onset diabetes aswell as in raising the treatment standard for diabetes.
The DIMSMD also aims to develop a system thatallows formulas to be developed to predict therapeutic
response to drugs as well as their safety to be
developed based on information available onenvironmental and genetic factors including gene
expression from patients being treated at University ofTokyo Hospital, and which allows safe and effective
use of drugs being developed in patients withlifestyle-related diseases.
The DIMSSMD has set as its final goal the
installment of a human metabolic disease tissue bankat University of Tokyo Hospital, which draws on an“integrated database” that offers comprehensive
information on gene expression in human hepatic andadipose tissue samples, electronic charts, SNP andlifestyle habits, which will allow validation ofmolecular targets in actual human diseases, design ofa clinical trial system based on SNP and gene
expression profiles, development of models forprediction of therapeutic response based on
environmental and genetic interactions, identificationof molecular targets, discovery of novel therapeutic
agents and safe and effective use of drugs thus
developed in time.

372

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.

Research activities(3)
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) Awazawa M, Ueki K, Inabe K, Yamauchi T,
Kaneko K, Okazaki Y, Bardeesy N, Ohnishi S,
Nagai R, Kadowaki T,: Adiponectin suppresses
hepatic
SREBP1cexpressioninanAdipoR1/LKB1/AMPK
dependent
pathway.
Biochem. Biophys. Res. Commun. 382: 51-56,
2009(2) Takazawa T, Yamauchi T, Tsuchida A, Takata M,
Hada Y, Iwabu M, Okada-Iwabu M, Ueki K,

(4)

(5)

(6)

(7)

Kadowaki T,: Peroxisome proliferator-activatedreceptor gamma agonist rosiglitazone increases theexpression of very low density lipoprotein receptor
gene in adipocytes. J.Biol.Chem. 284: 30049-30057,
2009
Hashimoto H, Arai T, Mori A, Kawai K, Hikishima
K, Ohnishi Y, Eto T, Ito M, Hioki K, Suzuki R,
Ohsugi M, Saito M, Ueyama Y, Okano H,
Yamauchi T, Kubota N, Ueki K, Tobe K, Tamaoki
N, Kadowaki T, Kosaka K,: Reconsideration of
insulin signals induced by improved laboratory
animal diets, Japanese and American diets, in IRS-2
deficcient mice. Exp. Clin. Endocrinol. Diabetes
117: 577-586, 2009
Kadowaki T, Yamauchi T, Kubota N, Fujisawa T,
Nakagama H, Nakajima A, Terauchi Y, Ueki K,:
Role of adiponectin and its receptors in
obesity-linked insulin resistance and metabolic
syndrome. Metabolic Syndrome: Carcinogenesis
and Prevention 91-96, 2009
Otani K, Kitayama J, Yasuda K, Nio Y, Iwabu M,
Okudaira S, Aoki J, Yamauchi T, Nagawa H,:
Adiponectin
suppresses
tumorigenesisin
Apo(Min)(/+)mice. Cancer Lett. 288: 177-182,
2010
Otani K, Kitayama J, Kamei T, Soma D, Miyato H,
Yamauchi T, Kadowaki T, Nagawa H,: Adiponectin
receptors are downregulated in human gastriccancer. J Gastroenterol. 2010 Mar 25. [Epub aheadof print]
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 K. Y, Yamauchi N, Waki H,
Fukayama M, Nishino I, Tokuyama K, Ueki K,
Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K
and Kadowaki T,: Adiponectin and AdipoR1
regulate PGC-1α and mitochondria by Ca2+ and
AMPK/SIRT1. Nature 434: 1313-1319, 2010

373

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.

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.

374

References
1. Suzuki J, Tezuka D, Morishita R, Isobe M.
Aninitial case of suppressed restenosis with
NF-kB decoy transfection after PCI. J GeneMed. 11: 89-91, 2009.
2. Hishikari K, Suzuki J, Ogawa M, Isobe K,
Takahashi T, Onishi M, Takayama K, Isobe M.
Pharmacological activation of the prostaglandin
E2 receptor EP4 improves cardiac function after
myocardialischemia/reperfusion
injury.
Cardiovasc Res. 81: 123-32, 2009.
3. Ogawa M, Suzuki J, Takayama K, Isobe M.
Matrix metalloproteinase suppression induced byclarithromycin in murine cardiac allografts.
Transplant Proc. 41:395-397, 2009.
4. Ogawa M, Suzuki J, Hirata Y, Nagai R, Isobe M.
A critical role of COX-2 in the progression of
neointimal formation after wire injury in mice.
Expert Opin Ther Targets. 13: 505-11, 2009.
5. Ogawa M, Suzuki J, Kosuge H, Takayama K,
Nagai R, Isobe M. The mechanism ofanti-inflammatory effects of prostaglandin E2
receptor 4 activation in murine cardiac
transplantation. Transplantation. 87:1645-53,
2009.
6. Haga T, Suzuki J, Kosuge H, Ogawa M, Saiki H,
Haraguchi G, Maejima Y, Isobe M, Uede T.
Attenuationofexperimental
autoimmune
myocarditis by blocking T cell activation through4-1BB pathway. J Mol Cell Cardiol. 46:719-27,
2009.
7. 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.
8. Konishi M, Maejima Y, Inagaki H, Haraguchi G,
Hachiya H, Suzuki J, Hirao K, Isobe M. Clinicalcharacteristics of acute decompensated heart
failure with rapid onset of symptoms. J Card Fail.
4: 300-304, 2009.
9. Suzuki J, Ogawa M, Takayama K, Taniyama Y,
Morishita T, Hirata Y, Nagai R, Isobe M.
Ultrasound-microbubble
mediated
ICAM-1siRNAtransfection
attenuates
neointimal
formation after arterial injury in mice. J Am Coll

Cardiol. 55: 904-913, 2010.
10. Komura M, Suzuki J, Adachi S, Takahashi A,
Kenichiro Otomo K, Nitta J, Nishizaki M,
Obayashi T, Nogami A, Satoh Y, Okishige K,
Hirao K, Isobe M. Clinical course ofarrhythmogenic right ventricular cardiomyopathy
in the era of implantable cardioverter-difibrillatorsand radiofrequency catheter ablation.
Int
Heart J. 51: 34-40, 2010.
11. 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.
12. Kosuge H, Ishihara T, Haraguchi G, Maejima Y,
Okada H, Saiki H, Suzuki J, Isobe M. Treatment
with telmisartan attenuates graft arteriosclerosis inmurine cardiac allografts. J Heart Lung
Transplant. 29: 562-7, 2010.
13. Nagata D, Kiyosue A, Takahashi M, Satonaka H,
Tanaka K, Sata M, Nagano T, Nagai R, Hirata Y:
A new costitutively-active muntant of AMPactivated protein kinase inhibits anoxia-induced
apoptosis of vascular endothelial cell. Hypertens
Res. 32:133-139 2009
14. Masuzawa A, Ohno T, Takamoto S, Motomura N,
Ono M, Fujita H, Ando J, Morita T, Hirata Y,
Nagai R, Hirose A, Shigeeda T, Kato S, Araie M.
In early-stage diabetic retinopathy, risk of cardiac
events after implantation of sirolimus-eluting
stent is higher than after coronary artery bypass
surgery. J Cardiol. 53:86-93, 2009.
15. Asaba K, Tojo A, Onozato ML, Kinugasa S,
Miyazaki H, Miyashita K, Uehara Y, Hirata Y,
Kimura K, Goto A, Omata M, Fujita T. Long-term
renal prognosis of IgA nephropathy withtherapeutic trend shifts. Intern Med. 48:883-90,
2009.
16. Nagata D, Hirata Y: The role of AMP-activatedprotein kinase in the cardiovascular system.
Hypertens Res, 33: 22-8, 2010.
17. 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:

375

H415-23, 2010.
18. 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.
19. Sanada F, Taniyama Y, Iekushi K, Azuma J,
Okayama K, Kusunoki H, Koibuchi N, Doi T,
Aizawa Y, Morishita R. Negative action ofhepatocyte growth factor/c-Met system on
angiotensin II signaling via ligand-dependent
epithelial growth factor receptor degradation
mechanism in vascular smooth muscle cells. Circ
Res. 105: 667-75; 2009.
20. Mori M, Nakagami H, Koibuchi N, Miura K,Takami Y, Koriyama H, Hayashi H, Sabe H,
Mochizuki N, Morishita R, Kaneda Y. Zyxin
mediates
actin
fiber
reorganizationinepithelial-mesenchymal transition and contributes
to endocardial morphogenesis. Mol Biol Cell. 20:
3115-24; 2009.
21. Sanada F, Taniyama Y, Azuma J, Iekushi K,
Dosaka N, Yokoi T, Koibuchi N, Kusunoki H,
Aizawa Y, Morishita R. Hepatocyte growth factor,
but not vascular endothelial growth factor,
attenuates angiotensin II-induced endothelial
progenitor cell senescence. Hypertension. 53:
77-82; 2009.
22. 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. Circ Res. 105: 906-11;
2009.
23. 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
24. Iwata H, Sata M, Hirta Y, Fujita H, Morita T,
Ando J, Sawaki D, Nagai R: Impact of primitive
cells in intracoronary thrombi on lesion prognosis:
Temporal analysis of cellular constituents ofthrombotic material obtained from patients withacute coronary syndrome. Heart, 96: 748-55.
English Review
1. Suzuki J, Isobe M, Morishita R, Nagai R. Effects
of tea catechins on inflammation-related

2.

3.

4.

5.

6.

cardiovascular disease. Curr Immnol Review.
5: 167-174, 2009.
Suzuki J, Isobe M, Morishita R, Nagai R. Tea
polyphenols regulate key mediators on
inflammatory cardiovascular diseases. Mediat
Inflamm. vol. 2009, Article ID 494928, 5pages,
2009.doi:10.1155/2009/494928
Suzuki J, Isobe M, Morishita R, Nagai R.
Characteristics of chronic rejection in hearttransplantation–Importantelementsofpathogenesis and future treatments-. Circ J. 74:
233-239, 2010.
Suzuki J, Isobe M, Morishita R, Nagai R. Nucleic
acid drugs for prevention of cardiac rejection. J
Biomed Biotechnol. Volume 2009, Article
ID916514, 5 pages, doi:10.1155/2009/916514
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.
Hirata Y: Significance of B-type natriuretic
peptide measurement in patients with chronic
kidney disease. Circ J. 74: 632-3, 2010

376

Department of Ischemic
Circulatory Physiology,
KAATSU training
Associate Professor
Toshiaki Nakajima, M.D., Ph.D.

Research Associate
Haruhito Madarame, Ph.D.

Fellow Researcher
Hiroyuki Imuta, Ph.D.
Toshihiro Morita, M.D., Ph.D.

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 with

377

respiratory diseases (COPD). There are several
mechanisms involving the effects of KAATSU
training including hypoxic effects of skeletal muscles,
GH responses, and shear stress to cardiovascularhemodynamics. Therefore, we have also examined thebasic experimental studies using a variety of methods
using electrophysiology and molecular physiology
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.

Atarashi H, Inoue H, Ohe T, Ohtsu H, Okumura K,
Katoh T, Kamakura S, Kumagai K, Kurachi Y,
Kodama I, Koretsune Y, Saikawa T, Sakurai M,
Sugi K, Tabuchi T, Nakaya H, Nakayama T, Hirai
M, Fukatani M, Mitamura H; J-RHYTHM
Investigators. Collaborators (224) Optimaltreatment strategy for patients with paroxysmal
atrial fibrillation: J-RHYTHM Study. Circ J. 2009
Feb;73(2):242-8.
4) Abe T, Ozaki H, Sugaya M, Fujita S, Sakamaki M,
Sato Y, Bembem MG, Nakajima T. Effects of 42
weeks walk training with blood flow reduction on
muscle size and strength in the elderly.
Proceedings of the ICSES, pp336-341, 20095) Ozaki H, Kusuhara K, Sato Y, Brechue WF, Ogita
F, Nakajima T, Abe T. Cardiovascular andmetabolic responses to walking with and without
leg blood flow reduction. Proceedings of the
ICSES, pp342-347, 2009

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) Nakajima T, Kubota N, Tsutsumi T, Oguri A, Imta
H, Jo T, Oonuma H, Soma M, Meguro K, Takano
H, Nagase T, Nagata T. Eicosapentaenoic acidinhibits voltage-gated sodium channels andinvasiveness in prostate cancer cells. Br J
Pharmacol 156, 420-431, 2009.
2) Meguro K, Iida H, Takano H, Morita T, Sata M,
Nagai R, Nakajima T. Function and Role ofVoltage-Gated Sodium Channel (NaV1.7)
Expressed in Aortic Smooth Muscle Cells. Am J
Physiol Heart Circ Physiol 2009. 296:H211-H219.
3) Ogawa S, Yamashita T, Yamazaki T, Aizawa Y,

6) Matsuyama N, Tsutsumi T, Kubota N, Nakajima T,
Suzuki H, Takeyama Y. Direct action of anangiotensin II receptor blocker on angiotensin
II-induced left atrial conduction delay inspontaneously hypertensive rats. Hypertens Res.
2009; 32: 721-26.
7) Abe T, Sakamaki M, Fujita S, Ozaki H, Sugaya M,
Sato Y, Nakajima T. Effects of low-intensity walktraining with restricted leg blood flow on muscle
strength and aerobic capacity in elderly subjects. J
Geriatr Phy Ther 33:34-40, 2010.
8) Madarame H, Kurano M, Takano H, Iida H, Sato
Y, Ohshima H, Abe T, Ishii N, Morita T and
Nakajima T. Effects of low-intensity resistance
exercise with blood flow restriction on
coagulation system in healthy subjects. ClinicalPhysiology and Functional Imaging (in press)
9) Fukuda T, Maegawa T, Matsumoto A, Komatsu Y,
Nakajima T, Nagai R, Kawahara T.T. Effects ofAcute Hypoxia at Moderate Altitude on Stroke
Volume and Cardiac Output During Exercise. Int
Heart J. 2010 May;51(3):170-5

37810) 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 Mar 2.
[Epub ahead of print]11) 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(in press)
12) 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
Apr 22. [Epub ahead of print]13) 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 inparoxysmal atrial fibrillation. Subanalysis from
J-RHYTHM study. Circ J. 2010 Apr
23;74(5):870-5. Epub 2010 Apr 3.

379

Department of Translational
Research for Healthcare andClinical Science
Project Associate Professor
Hiroyuki Morita, M.D.,Ph.D.

Project Research Associate
Takahide Kohro, M.D.,Ph.D.

Homepage

http://www.trhcs.org/en/

Introduction and Organization
Our department was open in January 2005,
contributed by Hitachi, Ltd. and Hitachi Medical
Corporation. Since then, the construction of clinicalinformation database has been performed incollaboration with the Department of Cardiovascular
Medicine of this University (Professor and Chairman;
Dr. Ryozo Nagai). In January 2008, our new missions
have started under the contribution of Theravalues
Corporation and Hitachi, Ltd. The aim of ourdepartment is to improve the clinical information
database to the better one and put that into practicaluse in developing the clinical research.
Our department belongs to the 22nd century medical
center in the University of Tokyo Hospital, which was
founded as the front line of university-industry
partnerships. As our research foothold is located in thehospital, we could keep the close connection with thebedside. Our department is thought to be suited for
obtaining the maximum output in clinical research.

Research activities
The onset and progression of the disease are thought
to be caused by the environmental and/or genetic
factors. What is the best way to identify thepathogenesis and the factors predicting the prognosis?

The answer should be the filing of the clinicalinformation.
We are constructing the effective framework to makethe relevant clinical data available for research andperforming the investigation to resolve the clinicalquestions, followed by the translation of its fruits tothe bedside.
Another mission is to confer the explicit scientificre-evaluation on the health issues (e.g. eating habits,
exercise, lifestyle) which have been believed to be
empirically effective. This mission has to be followedby the prompt publicity of the “accurate” data led byour re-evaluation.
The realization of these missions above could becompleted in a close collaboration with the academic
groups and private enterprises. In this regard, we areready to discuss and think together with anybody
anytime.
In summary, our research field covers the issues asfollows;
1. Development of information analysis system andsystematization of clinical information
2. Clinical and/or genomic research utilizing theclinical information analysis system
3. Scientific verification of eating habits, exercise
and lifestyle
4. Analysis on the current state of the medical
system380

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 Uehara Memorial Foundation (toMorita H)
Research Grant of Japan Medical Association (toMorita H)
Research Grant of Mitsubishi Pharma Research
Foundation (to Morita H)

References
1. Morita H, Nagai R. Genetically elevatedC-reactive protein and vascular disease.
New England Journal of Medicine 2009;360:934.
2. Kohro T, Yamazaki T. Cardiovascular clinical
trials in Japan and controversies regarding
prospective randomized open-label blinded
end-point design.
Hypertens Res 2009;32:109-114.
3. Kohro T, Yamazaki T. Mechanism ofstatin-induced myopathy investigated using
microarray technology.
J Atheroscler Thromb 2009;16:30-32.
4. Morita H, Nagai R. Smoking exposure, 17q21
variants, and early-onset asthma.
New
England
JournalofMedicine
2009;360:1255.
5. Kambara H, Yamazaki T, Hayashi D, Kohro T,
Okada Y, Nagai R; Japanese Coronary Artery
Disease Study Investigators. Gender differences inpatients with coronary artery disease in Japan: theJapanese Coronary Artery Disease Study (theJCAD study).
Circ J 2009;73:912-917.
6. Okura T, Higaki J, Kurata M, Irita J, Miyoshi K,
Yamazaki T, Hayashi D, Kohro T, Nagai R;
Japanese Coronary Artery Disease Study
Investigators. Elevated serum uric acid is anindependent predictor for cardiovascular events inpatients with severe coronary artery stenosis:
subanalysis of the Japanese Coronary Artery
Disease (JCAD) Study.
Circ J 2009;73: 885-891.
7. Kohro T, Yamazaki T. Eicosapentaenoic acid
(EPA) in reducing secondary cardiovascular
events in hypercholesterolemic Japanese patients.
Circ J 2009; 73:1197-1198.

381

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.

Yoshimura N, Muraki S, Oka H, Mabuchi A,
Kinoshita H, Yoshida M, Kawaguchi H,
Nakamura K, Akune T: Epidemiology of lumbar
osteoporosis and osteoarthritis and their causal
relationship - Is osteoarthritis a predictor for
osteoporosis, or vice-versa?: The Miyama Study.
Osteoporos Int 20, 999-1008, 2009 DOI:10.1007/
s00198-008-0771-3
Muraki S, Akune T, Oka H, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Nakamura K, Kawaguchi H,
Yoshimura N: Association of occupational
activity with radiographic knee osteoarthritis andlumbar spondylosis in elderly patients of
population-based
cohorts:alarge-scale
population-based study. Arthritis Care &Research (Arthritis Rheum) 61:779-786, 2009
Muraki S, Oka H, Akune T, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Prevalence of

382

4.

5.

6.

7.

8.

9.

radiographic lumbar spondylosis and its
association with low back pain in elderly subjectsof population-based cohorts: the ROAD study.
Ann Rheum Dis 68, 1401-1406, 2009
Yoshimura N, Muraki S, Oka H, Mabuchi A,
En-yo Y, Yoshida M, Saika A, Suzuki T, Yoshida
H, Kawaguchi H, Nakamura K, Akune T:
Prevalence of knee osteoarthritis, lumbar
spondylosis and osteoporosis in Japanese men
and women: the research on osteoarthritis/
osteoporosis against disability study. J Bone
Miner Metab 27, 620-628, 2009
Yanaoka K, Oka M, Yoshimura N, Deguchi H,
Mukoubayashi C, Enomoto S, Iguchi M, Magari
H, Utsunomiya H, Tamai H, Ohata H, Fujishiro
M, Takeshita T, Mohara O, Ichinose M:
Eradication of Helicobacter pylori prevents
cancer development in subjects with mild gastricatrophy identified by serum pepsinogen levels.
Int J Cancer 125, 2697-2703, 2009
Oka H, Akune T, Muraki S, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Sasaki S, Nakamura K,
Kawaguchi H, Yoshimura N: Low dietary vitamin
K intake is associated with radiographic knee
osteoarthritis in the Japanese elderly: Dietary
survey in a population-based cohort of the ROAD
study. J Orthopaedic Science 14, 687-692, 2009
Muraki S, Oka H, Akune T, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Prevalence ofradiographic knee osteoarthritis and its
association with knee pain in the elderly ofJapanese population-based cohorts: the ROAD
study. Osteoarthritis Cartilage 17, 1137-1143,
2009
Shoda N, Seichi A, Takeshita K, Chikuda H, Ono
T, Oka H, Kawaguchi H, Nakamura K: Sleep
apnea in rheumatoid arthritis patients withoccipitocervical lesions: the prevalence andassociated radiographic features. Eur Spine J 18:
905-910, 2009
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

10.

11.

12.

13.

14.

15.

16.

17.

etodolac, a selective cyclooxygenase-2 inhibitor,
on cancer development in extensive metaplastic
gastritis,aHelicobacter
pylori-negative
precancerous lesion. Int J Cancer 126, 14671473 , 2010
Itoh S, Miura T, Oka H, Nakagawa T, Nakamura
K. Reproducibility of measurements of thumb
abduction. Hand Surg. 15:7-10, 2010
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, in press
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, in press
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, inpress
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, in press
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 ROAD Study. Modern
Rheum, in press
Hara N, Oka H, Yamazaki T, Takeshita K,
Murakami M, Hoshi K, Terayama S, Seichi A,
Nakamura K, Kawaguchi H, Matsudaira K:
Predictors of residual symptoms in lower
extremities after decompression surgery on
lumbar spinal stenosis. Eur Spine J, in press
Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F,
Ohba S, Nishida N, Akune T, Yoshimura N,

383

Nakagawa T, Nakamura K, Tokunaga K, Chung
UI, Kawaguchi H: Transcriptional regulation of
endochondral ossification by HIF2A duringskeletal growth and osteoarthritis development.
Nat Med, in press
18. Kawaguchi H, Oka H, Jingushi S, Izumi T,
Fukunaga M, Sato K, Matsushita T, Nakamura K;
for the TESK GroupMembers of the TESK. A
local application of recombinant humanfibroblast growth factor-2 for tibial shaft
fractures: A randomized, placebo-controlled trial.
J Bone Miner Res. in press

384

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)

385(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

References
1. Yasunaga H. Who wants cancer screening with
PET: a contingent valuation survey in Japan.
European Journal of Radiology 2009;70:190–194.
2. Yasunaga H, Tsuchiya K, Matsuyama Y, Ohe K
High-volume surgeons in regard to reductions inoperating time, blood loss, and postoperativecomplications for total hip arthroplasty. Journalof Orthopaedic Science 2009;14(1):3-9.
3. Yasunaga H, Tsuchiya K, Matsuyama Y, Ohe K.
Analysis of factors affecting operating time,
postoperative complications, and length of stayfor total knee arthroplasty: nationwide web-based
survey. Journal of Orthopaedic Science
2009;14(1):10-16.
4. Yasunaga H, Nishii O, Hirai Y, Ochiai K,
Matsuyama Y, Ohe K Impact of Surgeon and
Hospital Volumes on Short-Term Postoperative
Complications after Radical Hysterectomy for
Cervical Cancer. The Journal of Obstetrics andGynaecology Research 2009;35(4):699-705.
5. Yasunaga H, Matsuyama Y, Ohe K, The Japan
Surgical Society. Effects of hospital and surgeon
case-volumes on postoperative complications andlength of stay after esophagectomy in Japan.
Surgery Today 2009;39:566-571.
6. Yasunaga H, Matsuyama Y, Ohe K, The Japan
Surgical Society. Volume-Outcome Relationshipin Rectal Cancer Surgery: a New Perspective.
Surgery Today 2009;39:663–668.
7. Yasunaga H, Matsuyama Y, Ohe K, The Japan
Surgical Society. Effects of hospital and surgeon
volumes on operating times, postoperativecomplications, and length of stay following
laparoscopic
colectomy
Surgery
Today
2009;39:955–961.
8. Hayashida K, Imanaka Y, Otsubo T, Kuwabara K,
Koichi B Ishikawa, Fushimi K, Hashimoto H,

Yasunaga H, Horiguchi H, Anan M, Fujimori
K,Ikeda S, Matsuda S. Development and analysis
of a nationwide cost database of acute-care
hospitals in Japan. Journal of Evaluation in
Clinical Practice 2009;15(4):626-33.
9. Ide H, Koike S, Kodama T, Yasunaga H,
Imamura T. The distribution and transitions ofphysicians in Japan: a 1974–2004 retrospective
cohort study. Human Resources for Health2009;7:73.
10. Ide H, Yasunaga H, Kodama T, Koike S, Taketani
Y, Imamura T. The Dynamics of Obstetricians andGynaecologists in Japan: A Retrospective Cohort
Model using the Nationwide Survey of Physicians
data. The Journal of Obstetrics and Gynaecology
Research 2009;35(4): 761-766.
11. Ide H, Yasunaga H, Koike S, Kodama T, Igarashi
T, Imamura T. Shortage of Pediatricians in Japan:
a Longitudinal Analysis Using Physicians' Survey
Data. Pediatrics International 2009;51(5):645-9.
12. Koike S, Yasunaga H, Matsumoto S, Ide H,
Kodama T, Imamura T. A future estimate ofphysician distribution in hospitals and clinics inJapan. Health Policy 2009;92: 244-249
13. Koike S, Matsumoto S, Kodama T, Ide H,
Yasunaga H, Imamura T. Estimation of Future
Physician Supply by Specialty and theDistribution Impact of Increasing Female
Physicians in Japan: Future Estimation. BMC
Health Service Research 2009;9:180

386

Department of Computational
Diagnostic Radiology andPreventive Medicine
Project Associate Professor
Naoto Hayashi, M.D., Ph.D.,

Kansei Uno, M.D., Ph.D.,

Project Research Associate
Takeharu Yoshikawa, M.D., Ph.D.,

Mika Nagasaki, M.D., Ph.D.,

Eriko Maeda, M.D.

Homepage

http://www.h.u-tokyo.ac.jp/center22/computer.html

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
themesincludeimage
analysissuchascomputer-assisted detection, or epidemiologic studies
employing health-screening data.

Research Activities
1) Health screening database
We have developed a unique health screening
information system in order to facilitate daily
management of the health screening activities and to
input health screening data. This information systemis still under constant revision. The medical images
acquired in the health screenings are stored in 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.

3872) 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
software, and epidemiological studies

ofResearches based on the health-screening database arecarried out in collaboration with other researchers ofvarious specialties. Images are analyzed using thedeveloped software.

References
Hanaoka S, Nomura Y, Nemoto M, Masutani Y,
Maeda E, Yoshikawa T, Hayashi , Yoshioka N,
Ohtomo K. Automated segmentation method forspinal column based on a dual elliptic column modeland its application for virtual spinal straightening. J
Comput Assist Tomogr. 2010 Jan;34(1):156-62.
Maeda E, Ohta S, Watadani T, Goto A, Nakajima A,
Ohtomo K. Imaging findings of thoracic low grade
fibromyxoid sarcoma: Report of three cases. Jpn JRadiol. 2009 Nov;27(9):375-80.
Furuta T, Maeda E, Akai H, Hanaoka S, Yoshioka N,
Akahane M, Watadani T, Ohtomo K.
Hepatic
segments and vasculature: Projecting CT anatomy
onto angiograms. Radiographics. 2009 Nov;29(7):1-22
Nishimura S, Manabe I, agasaki M, Eto K,
Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K,
Sugiura S, Yoshimura K, Kadowaki T, Nagai R.
CD8+ effector T cells contribute to macrophage
recruitment and adipose tissue inflammation in
obesity Nature Medicine, 2009, Aug, vol15, no8,
914-920.

Nishimura S*, agasaki M*, Manabe I, Kadowaki T,
Nagai R. (* These two authors contributed equally tothis work)
Obese adipose tissue remodeling,malfunctioning, and chronic inflammation visualized
by in vivo molecular imaging.
Inflammation and Regeneration, 2009, 29(2), 126130.
Kiryu S, Takeuchi K, Shibahara J, Uozaki H,
Fukayama M, Tanaka H, Maeda E, Akahane M,
Ohtomo K. Epstein-Barr virus-positive inflammatory
pseudotumour and inflammatory pseudotumour-likefollicular dendritic cell tumour.
Br J Radiol. 2009 Apr;82(976):e67-71.

388

Department of Hospital
Environment
Project Associate Professor
Yushi Uetera, MD. Ph.D.

Project Associate
Yuhei Saito M.Sc.

Introduction and Organization
Department of Hospital Environment was founded on
July 1, 2005, when the surgical center of Tokyo
University Hospital celebrated its 50th year
anniversary. Its aim is to improve the hospitalmanagement and environment on the basis of 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389

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.

Research activities
Our research field covers observational and genomic
epidemiology and main target diseases are
osteoarthritis,
spondylosis
andosteoporosis.
Osteoarthritis and osteoporosis are major public healthissues in the elderly that cause impairment of
ADL/QOL. The number of patients with these
diseases is rapidly increasing in Japan, however, few
epidemiologic indices have been established and there
is an urgent need for a comprehensive andevidence-based prevention strategy. We set up alarge-scale nationwide osteoarthritis/osteoporosis
cohort study called ROAD (Research on
Osteoarthritis/osteoporosis Against Disability) in 2005
for the pursue of genomic and etiological evidence.
We have to date created a baseline database withdetailed clinical and genomic information on three
population-based cohorts with total 3,040 participantsin urban, mountainous and seacoast communities ofJapan. Recruitment and baseline visits began in

October 2005 and were completed over a 1.5-year
period, with the last visit in March 2007. A second
comprehensive clinic visit is scheduled for October
2008 after a follow-up period of 3 years.

References
1. Muraki S, Oka H, Mabuchi A, Akune T, En-yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Prevalence ofradiographic lumbar spondylosis and its
association with low back pain in elderly subjectsof population-based cohorts: the ROAD study.
Ann Rheum Dis 68: 1401-1406, 2009.
2. Muraki S, Akune T, Oka H, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Nakamura K, Kawaguchi H,
Yoshimura N: Association of occupational activity
with radiographic knee osteoarthritis and lumbar
spondylosis in elderly patients of populationbased cohorts: a large-scale population-based
study. Arthritis Rheum 61: 779-786, 2009.
3. Muraki S, Oka H, Akune T, Mabuchi A, En-yo Y,
Yoshida M, Saika A, Suzuki T, Yoshida H,
Ishibashi H, Yamamoto S, Nakamura K,
Kawaguchi H, Yoshimura N: Prevalence ofradiographic knee osteoarthritis and its
association with knee pain in the elderly ofJapanese population-based cohorts: the ROAD
study. Osteoarthritis Cartilage 17: 1137-1143,
2009.

390

4. Yoshimura N, Muraki S, Oka H, Mabuchi A,
Kinoshita H, Yosihda M, Kawaguchi H,
Nakamura K, Akune T: Epidemiology of lumbar
osteoporosis and osteoarthritis and their causal
relationship - is osteoarthritis a predictor for
osteoporosis or vice versa?: the Miyama Study.
Osteoporos Int 20: 999-1008, 2009.
5. Yoshimura N, Muraki S, Oka H, Mabuchi A,
En-Yo Y, Yoshida M, Saika A, Yoshida H, Suzuki
T, Yamamoto S, Ishibashi H, Kawaguchi H,
Nakamura K, Akune T: Prevalence of knee
osteoarthritis,
lumbarspondylosis
andosteoporosis in Japanese men and women: theresearch on osteoarthritis/osteoporosis against
disability study. J Bone Miner Metab 27: 620-628,
2009.
6. Oka H, Akune T, Muraki S, En-yo Y, Yoshida M,
Saika A, Sasaki S, Nakamura K, Kawaguchi H,
Yoshimura N: Low dietary vitamin K intake isassociated with radiographic knee osteoarthritis in
the Japanese elderly: dietary survey in a
population-based cohort of the ROAD study. J
Orthop Sci 14: 687-692, 2009.
7. Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Cohort profile: researchon osteoarthritis/osteoporosis against disability
study. Int J Epidemiol (in press)
8. 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 (inpress)
9. 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
osteoarthritis in Japanese men: the ROAD study.
Arch Osteoporos (in press)
10. 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.
Nat Med (in press)
11. Yoshimura N, Muraki S, Oka H, Kawaguchi H,
Nakamura K, Akune T: Capacity of endogenous
sex steroids to predict bone loss in Japanese men:Ten-year follow-up of the Taiji Cohort Study. J
Bone Miner Metab (in press)

391

Department of Medical Safety
Management
Project Professor
Yasushi Kodama, M.D., LL.M., Ph.D.

Project Assistant Professor
Kenji Harada, M.D., Ph.D.

Project Researcher
Shiho Andoh, D.D.S., M.P.H.,
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 Medical Safety Management wasestablished in the 22nd century medical center of the
University of Tokyo Hospital by the contribution of
Tokio Marine & Nichido Fire Insurance Co., Ltd. in
December, 2005.
The public concern to the malpractice and the medical
affairs dispute has risen in developed countries withseveral events such as the public inquiry into
children’s heart surgery at the Bristol Royal Infirmary
and the accidental chemotherapy overdoses occurredin the Dana-Farber Cancer Institute at the end of the20th century. Reports of media in our country
concerning the malpractice and the medical affairs
dispute increase suddenly on the boundary of 1999.
Fears rise to making the criminal case through 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 health392

care provider.

Research activities
Malpractice events during recent years have beenfrequently reported, and medical treatment disputes
have become social problems. In this situation, basic
researches concerning both the prevention of
malpractice and the truthful resolution of medical
accidents by preventing disputes and lawsuits areurgent issues. Such research activities are vigorously
carried out in our department to return the result
widely to the society by the development ofeducational activities.

Teaching activities
We promote education based on the research results
described above for the purpose of training
researchers and graduate students in the university.
Furthermore, as an educational extension, we also
target medical staff for the purpose of training
high-level professionals. In order to advance theseeducational extension activities, the development ofvarious types of educational programs and teachingmaterials is also being carried out.
* Patient Safety Support Center Comprehensive
Support Project
Training and related activities are carried our targetingthe personnel of the “Patient Safety Support Centers”
established in each prefecture of Japan pursuant to theprovisions of the Medical Care Law (a Ministry of
Health, Labor and Welfare commissioned project).
* Model Project for 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 fromthe site and education for staff of the site.

References
1. Kodama Y. Medical malpractice: Looking back on
ten years of the medical treatment dispute. In:
Health Care and Social Policy Leadership
Program. Iryouseisaku Nyuumon. Igakushoin(Tokyo); 2009. p. 205-218. Japanese.
2. Kodama Y. Ten years of patient safety andmedical affairs dispute seen from medical
treatment site - Over three stories from 1999 to2006. Jurist. 2010;(1396):34-43. Japanese.
3. Kasanuki H, Aizawa Y, Kimura K, Minagawa T,
Sumitomo N, Takayama M, et al. Guideline
concerning cardiopulmonary resuscitation andcardiovascular system emergency for circulatoryorgans medicine. Circulation Journal 2009;73
Suppl.III:1361-1456. Japanese.
4. Kasanuki H, Aizawa Y, Kimura K, Minagawa T,
Sumitomo N, Takayama M, et al. Guideline
concerning cardiopulmonary resuscitation andcardiovascular system emergency for circulatoryorgans medicine (digest version). Circulation
Journal 2009;73 Suppl.III:1457-1506. Japanese.
5. Ishii T, Kanazawa N, Kodama Y, Mikami N,
Takagi M, Toriyama Y. About dental hygienist's
business. Nihon Shikaigakukai Zasshi. 2009;
62(4);433-452. Japanese.
6. Ooi T, Miyazaki H, Kodama Y, Sakamoto S,
Nakajima K, Fukunaga H, et al. As for medical
treatment
safetyinvestigationcommittee
installation bill (tentative name) outline idea, aquestionnaire survey total result. Nihon Byouinkai
Zasshi. 2009;56(6):676-740. Japanese.
7. Kodama Y. Pulmonary thromboembolism. Do not
overlook and do promp and adequate
correspondence. How should the acute pulmonary
thromboembolism be prevented? What can belearned from trial cases of pulmonary
thromboembolism? Guideline in trial. Medicina
2009;46(5):800-803. Japanese.
8. Andoh S, Kodama Y. About the dental hygienist
range of the business. Journal of Japan Society for
Dental Hygiene. 2010;4(2):17-21. Japanese.

393

9. Andoh S. Consultation drawn to patient safety
support centers. Osaka Hoken-i Zasshi. 2009;
37(516):10-13. Japanese.
10. Harada K. Risk management and prevention of
medical accidents in pediatric health care. Journalof Pediatric Practice. 2009;72(10):1767. Japanese.
11. Harada K. Problems and perspectives in risk
management policies for pediatric health care.
Journal of Pediatric Practice. 2009; 72(10):18971902. Japanese.
12. Harada K. Writing of documents for physicallyhandicapped person recognition, medical expense
promotion for intractable diseases, and nursing
assistance. In: Junkanki Kenshu Note. Shindan To
Chiryo Sha (Tokyo); 2010. p. 918-923. Japanese.
13. Harada K. Medical treatment lawsuit and medical
malpractice insurance in circulatory organs
disease. In: Junkanki Kenshu Note. Shindan To
Chiryo Sha (Tokyo); 2010. p. 924-925. Japanese.
14. Kitsuta Y, Yahagi N, Harada K, Tsukada H,
Akatsuka K, Ohara M, et al. Effect of usinge-learning system for familiarization with hospitalmajor incidents manual. Japanese Journal ofDisaster Medicine. 2009;14(2):181-190. Japanese.
15. Takahashi T. About the patient safety support
center comprehensive support project. Journal of
Safety Management for Medical Practice. 2009;(20):112-114. Japanese.
16. Takahashi T. Current state of medical treatment
participation of patient and the activity that will
be recommended in the future. Journal of Safety
Management for Medical Practice. 2009;(22):10-14. Japanese.
17. Takahashi T. Various patterns of patient safety
support centers. Journal of Safety Managementfor Medical Practice. 2009;(22):48. Japanese.

394

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 required for 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 similar mechanism existed inobese hypertension (1). Actually, high fat intake andsalt excess synergistically increase BP and progress
renal damage (2). Recently, our data suggest that thesimilar central mechanism contributes to increase in BP
and progression of renal damage in chronic kidneydisease (in preparation). This finding suggests that
sympathoexcitation by ROS in the brain is a common
and important mechanism for pahtophysiology of many
type of hypertensive disease.
Also, we demonstrated the role of ROS in dilated
cardiomyopathy (3). We elucidated the significance of
ROS in metabolic syndrome (4) and organ-protective
effects of dietary potassium via its antioxidant action(5).
In addition, we demonstrated that prepubertal saltloading caused more sever hypertension and renal
injury compared with high salt intake in adulthoodprobably due to mineralocorticoid receptor activation,
inflammatory and oxidant action, and rac-1 activation(6). This investigation may clarify the pathophsiology
of deflective lifestyle-induced hypertension and renal
damage in prepubertal age.
Clinical investigation: Now, we are doing

395

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 (7,8). In addition, we
published paper concerning small-sized clinical trial(9).
We are investigation a common disease such as
hypertension and metabolic syndrome, and can
indicate meaningful results.

References
1. Nagae A, Fujita M, Kawarazaki H, Matsui H,
Ando K, Fujita T: Sympathoexcitation byoxidative stress in the brain mediates arterialpressureelevationinobesity-induced
hypertension. Circulation. 2009; 119(7): 978-986.
2. Nagae A, Fujita M, Kawarazaki H, Matsui H,
Ando K, Fujita T: Effect of high fat loading in
Dahl salt-sensitive rats. Clin Exp Hypertens.
2009; 31(5): 451–461.
3. Kawakami S, Matsuda A, Sunagawa T, Noda Y,
Kaneko T, Tahara S, Hiraumi Y, Adachi S, Matsui
H, Ando K, Fujita T, Maruyama N, Shirasawa T,
Shimizu T. Antioxidant, EUK-8, prevents murine
dilated cardiomyopathy. Circ J. 2009; 73(11):2125-2134.
4. Ando K, Fujita T: Metabolic Syndrome andOxidative Stress. Free Radic Biol Med. 2009;47(3):213–218.
5. Ando K, Matsui H, Fujita M, Fujita T: Protective
Effectof
Dietary
Potassium
againstCardiovascularDamagein
Salt-sensitive
Hypertension: Possible Role of its Antioxidant
Action. Curr Vasc Pharmacol. 2010; 8(1): 59-63.
6. 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-sensitiverats. Nephrol Dial Transplant in press.
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,
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. Am
Heart J 2010; 159(3): 361-369.e4.
8. 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 inpress.
9. Ando K, Isshiki M, Takahashi K: Effect of
combination therapy with telmisartan andlow-dose hydrochlorothiazide switching from
amlodipine. Hypertens Res 2009; 32(9): 748-752.

396

Department of Healthcare Quality
Assessment
Associate Professor
Hiroaki Miyata, Ph.D.

Assistant Professor
Hiroyuki Tsukihara, M.D., Ph.D.

Researcher
Masafumi Okada, Ph.D.

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 April 2009.
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, department of Healthcare Quality
Assessment has collaborated with healthcare
professional committee. 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 health professionals at the heartof 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
Surgical Society, the Japanese Society for
Cardiovascular Surgery and the Japanese Society of397

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.

2.

3.

References4.
1. Miyata H, Motomura N, Kondo MJ, Fushimi K,
Ishikawa KB, Takamoto S. Toward quality
improvement of cardiovascular surgery in Japan:
an estimation of regionalization effects from anationwide survey. Health Policy. 2009 Aug;
91(3):246-51.
2. Miyata H, Kai I. Reconsidering evaluation criteria
for scientific adequacy in healthcare research: an
integrative framework of quantitative andqualitative criteria. International Journal of
Qualitative Methods. 2009;8(1):64-75.
3. Miyata H, Motomura N, Ueda Y, Tsukihara H,
Tabayashi K, Takamoto S. Toward quality
improvement of thoracic aortic surgery:estimating
volume-outcome
effectfromnationwide survey. Eur J Cardiothorac Surg. 2009
Sep;36 (3):517-21.
4. Miyata H, Motomura N, Takamoto S. Enhancing
the transferability of region-specific findings:
characteristics of Japan's cardiovascular surgery
system. Eur J Cardiothorac Surg. 2010 Jan;37(1):249.
5. Miyata H, Hashimoto H, Horiguchi H, Fushimi K,
Matsuda S. Assessment of hospital performancewith a case-mix standardized mortality modelusing an existing administrative database in Japan.
BMC Health Service and Research, 2010 May
19;10:130.

5.

6.

7.

Presentation
1. Miyata H, Hashimoto H, Horiguchi H, Fushimi K,

8.

Matsuda S. Hospital performance assessment withexisting administrative database: enhancement ofcase-mix In-hospital mortality risk-adjustment forbenchmarking. Academy Health 2009 Annual
Research Meeting. Chicago. 2009/6/29.
Takahashi M, Kohsaka S, Miyata H, Sakai T,
Maekawa Y, Takagi A, et al. Prehospital transportof patients with acute heart failure: prognostic
significance of delay in hospital arrival. American
Heart
Association
Resuscitation
Science
Symposium 2009. Orlando. 2009/11/14.
Miyata H, Motomura N, Takamoto S. How tohandle the cardiovascular surgery data in Asia.
Asian Society of Cardiovascular Thoracic Surgery
Annual Meeting. Delhi, India. 2010/3/1.
Motomura N, Miyata H, Takamoto S. New
challenge.starting up the Asian.Cardiovascular
Surgery
Database.
Asian
Societyof
Cardiovascular Thoracic Surgery Annual Meeting.
Delhi, India. 2010/3/1.
Miyata H, Motomura N, Murakami A, Takamoto
S, Japan Cardiovascular Surgery Database.
Effects of the benchmarking project on outcomesof CABG Surgery: challenges and prospects
regarding quality improvement initiative inJAPAN. American Heart Association: Quality ofCare and Outcome Research in Cardiovascular
Disease and Stroke Conference 2010. Washington
DC. 2010/05/21.
Motomura N, Miyata H, Tsukihara H, Takamoto S,
Japan
Cardiovascular
Surgery
Database.
Off-pump procedure reduced the risk adjusted
mortality of coronary artery bypass surgery byhalf in comparison with conventional 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 DC. 2010/05/21.
Saito A, Motomura N, Miyata H, Kyo S,
Tsukihara H, Ono M, Takamoto S. The Excellent
Performance of off-pump coronary artery bypass
Grafting for octage-, nonage-, and centenarians–
analysis of Japanese National Database. The 18th
ASCVS Annual Meeting, New Dehli, India.
2010/2/28.
Saito A, Motomura N, Miyata H, Takamoto S,

398

Kyo S, Ono M. Age specific risk stratification in
11948 isolated CABG procedures. The 24th
EACTS Annual Conference, Geneva. To bepresented.
9. Motomura N, Miyata H, Tsukihara H, Takamoto S,
JCVSDO. Off-pump procedure reduced the risk
adjusted mortality of coronary artery bypass
surgery by half in comparison with conventional
procedure. Propensity score analysis from theJapanese National Database (JACVSD). 59th
ESCVS. Izmir, Turkey. 2010/04/15-18.
10. Takahashi M, Kohsaka S, Miyata H, Harada K,
Anzai1 T, Nagao K, et al. Predictors of short-term
mortality for acute heart failure patients according
to baseline systolic function. Circulation Journal
Vol.74 Suppl.I,2010.
11. Takahashi M, Kohsaka S, Miyata H, Sakai T,
Maekawa Y, Takagi A, et al. Systolic bloodpressure on ER arrival and its impact on thein-hospital mortality in patients with acute heart
failure. Circulation Journal Vol.74 Suppl.I,2010.

399

Department of Anti-Aging
Medicine
Professor
Satoshi Inoue, M.D., Ph.D.

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

Homepage

http://www.h.u-tokyo.ac.jp/center22/koukarei.html

Introduction and Organization
The Department of Anti-Aging Medicine wasestablished at the 22nd Century Medical and ResearchCenter of University of Tokyo Hospital in 2006,
supported by the funds from Coca-Cola Tokyo
Research & Development Co. This department has aclose relationship with the Department of GeriatricMedicine at the Graduate School of Medicine,
University of Tokyo. The goal of this research
program is to understand the genetic andenvironmental factors that contribute to thepathogenesis of age-related disorders, including
obesity, diabetes, metabolic disorders, osteoporosis,
osteoarthritis, sarcopenia, atherosclerosis, dementia,
age-related macular degeneration, prostate cancer,
mammary carcinoma, and immunocompromised
conditions. In particular, the program aims to clarify
the roles of sex hormones estrogen and androgen in
normal, aging and disease processes. Through basic
biomedical research, our department will reveal
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 another importantrole in antiviral defenses. Extending our findings on
TRIM25, we also study the functions of other TRIM
proteins in normal states and in cancer and immune
response, including TRIM5α, TRIM17 (Terf), andTRIM44.
2. Using chromatin immunoprecipitation microarray400

analysis and systems biology approach, we discovered
novel androgen responsive genes including UGT1A1,
CDH2, APP, and FOXP1. The tumor-promoting effectof APP has been shown in in vivo models of prostatecancer.
3. As a genetic approach, we perform single
nucleotide polymorphisms (SNP) analysis to identify
disease-related factors for osteoporosis, osteoarthritis,
and age-related macular degeneration. Throughgenome-wide associated study and candidate geneapproach,
we
identify
severalinteresting
disease-related genes and focus on the functional
studies for these genes. We also combine mouse
genetics to solve the functions of disease-related genes
inphysiologicalstates
as
well
as
in
pathophysiological states.
Our intensive studies will provide novel molecularevidences for aging processes, which will be usefulfor the establishment of anti-aging medicine and thedevelopment of novel therapeutic modalities forage-related disorders.

References
1.

Kumagai J, Urano T, Ogushi T, Takahashi S,
Horie-Inoue K, Fujimura T, Azuma K,
Muramatsu M, Ouchi Y, Kitamura T, Inoue S:
EBAG9 is a tumor-promoting and prognostic
factor for bladder cancer. Int J Cancer 124,
799-805, 2009.

2.

Takayama K, Tsutsumi T, Suzuki T, Horie-Inoue
K, Ikeda K, Kaneshiro K, Fujimura T, Kumagai
J, Urano T, Sakaki Y, Shirahige K, Sasano H,
Takahashi S, Kitamura T, Ouchi Y, Aburatani H,
Inoue S: Amyloid precursor protein is a primary
androgen target gene that promotes prostatecancer growth. Cancer Res 69, 137-142, 2009.

3.

Kubo M, Ijichi N, Ikeda K, Horie-Inoue K,
TakedaS,
Inoue
S:
Modulationofadipogenesis-related gene expression by
estrogen-related receptor γ during adipocytic
differentiation. Biochim Biophys Acta - Gene
Regulatory Mechanisms 1789, 71-77, 2009.

4.

Azuma K, Urano T, Horie-Inoue K, Hayashi S,

Sakai R, Ouchi Y, Inoue S: Association of
estrogen receptor α and histone deacetylase 6
causes rapid decetylation of tubulin in breast
cancer cell. Cancer Res 69, 2935-2940, 2009.
5.

Takeo C, Ikeda K, Horie-Inoue K, Inoue S:
Identification of Igf2, Igfbp2 and Enpp2 as
estrogen-responsive genes in rat hippocampus.
Endocr J 56, 113-120, 2009.

6.

Fujimura T, Takahashi S, Urano T, Liu X,
Ogushi T, Muramatsu M, Ouchi Y, Kitamura T,
Homma Y, Inoue S: EBAG9 expression and its
clinical significance in human testicular cancer.
Int J Urol 16, 329-332, 2009.

7.

Furuya T, Urano T, Ikari K, Kotake S, Inoue S,
Hara M, Momohara S, Kamatani N, Yamanaka
H: A1330V polymorphism of low-density
lipoprotein receptor-related protein 5 gene andself-reported incident fractures in Japanese
female patients with rheumatoid arthritis. Mod
Rheumatol 19, 140-146, 2009.

8.

Suzuki H, Forrest AR, Erik van Nimwegen,
Daub CO, Balwierz PJ, Irvine KM, Lassmann T,
Ravasi R, Hasegawa Y, de Hoon MJ, Katayama
S, Schroder K, Carninci P, Tomaru Y,
Kanamori-Katayama M, Kubosaki A, Akalin A,
Ando Y, Arner E, Asada M, Asahara H, Bailey T,
Bajic VB, Bauer D, Beckhouse AG, Bertin N,
Björkegren J, Brombacher F, Bulger E, Chalk
AM, Chiba J, Cloonan N, Dawe A, Dostie J,
Engström PG, Essack M, Faulkner GJ, Fink JL,
Fredman D, Fujimori K, Furuno M, Gojobori T,
Gough J, Grimmond SM, Gustafsson M,
Hashimoto M, Hashimoto T, Hatakeyama M,
Heinzel S, Hide W, Hofmann O, Hörnquist M,
Huminiecki L, Ikeo K, Imamoto N, Inoue S,
Inoue Y, Ishihara R, Iwayanagi T, Jacobsen A,
Kaur M, Kawaji H, Kerr MC, Kimura R, Kimura
S, Kimura Y, Kitano H, Koga H, Kojima T,
Kondo S, Konno T, Krogh A, Kruger A, Kumar
A, Lenhard B, Lennartsson A, Lindow M, Lizio
M, MacPherson C, Maeda N, Maher CA,
Maqungo M, Mar J, Matigian NA, Matsuda H,
Mattick JS, Meier S, Miyamoto S,
Miyamoto-Sato E, Nakabayashi K, Nakachi Y,
Nakano M, Nygaard S, Okayama T, Okazaki Y,
Okuda-Yabukami H, Orlando V, Otomo J,401

Pachkov M, Petrovsky N, Plessy C,
Quackenbush J, Radovanovic A, Rehli M, Saito
R, Sandelin A, Schmeier S, Schönbach C,
Schwartz AS, Semple CA, Sera M, Severin J,
Shirahige K, Simons C, St-Laurent G, Suzuki
M, Suzuki T, Sweet MJ, Taft RJ, Takeda S,
Takenaka Y, Tan K, Taylor MS, Teasdale RD,
Tegnér J, Teichmann S, Valen E, Wahlestedt C,
Waki K, Waterhouse A, Wells CA, Winther O,
Wu L, Yamaguchi K, Yanagawa H, Yasuda J,
Zavolan M, Hume DA, Arakawa T, Fukuda S,
Imamura K, Kai C, Kaiho A, Kawashima T,
Kawazu C, Kitazume Y, Kojima M, Miura H,
Murakami K, Murata M, Ninomiya N, Nishiyori
H, Noma S, Ogawa C, Sano T, Simon C, Tagami
M, Takahashi Y, Kawai J, Hayashizaki Y: Thetranscriptional network that controls growtharrest and differentiation in a human myeloid
leukemia cell line. at Genet 41, 553-562, 2009.
9.

Gack MU, Albrecht RA, Urano T, Inn KS,
Huang IC, Carnero E, Farzan M, Inoue S, Jung
JU, García-Sastre A: Influenza A virus NS1
targets the ubiquitin ligase TRIM25 to evaderecognition by RIG-I. Cell Host Microbe 5,
439-449, 2009.

10.

Urano T, Usui T, Takeda S, Ikeda K, Okada A,
Ishida Y, Iwayanagi T, Otomo J, Ouchi Y, Inoue
S: TRIM44 interacts with and stabilizes terf, a
TRIM ubiquitin E3 ligase. Biochem Biophys
Res Commun 383, 263-268, 2009.

11.

Urano T, Shiraki M, Usui T, Sasaki N, Ouchi Y,
Inoue S: A1330V variant of the low-density
lipoprotein receptor-related protein 5 (LRP5)
gene decrease Wnt signaling and affect the total
body bone mineral density in Japanese women.
Endocr J 56, 625-631, 2009.

12.

Urano T, Shiraki M, Usui T, Sasaki N, Ouchi Y,
Inoue S: Bone mass effects of a Smad6 gene
polymorphism in Japanese postmenopausal
women. J Bone Miner Metab 27, 562-566,
2009.

13.

Urano W, Furuya T, Inoue E, Taniguchi A,
Urano T, Kotake S, Sekita C, Inoue S, Hara M,
Momohara S, Kamatani N, Yamanaka H:
Associations between methotrexate treatment
and methylenetetrahydrofolate reductase gene

polymorphisms with incident fractures inJapanese female rheumatoid arthritis patients. J
Bone Miner Metab 27, 574-583, 2009.
14.

Fujimura T, Takahashi S, Urano T, Kumagai J,
Murata T, Ogushi T, Horie-Inoue K, Ouchi Y,
Kitamura T, Muramatsu M, Homma Y, Inoue S:
Expression of cytochrome P450 3A4 and its
clinical significance in human prostate cancer.
Urology 74, 391-397, 2009.

15.

Urano T, Usui T, Shiraki M, Ouchi Y, Inoue S:
Association of a single nucleotide polymorphismin the constitutive androstane receptor gene withbone mineral density. Geriatric Gerontol Int 9,235-241, 2009.

16.

Azuma K, Urano T, Ouchi Y, Inoue S: Vitamin
K2 Suppresses Proliferation and Motility of
Hepatocellular Carcinoma Cells by Activating
Steroid and Xenobiotic Receptor. Endocr J 56,
843-849, 2009.

17.

Ijichi N, Ikeda K, Fujita M, Usui T, Urano T,
Azuma K, Ouchi Y, Horie-Inoue K, Inoue S:
EPAS1, a dexamethasone-inducible gene inosteoblasts, inhibits osteoblastic differentiation.
Open Bone J 1, 28-37, 2009.

18.

Urano T, Shiraki M, Yamaga R, Sasaki N, Ouchi
Y, Inoue S: Association of a sequence variationin the gene encoding adiponectin receptor 1(ADIPOR1) with body mass index in theJapanese population. Anti-Aging Med 6, 79-82,
2009.

402

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

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,andhigh-potential 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 , 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 ,
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

403

liver tumors in patients with previous adverse
reactions to iodinated contrast media. Kunishima K,
Takao H, Akahane M, Yoshioka , 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: acost-utility
andcost-effectivenessanalysis.
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
T2-weighted images: report of three cases andliterature review. Furukawa R, Akahane M, YamadaH, Kiryu S, Sato J, Komatsu S, Inoh S, Yoshioka ,
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 , Ohtomo K. J

Comput Assist Tomogr. 2010;34(1):156-62.

404

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 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405

developing common tool for clinical research such as
Standardized Operating Procedures (SOPs) in
conducting clinical research.
Research on Clinical Data Interchange Standards
Consortium (CDISC) in collaboration with University
Hospital Medical Information Network (UMIN) is
actively ongoing. The mission of CDISC is to develop
and support global, platform-independent data
standards
thatenableinformation
systeminteroperability to improve medical research andrelated areas of healthcare and we are challenging toconvert several academic clinical trial data to CDISC
Standards formats.
Finally, we started the Eplerenone Combination
Versus Conventional Agents to Lower Blood Pressure
on Urinary Antialbuminuric Treatment Effect Trial(EVALUATE) in collaboration with the Department ofNephrology and Endcrinology, Department ofPharmacoepidemiology, University of Tokyo ClinicalResearch Center and UMIN. The responsibility of theData Center is the data management including
operation of the internet system of the patient registry
and informing data and of handling the individual casesafety reports for the serious adverse events.

References
1. Ushio M, Iwasaki S, Murofushi T, Sugasawa K,
Chihara Y, Fujimoto C, Nakamura M, Yamaguchi
T, Yamasoba T. The diagnostic value ofvestibular-evoked myogenic potential in patientswithvestibular
schwannoma.
Clinical
Neurophysiology 2009; 120(6): 1149-53.
2. Fujimoto C, Murofushi T, Chihara Y, Ushio M,
Sugasawa K, Yamaguchi T, Yamasoba T, Iwasaki
S. Assessment of diagnostic accuracy of foam
posturography for peripheral vestibular disorders:
Analysis of parameters related to visual andsomatosensory
dependence.
Clinical
Neurophysiology 2009; 120(7): 1408-14.
3. Kanaya K, Ushio M, Kondo K, Hagisawa M,
Suzukawa K, Yamaguchi T, Tojima H, Suzuki M,
Yamasoba T. Recovery of facial movement andfacial synkinesis in Bell's palsy patients. Otology
and Neurotology 2009; 30(5): 640-4.
4. Konuma T, Takahashi S, Ooi J, Tomonari A,
Tsukada N, Kato S, Sato A, Monma F, Kasahara S,

Nagamura-Inoue T, Uchimaru K, Iseki T, Tojo A,
Yamaguchi T, Asano S. Myeloablative unrelated
cord blood transplantation for acute leukemia
patients between 50 and 55 years of age: single
institutional retrospective comparison withpatients younger than 50 years of age. Annals of
Hematology 2009; 88(6): 581-8.
5. Ueta T, Obata R, Inoue Y, Iriyama A, Takahashi H,
Yamaguchi T, Tamaki Y, Yanagi Y. Background
Comparison of Typical Age-Related Macular
Degeneration
andPolypoidal
Choroidal
VasculopathyinJapanese
Patients.
Ophthalmology 2009; 116(12): 2400-6.
6. Kusunoki T, Matsuoka K, Ohtsu H, Kagimura T
and Nakamura H. Relationship between Intraclassand Concordance correlation Coefficients:
Similarities and Differences. Japanese Journal of
Biometrics 2009; 30(1): 35-54.
7. Inoue Y, Sugawara Y, Tamura S, Ohtsu H, Taguri
M, Makuuchi M, Kokudo N. Validity andfeasibility of transient elastography for thetransplanted liver in the peritransplantation period.
Transplantation 2009; 88(1): 103-9.

406

Department of
Therapeutic Strategy forHeart Failure
Professor
Shunei Kyo, M.D.

Associate Professor
Satoshi Gojo, M.D.

Lecturer
Takashi Nishimura, M.D.,

Associate
Motoyuki Hisagi, M.D.,

Tuyoshi Shimizu, M.D.,

Yoko Ogawa, M.D.

Homepage

http: http://plaza.umin.ac.jp/~heart-f/

Introduction and Organization
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 hearttransplantation, ventricular assist device, andregenerative therapy. The Department is also
supported by thirteen companies,

Clinical Activities
1. Heart Transplantation (HTx)Patients who performed heart transplantation in
our hospital (9 patients) or in abroad transferred fromour hospital (7patients) 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.
14 patients underwent
myocardial biopsy in 2009 and four patients werediagnosed to have rejection (Grade 1A:3, Grade 3:1).
Due to social argument for revision of the Organ
Transplant Law the number of brain death cadaverdecreased in 2009, only one patient could receive
heart transplantation in the University of Tokyo
Hospital. The patient was supported by DuraHeart for
451 days and the clinical course after hearttransplantation is uneventful.
2. Ventricular Assist Device (VAD) Therapy
37 patients were treated with Ventricular assist
device (VAD) since November 2002 when the
University of Tokyo Hospital started hearttransplantation program. Toyobo paracorporeal VAD
was implanted in 6 patients in 2009 and 4 patients407

could recover from multi-organ failure and become
candidates for HTx. They were registered to JOTN
(Japanese Organ Transplant Network) are waiting for
HTx.. We assisted VAD implantation in three patientsin affiliate or cooperative hospital in 2009 to establish
VAD network in Kanto prefectures.
3. Compact CP (external counter-pulsation)
Compact CP is a system of externalcounter-pulsation circulatory support system, which
has been developed with collaboration of Nishimura
Co. Ltd. and the University of Tokyo Hospital.
Compact CP therapy was performed on 4 patients at
ICU for postcardiotomy cardia failure and on 1 patientin out-patient clinic for unstable angina after CABG
ad PCI.
4. Rota Flow circulatory support in pediatric patientsfor bridge to HTx
Rota Flow circulatory support system wasintroduced as bridge device for pediatric HTx
candidate with Government grant support. One patientwith 5kg of body weight was supported by Rota Flowsystem for more than 2 months and scheduled to go
Colombia Presbyterian Hospital in NY, however, thepatient died due to sepsis two days before to go NY.
Rota Flow is a promising system for pediatric bridge
device for HTx.

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..

References

University Hospital
Clinical Divisions

University Hospital
Central Clinical Facilities

410

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, 69 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
2009, 235,386 outpatient blood sampling were
performed in this section.
The 2nd Section
This section deals with clinical biochemistry andimmuno-serology tests. In 2009, 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 2009, 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 2009, 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411

section is going to be further expanded since there isso much demand from clinical doctors.

Teaching activities
2.
Lectures are given to the fourth and fifth grade
medical students on clinical tests including
hematology, chemistry, endocrinology, immunology,
bacteriology, cardiology, and pulmonary function.
The reversed CPC program is presented to the fifthand sixth grade students. Laboratory practice teachingis provided for the fifth year medical students, insmall groups of 6-7 students for one-week duration.
In this course, students learn clinical and practicalknowledge and techniques on various laboratory tests.
Students from professional schools also study
laboratory medicine under the guidance of members inClinical Laboratory Center.

3.

4.

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.

5.

6.

References
1. Furubayashi, T., Ushiyama, A., Terao, Y., Mizuno,
Y., Shirasawa, K., Pongpaibool, P., Simba, A.Y.,
Wake, K., Nishikawa, M., Miyawaki, K., Yasuda,A., Uchiyama, M., Yamashita, H.K., Masuda, H.,
Hirota, S., Takahashi, M., Okano, T.,
Inomata-Terada, S., Sokejima, S., Maruyama, E.,
Watanabe, S., Taki, M., Ohkubo, C., and Ugawa,7.

Y. Effects of short-term W-CDMA mobile phonebase station exposure on women with or without
mobilephone
relatedsymptoms.
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Hirahashi, J., Hishikawa, K., Kaname, S., Tsuboi,N., Wang, Y., Simon, D.I., Stavrakis, G.,
Shimosawa, T., Xiao, L., Nagahama, Y., Suzuki,
K., Fujita, T., and Mayadas, T.N. Mac-1(CD11b/CD18)
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Ikeda, H., Watanabe, N., Ishii, I., Shimosawa, T.,
Kume, Y., Tomiya, T., Inoue, Y., Nishikawa, T.,
Ohtomo, N., Tanoue, Y., Iitsuka, S., Fujita, R.,
Omata, M., Chun, J., and Yatomi, Y. Sphingosine
1-phosphate regulates regeneration and fibrosis
after liver injury via sphingosine 1-phosphate
receptor 2. J. Lipid Res. 50: 556-564, 2009.
Iwasawa, Y., Fujii, T., Nagamatsu, T., Kawana, K.,
Okudaira, S., Miura, S., Matsumoto, J., Tomio, A.,
Hyodo, H., Yamashita, T., Oda, K., Kozuma, S.,
Aoki, J., Yatomi, Y., and Taketani, Y. Expressionof autotaxin, an ectoenzyme that produces
lysophosphatidic acid, in human placenta. Am. J.
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Kusakabe, M., Watanabe, K., Emoto, N., Aki, N.,
Kage, H., Nagase, T., Nakajima, J., Yatomi, Y.,
Ohishi, N., and Takai, D. Impact of DNA
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Kurabe, N., Arai, S., Nishijima, A., Kubota, N.,
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Miyake, K., Ueki, K., Koga, H., Yatomi, Y.,
Tashiro, F., Noguchi, M., Kadowaki, T., andMiyazaki,
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8. Masuzaki, R., Tateishi, R., Yoshida, H., Goto, E.,
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9. Miyamoto, N., Tanaka, R., Shimosawa, T., Yatomi,Y., Fujita, T., Hattori, N., and Urabe, T. Protein
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A. Ann. Hematol., 88: 811-812, 2009.

413

Surgical Center
Director (Professor)
Hiroshi Yasuhara M.D., Ph.D.

Associate Professor
Yoshikazu Mimura, M.D., Ph.D.
Kazuhiro Fukatsu. M.D., Ph.D.
Yushi Uetera, M.D., Ph.D.

Lecturer
Takami Komatsu, M.D., Ph.D.
Ryoji Fukushima, M.D., Ph.D.

Associate
Toshihiko Obayashi, M.D., Ph.D.
Saito Yuhei, Ph.D.

Homepage
Introduction and Organization
Operating rooms were centralized for the first timein Japan in the University of Tokyo Hospital on July
1955. Surgical center was located in the surgical ward
building till December 1987. The center moved to the
new central building on January 1988, when thesurgical center had 14 operating rooms, including one
bio-clean room. The administration staffs consisted of
4 doctors, 75 nurses, 6 technical officials, 5 part-time
employees. The surgical center became to afford
services to 18 clinical departments after the newsurgical center started.
The total number of operations did not apparently
increase between 1999 and 2000, partly because of thelimited number of operating rooms and nursing staffs.
In July 2001, the branch hospital, which was
located in Mejiro, merged to the University of Tokyo
Hospital in Hongo and a new ward building opened in
October 2001. Then, the number of elective operations
remarkably increased and became over 7500. Efficacy
became a key to improve the availability of theoperating rooms. Two new operating rooms weretentatively used to overcome the tremendous increasein the number of elective operations. The one was on
the ICU/CCU/HCU floor in the new ward building
and the other room was in the outpatient building,which had been used for the orthopedic patients. This
operating room was used for the short-stay and day
surgery of orthopedics as well.
Until September 2001, the elective operations had
been performed daily in 9 operating rooms on average.
Then after October 2001, 12 rooms began to be used
for elective operations. In the year 2007, the newest
central building, which had 11 operating rooms, wasopen to solve the relative shortage of operating rooms.
As a result, the total number of operating rooms
became 23, and then the number of operations has
been dramatically increased. The number ofoperations increased thereafter.
A total of 8,322, 9,374 and 9,868 operations, whichcounts for 1.5 times comparing to those in 2001, were
performed in 2006, 2007 and 2008, respectively. Morerecently, the number of operations was 9,957 (1,282
emergency cases) in 2009.
There has been much concern about the apparent

414

increase in the patients who are positive for the
microbiological tests such as tuberculosis, MRSA,
pseudomonas aeruginosa, HBV, HCV and HIV. Thosepatients have been increasing by 5-18% per year overthe last 4 years. Administrative efforts might beneeded more in the near future to protect the staffs aswell as the patients against the new infectious agent
such as prion.

Activities of Surgical Center
Our works range from the management of operation
schedule to the teaching and research.

Management of Surgical CenterAll operations of in-patients are performed in 23
operating rooms of the surgical center. Computer
system has been introduced in order to deal with theinformation on the operation. In May 1999, on-line
computer system was introduced for ordering systemof the elective and emergency operations. Then, theoperations have become ordered through the computer
terminal of the clinical departments since May l999.
The doctors and nurses became to be able to see
postoperative information through the computer
system since March 2000.
For the efficacy of the operation, the information on
the status of the procedures has been displayed on thecomputer monitor screen since May 1997. This
monitor also tells the hospital staffs whether there are
any operating rooms available on the next day.
Furthermore, since November 2000, the hospital staffs
have become to be able to see how the clinicaldepartments plan the operations through the hospitalcomputer network.
As for digitalized visual information, thephotographs of operative fields, resected organs andreal-time visual images have been distributed to eachclinical department through hospital computer
network since February 1997.
In the new ward building, the SPD and progressive
patient care system started for the management of our
hospital in October 2001. Then, the SPD system wasintroduced for the surgical center in September 2002.
The complicated surgical procedures including
organtransplantation
microvascularsurgery,

cardiovascular surgery, minimally invasive surgery
and orthopedic surgery have increased dramatically.
In addition, more and more patients recently
underwent surgery using artificial implants such as
vascular prosthesis, joint prosthesis and intraocularlenses.
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 surgical415

instruments and medical devices are recently
introduced to perform highly advanced operations
such as in the navigation surgery, transplantation
surgery, cardiovascular surgery and so forth.
Consequently, education has become one of the mostimportant activities in the surgical center. The lecturesof advanced technologies are in the curriculum for thesurgeons, nursing staffs and medical electronics
engineers so that they can understand how to use themproperly.
Lectures for the nursing staffs consist of a freshmancourse and an advanced course. The freshman course
is a basic training course as a scrub nurse and acirculating nurse. It consists of lectures of aseptic
techniques, de-contamination methods, sterilization
methods, prevention of perioperative infections, andtraining of scrubbing and gown techniques as wall as
aseptic preparation of surgical instruments in theoperating room. An advanced course is also preparedto the experienced nurses. The purpose of this course
is to upgrade their perioperative nursing skills so thatthey can afford full nursing skills in the complex
surgical procedures such as transplantation surgery,open-heart surgery and neurosurgery.
There is also a training course to medical
electronics engineers and students of medical
electronics. This training course consists ofintroduction on the medical electronic instruments anddevices, precautions of accidental troubles in handlingsurgical
instruments
andmedicaldevices,development of new surgical instruments and medical
devices, cardiopulmonary bypass techniques andillumination techniques in the operating fields. The
contents of this course are summarized in the manual
for the nursing staffs and contribute to decrease thenumber of accidents in handling surgical instruments
and medical devices.
The on-job training are given to the non-nursing
staffs such as technical officials and temporary
employees and performed when they start their careers
in the surgical center. They are lectured on aseptic
techniques, sterilization methods, disinfection
methods, prevention of perioperative infections andhow to check the faults in the reusable surgicalinstruments such as forceps, scissors and clamps.
These contents are summarized in the manual.
Lectures are also given to senior technical officers andtemporary employees to upgrade their technicalknowledge and skills.

Research Activitiesl)Safety management of the surgical treatments inthe operation center2) Introduction of IT technology in the managementof surgical center3) Improvement of cost-effectiveness in the
management of surgical center and international
comparison of effectiveness in the management ofsurgical center
4) Precautions of accidental troubles in the handlingsurgical instruments and medical devises5) Introduction of aseptic environment in theoperating theaters
6) Perioperative infection control of patients
undergoing operations and prevention ofoccupational infection of medical staffs working
in the surgical center
7) Development of new sterilization methods8) Improvement of cost-effectiveness in sterilizationand preservation of medical instruments andintroduction of international standardization ofsterilization methods8) Cost-effectiveness analysis of disposable andreusable surgical instruments
9) Development of new surgical instruments andmedical devisesl0) Improvement of minimally invasive surgery andmicrosurgery11) Three dimensional processing of visual
information
12) Computer assisted surgery13) Computer assisted anesthesia
14) Inter-hospital visual communications via satellite
systemReferences（2007-2009）
1. Maeshima Y, Fukatsu K, Moriya T, Ikezawa F,
Ueno C, Saitoh D, Mochizuki H. Influence ofadding fish oil to parenteral nutrition on
gut-associated lymphoid tissue. JPEN J Parenter
Enteral Nutr. 2007 Sep-Oct;31(5):416-22.
2. Moriya T, Fukatsu K, Maeshima Y, Ikezawa F,

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Mochizuki, Miyazaki M. Nutritional route affects
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hepatic mononuclear cells. Ann Surg2007 Apr;245(4):642-50
Omata J, Fukatsu K, Ueno C, Hara E, Maeshima Y,
Nagayoshi H, Yaguchi Y, Hiraide H, Mochizuki H.
Intraluminal glutamine administration during
ischemia worsens survival after gut ischemia
reperfusion. J Surg Res 2007, 143(2):260-4
Ikezawa F, Fukatsu K, Moriya T, Ueno C,
Maeshima Y, Okamoto K, Hara E, Saitoh D.
Reversal of parenteral nutrition-induced gut
mucosal immunity impairment with small
amounts of a complex enteral diet. J Trauma 2008
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Moriya T, Saitoh D, Mochizuki H. Lack of enteralnutrition blunts extracellular regulated kinase
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Shock. 2007;27(3):320-325.
Yasuhara H, Ohara N, Hattori T, Shigeta O.
Importance of combination of persistentunderlying factors in deep vein thrombosis. Int
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Sotome K, Onishi T, Hirano A, Nakamaru M,
Furukawa A, Miyazaki H, Morozumi K, Tanaka Y,
Iri H, Mimura Y. A rare case of anaplastictransformation within the metastatic site of theretroperitoneal region in a patient 17 years after
total thyroidectomy for papillary carcinoma of the
thyroid beginning with multiple bone metastases.
Thyroid 17: 1309-1311, 2007
Kuwabara K, Nishishita T, Morishita M, Oyaizu
N, Yamashita S, Kanematsu T, Obara T, Mimura Y,
Inoue Y, Kaminishi M, Kaga K, Amino N,
Kitaoka M, Ito K, Miyauchi A, Noguchi S,
Uchimaru K, Akagawa E, Watanabe N, Takahashi
TA, Sato K, Inazawa T, Nakaoka T, Yamashita N.
Results of a phase I clinical study using dendritic
cell vaccinations for thyroid cancer. Thyroid 17:
53-58, 2007
Ogawa T, Tsuji E, Kanauchi H, Yamada K,
Mimura Y, Kaminishi M. Excision ofpostesophageal parathyroid adenoma in posterior
mediastinum with intraoperative 99mTechnetium
sestamibi scanning. Ann Thorac Surg 84:

1754-1756, 2007
10. 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
11. Ueda S, Tsuda H, Asakawa H, Omata J, Fukatsu
K, Kondo N, Kondo T, Hama Y, Tamura K,
Ishida J, Abe Y, Mochizuki H. Utility of
18F-fluoro-deoxyglucose emission tomography/
computed tomography fusion imaging (18F-FDG
PET/CT) in combination with ultrasonography foraxillary staging in primary breast cancer. BMC
Cancer. 9;8:165, 2008.
12. Ueda S, Kondoh N, Tsuda H, Yamamoto S,
Asakawa H, Fukatsu K, Kobayashi T, Yamamoto
J, Tamura K, Ishida J, Abe Y, Yamamoto M,
Mochizuki H. Expression of centromere protein F(CENP-F) associated with higher FDG uptake on
PET/CT, detected by cDNA microarray, predicts
high-risk patients with primary breast cancer.
BMC Cancer. 2008 Dec 22;8:384.
13. Ueda S, Tsuda H, Asakawa H, Shigekawa T,
Fukatsu K, Kondo N, Yamamoto M, Hama Y,
Tamura K, Ishida J, Abe Y, Mochizuki H.
Clinicopathological and prognostic relevance of
uptake level using 18F-fluorodeoxyglucose
positronemission
tomography/computed
tomography fusion imaging (18F-FDG PET/CT)
in primary breast cancer. Jpn J Clin Oncol.38(4):250-8, 2008.
14. Fukatsu K, Ueno C, Maeshima Y, Mochizuki H,
Saitoh D. Detrimental effects of early nutrition
administration after severe gut ischemiareperfusion. J Surg Res. 149(1):31-8, 2008
15. Fukatsu K, Nagayoshi H, Maeshima Y, Ueno C,
Saitoh D, Mochizuki H. Fish oil infusion reverses
5-fluorouracil-induced impairments in mucosal
immunity in mice. Clin Nutr. 27(2):269-75, 2008
16. Furuya Y, Yasuhara H, Naka S, Yamazaki K,
Yanagie H, Wakahara T, Akimoto H. Intestinal
evisceration through the anus caused by fragile
rectal wall. Int J Coplorectal Dis 2008; 23:721-22
17. Uetera Y, Saito Y, Ide K, Yasuhara H, Kumada N,
Saito R, Takahashi O. Reduced water supply to
the water ring vacuum pump. Central Sevice 16:
182-185, 2008.

417

18. 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 Sevice 16:372376, 2008.
19. 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.
20. Fukazawa S, Akase T, Saitoh D, Mochizuki H,
Yamamoto J, Hase K. Enteral refeeding rapidly
restores PN-induced reduction of hepaticmononuclear cell number through recovery ofsmall intestine and portal vein blood flows. JPENJ Parenter Enteral Nutr. 2009 Nov-Dec;33(6):618-25; discussion 626.
21. 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. 2009 Dec;28(6):668-73.
22. Furuya Y, Yanagie H, Wakahara T, Mishina Y,
Akimoto H, Quang le M, Hiroshima K, Yasuhara
H. Improved survival in patients with breast
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418

Department of Clinical Radiology
Professor (department manager)
Kuni Ohtomo, M.D.,Ph.D.

Associate Professor (vice manager)
Masaaki Akahane, M.D.,Ph.D.

Assistant Professor
Shinichi Inoh, M.D.

Homepage

http://www.ut-radiology.umin.jp/

Introduction and Organization
In the Department of Clinical Radiology, clinicalservices on Diagnostic Radiology (imaging andintervention), Radiation Oncology (radiotherapy),
Nuclear Medicine and the Radiation Safety Control
System are provided in cooperation with radiology
technologists and nurses. Present constituent members
are as follows: three medical doctors, 52 radiological
technicians, 2 assistants, 18 nurses, and 1 technicalofficial of the radiation control. The staff members of
the Department of Radiology (teachers, the graduate
school students, medical staffs, and the clinicaltrainees) join this. In addition, the doctors and thenurses of other clinical departments cooperate and arealso engaged in the clinical radiology activities. The
educational training and registration of the radiation
engaging persons are controlled according to the
University of Tokyo Hospital Ionizing Radiation
Injury Prevention Rules.
Department of Clinical Radiology covers four
major fields: (1) Diagnostic Radiology, (2) Radiation
Oncology, (3) Nuclear Medicine and (4) the Radiation
Safety Control System. The Diagnostic Radiology
Section is mainly operated at the first floor in theCentral Clinic Building 1. Parts of the diagnostic
activities are done at the Central Clinic Building 2(the MR rooms, the operation rooms, and theemergency department) and some other clinicaldepartments. The services provided are X-ray imaging,fluoroscopic imaging, computed tomography (CT),magnetic resonance imaging (MRI) and angiography.
Radiation Oncology Section is operated at thirdbasement floor of the Central Clinic Building 2. The
outpatient clinic is also located here and not in the
Outpatient Clinic building. The methods of therapy
providedarelinearaccelerator(LINAC),
gamma-knife, Remote After Loading System (RALS)
and Brachytherapy (Radioactive Seed Implantation
Therapy). Nuclear Medicine Section is operated at thebasement floor of the Central Clinic Building 1. The
methods of examination provided are conventional
scintigram, SPECT and PET. The office of Radiation
Safety Control System is located at the third floor of
the old Central Clinic Building.
Department of Clinical Radiology is actively
participating in the following projects. 1) PACS: We
have recently developed a radiology information
system (RIS) networking with hospital information
system (HIS) and PACS (picture archiving andcommunicating system). The PACS of the whole
hospital (the film-less imaging system) wasestablished in 2003. The new reporting system wasinstalled in 2002. 2) Radiation Safety Control:
Stimulated by the need for evaluating the individualaccumulated exposure dose by medical radiation, we
have started a working group to solve this problem.
We aim to provide the accumulated exposure dose419

data on RIS. 3) Image Computing & Analysis
Laboratory: The clinical section of this project islocated at the reading room in the Diagnostic
Radiology Section. The main services are processingof volume image data into clinical 3D-images andanalysis of imaging data. 4) Researches on new
radiology
techniques:
Ongoingcollaborative
researches are as follows: image-guided radiation
therapy, clinical PET, multi-detector row CT, 3-Tesla
MRI, flat panel detector.

Clinical activities
1) Diagnostic Radiology:
The section of diagnostic radiology is responsible
for all the clinical examinations of CT, MRI, andangiography and vascular interventional procedures
except for cardiac and peripheral arterial studies. Allof these examinations are performed under therequests of clinicians. Over one hundred and fifty CT
examinations are performed using five MDCT
scanners each day. Interventional procedure such as
percutaneous biopsy and abscess drainage are alsodone by CT guidance. About fifty MR examinations
are done using 1.5-Tesla and 3-Tesla scanners everyday. About six angiographies, most of which areinterventional
procedures
includingarterial
embolization, arterial infusion therapy, arterial
infusion port placement, and angioplasty, are done by
the radiologists using two angiographic units.
In clinical research works, efficacy of MDCT has
been investigated in all parts from the head to
extremities. New three-dimensional approaches havebeen also developed. Clinical research and basic
animal experiments are in progress in the field offunctional MR imaging and diffusion and perfusion
MR techniques.
2) Radiation Oncology:
The radiation therapy is performed with 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

420

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.

421

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 893 in 2009,
891 in 2008.
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.]

422

Rehabilitation Center
Professor
Nobuhiko Haga, M.D.

Associate
Takashi Maeno, M.D.,

Shun-ichi Furukawa, M.D.

Toshihiro Arao, M.D.

Homepage

http://todaireh.umin.ne.jp

Introduction and Organization
The physical therapy service started in 1963 at the
University of Tokyo Hospital, and then expanded toinclude occupational therapy and social work section.
In 1966 this service was converted to the central
rehabilitation service department as a part of theCentral Diagnostic and Therapeutic Service
Department. The Central Rehabilitation Service
became an independent unit in 1970. After the
reorganization of the University of Tokyo Hospital
according to major organic classification in 1998,
outpatient clinic as rehabilitation medicine wasinstalled. The formal title of our unit was changed
from the Physical Therapy Department to the
Rehabilitation Department by the budget measures in
the fiscal year 2001, and we integrated the related
personnel categories, which belonged to theorthopedic surgery department and the physicalmedicine department.
At the present time our department consists of four
sections. Rehabilitation physicians’ section includes
three full-time doctors and two other part-time doctors.
They work chiefly for clinical practice in medical
rehabilitation service, but also have to engage inteaching activities for medical students. Fourteen
physical therapists and five acupuncture therapists areworking in the physical therapy section. In theoccupational therapy section, three occupational
therapists work for the general rehabilitation service
and the other two therapists work for the psychiatricrehabilitation. In the Day-care Unit, a clinicalpsychologist and a nurse also work. In 2006, speechtherapists and orthoptists who belong to otherdepartments in the University of Tokyo Hospital aregoing to be included in our department.

Clinical activities
There is not enough doctors arranged for the
department of rehabilitation medicine, and we cannot
run own beds for rehabilitation patients at present. The
professor serves as a director of Rehabilitation Center,the University of Tokyo Hospital. Both departments
are united and engage in clinical practice. We have atpresent no charged ward, and treat about 1,000 newreferrals annually from almost all the departments of
the university hospital. We always take charge ofabout 150 patients corresponding about 15% of thewhole number of inpatients. We also see 15 people per
day at the outpatient rehabilitation setting. The
numerical ratio of outpatient is being reduced in orderto give priority to the clinical service corresponding toneeds expansion of service to inpatients.

Teaching activities
We have provided several clinical curriculums on
rehabilitation medicine for 4th, 5th, and 6th year
medical students since 1973. The systematic lecture
series for 4th year medical students (M2) include thesubjects on rehabilitation for disorders such ascerebrovascular disturbances, spinal cord injuries andspina bifida, neuromuscular diseases, bone and joint423

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. Haga N, Karita T, Amao R, Kanamori Y, Takatori
Y: Successful ambulation by surgical conversion
in a complex form of epigastric heteropagus. J
Pediatr Orthop Part B, Published online: 9 July2009.
2. Iijima M, Haga N: Evaluation of nonnociceptive
sensation in patients with congenital insensitivity
to pain with anhidrosis. Childs Nerv Syst,
Published online: 16 December 2009.
3. Uematsu H, Sumitani M, Yozu A, Otake Y,
Shibata M, Mashimo T, Miyauchi S: Complex
regional pain syndrome (CRPS) impairs
visuospatial perception, whereas post-herpetic
neuralgia does not: Possible implications forsupraspinal mechanism of CRPS. Ann Acad Med
Singapore 38: 931-6, 2009.

424

Division of Diagnostic Pathology
Professor (Director)
Masashi Fukayama, M.D., Ph.D.*

Associate Professor (Deputy Director)
Noriyoshi Fukushima, M.D., Ph.D.*, Hiroshi Uozaki, M.D., Ph.D. *Associate Professor
Shumpei Ishikawa, M.D., Ph.D.*

Lecturer
Yutaka Takazawa, M.D., Ph.D.,

Satoshi Ohta, M.D., Ph.D.*

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

Associate
Takashi Sakatani, M.D., Ph.D.,

Tetsuo Ushiku, M.D., Ph.D.,

Teppei Morikawa, M.D., Ph.D.,
Akiteru Goto, M.D., Ph.D. *,Rumi Hino, M.D., Ph.D. *,Takeo Nakaya, M.D., Ph.D.* (Human Genomics Project)

Clinical Fellow
Hiroki Miyazaki, M.D., Ph.D.,

Taichiro Yoshimoto, M.D.Ph.D.,

Akima Hayashi, 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. “Diagnostic Pathology” has been officiallyadmitted as one of departments of a hospital bygovernment decree in the fiscal year 2009, and the
independent chapter has been set up for thepathological examination fee as 13th category, apartfrom the 3rd category of laboratory examination in the
medical fee schedule of Health Insurance System.
These revisions gave delight to the pathologists as

indicating a general acceptance for the importance of
pathology diagnosis.
The proper staffs in the Division of Diagnostic
Pathology include a lecturer, a hospitall lecturer, two
associates, and three clinical staffs. Dr. Takazawa
moved to Division f Diagnostic Pathology, as Dr.
Uozaki was promoted to Associate Professor of the
Department of Pathology.

Clinical activities (diagnostic
pathology and autopsy)
The annual statistics of the pathologic practice in 2009

425

fiscal year consisted of 14,603 cases of histologicalexamination, 17,281 cases of cytology, 741 of frozen
histology, 502 of intra-operative cytology, 79 of
autopsy cases (19% as autopsy rate), and 2 autopsy
cases from other hospitals.
Clinico-pathological conferences (CPCs) for thetwo 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 (Drs.Fukushima,and Shibahara), male genitourinary (Dr. Morikawa)and female genital tracts (Dr. Ota and Talazawa),
breast (Dr. Sakatani), and bone and soft tissues (Dr.
Ushiku). Biopsy conferences are also held in the casesof 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 of pathologic images for clinicaldivisions. Dr. Uozaki is mainly in charge of thisproject.
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. Seven
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 2007 for the second year program of theirinternship.

Research activities
We have finished the two-year project, “Feasibility of
Post-Mortem Imaging as a Method Assisting theAutopsy Assessment of DRMT” (Grants-in-Aid from
Ministry of Health, Labor and Welfare). The report isnow open to public and available at the website of thestudy group (http://humanp.umin.jp/). In the study ofTokyo University Hospital, we moved a discarded
CT-apparatus next door to the autopsy room, andutilized it for nearly all autopsy cases of this fiscal
year for comparing images with autopsy findings.
Lecturer Takazawa was in charge of this project.
We continue the pathological studies ofneoplastic diseases on the basis of surgical pathology
conferences. We are also developing the tumor
specific antibodies in collaboration with Genome
Science Division, Research Center for Advanced
Science and Technology, the University of Tokyo. We
are evaluating the feasibility of antibody panels for
immunohistochemistry to detect the metastatis 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

426

Department of Corneal
Transplantation
Associate Professor
Shiro Amano, M.D., Ph.D.

Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/kakumaku.html

Introduction and Organization
The department of corneal transplantation wasestablished in 1976 as one of clinical sections in the
University of Tokyo Hospital. The purpose of theestablishment of this section is to carry out andpromote corneal transplantation and to perform
clinical and basic research in the corneal diseases andcorneal transplantation. The section is composed of adirector (associate professor).

Clinical activities
The clinical activities of this section include corneal
transplantation and outpatient clinics for various
corneal diseases as a consulting corneal service. The
director is responsible not only for corneal
transplantation but also for general ophthalmologicalpractice as a senior staff member of Department ofOphthalmology, University of Tokyo. The corneal
service is held every Wednesday. At the corneal
service, we determine indication for corneal
transplantation and follow up patients after the surgery.
We also diagnose and treat various corneal diseases.
The corneal service is conducted by the director anddoctors from related hospitals. The patients who
enrolled in the corneal service have exceeded 5000.
The total number of corneal transplantation hasreached 1500 cases since we started keratoplasties in
1971. Approximately 50 corneal transplantations havebeen performed annually.
The other important activities of the section include
mediation of donor eyes to other university hospitals

and medical institutes that need donor eyes for corneal
transplantation.
Followings are our main clinical themes to be pursued
to improve the safety and prognosis of corneal
transplantation.
1) Thorough examination of donor eyes not only byslit-lamp biomicroscope but also by specular
microscope.
2) Positive proof that donors were free of such
infectious diseases as viral hepatitis, syphilis,
AIDS and acute T-cell leukemia to prevent
transmission to recipient patients through grafting.
3) Introduction of sclero-corneal preservation ofdonor eyes, because sclero-corneal preservation ismore suitable for longer preservation thanconventional whole eye preservation.
4) The long-term natural course of keratoconus has
been investigated with corneal topography.

Teaching activities
As an undergraduate course, we give lectures on
corneal physiology, corneal diseases, and corneal
transplantation. In addition, we are engaged inpractical training for medical students on
ophthalmological examinations at the outpatient clinic.
As a postgraduate course, we give lectures on topics
concerning corneal transplantation, corneal diseases
and new medical therapies.

427

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.

Mimura T, Yamagami S, Usui T, Funatsu H,

Mimura Y, Noma H, Honda N, Amano S.
Changes of conjunctivochalasis with age in a
hospital-based study. Am J Ophthalmol
147:171-177, 2009
2. Arita R, Itoh K, Inoue K, Kuchiba A, Yamaguchi
T, Amano S. Contact lens wear is associated withdecrease of meibomian glands. Ophthalmology
116:379-384, 2009
3. Mimura T, Mimura Y, Arimoto A, Amano S,
Yamagami S, Funatsu H, Usui T, Noma H, Honda
N, Okamoto S. Relationship between refraction
and allergic conjunctivitis. Eye 23:63-66, 20094.
Fukuoka S, Honda N, Usui T, Inoue K,
Yamagami S, Araie M, Amano S. Penetrating
keratoplasty for bullous keratopathy after
trabeculectomy. Eye 23:940-944, 2009
5. Shirayama-Suzuki M, Amano S, Honda N, Usui T,
Yamagami S, Oshika T. Longitudinal analysis ofcorneal topography in suspect keratoconus. Br J
Ophthalmol 93:815-819, 2009
6. Miyata K, Otani S, Nejima R, Miyai T, Samejima
T, Honbo M, Minami K, Amano S. Comparisonof postoperative surface light scattering ofdifferent intraocular lenses. Br J Ophthalmol
93:684-687, 2009
7. 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, 2009
8. Mimura T, Usui T, Yamagami S, Funatsu H,
Noma H, Honda N, Amano S.
Recent causes of subconjunctival hemorrhage.
Ophthalmologica 224:133-137, 2009
9. Hayashi T, Yamagami S, Tanaka K, Yokoo
S, Usui T, Amano S, Mizuki N. Immunologicalmechanisms of corneal allografts reconstituted
from cultured allogeneic endothelial cells in an
immune-privileged site. Invest Ophthalmol Vis
Sci 50:3151-3158, 2009
10. Mimura T, Usui T, Yamamoto H, Yamagami S,
Funatsu H, Noma H, Honda N, Fukuoka S,
Amano S. Conjunctivochalasis and contact lenses.
Am J Ophthalmol 148:20-25, 2009
11. Honda N, Mimura T, Usui T, Amano S.
Descemet’s stripping automated endothelial
keratoplasty using cultured corneal endothelial
cells in a rabbit model. Arch Ophthalmol

428

12.

13.

14.

15.

16.

17.

18.

127:1321-1326, 2009
Mimura T, Usui T, Yamagami S, Funatsu H,
Noma H, Honda N, Fukuoka S, Shirakawa R,
Hotta H, Amano S. Subconjunctival hemorrhage
and conjunctivochalasis. Ophthalmology 116:
1880-1886, 2009
Albuquerque R, Hayashi T, Cho WG, Kleinman
ME, Dridi S, Takeda A, Baffi JZ, Yamada K,
Kaneko H, Green MG, Chappell J, Wilting J,
Weich HA, Yamagami S, Amano S, Mizuki N,
Alexander JS, Peterson ML, Brekken RA,
Hirashima M, Capoor S, Usui T, Ambati BK,
Ambati J. Alternatively spliced VEGF receptor-2
is an essential endogenous inhibitor of lymphatic
vessels. Nat Med 15:1023-1030, 2009
Mimura T, Yamagami S, Usui T, Funatsu H,
Noma H, Honda N, Amano S. Relationshipbetween myopia and allergen-specific serum IgElevels in patients with allergic conjunctivitis. Clin
Experiment Ophthalmol 37：670-677, 2009
Arita R, Itoh K, Maeda S, Maeda K, Furuta A,
Fukuoka S, Tomidokoro A, Amano S. Proposed
diagnostic criteria for obstructive meibomian
gland dysfunction. Ophthalmology 116:20582063, 2009
Shiroma H, Higa A, Sawaguchi S, Iwase A,
Tomidokoro A, Amano S, Araie M. Prevalence
and risk factors of pterygium in a southwesternisland of Japan: The Kumejima Study. Am J
Ophthalmol 148:766-771, 2009
Mimura T, Fujimura S, Yamagami S, Usui T,
Honda N, Shirakawa R, Fukuoka S, Amano S.
Severe hyperopic shift and irregular astigmatism
after radial keratotomy. Eye Contact Lens 35:
345-347, 2009
Usui T, Misawa Y, Honda N, Tomidokoro A,
Yamagami S, Amano S. Nontraumatic
keratomycosis caused by Alternaria in a
glaucoma patient. Int Ophthalmol 29:529-531,
2009

429

Department of Cell Therapy andTransplantation Medicine
Professor
Mineo Kurokawa, M.D., Ph.D. (Hematology-Oncology)

Lecturer
Junko Takita, M.D., Ph.D. (Pediatrics/Hematology-Oncology)

Special Lecturer (Hospital)
Keiki Kumano, M.D., Ph.D. (Hematology-Oncology)

Associate
Koji Kandabashi, M.D. (Hematology-Oncology)

Homepage

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

Introduction and Organization
Department of Cell Therapy and Transplantation
Medicine was institutionally established in 1995, andformally organized in 1996. At present, the staff
consists of four medical doctors listed above. Clinicalfacilities include 8 single-patient rooms with highefficiency particulate air filtration and other highstandards. Patients who are eligible for the treatment
with high-grade infectious prophylaxis are admitted to
the facilities.

Clinical activities
Allogeneic hematopoietic stem cell transplantation:
Bone marrow cells are operatively harvested andinfused without preservation. For peripheral blood
stem cell transplantation, leukapheresis is performed
with the use of an automated continuous flow blood
cell separator, and harvested cells are preserved at-196°C in cooperation with Department ofTransfusion Medicine. Recently, transplantation after
pre-conditioning of reduced intensity (RIST for
reduced-intensity stem cell transplantation or NST for
non-myeloabrative stem cell transplantation) is
commonly performed for the elderly patients andpatients with organ damages, etc. The development of
this strategy is expanding the eligibility of transplant
recipients. Allogeneic hematopoietic stem celltransplantations for the elderly are performed under
the admission of ethical committee of the Faculty of
Medicine.
High-dose chemotherapy with or without
autologous
stem
cell
support:High-dose
chemotherapy is administered according to themalignant disease. For the autologous stem cell
support, peripheral blood stem cell is usually selected
as a source of stem cells. Similar procedures used in
the allogeneic stem cell harvest are performed forleukapheresis and preservation of autologous stem
cell.
Clinical conference for hematopoietic stem celltransplantation : The conference is held monthly, inwhich the members of Department of Hematology/
Oncology and Hematology/Oncology group in the
Department of Pediatrics, and some members ofDepartment of Transfusion Medicine routinely
participate and discuss on the patients receiving
hematopoietic stem cell transplantation.

430

Teaching activities

haematopoietic stem cell transplantation from an
HLA-identical sibling in a patient with aplastic

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,
suchasneuroblastoma,
rhabdomyosarcoma,
andinfantleukemia.
Representative publications from our department
published in the past year are listed in the references.

References

anemiafollowing

HLA-haploidenticalliving-related liver transplantation for fulminant hepatitis.
Biology of Blood and Marrow Transplantation,
15:389-390, 2009.
(3) Yoshimi M, Nannya Y, Watanabe T, Asai T,
Ichikawa M, Yamamoto G, Kumano K, Hangaishi
A, Imai Y, Takahashi T, Chiba S, and Kurokawa M.
Acute eosinophilic pneumonia is a non-infectious
lung complication after allogeneic hematopoietic
stem cell transplantation. International Journal of
Hematology, 89:244-248, 2009.
(4) Yoshimi A, Takahashi T, Motokura T, Yatomi Y,
Chiba S, and Kurokawa M. Hemoperitoneum due
to spontaneous rupture of the left gastroepiploicartery in a patient with hemophilia A. Annals of
Hematology, 88:811-812, 2009.
(5) Ueda K, Yamamoto G, Shinohara A, Hangaishi A,
and Kurokawa M.

Early onset of acutelymphoblastic leukemia with MLL rearrangement
after autologous stem cell transplantation for
multiple myeloma.

Annals of Hematology, 88:

813-814, 2009.
(6) Kato T, Hangaishi A, Ichikawa M, Motokura T,
Takahashi T, and Kurokawa M. A new three-way
variantt (15;22;17) (q22;q11.2;q21)

in

acute

promyelocytic leukemia. International Journal of
Hematology, 89:204-208, 2009.
(7) Lee SY, Kumano K, Nakazaki K, Sanada M,
Matsumoto A Yamamoto G, Nannya Y, Suzuki R,
Ota S, Ota Y, Izutsu K, Sakata-Yanagimoto M,
Hangaishi A, Yagita H, Fukayama M, Seto M,(1) Kataoka K, Nannya Y, Hangaishi A, Imai Y, Chiba

Kurokawa

M,

Ogawa

S,

and

Chiba

S.

S, Takahashi T, and Kurokawa M. Influence ofGain-of-function mutations and copy number

pretransplantation serum ferritin on nonrelapse

increases of Notch2 in diffuse large B-cellmortality after myeloablative and nonmyeloablative

lymphoma. Cancer Science, 100:920-926, 2009.

allogeneic hematopoietic stem cell transplantation.

(8) Izumchenko

E,

Plotnikova

O,

Singh

M,

Biology of Blood and Marrow Transplantation,

Tikhmyanova N, Little J, Seo S, Kurokawa M,

15:195-204, 2009.

Egleston B, Klein-Szanto AJ, Pugacheva E, Hardy(2) Yoshimi A, Nannya Y, Asano D, Yamamoto G,

R, Connolly D, Wolfson M, and Golemis E.

Kumano K, Hangaishi A, Matsui Y, Takahashi T,

NEDD9 is required for activation of oncogenic

Imai Y, Kokudo N, and Kurokawa M. Successful

signaling

pathwaysinmammary

tumor

431

development.

Cancer Research, 69: 7198-7206,

2009.

syndrome.

International Journal of Hematology,

89:718-719, 2009.

(9) Goyama S and Kurokawa M.

Pathogenetic(16) Nakamura K, Igarashi K, Ohkawa R, Okubo S,

significance of ecotropic viral integration site-1 in

Yokota H, Kishimoto T, Ide K, Masuda A,

hematological malignancies. Cancer Science, 100:

Yamamoto T, Saito N, Kurokawa M, Tsuji S,

990-995, 2009.

Okudaira S, Ikeda H, Aoki J, and Yatomi Y.

(10) Yokoyama Y, Suzuki T, Sakata-Yanagimoto M,

Autotaxin

enzymeimmunoassay

in

human

Kumano K, Higashi K, Takato T, Kurokawa M,

cerebrospinal fluid samples. Clinica Chimica Acta,

Ogawa S, and Chiba S. Derivation of functional

405: 160-162, 2009.

mature neutrophils from human embryonic stem
cells. Blood, 113:6584-6592, 2009.

S, Fukayama M, Takahashi T, and Kurokawa M.

(11) Ueda K, Nannya Y, Kumano K, Hangaishi A,
Takahashi

T,

Imai

Y,

and

(17) Taoka K, Nannya Y, Yamamoto G, Sakatani T, Ota

Kurokawa

Progressive

transitionof

Epstein-Barr

virus

M.

associated lymphoproliferative disease subtypes

Monitoring trough concentration of voriconazole iswith the development of lung cancer. Amarican

important to ensure successful antifungal therapy

Journal of Hematology, 84: 600-603, 2009.

and to avoid hepatic damage in patients with(18) Takahashi T and Kurokawa M. Human invariant

hematological disorders. International Journal ofnaturalHematology, 89:592-599, 2009.

immunotherapy.

(12) Haraguchi K, Suzuki T, Koyama N, Kumano K,
Nakahara

F,

MatsumotoA,

Yokoyama

killerT

cells:

implication

International

JournalforofHematology, 90: 137-142, 2009.

Y,(19) Nagai S, Takahashi T, and Kurokawa M.

Sakata-Yanagimoto M, Masuda S, Takahashi T,

Beneficial and adverse effects of molecularly

Kamijo A, Takahashi K, Takanashi M, Okuyama Y,

targeted therapies for acutepromyelocytic leukemia

Yasutomo K, Sakano S, Yagita H, Kurokawa M,

in central nervous system. CNS and NeurologicalOgawaS, and Shigeru Chiba3.

Disorders-Drug Targets, 8: 387-392, 2009.

Notch activationinduces the generation of functional natural killer(20) Miyagaki T, Sugaya M, Minatani Y, Fujita H,

cells from human cord blood CD34-positive cells

Hangaishi A, Kurokawa M, Takazawa Y, anddevoid of interleukin-151.

Tamaki K. Mycosis fungoides with recurrent

The Journal of

Immunology, 182: 6168-6178, 2009.

Hodgkin’s lymphoma and diffuse large B cell(13) Nagai S, Nannya Y, Hangaishi A, Takahashi T, andKurokawa M. The race and dose of chemotherapy
should be considered for optimizing maintenancetherapy

for

acute

promyelocytic

leukemia.

Leukemia Research, 33:1427-1429, 2009.

lymphoma.

Acta Dermato-Venereologica, 89:

421-422, 2009.
(21) Shimabe M, Goyama S, Watanabe-Okochi N,
Yoshimi A, Ichikawa M, Imai Y, and Kurokawa M.
Pbx1 is a downstream target of Evi-1 in(14) Yoshimi A, Asai T, Maeda D, Hangaishi A,
Sakatani T, Takahashi T, Imai Y, Fukayama M, andhematopoietic stem/progenitors and leukemic cells.
Oncogene, 28: 4364-4374, 2009.

Kurokawa M. Chronic myelomonocytic leukemia(22) Masuda S, Kumano K, Suzuki T, Tomita T,

presenting as hemorrhagic shock due to uterine

Iwatsubo T, Natsugari H, Tojo A, Shibutani M,

infiltration of leukemic cells and early-stage

Mitsumori K, Hanazono Y, Ogawa S, Kurokawa M,

endometrial

and Chiba S.

adenocarcinoma.

ArchivesofDual antitumor mechanisms of

Gynecology and Obstetrics, 280: 1077-1078, 2009.

Notch signaling inhibitor in a T cell acute(15) Kataoka K, Ichikawa M, Hangaishi A, Takahashi T,

lymphoblastic leukemia xenograft model. Cancer

Imai Y, and Kurokawa M. Interstitial pneumonia
associated with progression of myelodysplastic

Science, 100: 2444- 2450, 2009.

432

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 of other departments including thedepartment of internal medicine, surgery, gynecology
and otorhinolaryngology participate the examinations.
The examination rooms moved to the new building in
Oct. 2006.

for esophageal, gastric and colorectal tumors, andpolypectomy for colonic polyps, are recently
increasing. Our recent clinical activities are
summarized in Table 1.
Another important activity of our department is thedisinfection and maintenance of endoscopic
apparatuses used in other units including outpatient
clinic, radiographic procedure rooms, surgery rooms
or intensive care units. All endoscopes are collectedin our department after use and disinfected.

Clinical activities

Teaching activities

Endoscopic
examinations,
includinguppergastrointestinalendoscopy,colonoscopy,
bronchoscopy, otorhinolaryngological examinations
and gynecologycal examinations, are performed from
Monday to Friday. Therapeutic endoscopies, including
endoscopic variceal ligation and sclerotherapy,
endoscopic resection including submucosal dissection

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
2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

*

EGD
Colonoscopy
Bronchoscopy
EUS**Enteroscopy
Laryngoscopy
Colposcopy

5923
2799
233
470
115
149

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

9689

10566

11852

12778

12195

13199

13282

14043 15520

16566*Esophagogastroduodenoscopy, **Endoscopic ultarasonography

433

Research activities
Our researches cover a variety of endoscopic fields incooperation with other departments.

References(1) Ono S, Fujishiro M, Goto O, Kodashima S,
Omata M: En bloc resection of cardia cancer andlipoma with endoscopic submucosal dissection.
Dig Liver Dis. 41:237, 2009
(2) Fujishiro M, Oda I, Yamamoto Y, Akiyama J,
Ishii N, Kakushima N, Fujiwara J, Morishita S,
Kawachi H, Taniguchi H, Gotoda T: Multi-center
surveyregardingthemanagementof
anticoagulation and antiplatelet therapy forendoscopic procedures in Japan. J Gastroenterol
Hepatol 24:214-8, 2009
(3) Fujishiro
M:
Gastrointestinal
epithelial
neoplasms: Endoscopic submucosal dissection(Methodology). In: Hayat MA. (Ed): Methods ofCancer Diagnosis, Therapy and Prognosis,
volume 3, Gastrointestinal carcinoma, Springer,
USA, pp29-36, 2009(4) Goto O, Fujishiro M, Kodashima S, Ono S,
Omata M: Is it possible to predict proceduraltime of endoscopic submucosal dissection forearly gastric cancer? J Gastroenterol Hepatol. 24:
379–83, 2009(5) Ono S, Fujishiro M, Niimi K, Goto O,
Kodashima S, Yamamichi N, Omata M.
Technical feasibility of endoscopic submucosal
dissection for early gastric cancer in patientstaking anti-coagulants or anti-platelet agents. Dig
Liver Dis 41:725–8, 2009(6) Goto O, Fujishiro M, Kodashima S, Ono S,
Omata M: Outcomes of endoscopic submucosal
dissection for early gastric cancer with specialreference to validation for curability criteria.
Endoscopy 41: 118-22, 2009(7) Ono S, Fujishiro M, Goto O, Kodashima S,
Omata M: Endoscopic submucosal dissection forcolonic laterally spreading tumors is difficult
after target tattooing. Gastrointest Endosc 69:
763-6, 2009(8) Miki K, Fujishiro M, Kodashima S, Yahagi N:
Long term results of gastric cancer screening

using the serum pepsinogen test method amonganasymptomatic
middle-aged
Japanese
population. Dig Endosc 21: 78–81, 2009
(9) Fujishiro M, Kodashima S, Goto O, Ono S, Niimi
K, Yamamichi N, Oka M, Ichinose M, Omata M:
Endoscopic
submucosal
dissectionforesophageal squamous cell neoplasms. Dig
Endosc 21: 109–15, 2009(10) Miki K, Fujishiro M: Cautious comparison
between East and West is necessary in terms ofserum pepsinogen test Dig Endosc 21: 134–5,
2009(11) Yahagi N, Neuhaus H, Schumacher B,
Neugebauer A, Kaehler GF, Schenk Martin,
Fischer K, Fujishiro M, Enderle MD:
Comparison of standard endoscopic submucosal
dissection (ESD) versus an optimized ESD
technique for colon: an animal study. Endoscopy
41: 340–345, 2009(12) Yamamichi N, Inada KI, Furukawa C, Sakurai K,
Tando T, Ishizaka A, Haraguchi T, Mizutani T,
Fujishiro M, Shimomura R, Oka M, Ichinose M,
Tsutsumi Y, Omata M, Iba H: Cdx2 and theBrm-type SWI/SNF complex cooperatively
regulate villin expression in gastrointestinal cells.
Exp Cell Res 315:1779-8, 2009(13) Yamamichi N, Shimomura R, Inada KI, Sakurai
K, Haraguchi T, Ozaki Y, Fujita S, Mizutani T,
Furukawa C, Fujishiro M, Ichinose M, Shiogama
K, Tsutsumi Y, Omata M, Iba H: Locked Nucleic
Acid In situ Hybridization Analysis of miR-21
Expression
duringColorectal
CancerDevelopment. Clin Cancer Res. 15:4009-16,
2009(14) Ono S, Fujishiro M, Niimi K, Goto O,
Kodashima S, Yamamichi N, Omata M:
Long-term outcomes of endoscopic submucosal
dissection for superficial esophageal squamouscell neoplasms. Gastrointest Endosc 70: 860-6,
2009(15) Fujishiro M, Kodashima S: Indications,
techniques, and outcomes of endoscopic
submucosal dissection for esophageal squamouscell carcinoma. Esophagus 6:143-8, 2009(16) Ono S, Fujishiro M, Niimi K, Goto O,
Kodashima S, Yamamichi N, Omata M:
Predictors of postoperative stricture after

434

esophageal endoscopic submucosal dissection forsuperficial squamous cell neoplasms. Endoscopy
41: 661–5, 2009(17) Yanaoka K, Oka M, Ohata H, Yoshimura Noriko,
Deguchi H, Mukoubayashi C, Enomoto S, Inoue
I, Iguchi M, Maekita T, Ueda K, Utsunomiya H,
Tamai H, Fujishiro M, Iwane M, TakeshitaT,
Mohara O, Ichinose M. Eradication of
Helicobacter pylori prevents cancer developmentin subjects with mild gastric atrophy identified byserum pepsinogen levels. Int J Cancer 125:2697-703, 2009(18) Fujishiro M: Japan aims toward appropriateconcomitant use of antiplatelets and antisecretory
agents? Inter Med 48: 1845-1846, 2009(19) Ono S, Fujishiro M, Hirano K, Niimi K, Goto O,
Kodashima S, Yamamichi N, Koike K:
Retrospective analysis on the management of
anticoagulants and antiplatelet agents forscheduled endoscopy. J Gastroenterol 44:1185-9, 2009(20) Niimi K, Kodashima S, Ono S, Goto O,
Yamamichi N, Fujishiro M: Curative ESD for
intraepithelial esophageal carcinoma withleiomyoma mimicking submucosal invasive
carcinoma. World J Gastrointest Endosc 1: 68-71,
2009(21) Fujishiro M: Endoscopic submucosal dissection
for colorectal neoplasms. World J Gastrointest
Endosc 1: 32-8, 2009(22) Niimi K, Fujishiro M, Kodashima S, Ono S, GotoO, Yamamichi N, Koike K: Subserosal injectionof hyaluronic acid may prevent perforation afterendoscopic resection. World J Gastrointest
Endosc 1: 61-4, 2009(23) Enomoto S, Yahagi N, Fujishiro M, Oka M,
Muraki Y, Deguchi H, Ueda K, Inoue I, Maekita
T, Magari H, Mukobayashi C, Nakazawa K,
Iguchi M, Yanaoka K, Arii K, Tamai H, Omata
M, Ichinose M. Assessment of Intraoperative
bleeding
duringendoscopic
submucosal
dissection and endoscopic hemostasis using
high-frequenecy hemostatic forceps. J Wakayama
Med Soc 60: 124-9, 2009

435

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.

Education
1. A systematic review course for M2 students,
which covers clinical features, diagnosis, and

2.
3.
4.
5.

evidence-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 thespeciality 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.

Medical Care
1. Start of maintenance hemodialysis therapy forend-stage renal disease (ESRD).
2. Regular hemodialysis therapy for hospitalized
ESRD patients. Please note that our center does
not accept holiday dialysis.
3. Emergency hemodialysis and hemodiafiltration
for ICU patients.
4. Plasma exchange for neurodegenerative diseases,
SLE, TTP, TMA, and pre/post-liver transplantpatients.
5. DFPP for collagenous diseases, MG, HCV, anddermatological disorders.
6. LDL apheresis for nephrotic syndrome and ASO
patients.
7. White blood cell elimination therapy forulcerative colitis and rheumatological arthritis.

436

Research
1. Prognostic analysis for post-liver transplantpatients received plasma exchange therapy.
2. Development and application of a non-invasive
pulse hemoglobin meter.
3. Genome wide association study for Nephrotic
syndrome and those functional analyses.
4. Elucidation of basic mechanisms in cardio-renal
syndrome and intervention.
5. Pathophysiology of acute kidney injury and its
applicability for renal regenerative study.
6. AKI biomarkers and those clinical significance in
ICU/CCU.
7. Renal
biomarker
todetermine
clinicalactionability in CKD and type-2 DN.
8. The potentiality of urine biomarker tests fordeveloping country [JST/JICA SATREPS: Scienceand Technology Research Partnership for
Sustainable Development].

References
1. 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 by cationic
tetraamino fullerene. Proc atl Acad Sci U S A
23;107:5339-5344, 2010
2. Okamoto K, Iwasaki N, Nishimura C, Doi K,
Noiri E, Nakamura S, Takizawa M, Ogata M,
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,
Tokunaga K: Identification of KCNJ15 as asusceptibility gene in Asian patients with type 2
diabetes mellitus. Am J Hum Genet 86:54-64,
2010
3. 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 toenhanced plasma ADAMTS13 activity in rat
models of cholestasis and steatohepatitis. Thromb
Haemost 102:389-396, 2010
4. Doi K, Noiri E, Fujita T: Role of vascularendothelial growth factor in kidney disease. Curr
Vasc Pharmacol 8:122-128, 2010
5. Doi K, Leelahavanichkul A, Yuen PS, Star RA:
Animal models of sepsis and sepsis-induced
kidney injury. J Clin Invest 119:2868-2878, 2009
6. 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
7. Tanaka T, Doi K, Maeda-Mamiya R, Negishi K,
Portilla D, Sugaya T, Fujita T, Noiri E: Urinary
L-type fatty acid binding protein can reflect renal
tubulointerstitial injury. Am J Pathol 174:1203-11,
2009
8. 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
9. Noiri E, Doi K, Inagi R, Nangaku M, Fujita T:
Contribution of T-lymphocytes to rat renal
ischemia/reperfusion injury. Clin Exp ephrol
13:25-32, 2009
10. 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. Bone marrowstromal cells attenuates sepsis via prostaglandin
E2-dependent
reprogrammingofhostmacrophages to increase their interleukin-10
production. at Med 15:42-9,2009
11. Doi K, Yuen PST, Eisner C, Hu X,
Leelahavanichkul A, Schnermann J, and Star RA.
Reduced creatinine production limits serum
creatinine as an indicator of acute kidney injury insepsis. J Am Soc ephrol 20:1217-21,2009
12. 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 of regulardialysis treatment in Japan (as of 31 December2007). Ther Apher Dial 13:457-504, 2009
13. Yamazaki O, Hanafusa N, Yamada A, Noiri E,

437

Fujita T: Recurrent intestinal bleeding treated bydouble-balloon endoscopy in haemodialysis
patients. DT Plus 2: 469-472, 2009
14. 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
15. 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
16. 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.
17. Doi K, Hu X, Yuen PST, Leelahavanichkul A,
Yasuda H, Kim SM, Schnermann J, Jonassen TEN,
Frøkiær J, Nielsen S, and Star RA. Effect of
α-melanocyte-stimulating hormone analogue
AP214 on sepsis-induced acute kidney injury andmortality. Kidney Int 73: 1266-1274, 2008.
18. 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 ephrol 18:2894, 2007
19. 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
ephrol 1:811, 2006
20. Hanafusa N, Noiri E, Yamashita T, Kondo Y,
Suzuki M, Watanabe Y, Kanai T, Miyashita E,
Tsuno NH, Fujii T, Kozuma S, Takahashi K,
Taketani Y, Nakao A, Fujita T: Successfultreatment by double filtrate plasmapheresis in apregnant woman with the rare P blood group and ahistory of multiple early micharges. Ther Apher
Dial 10:498, 2006

21. Okamoto K, Kobayashi S, Noiri E: Longer
treatment time and slower ultrafiltration inhemodialysis: associations with reduced mortality
in the Dialysis Outcomes and Practice Patterns
Study. Kidney Int 70:1877, 2006
22. 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

438

Clinical Research Center
Professor
Takashi Kadowaki, M.D., Ph.D.

Associate Professor
Yoshihiro Arakawa, Ph.D.

Research Associate
Keiji Ogura, M.D., Ph.D. (till September 2009)
Koji Nozaki, M.D., Ph.D. (since October 2009)
Hiroshi Satonaka, M.D., Ph.D. (since September 2009)
Yuzaburo Uetake, M.D., Ph.D. (since November 2009)

Homepage http://www.cresc.h.u-tokyo.ac.jp/site/index.html
Introduction and Organization

Clinical activities

The Clinical Research Center was established in
April 2001 as one of the regular departments in thecentral division in our hospital. The Center not only
took over the duties of the former provisional Clinical
Trial Research Center, which dealt industry-initiatedclinical trials, but also newly-incorporated thecommission to support investigator-initiated clinical
trials. The staff of the center as of March, 2010, is
comprised of one professor, one associate professor,
three research associate, nine pharmacists, eightnurses, one medical laboratory technologist and four
officials, of which five pharmacist, four nurses andone official were full-time workers with three years'
tenure and one nurse, one medical laboratory
technologist and three officials were part-timeworkers. The center consists of four subdivisions:
Division of consultation on protocol development(one associate professor and three research associate),
division of pharmaceutical administration (threepharmacists),
divisionofclinicalresearchcoordination (eight nurses, six pharmacists, one
medical laboratory technologist and one official) anddivision of clerkship (three officials).

The duties of the center are wide-ranging fromserving as a secretariat for the institutional review
board (IRB) to supporting the conduct of clinical trials.
Clinical trials that we dealt with covered all regulatory
clinical trials for marketing approval andinvestigator-initiated clinical trials concerned withmedicinal treatments.
As an IRB secretariat, to which all the staffs are
responsible, we dealt 28 new protocols and 77
ongoing protocols for industry-sponsored clinical
trials in fiscal 2009. We also dealt with 32
investigator-initiated non-regulatory clinical trials andfour ‘ethical use’ of non-approved drugs. A protocolhearing was held every month for applications of new
industry-initiated protocols to facilitate a review withmeaningful discussion in the IRB and to give practicaladvice in carrying out the protocols properly. The
meeting was held with the attendance of applicant
company representatives, principal and subinvestigators and the staffs of the center. We also dealt
applications for changes in the initial application
documents (467 applications), safety information (857reports), and other reports in fiscal 2009.
To solve a so-called ‘un-approved drugs issue’ or439‘drug lag issue’, participation to global trials was a
key issue. For this purpose, University Hospital
Clinical Trial Alliance (UHCT Alliance) comprised of
7 national university hospitals (Tokyo University,
Niigata University, Gunma University, Shinshu
University, Tsukuba University, Tokyo Medical and
Dental University and Chiba University) wasestablished in 2006 and is collaborating with eachother in continuing improvement of our clinical trial
environments. Until March 2010, 43 protocols wereintroduced to the alliance including 21 multi-national
trials. The alliance got financial support from thegovernment since 2009 and set up several projects
including the establishment of the alliance office inour hospital.
As for pharmaceutical administration, we tookcharge of 151 clinical trial drugs and medical devices
and filled 1816 prescriptions in fiscal 2009. We also
took charge of central drug management in a
multi-center double blind clinical trial. Pharmacists inthe division are also in charge of the primary review
of safety information about clinical trial drugs and the
database management in the Center.
Clinical research coordinators (CRC) support theimplementation of all regulatory clinical trials. The
coordination covered all aspects in pursuing clinical
trials: preparation for the trials, screening for patients,
assistance to obtain patients’ informed consent,
coordinating outpatients’ visit, assistance withinspections, assistance in the preparation of casereport forms (CRF), arrangements for monitoring andaudits, and arrangements for medical accounting.
There were a total of 4761 times of coordination of
outpatients' visits and medical treatments of inpatientsin fiscal 2009. CRCs also support the implementationof some of the investigator-initiated non-regulatory
clinical trials. In 2005, we introduced a principle that
beneficiaries should pay for part of a personnel cost of
CRCs and adopted six investigator-initiated protocols
for the CRC support on this principle.
Publicity activity has been continued including theprovision of the information about the protocols undersubject recruitment both in our internet home pageand in our takeaway leaflets.
The outpatient clinic dedicated for clinical trials
moved new building in Nov. 2006 and was newly
equipped with consultation counters and a waitingroom.
The consultation division started in May 2002 to
support the investigator-initiated clinical trial. The
mission of the division is to help investigators to
conduct clinical research under the ethically andscientifically reviewed protocols. Namely, the division
supports protocol development, application to IRB
and monitoring of the progress and amendment ofclinical trials. As for educational programs of clinicalresearch for investigators, the division also gives a
training course 3 times a year every year. The division
dealt with 32 investigator-initiated non-regulatory
clinical trials and four ‘ethical use’ of non-approved
drugs in fiscal 2009.

Teaching activities
The Center accepted 6 senior students for training
in collaboration with the Pharmaceutical Department.
Arakawa is taking charge of one half-year lecture on
clinical pharmacology for the graduate course students
in the Faculty of Pharmaceutical Sciences every year.
One student belonged to our research labs in fiscal
2009.
The Center is involved as an on-the-job training
institution in CRC training programs. In fiscal 2009,
we accepted four three-week trainees from theprogram operated by Pharmacist Training Center.

Research activities
We performed the publication of five original
papers written in English, one original paper inJapanese and eight review papers in Japanese and the
19 presentations in academic conferences in 2009.

References(1) Hayakawa Y, Maeda S, Nakagawa H, Hikiba Y,
Shibata W, Sakamoto K, Yanai A, Hirata Y,
Ogura K, Muto S, Itai A, Omata M. Effectivenessof IkappaB kinase inhibitors in murine colitisassociated tumorigenesis. J Gastroenterol. 44(9):935-43, 2009.
(2) Maeda S, Hikiba Y, Sakamoto K, Nakagawa H,
Hirata Y, Hayakawa Y, Yanai A, Ogura K, Karin
M, Omata M. Ikappa B kinasebeta/nuclear

440

factor-kappaB
activation
controls
thedevelopment of liver metastasis by way ofinterleukin-6 expression. Hepatology. 50(6):1851-60, 2009.
(3) Sakamoto K, Maeda S, Hikiba Y, Nakagawa H,
Hayakawa Y, Shibata W, Yanai A, Ogura K,
Omata M. Constitutive NF-kappaB activation incolorectal carcinoma plays a key role inangiogenesis, promoting tumor growth. Clin
Cancer Res. 15(7):2248-58, 2009.
(4) Aikou S, Fukushima Y, Ogawa M, Nozaki K,
Saito T, Matsui T, Goldenring JR, Kaminishi M,
Nomura S. Alterations in gastric mucosal
lineages before or after acute oxyntic atrophy ingastrin receptor and H2 histamine receptordeficient mice. Dig Dis Sci. 54:1625-1635,
2009.
(5) Nozaki K, Weis V, Wang TC, Falus A,
Goldenring JR. Altered gastric chief cell lineage
differentiation in histamine- deficient mice. Am
J Physiol Gastrointest Liver Physiol. 296:
G1211-1220, 2009.

441

University hospital Medical
Information etwork (UMI)
CenterProfessor
Takahiro Kiuchi, M.D., Ph.D.

Instructor
Hiroshi Nishiuchi, M.S.

Homepage

http://www.umin.ac.jp/umin/

Introduction and Organization
The University hospital Medical Information Network(UMIN) (the original name was the University
Medical Information Network), was established in
1989. While general-use computer systems were
implemented at all national university hospitals
around the end of the Showa era (late 1980s), Dr.
Shigekoto Kaihara, chair and professor at the HospitalComputer Center, University of Tokyo Hospital, led aproject to connect these computer systems in a
network in order to share information for better
communication. Finally, the Ministry of Education,
Culture, Sports, Science and Technology approved abudget to initiate the UMIN Center. The UMIN Center
was founded within the Hospital Computer Center,
University of Tokyo Hospital, and was officiallyopened in March 1989.
Dr. Tsunetaro Sakurai
became an associate professor as the first full-time
UMIN staff. The following are the objectives of the
UMIN Center, as initially outlined in 1989 (No.6 wasadded later):
1. Provide up-to-date information for healthcare
professionals
2. Promote digitalized communication among
healthcare professionals
3. Support collaborative projects among university

hospitals
4. Support collaborative medical research
5. Standardize data format and support datacollection
6. Support medical education and clinical training
The original UMIN system utilized an N1 protocol,
which was developed in Japan and was the only
solution at the time to connect general-use computersof the five major computer vendors in Japan, although
it was poor in function, supporting only line-mode,character-based terminals.
In 1994, we launched a service through the Internet,
and it began to spread in those days. The number of
UMIN users gradually increased, mainly in the E-mailservice.
In 1996, Dr. Takahiro Kiuchi took up a new post while
Dr. Sakurai was promoted to professor at Hokkaido
University. Dr, Kiuchi updated the system to be
web-based. With the rapid spread of the Internet in
Japan, UMIN users dramatically increased.
The UMIN Center subsequently started to provide
three major information services: (1) the ELBIS(Electronic Library for Biomedical Sciences) as of1997, (2) the INDICE (Internet Data and Information
Center of Clinical Research) as of 2000, and (3) the
EPOC (Evaluation System of Postgraduate ClinicalTraining) as of 2004.

442

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443(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444

Organ Transplantation Service
Director and Professor
Norihiro KOKUDO

Homepage
The University of Tokyo Hospital has aggressively
performed organ transplantation. In 1966, the firstkidney transplantation in Japan was performed. In
1996, the first living donor liver transplantation was
performed. Organ Transplant Service started tofunction since 2003. Until today, more than 400 casesof living donor liver transplantation has been
performed, and the 5-year survival rate is around 85%
which is much superior to the national average(~70%). The University of Tokyo Hospital has been
one of the authorized institutions for hearttransplantation
anddeceased
donor
liver
transplantation.

4. 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. 2009 Oct 22.
[Epub ahead of print] PubMed PMID: 19849703.
5. Kaneko J, Sugawara Y, Matsui Y, Sakata H,
Kokudo N. Comparison of near-infrared
spectroscopy and laser Doppler flowmetry for
detecting decreased hepatic inflow in the porcine
liver. J Invest Surg. 2009 Jul-Aug;22(4):268-74.
Erratum in: J Invest Surg. 2010 Feb;23(1):68.
PubMed PMID: 19842902.

References (2009)
1. 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. 2009 Dec 15. [Epubahead of print] PubMed PMID: 20028490.

6. Tamura S, Sugawara Y, Yamashiki N, Kaneko J,
Kokudo N. The urgent need for evaluating
recurrent primary sclerosing cholangitis in living
donor liver transplantation. Liver Transpl. 2009
Oct;15(10):1383-4; author reply 1385. PubMed
PMID: 19790228.

2. Kaneko J, Sugawara Y, Tamura S, Kokudo N,
Makuuchi M. Left liver with right paramedian
sector--can it be an option in living donor livertransplantation? Transplantation. 2009 Oct 15;88(7):952; author reply 953. PubMed PMID:
19935468.

7. Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Ohki T, Yoshida H, Omata M,
Makuuchi M, Kokudo N. Noninvasive estimationof hepatic steatosis in living liver donors:
usefulness of visceral fat area measurement.
Transplantation. 2009 Aug 27;88(4):575-81.
PubMed PMID: 19696642.

3. Kishi Y, Imamura H, Sugawara Y, Sano K,
Kaneko J, Kokudo N, Makuuchi M. Evaluation ofdonor vasculobiliary anatomic variations in livergraft procurements. Surgery. 2010 Jan;147(1):30-9. Epub 2009 Oct 31. PubMed PMID:
19879610.

8. Yamamoto K, Imamura H, Matsuyama Y,
Hasegawa K, Beck Y, Sugawara Y, Makuuchi M,
Kokudo N. Significance of alpha-fetoprotein anddes-gamma-carboxy prothrombin in patients with
hepatocellular carcinoma undergoing hepatectomy.
Ann Surg Oncol. 2009 Oct;16(10):2795-804.

445

Epub 2009 Aug 11. PubMed PMID: 19669841.
9. Ikeda M, Hasegawa K, Sano K, Imamura H, Beck
Y, Sugawara Y, Kokudo N, Makuuchi M. The
vessel sealing system (LigaSure) in hepatic
resection: a randomized controlled trial. Ann Surg.
2009 Aug;250(2):199-203. PubMed PMID:
19638927.
10. Inoue Y, Sugawara Y, Tamura S, Ohtsu H, Taguri
M, Makuuchi M, Kokudo N. Validity andfeasibility of transient elastography for thetransplanted liver in the peritransplantation period.
Transplantation. 2009 Jul 15;88(1):103-9.
PubMed PMID: 19584688.
11. Masuzaki R, Yamashiki N, Sugawara Y, Yoshida
H, Tateishi R, Tamura S, Kaneko J, Hasegawa K,
Kokudo N, Makuuchi M, Omata M. Assessmentof liver stiffness in patients after living donor livertransplantation by transient elastography. Scand J
Gastroenterol.
2009;44(9):1115-20.
PubMedPMID: 19562623.
12. Kishi Y, Kokudo N, Tamura S, Makuuchi M.
Viable liver parenchyma in a living donor livergraft: an "egg of Columbus" or a challenge to anaxiom of liver surgery? Hepatogastroenterology.
2009 Jan-Feb;56(89):174-5. PubMed PMID:
19453052.
13. Ishizawa T, Fukushima N, Shibahara J, Masuda K,
Tamura S, Aoki T, Hasegawa K, Beck Y,
Fukayama M, Kokudo N. Real-time identificationof liver cancers by using indocyanine green
fluorescent imaging. Cancer. 2009 Jun 1;115(11):2491-504. PubMed PMID: 19326450.
14. Kokudo N, Makuuchi M. Evidence-based clinicalpractice guidelines for hepatocellular carcinoma
in Japan: the J-HCC guidelines. J Gastroenterol.
2009;44 Suppl 19:119-21. Epub 2009 Jan 16.
PubMed PMID: 19148805.
15. Seyama Y, Kokudo N. Assessment of liverfunction for safe hepatic resection. Hepatol Res.
2009
Feb;39(2):107-16.
PubMedPMID:

19208031.
16. Yoshimi A, Nannya Y, Ueda K, Asano D,
Yamamoto G, Kumano K, Hangaishi A, Matsui Y,
Takahashi T, Imai Y, Sugawara Y, Kokudo N,
Kurokawa M. Successful hematopoietic stem celltransplantation from an HLA-identical sibling in apatient with aplastic anemia after HLAhaploidentical living-related liver transplantation
for fulminant hepatitis. Biol Blood Marrow
Transplant. 2009 Mar;15(3):389-90. PubMed
PMID: 19203732.
17. Inoue Y, Hasegawa K, Ishizawa T, Aoki T, Sano K,
Beck Y, Imamura H, Sugawara Y, Kokudo N,
Makuuchi M. Is there any difference in survival
according to the portal tumor thrombectomy
method in patients with hepatocellular carcinoma?
Surgery. 2009 Jan;145(1):9-19. PubMed PMID:
19081470.
18. Hashimoto M, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Kokudo N, Makuuchi M. Pseudomonas
aeruginosa infection after living-donor livertransplantation in adults. Transpl Infect Dis. 2009
Feb;11(1):11-9. Epub 2008 Sep 21. PubMed
PMID: 18811632.
19. Yamashiki N, Sugawara Y, Tamura S, Kaneko J,
Matsui Y, Togashi J, Kokudo N, Omata M,
Makuuchi M. Double-dose double-phase use of
second generation hepatitis B virus vaccine inpatients after living donor liver transplantation:
Not an effective measure in transplant recipients.
Hepatol Res. 2009 Jan;39(1):7-13. Epub 2008
Aug 28. PubMed PMID: 18761679.

446

Center for Epidemiology andPreventive Medicine
Director & Professor
Tsutomu Yamazaki, M.D., Ph.D. (Department of Clinical Epidemiology and Systems)

Associate Professor
Toru Suzuki, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Associates
Yumiko Oike, M.D., Ph.D., Motoko Seto, M.D., Ph.D.
Kazushi Suzuki, M.D., Ph.D.
Kenichi Aizawa, M.D., Ph.D. (Department of Ubiquitous Preventive Medicine)

Homepage:

http://www.h.u-tokyo.ac.jp/patient/depts/kenshin.html

Introduction and Organization
Following the inauguration of a new Central Clinical
Service Building (Central Care 2) in November 2006
(Heisei 18) in the University of Tokyo Hospital, theCenter for Epidemiology and Preventive Medicine
was established on January 1, 2007, within the Central
Clinical Facilities and the relevant regulations wererevised. On January 9, the Working Group for the
Establishment of the Center for Epidemiology andPreventive Medicine was organized; on April 1,
Steering Committee for the Establishment of theCenter for Epidemiology and Preventive Medicine
was organized; preparation for offering its services
continued until May 31; on June 4, the department
started offering its services on a trial basis (in-hospital
services) and was officially inaugurated in July,
starting to provide public services.
The principal objectives of the establishment of
the Center for Epidemiology and Preventive Medicine
are 1) to scientifically demonstrate the utility andeffectiveness of examinations and preventive
interventions, 2) to integrate a vast amount of clinicaldata and health-related information to develop more
efficient models for disease management, 3) by doing

the above 1) and 2), to promote preventive medicine
and medicine for health promotion in an effort tocontribute to the improvement of public health, and 4)
to train medical personnel who can put the above 1),2) and 3) into practice.
In the administrative organization of the Center for
Epidemiology and Preventive Medicine, its Director
directly under the Director of the Hospital is
responsible for the entire organization. The
management of the Department is also supported by
the Department of Clinical Epidemiology and Systems
and the Department of Ubiquitous Preventive
Medicine. In addition, examinations in the
Department are administered in collaboration withthree Central Clinical Facilities (Clinical Laboratory
Center, Radiological Center, and Department ofEndoscopy and Endoscopic Surgery) and 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 five physicians(two regular physicians and three physicians from therelated departments). One of the regular physicians447

also performs upper gastrointestinal endoscopy andcolonoscopy in the Department of Endoscopy andEndoscopic Surgery. Our department also has three
regular nurses and three regular secretaries (from theMedical Affairs Department). When our department
was established, the number of staff was increased inother divisions. Among our staff, one nurse (fulltime), three radiological technologists (full-time) andthree medical technologists (full-time) are assigned
respectively to the Department of Endoscopy andEndoscopic Surgery, the Radiological Center and theClinical Laboratory Center.

Clinical activities
In addition to basic examinations which are open
to the public, our department provides these elevenoptions: 1) comprehensive cardiovascular examinations, 2) home blood pressure screening, 3)
comprehensive
cerebrovascularexaminations,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, and11) oral/dental examinations. While meeting the needsof 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) 2009 from April 1, to March 31,
2010, the total number of examinees (who had basic
examinations and optional examinations) was 5,352,
including 1,750 in basic examinations, 421 incomplete cardiovascular examinations, 9 in home
blood pressure screening, 450 in complete
cerebrovascular examinations, 33 in check up
dementia, 335 in colorectal cancer screening, 332 in
uterine cancer screening, 403 in breast cancer
screening, 496 in lung cancer screening, 570 in tumor
marker diagnosis, 447 in estimation of gastric cancer
risk, and 99 in oral/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 2009, we issued 775
letters of referral to other departments in our hospitaland 38 to other hospitals.
We have expanded our public relations efforts andduring the FY 2009 our brochure has reached its third
edition and 15,000 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.

448

References
Academic Papers in English(1) Ogawa S., Yamashita T., Yamazaki T., Aizawa Y.,
Atarashi H., Inoue H., Ohe T., Ohtsu H.,
Okumura K., Katoh T., Kamakura S., KumagaiK., Kurachi Y., Kodama I., Koretsune Y.,
Saikawa T., Sakurai M., Sugi K., Tabuchi T.,
Nakaya H., Nakayama T., Hirai M., Fukatani M.,
Mitamura H. for the J-RHYTHM Investigators
Optimal treatment strategy for patients withparoxysmal atrial fibrillation Circulation J 73;
242-248,2009(2) Okura T., Higaki J., Kurata M., Irita J., Miyoshi
K., Yamazaki T., Hayashi D., Kohro T., Nagai R.
and The JCAD Study Investigators ElevatedSerum Uric Acid is an Independent Predictor for
Cardiovascular Events in Patients With SevereCoronary Artery StenosisSubanalysis of theJapanese Coronary Artery Disease (JCAD)
Study
Circ J 73(5); 885-891,2009(3) Kambara H., Yamazaki T., Hayashi D., Kohro T.,
Okada Y., Nagai R. and The JCAD Study
Investigators
Gender Differences in Patients
With Coronary Artery Disease in Japan The
Japanese Coronary Artery Disease Study (TheJCAD Study) Circ J 73(5); 912-917,2009(4) Tanaka Y., Daida H., Imai Y., Miyauchi K., SatoY., Hiwatari M., Kitagawa A., Kishimoto J.,
Yamazaki T., Kawamori R. Morning home
blood pressure may be a significant marker ofnephropathy in Japanese patients with type 2
diabetes: ADVANCED-J study 1 Hypertens R
32; 770-774,2009(5) Uchiyama S., Goto S., Matsumoto M., Nagai R.,
Origasa H., Yamazaki T., Shigematsu H.,
Shimada K., Yamada N., Bhatt DL., Steg PG.,
Ikeda Y. on behalf of the REACH Registry
Investigators Cardiovascular event rates inpatients with cerebrovascular disease andatherothrombosis at other vascular locations:
Results from 1-year outcomes in the Japanese
REACH Registry J Neurol Sci 15;287(1-2):
45-51,2009(6) 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. Treatment
strategy and clinical outcome in Japanesepatients with atrial fibrillation. Heart Vessels
24(4):287-93,2009(7) Kaku K., Daida H., Kashiwagi A., Yamashina A.,
Yamazaki T., Momomura S., Iwase T., Yamasaki
Y., Nagatsuka K., Kitagawa K., Kawamori R.:
Long-term effects of pioglitazone in Japanesepatients with type 2 diabetes without a recent
history of macrovascular morbidity Current
Medical Research & Opinion 25:2925-2932,
2009(8) Yamazaki T., Kurabayashi M., and theASTRO-1 Study Group.
A Randomized
Controlled Study to Compare the Effects of
Rosuvastatin 2.5mg and Pravastatin 10mg on the
Plasma Lipid Profile in Japanese Patients with
Hypercholesterolemia (ASTRO-1) Annals of
Vascular Diseases (2,3):148-158,2009(9) Yamazaki T., Kurabayashi M., and theASTRO-2 Study Group.
A Randomized
Controlled Study to Compare the Effects of
Rosuvastatin 5mg and Atorvastatin 10 mg on the
Plasma Lipid Profile in Japanese Patients with
Hypercholesterolemia (ASTRO-2) Annals of
Vascular Diseases (2,3):159-173,2009(10) Matsumura T, Suzuki T, Aizawa K, Sawaki D,
Munemasa Y, Ishida J, Nagai R. Regulation oftransforming
growthfactor-beta-dependent
cyclooxygenase-2 expression in fibroblasts. J
Biol Chem 284(51): 35861-35871, 2009(11) Suzuki T, Distante A, Zizza A, Trimarchi S,
Villani M, Salerno Uriarte JA, de Luca Tupputi
Schinosa L, Renzulli A, Sabino F, Nowak R,
Birkhahn R, Hollander JE, Counselman F,
Vijayendran R, Bossone E, Eagle K; for the
IRAD-Bio Investigators. Diagnosis of acuteaortic dissection by D-Dimer. The International
Registry of Acute Aortic Dissection substudy on
biomarkers (IRAD-Bio) experience. Circulation
119(20): 2702-2707, 2009(12) Suzuki T. Cardiovascular diagnostic biomarkers–The past, present and future–. Circ J 73(5):806-809, 2009(13) Suzuki T, Sawaki D, Aizawa K, Munemasa Y,
Matsumura T, Ishida J, Nagai R. Krüppel-likefactor 5 shows proliferation-specific roles in449

vascular remodeling, direct stimulation of cell
growth, and inhibition of apoptosis. J Biol Chem
284(14): 9549-9557, 2009(14) Ohta M, Seto M, Ijichi H, Miyabayashi K, Kudo
Y, Mohri D, Asaoka Y, Tada M, Tanaka Y,
Ikenoue T, Kanai F, Kawabe T, Omata M.
Decreased expression of the RAS-GTPase
activating protein RASAL1 is associated withcolorectal tumor progression. Gastroenterology.
2009 Jan;136(1):206-16.
(15) Seto M, Ohta M, Asaoka Y, Ikenoue T, Tada M,
Miyabayashi K, Mohri D, Tanaka Y, Ijichi H,
Tateishi K, Kanai F, Kawabe T, Omata M.
Regulation of the hedgehog signaling by the
mitogen-activated protein kinase cascade in
gastric
cancer.
Mol
Carcinog.
2009
Aug;48(8):703-12.
(16) 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.
2010 Feb;285(6):4185-94.
Academic Papers in Japanese(1) Suzuki T, Sawaki D: Review; IRAD, The results
and significance. Cardiology 66(5): 561-566, 2009
(2) Aizawa K, Suzuki T: Utility of the biomarker in adiagnosis and the treatment of the cardiovasculardisease; oxidized LDL. Mebio 26(12): 104-110,
2009
Books
(1) Aizawa K, Suzuki T: New mensuration of theoxidized LDL. Supervised by Kiyohiko Seino.
“Cardiovascular multi-biomarker strategy”.
Ishiyaku Shuppan. pp91-94, 2009
Reviews(1) Kohro T., Yamazaki T. Cardiovascular clinical
trials in Japan and controversies regarding
prospective randomized open-label blinded
end-point design Hypertens Res 32: 109-114,
2009(2) Kohro T., Yamazaki T.
Mechanism ofstatin-induced myopathy investigated using
microarray technology J of Atherosclerosis andThrombosis 16: 30-32, 2009
(3) Kohro T., Yamazaki T. Eicosapentaenoic acid

(EPA) in reducing secondary cardiovascular
events in hypercholesterolemic Japanese patients
Circ J 73(7): 1197-1198, 2009
(4) Aizawa K, Suzuki T: The measurement of thedenaturation protein. Kokyu to Junkan 57(7):723-728, 2009
International Conferences(1) Ishida J, Suzuki T, Aizawa K, Sawaki D,
Matsumura T, Nagai R: Krüppel-like facter 6 isa key transcription factor in adipocyte
differentiation. American Heart Association 82th
Scientific Sessions (November 14-18, 2009,
Orland, FL, USA)
(2) Suzuki T: The potential for development of acirculating marker for acute aortic dissection:
opportunities and challenges. Aortic Diseases
Summit (September 22-23, 2009, Baltimore, ML,
USA)(3) Suzuki T: Genetics of fibrillinopathies. Advancesin Understanding Aortic Diseases (September
11-12, 2009, Hamburg, Germany)(4) Mohri D, Asaoka Y, Ijichi H, Kudo Y, Seto M, Ohta
M, Tada M, Tanaka Y, Ikenoue T, Kanai F, Tada M,
Kawabe T, Omata M. Different subtypes of
intraductal papillary-mucinous neoplasm inpancreas have distinct pathways to pancreaticcancer progression. Digestive disease week 2009
(May 30-June 4, 2009, Chicago, IL, USA)
(5) Seto M, Ohta M, Tada M, Miyabayashi K, Mohri D,
Asaoka Y, Tanaka Y, Ijichi H, Ikenoue T, Kanai F,
Kawabe T, Omata M. Decreased expression of RAS
protein activator like 1 in gastric cancer. Digestive
disease week 2009 (May 30-June 4, 2009, Chicago,
IL, USA)ational Conferences(1) Suzuki T: The analysis of the cardiovascularpathologies by the function control abnormality of
the nucleus. 50th Annual Meeting of the Japan
Radiation Research Society (November 11-13,
2009, Hiroshima, Japan)(2) Aizawa K, Suzuki T, Kohro T, Ohike Y, Seto M,
Suzuki K, Suzuki S, Nagai R, Yamazaki T:
Association of masked hypertension and metabolic
syndrome detected through automatic home Blood
Pressure Measurement in Health Screening. The
32nd Annual Scientific Meeting of the JapaneseHypertension Society (October 1-3, 2009, Otsu,

450

Japan)(3) Suzuki T: About utility of the BNP measurement in
the clinical survey. The 50th Scientific Meeting ofJapan Society of Ningen Dock/The 2nd World
Congress on Ningen Dock (September 3-4, 2009,
Tokyo, Japan)(4) Suzuki T: Aiming at the prophylactic treatment of
the cardiovascular disease by cardiovascularpreventive medicine. The 50th Scientific Meeting ofJapan Society of Ningen Dock/The 2nd World
Congress on Ningen Dock (September 3-4, 2009,
Tokyo, Japan)(5) Suzuki T: Current approaches to aortic dissection;from biomarkers to the international registry ofacute aortic dissection (IRAD). The 73rd Annual
Scientific Meeting of the Japanese Circulation
Society (March 20-22, 2009, Osaka, Japan)(6) Munemasa Y, Suzuki T, Aizawa K, Matsumura T,
Sawaki D, Nagai R: Positive regulation ofpromoter-region specific histone incorporation byhistone chaperones ANP32B and TAF-I, histone
deacetylase HDAC1 and DNA-binding factor
KLF5. The 73rd Annual Scientific Meeting of theJapanese Circulation Society (March 20-22, 2009,
Osaka, Japan)(7) Ishida J, Suzuki T, Aizawa K, Sawaki D,
Matsumura T, Nagai R: Krüppel-like factor 6 is a
key transcription factor in adipocyte differentiation.
The 73rd Annual Scientific Meeting of theJapanese Circulation Society (March 20-22, 2009,
Osaka, Japan)(8) Sawaki D, Suzuki T, Aizawa K, Matsumura T,
Munemasa Y, Ishida J, Nagai R: Krüppel-like factor
6 modulates cardiovascular fibrosis. The 73rd
Annual Scientific Meeting of the Japanese
Circulation Society (March 20-22, 2009, Osaka,
Japan)(9) Aizawa K, Suzuki T, Zhan H, Matsumura T,
Sawaki D, Ishida J, Nagai R: A novel pathogenic
pathway of DNA damage response as mediated by
KLF5 and its transcriptional complexes in the
cardiovasculature. The 73rd Annual Scientific
Meeting of the Japanese Circulation Society(March 20-22, 2009, Osaka, Japan)(10) Fujimoto H, Suzuki T, Aizawa K, Matsumura T,
Sawaki D, Nagai R: Different molecular forms ofbrain natriuretic peptide measured using mass

spectrometry-based immunoassay are a new
biomarker of coronary artery disease. The 73rd
Annual Scientific Meeting of the Japanese
Circulation Society (March 20-22, 2009, Osaka,
Japan)(11) Kazushi Suzuki, Yoshitaka Kumakura, Toshiya
Sato, Toshimitsu Momose, Shoji Tsuji: In vivo
imaging of regional glucose metabolism in
DRPLA transgenic
mouse
brain
using
18F-fluorodeoxyglucose (FDG) PET. The 1st
retreat of University of Tokyo Global COE“Global center of education and research forchemical biology of the diseases” (February 28March 1, 2009, Chiba, Japan)(12) Kazushi Suzuki, Yoshitaka Kumakura, Toshiya
Sato, Toshimitsu Momose, Shoji Tsuji: In vivo
imaging of regional glucose metabolism in DRPLA
transgenic
mouse
brain
using
18F-fluorodeoxyglucose (FDG) PET. The 50th
Annual meeting of Japanese Society of Neurology.
(May 20-22, 2009, Sendai, Japan)(13) Kazushi Suzuki, Shoji, Tsuji: The study ofpolyglutamine
diseasepathogenesis
using
Dentatorubral-pallidoluysian atrophy (DRPLA)
transgenic mice. “Frotier medical research using
model animals” The workshop in The 32nd Annual
meeting of the Molecular Biology Society of Japan.
(December 9-12, 2009, Yokohama, Japan)

451

Division of Tissue Engineering
Director & Professor
Tsuyoshi Takato, M.D., Ph.D.

Vice Director & Professor
Ung-il Chung, M.D., Ph.D.

Project Associate Professors
Naoshi Ogata, M.D., Ph.D.,

Seishi Ogawa, M.D., Ph.D.,

Keiichi Hishikawa, M.D., Ph.D.,

Hiroyuki Koyama, M.D., Ph.D.,

Kazuto Hoshi, M.D., Ph.D.,

Research Associates
Makoto Ohba, Ph.D.,

Makoto Komura, Ph.D.,

Taku Saitou,Ph.D.,

Yuko Fujihara, D.D.S., Ph.D.,

Takeshi Marumo, 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
industry-university-government
cooperationisessential to the success, it seems that state-level
efforts are necessary. It is expected that broad progressin tissue engineering technologies and regenerative
medicine contributes to treatment and drug discoveryof all medical fields regardless of specialties.
October, 2001 Division of Tissue Engineeringfounded as special medical office in the 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

452

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453

inducing various hematopoietic components from
HSCs and embryonic stem cells. To achieve thesegoals, we are conducting research on the regulatory
mechanisms of proliferation, self-renewal, anddifferentiation of human hematopoietic stem cells(HSCs), plasticity of HSCs and clinical application of
the in vitro expansion and differentiation system of
HSCs.
In the department donated by FUJISOFT ABC, we
aim to produce regenerated cartilage and bone withhigh safety and usefulness, to realize production
system and establish practical quality control and topromote the application of regenerated cartilage andbone. To achieve these goals, we are conducting
research on adult stem cell biology in mesenchymal
tissues, application of molecular biology on cartilage
repair for regenerative medicine, development ofnovel scaffolds in cartilage and bone regeneration,
development of 3-D reconstruction system forregenerated tissues, evaluation on biochemical andbiophysical properties of regenerated tissues in vivo
and clinical trials and application of regenerated
cartilage and bones.
In the laboratory for pediatric regenerative medicine,
we are doing research to fabricate an engineered
airway by cells originated from trachea tissue. In
addition, the fundamental study of the amniotic fluid
cell is performed to create new therapy for new bornbabies.
Basic Research on human ES cells
Besides, to promote basic research on humanembryonic stem cells with our eyes set on applicationsin the future, Department of Clinical Renal
Regeneration and Department of Bone and Cartilage
Regenerative Medicine are carrying forward theapplication procedures to obtain human ES cells from
Institute for Frontier Medical Sciences, Kyoto
University, which will be approved shortly.
Clinical Studies
Of particular note is clinical studies started in thefour departments as a result of basic research. In
Project for Regenerative Medicine of Hematopoiesis,
clinical study on expansion of human cord blood
hematopoietic cells (Institutional Review Board
approval number #351) has been started. In
Department of Vascular Regeneration, clinical studies

on claudication limbs and severe ischemic limbs
caused by peripheral vascular diseases (IRB approval
number #825 and #826) have been started andcontinued without causing major side effects. In
Department of Corneal Tissue Regeneration, clinicalstudies on transplantation of cultured autologous oral
mucous epithelial sheet on amniotic membrane forocular surface reconstruction, and corneal endothelial
stem cell transplantation for decrease in number ofcorneal endotheliums (IRB approval number #363 and#898) have been started. In Department of Bone &Cartilage Regenerative Medicine, a clinical study onbone implants into non-loading parts (IRB approval
number #1310) was conducted on 10 patients
successfully and a large-scale clinical trial was started
across the nation. As stated above, we are proceedingtranslational research aiming at clinical application oftissue engineering and regenerative medicine.
Contribution to the Hospital
Division of Tissue Engineering, as a cooperative
research facility in the Hospital, opens expensive
special machines that each laboratory cannot afford toequip with, such as a confocal laser scanningmicroscope, a cell analyzer and a cell sorter to the
Hospital staff, letting them use with cost sharing.
Department of Plastic Surgery is conducting researchusing this facility.

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457

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 13
administrative staff.

Clinical activities
Hospital Planning and Management is responsible
for all of the organizational and strategic businessaffairs of the University of Tokyo Hospital. It
conducts the following kinds of clinical-management
duties.
(1) Analysis of hospital management
The division manages and analyzes hospital
accounting information, and conducts hospitalmanagement analyses by utilizing management
information
andstandardized
hospital
information.
(2) Planning
Based on the hospital management analyses, thedivision designs short-term management planningand strategy, and provides effective support for
the Hospital Executives to make swift
management decisions. The division is also
responsible for formulating medium- andlong-term plans. Following is a list of hospitalmanagement achievements in which Hospital
Planning and Management was deeply involved.
・ Launched the “22nd Century Medical Center”
・ Launched the new central hospital building
・ Enhanced functions in the inpatient ward
(expansion of ICU/CCU, increase in number ofbeds in the Psychiatry Department and GCU)

458

・ Reduced the average length of hospital stays,
and improved the bed occupancy rate
・ Achieved reductions in drug costs and costs for
medical materials
In addition to these achievements, the division
has also strived to improve innovative patient
services, such as introducing a credit card forpatients, attracting commercial stores in thehospital, and illuminating the hospitalbuildings. At the same time, the division has
worked to develop an environment in which
medical care staff can provide high-quality andsafe medical treatment in a more composed
fashion.
(3) Medical policy recommendations
The division is not just restricted to the
management of the University of Tokyo Hospital.
It
also
actively
implements
policyrecommendations aimed at improving the
medical system in Japan and at deregulating
medical care.
Furthermore, we point out issues related toJapan’s medical insurance system based onevidence, and we constantly issue messages fortheir improvement.

Teaching activities
Turning to postgraduate education, the division
accepts 1 doctoral student from the Department ofMedical Informatics and Economics at the Graduate
School of Medicine, and 1 research student from the
Graduate School of Medicine.
Postgraduate students and research students pursue
their own research projects, not just from the researchareas of healthcare management and hospitalmanagement, but also from such areas as healthcare
economics and healthcare policy. The students review
previous literature and materials, and they are actively
engaged in developing research designs and thecollection of data. The students present regularresearch progress reports, they are given thoroughinstruction on writing academic papers, and they also
follow a rigid schedule of academic presentations.

Research activities
The research activities of the division are notlimited to merely healthcare management and hospitalmanagement, but cover a broader area, including
health policy and health economics.
(1) Research in healthcare management
In the past, the division analyzed the impact thata prospective payment system, which is based on
Diagnosis Procedure Combination (DPC), has on
the healthcare workplace, and it conducted
research to estimate the effects that this system
has on the length of hospital stays. The divisionalso conducted research related to the efficientuse of medical facilities, by studying therelationship between the running of operatingrooms and the number of hospital beds.
In an attempt to systemize healthcare management,
the division edited a standard textbook. The
division is also conducting research into thedevelopment of an education program for
healthcare management, and educates students
working in health sector since 2007.
(2) Research in healthcare policy
The division undertook comparative studies
between medical systems in Japan and otherdeveloped countries. Empirical studies related tothe disparity in domestic and imported prices of
medical materials among multi countries, andstudies into the career paths of medical doctors
and health workers’ migration are ongoing.
The division carried out assessments related toJapan’s medical insurance system, and inparticular, conducted research into improvements
to the prospective payment system based on DPC,
and the effectiveness of such improvements.
(3) Research in healthcare economics
In cooperation with hospitals providing cares for
HIV/AIDS patients, the division is conducting
cost-accounting study in HIV/AIDS care.
Recently, we began cost-effectiveness analysis
for hepatitis B prevention strategies.
(4) Other research topic
The division commits a research project
regarding socio-economic impacts on childhood
obesity using a large panel data set, with otherresearch institutes

459

References
1. Koike S, Matsumoto S, Kodama T, Ide H,
Yasunaga H, Imamura T. Estimation of physician
supply by specialty and the distribution impact ofincreasing female physicians in Japan. BMC
Health Services Research 2009; 9:180.
2. Koike S, Yasunaga H, Matsumoto S, Ide H,
Kodama T, Imamura T. A future estimate ofphysician distribution in hospitals and clinics inJapan. Health Policy 2009; 92: 244-249.
3. Ide H, Koike S, Kodama T, Yasunaga H, Imamura
T. The distribution and transitions of physicians inJapan: a 1974-2004 retrospective cohort study.
Human Resources for Health 2009; 7:73.
4. Ide H, Yasunaga H, Kodama T, Koike S, Taketani
Y, Imamura T. The Dynamics of Obstetricians andGynaecologists in Japan: A Retrospective Cohort
Model using the Nationwide Survey of Physicians
data. Journal of Obstetrics and Gynaecology
Research 2009;35(4):761-766.
5. Ide H, Yasunaga Y, Koike S, Kodama T, Igarashi T,
Imamura T. Shortage of Pediatricians in Japan: aLongitudinal Analysis Using Physicians' Survey
Data. Pediatrics International 2009;51:645-649.
6. Ide H, Mollahaliloglu S. How firms set prices for
medical materials: A multi-country study. Health
Policy 2009;92(1):73-78.
7. Atarashi H, Tanaka K, Tamai H, Ohe K.
Development and Evaluation of a WiFi-based
Location Detection System for Medical
Equipment Management. The Japanese Journal of
Medical Instrumentation. 2009; 79(6) : 373-381.
8. Matsumoto S, Akahane M, Kanagawa Y, Koike S,
Yoshimura T, Mitoma C, et al. Variation in
Half-life of Penta-chlorodibenzofuran (PeCDF)
Blood Level among Yusho Patients. Chemosphere2009;77(5): 658-662.
9. Kanagawa Y, Matsumoto S, Koike S, Imamura T.
Association Analysis of Food Allergens. PediatricAllergy and Immunology 2009;20:347-352.
10. Imamura T, Matsumoto S, Kanagawa Y, Tajima B,
Matsuya S, Uchi H, et al. Cutaneous symptoms
such as acneform eruption and pigmentation areclosely associated with blood levels of
2,3,4,7,8-penta-chlorodibenzofurans in Yusho
patients,
using
data
mininganalysis.

BMCResearch Notes .2009;2:27.

460

Department of Child Psychiatry
Professor
Takashi Igarashi, M.D.,Ph.D.

Associate Professor
Yukiko Kano, M.D.,Ph.D.

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

Associate
Ayako Todokoro, M.D.

Homepage

http://kokoro.umin.jp/

Introduction and Organization

Clinical activities

The Department of Child Psychiatry wasestablished in April 2005 as the clinical counterpart
to the Clinical Education Center of Mental
Development, both of which are funded by the
special grant 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. The 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 complements the Clinical Education
Center by providing fieldwork for clinical training.
It also offers clinical services to patients withvarious development problems and places anemphasis on research to provide evidence-based
clinical and educational activities.

In the year 2008, the Department of Child
Psychiatry consisted of 6 psychiatrists including 3
full-time child psychiatrists and 9 psychologists(full-time and part-time). Although patients withvarious disorders are seen, the focus of thedepartment is mainly on patients with
developmental disorders. We offer services topatients with a broad range of developmental
disorders including Pervasive Developmental
Disorders (PDD), Attention-Deficit/Hyperactivity
Disorder (AD/HD), Learning Disabilities (LD),
Mental Retardation (MR), tic disorders and childObsessive-Compulsive Disorders (OCD).
From the year 2005 to 2009, the number of newpatients remained within a range of 300 to 500. In
the year 2009, among the new patients, about 50%
were patients with PDD, and about 40% were
patients with non-PDD developmental disorders
including tic disorder, AD/HD, MR. The other 10%
were patients with stress-related disorders. The agegroup of these patients was distributed widely fromearly infancy to adulthood, and the largest numberof patients being those in the late infancy to earlychildhood group.
The number of follow-up patients has been
increasing consistently and become twice of that in461

the year 2005. Among follow-up patients, PDD wasagain the most prevalent at about 50%, followed bytic disorders, stress-related disorders, AD/HD andmood disorders. About half of the patients atfollow-up were adult patients, especially high in
number were patients in their twenties, constituting
a total of 20%. This highlights the need forlong-term follow-up in patients with developmental
disabilities.
Clinical activities are largely divided into twoareas of general child psychiatry outpatient services
and interventions for children with developmental
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 disabledchildren consist of “developmental psychology
outpatient services” and “short-term group therapy”.
Patients involved in interventions are children with
developmental disabilities, and individualized
cognitive developmental therapy is planned for eachchild. “Developmental psychology outpatient
clinic” provides services in the following areas: (1)evaluation of cognitive and behavioral development,(2) individual treatment of the child (3) counselingof parents and providing information to the child’s
support network (relatives, schools). “Short-termgroup therapy” is a 10 session group therapy for asmall group of children with PDD and similar
developmental levels. These services are provided
mainly by psychologists under the supervision ofchild psychiatrists.

participation in intervention and psychologicalassessment.
Course A is composed of 11 sessions of 3 hour
lectures. In the year 2009, this course was offeredonce, with a total of approximately 50 trainees.
Trainees consisted of a wide range of professionals,
including those in the medical field, such as
physicians, psychologists, educators and social
workers. This mixture of a variety of professions
laid the groundwork for creating a multidisciplinary
network for professionals involved in issues relatedtomentaldevelopment.
Feedback
fromquestionnaires indicated that 80% of the trainees
found the course useful. In later half of the year, we
reviewed content of the lectures with editing a
textbook for application to the future training.
Course B is offered for a duration of 6 months,
with 3 days per week of clinical training. Trainees
were a psychiatrist and a psychologist.
A seminar and symposium is held annually inorder to facilitate understanding of mental
development and developmental disorders among
the general public. In the year 2009, a seminar
entitled “Developmental disorders and support forchild raising” and a symposium entitled “Opening abright future for developmental disorders” each
attracted an audience of about 200 and 700 people
respectively.
Undergraduates and psychiatry residents from the
University of Tokyo have opportunities to observe
evaluations and outpatients services as part of theircourse. They are also required to actively
participate in “short-term group therapy”.

Education

We participate in investigation of etiology anddevelopment of effective treatment on PDD and
AD/HD, which are organized in collaboration with
the Department of Neuropsychiatry and otherresearch, educational and clinical facilities. In
addition, research related specifically to the clinicalactivities in the Department of Child Psychiatry iscurrently being investigated.

As part of the Clinical Education Center ofMental Development, two training courses (Course
A and B) are offered for graduate level students andvarious mental health professionals including
psychiatrists and pediatricians. Course A is a lecture
course which incorporates an interactive component
with role-play exercises and case conferences.
Course B is an intensive training course, which
includes more clinical experience throughResearch

Clinical evaluation and treatment
The reexamination of reliability and validity of462

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 PDD are being conducted.
A comparison study of the effectiveness of
individual treatment and “short-term group therapy”
in a randomized control study is being undertaken.
In another study, the possible relations among
clinical characteristics such as tics and obsessivecompulsive symptoms in Tourette syndrome(chronic tic disorder with multiple motor tics andone or more vocal tics) and child OCD are being
evaluated.

References1.

Freeman RD, Zinner SH, Müller-Vahl KR, Fast
DK, Burd LA, Kano Y, Rothenberger A,
RoessnerV,

Kerbeshian

J,

Stern

JS:

Coprophenomena in Tourette syndrome. Dev
Med Child Neurol, 51(3):218-27, 2009.
2.

Kano Y, Ohta M, Nagai Y, Scahill L: Association
between Tourette syndrome and comorbidities inJapan. Brain Dev. (in press)

3.

Kawakubo Y, Kuwabara H, Watanabe K,
Minowa M, Someya T, Minowa I, Kono T,
Nishida H, Sugiyama T, Kato N, Kasai K:
Impaired prefrontal hemodynamic maturation in
autism and unaffected siblings. PLoS One, 4:europsychological research
Neuropsychological data on PDD, AD/HD 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.

e6881, 2009.
4. Konno C, Shishikura K, Oiji A, Sho N, Usami M,
Kodaira M, Kono T, Miyaoka H, KanoY:
Cognitive impairments and attention deficits inobsessive-compulsive disorder. The Kitasato
Medical Journal, 39(1): 82-90, 2009.
5.

Genetic research
Research exploring susceptibility genes of PDD
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 endocrinologic change
including thyroid hormone in PDD. In addition to
the molecular genetic study, investigation of
specific family and environment of Tourette
syndrome is being undertaken.
euroimaging
Studies include structural MRI, MEG and NearInfrared Spectroscopy (NIRS) and exploration of
the pathogenesis of developmental disorders suchas PDD. The main focus is the examination of
prefrontal blood flow in PDD, AD/HD and Tourette
syndrome by NIRS which is non invasive and easily
applicable to children and developmentally disabledindividuals.

Marui T, Funatogawa I, Koisi S, Yamamoto K,
Matsumoto H, Hashimoto O, Nanba E, Nishida
H, Sugiyama T, Kasai K, Watanabe K, Kano Y,
Kato N: Association of the neuronal celladhesion molecule (NRCAM) gene variants with
autism. Int J Neuropsychopharmacol, 12: 1-10,
2009.

6.

Marumo K, Takizawa R, Kawakubo Y, Kasai K.
Gender difference in right lateral prefrontal
hemodynamic response while viewing fearfulfaces: a multichannel near-infrared spectroscopy
study. Neurosci Res, 63(2):89-94, 2009.

7.

Otowa T, Shimada T, Kawamura Y, Liu X, Inoue
K, Sugaya N, Minato T, Nakagami R, Tochigi
M, Umekage T, Kasai K, Kato N, Tanii H,
Okazakia Y, Kaiya H, Sasaki T: No association
between the brain-derived neurotrophic factor(BDNF) gene and panic disorder in Japanese
population. J Hum Gene, 54: 437-439, 2009.

8.

Takei Y, Kumano S, Hattori S, Uehara T,
Kawakubo Y, Kasai K, Fukuda M, Mikuni M:
Preattentive dysfunction in major depression:

463

magnetoencephalography study using auditory
mismatch negativity. Psychophysiology, 46(1):52-61, 2009.
9.

Takizawa

R,

HashimotoK,

Tochigi

M,

Kawakubo Y, Marumo K, Sasaki T, Fukuda M,
Kasai K. Association between sigma-1 receptor
gene polymorphism and prefrontal hemodynamic
response induced by cognitive activation inschizophrenia. Prog Neuropsychopharmacol Biol
Psychiatry, 33(3): 491-498, 2009.
10. Takizawa R, Tochigi M, Kawakubo Y, Marumo
K, Sasaki T, Fukuda M, Kasai K. Association
between Catechol-O-Methyltrasferase Val108/
158Met Genotype and Prefrontal Hemodynamic
Response in Schizophrenia. PLoS ONE, 4(5):e5495, 2009.
11. Yamasue H, Kuwabara H, Kawakubo Y, Kasai K:
Oxytocin, sexually dimorphic features of thesocial brain, and autism. Psychiatry Clin
Neurosci, 63: 129–140, 2009.

464

Department of Palliative Medicine
Homepage

http://www.h.u-tokyo.ac.jp/patient/depts/pailiative.html

History and outline of organization
Half of the cancer patients die of original cancer inspite of the advanced cancer treatment technology.
The success or failure of the first treatment against
cancer results in its cure or non-cure. Almost all thepatients who underwent unsuccessful initial treatment
die after the struggle against disease within several
years. It is sure to need the proper medical care only
for such patients.
However, most attention has been entirely paid to theimprovement of cure rates of cancer patients in Japanso far. Therefore, the sense of palliative care is very
poor and immature consequentially.
Palliative care means active treatment approach and a
total human care for the patients who do not respondto any treatment. In addition, pain relief, othersymptomatic controls, psychiatric, social and mental
care are as a top priority for these patients. However,palliative care is necessary to be applied in the cancer
treatment even for patient in early stage of the disease
as well as the progressive disease.
In Department of Palliative Medicine of The
University of Tokyo Hospital, our palliative care teamtakes a leading role not only to control physicalsymptoms of patients but also to care for the mind andsocial support at the same time, and to improve theoverall QOL (Quality of life) of patients. Moreover, italso becomes base of the education and palliative
medicine research for medical students.
Palliative care is described clearly in "Fundamental
law of the cancer measures" passed in the National
Diet on June 2006, "The medical treatment to aim atrelieving pains according to the condition of cancer
patient is appropriate from the early stage of thedisease". In a word, palliative care is provided by thelaw as a medical treatment that should be offered at

the early stage when the patient receives the cancer
treatment.

Consultation
In The University of Tokyo Hospital, the palliative
care team is composed of a lot of specialists such as
one full-time staff doctor, one full-time doctor, andthe designated hospice care nurse who take an
initiative in working. They visited the general ward
and offer palliative care to the patient who hasreceived the cancer care in cooperation withpatients’ attending doctors and ward staff andrehabilitation staff, etc.
Hereafter, we concretely show the consultation
situation in fiscal year 2009.
The cumulative number of patients who consulted our
palliative care team was over 1300 (20.3 average daily
patients). The maximum monthly patients were 58 of
December (28.9 daily patients). According to site of
the cancer, 337 cancers were divided into 49 pancreas,
36 uterine, 32 lungs and so on. We visited almost all
the ward in the hospital. According to gender, a totalof 337 patients were divided into 186 males and 193
females. According to the age group, there were 117,
98, and 59 in sixties, seventies, and 50 years old,
respectively. These figures proved significantly theimportance of the palliative care.

Education
In the training at the Department of Palliative
Medicine, medical students of the first and second
year can learn the basic knowledge of palliative careby selecting an optional subject for one, two, four oreight months. And then they can participate in thepalliative care team and attend the daily conference of465

palliative care on weekdays.
1) Palliative care training program
The training course (selection) for two months ( or *for one month )･ Program to acquire basic knowledge andtechnology of palliative care for targeting all
resident physicians. * Only in "Comprehensive
Internal Medicine” selection.
The training course (selection) for four or eightmonths･ Program to acquire basic knowledge, basic
technology, and communications skills for doctor
who aims at medical oncologists or palliative caredoctor.
2) Curriculum
Resident physician arrangement and content oftraining･ All resident physicians are assigned to the palliative
care team. They chiefly participate in ward
palliative care as a member of the team, and also
learn the cancer registry of palliative care.
･ In the course for four and eight months, they makepalliative care program for patients in charge,
discuss their palliative care with patients’ attending
doctors, ward staff, and execute their palliative careprogram.
Content of training and attainment goal･ The ward palliative care (3-5 patients in charge permonth and around 20 consultation patients a day):
They acquire the outline of control of physical andpsychiatric symptoms of the patients with common
disease in Japan such as digestive cancers in thegeneral ward. They also acquire the outline of
spiritual and family care.
･ Cancer registry: In The University of Tokyo
Hospital, it is not unusual that the patient whom thepalliative care team treats is often in an end stage,and his or her condition changes physically andmentally day by day. Residents should input theconcise and plain content of the offered palliative
care for such a patient to the data base. Theyacquire the outline of data management of thepalliative care connected directly to a clinicalresearch.
･ The communications skills: The clinician shouldtell "Bad news" time after time by all the processesof examining the patient. It is very difficult for theclinician to explain the accurate information ofdiagnosis, progression and prognosis of cancer tothe patient. This is a lot of work of the stress to theclinician. The clinician should deal with patient's
disappointment or failure feeling when treatment
does not go well while should do the balance of"Bad news" and "The patient's hope andexpectation". We introduce Protocol (SPIKES) of
the communications skills that psychiatricallysupport the patient in Department of Palliative
Medicine of The University of Tokyo Hospital.
Resident can make the palliative care execution
program based on this Protocol, and intend toobtain the communications skills in the course offour or eight months.
Event concerning education･ Concerning the intensive course to the first stage
resident physicians, following lectures are done by
the staff.
O pain control
O delirium control
O Introduction of the guideline and its use
O Basic drug therapy for palliative care
O Spiritual care for Japanese
Clinical training schedule･ Conference: Monday - Friday (every day)9:00-10:30･ Ward consultation: Monday - Friday (every day);up to the end of request patient's consultation after
conference.
･ The cancer registry: They input data in the ward
round with the HIS (Hospital information system)
terminal on each floor.
System of guidance･ The ward consultation: Resident participate in the
consultation team (or palliative care team) thatconsists of two guidance medical doctors (oneassistant or lecturer, one designated hospice carenurse, and one resident physician). A palliative careteam examines about 20 – 30 in-patients a day.
･ The conference: Psychiatrist, Chinese medicine
specialist, morphine special pharmacist, and nurseof The Tokyo University Graduate School of
Medicine and others participate in the daily
conference besides the regular member of the466

palliative care team in the ward round. They discuss
the multidisciplinary palliative care program thatthe palliative care team offers. They also guide theresident's palliative care program from their special
viewpoints.

Research
The content accumulated from the palliative careconsultation is input to the data base concise andplainly, and submitted to the international medical
journal such as "International Journal of Radiation
Oncology Biology Physics", "American Journal of
Hospice & Palliative Medicine" and "Biomed" as aresult of a clinical research.
The following fields of investigations are the one that
had been executed in our Department of Palliative
Medicine. Please refer to the homepage for results indetails and acquisition of the research fund.
1) Evaluation and quality assurance of special
palliative care team2) Development of the scale to measure execution ofpreferable death and its nationwide investigation
3) Development of target system in extracranialstereotactic radiotherapy4) Home care of cancer patients in terminal stage andregional liaison
5) Palliative care supporting metastatic breast cancer
patient6) Chinese medicine in palliative care

Publications etc.
1. Yamashita H, Nakagawa K, Hosoi Y, Kurokawa
A, Fukuda Y, Matsumoto I, Misaka T, Abe K.
Umami taste dysfunction in patients receiving
radiotherapy for head and neck cancer. Oral
Oncol. 2009 Mar;45(3):e19-23.
2. MIYASHITA M., YASUDA M., BABA R.,
IWASE S., TERAMOTO R., NAKAGAWA K.,
KIZAWA Y. & SHIMA: Inter-rater reliability ofproxy simple symptom assessment scale between
physician and nurse: a hospital-based palliative
care team setting. European Journal of Cancer
Care, in press
3. Igaki H, Nakagawa K, Yamashita H, Terahara A,
Haga A, Shiraishi K, Sasano N, Yamamoto K,

Onoe T, Yoda K, Ohtomo K. Contrast
media-assisted visualization of brain metastases
by kilovoltage cone-beam CT. Acta Oncol.
2009;48(2):314-7
4. 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.
5. Kan Y, Yamashita H, Le Pavoux A, Ushiku T,
Ohtomo K, Nakagawa K. Histological changes
after single high-dose irradiation for squamouscell carcinoma arising from a burn scar. Med
Oncol. 2009
6. 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. PMID:
19634051
7. 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. 200990(3):422-3. PMID: 19062117
8. Keiichi Nakagawa, Akihiro Haga, Kenshiro
Shiraishi, Hideomi Yamashita, Hiroshi Igaki,
Atsuro Terahara, Kuni Ohtomo, Shigeki Saegusa,
Takashi Shiraki, Takashi Oritate
Letter to the Editor – First clinical cone-beam CT
imaging during volumetric modulated arc therapy.
Radiotherapy and Oncology 90 (2009) 422-423
9. Masatoshi Hashimoto, Tetsuya Tomita, Koichi
Sawada, Toshioh Fujibuchi,Teiji Nishio, andKeiichi Nakagawa:
Dose profile measurement using an imaging plate:
Evaluation of filters using Monte Carlo simulationof 4 MV x-rays REVIEW OF SCIENTIFICINSTRUMENTS 80, 045101 2009,2.
10. Yamashita H, Okuma K, Nakagawa K. Iatrogenic
vulvarskin
metastases
afterinterstitialradiotherapy for recurrent cervical cancer. J
Dermatol. 2009 Dec;36(12):663-5. PubMed
PMID: 19958454

467

11. Mori-Uchino M, Takeuchi T, Murakami I, Yano T,
Yasugi T, Taketani Y, Nakagawa, K, Kanda T.
Enhanced transgene expression in the mouseskeletal muscle infected by the adeno-associatedviral vector with the human elongation factor
1alpha promoter and a human chromatin insulator.
J Gene Med. 2009 Jul;11(7):598-604. PubMed
PMID: 19399759.
12. Haga A, Nakagawa K, Shiraishi K, Itoh S,
Terahara A, Yamashita H, Ohtomo K, Saegusa S,
Imae T, Yoda K, Pellegrini R. Quality assuranceof volumetric modulated arc therapy using Elekta
Synergy. Acta Oncol. 2009;48(8):1193-7.
PubMed PMID: 19863228.
13. Igaki H, Maruyama K, Koga T, Murakami N,
Tago M, Terahara A, Shin M, Nakagawa K,
Ohtomo K. Stereotactic radiosurgery for skull
base meningioma. Neurol Med Chir. 2009 Oct;49(10):456-61. PubMed PMID: 19855141.
14. Yamashita H, Okuma K, Seto Y, Mori K,
Kobayashi S, Wakui R, Ohtomo K, Nakagawa K.
A retrospective comparison of clinical outcomesand quality of life measures between definitive
chemoradiation alone and radical surgery forclinical stage II-III esophageal carcinoma. J Surg
Oncol. 2009 Nov 1;100(6):435-41. PubMed
PMID: 19653240.
15. Haga A, Nakagawa K, Shiraishi K, Itoh S,
Terahara A, Yamashita H, Ohtomo K, Saegusa S,
Imae T, Yoda K, Pellegrini R. Quality assuranceof volumetric modulated arc therapy using Elekta
Synergy. Acta Oncol. 2009;48(8):1193-7. PubMed
PMID: 19863228.
16. Yoda K, Nakagawa K, Shiraishi K, Okano Y,
Ohtomo K, Pellegrini RG. Dose verification of
intensity modulated arc therapy using ERGO ++treatment planning system and Elekta internal
multileaf collimators for prostate treatment. Br J
Radiol 82(976) : 328-31, 2009
17. Kawaguchi
T,
Iwase
S,
KurodaY
Chemotherapy with low-dose capecitabine as
palliative treatment in a patient with metastatic
breast cancer: A case report Cases Journal Cases
J. 2009 Nov 24;2:9081 2009
18. Iwase S, Kuroda Y. Guideline for Lymphedema,
Kanehara Publication, 2009
19. Kuroda Y, Iwase S. Menopausal symptom and its

affects to quality of life among breast cancer
patients. General Hospital Psychiatry, 2009
20. Kuroda Y, Iwase S. Comparative study of qualityof life among breast cancer patients. Japanese
Breast Cancer Society, 2009
21. Kuroda
Y,
Iwase
S,
Nakagawa
K.
Chemoradiotherapy. Nanzando, 2009
22. Kuroda Y, Iwase S, Nakagawa K. The practice of
medical oncology, 2009.

468

Clinical Genomics
Director & Professor
Shoji Tsuji, M.D., Ph.D.

Vice-director & Lecturer
Jun Goto, M.D., Ph.D.

Organization
The Department of Clinical Genomics started as a
special unit conducting genomic medicine or clinicalhuman genetics services in 2003. Our department
functions as the core unit to accomplish an appropriate
and efficient application of results of recently
advanced human genetics and genomics to clinicalpractice in the hospital and as the unit of training andeducating specialists of human genetics practice. It
consists of one professor and many different
specialties participate in the department. They include
pediatricians, obstetricians, internist (cardiologists,diabetologists, and neurologists),dermatologists,and staffs of the Departments of Clinical Laboratory
Medicine, Human Genetics and Nursing Science.

Activities
The exclusive consultation room (Room 200) is
allocated in the outpatient clinic. Consultation andcounseling is performed by a team of medical doctor
and non-M.D. staffs. All cases are reviewed anddiscussed at the conference which is held on the 1st
Monday every month.
Counseling of participants in researches including
genome or gene analysis is a duty with which thehospital and the faculty charge the department.
To build suitable clinical systems including
modern genomic medicine we are cooperating 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.
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 started the lecture series “Seminar for Clinical
Genetic Medicine” bimonthly.

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3. 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
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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.
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6. 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
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7. Hara K, Kokubo Y, Ishiura H, Fukuda Y,
Miyashita A, Kuwano R, Sasaki R, Goto J,
Nishizawa M, Kuzuhara S, Tsuji S. TRPM7 is not
associated with amyotrophic lateral sclerosisparkinsonism dementia complex in the Kii
peninsula of Japan. Am J Med Genet B
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8. Matsumoto H, Hanajima R, Terao Y, Hamada M,
Yugeta A, Shirota Y, Yuasa K, Sato F,
Matsukawa T, Takahashi Y, Goto J, Tsuji S,
Ugawa Y. Efferent and afferent evoked potentials
in patients with adrenomyeloneuropathy. Clin
Neurol Neurosurg. 2010 Feb;112(2):131-6. Epub
2009 Dec 5. PubMed PMID: 19963315.
9. Hanajima R, Terao Y, Nakatani-Enomoto S,
Hamada M, Yugeta A, Matsumoto H, Yamamoto
T, Tsuji S, Ugawa Y. Postural tremor in X-linked
spinal and bulbar muscular atrophy. Mov Disord.
2009 Oct 30;24(14):2063-9. PubMed PMID:
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10. Sato N, Amino T, Kobayashi K, Asakawa S,
Ishiguro T, Tsunemi T, Takahashi M, Matsuura T,
Flanigan KM, Iwasaki S, Ishino F, Saito Y,
Murayama S, Yoshida M, Hashizume Y,
Takahashi Y, Tsuji S, Shimizu N, Toda T,
Ishikawa K, Mizusawa H. Spinocerebellar ataxia
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471

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. Configurationof each project in a space of 554.4m2 that is consistedof a portion of the first floor and the basement of an472

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.

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, eurosurgery
Dept. Engineering Synthesis, M Mitsuishi
To develop Microsurgical robotic system and 3D
visual system for telesurgery

Research activities
Development of Advanced Sterotactic Rediation
Cancer Rherapy System
Department of Radiation Oncology
uclear Professional school, Department of uclear
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 ano-crystals in Oncology
Department of Chemical System Engineering
Department of Surgical Oncology
To develop an exact diagnosis and treatment system
for the micro-metastasis of neoplasm by using
nano-crystal particles, and to introduce it to clinicaluse. To visualize peritoneum metastases (peritonitis)
and micro-metastasis of neoplasm which cannot bechecked in naked eye, and apply it to an operation or
the determination of a medical treatment plan. To

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
medicineastranslational research, selection of drug targets byproteomics,
interpretationoftranscriptional
regulations and drug development by targetingtranscription factors in cardiovascular diseases(arteriosclerosis, cardiac hypertrophy, cardiac failure,473etc.). Other analyses and development are also quite
active, such as creation of transgenic animals,
analyses of genomic functions, clinical safety
monitoring by clinical database and assessments ofclinical information systems.
Surgical Robot System Lab.
Robotics, Dynamics, and Control Laboratory
Department of Mechano-Informatics
University of Tokyo
Development of motion synchronization technology
for in-vivo molecular imaging of small animals, basedon robot systems for endoscopic cardiac surgery.
Neuro-musculo-skeletal model and its parameter
identification for diagnosis and rehabilitation ofneuromuscular disorders.
Vascular Biomebical Engineering Laboratory
Department of Vascular Surgery
Department of Tissue Engineering, The University ofTokyo Hospital
Bio-Medical Precision Engineering Laboratory,
Department of Precision Engineering , The Universityof Tokyo
Development of minimally invasive diagnostic andtherapeutic technologies for vascular surgery throughcollaboration research.
Orthopedic clinical biomechanics laboratory
The Department of Orthopaedic Surgery, The
University of Tokyo.
Graduate School of Information Science andTechnology, The University of Tokyo.
To develop a non-invasive method for predicting bonestrength by finite element method analysis.
To develop a new method for evaluation of fracture
healing by echo tracking.
To develop a non-invasive method for morphologicalevaluation.
Minimally invasive cardiac surgery with the
integral videography system
Department of Cardiothoracic Surgery, Graduate
School of Medicine, University of Tokyo
Advanced Therapeutic and Rehabilitation Engineering
Laboratory, Department of Mechano-Informatics,
Graduate School of Information Science andTechnology, University of TokyoTo
develop:real-time
three-dimensional
echocardiography, suture device with liner probe,
integral videography, and minimal invasive cardiac
surgery monitored by real-time three-dimensional
echocardiography without cardiopulmonary bypass
Division of eutron Capture Therapy &Immunotherapy for Cancer
Department of Cardiothoratic Surgery, Graduate /School of Medicine
Department of Radiology, University of Tokyo
Hospital
Department of Quantum Engineering and System
Science, School of Engineering
Department of uclear Engineering and Management,
School of Engineering
Research Center for Advanced Science & Technology
Endowment
Department,
Department
ofImmunotherapeutics (Medinet)
In order to control and eliminate human cancers, wedevelop the neutron capture therapy (BNCT) using
small neutron accerelator equipped to hospital andalso develp more effective immumotherapeutic
approaches.
Molecular Imaging Laboratory, Cooperative Unitof Medicine, Engineering and Pharmaceutical
ReserchTetsuo agano, Laboratory of Chemistry and Biology,
Graduate School of Pharmaceutical Sciences
Yasunobu Hirata, Department of Cardiovascular
Medicine
To develop chemical probes for imaging of
biomolecules To elucidate mechanisms and toestablish cures of arteriosclerosis
Laboratory of Artificial Organs
Division of Artificial Organs & Transplantation:
Katsutoshi aruse and Lei Guo
Institute of Industrial Science and Center for Disease
Biology and Integrative Medicine, Graduate School of
Medicine: Yasuyuki Sakai
Laboratory of Artificial Organs consists of researchers
belonging to Division of Artificial Organs &Transplantation, and Sakai Laboratory. We have beencollaborating in the research of bioartificial liver474

support systems in the past 10 years. Our current
specialization is, development of artificial liver
support, clinical use of new apheresis therapy,
development of transgenic pig producing humanserum albumin, and development of implantable livertissue equivalents.

We are developing multi-scale, multi-physics heart
simulator for the in-silico diagnosis and treatment ofheart diseases by the synergistic effort of cellularphysiology and computational mechanics. For
collecting quantitative data for the simulator,
mechanical analysis of cardiomyocytes is performed.

Laboratory of Applied Metabolic Biotechnology
Department of Cardiovascular Medicine, Graduate
School of Medicine
Department of Metabolic Diseases, Graduate Schoolof Medicine
Department of Chemistry and Biotechnology, Schoolof Engineering
To establish the system and methods for engineering
the novel model mice of life style-related diseases
using RNAi technology and biotechnology. To
elucidate the mechanisms by which adipose tissue
derived factors, adipokines, contribute to thedevelopment of the metabolic syndrome. To explore
the signal transduction pathways of major adipokines
including adiponectin

Laboratory of Hard-Tissue anomedicine
Kataoka & Yamasaki Lab, Department of Materials
Science, Graduate School of Engineering, The
University of Tokyo
Department of ″Menicon″ Cartilage & BoneRegeneration, Graduate School of Medicine, The
University of Tokyo
Department of Bone & Cartilage Regenerative
Medicine, Graduate School of Medicine, The
University of Tokyo
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo Department of Oraland Maxillofacial Surgery, Faculty of Medicine, The
University of Tokyo
Division of Clinical Biotechnology, Center for Disease
Biology and Integrative
Medicine, Graduate School of Medicine, The
University of Tokyo
Division of Tissue Engineering, The University ofTokyo Hospital
Development of a non-viral gene delivery system bysupramolecular nanotechnology. Development of anon-viral siRNA delivery system by supramolecular
nanotechnology. Production of regenerated cartilage
and bone with high safety and usefulness .
Establishment of practical production and quality
control systems. Promotion of the clinical applicationof regenerated cartilage and bone. Development ofeasy, precise, non-invasive systems to detect
osteoblastic and chondroocytic differentiation.
Determination of a finite set of signaling factors
sufficient for induction of osteoblasts andchondrocytes. Development of a method to induce
osteogenesis and angiogenesis simultaneously .
Development of a cell-sheet culture system for bone
and cartilage. Screening for compounds that inducebone and cartilage regeneration

Laboratory of Biomaterial Science
Department of Orthopaedic Surgery, Faculty of
Medicine, The University of Tokyo
Ishihara & Takai Lab, Department of Materials
Science, Graduate School of Engineering, The
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

Cooperative Unit of Kataoka Laboratory andDepartment of Vascular Regeneration

475

Department of Vascular Regeneration, Division of
Tissue Engineering, The University of Tokyo Hospital
Kataoka Laboratory, Department of Materials Scienceand Engineering, Graduate School of Engineering,
The University of Tokyo
To achieve effective and safe in vivo gene therapy ofcardiovascular and vascular diseases, we aredeveloping non-viral gene vectors based on
nano-scaled polymer assemblies (polymeric micelles).
Polymeric micelles, which are spontaneously formed
from block copolymers, have a core containing
packaged genes surrounded by biocompatiblepoly(ethylene glycol) (PEG) palisades, and a varietyof pilot molecules can be installed on the surface ofpolymericmicelles.
This"virusmimicking"
nanoparticles might achieve efficient gene transfer tothe targeted tissues or cells because of protection of
the loaded DNA from nuclease attack, their lowered
non-specific interaction with proteins and cells andfacilitated internalization by the targeted cells throughspecific interaction of the pilot molecules. Currently,
our research has been focused on in vivo gene transfer
to artery walls and muscles using polymeric micelles
incorporated genes.

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Ueki K, Kadowaki T: Rimonabant ameliorates
insulin resistance via both adiponectin-dependentand adiponectin-independent pathways. J.Biol.
Chem. 284: 1803-1812, 2009
23. Kurabe N, Arai S, Nishijima A, Kubota N, Suizu F,
Mori M, Kurokawa J, Miyazaki MK, Ide T,
Murakami K, Miyake K, Ueki K, Koga H, 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
24. Nishimura S, Manabe I, Nagasaki M, Eto K,
Yamashita H, Ohsugi M, Otsu M, Hara K,Ueki K,
Sugiura S, Yoshimura K, Kadowaki T, Nagai R :CD8+ effector T cells contribute to macrophage
recruitment and adipose tissue inflammation in
obesity. Nature Medicine 15: 914-920, 2009
25. Takazawa T, Yamauchi T, Tsuchida A, Takata M,
Hada Y, Iwabu M, Okada-Iwabu M, Ueki K,
Kadowaki T,: Peroxisome proliferator-activatedreceptor gamma agonist rosiglitazone increases
the expression of very low density lipoprotein
receptor gene in adipocytes. J.Biol.Chem. 30:
30049-30057, 2009
26. Matsuda S, Mikami Y, Ohtani M, Fujiwara M,
Hirata Y, Minowa A, Terauchi Y,Kadowaki T,
Koyasu S: Critical role of class IA PI3K for c-Rel
expression in B lymphocytes. Blood 113: 10371044, 2009
27. Igarashi M, Osuga JI, 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 neutral

477cholesterol ester hydrolase to the endoplasmic
reticulum via its N-terminal sequence. J. Lipid
Res. 51: 274-285, 2009
28. Kadowaki T, Yamauchi T, Kubota N, Fujisawa T,
Nakagama H, Nakajima A, Terauchi Y, Ueki K:
Role of adiponectin and its receptors in
obesity-linked insulin resistance and metabolic
syndrome. Metabolic Syndrome: Carcinogenesis
and Prevention 91-96, 2009
29. Kambara H., Yamazaki T., Hayashi D., Kohro T.,
Okada Y., Nagai R.and The JCAD Study
Investigators Gender Differences in Patients
With Coronary Artery Disease in Japan The
Japanese Coronary Artery Disease Study (TheJCAD Study) Circ J 73(5); 912-917,2009
30. Tanaka Y., Daida H., Imai Y., Miyauchi K., SatoY., Hiwatari M., Kitagawa A., Kishimoto J.,
Yamazaki T., Kawamori R.
Morning home
blood pressure may be a significant marker ofnephropathy in Japanese patients with type 2
diabetes: ADVANCED-J study 1 Hypertens R
32; 770-774,2009
31. Uchiyama S., Goto S., Matsumoto M., Nagai R.,
Origasa H., Yamazaki T., Shigematsu H., Shimada
K., Yamada N., Bhatt DL., Steg PG., Ikeda Y. on
behalf of the REACH Registry Investigators
Cardiovascular event rates in patients withcerebrovascular disease and atherothrombosis atother vascular locations: Results from 1-year
outcomes in the Japanese REACH Registry J
Neurol Sci 15;287(1-2):45-51,2009
32. Kaku K., Daida H., Kashiwagi A., Yamashina A.,
Yamazaki T., Momomura S., Iwase T., Yamasaki
Y., Nagatsuka K., Kitagawa K., Kawamori R.:
Long-term effects of pioglitazone in Japanesepatients with type 2 diabetes without a recent
history of macrovascular morbidity Current
Medical Research & Opinion 25:2925-2932,2009
33. Yamazaki T., Kurabayashi M., and the ASTRO-1
Study Group. A Randomized Controlled Studyto Compare the Effects of Rosuvastatin 2.5mg andPravastatin 10mg on the Plasma Lipid Profile inJapanese Patients with Hypercholesterolemia
ASTRO-1) Annals of Vascular Diseases(2,3):148-158,2009
34. Yamazaki T., Kurabayashi M., and the ASTRO-2
Study Group. A Randomized Controlled Studyto Compare the Effects of Rosuvastatin 5mg andAtorvastatin 10 mg on the Plasma Lipid Profile inJapanese Patients with Hypercholesterolemia(ASTRO-2) Annals of Vascular Diseases(2,3):159-173,2009
35. 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
36. Kohro T., Yamazaki T. Cardiovascular clinical
trials in Japan and controversies regarding
prospective randomized open-label blinded
end-point design Hypertens Res 32: 109-114,
2009
37. Kohro T., Yamazaki T.
Mechanism ofstatin-induced myopathy investigated using
microarray technology J of Atherosclerosis andThrombosis 16: 30-32, 2009
38. Kohro T., Yamazaki T. Eicosapentaenoic acid
(EPA) in reducing secondary cardiovascular
events in hypercholesterolemic Japanese patients
Circ J 73(7): 1197-1198, 2009
39. Yoshinori Iizuka, Masahiko Munechika, Satoko
Tsuru: Quality Approach to Healthcare Fundamentals -, Proceedings of 53rd EOQCongress, scientific paper total 8p, CD-ROM,
2009
40. Satoko Tsuru, Yoshinori Iizuka, Masahiko
Munechika: A Framework for Structured ClinicalKnowledge - PCAPS, Proceedings of 53rd EOQCongress, scientific paper total 8p, CD-ROM,
2009
41. Shogo Kato, Satoko Tsuru, Yoshinori Iizuka : A
Model for Preventing Accidental Falls in
Hospitals -Management Plan for Each Individual
Patient- , Proceedings of the 7th Asian Network
for Quality Congress, scientific paper 477-486,
2009
42. Misako Harada, Shogo Kato, Satoko Tsuru,
Yoshinori Iizuka : Designing PCAPS Regional
Healthcare Cooperation Model for Cancer
Treatment, Proceedings of the 7th Asian Network
for Quality Congress, scientific paper 875-884,
2009
43. Satoko Tsuru, Yoshinori Iizuka, Masahiko
Munechika:
Structuring
ClinicalNursing
Knowledge using PCAPS :Patient Condition

478

Adaptive path System, Proceedings of NI2009(Connecting Health and Humans IOS-Press ISBN
978-1-60750-024-7), scientific paper 391-395,
2009
44. Shogo Kato, Satoko Tsuru, Yoshinori Iizuka :Framework for Preventing Accidental Falls in
Hospitals - Management Plan for ADL,
Medication, and Medical Conditions - ,Proceedings of NI2009(Connecting Health andHumans IOS-Press ISBN 978-1-60750-024-7),
scientific paper 450-454, 2009
45. Ryoko Shimono, Satoko Tsuru, Yoshinori Iizuka,
Shogo Kato, Masahiko Munechika : The Mapping
Model of Employee on Hospital job Based onCompetence, Proceedings of the 7th Asian
Network for Quality Congress, 922-928, 2009
46. Ryoko Shimono, Satoko Tsuru, Yoshinori Iizuka,
Shogo Kato, Masahiko Munechika, Masaaki
Kaneko: A Method to Improve a Job Process at a
Hospital Using the "Unit Process Flow Chart",
Proceedings of NI2009(Connecting Health andHumans IOS-Press ISBN 978-1-60750-024-7),
scientific paper 15-19, 2009
47. Du D, Furukawa KS, Ushida T,3D culture ofosteoblast-like cells by unidirectional oroscillatory flow for bone tissue engineering,
Biotechnol.and Bioeng., 102(6): 1670-1678(2009)
48. Du D, Furukawa KS, Ushida T, Oscillatory
perfusion culture of CaP-based tissue engineeringbone with and without dexamethasone, Ann. of
Biomed.Eng., 37(1): 146-155 (2009)
49. Furukawa KS, Seki S, Hirano Y, Miki H,
Mizuhara K, Yamane T, Tateishi T, Ushida T,
Real-time evaluation of hemocompatible materials
by human platelets as an alternative to animal
experimentation, AATEX J., 14(2),879-886 (2009)
50. Miyata K, Gouda N, Takemoto H, Oba M, Lee Y,
Koyama H, Yamasaki Y, Itaka K, Nishiyama N,
Kataoka K. Enhanced transfection withsilica-coated polyplexes loading plasmid DNA.
Biomaterials. Epub 2010 Mar 20.
51. Oba M, Vachutinsky Y, Miyata K, Kano MR,
Ikeda S, Nishiyama N, Itaka K, Miyazono K,
Koyama H, Kataoka K. Antiangiogenic genetherapy of solid tumor by systemic injection ofpolyplex micelles loading plasmid DNA encoding

soluble flt-1. Mol Pharm. 2010; 7(2):501-509.
52. Vachutinsky Y, Oba M, Miyata K, Hiki S, Kano
MR, Nishiyama N, Koyama H, Miyazono K,
Kataoka K. Antiangiogenic gene therapy ofexperimental pancreatic tumor by sFlt-1 plasmid
DNA carried by RGD-modified crosslinked
polyplex micelles. J Control Release. 2010
53. Takayama T, Taguchi T, Koyama H, Sakari M,
Kamimura W, Takato T, Miyata T, Nagawa H.
The growth of a vascular network inside acollagen-citric acid derivative hydrogel in rats.
Biomaterials. 2009, 30(21):3580-3587.
54. Hashimoto T, Koyama H, Miyata T, Hosaka A,
Tabata Y, Takato T, Nagawa H. Selective andsustained delivery of basic fibroblast growth
factor (bFGF) for treatment of peripheral arterial
disease: results of a phase I trial. Eur J Vasc
Endovasc Surg. 2009 ;38:71-75.
55. Katsu M, Koyama H, Maekawa H, Kurihara H,
Uchida H, Hamada H. Ex vivo gene delivery ofephrin-B2 induces development of functional
collateral vessels in a rabbit model of hind limb
ischemia. J Vasc Surg. 2009;49:192-198.
56. Matsumoto S, Christie RJ, Nishiyama N, Miyata
K, Ishii A, Oba M, Koyama H, Yamasaki Y,
Kataoka K.
Environment-responsive block
copolymer micelles with a disulfide cross-linked
corefor
enhanced
siRNA
delivery.
Biomacromolecules. 2009 ;10:119-127.
57. M. Kumagai, M. R. Kano, Y. Morishita, M. Ota, Y.
Imai, N. Nishiyama, M. Sekino, S. Ueno, K.
Miyazono, K. Kataoka, Enhanced magnetic
resonance imaging of experimental pancreatictumor in vivo by block-copolymer-coatedmagnetite nanoparticles with TGF-beta inhibitor. J.
Control. Release 140 (3) 306-311 (2009)
58. M. Zhang, A. Ishii, N. Nishiyama, S. Matsumoto,
T. Ishii, Y. Yamasaki, K. Kataoka, PEGylated
calcium phosphate nanocomposites as smart
environment-sensitive carriers for siRNA delivery.
Adv. Mater. 21 (34) 3520-3525 (2009)
59. M. Han, M. Oba, N. Nishiyama, M.R. Kano, S.
Kizaka-Kondoh,K.
Kataoka,Enhancedpercolation and gene expression in tumor hypoxia
by PEGylated polyplex micelles. Mol. Ther. 17(8) 1404-1410 (2009)
60. Y. Lee, T. Ishii, H. Cabral, H. -J. Kim, J. -H. Seo,

479

N. Nishiyama, H. Oshima, K. Osada, K. Kataoka,
Charge-conversional polyionic complex micellesefficient nanocarriers for protein delivery intocytoplasm. Angew. Chem. Int. Ed. 48 (29) 53095312 (2009)
61. M. Harada-Shiba, I. Takamisawa, K. Miyata, T.
Ishii, N. Nishiyama, K. Itaka, K. Kangawa, F.
Yoshihara, Y. Asada, K. Hatakeyama, N. Nagaya,
K. Kataoka, Intratracheal gene transfer ofadrenomedullin using polyplex nanomicelles
attenuates monocrotaline-induced pulmonary
hypertension in rats. Mol Ther. 17 (7) 1180-1186(2009)
62. W. Wang, K. Itaka, S. Ohba, N. Nishiyama, U.
Chung, Y. Yamasaki, K. Kataoka, 3D spheroid
culture system on micropatterned substrates for
improved differentiation efficiency of multipotent
mesenchymal stem cells. Biomaterials 30 (14)2705-2715 (2009)
63. N. Nishiyama, Y. Nakagishi, Y. Morimoto, P.-S.
Lai, K. Miyazaki, K. Urano, S. Horie, M.
Kumagai, S. Fukushima, Y. Cheng, W.-D. Jang, M.
Kikuchi, K. Kataoka, Enhanced photodynamic
cancer treatment by supramolecular nanocarriers
charged with dendrimer phthalocyanine. J.
Control. Release 133 (3) 245-251 (2009)64. H. Cabral, M. Nakanishi, M. Kumagai, W.-D.
Jang,
N.
Nishiyama,K.
Kataoka,A
photo-activated targeting chemotherapy using
glutathione
sensitive
camptothecin-loaded
polymeric micelles. Pharm. Res. 26 (1) 82-92(2009)
65. A. Kishimura, S. Liamsuwan, H. Matsuda, W. -F.
Dong, K. Osada, Y. Yamasaki, K. Kataoka,
pH-Dependent permeability change and reversible
structural transition of PEGylated polyion
complex vesicles (PICsomes) in aqueous media.
Soft Matter 5 (3) 529-532 (2009)
66. S. Matsumoto, R. J. Christie, N. Nishiyama, K.
Miyata, A. Ishii, M. Oba, H. Koyama, Y.
Yamasaki, K. Kataoka, Environment-responsive
block copolymer micelles with a disulfide
cross-linked core for enhanced siRNA delivery.
Biomacromolecules 10 (1) 119-127 (2009)
67. Katsu Yamane, Akihiko Murai, Sadahiro Takaya,
and Yoshihiko Nakamura, “Muscle Tension
Database for Contact-Free Estimation of Human

Somatosensory Information,” Proc. of IEEE
International Conference on Robotics andAutomation, pp.633-638, 12-17 May 2009.
68. Gentiane Venture, Ko Ayusawa, and YoshihikoNakamura, “Realtime Identification Software for
Human Whole-Body Segment Parameters Using
Motion Capture and its Visualization Interface,”
Proc. of IEEE International Conference on
Rehabilitation Robotics, pp.109-114, June 23-26,
2009.
69. Gentiane Venture, Ko Ayusawa, and YoshihikoNakamura,"Real-Time
Identification
andVisualization of Human Segment Parameters"
Proc. of 31st Annual International Conference ofIEEE Engineering in Medicine and Biology
Society, pp.3983-3986, September 4-6, 2009.
70. Gentiane Venture, Ko Ayusawa, Dana Kulic, andYoshihiko Nakamura, “Monitoring the Segment
Parameters During Long Term Physical Training
from Motion Capture Data," Proc. of 31st Annual
International Conference of IEEE Engineering in
Medicine and Biology Society, pp 5247-5250,
September 4-6, 2009.
71. Akihiko Murai, Yamane Katsu, and YoshihikoNakamura, "Characterization of Motor Skill
Based on Musculoskeletal Model," Proc. of 31st
Annual International Conference of IEEE
Engineering in Medicine and Biology Society,
September 4-6, 2009.
72. Akihiko Murai, Kosuke Kurosaki, Yamane Katsu,
and Yoshihiko Nakamura, "Computationally Fast
Estimation of Muscle Tension for Realtime
Bio-feedback," Proc. of 31st Annual International
Conference of IEEE Engineering in Medicine andBiology Society, pp. 6546-6549, September 4-6,
2009.
73. Gentiane Venture, Ko Ayusawa, YoshihikoNakamura, "Optimal Estimation of Human Body
Segments Dynamics Using Realtime VisualFeedback," Proc. of IEEE/RSJ International
Conference on Intelligent Robots and Systems,
pp.1627-1632, St. Louis, USA, October 11-15,
2009.
74. 2009 講演論文集, 1A1-M04, 2009.
75. Nicholas Herlambang, Hiromasa Yamashita,
Hongen Liao, Ken Masamune, Takeyoshi Dohi:
Realtime Integral Videography Auto-stereoscopic

480

Surgery Navigation System using Intra-operative
3D Ultrasound: System Design and In-vivo
Feasibility Study, Proceedings of 5th Workshop
on Augmented Environments for Medical Imaging
including Augmented Reality in Computer-Aided
Surgery(AMI-ARCS2009,
London,UK,
September 24, 2009), pp. 61-68, 2009
76. Ken Masamune, Tetsuya Horiuchi, Masahiro
Mizutani,
Hiromasa
Yamashita,
Hiroyuki
Tsukihara, Noboru Motomura, Shinichi Takamoto,
Hongen Liao, Takeyoshi Dohi: Novel Endoscope
System with Plasma Flushing for Off-Pump
Cardiac Surgery, Medical Image Computing andComputer-Assisted Intervention - MICCAI 2009,
12th International Conference London, UK,
September 2009 Proceedings, Part I, Lecture
Notes in Computer Science 5761, pp. 451-458,
2009
77. T. Horiuchi, K. Masamune, H. Yamashita, H.
Tsukihara, S. Takamoto, H. Liao, T. Dohi:
Endoscope system with plasma flushing andseparator for off-pump cardiac surgery, World
Congress on Medical Physics and Biomedical
Engineering (WC 2009), IFMBE Proceedings
25/VI, pp. 324-327, September 2009
78. Ohnishi I. Matsuyama J. Bone fracture and thehealing mechanisms. A new method for evaluationof fracture healing by echo tracking. ClinicalCalcium. 19(5):682-90, 2009
79. Ohnishi I. Prediction of vertebral strength using a
CT based finite element method--clinicalapplication in evaluation of the efficacy ofalendronate. Nippon Rinsho - Japanese Journal of
Clinical Medicine. 67(5):932-7, 2009
80. Matsumoto T. Ohnishi I. Bessho M. Imai K.
Ohashi S. Nakamura K. Prediction of vertebral
strength under loading conditions occurring in
activities of daily living using a computed
tomography-based nonlinear finite element
method. Spine. 34(14):1464-9, 2009.
81. Bessho M. Ohnishi I. Matsumoto T. Ohashi S.
Matsuyama J. Tobita K. Kaneko M. Nakamura K.
Prediction of proximal femur strength using a
CT-based nonlinear finite element method:
differences in predicted fracture load and site withchanging load and boundary conditions. Bone.
45(2):226-31, 2009 Aug.

82. Imai K. Ohnishi I. Matsumoto T. Yamamoto S.
Nakamura K. Assessment of vertebral fracturerisk and therapeutic effects of alendronate inpostmenopausal women using a quantitative
computed tomography-based nonlinear finite
element method. Osteoporosis International.
20(5):801-10, 2009.
83. Low O2 metabolism of Hep G2 cells cultured athigh cell density in a 3D microstructured scaffolds
C. Provin, K. Takano, T. Yoshida, Y. Sakai, T.
Fujii and R. Shirakashi Biomed. Microdev., 11(2),485-494 (2009).
84. Spontaneous formation of highly functional
three-dimensional multilayer from humanhepatoma Hep G2 cells cultured on an
oxygen-permeable
polydimethylsiloxane
membrane F. Evenou, T. Fujii, and Y. Sakai Tissue
Engineering Part C: Methods, 16(2):311-318(2010).
85. Study of on-chip individual embryo coculture
withmicroporous
membranesupported
endometrial cells Hiroshi Kimura, Hiroko
Nakamura, Tomonori Akai, Takatoki Yamamoto,
Hideshi Hattori, Yasuyuki Sakai, Teruo Fujii IEEE
Trans. anoBiosci., 8(4), 318-324 (2010).
86. Simultaneous evaluation of toxicities using a
mammalian cell array chip prepared byphotocatalytic lithography K. Komori, Jun Nada,
Masaki Nishikawa, Hideo Notsu, Tetsu Tatsuma,
Yasuyuki Sakai Analytica Chimica Acta, 653,
222-227 (2009).
87. A micropatterned cell array with an integrated
oxygen-sensitive fluorescent membrane Kevin
Montagne, Kikuo Komori, Fei Yang, Tetsu
Tatsuma, Teruo Fujii and Yasuyuki Sakai
Photochemical & Photobiological Science, 8,1529-1533 (2009).
88. Modeling of Reaction and Diffusion Processes ina High-Surface-Area Biofuel Cell Electrode Madeof Redox Polymer-Grafted Carbon Takanori
Tamaki, Taichi Ito, Takeo Yamaguchi, Fuel Cells,2009(9)37-43
89. A New Free Volume Theory Based on
Microscopic Concept of Molecular Collisions for
Penetrant Self-diffusivity in Polymers Hidenori
Ohashi, Taichi Ito, Takeo Yamaguchi, Journal ofChemical Engineering of Japan, 2009(42)86-96

481

90. Evaluation of Immobilized Enzyme in a
High-Surface-Area Biofuel Cell Electrode Madeof
Redox-Polymer-Grafted
CarbonBlack
Takanori Tamaki, Atsushi Hiraide, Faizly B.
Asmat, Hidenori Ohashi, Taichi Ito,
Takeo
Yamaguchi Industrial & Engineering Chemistry
Research 2010(49)6394-6398
91. Isolation and Analysis of a Grafted Polymer ontoa Straight Cylindrical Pore in a ThermalResponsive Gating Membrane and Elucidation of
its Permeation Behavior Hidenori Kuroki,
Hidenori Ohashi, Taichi Ito, Takanori Tamaki,
Takeo Yamaguchi Journal of Membrane Science2010(352)22-31
92. Sensitivity enhancement of a molecular
recognition ion gating membrane in an aqueous
ethanol solution Taichi Ito, Yuhei Oshiba,
Hidenori Ohashi, Takanori Tamaki, Takeo
Yamaguchi Journal of Membrane Science2010(348)369-375

482

Medical Specialists Training Center(newly established)
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

484

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, 53 pharmacy staffs, 33
pharmacy residents, and 19 graduate students and 5
undergraduate students from the faculty ofpharmaceutical sciences (as of December 1st, 2009).
In addition, project associate professor (Akihiro
Hisaka,Ph.D.)
fromPharmacology
andPharmacokinetics department, and project research
associate (Shogo Miura, Ph.D.) from Cancer
Professional Training Plan are involved in our work.

Clinical activities
Department of Pharmacy consists of the following
six sections:1) Drug information and research section
This section offers drug information for questions
from the medical person, executes and supports
the medicine management to inpatients. In
addition, the section prepares materials forpharmaceutical affair committee, where each
medicine is discussed whether it should be
adopted or deleted. Preparation of several
periodicals regarding drug information forclinicians is also included.
2) The dispensing sectionAfterinspecting
allprescriptionsforcontraindications or improper use, medications
are dispensed. Drug information is given to
outpatients from this section, using a private room
if necessary. The computerized order system islinked with automatic packaging machines fororal medicines, automatic dispensing system andbar code label printer for injection drugs.
3) Pharmaceutical section
This section sterilizes formulations of apharmaceutical such as injection medicines,
instillation medicines and decontaminatingchemicals. They prepare capsule medicines,
ointment medicines, suppositories, central vein
nutrition (IVH) for inpatients and in-home carepatients. After strict inspection of prescriptions,they also dispense anti- malignant tumor medicine(database is constructed based on the submitted
protocols and the patient information). In order tosupport advanced medical care, they develop andcheck formulations (characterization of theuniformity, stability and so on) of the medicine
which is quite necessary for certain patients, but is
not marketed.
4) Drug matters and drug management section
Drug matter section manages the adoption of
medical supplies (in-hospital and out-hospital),
periodically reconsiders the adopted medicines,
and also manages the accountings of all the
medicines and other materials used in our485

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. 2,270 items), out-patient medicines,
anesthetics, muscle relaxation drugs, psychotropic
drugs, poison medicines.
5) Nacrotic section
Under the supervision of authorized manager fornarcotics (the director of the pharmacy
department), narcotics are properly managed,
recorded, reported, inspected and directed.
Nacrotics are properly arranged and managed at
the dispensing section and each medical caresection.
6) Ward section
They contribute to the team medical care byproviding specialized drug information andsharing them with all the staffs involved in thetreatment as follows;① Supporting the proper use of medication bypharmacists stationed at 1st and 2nd ICU section.
② Arrangement and mixing of injections forpatients at the staff station of Hematology andOncology.
③ Investigation of carrying medicines and the side
effect histories, allergy histories etc. at the timeof hospitalization. Participation for conferences.
Procurement and appraisal of patient’s basic
information about the disease, compilation of
the medicine history. Monitoring of medication
guidance and the side effect for the patient, andcompilation of guidance record. Offering thedoctor with drug information, prescription
design support and detailed contents ofmedication guidance to each patient.
④ Investigation and management of ward stock
medicine.
⑤ Nutrient support of the patients as a member of
NST.
⑥ Management of proper use of narcotics as amember of palliative care team.
⑦ Management of proper use of antibiotics,
rounds of a hospital ward, and training of thestaffs as a member of ICT.

Statistical Data (fiscal year 2009)
Number of items on in-hospital formulary: 2,270
Number of prescriptions (ps.) filled or preparation(pp.) (annual)out-patients:
478,410 ps.
(outside :394,964 ps.)(inside :83,446 ps.)out-patient chemotherapy:
6,694 ps.
in-patients:
210,719 ps.
injection drugs:
220,452 ps.
IVH:
13,635 pp.
chemotherapy:
11,616 pp.
TDM consultations (annual) :8,911
Numbers of hospital pharmaceutical cares (annual):
3,641

Educational Activities
The department of pharmacy takes various
responsibilities of education with regard to clinicalpharmacy, pharmacology, and pharmacokinetics forstudents and graduate students in the faculty of
medicine, in the faculty of pharmacy, and in theschool of health sciences and nursing. We also have
our own one-year post-graduate training course
optimized for new pharmacists.
For students in the faculty of medicine, we are in
charge of "Pathogenetic and Pathology" as an optionalcourse lecture. We are providing a free quarter
practice course for some M1 and M2 students for 2
weeks and teach basic molecular and biochemical
techniques as well as the pharmacokinetic theory tothem. We are providing a 3-days practice course as apart of compulsory clinical practice for the M3 andM4 students and teach clinical pharmaceutics andpractical knowledge of prescription and risk
management to them. For the students in the healthsciences and nursing, we are in charge of clinicalpharmacokinetics lectures as a part of a compulsory
subject, "Pharmacology and Toxicology".
For students in the faculty of pharmacy, we are in
charge of two series of lectures for the undergraduate
students: "Clinical Pharmacy I" (compulsory subject)and "Clinical Pharmacy II" (an optional course).
They are educated for the clinical pharmacology andpharmacokinetics. For the graduate students, we arein charge of "Advanced Course of Medical Pharmacy"486(every other year) as a cooperator of the ClinicalPharmacokinetic. Recent trends of the medical
pharmacy as well as the practical developments andfuture visions of the department of pharmacy arepresented in this lecture. We are responsible for thehospital practice courses (10 days in total) and teachpractical techniques of pharmacists such as drug
preparations and patient consultation. In addition tothese, we educate 4th year students and graduate
students who moved to the Clinical Pharmacokinetics.
In 2009, 33 pharmacists completed our one-year
post-graduate training course. They learned various
practical knowledge and techniques necessary for
hospital pharmacists. This education style is agroundwork of long-term practice for 6-year course
students in the faculty of pharmacy which will start in2010.
In addition, we are promoting life-long
education of pharmacists in the local area by holding
regular technical workshop.

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
andpredictionofpharmacological-effect 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 toprevent / treat the side effect.
5. Absolute quantification of factors determining thepharmacokinetic profiles of drugs and its application
to clinical pharmacokinetics and pharmacology 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
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) Ikebuchi Y, Takada T, Ito K, Yoshikado T, Anzai
N, Kanai Y and Suzuki H (2009) Receptor for
activated C-kinase 1 regulates the cellular
localization and function of ABCB4. Hepatol Res
39(11):1091-1107.
(2) Kariya Y, Honma M, Aoki S, Chiba A and Suzuki
H (2009) Vps33a mediates RANKL storage insecretory lysosomes in osteoblastic cells. J Bone
Miner Res 24(10):1741-1752.
(3) Koh S, Takada T, Kukuu I and Suzuki H (2009)
FIC1-mediated stimulation of FXR activity isdecreased with PFIC1 mutations in HepG2 cells.
J Gastroenterol 44(6):592-600.
(4) Kozawa M, Honma M and Suzuki H (2009)
Quantitative prediction of in vivo profiles of
CYP3A4 induction in humans from in vitro
results with a reporter gene assay. Drug Metab
Dispos 37(6):1234-1241.
(5) Hisaka A, Kusama M, Ohno Y, Sugiyama Y and
Suzuki H (2009) A proposal for a
pharmacokinetic
interaction
significanceclassification system (PISCS) based on predicted
drug exposure changes and its potential
application to alert classifications in productlabelling. Clin Pharmacokinet 48(10):653-666.

1. Elucidation of the molecular mechanism which
controls in vivo disposition of lipids / bile acids / theuric acid, and establishment of new therapy forlife-style related diseases based on those integrated

487(6) Li T, Ito K, Sumi S, Fuwa T and Horie T (2009)
Protective effect of aged garlic extract (AGE) on
the apoptosis of intestinal epithelial cells causedby methotrexate. Cancer Chemother Pharmacol
63(5):873-880.
(7) Matsuo H, Takada T, Ichida K, Nakamura T,
Nakayama A, Ikebuchi Y, Ito K, Kusanagi Y,
Chiba T, Tadokoro S, Takada Y, Oikawa Y, Inoue
H, Suzuki K, Okada R, Nishiyama J, Domoto H,
Watanabe S, Fujita M, Morimoto Y, Naito M,
Nishio K, Hishida A, Wakai K, Asai Y, Niwa K,
Kamakura K, Nonoyama S, Sakurai Y, Hosoya T,
Kanai Y, Suzuki H, Hamajima N and Shinomiya
N (2009) Common Defects of ABCG2, a
High-capacity Urate Exporter, Cause Gout: A
Function-based Genetic Analysis in a Japanese
Population. Science Translational Medicine
1(5ra11):41-48.
(8) Minami S, Ito K, Honma M, Ikebuchi Y, Anzai N,
Kanai Y, Nishida T, Tsukita S, Sekine S, Horie T
and Suzuki H (2009) Posttranslational regulationof Abcc2 expression by SUMOylation system.
Am J Physiol Gastrointest Liver Physiol 296(2):G406-413.
(9) Nakano T, Sekine S, Ito K and Horie T (2009)
Correlation between apical localization of
Abcc2/Mrp2 and phosphorylation status of ezrin
in rat intestine. Drug Metab Dispos 37(7):1521-1527.
(10) Yamanashi Y, Takada T and Suzuki H (2009)
In-vitro characterization of the six clusteredvariants of NPC1L1 observed in cholesterol low
absorbers. Pharmacogenet Genomics 19(11):884892.
(11) Takada T, Suzuki H (2009) Mechanisms ofregulation of bile acid transport in the small
intestine. “Bile Acid Biology and Therapeutic
Actions” (edited by D Keppler, U Beuers, A
Stiehl and M Trauner, Springer).

Center for Disease Biology andIntegrative Medicine

489

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

490

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:
479-492 (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

491

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
short-chain fatty acid mediated reversed globin
gene switch 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.,
Kondo-Miyazaki, M., Ide, T., Murakami, K.,
Miyake, K., Ueki, K., Koga, K., Yatomi, Y.,
Tashiro, F., Noguchi, M., Kadowaki, T., &Miyazaki, T. The death effector domaincontaining 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. atl. 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
NF-ATc1 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

492

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. atl. 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. ature 345: 722-724 (1990).

493

Laboratory ofStructural Physiology
Professor
Haruo Kasai, M.D.,Ph.D.

Associate Professor
Masanori Matsuzaki, Ph.D.

Lecturer
Noriko Takahashi, M.D., Ph.D.

Research Associate
Jun Nogichi, Ph.D., Satoshi Watanabe, Ph.D.

Homepage

http://www.bm2.m.u-tokyo.ac.jp/

Introduction and Organization

Research activities

The Center for Disease Biology and Integrative
Medicine (CDBIM) has been established in 2003, andelected Dr. Kasai as the professor of the Division of
Basic Medical Sciences (2) of CDBIM in July of 2004.
Dr. Kasai was in the National Institute forPhysiological Sciences at that time, and officially took
office in the University of Tokyo in November, 2005.
The Kasai laboratory has moved to the first buildingof Faculty of Medicine in January, 2006. Ourlaboratory belongs to the Section of Functional
Biology in the Graduate School of Medicine. The
name of our laboratory has been changed from
Division of Biophysics to Laboratory of Structural
Physiology in the April, 2008.

Functional imaging is a central theme in modern
biology and medicine. All biological functions involvea multitude of interactions at the molecular, cellular,
and system levels, and it is ultimately desirable toperform molecular and cellular imaging in intact
preparations in which the original in vivo functions
are preserved. We have been exploring two-photon
excitation microscopy with a new type of laser, an
infrared femtosecond-pulse laser, as a means toachieve this goal. The two-photon microscope has theability to penetrate deep into tissues and is the only
imaging instrument that allows investigations of intact
tissues at the cellular and molecular levels.
Two-photon microscopy can also be readily combinedwith molecular biological and other physiologicalmethods, and it promises to provide important insight
into various biological processes in the coming years.
Our research interests have two main focuses: (1) the
dynamics of synapses in the cerebral cortex and (2)exocytosis in both neurons and secretory cells. We
welcome multidisciplinary collaborations to promote
our research goals and to help to adapt the new
microscopic techniques and lasers to a wide range of

Teaching activities
In 2009, we were involved in undergraduate
education of Physiology. Particularly, we taught
endocrine physiology and was responsible for the
student experiments. We have 5 doctor and 3 mastercourse students.

494

biomedical applications.
1) Functional mapping is a crucial tool for assessing
the architecture, function, and plasticity of the motor
cortex. In such experiments, neurons within the cortex
are electrically stimulated, while the resulting
movements define the function of the stimulated
region. Since the pioneering work of Penfield, several
approaches have been employed for mapping motor
cortex. Intracortical microstimulation (ICMS) has
high spatial resolution but stimulating electrodepenetration damages cortical integrity. Epidural
microstimulation does not require insertion ofelectrodes into cortical tissue but does require
implantation of microelectrode arrays, yielding a fixed
number of stimulation points. Transcranial magnetic
stimulation is non-invasive, but lacks focality andspatial resolution. Thus, while all of these approaches
are effective ways to generate motor maps, each also
suffers from limitations.
Recent work demonstrates that neuronal activity
can be stimulated by the illumination of thelight-activated ion channelchannelrhodopsin-2 (ChR2).
ChR2-based photostimulation can give rise to safe andeffective excitation of mammalian central nervous
system neurons on a time scale of milliseconds. It has
been reported that such photostimulation can induce
limb and whisker movement, wakefulness, andperception in intact rodents expressing ChR2 inneurons. However, in these studies the devices used
for the illumination of ChR2 were fixed on the skull,
making it difficult to use such methods for mapping
because the location of the photostimulated area could
not be varied. In addition, in many cases
photostimulation was invasive, requiring light to bedelivered by an optical fibre that was inserted into thebrain or through a glass window in an opened skull.
Here, we describe the first non-invasive opticalstimulation method for cortical mapping, termed“transcranial optogenetic stimulation” (TOS), anddemonstrate how this method can be used toefficiently map the regions of the motor cortex
thatcontrol limb movement.
Wedevelopedamethodthat
uses
Channelrhodopsin-2(ChR2)
fortranscranial
optogenetic stimulation. This method is based onscanning a light beam over the brain, thereby

photostimulating ChR2-expressing neurons in intact
mice. As a proof of principle,we applied thistechnique to the motor cortex of transgenic miceexpressing ChR2 in cortical pyramidal cells.
Photostimulation induced limb movements that weretime-locked with millisecond precision and could be
induced at frequencies up to 20 Hz. By scanning thislight beam, we could map the distribution of neurons
associated with limb movement. With this approach
we could simultaneously define motor maps
controlling two limbs and could reproducibly generatesuch cortical motor maps over periods of weeks. Thismethod allows non-invasive mapping of brain
circuitry in living animals and could help define theconnection between behavior and brain circuitry. (Ref.
1).
2) We have synthesized a photosensitive (or caged)
4-carboxymethoxy-5,7-dinitroindolinyl(CDNI)
derivativeof
γ-aminobutyricacid(GABA).
Two-photon excitation of CDNI-GABAproduced
rapid activation of GABAergic currents in neuronsin
brain slices with an axial resolution of approximately
2 μm and enabled high-resolution functional mappingof GABA-Areceptors. Two-photon uncaging of
GABA, the main inhibitoryneurotransmitter, should
allow detailed studies of receptorfunction and synaptic
integration with subcellular precision. (Ref. 3).

References
1. Hira, R., Honkura, N., Noguchi, J., Maruyama, Y.,
Augustine, G.J., Kasai, H., & Matsuzaki, M.
Transcranial
optogenetic
stimulationforfunctional mapping of the motor cortex. J.
eurosci. Methods 2009;179:258-263.
2. Morita, S., Yasumatsu, N. Noguchi, J. & Kasai, H.
Generation, elimination and weight fluctuations ofsynapses in the cerebral cortex. Communicativeand Integrative Biology 2009; 2:1-4.
3. Matsuzaki, M. Hayama, T., Kasai, H. &Ellis-Davies, G.C.R. Two photon uncaging of
γ-aminobutyric acid probes on neurons in intact
brain tissue. ature Chemical Biology 2010; 6:
255-257.

495

Laboratory of Regenerative
Medical Engineering
Professor
Takashi Ushida, Ph.D.

Associate Professor
Taichi Ito, Ph.D.

Homepage

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

Introduction and Organization

at Graduate School of Engineering School.

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.

Research activities

Teaching activities
Prof. Ushida and Prof. Sakai are sharing duties forundergraduate and graduate students of both Graduate
School of Medicine and Graduate School ofEngineering. They give lectures on biomedical
engineering at Graduate School of Medicine. Prof.
Ushida has also lectures on tissue engineering,
advanced biomaterials and biomechanics at Graduate
School of Engineering. Prof. Sakai gives a lecture
concerning biosystem engineering at the Chemical
System Engineering course and Bioengineering course

Prof. Ushida’s laboratory aims to establish key
technologies for regenerative medicine. One of the
projects of our research targets the hard tissue
regeneration, such as cartilage or bone by tissue
engineering technology. Hard tissue engineering
requires the control of its shape in addition to the cell
accumulation and scaffold play a key role in meeting
this requirement. We focus on the development of
biocompatible materials such as synthetic polymer orinorganic materials combined with stem cellbiotechnology. Secondly, we try to elucidate
mechanisms of cellular responses to physicalstimulations such as hydrostatic pressure, shear stress,
stretch, through observing intracellular signaling, andto adopt those effects to tissue engineering.
1) Tissue engineering of cartilage or bone defect- Design and development of biocompatible materials
for cartilage or bone using synthetic polymer,
inorganic materials or those combination.
- Development of osteoinductive biomaterials
hybridized with bioactive substances.
- Order made shaping of scaffolds by router system
according to the graphical images of tissue defects- Establishment of vascular rich graft bed bybiomaterials that spur new blood vessel growth.
2) Cellular signal transduction induced by physical496

stimulations- Hydrostatic pressure loading to chondrocytes orarticular cartilage- Shear stress loading to endothelial cells- Stretch loading to endothelial cells, smooth muscle
cells

References

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.

2.

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,
especially using the hybrid model of cell automaton
and partial differential equations.

3.

1.
Du D, Furukawa KS, Ushida T,3D cultureof osteoblast-like cells by unidirectional oroscillatory flow for bone tissue engineering,
Biotechnol. and Bioeng., 102(6): 1670-1678(2009)Du D, Furukawa KS, Ushida T, Oscillatory
perfusion culture of CaP-based tissue engineeringbone with and without dexamethasone, Ann. of
Biomed. Eng., 37(1): 146-155 (2009)
Furukawa KS, Seki S, Hirano Y, Miki H,
Mizuhara K, Yamane T, Tateishi T, Ushida T,
Real-timeevaluation of hemocompatible
materials by human platelets as an alternative toanimal experimentation, AATEX J., 14(2),879-886 (2009)

4. Takanori Tamaki, Taichi Ito, Takeo, Yamaguchi,
Modeling of Reaction and Diffusion Processes in a
High-Surface-Area Biofuel Cell Electrode Made ofRedox Polymer-Grafted Carbon, Fuel Cells, 9,37-43 (2009)5.

Nobuo Hara, Hidenori Ohashi, Taichi Ito, Takeo
Yamaguchi, Rapid proton conduction throughunfreezable and bound water in a wholly aromaticpore-filling electrolyte membrane, Journal of
Physical Chemistry B, 113, 4656-4663 (2009)

497

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 theatomic/molecular level to produce units withsophisticated functions. Nanodevices produced bynanotechnology integrate materials and systems on ananometer scale, and hold the key to realizing thefuturistic medical system that can serve the needed
function at the right time and the right place withminimal invasiveness. Furthermore, nanodevices are
expected to become an important interface between
basic biomedical science and clinical medicine byfacilitating the translation of basic achievements into
clinical applications. Our division wishes to produce
revolutionary medical nanodevices based on
nanotechnology and thereby to spread the idea of"Nanomedicine" intranationally and internationally.

Teaching activities
Traditional medicine-engineering interdisciplinary
programs have focused on the exchange of researchers
and the promotion of collaborative researches between
these two different academic areas. However, the next
generation medicine such as "minimum-invasive

498

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) and cisplatin (CDDP) by
polymeric micelles, and observed enhanced antitumor
activity with reduced side effects. These micellar
formulations are currently being tested in clinical
trials.
Recently, plasmid DNA (pDNA) and siRNA are
receiving much attention as promising tools for thetreatment of genetic and intractable diseases. One of
the major requirements for therapeutic use of pDNA
and siRNA is the development of gene vectors, which
can safely and effectively deliver them into specificcells and regulate their expressions. Recently, we have
prepared polymeric micelles incorporating pDNA
through the electrostatic interaction between DNA 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.

Y. Vachutinsky, M. Oba, K. Miyata, S. Hiki, M.
R. Kano, N. Nishiyama, H. Koyama, K.
Miyazono, K. Kataoka, Antiangiogenic genetherapy of experimental pancreatic tumor bysFlt-1 plasmid DNA carried by RGD-modified
crosslinked polyplex micelles . J. Control.
Release in press
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499

Human Umbilical Vein Endothelial Cells.
Macromol. Rapid Commun. in press
3. 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 in press
4. 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)
5. 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)
6. A. 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)
7. M. Oba, Y. Vachutinsky, K. Miyata, M. R. Kano,
S. Ikeda, N. Nishiyama, K. Itaka, K. Miyazono,
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)
8. 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)
9. 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)
10. 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)

11. 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)
12. 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)
13. M. Kumagai, M. R. Kano, Y. Morishita, M. Ota,
Y. Imai, N. Nishiyama, M. Sekino, S. Ueno, K.
Miyazono, K. Kataoka, Enhanced magnetic
resonance imaging of experimental pancreatictumor in vivo by block-copolymer-coatedmagnetite nanoparticles with TGF-beta inhibitor.
J. Control. Release 140 (3) 306-311 (2009)
14. M. Zhang, A. Ishii, N. Nishiyama, S. Matsumoto,
T. Ishii, Y. Yamasaki, K. Kataoka, PEGylated
calcium phosphate nanocomposites as smart
environment-sensitive carriers for siRNAdelivery. Adv. Mater. 21 (34) 3520-3525 (2009)
15. M. Han, M. Oba, N. Nishiyama, M.R. Kano, S.
Kizaka-Kondoh,K.
Kataoka,Enhancedpercolation and gene expression in tumor
hypoxia by PEGylated polyplex micelles. Mol.
Ther. 17 (8) 1404-1410 (2009)
16. Y. Lee, T. Ishii, H. Cabral, H. -J. Kim, J. -H. Seo,
N. Nishiyama, H. Oshima, K. Osada, K. Kataoka,
Charge-conversional
polyionic
complexmicelles-efficient nanocarriers for protein
delivery into cytoplasm. Angew. Chem. Int. Ed.
48 (29) 5309-5312 (2009)
17. M. Harada-Shiba, I. Takamisawa, K. Miyata, T.
Ishii, N. Nishiyama, K. Itaka, K. Kangawa, F.
Yoshihara, Y. Asada, K. Hatakeyama, N. Nagaya,
K. Kataoka, Intratracheal gene transfer ofadrenomedullin using polyplex nanomicelles
attenuates monocrotaline-induced pulmonary
hypertension in rats. Mol Ther. 17 (7) 1180-1186(2009)
18. Y. Matsumoto, K. Itaka, T. Yamasoba, K.
Kataoka, Intranuclear fluorescence resonanceenergy transfer analysis of plasmid DNA
decondensation from nonviral gene carriers. J.
Gene. Med. 11 (7) 615-623 (2009)
19. W. Wang, K. Itaka, S. Ohba, N. Nishiyama, U.

500

20.

21.

22.

23.

Chung, Y. Yamasaki, K. Kataoka, 3D spheroid
culture system on micropatterned substrates for
improveddifferentiation
efficiency
ofmultipotent
mesenchymal
stem
cells.
Biomaterials 30 (14) 2705-2715 (2009)
W. -F. Dong, A. Kishimura, Y. Anraku, S.
Chuanoi, K. Kataoka, Monodispersed polymericnanocapsules: Spontaneous evolution andmorphology transition from reducible heteroPEG PICmicelles by controlled degradation. J.
Am. Chem. Soc. 131 (11) 3804-3805 (2009)
N. Nishiyama, Y. Nakagishi, Y. Morimoto, P.-S.
Lai, K. Miyazaki, K. Urano, S. Horie, M.
Kumagai, S. Fukushima, Y. Cheng, W.-D. Jang,
M.
Kikuchi,K.
Kataoka,Enhancedphotodynamic
cancertreatmentbysupramolecular nanocarriers charged withdendrimer phthalocyanine. J. Control. Release133 (3) 245-251 (2009)
H. Cabral, M. Nakanishi, M. Kumagai, W.-D.
Jang, N. Nishiyama, K. Kataoka, A
photo-activated targeting chemotherapy using
glutathione
sensitive
camptothecin-loaded
polymeric micelles. Pharm. Res. 26 (1) 82-92(2009)
A. Kishimura, S. Liamsuwan, H. Matsuda, W. -F.
Dong, K. Osada, Y. Yamasaki, K. Kataoka,
pH-Dependent
permeabilitychangeandreversible structural transition of PEGylated
polyion complex vesicles (PICsomes) in aqueous
media. Soft Matter 5 (3) 529-532 (2009)

501

Laboratory of Environmental
Health Sciences
Professor
Chiharu Tohyama, Ph.D., Dr.Med.Sci.

Associate Professor
Seiichiroh Ohsako, Ph.D., D.V.M.

Assistant Professor
Masaki Kakeyama, Ph.D.

Project Research Associate
Wataru Yoshioka, Ph.D.

Homepage

http://env-health.m.u-tokyo.ac.jp

Introduction and Organization
Laboratory of Environmental Health Sciences is alaboratory established as a part of the Center for
Disease Biology and Integrative medicine, andcomprises of Professor, Associate Professor, andAssistant Professor and other staff members as well as
postdoctoral fellows, graduate and undergraduate
students. The laboratory settings have been renovated,which makes it possible to start research andeducational activities in full capacity as of January,
2006. Staff members have been engaged inenvironmental toxicology for many years at the
National Institute for Environmental Studies, Tsukuba,
and the mission of this division for research andeducation is described below.

Research activities
Children’s health problems of today include suchconditions as disorders in the reproductive andimmune functions, learning deficits, mental problem
and ‘metabolic syndrome’. Our research is carried out
on the recognition that the homeostasis is disrupted byvarious environmentally hazardous chemicals, towhich expectant mothers and their newborn babies are
exposed during their highly sensitive period of life,
and that the contamination with these chemicals maylead to various disease conditions in children after
birth. Our experimental investigations are focused on
the epigenetic mechanisms that alter the susceptibility
to chemicals, effects of chemicals on the learning andemotion and the identification of molecular target ofchemicals. Our research efforts are further directed todevelop methodologies for evaluating behavioral
toxicities in 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’502

approaches are used to determine how adverse
responses of laboratory animals, which are used as anexperimental substitute for humans, to a particularchemical are similar to or different from the adverse
responses of humans.
The outcomes of our research provide not only
fundamental information for human health risk
assessment that can lead to the establishment ofadequate margins of safety for human exposure toenvironmental chemicals. They give the generalpublic a greater sense of security in their surroundings
and they provide clinical medicine and the basic life
sciences new knowledge that is human health relevant.

Laboratory’s Research Themes
1.

2.
3.

4.

Elucidation of mechanisms involved in the
manifestation of toxicity at the molecular andcellular level due to exposure to environmental
pollutants, such as dioxin/PCBs and heavy
metals.
Clarification of epigenetic mechanisms that altersusceptibility to environmental chemicals.
Development of methodologies for evaluating thetoxicity of chemicals to the learning and emotionof rodents and of in 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.

Teaching activities
The Laboratory of Environmental Health Sciences
has important missions to train postdoctoral fellows to
become promising scientist leaders in the field ofenvironmental toxicology in the future and to give a
toxicology and environmental health courses forgraduate and undergraduate students. This laboratoryis actively involved in these tasks. The Laboratory
will be responsible for full a credit course on‘Principles and Applications of Environmental Health
Sciences’. In addition, several lectures are given toundergraduate students at School of Medicine andSchool of Health Sciences and Nursing. From 2008
this laboratory has become a member of a Global COE

project, ‘Medical system innovation’.

Publications
1. 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 HealthPrev Med, (in press)
2. Haijima A, Endo T, Zhang Y, Miyazaki W,
Kakeyama M, Tohyama C. In utero and lactational
exposure to low doses of chlorinated and brominateddioxins induces deficits in the fear memory of malemice (in press)
3. 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. (inpress)
4. Ohsako S., Fukuzawa N., Ishimura R., Kawakami T.,
Wu Q., Nagano R., Zaha H., Sone H., Yonemoto J.,
and Tohyama C. Comparative contribution of thearyl hydrocarbon receptor gene to perinatal stage
development and dioxin-induced toxicity between
the urogenital complex and testis in the mouse. Biol
Reprod. (in press)
5. 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. (inpress)
6. Sone H, Okura M, Zaha H, Fujibuchi W, Taniguchi
T, Akanuma H, Nagano
R, Ohsako S, and Yonemoto J. pCEC: atoxicogenomics database with a toxicoinformatics
system for risk evaluation and toxicity prediction ofenvironmental chemicals. J Toxcol Sci. (in press).
7. 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 offspring of the paternal
2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)

503

exposure decrease: In the spermatozoa stage or at
fertilization? Reprod Toxicol. (in press)
8. 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(3):487-97, 2009
9. Kurita H, Yoshioka W, Nishimura N, Kubota N,
Kadowaki T, Tohyama C. Arylhydrocarbon receptormediated effects of 2,3,7,8-tetrachlorodibenzo- p-dioxin on glucose-stimulated insulin secretion in
mice. J. Appl. Toxicol. 29:689-694,2009
10. Yoshioka W, Akagi T, Nishimura N, Shimizu H,
Watanabe C, Tohyama C. Severe toxicity andcyclooxygenase (COX)-2 mRNA increase bylithium in the neonatal mouse kidney. J Toxicol Sci.
34:519-525, 2009
11. Nohara K, Suzuki T, Ao K, Murai H, Miyamoto Y,
Inouye K, Pan X, Motohashi H, Fujii-Kuriyama Y,
Yamamoto M, Tohyama C. Constitutively active
aryl hydrocarbon receptor expressed in T cells
increases immunization-induced IFN-g production
in mice but does not suppress Th2-cytokine
production or antibody production. International
Immunology 21: 769-777, 2009
12. Matsumura F, Puga A, Tohyama C. Biological
functions of the arylhydrocarbon receptor: beyond
induction of cytochrome P450s. Introduction to thisspecial issue. Biochem Pharmacol. 77(4):473, 2009
13. Ishimura Ishimura R, Kawakami T, Ohsako S,
Tohyama C. Dioxin-induced toxicity on vascularremodeling of the placenta. Biochem. Pharamcol.,77 : 660-669, 2009.
14. Ao K, Suzuki T, Murai H, Matsumoto M, Nagai H,
Miyamoto Y, Tohyama C, Nohara K. Comparison of
immunotoxicity among tetrachloro-, pentachloro-,
tetrabromo- and pentabromo-dibenzo-p-dioxins in
mice. Toxicology. 256:25-31, 2009.
15. Kawakami T, Ito T, Ohsako S, Shiizaki K,
Murakami Y, Hirowatari K, Sato M, Tohyama C.
Possible involvement of arylhydrocarbon receptor
variants in TCDD-induced thymic atrophy and
XRE-dependent transcriptional activity in Wistar
Hannover GALAS rats. J Toxicol Sci. 34(2):209-20,
2009

504

Laboratory of Animal Resources
Professor
Atsu Aiba, 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 3
teaching staffs, 3 technical support staffs, an assistantmanager of CDBIM, a teaching assistant, 8 assistantlaboratory animal technicians, and 2 assistant clerks.
In addition, about 10 contracted employees are
involved in animal breeding and maintenance of theanimal facility.
The laboratory animals in our facility include
macaque monkeys, dogs, swine, rabbits, guinea pigs,
rats, mice, and chickens. The number of registeredusers of our facility was 298 at the end of academic
year 2009.
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 generateknockout mice and inducible knockout mice of signaltransduction molecules including the glutamate
receptors and Rho family GTPases. We have recently
applied proteomics analysis to these mice. We also try
to generate murine models for human genetic diseases.
1. Genetic approaches to cerebellar function using
metabotropic
glutamatesubtype-1(mGluR1)
transgenic mice
We previously demonstrated that the mice lacking

505

mGluR1 showed ataxic gait, deficient long-term
depression and impaired synapse elimination. Thesephenotypes were rescued by expression of an mGluR1
transgene with Purkinje cell-specific promoter(mGluR1-rescue mice). However, the role of mGluR1
in the adult mice remains elusive, mainly due to lackof conventional and 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 to understand roles of mGluR1 in
adult brain. The mGluR1 cKO mice express mGluR1
only in Purkinje cells and its expression can becontrolled with oral administration of a tetracycline
analog, doxycycline. We found that suppression of themGluR1 expression in the adult mGluR1 cKO miceled to ataxic gait and impaired motor coordination.
These results suggested that mGluR1 is essential for
cerebellar function in mice not only during postnatal
development but also in adulthood.
2. Role of Rho family GTPases in the central nervous
systemRac1 is a ubiquitously expressed member of the
Rho family GTPases and is assumed to serve as amolecular switch regulating many aspects of cellularfunction through actin-cytoskeleton reorganization.
Indeed, previous studies in vitro demonstrated an
important role of Rac1 in neuronal migration, neurite
formation and axonal elongation during corticaldevelopment. We have shed light on an unexpectedly
selective role of Rac1 using cortex-restricted Rac1
knockout mice. In the mutant mice, commissuralaxons of the cerebral cortex never crossed the midline,
although other corticofugal axons were almost
unaffected by Rac1 deletion. Thus, during corticaldevelopment, Rac1 specifically regulates midline
crossing of the cortical commissural neurons, rather
than axonal projection such as neurite formation andaxonal elongation.
3. Role of ERK/MAP kinase in the central nervous
systemThe ERK/MAP kinase plays a central role invarious situation of signal transduction in eukaryotic
cells. To clarify a role of ERK in the central nervous
system, we generated transgenic mice expressing

dominant negative MEK1 (dnMEK1 Tg) in forebrain
with tetracycline-regulated gene expression system.
The dnMEK1 Tg mice were viable, fertile, normal insize and did not display apparent abnormalities.
However, the adult dnMEK1 Tg mice displayed areduction of the granule cell number in the dentate
gyrus of the hippocampus. Although the number of
apoptotic cells detected by TUNEL staining in thedentate gyrus of dnMEK1 Tg mice wasindistinguishable from that of wild-type mice, thenumber of microglia cells was increased in the dentate
gyrus of dnMEK1 Tg mice. Moreover, the number ofastrocytic adult neural stem cells in the dentate gyrusof dnMEK1 Tg mice was also increased, comparedwith wild-type mice. These results suggest that ERK
cascade plays important roles in regulation of thesurvival of granule cells in the dentate gyrus of the
hippocampus.
4. Generation of hyperactive mTOR transgenic mice
Mammalian target of rapamycin (mTOR) is ahighly conserved serine/threonine kinase that
regulates a broad range of cellular functions in cell
growth. mTOR forms two functionally distinct
complexes, mTOR complex 1 (mTORC1) andmTORC2. mTORC1 contains raptor and mLst8,
whereas mTORC2 contains rictor, mSin1, and mLst8.
The hyperactive mTOR mutant shows enhanced
kinase activity and activates the mTORC1 pathway
strongly and chronically in cultured cells. We
generated transgenic mice which express a
hyperactive mTOR mutant in skeletal muscle.
Unexpectedly, expression of hyperactive mTOR
mutant in skeletal muscle resulted in reduction inskeletal muscle mass. We are currently investigating
molecular mechanisms underlying the phenotypes ofmTOR transgenic mice.

References
1. Matsumoto H, Kashiwadani H, Nagao H, Aiba A,
and Mori K. Odor-induced persistent discharge of
mitral cells in mouse olfactory bulb. J
europhysiol, 101, 1890-1900, 2009.
2. Inoue N, Nakao H, Migishima R, Hino T, Matsui
M, Hayashi F, Nakao K, Manabe T, Aiba A, andInokuchi K. Requirement of the immediate early

506gene vesl-1S/homer-1a for fear memory formation.
Mol Brain, 2, 7, 2009.
3. Bilasy S E, Satoh T, Ueda S, Wei P, Kanemura H,
Aiba A, Terashima T, and Kataoka T. Dorsal
telencephalon-specific RA-GEF-1 knockout micedevelop
heterotopic
corticalmassandcommissural fiber defect. Eur J eurosci, 29,
1994-2008, 2009.
4. Suzuki D, Yamada A, Amano T, Yasuhara R,
Kimura A, Sakahara M, Tsumaki N, Takeda S,
Tamura M, Nakamura M, Wada N, Nohno T,
Shiroishi T, Aiba A, Kamijo R. Essential
mesenchymal role of small GTPase Rac1 ininterdigital programmed cell death during limb
development. Dev Biol, 335, 396-406, 2009.

507

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.

508

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. Tomoda Y, Katsura M, Okajima M, Hosoya N,
Kohno N, Miyagawa K. Functional evidence for
Eme1 as a marker of cisplatin resistance. Int J
Cancer. 2009;124:2997-3001.
2. Hosoya N, Miyagawa K. Clinical importance of
DNA repair inhibitors in cancer therapy Magazineof European Medical Oncology. 2009; 2:9-14.
3. Takaku M, Machida S, Hosoya N, Nakayama S,
Takizawa Y, Sakane I, Shibata T, Miyagawa K,
Kurumizaka H: Recombination activator functionof the novel RAD51- and RAD51B-binding
protein, human EVL. J Biol Chem. 2009; 22:14326-14336.
4. Katsura M, Tsuruga T, Date O, Yoshihara T, Ishida509

M, Tomoda Y, Okajima M, Takaku M,
Kurumizaka H, Kinomura A, Mishima HK and
Miyagawa K: The ATR-Chk1 pathway plays arole in the generation of centrosome aberrations
induced by Rad51C dysfunction. Nucleic Acids
Res. 2009; 37:3959-3968.

510

Office ofInternational Academic Affairs
Head
Tatsuya Yamasoba

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 2009 (April
through March).
1. International Educational Exchange
1.1 Student counseling about education and research
In 2009, there were 151 foreign students (38countries) 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 75 people attended in 2009, 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 2009
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
University of Tokyo was renewed in May 2004. Since
that time, ten University of Tokyo students have taken

511

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 ofWashington Medical School in November 2005. Since
the start of the program in 2005, six University ofTokyo students have attended clinical electives at the
University of Washington Medical School, and one
student from the University of Washington Medical
School has taken clinical electives at the University ofTokyo.
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 forcounselingregarding
pre-graduationor
post-graduation studies abroad are received by the
Office of International Academic Affairs. The office
responds to these requests by providing information,
advice, and letters of recommendation.

2. ew 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.

512

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. Takegami M, Suzukamo Y, Wakita T, Noguchi H,
Chin K, Kadotani H, Inoue Y, Oka Y, Nakamura T,
Green J, Johns MW, Fukuhara S. Development of aJapanese version of the Epworth Sleepiness Scale(JESS) based on Item Response Theory. Sleep Med.
2009 May;10(5):556-65.

513

The International Research Center
for Medical Education (IRCME)
Director & Professor
Kazuhiko Yamamoto, M.D., Ph.D.

Professor
Kiyoshi Kitamura, M.D., Ph.D.

Lecturer
Hirotaka Onishi, M.D., M.H.P.E.

Lecturer
Hiroshi Nishigori, M.D., M.M.E., Ph.D.

Homepage

http://www.ircme.u-tokyo.ac.jp

History and organization
The University of Tokyo has establishedInternational Research Center for Medical Education(IRCME) in 2000. The Ministry of Education (in2001 reformed to Ministry of Education, Culture,
Science and Sports), the University of Tokyo, and the
Graduate School of Medicine positioned IRCME as abase for promoting international cooperative studiesof medical education.
IRCME consists of three departments ofInternational Cooperative Study for Medical
Education, Planning & Coordination for International
Cooperative Projects and Information on Medical
Education, and visiting professor from abroad. We
hope that the research in medical education carried out
by IRCME will improve medical education and healthcare in many countries.
The mission of IRCME includes research ininternational cooperation in medical education,
research in medical education, and development of
human resource in medical education. Promotion ofand contribution to education in the Faculty of
Medicine, University of Tokyo and University ofTokyo Hospital is also our fundamental role.

International Cooperative Study in
Medical Education
The University of Tokyo, especially the Faculty of
Medicine, takes pride in its academic excellence not
only in Japan but also other foreign countries.
Compared with other Western distinguisheduniversities, however, activities and research ininternational cooperation area have been weak. The
strength of IRCME is to implement educational
cooperation projects in health area supported by
official development assistance. Such an approachtakes longer time but will influence people indeveloping countries with sustainability andindependence.
To fulfill the mission, faculty and staff in IRCME
conduct research on a wide range of topics inundergraduate and postgraduate medical education.
One of our objectives is to establish a new
methodology of effective and efficient implementationof medical education reform by the information
obtained from the practice of international cooperation
in medical education.
IRCME also makes important contributions toundergraduate and postgraduate medical curricula of

514

the Faculty of Medicine to raise awareness ofinternational cooperation and help Japanese medical
practitioners develop interest in international
activities.

Planning & Cooperation forInternational Cooperative Projects
and Information on Medical
Education
Department of Planning & Coordination forInternational Cooperative Projects and Information on
Medical Education is responsible for developing
international cooperation in health professions
education area (medicine, dentistry, pharmacy, nursing,public health, rehabilitation, etc) facilitated by the
Ministry of Education, Culture, Sports, Science, andTechnology. This department should lead any
international cooperation projects in healthprofessions education area in Japan and aim at
face-to-faceandheart-to-heart
international
cooperation. Activities are listed below.
1． Japan International Cooperation Agency (JICA)
appointed IRCME as the cooperative agency for
JICA Medical Education Project, Afghanistan.
Currently IRCME is working for the follow-up
scheme of the above project. 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.
2. JICA entrusted Joint Venture of University ofTokyo and System Science Consultants with the
Project for Medical Education and Research for
the Setthathirath Hospital, the Lao People’s
Democratic Republic (2007 Dec-2010 Nov).
Kitamura, Nishigori and Onishi visited thehospital to provide trainings and advices to help
them establish the national standard of clinicaleducation.
3. 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 2009, we welcomed two visiting professors:
Dr. Nurjahan binti Mohamed Ibrahim (1 Feb – 30
May, 2009), Associate Professor of Family
Medicine, Department of Family Medicine,International Medical University (IMU),
Malaysia
Dr. Rebecca A Harrison (1 Apr – 31 July, 2009),
Associate Professor of Medicine, Division of
Hospital Medicine, Oregon Health & Science
University, U.S.A.
They offered several seminars, lectures forinternational trainees, and many suggestions to
IRCME.

References
1. Nishigori H, Otani T, Uchino M, Plint S, Ban N. I
came, I saw, I reflected: a qualitative study into
learning outcomes of international electives forJapanese and British medical students. Med Teach.
2009;31:e196-e201.
2. Nishigori H, Nishigori M, Yoshimura H. DREEM,PHEEM, ATEEM and STEEM in Japanese, Med
Teach. 2009;31:560.
3. Yudkowsky R, Otaki J, Lowenstein T, Riddle J,
Nishigori H, Bordage G. A hypothesis-driven
physical examination learning and assessment
procedure for medical students: initial validity
evidence. Med Educ. 2009;43:729-740.